Organophosphorus Chemistry (Volume 21)

Organophosphorus Chemistry Volume 21

A Specialist Periodical Report

Organophosphorus Chemistry Volume 21

A Review of the Recent Literature Published between July 1 9 8 8 and June 1 9 8 9 Senior Reporters

B. J. Walker, Department of Chemistry, David Keir Building, The Queen's University of Belfast J. B. Hobbs, University of British Columbia, Canada Reporters

C.W. Allen,

University of Vermont, U S A . D. W. Allen, Sheffield City Polytechnic 0.Dahl, University of Copenhagen, Denmark R. S. Edmundson, formerly of University of Bradford C. D. Hall, King's College, London

SOCIETY OF HEM1STRY

ISBN 0-85 186- 196-2 ISSN 0306-0713 Copyright 0 I990 The Royal Society of Chemistry A I I Rights Re.wwd No p r r t o j this hook mu-v hr rrproduccd or traristnitted it7 ari-vform or l7y N t I-vtnra ris -grup hic, r lrcwoti ic, iti c lu ding p h otocoping. r t mrding, tapirig or ir!fortnatiori storage arid retrievcrl .s?i.\.trm.s-wwithout writtrti permission ,from The Rqval Societv of Chemisty

Published by The Royal Society of Chemistry, Thomas Graham House, The Science Park, Cambridge CB4 4WF Printed and bound in Great Britain by Bookcraft (Bath) Ltd.

Introduction Considerable research effort has been focused on the preparation of compounds of biochemical interest, using electrophilic reactions of phosphoramidites and phosphorochloridites to prepare modified phosphates of nucleosides or lipids. Intense interest has been shown in the synthesis of myoinositol phosphates, and also of aminoalkylphosphonic acids and their derivatives and analogues. Away from the biological emphasis, however, the first (recorded) syntheses of acetylenic phosphates have been described, and so have the first 1-alkoxyphosphole, the first cis aminoiminophosphine, and the first dithiaphospholiumions: ex Phosphorus semper ahquid now1 The use of silyl phosphites for synthetic purposes seems to be an increasing trend, while the number of papers on metaphosphate seems to be in decline. In the nucleotide and nucleic acid field, considerable numbers of phosphonylalkyl and phosphonylmethoxyalkylderivatives of adenine, analogues of the antiviral (S)-9-(3hydroxy-2-phosphonomethoxypropyl) adenine (HMPA) have been reported, as have many phosphonoformate and phosphonoacetate derivatives of 5-substituted 2'deoxyuridine species, showing that antiviral research continues to provide a major stimulus to synthesis in this area. The use of salicyl chlorophosphite, a convenient reagent for preparing H-phosphonates, has been extended to prepare nucleoside 5'polyphosphates and their analogues. The chief chemical thrust, however, as noted above, is in the continuing exploitation of nucleoside phosphoramidites to prepare oligonucleotides with modified internucleotidic links, including some with cationic groups attached at the internucleotidic link, and with reporter groups attached to the oligonucleotide for analytical use - as, for instance, in diagnostics and sequencing. The use of anti-sense oligonucleotide analogues to arrest translation has afforded results which appear cautiously promising for the control of retroviral infection - so long as the agent can be delivered to the infected cells efficiently and without significant side effects and 'addressed modification' of complementary sequences by chemically reactive oligonucleotide agents has spurred the development of agents of impressive elegance and selectivity. The applications of the Polymerase Chain Reaction (PCR) are already legion, largely in the area of molecular biology, but the disclosure that Taq DNA polymerase accepts deoxynucleoside 5'(1-thio)triphosphates as substrates is of considerable interest for those seeking to prepare and exploit oligonucleotides with thiophosphate links. Although interest in pn-bonded compounds continues at a high level the pace of advance seems to be slackening, perhaps reflecting that the most interesting chemistry in this area has now been revealed. The year has seen a further consolidation of knowledge in the area of hypervalent phosphorus chemistry and the principles established in this area have expanded further into the Chemistry of As, Sb,Bi and Si. Notable contributions have appeared on the importance of the conformational transmissions effect to ligand

vi

Introduction

reorganisation in the phosphoranes, the mechanism of the Mitsunobu reaction, and the hydrolysis of pentaco-ordinate arsenic compounds. Further progress has also been made in the chemistry of phosphatrans and silatrans and this work has also been expanded to include tetraco-ordinate platinum. Phosphorus-based olefinations continue to be the most widely used methods for the synthesis of alkenes. An understanding of most facets of the mechanism of the Wittig reaction seems to have been achieved and this has been summarised in a substantive review. Some of the principles established in these mechanistic studies can be applied to phosphorus-based olefinations other than the Wittig reaction. However, substantive mechanistic studies of phosphine oxide-based and phosphonate-based olefinations are urgently required. A combination of the variety of phosphorus-based methods and the improved understanding of their mechanisms now allows a substantial degree of control of both reactivity and stereochemistry in olefin synthesis, However, studies are required of the applications of established structure-reactivity relationships in ylides and of the various carbon and nitrogen ylide-anions recently reported. In phosphazene chemistry, preparation and reactions of small molecule, linear phosphazenes continue to attract interest. This year numerous papers have explored the utility of the aza-Wittig reaction in the synthesis of complex molecules with particular reference to nitrogen heterocycles. In cyclophosphazenechemistry, the shift of emphasis to materials which are monomers themselves or models for phosphazene polymers is apparent. The synthesis and characterization of poly(phosphazenes) is an active area with extensive interest in phosphazene based polyelectrolytes being noted. Solid state NMR has been shown to be a valuable tool for the study of both structure and phase changes in poly(phosphazenes). In Volume 20, and now in Volume 21, we have not been able to provide the chapter on "Physical Methods". John Tebby has made a superb job of this chapter each year since the first volume of "OrganophosphorusChemistry" in 1968. All of us who have read it over the years will appreciate its usefulness and the immense amount of work required each year for its completion. Many thanks John. We hope that coverage of Physical Methods will be included in Volume 22.

J.B. Hobbs and B.J. Walker

Contents

CHAPTER

1

Phosphines and Phosphonium Salts By D.W. Allen

1

Phosphines

1

1.1 Preparation

1

1.1.1 1.1.2 1.1.3 1.1.4

From Halogenophosphines and Organometallic Reagents From Metallated Phosphines By Addition of P-H to Unsaturated Compounds Miscellaneous Methods

1.2 Reactions 1.2.1 1.2.2 1.2.3 1.2.4

3 7 9

11

11 12 12 15

Halogenophosphines

18

2.1 Preparations 2.2 Reactions

18 20

Phosphonium Salts

23

3.1 Preparation 3.2 Reactions

23

4

pn -Bonded Phosphorus Compounds

27

5

Phosphirenes, Phospholes, and Phosphinines

37

References

41

2

3

CHAPTER

Nucleophilic Attack at Carbon Nucleophilic Attack at Halogen Nucleophilic Attack at Other Atoms Miscellaneous Reactions

1

25

2

Pentaco-ordinated and Hexaco-ordinated Compounds By C.D. Hall

1

Introduction

51

2

Structure, Bonding, and Ligand Reorganization

51

3

Acyclic Phosphoranes

53

4

Ring Containing Phosphoranes

59

4.1 Monocyclic Phosphoranes 4.2 Bicyclic and Tetracyclic Phosphoranes

59 61

...

Contents

Vlll

5

CHAPTER

CHAPTER

3

4

67

References

71

Phosphine Oxide and Related Compounds By B.J. Walker

Preparation of Acyclic Phosphine Oxides

73

Preparatfon of Cyclic Phosphine Oxides

77

Structure and Physical Aspects

77

Reactions at Phosphorus

77

Reactions at the Side-chain

80

Phosphine Oxide Complexes

88

References

88

Tervalent Phosphorus Acids By 0. Dahl

1

Introduction

90

2

Nucleophilic Reactions

90

2.1 Attack on Saturated Carbon 2.2 Attack on Unsaturated Carbon 2.3 Attack on Nitrogen, Chalcogen, or Halogen

90 92 95

Electrophilic Reactions

97

3

CHAPTER

Hexaco-ordinate Phosphorus Compounds

3.1 Preparation 3.2 Mechanistic Studies 3.3 Use for Nucleotide, Sugar Phosphate,

97 102 102

Phospholipid, or Phosphoprotein Synthesis 3.4 Miscellaneous

110

4

Reactions involving Two-co-ordinating Phosphorus 110

5

Miscellaneous Reactions

113

References

116

5

Quinquevalent Phosphorus Acids By R . S . Edmundson

1

Phosphoric Acids and their Derivatives

123

1.1 Synthesis 1.2 Reactions 1.3 Uses

123 142 147

Phosphonic and Phosphinic Acids and their Derivatives

149

2.1 Synthesis 2.2 Reactions 2.3 Uses

149 183 193

References

193

2

ix

Coritents CHAPTER

6

Nucleotides and Nucleic Acids By J.B.

1

Introduction

201

2

Mononucleotides

201

2.1 Chemical Synthesis 2.2 Cyclic Nucleotides

201 226

3

Nucleoside Polyphosphates

230

4

Oligo- and Polynucleotides

242

4.1 Chemical Synthesis 4.2 Enzymatic Synthesis

242 264

Other Studies

272

5.1 5.2 5.3 5.4 5.5

272 273 277 291 297

5

6

CHAPTER

Hobbs

7

Affinity Separation Affinity Labelling Sequencing and Cleavage Studies Post-Synthetic Modification Metal Complexes

Analytical Techniques and Physical Methods

301

References

307

Ylides and Related Compounds Walker

B y B.J. 1

Introduction

322

2

Methylenephosphoranes

322

2 . 1 Preparation and Structure 2.2 Reactions

322

2.2.1 2.2.2 2.2.3 2.2.4

Aldehydes Ketones Ylides Co-ordinated to Metals Miscellaneous Reactions

322

322 330 334 334

3

Reactions of Phosphonate Anions

349

4

Selected Applications in Synthesis

353

4.1 Carotenoids and Related Compounds 4.2 Leukotrienes, Prostaglandins and Related Compounds 4.3 Macrolides and Related Compounds 4 . 4 Pheromones 4.5 Miscellaneous Reactions

353 3 53

References

363

356 356 356

Contents

X

CHAPTER

8

Phosphazenes

By C.W.

Allen

Introduction

368

Acyclic Phosphazenes

368

Cyclophosphazenes

376

Cyclophospha(thia)zenes

384

Miscellaneous Phosphazene Containing Ring Systems

386

6

Poly(phosphazenes)

387

7

Molecular Structure of Phosphazenes

394

References

397

AUTHOR INDEX

405

Abbreviations

AIBN CIDNP CNDO CP DAD DBN DBU DCC DIOP

DMF DMSO DMTr EDTA E.H.T. ENU FID g.1.c.-m.s HMPT h.p. 1.c. i.r. L. F.E . R . MIND0 MMTr MO MS-C1 MS-nt MS-tet NBS n.q.r. p.e. PPA SCF TBDMS TDAP TFAA Tf2 0 THF Thf ThP TIPS t.1.c. TPS-C1 TPS-nt TPS-tet TsOH U.V.

bisazoisobutyronitrile Chemically Induced Dynamic Nuclear Polarization Complete Neglect of Differential Overlap cyclopentadienyl diethyl azodicarboxylate 1,5-diazabicyclo[4.3.O]non-5-ene 1,5-diazabicyclo[5.4.O]lundec-5-ene dicyclohexylcarbodi-imide [(2,2-dimethyl-1,3-dioxolan-4,5-diyl)bis-(methylene)l bis(dipheny1phosphine) dimethylformamide dimethyl sulphoxide 4,4'-dimethoxytrityl ethylenediaminetetra-aceticacid Extended Huckle Treatment N-ethyl-N-nitrosourea Free Induction Decay gas-liquid chromatography-mass spectrometry hexamethylphosphortriamide high-performance liquid chromatography infrared Linear Free-Energy Relationship Modified Intermediate Neglect of Differential Overlap 4-monomethoxytrityl Molecular Orbital mesitylenesulphonyl chloride mesitylenesulphonyl 3-nitro-1,2,4-triazole mesitylenesulphonyltetrazole N-bromosuccinimide nuclear quadrupole resonance photoelectron polyphosphoric acid Self-consistent Field t-butyldimethylsilyl tris(diethy1amino)phosphine

trifluoroacetic acid trifluoremethanesulphonic anhydride Tetrahydrofuran 2-tetrahydrofuranyl 2-tetrahydropyranyl tetraisopropyldisiloxanyl thin-layer chromatography tri-isopropylbenzenesulphonyl chloride tri-isopropylbenzenesulphonyl-3-nitro-l,2,4-triazole

tri-isopropylbenzenesulphonyltetrazole toluene-p-sulphonic acid ultraviolet

* Abbreviations used in Chapter 6 are detailed in Biochem. J.,1970,120,449 and 1978,171,l

1 Phosphines and Phosphonium Salts BY D. W. ALLEN

1 Phosphines 1.1 Preparation 1.1.1 From Halogenophosphines and Organometallic Reagents.- Grignard procedures have been used to prepare a series of methoxyarylphosphines (1) which have been employed in a study of the extraction of gallium (111) from acid solution.' Treatment of bis(dich1orophosphin0)methane with methallylmagnesium chloride provides the unsaturated diphosphine (2), the precursor of new caged phosphorus systems. Both Grignard and organolithium reagents derived from terminal alkynes have found use in the synthesis of alkynylphosphines, e.g., ( 3 ) 3 and ( 4 1 4 , the latter rearranging in solution Direct alkylation of to form isqmeric k e t e n y l i d e n e p h o s p h o r a n e s . 1,2-bis(dichlorophosphino)ethane with perfluoroethyllithium at low temperatures provides an efficient route to the chelating diphosphine ( 5 1 , which is reported to rival fluorophosphines in its 5 7r- ac cep tor streng th . The generation of organolithium reagents by the metallation of readily available substrates using butyllithium, or lithium dialkylamides, has continued to be a popular approach for the Metallation of thiophenols using synthesis oE unusual phosphines. the butyllithium-TMEDA complex proceeds with metallation ortho to the thiophenol functionality, and subsequent reactions with halogenophosphines have afforded a range of phosphinobenzenethiols, e.g. , (6). (6) Metallation of 2-bromophenols with butyllithium followed by sequential treatment with phosphorus trichloride and phosphorus oxychloride has given the chiral C 3 - symmetric phosphines ( 7 ) which do not have a stereogenic carbon atom.7 Crownether modified phosphines ( 8 ) have been obtained from the direct metallation of the parent benzocrown ethers with butyllithium, A similar followed by treatment with chlorodiphenylphosphine. metallation of the furan system has given the phosphine ( 9 ) . 9 The nuclear metallation of aminoalkylferrocenes has provided a route to 11 new chiral ferrocenyldiphosphine chelating ligandslO~lle.g. (10). The reactions of lithium enolates, derived from the metallation

2

Organophosphorus Chemistry

0

(8) n = 4 - 7

( 7 ) R = B u t or H

I

Fe

(!jPR* CH( Me)NMe 2

(10) R = Ar or C y

(11)

R 2 R 3 C-CH=NR4

I

PR'2

(12) R1 - R 3 = tower alkyl R 4 = But or C y

1: Phosphines and Phosphonium Salts

3

of acetylferrocenes with lithium di-isopropylamide, with chlorodiphenylphosphine have given new side-chain functionalised ferrocenyl derivatives, e.g., (ll).” A similar metallation of imines has provided a route to the functionalised phosphines ( 1 2 ) . 13 Anionic oligomerisation of ethylene, promoted by the butyllithiumTMEDA complex, followed by quenching with c h l o r o d i p h e n y l p h o s p h i n e , results in the formation of a series of phosphinated oligomers (13) which aid catalyst recovery when employed as ligands in homogeneous catalyst systems. l4 The arylation of methyl dichlorophosphinoacetate appears to provide the most widely applicable route to a range of substituted arylphosphinocarboxylic acid derivatives(l41.:15 A high yield procedure for the synthesis of 2,6-dimethoxyphenylphosphines involves the use of arylsodium reagents. l6 A zirconium reagent has been used as a dienyl transfer agent in the synthesis of the phosphines (15). 17 1 . 1 . 2 Preparation of Phosphines from Metallated Phosphines.- This route contines to find wide application. New polydentate ligands, e.g., (16), have been isolated from the reactions of halogenated heterocyclic imines with lithium diphenylphosphide. l8 The reactions of chloromethyl derivatives of cyclic ethers with lithium diorganophosphide reagents have given new phosphinoether systems, A range of a l k o x y m e t h y l e n e p h o s p h i n e s (18) has been e.g., ( 1 7 ) .19 obtained via the reactions of lithium dialkylphosphides with alkoxycarbonium ions. 2o Further examples of chiral diphosphines in the DIOP series have been prepared from the reactions o f lithium di(substituted-aryllphosphides with halide and tosylate precursors, 21 and the phosphide-tosylate route has also been applied in the synthesis of the c y c l o p e n t a d i e n y l - f u n c t i o n a l i s e d phosphine (19). 22 The tetraphosphinoalkene (20) has been isolated from the reaction of 1,2-dilithio-1,2-diphenylphosphinoethane with tetrachloroethene at -5OOC. This compound has much greater stability to air and water than has the related acyclic product (21) isolated from the reaction If of lithium diphenylphosphide with tetrachloroethene at - 7 8 O C . the latter reaction is conducted at room temperature, 1,2-bis(diIn related pheny1phosphino)ethyne is isolated instead of (21). 23 work, the reactions with tetrachloroethene of diphosphide reagents obtained by lithium-induced ring-opening of the 1,2-dihydro-1,2diphosphete system (22) have given the tetraphosphafulvalenes(23). 24 The phosphinoaluminate reagent ( 2 4 ) has found application in

the synthesis of unsaturated primary phosphines, eii., (25lz5 a l s o a range of organotris(phosphino)silanes (26).

and

4

Organophosphoms Chemistry

(15) R'= Me,Pr or Ph

(17) R = Ph,Mes

R 2 = H or Me

or Cy

pXpph2

Phz Ph2P

'PPhz

Ph

Ph

Ph

Ph

PPh

R 'iPh

( 2 2 ) R = Me,Et, or Ph

L

L i AI(PH2)4] (24)

HC=C

CH2PH2

(25)

RSi( PH2)3 ( 2 6 ) R = Me,Et,Pri or Ph

1: Phosphines and Phosphonium Salts

5

The past year has seen many reports of the use of metallophosphide reagents in the synthesis of new heterocyclic phosphorus compounds in which phosphorus is linked to elements such as boron, silicon, tin and zirconium as ring-members.27-35 Thus, e.g., the reagent (27) (as a complex with TMEDA) has been used in reactions with various sterically-crowded dichloro-element precursors to give a range of 1,3-diphospha-2-metallapentanes (28). 35 Similarly, Baudler's group, and others, continue to employ metallophosphide reagents in the development of the chemistry of cyclic polyphosphorus compounds. 36-41 Interest has also continued in the synthesis and solid-state structural characterisation of organophosphido derivatives of main group elements 42-49 including aluminium,45 indium,46 ,47 zinc and cadmium,48 and lead.4 9 Sodium and potassium organophosphide reagents also continue to find application in synthesis. Several studies have been reported of the cleavage of substituted triarylphosphines with sodium in liquid ammonia, and the resulting phosphide reagents used in the synthesis of new chelating ligands, e.g., (29).50-52 Only moderate to low yields of the diphosphinoalkylamine ( 3 0 ) are obtained in the reaction of bis(2-chloroethylamine) with sodium dimethylphosphide. However, some improvement in yield is achieved if the amine The related hydrochloride is used instead of the free amine. bis(diethy1phosphino)alkylamine can only be prepared by the latter approach, but even this fails for the corresponding bis(diisopropylphosphino) system. 53 The new chiral, hybrid phosphinephosphine oxide ligand ( 3 1 ) has been prepared by the action of A I I isomers sodium diphenylphosphide on a bromoalkyl precursor. 54 of the phosphinobenzenes, ( P h 2 P ) , C6H6-n (n = 1-4), have been prepared by the reactions of the corresponding isomeric fluorobenzenes with sodium diphenylphosphide in 1 iquid ammonia. 55 The reactions of a series of methylphenylchlorosilanes with a mixed sodium-potassium phosphide reagent have given the related (methylphenylsily1)phosphines (32). 56 A more detailed study of the products of the reaction of potassium phenylphosphide with dichloromethane has enabled the isolation of the cyclic The secondary phosphine ( 3 5 ) has polyphosphines ( 3 3 ) and (34). 5 7 been prepared by the reaction of potassium phenylphosphide with o-bromobenzyl chloride. 58 Reagents generated by metallation of phosphines at carbon continue to attract interest. More has been reported on the solid state structures of lithium bisphosphinomethanide complexes,59 and these

6

Organophosphorus Chemistry

Ph

aPLi PLi Ph

( 28)

OMe

Ph

EL, = (C5Me5I2Z r , RzSn, or ArB

Me0

P(SiMenPh3-n)3

PhP,

t 2

,PPh

PhP-PPh

(32)

-

=1-3

PhP-PPh I

PhP

Me2PCH(SiMe3 l2

1

PPh

(34)

(37)

(33)

(35)

(38) R = E t or Ph

(36 1

(39)

1: Phosphines and Phosphoniurn Salts

7

and related reagents have found application for the synthesis of sterically crowded phosphines, e.g., (36).60 Complexes of lithium phosphinomethanides with chiral amines have been described, and the same group has reported the synthesis of highly hindered arylphosphines, e.g., (371, via the sequential metallation and silylation of 2-tolylphosphines. 1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. - The second part of a review of P-H addition to carboncarbon multiple bonds has appeared. 6 2 A range of heterogeneous catalysts has been developed for the addition of phosphine to alkenes.63 Radical-induced addition of bis(pheny1phosphino)methane to vinylphosphines is the key step in the synthesis of the tetra(tertiary phosphines),C38) each of which exists in meso- and rac- forms. 6 4 Similar radical addition of primary and secondary phosphines to vinylsilanes has been used for the synthesis of a wide range of @-phosphinoethylsilane systems.65-69 Thus, e .g. , a route to 4-silaphosphorinanest39) is provided by addition of trimethylsilylphosphine to divinylsilanes. Methanolysis of ( 3 9 ) produces the related cyclic secondary phosphine which is capable of further elaboration. Spirocyclic silaphosphorinanes have been Full formed in the related reactions of tetravinylsilanes. 6 9 details of the addition reactions of diphenylphosphine to asubstituted vinylstannanes have now appeared. 7 0 In this work it was noted that the alternative synthetic strategy of radical hydrostannation of the corresponding vinylphosphines is a much In more complex process, which is of little synthetic value. contrast, radical addition of dimethylstannane to divinylphosphines 71 has given a useful route to the 1,4-phosphastanninanes ( 4 0 ) . Studies o f the course of addition of primary phosphines to 72 a@-unsaturated carbonyl compounds have also continued. The base-catalysed addition of diphenylphosphine to unsaturated compounds has been used in the synthesis of new phosphine ligand systems. The formation of the triphosphine (41) by the addition of diphenylphosphine to bis(dipheny1phosphino)ethyne has been reported by two groups,73y74 and the saturated triphosphine (42) has been prepared by base-catalysed addition of diphenylphosphine A similar base-catalysed to 1,l-bis(dipheny1phosphino)ethylene. 7 4 addition to the acetylene ( 4 3 ) has given the phosphine ( 4 4 1 , which has been further elaborated by sequential metallation and phosphination at the benzylic carbon t o give the unsaturated diphosphine ( 4 5 ) . 7 5

Organophosp hot-us Chemistly

8

n

Me2Sn

PR

LJ

Ph2pXpph2 Ph2P

(41 1

(40)R = But or Ph

Ph C =C

CHZPh

,XCHZPh Ph

(43)

H

Ph

PPh2

PPh,

(451

(44 )

Me

( 5 0 ) X = H or Me

(49)X = H , M e , E t or But Y = H or Me

F3CP-PCF3

I

I

R1 C=CR2 (51) R =Me,Ph or CH2Ph

( 5 2 ) R’ = SiMe3 R2 = Me or Ph

(PhCH=CH )3P

(53)

1: Phosphines crnd Phosphoniurn Salts

9

1.1.4 Miscellaneous Methods of Preparing Phosphines. - A new approach for the synthesis of chiral phosphorus compounds is afforded by the action of 2-methoxyphenylmagnesium bromide on the chiral methyl ester of methylphenylphosphinic acid to give the chiral phosphine oxide (46), which is then easily reduced to the chiral phosphine with trichlorosilane. Additionally, metallation of the methyl group of (46) using lithium di-isopropylamide, followed by oxidative coupling promoted by copper(I1) chloride, affords the chiral diphosphine dioxide (47), again easily Trichlororeducible to the corresponding chiral diphosphine.76 silane reduction of the phosphine oxide has also been employed in the final stage of the synthesis of the C -symmetric phospha3 [2,2,2]cyclophane ( 4 8 ) which undergoes quaternization and complexation at phosphorus in the normal way. 7 7 Full details of the formation of the bicyclic system ( 4 9 1 , from the reactions of aryl(methy1)thioethers with phosphorus trichloride and aluminium chloride, have appeared. 78 On treatment with acetyl chloride, again in the presence of aluminium chloride, (49) is converted into the benzo-1,3-thiaphosphole system (50). 79 The first example of the benzo-1,2,3-thiadiphosphole system ( 5 1 ) has been isolated from the reaction of methyl(p-toly1)sulphide with the phosphorus The established trichloride/aluminium chloride reagent. 8o reactions of cyclopolyphosphines with alkynes have been applied to Heating red the synthesis of the new diphosphetenes (52). phosphorus with phenylacetylene in alkaline polar aprotic media has led to the isolation of the vinylphosphine (53).82 Metallation of the methyl group of the configurationally stable, chira1,p-tolyl(methyl)sulphoxide, followed by treatment with chlorodiphenylphosphine, has given the chiral phosphine (54). 8 3 A metal template effect has been utilised in the synthesis of the diphosphine (55) via N-alkylation of the nickel(I1) complex of 2-aminophenyldiphenylphosphine. 84 Metal template effects are also involved in the thermal rearrangement of the vinyldiphenylphosphine complex ( 5 6 ) on heating in butanol, which leads to the nickel(I1) complex (57) of 1,2-bis(diphenylphosphino)ethane via a reverse Michael elimination of acetylene from one vinyldiphenylphosphine ligand, followed by intramolecular addition of the 85 resulting secondary phosphine to the other vinylphosphine. Various three-and four-membered phosphorus-arsenic ring systems, e.g., (581, have been isolated from the reactions of aryldichloroarsines with bis(trimethylsily1)phosphido complexes of

10

Organophosphorus Chemistry

(54)

(55)

Br

Br

(57) Ar As [Fe]P

(58) [Fe]

Ph,,,,

=

/ \

-P[Fe]

[Me&,(CO)2Fe]

( 5 9 ) n = 2or 3

P( C H2COz M e I,,

(60) n = 1 - 3

a

R’ R 3 x+ I I P-C -C -C02H

Na03S

I

t

R2 H

( 6 2 ) R ’ = R 2 = H or Me R 3 = Me or CHzCHzCOOH

(63) R = H,CsHg,Ph or C02H

0 R’ R 3

0

II

P~CHZCH-PBU~

I

Na03S

R2 H

(64)

Bu

(65 1

I: Phosphines and Phosphonium Salts

11

iron. 8G Elaboration of sites remote from phosphorus has also been a strategy for the synthesis of new phosphines. Thus, e.g., easily recoverable phosphinopolysiloxane ligands have been prepared by the hydrolytic condensation of the triethoxysilyTalky1phosphines ( 5 9 ) with t e t r a e t h ~ x y s i l a n e ,and ~ ~ a range of phosphinoesters (60) has been obtained via esterification of the corresponding phosphinocarboxylic acids. 8 8 1.2 Reactions of Phosphines 1.2.1 Nucleophilic Attack at Carbon. - Water-soluble sulphonated triarylphosphines, e.g., (61), have been shown to undergo quaternization in the usual way at phosphorus on treatment with a two-phase system consisting of water and the alkyl halide. These phosphines also react with activated alkenes under aqueous conditions at pH 4 to generate the phosphonium salts (62). By conduccing these reactions in D20, deuterium can be regiospecifically introduced into the above salts at the carbon adjacent to the electron-withdrawing group. In a similar manner, the corresponding reactions in H20 or D20 with acetylenic carboxylic acids give the substituted vinylphosphonium salts (631, which undergo alkaline hydrolysis with loss of the vinyl group to form the related alkene, offering a route to regiospecifically deuteriated alkenes. Alkaline hydrolysis of the saturated salts (62) occurs with loss of a sulphonated aryl group from phosphorus to give the waterAmong the mixture of products soluble phosphine oxides (64)8 9 90 obtained from the reaction of tributylphosphine with phenylacetylene under aqueous conditions is the phosphine oxide (651, arising from migration of an alkyl group from phosphorus to A related alkyl migration has been observed in the carbon. 91 reaction of trialkylphosphines with an acetylenic tertiary The halogen-free zwitterion (66) is formed in the alcohol.9 2 reaction of triphenylphosphine with dichloromaleic anhydride in the presence of water. 93 The reactions of 1,4-diketones with phosphine have given the phospholanes (671, capable of further Migration of silicon from phosphorus elaboration at phosphorus. 9 4 to oxygen occurs in the reactions of diphenyltrimethylsilylphosphine with trifluoromethylketones, with the formation of the phosphines (68). The product from bis(trifluoromethy1)ketone breaks down in the presence of water t o form a number of products, including diphenylphosphine and the phosphinate (69).9 5 y

12

Organophosphorus Chemistry

1.2.2 Nucleophilic Attack at Halogen. - Reductive debromination of 8-bromoguanosine occurs on treatment with tributylphosphine in the presence of a protic solvent. 96 The combination of chlorodiphenylphosphine or p - d i m e t h y l a m i n o p h e n y l d i p h e n y l p h o s p h i n e with bromine or iodine, in the presence of imidazole, offers a choice of reagent systems for the conversion of alcohols to the respective alkyl halide, which have the added advantage that the unwanted phosphorus biproduct is either alkali- or acid-soluble, thereby aiding separation in the work-up. 9 7 Treatment of primary aliphatic or aromatic amines with carbon disulphide and triethylamine, followed by the triphenylphosphinetetrachloromethane reagent, provides a direct conversion of the amine to the corresponding isothiocyanate. 98 Tr iphenylphosphine in combination with either tetrachloromethane or N-bromosuccinimide has been used for the conversion of @-amino acids into the related p-lactams ,99 and, in combination with tetrabromomethane, for the cyclisation of acetals to tetrahydropyrans. loo The treatment of triarylphosphines with tetrachloromethane and methanol has been patented as a procedure for the preparation of triarylphosphine oxides. Solid state 31P n.m.r. studies have shown that the adducts of triphenylphosphine with iodine mono-chloride and -bromide have ionic structures, being iodophosphonium halides. 102 The reactions of the alkyldiaminophosphines ( 7 0 ) with either bromotrichloromethane below O°C give rise to tetrachloromethane the P-halogeno ylides (71 1, which, above O°C, undergo 1,2-halogenotropy to form the isomeric a-halogenoalkylphosphines, (72).Io3 1.2.3 Nucleophilic Attack at Other Atoms. - The chemistry of phosphine-borane adducts continues to develop. The diphenylphosphine-borane adduct has been employed in the synthesis of linear systems having a skeleton consisting of alternating phosphorus and boron atoms, e.g., (73).Io4 Unusual salt-like systems, e.g., (74), have been isolated from the reactions of trialkylphosphines with the dimethylsulphide adduct of dibromoborane. 1 0 5 The mechanism of the Mitsunobu reaction is proving to be more Evidence has been presented complex than previously recognised. for the irreversibility of betaine formation between The course of triphenylphosphine and azodicarboxylate esters. the subsequent reaction of the betaine with m-chloroperoxybenzoic

I : Phosphines and Phosphonium Salts

13

acid and a steroidal alcohol, to give the m_-chlorobenzoate ester, rather than a per-ester, has been interpreted as indicating the involvement of a dialkoxyphosphorane intermediate prior to the addition of the acidic component. lo6 Similarly, the nature of the products of the Mitsunobu reaction between 1,2-diols and benzoic acid also requires the participation of dialkoxyphosphorane intermediates. lo7 In contrast, a study of the effects of carboxylate basicity on the Mitsunobu esterification of a 2-hydroxyethylazetidone has stressed the key intermediacy of four The significant co-ordinate a l k o x y t r i p h e n y l p h o s p h o n i u m ions. lo8 involvement of both alkoxyphosphonium and phosphorane species in the Mitsunobu esterifications of unreactive alcohols has been observed by 31P n.m. r. techniques. 109'110 Further applications of the Mitsunobu reaction in synthesis have also appeared. The use of polymer-bound alkyl azodicarboxylates eases separation problems and other hazards, oxidation of the used polymer being easily achieved to enable re-use. Product separation is also aided by the use of the pyridylphosphine (75) instead of triphenylphosphine, since the corresponding phosphine oxide is acid-soluble. The reactions of a-aminoacids with azodicarboxylates and triphenylphosphine results in oxidation at the a-carbon, the nature of the products depending on the type of The substituents on the amino group of the amino-acid.'13 Mitsunobu reaction has also found use for the synthesis of nucleoside analogues. The reactions of diphosphines with cyanamide or sulphamide in the presence of diethyl azodicarboxylate have given bis-azenes, e.g.,(76). In a similar manner tris-h5 azenes have been obtained from triph~sphinesf'~ Bis(dipheny1phosphin0)methane reacts cleanly with trimethylsilylazide to give, initially, one isomeric form of the silylated monophosphazenc ( 7 7 ) which, on heating, undergoes subsequent rearrangements to other isomeric products. 116 A kinetic study of the oxidation of triphenylphosphine by hydrogen peroxide has revealed a second order rate law consistent with the A further initial formation of the phosphonium species (78). '17 example has been reported of the use of triphenylphosphine for the Tr iaryl phosphine s deoxygenation of cyclic peroxo compounds. bearing polynuclear hydrocarbon substituents have been used for the determination of lipid peroxides. Several routes have been devised for the preparation of monoxides and monosulphides of Oxidation of primary or 1,2-bis(dimethylphosphino)ethane. 120 secondary phosphines with sulphuryl chloride provides a procedure

*

14

Organophosphorus Chernistry

+

Ph3 P Ph;! P-C(C

I

0

F3 )R

OSiMe3

(68)

(66)

X

0 II

Ph;! P-0 C H( C F3) 2

I

( Pri2N)2PCH2R

(Pri2N)2P=CHR

( 7 0 ) R = H,Me,Pr,Pr' CI,Br or P h

(69)

( Pri2N)2P CH(X)R

+

(71) X = C I or Br

Ph

-

Ph

I+-

I+-

I

I

I

Ph

Ph

Me3P- BH2- P-BH2-P

(72)

Ph

I+-

Ph

-BH2-P-

BH3

(76) X = CN or SO,NH, n = 1 or 2

(74)

Ph2PnPPh2

+

II

N( S iMe3)

(77)

-

Ph3POH OH

a 0 b PN' h 3

(78)

H (79)

I: Phosphines and Phosphonium Salts

15

for the synthesis of phosphonic and phosphinic chlorides, respectively. The reaction of triphenylphosphine with o-quinone mono-imines (or with 2-quinones in the presence of 1 iquid ammonia, under pressure) gives 2,3-dihydro-X5-1,3,2benzoxazaphospholes, e.g., ( 7 9 ) , which have been shown to exist in equilibrium with the phosphazene system (80) Nucleophilic attack by phosphorus at sulphur is involved in the t r i p h e n y l p h o s p h i n e - i n d u c e d cleavage of 1,2,4-thiadiazol-3-ones, 123 in the reactions of m e t h y l i d e n e a m i n o p h o s p h i n e s with carbon disulphide, which gives the unstable four-membered ring system (81) as the initial product,124 and in the reaction with sulphur of the acetylenic phosphine (82) which results in the ketenylidenephosphorane (83)via the initial formation of the phosphine sulphide.125 Various heterocyclic products, e.g., (84)and (851, are formed in the reaction of pentaphenylcyclopentaphosphine with selenium, although mechanistic details of these reactions are far from clear.126 The reactions of tetra(t-buty1)diphosphine with selenium and tellurium have been studied. Both insertion into the P-P bond, (to give, e.g., (8611, and oxidation at phosphorus, have been observed, depending on the nature of the chalcogen and conditions.127 1 . 2 . 4 Miscellaneous Reactions of Phosphines. - The chemistry of macrocyclic phosphine ligands has been reviewed. 128 Trivalent phosphorus ligands have been classified into two distinct g r o u p s , identified as pure a-donors and a-donors/?r-acceptors. It has been concluded that pKa values of the protonated ligands are a reasonable measure of the a-donicity for those ligands that are purely a-donors. On the basis of proton-transfer reactions involving trimethylphosphine in the gas phase, it has been concluded that this phosphine is more acidic than water, resembling the hydroxylradical in this respect.130 Sulphonation of the benzene ring has little influence on the basicity of triphenylphosphine.13' A range of water-soluble, chiral, diphosphine ligands havebeen prepared by sulphonation of diphenylphosphino groups present in the parent, chiral diphosphines Unexpected dipolarophilic activity of diphenylvinylphosphine has been revealed in its reactions with nitrones which result in the predominant formation of the adducts (87) Full details of Michael-type nucleophilic additions to coordinated

Organophosphorus Chemistry

16

6 ut2 PC E C O E t

(81) R = Me or Et

(80)

pt Bu' 2P =C

=O

I

Se Se \pd / \ Se Ph

Ph \p'

4\

SEt

Se

(83)

,Ph

'P-P

/

\

Se,

,Se P Ph

(85)

R' Bu$P

- Te -P

But2

(86)

R2N T P P h 2

'0 (87) R ' = a l k y l or a r y l R 2 = alkyl

(88)

P\h ,Ph

Rz PCFzCFCF3 0 (89)

R2P-C -SiMe3

( 9 2 ) R = RZN

(90)n = 1 or 2

.. .. R2 P-C-Si (93)

( 91 1 R = Me ,Et, or But

f2-l P

MeSi

Me3 (94)

1: Piiosphint.s and Phosphonium Salts

17

1,l-bis(dipheny1phosphino)ethene have now been reported.134

Except with sterically crowded reagents,nucleophilic ring-opening of coordinated phosphiranes (88) involves initial attack at phosphorus, followed by either ring-opening to generate a The carbanion c~ with loss of the whole C-C unit.135 phosphametallacycle (89) is formed in the reaction of o - d i p h e n y l p h o s p h i n o b e n z a l d e h y d e with ethylenebis(tripheny1Metal-induced reorganisation of phosphine)platinum [0] 136 phosphinoalkynes to co-ordinated vinylphosphido ligands has been reported,137 and examples of transition metal-promoted cleavage of aryl-phosphorus linkages of arylphosphines continue to appear. 138 The new phosphines (90) have been used as ligands in a homogeneous The varying dissociation pressures of the catalyst system.139 adducts of trimethyl-aluminium, -gallium, and -indium, with 1,2-bis(diphenylphosphino)ethane enable the separation of gallium and indium by reversible adduct formation. Trimethylaluminium forms a very strong complex with diphos which only dissociates on 140 distillation. Whereas both tri(t-buty1)phosphine and secondary phosphines react with perfluoropropene to give the p e r f l u o r o v i n y l p h o s p h i n e s (911, the corresponding reactions of triethylphosphine (and methylarylphosphines) proceed with insertion into the 1-(fluorine-carbon) The lability of the bond to give monofluorophosphoranes. 14' carbon-phosphorus bond of tris(pentamethylcyclopentadieny1)phosphine on thermolysis in refluxing benzene has been exploited in the synthesis of new polyphosphorus systems,142 and as a source of polyphosphorus units, e.g., P 3 , stabilised as ligands in new 143 transition metal complexes. As indicated by their pattern of reactivity,the products of pyrolysis of the a-diazomethylphosphines (92) are best regarded as nucleophilic carbenes (931. 145 Some aspects of the reactivity of the bicyclic system (94) have been explored. With chlorodiethylphosphine, the salt (95) is formed, which is converted into the bicyclic phosphine oxide on methanolysis. The phosphine oxide is also formed in the reaction of the bicyclic phosphine with The reactivity of the anionic cyclic nitric oxide in pentane. 146 phosphine system (96) towards a range of electrophilic and Cyclic ylides, nucleophilic reagents has been studied.147y148 e.g., (971, are formed in the reactions of alkoxyethynylphosphines with halogenophosphines. 149 Primary silyl and germyl-phosphines

.

undergo redistribution, in the presence of a boron trihalide, to

18

Organophosphorus Chemistry

form the related trisilyl- and trigermyl-phosphines and a new route to dialkylaminophosphines is afforded by the exchange reactions of t e t r a - o r g a n o d i p h o s p h i n e s with dialkylaminodialkylars ines 50 ' 51 Exchange reactions of cyclopolyphosphines bearing trifluoromethyl substituents with secondary phosphines and of tetrakis(trifluoromethy1)diphosphine with secondary phosphines, other P ,P-diphosphines, and halogenophosphines have given a range of new trifluoromethylphosphines, e.g., the chiral secondary These compounds are also accessible by insertion phosphines ( 9 8 ) . of p e r f l u o r o a l k y l p h o s p h i n i d e n e s , RfP:, into the P=P bond of diphosphenes, followed by hydrolysis of the intermediate triphosphine.1 5 4 A new C=C forming reaction is afforded by the reactions of aldehydes and alkyl bromoacetates in the presence of zinc and tributylphosphine, which results inarp-unsaturated esters of exclusively E-configuration. 155

.

2 Halogenophosphines 2.1 Preparation. - Routes to alkyldifluorophosphines have been developed which involve exchange reactions of the corresponding chlorophosphine with hydrogen fluoride,156 antimony trifluoride,157 and zinc fluoride,158 respectively. A widely applicable route to substituted aryldifluorophosphines ( 9 9 ) is afforded by the reactions of the appropriate aryllithium reagent with c h l o r o d i f l u o r o p h o s p h i n e , the most stable systems being those in which the difluorophosphino group is flanked by substituents in Two reports have appeared describing the 2 - and 6 - positions.15' the synthesis of the bis(aminoha1ogenophosphines) (100) by the reactions of appropriate chlorophosphines withN,N'The sterically crowded bis( trimethylsilyl(methyl1 )urea. l6OY 16' dichlorophosphines (101) are accessible via the reactions of the 162 appropriate silyllithium reagent with phosphorus trichloride. The reaction of bis(trimethylsily1)methyldichlorophosphine with bis(trimethylsilyl)(chloro)methyllithium affords the hindered chlorophosphine ( 1 0 2 1 , which rearranges to give the chlorophosphirane ( 1 0 3 ) . Cycloalkyl Grignard reagents have been employed in the synthesis of unsymmetrical diorgano(ch1oro)Ar yl a1kyny 1d iha1ogenophos pho sphines from d ichloropho sphines 64 phines ( 1 0 4 ) are accessible by the reactions of the parent arylacetylene with a phosphorus trihalide under either 165,166 photochemical activation or in the presence of a base.

.

I : Phosphines and Phosphonium Salts

19

R r0,PhP BPhZ M+ R 0’

(96 1

(95)

(97)

0 MeNKNMe

-

R2P-PHCF3

R2 0 ’ P F 2

1

R3

(98) R =Me or Ph

1

X2P

(99) R’ = H.OMe,NMez, or OPh R2 = H , M e , or CF3 R 3 = H, OMe, CF,, or NMez

PXZ

(100) X = F, Cl,or R

CI I R2 C -P- C HR 2

I

Cl (101) R

= Me or Ph

R

R

(103) R = MeSSi

(102) R =Me3Si

Ph2FzP-CHR-OPPh2

ArCECPX;! (104) X = CI or Br

(105)

S

S

II

II C HzPF2

Fz PCH, ‘P-P’ P ,P -, F2 PCH2 II S

I

I

(107)

CH,PFz

II

Ph

&gh II

0

S (108)

20

Organophosphorus Chemistry

Various phosphate esters have been used for the decomplexation of phenyldichlorophosphine in the aluminium chloride-catalysed reaction of benzene with phosphorus trichloride.167 2.2 Reactions of Halogenophosphines. - The fluorophosphoranes (105) are formed in che reactions of fluorodiphenylphosphine with aldehydes. The dif luorophosphorane (1061 has been identified as an intermediate in the disproportionation of fluorodiphenylDifluoro(pheny1)phosphine phosphine, which is catalysed by acids. has also been shown to undergo disproportionation, among the Surprisingly, products being h e x a p h e n y l c y c l o h e x a p h o s p h i n e . t-butylphosphine is formed in the reaction of t-butyldifluoroThermolysis of the phosphine with ethoxytrimethylsilane.I 7 O monosulphide of bis(dif1uorophosphino)methane gives rise to the The reactions of four-membered ring system ( 1 0 7 ) . 17’ dialkylamino(f1uoro)phosphines with tetrachloromethane have been The kinetics of solvolysis of chlorodialkylinvestigated.172 phosphines and chlorodiphenylphosphine in ethanol and other mixed solvents has been studied by conductivity techniques, the solvolysis of chlorodiphenylphosphine occurring much faster than that of the related c h l o r o d i a l k y l p h d s p h i n e s . 173 Interest in the reactions of halogenophosphines with carbonyl and related compounds has continued. The phosphinate ester ( 1 0 8 ) has been isolated from the reaction of dichloro(pheny1)phosphine with dibenzqlmethane in A variety of products has been the presence of triethylamine.1 7 4 isolated from the reaction of chlorodiethylphosphine with Oxidative addition of hexaf luoroacetone to cyclohexanone.1 7 5 3 1 76 the chlorophosphorinane ( 1 0 9 ) results in the formation of the A route to phosphorane (1101, together with other products. 177 diazaphospholenes (111) is provided by the reactions of di-imines derived from a-dicarbonyl compounds with phosphorus trichloride, or a l k y l d i c h l o r o p h o s p h i n e s , in the presence of The related heterocyclic system (112) has triethylamine. 178-180 been isolated in the corresponding reaction of a 2,3-butanedi-imine with chlorobis(diethy1amino)phosphine. The reactions of aldimines with chlorodiphenylphosphine in the presence of triethylamine are reported to lead to the iminophosphines ( 1 1 3 ) On treatment with dichloro(phenyl)phosphine, the silylated imino 183 A system (114) is converted into the bicyclic system (115). range o f P-aryl-5,lO-dihydrophenophosphazines (116) has been isolated from the reactions of substituted diarylamines with

I: Phosphines und Phosphonium Salts

21

0 CI

(111) R'= H,Me,or C l R ~ BU = or~y $ = CI or Et //NSiMej PhC

(110)

(109)

Ar C=NAr

I

Ph2P

'N(SiMe31,

H

R4

Ar (116) R'-R4

= H, Me, or But

RP( C l ) CCI 3

(1171 R=R2N,But,or OR

0 II

R~~P-ON=CR~CL

(120)

(121)

R ' = alkyl,Ph,orCl R 2 = alkyl

I?' P(S2CNR22)2

(122) R ' = M e or P h $=alkyl or Ph Ph

Ph

22

Organophosphorus Chemistry

dichloro(pheny1 Iphosphine at 20OoC. lg4 Alkyldiphenylphosphine oxides have been isolated from the reactions ofalkyl halides or substituted alkenes with the aluminium chloride complex of chlorodiphenylphosphine and hydrogen chloride.185 The chlorophosphines ( 1 1 7 ) are formed in the reactions of various dichlorophosphino compounds with tetrachloromethane in the presence of tri~(diethy1amino)phosphine.l~~ A route to bis(dipheny1phosphino)amine (118) has been developed which involves the reaction of chlorodiphenylphosphine with bis(trimethylsily1)amine, followed by treatment with ammonia. The heterocyclic system (119) is formed in the reaction of 1,2-bis((t-butyl)(ch1oro)phosphino)ethane with secondary amines. 189 The general reactivity of 1,3-bis(dichlorophosphino)benzene (120) has been explored. A series of phosphinic acid derivatives (121) has been isolated from the reactions of halogenophosphines (and secondary phosphines) with 1,l-dichloro-1nitrosoalkanes.191-193 The synthesis of new ligand systems via nucleophilic displacement reactions of halogenophosphines with oxygen, nitrogen and sulphur nucleophiles continues to attract attention. New chiral ligands have been prepared from the reactions of chlorodiphenylphosphine with natural amino acids and Further details related alcohols , I g 4 and with carbohydrates. have been reported of the reactions of coordinated phosphinoenolates towards chlorophosphines, which lead to the diastereoselective formation of P-C and P - 0 bonds!g6 In a similar vein, the metal template-promoted synthesis of mixed The reactions phosphino-phosphonite ligands h a s been reported. of chlorophosphines with sodium dithiocarbamates have afforded the The corresponding d i t h i o c a r b a m a t o p h o s p h i n e s , e.g., (122). I g 8 heterocyclic systems (123) and ( 1 2 4 ) have been isolated from the reactions of 2-xylylene dithiols with dichloro(pheny1)phosphine in the presence of base. 199 The reactions of halogenophosphines with phenolic derivatives of amino acids are involved in the synthesis of chiral phosphonyl and phosphinyl systems, e .g. , ( 1 2 5 ) . 2oo An alternative strategy for the controlled formation of N-P links is afforded by the reactions of trimethylsilylamino compounds with halogenophosphines, and this has enabled the preparation of the alkylamino(ch1oro)phosphines (126). 201 The final products of the reactions of dialkyl(iodo)phosphines with diethyl(trimethylsily1)amine are the aminophosphonium salts ( 1 2 7 ) . 202 The hydrolysis and alcoholysis of dialkyl(iodo)phosphines results in the formation

I : Phosphines and Phosphonium Salts

23

of both dialkyl-phosphinous and - phosphinic acids, together with the hydroiodide of the corresponding secondary phosphine. 203 The phosphine oxides (128) have been obtained from the ring-opening of trimethylene oxide with dialkyl(iodo)phosphines. 2 04 3 Phosphonium Salts Preparation. - Quaternization of tertiary phosphines with propargylic halides has provided the salts (129) which, on treatment with dimethylformamide, are isomerised to the allenyl systems (130). 205 Conventional quaternization procedures have also been used for the preparation of h e t e r o a r y l m e t h y l p h o s p h o n i u m salts,206,207 e.g., (131),207 a range of unsaturated salts, e.g., (132) ,208 (133) ,209 and (134) ,210 and the substituted phenacylphosphonium salts (135). 211 A patent has described a process for the preparation of high purity tetrabutylphosphonium chloride 212 A simple, highly stereospecific route to vinylphosphonium salts, e.g., (1361, is afforded by the palladiumcatalysed reactions of triphenylphosphine with vinyl triflates.213 A general synthesis of 2 - , 3 - , and 4-hydroxyalkylphosphonium salts (137) is provided by the reactions of triphenylphosphine with cyclic ethers in the presence of strong acids. 214 Dialkyldiphenylphosphonium salts have been obtained by the double alkylation of lithium d i p h e n y l p h ~ s p h i d e ,and ~ ~ ~a general route to a l k y l t r i c y c l o h e x y l p h o s p h o n i u m salts is afforded by the reactions of alkyl halides with the t r i c y c l o h e x y l p h o s p h i n e - c a r b o n disulphide adduct, thereby eliminating the isolation and handling of the free phosphine.216 Electrochemical oxidation of triphenylphosphine in the presence of alkenes in dichloromethane has given 1-alkenyl-, allyl-, and 3-oxoalkyl-phosphonium salts.217 A similar oxidation in acetonitrile in the presence o f 1,3-dicarbonyl compounds leads to the salts (138). 218 Another example of a coordination kinetic template effect in arylphosphonium salt formation is the nickel(I1)- and copper(I1)- catalysed reactions of the bipyridyl system (139, X=Br) with tertiary phosphines, which lead to the salts (139, X=R3P+Br-) with regiospecific replacement of the Two bromine in the ortho- position to the bipyridyl template.219 routes to the zwitterionic heterocyclic system (140) have been described. 220 9221 Treatment of allenylphosphine oxides with electrophilic reagents provide a route to the 2,5-dihydro-1,2oxaphospholium salts (141).222

.

Organophosphorus Chnistry

24

H2 N HCOO H Me2NCHzCH*N(Me)B, NR

CI

I

(129) R'=Me.Bu, or P h R2= Me,Ph,or vinyl

(128)

NEb2

+

R3PCH=C=CHPh

BrB r-

(130)

(131) n

+

1 or 2

+

CI-

A r NHCH=CHCOCH2PPh3

=

Ph2P C(Ph)=CH2 CI H2 COR

(132)

(133) R

CI-

= Me or Ph 0

II

+

Br-

Ph3PCH2C

(135) R' = H or F R2 = H or Me

( 1 3 4 ) 2 = C02Me or CH2CHzOSi But Ph2

+

F C H P P h 3 OTf -

+

Ph3P(CH2),CH2 OH

+

COR'

Ph3P-CH

CiOb-

\

BPhi

(137) n = 1 - 3

/

COR2

(138) R R

= Ph = Me,Ph.or OEt

1: Phosphities and Phosphonium Salts

25

Interest continues in the preparation of phosphonium salts which involve unusual anions. The tetraphenylphosphonium arenethiolate (142) and the selenium analogue have been prepared by metathesis, and shown to be ionic in the solid state and also in solution. The anions are strongly nucleophilic to halocarbon solvents, and very susceptible to hydrolysis. 223 A series of m e t h y l t r i a r y l p h o s p h o n i u m arenesulphonates (143) has been prepared by either the reactions of triarylphosphine with an excess of the methyl ester of the arenesulphonic acid by metathesis. 224 Patents have described the preparation of phosphonium carboxylates, 225 and salts involving the anion of dibenzoylmethane. 226 Full details have now appeared of the preparation, structure and properties of salts of the bis(tripheny1phosphine)iminium cation with tetracyanoquinodimethanide anions. 227 Tetraphenylphosphonium salts involving complex silver228 and arsenic229 anions have also been described. Polymer-bound a l k y l t r i b u t y l p h o s p h o n i u m halometallates have been prepared and used as catalysts in the hydrosilylation of phenylacetylene. 230 3.2 Reactions of Phosphonium Salts. - Alkaline hydrolysis of the bis(2-hydroxyethyl)phosphonium salt (144) results in the formation

Full details of the of the cyclic phosphine oxide (145). 231 chemistry of phosphonio-azines, e.g., ( 1 4 6 1 , are now available. The heteroaryl groups are readily cleaved under alkaline aqueous conditions. With other nucleophiles, it is possible to displace the 4-triphenylphosphonio group with the introduction of a range of substituents into the heterocyclic ring.2329233 The reversible dissociation of the salt ( 1 4 7 ) to form triphenylphosphine and a pyrilium salt has been studied by various techniques. 2 3 4 Alkoxycarbonylphosphonium salts (148) readily decompose with elimination of alkyl halide and carbon dioxide to form a tertiary phosphine.235 Nucleophilic addition of carboxylate ions to propargylphosphonium salts results in the substituted vinylA route to keto-functionalised phosphonium salts (1491?36 morpholines is afforded by nucleophilic additions of various 2-aminoethanols to the vinylphosphonium salt (150). 2 3 7 Nucleophilic addition of amines to the double bond is involved in the partial geometric isomerisation of the alkoxypropenylphosThe phosphonium salt ( 1 5 2 ) is a useful phonium salts ( 1 5 1 ) . 2 3 8 intermediate in the synthesis of the heterocyclic systems (153)

26

Organophosphorus Chemistly

Bu Ph

-m+

Me

Bu~B

PPh2

'O< (140) R = CC13,Me Pr! or ~r

(141) E = Br,I,RS or RSe

+/

CHzC H2OH

c1-

PhzP,

CHzCH 20H (143)

7"' /

H

(144)

+

PPb

(304-

ph)jph +

R',PC02 R2 Cl-

2x-

+

R C 0 2 C( Me)=CH

7 -

ph3p

+

P Ph3 Br -

0

0

(149)

+

+ Ph,P-CH=C

X-

'R ( 1 5 1 ) R = Me or Et

PPh3

+

,OMe

PhC=NCH2PPh3

I

CL

Cl

H (152)

(153)

I: Phosphines and Phosphonium Salts

27

and (1541,formed in its reactions with sodium thiocyanate, or with aroyl chlorides in the presence of triethylamine, The salt ( 1 5 5 ) is unstable in solution, respectively. 2 3 9 ' 2 4 0 undergoing rearrangement to form ( 1 5 6 ) .241 Treatment of the aminophosphonium salts ( 1 5 7 ) with secondary amines results in ringopening of the three-membered ring, to form the new salts (158).2 4 2 The amidomethylphosphonium salts ( 1 5 9 ) have been prepared by treatment of the related alkoxycarbonylmethylphosphonium salts with amines 243 A route to benzothiophenes and other sulphur heterocycles is offered by the reactions of the salt ( 1 6 0 ) with acid chlorides and other carbonyl reagents. 244 The salt ( 1 6 1 ) has been used as a synthon in the preparation of annelated cyclobutanes. 245 Thioalkylphosphonium salts (obtained from the reactions of tertiary phosphines with disulphides) have been applied in the synthesis of thiol esters and unsymmetrical The hydrobromide of triphenylphosphine is a thioethers. 246 highly effective catalyst for the tetrahydropyranylation of tertiary alcohols in dichloromethane at room temperature. 247

.

Various phosphonium salts have been found to catalyse the chlorination of butadiene. 248 "Phosphonium anhydride", obtained by dissolution of triphenylphosphine oxide in trifluoroacetic anhydride, has been shown to act as a powerful dehydrating agent in the conversion of carboxylic acids to esters, amides, benzimidazoles and cyclic aryl ketones, in good yields. 2 4 9 QT-Bonded

Phosphorus Compounds

Although this area continues to attract considerable interest, the pace of advance seems to be slackening. Compared with recent years, there has been a significant reduction in the number of publications in the period under review. The 2,4,6-tris(trifluoromethyl)phenyl group provides another The example of a stabilising substituent for the P=P bond. 250 first examples of stable cis-diphosphene systems ( 1 6 2 ) have been prepared. In solution, conversion to the corresponding transisomers occurs over a few days, and in the solid state,X-ray studies reveal possible interactions between the cis-substituents. 251 These molecules form the usual complexes with metal acceptors. Photolysis of the E_-isomer of the diphosphene (163) using a mercury lamp with a pyrex filter results in the formation of a mixture of

g- and &-

isomers in equilibrium.

However, photolysis

OrganophosphorusChemistry

28

+

PPh3 CI0,CF,CH=NCH

Ph

/

Cl-

\+

Ph!-$Ar0

PPh,

(155)

(154)

/

Ph

CF3CH2N=Cr

\+

PPh3 Cl-

/p=p\ RNH Ar

d*PPh3 = clO;

(162) R Ar

A r P=PAr

(163) A r = 2,4,6 -But3C6H2

(165) X R

=

C I or Br

= 2,4,6-BUt3C6H2 or TMS

B u t , Adamantyl , Et3 C , o r 2,4,6 Pr'3C6Hz 2,4,6 - But3C6H2

-

( 1611

=

I: Phosphines and Phosphonium Salts

29

in the absence of a pyrex filter leads to the generation of the phosphinidine, ArP:, which undergoes self-trapping to form the phosphaindane ( 164)?52 Two groups have reported the reactions of diphosphenes with dihalogenocarbenes which lead to the diphosphiranes (165). Anionic ring-opening of the latter with alkyllithium reagents yields 1,3-diphospha-a1lenes (166). 2539254 The diphosphiranes also rearrange in solution, or in the presence of silica gel, to form the new 1,3-diphosphapropenes (167), in which the lone pairs at phosphorus and the P=C double bond system are coplanar.255 Deprotonation of the phosphino-phosphene (168) generates the triphospha-allyllithium reagent (169), which exists in two isomeric forms.256 Two reports have also appeared of the transient formation of the 1,2,3-triphosphabutadienes (170) which undergo intramolecular[2+2] cycloaddition to give the first examples of the triphosphacyclobutane system (171).257y258 Further studies have been made of the reactivity of diphosphenes and phosphaarsenes which bear a complexed transition metal substituent at phosphorus.259 260 The coordination chemistry of diphosphenes 261,262 also continues to attract attention. The metallated phospha-alkenes (172) and (173) offer considerable potential for the synthesis of P=C compounds. Treatment of (172) with carbonyl compounds has given the 1-phospha-allenes (174), and (173) has been used in a synthesis of 1,3-diphospha-allenes (166).263 Metallation of (175) with t-butyllithium has given the related reagent (176), which undergoes alkylation at carbon on treatment with alkyl halides, and which also rearranges in solution with migration of an aryl group from phosphorus to carbon with the formation of the phospha-alkyne (177). 264 Established routes to phospha-alkenes have been applied in the synthesis of a series of The unusual phospha-alkene (179) phosphafulvenes, e.g., (178). 2 6 5 has been isolated from the reaction of 2,4,6-tri(t-butyl)A full phenyldichlorophosphine with the bicyclic base DBU. 266 267 structural study of the phospha-alkene (180) has been reported. Interest has continued in the synthesis and characterisation of less-hindered (and therefore more reactive) phospha-alkene systems. Alkali metal bis(trifluoromethy1)phosphides decompose above 215 K to form the p e r f l u o r o p h o s p h a - a l k e n e , CF3P=CF2.268 The stannylphosphines ( 1 8 1 ) have been used as precursors for the in-situ generation of the phospha-alkenes (182), which can be trapped with Full details have now been given of the synthesis of dienes. 269 phospha-ethene, HP=CH2, and 1-phosphapropene, CH3CH=PH, by the

Organophosphorus Chernistiy

30

ArPH-P=PAr (168) Ar

K

= 2,4,6 - But3C&

RP

\P=P \ P =C( S iMe

I2

Ar CL \ / P=C

Ar \

P=C

\

\L i

(173)

Li P=C

/ \

CL

(176)

Q-p p,

H

CI

(175)

Ar

\

I

Ar

H

P=C(SiMe,),

(180)

1: Phosphine.7 and Phosphonium Salts

31

gas-solid reactions of chloroalkylphosphines with potassium carbonate, and of their spectroscopic characterisation. 270 On heating, the secondary vinylphosphine (183) undergoes conversion to the phospha-alkene (184).271 The 1,3-azaphospholene (1851, obtained from the reaction of 2-(methy1amino)ethylphosphine with an amidoacetal, undergoes dimerisation to form the diphosphetane ( 186)272. The simple phospha-alkene, PhP=CH2, has been synthesised in the coordination sphere of a transition metal. 2 73 Further aspects of the coordination chemistry of phospha-alkenes have been reported. 274 A novel entry to the P=C system is provided by the reactions of the phosphido complex (187) with carbonyl compounds which lead to the phospha-alkene complexes ( 1 8 8 ) .275 The chemistry of the P-halophospha-alkene (189) has continued to develop. The chlorine atom can be replaced by a variety of anionic reagents,276 and the parent system has been shown to undergo a range of cycloaddition reactions with diazo compounds. 277 The coordination chemistry of P-halophosphaalkenes is now starting to receive attention. 2 7 8 The lithiated 1-phospha-allene (190) is a key reagent in the synthesis of the first examples of the 1,4-diphosphabutatriene system (1911, and doubtless has potential for the synthesis of higher phosphacumulenes. 279 The 1,3-diphospha-allene (166, R=2,4 ,6-Bu:C6H2 1 reacts with water at elevated temperatures to form the bis(secondary phosphine oxide) (192). 280 Treatment of the 1,4-phosphabutadiene (193) with molybdenum-or tungstencarbonyl complexes gives the m e t a l l a d i p h o s p h a p e n t a d i e n e s (194). 281 Routes to the P=C=N system (195) have been described, together with a structural study of one example, which reveals that the P=C=N system is almost linear. 282 The reactivity of the first stable stannaphosphene (196) has been explored. Protic reagents attack the double bond in a regiospecific manner to give secondary phosphines, and the reaction with selenium gives the heterocyclic system (197).283 A similar addition of sulphur or selenium to the P=Ge bond of the germaphosphene (198) occurs to give the related three-membered ring system (199).284 A series of papers describing dipole moment studies of p*-bonded phosphorus compounds has appeared.285-287 The chemistry of phospha-alkynes has been reviewed. 288 The first example of the p h o s p h a d i s t a n n a c y c l o b u t e n e system (200) has been prepared by the addition of a distannene to the phospha-alkyne, A novel 1,2-migration of a phenyl group from carbon t o ButCEP.289

32

Organophosphorus Chemistry

Me

0

II

-

(EtO),P-PR
.c

N

(MesSi);! C=PCl

R’-P=C

Ar-

P=C=C,

/

4

/

‘R3

Li X

(189)

Ar P( H) CH2 P( H)Ar

II

0

8

ArPnPAr

/

Ar(H)P

Ar

“M(CO),

Ar P =C =NR

( 1 9 4 ) M = M o or W

[( Me3Si

C H] S n -P A r

\ /

Se

Mesz Ge=PAr

Mesz Ge -PAr ‘X

(199) X = S or Se

R2

1: Phosphirrrs and Phosphonium Salts

33

phosphorus is involved in the transformation of (2011, the initial product of addition of diphenyldiazomethane to ButCrP, into the The 1-metallaphosphaindanes (203) have diazaphosphole (202).290 been obtained from the reactions of bis(cyclopentadieny1)diphenyltitanium or -zirconium with an excess of the phospha-alkyne, ButCEP 291 Various other papers have described the reactions of this phospha-alkyne with complex metallic species, leading to the synthesis of unusual systems. 292-297 There has been considerable interest in the synthesis of phosphorus-boron systems in which there is the potential for The reactions of lithiophosphide reagents P r d B T interactions. with halogenoboranes provide direct access to phosphinoboranes, e.g., the first monomeric t e t r a - a l k y l p h o s p h i n o b o r a n e (204), and the first triphosphinoborane (205). 298 A structural study of the diborylphosphine (206) reveals that it has a planar core involving the phosphorus, two boron and the five ips0 carbon atoms o f the aromatic rings. The boron-phosphorus bond length is also shortened. In contrast, in the diphosphinoborane (2071, while the coordination at borop remains planar, each phosphorus has the usual pyramidal geometry, and the boron-phosphorus bond is longer than that in (206). 299 The degree of r-interaction between phosphorus and boron is markedly influenced by the nature of the substituents at boron, being favoured by the presence of an electron-withdrawing group. Thus, whereas a structural study of (208; X=Br) reveals a planar skeleton involving the ipso-carbons of the phosphorus substituents, together with a shortened phosphorusboron bond length, there is greater evidence of pyramidality at phosphorus, and a longer phosphorus-boron bond, in the ethoxy Deprotonation of the phosphinoboranes analogue (208; X=OEt). 300 (209), using butyllithium in the presence of crown ethers, has given the lithium salts of borylphosphides. A structural study of one example has revealed the shortest boron-phosphorus bond Full details of the synthesis of recorded to date. 301 boraphosphabenzenes (210) have now appeared. Structural studies show that the boraphosphabenzene system is planar, and exhibits considerable aromatic character. 302 A The area of P=N systems has continued to attract attention. full structural study of the amino-iminophosphene (211) has been Among new systems prepared are the ester (212)304 reported. 303 and the unhindered iminophosphene (213), described as a volatile

.

white solid.305

The reactions of the phosphinoiminophosphene (214)

34

Organophosphoms Chemistiy

(200) R = (Me3Si),CH

(202)

Me2 P

il

But2P--'B

.p\.

But2

Me2P

PMe

(204)

cp2

(205)

(203) M = Ti or Zr

R' R2B /p%

BR2

R'P

PR'

It

R'2 B-PHR'

I

\

(209)

R2

(210) R' = Ph,Mes,C6HlI,or Bu' R2 = M e s or Ph

( M e 3 S i ) 2N-

( 2 1 1 ) Ar = 2 , 4 , 6

P=NAr

-

But3C6H2

@OP=NAr

( 2 1 2 1 Ar = 2 , 4 , 6 - B u t 3 C ~ H 2

f : Phosphines and Phosphonium Salts

35

with electrophilic reagents, have been studied.306 Cycloaddition of iminophosphenes to the phospha-alkyne, B u t S P , leads to the diphosphirene system (215), which undergoes isomerisation to the azadiphosphetines (216). 307 The reactions of iminophosphenes with photochemically-genera.ted phosphonitriles ,3 0 8 and boronThe sulphur heterocyclic systems,309 have also been investigated. reaction of a hindered aromatic primary amine and phosphorus trichloride in the presence of triethylamine gives the bright red P-haloiminophosphene (217) (as the %-isomer), which, when treated with aluminium trichloride in toluene, is converted into the A salt (218), the first stable compound having a F%N link.310 related salt (219) has been obtained from the reaction of a P-phosphinoiminophosphene with selenium. A structural study reveals that the PzN bond is markedly shorter than P=N. 311 Further progress has been reported in the area of terminal phosphinidene complexes. A range of tungsten phosphinidene complexes (220), bearing new substituents at phosphorus, has been prepared by previously established routes.312 A new route to phospha-alkenes is provided by the reactions of terminal A study phosphinidene complexes with metal-carbene complexes. 313 of the reactivity of a terminal phosphinidene complex towards 314 styrenes suggests carbene-like character at phosphorus. Various aspects of the coordination chemistry of phosphinidene Two routes for the complexes have also been reported. 315-317 generation of the free phosphinophosphinidene (221) have been developed, and clear evidence of its formation adduced from the results of trapping experiments. 318,319 Efforts have also continued in the characterisation of twoVarious routes have been coordinate phosphenium ions, R2P+. developed for the synthesis of stable pentamethylcyclopentadienylphosphenium ions (222). In the solid state, q2-attachment of the ring system to phosphorus is evident, whereas in solution, the The salts (223) have been isolated structure is fluxional.320 from the reactions of dichlorophosphines with a silylated N , N ’ trimethyl-substituted ethylenediamine. 321 Phosphenium ions have been shown to insert into cyclopropanes to form phosphetanes,322 The and also to add to the P=N bond of iminophosphenes.323 sulphur-stabilised species (224) has been fully characterised, the ring system being planar, consistent with a delocalised Arsenic and antimony dithiaphospholium structure. 324’325 analogues have also been prepared.3267327

36

Organophosphoms Chemistiy

(CF3 J2 NON=P H

(Me,Si )2 N-PPN-PBU~~

(213)

(214)

( 2 1 9 ) Ar = 2,4,6 R = But

- But3C6H2

But A'P

( 2 1 5 ) R1 = Bu' or Et3C R 2 = But or Mes

( 2 2 0 ) R = Et02CnMe3C0, or 9 - fluorenyl

*.

But2P-

P:

[a]+MeN,

,NMe2

+

-l

BPh4

( 2 2 3 ) 2 = CC13, Me,Ph, But, OMe or NEt2

(224)

R = H or Me

(225)

S

Li

+

6'\\

S

(226)

(228)

I : Phosphines and Phosphonium Salts

37

The chemistry of a3-k5 systems has also received further study. A theoretical treatment of the bis-silylenephosphorane (225)

predicts significant strength for the P=Si link and makes it an attractive synthetic target. 328 Nucleophilic displacement of the chlorine of (226; X=C1) by arylamido reagents results in the formation of the related arylamino system (226; X=ArNH), deprotonation of which yields the i m i n o b i s m e t h y l e n e p h o s p h a t e system (227). 329 A study of the action of nucleophiles on the dithiophosphorane (228) has been reported. With triethylamine, an intramolecular oxidative addition ensues, resulting in the cyclic dithiophosphinate (229). 330 The reactions of the amino(imino)methylenephosphorane (230) with both nucleophilic and electrophilic reagents, have been explored. 331 5 Phosphirenes, Phospholes and Phosphinines

The addition of monochlorocarbenes to phospha-alkynes results initially in the formation of the transient 2H-phosphirenes (2311, which then undergo rearrangement, with migration of chlorine from carbon to phosphorus, to give the stable P-halo-1H-phosphirenes (232). Unlike their nitrogen analogues, the latter cannot therefore be antiaromatic. Nucleophilic displacement of the halogen proceeds normally leading to a range of new systems.332 A route to 2-amino-1-phenylphospholes (233) is provided by the reactions of dichloro(pheny1)phosphine with enamines at room temperature.333 Intramolecular [4+2] cycloadditions of phospholes with vinylphosphines (both present as their complexes with palladium or platinum) occur at ambient temperature with very high diastereoselectivity, providing a route to a new class of rigid, chiral, bidentate phosphines (234).334 A similar cycloaddition between a phosphole and a vinylcarbene complex has given the The reaction between phosphinocarbene chelate (235). 335 l-phenyl-3,4-dimethylphosphole anddiphenylketene at high pressure has resulted, unexpectedly, in the phosphorane (236) rather than the expected cycloadduct. 336 Complexes of phospholyl anions in which the ring system is .?r-bondedto titanium337 and rare earth elements338 have been prepared by the reactions of lithio- or t r i m e t h y l s t a n n y l - p h o s p h o l e s with the appropriate metal halide. Interest has continued in the chemistry of phosphaferrocenes, their electrochemical oxidation,339 the stability of a-phosphaferrocenyl carbonium ions,340 and the protonation of

38

Organophosphorus Chemistry

//NSi Me3 ( Me3Si ) * N-P

‘CHSi ( 2 29)

(230)

R’

R’ CL (231)

Me3

R2

‘d CI

hR2 P

R’= Ph,Bu’,PhO, or OMe R2 = But, CMe, E t , or 1 - adarnantyl

n

Ph

( 2 3 3 ) R’ = Me or Et n =Oar?

(234)

R’ = But ,Ph, or PhCH;! R2 = E t , Ph. or vinyl

Ph (235)

(236)

(237)

(238)

1: Phosphines and Phosphonium Salts

39

%pr

N-S

A r 4 pJR

‘I OH

N-

P

(239)

R

J(R

CI

(245)R = H or Me

( 2 4 6 )R’ = M e , Pr , B u , P h , o r OMe R 2 = CL or Me R 3 = Me or CL

(247)R’ = alkyl or Ar R Z = M e or E t

qp5J Me2N

/

\

NMe2

40

Organophosphorus Chemimy

acylmonophosphaferrocenes341 having been investigated in the past year. Further examples of metal 7r- complexes of triphospholyl ligands have also been described.342,343 Metallation of phenylisocyanide with t-butyllithium in the presence of TMEDA generates a difunctional reagent which, on treatment with dichlorophosphines, gives the 1,3-benzazaphosphole system (237). Flash vacuum pyrolysis of (237; R=But) results in the formation of the 1H-1,3-benzazaphosphole system (238). 344 A route to the 3-hydroxy-l,2,4h3-diazaphosphole (239) has been developed. This molecule behaves as a heterocyclic phenol, showing no tendency to The reactions of tautomerise to a keto structure.345 1,2,4,5-tetrazinedicarboxylates with an excess of the phosphaalkyne, ButCZP, have given the unusual system (240). 346 Interest has continued in the study of cycloaddition reactions of diazaphospholes. 347-350 The coordination chemistry of 1,2,3-diazaphospholes and 1,2,4,3-triazaphospholes has also been Cycloadditions of 1,3,4-oxathiazol-2-oneswith investigated.351 phospha-alkenes have given the first examples of the 1,2,4-thiazaphosphole (2411, 1,2,4-thiadiphosphole (2421, and 1,2-thiaphosphole (243) systems.3 5 2 The 1,3-0xaphosphole system (244) has been prepared by the reaction of a phospha-alkyne with a chromium carbene complex. 353 A simple one-pot synthesis of 2-chlorophosphinines (245) is afforded by the cycloaddition reactions with dienes of the phospha-alkene, C1P=CC12, (generated by the action of triethylamine on d i c h l o r o m e t h y l d i c h l o r o p h o s p h i n e ) . 354 A route to 1,2-dihydrophosphinines (246) (as a mixture of two regioisomers) is provided by the thermal transformation of p h o s p h o l e - d i c h l o r o c a r b e n e adduct s 3 5 5 The 1,2-dihydrophosphinine system has also been obtained from the reactions of phosphinidene complexes with a b u t a d i e n y l c a r b e n e - c h r o m i u m complex, via the spontaneous cyclisation of an intermediate l-phosphahexatriene.356 The reaction of 2-aza-1,3-dienes with dichlorophosphines gives an efficient, 357 general route to the 1,4-dihydro-azaphosphinine system (247). A route to the 1,3-azaphosphinine system (248) has also been Cyclisation of the ylide (249) with dimethyl described. 358 acetylenedicarboxylate has given the lh5 , 3h5-diphosphorin (250) .359 The chemistry of the triazaphosphinine (251) has also been explored.360

.

I: Phosphines und Phosphonium Sults

41

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40 41 42 43

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I: Phosphines and Phosphonium Salts 73 74 75 76 77 78 79

80 81 82 83

84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103

104 105 106 107 108 109 110 111 112 113 114 115

43

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29.

36,

D.W.Allen, P.E.Cropper, and I.W.Nowel1, Polyhedron, 1989, 8, 1039. A.S.Balueva, and D.A.Erastov, Izv. Akad. Nauk SSSR, Ser. Khim, 1987, 1199 (Chem. Abstr., 1988, 109, 54 8 4 2 ) . A.S.Balueva and O.A.Erastov, Izv. Akad. Nauk SSSR, Ser. Khim., 1988, 163 (Chem. Abstr., 1989, 110, 75 627).

1: Phosphiries and Phosphonium Salts

47

224 225

C.M.Angelov and D.D.Enchev, Phosphorus Sulfur, 1988, 37, 125. J.M.Bal1, P.M.Boorman, J.F.Fait, A.S.Hinman, and P.J.Lundmark, Can. J. Chem., 1989, 67, 751. D.E.Bugner, J. Org. Chem., 1989, 54, 2580. H.Koyama, and S.Yokota, Jpn. Kokai Tokkyo Koho, 6 3 190 8 9 3 (Chem. Abstr.,

226

M.Matsumoto, Jpn. Kokai Tokkyo Koho, 6 3 264 593 (Chem. Abstr., 1 9 8 9 ,

227

M.R.Bryce, M.M.Ahmad, R.H.Friend, D.Obertelli, S.A.Fairhust, and J.N.Winter. J.Chem. SOC., Perkin Trans. 2 , 1988, 1151. G.Helgesson and S . Jagner, J.Chem.Soc., Dalton Trans., 1988, 2117. H.Sinning and U.Muller, Z.Anorg. Allg. Chem., 1 9 8 9 , 568, 108. I.Iove1, Yu.Goldberg, M.Shymanska, and E.Lukevics, Appl. Organornet. Chem.

222 223

1988,

2,231

301).

110,

135 5 0 2 ) . 228 229 230

1987. 1. 371. 231

N,A. Bozarenko. M. V. Raitarskava. M. V. Rudomino. and E.N. Tsvetkov. Izv. Akad. Nauk SSSR, SerI Khim., 1 9 8 7 , i 3 9 7 (Chem. Abst;., 1988, 109, 1 4 9 ' 6 2 7 ) . 232 E.Anders and F.Markus, Chem.Ber., 1 9 8 9 , 122, 113. 233 E.Anders and F.Markus, Chem. Ber., 1 9 8 9 , 122, 119. 234 V.T.Abaev. L.I.Kisarova. A.A.Bumber. L.E.Mikhailov. S.E.Emanuilidi. and O.Yu.Okhlobystin, Dokl. 'Akad. Nauk SSSR, 1988, 301; 359 (Chem. Absir., 1 9 8 9 , 110, 114 9 6 9 ) . 235 A.A.Prishchenko, M.V.Livantsov, S.A.Mosh and I.F.Lutsenko, Zh. Obshch. Khim., 1987, 57, 1664 (Chem. Abstr., 1 9 8 8 , 109,6 6 2 0 ) . 236 M.N.I.Khandker, A.Ahmad and M.G.Hossain, Ind. J. Chem., Sect. B, 1 9 8 7 , 26, 773. 237 238

H.J.Cristau, M.Fonte, and E.Torreilles, Synthesis, 1 9 8 9 , 301. N.A.Nesmeyanov, V.G.Kharitonov, O.A.Rebrova, P.V.Petrovskii, and O.A.Reutov, Izv. Akad. Nauk SSSR, Ser. Khim., 1 9 8 8 , 456 (Chem. Abstr., 1 9 8 9 , E,

239

244 245 246

O.B.Smolii, V. .Brovarets, and B.S.Drach, Zh. Obshch. Khim., 1987, 5 7 , 2145 (Chem. Abstr., 1988, 109, 9 3 1 6 4 ) . 5 8 , 1670 O.B.Smolii, V. .Brovarets, and B.S.Drach, Zh. Obshch. Khim., 1988, 110, 192 9 5 0 ) . (Chem. Abstr., 1989, P.P.Onvsko. T. '.Kim. E.I.Kiseleva. V.P.Proko~enko. and A.D.Si .nitsa Zh. Obshch: Khim., 1988, 58, 3 5 (Chem. Abstr:, 1988, 109, 148 9 7 4 ) : I.S.Zaltsman, A.P.Marchenko, A.A.Kudryavtsev, and A.M.Pinchuk, Zh. Obshch. Khim., 1 9 8 7 , 57, 2272 (Chem. Abstr., 1 9 8 8 , 109, 149 6 3 2 ) . M.A.Boikova, N.L.Burtseva, and A.V.Kazymov, Zh. Obshch. Khim., 1987, 57, 1955 (Chem. Abstr., 1 9 8 8 , 109, 1 2 9 1 4 1 ) . A.Arnoldi and M.Carughi, Synthesis, 1 9 8 8 , 155. Y.Okada, T.Minami, S.Yahiro, and K.Akinaga, J. Org. Chem., 1 9 8 9 , 54, 974. H.Ohmori, H.Maeda, K.Konomoto, K.Sakai, and M.Masui, Chem. Pharm. Bull.,

247

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114 9 3 8 ) .

240 241 242 243

1987, 248

29, -

35, 4473.

4583.

S.S.Shavanov, G.A.Tolstikov, F.Kh.Nizamutdinov, and V.D.Komissarov, 2h.Obshch. Khim., 1987, 57, 1 9 8 6 , (Chem. Abstr., 1 9 8 8 , 109, 92 2 2 5 ) . 249 J.B. Hendrickson and M.S.Hussoin, J. Org. Chem., 1989, 54, 1144. 250 M.Scholz, H.W.Roesky, D.Stalke, K.Keller, and F.T.Edelmann, J. Organomet. Chem., 1989, 366, 73. 25 1 E.Niecke, B.Kramer, and M.Nieger, Angew. Chem., Int. Ed. Engl., 1 9 8 9 , 28, 215. 252 253 254

M.Yoshifuji, T.Sato, and N.Inamoto, Chem. Lett., 1988, 1735. M.Gouygou, C. Tachon, R.El.Ouatib, O.Ramarijaona, G.Etemad-Moghadham, and M.Koenig, Tetrahedron Lett., 1 9 8 8 , 30, 177. M.Yoshifuji, S.Sasaki, T.Niitsu, and N.Inamoto, Tetrahedron Lett., 1 9 8 8 , 30, 187,

255 256

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48 257 258 259 260 26 1 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292

Orgunoph osphorus Chm iistry R.Appe1, B.Niemann, and M.Nieger, Angew. Chem., Int. Ed. Engl., 1988, 27, 957* E.Niecke, 0-Altmeyer, and M.Nieger, J. Chem. S o c . , Chem. Commun., 1988, 945. L.Weber, G.Meine, R.Boese, and N.Niederprum, 2.Naturforsch.B: Anorg Chem., Org. Chem., 1988, 43, 715. L.Weber, D.Bungardt, and R.Boese, Chem. Ber., 1988, 121,1535. R.A.Bartlett, H.V.R.Dias, and P.P.Power, J. Organomet. Chem., 1989, 362, 87. J.C.Leblanc and C.Mose, J.Organomet. Chem., 1989, 364, C3. M.Yoshifuji, S.Sasaki, and N.Inamoto, Tetrahedron. Lett., 1989, 30, 839. M.Yoshifuji, T.Niitsu, and N.Inamoto, Chem. Lett., 1988, 1733. G.Mark1 and K.M.Raab, Tetrahedron Lett., 1989, 30, 1077. R.Appel and L.Krieger, J.Organomet. Chem., 1988, 354, 309. A.N.Chernena, M.Yu.Antipin, .~ Yu.T.Struchkov, I.E.Boldesku1, O.I.Kholodyazhnyi, 1.V.Shevchenko and V.P.Kukhar, Zh Obshch. Khim., 1987, 57, 1975 (Chem. Abstr., 1988, 2, 129 143). R.Minkwitz, and A.Liedtke, Inorg. Chem., 1989, 28, 1627. U.Althoff, J.Grobe, D.LeVan, and E-U.Wurthwein, Z.Naturforsch. B: Anorg. Chem., Org. Chem., 1989, 44, 175. S.Lacombe, D.Gonbeau, J-L.Cabioch, B.Pellerin, J-M.Denis, and G.PfisterGuillouzo, J. Am. Chem. S o c . , 1988, 110, 6964. F.Mercier, C.Huge1-LeGoff, and F.Mathey, Tetrahedron Lett., 1989, 30, 2397. K.Issleib, H.Schmidt, and E.Leissring, J. Organomet. Chem., 1988, 355, 71. H.Werner, W.Pau1, J.Wolf, M.Steinmetz, R.Zolk, G.Muller, O.Steigelmann, and J.Riede, Chem. Ber., 1989, 122, 1061. D.S.Bohle, G.R.Clark, C.E.F.Rickard, and W.R.Roper, J. Organomet. Chem., 1988, 353, 355. A.Marinetti and R. Mathey, Angew. Chem., Int. Ed. Engl., 1988, 27, 1382. V.D.Romanenko, L.S.Kachkovskaya, M.I.Povolotskii, A.N.Chernega, M.Yu.Antipin, Yu.T.Struchkov, and L.N.Markovskii, Zh. Obshch. Khim., 1988, 58, 958 Abstr., 1989, 110,212 925). W.Schnurr and M.Regitz, Z.Naturforsch. B: Anorg. Chem., Org. Chem., 1988, 43, 1285. P.B.Hitchcock, M.F.Meidine, J.F.Nixon, and H. Wang, J. Organomet. Chem., 1989, 368, C29. G.Mark1 and P. Kreitmeier, Angew. Chem., Int. Ed. Engl., 1988, 27, 1360. H.H.Karsch, and H-U.Reisacher, Phosphorus Sulfur, 1988, 37, 241. R.Appe1 and N.Siabalis, Phosphorus Sulfur, 1988, 2, 273. M.Yoshifuji, T. Niitsu, K.Toyota, N.Inamoto, K.Hirotsu, Y.Odagaki, T.Higuchi, and S.Nagase, Polyhedron, 1988, 7, 2213. J.Escudie, C.Couret, A. Raharinirina, and J.Satge, New. J. Chem., 1987, 11, 627. M.Andrianarison, C.Couret, J-P.Declercq, A.Dubourg, J.Escudie, H.Ranaivonjatovo, and J.Satge, Organometallics, 1988, 7,1545. I.I.Patsanovskii, Yu.Z.Stepanova, E.A.Ishmaeva, V.D.Romanenko, and L.N.Markovskii, Zh. Obshch. Khim., 1987, 57, 1464 (Chem. Abstr., 1988, 109, 6613). Yu.Z.Stepanova, I.I.Patsanovskii, E.A.Ishmaeva, L.S.Kachovskaya, V.D.Romenenko, and L.N.Markovskii, 2. Obshch. Khim., 1987, 57, 2446 (E. Abstr., 1988, 109, 211 144). Yu.Z.Stepanova, I.I.Patsanovskii, E.A.Ishmaeva, V.D.Romanenko, and L.N.Markovskii, Zh. Obshch. Khim., 1987, 57, 2449 (Chem. Abstr., 1988, 109, 211 145). M.Regitz and P.Binger, Angew. Chem., Int. Ed. Engl., 1988, 27, 1484. A.H.Cowley, S.W,Hall, C.M.Nunn, and J.M.Power, Angew. Chem., Int. Ed. Engl., 1988, 27, 838. A.H.Cowley, S.W.Hal1, R.A.Jones, and C.M.Nunn, J.Chem. S O C . , Chem. Commun., 1988, 867. P.Binger, B.Biedenbach, R.Mynott, and M.Regitz, Chem. Ber., 1988, 121, 1455. K.Eller, T.Drewello, W.Zummack, T.AlLspach, U.Annen, M.Regitz, and H.Schwarz, J . Am. Chem. S O C . , 1989, 111,4228.

,.

I

,

(m.

1: Phoy)h inev and Phosphoniurn Scr Its

49

293 A.F.Hil1, J.A.K.Howard, T.P.Spanio1, F.G.A.Stone, and J.Szameitat, Angew. Chem., Int. Ed. Engl., 1989, 28, 210. 294 A.Recknage1, D.Stalke, H.W.Roesky, and F.T.Edelmann, Angew. Chem., Int. Ed. Engl., 1989, 28, 445. 295 A.R.Barron, A.H.Cowley, S.W.Hal1, and C.M.Nunn, Angew. Chem., Int. Ed. Engl., 1988, 100,837. 296 P.Binger, B.Biedenbach, R.Mynott, C.Kruger, P.Betz, and M.Regitz, Angew. Cbem., Int. Ed. Engl., 1988, 27, 1157. 297 A.H.Cowley and S.W.Hal1, Polyhedron, 1989, 8, 849. 298 H.H.Karsch, G.Hanika, B.Huber, J.Riede, and G.Muller, J.Organomet. Chem., 1989, 361, C29. 299 K.A.Bartlett, H.V.R.Dias, and P.P.Power, Inorg. Chem., 1988, 27, 3919. 300 H.H.Karsch, G.Hanika, B.Huber, K.Meind1, S.Konig, C.Kruger, and G.Muller, J. Chem. SOC., Chem. Commun., 1989, 373. 301 R.A.Bartlett, H.V.R.Dras, X.Feng, and P.P.Power, J. Am. Chem. SOC., 1989, 111, 1306. 302 H.V.R.Dias and P.P.Power, J. Am Chem. SOC., 1989, 111,144. 303 A.N.Chernega, M.Yu.Antipin, Yu.T.Struchkov, A.B.Drapai10, A.V.Ruban, and V.D.Romanenko, Izv. Akad. Nauk SSSK, Ser. Khim.,1987, 1304 (Chem. Abstr., 1988, 109, 37 860). 304 L.N.Markowskii, V.D.Romanenko, A.V.Ruban, A.B.Drapailo, A.N.Chernega, M.Yu.Antipin, and Yu.T.Struchkov, Zh. Obshch. Khim., 1988, 58, 291, Abstr., 1989, 110, 135 342). 305 H.G.Ang and K.K.Lee, Polyhedron, 1989, 8, 379. 306 L.N.Markovskii, V.D.Romanenko, E.O.Klebanskii, M.I.Povolotskii, A.N.Chernega, M.Yu.Antipin, and Yu.T.Struchkov, Zh.Obshch.Khim., 1987, 57, 1020 (Chem. Abstr., 1988, 109, 54 841). 307 E.Niecke and D.Bqrion, Tetrahedron Lett., 1989, 0, 459. 308 J.Boske, E.Niecke, M.Nieger, E.Ocando, J-P.Majora1, and G.Bertrand, Inorg. Chem., 1989, 28, 499. 309 D.Fest, C.D.Habben, and A.Meller, Chem. Ber., 1989, 122, 861. 310 E.Niecke, M.Nieger, and F.Reichert, Angew. Chem., Int. Ed. Engl., 1988, 27 1715. 311 E.Niecke, M.Nieger, F.Reichert, and W.W.Schoeller, Angew. Chem. Int. Ed. Engl., 1988, 27, 1713. 312 S.Holand, and F.Mathey, Organometallics, 1988, 1796. 1791. 313 N.H.T.Huy, L.Ricard, and F.Mathey, Organometallics, 1988, 314 K.Lammertsma, P.Chand, S.W.Yang, and J.T.Hung, aanometallics, 1988, L , 1875. 315 R.deVaumas, A.Marinetti, F.Mathey, and L.Ricard, J. Chem. SOC., Chem. Commun., 1988, 1325. 316 A.M.Arif, A.H.Cowley, M.Pakulski, M.A.Pearsal1, W.Clegg, N.C.Norman, and A.G.Orpen, J.Chem.Soc., Dalton Trans., 1988, 2713. 317 V.D.Alexiev, N.Binsted, S.L.Cook, J.Evans, R.J.Price, N.J.Clayden, C.M.Dobson, D.J.Smith, and G.N.Greaves, J. Chem. SOC., Dalton Trans., 1988, 2649. 318 G.Fritz, T.Vaahs, H.Fleischer, and E.Matern, Z. Anorg. Allg. Chem., 1989, 570, 54. 319 G.Fritz, T.Vaahs, H.Fleischer and E.Matern, Angew. Chem., Int. Ed. Engl., 1989, 28, 315. 320 D.Gudat, M.Nieger, and E.Niecke, J. Chem. SOC., Dalton Trans., 1989, 693. 321 W.Becker, D.Schomburg, and R.Schmutzler, Phosphorus Sulfur, 1989, 42, 21. 322 S.A.Weissman and S.G.Baxter, Tetrahedron Lett., 1988, 29, 1219. 323 C.Roques, M-R.Mazieres, J.P.Majora1, and M.Sanchez, Tetrahedron Lett., 1988, 29, 4547. 324 N.Burford, B.W.Royan, A.Linden, and T.S.Cameron, J.Chem. SOC., Chem. Commun., 1988, 842.

(w.

I,

I,

Organophosphorus Chemistry

50

325 N.Burford, B.W.Royan, A.Linden, and T.S.Cameron, Inorg. Chem., 1989,

28,

144. 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360

N.Burford, B.W.Royan, and P.S.White, J. Am. Chem. Soc., 1989, 111, 3747. N.Burford and B.W.Royan, J. Chem. SOC. , Chem. Commun., 1989, 19. W.W.Schoeller and T.Busch, J. Chem. Soc., Chem. Commun., 1989, 234. R.Appe1, P.Schulte, and F.Knoch, Phosphorus Sulfur, 1988, 37, 195. J.Navech, M.Reve1, and S.Mathieu, Phosphorus Sulfur, 1988, 39, 33. D.A.DuBois and R.H.Neilson, Inorg. Chem., 1989, 28, 899. O.Wagner, M.Ehle, and M.Regitz, Angew. Chem., Int. Ed. Engl., 1989, g,, 225. W.He-Line, W.Tan and A. Foucaud, Tetrahedron Lett., 1988, 29, 4581. J.A.Rahn, M.S.Holt, G.A.Gray, N.W.Alcock, and J.H.Nelson, Inorg. Chem., 1989, 28, 217. N.H.T.Hoy and F.Mathey, Organometallics, 1988, 1,2233. N.S.Isaacs, G.N.El-Din, and M.G.B.Drew, Rec. Trav. Chim. Pays-Bas, 1989 108, 120. F.Nief, L.Ricard, and F.Mathey, Organometallics, 1989, 2, 1473. F.Nief and F.Mathey, J.Chem. Soc., Chem. Commun., 1989, 800. P.Lemoine, J. Organomet. Chem., 1989, 359, 61. R.M.G.Roberts, J.Silver, and A.S.Wells, Inorg. Chim. Acta, 1989, 155, 1917 R.M.G.Roberts, J.Silver, and A.S.Wells, Inorg. Chim. Acta., 1989, 157, 4.5. R.Bartsch, P.B.Hitchcock, T.J.Madden, M.F.Meidine, J.F.Nixon and H.Wang, J.Chem.Soc., Chem. Commun., 1988, 1475. R.Bartsch, D.Carmichae1, P.B.Hitchcock, M.F.Meidine, J.F.Nixon, and G.J.D.Sillett, J. Chem. Soc., Chem. Commun., 1988, 1615. J.Heinicke, J. Organomet. Chem., 1989, 364, C17. G.Mark1 and S.Pflaum, Tetrahedron Lett., 1988, 2, 3387. G.Mark1, S.Diet1, M.L.Ziegler, and B.Nuber, Tetrahedron Lett., 1988, 2, 5867. B.A.Arbuzov, E.N.Dianova, and E.Ya Zabotina, Zh. Obshch. Khim., 1987, 57, 1699 (Chem. Abstr., 1988, 109, 93 143). B.A.Arbuzov. E.N.Dianova, R.T.Galiaskarova, P.P.Chernov. 1.A.Litvinov. and V.A.Naumov,-Zh. Obshch. Khim., 1987, 57, 1949 (Chem. Abstr., 1988, 129 140). B.A.Arbuzov, E.N.Dianova, and R.T.Galiaskarova, Izv. Akad. Nauk SSSR, Ser. Khim., 1987, 1376 (Chem. Abstr., 1988, 109,23 032). B.A.Arbuzov, E.N.Dianova and E.Ya.Zabotina, 1zv.Akad. Nauk SSSR, Ser. Khim., 1987, 2819 (Chem. Abstr., 1989, 9, 154 386). J.G.Kraaijkamp, D.M.Grove, G.VanKoten, and A. Schmidpeter, Inorg. Chem., 1988, 2612. G.Mark1 and W. Holzl, Tetrahedron Lett., 1988, 2, 4535. K.H.Dotz, A.Tiriliomis, and K.Harms, J. Chem. Soc., Chem. Commun, 1989, 788. P.LeFloch and F.Mathey, Tetrahedron Lett., 1989, 30, 817. G.Keglevich, B.Androsits, and L.Toke, J.Org.Chem., 1988, 53, 4106. N.HoaTranHuy, F.Mathey, and L.Ricard, Tetrahedron Lett., 1988, 2, 4289. J.Barluenga, F.Palacios, F.J.Gonzalez, and S.Fustero, J. Chem. Soc., Chem. Commun., 1988, 1596. R.Appe1, and M.Poppe, Angew. Chem., Int. Ed. Engl., 1989, 28, 53 E.Fluck, B.Neumuller, and G.Heckmann, Chem. Ztg., 1987, 111,309. M.Meyer, U.Klingebie1, J.Kade1, and H.Oberhammer, Z.Naturforsch. B: Anorg. Chem., Org. Chem., 1988, 43, 1010.

109,

27,

~

2 Pentaco-ordinated and Hexaco-ordinated Compounds BY C. D. HALL

1. Introduction

- The year has again seen a consolidation

of knowledge in the area of

hypervalent phosphorus chemistry with emphasis on the synthesis and properties of monocyclic and bicyclic phosphoranes. A considerable effort has been made to resolve the mechanism of the Mitsunobu Reaction (see Section 3) and the principles established by studies of pentaco-ordinate phosphorus compounds have again been extended to hypervalent compounds of other elements (e.g. As, Sb, and Si). A comprehensive review of the reactions of phosphorus acids with chlorine includes a number of examples of acyclic, monocyclic and bicyclic phosphoranes prepared by this route 1, together with a useful catalogue of their 31P &values. 2. Structure.,. Bonding and Lipand Reorganization

-

Several pentaaryl bismuth

compounds (3) have been synthesised by the conventional reaction of (1) with arylithium (2) and three were characterised by single-crystal X-ray structure analysis2. In contrast to pentaphenylphosphorus (and AsPhg) which are trigonal bipyramids3, the bismuth compounds exhibit almost ideal square pyramidal geometry. The bicyclic A5, (J 5 - phosphoranes (9 a-d) and (10 ab) were synthesised from the isocyanatophosphites (4a-d) and the 3-pentene-2-ones (5) and (6) respectively, by a double cycloaddition via (7) and (8)4. The axial-equatorial arrangement of the bicyclus was confirmed for (9d) and (10a) by X-ray analysis and the f b p structure in solution was established by 13C n.m.r. spectra with IJpCvalues varying from 117.9 to 127.1Hz, typical

of carbon in an axial position5. The MNDO approximation has been used to study the effect of structural and electronic factors on the formation of the donor-acceptor P-N bond in phosphatranes using XPF3. NH3 as the model where X is the lone pair np , 0, H+ and +OH6. The effects of these substi tuents at phosphorus on the P-N bonding were rationalized by changes in the acceptor properties of the low-lying unoccupied MO localized at phosphorus.

52

-

+ 2Ar'Li

Ar,BiX, (11

(2)

Organophosphorus Chemistty Ar,BiAr',

+

2LiX

(3)

H

0

+

(R'o),P-N=c=o

II

H-0

F,CC-CH=C-R~

I

(5) R 2 = CF3 (6) R 2 = M e

(4a -d) a ) R 1 = Me b) R 1 = E t C ) R' = CH,CH, d) R1 = CMe2CMe2

( 9 a - d ) R 2 = CF, (10a,b) R 2 = M e

-N co

( R'o),~

CF3-

I C -0I /OH

CF3-

C

I HC

-0

H

(8)

Me

Me

cxtx, (12a-d)

(lla- d) a) b) c) d)

X X X X

= C H Z i R 1 Hi R 2 = Ph = 0, R = H , R = P h = CH , R ' = R 2 = M e = 0, R ' = R 2 = Me

a) b) c) d)

X CH,, R' = H, R 2 = Ph, R 3 = M e X = 0, R' = H, R 2 = Ph, R 3 = Me X = CH2, R ' = R 2 = Me, R 3 = OEt X = 0, R' = R 2 = Me, R 3 = OEt

2: Pentaco-ordinutedand Hexaco-ordinated Compounds

53

Further work has appeared on the influence of the conformational transmission effect on the barriers to pseudorotation in cyclic alkoxyphosphoranes7~8. In the first paper, a variable-temperature 13C n.m.r. study of ligand reorganization within the phosphoranes (lla-d) and (12a-d) reached the conclusion that the conformational transmission effect plays an important role in the isomerisation pathways of the phosphoranes examined. In particular, phosphoranes (1la,c) and (12 a,c) isomerise through a sp transition state comparable to that established for (13) whereas the conformational transmission effect is responsible for lowering of the activation barriers to

x

by 2-3kJ mol-1 in (llb,d) and (12 b,d). It is interesting to note

that in the latter systems, the transition state is depicted as a tbp structure (14) with the sp structure (15) as a lower energy species on the ligand reorganization energy profile. The alternative explanation of zwitterionic hexaco-ordinated intermediates (or transition states) to account for the faster pseudorotation rates with X=O, appears to be negated by studies of pseudorotational barriers in (16ab)g. In these molecules, no conformational transmission effect is possible but the presence of the tetrahydrofuran oxygen atoms would permit a zwitterionic T.S. to accelerate ligand reorganization.

In

fact the pseudorotational barriers for (16a) and (16b) at 55.2 and 71.9 kJmol-1 respectively, are in excellent agreement with those found for (lla) and (llc) where no hexaco-ordinate species are possible along the isomerisation pathway. 3. Acyclic Phosphoranes - The thermal stability of pentaphenyl derivatives of the Group VA elements (Ph5E) falls in the order E= Sb > As > P > Bi and this is ascribed in part to steric factors within the hypervalent molecules9. With E=P, the molecular system (17) is "overloaded" with ligands and the decomposition is alleged to occur through the formation of an intermediate tetraphenyl phosphonium dipolar ion (18) which may be trapped by a variety of reagents including carbon dioxide and sulphur giving rise to (19) and (20) respectively. In a related study, pentaphenylantimony (21) was found to decompose at room temperature in toluene and in the presence of catalytic amounts of cupric acetate to form triphenylantimony and a 4 : 1 ratio of diphenyl to benzenelo. In butyl alcohol as solvent, however, the products were triphenylantimony (0.43 mole), benzene (1.67 mole), ethanoic acid (0.07 mole) and butyl phenyl ether (0.44 mole) together with Sb(OAc)3and cuprous acetate. The mechanisms of these reactions were not discussed. Diphenylfluorophosphine (22) reacts with piperonal (23) to form the difluorophosphorane (27) via (241426). The structure of the product was determined by a

combination of mass spectrometry, multinuclear n.m.r. and .X-ray analysis.ll

Although alkyltrifluoroalkoxyphosphoranes are thermally unstable above OOC, the reaction of alkyltetrafluorophosphoranes (28) with trimethylalkoxysilanes (29) at 20OC

Organophosphorus Chemistry

54 Me

!

THFFO

FOMe

he

OTHFF (14)

THFF

(15) = tetrahydrofurfuryl

a ) R1 = H, R 2 = Ph, R 3 = Me b ) R’ = R 2 = Me, R3 = OEt

Ph,P

A

C

II

0

[

e h P h 3 ]

+

PhH

55

2: Pentaco-ordinuted and Hexaco-ordinated Compounds

2Ph,PF

R Ph,PF,-PPh,

+

(24)

RCHO

(23)

(25)

Ph,PF,-CH

I

-OPPh,

(27)

(26)

Organophosphorus Chemistry

56

gives alkyldifluorodialkoxyphosphoranes(31) presumably via (30) 12. Similar work on the reaction of (28) with the O-silylated acetoxime (32) gave an N-fluoroimine (34) apparently via the fluorophosphorane (33) which was characterised by its 31P n.m.r. spectrum at 6 = - 119.1 with lJpF= 875Hz.13 The synthesis of P-fluoro-ylids (36) by treatment of difluorophosphoranes (35) with BuLi or (Me3Si)zNLi has also been reported14. The n.m.r. spectra and chemical properties of these unusual ylids are detailed in the paper but since they are not relevant to pentaco-ordinate phosphorus chemistry, will not be discussed further in this review. The Mitsunobu reaction is also not formally the province of pentaco-ordinate phosphorus chemistry but the mechanism of this synthetically useful reaction received considerable attention during the year15-lg. Since such a discussion inevitably includes the possible involvement

of pentaco-ordinate intermediates prior to the final

dealkylation ( or deacylation) step, it is pertinent to summarise the current findings on this subject. The definitive papers originate from Jenkins' studies of the involvement of dialkoxyphosphoranes, oxyphosphonium salts and (acyloxy) alkoxyphosphoranes.17.18 A 3IP n.m.r. examination of the Mitsunobu reaction using an unreactive alcohol

(ROH, where R = Me3CCH2 or 1,2,5,6-di-O-isopropylidene-a-D-glucofuranoyl) and a carboxylic acid R ' C 0 2 H revealed the presence of two intermediates,

-

an

alkoxytriphenylphosphonium salt, Ph3P+OR R'CO2-, in equilibrium with a dialkoxyphosphorane, Ph3P(OR)2. This situation was observed irrespective of the order of addition of the reagents (p.ref. 20).The position of the equilibrium was dependent on the pKa of the acid and the polarity of the medium with the phosphonium salt being favoured by acids of low pKa and polar solvents 17.The acids used exerted a marked catalytic effect on the rate of equilibration of the phosphorane and alkoxyphosphonium intermediates and where a choice of alcohols (10 us. 20) was presented, only the more stable intermediates corresponding to the l o alcohol were observed. This fact, together with the preferential S N displacement ~ at a primary carbon atom accounts for the known regioselectivity of the Mitsunobu reaction. In this context the paper by Evans 19 demonstrates that (39) - the intermediate generated by the reaction of (37) with (381,

-

when treated with benzoic acid, gives (41) as the major

product by protonation, ring opening and de-alkylation at the secondary carbon. Dealkylation to (43) via (42) represents the minor pathway in this molecular system. Evans also concludes that phosphoranes of types (39) and their acyclic analogues, Ph3P(OR)2, are certainly observable in the Mitsunobu reaction "even when the acid is added before the alcohol", which implies that the use of the stronger acid (e.g.

CF3C02H) 20 simply shifts the equilibrium in favour of the oxyphosphonium ion.

2: Pentuco- ordin urea' and Hexuco -ordinatc.d Cornyoun ds

+

RPF,,

1

*

RP F 3OR'

1

(29)

R = C,H9CtiCICH, R' = Me3C

20" c

Me3SiOR'

(28)

57

or Me2CCICH2 (29)

or Et

RPF,(OR'),

+

Me3SiF

(31)

+

(28)

+ RP(OIF2

Me2C=NF

Me3SiON=CMe2

R = Pr' (32 1

(34)

\ -

/

F

R-P<

I

ON=CMe,

I F

F

(33)

R4Li

R2R3PF,CH RR' R4

=

R2\ P NF

*

R3'

B u n or ( M e 3 S i l 2 N

\CRR'

(35)

H

P h C0,-

+

Ph,PN-

NHC0,R'

I

CO, R'

(37)R' = Et or Pr

+

b

HO

P h ; 'O 0 r R

OH

(38) R = Me, P h

(39)

Organophosphorus Chemistry

58

1 P h 3 P c p R

p

H0,Ph

+

Ph3P%

HO/

-0,CPh

(40)

Ph3P=0

+

! Ph3P=0

+

P h C 0 2 x o H

0H

H

,OCOR’

____)

P h 3 h R 5,CR’ (44)

Ph3P\OR (45)

Ph3:OCOR’

R

6R

2: Pen taco- ordin uted and Hexuco -ordinated Compounds

In his second

paperl8,

Jenkins discusses

59 the

involvement

of

(acy1oxy)alkoxyphosphoranes(45) in the Mitsunobu reaction as generalised by (44) - (46). Clearly such an equilibrium would tend towards (44) or (45)

-

dependent on the

conditions, but deacylation via (46) would lead to an ester with retention of configuration in the alkyl group of the starting alcohol, a feature which is in fact observed with highly hindered secondary alcohols. The main thrust of the paper, however, involves a 31P n.m.r. examination of the reaction using Ph3P or diphenyl-2pyridylphosphine with di-isopropylazodicarboxylate(DIAD) and alcohol (ROH) and a carboxylic acid (RIC02H). It reveals the presence of a dialkoxyphosphorane, Ar3P(OR)2 in equilibrium with alkoxyphosphonium carboxylate, Ar3P+OR R1C02-, in which the 31P chemical shift of the latter species is extremely sensitive (over a range of 100 p.p.m) to the presence of proton sources and the nature of the solvent. These latter data are interpreted in terms of an equilibrium between species analogous to (44) and (45) and the authors suggest that these intermediates are important in those reactions where the Michaelis-Arbusov dealkylation is kinetically slow or not possible (R=aryl). Whether phosphoranes such as Ar3P(OR)2 or (45) play a role in "normal" Mitsunobu reactions is less clear but it seems highly likely that the vital intermediate leading to the inversion

of configuration of the alcohol is (44). A recent paper by Hughes et al.15 reaches the same conclusion and summarises the factors affecting the rate of formation of (44)and its subsequent breakdown. Finally, a paper by Crick16 involving the use of m-chloroperbenzoic acid (48) in the Mitsunobu reaction with (47) proposes (49) as an intermediate in the formation of the products (501452). 4. Ring Containing Phosphoranes. 4.1 Monocvclic Phosphoranes. - Further studies of the reaction of P-fluoro-ylids (53)

with carbonyl compounds (54) reveals formation of P-fluoro-oxaphosphetans (55) as the initial addition products. These may decompose in a conventional Wittig reaction to form alkenes (56I2l but may also lose HF to form alkyl phosphonates (57).22 A further mechanistic study of the Wittig reaction between lithium-free

isopropylidenetriphenylphosphorane (58) and benzophenone (59) in THF was shown by 31P n.m.r. to proceed via the oxaphosphetan intermediate (60) with k l = 1.3 x 10-3 lmol-1 s-1, k2 = 4.0 x 10-4 s-1 and k3 = 7.0 x 10-4 s-1. In addition carbonyl kinetic isotope effects and a value of p

=

+1.4 based on variations of substituents in the aryl group of

the ketone, were consistent with rate-determining formation of the oxaphosphetan (60).23 The oxidative addition of alcohols and primary amines to 2-alkyl (or aryl) -

Organophosphorns Chemistly

60

c

Ph, PO

Et 0,C

+

m - CL C6H4C02H

(511

(50) _____)

C6H4

+

-c

EtO,CN=NCO,

0

Et

(52)

b

(49)

F

0

I

R'

(Et2N)2P=C'

+

R3R4C==0

PrCH=CC12

+

'R2

(55) 6 3 1 P , - L O

Ph3P=CMe2

+

(57)

ArZC=O

Ph,P=O

(58) ofPh I Ph3P

(60)

Me Me

631P , - 5 4

+

II

(Et,N),PF

Me2C=CPh,

2: Pen taco-ordinated and Hexaco -ordinated Compounds

61

1,3,2-dioxa, oxaza and diazaphospholanes (61)-(63) leads to a range of monocyclic phosphoranes (e.g. 64-66) containing a P-H bond24. The large variation of *Jp, values (759-363 Hz) reveals an equilibrium between axial and equatorial hydrogen atoms in the trigonal bypyramidal phosphoranes; in the dialkylaminophosphoranes (68) the

-

hydrogen atom ( l J p p ~ 360Hz) prefers an axial position. A further investigation of these oxidative addition reactions revealed a

complete redistribution of ligands between (69) and (70) involving a series of observable phosphoranes (71), (73), (75) and (76) containing P-H bonds (Scheme I) 25. Monocyclic phosphoranes with P-H bonds have also been shown to add to activated carbon-carbon and carbon-nitrogen double bonds to form new phosphoranes containing P-C bonds. For example (78) reacts with acrylonitrile (79) or the imine (80) to give (81) and (82) respectively. Phosphoroisocyanatidites (e.g. 83) react with 3-alkylidene-2,4-pentanediones (e.g. 84a) or 2-alkylideneacetoaceticesters (e.g. 84b) to form phosphoranes (85,a,b) which decompose on heating to the cyclic phosphonates (86a, b)27. In an analogous study,

dialkylalkynylphosphonates (87) have been shown to react with alkyl pyruvates (88) below OOC to form mixtures of alkynyl phosphonates (90) and monocyclic tetraoxaphosphoranes (91) via (89)28. At 80OC, however, (89) reacts with excess (88) via (92) to form the bicyclic phosphorane (93). Multinuclear dynamic n.m.r. has been used to study the influence of temperature, solvent polarity and the electronic and steric properties of the C- and Nsubstituents on the chlorotropic tautomerism between tetrachlorophosphoranes (94) and the 6-co-ordinate amidiniotetrachlorophosphates (95129. The high negative entropies of activation ( AS+ =

- 67 to

-142 Jmol-1K-1) found for the tautomerism

indicate the formation of a contact ion-pair in the T.S. and with R = Pri, restricted rotation about the N-R bond in (95) was observed. 4.2 Bicvclic and Tricyclic Phosphoranes. - The reaction of phosphorocyanatidites (96ab) with alkylidene acetamide (97) proceed via the common intermediate (98) to form either (99, R= Me) by reaction with a second mole of (97) or (100) by dimerisation.30131 An analogous dimerisation product (102) is also obtained with diphenyl carbodiimide (loll31 and the reactions of alkynylphosphonates with (101) are reported in the same paper. The reaction of pyrocatechol (103) with PCl3 gives a mixture of (104) and (105) with the ratio of products depending upon the nature of the base used and the experimental c0nditions3~.A preparative variant of this reaction has been used to obtain (107) with (105) as a by-product, by reaction of (103) with hexamethylphosphorus

Organophosphorus Chemistry

62

(61) R1 = Ph or Me

= 656, R' = Ph

(64) 'J,,

(62) R ' = Me, R 2 = H R 1 = Ph, R 2 = Me

(63) R ' = Me, R2= Bz

Ph

Pr'NH2

1;P-M. Me

(66) ' J p H = 6 2 7

I

Ph

* Me

Me (67)

(68) 6

,

-62.1,'Jp"

=363

63

2: Pentam-ordinated arid Hexaco-ordinatrd Compounds

I Me

Me

(71) 631P, -46.1, 'JPH= 717

(70)

(69)

Hz N

Me

(73)6,- 3 8 . 4 , 'J = 6 8 8

(75)631P, -33, ' J p H = 7 1 9

(74)

(76) 6, - 4 0 . 8 , 'JPH=732

(77) Scheme

1

Orgunophosphorus Chemistry

64

NCC

(81) 631P, -24 ( R = Me)

PhC H =NMe

I

Ph

OR

(82) d3’ P, - 2 3 ( R = Me1

(R’OI~PNCO

(83) R 1 = CHFZCF,CH2

+

CO Me R2 ~ ~ = ~ ’ \COR~

R’’ 0 (86a, b)

(84a, b) a ) R2, R 3 = Me b) R 3 = O E t

\

COR~

/ Me

COR

2: Pen taco-ordinated and Hexuco -ordinated Cornpou nds

65

0

+

(R'O),PC=CR2

II

R1O-

MeCOC02R3

P-C=C-

R2

I

- C - C0,R / \

Me (87)

(88)

R'

(90)

C'.CR2 +C ,E CR2 (R1OI P 2 'O--CCO~R~

(88) e

I

(R'O),P -0

I

I

Me ~

(R'O)

\AMe

O ~ C O , R ~ Me 3

0

$'TR' -'0

C O ~ R ~

(88)

Me

Me

(93)

Me

Me

R

R

(94)

(95)

~

~

Organop hosphoms Chemistry

66

H OPh OPh ( R’o), PN c o

+

CI,CCH

=NCOMe &N-P-C

/\

PhO

CCI,

(100)

(97)

(96a b) a ) R 1 = Me b ) R ’ = Ph

\

OPh H

/ R ’ = Ph

r

Me

0-CL N=CHCC I

I

C13CCH-N,

(Me012P=N

I

C13CCH-N, COMe

+

PCI,

-

OH

But

But

But

But

2: Pen taco-ordinated and Hexaco-ordinated Compounds triamide (106)33.

67

The reaction of silylcyclophosphites (108) with a- dicarbonyl

compounds (e.g. 109) gives spirophosphoranes (e.g. 110) which rearrange to the cyclic phosphates (1111.34 The adduct (112) from phenyldichlorophosphine and stilbene undergoes a highly stereo selective oxidative addition reaction with o-aminophenol to form the cis-spirophosphorane (113) whose structure was confirmed (as the benzyl derivative) by X-ray crystallography and found to possess almost perfect tbp geometry. On the other hand, the reaction of (112) with catechol led stereoselectively to the trans configuration of the spirophosphorane (11 4 p . Cyclisation of (115) with PhPC12 yields (116) which undergoes oxidative cycloaddition with 2,3-butanedione (117) to form the

cis and fruns forms of the h5, h4 - diphosphaspiro [4,4] -nonane (1181.36 The kinetics and mechanism of the base hydrolysis of a series of biologicallyactive spiroarsoranes (1 1 9 p offer an interesting comparison with previous studies38-40 in the phosphorus series. The pseudo-first-order rate coefficients for hydrolysis show a linear relationship with [-OH] and the activation parameters (negative AS+ values) plus a p-value of +1.39 ( for variation of substituents in Ar) suggest an associative mechanism via (120) and (121) to products (122). Although not mentioned in the paper, the steric inhibition associated with the ortho-substituents in the Ar group is also indicative of an associative mechanism. These compounds appear to be surprisingly stable in aqueous acidic and biological media. Spirocyclic pentaoxy anionic silicates have been synthesised and their molecular structures, as determined by X-ray crystallography, have been compared with related five-co-ordinate silicon and phosphorus compounds to support their use as model compounds in nucleophilic substitution reactions. 41

The protonation of (123) by weak acids (including water) forms the unusually stable cation (124) which has been prepared as the chloride and tetrafluoroborate salts and characterised by multinuclear n.m.r. (6 3lP = -10.5) and by X-ray diffraction (X = BF4).42 In a slightly earlier publication 43, Verkade et al. report the preparation of (125a b) from (123) together with an analogous series of azasilatranes (126a-c) The interconversion of (127) and (128) has now been achieved and (127) has been shown to react with HBF4 to give the pentaco-ordinate structure (129) which in turn reacts with HC1 in THF to give (130) Compounds (128) and (129) were characterised by &ray ~rystallography.~~

5. Hexaco-ordinate Phosphorus Compounds - A series of heterocyclic phosphorates (133) with a P-C Bond in the ring have been prepared by the reaction of phosphonates

Organophosphorus Chemistry

68

Me POSiMe3

+

Me

Br

\

/ Br (110) 6,'P,

Ph-N

-33

..CPh +

PhPCt,

r

Ph

(112)

(114) 631P, -110

69

2: Pentaco-ordinatedand Hexaco-ordinatedCompounds Et

(118) b3'P, - 4 3 . 3 , - 2 . 8 ( t r a n s ) b3'P, -44.2, - 3.1 (cis)

0

+

II I

Ar-As-0-

0-

t IGH

Y

,Me

(125a, b) CH,Br, X = Br a) Y b ) X, Y = Br

70

OrganophosphorusChemistry

-

(126a c )

a ) R1 = M e , R 2 = H b) R1 = Me, R 2 = OEt c ) R1 = Me3Si, R 2 = H

PPh,

IN ‘

-

2 HCl

*

3

HCll

THF

Me

II I I

(R’O),P-CN=C=NCF,

+

R;NH

-

R2

(131) R ’ = Me or Et R 2 = Me or Et

(132)

1

BF4-

H

0

I

.-C[ CI-

2NaOH

(133)

2: Pentuco-ordincited urid H e , ~ a ~ , ~ ~ - o r Compounds diri~~t~~~

71

(131) with dialkylamines (1321.45146 The compounds were characterised by analysis, 1H, 19F and 31P n.m.r. and X-ray diffraction data (R2= Me, R3 = Et). Finally, an X-ray study of

the potassium salt of tris - (3,6-di-t-butyl-o-phenylenedioxy) phosphorate (134) - which crystallises as the solvate, (C14H20 O2)3K : 1.5 CgH6 : 2.5 CH3CN has been carried out 47 and represents one of the rare examples of structural studies of six-co-ordinate phosphorus compounds not containing P-halogen bonds. The distortion of the octahedral structure is due to co-ordinative interaction of the cation with the oxygen atom of the anion. References 1. J. Gloede, Z. Chem., 1988, 28, 352.

2. A. Schmuck and K. Seppelt, Chem.Ber., 1989,122,803.

3. a ) I'.J.Wheatley and G.Wittig, Proc. Chem. SOC.,London, 1962, 251. b) I'.J.Wheatley, J. Chem. Soc., 1964, 2206. 4. R. Francke, W.S. Sheldrick, and G.-V. Roschcnthaler, Chem.Ber., 1989, 122, 301.

5. G.Buono and J.R. Llinas, 1. Am. Chem. SOC., 1981,103,4532. 6. A.A. Korkin, W.A. Aksinenko and E.N.Tsvctkov, Phosphorus Sulfur, 1988,40,149. 7. A.E.H. d e Keijzer, L.H. Koole and H.M. Buck, J. Am. Chem. SOC.,1988,110,5995.

8. A.E.H. d e Keijzer and H.M. Buck, 1. Org. Chem., 1988, 53,4827. 9. V.V. Sharatin, J. Gen. Chem. USSR, (Engl .fransl.), 1988, 58, 2050. 10. V.A. Dodonov, O.P. Bolotova and A.V. Gushchin, J. Gen. Chem. USSR (Eng.Transl.), 1988,58,629. 11. J. Haenel, B. Ziemer, L. Riesel , I'. Leibnitz and G. Ohms, Z . anorg. allg. Chem., 1988,563, 173.

12. A.A. Krolevets, A.G. Popor, A.V. Adamov and I.V. Martynov,

1. Gen. Chem. USSR(Engl.transl), 1988,

58,2337. 13. A.A. Krolevets, A.V.Adamov, A.G. Popov and I.V. Martynov, Bull. Acad. Sci. USSR (Engl.transl1, 1988,37, 2392. 14. E. Fluck and R. Braun, Phosphorus Sulfur, 1988,40,83.

15. D.L. Hughes, R.A. Reamer, J.J. Bergen and E.J.J. Grabowski, J. Am. Chem. SOC.,1988,110,6487. 16. D. Crich, H. Dyker and R.J. Harris, J. Org. Chem., 1989, 54, 257.

17. D. Camp and I.D. Jenkins, 1. Org. Chem., 1989,54,3045. 18. D. Camp and I.D. Jenkins, 1. Org. Chem., 1989,54,3049. 19. A. Pautard-Cooper and S.A. Evans, Jr., 1. Org. Chem.,1989, 54, 2485. 20.. M.Varasi, K.A.M. Walker and M.L. Maddox, 21. 0.1. Kolodyazhnyi and D.B. Golokhov,

1. Org. Chem., 1987, 52, 4235.

1. Gen. Chem., USSR (Engl.truns1.) 1988, 58,426.

22. 0.1. Kolodyazhnyi, Tetrahedron Letters, 1988, 29, 3663. 23. H. Yamataka, K. Nagareda, Y. Takai, M. Sawada and T. Hanafusa, 1. Org. Chem., 1988,53.3877. 24. B.Tangour, C. Malavaud, M.T. Boisdon and J. Barrans, Phosphorus Sulfur, 1988,40,33.

Organophosphorus Chemistry

72

25. B.Tangour, C. Malavaud, M.T. Boisdon and J. Barrans, Phosphorus ,Sulfur and Silicon, 1989, 45,189. 26. B.Tangour, M.T. Boisdon, C. Malavaud and J.Barrans, Tetrahedron, 1988,44,6087. 27. I.V. Konovalova, E.K. Khusnutdinova, L.A. Burnaeva, G.Kh. Fakhrutdinova and A.N. Pudovik, J. Gen.

Chem. USSR (Engl.trnnsl), 1988, 58, 2466. 28. Yu G.Trishin, I.V. Konovalova, R.N. Barangulova, L.A. Burnaeva,

V.N. Chistokletov and A.N.

Pudovik, J. Gen. Chem. USSR (Engl.transl.), 1988, 58, 2165. 29. V.I. Kal'chenko, V.V. Negrebetskii, R.A. Rudyi and L.N. Markovskii, J. Gen. Chem.USSR

(Engl.trans1.) 1988, 58, 1079. 30. I.V. Konovalova, E.G. Yarkova, L.A. Burnaeva, G.S. Khafizova,E.K. Khusnutdinova, L.F. Il'ina and

A.N. Pudovik, J. Gen. Chem.USSR (Engl.transl.), 1988, 58, 876. 31. I.V. Konovalova, Yu G.Trishin, L.A. Burnaeva, E.K. Khusnutdinova,V.N. Chistokletov and

A.N. Pudovik, J. Gen. Chem. USSR (Engl.trans1.) 1988, 58, 1148. 32. I S . Belostotskaya, N.L. Komissarova, T.I. Prokof'eva, V.B.Vol'eva and

V.V. Ershov, lzv. Akad. Nauk., SSSR, Ser. Khim., 1978, 2385. 33. E.E. Nifant'ev, T.S. Kukhareva, I.A. Soldatova, I.S. Belostotskaya, V.V. Ershov and

L.K.Vasyanina, J. Gen. Chem USSR(Engl.trans1.) 1988,58, 1996. 34. V.V. Orchinnikov, Yu. G. Safina, R.A. Cherkasov, F.Kh. Karataeva and

A.N. Pudovik, 1. Gen. Chem.USSR (Engl.transl), 1988, 58, 1841. 35. G. Baccolini, R. Dalpozzo and E. Mezzina, Phosphorus, Sulfur and Silicon, 1989,45, 255. 36. C. Ru-Yu and C. Leifeng ,Phosphorus, Sulfur and Silicon, 1989,44, 193. 37. L. L. Rekik, P. Loiseau, Y. Madaule, P.Tisnes and J.-G. Wolf, 1. Chem. Res.(S), 1989,20. 38. F.H.Westheimer, Chem.Rev., 1981,4, 314. 39. W.C. Archie and F.H.Westhcimer, J. Amer. Chem. SOC.,1973,95, 5955. 40. N. Lowther and C.D.Hal1, J.Chem. SOC., Chem. Commun., 1985,1303.

41. R.R. Holmes, R.A. Day and J.S. Payne, Phosphorus, Sulfur and Silicon,l981, 42, 1. 42. C.Lensink, S-K. Xi, L.M. Daniels and J.G. Verkade, J. Am. Chem. SOC.,1989,111,3478. 43. D. Gudat, C. Lensink, M. Schmidt, S.-K. Xi and J.G.Verkade,

Phosphorus, Sulfur nnd Silicon, 1989,41, 21. 44. D.V. Khasnis, M. Lattman and U. Siriwardane, Inorg. Chem., 1989,28, 681. 45. I.V. Martynov, A.Yu. Aksinenko, A.N. Pushin, A.N. Chekhlov, E.A. Fokin and

V.A. Sokolov, Bull. Acad. Sci., USSR (Eng1,transl.) 1988,37, 1906. 46. I.V.Martynov, A.Yu Aksinenko, O.V. Korenchenko, A.N. Chekhlov, E.A.Fokin and

V.A.Sokolov, J. Gen. Chem.USSR (Engl.transl.), 1988, 58, 1929. 47. D.S.Yufit, Yu. T. Struchkov, E.I. Matrosov, D.N. Lobanov, N.V. Matrosova and

M.I. Kabachnik,

I. Strucfural Chem.USSR. (Engl.transl.), 1988, 29, 113.

3 Phosphine Oxides and Related Compounds BY 6. J. WALKER

1 Preparation of Acyclic PhQSphine Oxiiia Both new and modifications of existing routes have been used to synthesise substituted-aryl tertiary phosphine oxides. Electrochemical oxidation of phosphinites in the appropriate aromatic hydrocarbon as solvent leads to the formation of oxides ( 1 ) . 1 A new route to (2hydroxyary1)diphenylphosphine oxides (3) is provided by the reported2 base-induced rearrangement of aryl diphenylphosphinates ( 2 ) and a range of 2-phosphinylbenzene thiols (e.g. 4 ) have been prepared in moderate to good yield by phosphinylation of lithium 2 lithiobenzenethiolate (Scheme l).3 Both (R)-(+)- and (S)-(-)-tertiarybutylphenylphosphine sulphides (6) have been synthesised in high optical purity from (S)-(-)- and (R)-(+)tertiarybutylphosphinothioic acids, respectively, by formation of the mixed anhydride ( 5 ) followed by borohydride reduction (Scheme 2).4 Reactions of the product (6) have been used to provide routes to optically active phosphinothioic iodides, phosphinodithioates and thioselenophosphinic acids of known configurations. A new method for the asymmetric synthesis of tertiary phosphine oxides has been An Arbusov reaction of the optically active 1,3,2reported .5 dioxaphosphacycloheptane (7) gave the acyclic phosphinates (8) in moderate to high diastereomeric excess. The phosphinates (8) were converted to optically active phosphine oxides (9) by reaction with the appropriate Grignard reagent. The first synthesis of a phosphorus analogue (10) of vitamin D3 has been reported (Scheme 3).6 Attempts to use the corresponding iodide in the reaction with dimethylphosphide led to products resulting from reduction of the halide. Nitrones are generally deoxygenated by phosphines to give phosphine oxides. However, it is now reported that the vinylphosphine (11) can react with nitrones to give 1,3-~ycloaddition products with or without oxidation depending on the nitrone used.7 Phosphine oxides (e.g. 13) carrying benzenesulphonate groups are the products of the addition of the corresponding water soluble phosphines (e.g. 12) to acrylonitrile in neutral aqueous solution,g presumably via hydrolysis of the initially formed phosphonium salt.

74 0

0 Ph2P-0 "

-

-@,

LINPrl2

R

0 Ph2!'-@, R

OH

0

bLi SL i

I,

ii

b"...

*

0 Reagents

II

I,

P h Z P C I , THF,

ii, H30+

Scheme 1

Reagents

i, ( C F 3 S O 2 I 2 0 , C H z C 1 2 , 5 0 ° C ;

11,

NaBH4, E t O H

Scheme 2

0

R'X

MeO-H

H

II R2MgX

3: Phosphine Oxides and Related Compounds

75

0

FC‘ FF i-iv

RO

0

I

v, i i i

0

II

PMez

H

Reagents.

1,

MeZPNa, T H F ,

11,

O=PPh2,

v,

H202,

III,

Bun4NF,

THF,

IV,

( c O C L ) ~ ,DMSO, TEA, C H p , ;

B u L i , THF

I

RO’

Scheme 3

R’

0-

=

R z = CH2CH2CMe3

‘PPh,

R’ R z N b P P h 2

\ \R1

R1

=

R2

=

Ph

’

0

II

+

YPh2

PhN,

b]

Na 0,s

P

+

20

&CN

0

!CH2CH2CN

pH -7

3

+

2

(13

R’

R2

+

R3P(CL)SMe

-

6;

R’

R3’

Me 0,

Ph

> p Q Ph

0 R,N C H,

Ns

77

2 P r e p m i o n of Cvclic Phosphine Oxides 3-Phospholene sulphides ( 1 5 ) and oxides have been prepared by [1+4] cycloaddition reactions of (14) with various dienes.9 Phosphorus analogues ( 1 7 ) and ( 1 9 ) of erythrofuranose have been prepared by stereospecific c i s - h y d r o x y l a t i o n of the 2-phospholene-1-oxides ( 1 6 ) and ( 1 S ) , respectively.10 Compounds (17) and ( 1 9 ) readily epimerise at C-2 on treatment with base. A number of papers by Russian authors covering the synthesis and reactions of the oxides and sulphides (e.g. 20) of phosphadecalins have been published.11 A new route to 1,4-dihydro-azaphosphinine derivatives has been reported (Scheme 4).12 The previously r e p o r t e d 1 3 ring-expansion of phospholedichlorocarbene adducts to dihydrophosphorins has now been studied in d e t a i l . l 4 * 1 5 Heating the adducts ( 2 1 ) at 135OC for 3 minutes leads to optimum yields of a mixture of isomeric 1,2-dihydrophosphorin 1-oxides (22) and ( 2 3 ) . 14 Mercuric-catalysed ring-opening in acetic acid leads to the isomers (24) and (25).15 Both chlorine atoms in (21) may be replaced by phenyl groups in a Friedel-Crafts reaction. The novel heterocycle ( 2 7 ) has been obtained in low yield from multiple Aldol reaction of the tetraketone (26).*6 The structure assigned to (27) is based on detailed 'H, 13C and 3 l P n.m.r. studies. 3 S t r u c t u r e i c a l AsB.!xh The structures of the carbanions generated by lithiated bases (or in the presence of lithium halides) from p -carbonylalkylphosphonates and phosphine oxides have been reviewed.17 A study of the conformation of 2-(diphenylphosphinoyl)-5,5dimethyl-1.3-dioxane ( 2 8 ) , both in solution and in the solid state, and comparisons with similar studies of various 1,3-dithiane analogues have been reported.18 Certainly in the solid, and probably in solution, the diphenylphosphinoyl group preferentially occupies an equatorial position. The carbon bonding network around phosphorus centres can be determined in solids by the use of the double cross polarization 13C n.m.r. technique as illustrated for the phosphine oxide (29).19 Nine of the nineteen possible phosphine sulphides of the pentaphosphine ( 3 0 ) have been prepared (by progressive reaction of ( 3 0 ) with sulphur) and their structures have been investigated by 2D 3 l P n.m.r. spectroscopy.20

4

Reactions at P-

Phosphine oxides (31) bearing two or three pyridyl groups undergo ligand displacement on reaction with organometallic reagents to give substituted

Orgoriophosphorus Chemistq.

78

Ph

Reagents

I,

hexane,

H20, R T ,

11,

2

x

Et3N,

Scheme

o::c

// 0

‘R

+

III,

H202,

IV,

Sg

4

“‘-o-”” // R‘

0

79

3: Phosphine Oxides and Reluted Cotripourids Me

I

Me

OCOCH, (27)

0

Me0

II

MePoTpph2 Me

Ph ( P h,P

I

I2CH CH, PC H2CH ( P P h,)2

W + Q R'

Reagents

I,

R L M , THF,

11,

+

H20

Scheme 5

QR2

+

0

pyridines and 2,2'-bipyridyl (Scheme 5).2 Triphenylphosphine oxide can be reduced to the phosphine in good yield by reaction with samarium diiodide in the presence of HMPA.22

5

k i m i 9 n s at the Side-Chain

Warren has used a variation of his phosphine oxide-based olefination method to synthesise single isomers (E or Z) of unsaturated carboxylic a c i d s . 2 3 a-Diphenylphosphinoyl ketones ( 3 2 ) are reduced by sodium borohydride to give diastereomeric mixtures of the corresponding alcohols (33) and ( 3 4 ) . These alcohols can be converted to the lactones (35) and (36) which can be separated and individually converted stereospecifically into (2)-(37) and (E)-(38) alkenes by base treatment (Scheme 6). In many cases it is possible to reduce P-ketopkosphine oxides (39) and enones ( 4 1 ) stereoselectively to the erythro-alcohols ( 4 0 ) and (42), respectively, using sodium borohydride in the presence of cerium chloride (Scheme 7).24 An earlier report that reduction in the presence of cerium salts did not cause reversal of stereochemistry compared to reduction with borohydride alone appears to be true only of the compounds studied in that report. The carbanions of 3-hydroxypropylphosphine oxides ( 4 3 ) have been reported to undergo 0- to C-acyl transfer to give the P-ketoalkylphosphine oxides ( 4 4 ) in moderate to excellent yield.25 The products ( 4 4 ) can be reduced stereoselectively to the corresponding threo-P-hydroxyphosphine oxides by established methods and hence provide a route to (E)-4-hydroxybutenes (45) (Scheme 8). Base treatment of (44) under appropriate conditions also provides routes to cyclopropylketones ( 4 6 ) and hydroxyketones ( 4 7 ) . p Hydroxyalkylphosphine oxides (49) can also be prepared directly from the corresponding epoxyalkyl phosphine oxide (48) by reaction with lithal.26 CAMEO, an interactive computer program for the mechanistic evaluation of organic reactions, has been extended to include the reactions of phosphine oxide-stabilised carbanions.27 A convenient route to 3methoxy-l-trimethylsilyl-1,3-dienes ( 5 0 ) is available from a one-pot reaction involving regiospecific y-silylation followed by Horner-Wittig reaction (Scheme 9).28 Phosphine oxide-based olefination has been used to synthesise a variety of natural products. The pheromones ( 5 2 ) and ( 5 3 ) of the 9 Japanese female peach fruit moth have been synthesised (Scheme The phosphine oxide starting material ( 5 1 ) was obtained from a Wittig reaction of the ylide derived from 1 , l -diphenylphospholanium perchlorate. The reaction of (1 -methyl-2-propenyl)diphenylphosphine oxide carbanion ( 5 5 ) with the optically active aldehyde ( 5 4 ) is the key step in a short synthesis of the sesqui terpenes (-)-a -selinene ( 5 8 ) and (+)-a - h e 1 mi s c ape n e

81

0 Rco\ (C H2In

0 &,P h !z

O/CO\(CHz)n P

+

H )’

h

2

!

e

H’

R

R (35)

(36)

1

Ill,

IV

...

Reagents

I,

NaBH4.

11,

TsOH, t o l u e n e ,

III,

KOH, HzO, THF,

IV,

DMSO, 5 0 ° C

Scheme 6

0

0

II

P h, ! y R 1

Ph2 PyR’ I

0A

*

2

(391

(40) Major product

0

0

II

I

HO (411 Reagents

I,

(42) M a j o r product

N a B H 4 , CeC13, MeOH, - 7 8 ° C

Scheme 7

82

Organophosphorus Chemistry

R’n R’nR3 R3

R4

R ~ C O OH

R e a g e n t s : i , L D A ; ii, ButOK, B u t O H ;

iii, N a B H 4 ,

IV,

NOH, DMF; v, NaOH,

HP, E t O H

Scheme 8

0

II

. )

( 4 8 ) R ’ = H or a l k y l , R2 = alkyl or aryl, R’R* = (CH~),,

-

0

II

I, I I

(49)

0

II

P h 2 P , q . S i M e 3 -Elll_

phzpn R’

Me0

Reagents’

I,

LDA, THF,

Me0

11,

P h 2P C H R2CH(OH1 R’

Me3S1CI,

III,

R’CHO

Scheme 9

3: Phosphine Oxides und Related Compounds

83

Q / \

Ph

Ph

I

0

R e a g e n t s : i, ButOK;

ii, C g H l 3 C H O ;

B u n L i ; iv, MeSSMe;

V,

0 Ph2!<

III,

v, v i

R C H O ; vi, HCL, H20

S c h e m e 10

+

...

-

OHC

(54)

I

OH (60)

84

Organoph osph oms Chemistly

(59).30 The olefination reaction leads to a mixture of alkenes (56) and (57) which on heating forms (58) and ( 5 9 ) . Both the Wittig reaction and the Homer-Wittig have been used in the synthesis of leukotrienes and their metabolic products, for example 12-(S)-hydroxyeicosatetraenoic acid (60) . 3 1 The isomeric isoxazole-substituted phosphine oxides (61) and (63) have been synthesised and used in Horner-Wittig reactions to prepare isoxazoles of types ( 6 2 ) and ( 6 4 ) regiospecifically.32 An alternative approach to (62) and (64) involves reaction of the isoxazole aldehydes (e.g. 65) with alkyldiphenylphosphine oxide anions (Scheme 11). The routes described have been applied to the synthesis of isoxazoles containing leukotriene-like carbon chains. The major product obtained by alkylation of the carbanion derived from 2-(dimethylamino)ethylmethylphenylphosphine oxide (66) is ( 6 7 ) rather than ( 6 8 ) , while alkylation of the carbanion derived from ethylmethylphenylphosphine oxide ( 7 0 ) takes place exclusively at the methyl group.33 The former reaction provides a useful synthesis of appropriately alkylated vinylphosphine oxides ( 6 9 ) which are not otherwise easily prepared (Scheme 12). The N-silylated nitrile imines ( 7 2 ) have been prepared in solution by silylation of carbanions ( 7 1 ) of diazomethylphosphine sulphides.34 At room temperature compounds (72) rearrange to the isomeric diazo compounds (73). In view of the usefulness of alkoxyphosphonium salts in synthesis it is of interest to note that, depending on the mode of addition of the reagents, either the alkoxyphosphonium salt (74) or the oxygen-bridged disalt (75) can be isolated from the reaction of triphenylphosphine oxide with triethyloxonium tetrafluoroborate.35 Compound ( 7 5 ) has been prepared before as a triflate by the reaction of triphenylphosphine oxide with trifluoromethanesulphonate anhydride. However, it is surprising that ( 7 5 ) can be obtained in the presence of a nucleophile as effective as ethoxide. Presumably its isolation depends on the low solubility of the tetrafluoroborate salt. An addition-elimination reaction of 1-halogenovinyldiphenylphosphine oxides (76) has been used to prepare a wide variety of trans1 , 2 - d i p h o s p h i n y 1 - ( 7 7 ) , 1-sulphinyl-2-phosphinyl-(78), 1-sulphoxyl-2phosphinyl- and 1-sulphonyl-2-phosphinyl ethenes.36 Similar reactions of the optically active 1-halogenovinylmethylphenylphosphine oxide ( 7 9 ) provide routes to optically active 1,2-diphosphinyl ethenes (80) and ( 8 1) and 1-sulphinyl-2-phosphinyl ethene (82). Photolysis of the phosphinic aminimide (83) in methanol gives the amide ( 8 5 ) in high yield, not via nitrene formation but by initial

3: Phosphine Oxides and Related Compounds

Reagents

I,

BunLi;

11,

R2CHO;

ti,

85

oHcrTrR2 0-N (65)

Scheme 11

Ph

jpCcoH3

Ph

I, I I

Me2N

Et'

Me2N

Me2N

(67)

"y

'CH,

(70) I,

(69) Bu"LI,

THF,

11,

RX,

Ili,

CH31, T H F ,

S c h e m e 12

P'CH2R

(68)

Ph \p//o

'

CH3

Reagents.

40

Rfpc:H3 + RY

-

(66)

ph,p@o

Ph'

IV,

N a 2 C 0 3 , THF, H20

86

Organophosphorus Chemistly

-

S

II

R3SiCL

R,PC=N,

- 40°C

I

-

S

II

+

-

S

RT

R,P-CFN-N-SiR,

II

R2P-C-SiR,

I1

Li

N2

(71)

(73)

Et30+

Add

BF;

+

P h3POEt

rn

BF,-

P h P=O

3

Add

Ph,P=O

Et,O+

+

+

Ph,P-0-PPh,

+

+

(74)

BFL

2 BF4-

0

II

0

0 +

II

Ph,PH

0

pyridine

0

II

YYPPh2 + (76)

0 c

11

PhS/

PhSH (78)

PPh,

3: Yhosphine Oxides and Related Compounds

87

0

0

II X )'(kiPh Me (79) X = Cl, B r

(80) R ' = B u t , R 2 = Ph (81) R 1 = M e , R 2 = P h

0

Me

0

II

PhzP-N-

-

-[ hv

-t

NMe,

MeoH

0

II

Ph,PNHCH,N

Mez

1

MeOH ___)

0

II

Ph, PNH,

Orgrrnophosphorus Chcmisty

88

rearrangement

of

(83) to the phosphinoyl aminal ( 8 4 )

followed

by

solvolysis to (85).3 7

Oxide Cqmplexes The

intramolecular

phosphine

o x i d e - tin

complexes

(86) have been

prepared and studied by 119Sn. 3 1 P and 1 H n.m.r. spectroscopy.38 Manganese complexes (87) of dialkylarylphosphine sulphides have been

as dimers or monomers depending on the nature of the The reactions of (87) with acetylene substituents.39 dicarboxylate diesters lead to a variety of products which are of interest to prepared

phosphorus

those studying alkyne cyclotrimerization.

The details of 1 3 C , I H and 3 1 P n.m.r. spectra f o r a range of carbamoylmethylphosphine oxides have been reported.40 From this data a correlation

between

3 P chemical

shift and

the

nitric

acid extraction

constant has been determined.

REFERENCES 1.

A S . Romakhin, Yu. A. Babkin, D.R. Khusainova, E.V. Nikitin and Yu. M. Kargin,

Zh. Obshch. Khim., 1988, 5 8 , 484 (Chem. Abstr., 1989, 110, 114941).

2.

B. Dhawan and D. Redmore, J. Chem. Research (S), 1988, 222.

3.

E. Block, G. Ofori-Okai and J. Zubieta, J. Am. Chem. SOC.,1989, 111, 2327.

4.

Z. Skrzypczynski and J. Michalski, J. Org. Chem., 1988, 5 3 , 4549.

5.

T. Kato, K. Kobayashi, S. Masuda, M. Segi, T. Nakajima and S. Suga, Chem. Lett.,

6.

W.G. Dauben, R.R. Ollmann, Jr., A S . Funhoff and R. Neidlein, Tetrahedron Lett.,

7.

A. Brandi, A. Goti and K.M. Pietrusiewicz, J. Chem. Soc., Chem. Commun., 1989,

1987, 1915. 1989, 30, 677. 388. 8.

C. Larpent and H. Patin, Tetrahedron, 1988, 44, 6107.

9.

J. Apitz, J. Grobe and Duc Le Van, Z . Naturfosch, B. Chem. Sci., 1988, 4 3 , 257

10.

R. Bodalski and T. Janecki, Bull. Pol. Acad. Sci. Chem.. 1988, 35, 529 (Chem. Abstr.,

11.

e.g. Yu. G. Bosyakov, G.P. Revenko and A.P. Logunov, Zh. Obshch. Khim, 1988, 5 8 ,

(Chem. Abstr., 1989. 110, 154399).

1989, 110, 114967). 21 (Chem. Abstr., 12.

1989. 110, 39065).

J. Barluenga. F. Palacios, F.J. Gonzalez and S. Fustero, J. Chem. SOC., Chem.

Commun., 1988, 1596.

13.

B.J. Walker in 'Organophosphorus Chemistry', Ed. B.J. Walker and J.B. Hobbs, (Specialist Periodical Reports), The Royal Society of Chemistry, London 1989,

v01.20. p.74. 14.

G. Keglevich, B. Androsits and L. Toke, J. Org. Chem., 1988, 53, 4106.

3: Phosy h it it. Oxides and Related Compounds 15.

89

G. Keglevich, F. Janke, I. Petnehazy, A. Szollosy. P. Miklos, G. Toth and L. Toke,

Phosphorus Sulfur, 1988, 3 6 , 61 (Chem. Abstr., 1989, 110, 212930);

G. Keglevich,

I. Petnehazy, L. Toke, P. Miklos, A. Almasy and G. Toth, Magy. Kem. Foly, 1988, 94, 255 (Chem. Abstr., 1989, 111, 7507).

16.

R. Neidlein, W.G. Dauben, A.S. Funhoff and R.R. Ollmann, Jr., Chem. Ber.,

1988,

1 2 1 , 2121.

17. 18.

J. Seyden-Penne, Bull. SOC. Chim, Fr., 1988, 238. M. Mikolajczyk, P. Graczyk, M.W. Wieczorek, G. Bujacz, Y.T. Struchkov and M.Y. Antipin, J. Org. Chem., 1988, 53, 3609.

19.

E.W. Hagaman, J . Am. Chem. SOC., 1988, 110, 5594.

20.

J.L. Bookham and W. McFarlane, Polyhedron, 1988, 7 , 129 (Chem. Abstr., 1989,

21.

Y. Uchida, K. Onoue, N. Tada and F. Nagao, Tetrahedron Left., 1989, 3 0 , 567.

110, 23970). 22.

Y. Handa, J. Inanaga and M. Yamaguchi, J. Chem. S O C . , Chem. Commun., 1989,

298. 23.

D. Levin and S. Warren, J. Chem. SOC., Perkin Trans.1, 1988, 1799.

24.

J. Elliott, D. Hall and S. Warren, Tetrahedron Lett.,

25.

P. Wallace and S. Warren, J. Chem. SOC., Perkin Trans.1, 1988, 2971.

26.

H. Imoto and M. Yamashita, Synthesis, 1988, 323, (Chem. Abstr., 1989, 110, 8302).

27.

A.J. Gushurst and W.L. Jorgensen, J. Org. Chem., 1988, 53, 3397.

28.

M.D. Ironside and A.W. Murray, Tetrahedron Lett., 1989, 30, 1691.

29.

I. Yamamoto, S. Tanaka, T. Fujimoto and K. Ohta, J. Org. Chem., 1989, 54, 747.

30.

D. Caine, B. Stanhope and S. Fiddler, J . Org. Chem., 1988, 53, 4124.

31.

R. Nagata, M. Kawakami, T. Matsuura and I. Saito, Tetrahedron Lett., 1989, 3 0 ,

1989, 30, 601.

2817. 32.

E.W. Collington, J.G. Knight, C.J. Wallis and S. Warren, Tetrahedron Lett., 1989,

30, 877. 33.

K.M. Pietrusiewicz and M. Zablocka, Tetrahedron Lett., 1989, 30, 477.

34.

M. Granier, A. Baceiredo and G. Betrand, Angew. Chem., Int. Ed. Engl., 1988, 2 7 ,

35.

D. Critch and H. Dyker, Tetrahedron Lett., 1989, 3 0 , 475.

1350. 36.

K.M. Pietrusiewicz, W. Wisniewski and M. Zablocka, Tetrahedron, 1989, 4 5 , 337.

37.

S. Freeman and M.J.P. Harger, J. Chem. Soc., Perkin Trans.1, 1989, 571.

38.

H.P. Abicht and H. Weichrnann, Z. Chem., 1988, 2 8 , 69. (Chern. Abstr., 1989, 110,

39.

E. Linder. V. Kass, W. Hiller and R. Fawzi, Angew. Chem., Int. Ed. Engl., 1989, 2 8 ,

8330). 448. 40.

R.C. Gatrone and P.G. Rickert. Solvent Extr. Ion Exch., 1987, 5 , 1117 ( C h e m .

Abstr., 1989, 110, 39064).

4 Tervalent Phosphorus Acids BY 0.DAHL

1 Introduction

The activities in the field of tervalent phosphorus acid chemistryhaveagain this year been concentrated on the preparation, by electrophilic reactions of phosphoramidites or chloridites, of compounds of biochemical interest, e.g. modified phosphates of nucleosides or lipids, although basic research continueson the preparation of new compound types, and on studies of their properties. Proceedings of the 2nd Swedish-German Workshop on Modern Aspects of Chemistry and Biochemistry of Nucleic Acids and their Components, West Germany 1988, have been published;' they contain several papers on the preparation of nucleoside phosphates and modified phosphates by tervalent phosphorus acid chemistry. A review on the halogenation of tervalent phosphorus acid derivatives and studies of the structure of the products (dihalophosphoranes or halophosphonium halides) by 31P n.m. r. has appeared.

2 Nucleophilic Reactions

2.1 Attack on Saturated Carbon.- a-Hydroxyketones with diethylphosphorochloridite and ferric chloride gave 2-oxoalkylphosphonates (1), probably v i a 2-oxoalkyl phosphites (2) which rearrange No rearranged to (1) in the presence of the Lewis acid ~atalyst.~ product was observed in the absence of the 0x0 group, and ahydroxy esters gave the H-phosphonates (3). The 1,3,2-oxaza-

4: Tevvalent Phosphorus Acids

91

R' = R2 = alkyl R' = H, R2 = Ph

R2 '@OR3 0

'om

H'

(3)

Me

Me

! ! -

Me2NnN-P&0 ' Me

I

Me3N +A y-P< N)=O

N I

I-

Me

Me

N I

Me

(6)

?

PhCH,OCNHFHCOOMe

(9)

+ (Et0)3P

BF3*Et@

-

?

PhCH,OCNH YHCOOMe

Organophosphorus Chemistry

92

phospholan (4), obtained from ( - ) -ephedrine, reacts with alkyl halides to give phosphinamides with predominant retention of configuration at phosphorus. Acid methanolysis gave methyl phosphinates (5) with a high degree of inversion, and (5) was shown to be a useful starting material for the asymmetric synthesis of phosphine oxides and phosphines. The new 1,3,2-diazaphosphetidine (6) reacts with halogens to give P-halospirophosphoranes by participation of the dimethylamino group; with methyl iodide quaternization occurs at the dimethylamino group, not at phosphorus. Tris (trimethylsilyl) phosphite and 1-acylaziridines gave substituted 2-aminoethylphosphonic acids (7), and a high yield of 2-aminoethylphosphonic acid (8) after hydrolysis.6 The alkylation of phosphites using an ether (9) as the alkylating agent was successful in the presence of boron trifluoride and gave 2-phosphonoglycine (10) after hydrolysis. Attack on Unsaturated Carbon.- Ethyl trimethylsilyl (diethoxymethy1)phosphonite (11) has been used to prepare a series of a-, P - , and 7-aminoalkylphosphonous acids, e . g . (12) and (13) Arylmethylenemalonaldehydes (14) with trimethyl phosphite gave the phosphonates (15) via an intermediate which has been isolated in one case and shown to have the cyclic structure (16) Benzothiete (17) and trialkyl phosphites in boiling 2.2

.

.

toluene gave the benzylphosphonates (18), probably by attack of phosphorus at the o-quinoidal form (19).lo A number of analogues of phosphinothricin (20), e.g. (21), have been prepared by a route which begins with a Michael addition of diethyl methylphosphinite to an a,@-unsaturated ketone. Tris (dimethylamino)

''

-

phosphine and the arylideneoxazolones (22) gave the unexpected products (23) l2 Since trimethyl phosphite was unreactive the

.

usual mechanism v i a a Michael addition seems unlikely, and attack at the carbonyl group as shown is proposed instead. Diethyl formylphosphonate (24) can be prepared fromtriethyl phosphite and acetic formic anhydride, but is thermally unstable. It eliminates carbon monoxide at -10 OC giving the phosphate (25)

4: Tervalenr Phosphorus Acids

93

?

i, H2/Ni ii, HCI

(Et0)2CHYH2CH2NO, CH,=CHNO

(Et0)2CHP,

I

OEt

OH (12)

,OEt OSiMe3

0 II

NHCOCH3 I

(Et0)2CHPCH2CHCOOSiMe,

hydrolysis

I

OEt

COOH

CHO (Me0)3P

?

* H-PCH~CH~NHZ

+

ArCH=C= CHO

?

YH2

* H-PCH2CHCOOH I

OH

-

CHO

ACH-C; (MeO),P+I

___t

CHO-

CHO A~CH-C~ (MeO)2b=0 CHoMe (15)

(14)

(16)

0 Me’

‘b-COOH

y42

94

Organophosp horns Chemisty Ar

Ar

P(NMe2)3 +

D

(22)

/

Ar

I

1

(EtS)3P

+

OH

HCI

(EtS)zPCI

EtSH

R2CO

RZC,

/OH EtSH_ c -

+

EtSH

R*C(SEt)2

SEt

R'S-PC12

+

R2R3C0

-

(31)

+

RCHO

It

(30)

(29) (EtS)2PH

0 SR'

C12P-CR2R3

?H (EtS)zP-CHR

++

(32) R = Ph, CC13

(EtS)ZP-OCH*R

1

95

4: Tewalent Phosphorus Acids

as the stable end product.13 A full paper has appeared on reactions of the tervalent thiophosphorus acid esters (26)-(28) with aldehydes and ketones.l4 The reactions are strongly catalysed by hydrogen chloride, and do not occur with carefully purified reagents. A mechanism involving exchange of ethylthio groups with chloride is proposed (Scheme 1). In accordance with this mechanismthiophosphorodichloridites(29) gave (30) with 0x0 compounds.l5 Di (ethylthio)phosphine (31) adds to aldehydes to give 1-hydroxyalkyldithiophosphonites (32), which do not rearrange like the corresponding oxygen analogues.

on Nitrogen, chalcogen, or Halogen.- Phosphites are oxidized by oxaziridines, e . g . (33), under mild, anhydrous conditions, presumably via a phosphorane intermediate as shown.l7 Acylphosphonites (34) gave the phosphites (35) with aromatic aldehydes; this insertion reaction is formulated as a nucleophilic attack at the aldehyde oxygen, followed by an acylium ion migration;" an attack at the carbonyl carbon, followed by the usual carbon to oxygen rearrangement and an acyl migration would give the same product. Symmetrical monothio- and monoselenopyrophosphate esters (36) have been prepared in high yields from dialkyl trimethylsilyl phosphites and the sulphenyl or selenenyl chlorides (37) l9 The unstable seleno compounds (36, R1 = R2) are best obtained from twomolesof a dialkyl trimethylsilyl phosphite, one mole of selenium, and one mole of sulphuryl chloride at -78 OC. Pentaphenylcyclopentaphosphine (38) and elemental selenium gave an unidentified intermediate which was slowly transformed to a mixture of the selenium analogue of Lawesson's reagent (39) and (40). 2 0 Pure (40) can be obtained from the mixture by crystallisation, or by reduction of (39) with triphenylphosphine. A review on the reaction of tervalent phosphorus acid derivatives with halogens has appeared. Alkylbis (diisopropylamino)phosphines (41) react with carbon tetrachloride or bromotrichloromethane to give the P-halogeno ylides ( 4 2 ) below 0 0C.21 The ylides rearrange to the substituted phosphines (43) 2.3 Attack

.

*

Organophosphorus Chemi s t y

96

?

+

(Et0)2P-CR

ArCHO

-

1

(EtO),f-O-EHAr RC=O

(34) R = P i , BU'

-

II

(35)

f

+ (R20),P-0SiMe3

(36) X = S,Se

P,h

+

(Pri2N)2P-CH2R

Se

-

+ CXCI,

/S? Se P P" Se4 'S6 'Ph

Ph,

COOC

-

- CHCLj

+

,Ph

p-7 Se

Se,

P/

>Ic

>0

-

"C

(Pr',N),P=CHR (42) X = CI, Br

(EtS)3P

+

f

(R10)2P-X-P(OR2)2

(37)

(PhP)5

I

RC=O

0 (R10)2P-X-CI

(Et0)2P-O-CHAr

B L J ~ S ~ H ~ EtS-PH, (44)

(R2N)2PH (46) R = Me3Si (47) R = Ph

2 RP(SEt)2 + Bu2SnH2

Ph3P

(39)

'I'

(Pri2N),P-CHR (43)

(45) R = Et, But. EtS

4: Tervalent Phosphorus Acids

97

above 0 OC in a reaction which is first-order and accelerated in polar solvents; an ionic intermediate is presumably involved.

3 Electrophilic Reactions

3.1 Preparation.. The primary ethylthiophosphine (44) and some secondary ethylthiophosphines (45) have been prepared using dibutylstannane as the reducing agent. 22 The secondary ethylthio-

phosphines add to activated double bonds, e.g. acrylonitrile, although more slowly than the oxygen analogues. X-ray crystal structure determinations on two secondary aminophosphines reveal a dimeric hydrogen-bridged structure for (46) and a normal monomer structure for (47);23 the arsenic analogue of (46) was likewise monomeric. Very high yields of alkyl phosphorodiamidites (48), or unsymmetrical dialkyl phosphoramidites (49), are realised by treatmentoftris(dialky1amino)phosphines (50) with the stoichiometric amount of alcohol in the presence of catalytic amounts of iodine. 24 Instead of iodine, a diethylammonium diethyldithiocarbamate/diethylamine catalyst also effects the selective transformation of (50, R = Et) to (48).25 A series of tris(dialky1-

-

amino)phosphines (51) has been prepared from tris (diethylamino) phosphine by transamination;26 no catalyst was added, and di-

ethylamine was removed by pumping. The new phosphatrane precursor (52) has been synthesized from (53) and tris(dimethylamino)phosphine, and some phosphatranes prepared, e.g. (54).27 (54) however is best prepared directly from the amine (53) and bis(dimethy1amino)chlorophosphine. It is unusually stable, and removal of the proton is very difficult; the structure has been confirmed by an X-ray crystal structure determination. 28 Some cyclophosph (111)azanes (55) have been prepared

as shown;2g they contain cavities enclosed by two

phosphorus atoms and two R groups which make them interesting from a coordination chemistry standpoint. The same group has

Organophosphorus Chemistry

98

R2N= N a ,

N

3

, N

D

NANMe

N n O I

w, u Me

N(CH2CH2NHMe)3

I

H'

\1 (55) R = Me,Et, Ph

6h

I

Ph (57) x = Y = 0 , n = 2,3 X = 0, NMe, Y = NMe, n = 2

4: Ervalent Phosphorus Acids

99

obtained a monomeric benz-1,3,2-diazaphosphole (56) from ophenylenediamine and bis (dimethylamino)methylphosphine.30 Some bicyclic 1,3,2,4-diazadiphosphetidines (57) have been prepared and the crystal structure determined in two cases.31 The 1,3,2oxazaphospholan ( 5 8 ) has been treated with a series of hindered phenols;32 the biphenyldiol (59) gave (60) which has a chiral axis due to hindered rotation around the biphenyl bond. One diastereomer was obtained, with nonequivalent phosphorus atoms and a 7J,, of 30.3 Hz! An improved preparation of (61) and of the new (62) has been published.33 Some new dialkyl trichloromethylphosphonites (63) have been prepared by a simplified method.34 The new, chelating bis-phosphite (64) has been prepared as shown.35 Some (methylthiomethy1)phosphonous acid derivatives (65)-(67) have been synthesized from phosphorus trichloride and the (methylthiomethyl)stannane (68) 36 A series of unsymmetrically substituted (thiophosphonomethy1)phosphonous acid derivatives (69) and (70) has been prepared as shown for use as ligands.37 The first 1-alkoxyphosphole (71) has been prepared via a 1-cyanophosphole, which is quite stable in contrast to l-chlorophospholes. 38 Tervalent phosphorus acid halides react with imines at the nitrogen atom to give e.g. (72), although with iodides a 2:l addition product, e.g. (73), is ~btained.~’Bis(diethy1amino)ethynylphosphine ( 7 4 ) has been prepared as shown and used to prepare the 1,3,4-thiazaphospholan (75);40 the latter rearranged upon heating to (76).41 Some 0,O-dialkyl S-acyl thiophosphites (77) have been prepared and characterized.42 The best preparative route of several investigated was the one shown; all routes gave a 95:5 (R2 = Me) or a 50:50 (R2 = Ph) mixture of (77) and ( 7 8 ) , which are probably equilibrium mixtures. As expected, the thioacyl group is a good leaving group, and (77) with alcohols or diethylamine gave (79), the products of phosphorus attack.42 With hydrogen chloride (79) reversibly formed at -78 OC, but the products of thioacyl attack, (80) and acetyl chloride, were obtained at room temperature.43 The first examples of benz-l,2,3-

.

100

Organophosphorus Chemistly

MeSCH2SnBu3 + PC13

MeSCH2P(NEt& (66)

7

-

MeSCH2PCI2

(68)

(65) MeSCH2P(OP& (67)

f

F2PCH2PC12

-f

t

X2PCH2Li

F2PCH2PX2

+

CIPY2

-

(70) X,Y = NMe: OPr', Ph

(69) X = NMe2, O p t

)-$

BrCN *

I Li

ButOK

I

CN

-

Hr OBut

(71)

/

But I

(Et0)2P -N-CH=CHCH

X = CI,Br

(Et0)zPX

+

CH,CH~CH=NBU'

f

X2PCH2PY2

(72) Et EtO,

bNRBU'

O + p I\ N A E t

But

(73)

4: Tervalent Phosphorus Acids

HC=CMgBr

+

CIP(NEt2)2

101

-

MeNHCSNHMet

HCrC-P(NEt,),

+i%L '

,Me

NMe

(R10)2PCI

+

f

R2C-OSiMe3

-

f

+

(R10)2P-S-CR2

R' =Et, Pr, Pr' R2 = Me, Ph

f

(R10)2P-O-CR2

(77)

(RIO),P(H

+

R2COCI

(78)

+

(R'0)2P-X

R2COSH

(79) X = NEt2, OR1, CI

(80) SMe

I

Q

+

RPC'2

AIC13 80OC

*

'

a s \ P - R P' Me I

R (81) R = Me, CH2Ph, Ph

I Et2N.. OBu' P-R Et2N' XI

-

BdO, P-X Et2N'

+

Et2N-R

102

Organophosphoms Chemistry

thiadiphospholes (81) have been prepared as shown.44 t-Butyl tetraethylphosphorodiamidite (82) with hydrogen halides or acetyl chloride gave products of substitution of a diethylamino group, (83), as well as products of Arbuzov dealkylations, ( 8 4 ) .45 The amount of substitution increased when a less polar solvent was used, which was explained by the involvement of a less polar phosphorane intermediate in the substitution reactions. 3.2 Mechanistic Studies.- The mechanism ofthe reaction of tetra-

zole-activated phosphoramidites with alcohols has been studied.46 A series of diethyl azolyl phosphoramidites (85) was prepared from diethyl phosphorochloridite and fully characterized, and the same compounds shown to be formed from the phosphoramidite (86) and azole. The degree of formation of ( 8 5 ) from (86) increases with the acidity of the azole, and the proposed mechanism is a fast protonation of ( 8 6 ) , followed by a slow, reversible formation of ( 8 5 ) and a fast reaction of ( 8 5 ) with alcohols. Another study was concerned with the influence of amine hydrochlorides on the rate of methanolysis of the phosphoramidites (87) or (88), or tris (diethylamino)phosphine.47 The chloride content was measured to be 10-20 mM in doubly distilled samples which explains that "uncatalysed" alcoholysis is possible. Intensive purification, including treatment with butyllithium and distillation from sodium, brought the chloride content down to 0.1-1 mM. The methanolysis reaction, in methanol as the solvent, was found to be first-order in catalyst concentration. An ab i n i t i o calculation on N- and P-protonated aminophosphine (89) gave similar proton affinities for N and P;48 this contrasts with earlier MNDO calculations which had N-protonated species as the most stable. The N-protonated compound had an electronic structure reminiscent of a phosphenium ion-ammonia complex. 3.3 Use for Nucleotide, Sugar Phosphate, Phospholipid, or Phosphoprotein Synthesis.- Methyl or phenyl phosphorodichloridite (90) has been used to prepare several phospholipids in high yields.49 A triphosphoinositide has been made using (91) and

4: Tmalent Phosphorus Acids

(Et0)2PCI

+

R-N,

/'f

X s=Y

R = Na, K, Me3Si

103

(EtO)*P--N,

(PhCH20)2PNPri2

(911

(92)

H', H20

[~lpc'

ii, N204 *

Me

+Z

(86)

CH2=CHCH20-P(NPri2)2

0 Me II

I

RO-T-Nm+

0-

I

X5 Y

(93)

I

i, ROH

(94)

+ H-N,

(EtO),P-NPr',

Me

I

I

-

*I

X6Y

(85) X,Y,Z = CH, N

PhCH20-P(NPri2)2

Me

+z

NH2Me

Me (95)

i, S8

ii, hydrolysis

(97) R = 5' - nucleosidyl

Organophosphorus Chemistry

104

(92).50 (91) was used also in a synthesis of a mycobacterial phospholipid. 51 The allyl phosphorodiamidite (93) was used to phosphitylate serine in a tripeptide, and the resulting phosphoramidite was coupled to a nucleotide in high yield;52 the allyl group is preferable to other phosphorus protecting groups since it could be removed with pyridine-water without cleavage of the highly base-labile nucleotidyl-peptidyl phosphotriester bond. The 1,3,2-diazaphospholan (94) has been recommended to prepare phospholipid analogues (95) 53 Salicylchlorophosphite (96) has been used to phosphitylate a natural allyl alcohol, eati in.^^ The same reagent is the starting material for a facile preparation of nucleoside 5 I-0- (1-thiotriphosphates) (97),55 used for enzymatic preparation of oligonucleoside phosphorothioates. A thiophosphonic acid analogue of a phospholipid, (98), has been prepared via hydrogen sulphide addition to the phosphoramidite

.

(99).56

A range of biologically active groups or reporter groups have been attached to the 5I-end of oligonucleotides by the use of phosphoramidites which contain the active group. Such phosphoramidites include the psoralen derivative (100),57 the biotinol derivative (101),58 a fluorescence marker (102),59 containing a covalently bound bathophenanthroline-Ru(I1) complex with a long lasting, strong fluorescence, and an acridine derivative (103). 6 0 The binding of similar groups to the 3I-end of oligonucleotides has been accomplished for an acridine derivative by using the nucleoside phosphoramidite (104) as the first monomer in a solid-phase synthesis;61 by using a normal nucleosi.de phosphoramidite, but oxidizing with sulphur instead of iodine-water, a 3v-monothiophosphatewas introduced for further modification by alkylation. Tris(hexafluoroisopropy1) phosphite (105) has been used to prepare ribonucleoside H-phosphonates ( 106),62 and deoxyribonucleoside phosphites (107);63 both were used as monomers to prepare oligonucleoside H-phosphonates on a solid support, with N-methylimidazole as catalyst for the coupling of (107). Several new alkyl phosphorodiamidites (108)64 and (109)65 have been used

4: Trvvalent Phosphorus Acids MeO, PCI Pri,N'

+

c

105

0C16H33

HO

base

MeO,

L

OMMTr

Pri2N

OMMTr (99)

OMMTr

AlBN

OC1sH33

/'Io I

C1,H3[pNs

+

O m N H 3

0-

(98)

[Ru-complex]-0, NC\/\O' P-N Pri2

--

,0{0c16H33 c16H3[p\S OMMTr MeO,

106

Organophosphorus Chemistry

DMTrov DMTro <. ,oD M rT ___c

PY.

DMTrow x

o,

DM

((CF3)2CH0)2P

(107) X = H

o,\ o , x YP\

H

0-

-.Qb

(106)X = M e 0

MTro-Pbz

PY.

L

Me

DM

4: Tentalent Phosphorus Acids

107

as reagents for the preparation of deoxyribonucleoside phosphoramidites. Following oligonucleotide synthesis, the 4-pyridylethyl group of (108) could be removed more easily than the previously described 2-pyridylethyl group by phenyl chloroformate followed by aqueous ammonia, 64and substituted benzyl groups more easily than a methyl group by thiophenolate ions; in the case of (109, Ar = 2-methylphenyl), the group was cleanly removed during standard oxidation with iodine-water 6 5 Neutral H-phosphonate

.

diesters, e.g. (110), can not be activated by the usual condensing reagents, butthey are transformed in situ to very reactive phosphorochloridites, e . g . (lll), by the dichlorophosphorane (112) 66

.

Successful oligoribonucleotide syntheses have been reported using the phosphoramidites (113),67 (114),65 and (115);68 the preparation of a functional 77-mer tRNA-ana10gue~~ show that RNA synthesis has come of age, although problems with low coupling efficiencies and non-ideal protecting groups still exist. 6 5 # 6 8 A ribosylribitol phosphate hexamer has been assembled by solidphase synthesis using (116) as the monomeric phosphoramidite unit. 69 Several papers have appeared this year on the preparation of phosphate-modified deoxyribo-di- or oligonucleotides. Protected dinucleoside phosphorodithioates (117) have been prepared from thiophosphoramidites (118)70 or dinucleoside phosphoramidites (119)71 as shown, and (117) converted to a phosphoramidite (R = P (NPri2)OCH2CH2CN) and built into oligonucleotides at various positions. The phosphorodithioate linkage was shown to be highly resistant to nuclease cleavage, 71 a property important for the use of such modified oligonucleotides as antiviral agents. Thiophosphoramidites like (118) are new compounds which are easily made from the likewise new thiophosphorodiamidite (120).70 Another method has been published to prepare nucleoside thiophosphoramidites (121) which are more reactive than (118) due to smaller N-alkyl groups;72 the thioamidites (121) could be activated by tetrazole and used on a DNA synthesizer to prepare o1igodeoxyribonucleosi.de phosphorodithioates. Another group has

Organophosphorus Chemistry

108

MMTro-r/ DMTrO

0 OSiButMe2

0 0

NC-0-P:

MeO-P;

NPri2 (113)

FmocO

NC

OH

0

DMTro-vl / Py.H’BFi

DMTro

Y’

(117)

0‘

4: Ervalent Phosphorus Acids

109

DMTro-v DMTro DM R~SH

+

____t

CIP(NR'2)2 base_

OH

3

(121) NR'2 = NMe2, N

DMTav MMTro MMTrov NPri2

+

OH

CIP,

base

'SMe

(1 23)

-

; iii, air

SH

ii'

OAc

(124)

OH

OAC

Organophosphorus Chemisty

110

prepared a similar nucleoside thiophosphoramidite (122) using the new thiophosphoramidochloridite (123);73 only preliminary coupling experiments of (122) are described. Other reports on preparations of phosphate-modified nucleotides include the monothioates (124),74 and the amidates (125)75 and (126) 7 6 Alkylphosphonates were not obtained in useful amounts by alkylation of (127), 7 6 in contrast to the silyl dinucleoside

.

phosphites (128) which underwent the Arbuzov reaction to give alkylphosphonates (129) in good yields. 77 Some acyclic oligonucleotide analogues have been prepared by solid-phase syntheses using the phosphoramidites (130) 78

.

3.4 Miscellaneous.- New tervalent phosphorus acid derivatives which have been used for asymmetric catalysis reactions are (131),79 (132) and its enantiomer," and (133)

4 Reactions involving Two-co-ordinate Phosphorus

The new, thermally stable 1-phosphadiene (134) has been prepared as shown, using a deficiency of DBU;82 with excess DBU a mixture

of (134) and (135) is obtained. Phosphonio-phospha-alkenes (136) has been prepared by elimination of an amino group of (137) by treatment with Lewis acids. 83 Iminophosphines (138) and the phospha-alkyne (139) gave diphosphirenes (140) which rearranged at higher temperatures to the azadiphosphetines (141) 84 The same phospha-alkyne (139) and tetrazines (142) gave the 1,2,3-azadiphospholes (143);85 a plausible multistep mechanism for this

.

unusual reaction is proposed. Amino-iminophosphines have been known for more than a decade and have always been isolated as the t r a n s isomers. The first example of a cis amino-iminophosphine, (144), has now been isolated;86 (144) does not isomerize when heated or exposed to W irradiation! New, thermally stable heteroatom substituted iminophosphines include the aryloxy-iminophosphinese .g. (145) ,87 and

4: Tentalent Phosphorus Acids

111

DMTrov DMTro (126) OAc ButMe2Si0

9 R1M e 2 S i d p - ' T T OSiButMe2

(128)R' = Me, But

OSiButMe2 (129) R2 = Me, allyl, D M T r , C I n C O

::j

DMTrO

-0

9 M e 0d

R

R (1 34) R = Me3Si

+

-/

R

Ph3P-C,

P(NPri2)2 (137)

(136) R = H, CH3

Organophosphorus Chemistry

112

R'\

+

P=N,

-30 '2

Bu'CEP

R2

(138) R' = But, Et3C

R,'

4NR2 P

R,'

$P But

39)

R2 P-N'

-c5--

)==$ But

(1 40)

(141)

R~ = BU', mesityt COOR 4 Bu'CEP

+

N A N COOR

(139)

rft

-

"N

COOR

I

fr

But

(142)

(143) N=P,

+

Ct2PNMe2

D

@

NMe2

SiMe,

+q =p?

(145)Ar=

-Ar

(148) X = SBU' (149) X = PBu'~

Me

4: Tervulmt Phosphorus Acids

113

.

.

halo-iminophosphines, e g. ( 146) 88 Both have large C-N=P angles, and short N=P and long P-X bonds, and (146) gave with aluminium trichloride smoothly the iminophosphenium ion (147), a phosphorus analogue of a diazonium ion.88 The weak P-0 bond in aryloxyiminophosphines is disclosed by facile substitution reactions, e.g. the formation of the new P-thio- and phosphino-iminophosphines (148) and (149) from (150).89 A phosphenium ion with one pentamethylcyclopentadienyl substituent, (151), has been isolated for the first time, and its structure studied by z-ray diffractometry; the cyclopentadienyl group is q2 bonded to phosphorus, with equal P-C distances to two ring carbon atoms. Reactions of (151) with a variety of bases showed it to have both Lewis acid and Brmsted acid proper tie^.^' The first examples of a dithiaphospholium ion, (152), have been prepared and characteri~ed;~’the planar cation is thermally stable, but very air-sensitive. A cyclic aminodiphosphene, the 1,2,3-azadiphosphole (153), has been prepared in low yield by pyrolysis OP bis(diisopropy1amino)phosphine. 92 Unlike dialkylaminodiphosphenes the monoalkylaminodiphosphenes (154) have the cis configuration when prepared in a standard way;93 upon heating, they decompose without giving the t r a n s isomer. The diphosphenes (155) and (156) have been used to obtain the new 1,3-diphospha-allene (157)94 and the 1,3-diphosphapropenes (158),” respectively. A full paper has appeared on the preparation of phosphoranylidene-, e.g. (159), or sulphuranylidene-phosphines, e.g. (160);96 the iminophosphine (161) was similarly obtained.

5

Miscellaneous Reactions

A photochemical Arbuzov rearrangement occurs on UV radiation of benzyl dialkyl phosphites, e . g . (162).97 The reaction has been shown to be largely intramolecular with retention at the migrating carbon,” and also retention at phosphorus,98 corre-

Organophosphorus Chemistry

114

(152)R = H, Me

(151)

(PriN)2PH

A

Pri”

3

cl\ RdIQ

/’

Me

,H

Et3N

R

-

N

L

(153)

(154) R = Bu‘, Et&,

adamantyl,

R

x2

C R

p:x‘C(SiMe3)3

P

.A /* \ (158) X = CI, Br (155) R =

(156) R = C(SiMe3),

SiMe, -P{ Li

G

115

4: Tervalent Phosphorus Acids

(

..-C..-SiMe3

-

+ -

=C -Si Me3

(

-

( P T $ N ) ~-C P -SiMe3

(167)

(Pri2N)2P SiMe3

x,

(Pri2N),Y=CH2 NMe2

R‘ (168)

R

(169) II

PR’, Ph2C,/ NCS

Ph2C=N-PR12

+

CS2

(170) R’ = Me, Ph

Ph2C:N=PR1

=[

S (171)

Organophosphorus Chemistry

116

sponding to a suprafacial 1,2-sigmatropic shift. N-Methyl-ptoluohydroxamic acid (163) and tervalent phosphorus acid chlorides, e.g. (164), gave the tervalent ester (165) at low temperatures; (165) rearranged upon warming to (166) and other products by a homolytic N-0 bond cleavage, as shown by CIDNP A full paper has appeared on the properties of experiments.” the thermally stable (167), which may be formulated as a phosphinocarbene or as one of the two multiple-bond structures shown.100 It reacts with e.g. dimethylamine to give an 1,2addition product (168), in accord with a multiple-bond structure; evidence for a carbene structure has now been obtained, e.g. (167) and alkenes gave the cyclopropanes (169).lo’ The alkylideneaminophosphine (170, R1

=

Me) with carbon disulphide gave a

precipitate, which was formulated as (171) since it gave (172) with dialkyl acetylenedicarboxylates. (171) rearranged slowly to (173) on standing; the latter was the only observable product for

R1 = ph.lo2

References 1. 2. 3. 4. 5.

6. 7. 8. 9. 10.

H. Seliger (ed.) , 1988, Nucleosides Nucleotides, 7, 551830. J. Gloede, 1988, 2. Chem., 28, 352-361. V. Roussis and D. F. Wiemer, 1989, J. org. Chem., 5 4 , 627. S. Juge and J. P. Genet, 1989, Tetrahedron Lett., 30, 2783. T. Kaukorat and R. Schmutzler, 1989, 2. Naturforsch., lib, 481. L. A . Lazukina and V. P. Kukhar, 1988, J. Gen. Chem. USSR, 58, 833. €3. Ku and D. Y. Oh, 1988, Tetrahedron Lett., 29, 4465. J. G. Dingwall, J. Ehrenfreund, and R. G. Hall, 1989, Tetrahedron, 4 5 , 3787. D. Dvorak, D. Saman, M. Budesinsky, and Z. Arnold, 1987, Coll. Czech. Chem. Commun., 52, 2926. H.-P. Niedermann, H.-L. Eckes, and H. Meier, 1989, Tetrahedron Lett., 30, 155.

4: Tervalerit Phosphorus Acids 11. 12. 13.

E. W. J. E. R. K. Chem. V. V. 57,

14.

117

Logusch, D. M. Walker, J. F. McDonald, G . C . Leo, and Franz, 1988, J. Org. Chem., 53, 4069. Bansal, K. Karaghiosoff, and A. Schmidpeter, 1988, Ber., 121, 2067. Moskva and V. Yu. Mavrin, 1987, J. Gen. Chem. USSR,

2492.

V. A. Al'fonsov, I. S. Nizamov, S . A. Katsyuba, E. S. Batyeva, and A. N. Pudovik, 1988, J. Gen. Chem. USSR, 5 8 , 1131.

15. 16.

I . S . Nizamov, V. A. Al'fonsov, E. S. Batyeva, and A. N. Pudovik, 1988, J. Den. Chem. USSR, 5 8 , 1314. 0 . G. Sinyashin, I. Yu. Gorshunov, R. Z. Musin, E. S. Batyeva, and A. N. Pudovik, 1988, J. Gen. Chem, USSR, 5 8 ,

2161.

24.

I. Ugi, P. Jacob, B. Landgraf, C. Rupp, P. Lemmen, and U. Verfiirth, 1988, Nucleosides Nucleotides, 7, 605. A. A. Prischenko, M. V. Livantsov, N. V. Boganova, and I. F. Lutsenko, 1988, J. Gen. Chem. USSR, 5 8 , 1721. A. Skowronska, R. Dembinski, R. Kaminski, and J. Michalski, 1988, J. Chem, SOC., Perkin Trans. I, 2197. P. T. Wood and J. D. Woollins, 1988, J, Chem. SOC., Chem. Commun., 1190. 0. I. Kolodiazhnyi, D. B. Golokhov, and I. Boldeskul, 1988, Tetrahedron Lett., 30, 2445; 0. I. Kolodiazhnyi and D. B. Golokhov, 1988, J. Gen. Chem. USSR, 5 8 , 2493. 0 . G . Sinyashin, I. Yu. Gorshunov, E. S. Batyeva, and A. N. Pudovik, 1988, J. Gen. Chem. USSR, 5 8 , 1310. M . M. Olmstead, P. P. Power, and G. A. Sigel, 1988, Inorg. Chem., 27, 2045. S. D. Stamatov and S . A. Ivanov, 1988, Phosphorus Sulfur,

25.

S. D. Stamatov and S. A. Ivanov, 1988, Phosphorus Sulfur,

26.

L. A . Hussain, A. J. Elias, and M. Tetrahedron Lett,, 29, 5983.

27.

D. Gudat, C. Lensink, H. Schmidt, S.-K. Xi, and J. G. Verkade, 1989, Phosphorus, Sulfur and Silicon, 41, 21.

17. 18. 19. 20. 21.

22. 23.

40,

167.

37, 213.

N.

S.

Rao, 1988,

118 28.

Organophosphorus Chemistry

Lensink, S.-K. Xi, L. M. Daniels, and J. G. Verkade, 111, 3478. A. D. Norman, E. G. Bent, R. C. Haltiwanger, and T. R. Prout, 1989, Phosphorus, Sulfur and Silicon, 41, 63. E. G. Bent, R. Schaeffer, R. C. Haltiwanger, and A. D. Norman, 1989, J. Organometal. Chem., 364, C25. S. S. Kumaravel, S . S. Krishnamurthy, T. S. Cameron, and A. Linden, 1988, Inorg. Chem., 27, 4546. S. D. Pastor, J. L. Hyun, P. A. Odorisio, and R. K. Rodebaugh, 1988, J. Am. Chem. SOC., 110, 6547. M. Schopferer, G. Schmitt, H. Pritzkow, and H. P. Latscha, 1988, 2. Anorg. Allgem. Chem., 564, 121. T. Kh. Gazizov, L. N. Usmanova, and A. N. Pudovik, 1988, J. Gen. Chem. USSR, 58, 2171. J. R. Bleeke, A. J. Donaldson, and W.-J. Peng, 1988, organometallics, 7 , 33. M. Fild and M. Vahldiek, 1988, Phosphorus Sulfur, 40, 207. M. Fild, D. Bunke, and D. Schomburg, 1988, 2. Anorg. Allgem. Chem., 566, 90. S. Holand and F. Mathey, 1988, Organometallics, 7, 1796. Z. S. Novikova, M. M. Kabachnik, and I. F. Lutsenko, 1988, J. Gen. Chem. USSR, 58, 1809. E. Fluck and P. Kuhm, 1989, Phosphorus, Sulfur and SiliCon, 42, 123. E. Fluck, P. Kuhm, and H. Riffel, 1988, 2. Natuforsch., 43b, 1481. V. A. Al'fonsov, D. A . Pudovik, R . Z . Musin, V. N. Nazmutdinova, Yu. Ya. Efremov, E. S. Batyeva, and A. N. Pudovik, 1988, J. Gen. Chem. USSR, 58, 1548. V. A. Al'fonsov, D. A. Pudovik, E. S. Batyeva, and A. N. Pudovik, 1988, J. Gen. Chem. USSR, 58, 1554. G. Baccolini, E. Mezzina, and P. E. Todesco, 1989, Phosphorus, Sulfur and Silicon, 42, 37. T. Kh. Gazizov, L. K. Sal'keeva, E. K. Gafurov, and A. V. Kazantsev, 1988, J. Gen. Chem. USSR, 58, 1028. S. Berner, K. Muhlegger, and H. Seliger, 1989, Nucleic Acids Res., 17, 853. C.

1989, J. Am. Chem. SOC.,

29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.

41. 42.

43. 44. 45. 46.

119

I: EvvulLwt Phosphorus Acids 47. 48.

49.

E. E. Nifant'ev, M. M. Grachev, S . Yu. Burmistrov, and L. K. Basyanina, 1988, J. Gen. Chem. USSR, 5 8 , 895. A. A. Korkin and E. N. Tsvetkov, 1988, Bull. SOC. Chim. Fr., 335; A. A. Korkin, A. M. Mebell, and E. N. Tvetkov, 1988, J. Gen. Chem. USSR, 58, 900. S. F. Martin and J. A. Josey, 1988, Tetrahedron Lett., 29, 3631.

50.

C. E. Dreef, C. J. J. Elie, P. Hoogerhout, G. A. van der Marel, and J. H. van Boom, 1988, Tetrahedron Lett., 29,

51.

C. J. J. Elie, C. E. Dreef, R. Verduym, G. A. van der Marel,

52.

and J. H. van Boom, 1989, Tetrahedron, 4 5 , 3477. E. Kuyl-Yeheskiely, C. M. Tromp, A. W. M. Lefeber, G. A. van der Marel, and J. H. van Boom, 1988, Tetrahedron, 4 4 ,

6513.

6515.

56.

M. S. Anson and C. McGuigan, 1989, J. Chem. SOC., Perkin Trans. 1, 715. B. Shadid, H. C. van der Plas, C. R. Vonk, E. Davelaar, and S. A. Ribot, 1989, Tetrahedron, 4 5 , 3889. J. Ludwig and F. Eckstein, 1989, J. Org. Chem., 5 4 , 631. W. Yuan, K. Fearon, and M. H. Gelb, 1989, J. org. Chem.,

57.

U. Pieles and U. Englisch, 1989, Nucleic Acids Res.,

53. 54 55.

54,

906. 17,

285. 58.

A. M. Alves, D. Holland, and M. D. Edge, 1989, Tetrahedron

59.

W. Bannwarth and D. Schmidt, 1989, Tetrahedron Lett.,

Lett.,

30, 3089. 30,

1513.

61.

N. T. Thuong and M. Chassignol, 1988, Tetrahedron Lett., 29, 5905. U. Asseline and N. T. Thuong, 1989, Tetrahedron Lett., 30,

62.

0. Sakatsume, M. Ohtsuki, H. Takaku, and C. B. Reese, 1989,

60.

2521.

Nucleic Acids Res., 63.

17, 3689.

T. Watanabe, H. Sato, and H. Takaku, 1989, J. Am. Chem. aoc.,

111, 3437.

Organophosphorus Chemistty

120 64.

S.

Hamarnoto, Y . S h i S h i d o , M . F u r u t a , H . T a k a k u , M . Kawashima,

and M. Takaki,

65.

66. 67. 68. 69.

70. 71. 72. 73. 74. 75.

1989,

Nucleosides, Nucleotides,

8, 317.

M. H. Caruthers, R. Kierzek, and J. Y. Tang, in K. S. Bruzik and W. J. Stec (eds), Biophosphates and Their Analogues Synthesis, Structure, Metabolism and Activity, Elsevier, Amsterdam 1987, 3. T. Wada, H. Hotoda, M. Sekine, and T. Hata, 1988, Tetrahedron Lett., 29, 4143. K. K. Ogilvie, N. Usman, K. Nicoghosian, and R. J. Cedergren, 1988, Proc. Natl. Acad. Sci. USA, 85, 5764. C. Lehmann, Y.-2. Xu, C. Christodoulou, 2.-K. Tan, and M. J. Gait, 1989, Nucleic Acids Res., 17, 2379. C. J. J. Elie, H. J. Muntendam, H. van der Elst, G. A . van der Marel, P. Hoogerbout, and J. H. van Boom, 1989, Recl. Trav. Chim. Pays-Bas, 108, 219. W. K.-D. Brill, J. Nielsen, and M. H. Caruthers, 1988, Tetrahedron Lett., 29, 5517. A. Grandas, W. S. Marshall, J. Nielsen, and M. H. Caruthers, 1989, Tetrahedron Lett., 30, 543. W. K.-D. Brill, J.-Y. Tang, Y.-X. Ma, and M. H. Caruthers, 1989, J. Am. Chem. SOC., 111, 2321. N. Farschtschi and D. G. Gorenstein, 1988, Tetrahedron Lett., 29, 6843. R. Cosstick and J. S. Vyle, 1988, if. Chem. SOC., Chem. commun., 992. T. Shimidzu, H. Ozaki, S. Yamoto, S. Maikuma, K. Honda, and K. Yamana, 1988, Nucleic Acids Res., Symposium Series, 19,

-

1.

76. 77.

78.

J. Nielsen and M. H. Caruthers, 1988, J. Am. Chem. SOC.,

110, 6275. E. de Vroom, C . E. Dreef, H. van den Elst, G. A . van der Marel, and J. H. van Boom, 1988, Recl. Trav. Chim. PaysBas, 107, 592. N. Usman, C. D. Juby, and K. K. Ogilvie, 1988, Tetrahedron Lett., 29, 4831.

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H. Arzoumanian, G. Buono, M. Choukrad, and J.-F.

Petrig-

nani,1988, Organometallics, 7, 59. 80. 81. 82. 83. 84. 85. 86.

87.

88. 89. 90. 91.

C. Dobler, H.-J. Kreuzfeld, and H. Pracejus, 1988, J. Organometal. Chem. 344, 89. M. Yamashita, M. Naoi, H. Imoto, and T. Oshikama, 1989, Bull. Chem. SOC. Japan, 62, 942. B. A . Boyd, R. J. Thoma, W. H. Watson, and R. H. Neilson, 1988, Organometallics, 7, 572. H. Grutzmacher and H. Pritzkow, 1989, Angew. Chem., Int. Ed. Engl., 28, 740. E. Niecke and D. Barion, 1989, Tetrahedron Lett., 30, 459. G. Markl, S. Dietl, M. L. Ziegler, and B. Nuber, 1988, Tetrahedron Lett., 29, 5867. V. D. Romanenko, A. V. Ruban, A. N. Chernega, M. I. Povolotskii, M. Yu. Antipin, Yu. T. Struchkov, and L. N. Markovskii, 1988, J. Gen. Chem. USSR, 58, 842. L. N. Markovskii, V. D. Romanenko, A . V. Ruban, A . B. Drapailo, A. N. Chernega, M. Yu. Antipin, and Yu. T. Struchkov, 1988, J. Gen, Chem. USSR, 58, 255;V. D. Romanenko, A . V. Ruban, A. B. Drapailo, M. I. Povolotskii, and L. N. Markovskii, 1987, J. Gen. Chem. U S S R , 57, 206. E. Niecke, M. Nieger, and F. Reichert, 1988, Angew. Chem., Int. Ed. Engl., 27, 1715. V. D. Romanenko, A. V. Ruban, A. N. Chernega, and L. N. Markovskii, 1988, J. Gen. Chem. USSR, 58, 2494. D. Gudat, M. Nieger, and E. Niecke, 1989, J. Chem. SOC., Dalton Trans., 693. N. Burford, B. W. Royan, A. Linden, and T. S. Cameron, 1989, Inorg, Chem., 28, 144; 1988, J. Chem. SOC., Chem. comun., 842.

92.

W. Guth, T. Busch, W. W. Schoeller, E. Niecke, B. Krebs, M. Dartmann, and P. Rademacher, 1989, New. J. Chem., 13,

93.

E. Niecke, B. Kramer, and M. Nieger, 1989, Angew. Chem., Int. Ed. Engl., 28, 215. M. Yoshifuji, S. Sasaki, T. Niitsu, and N. Inamoto, 1989, Tetrahedron Lett., 30, 187.

309.

94.

122 94.

Organophosphorus Chemistry M. Yoshifuji, S. Sasaki, T. Niitsu, and N. Inamoto, 1989, T e t r a h e d r o n L e t t . , 30, 187.

M. Gouygou, J. Bellan, J. Escudie, C. Couret, A. Dubourg, J . - P . Declerq, and M. Koenig, 1989, J. Chem. Soc.8 Chem. Commun., 593. 96. F. Zurmuhlen and M. Regitz, 1989, New J. C h e m . , 1 3 , 335. 97. J. Omelanzcuk, A. E. Sopchik, S.-G. Lee, K. Akutagawa, S. M. Cairns, and W. G. Bentrude, 1988, J. Am. Chem. S O C . , 1 1 0 , 6908. 98. S. M. Cairns and W. G. Bentrude, 1989, T e t r a h e d r o n L e t t . , 30, 1025. 99. M. R. Banks and R. F. Hudson, 1989, J. Chem. 8 0 C . 8 Perkin T r a n s . 11, 463. 100. A. Igau, H. Grutzmacher, A. Baceiredo, and G. Bertrand, 1988, J. Am. Chem. 8Oc. 110, 6463. 101. A . Igau, A. Baceiredo, G. Trinquier, and G. Bertrand, 1989, Angew. C h e m . , Int. E d . E n g l . , 2a8 621. 102. M. Fulde, W. Ried, and J. W. Bats, 1989, H e l v . C h i m . A c t a , 7 2 , 139. 95.

5

Quinquevalent Phosphorus Acids BY R. S. EDMUNDSON

The year has seen an increase in reported results with an emphasis on the synthesis of phosphonic and phosphinic acid derivatives, ana on the synthesis of inositol phosphates. Some topics relevant to the present Chapter are described in general reviews dealing with the reactions of organophosphorus compounds with quinones , the syntnesis of phosphorus-containing macrocyclic compounds and their ability to form complexes, and the surface cnemistry of organophosphorus compounas. 3 1.Phosphoric Acids and their Derivatives.

1.1 Synthesis of Phosphoric Acids and their Derivatives.-New approaches c o the preparation of dialkyl phosphorofluoridaces include the treatmenc of a vinyl phosphace, e.g.,(l), or an irninophosphate, e.g.,(2), with triethylamine tris(hydrogen fluoride); 4 when the alkyl group consists of a suitably protected nucleoside, the reaction between mono(crimethylsilyl1 phosphite in pyridine and sulphuryl chloride fluoride at -30" has been successfully explored. Dibenzyl phosphorofluoridate, hitherto unreported, has been obtained from tecrabenzyl diphosphate and caesium fluoride, anci also from the reaction beiween dibenzyl hydrogen phosphace and 2-fluoro-N-methylpyridinium cosylate.6 Polyfluoroalkyl phosphorodichloridates and bis(po1yfluoroalkyl) pnosphorochloridates have been prepared from Lhe corresponding alcohols. The reactions between polychloro-1nitrosoethanes and phosphorus(II1) chlorides have provided the phosphoryl chlorides ( 3 ) and ( 4 ) whilst the same procedure Other mixed using izriethyl phosphite leads to the esters ( 5 ) trialkyl phosphates are obtained when mixtures of dialkyl phosphites and alcohols under oxygen are treated with copper(i1) chloride.9 The formation of phosphate esters from amine-catalyzed reactions between dialkyl phosphites and ketones often accompanies the expected production of (a-hydroxyalky1)phosphonic acid escers (see Section 2.1). 'It is a l s o known that under

.'

Organophosph oms Chemistry

124

0

0

II ( Et 0 12 POX

R’

=CCL 2

II

>PON=CR3Cl R2 R 3 = Me, CH,Cl, or CHC12

(1) X

= CH

( 3 ) R’ = alkoxy. R 2 = C l

(2) X = N

( 4 ) R’ = R 2 = C l (51

0

II

ArCRf

+

(RO),P(O)H

-

R’ = R2 = alkoxy

-

0

II

(RO),POCHArR,

(6)

(7)

R’ 0, ,POSiMe,

[ ysi i 3

(CF3) 2 C 0

R ’ O ‘P-C(CF,), R20’+

OSiMe, (11 1

(8)

\

/ \

F3c

(13)

5: Quinquevalent Phosphorus Acids

125

conditions of basic catalysis, (a-hydroxyalky1)phosphonic acid esters may rearrange to esters of phosphoric acid. Thus, aryl perfluoroalkyl (or pentafluorophenyl) ketones afford the phosphates ( 7 1 , presumably by way of the initial phosphonate (6);this reaction does not occur with alkyl perfluoroalkyl ketones, nor with acetophenone," but ic has been noted that alkyl (or phenyl) chlorodifluoromethyl ketones and dialkyl (or diaryl) phosphites in the presence of triethylamine in boiling THF yield dialkyl (or diaryl) 2,2-difluoroethenyl phosphates: at lower temperatures, che expec-ced (a-hydroxyalky1)phosphonic dialkyl (or diphenyl) esters are formed." The phosphonatephosphace rearrangement has been observed also in the conversion of (a-hydroxyalkyl)bis(phosphonic diesters) into mixed phosphonicphosphoric esters (see Section Z.l.(e) 1 . Dialkyl trimethylsilyl phosphites and perfluoroacetone react together t o yield one, or more, of the products ( 9 1 , (10) (2 the intermediate ( 8 ) 1 , and either (12) or ( 1 3 ) produced through the isomerized intermediate (11). The relative proportions of acyclic phospiionic ester, 1,2,4- and 1,3,2-dioxaphospholanes appear to depend on the nature of the groups R1 and R2; in the examples examined these were normally alkyl groups, but other examples included trimethylsilyl, and the system OR 1-R 20 may also be cyclic.12 Other phosphate esters in the 1,3,2-dioxaphospholane series have been obtained from hydrospirophosphoranes and ai-t-butyl peroxide .I3 The addition of dihalogenocarbenes co dialkyl 1-arylalkenyl phosphaces occurs under phase transfer conditions when the products are dialkyl l-aryl-2,2-ditialogenocyclopropyl phosphares (14).14 The phosphorylation of a , 6 or 6,y-unsaturaced ketones (as carbanions obtained through the use of lithium tetramethylpiperidide) with dialkyl or diaryl phosphorochloridates affords conjugaced dienol phosphates substituted at either of positions 1 and 2;an example is che conversion of (15) into (16).15 Diphosphoric acid tetraesters incorporating two allylic ester groups e.g.,(17; R 2 = H or Me) as well as the homoallylic compounds (18) have been prepared by essentially conventional means as indicated. Such aiallyl esters are rather unstable (those with R 1= M e are not isolable) but an increase in stability is achieved with larger R1 groups(the dipropyl esters are isolable although thermally unscable). A l s o described in the same communication are the monoallyl aiphosphates (19).1 6

Organophosphorus Chemistry

126

0 II

Q -0

OP(OR1,

X

X

0

II R’OPCL,

R2

w

+ 1

R2

-w

0 II 0-PCl

v

OH

HCO 3-

I

OR’

0

0- P-

R2

0

II

II

I

0-

I

R’O

R2

P-0

-

\

OR’ (171

0 II

0

0 II

R2

A r C =O

I

,

I

R’O

OR’

(191

(18 1

I

11

0-PP-0-PP-OR

w

OR’

ArC=O

0

ii

2 Na

ArC-6No

T HF

A t C-

II -

:)

ON0

(20)

Mee R’

Me

0

0

>P’ X’ ‘RZ ( 2 11

Me

127

5: Quinyuevulent Phosphorus Acids

Several 4,5-diaryl-l,3,2--dioxaphospholes(20; K=Lt or Ph 1 have been prepared by che direct phosphorylacion of benzil uianions; mild hydrolysis of the initial ester products yields che corresponding free cyclic acids (20; R=H) l 7 3-Hydroxypyridine y the aihyarogen pnosphates are obtainable from che pyridinol & aiechyl and bis(trimechylsily1) esters. 18 Ocher cyclic esters based on phenolic systems which have recenily been prepared, mostly for structural studies, include 2 1 several 6-R -2,4,8,10-~etramethy1-12-K -12H-dibenzo[d,g][l,3,2]2 dioxaphosphocins (21: X = O , K =0-alkyl) and their dithio analogues 2 ( 2 1 ; X=S, R =S-alkyl )I9'"and also dinaphtho analogues. 21 Phosphorylation (POC13-Ec3N) of 2,2',2"-nitrilotriphenol provides ( 22),22 and the sequential treatment of the appropriate bromophenol with bucyllichium, PC1 and P0Cl3, affords the related phosphine-phosphates ( 23 1 . 3 i 3 The cyclic 1,l '-bi-2,2 I naphchyl hydrogen phosphate has been resolved using 2-amino-124 (4-nitrophenyl)-1,3-propanediol. The first known alkynol dialkyl phosphates ( 2 5 ; R 1= 2 alkyl, K =alkyl or benzyl) have been described. Three procedures were employed (Scheme 1) to prepare the intermediace (24) which was then decomposed on slight warming or ac room temperacure; che stabilicies of the intermediates (24) lie between those of the analogous arenesulphonaces (stable) and carboxylates (unstable).25 There has been a continuing high level of activity directed towards the synthesis of phosphates and thiophosphates derived from G - i n o s i t o l . Phosphorylation (P0Cl3 or PSC13, has yielded, pyridine) of l&-1,2,4,5,6-penta-~-acecyl-myo-inositol afcer aeprotection with methanolic-ammonia, che 1-(dihydrogen phosphate) and its chiophosphate analogue;26 the 1- and 2-monophosphates, and tne 1,2-cyclophosphate have been prepared by a 27 cranz-phosphoranylation procedure using compound (26). -L - 1 , Z - v Pure stereoisomeric forms (28 a,b) of D inosiiol cyclochiophosphate have been obtained, initially as tetra-0-acetaces or tecrabenzyl ethers ( 2 7 a,b; R=Ac or Bn"c), by direct phosphorylation ( P S C 1 3 , pyridine) followed by hydrolysis and deproteccion. 2g Further syntheses of the 1,2-~yclothiophosphate have involved the reactions outlined in Schemes 2 and 3 . The

.

;t

Throughout this chapter, Bn Bz = benzoyl

=

benzyl, All

=

ally1

128

Organophosphorus Chemistry

R

+

RIC,CH

I PhSOP(ORZ),

R

II

1

CECfPh (26)

0 R'C=CiPh

6,P(OR2),

TsO

0 R'C=

ii

COP(OR21,

Reagents: i, BF3. ( R Z O 1 2 P 0 2 - ; ii, CH2ClZ; iii. Resin- 02P(OR212

Scheme 1

( 2 7 a.b; R = H I

RO

OR R = Bn or Ac

OR

( 2 7 ) ( a ) A = 0-,8 = = S (b) A

= =S,

B = 0-

129

5: Quinquevalent Phosphorus Acids

(291

li

( 3 0 1 (29; X = P(OMe)NPriP)

Reagents: i. C l P ( O M e ) N P r ' 2 . Et,N,

CH2C12; ii. ( a ) 1.2-dipalmitoyl-sn-glycerol, 1

t e t r a z o l e . T H F - MeCN (b) GS,.

( b l NMe,.

toluene; iii. ( a ) 80% HOAc. 100°C.

toluene, room temp. ; i v . bee venom phospholipase A 2 ;

v , phosphatidylinositide - s p e c i f i c phospholipase C

Scheme

2

Organophosphorns Chemistry

130

0R' I

+

(360)

____)

(35; R ' = P(OMelNPri2.

(35; R ' = H , OBn

0 R2= H 1

RZ= P( OMe)NPri2 1

( 3 5 ) ( R ' = R2= H I

0-P---B

BnOI

.OBn

iii

+

(380 1

(37a: A = =Sl

(38bl (37b; B =

=Sl

OBn iv

A

OH

(39) (a) A = S, B = 0

(bl A=O, B = S Reagents: i . C l P ( O M e ) N P r ' 2 . Pr',NEt. iii. '/eS8, toluene

;

CH,CI,;

i i . 1,

M tetrazole, THF-MeCN;

iv, LO equiv. L i . THF- NH3. -78OC

Scheme 3

5: Quinquevalent Phosphorus Acids

131

D-biscyclohexylidene derivative (29; X=H), obtained by procedures involving a resolution step, was converted into the (RP+SP mixture (32) by the use of a phosphitylating agent (to give (31) 1 and deprotection. Treatment of the mixture (32) with bee-venom phospholipase A 2 removed one palmitoyl group to give (Sp)-(33), leaving the ( R p ) form of (32) unchanged; the alternative treatment of mixture (32) with phosphariaylinositiaes-specific pnospholipase C left (Sp)-(32) untouched, but converted the ( R p ) form into the cyclothiophosphate (Rp)-(34). In the second approach (Scheme 31, (DL)-(35) was phosphicylated to mixture (36 a,b) in situ, and cyclized to mixture (37 a,b: X=l.p.), and che cyclic phosphites converted into che cyclic 2-methyl thiophosphates (38 a,b). Final demethylation led to the mixed 29 stereoisomeric cyclothiophosphates (39 a,b). The 4,5-bis[di(benzyloxy)phosphinyl]-myo-inositol derivative (40) is the key intermediate in syntheses of the 1,2-cyclic hydrogen phosphate-4,5-bis(dihydrogen phosphate) (411, and che 1,4,5- and 2,4,5-tris(dihydrogen phosphatels (42) and (43) respectively. p-(40) was prepared through a multi-stage sequence from che resolved (44; R1=COCH20Menthyl, R 2=H, R 3=Allyl) involving benzoylation, deallylation, acidolysis, and phosphorylation of che resulcanc diol with butyllithium and tetrabenzyl diphosphate followed by ammonolysis. Phosphorylation of (40) with N-mechylpyridinium phosphorodichloriaate and subsequent hydrogenolysis gave the cyclophosphate (41). Sequential silylation, benzoylation, and desilylation of racemic (40) gave (44; R 1=H, K 2=Bz, R3= (Bn0)2P(0) 1 ; further pnosphorylation (PC13), alcoholysis (BnGH), and oxidacion (t-BuOOH) afforded (44; R1=-P03H2,R 2=Bz, K 3=(Bn0I2P(O) 1 . Finally, hydrogenolysis and ammonolysis gave the 1,4,5-tris(dinydrogen phosphace) (42). From (44; R 1=Et3Si, R2=H, R3=(BnG)2P(0) 1 , phosphorylation, hydrogenolysis, and ammonolysis led to the 2,4,5-tris(dihydrogen phosphate) (43).30 Syntheses of opcically active forms of myo-inositol1,4,5-tris(dinydrogen phosphate) are outlined in Schemes 4 and 5. In ?he first of these two sequences, the starting material was (+)-1,2:5,6-di-~-cyclohexylidene-myo-inositol (45). Acecylation and aciaolysis of the monobenzyl ether (46) gave (+)-(48),% (471, which was phosphorylated, hydrogenolysed, and acidolysed.31 The other sequence commenced with ( + 1 - ( 50 1 and proceeded via its dibenzyl ether (51) to give (52; R=H); this was

132

Organophosphorus Chemistry

B n 0QOH

HOQOf?’

B

n

oOR2 q

I

I

0

II

OBn

(BnO),PO’#

H~O~PO**

0 P(OBn12

R3

*\OH

~ 0 -

OR^

OPV2

II 0

( 4 1 1 R’-”

R 2 = P(O1OH 2

1

( 4 2 1 R = P03H2, R = H

(431 R’= H . R 2 = P0,H2

(40)

(46)

ii

( 4 5 ; R 1 = H, R 2 = B n )

1

(441

(471

(45; R ’ = Ac, R 2 = Bn)

2

(45) R = R = H

(49)

vi, vii

( 4 21

( 4 8 ; R = (0)P(OBn)2)

R 0’ OR (481 R = H

Reagents: i , Bu,SnO. BnBr, CsF; ii, Ac,O,

DMAP ; iii. TsOH, CH2CL2;

i v . 1 M KOH- MeOH; v , (Bn012 PNPrI2. tetratole, MCPBA; v i . H,.

Pd/C.

EtOH aq.; v i i . HOAc Scheme 4

5: Quinquevalent Phosphorus Acids

133

R20-cy..n -

OAllyl

(50; R'= R 2 = Bn1

OBn

A1Iy 10'.

ii

(511

RO' OR

1

(501 R = R2= H

(521 R = H

-

iii

iv

(42) Reagents: i , BnBr, NaH.

Bu'OOH;

iv,

( 5 2 ; R = (BnOI,P(Ol)

ii, Pd(O), TsOH, MeOH aq.

DMF; H,

PdK.

I

1

;

iii, (Bn01,PNEt2,

EtOH.

Scheme 5

-

ii

(541

OBn

(53;R = (OIP(OR'1,1

0'

0 "

OH

(531 R = H iii

I

iv 1

II OP(X 1 (OH12

x

OP(X1 (OR'1'

= 0

(551 ( X = 0, R = B n l

(58) X = S

(561 ( X = S, R = Bn1

(571

Reagents: i, ( a ) (R'Ol,P(OICL,

Py. ( b 1 H30+; ii, (R'O),P(O)Cl,

( c l But OOH or '/8S8; R' = CI,CCH2-;

Py., CH'Cl,;

EtNPri2, MeCN ( b l R20H. tetrazole, MeCN;

iii.(a1 ClP(OR21NPri2,

iv. N a - NH3( I1

R2=

NCCH2CHzScheme

6

134

Organophosphorus Chetnistiy

phosphorylated t o (52; R=(Bn0)2P(0) 1 and subsequently deprotected. Scheme 6 outlines a synthesis of the novel 9 - i n o s i t o l lY4-bis(dihydrogen phosphate)-5-dihydrogen phosphorothioate in racemic torm. 33 Two syntheses of the 1,3,4,5-tetrakis(dihydrogen phosphate), in optically active forms, have been documented. In che first,(Scheme 71, the starting point was (50; R 1=R 2=HI and ally1 groups were used extensively for protection purposes. 32 In che second synchesis, _U and L-myo-inositol-2,4-dibenzyl ethers were boch phosphicylated with (in012PNPri2-tetrazole; subsequent oxidation with MCPBA and hydrogenolysis afforded the desired tetraphosphate (61).34 Both tne novel phosphitylating agent, 3-diethylamino1,5-dihydrobenzo-2,4,3-dioxaphosphepin (621, and the novel procection agent, 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (63; = TIPSC1) were employed in a recently described synthesis (outlined in Scheme 8 ) of the symmetrical ~ - i n o s i t o l - 1 , 3 , 4 , 6 cetrakis(dihydr0gen phosphate) (68). The monosilylated compound was a source of both the 4- and 5-mono(dihydrogen phosphatels. 35 Chromatographically separable mixtures of 0- and S-alkyl triesters are produced from reactions between dialkyl hydrogen phosrhorothioates and alcohols in the presence of diechyl azodicarboxylate. 36 e-Alkylchloroformimino ( 69 1 and 0-(dialkylformimino) (70) ~ , ~ - d i a l k yphosphorothioates l are the products from the reactions between dialkyl hydrogen phosphorothiosces and 1-chloro-1-ni trosoalkanes. 37 38 Some transformations based on salicylaldehyde (Scheme 9 ) have been studied in connection with the scereochemistry of salichion (72; K=OMe). The configurations of aiastereoisomers of boch (72; K=OIvie or EL) and (73; R = C 1 or OMe) were assigned on che basis of spectroscopic and crystallographic evidence. 39 The aadition of dialkyl hydrogen phosphorodithioates to fully protected lY2-unsaturated pyranoses affords S-(2-deoxyglycosyl) phosphorodithioates in high yields. The stereoisomeric product ratio is generally in favour of the a isomer, e.g., 3,4,6-tri-~-acetyl-~-glucal (74) yields (75; R=Me or CH2CMe3, or R2=CH2CMe2CH2). The reverse reaction,i.e., elimination of the phosphorodithioate moiety from compounds such as (751, is achieved by the use of mercury(I1) cyanide or K2C03 in acetonitrile-benzene. 40 The useful direct conversion of dialkyl phosphorodithioic acids into their anhydrosulphides i s possible

32

5: Quinquevalent Phosphorus Acids

-

AI Iyi 0

i, ii

(501 R1= R 2 = H

09 135

9

Al I yl Oe#

0At L y i

...

____) Ill

R

R0’.

*OBn

OAllyI

OR (59 1

Reagents: i, ( a 1 Bu2Sn0. MeOH, heat ( b ) AlBr, Bu4N+Br-. PhMe, heat;

i i . NaH, BnBr, DMF; iii, Pd/C. ( b 1 Bu‘OOH;

TsOH, MeOH aq.; iv. ( a ) ( B n 0 I 2 P N E t 2

H2. Pd/C

V.

Scheme 7

K

>

P

-

N Et

( 6 2 1 B D P - NEt 2

(631

OR’

OH

OH iii

( 6 4 1 R’= H

I

I

4

OR’

(681

V 4

(66; R1= H, R2= PO,H,I

(671

4

(66;R’= Bz. RZ= BDP)

IV

R20+YoR R 2 o ~ * y *OR2 * 1

(66) R

2

Bz, R = H

Reagents: i. (631, Py.; i i . B z C I . Py.;iii, HF a q . , M e C N ; i v . (62). t h e n MCPBA; v. H., Pd/C, then NH3

Scheme 8

Organop hospho rus Chemistry

136

S

II

( R'O)ZP-O-N=CR~X

(691 X = C l

(70) X = a l k y l

(71 1 iii

1

R = CI

(731 Reagents: i , RP(S)CI,,

Py.; ii, NaBH4. H O - ; iii, KCN. aq.

Scheme 9 OAc

AcO OAc ( 76 1

II

(75 1 S

(RS),P=S

S

Ac 0

' 4 ' 1 0 180'C

b S , RSP, ,PSR

s II

(761

(801

S

+

S-PP(ORI2

S

S

II

II

( R S 12P-S-P

(771

(SR12

5: Quinquevalent Phosphorus Acids

137

by che treatment of salts of the acids with 2-chloro-!-methylpyridinium sa1ts;the reaction is equally applicable to phosphinodithioic acids. Under the same conditions, monothiophosphoric 41 acids undergo dehydration. The interaction of trialkyl or triaryl esters of phosphorotetrathioic acid with P4Sl0 at 180° leads to a scrambling of P-SP and P-SC bonds. The products consist of mixtures of 1,3,2,4-dithiadiphosphetane 2,4-disulphides (76) and the perthiodiphosphates (771, the former being formed in large excess. The same products are obtained in essentially the same ratios from P4Sl0 and the thiols RSH. In the case of alkane-a,wdichiols, the products are the dithiaphosphorinanes (78) and (791, both of which are isolable. This last reaction, during which che cyclic acids (80) appear not to be involved, proceeds well for n=2 or 3 , but poorly when n=4.42 Improved procedures for the preparation of symmecrical monothio- and monoselenodiphosphaces (83; X=S or Se) have been described. For the sulphur compounds, a dialkyl oxophosphoranesulphenyl chloride (81.; X=S , R 1=Et or CH2CMe3, orRL2=CH2CMe2CH21 in a solvent is made to react with a dialkyl trimethylsilyl phosphite (rather than a trialkyl phosphite).43 The selenium compounds (83; X=Se) can be prepared in an analogous manner,but for such compounds an even better procedure involves the chlorination 2-trimethylsilyl (S02C12) of a mixture of a Q-dialkyl phosphoroselenoate and dialkyl trimethylsilyl phosphite. The rapidity of these particular reactions compared to those of the sulphur-concaining compounds has led to the suggestion that diphosphonium incerrnediates might be involved, and for these the structure (84) was proposed. When warmed to 60° or above, the selenides (83;X=Se) isomerize to the unsymmetrical isomers.44 The symmetrical monoselenodiphosphates have also been prepared using dialkyl trimethylsilyl phosphites for che deselenation of diphosphoryl diselenides 45 An improved synthesis of dialkyl t h i o x a p h o s p h o r a n e s u l p h e n y l chlorides and bromides lies in the treatment of the sulphenylamides (R0l2P(S)SNR2 with a halogenocrimechylsilane followed by ethanol.46 The dithiophosphoric acid ( 8 5 ) has been resolved through its cinchonidine or cinchonine salts.47 It has been known for a considerable time thata 2-substituted-1,3,2-dioxaphosphorinane 2-sulphide isomerizes to the 2-substituted- lY3,2-oxathiaphosphorinane 2-oxide under the

.

Organophosphorus Chemistry

138

0 II (R'O1,PXCl

+

CHZCIZ

(

R20I2POSiMe3

(81 1

0 II

(R'O),P-X-~OR~

I OSi Me

(82)

1,

1

- Me3SiCI

1

c I-

( R ' O 1,P-X-P(OR21,

II

II

0

0

(

I

+'

SeC I

cI-]

( R'O),P,

1

(82)

I

X = Se

1R'01z6-Se-6(ORZ1z

I

OSi M e

OSiMe3

Se

II

( R'O

83 1

),POSi Me3 t SO,CL,

(851

I

OSiMe3

2CI-

5: Quinquevalent Phosphorus Acids

139

influence of triphenylphosphine or a tetraethylammonium salt, or to a 1,3,2-dioxaphosphorinane 2-oxide with an exocyclic P-S bond when Ehe catalyst is trifluoroacetic acid. The course of the isomerization catalyzed by phosphonium salts has now been shown to depend on the particular salt and also on the substituents on the phosphorus-containing ring; thus, (86;R=Me) is converted into (871, whereas (86;R=H) leads to ( 8 8 ).48 Endocyclic P-Se bond formation has been observed for 1,3,2-dioxaphosphorinane 2-selenides lacking ring substituents on carbon using b e n z y l t r i p h e n y l p h o s p h o n i u m bromide as catalyst.49 The combination of isomerization of (89; X , Y , or Z=O,S, or Se) by a phosphonium salt and ring opening by trimethylamine thus allows the synthesis of isomeric homocholine analogues from a single starting material (Scheme 10). The formation of dialkyl phosphoramidates from Crialkyl phosphites and b e n z o t h i a z o l - 2 y l s u l p h e n a m i d e s has been discussed. 50 (Diaryloxyphosphinyl1 phosphoramidic acids have been prepared by a short conventional sequence.51 A convenient one-poc synthesis of 1,3-dihydro-1,3,2-diazaphosphole 2-oxides (90) is based on the interaction of a trialkyl phosphite with a 2-nitrodiphenylamine.52 The rapid acid catalyzed hydrolysis of 2-alkoxy-1,3,2oxazaphospholidine 2-oxides (91) provides a route to phosphorylethanolamine derivatives (92);53 the related compounds (94) are similarly obtained from the lY3-dimethyl-1,3,2-diazaphospholidines (93).54 N-allylic phosphoramidates (95) isomerize to Diethyl diethyl 1-alkenylphosphoramidates when irradiated (uv) in the presence of Fe(CO)5; the (El-form of the product ( 9 6 ) is favoured and the yields are better than those obtained during alkylation reactions of: ( 9 7 ) to form (98) as indicated.55 3-Substituted-inaoles have been N-phosphorylated with dialkyl phosphorochloridates after initial metallation with lithium diisopropy1amide;che reverse dephosphorylation is brought about by tetrabutylammonium fluoride.56 N,O-Diprotected cryptophane has been phosphorylated and then deprotected to give N(1)-phosphotryptophane. 57 Several carbohydrate-based bicyclic and tricyclic phosphoramidates and phosphoramidochioates have been prepared in selected pure diastereoisomeric forms characterized structurally X-ray techniques. Such compounds include (99) derived from by -

Organophosphorus Chemistry

140

I

+

X-

4 A

Y

Y (89)

E

iii

O.COR

O

r

O.COR

t

P-Z(CH213NMe,

m

o.CoR 0.COR

rro.coR

0.COR

o.CoR

0.COR

X-

I + LX-P-Y(CH21JNMe3

4-

P-Z( CH 2)3NMe 4: Y

k-5

z

O

Reagents: i , Me3N; ii, RCOCI; iii, RiP'XScheme 10

o

141

5: Quinquevalent Phosphorus Acids

1

X = 0, R’= Me

(91) X = 0. R = Me

(92)

(93) X = NMe, R’= Me

( 9 4 ) X = NMe, R’= Me

Rf=

long chain alkyl o r alkenyl

(97)

( 98

1

0 4

TpQS 0’ “Et2

I ,!

PNEt S

199)

(1001

142

Organoph osph oms Chemi s t y

mannitol ,” together with others of a similar nature from g a l a c t i L 0 1 ~and ~ sucrose.6 0 The phosphoramidates (100;X=Br or C1, NR2=pip or morph 1 have been obtained by stereospecific methods from bis (tricyclic 1 phosphorus (1111 esters. Tne macrocyclic compounds (101) have been prepared from the dihydrazides RP(Y)(NMeNH2j2 and the dialdehydes OHC-X-CHO (examples of the X moiety are illustrated). These compounds appear to be remarkably stable to acids and, in those cases where Y=S, their treatment with tributylphosphine fails to bring about desulphurization. 62

1.2 Reactions of Phosphoric Acids and their Derivatives.The hydrolyses of sodium di-4-nitrophenyl phosphate and lithium ethyl 4-nicrophenyl phosphate at pH 5.8-8.3 and 75” are catalyzed by Cu(bpyI2+ by factors of 2000 and 150,63 but much greater catalytic effects by metal ions are to be seen in the hydrolysis of 2-(1,10-phenanthryl) dihydrogen phosphate in aqueous solution by divalent mecal cations, the maximum effect being seen wich copper(I1) when the hydrolysis is faster than that of phenyl phosphate and 3-nitrophenyl phospnate dianions by factors of l o 6 and 6 x lo4 respectively. 64 The synthesis and hydrolysis of several 1-phospha[ZY6,7]bicyclooctane 1-oxides and 1-sulphides (102) have been reported. Under alkaline conditions, substrate half-lives are seconds to mirlutes for (102;X=O) and minutes to hours for (102;X=S). It is interesting that the 4-nitro compounds show particularly high reactivity.6’ This feature might be the result of a through space effect, and it is tempting to relace this to the apparent difference in reactivity between stereoisomeric 2-chloro-5-methyl5-nitro-1,3,2-dioxaphosphorinanes, commented on elsewhere. 66 For diastereoisomeric 2-chloro-4-isopropyl-5,5-dimethyl1 ,3 ,2~5-dioxaphosphorinanes, the displacement of chlorine by aryloxide anions proceeds readi1y;complete inversion was observed with che weakest nucleophile examined,viz., 4-nitrophenoxide, a feature already recorded for less substituted 1,3,2-dioxaphosphorinanes, and a comparison of the inversion, or retention (as observed with other nucleophiles) ratios with those for orsner cyclic phosphorus(V) chlorides in the same series suggests that the 4-isopropyl group exerts an appreciable steric control on the stereochemistry of the displacement process. 67

j : Quinquevalent Phosphorus Acids

143

X =

R'

Me, N

N

N ,Me

'Me N\

N

N/le

Y

R R = PhO, MezN, or P h Y = 0 or S

(1011

0

1

R, RZ2N'

0

R2= Et

p// 'S(CH21,CHMe

-R2,NH

1

*

R-P,

Il,s'(CH21, I 0-CHMe

I OH

(1031 S(RO)fP(S) SM

CL,C=NSCl

[ I RO I,P(SISl, (

s

S

II (RO),PNCS (107 I

C= NS.SP(S I(OR)2]

(105 I

(1041

+

II

s

II

(RO),PSSSP(OR),

(1061

-

II II /(OR12

(RO),PSCN,

SSP(0R l 2

II

S

144

Organophosphorus Chemistly

Argumenrss have been presented to suggest that the mechanism of catalyzed nucleophilic displacement at a phosphoryl or thiophosphoryl centre may not be as had been previously thought. Thus far, nucleophilic displacements have been thought to involve double SN2 displacements involving the catalyst and/or, pentacoordinate intermediates. Measurements of reaction rates and stereochemical changes €or a variety of linear and cyclic phosphorochloridates (and also phosphonochloridates and phosphonochloridothioaces) in alcoholysis reactions catalyzed by hexamethylphosphorous triamiae, pyridine, or y-methylimidazole (tne order of increasing reaccivity) have been used to question the earlier iaeas, and it has now been proposed that the displacernenc process occurs at an already existing pentacoordinate phosphorus centre.68 The compounds (103; R 1=OMe, n=l or 2) cyclize spontaneously, but steric hindrance may be the explanation for the greatly reduced race of cyclization for n=2 (but not for n=l) when R 1=C13C.CMe20.6 9 A theoretical analysis has been made of che dual reactivity of salts of phosphorus(V) thio acids. In alkylation reactions, the variacion in products brought about by changes in alkylating agent can be illustrated by reference to the diethyl phosphorochioate anion;for this, triethoxonium fluoroborate yields almost exclusively the 2-echyl derivative, alkyl cosylates in HMPT react to yield both 5 and 2-alkyl derivatives, S-alkylation and chlorotrimethylsilane reacts only at oxygen. occurs almost exclusively in non-polar or weakly polar solvents, but a l s o in ethanol. In HMPT the S : ? ratio was shown to depend on the substicuents attached to phosphorus. It was suggested that 0alkylation occurs when the free ion is available, whereas reaction at sulphur occurs when the oxygen end of the 0-P-S triad is preferentially solvated and so shielded.70 Selective cleavage of a P-S bond in O,S,S-triphenyl phosphorodithioate takes place on treatment with H PO - E t 3 N . 7 1 3 2 Interest has been renewed in the reacilions between diazo compounds and organophosphorus compounds with P-Sn-P groupings ( s e e Organophosphorus Chemistry, 1985, g,1 2 4 ; 1986, g,138). The ease of insertion of an acylmethylene group (derived as the carbene from a diazokerone) is dependent on the nature of the bonding at tetracoordinate quinquevalent phosphorus. Thus, insertion is accompanied by rearrangement during reactions with

5: Quinquevalent Phosphorus Acids

145

che disulphides K2P(0)SSP(O)R2 in the absence of a cata1yst;no rearrangemenc occurs €or reactions carried out in Che presence of copper powder. For the tecrasulphides R2P(S)SSP(S)R2 even insertion requires the presence of a catalyst, che position of insertion chen depending on the individual carbene; acetylcarbene insercs inco both P-S and S-S bonds, but benzoylcarbene reacts 72 only at the S-S bond. Tne reaccions between salts of O,O-dialkyl phosphorodiChioic acids and the sulphenyl chloride (104)take an unusual course and in place of the expected substitution product ( 1 0 5 ) , rearrangement and breakaown yields the isolable products (106) and (107)as well as dialkyl p h o s p h o r o c h l o r i d o t h i o a t e . 7 3 Full decails have appeared of experiments reported earlier (Organophosphorus Chemistry, 1986, 156) on the iodine-induced cyclization of the unsacurated phosphates and phosphoramidates (and also phosphonic acid derivatives) (108; X=O,NH,NMe, or C H 2 ; Y=alkoxy or aryloxy). For a fixed atom or group X, the ease of the cyclization is profoundly affected by changes in group Y. Electron donation to the phosphoryl group by X, e.g., when X=O, which would adversely affect the cyclization, may beoffset by an appropriate change i n Y. 74 The presumed stereochemistry of displacement of chlorine at a phosphoryl centre by a primary amine (benzylamine) and crystallographic determination of the configuration of 2-benzylamino-4-phenyl-l,3,2-dioxaphosphorinane 2-oxide has allowed an assignment of stereochemistry (trans chlorine and pnenyl) in a diastereoisomeric 2-chloro-4-phenyl-l,3,2-dioxaphosphorinane 2-oxiae; the more stable of the two cyclic 75 phosphoryl cnlorides has chlorine in the axial position. In aqueous solution, dimethyl phosphates whicn also possess a pyridinyl or quinolinyl moiety, unaergo bimolecular demethylation and quaLernizacion, e.g.,(llO; n=O) is formed from (109; n=O); solvolysis without quaternization represents only a minor reaction. The pyridinylmethyl phosphates e.g., (109;n=l),are more stable. In the case of 2-pyridinylethyl phosphate (109;n=2) elimination becomes tne main route of degradation. 76 Phosphoramidates and their analogues of type (111) are hydroborated with borane-dimethyl sulphide to give boranes which are sources of the h a l o g e n o p r o p y l p h o s p h o r a m i d a t e s (1121 . 7 7 Novel metal-induced rearrangemencs within

c,

Organophosphorus Chemistry

146

Y

(108 1

KH2InOP- OMe

I

0-

Me

OMe

(109)

(110)

1 2 3 R ,P(YINR CH,CR =CH2

BH3- Me2S

-

( R', P(Y N R 'CH ,CH R3 C H ,138

(11 1)

R', P(Y1 N

I , o r Br,

X,=

Y = O

or

I

X 2 / NaOAc

d CH 2CH R3CH,X (112)

S

R ' = EtO o r Me2N R 2 = Me.Ph. PhCH,,

o r c-CGH,,

R3= H or Me

0 OH

0

I'D

OH

II

(Ph01,PNMePh

(113)

(11 5 1 0

...

+

Ill

i.

-

1 1.2 equiv. LDA

ii. 1.2

-

iii, 10 +

10 equiv. LDA equiv. LDA

(1161

(115)

5: Quinquevalent Phosphorus Acids

147

phosphoramidates and phosphorodiamidates, consisting of the migration of phosphorus from nitrogen to carbon, depend, for rshe final outcome, on the relative amount of metal reagent. Such a rearrangement may be preceded by the already well-known migration of phosphorus from oxygen to carbon, as in the formation of phosphonate (114) from phosphate (1131, and & (114).78 phosphinate (1151, also from (1131, but presumably y When the mixed anhydride (117) is heated in boiling chloroform, the observed transfer of the benzoyl group from oxygen co nitrogen is accompanied by ring opening. The observed difference in rate of rearrangement of the cyclic anhydride and the acyclic analogue (Me01(Me2N)P(0)OCOPh (the latter faster by the faccor of 60 x) was ascribed co conformational effects.79 The reactions between the hydrazides (118) and p-benzoquinones can be stopped at the halfway stage. At temperatures below Z O O , the isolable quinone tiydrazides ( 1 1 9 ) may react further to give (120);the compounds (119) are tautomeric with the azophosphonates ( 1 2 1 1 , a feature which is preventableby appropriately sited substituents (e.g. Me or C1) on the quinone nucleus. At higher temperatures, the reaction products are dialkyl phosphonate, quinhydrone and nitrogen. The bromination of compounds (119) yields dialkyl phosphorobromidate and 4-hydroxybenzenediazonium bromide. 80

1.3 Uses of Phosphoric Acids and their derivatives.-The phosphorothioate (122) has been used as a new phosphorylating agent for oligonucleotide synthesis." Phenyl phosphorodichloridate in combination wich DMSO has been employed as an activating agent in the Pfitzer-MoffatC oxidation of alcohols to ketones.82 lsotopically labelled 2-chloro-4,5-diphenyl-ly3,2-dioxaphospholane 2-oxide was used in a synthesis of inorganic _P 1- [ (5)-160,170,180] diphosphate.83 Further examples of the use of enone cyanohydrin diethyl pnosphates for the synthesis of a,@-unsaturated nitriles have been reported.84 The use of diphenyl phosphorazidate in modified 85 Curtius reaccions in the synthesis of peptides has been described. There has been a continued use of phosphates (and a l s o phosphonates) based on 1-hydroxybenzotriazole for both peptide86 and syntheses, and of phosphorus derivacives of n ~ c l e o t i d e 88 ~~' 1,3-oxazolidin-2-one for peptide synthesis.89 The alkylation of N-substituted-Pjl,N1,N2 ,N 2-tetramethylphosphoric triamide,followed by acidolysis, yields a

Organophosphorus Chem istiy

148

c>!-

0 0- CPh II

heat

*

CHC13

I PhCONMc(CHz)jOPOzJn

Me

(117 1

0 ( R ' O I ~"P N H 0 N

0

(1191

0

(122) R = monomethoxytrityl

(1201

0

I1

( E t 0 I,PN=CHOEt (1231

0

r

'.'OR CO.COR

11

r ! H - O l

L O . COR

5: Quinquevalent Phosphorus Acids

149

separable mixture of R 1R 2NH and Me2NH.90 The reaction between ethyl [N-(diethoxyphosphinyl)I formimidate (123) and a Grignard reagent RMgBr represents a new approach for the conversion of RBr into RCH2NH2 or R2CHNH2.91 The (22,42,5R) hydrazide (124) has been employed, albeit with only limited success, in the determination of the enantiomeric puricy of chiral carbonyl compounds.92

2. Phosphonic and Phosphinic Acids and their Derivatives.

2.1 Synthesis of Phosphonic and Phosphinic Acids and their Derivatives.-(a)Gkyl and Aralkyl Acids:The synthesis of phosphonic acid esters from trialkyl phosphates has been discussed.93 Classical Arbuzov reactions have been used to prepare esters of 4-pyridinylmetnyl- and 2-quinolinylmethylphosphonic acids,94 and also of several acids based on oxygenheterocyclic systems.95 The preparacions of ( 2 ,3-dihydroxypropyl lphosphonic acid and its monomethyl dipalmitate triester, also by convencional Arbuzov procedures, led to a successful synthesis ZI€ a diphosphonic analogue (125) of a ~ a r d i o l i p i n .The ~ ~ diethyl escer of [2-chloro(or bromo)ethoxymethyl]phosphonic acid has been prepared scarting with (2-acetyloxyethoxy)methyl chloride, and used in the synthesis of 9-(2-phosphonylmethoxyethyl~adenosine and related compounds (see also ref. 107).97 The interaction of methyl diphenylphosphinite and phenyl bis(iodomethy1)phosphinate has afforded the pnosphonate-phosphinate (126) and lrhus the quaternary salt (127), the last a novel compound evidently unreacrive in Wittig type reactions.98 The reaclsions which occur between benzothiete and phosphorus(II1) trichloride (followed by alcoholysis), or trialkyl phosphite, or dimethyl phenylphosphonite, lead to the compounds (128)-(130), and rhe novel heterocyclic compounds 11311 and (132) are obcained by similar means using cyclic 99 phosphorus precursors. A new and facile synthesis of diechyl (a-cyanobenzy1)phosphonaKes starcs from dieth 1 trimethylsilyl phosphite in reactions catalyzed by TiC14 lZ0 and displacements in triphenylphosphoniomethyl(hezerocyc1e) salts, e.g., (133) to (134), have been used to obtain some unusual phosphonic acid esters."' High yields of che phosphonic acid esters (135) are derived from unsacurated five and six-membered oxygen-containing

150

Organophosphorus Chemistry

0 II

0 II

0

.

R-P-P-OPh

(1261 R

I

I

OPh

OPh 3

= I

(1281 R’ = R 2 = alkoxy, R = H

(1271 R = Ph3Pi I -

(129 1

(1301

Ph

>

lo

PhP

Ph

R’O

0

\p&

’ ‘CH2COOR2

(136 1 R

1

,

2

R = alkyl

R = R 2 = alkoxy, R 3= a l k y l 1 2 3 R = Ph. R = OMe. R = Me 1

5: Quinquevalent Phosphorus Acids

151

ring compounds after initial protonation. 102 Copper(1) triflate is a new catalyst for the preparation of dialkyl cyclopropylphosphonates from alkenes and d i e t h o x y p h o s p h i n y l d i a z o m e t h a n e . 103 Phosphonous acids have been alkylated with chloroacetic esters to give the phosphinic acid esters (136).'04 The appropriately catalyzed reaction between trimethyl l-phosphonoacrylate and methyl phenylphosphonite yields an intermediate which, when treated with an aldehyde, furnishes a mixture of the ( E l and (5)forms of the ester (137),lo5 a useful intermediate for the synthesis of a variety of compound types. A synthesis of 3 , 3 - d i c h l o r o - l - p h o s p h o n o m e t h a c r y l i c acid (138) is illustrated; other compounds of type (139) were obtained with (a), or without (b), allylic shifts,as illustrated in Scheme 11 .Io6 9-~S~-~3-Hydroxy-2-phosphonomethoxypropyl~adenine -

(140) is a useful intermediate; its reaccion with DCC yields the cyclic phosphonic acid (141) from which the ester (142) can be obtained by treatment with methoxide. With DCC and morpholine, (140) yields (143), a precursor to the tripnosphonace (144) and the corresponding diphosphonate. 107 The chemistry of methylenediphosphonic acids has been reviewed.108 The use of NiC12 catalysts in Lhe rearrangement of allylic phosphites (and related compounds) to allylic phosphonic (or phosphinic) acids has already been reported (Organophosphorus Chemistry, 1988, 19, 1441, and the same authors have now described the use of Ni(cyc1ooctadiene) catalysts in the presence of b i s t r i m e t h y l s i l y l a c e t a m i d e in the reactions between allylic esters,or carbonates, and dialkyl phosphites, monoalkyl alkylphosphonaces,or monoalkyl arylphosphonates, to give allylphosphonic or allylphosphinic esters.109 (b)Aryl and 1-Alkenyl Acids:The nickel(I1)-catalyzed reactions becween dialkyl trimethylsilyl phosphites and aryl bromides yield dialkyl arylphosphonates, alkyl trimethylsilyl arylphosphonates, and the corresponding bis(trimetnylsily1) esters inrmrtures which are difficult to separate and hence, generally, Replacement of the process is of little synthetic value.'" che halogen in (145) with butyllithium, and phosphorylation with diethyl phosphorochloridate yields ( 1 4 6 1 , from which uracil-5-phosphinic acid and the 5-thiophosphonic acid are

Organophosy horus Chemistn,

152

C0,Me

(137 1

AC02Me

0

0

II

ti EtOOC

C1,C

P(OEtl2

COZEt

P(OHl2

H+

C0,E t

CO *H

Cl

Cl (1381

0

\ i , (b)

C (a) XCHRZX C0,R' i,

~

0

II

P(0 ~ ~ 1 , R2$

C0,R' H

(1391 1

3

R = M e or E t ; R = Me, a r y l . or CN

A;

R

B;

R , R =

,

1

2

3

Me;

R 2 = (Me012P(01

C: R' = E t . R Z = CCl,. Reagents:

i,

R 3 = Me

( R 3O 1,P

Scheme 11

5: Quirr q u evalen t Phosphorus Acids

153

1

(1401 R = H

(141)

;;yholine

ACHZCH-CH20H

ACHzCH-CH,OH

I ;

p20;m

0

OCHZP-N

I

U

I

-

I

OH OH (144)

(143)

= 9

II

OCHZP-0-P-0-

OH

A

0

0

II P- OH

I OH

GR

adeninyl

Me0

( 1 4 5 ) R = Br

( 1 4 6 ) R = P(Hl(O1OEt

0 0

II

-

MeP( OE t l2

i

HO

II

0 OH )(/P(OEtIZ

F3C

II F3C

I

H

iii

P(OEt1,

H

II

0 (1471

Reagents:

i. BuLi. CF3COOEt; ii. heat; iii. NaBH4. EtOH; i v . M s C I . E t 3 N

Scheme 12

154

Organophosphorus Chemistry

readily available.ll' A study has been made of the directive effects in mono-meta-substituted diphenyl ethers in the synthesis of phenoxaphosphinic acids following their treatment with PC13-A1C13. Such substituents would normally block any attack at the 4-position, and reaction occurs in the even more sterically shielded 2-position to give product mixtures. 112 The chemistry of (fluoroalkeny1)phosphonic acids has been reviewed.'l3 Contrary to earlier reports, dialkyl phosphonazes reacr with 3,3,3-trifluoropropyne only in the presence of a trace of triethylamine; the vigorous reaction can then be made to yield' small amounts of diethyl (?)-(3,3,3-trifluoro1-propenyllphosphonate; the preparation of the ( E l ester ( 1 4 7 ) requires a more involved synthetic route (Scheme 12).114 A successful route to the dialkyl (1-methyl-3-0x0-1buteny1)phosphonates ( 1 5 0 ) involves the conversion of compounds (148) via their enol silyl ethers into the phosphonic acid escers (149) which are then desilylated to give the desired esters (150) (Scheme 1 3 ) The e t h e n y l i d e n e b i s p h o s p h o n i c acid derivatives (151; X=O or S ) have been prepared from methylenebisphosphon(othio)ic difluorides and the carbodiimides RN=C=NR. 116 Further examples of the preparations of (2-hydroxyphenyllphosphonic and bis(2-hydroxypheny1)phosphinic acids and their derivatives by metal-catalyzed rearrangements of compounds with P-O-C(ary1) groups have already been referred to. 7 8 Tne enantiomerically pure forms of isopropyl alkenylmethylphosphinaces have been prepared by the reactions becween 1-bromoalkenes and ( E l or ( $ 1 isopropyl methylphosphinace catalyzed by Pd(0)-Et3N.117 The anion from ethyl d i e t h o x y p h o s p h i n y l t h t o a c e c a t e may be alkylated but yields an ene-2-alkyl ether e.g., (152; R=Me). When che alkylating agent is propargyl chloride, S-propynyl ether rearranges to give finally the the resulcanc phosphorylated chiopyran (1531 . Dimechyl (bromoethynyl1 phosphonare (154) undergoes Diels-Alder reaccions;wich dimethylI>uca-l,3-aiene , the ( cyclohexa-1,Lc-ciienylj pnosphona~e ( 155 1 is formed.1 1 9 A review of the syntheses, struccures, and reactions of (1,2-alkadienelphosphinic acids has been published.1 2 0

155

5: Quinquevalent Phosphorus Acids

0 II

-

0

II

i

MeCCH2CX

-

OSiMe3 0

I

II

II

MeC=CHCX

0

OSiMe3

II

I

XCCH2CMc I

(1481 ( a ) X = Me ( b l X = OEt

/

iii

Jiv

0

II

XCCH=CMe

I

O= P(ORIZ (150 a,b) Reagents: i . Me3SiCI, Et3N : i i , (RO),P(OlH;

i i i , (R012POSiMe3;

iv, CF3COOH o r I,

Scheme 13

IP (X 1F,]

( R N H ),C=C

,

(151)

0 0

s

11

11

(EtOI,PCH,COEt

i, Na

-(EtO),PCH=C, 11, RI

0 II

,SR

II

--

P(OEt1,

R=CHzC=CH

OEt

f x o n

(15 2 1

(153)

O=P( OMc),

0

II

( Me0I2PC G C B r

Me

0

(154 1

(155)

‘i--

R2

R2

PH3/H+,

R’

0

Me

-HBr

Me

Ph

H2°2

HO

Ph

o4

H ‘

R

1

a

HO

Ph

ON

‘OH

(1561

156

Organophosphorus Chemistry

(c) Phospholanes: Oxidation of she initial products obtained from phosphine and 1,4-diketones under acid conditions yields 1-hydroxyphospholane 1-oxides ('phospholanic acids') ( 1 5 6 ; R 1+R 2=(CH2ln, n=3 or 4). 21 A i:etrahydroxyphospho lanic acid ( 1 5 8 ) was prepared from the carbohydrate phosphonate ( 1 5 7 ) as indicated in Scheme 14. Chromatography of the mixed methyl ester tetraacecates afforded a separation of the compounds (159) and (160).122 (d) Halogenoalkyl Acids:The halogenation of tetraesters of methylenebisphosphonic acid has been performed using sodium hypochlorite or hypobromice;reductive monodehalogenation of the produccs was successfully achieved using tin(I1) chloride or sodium sulphite . I z 3 Perchloryl fluoride monofluorinates anions of the esters (161;R=H) to (161;R=F, n=l or 2).124The treatment of diethyl (bromodifluoromethy1)phosphonate wich Na2S204 yields che compound (162;n=2)readily oxidized by hydrogen peroxide to (162;n=3); the last, with acid and ion-exchange affords the methylenephosphonicsulphonic acid ( 1 6 3 ) The zinc reagenc from diethyl (bromodifluoromethy1)phosphonate couples with ally1 or other reactive ha1ides;with propynyl chloride, a mixture of the compounds (164) and ( 1 6 5 ) results.126 Evidence has been presenced which appears KO support an earlier hypothesis regarding the reacsion between sodium dialkyl phosphites and polyhalogeno - methanes; according to this, the phosphite salt and bromotrifluoromethane yield (difluoromethy1ene)bisphosphonic tetraesters through the abscraction of the bromonium cation by the phosphite anion, and this is followed by phosphorylation of the subsequent carbanion. The present evidence is based on the treatment of diethyl (dichlorofluoromethy1)phosphonate with sodium diethyl phosphite in the presence of diec'nyl phosphite, when diethyl ( chlorofluoromethyl ) phosphonate is obtained. N-Chlorosuccinimide monochlorinates diethyl (alkylthiomethy1)phosphonates.128 The jdichloro(trimetnylsilyl)methyl]phosphonic acid derivacives (166;R1=Me0 or Et2iJ) are readilyavailable from che corresponding derivacive of (trichloromethy1)phosphonic acid, chlorotrimethylsilane, and hexamethylphosphorous triamide. They are versatile intermediates from which the silyl group can be removed during alkylation or acylarion so yielding (a,a-dichloroalky1)-or (cx,a-dichloro-2-oxoalkyl~phosphonic

5: Quinquevalent Phosphorus Acids

157 HO

OH

x,xx,

AcO

I

OAc

(1591 1

2

(1601(aIR = =O. R = OMe, X = H. Y = OAc (b1 R'= OMe. R2= =O. X = OAc. Y = H

Reagents : i , Na[ Hz(OCzH40Me)zAII ; ii. PriOH, H30+. then H202:

iii, CH,N,.

MeOH. DMSO, t h e n A c 2 0 , Py.

Scheme 14

0

0 II (EtO),PCHRS(O),SPh (161 1

0

0

II

It

(Et01zPCF2S(01,Na

( H0 1 PC F2SO 3H

(162)

(1631

0

0

I1 H C E C C H 2C I II (Et 01zPCF2Z nBr * (Et012PCFzCH=C=CHz (1641

+

II

(EtO)ZPCFzCH2C=CH (165)

(1671 (a1 R'= Me0

( b 1 R12= OCMezCMe20

Organophosphorus Chemistry

derivatives. 129 (e)Hydroxy-,Eercapto-, and Silyl-alkyl Acids:The interaction of dialkyl phosphonates with alkyl trifluoromethyl ketones yields 130 the isolable, and expecced, (a-hydroxyalky1)phosphonic diesters; In some cases the formation of such compounds is presmed, since isomerizacion to a phosphate ester may occur in the When c h l o r o d i f luoromethyl presence of a suitable base. lo ketones C1F2CCORare employed, the (a-hydroxyalky1)phosphonic diester is isolable even when the reaction is carried out at 0-20° in the presence of a tertiary arnine; at higher cernperatures the extenc of rearrangement to difluoroalkenyl phosphate depends on the tertiary amine (triethylamine or pyriaine) ana also on R.ll The use of dialkyl trimethylsilyl phcsphites in similar reactions has been shown to give [(trimethylsilyloxy)alkyl]phosphonic acid diesters. 12,130,131 In continuation of studies on the formation and reactions of 1-hydroxyalkyl-1,l-bisphosphonic acid cyclic esters (Organophosphorus Chemiscry, 1988, 19, 161), che a,w-aioxoalkanediphosphonic tetraesters (167;n=3-8) have been shown to react with more hydrogen phosphonace to give Lhe a,w-dihydroxy-a,a,w,w-bis[bis(phosphosphonic acid)] esilers (168); 'cross-reactions' e.g., between (167b) and dimethyl phosphonate (affording the same proauct as that obtained from (167a) and ihe cyclic pinacolyl hydrogen phosphonate) are equally feasible. 132 Ijiethyl trimethylsilyl phosphite reacts with benzylic gem-disulphides in the presence of tin(IV) chloride to give diethyl (a-alkylthiobenzy1)phosphonates (169).133 The gem-disulphides (170) are obtainable from the a-chloroalkyl compounds and the thiol R 2SH also in the presence of tin(1V) chloride128 and electrolysis of a mixture of diethyl [(alkylrhio)methyl]phosphonates in acetic acid yields compounds (171). A furcher route K O che a-halogeno compound consists in the treatment of the compounds (171) with acetyl chloride or bromide, or with thionyl halides. 134 Three routes are available for the synthesis of compound (172);(a)silylation of Che anion from (170;X=H) (b) creatment of the anion from (174) with MeSSMe or MeSC1, and (c) bromination of Me3SiCH2SK 1 followed by an Arbuzov reaction with trieihyl phosphice. 135 A synthesis of dialkyl (trimethylsilyl136 methy1)phosphonates (174) involves the chloroylides (173).

5: Quinquevalent Phosphorus Acids

0

159

0

0 I1

I1 II ( R ~P I c(cH,I,c(PR',), 21 I OH

0 II

( E t 0 Iz P C H ( S R' 1 X

(EtO1,PCH(SRIAr

(1701 X = SRZ (171) X = OAc (172) X = SiMe3

OH

(1 68 1

(1 6 9 )

I

4

(R0lZPCH;jiMe3

-

Cl

cc I

(RO 12P=CHSiMe3

-CHC13

0 II

MeOH

(1731

( R O 12PCH2SiMe3 11741

0

II

(EtOI,PCH,C 1

or 0 II

. ..

I, II

I1

I

(EtO1,P-C-

(EtO),PCCl,

0 II

ti, v i

(Et01,PCRXISiMe3I

(X=Br)

-

0 SiMe3 Li+

II

(Et012PCHCl(SiMe31

IiiC, I

:

iv

(EtOl2PCRC1(SiMe31

I

0

( Et0I2PCHRCl

ii, v i ( X = C I )

0 I1

( E t 012PCHR(SiMe31

Reagents: i, Me3SiCl; ii, BuLi, T H F : i i i . RX

;

iv. E t O - i

v, HCOOH

vi, XCH2CH2X S c h e m e 15

0 R'P(SR'1,

+

R3R4C0

H+

*

0 II

2R1>!-+R4 R S

R3

5r2

( 1 7 5 ) R ' = SR2 (1761 R ' = R Z = E t

160

Organophosphorus Chemistry

The silylation of either (chloromechy1)phosphonic o r (trichloromethy1)phosphonic diesters in the presence of an excess of butyl lithium yields dialkyl ilithio(trimethylsily1)chloromethyl]phosphonates;these undergo many reactions of potential synthetic utility (Scheme 15) The reactions which occur between trithiophosphite triesters or dithiophosphonite diesters and ketones under acid conditions yield the [a-(alkylthio)alkyl]phosphonodithioic S,S-dialkyl esters (175) or [a-(alkylthio)alkyl]phosphinothioic esters (176).138 (f)Oxo- and Thioxo-Acids:Several free a-oxoalkyl- and a-oxoalkenylphosphonic acids have been prepared by the stepwise dealkylation of their dimethyl esters.139 Diethyl formylphosphonate (from triethyl phosphite and formyl-acetic anhydride) is rather unscable and decomposes at below -10" yielding ultimately diechyl [ (diethoxyphosphinyl)oxymethyl]phosphonate.140 Earlier claims to have prepared the acylphosphonate ester (177) are apparencly unsubstantiable, but it has now been obtained,as a discillable, greenish-yellow oil, as indicated in Scheme 16. Moreover the bis(trimethylsily1) ester (178) has also been prepared and this has allowed tne synthesis of the free acids (179) and (180). In aadition to (1791, the hydrate (i.e. gem-dihydroxy compound) corresponding to (177) is readily formed.141 In the presence of a Lewis acid, dialkyl phosphorochloridites react with a-hydroxy-B-ketones (or their silyl ethers) to give (8-oxoalkyl)phosphonic esters (18l);benzoin behaves similarly, but attempts to use 2-hydroxycyclohexanone in such reactions have met with no success.142 The known (OrganophosphorusChemistry, Vol. 2 0 ) epoxides (182) are a source of the new (2,4-dioxoalkyl)phosphonic esters (183);these exist largely in their enol forms.143 The acylation of the anions of dialkoxyphosphinylacetic esters or a l k o x y a l k y l p h o s p h i n y l a c e t i c esters with acetylaminoacyl chlorides yields the 2-0x0 esters (184); appropriate enzymic treatment of such compounds leads to optically active (2-oxoalkyl)phosphonic and -phosphinic acids (Scheme 17 ) .144 The reactions between tervalent phosphorus esters and chlorochioformamides or thiochloroformates yield the thioamides (185)145 or che thio escers (186)146 respectively.

5: Quirzquevalent Phosphorus Acids

0 II

I

(Et O),PCH,COO€t

161

0

Nv

II

IIL

I1

( E t OI,P-CCOOEt

0

II

1 E t 0 1 2 P C 0 . C O O Et ( 1 77 I

0 II ( Me3Si012PC0.COO€ t

(176)

-

0 II

v

(HO1,PC (OH1,COOEt

Reagents:

0

H0,ll

,PCO.

COO-

2R2NH2+

0

i. TsN3. Bu'OH : ii. R h ( I I 1 . propylene oxide; iii. ( a ) M e 3 S i B r .

( b l ii: i v . H,O;

v , ( a 1 i v , heat ( b ) R2NH

Scheme 16

,

(R30 ) PC I t

Fecl OR R ' = H or

Etgi

(181)

toluene, 120'

(182)

c (1 83 1

Organophosphorns Chemistry

162

-

0

II OEt

A~NHCHCOCHP’ I I ‘R2 R’ COOEt (1841

i

0

*,IEt

A ~ N H C H C O C2HP\R2

I R’

ii

0

11,

ot

A~NHCHCOCH~P, . I R’ R’

1

1

iv

iii

0 IIO ,H

0 H,OH H,NCHCOCHP I I ‘R2 R’ COOH

HZNCHCOCHZP,

I.

R

R’

R ’ = H. Me, or PhCH2

E’ =

alkaline

m e s i n tericopeptidase; E 2 = phosphodiesterase I

E 3 = a l k a l i n e phosphatase; Reagents: i . E ’ ; i i .

E4=

OL

- chymotrypsin

E2 or E3; iii. E4 then E 2 ; i v . H 3 0 + Scheme 17

1 0

R\ II

,P-CNR

R20 (185 1

$

3 2

R’O ‘PR22N’

COR3 11 S

(186 1

;

5: Quinquevalent Phosphorus Acids

163

(gIEpoxyalky1 Acids:The first nonmicrobial asymmetric synthesis of (1~,2~)-(-)-(1,2-epoxypropyl)phosphonicacid ( 1 9 1 ; Fosfomycin) has been described. In this sequence,(Scheme 181, the cyclic esters (188) derived from the tartaric acid / derivatives (187;R=Me0,RNH, R>N 1 were not isolated but were hydrolysed directly to the monoesters (189);these,when bromohydroxylated with 2-bromoacetamide, gave the esters (190) together with their diastereoisomers. Further hydrolysis and dehydrobromination gave the desired ( 1 9 1 ) . The diastereoselectivity in favour of the formation of the (lR,2S) isomer of (190) is 20-40%, or even higher, depending on R.€47 (2,3-Epoxyalkyl)phosphonic esters have been prepared by the reactions between the corresponding allylphosphonic esters and trifluoroperoxyacetic acid.148 (h)Phospholes and 0xaphospholes:The cyclic phosphinic acid (192;X=OH) has been obtained, together with dibenzylphosphinic acid, in the reaction between elemental phosphorus and benzaldehyde in phosphoric acid containing potassium iodide,149 and it has been converted inco the derivatives (192;X=C1, F, or MeO) as well as its anhydride.15' The analogous 2,3-dihydrobenzoxaphosphole (193;X=C1)has been prepared from phosphorus(II1) trichloride and salicylaldehyde, and it, also, has afforded several derivatives (193;X=Et0,R2N) of the acid (193;X-OH) For both systems (192) and (1931, diastereoisomeric forms have been recognized spectroscopically. 2,5-Dihydro-l,2-oxaphospholes are generally obtained in che reactions between (1,2-alkadienyl)phosphonic acid derivatives (thus far, chlorides and esters have been examined) and electrophilic reagenirs (halogens, or sulphenyl The scope of halides); (195) is thus obtained from ( 1 9 4 ) the synthesis has now been extended 50 include phosphonic amides, and the compounds (197) have been obtained from (196) when EX=C12, Br2, 12, S02C12, PhSC1, MeSC1, or PhSeC1.153' The chlorination of 1,2,4- and 1,3,4-(alkatrienyl)phosphonic dichlorides provides isomeric vinyl-2,5-dihydro-l,2-oxaphospholes; in this way (199) and (201) were obtained from (198) and ( 2 0 0 1 , but the reac'lions between MeXCl (X=S or Se) and (198) and (200) proceed differently. Thus, ( 1 9 8 ) yields (202;X=S or Se) in a reaction already known to be followed by the corresponding dialkyl esters. On the other hand, ( 2 0 0 ) with MeSCl gives the linear phosphonic dichloride ( 2 0 3 ) whereas MeSeCl gives the

Organophosphorus Chemistry

164

H

XH PC 1

Me

II 0

lii Me

OH HO

(1891

(190)

Iiv H

H V ____)

0 (191)

Reagents: i. Et3N, CH,CI,at -1O’C: v.

ii H 2 0 ; iii, NBA-H,O; i v . HBr aq.

NaOMe. MeOH Scheme 18

mo ‘X

\

Ph (1921

f&yo X

Cl (1931

5: Quinquevalent Phosphorus Acids

165

0

Br

Ph

II

BrZ

(1951

(1941

E EX b

L

(1971

(196 1

0

II

so2c12

CIZP /Me R’ > = c = C k R *

D

(198) R’ = H, RZ = CH=CH,

( 1 9 9 ) R ’ = H , R 2 = CH=CH,

(2001 R’= CH=CH,,

( 2 0 1 ) R ’ = CH=CH,,

R2= Me

0

0

c 1 c H ze*

(Ji CH,PCI,

H

II

II

$

H MeS

f 202 1

2

R = Me

Me

( 2 0 11

(2031

Cl

H

CI

RZSCl

(R’O),P

11

R’O’

‘0

0 (2051

166

Organophosphorus Chemistry

selenophenphosphonic dichloride (204).154 Dialkyl [2-chloro-2-(l-cyclohexenyl)ethenyl]phosphona~es with alkyl ( o r aryll sulphenyl chlorides afford derivatives of che bicyclic 5,6,7,8,9,10-hexahydro-2_H-1,2-benzoxaphosphorin (205) rather than spirocyclic 1,2-oxaphospholes.1 5 5 For further syntheses of benzoxaphospholes, see ref.170, and ref. 223 for other reactions leading to 2,5-dihydro-1,2oxaphospholes. (i)Aminoalkyl and Aminoalkenyl Acids:SeveraL papers have described aspects of the phosphonomethylation reaction. The process has been applied to the synthesis of the compounds (206;K=H, Me, or and K O The lactam bis(phosphonic) and bis(phosphinic) acids (2071; their hydrolysis by alkali yields the linear acids ( 2 0 8 ; n=1-3, R=OH or Me). 157 Elsewhere , 2-phosphonomethyl derivatives of nicotinamide ,15' the bis ( phosphinic 1 acids ( 'LO9 ) 15' and the mixed phosphonic-phosphinic acids ( 2 1 0 )16' have a11 been prepared. The reaction between the phosphonite (211) and CC14-Et3N in the presence of a nucleophile R 2YH can be so regulated that the intermediate phosphonic chloride does noi: accumulate but is removed immediately by R 2YH (PhOH, PhSH, KOH, 0-protecced peptide) K O give the 1-procected (a-aminoalky1)or phosphonic derivatives (212).16' The a-amino group has been introduced by reduction of a nicroso group with zinc-acecic acid, as in the formacion of (214) from (213) (although side reactions are known K O occur). 162 Compounds of type ( 2 1 5 ) are obtainable by the addition of the P-ti of phosphinic acids RP(O)H(OH) across the aldimine C=N bond the [ (pyridineamino1 alkyl jphosphonic esters (216) were similarly prepared.164 (aminomethy1)phosphonate The alkylation of diechyl Schiff bases e.g. (217;R1=H or Ph, R2=Ph), with (218; Y=Cl, O A c , or OC02Et) is catalyzed by Pd(0).165 'The alkylation o t the Schiff base (219) ( from diethyl (aminomethy1)phosphonate and either (lR,2R,5R)-(+)- or (lS,2Sy5S)-(-)-2-hydroxy-3-pinanone) followed by separation of the diastereoisomeric products (220) and their subsequent acidolysis, afforded the resolved escers (221). Amongst the various compounds so prepared was the optically active 2-piperidinephosphonic acid (222), regardable as the phosphonic acid analogue of homoproline.166 The racemic acid was described elsewhere. Enantiomeric forms of (a-arninoalky1)-

5: Quinquevalent Phosphorus Acids

167

0

II

HOOCCH,NH CH,P-OH

I R

(206 1 COOH R R, I / O=PCH2NH(CH21,+, C H N H C H 2 P ~ 0 HO’

OH 1

(2081

(2091

0 II

RL (2101

x

R’

OE t

CbzNH

R’

R’

CC14/E1 3N

OSiMe3

Cbz NH

Cl

CbzNH YR2 (2121

(2111

o x (Et 0 1, !+CG0

0

D

o H,C

‘Y

II

=c =CH-

0 11

NHR’

I

P-CHR’

(RO 1,P-CH

HOI

Me (213) X = NO. Y = OMe or NH2

NH

1

Ar

(2151

(2161

(2141 X = NH,. Y = OMe or NH,

0

II

( n oy c H, N=(R2 (2171

R’

+

3JLPd (0)

R

Y

(218 1

qR’ R2

&N

R3

P(OEt 1,

II

0

Organophosphorus Chernistly

168

0

R O

II

I II

-

NCH ,P(OE t

H 30+

LDA/RX

(2191

R

O

I II H,NCH-PPOEt), *

(2201

(2211

(2221

0 II

0 II

R2 8’&p(oR’1z

A

(R101ZPCH2NC

0 ii

~

R2TP(OR112II

0

*N

(2231

&+-!

xY (225)

(224 1

J P(OR’ 1

NHCHO

iii

v (X =OH)

NH3 (2271

-$(”

P(OH 12

R2

2

(2261

(2281 Reagents:

i. R‘CHO,

c a t a l y s t ; ii. H,

p r o p y l e n e oxide;

P d K , E t O H ; i i i . HBr, HOAc. then

iv. HCl -EtOH: v. HCO;.

oxide. Scheme 19

Me3SiI. t h e n propylene

5: Quinquevalent Phosphorus Acids

169

phosphonic acids have also been obtainea in the manner outlined in Scheme 19.168 The asymmecric reaction between the isocyanide '223) and an aldehyde in the presence of the gold complex (che catalysc) of ( g ) - ( S ) form of the bis(dipheny1phosphino)ferrocene (228) occurs co give the (4~,5~)-oxazolidinephosphonic acid esters (2241, hydrogenolysis of which affords the E-formyl derivatives (225) readily convertible into the (a-aminoalky1)phosphonic acid (226). An alternative route from (224) to (226) proceeds by way of Che (1-acylamino-2-hydroxyalky1)phosphonic esters (227). The reaction together of triethyl phosphorotrithioite, an aromatic aldehyde, and a N-acylthiourea yields derivatives of ?,?-diethy1 (a-aminobenzy1)phosphonodithioate (229).169 The reaction between 2-&(trirnethylsilyloxy)phenyl1,3-oxazolidine and either diethyl trimethylsilyl phosphite ( 2 3 0 ) or tris(trimethylsily1) phosphite provides unusual derivatives 1231;X=Et or Me3Si) of ( a - a m i n o b e n z y l l p h o s p h o n i c acid. The presence of a free phenolic O H group, as in (232;R1=H or t-bucyl, R 2=H or Pie) resul'ts in a moditied reaction which leads to the benzoxaphospholes (233;X=Et or Me3Si); hydrolysis of this last compound type results in ring opening to (234);ring closure reoccurs during basification. 170 The bromination of ethyl (aminomethy1)methylphosphinate followed by alkylation gives the phosphinic ester (236). As an alternative to the use of a Grignard reagent in the latter step, coupling can be achieved using a lithium-copper complex. (235a) is the precursor to the mixed phosphonic-phosphinic triester (2371 . 17' The addition of the P-H bond to the ketimine C = N grouping has been employed in the preparation of the hydrazine derivative (238) and thus of the free (hydrazinomethy1)phosphonic acids (239;K3= O H ) and their !'-derivatives (2401, and of the 3 112 (hydrazinomethy1)phosphinic acids (239;K =Me or CH(OEtI2 J . Scheme 21 also outlines routes whicn have been followed to allow the syntheses of IN-aminoglyphosate' (241) and 'azaglyphosate' (243). Compounds (241),(242), and (243) all exhibit plant growth regulatory properties. 173 [(w-Aminoalky1amino)meChyljphosphonic acids and methylisothiouronium chloride are the precursors to [N-(w-guanidinoalkylamino)methyl]phosphonic acids (2441, alchough when n=2 the product i s accually the imiciazolidinjmine (245)

Organophosphorus Chemistly

170

0 II

S

(EtSI3P

+

Ar’ CHO

II

4-

Ar2NHCNH2-

(EtSI,P-CHAr’ I hHCNHAr2

II

S (229)

0

Me3Si 0

+

. )

NH(CH2I2OSiMe,

(2301 X = E t or Me3Si

HO

&7H!OXl2

( X O l2 POSiMe3 (231) X

= E t or Me3Si

H R’ (230) ____)

RL

(2331

(2321

IH2O

R’

R’ Li OH

(23L) Br

R2

R ’ = ( a ) C13CCH202C

( b 1 PhSO, ( c l PhCO Reagents: i . NBS, h v ; i i . R’MgX,

(237) t h e n H30+, iii, (EtO),P, Scheme 2 0

THF

5: Quinquevalent Phosphorus Acids

171

0 R’ II I

EtO-P-C

NHNH,

iii

0

a3

40

R30p,

i

H

0 R’ II I

I

;2

(239)

4C02Bn

EtO-P-CNHI

I

I

a3

lii

‘‘0,

R’

It

HO- P-CNHNHZ

1

iv

0

R’

I

II

( H O ,P-C NHNHC0,Bn

‘

R3= EtO

I

R2

R3 R2

I

( 240)

(2381

0

I

v R1= R2= H

-

II Et O-P-CH,NNHCO,Bn I I R3

0

II

ii

EtO-P-CH2NCH2COOEt

CH,COOEt

I

I

R3

NH,

I

0

II

(H 0 I,PCH,NC

I

i v R 3 = EtO

H,COOEt

NHZ

(241 1

0

I1

-

0

II

ii, iv

(EtO12PCH,NHNCOOBn

I

( H012PCHpHNHCH,COOEt

(242)

CH,COOEt

1

vii

0

I1

( 61,PCHPH NHCH,COO-

3Na’

(243)

Reagents: i . R’R2C=NNHC02Bn:

ii. H,,Pd/C:

iii. HCI : iv. Me,SiBr.

propylene oxide; v. BrCH2COOEt: v i . H,C=NNHCOOBn: Scheme 2 1

MeOH,

vii. NaOH aq.

172

H,N-

Organophosphorns Chemistry NH

0

I1

I1

C- NH(CH,l,

0

nNCH,P(OHI, II HN

NHCH,P(OHl,

K NH

(2451

(2441

(R

,

II

I1

F C=NCF

0 1 P+

NH

vIR101P ,

2

R2 (2L6 l

(Me,SiO l,P

~+,

0 Me

0 Me

0 Me

N= C= NC F,

R2 (2671 R

0

I1

*

II

2( R' 0 12P11~+NH-C-NH2

R2

CN-R

N CN

NH

/

HBr aq.

( Me3Si012PCH2CH2N

\

-

0

I1

(HOl,PCH,CH,NH2

SiMe,

(248I

R = C O O a l k y l o r P(Ol(OEtl,

(MeOl,P(OlH

-

OH I BnOCH2CHP(OMe12

0 II

-

0 KN ~ *H I(-

I1

B"0J

Ph I

(2491

P(OMe1,

(2501

lv IS)- (+I(HOAEPI Reagents: i. BnOCH,CHO; iv. H,.

Pd/C;

ii, PhMeCH(NC0) ; iii. ButMe2SiCL, imidazole, DMF; v. Ph3P, DEAD, HN,;

6 M HCl. heat. Scheme

22

vi. H,.Pd/C,

HCI. t h e n

5: Quinquevalent Phosphorus Acids

173

The [a-(cyanoguanidino)alkyl]phosphonic diesters (247) can be made from the (a-aminoalky1)phosphonic esters ( 2 4 6 ) through the two steps illustra~ed.'~~ (2-Aminoethy1)phosphonic acid (AEP) has been prepared, together with other (w-aminoalky1)phosphonic acids, by the borane-Me2S reduction of w-(dialkoxyphosphinyl)carboxamides, and also its N,O,O-tris(trimethylsily1) derivative (248) obtained 177 from an Ij-acylaziridine. The possibility of P-C bond biosynthesis for AEP through a phosphate-phosphonate rearrangement has been tested in Tetrahymena thermophila by growth on a medium containing and isolation of the labelled AEP. The (D)-[6,6-D2]glucose latter, labelled l,l-D2, was isolated in amounts not consistent with an enzymic phosphate-phosphonate rearrangement of dihydroxyacetone phosphate from which monodeuteriated AEP was expected.178 Several papers179,180 have discussed the biosynthesis of (2-amino-1-hydroxyethy1)phosphonic acid (HO-AEP) from AEP in Acanchamoeba castellari(Neff). [l-Dl]-(AEP) is evidently hydroxylaced directly using atmospheric oxygen with no isotope effect; the ueuterium of (S)-[l-D1]-(AEP) and the 1-H of (~)-[l-ljlj-(AEP)are each replaced by HO with retenizion of configuracion at C-1. [2,2-D2]-(AEP) is partly transformed unchanged inco (HO-AEP), and parcly converted into [2-D1]-(AEP) cP) is converted into prior to hydroxylation;12~)-(+)-[2-Dl]-(Ab (HO-ALP) with no change in configuration at C - 2 . During the course of this work,[2,2-D2]-(AEP) was prepared from (2-benzyloxy)-[l,l-D2jethanol, and 2-phthalimido[l-Dl]ethanol was used to prepared the [l-D1]-(AEP) ( E l - ( - ) - and (~)-(+)-(2-amino[2-Dllethyl)phosphonicacid were obtained from ( 21 - ( + 1 - 2-benzyloxy [ 1-D1 3 ethan01 . 178c The absolute configuration of the (HO-AEP) isolated from A.castellaC was a l s o determined, with the aid of an X-ray crystallographic study of the urethane (250) from the aextrorotatory enantiorner of dimethyl (2-benzyloxy-1-hydroxyethy1)phosphonate (249). Thereafter (S)-(+)-(HO-AEP) was prepared as indicated in Scheme 22 .I8' By employing similar reactions, (K)-(-)-(l-amino-2-hydroxyethyl)phosphonic acid was otained from (2)-(+)-(249). _DL-Yhosphinothricine (252;n=2)has been synchesized starring from the aldehyde (251;n=2).The 1,2-azaphospholidine (253)

Organophosphorus Chemistry

174 0

HN , CH-COOH

I1

//o

I

i , ii, iii

Me P(CH21nCH0

(CH2InP~Me

I

OH

OR

(252)

(251 1

I

ii, i v

J

(253)

iii

D- ( 2 5 2 ) Reagents: i, HCOONH4; ii,cyclo CGHllNC;

iii, H 3 0 + ; iv. NH,:

I

iii

L-(2521 v. phosphodiesterase ( 1 1

Scheme 23

dl

lo iii

NH,

R'

(2541 Reagents: i , MeP(OEtI2, EtOH

;

i i , 2M HCI aq.; iii. KCN, (NH4l2CO3, EtOH, aq.;

iv, Ba(OH1, aq.,heat. then H 3 0 + Scheme 2 4

5: Quinquevalent Phosphorus Acids

175

was also obtained in this stuay; when aciaolysed, it,too, could be used to obtain phosphinothricine (Scheme 23 1 Analogues (252;n=3-6) of phosphinothricine do not possess the a- and u-substituted phosphinosame biological properties thricines display competitive inhibition of sheep brain glutamine synthetase, and were obtained (254) by the route indicated in Scheme 24.183 The rather more novel analogue (257) has been obtained in optically-active forms (Scheme 25); here, the starting material was (2)-(2551 and thesecond chiral carbon centre was created by the asymmetric hydrogenaiion of the acid (2561 Other new phosphonoaminocarboxylic acids include the compounds (258) based on glycine.185 A synthesis of 2-amino-4-phosphonobutanoic acid esters (262) starts with a dialkyl trimethylsilyl phosphite;this, when acted upon by the alaehyde (2)-(259) affords amixcure of diastereoisomeric phosphonate esters (260) generally in ca. 1 : l proportions. In these the trimethylsilyloxy group is unusually stable to aqueous methanol, but the group can be cleaved wich acetic acid to give ca. 1:l mixtures of ( 2 S Y 4 R ) and (2SY4S)-(261),from which removal of the hydroxyl group is carried out as outlined in Scheme 26. 1 8 6 New oligopeptides (rhizocticins) from B.subtilis ATCC 6633 have been shown, very unusually, to contain cis-L-2amino-5-phosphono-3-pentenoic acid (2651, rather than the 2-form which occurs as a component in the antibiotics plumbemicins A and B.187 The synthesis of the new phosphono amino acid has been described in two publications which are summarized in Scheme 27; two routes each start with 4-bromobutenal, and ultimately provide racemic and resolved forms of the compound. In the first synthesis,188 the aldehyde was converted into the ester (263);thiscould not be hydrolysed chemically and enzymic hydrolysis was necessary for the synthesis to proceed to the desired compound ( 2 6 5 ) in DL form. In the second synthesis189 the aldehyde was convercea into its acetal inco which the phosphono group was ineroduced to give (266); with thionyl chloride tollowed by ethanol the acid (265) gave the 5-ethyl ester (267;K1=Et,R 2 = H ) (as the hyaroch1oride);acting upon the latter with a-chymotrypsin provided L-(265) and left _D-1267; K 1 = E r , K 2 = H ) , hydrolysable by base t i 2-(265). The reaction between (265) and PC15-Et3N gave the C,P,P-triethyl ester

176

Organophosphorus Chemistry

-

0

Me

I

II

I

(255) R

=

0 II

Me

I

i,ii

CbzNH-CH-P-H

Pi01( OMe l2

I

CbzNHCH- P - CH2CHCOOMe

I

OR Me

OR

R = Me

-

(2561 R = H

iH2

0 II

Me

I

iv

CbzNHCH-P-CH,CCOOMe

*

I OR

( 2 5 6 1 R = Me Me

0

Me

I

II

I

*

I

Cb z NHC H-P-

Me vi

*

CH2$ HCOOMe

I

*

OH

R e a g e n t s : i. NaOMe, MeOH; ii, H,C=C(COOMe)PIO)(OMe),;

v, H,

0

Me

II

I

I

*

H,NCH-P-CH,CH OH (257)

COOH

iii, HCHO; iv, LiF,THF

l(COD)RhCl2I2, (-1-DIOP; v i , HBr, HOAc, HCI, propylene oxide

Scheme 25 R’CONHCH COOMe

I

( R20 1, POR

R’ CONHCHCOOMe

*

I O = P(OR21,

OMe

(2581 2

R’ = Ph o r E n , R = a l k y l o r Ph. R3= R2 o r Me3Si

iii, i v

0 Ho+6(OR12

Z = COOBn

NHZ

NHZ

(262 I Reagents: i, (R012POSiMe3; ii. HOAc. aq.; iii, (C3H3N212C=S, ClCH2CH2Cl ; iv, BuGnH. CsHs, heat; v. 4 M HCI aq.. dioxane; vi. H, HOAc

Scheme 26

Pd-Ac,O.

5: Quinyuevtrlent Phosphorus Aci&

-

OHCCH=CHCH,Br

I

177

. .. Ill

CH=CHCH,P(OR),

(2641(263:R

=

HI

0 vi, ii

(263) R = E t

iv, v

H,N CH COOH

0

II

t1

( EtO 1C , HCH=CHCH,P(OE

0

I

II

CH=CHCH,P(OHI,

(2661

(2651

vii

I

0 II

OHCCH=CHCH,P(OEt

H~NCH-COOR'

1,

o 11

i

CH=CHCH,P(OR

(2671 Reagents: i, KCN, (NH 1 CO,; 4.2

i v , TsCl. KOH aq.;

ii, (EtO1,P;

iii, phosphodiesterase ( I ) ;

v . H30+; vi. (EtO1,CH.

NH,N03,

EtOH;

vii, aq. t a r t a r i c acid ; viii, cyclo C6HIl NC , HCOONH4 , NaOH

Scheme 27

OH

0 C 0,H (HO; ,1 I

(269) Reagents:

i. Me3SiBr.

CH,Cl,,

r.t., then 6M HCI aq.; ii H., Scheme 2 8

NH2

Pd/C

2

l2

Organophosphoms Chemistiy

178

(267;K1=R 2=Et) of (2651, also as the hydrochloride. Further treatment with a-chymotrypsin gave L-(267;R1=H, R 2=Et) D-(267; leaving the D-triester hydrolysable by dilute acid to - The _P and L forms of (267;K1=H, R 2=Et) were R1=H, R 2=Et). each hydrolysed by phosphodiesterase I to the corresponding forms of (265).I8' D-(-)-2-Amino-5-phosphonopentanoic acid (269) has been prepared by the appropriate treatment of (268)(derived in turn from diethyl (3-bromo-1-propeny1)phosphonate 1 as outlined in Scheme 28,19' and a route has been devised for the synthesis of the antitumour active tripeptide 'bialaphos' (270) from the resolved diethyl ester of (2521 .I8' Several (phosphonoalky1)pyridine compounds e . ~ . , (271) and ( 2 7 3 ) have been reduced to the corresponding piperidinecarboxylic acids, in these cases, to (2721 and (2741 New 1,4-dihyaro-3-pyridinephosphonic diesters (275) have been aescribedlq2 and details have been provided for the preparation of ( 275 ; Ar=3-nitrophenyl, ( R1O 1 2=OCH2CH2CH20, R2=Me ) , a compound evidently now undergoing clinical trials as a prom1.sing antihypercensive substance. 193 Arylhydrazones of 1- and (2-oxoalky1)phosphonic acid diescers cyclize in polyphosphoric acia to give indolephosphonic aciu aiesters e.g., (277) from ( 2 7 6 1 , and (279) from (2781, reauily convertible by reaciion with bromotrimethylsilane followed by methanolysis to che free acids The indolephosphonic acid derivatives (281) have also been prepared by the Bischler cyclization of (1-arylamino-2-oxopropy1)phosphonic acid derivatives (280). In this synthetic sequence, the preparacion of the intermediaces requires the steps illustrated in Scheme 2 9 , since they are not obtained directly from the corresponding 1 The analogous halogeno compound by reaction with ArNHR (3-arylamino-2-oxopropy1)phosphonic acid derivatives lead to phosphonomethylindoles after treatment with zinc chloride. 195 (j)Sulphur and Selenium-containing Acids Optical forms of soman have been prepared via the resolved 2-pinacolyl merhylphosphonothioic a ~ i d , 1and ~ ~ stereoisomeric forms of the triphosphorus syskem ( 2 8 2 ) have been characterized. 19 7 0-Alkyl arylphosphonodithioates (284) are obtainable by alcoholysis of the dithioxophosphorane ( 2 8 3 ; Ar=2,4,6-tri-tertana the di thioxophosphorane dimers butylphenyl 1 (aithiaaiphosphetane ciisulphides)( 2 8 5 ; A r = 2 , 6 - a i - t e r t - b u t y l - 4 c

.

179

5: Quinquevalent Phosphorus Acids A1a

I

-Ala -OH

0

0

II

H2NCHC0 0

I

II

CH2C H2 P- OH

I

Me ( 270 1

(271 1

(272)

0

I1

,

C H COMe

( R’ O),P

0

I

I1

(R’ 0 If-

ArCHO M ~IC = C H C O ~ R ~

C= C HA r

NH 2

b

I

R200C

bi P(OR’1,

Me

COMe

Me

(275)

0

II

(EtO12P-C CH2RP

II

-

NNHAr

(277 1

(276)

0 II

P(OEt l2

0 (Et 0 1P ,

0

II

- C H2C H =NNHA r (2781

rn

H (2791

Organophosphorus Chemistly

180 X

(Et 012P II

)K -

X (EtO),P0 II

NNHC02Me

0 0 X = CI o r Br

- 7 (EtO1,P

\

II

0

N=NC02Me

liii

@ , .-

R'N' iv c--

I

I

1( II

( E tO1,P

0 ( 2 8 1I

0

0

NNHC02Me

(280I

Reagents: i , MeCOONHNH,; ii, Et,N ; iii. R2%H4NHR1; iv. 3M HCI aq. o r TiCI,; v, ZnCI,,

PhMe Scheme

S X Et,II II ,P-o-P-o-P< EtO I R

(2821 (a1 R = Ph, X =

29

&

S II Et

%p,SH

OEt

:o r

S

12861

(b1 R = Me, X = 0

gS

ArP*

S

-

-

S

II

Ar-P-SH

I

Z

a+x-

II

bS\

ArP,

,PAr

s II

S

OR (2841

(283 1

S

(2851 Y

II

PBU'~

5: Quinquevalent Phosphoms Acids

181

hydroxyphenyl J the reaction between the former and primary alcohols is practically instantaneous, that with secondary alcohols is slower, and tert-butyl alcohol gives a substance believed to be the cyclic phosphinodithioic acid (286) Selenation or telluracion of t e t r a - t e r t - b u c y l d i p h o s p h i n e yields che compounds ( 2r37;x-Te, Se, or SeSe;Z,Y= l.p., Se, or 0 ) .200 The method outlined earlier43 for the preparation of oxophosphoranesulphenyl chlorides has also been applied to phosphonic and phosphinic acid analogues. (k)Acid amides and enamides:Many dimechylamides (288;A,B=l.p., 0 , or S ; X1,X2,Y1,Y2=C1,F, or NMe2I2O1 and related compounds (289;X=F,Cl,Oalkyl,Ph,or Me2N; Y=PrlO,Ph, or M e 2 N ) 202 derived from methylenediphosphonic acid have been described; a by-product isolated during the course of this work was the novel tetraphosphetane ( 2 9 0 1 , whose structure was confirmed by X-ray crystallographic analysis. e-Cyanophosphorylamides may be obtained from reactions between phosphorus(v) chlorides and sodium cyanamides. 203 The treatment o f perfluoroalkyl phosphine oxides (291) with ammonia methylamine, or dimethylamine, results in C-P bond cleavage with ihe formation of bis(perfluoroalky1)phosphinic and thence (perfluoroalky1)phosphonic amides; the reactions of bis(perfluorobuty1)phosphinic fluoride are similar,except that with dimethylamine when the main product is C F P(0)F(NMe2). 204 4 9 Lawesson's reagent converts aryl isocyanates into the corresponding isothiocyanaces, but the thiazadiphosphetidine disulphides (292) are also important products of these reactions. 205 The diazadiphosphetiaines (293;R1=MeI2O6 and (293;K1=Ph)207 have been obtained during the aminolysis of the phosphonothioic dichlorides R1P(S)C12. The ready production of high yields of O-diphenylphosphinylhydroxylamines (294;R=alkyl) b y reaction between bistdiphenylphosphinyl) peroxide and primary amines has an obvious synthetic attraction in its simplicity. In boiling 0-substituted compounds rearrange to N-diphenylchloroform, the phosphinylhydroxylamines. The tirst example of a stable oxaziridine (295; Ar=2-chlorophenyl) has been obcained following che rearrangement of an 0-diphenylphosphinyl aldoxime. 209 A brief reference has already been made (Scheme 23) co recenily encounterea 1,2-azaphospholidines.18' The formation of trie chy 1 &amino- 5-pho sphono- 3-pen t enoa t e from 2-am1 no- 5-

Organophosp homs Chemistry

I82 A

B

1 2‘1-

II

XX P

S

II

CH,-PY’Yz

X,PC H,PY2 (2891

(2881

(291 1

S

Ar (292 l

0

I1

0

II

Ph,POOPPh,

(2931

RNH,

0

II

Ph,PONHR

heat

(2941

Ph2PC I

H

‘OH

H

II

OH

PhZPN’ R ‘

MCPBA

Ar

H C O C a q . m Ar&N

c )

* ‘ F N

0

\

Ph

Ph

/p\ Ph

$0 Ph

5: Quiuyuevalmt Phosphorus Acids

183

phospnono-3-pentenoic acid, again, already referred to, i s accompanied by that of che tecrahydro-lY2-azaphosphorine (2Y6; K 1 = K 2=Et); the phosphorus esi-er eilhyl group is removed in the presence o t phosphodiesterase,and subsequent alkali treatment yields the acid (296;R1=R 2= H I . Alternatively, removal of the carboxyL ester group occurs in the presence of a-chymotrypsin.188 second synthesis of the same compound starts with (2971, available from ( 2 6 6 ) by the action of alkaline phosphatase followed by acidolysis. With ammonia and cyclohexyl isocyanide, the product from i 297 ) is ( 298;K1=EC , R2=NHCbHlIcyclo1. Phosphodiesterase I removes the ester group from chis, and furcher treatment with a-chymotrypsin yielas, as before, the diacid 1296;R1=R2 =H);the reverse enzymic hydrolytic sequence is equally a p p 1 i ~ a b l e . l ~ ~ The chemistry of azaphosphorines forms the subject of a recent review.210 'l'hereactions between Lawesson's reagent and the isomeric aminoketones (249) and (300)(KF=perfluoro C1-C4 alkyl, R1=alky1 or Ph) result in thiation of the carbonyl group, as well as formation of isomeric lY3,2-thiazaphosphorine 2-sulphides having the structures (301) and ( 3 0 2 ) together with,in some cases, smaller amounts of the 1,3,2-oxazaphosphorine 2-sulphides (3031 . 211 When phosphorylated with the dichlorides YP(X)Cl, (X=O or S ) the diamine (304;K=H) yields the lY3,2-benzodiazaphosphorines i305;X=OY Y = C 1 or Ph; X=S, Y=Me, Et, or Ph). The compound (305;X=O,Y=C1) is much more reactive towards nucleophiles (alkoxides, E-methylarylamines) than the analogous 1,3,2212 dibenzodiazaphosphocine oxide. A

2.2 Reactions of Phosphonic and Phosphinic A c i d s and their Derivatives.-The reaccions which take place between methylphosphonic difluoride and tetraalkoxysilanes lead to partial or complete replacement of fluorine, and the process has potential for the 213 synthesis of alkyl alkylphosphonofluoridates. The extent of configurational inversion which occurs in the alcoholysis of the phosphonic chlorides (306;X=O, R=Me or Pri; X-S, K = E t ) decreases in the presence of DMF or hexamethylphosphoric criamide, alchough the substrates themselves do not racemize under the same conditions. In the presence of pyridine or N-methylimidazole, methanolysis of (306;X=O, R=Me) yields

Orgunophosphorns Chom istry

184

L.R.

(301 1

(299 1 L.R.

(3021

(300)

(3031

L.R. = Lawesson’s reagent R2 = M e O D

H N ‘’

R H X

X

II Ph-

P-Cl

I

OR Me

( 3 0 41

(306)

(3051

o + o

0 ’ 0

II

II,OR’ I R 1 0 1 2 P Y P \ Me

A2 0

It

MeCHCH =CH P(OR1,-

I

McO-

0 II

C I MeC = CHCH2P(OR1,

Me 0

I

ClCH2CH=C-

Cl

(308)

(309)

(310)

II P (OR),

5: Quinyurvalmt Phosphorus Acids

185

a tnerrnodyanamically controlled mixture of products, with racemization being faster than alcoholysis. 68 'l'he thermolysis of (1-pheny1ethenyl)phosphonic acid arfords a separable mixture o t cis and trans-l-phenyltetralin214 1,4-diphosphonic acia. Acylphosphonic acids (1-oxoalkylphosphonic acids) and their trialkyl esters undergo acid-catalyzed fission with the formation of carboxylic acids (or their alkyl esters); using a sulphonic acid as the catalyst the formacion of an alkyl carboxylace is accompanied by thac of an alkyl sulphonate. The reaction may be visualized as occurring through protonation on the carbonyl oxygen and migration of an alkoxy group from phosphorus to C+ followed by the fragmentation with release of phosphenous acid ester, ROP=0.215 For dimethyl benzoylphosphonate, the proposed mechanism involves protonation on phosphoryl oxygen, and fission to the benzoyl cation and dimethyl phosphonate (isolable in at least 30% yield): when the catalyst is -p - t o l u e n e s u l p h o n i c , a c i d , the expected by-product v&., benzoictoluenesulphonic anhydride, is further tosylated to give 2-toluenesulphonic anhydride together with benzoic acid, and these interact with dimethyl phosphonate to give the methyl esters of p-toluenesulphonic and benzoic acids. [ H P U 2 ] was postulated as a by-product in this sequence. 216 Lithium diisopropylamide causes the isomerizacion o t aryl esLers of diphenylphosphinic acia to 2-(diphenylphosphinyl)phenols, a useful procedure trom the synthetical viewpoint. 21 1 The phosphonic-phosphinic system (307; cf. 126, ref.98) is deprotonatea initially at the central methylene group, and so can be alkylated at this position, but further treatment o t the monoanion with butyllithium results in the l o s s of a proton from the second site: this, and the subsequent behaviour of the dianion during alkylation are reminiscent of the behaviour o t 1,3-aicarbonyl compounds. 218 Some features of the prototropic isomerization o f (1-a1kenyl)phosphonic acids and their derivatives have been investigated for basic conditions. By using (halogenoalkeny1)phosphonic esters, together with CD30D + C D 3 0 - , it was shown that the speed of isomerization of (1-alkeny1)phosphonic acid derivatives e.g., ( 3 0 8 1 , to the (2-alkeny1)phosphonic isarners, here ( 3 0 9 1 , was faster than H/D exchange ae position 3; isotope exchange occurs at position 1 in ( 3 0 9 ) . The 1-alkenyl structure

186

Organophosphorns Chemistry

can be scabilized by the presence of an appropriate substituent e.g., a methyl group, as in ( 3 1 0 1 , a compound in which the protons at position 3 are very mobile in isotope exchange. 219 In the presence of strong bases (ethoxide, t-butoxide, or butyllithium, but not pyridine), (2-chloropentyl)phosphonic acid and its esters yield, as the kinetically-controlled products, the derivatives of \E)-(l-pentenyl)phosphonic acid. Extended treatment o t the dialkyl esters of this acid with alkoxide result in their isomerization to derivatives of (E)-(2-pentenylJphosphonic acid. During this process,H/D exchange occurs to the extents of 100% at position 1, 23% at position 2, but n o t at all at position 3 . The 2-alkenyl isomer is itself stable in the presence of strong base, but with CU30D + CD30- does undergo isotope exchangeat positions i.and 3 , being faster at the former site by a factor of 1 6 0 for the dimethyl ester. lnterestingly monoalkyl (1-penteny1)phosphonates do not isomerize in chis way. Neither these, nor the monoalkyl (2-penteny1)phosphonates undergo isotope exchange with CD30- in C D 3 0 D , but in DMSO-d6, exchange does occur, she extents then being 100, 90, and 5% at positions 1,3, and 4 . 220 lhe reactions of (1-1ithioaLkyl)phosphonic acid esters have been s u m m a r i ~ e d .Very ~ ~ often, and particularly when the alkyl group also carries a halogen atom, the stability of the lithium salt is very low, even at much lowered temperatures. The use of lithium diisopropylamide to obtain the salts appears to have distinct advantages by comparison with the more conventionally used butyllithium,since it seems that some masking of the phosphoryl centre occurs with the rormer reagenrr with the consequent increases in stability ok the derived salts. Other lithiumdialkylamides do not necessarily have the same beneficial effect. 221 Phosphinodithioic acids add to p-benzoquinones,222 and to (lY2-alkadiene)phosphonic acid derivatives, although here the reactions can be rendered more complex by the formation of dihydro-1,2-oxaphospholes. 223 Phosphino and phosphono-dithioic acids also add to B-aroylacrylic acids to give the adducts ( 3 1 1 1 224 and dithiobenzoate adds to allenylphosphonate esters to give, e.g., the adduct t 312).L25 The formation of the dialkoxyphosphinyl-2-isopropylidene2,5-dihydro~hiophene1,l-dioxides (313) from sulphur dioxide and (a1katrienyl)phosphonic diesters has been observed. 226

5: Quinquevalent Phosphorus Acids

187

0

0

II

II

RzP(S)S H

ArCCH=CHCOOH

m

R = EtO. Ph

A r c CH,CHCOOH

I

SP[S)RZ (3111

0

0 PhCSS-

I I =C=C /Me (Et O1,PCH

*

I

I

Cl

P(OI(ORI,

Me

I ‘R SCSPh (312)

‘R

CICH2C =CC H2CI

,

il

( E t O I,PCH,-C=C

Hfi

KI

=C- C=CH2 I I

_ _ _ ) A

C l P(OI(OR1,

(3141

(3151

0

0 Me ROH

+

( Et 0 12P

“

(3161

+ Me

CH20H

OR

0

II

ROH

(Et 0 I,P CH2CHCH20R

I

OH (3171

,

1 0 R II P-C-CHO R’2 II N NHAr (318 I

R’, R’2

it

P - C=

I

NNH Ar’

N=NAr2 ( 319 I

Organophosphorus Chemistry

188

Other recorded reactions of unsaturated phosphonic acid derivatives include the di-aechlorination of the esters ( 3 1 4 )2 2 7 and the oxidative reactions between (l-vinyl-l,2alkadieny1)phosphonates or (l-acyL-1,2-alkadienyl~phosphonates and c'hromyl chloride when the products include 5-phosphorylated cyclopentenones, cyclopentadienones, furans, furfuryl alcohols, and furanones. Differences in response to catalysts have been observed for the ring-opening reactions of (epoxyalky1)phosphonates thus the 1,2-epoxyalkyl compounds ( 3 1 6 ) undergo alcoholysis under acid, but not base, conditions, whereas the 2,3-epoxyaLkyl analogues ( 3 1 7 ) react under base, and not acid, conditions; basic conditions are required for the reactions of both types of epoxides with phenols. 2 2 9 In weakly acid media, the coupling of diethoxyphosphinylacetaldehyde and aryldiazonium salts yields Khe phosphorylated glyoxal a-arylhydrazones ( 3 1 8 ) as the principal products with the phosphorylated formazans ( 3 1 9 ) as minor products. With an excess of diazonium salt, or when pyridine is used as the solvent, the phosphorylated formazans become the main products 2 3 0 The methylation of the oximes of (1-oxoaLky1)phosphonic dialkyl esters yields 0 or 1" aerivatives depending on the structure of the arnbident anion;the nature of the electrophile is a l s o influential. Methyl iodide or dimethyl sulphate yields only methyl ethers. On the other hand diazomethane affords mixtures of both fl and 0-methyl derivatives, to be followed, possibly, by methylene insertion. 231 A detailed study of the structure and reactivity of aimethyl (a-hydroxyiminobenzy1)phosphonate has centred around its geometrical isomers, its dealkylation, and also its thermolysis to dimethyl phosphonate and benzonitrile, a process isomer cleaves faster then the ( g ) isomer. 2 3 2 in which the The alkaline cleavage of the P-C bond in (trichloromethyl)phosphonic acid and its esters,2 3 3 , and the alkaline hyarolysis of 2-alkoxy-3H-1,4,2-benzodioxaphosphorin 2-oxides ( 320),234 and of 2-alkyL-l,3,2-dioxaphosphorinane 2-oxides and 2-aLkyL-1,3,2-dioxaphosphepane2-oxides ( 3 2 1 ; n=O and 1 ) 2 3 5 have all been examined. Differences in reactivities towards nucleophiles of diphenyl-, dimethyl-, and methylphenylphosphinic and -thiophosphinic acids have been discussed in terms of the higher polarity of the P=S bond compared to the

.

(z)

189

5: Quinquevalent Phosphorus Acids

(3211

(3201

0 But SH Bu3 SnH or

I

R' H

OR2 (323)

Me (325)

(326) (a)

\

(328) (a)

0 But--&

*NR' (327)

But (326) (b)

R' =

3 - H . Ph

R * = ~ r o r'

BU'

190

Organophosphorus Chemistry

P 4 bond and the resultant charge on phosphorus.L36. The rate of methanolysis of the diphenylphosphinic ester ( 3 2 2 ; X - 0 ) has been shown to be greater than that of (322;X=CH2) by a factor of ca. 2 0 . lhe explanation for this result is based on che probable conformational preference for the POCCO group in the pentaco-ordinated reaction intermediate. Evidence tor this phenomenon includes the results of earlier examinations of the 13C nmr spectral behaviour ot stable oxyphosphoranes and the influence of conformational transmission effects on the races of Ligand reorganization.237 'The formation o t metapnosphate during radical reactions of organopnosphorus compounds has been claimed. ihus,the addicion of c-butanol to the fragmentation of ( 323;R1= . 4-PieOCbH4CH2, R 2 =Prl ) using radical-iorming agents resulted in the formation of [ MeOC6H4CH2 P ( 0 j (OPr') 2O ana 4 - methoxytoluene . In addition, however, t-butyl isopropyl hydrogen phosphate was tormed, possibly y & PrLOP(=O)2.2 3 8 The selective cleavage of the 2-met'noxy group in (2-methoxyphenyl)(4-rnethoxypheny1)phosphinothioic acid by tribromoborane nas been noted,2 3 9 and pseudophosphonium salts have been observed during thiono-thiolo rearrangements of phosphinothioic esters. 240 The rapid oxidation of [2-(methylthio)ethyL]phosphonic acid by iodine is thought to be the result of neighbouring group participation through a five-membered ring intermediate (324).241 In an attempt to obtain aiastereoselectivity in the alkylation of derivatives of (aminomethy1)phosphonic acid and so prepare other (1-aminoalky1)phosphoriic acid derivatives in optically active forms, the alkylation (by Me1 and PhCH2Br) of the chiral 1,3,2-dioxaphosphorinanes (325; Y = H , CHG; C=; CHPh; or CPh2) as their anions, has been examined. The substrates were derived from 2,4-pentanediol (325;R=H) when the exocyclic P-C bond is orientea equatorially preferentially, and from 2-methyl-Z,4-pentaneuiol (325;R=he) in which the P-C bond prefers the axial position. Unfortunately, in spite of the differences in conformational preferences the diastereoisomeric excesses so obtained were never greater than 50%. 2 4 2 Full accounts have appeared of work dealing with the reactivity of phosphonamidic halides and reported in preliminary form during 1985-86. The reactions between diastereoisomers of N-(S)-a-phenylethyl-P-t-butylphosphonamidic chloride ( 3 2 6 a,b)

5: Quinquevalent Phosphorus Acids

191

and t-butylamine or isopropylamine in either acetonitrile or dichloromethane gave che same producrs (328 a,b) in the ratio 5 5 : 4 5 ac low amine concentrations. Possible interference by SN 2 ( P ) reactions was precluded by the use of substrates possessing the bulky t-butyl group, and it was cherefore concluded that the reactions proceeded through a monomeric mecaphosphonimidate intermediate (327). However, it was also noted that, as the concentration of the attacking amine was increasea, the very low selectivity previously noted became much more pronounced, reaching 87:13 for o n e , or 31:69 f o r t h e o t h e r diastereoisomer of (326) in neaC t-butylamine, a figure differing very little from that observed for isopropylamine. 243 In the presence of sodium methoxide, alkyl N-alkyl(1-chloroalky1)phosphonamidates rearrange to (1-aminoalkyl)phosphonates ( a reaction previously observed) together with phosphoramidates-the latter a new feature of mechanistic significance.The use of methoxide dld Lead, however, to complications due to the further degradation of the products, and the use of benzyLtrimethyLammonium methoxide was found to be more satisfactory. This brought about rhe conversion of (329;R1 =K 2=Me) into a mixture of (331;R1=R 2=Me) and (332; R 1=K 2=Pie) in the ratio 9:l. The production of the two compound cypes might occur through the participation of one or both of che reaction pathways A , in which methoxide acts as a base, and B y in which methoxide acts as a nucleophile. In order to 'encourage' route A - since this appeared to be the only logical route by which the phosphoramidate would be obtained,and to 'discourage' route €3- the effect of ethoxide(R2=Et) on the ethyl ester (329;R1=Me,K2=Er_) was examined, and it was observed that the phosphoramidate:(aminoalkyl)phosphonate ratio did increase, although not to the excent expected had pathway B been important. The phosphoramidate:phosphonate ratio was reversed for (329;R1=H, R 2 =Me). The formation of the phosphoramidate (332) was thus advanced as very strong evidence for the participation of the azaphosphiridine intermediates (330). For K 1=Ph, the expected increase in reactivity of the phosphiridine would be expected to favour phosphoramidate formation at the expense of that of the phosphonate. This was the case;indeed, to the extent that phosphonate accounted for only ca. 1% o f the p r o d u c ~ . ~ ~ ~ The stereochemical course of a migration from

Organophosp horns Chemistly

192 Route A -H+ +H+

0

CI

>!-OR2 R'

N HBJ

-

0

CI R' >!-OR2

NBU'

(3291 R20-

I

0

Cl

B

Route

-

OR

?

0

II

R'

>T-ORz

BU'NH

OR

NHBU~

*

-

( 331 1

0

R17 II N-PPtOR

B Ut

2

l2

/ ( 332 1

hV / MeOH

Ph $;

Ph Me 0

b

Me

(3331

0

II -

+

Ph,P-N-NMe3

(3351

(335)

-

MeOH

hV

(336)

0

II

Ph2PNH2

5: Quinquevalent Phosphorus Acids

193

phosphorus to nitrogen has also been investigaced for t h e photo-Curtius rearrangement of a phospninic azide. t _R , R ) and (s,S)-(333) were each found to rearrange in methanol with the migration of the stereogenic carbon moiety 110 give the phosphinic amide (334);this,whet-, hydrolysed yielded a-phenyl.echylamine having 99% e . e . and with the same configuration as that present in the starting azide. 245 The photolysis oF compound (335) ultimately affords aiphenylphosphinic amide in high yield, buc this is not thought to occur directly, b u t rather by inicial rearrangement to the phosphinylaminal ( 3 3 6 ) before solvolytic cleavage to the amide.2 4 6

2.3 Uses of Phosphonic and Phosphinic Acid Derivatives:-Analogues of Lawesson's reagent have been employed in the preparation of thiopeprides 2 4 i and the diphenylphosphinothioyl group protects cryptophane during peptide synthesis.2 4 H Diphenylphosphinic chloride assists in the formation of 3-lactams from B-amino aci ds249 and pnenylphosphonoselenoic dichf oride converts carbonyL*compounds into their C=Se analogues.2 50 0-Diphenylphosphinylhydroxylamine offers some acid as an advantages over hydroxylamine-0-sulphonic N-heterocycles. 251 aminating reagent,e.g. for References

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,

e,

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194 11. 12. 13.

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14.

15. 16. 17. 18.

19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. -

43. 44.

~

s,

5: Quinquevalent Phosphorus Acids

195

45. DembiLski, R., Krawczyk, E., and Skowron/ska, A,, Phosphorus Sulfur, 1988, 35, 345. 46. Xopusirkki, A . , Xuczak, L., and Michalski, J., Phosphorus Sulfur, 1988, 40, 233. 47. Hu, B., Sherfg, Q., and Li; Z., Phosphorus Sulfur, 1988, 2 , 371. 48. Nifant'ev, E.E., Predviditelev, D.A., Rasadkina, E.N., and Bekker, A.R., Phosphorus Sulfur, 1987, 34, 109. / 49. Predvoditelev, D.A., Razadkina, E.N., Bekker, A.R., and Nifant'ev, E.E., J. Gen.Chem.USSR,(Engl.transl.), 1988, 58, 1341. 50. Brownbridge, P. and Jowett, I.C., Phosphorus Sulfur, 1988, 35, 311. 51. Khodak, A.A., Tikhonina, N.A., Porshnev, Yu.N., and Gilyarov, V.A., Bull.Acad.Sci.USSR, Div-Chem., 1987, 2365. 52. Pilgram, K.H. and Skiles, R.D., Phosphorus Sulfur, 1988, 36, 117. 53. h e r b y , M.R., Partridge, L.Z., and Gibbons, W.A.,J.Chem.Res.(S), 1988, 394.. 54. Anson, M.S. and McQuigan, C., J.Chem.Soc.Perkin Trans. 1. 1989, 715. 55. Igueld, S., Baboulhe, M., Dicko, A., and-ynthesis, 1989, 200. 56. Guillaume, H.A., Perich, J.W., Johns, R.B., and Tregear, G.W., J.Org.Chem., 1989, 54, 1664. 57. Guillaume, H.A., Perich, J.W., Johns, R.B., and Tregear, G.W., J.Chern.Soc.,Chem.Commun., 1988, 970. / 58. Gurarii, L.I., Litvinov, I.A., Naumov, V.A., Mukmenev, E.T. Arbuzov, B.A., Bull.Acad.Sci.USSR,Div.Chem., 1987, 1689. , 59. Litvinov, I.A., Gurarii, L.I., and Mukmenev, E.T., Bull.Acad.Sci.USSR, Div.Chem., 1988, 1243. , 60. Gurarii, L.I., Mukmenev, E.T., and Arbuzov, B.A.,J.Gen.Chem.USSR, / (Engl.transl.1, 1988, 58, 823. 61. ( a ) Gurarii, L.I., Litvinov, I.A., Mukmenev, E.T., and Arbuzov, B.A., , Bull.Acad.Sci.USSR,Div.Chern., 1987, 1106; (b) Gurarii, L.I. Mukmenev, E.T., and Arbuzov, B.A., J.Gen.Chem.USSR(Engl.transl.), 1988, 58, 619;, (c) Gurarii, L.I., Pozdeev, O.K., Gil'manova, G.Kh., Mukmenev, E.T., and Arbuzov, B.A.,J.Gen.Chem.USSR(Engl.transl.), 1988, 58, 1482. 62. Majoral, J.P., Badri, M., Caminade, A.M., Delmas, M., and Gaset, A. , Inorg.Chem., 1988, 27, 3873. 63. Morrow, J.R., and Trogler, W.C., Inorg.Chem., 1988, 27, 3387. 64. Fife, T.H. and Pujari, M.P.,J.Amer.Chem.Soc., 1988, 110,7790. 65. Legocki, J., Czajka, M., and Nowacka-Krukowska, H., Organiika, 1986, 25; Chem.Abstr., 1989, 110, 135360: Legocki, J., Bukowska, D., and Narkiewicz, D., O r g z k a , 1986, lS;Chem.Abstr., 1989, 110,135359. 66. Johnson, O., Jones, D.W., and Edmundson, R.S., Acta Crystallogr., Sect. C , 1989, 45, 142. 67. Edmundson, R.S. and King, T.J., J.Chem.Res.(S), 1989, 120. 68. Corriu, R . J . P . , Lanneau, G.F., and Leclercq, D., Tetrahedron, 1989, 45. 1959. 69. Nuretdinova, O.N., and Novikova, V.G., Bull.Acad.Sci.USSR,Div.Chem., 1987, 2190. 70. (a) Mastryukova, T.A., Genkina, G.K., Kalyanova, R.M., Shcherbina, T.M., and Kabachnik, M.I.,J.Gen.Chem.USSR(Eng.transl.), 1987, 57, 1981: (b)Shkodin, A.M., Podolyanko, V.A., Svyat-skaya, T.N., Kalyanova, R.M., Genkina, G.K., Nastryukova, T.A., and Kabachnik. M.I.,J.Gen.Chem.USSR, (Engl.trarisl.), 1987, 57, 1987:(c) Mastryukova, T.A., Aladzhova, I.G., Genkina, G.K., Kalyanova, R.M., and Kabachnik, M.I., J.Gen.Chem.USSR, (Engl.trans1.). 1987, 57, 2172. 71. Hotoda, H., Ueno, Y., Sekine, M., and Hata, T., Tetrahedron Lett., 1989, 30, 2117. 72. Khaskin, B.A., Sheluchenko, O.D., Torgasheva, N.A., and Ishmuratov, A.S., J.Gen.Chem.USSR,(Engl.transl.), 1988, 58, 923.

196

Organophosphorus Chemistry

Kamalov, R.M., Makarov, G.M., Zimin, M.G., Cherkasov, R.A., and Pudovik, A.N., J.Gen.Chem.USSR,(Engl.transl.), 1988, 58, 202. 74. Ye, M-C., Li, Li-P., Zhao, Y-F., and Zhai, C.,Phosphorus Sulfur, 1988, 39, 79. 75. Edmundson,R.S. and King, T.J.,J.Chem.Res.(S), 1989, 122. 76. Cocks, S. and Modro, T.A., S.Afr.J.Chem., 1988, 41, 56. 77. Benmaarouf-Khallaayoun, Z., Baboulsne, M., and Speziale, V., Phosphorus Sulfur, 1988, 36, 181. 78. Jardine, A.M., Vather, S.M., and Modro, T.A., J.Org.Chem., 1988, 53, 3983. 79. Symes, J., Modro, T.A., and Niven, M.L., Phosphorus Sulfur, 1988, 36. 171. 80. Kutyrev, A.A., Ovrutskii, D.G., and Moskva, V.V., J.Gen.Chem.USSR, (Engl.transl.), 1988, 699. 81. Tanaka, T., Yamada, Y., Uesugi, S., and Ikehara, M., Tetrahedron, 1989, 45, 651. 82. Liu, H-J., and Nyangulu, J.M., Tetrahedron Lett., 1988, 29, 3167. 83. Lowe, G. and Potter, B.V.L., J.Labelled Compd.Radiopharm., 1989, g,63. 84. Yoneda, R., Harusawa, S., and Kurihara, T., J.Chem.Soc.Perkin 1, 1988, 3163. 85. Shiori, T., Murata, M., and Hamada, Y., Chem.Pharm.Bull., 1987, 35, 2698. 86. Kim, S., Chang, H., and KO, Y.K., Bull.Korean Chem.Soc., 1987, 8, 471; Chem.Abstr., 1988, 109, 190790. 87. Capobianco,M., Colonna, F.P., and Garbesi, A., Gazz.Chim.Ital., 95695. 1988, 118,549;Chem.Abstr., 1989, g , 88. Roelen, H.C.P.F., de Vroorn, E., van der Marel, G.A., van Boom, J.H., Nucleic Acids Res.. 1988, Is, 7633. (a) Horiki, K., Pept.Chem., 1987 (Pub1.1988), 239: (b) Katti, S.B., Misra, P.K., Haq, W., and Mathur, K.B., Indian J.Chem. Sect.B., 1988, 11,3. 90. Masse, G. and Sturtz, G., Synthesis, 1988, 907. 91. Zawadzki, S., Phosphorus Sulfur, 1988, 40, 263. 92. Dehmlow, E.V. and Sauerbier, C., Z.Naturforsch. Teil B, 1989, 44, 240. 93. Teulade, M.P. and Savignac, P., Janssen Chim.Acta, 1988, 2, 3; Chem. Abstr., 1989, 2, 95397. 94. Kostka, K., and Ochocki, J., Pol.J.Chem., 1987, 177;Chem.Abstr., 1989, 110, 192922. 95. Mouysset, G., Bellan, J., Payard, M., and Tisne-Versailles, J., Farmaco.,Ed. Sci., 1987, 42, 805; Chem.Abstr., 1988, 109, 170552. 96. Mos?hidis, M.C., Chem.Phys.Lipids, 1988, 46, 253. 97. Hol9. A. and Rosenburg, I., Coll.Czech.Chem.Commun., 1987,x. 2801. 98. McClard, R.W., and Jackson, S.A., Phosphorus Sulfur, 1988, 39, 27. 99. Niedermann. H-P., Eckes, H-L., and Meier, H., Tetrahedron Lett., 1989, 30, 155. 100. Kirn,D.c and Oh, D.Y., Synth.Comrnun., 1987, 17,953. 101. Zbiral, E. and Drescher, M., Synthesis, 1988, 735. 102. Epstein, W.W. and Garrossian, M., Phosphorus Sulfur, 1988, 2,349. 103. Lewis, R.T. and Motherwell, W.B., Tetrahedron Lett., 1988, 29, 5033. 104. Ye, W., Liao,X., and Luo, Y., Youji Huaxue, 1988, 8, 361; Chem.Abstr., 1989, 110, 135370. 105. Schoen, W.R. and Parsons, W.H., Tetrahedron Lett., 1988, 2,5201. 106. McFadden, H.G., Harris, R.L.N., and Jenkins, C.L.D., Aust.J.Chern., 1989, 92, 301. 107. Rosenberg, I. and Holy/, A., Collect.Czech.Chem.Commun., 1987, 52, 2792, 2801. 108. Czekanski, T., Witek, S., Gross, H., and Costisella, B., Wiad. Chem., 1987, 41,801. 109. Lu, X., Zhu, J., Huang, J., and Tao, X., J.Mol.Catal., 1987, 5, 235. 110. Berdnik, I.V., Sentemov, V.V., Shegvaleev, F.Sh., Zykova, T.V., and Krasil’nikova, E.A., J.Cen.Chem.USSR,(Engl.transl.), 1988, 58, 265. 111. Maruyama, T., Kimura, S., and Honjo, M., Org.Prep.Proced.Int., 1988, 3 , 485. 112. Renger, B., Phosphorus Sulfur, 1988, 35, 215. 73.

s,

197

5: Quinquevalent Phosphorus Acids

113. Kadyrev, A.A. and Rokhlin, E.M., Russ.Chem.Revs.(Engl.transl.), 1988, 57, 852. 114. Nickson, T.E., J.Org.Chem., 1988, 53, 3870. 115. Zhao, Y., Wei, S., Song, A., and Zhai, C.,Phosphorus Sulfur, 1987, 33, 53. 116. Fild,M., Handke, W., and Rieck, _____ Chem.-Ztg., 1988, 112, 107. 117. Xu, Y., Wei, H., Zhang, J., and Huang, G., Tetrahedron Lett., 1989, 30, 949. 118. k v r i n , V.Yu. and Moskva, V.V., J .Gen.Chem.USSR (Engl.transl. 1 , 1988, 58, 617. 119. Sonderikhin, A.I., Dogadina, A.V.. Ionin, B.I., and Fetrov,A.A., J.Gen.Chem.USSR (Engl. transl.), 1988, 58, 1483. 120. Belakhov, V.V., Yudelevich, V.I., Ionin, B.I., Komarov, E..V., and Petrov, A.A., J.Gen.Chen. USSR(Eng1. transl.), 1988, 58, 1059. 121. Kalinov, S.M., Rostovskaya, M.F., and Vysotskii, V.I., J.Gen.Chem.USSR (Engl.transl.), 1988, 2 , 693. 122. Yamamoto, H., Hanaya, T . , Kawamoto, H., and Inokawa, S., Chem.Lett., 1989, 121. 123. McKenna, C.E., Khawli, L.A., Ahmad, W-Y., Fham, P., and Bongartz, J-P., Phosphorus Sulfur, 1988, 37, 1. 124. Koizumi, T., Hagi, T., Horie, Y., and Takeuchi, Y., Chem.Pharm.Bull., 1987, 35, 3959. 125. Burton, D.J.,Modak, A.S., Guneratne, R., Su,D., Cen,W., Kuchmeier, R.L., and Shreeve, J.M., J.Amer.Chem.Soc., 1989, 111,i773. 126. Burton, D.J. and Sprague, L.G., J.Org.Chen., 1989, 54, 613. 127. Blackburn, G.M. and Taylor, G.E., J.Organomet.Chem., 1988, 348, 55. 128. Kim, T.H. and Oh, D.Y., Synth.Commun., 1988, 18, 1611. 129. Filonenko, L.P., Bespal'ko, G.K., Marchenko, A.P., and Pinchuk, A.M., J.Gen.Chem.USSR (Engl. transl.), 1987, 57, 2074. 130. Francke,R. and Rueschenthaler, G.V., Chem.-Ztg., 1987, 111,307. 131. Francke, R. and Roeschenthaler, G.V., Phosphorus Sulfur, 1988, 36, 125. 132. Kanaan, M. and Burgada, R., Phosphorus Sulfur, 1988, 58, 217. 133. Kim, D.Y., Kim, T.H., and Oh, D.Y., Phosphorus Sulfur, 1987, 34, 179. 134. Costisella, B., and Keitel, I., Phosphorus Sulfur, 1988, 40, 161. 135. Mikodajczyk, M., and Bal'czowski, P., Synthesis, 1989, 101. 136. Kolodyazhnyi, 0.1. and Golokhov, D.B., J.Gen.Chem.USSR (Engl.transl.), 1987, 57, 2353. 137. Teulade,M.P. and Savignac, P., J.Organomet.Chem., 1988, 338, 795. 138. Al'fonsov, V.A., Nizamov, I.S., and Katsyubova, S.A., J.Gen.Chem. USSR(Eng1. transl.), 1988, 58, 1131. 139. Karaman, R., Goldblum, A., Breuer, E., and Leader, H., J.Chem.Soc.,Perkin Trans. 1, 1989, 765. 140. Moskva, V.V. and Mavrin, V.Yu., J.Gen.Chern.USSR(Engl.Transl.), 1987, 57, 2492. 141. McKenna,C.E. and Levy, J.N., J.Chern.Soc.,Chem.Cornmun., 1989, 246. 142. Roussis, V. and Wiemer, D.F., J.Org.Chem., 1989, 627. 143. Oehler, E., Kang, H-S., and Zbiral., E., Synthesis, 1988, 623. 144. Natchev, I.A., Tetrahedron, 1988, 44, 6455. 145. Pudovik, A.N., Khairullin, V.K., and Vasyanina, M.A., J.Gen.Chem.USSR (Engl. transl.), 1988, 58, 1328. 146. Kovalenko, L.V., Sosnov, A.V., and Buvashkina, N. I., J .Gen.Chem.USSR (Engl. transl.), 1987, 57, 2351. 147. Giordano, C. and Castaldi, G., J.Org.Chem., 1989, 54, 1470. 148. Rynbov, B.V., Ionin, B.I., and Terov, A.A., J.Gen.Chem.USSR (Engl.transl.), 1988, 859. 149. Fluck, E., Riedel, R., and Fischer, P., Phosphorus Sulfur, 1987, 33, 115. 150. Fluck, E., and Riedel, R., Phosphorus Sulfur, 1987, 33, 121. 151. Litvinov, I.A., Struchkov, Yu.T., Naumov, V.A., Shapirov, S.M., and Vizel, A.O., Bull.Acad.Sci.USSR,Div.Chern., 1987, 1399. 152. Brel', V.K., Cheklov, A.N., IOnin, B . I . , and Martynov, I.V., J.I;en.Chen.USSR(Engl.tr-ansl.), 1988, 58, 663

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Organophosph oms Chemistry

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,

153. Angelov, Kh. and Enchev, D.D., Phosphorus Sulfur, 1987, 34, 163. 154. Angelov, C.M., Enchev, D.D., and Kirilov, M., Phosphorus Sulfur, 1988, 35, 35. 155. Christov, V.Ch. and Angelov, C.M., Phosphorus Sulfur, 1988, 40, 155. 156. Natchev,I., Phosphorus Sulfur, 1988, 37, 133. 15'7. Natchev,I., Phosphorus Sulfur, 1988, 37, 143. 158. Natchev,I., Tetrahedron, 1988, 2 , 6465. 159. Dhawan, B. and Redmore, D., J.Chem.Res.(S), 1988, 34. 160. Tyka, R., Haegele, G., and Peters, J., Phosphorus Sulfur, 1987, 2, 31. 161. Sampson, N.S. and Bartlett, P.A., J.Org.Chem., 1988, 53, 4500. 162. Kashemirov, B.A., Skoblikova, L.I., and Khokhlov, P.S., J.Gen.Chem.USSR(Engl.transl,), 1988, 58, 621. 163. Belakhov,V.V., Yudelevich, V.I., Ionin, B.I., and Shneider, M.A., J.Gen.Chem.USSR (Engl.transl.), 1988, 58, 1097. 164. Burkhouse, D.W. and Zimrner, H., Synth.Commun., 1988, 18, 1437. 165. Genet, J.P., Uziel, J., and Juge, S., Tetrahedron Lett., 1986, 2 , 4559. 166. Jacquier, R., Ouazzani, F., Rournestant, M.L., and Viallefont, P., Phosphorus Sulfur, 1988, 36, 73. 16'7. Solodenko, V.A. and Kukhar', V.P., J.Gen.Chem.USSR (Engl. transl.), 1987, 57, 2139. 168. Sawamura, M., Ito,Y., and Hayashi, T., Tetrahedron Lett., 1989, 30, 2247 169. Nizamov, I.S., Al'fonsov, V.A., Batyeva, E . S . , and Pudovik, A.N., BulL.Acad.Sci.USSR,Div.Chem., 1987, 2412. 170. Nifant'ev,E.E., Popkova, T.N., Kukhareva, T.S., and Bekker, A.R., J.Gen.Chern.USSR(Engl.transl.), 1988, 58, 1379. 171. Schrader, T. and Steglich, W., Synthesis, 1989, 97. 172.3 Diel , P.J. and Maier, L . , Phosphorus Sulfur, 1988, 36, 85. 173. Diel, P.J. and Maier, L., Phosphorus Sulfur, 1988, 2 , 159. 1 7 4 , Cameron, D.G., Hudson, H.R., Ojo, I.A.O., and Pianka, M., Phosphorus Sulfur, 1988, 40, 183. 175. (a) Aksinenko, A.Yu., Pushin, A.N., Sokolov, V.B., Gontar', A.F., and Martynov, I.V., Rull.Acad.Sci.USSR, Div.Chem., 1987, 1090; (b) Martynov, I.V., Chekhlov, A.N., Aksinenko, A.Yu., Pushin, A.N., Sokolov, V.B., and Gontar', A.F., J.Gen.Chern.USSR (Engl.transl.), 198'7,57, 2043. S y n t h e s i s , 1989, 52. 176. Wasiel ewski , C . , Dembkowski , L. , and Topolski, 177. Lazukina, L.A. and Kukhar-, V.P., J.Gen.Chem.USSR (Engl. transl.), 1988, 58, 833. 178. Harnmerschmidt, F., Justus Liebigs Ann.Chem., 1988, 531. 179. Hammerschmidt, F., Justus Liebigs Ann.Chem., (a) 1988, 537; (b) 1988, 955; (c) 1988, 961. 180. Hammerschmidt, F. and V6llenkle, H., Justus Liebigs Ann. Chem., 1989, 577. 181. Natchev, I.A., J.Chem.Soc.,Perkin Trans. 1, 1989, 125 182. Diel, P.J., Dingwall, J.G., and Maier, L.,Phosphorus S u l f u r , 1988, 39, 253. 183. Logusch, E.W., Walker, D . M . , McDonald, J.F., Leo, G.C., and Frariz, J.E., J.Org.Chem., 1988, 53, 4069. 184. Parsons, W.H., Patchett, A.A., Bull, H.G., Schoen, W.R., Taub, D., Davidson, J., Combs, P.L., Springer, J.P., Gadebusch, H., Weissberger, B., Valiant, M.E., Mellin, T.N., and Busch, R.D., J.Med.Chem., 1988, 31, 1772. 185. Ku, B. and Oh, D.Y., Tetrahedron Lett., 1988, 29, 4465. 186. Valerio, R.M., Alewood, P.F., and Johns, R.B., Synthesis, 1988, 786. 187. Rapp, C., Jung, G., Kugler, M., and Loeffler, W., Justus Liebigs Ann.Chem., 1988, 655. 188. Natchev, I.A., g.Chem.Soc.Japan, 1988, 5,3711. 189. Natchev, I.A., Tetrahedron, 1988, 44, 1511. 190. Ornstein, P.L., J.Org.Chem., 1989, 54, 2251. 191. Ornstein, P.L., Schaus, J.M., Chambers, J.W., Huser, D.L., Leander, J.D., Wong, D.T., Paschal, J.W., Jones, N.D., and Deeter, J.B.. J.Med.Chem., 1989, 32, 827. Is;,

5: Quinquevalent Phosphorus Acids

I99

192. Morita, I., Tada, S., Kunimoto, K., Tsuda, M., Kise, M., and Kirnura, K., Chem.Pharm.Bull., 1987, 33, 3898. 193. Morita, I., Tsuda, M., Kise, M., and Sugiyama, M., Chem.Pharrn.Bull., 1988, 36, 1139. 194. Haelters, J.P., Corbel, B., and Sturtz, G., Phosphorus S u l f u r , 1988, 3'7, 41. __ 195. Haelters, :.P., Corbel, B., a n d SturLz, G., Phosphorus S u l f u r , 1988, 37, 65. 196. Fentiman, A.F., NTIS Report Order No. AD-A179265/4/GAR;Chem.Abstr., 1'388, 9, 149622. / 197, Dimukharnetov, M.N. and Isrnaev, I . E . , Bull.Acad.Sci.USSR, Div.Chem., 1'388, 331. 198. Nsvech, J., Revcl , M. ,and MCitlii~u, S .,Phosphorus S u l f u r , 1988, 2 , 33. 199, Cherezova, E.N., Cherkasova, O.A., and Mukrneneva, N.A., J.Gen.Chern.USSI3 (Engl. transl.), 1987, 5'7, 2402. 200. D;J Mont, W-W., Hensel, R., McFarlane, W., Colquhoun, I.J., Ziegler, M.L., and Serhadll, O., Chem. Ber., 1989, 122, 37. 201. Fild, M., Fischer, R. , d n d Hdndkc:,W., Z.Anorg.Allg.Chem., 1988, 3 1 , 157. 202. Fild, M., Bunk?, 3., and Schomburg, D., Z.Anorg.Allg.Chem., 1988, 566, 90. 203. Kohler, H., Kretschmann, M., Jager, L., Gebel, W., Uebel, R., Heine, P., and Fischer, R., Z.Anorg. Allg.Chem., 1989, 568, 35. 204. Mahrnood, 'I.,Bat,, J.M., Kirchrneier, R.L., and Shreeve, J.M., Inorg.Chem., 1988, 27, 2913. 205. Vovk, M.V. and Lanin, A.G., J.Gen.Chem.USSR ( E n g l . transl.), 1988, 58, 1035. 206. Ibrahirn, E.H. and Alnaimi, I.S., Arab. Gulf J.Sci.Res.,Sect.A, 1987, 2, 37. 207. Snaw, R.A. and Watkins, D.A., J.Chem.Soc.Dalton Trans., 1988, 2591. 208. Masse, G. and Sturtz, G., Synthesis, 1988, 904. 209. B3yd, D.R., Malone, J.F., McGuckin, M.R., Jennings, W.B., Rutherford, M., arld Saket, B.M., J.Shem.Soc.,PerL,in Trans. 2, 1988, 1145. 210. Hewitt, D., Adv. Heterocycl. Chem., 1988, 43, 1. 107. 211. Pashkevich, K.I. and Busygin, I.G., Sulfur Lett., 1988, 212. Demir, T., Raveney, F.J., and Shaw, R.A., Phosphorus Sulfur, 1987, 33, 155. 213. Muller, A.J., J.Org.Chem., 1988, 53, 3364. 214. Pieper, W., HaFgele, G., and Gaedcke, A., Chern.-Ztg., 1987, 111, 229. 215. Breuer, E., Xaraman, R., Leader, H., and Goldblurn, A. ,Phosphorus Sulfur, 1987, 33, 61. 216. Breuer, E., Kararnan, R., Goldblurn, A., and Leader,H.,J.Chem.Soc., Perkin Trans. 2 , 1988, 2029. 217. Dhawan, B. and Redmore, D., J.Chern.Res.(S), 1988, 222. 218. Stowell, M.H.B., Witte, J.F., and McClard, R.W.,Tetrahedrori Lctt., 1989, 30, 411. 219. Belykh, O.A., Dogadina, A.V., Ionin, B.I., and Petrov, A.A., J.Gen.Chern.USSR (Engl.transl.), 1987, 57, 2404. 220. Modro, A.M. and Modro, T.A., Can.J.Chern., 1988, 66, 1541. 221. Teulade, M.P., Savignac, P., A-Jaudet, E., and Collignon,N., Phosphorus S u l f u r , 1988, 5, 105. 222. Kutyrev, G.A., Korolev, O.S., Yarkova, E.G., Lebedeva, O . E . , Cherkasov, R.A., and Pudovik, A.N.,J.Gen.Chern.USSR (Engl.transl.1, 1988, 58, 1145. 223. Khusainova, N.G., Sippel', I.Ya., Berdnikov, E.A., Cherkasov, R.A., and Pudovik, A.N., J.Gen.Chern.USSR (Engl-transl.), 1988, 58, 880. 224. Mahran, M . R . , Abdou, W.M., Ganoub, N.A.F., and Sidky, M.M., Phosphorus Sulfur, 1988, 40, 19. 225. Khusainova, N.G., Sippel', I.Ya., Cherkasov, R.A., and Pudovik, A.N., J.Gen.Chem.USSR (Engl.transl.), 1988, 58, 1025. 226. Enchev, D., Angelov, C.M., and Kirilov,M., Chern.Scr., 1987, g ,295. 227. Belykh, O.A., Sokolov, V.V., Dogadina, A.V., Ionin, B.I., and Petrov,A.A., J.Gen.Chern.USSR (Engl.transl.), 1988, 58, 837.

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228. Dangyaii, Yu.M., Tirakyan, M.R., Panosyan, G.A., Denisenko, V.I., and Badanyan, Sh.O., J.Gen. Chem.USSR (Engl.transl.), 1988, 58, 1102. 229. Ryazantsev. E .N., Ponoiliarev, D.A., arid *il 'bitskaya, V.M., J.Gen.Chem.USSR (Engl.transl.1, 1987, 57, 2056. 230. Ivanova, V.N., Sokolov, M.P.,Buzykin, B.I.,Pavlov, V.A., Liorber, B.G., Zykova, T.V., Shagvaleev, F.Sh., Alparova, M.V., and Chertanova, L.F., J.Gen.Chem.USSR (Engl.transl.), 1987, 57, 2198. 231. Mikityuk, A.D., Kashemirov, B.A., Strepikheev, Yu.A.,and Khokhlov, P.S., J.Gen.Chem.USSR (Engl.transl.), 1987, 57, 2047. 232. Breuer, E., Karaman, R., Goldblum, A., Gibson, D., Leader, H., Potter, B.V.L. and Cummins, J.H., J.Chem.Soc.,Perkin Trans. 1, 1988, 3047. 233. Aksnes, G., Gierstae, R., and Wulvik,E.A.,chosphorus Sulfur, 1988, 2 , 141. 234. Chekhlov, A.N., Solov'iev, V.N., Makhaeva, G.F.,Yankovskaya, V.L., Bovin, A,N., Degtyarev, A.N., Tsvetkov, E.N., and Martynov, I . V . , J.Gen.Chem.USSR (Engl.transl.), 1988, 58, 1299. 235. Yuan,G., Li,S., and Liao,X., Phosphorus Sulfur, 1988, 37, 205. 236. Baranskii,V.A., Eliseeva,G.D., and Sukharukova, N.A., J.Gen.Chem.USSR 687. (Engl.transl.), 1988, 237. De Keijzer,A.E.H., Koole, L.H., Van der Hofstad, W.J.M., and Buck, H.M., J.Org.Chem., 1989, 54, 1453. 238. Avila,L.Z., and Frost,J.W.,J.Amer.Chem.Soc., 1988, 110, 7904. 239. Krauch,T and Schweizer,B.,Phosphorus Sulfur, 1988, 35, 207. 240. Bruzik,K.S., and Stec,W.J., Phosphorus Sulfur, 1988, 35, 229. 241. Doi,J.T. and Musker, W.K., Phosphorus Sulfur, 1988, 35, 173. 242. Bartlett, P.A. and McLaren,K.L., Phosphorus Sulfur, 1987, 2,1. 243. Freeman,S. and Harger, M.J.P., J.Chem.Soc.,Perkin Trans. 1, 1988, 2737. Trans.1, 1989, 563. 244. Harger, M.J.P. and Williams,A.,J.Chem.Soc.,Perkin__245. Denmark, S.E. and Dorow, R.L., J.Org.Chem., 1989, 54, 5. 246. Freeman,S and Harger, M.J.P., J.Chem.Soc.,Perkin Trans.1, 1989, 571. 247. Ripperger, H., J.Prakt.Chem., 1987, 329, 1039. 248. Kiso, Y., Shimokura,M., Narukami, T., and Kimura, T., Pept.Chem., 1987 (Publ. 1988), 219. 249. Kim,S., Lee,P.H., and Lee, T.A., J.Chem.Soc.,Chem.Commun., 1988, 1242. 250. Michael, J.P., Reid, D.H., Rose, B.G., and Speirs, R.A., J.Chem.Soc.,Chem.Commun., 1988, 1494. 251. Sosnovsky, G. and Purgstaller, K.,Z.Naturforsch. Teil B, 1989, 44, 582.

z,

Nucleotides and Nucleic Acids 1. Introduction

BY J. B. HOBBS

While efforts to optimize DNA synthesis and improve RNA synthesis continue in chemical laboratories, those laboratories concerned with molecular biology appear content to utilize the current state-of-the-art in DNA synthetic technology without worrying about perfection. Beyond question, the advent of modern DNA synthesizers has revolutionized molecular biology, and it was noted, in a preface to a comprehensive list of the genes synthesized chemically up to May lst, 1988, that 'entries on synthetic genes multiplied by a factor of approximately twelve in only six years between 1982 and 1987'!l And little wonder: in a survey of the capabilities and output of 40 protein and nucleic acid synthesizing core facilities, it was determined that a 25-residue oligodeoxyribonucleotide can be synthesized for US $250.00, the total work output per month of an average facility being 16 oligonucleotides (besides other items).2 So, forty such facilities could prepare around 8,000 oligonudeotides per year: no wonder the journals dealing with research involving nucleic acids are expanding at an explosive rate. The potential rewards of control of translation and other gene-associated processes via the use of anti-sense oligonucleotides are now stimulating much interest in oligodeoxyribonucleotidescontaining modified internutleotidic links such as phosphorodithioates, phosphoramidates, and even with cationic groups attached to the link, while interest in phosphorothioates continues high. Many new uses of the Polymerase Chain Reaction (PCR) have been described, including its application for DNA sequencing. Automated sequencers, their development no doubt stimulated by the Human Genome Project, have been described, and in many cases function by automated reading of gel-separated bands generated by extension of fluorophore-bearing oligonucleotide primers. A substantial book dealing with new nucleic acid techniques, both chemical and molecular biological, has appeared3, and, as usual, several symposium reports demand commendation for the wealth of interesting papers which they contain.4 2. Mononucleotides 2.1 Chemical Svnthesis - Bis[2-(4-nitrophenyl)ethyl]phosphorochloridate has been described as a highly efficient phosphorylating agent, reacting at the 5' - or 3'positions of appropriately protected nucleosides to form the nucleosidyl bis 1244nitrophenyl) ethyl] phosphotriesters in high yield.5 Deblocking via P-elimination gives the corresponding 5'- or 3'-phosphates. The reagent also conveniently permits

202

Organophosphorns Chemistly

introduction of 5'- or 3'- terminal phosphates in oligonucleotide synthesis. The rate by diethylphosphoroof phosphorylation of 3'-Q-benzoyl-2'-deoxythymidine chloridate in pyridine is enhanced to a remarkable degree by a quantity of sodium iodide equimolar with the phosphorylating agent: similar rate enhancement was seen with diphenylphosphorochloridate,diphenylphosphoro-1~-l,2,4-triazolide, tetraphenylpyrophosphate and 2-chloropheny1(2,2,2-trichloroethyl) phosphorochloridate.6 The corresponding iodophosphates (1) are thought to be formed as intermediates. Elemental iodine could act in place of iodide as a catalyst in the presence of pyridine in reactions using phosphorochloridates but not the other agents: again species (1) are thought to be formed with co-production of iodine monochloride. Iodide was similarly effective to &J-methylimidazole in catalyzing the condensation of 5'-~-dimethoxytrityl-2'-deoxythymidine-3'-(4-chlorophenyl) phosphate with 3'-Q-benzoyl-2'-deoxythymidine using N-N-bis(2-0x0-3oxazolidinyl) phosphorodiamidic chloride. The attempted use of iodide with arylsulphonyl chlorides led to redox reactions, however. 942-Deoxy-P-Dribofuranosyl)-2,6-diaminopurineis not phosphorylated easily by conventional procedures owing to its high lability in acid. However, treatment of the nucleoside with tributylammonium phosphite and DCC in DMF-pyridine affords a moderate yield of the H-phosphonate (2) which gives the 5'-phosphate on oxidation with alkaline permanganate.7 Very high yields of deoxynucleoside 5'-phosphorothioates have been reported on treating the unprotected nucleosides with thiophosphoryl chloride in triethyl- or trimethylphosphate at 00 C in the presence of pyridine, followed by aqueous workup.8 Alternatively, treatment of the intermediate 2'-deoxynucleoside 5'thiophosphorodichloridates with pyrophosphate affords the corresponding 5'- (1-thiotriphosphates, again in high yields. 6-15N- and l-I5 N- labelled AMP species have been prepared from the 2',3'-~-isopropylidenederivatives of the correspondingly labelled nucleosides using 2-cyanoethylphosphate and DCC . 9 The first-order rate constants for mutual isomerization, hydrolytic dephosphorylation and depurination of 2-AMP and 3'-AMP have been measured over a wide range of pH values using h.p.l.c.10 Interconversion of the nucleotides is first order with respect to hydronium ion concentration at pH 4, approaches second order in the pH range between 1 and 2, and is essentially independent of pH between 3 and 6, the equilibrium mixture containing 30 % 2'-AMP and 70% 3'-AMP. Hydrolysis of adenosine-2', 3'-monophosphate gives the same product distribution, but incorporation of oxygen-18 from labelled solvent water is much slower than acidcatalyzed interconversion, indicating that the main reaction pathway does not proceed via the cyclophosphate. The putative mechanism of isomerization in the pH range 3-6 is shown (Figure 1). Dephosphorylation was thought to proceed without invohement of neighbouring hydroxy groups via intermediates of type ( 3 ) which decompose to afford the nucleoside and monomeric metaphosphate, either

6: Nucleotides and Nucleic Acids

203

0 R'-O-P-I

II I

R Z0 HO (?) R ' = R Z = Et or Ph or R ' = 2 CIC6H4- ; R 2 = CC13CH2-

-

HO 0

I

-0-P-

OH

II 0

0 OH

I

H0-P -0-

II

0 Figure 1

(2)

204

Organophosphorus Chemistry

free or pre-associated with water. In a study of the acidic hydrolysis of the glycosidic bond in deoxynucleotides under various conditions of pH and temperature, the presence of a 5'-phosphate group was reported to reduce the rate of glycosidic hydrolysis from that observed in the corresponding deoxynucleosides, and the additional presence of a 3'-phosphate group to reduce the rate still further.ll The basecatalyzed cyclization of a series of aryl esters of 3'-UMP (4), prepared conventionally from 2;5'-Q,Qbis (tetrahydropyranyl) uridine and the corresponding aryl phosphorodichloridates, has been investigated using imidazole and hydroxide ion at 250 C and constant (0.25 M) ionic strength.12 Calculations using the resultant data suggest that the changes in the charges on the base and the leaving group in the transition state do not balance and indicate a build-up of negative charge on the 2'-oxygen and/or the phosphorus atom and its pendant oxygens. Comparison with other literature data on intermolecular reactions of this type suggest that the excess charge is localized largely on the 2'-oxygen atom, i.e. that (5) represents the charge distribution rather than (6). The same esters (4) are substrates for bovine RNase A, and again Br+nsted dependence of the rate constants is seen, but the Brqnsted coefficients indicate that now far less development of negative charge on the leaving group oxygen occurs, in the transition state, compared with that seen in imidazole-catalyzed non-enzymic cyclization, suggesting that electrophilic assistance is involved in enzymic catalysis.13 From an extensive and intriguing study of the cleavage and isomerization of UpU and U (2') pU by imidazole buffers, it has been deduced that a sequential bifunctional mechanism occurs, with imidazolium ion catalyzing the formation of a phosphorane anion intermediate (7)) and imidazole catalyzing its decompostion to cleavage products.14 A critical observation in reaching this conclusion was that the rates of isomerization of UpU and U(2')pU are first order in total buffer concentration at constant pH, but increase steadily with increasing ratio of imidazolium ion: imidazole, showing that buffer-catalyzed isomerization (involving (7) as intermediate) is catalyzed solely by the imidazolium cation. Since a plot of the rate of cleavage versus pH shows a bell-shaped curve, catalysis by imidazole is also involved in the overall cleavage reaction, and, since the rate constants for cleavage are first order in total buffer concentration and exclude simultaneous catalysis by imidazolium ion and imidazole, the cyclization step to form (7)is thought to be catalyzed by imidazolium ion and the cleavage of (7) by imidazole. Note that this is the reverse of the prediction made on stereoelectronic grounds and reported last year.15 The authors argue that in the cyclization step, protonation of phosphate occurs, followed by nucleophilic attack by the 2'-OH group with imidazole acting as general base: the catalytic combination of proton and imidazole is kinetically equivalent to imidazolium ion. In the cleavage step, the preferred suggestion is that imidazolium ion protonates -OR, the leaving group, with hydroxide ion also acting to remove the proton from P-0-H of (7), the combined effect of hydroxide and imidazolium being kinetically equivalent to

205

6: Nucleotides and Nucleic Acids

Hovra 0 OH

HO +OH

I 0=6-mr

I

o=p-o-

I

I 0-

-0

(3)

0 (5)

0 -(Urd - 5 ’ ) (8)

His-12

0- (Urd - 5’) (9) Figure 2

206

Orguri ophosphoms Chemistiy

imidazole. Based on this mechanism, the authors have offered a reinterpretation of the mechanism of RNA cleavage by bovine pancreatic ribonuclease, which begins (Figure 2) with the enzyme-bound substrate (8) becoming transformed either in two steps or possibly concertedly to intermediate (9). Protonated lysine-41 (not shown in the diagram) stabilizes (9) by ion-pairing. Histidine-119 then serves as recipient of the phosphorane proton, transferring it to the 5'-oxygen of the uridyl leaving group, which is expelled with collapse of the phosphorane and formation of the cyclic phosphate. The suggested mechanism for cleavage of the cyclic phosphate also incorporates elements derived from the model study. The structure of the complex of ribonuclease Ti with 2'-GMP has been solved at 1.9%,resolution, the geometry of the active site being consistent with a mechanism wherein histidine -40 and/or glutamate-58 play roles corresponding to that of histidine -12 in (8), with histidine 92 having similar function to that of histidine -119 in (8)16. An improved synthesis of glycinamide ribonucleotide has been achieved by treating (10) with dibenzyl J F N-diisopropylphosphoramidite and tetrazole, oxidizing the phosphite triester obtained using MCPBA, and conventional deb10cking.l~ In a study of the rate constants for the alkaline ring-opening of the imidazole ring of 7-methyl-5I-GMP and several analogues (including 7-methylguanosine), the negative charge on the phosphate group markedly retarded attack by hydroxide ion at C-8 in the nucleotide.18 However, in a comparison of the hydrolytic stability of (111, the the glycosidic bond in 7-methyl-5I-GMPwith that of its =-counterpart influence of the intramolecular electrostatic interactions was found to be negligible.19 A substantial number of analogues (1 2) of 7-methyl-5I-GMP have been prepared by alkylation of GMP and assayed as competitive inhibitors of translation of capped mRNA in rabbit reticulocyte lysate. Generally, substituents at N-7 larger than the ethyl group decreased the inhibitory activity compared with 7-methylGMP, but the 7-benzyl- and 7-(2-phenyl) ethyl-analogues were more effective.20 The 7-benzyl- and 7-ethyl-analogues of the 'cap' structure m7G(5') pppG were prepared by methods reported previously and incorporated into artificial globin mRNA species by transcriptional priming using the 'cap' analogue, DNA complementary to rabbit P-globin, and T7 RNA polymerase. The 7-benzylguanine-capped globin mRNA displayed nearly twice the activity of normal 7-methylguanine-capped globin mRNA in a transcription assay, while that of 7-ethylguanine-capped mRNA was somewhat less. The differences are ascribed to relative affinities for the capbinding proteins. The search for efficacious anti-HIV agents shows no sign of slackening. 2',3'-Didehydro-2',3'-dideoxythymidine (13) has been converted to its 5'monophosphate (14)conventionally using phosphoryl chloride in trimethylphosphate followed by hydrolysis, and to its 5'-triphosphate (15) by intercepting the 5'-phosphordichloridate intermediate with pyrophosphate.21 The

6: Nucleotides and Nucleic Acids

207

0 II

H o ~ ~ H C O C H 2 N H C O O C Ph H2

-0

0 0

CH20H

CHzOH

MeXMe

(10 1

(11 1

Rib- 5'- P (12) R = Et.Prn, P r ' , B u n , B u i ,PhCH2, PhCH2CH2, PhCHCH,, CH,COOH, c yclopenty l

OCHF2 N

y

Fhy DMT OA N

HO

0

NH I

0

CN-P=O HO

I

A (16)

(1 7)

AcO (18) R1=Br;R 2 = 4 - C I C ~ H ~ (19) R1=Me ; R Z =H

208

Organophosphorus Chemistry

triphosphate is a comparably powerful inhibitor of HIV reverse transcriptase in a (AZT), but model system to the 5'-triphosphate of 3'-azido-2',3'-dideoxythymidine (13) appears less cytotoxic than AZT. However, AZT is readily phosphorylated to its 5'-monophosphate in a test cell line (MT-4 cells) while (13) is phosphorylated far less efficiently, and work using a different, thymidine kinase-deficient, cell line suggests that different kinases may be responsible for the phosphorylation of AZT and (13), at least in some cells. Studies on the activation of 2',3'-dideoxyadenosine, another anti-HIV agent, in human T-lymphoid cells suggest that the main pathway of phosphorylation to the active nucleotides involves deamination to 2',3'-dideoxyinosine, which is then phosphorylated to its 5'-monophosphate by a kinase of uncertain identity (not adenosine kinase or deoxycytidine kinase) and then aminated enzymically to 2',3'-dideoxyadenosine 5'-monophosphate.23 Direct phosphorylation of the nucleoside by adenosine kinase or deoxycytidine kinase makes a relatively minor contribution. 5'-Amino-2',5'-dideoxythymidine has been treated with bis(ethy1eneimine) phosphinic chloride to afford the diaziridinylphosphinic amide (161, and its isomer (17) has reportedly been prepared by treating 3'-amino-2',3'-dideoxythymidinewith phosphoryl chloride and triethylamine in THF-DMSO, followed by a ~ i r i d i n e The .~~ latter showed higher activity in inhibiting replication of L1210 cells. Several dinucleoside monophosphates containing modified bases have been reported and studied. Analogues of d(TpT) with @ethylthymine replacing either of the thymine bases have been prepared using standard phosphotriester procedures, with introduction of the ethoxy group being realized by displacement of triazole from a 4-triazolylpyrimidin-2-one species by ethoxide at an appropriate point in the syntheses.25 The products were subjected to IH-n.m.r., CD and FABm.s. analysis. 5-Substitu ted-4-Q-difluorome thy lp yrimidin-2-one-con taining nucleotides have also been described: while (18), prepared by a phosphotriester method, could not be unblocked at phosphorus without loss of the difluoromethyl group compound (19), prepared by a phosphodiester method, was deprotected successfully at its sugar moieties, the difluoromethyl group remaining intact.*6 N-[2'-Deoxycytidylyl (3'-5') guanosin-&yl] aniline has been prepared from appropriately protected derivatives of 3'-dCMP and N-(guanosin-S-yl) aniline by a phosphotriester method and subjected to conformational study.27 Dinucleoside uridine phosphates (dC)pX, where X is 2'-deoxythymidine, 2'-deoxy---thymidine, or lyxo, xYlo, or m-uridine, have also been prepared by phosphotriester methods and introduced as the 3'-terminal residues of oligonucleotides.28 The 3'-5'-, 3'-3'-, and 5'-5'-linked dinucleoside monophosphates and methylphosphonates of madenosine &-A) have been prepared, together with (=-A)p(&-A) and the 5'-hydrogenphosphonate and 5'-(methyl methanephosphonate) of m-A.29 Generally standard procedures were used with methyl dichlorophosphine or methylphosphonicbis(triazo1ide) being used to make the methanephosphonates.

6: Nucleotidos arid Nucleic Acids

209

(&-A)p(g-A), ( a r a - A ) p W - A ) and =-adenosine 5'-hydrogenphosphonate showed modest cytostatic and antiviral activity in test systems, apparently due to release of =-adenosine or =-AMP by enzymic action. Nucleotides containing trigonal bipyramidal phosphorus at the internucleotidic linkage (20) have been prepared by treating the corresponding phosphite triester nucleotides with butane -2, 3-dione in an n.m.r. tube, and their conformational properties examined.30 Hydrogen bonding was found to determine the conformation in d6-acetone, resulting in a (+>gauche conformation, but in d6-DMSO conformational transmission was apparent with a preference displayed for the (-> gauche rotamer, in opposition to base-stacking influences. The same research group has prepared a set of phosphate-methylated dinucleoside phosphates (21,22) using standard phosphite methods, the phosphi te triesters formed being oxidized to phosphates using t-butyl hydr0peroxide.3~ The fluorenylmethyloxycarbonyl (Fmoc) group was conveniently used to protect base exocyclic amino functions, and readily removed with triethylamine and pyridine without affecting the methylated phosphate group (although deacetylation caused some concomitant and (S&diastereoisomers were separable using reversed demethylation). The phase h.p.1.c. The methyl phosphotriesters preferentially adopt a conformation resembling B-DNA, the methyl group being satisfactorily accommodated in the B helix; methylphosphona te sys tems, by contrast, do not. The (w-diastereoisomer of phosphate-methylated d(CpC) appears, from variable temperature IH n.m.r. studies, to form a parallel right-handed mini-duplex.32 In a comparison of various methods for forming oligodeoxyribonucleotide N-alkylphosphoramidates examined at the dinucleoside phosphate (or phosphite) level, in which the Appel reaction, the reaction of phosphite triesters with alkyl a i d e s , and the oxidation of phosphite triesters with iodine in the presence of amines were all investigated as routes to these compounds, the last method was preferred on the basis of convenience and favorable yields33 5I-Q-Tritylated or deprotected dinucleoside N-alkylphosphoramidates were separable by h.p.1.c. into their diastereoisomers. The stabilities of the complexes formed between deoxyadenosine-derived oligonucleotides containing N-alkylphosphoramidate links and poly (dT) were found to increase with the length of the alkyl chain. An intercalator was also introduced at the internucleotidic link by preparing (23) and to give (24). In a treating it with 6-chloro-9-(4-chlorophenoxy)-2-methoxyacridine new route to the synthesis of deoxynucleoside phosphorofluoridates, the protected deoxynucleosides were treated with bis (N-N-diisopropylamino) trimethylsilylphosphite or bis (2,2,2-trifluoroethyl) trimethylsilylphosphite to give (25) which reacted with sulphuryl chloride fluoride in pyridine at low temperature to give the phosphorofluoridate (26).34 Also, starting from the bis (N-N-diisopropylamino) compound, sequential displacements of the diisopropylamino groups using two appropriately protected nucleosides, followed by the same reaction using S02ClF as

Organophosphoms Chemistry

210

Me

AcO (20) R = A c or Tr ; B

= Thy

BIFmoc I

or H

jHiH 0-P-0

0 MMTr

1 ; M M

I (CH,

I

NHR

(21 ) (22

>

€31 €31

=Cytor Gua; B,=Cyt orGua = Ade ; B2 = Ade,Thy or Cyt

(23) R = H

=$ CI

Me0

Me3SiO-P-0-(Protected

-

nucleoside $-or 5 ' - >

I R ( 2 5 ) R=NPri2 or OCH2CF3

0

II

F-P-O-(

I

P r o t e c t e d nucleoside -3'- or 5'-

R

( 2 6 ) R = NPri, orOCH2CF,

Tr

6: Nucleotides and Nuclric Acids

21 1

above, afforded protected dideoxynucleosidyl phosphorofluoridates in very high yields. Treatment of 5'-Q-monomethoxytrityl -2',3'- dideoxy-3'-thiothymidine successively with 2-cyanoethoxydichlorophosphineand 3'-Q-acetyl-2'-deoxythymidine in a conventional protocol affords (27), which may be oxidized to (28) by partitioning between dichloromethane and aqueous bicarbonate at low temperature.35 Conventional deprotection affords (29), which is cleaved to dTMP and 2',3'-dideoxy-3'-thiothymidineby snake venom phosphodiesterase, but resistant to nuclease P1. Oxidation of (29) using iodine affords dTMP and bis(2',3'dideoxythymidine-3') disulphide as sole products. Nucleoside a-phosphonates are finding wide use in oligonucleotide synthesis, and a review on their use for this purpose is timely.36 The reaction of nucleoside a-phosphonates with arenesulphonyl chlorides in pyridine has been investigated using 31P n.m.r. Reaction of 5'-Q-dimethoxytrityl-2'-deoxythymidine3'-a-phosphonate with TPS-cl gave a complex spectrum after 18 hours, simplifying on addition of water to give three signals which were assigned to the 3'-phosphate, the corresponding pyrophosphate, and (301.37 Evidently redox reactions are involved: in the rationale proposed, reaction of the H-phosphonate with TPS-cl leads initially to formation of a trimetaphosphite (31), a prerequisite for the redox processes to occur. Further reaction with TPS-cl leads to the formation of (30) [which reacts further to give (32) and (33), either of which may react with chloride to give rise to (34)] and (35), which may be oxidized to the pyrophosphate (36) or the analogous linear triphosphate (37), any of which three compounds may give rise to the pyridinium metaphosphate adduct in the solvent used. The structures of most of the novel intermediates proposed were confirmed by independent synthesis. In an extension of these studies to the use of arenesulphonyl chlorides in forming dinucleosidyl €-J-phosphonate diesters, coupling was found to be rapid and efficient but oxidation products (including dinucleosidyl 5-aryl phosphorothioates) arose on longer exposure to excess reagent, their formation being accelerated by the presence of N-methylimidazole or triethylamine.38 Possibly proton abstraction from the H-phosphonate is the ratelimiting process in oxidation. Diphenylphosphorochloridate and pivaloyl chloride effect rapid coupling to give H-phosphonate diesters, but also give side reactions at guanine bases, less seriously in the latter case. Bis-oxazolidinylphosphorochloridate was judged the reagent of choice, coupling efficiently without side-reactions. A caveat against the use of arylsulphonyl reagents with H-phosphonates in solidphase synthesis was given, since the repeated exposure to these reagents is likely to cause side reactions eventually. Also H-phosphonates can react with the acetic anhydride and DMAP or N-methylimidazole, often used as capping reagents, to give acylphosphonates which may eventually hydrolyse back to H-phosphonates, but may also give rise to chain cleavage. Transesterification of bis(1,1,1,3,3,3-hexafluoro2-propyl)-H-phosphonate with appropriately protected 2'-deoxynucleosides has been

Organophosphorns Chemistry

212

~

3

pri@pri 1 . Pr I

0

(30) X = O x = CI

( 2 7 ) R 1 = M M T r ; R 2 = A c ;R3=CH2CH2CN X is missing (28) AS (27) ; X

(34)

=O

(29) R'= R2= R3=H;X

=O

OR

I

0

II

ONP'O

I RO

,p\OOp\

(31)R

RO-P-0-P-OR

I

I

X

OR

= DMTrO

Y

(37)X=O;Y=H (38) X a b s e n t ; Y = OSiMes ( 3 9 ) X = O ;Y= DMTr.4-CL CsHi,CO, 2 - NO~C~HL,S (40)X = 0 ;Y = Me or CH2CH=CH2

(32) X (33) X (35) X (36)X

0

II

I

Y

=Pri3ArS; Y = 0'; R a s ( 3 1 ) = Y = Pri3ArS-; R as ( 3 1 ) = H ; Y=O- ; R a s (31) = O - ; Y = O - ; R a s (31)

R' (41) R' = H ;R2=OBz ;R3=B2 ; B = U r a ( 4 2 ) R1=OH; R2=OH;R3=H; B=Ura ( 4 3 ) R ' = H ; R 2 = H ; R 3 =B z ; B = Thy

6: Nucleotides and Nuckic Acids

213

described as a convenient route to preparation of the deoxynucleoside-3'-H_ phosphonates.39 Salicylchlorophosphine seems to be retaining an edge as the reagent of favour, however, and has been used to prepare ribonucleoside-3'- and -5'-H-phosphonates from appropriately protected ribon~cleosides.~0 It has also been used in a straightforward preparation of the bis (2'-deoxythymidyl) _H-phosphonate Q - bis (trimethylsilyl) acetamide, afforded the silyl (37) which, when treated with phosphite (38). Further treatment with alkyl or aroyl chlorides permitted a variety of substituents to be introduced at the phosphonate link (39).41 Alternatively, treatment of (37) with t-butyldimethylsilylchloride and diisopropylethylamine followed by methyl iodide or ally1 bromide allows synthesis of the corresponding dinucleosidyl lower alkyl phosphonates (40). Several model compounds have been prepared and employed to study the stability of the TBDMS group as protection for the 2'-hydroxy function during oligoribonucleotide synthesis by the H-phosphonate approach. The H-phosphona te link and TBDMS group of (41) remained intact during detritylation using standard conditions, and TBDMS could be removed from (42) using TBAF in THF in less than 4 hours without cleavage or isomerization of the phosphodiester link.42 Some loss of TBDMS and internucleotidic cleavage in (42) was observed on exposure to concentrated ammonia, but these reactions were largely suppressed in ethanolic ammonia. The attempted desilylation of (43) using TBAF led to immediate internucleotidic cleavage, and it appears from this, and other model reactions, that it is impossible to form an internucleotidic a-phosphonate diester in the presence of a vicinal hydroxy group: intramolecular cyclization ensues immediately, with or without the presence of base, to afford 2,3'-cyclic u-phosphonate d i e ~ t e r s The .~~ migratory aptitude of the 2'Q-TBDMS group in ribonucleosides in typical phosphorylation protocols using 4-chlorophenylphosphorobis(l~-1,2,4-triazolide~, bis (N,N-diisopropylamino) (2-cyanoethoxy) phosphine, chloro (N,N-diisopropylamino) methoxyphosphine or tris (1,3-imidazoyl) phosphine has been studied using 3IP n.m.r. spectroscopf14. The use of diisopropylammonium tetrazolide in combination with bis @I-N-diisopropylamino) (2-cyanoethoxy) phosphine was found to lead to substantial isomerization, caused by the tetrazolide, and its avoidance was recommended. Its replacement by tetrazole suppressed isomerization, but some 3'-3'-linked dimer was formed. The other conventional reagent combinations caused no isomerization. The role of tetrazole in the activation of phosphoramidites has also been investigated using 3IP n.m.r.45 Treatment of diethoxy (N-N-diisopropylamino) phosphine (44) with tetrazole gives rise to a signal at 126 p.p.m. ascribed to (451, which is identical with a signal seen during internucleotide bond formation, and (451, prepared independently by an unequivocal route, reacts quantitatively with nucleosides to give the corresponding phosphites. Model reactions of (44) with other bases of different pKa values gave rapid formation of species analogous to (45) from the good proton donors,

214

Organophosph oms Chemistry

S

II

, NPr i 2 \

EtO

OMe

Ac 0

I

EtO-P-R AcO OAc

(44) R = NPri2

(46) R =NHAc or H

Ade

OCH2CH2CN

(47)X = O ; Y = H ( 4 8 ) X is a b s e n t ; Y

=CL

( 4 9 ) X is absent ; Y=OC(Me)2CH2CN ( 5 0 ) X = 0 ; Y = NHBu" H ( 5 1 ) X =O;Y=N=N-N-

*B

NPri2

*B

6: Nucleorides and Nucleic Acids

215

suggesting a dual role for catalysis by tetrazole: first as a proton donor to form protonated (44), and then as a nucleophile, displacing diisopropylamine to form (45). In an investigation of the phosphitylation of guanosine or inosine bases during the preparation of nucleoside phosphoramidi tes, the acid-catalyzed reaction of bid"diisopropylamino) methoxyphosphine with model compounds such as N2,Q2',Q3',Q5'-tetraacetylguanosineand 2',3',5'-tri-Q-acetylinosine gave labile 06-phosphitylated compounds which were oxidized to stable thiophosphoramidates of type (461.46 Using 15N-n.m.r.spectroscopy the site of phosphitylation was shown to be 06 rather than N-1. Treatment of ~~-benzoyl-5'-~-dimethoxytrityl-2'-deoxyadenosine with 2-cyanoethyldichlorophosphineand triazole at low temperature affords, after ' aqueous work-up, the 3'-cyanoethylu-phosphonate (47). Chlorination of (47) with tris (2,4,6-tribromophenoxy)dichlorophosphorane then rapidly affords the reactive phosphorochloridite (48)which readily couples with the 5'-hydroxy group of a protected nucleoside to give the corresponding phosphite and, following oxidation with iodine, the dinucleoside ph0sphate.4~In certain cases, however, when a bulky protecting group [e.g. 2-cyano-1, l-dimethylethyl as in (49)] protects the phosphite, oxidation with aqueous iodine affords the phosphodiester rather than the usual phosphotriester, possibly via formation of an iodophosphonium intermediate which undergoes Arbuzov-type reaction to eliminate specifically the phosphateprotecting group. This behavior has now been exploited to prepare modified internucleotidic links48: treatment of (49) with iodine and n-butylamine affords the phosphoramidate (50); the same product was formed by treating (48) with n-butyl azide. Reaction of (49) with 3-azido-l-ethylcarbazoleafforded (51), in contrast, while treatment of (49) with methyl iodide resulted in detritylation at the 5'-hydroxy function and formation of the dimethoxytritylphosphonate. Since in addition the reaction of (49) with t-butylhydroperoxide or sulphur affords the corresponding phosphate or thiophosphate triester without loss of the 2-cyano-1, 1-dimethylethyl protecting group, it appears that a single synthon, a deoxynucleoside 3'-phosphoramidite with this protecting group, could be used to generate a variety of modified internucleotidic links at specific sites in combination with natural internucleotidic links during oligonucleotide synthesis. Treatment of bis (N,N-diisopropylamino) chlorophosphine with 4-chlorobenzylthiol and sodium hydride affords ~-(4-~hlorobenzyl)-N,N,N',tetraisopropylphosphorothiodiamidite which reacts with appropriately protected 2'-deoxynucleosides to give synthons of type (52).49 Condensation with the 5'-hydroxy group of a protected nucleoside in the presence of pyridinium tetrafluoroborate followed by oxidation with sulphur gives 5-4-chlorobenzylphosphorodithioates (53). The intermediates must be handled in an inert atmosphere to prevent oxidation. The 4-chlorophenoxycarbonylgroup can be removed from (53) with imidazole in aqueous acetonitrile without removing acyl

216

Orgutioplzosphori~sChemistry

functions protecting exocyclic amino groups on bases, and subsequent conversion to affords a synthon which permits introduction the 3'-(2-~yanoethyl)phosphoramidite of the phosphorodithioate link into DNA sequences. The 4-chlorobenzyl protecting group is removed at the completion of synthesis using thiophenol and triethylamine. An improved route to synthesis of oligodeoxynucleoside phosphorodithioates consists in the synthesis of protected 2'-deoxynucleoside-3'pyrrolidinyl- or -3'-(dimethylamino)-phosphorothioamidites(54) by treatment of the protected nucleoside successively with bis (pyrrolidinyl) or bis(dimethy1amino) chlorophosphine followed by 4-chloro-or 2,4-dichlorobenzylthiol.50The synthons (54) are then used in a standard solid phase DNA synthesis protocol, using tetrazole to catalyze the coupling step and sulphur to oxidize the thiophosphite link formed to the phosphorodithioate. Depending on the synthon and oxidation used, phosphate, thiophosphate and phosphorodithioate links can thus be introduced (54, R1=Pri) were into DNA ad lib. The 3'-~,N-diisopropylphosphorothioamidites found to be relatively inert, requiring strong acids for activation which caused detritylation as a side reaction. Others, however, have prepared (55) by treating the protected deoxynucleoside with chloro-N, N-diisopropylaminomethylthiophosphine (itself prepared from the aminodichlorophosphine using sodium thiomethoxide in the presence of potassium iodide and aluminium chloride) and diisopropylethylamine, and coupled it to methanol or the 5'-OH group of a protected 2'-deoxythymidine to give, after oxidation with sulphur, the corresponding phosphorodithioates. 51 Condensation of 5'-Qdimethoxytri tyl-2'deoxythymidine with triethylammonium phosphinate using pivaloyl chloride or diphenylphosphorochloridate, followed by oxidation with sulphur, affords the 3I-Hphosphonothioate (56).52 Activation using diphenylphosphorochloridate and then affords (57) which may be condensation with 3'-Q-benzoyl-2'-deoxythymidine oxidized variously with aqueous iodine, sulphur, or selenium to afford respectively the phosphorothioate (58)) phosphorodithioate (59), or phosphoroselenothioate (60). The P-H bond in (56) is highly reactive, and while use of a stoichiometric quantity of pivaloyl chloride similarly effects condensation to form (57), the use of excess reagent seems to result in further activation of (57) with loss of sulphur and formation of the trinucleoside phosphite. Treatment of methylphosphonothioic dichloride with 1-hydroxy-6-trifluoromethylbenzotriazoleaffords, presumably, (611, which may be used in phosphorylating protocols typical of reagents of this type to form dinucleosidyl methylphosphonothioates of type (62).53 In some cases the diastereoisomers formed could be separated. The diastereoisomers of (62:Bl=Thy; B2=Ade) were subsequently extended by block coupling methods to afford analogues of d(CpCpTpApGpG) containing a single central methylphosphonothioate link. Diastereoisomers of 2'-deoxythymidine -3'-Q-(methanephosphonothioate)have been prepared and their absolute configurations determined.54 A coupling reaction with 3'-Q-methoxyacetyl-2'-deoxythymidineusing TPS-nt as coupling agent failed to

6: Nucleotides arid Nudeic' Acids

217

H

R

(57) R = H

(56)

(58) R = O (59) R = S (60) R = S e -

CHF2

0

(63)

0

I1

(64)

0

II

218

Organophosphorus Chemistry

show chemo- or stereoselectivity, affording diastereoisomeric mixtures of dithymidylyl (3'-5') methanephosphonate and -(3'-5') methanephosphonothioate. Bis (I-Q-benzotriazolyl) difluoromethanephosphonate reacts successively with 5'-0dimethoxytrityl -2'-deoxythymidine and 3'-Q-laevulinyl-2'-deoxythymidine to afford separable diastereoisomers of the difluoromethanephosphonate (63).55 Following deprotection by standard methods, the separate diastereoisomers showed substantial differences in their I9F n.m.r. spectra. Considerable effort has been expended in preparing phosphonate derivatives of nucleosides and acyclonucleosides. Treatment of the oxetane (64)with the lithium salt of a dialkylmethanephosphonateresults in attack at C-5' to open the oxetane ring, after which mesylation of the (2-3' oxygen function, displacement of mesylate with a i d e , and finally (for the dimethyl ester) demethylation with TMSbromide affords the phosphonate analogue (65) of AZT-5'-monopho~phate.~~ A phosphonate analogue (66) of GMP has been prepared by condensing the 5'-aldehyde obtained from base- and sugar-protected guanosine with diphenyl tributylphosphoranylidenemethanephosphonate,and reducing the product with diimide, followed by transes terification using sodium benzoxide, acidic removal of the protecting groups and hydrogenolysis.57 A large number of phosphonylmethoxyalkyl and phosphonylalkyl derivatives of adenine, analogues of (67) modified in the alkyl chain, have been prepared by condensing the sodium alkoxides of the hydroxyalkylated adenine species (or their N-protected derivatives) with dimethyl 4-tosyloxymethanephosphonate followed by alkaline hydrolysis and demethylation using TMS halides, or by reaction of vicinal 9-(dihydroxyalkyl) adenines with chloromethanephosphonyl dichloride and subsequent cyclization of the products in aqueous alkali, followed by hydrolytic r i n g - ~ p e n i n g .Other ~ ~ related phosphonylalkyl derivatives of both adenine and guanine were prepared using the Arbuzov reaction. The interest in these compounds stems, of course, from the previously reported disclosure that (S)-HPMPA (67, R = CH20H) is a broad spectrum antiviral: a preparation of 6)-HPMPA from (68) using the diethyl tosyloxymethanephosphonate procedure outlined above has been described58 ,while the analogous derivative of cytosine has been prepared by alkylation of cytosine at the N-1 position with (69) (prepared from a derivative of glycerol) followed by standard deprotection, and found to have a higher therapeutic index than DHPG against cytomegalovirus.60 The 3-azido- and 3-amino analogues of racemic HPMPA have been prepared using dimethyl 4-tosyloxymethanephosphonate~*,as above, and 6)-HPMPA (67) and (70) converted to their l,N6-etheno-derivatives using chloroacetaldehyde.62 A large number of phosphonoformate and phosphonoacetate derivatives of 5-substituted 2'-deoxyuridine species 6% 61 (e.g. (71))and some related sugarmodified and acyc10nuc1eosides6* have been prepared, either by reaction of the unprotected nucleoside with the corresponding chlorophosphonoformate or acetate

6: Nucleorides and Nucleic Acids

219

NHR~

CH2

OMS

H

0

0 ‘C/

A

R’

I1 I

I

-‘OCH2P-OH OCH2Ph

OH

( 6 7 ) R’=CHzOH or H ; R 2 = H ( 6 8 ) R 1 = CH20Tr ; R 2 =Tr (70) R ’ = R * = H

(69)

0 II

HO-

P-CH2COO

I HO OH

HO

( 7 1 ) n = Oor 1 ; R = H , M e , I , CH2 CH2 C I

( 7 2 ) R = M e , I ,CH2CH2CL,Br

PhCH20

(73) R1 = H ; R2 = CH20P(OMe)2 or R1 = CH20P(OMe)2 ; R 2 = H (74) R1 = H ; R2= CH20P(OMe)CH2COOEt II 0

or R1= CH20P(OMe)CHzCOOEt ; Rl =H

II 0

(75)

220

Organophosphorus Chemisrty

ester, or by coupling ethyl phosphonoformate or phosphonoacetate to the nucleoside using TPS-cl or DCC. Some nucleosidyl phosphonoacetates of type (72) were also prepared, by coupling dimethyl or diethylphosphonoacetic acid to the nucleoside using DCC or trifluoroacetic anhydride, followed by dealkylation. Some of the compounds prepared, notably those with 5-halogeno-, 5-bromovinyl-, or 542ch1oro)ethyl substituents, displayed activity against herpes simplex virus 1 (and sometimes also HSV-2) but appeared to act as prodrugs for the nucleosides, giving no evidence of synergistic effect with the phosphonoalkanoates in the mouse model used. The fructofuranose-derived phosphites (73) have been submitted to Arbuzov reaction with ethyl bromoacetate to afford (74) which was condensed successively with DMF dimethyl acetal and guanidine to afford after debenzylatiori the isocytosine 5fructofuranosylphosphonates (75, and its P-anomer).65 These compounds showed no activity against HSV-1 or -2. Irradiation of sugar-protected 5-bromouridine or 8-bromoadenosine or -panosine in the presence of triethylphosphite results in displacement of halogen with formation of the corresponding diethylphosphonate.66 Arbuzov reaction between triethylphosphite 2-Q-isopropylidene-a-D-ribo-hexofuranose, and 3-Q-benzoyl-6-bromo-5,6-dideoxy-l, followed by acetolysis, affords (76) which has been condensed with silylated bases using standard methods to give, after deblocking, the phosphonates of the uracil and adenine nucleoside homologues.67 Nucleoside 5'-phosphonates have been prepared by essentially the same route, starting from (77) which underwent Arbuzov reaction to afford (781.68 The j3-anomers of the analogues of AMP, IMP, GMP, CMP and UMP were prepared, but none showed antitumour or antiviral activity, although the CMP and GMP analogues were phosphorylated in vitro by NMP kinase and guanylate kinase, respectively, to higher phosphate analogues. As a move towards 3'-phosphonates of analogous structure (i.e. containing C(3')-CH2-P bonds) which are difficult of synthetic access, 3'-[(2-chlorophenoxy) phosphinylmethyl]-~2-isobutyryl-5'-~-monomethoxytrityl-2',3'-dideoxyguanosine has been prepared starting from glucose, and used to prepare a phosphonate analogue of ~ ( G P C )A . ~number ~ of phosphono- (79) and methylphosphino- (80) analogues of aminoacyladenylates have been prepared via coupling the ethyl (N-acetylaminoacy1)methylphosphonate or (N-acety1aminoacyl)methyl methylphosphinate, respectively, to the 5'-OH group of base- and sugar-protected adenosine using DCC followed by deprote~tion.~o Removal of the ethyl group from the ethyl phosphonate intermediate proved difficult: it was eventually removed, in modest yield, using phosphorus pentachloride, while N-acetyl groups were removed using chymotrypsin. Compounds (79) displayed some bactericidal activity and compounds (80) fungicidal activity. A review on the rational design of enzyme inhibitors with particular regard to multisubstrate analogue inhibitors includes extensive discussion of examples drawn from the nucleotide field.71 The compounds (81) have been prepared by

22 1

6: Nucleotides and Nucleic Acids

0

II

( E t 0)2 P CH2 5H2

WoAc

BzO OAc

RCH;!

P

O

A

c

B z O OBz ( 7 7 ) R = Br

(76)

(78) R R'

"

I

R'

--ic\cA H2N 11

0

I

p - 0 -(Ado -5 )

11 0

( 7 9 ) R' = O H ; R 2 = H,Me,PhCH2

(80) R1 = M e ; R 2 = H , M e ,PhCH2

( 8 1 ) R = H or Me

0 It (Et0)2P

222

Organophosphorus Chemistry

condensation of the diethyl esters of the corresponding secondary amines with the bis (2,2,2-trichloroethyl) ester of 5-bromomethyl-2'-deoxyuridine-5'-phosphate, followed by deprotection .7* Use of the pyrimidine ring to replace the tetrahydrofolate moiety in these mechanism-based inhibitors of thymidylate synthetase minimizes steric constraints while retaining known binding sites, and (81) proved to be potent competitive inhibitors of the human enzyme with respect to dUMP and 5,lO-methylenetetrahydrofolate. A related inhibitor containing an 8-deaza-N10-propargyl-5,6,7,8-tetrahydrofolatemoiety (i.e. ring-closed at the dotted line in (81)with R = propargyl) was a slightly stronger inhibitor of the same enzyme than its non-propargylated analogue.73 The species (82) has been prepared by alkylation of 1-~-(2-thio)acetyl-5-phosphoribofuranosylamine with the appropriate N-bromoacetylated secondary amine, the p-anomer being isolated by reversephase h.p.l.~.~* The compound is a slow, tight-binding inhibitor of glycinamide ribonucleotide transformylase with a dissociation constant in the picomolar range. The crystal structure of formycin 5'-phosphate has been published, revealing that its glycosyl torsion angle is syn, differing by 1900 from that of AMP75. The computed energy required to twist AMP around to the glycosyl torsion angle found in formycin -5'-phosphate is 4.6 kcal mole-', which explains nicely the observed much tighter binding of the analogue to AMP nucleosidase compared with AMP itself. Treatment of mitomycin C with pyrimidine nucleotides in acid media results in formation of phosphodiesters (83) which are derivatives of 2,7-diaminomitosene.76 Upon reduction, these liberate the nucleotide, apparently by an elimination mechanism (84): the reduced mitosene subsequently ring-closes to form a DNA-alkylating species, probably the aziridine. The conjugates (83) are readily taken up by L1210 leukemia cells and display powerful cytotoxicity, possibly acting as prodrugs of two active species. One wonders whether similar oligonucleotide adducts would be useful for 'addressed modification': the intracellular lifetime of the conjugates evidently needs to be ascertained. An improved synthesis of D-luciferyl-D-adenylatehas been reported.77 The synthesis in good yield of long-chain alkyl esters of a number of nucleoside 5'-phosphates (85) by phospholipase-D-catalysed transesterification of the corresponding alkyl ester of phosphocholine with the appropriate nucleoside has been described.78 A two-phase system of chloroform and acetate buffer, pH 5.8,was employed, using a large excess of organic phase to disfavour hydrolysis. 1,2,3,4Tetra-Q-acetyl-D-glucopyranose-6-phosphate has been condensed with 3'-Qbenzoyl2'-deoxythymidine using trichloroacetonitrile to give, after deacylation, (86),which reacted with 1-bromohexadecaneto give the hexadecyl ester (871.79 N.m.r. spectroscopic studies (lH, 13C and 3lP) of the interaction of (87) with large unilamellar vesicles formed from phosphatidylcholine and phosphatidic acid indicated that (87) could cross the lipid bilayer to the interior of the vesicles, while the hexadecyl ester of dTMP appeared to become associated with the membrane, but

223

6: Nucleotides and Nucleic Acids

HO R '

( 8 3 ) R 1 = H ; R 2 = F or

R1=OH;R2=H

0 II

- 5')

NH3 HO

II &iO-(d0

Thd-5')

0 RO-P-

II

I

-0 (85) R

HO

= Stearyl.cetyl.

myristyl,

eicosyl , oleyl Nuc

OH

0- ( NUC - 5 ' ) OH

(86) R = H ( 8 7 ) R =n-C16H33

= (variously) Cyd, a m - Cyd , f 5 - U r d , f 5 - d U r d , dThd, Neplanocin A , Bredinin.

0-C-OPh

0C6 H, C I -4 (88)

OCGHbCI -4

(89)

224

Organophosphoms Chemistly

not to cross it. Compounds similar to (87) may thus have potential as transport species for biologically active nucleosides. Dimyristoyl-5'-phosphatidyldeoxycytidine has been prepared from 1,2-dimyristoyl-~-glycero-3-phosphocholir,e and 2'-deoxycytidine using phospholipase D, and found to assemble spontaneously in 0.05 M Tris buffer, pH 8.0 to form right-handed helical aggregates, which in turn formed superhelical structure.80 A melting temperature of 210 C was observed for these aggregates, in which it was suggested that the hydrophobic alkyl chains form a helical stack in the centre with the nucleotidyl moieties on the outside of the helix, exposed to water. An increasing amount of attention is being paid to the redox chemistry of purine nucleotides and their radical derivatives, and a review on this subject is timely.81 Treatment of AMP with potassium hydrogen persulphate alone leads to the formation of its Nl-oxide derivative and the same reaction occurs when poly(A) is used as substrate.82 However, if meso-tetrakis (N-methyl-4-pyridyl) porphyrinatomanganese (111) pentaacetate is also present, the products are 8-hydroxy-AMP (25 %) and unreacted AMP.83 Of various nucleotides tested, in similar conditions, the only one displaying regiospecific hydroxylation leading to a reasonable yield of an identifiable product was AMP. Adenine-porphyrin stacking with electrostatic interaction between the phosphate group and the pyridinium system, together with a P-450-like oxidation process, have been proposed to occur. In a study of the species formed by reaction of the hydroxyl radical with adenine and guanine nucleoside and deoxynucleoside monophosphates in aqueous solution which involved spin trapping and e.s.r. spectroscopy, radicals due to abstraction of the C-4' hydrogen atom from 5'-dAMP and 5'-dGMP were identified, and in all cases secondary doublets assigned as being due to hydrogen abstraction from the C-5' position were 0bserved.w In a brief review, the reactions of hydroxyl radicals and sulphate radical anions with uracil-containing nucleotides and poly(U) have been compared.85 Reduction of (88) using tributyltin hydride in the presence of AIBN caused the selective removal of the 4-chlorophenyl group.86 Reduction of (89) using tributyltin hydride, followed by deblocking, afforded d(TpU) in good yield.8' A diuridine analogue was reduced similarly but, not surprisingly, it could not be deprotected without decomposition. Curiously, the ~-1,4-~-acetylmuramoylhydrolase from Streptococcus faeciurn appears to be linked covalently to about twelve residues of monomeric 5-mercaptouridine-5'-monophosphate, possibly via phosphodiester linkage to phenolic hydroxy groups of tyrosine residues88 This nucleotide had not previously been observed in any organism. Transfer RNA is a perennial source of unusual nucleotides, and evidence has been presented that 2'-Q-ribosyladenosine (9) occurs in the T-Y stem of yeast methionine initiator tRNA.89 There appears, in addition, to be a phosphate group attached to (901, but its position has not been determined unequivocally beyond the fact that it is not at the 3'-or 5'- positions of the adenosine

225

6: Nucleotides and Nucleic Acids

""TIde HO OH

HO OH (91 1

(90)

HNR~ I

SMe

HO OH

-0 ( 9 2 ) R ' = PhCHZS or H ; R2=CH3(CHZ)"(n=1-9,13), B u i , Furfuryl, Benryl

OAN

NV

( 9 3 ) R = NH2 (94) R =OH

R

0

-0 ( 9 5 ) R = Me(CH2)n( n = O - 5.7)or P r i

(96) R =PhNH (97) R =OH

226

Organophosphorus Chemistry

moiety. Also, a novel nucleoside found in the first position of the anticodon of a minor tRNA Ile from E. coli has been shown to be 4-amino-2-@6-lysino)-l-(~-Dribofuranosyl) pyrimidinium (91), a modified cytidine structure which probably permits adenine, but not guanine, to be recognized in the third position of the codon.90 2.2 Cvclic Nucleotides - A series (92) of N6-alkyladenosine 3',5'-monophosphates and their 8-benzylthio derivatives has been prepared from cAMP and 8benzylthio- CAMP, respectively, by reductive alkylation with the appropriate aldehyde and cyanoborohydride.91 The compounds were assayed for cardiotonic effects, and some of the N6-alkylated cAMP species [e.g. (91; R1 = H, R2= hexyl or heptyl)] found to be more active than the corresponding 8-benzylthio derivatives. The pyrazolo [3,4-d] pyrimidine (i.e. 7-deaza-8-aza purine) analogues of CAMP,cIMP and cGMP have been prepared from (93) (for the cAMP analogue) and (94) (for the cIMP and cGMP analogues) using standard phosphorylation and cyclization methods followed by removal of the methylthio group with Raney nickel or (for the cGMP analogue) oxidation with MCPBA and nucleophilic displacement by ammonia.92 A set of thirteen cAMP derivatives [including the @p) and @p)diastereoisomers of the 3',5'-phosphorothioa te, CAMPS]have been used to define the cyclic nucleotide-binding specificity of eight CAMP-binding proteins in Dictyostelium discoideum and classify them into three groups.93 Binding to the cell surface and extracellular phosphodiesterase involved interactions with 0-3' and the exocyclic (phosphate) oxygen, while binding to intracellular receptors involved additional interactions at 0-2' and 0-5', and required that the base adopt the conformation. A series of 5-alkylcytidine 3',5'-monophosphates (95) has been prepared from the corresponding 5-alkylcytidine nucleosides by conventional procedures, but the compounds displayed no significant antiviral or cytostatic a ~ t i v i t y . 9These ~ nucleotides thus appear ineffective as prodrugs of active 5-alkyl-2'deoxyuridine species. The preparation of (I7p) and 6p)-N6, N6,02-tribenzoyladenosine 3',5'phosphoranilidates (96) has been greatly improved by treating the cyclic phosphate (97) with oxalyl chloride and a catalytic amount of DMF, rather than the triphenylphosphine-carbon tetrachloride mixture (Appel reaction) used previously, followed by addition of aniline.95 The near-quantitative yield of (97) obtained as a mixture of diastereoisomers is easily separated. The cyclic phosphoramidates (98-100) have also been obtained in improved yield by treating cAMP with a mixture of phosphoryl chloride and trimethyl phosphate (which had previously been pretreated with one-half a molar equivalent of water) at 00, followed by ammonium carbonate or the appropriate amine.96 The (Sp)-diastereoisomers are formed in excess, e.g. for (100) yields of 13 % of the lXp-isomer and 54 % of the Sp-isomer are obtained, and the proportion of I?p-product decreases further if pre-treatment with

6: Nucleotides and Nucleic Acids

227

water is omitted. Diphenylphosphorochloridate (without water) could also be used, affording similar results, the CAMP-diphenylphosphoric anhydride intermediate being characterized by 31P n.m.r. spectro~copy9~ A study of the hydrolysis of these phosphoramidates in 0.1 M NaOH and 0.1 M HC1 revealed that while the ester bonds (predominantly P-aC5') of (98)-(700) were cleaved in alkali, in acid (98) was hydrolysed with predominant ester bond breakage, (100) with exclusive amide bond breakage, and (99) with amide and ester bond breakage in comparable amounts.98 Significant differences were seen between the rates of cleavage of the different diastereoisomers. The differences in behaviour between (98), (99) and (100) were ascribed largely to stereoelectronic and steric effects, apparently in the ground state, a1though steric compression in the trigonal bipyramidal intermediates could also help to determine the behaviour observed. In alkali, (98) and (99) were hydrolyzed much more rapidly than (1001, possibly due to elimination to form metaphosphorimidates followed by reaction with water. Treatment of 8-bromo-cGMP successively with thiourea and 5-iOdOacetamidofluorescein afforded 8-([(fluorescein-5-ylcarbamoyl)methyl]thio)-cGMP which stimulated cyclic nucleotide-activated sodium ion currents in photoreceptor outer segment membrane patches maximally at even lower concentration than cGMP.99 It was thought that the nucleotide bound to the membrane in the SJJ conformation. The cGMP phosphodiesterase from retinal rod outer segments hydrolyzed (Sp)-cGMPS (1011, the cyclic phosphorothioate, in [lSO] water, to give [160,180] GMPS, which reacted with diphenylphosphorochloridateto form the two 0-phosphorylated diastereoisomers of ~-(5'-guanosyl)-~2-diphenyl-l-thiodiphosphate.100 The 3lP n.m.r. spectrum of the mixture of diastereoisomers formed was identical to that obtained from the products of hydrolysis of @p)-guanosine 5'(4-nitropheny1)phosphorothioateby snake venom phosphodiesterase in "*OI water, followed by similar treatment with diphenylphosphorochloridate. Since hydrolysis by the venom enzyme proceeds with known retention of configuration, the identity of the n.m.r. spectra showed that hydrolysis by the cGMP phosphodiesterase had proceeded with inversion. The AIBN-initiated oxidation by oxygen of the cyclic methyl 3',5'-phosphite of 2'-deoxythymidine [(102) or (10311 in benzene affords the corresponding phosphotriester [(lo41or (105), respectively] in high yield with retention of the configuration at phosphorus: this affords a convenient means for regiospecific introduction of oxygen isotopes.lol Regiospecific introduction of oxygen isotopes with retention may also be performed in non-aqueous media using dinitrogen tetroxide, or in aqueous media using iodine in appropriately labelled water. The methyl group is readily removed in t-butylamine under reflux. Oxidation of, e.g., (102) by iodine is proposed to form an iodophosphonium species which is attacked by labelled water to give initially, (106): pseudorotation to bring the iodine atom to an apical position followed by loss of HI results in oxidation with retention of

Organoph osphoms Chemistly

228

R’ \ N

R2

’

0 ‘“0

OH

(98) R ’ = R 2 = H (99) R’ = M e ; R2=H (100) R’ = R2 = Me

Me0

I

X

I

MeO ’ p\‘ (102) X is missing

(104) X = “ O ;n =16,17,or 18 (108) X = M e or Me2N

(106)

039T

0

hy

(103) X is missing (105) X = “ O ;n=16,17, or 18 (109) X = Me or Me2N

6: Nuclrotides and Nucleic Acids

229

configuration giving (104). Oxidation using AIBN is believed to involve the intermediacy of a phosphoranyl radical (1071, which loses the isobutyronitrile radical to give (104). Markedly different chemical shifts were observed in the 1 7 0 n.m.r. spectra when I7O was introduced at X in (104) and (105): it has been proposed that these be used to assign configurational purity and absolute configuration in isotopically labelled P-chiral 4-nitrophenyl diesters of nucleoside 3'- and 5'-monophosphates.102 The nitrophenyl esters are cyclized using base, the resultant 3',5'-cyclophosphates methylated, and the integrals of the resultant P=I7O resonances, normalized for the relative amounts of & (104) and trans (105) isomers formed, permit the (Rp):(sp) ratio in the chiral starting material to be determined. Similar differences in chemical shifts are seen in the 170-labelled methanephosphonates and N-N-dimethylphosphoramidates (108, log), but the relative 170-chemical shifts found are inconsistent with those observed for the methyl phosphotriesters (104, 105, n = 17), and may be extremely sensitive to the substituents at phosphor us. Adenosine 3'-monophospha te is readily cyclized to the 2',3'-monophosphate by cyanogen bromide in imidazole buffer.103 It appears that both N-cyanoimidazole and diimidazoleimine are formed, and both reagents can effect the cyclization in aqueous solution, with N-cyanoimidazole being the more effective reagent, particularly in the presence of divalent metal ions (Cu2+,Ni2+, Zn2+). They may represent useful alternatives to DCC or carbonylbis(imidazo1e) in condensation reactions. The capacity of the cyclodextrins to induce regioselective cleavage of nucleoside 2,3'-monophosphates has been explored in a series of papers. a-Cyclodextrin catalyses regioselective P-0(2;) cleavage of these compounds at pH 11.08 at 200104#Io5, with selectivity as high as 98 70for cytidine 2',3'-monophosphate. While p- and y-cyclodextrins show little regioselective catalysis, 6-Q-a-glucopyranosyl-j3-cyclodextrin effects regioselective P-0 (3') cleavage of adenosine-and ~~~ also effects cleavage of the guanosine 2', 3 ' - m o n o p h o ~ p h a t e s .a-Cyclodextrin dinucleoside phosphates CpN (N = A,C,U,G) under similar conditions to give 3'-CMP with high selectivity105, while ApA gives 3'-AMP.lo7 However, p- and ycyclodextrins catalyze cleavage of ApA to form predominantly 2'-AMP. In a model (110) of the complex of cytidine 2',3'-phosphate formed with y-cyclodextrin which is consistent with 'H n.m.r. data, the plane of the cyclophosphate ring is virtually aligned with the longitudinal axis of the a-cyclodextrin cavity. Attack of water results in formation of a trigonal bipyramid with 0-2' in the apical (leaving) position: if 0-3' were to occupy the apical position, hydrogen-bonding to secondary hydroxy groups on the cyclodextrin would be compromised. Alternatively, more efficient solvation at 0-2' may direct the selectivity. 5'-Q-Succinyladenosine-2',3'monophosphate has been prepared by direct succinylation of the cyclic nucleotide with succinic anhydride in the presence of morpholine and DCC, the

230

Organophosphoms Chernistry

phosphodiester ring remaining intact.108 The material was required as a step towards preparing antibodies to 2',3'-cyclic nucleotides. Phosphitylation of 8-bromo-2',3'-~-isopropylideneadenosine with diethyl phosphorochloridite and triethylamine followed by irradiation of the resultant phosphite triester in acetonitrile affords (111) as a mixture of diastereoisomers 5'-anhydroadenosine-8-phosphonicacid.109 The which on deprotection gives mechanism proposed involves homolytic fission of the carbon-bromine bond followed by attack on the phosphite by the C-8radical. 3. Nucleoside Polyuhosuhates

Treatment of nucleoside and deoxynucleoside 5'-monophosphates with inorganic diphosphonate in q u o at pH 6 at elevated temperatures has been reported to afford the corresponding 5'-phosphonylphosphates (112) in yields of up to 70 %.I10 The compounds were characterized largely using 31P n.m.r. spectroscopy. Alkylation of ATP, adenylyl imidodiphosphate, and adenosine 5'- (3-thio) triphosphate with 1-(2-nitrophenyl) diazoethane leads to alkylation of the terminal phosphate group in each case, the ATPfi being alkylated at oxygen and sulphur atoms in roughly equal amounts.1l1 The resultant 'caged' nucleotides liberate the free nucleotides and 2-nitrosoacetophenone, upon photolysis, with ATQS being the sole nucleotidic product of its 'caged' form irrespective of whether it was alkylated at oxygen or sulphur. Analysis of the kinetics of photolysis suggests that at neutral pH an intermediate (113) is formed, and that ring-closure then yields (114)from which the phosphate moiety is expelled to yield the observed products. The 'caged' A T V has been subjected to laser photolysis in the presence of muscle fibres to investigate muscle relaxation processes.112 Continuous wave microwave irradiation has been found to enhance the hydrolysis of nucleoside 5'-triphosphates substantially compared with that of controls subjected to normal convection heating.113 The primary product of ATP hydrolysis was ADP, while GTP and adenylyl imidodiphosphate formed their 5'-monophosphates as primary and only products respectively. It was suggested that the enhanced kinetic energy of solvent water (with possible selective heating of water molecules solvating the triphosphate chain) promoted the hydrolysis. The -triazacyclopentadecane has been binding of ATP to (S)-2-hydroxymethyl-1,6,11 monitored using 31l' n.m.r. s p e c t r o ~ c o p y ~Binding ~4 occurred with 1:l stoicheiometry, with only Py showing a significant chemical shift: the quasi-Q symmetry of the macrocycle did not appear to enhance binding to the (similarly C3) Pyphosphate. Similar studies of the binding of AMP, ADP and ATP to other macrocyclic polyamines (115, 116) have been reported.115 While (115) and (116, n = 6 ) formed 1:l complexes with ADP and ATP, (116, n = 8) formed 1:2 complexes. The macrocycle 1,4,7,13,16,19-hexaaza-l0,22-dioxatetraeicosanehas been found to

23 1

6: Nucleotides arid Nucfeic Acids

II

H-P-0-

I

P-0

0 II

P-Y

I

I

HO R

0-

-0 (112) R = O H ; B = A d e , G u a , H y p , C y t , U r a R=H, B=Ade,Thy

= A D P , etc.

(113) Y

(116) n = 6 or 8

(114) Y

= ADP,etc.

(115)

P 0 II

HO - V

I -0

(117)

0 II

- 0 -P-O-(AdoI

-0

5')

232

Organophosphorus Chetn istry

catalyze positional isotope exchange (PIX) in [p-1802] ATP in the presence of calcium ions, but not in their absence.116 While roughly a hundred-fold rate enhancement of hydrolysis was observed for ATP, enhancement of ATPyS hydrolysis was only about three-fold, and no evidence for intermediate formation of the thiophosphorylated macrocycle could be obtained. Using adenosine 5'-[$E)-170, 180, thio] triphosphate, hydrolysis of ATPyS with inversion at phosphorus was demonstrated. It is thought that PIX in the presence of Ca*+ ions is due to the formation of a hexacoordinated complex with the phosphorylated macrocycle (117) in which electrostatic repulsion to the approach of ADP is lowered, permitting rephosphorylation of ADP from the phospho-macrocycle. In the absence of calcium ions, repulsion prevents this occurring. Probably the ATPyS, which binds tightly to the macrocycle, follows a dissociative mechanism with direct thiophosphoryl transfer to water, while ATP displays associative behavior, phosphorylating the macrocycle. Evidence from vanadium-51 n.m.r. spectroscopic studies suggests that AMP can form an anhydride (118) with vanadate ions which is an analogue of ADP: an association constant of 37 k 3 M-l and a pKag value of 7.1 could be calculated.117 Condensation of AMP with a divanadate anhydride to form an ATP analogue also appeared to occur, but definitive physical data were less easy to obtain. The inhibition of F1-type ATPases by fluoride ions in the presence of aluminium ions and ADP appears to be due to the formation of fluoroaluminate ion which mimics the y-phosphate group of ATP, binding together with ADP at the catalytic site to form a pseudo-ATP in an abortive complex.ll8 Reaction of 1,5-difluoro-2,4-dinitrobenzene with [8-1*C] ADP or ATP in bicarbonate buffer at pH 9.2 affords the corresponding 3'-0-(5-fluoro-2,4dinitrophenyl) ethers of ADP and ATP, the position of substitution being assigned on the basis of IH n.m.r. data.ll9 No evidence was adduced for the formation of Meisenheimer-type complexes, although this appears at least possible. The ADP ether was used as an affinity label for the active site of mitochondria1 F1-ATPase. Adenylyl methylenediphosphonate, ATP and dATP, all with a l-oxy-2,2,5,5tetramethylpyrroline-3-carbonyl spin label attached at the 3'-position, have been used to study the nucleotide binding site stoicheiometry of ATPase from sarcoplasmic reticulum.120 Although isomerization of the spin-label attachment between the 2'- and 3'-positions was anticipated in the ribonucleotide derivatives, localization of the spin label at the 3'-position in the deoxyribonucleotide was found not to alter its binding properties significantly from those of the ribonucleotide derivatives. The NAD+-analogue containing 1,@-ethenoadenosine in place of the normal adenosine moiety can serve as a substrate for the bacterial toxin-catalyzed l,I$etheno-ADP-ribosylation of signal-transducing G proteins, permitting their florescent labelling.121 5-Vinyl- and 5-ethynyl-2'-dUTP have been prepared by treating the unprotected nucleosides with phosphoryl chloride at ice temperature in the

6: Nucleotides und Nucleic Acid.v

233

presence of powdered 'proton sponge' (1,$-bis (dimethylamino) naphthalene) to form the corresponding 5'-phosphorodichloridates which were not isolated, but treated briefly with pyrophosphate in DMF and then subjected to aqueous work-up and separation on DEAE-cellulose. Yields of the triphosphates of 60 % or better, with purity greater than 95 %, could be obtained rapidly by this method.122 In the continuing search for isozyme-specific inhibitors of rat methionine adenosyltransferases, the covalent conjugate (119) of L-ethionine and adenylyl imidodiphosphate has been prepared.123 In the synthetic route, protected adenosine was converted to its 5'-aldehyde, condensed with vinylmagnesium bromide, and hydroboration, tosylation and condensation with L-homocysteinate served to introduce the L-ethionine moiety, the 5'-hydroxy group then being phosphorylated by Tener's method and converted conventionally to the j3, y-imidotriphosphate. The epimeric mixture of (119) obtained was a powerful inhibitor of the rat enzymes from normal and hepatoma tissues, acting as a multisubstrate inhibitor against both ATP and L-methionine. When 3'-tritiated Z'-chloro-2'-deoxy-UTP is incubated with ribonucleoside triphosphate reductase from Lactobacillus leichmannii in the presence of borohydride, and the 3'-keto-2'-dUTP transiently produced trapped by reduction, degradative analysis of the xylo-dUTP and dUTP formed as products in 4:l ratio shows that the tritium has migrated predominantly to the 2'(S) position - i.e. (120) is formed.124 This demonstration of the 3'+2' hydrogen shift, believed to be mediated via a radical moiety on the enzyme, is in excellent accordance with a model for the inactivation of the enzyme by Z'-Cl-dUTP previously proposed. Cyclopentenylcytosine (121), which exhibits antitumor activity, is phosphorylated in mouse L1210 cells by a uridine-cytidine kinase to form its triphosphate as the major metabolite.I25 The triphosphate is a powerful inhibitor of bovine CTP synthetase, a key enzyme in the de nuvu pyrimidine nucleotide biosynthetic pathway, thus presenting a likely of rationale for its antimetabolic activity. The 3'-azido-2',3'-dideoxy-analogues of thymidine, uridine, and 5-ethyluridine, and the 3'-fluoro-2',3'-dideoxy-analogues thymidine and 5-ethyluridine have been converted to their 5'-triphosphates and tested as inhibitors of the reverse transcriptases from HIV and Moloney murine leukemia virus (MMLV).126 The 5'-triphosphates of 3'-azido- and 3'-fluoro-2',3'dideoxythymidine were equipotent against the HIV enzyme, and more effective than the other analogues (which were ineffective against the MMLV enzyme). The 5'-triphosphates of 3'-chloro, 3'-thiocyanato, 3'-methanesulphonamido- and 3'-sulphonamido-2',3'-dideoxythymidines, together with those of 2',3'-anhydroribo-adenosine, 2,3'-anhydro-&-adenosine, and 2',3'-QQisopropylidenecytidine have been prepared from the nucleosides using phosphoryltris (triazolide) and bis(tributy1ammonium) pyrophosphate, and the triphosphates tested as termination substrates for various DNA polymerases in cellfree systems.127 Acyclovir triphosphate, prepared enzymatically from the nucleoside using herpes simplex

Organophosphoms Chemistv

234

H

O

W

C

Y

HO

OH

4-09p3 0

t

-,

jUa

CI

II

0

-0

-0

HO R (123) B = Ade or G u a R = H or OH

(122)

0

0

-O-P-N-T-OQ~ III H II

I

0 II

0 II

I -0

I -0

-0-P-X-P-Y-

Ct -P-N=P--CI

I

I

CL

CL

0 II

P-O-(Ado-

5’)

I -0

(125) X = 0 ; Y = NMe (126) X = NMe; Y

-

=O

0

O\ 11 /p-o\

*

MeOCHzCOO H “B

= AdeBZ;GuaBUI; T h y ; c y t B z

0 I

//‘;-o\

0 0 ‘’, z ’I HzO-Mn’---Y

\ \\

p/

4\

x O-(Ado-5’)

HZ)J ‘OH2

(129) Y d 7 0 ;X = S (130) X =170;Y = S ( Z = nitrate, azide , e t c . 1

s\

P-

0

f : a

0- P-0-P-

I

I

0-(Gua-5‘)

6: Nucleotides and Nucleic Acids

235

virus type 2 (HSV-2) thymidine kinase, pyruvate kinase, guanylate kinase, and the appropriate cofactors, is rapidly incorporated by HSV-1 DNA polymerase into a synthetic template-primer.128 Neither (122) nor the presence of acyclovir at the 3'-terminus inhibit the enzyme directly, but binding dCTP - the next nucleotide encoded for incorporation - results in powerful inhibition by formation of a deadend complex, the apparent loss of activity being the same as that generated by a mechanism-based inactivator. 3'-Amino-2',3'-dideoxycytidine is converted to its 5'-triphosphate in L1210 cells, and specifically blocks S phase of cell growth in the exponentially growing cells. While inhibition of the incorporation of dCTP into calf thymus DNA by purified DNA polymerase a by the analogue could be shown in vitro, the 3'-amino nucleotide could not be demonstrated as becoming incorporated into the DNA.129 However, its presence induced single strand breaks in the newly synthesized DNA, and chain termination remains a possibility. Purine nucleoside 5'- [a,P-imido] diphosphates (123) have been prepared by treating unprotected nucleosides dissolved in trimethylphosphate with trichloro [(dichlorophosphoryl)imido] phosphorane (124) at -20 to -150 C, followed by work-up with aqueous triethylammonium bicarbonate.130 The purine ribonucleosides as byafforded also significant quantities of the 5'-chloro-5'-deoxynucleosides products, while the 2'-deoxynucleosides gave additionally the 3',5'-bis (imidodiphosphates) as major co-products and some of the 5'-chloro-2',5'-dideoxynucleoside-3'-imidodiphosphatein each case. Species (123) are reasonably stable at room temperature as their triethylammonium salts, but are hydrolyzed in acid, neutral or alkaline solution to afford the 5'-phosphoramidates, possibly releasing metaphosphate by dissociative cleavage of the dianion. Alkaline phosphatase from E. coli caused hydrolysis of (123; B=Ade or Gua; R=OH) to the corresponding 5'-phosphoramidates, while snake venom phosphodiesterase effected release of the nucleoside from the same substrates. In an alternative synthesis, (123; B=Ade; R=OH) was prepared by treating adenosine 5'-H-phosphonate with bidtrimethylsilyl) phosphorazidate and TMS-chloride, followed by hydrolytic w0rk-up.l3~ In an amendment to a paper described in last year's Report,l32 adenosine 5'-[a, P-imidol triphosphate has now been found not to be a substrate for T7 RNA polymerase.l33 The apparent substrate behavior reported previously seems to have been due to a low level of contamination by ATP. It is tempting to speculate that the imidotriphosphate itself might be the source of the apparent contaminant ATP, possible via phosphoryl transfer processes catalyzed by metal cations. N-Methylimidodiphosphate, prepared by hydrolysis of N-methylimido-diphosphoryltetrachloride, has been used to displace toluenesulphonate from 5'-@tosyladenosine, affording adenosine 5'-[a, P-N-methylimido] diphosphate, which was phosphorylated to the corresponding triphosphate analogue (125) using creatine kina~e.13~ Also, AMP was converted to (126) by successive treatment with diphenylphosphorochloridate and

236

Organophosphorus Chemistry

N-methylimidodiphosphate. While (125) was a substrate for creatine kinase, (126) showed no detectable inhibitory properties. Treatment of base-protected 3'-Q-methoxyacetyl-2'-deoxyribonucleosideswith 2-chloro-4~-1,3,2-benzodioxaphosphorin-4-one ('salicyl chlorophosphite') followed by inorganic pyrophosphate affords the r2,p3 - dioxo-P1-(5'-nucleosidyl)cyclotriphosphite (1271.135 Sugar-protected ribonucleosides lacking base protection could be used similarly. Oxidation of species (127) using sulphur affords, after deblocking, the nucleoside 5'-(l-thio)triphosphates in good yield, while oxidation with aqueous iodine affords the triphosphates. Small quantities of the putative l-thiocyclotriphosphate and cyclotriphosphate, respectively, are formed as by-products. Also, treatment of 5'-hydroxy group-protected ribonucleosides with salicylchlorophosphite, followed by oxidation with sulphur in the presence of tri-n-butylamine and conventional deprotecting work-up, affords a rapid route to the nucleoside 2',3'is cyclophosphorothioates. When adenosine 5'-Q-[(~-methyl)-l-thiotriphosphatel hydrolyzed in [I8 01 water, inorganic pyrophosphate containing a single atom of 1 8 0 in a non-bridging position is formed, while the adenosine 5'- 6-methyl) thiophosphate co-product contains no oxygen-18.136 By-products included ATP containing a single non-bridging atom of 1 8 0 at Pr, and 180-labelled linear tetraphosphate. Evidently SN2 displacement of pyrophosphate is not occurring, and the observations made may be accommodated and rationalized nicely by postulating the transient formation of the cyclodiphosphate (128) by intramolecular cyclization with expulsion of AMPS(Me). Hydrolysis of (128) by [I801 water affords the labelled pyrophosphate, which may attack more (128) to generate the linear tetraphosphate. In a competing reaction, cyclization occurs to expel methylthiolate and give adenosine 5'-cyclotriphosphate which undergoes hydrolytic ring-opening. If, instead, the methylation of ATPaS used to generate the starting material is performed in dry acetonitrile, in addition to AMPS(Me) and polyphosphate products, a sharp singlet is observed at -16.7 p.p.m. in the 31P n.m.r. spectrum, which has been tentatively assigned to (128) and may represent the first direct physical evidence for a dioxadiphosphetane. A study of the modes of co-ordination of manganese (11) ions to Pa in (Rp)- and (Sp)-[a-170]ADPaSin nitrate-stabilized deadend complexes with creatine kinase has been performed.137 The e.p.r. spectrum for the complex with (Ep)-[a-l70]ADPaS (129) exhibits inhomogeneous broadening due to unresolved superhyperfine coupling to the 1 7 0 atom at Pa, while that for the ( s ~ ) - [ a - ~ ADPaS-containing ~Ol complex shows no such broadening, showing that co-ordination to sulphur is occurring (130). The enzyme is thus discriminatory for binding complexes (129, 130) with the A-screw sense stereoselectively, overcoming the intrinsic preference for the hard Lewis acid (manganese ion) to coordinate to oxygen which would dictate predominant formation of the A-screw sense complex with (SpI-ADPaS in the absence of the enzyme. The exchange-inert chromium (111) complexes of guanylylimido-diphosphate and GTP have lower binding affinity for

6: Nucleotides arid Nucleic Acids

237

transducin (involved in activating the retinal cGMP cascade) than the corresponding magnesium complexes, but the latter is hydrolyzed at a similar rate to its magnesium counterpart, while both A and A screw sense isomers of the former activate the &MI'-phospho- diesterase of photolyzed rod outer segment membranes with efficiency comparable to that of Mg(II).Gpp(NH)p but without apparent stereo~electivity.l3~ The GTPase activity of the protein p21-c-Ha-ras, which is believed to be involved in regulating cell growth, permits it to utilize ( 2 ~ ) guanosine 5'-0-[y-170,180, thio] triphosphate [the actual species used was (131)l as a substrate, and stereochemical analysis by previously reported procedures of the chiral thiophosphate released has shown that hydrolysis proceeds with inversion, 5'-[y160,170, 180] probably by direct in-line transfer to ~ a t e r . l 3(Sp)-Adenosine ~ triphosphate has been used, with D-fructose-6-phosphate, as a substrate for the from rat 'tandem enzyme' 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1801 bisphosphate formed used, in turn, as liver, and the D-fructose-2,6-[2-160,170, substrate for the alkaline phosphatase-mediated transfer of the phosphate groups to (~-butane-1,3-diol.~40Cyclization, methylation, and stereochemical analysis indicated that phosphoryl transfer by the kinase had proceeded with net inversion at phosphorus, probably directly in a ternary complex without the involvement of a phosphoenzyme intermediate. In attempts to determine whether ATP activates bicarbonate to form carboxyphosphate or biotin to form Q-phosphobiotin in the course of ATP-dependent carboxylation of biotin, no partial isotopic exchange in adenosine ~ ' - [ ( C L P - p-1802)] ~ ~ O , triphosphate was observed when biotin or bicarbonate was absent, or in the presence of N-1-methylbiotin and bicarbonate, and the putative carboxyphosphate could not be trapped as its trimethylester in conditions in which the authentic triester was stable, but the ATPase activity of biotin carboxylase which occurs in the absence of biotin was shown to effect transfer of an '80 label directly from ' 8 0 bicarbonate into the orthophosphate product.141 It has therefore been suggested that the bicarbonate-dependent biotin-independent ATPase activity of biotin carboxylase involves transient formation of the carboxyphosphate (132) (via attack of 180-bicarbonate on ATP) which breaks down to yield the observed products, and that the carboxylation of biotin may proceed analogously. Condensation of the 'capping' reagent (133) with 2'-Q-tetrahydropyranylated pGpUpA using silver nitrate and imidazole, followed by deblocking, has afforded the 'capped' trimer m7G (5')pppGpUpA in 11 % yield, and a similarly capped hexamer was formed in even lower yield.142 The problem of low solubility in solvent DMF was overcome by treating 2'-Q-tetrahydropyranylated pGpUpApUpUpA with carbonylbis (imidazole) to form the 5'-phosphorimidazolidate which was condensed with (134) and deblocked to give the capped hexamer in far better yield. N2-Methylguanosine and N2,N2-dimethylguanosine have been prepared and phosphorylated by standard methods and further

Organophosphorus Chemistly

238

R F I

0

II -0-P-0 I -0

R- P-0-P-0

I -0

-c

/I0

NHTMTr

-0

'0-

0 0 HXOMe

(13 2 ) (133) R =PhS (134) R =OCH3

I

x-+YO

R'Y

@

0

0

0-

0-

II

0

(135) X = CHZOP03*0 I1

(136) X = C-0-N

(139) X (140) X

= O ;R =OH,Me, or = S ; R =Me

Ph

(141) R1 = H ; R 2 = O H ( 1 4 2 ) R' = OH ; R2= H

6: Nucleotides and Nucleic Acids

239

methylated at N-7 to afford mz2r7-GMP and m32L7-GMP respectively.143 Literature methods were then used to prepare m&2'7G(5')pppG and m22f7G(5')pppG,which in turn were incorporated transcriptionally using T7 RNA polymerase and a @globin cDNA template into mRNA containing sequences encoding rabbit P-globin. In a reticulocyte lysate assay, the m22#7G-capped mRNA was more active, and the rn3*t2t7G-cappedmRNA less active, than normal m7G-capped mRNA, suggesting that N2-methylation may be used to influence translation efficiency. Conjugates of 1l-a-hydroxyprogesterone with ATP have been prepared, both by successive treatment of ATE' with diphenylphosphorochloridate and (135) to form a tetraphosphate bridge to the steroid, and also by condensing 8-(6aminohexy1)amino-ATP with the NHS ester (136).144 The conjugates, prepared for testing in bioluminescence assays, proved to give only about 1 % of the bioluminescence yield of ATP. Uridine 5'-(2-acetamido-2,4-dideoxy-4-fluoro-a-D-galactopyranosyl)diphosphate (137) and uridine 5'-(2-acetamido-2,6-dideoxy-6-fluoro-2-Dglucopyranosyl) diphosphate (138) have been prepared by synthesis of the l-adibenzyl phosphates of the acetylated sugars followed by catalytic debenzylation and Other analogues condensation with uridine 5'-phosphoromorpholidate.14~ (139,140) of UDP-glucose have been prepared for testing as glycosyltransferase inhibj tors by treating 2',3'-QQdibenzoyluridine with the appropriate phosphoro-, phosphono- or thiophosphono-0-0-bis (6-trifluoromethylbenzotriazolide)and then with 3,7-anhydro-4,5,6,&tetra-~-acetyl-2-d~xy-D-erythro-L-gul~oct~tol in the presence of N-methylimidazole.l46 The products blocked glycolipid synthesis in permeabilized cells. Uridine 5'-~-(2-thiodiphosphoglucose) (141) has been prepared in high yield by incubating UTP and a-glucose-l-thiophosphatewith UDPG pyrophosphorylase and pyrophosphatase.147 Galactose-l-thiophosphate, prepared from galactose and ATPyS using galactokinase, has been incubated with UDPglucose, galactose-l-phosphate uridylyltransferase and phosphoglucomutase to afford the UDP-galactose analogue (142). While (141) and (142) were substrates for UDP-galactose-4-epimerase, (141) was not a substrate for glycogen or sucrose synthetases. CDP-D-Quinovose (quinovose is 6-deoxy-D-glucose) has been prepared by two methods, the better yield being obtained by condensing quinovose-lphosphate with cytidine-5'-phosphoromorpholidate.~~~ CMP-N-Acetylneuraminic acid has been prepared on a multigram scale by incubating CTP (generated in situ from CMP using pyruvate kinase, PEP, and adenylate kinase in large amounts) and N-acetylneuraminic acid (formed enzymically from N-acetylmannosamine and pyruvate) in the presence of CMP-N-acetylneuraminic acid synthetase.149 It may be used in sialyltransferase-catalyzed reactions to form sialic acid-terminated sugar conjugates. 1-P-D-Ara-cytidine S'-diphosphate-1,2-dipalmitins(143, 144) have been prepared by condensing k 12-,and m-a-dipalmitoylphosphatidicacid with mcytidine-5'-phosphoromorpholidate.~~~ While (143) (but not (144)) and the racemate

Organophosphoms Chemistry

240

showed impressive activity against two m-cytidine-resistant L1210 leukemia cell sublines in mice (against which u-CMP and the corresponding phosphatidic acid, administered separately, had little effect), (143) was completely ineffective against a comparable L1210 subline which was additionally deficient in deoxycytidine kinase. This puzzling result requires further examination. A number of dinucleotide analogues of type A(5')pn(dT)(n = 3-6) and A(5')pmcp(dT) (m = 2-5; pcp is methylenediphosphonate) have been prepared using several conventional phosphate-coupling methods, with the use of phosphoromorpholidates proving generally best, especially for longer chain lengths.151 The analogues were tested as inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase, from tumour cell sources, and A(5')pn(dT) (n = 5 or 6) found to inhibit all three enzymes strongly, while A(5')pmcp(dT)(m = 4 or 5) inhibited the kinases but not the reductase. In a new procedure for preparing compounds of this type, nucleoside 5'-mOnO- or diphosphates have been treated with DMAP in the presence of triphenylphosphine/2,2'-dipyridyl disulphide to form presumably, the DMAP-derived phosphoramidates which are then condensed with the appropriate nucleoside 5'-polyphosphate to give the desired pr0duct.l5~By activating ADP, for instance, and coupling it to 8-(6-aminohexyl)amino-ADP, 8-(6-aminohexyl)amino-A(5')p4A could be prepared in good yield. The binding interactions of A(5')ps A, and also of 3'-fluoro-3'-deoxy-&-AMP and -ATP with porcine adenylate kinase have been investigated using IH and I9F n.m.r. spectroscopy, and the apparent dissociations constants evaluated.153 The self-condensation of (Sp)-[l-l8O21ADPaSusing diphenyl phosphorochloridate affords predominantly (Sp, Sp)-P', P4-bis(5'-adenosyl)-1[thio'8021, 4[thio-l802]tetraphosphate(145).'54 In fact, some of the (Ep, Sp) isomer is also formed as a minor product, possibly via intermediate dismutation to AMPaS and (Sp)ATPaS, but the diastereoisomers are separable on a Mono Q column. Treatment of (145) with cyanogen bromide and [I701 water then affords (146), the stereochemistry at the phosphorus a tom having been predominantly retained. Model reactions show that in fact some 30 70 of the oxygen isotope is introduced at P2 and p3, indicating that the central phosphate groups can participate in formation of cyclodiphosphate and cyclotriphosphate intermediates. These cyclic intermediates are not formed exclusively, since stereochemical analysis shows that is not exclusive. When (146) (which is now retention of configuration at P1 and the (Ep, Ep) stereoisomer) was used as substrate in [l601-water for the unsymmetrical A(5')p4A phosphodiesterase from lupin seeds, ( E ~ ) - 5 ' - [ ~ 6I7O, 0 , *sO]AMP was released, showing that hydrolysis had occurred with inversion, probably via an 'inline' mechanism. A total of 13 PI P'-substituted (147) and aP,alp'-disubstituted (148) phosphonate analogues of A(5')p4A have been prepared as substrates or inhibitors of the bis(5'-nucleosidyl) tetraphosphatase from Arternia embryos (which hydrolyzes Ap4 A symmetrically) or from E. coli (which hydrolyzes asymme-

r4

6: Nucleotides and Nuclric Acids

/. .\

x 0 i'0-P-0-P-.'! II

(AdO-5')-0-P-

I

-0

0

24 1

P-O-(Ado-5')

II

*'

I

-0

(146) X d70

(Ad0-5')-0-

0 II

P-X-

0 II P-Yy-

I

I

-0

-0

0 II P-

I

-0

X-

0 II P-o-(Ad0-5')

I

-0

OEt

I Silica-Si(CH2)3NH [CONH ( CH2),,X],M

I

OE t

(149) n = 6 , m = 3 , X = NH or 0 or n = l Z , m = Z , X = N H or 0

LCAA - C P G G - N H C O C H ~ C H ~COO

0 0

M H I COPh

*B

242

Orgariophosphorus Chemistry

trically).155 Preparation of species (147) was performed by reacting the bisphosphonate with adenosine 5'-phosphoromorpholidate, and of (148)by treating 5'-Q-tosy1-2',3'-0- Q-isopropylideneadenosine with the appropriate bisphosphonate and dimerizing the product using DCC. Excepting the compounds with ethylene or ethene bridges, species (147)and (148) were either substrates or competitive inhibitors for both enzymes, the substrate efficiency correlating with substituent electronegativity in the methylene groups. Interestingly, (148; X = CF2) was hydrolyzed svmmetricallv by the E. coli enzyme, suggesting that a 'frameshift' on the oligophosphate chain is possible. It has been observed that re/+ strains of Salmonella typhimurium, which form large quantities of ppGpp as part of their response to stringent conditions, exhibit far lower levels of mistranslation during protein synthesis in aminoacid starvation conditions than do rel- strains (which do not form ppGpp under these conditions).l56 It has thus been conjectured that ppGpp is the molecule responsible in vivo for maintaining fidelity of translation in rel+ bacteria in stringent conditions. 4. Oligo- and Polvnucleotides

4.1 Chemical Svnthesis. A number of reviews on the subject of the evolution of the chemical synthesis of oligodeoxyribonucleotides, with particular emphasis on the phosphoramidite method and its use on solid supports, have a ~ p e a r e d . 1 5In ~ some cases these topics are extended to discuss specifically gene synthesis and technology.158 The synthesis of genes, of 1 - 2 kilobases in length or even longer, has now become routine, by chemical synthesis of oligodeoxyribonucleotides of greater than 100 bases in length, chemical phosphorylation, purification using low-meltingtemperature agarose gels, and enzymatic ligation.l59 Another account of the rapid automated synthesis of oligodeoxyribonucleotides using 5'-Q-dimethoxytrityl-2'-deoxynucleoside-3'-~-phosphonateshas been described.160 Significant attention has been paid to improving the properties of the solid support used in solid-phase oligonucleotide synthesis: for instance, macroporous silica has been derivatized with polyethyleneimine and polyvinyl alcohol to increase its loading density.161 An improved simplified procedure in which l-ethyl-3-(3-dimethylamino)propylcarbodiimideis used to couple nucleoside 3'-succinates directly to long-chain alkylamine-controlled pore glass (LCAA-CPG) has been described.162 The LCAA-CPG is activated by acid treatment prior to derivatization, and also subjected to a 'capping' step to block unreacted amino groups prior to the start of oligonucleotide synthesis, to prevent formation of oligonucleotides linked directly to the LCAA-CPG via their 3'-phosphates. Silica gel supports functionalized with different lengths of spacer arm have been evaluated for possible advantage in oligonucleotide synthesis. In a limited study in which

6: Nucleotides mid Nucleic Acids

243

spacer arms [(CH2)11NH21, [(CH~>~N(COCHZNH)~H], and [(CH2)3NH (COCH2CH2NH)2H]were attached separately to silica, only the double glycine spacer improved the yields of the initial coupling steps.163 In much more extensive studies involving poly (alkylureide), polyglycine, polyethyleneglycol, and succinimide spacers, and also polyureides containing benzene, biphenyl, or biphenyl ether groups, attached to Fractosil, Proasil, or CPG supports, and involving various types of covalent linkage to the terminal nucleoside, the best results in terms of average yield per cycle were obtained with long spacers of the polyureido type (149) with fully extended conformation on supports of wide pore size (CPG 500 or Fractosil 1000 and 2500).l@ Good results were also obtained with [-CONHC&NH]3H and tetra(ethyleneglyco1)spacers on CPG 500. The type of covalent linkage to the terminal nucleoside was found to have little influence. The use of a single type of LCAA-CPG derivatized with 3-anisoyl-2'(3')-Q-benzoyluridine 5'-Q-succinyl residues (150) has been advocated for oligoribo- or oligodeoxyribonucleotide synthesis.l65 For instance, oligoribonucleotides are built u p on (150) via addition cycles utilizing 5'-protected 2'-Q-(2-nitrobenzyl) ribonucleoside 3'-(2-cyanoethyl)-N, N-diisopropylphosphoramidites, after which a single treatment with ammonia-pyridine releases the oligomers and removes base- and phosphateprotecting groups. Partial acetolysis of bis(2, 4, 6-tribromophenyl) trichlorophosphorane affords bis(2, 4, 6-tribromophenyl) phosphorochloridate which, in the presence of 3-nitrotriazolet gave better (if slower) coupling yields for the condensation of phosphorothioates with the 5'-hydroxy protected 2'-deoxynucleoside-3'-(~-phenyl) groups of other nucleotidic species than MS-nt.l& Reaction was less efficient if tetrazole was used instead of 3-nitrotriazole. In the absence of 3-nitrotriazole, an unsymmetrical pyrophosphate appears to be formed transiently. Durenesulphonyl chloride in the presence of N-methylimidazole, or l-(3-durylsuphonyloxy)-6nitrobenzotriazole, have also been introduced as coupling agents in oligonucleotide synthesis by the phosphotriester route, and found comparably efficient to TPS-cl with E-methylimidazole and superior to MS-cl with N-methylimida~ole.l6~ Tris(1, 1, 1,3,3, 3-hexafluoro-2-propyl) phosphite reacts readily with base- and 5'-protected 2'-deoxynucleosides with two equivalents of pyridine in dichloromethane to afford (151) which is readily activated by N-methylimidazole to couple with the 5'-hydroxy group of another nucleosidic species, affording (after treatment with water) the dinucleosidyl H-phosphonate.I68 Intermediates of type (151) are reasonably stable during long-term storage, and have been used in solid phase oligodeoxyribonucleotide synthesis, affording 96 % average coupling yield and a cycle time of 15 1/2 minutes. Treatment of 2-(4-pyridyl) ethanol with bis(N, Ndiisopropylamino) chlorophosphine affords 2-(4-pyridyl)ethylphosphorobis(N, Ndiisopropylamidite), which reacts with appropriately protected 2'-deoxynucleosides in the presence of diisopropylammonium tetrazolide to form (152).169 The use of

244

Orgunophosphortis Clieniistry

(152) in oligonucleotide synthesis gives, following the oxidation steps, internucleotidic phosphates protected by the 2-(4-pyridyl)ethyl group, which is removed using phenylchloroformate in acetonitrile. (2-PyridyUmethyl phosphorobis (triazolide) (153) has also been used to phosphorylate 5'- and baseprotected deoxynucleosides for the purpose of introducing the nucleotide b0nd.1~0 Treatment of 2-chlorophenylphosphorothioyl chloride successively with aqueous pyridine and 2-(N-monomethoxytrityl)aminoethyl bromide affords (1541, which may be coupled to the 5'-hydroxy group of a protected oligonucleotide using MSnt to give, kfter conventional deblocking, an S-(Z-aminoethyl)thiophosphate group at the 5'-terminus, to permit attachment of fluorescent or other ligands.171 Alternatively, oxidation with aqueous iodine leaves the 5'-phosphate terminus. Otherwise, detritylation of (154) gives (155) which can be used to displace the phenol from a succinylated resin esterified with pentachlorophenol, forming (156) which in turn can act as the attachment point for the 3'-residue in standard solid phase phosphotriester oligodeoxyribonucleotide synthesis. At the completion of synthesis, detachment from the solid support using aqueous iodine affords the 3'-phosphorylated oligonucleotide. The use of 2-mercaptobenzothiazole in the presence of diisopropylethylamine in 1-methyl-2-pyrrolidinone effects the removal of phosphate-protecting methyl groups from oligodeoxyribonucleotides as efficiently as No evidence of associated internucleotidic phenylthiolate but without the cleavage was found. The side-reactions which may arise in oligodeoxyribonucleotide synthesis employing phosphoramidites are a source of concern, and methods to detect reactions which occur at the guanine base have been reported, one involving the higher susceptibility (than thymine) of the modified guanine to oxidation by permanganate which allows selective identification, and the other utilizing the Uvr ABC endonuclease (excision repair) enzyme to detect the increased bulk of the modified base.I73 The exact nature of the guanine lesion, which arises during synthesis using methoxydiisopropylphosphoramiditesbut not when 2-cyanoethyldiisopropylphosphoramidites are used, has not been defined. It may occur due to oxidation with iodine generating methyl iodide (from the phosphotriesters) to alkylate guanine bases at N-7, followed by addition of deblocking thiophenolate at C-8. In another study, the cleavage by two restriction enzymes of the same (supposedly) 35-mer sequence was considerably impaired for the sequence which had been prepared using Q-me thyl-N, N-diisopropylphosphoramidites compared with that prepared using Q-(Z-cyanoethyl)-N, Ndiisopropylphosphoramidites, with sequence analysis suggesting that some 3 % of modified bases, including N6-methyl-2'-deoxyadenosine,N1-methyl-2'-deoxywere formed using the former guanosine, and N3-rnethyl-Z'-deoxythymidine reagents.174 The use of DMAP in the capping step of synthetic cycles is also thought to be a source of unintentional base modification, since it reacts at 0 6 of activated

6: Nucleotides urid Nucleic Acids

245

(154) R = MMTr (155) R = H

(153)

*B MM Tr NH(C HZ),, 0 Me0

(157) n = 2 or 6

0 II

HS CH2CHzCONH (CH2)4 0 - P I

0 - [oligodeox yribonucleotide

0 R: R2

II

N(CH;!), P - 0 -

’

I

DMTro 0

1

-0 Pri,N-

(159) R1,R2=P h t h a l o y l ; n = 4 or 10 (160) R1 = Fmoc ; R 2 = H ; n = 10

-

P-OR2

(161) R’= C E C CHzNHCOCF3; R2= CHZCHzCN (1 6 2 ) R1= CHz CHz CHzN Phthaloyl R2= Me

246

Organophosphoms Chemistry

guanine to form a fluorescent adduct which gives rise to 2, 6-diaminopurine on reaction with ammonia, with consequent transitional mutations.175 The replacement of DMAP by N-methylimidazole in the capping step reduces or eliminates the formation of modified bases and consequent mutation via this route.174,175 At the completion of oligodeoxyribonucleotidesynthesis, if apurinic sites have arisen during the synthesis, cleavage during ammonia treatment will generate 5'-tritylated but truncated versions of the target sequence which may prove troublesome to separate from the desired intact sequence, especially for longer oligomers. The introduction of an extra cleavage step (1 M lysine hydrochloride, pH 9,600,90 minutes) into the deprotection protocol has been recommended: using this, apurinic sites are cleaved and the 5'-tritylated truncated fragments may be washed away prior to release and purification of the intact 5'-tritylated target sequence.176 The development of new protecting functions for sugar hydroxy groups during chemical nucleic acid synthesis has been reviewed.lir7 When performing automated oligodeoxyribonucleotide synthesis using chlorophosphite intermediates, the greater stability of 5'-Q-dimethoxytrityl-N2-dimethylaminomethylene-2'-deoxyguanosine-3'-methylchlorophosphite compared to its I$-isobutyrylated counterpart renders amidine protection of the purine bases preferable, but generally phosphoramidite methodology is to be preferred.178 The use of the phenoxyacetyl group to protect exocyclic amino functions on purine 179181 and pyrimidine 180 bases during oligonucleotide synthesis is finding increasing advocacy. However, capping using acetic anhydride may cause exchange of acetyl for phenoxyacetyl at guanine residues, so capping using phenoxyacetic anhydride has been i n t r 0 d ~ c e d . lDepurination ~~ during oligodeoxyribonucleotidesynthesis is minimall80 and base deprotection is readily effected with ammonia in mild conditions, with little associated internucleotidic cleavage in oligoribonuc1eotides.l79r 181 The naphthaloyl group has also been introduced for protection of the exocyclic amino groups of nucleic acid bases, using naphthalic anhydride.lS* It is removed using concentrated ammonia, in similar conditions to those employed for benzoyl removal. Protection of the 06-function of guanine by the diisobutyryloxyethylene group (in addition to isobutyrylation at the amino group) was employed in the phosphotriester synthesis of segments of the dinorphine structural gene: a significant decrease in side-reactions and improvement in stability to acidcatalyzed depurination were noted .I83 Once again, various methods permitting the introduction of a specific functional group (amino or thiol) to allow an oligonucleotide to be 'tagged' have been reported. For instance, treatment of a protected 2'-deoxynucleoside 5'-0methyl-N, N-diisopropylphosphoramidite with an N"-monomethoxytritylalkan-l01 in the presence of tetrazole, and subsequent oxidation with aqueous iodine,

6: Nucleotides and Nucleic Acids

247

affords (157) which may be debenzoylated, phosphitylated, and used in the terminal elongation cycle of oligonucleotide synthesis to place an aminoalkyl group at the 5'-termin~s.'~ Comparison ~ of two 23-mers differing only in having aminoethyl and aminohexyl groups, which had been reacted with fluorescein isothiocyanate, at the 5'-termini, showed that conjugation of the bulky fluorescein via the longer linker caused less destabilization of hybrids formed by the attached oligonucleotide. Also, reaction of such aminoalkyla ted 5'-termini of oligodeoxyribonucleotideswith the N-hydroxysuccinimide ester of 3-(2-pyridyldithio)propionate, followed by thiolysis with DTT,affords (1581, thus permitting easy introduction of a thiol group.185 The a-phosphonate procedure for oligonucleotide synthesis also lends itself readily to the introduction of amino and sulphydryl groups.186 5'-Aminoalkylphosphonates have been introduced into oligonucleotides by coupling (159) or (160) to the 5'-hydroxy groups of otherwise protected oligonucleotides (which may be attached to a solid support) using DCC and N-methylimida~ole.l8~ Following deblocking, conjugation to fluorescein or biotin was achieved by conventional methods. Alternatively, oligonucleotides may be labelled via derivatized bases: alkylation of 5'-Q-dimethoxytrityl-2'-deoxy-5iodouridine with &I-trifluoroacetylpropargylamine using bis(tripheny1phosphine) palladium (11) chloride and cuprous iodide, followed by conventional phosphitylation, affords (161) which may be incorporated into oligodeoxyribonucleotides by normal solid-phase synthetic methods, and, after deprotection, used for attachment of fluorescein, etc.I88 In another study, the closely related (162) was used similarly, then derivatized with mansyl [6-(N-methylanilino)naphthalene-2-sulphonyl] chloride to introduce a fluorescent tag.l89 The fluorescence changes of the resultant nucleotide within a duplex were used to gain information on enzyme-DNA interactions on binding to Klenow fragment of E. coli DNA polymerase I. In other studies, the tagging group itself has been derivatized to form a phosphoramidite, which is then used to phosphitylate the 5'-hydroxy function of an otherwise fully protected oligonucleotide linked to a solid support. For example, biotin was esterified, protected, and reduced to its corresponding alcohol which was phosphitylated to give (163).190 Similarly, a bathophenanthroline-ruthenium (11) complex bearing a 5-hydroxypentyl group on one of the phenyl rings was converted A biotinylated 15-mer to its 2-cyanoethyl N, N-diisopropy1ph0sphoramidite.l~~ prepared in this way functioned successfully as a hybridization probe in an alkaline phosphatase-based detection system,l9" while the ruthenium-labelled oligodeoxyribonucleotides were used as non-radioactive sequencing primers in 'dideoxy' sequencing.lgl Oligo-a-deoxyribonucleotideshave been prepared on Fractosil500 using cyanoethylphosphoramidite chemistry.192 A coupling efficiency of 96.5 70 was has been estimated. 2-Methoxy-6-chloro-9-(5-hydroxypentyl)aminoacridine

248

Organophosphorus Clwmistry

converted to its cyanoethyl & N-diisopropylphosphoramidite and used, as above, to introduce the acridine group covalently at the 5'- terminus of both a- and po1igodeoxyribonuc1eotides.l~~ The same acridine group has been introduced at the with bis(N, N3'-terminus by treating 5'-Q-dimethoxytrityl-2'-deoxythymidine diisopropylamino)chlorophosphine, and treating the product with the same hydroxypentylaminoacridine, giving (164), which in turn reacted with derivatized Fractosil 500, displacing diisopropylamine to attach (164) to the solid support, where it became the 3'-terminus of a conventionally synthesized oligonucleotide. 2-Methoxy-6-chloro-9-aminoacridine has also been attached, via polymethylene linkers of various lengths, either to the 5'-terminus, or to the 3'- and 5'-termini simultaneously, or to an internucleo tidic phosphate, of oligo (dT) species.lg5 The oligothymidylates, protected at phosphate by the 4-chlorophenyl group in all cases except that in which attachment to a single internucleotidic phosphate was performed, were esterified by the hydroxyalkylaminoacridinesusing MStet for coupling. Subsequent deblocking using oximates and DBU removed the chlorophenyl groups but left the acridinylalkyl esters intact, even when internucleotidic phosphate was esterified. Tetrathymidylate analogues of structure d(TpYTpTpYTp)-0Acr, where p* is a methylphosphonate or an alkyl (ethyl or neopenty1)phosphotriester link of a single diastereomeric configuration, and an acridine ring is covalently attached to the 3'-terminal hydroxy group, have been prepared and their hybridization to complementary sequences studied by c.d. spectroscopy.l96 While all the oligothymidylate analogues, like oligo(dT1, formed double-stranded complexes with poly(rA), the methylphosphonate and alkyl phosphotriester species could additionally form triple-stranded complexes with poly(dA). The thermal stabilities of the complexes with poly(dA) and poly(rA) depended strongly on the configuration at the internucleotidic links, those containing pseudoequatorial links (165) in the tetrathymidylate being more stable than those with all-phosphodiester links, and those with pseudoaxial links being less stable. The melting temperature of a-d(CCTTCC) complexed to P-d(GGAAGG) (a 1:l duplex) significantly exceeds that of P-d(CCTTCC) complexed to P-d(GGAAGG), but that of a-d(GGAAGG) complexed to P-d(CCTTCC) is markedly 1 0 w e r . l ~Evidently, ~ while the stability of an aP duplex may exceed that of a pp duplex, the sequence is a major determinant in dictating stability. The total synthesis of yeast tRNA *la has been reviewed 198 and the total synthesis of a 77-nucleotide R N A sequence with methionine acceptor activity has also been described.lg9 A solid-phase procedure for RNA synthesis has been described wherein the nucleoside is attached covalently to the silica support, through the 5'-OH group via an ester bond, and then treated with excess bisdiisopropylaminomethoxyphosphine and isopropylammonium tetrazolide to form the immobilized nucleoside 3'-phosphoramidite in situ.*OO Treatment with a base-protected 2'-Qtetrahydropyranylnucleoside and tetrazole followed by oxidation

249

6: Nuclrotides and Nucleic Acids

A

RN

(163) R

NH

= DMTr,Thp

, O r MThp

‘“V” - ,o

0%

R’-’ovhy P’

( 1 6 5 ) R = M e , O E t .OCH2CMe3

MMTro$

(166)

DMTroY2 0I

Pr‘2N- P-OMe

(167) R = CH2CH2CN;*B AdeBZor U r a (168) R = Me ;*B = C y t A C

(169) *B = AdeBZ,Thy

@

’

HO

250

Orgunophosphorus Chew istry

of the resultant phosphite triester completes one round of addition. The use of the TBDMS group for 2'-protection during large-scale oligoribonucleotide synthesis has been declared unequivocally to be more advantageous than that of tetrahydropyranyl or methoxytetrahydropyranyl protection, affording higher coupling yields, and stability throughout the synthesis with little detectable isomerization or chain cleavage.201 However, methylphosphoramidites (which, as noted above, may have associated drawbacks) gave better coupling yields than 2-cyanoethylphosphoramidites,possibly due to steric hindrance by the bulky TBDMS inhibiting coupling. In a study which compared the influence of the 2-protecting groups on coupling in oligoribonucleotide synthesis with that in oligodeoxyribonucleotide synthesis, similar conclusions were reached.2*2 Use of the phenoxyacetyl group (mentioned earlier) to protect the exocyclic amino groups of adenosine and guanosine residues during oligoribonucleotide synthesis permits deacylation with anhydrous methanolic ammonia in mild conditions and virtually eliminates the premature removal of alkylsilyl groups and chain cleavage associated with the use of 30 % ammonium hydroxide for base deacylation.203 In other accounts of oligoribonucleotide synthesis, various combinations of protecting groups and methodology have been reported as advantageous. A solidphase synthetic procedure employing nucleoside H-phosphonate units (formed using tris(1, 1, 1, 3, 3, 3-hexafluoro-2-propy1)phosphite and 1-[(2-chloro-4methyl)phenyll-4-methoxypiperidin-4-yl (Ctmp) protection of the 2'-hydroxy group, with pivaloyl chloride as condensing agent, was efficient (95 % average coupling yield) and no side-reactions were observed.204 The photolabile 2-nitrobenzyl group has been used to block the 2'-hydroxy group in oligoribonucleotide synthesis on a polystyrene support by the phosphotriester approachZ05and on aminopropyl-CPG using a phosphoramidite procedure.206 In the phosphotriester approach the use of 1-methylimidazole (with MS-nt in pyridine for condensation steps) was found superior to that of 4-methoxypyridine -1-oxide.*05 Oligoribonucleotide synthesis employing acid-labile protection at the 2'-hydroxy group in the form of 2'-Q-(2methoxy-2-propyl) nucleosides has also been reported.207 The combination of 5'-0laevulinyl and 2'-Q-tetrahydrofuranyl protection has been used in solid-phase synthesis by the phosphoramidite approach.208 Monomer units of type (166) were used as building blocks: the hydrazine treatment used to remove the laevulinyl group after each elongation cycle partially debenzoylates adenine and cytosine bases, and subsequent reaction of the phosphoramidite at unblocked adenine may occur. However, the by-products formed seem to undergo slow hydrolysis back to adenine during terminal deblocking at the conclusion of synthesis. The 5'-deblocking and coupling steps appear relatively slow by the standards of automated cycles, but not unacceptably so. The 9-fluorenylmethoxycarbonyl (Fmoc) group has been strongly recommended for protection of the 5'-hydroxy function during oligoribonucleotide synthesis using 3'-(cyanoethyl)diisopropylphosphoramidite units with 2'-Q

6: Nuckotides and Nucleic Acids

25 1

methoxytetrahydropyranyl pr~tection.~og Following each coupling step, it is removed using DBU in acetonitrile. However, it cannot be used with the Hphosphonate approach since treatment with DBU causes side reactions with chain cleavage. 4,4',4"- Tris(acy1oxy)tritylgroups have been employed for protection of the amino group of adenosine210 and the tritylsulphenyl group (introduced using triphenylmethanesulphenyl chloride) has been used for protection of the N3-imido function of uridin&I1 during oligoribonucleotide synthesis. The latter group is readily removed during terminal deblocking by using aqueous iodine. As usual, many syntheses of oligonucleotides containing modified bases have been described. Thus oligodeoxyribonucleotides containing 2-deoxyinosine212 and also 6-thioguanine and 5-methyl-2-pyrimidinone213have been prepared using conventional phosphotriester methodology. The thioketo group of 6-thioguanine was found to react with MS-nt, but could subsequently be regenerated from the adduct using thiophenol. For the most part, modified residues have been incorporated into oligodeoxyribonucleotides via their 3'-(methyl- or cyanoethy1)-N. N-diisopropylaminophosphoramidites,and examples include the 2'-deoxynucleoside of 2-pyrimidinone1214~6-(carbamoylmethyl)-2'-deoxyadenosine,215 8-aza-7-deaza-2'-deoxyguanosine216.217 and 7-deaza-2'-deoxy(for which formyl protection guanosine,2I7 7-deaza-2'-deoxy-Q6-methylguanosine2~8 was employed at N-2 since the isobutyryl group was difficult to remove), 8-aza-7and ~g-(~-D-2'-deoxyribof~ranosides),2~~ (E)-5-(2-bromovinyl)-2'deazaadenine N8deoxyuridine,2208-oxo-7,8-dihydroadenine-9-(~-D-2'-deoxyribofuranoside)~a product of y-irradiation of DNA),221@-methyl and -isopropyl, and 04-methyl, -isopropyl, and -pbutyl-Z'-deoxythymidines (in a study which presented many difficulties due to dealkylation by thiophenoxide and alkoxy exchange by DBU during deprotection 224 Generally, the influence of protocols),222 and Q6-methyl-2'-deoxyguanosine.223~ the base modification on the stability of 'complementary' duplexes and/or conformation and base pairing in those duplexes and/or the effect of the modified base in the restriction sequence upon cleavage by a restriction endonuclease was studied. For some oligomers containing @-methylguanine, excision repair by ABC excinuclease of E . coii (previously thought to repair bulky adducts causing helical deformity) was shown to occur, via incisions at the eighth phosphodiester bond 5'-, and the fifth or sixth phosphodiester bond 3'-, to the modified guanine.224 Oligonucleotides containing modified sugars which have been synthesized via phosphoramidite units, as above, include 2'-Q-methyloligoribonucleotides (which were resistant to DNA- and RNA-specific nucleases but variously susceptible to nucleases with dual specificity, and formed convenient hybridization probes following 5'-terminal biotinylation),225 and oligo(arabinonucleotides), in which regioselectivity of reaction at the 3'-hydroxy group as opposed to the sterically blocked 2'-hydroxy group facilitated the synthesis of the phosphoramidite

252

Orgunophasp horus Clierni s t y

monomers.226 However, in solid-phase synthesis on aminopropylsuccinylated silica, high excesses of phosphoramidite caused some reaction at unprotected 2'-hydroxy groups, so monomers of type (167) were employed. The oligonucleotides formed could be unblocked by a single treatment with aqueous ammonia, since the stereochemistry of the 2'-hydroxy group is 'wrong' for neighboring group-assisted internucleotidic cleavage by transesterification to occur. DNA oligomers containing cytosine arabinoside have also been prepared, employing (168).2Z7*228 When located at the 3'-termini of primer oligodeoxyribonucleotides, ara-cytidine drastically reduced the rate of insertion of the next complementary nucleotide specified by a complexed template strand in in vitro DNA synthesis for a variety of DNA polymerases (proofreading polymerases preferentially excised ara-CMP prior to elongation), and depressed the rate of ligation by T4 DNA ligase.228 Glyceronucleoside phosphoramidite synthons of type (169) have also been prepared by conventional methods and underwent efficient coupling in solid-phase syntheses in which oligomers u p to a hexamer and octamer were f0rmed.2~9 Conventional deblocking permitted isolation of the 'oligonucleotides' which were resistant to spleen and snake venom phosphodiesterases but substrates for polynucleotide kinase. It would be of interest to see if they could be used to protect regular oligonucleotide sequences from exonuclease digestion by attaching them as 'tails' to the 3'- or 5'-termini. The nucleosides (170) and (171), formed from 4-Q-[(2,4, 6triisopropylbenzene)sulphonyl]pyrimidine nucleosides and the corresponding aromatic diamines, have been converted by conventional methods to their 5I-Qdimethoxytrityl-3'-H-phosphonatederivatives and incorporated into oligodeoxyribonucleotides using the standard a-phosphonate protocol.230 Again the effects on stability in duplexes were studied: generally incorporation of (170) resulted in greater increase in helical stability than (171), which appeared to adopt intercalation geometry. In other studies involving the incorporation of modified residues in oligodeoxyribonucleotides, 5-bromo-2'-deoxyuridine and 5-methyl-2'deoxycytidine were incorporated in to oligomers with a 5'-terminal EDTA-2'deoxythymidine residue which proved capable of binding to duplex DNA and cleaving it at a homopurine target sequence with higher affinity and over a greater pH range than the corresponding dT/dC containing oligomers, thus evidently extending the capacity for triple helix formation to the physiological pH range.231 Decadeoxyribonucleotides containing 2-aminoadenylate (i.e. ribonucleotide) residues have been prepared, and the extra stability resulting from the presence of the 2-amino group in their hybrids found to be very small, the DNA/RNA pairs apparently distorting the B-DNA structure to diminish efficient H-bonding and base stacking.232 The molecular structure of a hexadeoxyribonucleotide containing 5-fluorouracil residues forming wobble pairs with guanine has been determined, and no evidence of enolised or ionised forms of 5-fluorouracil was found.233

6: Nuc1rotidt.s trttd Nuclric Acids

253

Synthetic 13-mer templates containing a single residue of 3-deaza-2'-deoxycytidylate at position 11 have been prepared, annealed to a complementary octamer, and the octamer strand elongated using E. coli DNA polymerase I and deoxynucleoside triphosphates to establish what base was inserted opposite the modified nucleotide.234 The answer was, exclusively, cytosine, indicating that it can base-pair efficiently with 3-deazacytosiner possibly via the imino-enol tautomer of the latter. However, 3-deaza-dCTP could not act as a substrate for DNA polymerase I. Two series of decadeoxyribonucleotides have been prepared, each containing a single base change in the restriction sequence of Eco RV restriction endonuclease (in which hypoxanthine, 6-methyladenine, 7-deazaadenine, 2-aminopurine, uracil, 5-bromouracil, 5-methylcytosine or 5-bromocytosine were inserted variously in place of the normal bases) and the cleavage susceptibilities evaluated to establish which structural features of the recognition sequence are essential for cleavage to occur.235 Protocols for the introduction of aliphatic diamines such as 1, 3diaminopropane, or glycols such as propane-1, 3-dio1, into the sugar-phosphate backbone of an oligodeoxyribonucleotide as 'no-base' residues have been described.236 Propanediol was introduced via a solid phase phosphoramidite procedure, or by 'chemical ligation' using the N-hydroxybenzotriazole esters of oligonucleotides, while the diamines were introduced by ligation, including template-directed chemical ligation. The 'no-base' residues appeared to destabilize duplexes significantly without apparent distortion of the double helix. The cyclic dimers d[c(ApAp)] and d[c(CpGp)] have been prepared in a one-pot reaction from their open chain precursors, using 2-chlorophenylphosphorobis(10xybenzotriazolide).23~The corresponding cyclic dimer of 5-fluoro-2'deoxyuridylate, d[c(f%Jpf%Jp)lhas been prepared by standard phosphotriester methods which included employing MS-cl/ tetrazole for cyclization, and proved equally effective to 5-fluoro-2'-deoxyuridine in inhibiting adenocarcinoma growth in mice, and less t0xic.~38 It is thought to act as a prodrug of the nucleoside. Cyclic oligonucleotides of up to octamer size (including two tetraribonucleotides, one containing N6, @-dimethyladenylate residues) have been prepared by a modified phosphotriester approach using protected nucleosidyl 3'-(2-chlorophenyl)phosphorobenzotriazolide units.239 The final cyclization was achieved using TPSnt. The synthesis of nucleopeptides offers considerable challenges in the manipulation of protecting groups and procedures used, and is receiving increasing attention. In the synthesis of H-Ala-Tyr(pUpU)-OH, in which the dinucleotide is attached to the dipeptide via phosphodiester linkage at the phenolic hydroxy group of tyrosine, (172) was condensed with the 5'-hydroxy group of base- and sugarprotected UpU, using isodurenesulphonyl chloride and 3-nitro-1H-1, 2, 4-triazole.240 The internucleotidic link was also protected as an 2-phenyl phosphorothioate. In

254

Organophosphorus Chemistry

the deprotection protocol, n-tributyltin oxide was used, permitting removal of the thiophenyl groups without dephosphorylation of tyrosine. In other nucleopeptide syntheses the 2-nitrophenylsulphenyl (NPS) group has been used to protect the Nterminus of the peptides and the exocyclic amino group of adenine and cytosine bases.241.242 The protected dipeptide NPSPhe-Tyr-NH2 was phosphorylated at its phenolic hydroxy group using Q-(2-chlorophenyl)-Q Q-bis(1-benzotriazolyl) phosphate, and the product treated with d(ATAT) fully protected apart from its 5'hydroxy group.241 Tri-n-butyl phosphine in aqueous dioxane was used to remove the phenylsulphenyl group in the deblocking procedure. In a synthesis using NPSAla-Ser-Ala-0 Ally1 and bis(diisopropy1amino)allyloxyphosphine to introduce the nucleopeptide link, high yields were obtained but the ally1 group could not be removed from the C-terminus of the peptide by the usual method. The serinyl nucleotidyl phosphodiester bond is highly prone to p-elimination, and in other syntheses, which followed the same general outline, di-n-butylformamidine was used to mask the exocyclic amino group of guanine, and the C-terminus of the peptide protected as its 2-(hydroxymethyl)-9, 10-anthraquinone ester.242 This last is removed by reductive cleavage using sodium dithionite at pH 8.5. A substantial number of 2'(3')-Q-aminoacyl triribonucleotides have been prepared by using the benzotriazolyl phosphotriester approach to assemble the protected trinucleotide, after which the 3'-hydroxy group of the 3'-terminal residue was condensed with N-[ [2-(4-biphenylyl)isopropyl)oxy]carbonylphenylalanine using MS-tet.243 Among other ploys, Fmoc was used to protect the amino groups of adenine, cytosine and guanine, the phenyl group to protect the carbonyl group of uracil, the cyanoethyl group to protect the 06-function of guanine, and the dimethoxytrityl or 4, 4',4"tris(4, 5-dichlorophthalimido) trityl group to protect the 5'-hydroxy function. 2'(3')0-L-a-Alanyl-CpCpA has also been prepared via the benzotriazolyl phosphotriester approach: the 2-phenylsulphonylethoxycarbonylgroup was used to protect the exocyclic amino functions of cytosine and adenine, and the 3-methoxy-l,5dicarbomethoxypentan-3-yl group to protect the 2'-hydroxy groups.244 A number of 2'(3')-Q-(bJ-acetyl)aminoacyl esters of 5'-AMP have been prepared by conventional methods and the equilibrium constants for the distribution of the amino acid residues between the 2'-and 3'-positions at neutral pH investigated using n.m.r. and h.p.l.~.2~5 Glycine and L-amino acids distributed preferentially to the 3'-position, while D-amino acids did so to a lesser extent and in inverse relation to their hydrophobicity. The Boc-protected derivative of the photoactivatable carbenegenerating phenylalanine analogue L-4'-[(3-trifluoromethyl)-3H-diazirin-3yllphenylalanine has similarly been coupled to the Z'(3')hydroxy group(s) of pCpA, after which treatment with acid was used to generate a mixture of the 2', 5'- and 3', 5'-linked is0mers.*~6T4 ,RNA Ligase and ATP were then used to couple the 3', 5'linked aminoacylated pCpA to tRNA Phc (E. coli) lacking its pCpA terminus, to produce the 'chemically misaminoacylated' tRNA, which was competent to

255

6: Nucleotides arid Nuclric Acids

0

II

-0-P-SPh

I

0

H COCH,COPh

CL3CCMe

II

0

‘OH

\

0-

0

I Pr’2 N-

P- OCH,C H 2 C N

-OH

256

Organophosphorus Chemistry

perform in an in vitro translation system. A number of other structurally modified peptidyl tRNA Phe species, some containing 2 - or 3'-deoxyadenosine in place of adenosine at the 3'-terminus, have been prepared by 'chemical misaminoacylation' as above and examined for their ability to function as donors in the peptidyltransferase-catalyzed reacti0n.24~The species with deoxyadenosine-containing termini proved inactive in tests with L-Phe-tRNAphe as acceptor. Conjugates with poly(L-lysine) of 15-mer P-oligonucleotides complementary to the viral N-protein mRNA initiation site or viral intergenic regions conferred specific protection of various ce!l lines against infection by vesicular stomatitis virus, but conjugates of the a-anomeric analogues proved inactive despite their heightened resistance to nucleases and proven ability to form stable hybrids with complementary sequences in vitro.248 The 3'-Q-methoxyphosphoromorpholiditeof the cis-syn thymine dimer, of which the synthesis was reported last ~ e a r ' 3has ~ been used to synthesize a decadeoxyribonucleotide containing the lesion which in turn was ligated into a single-stranded gap engineered in the plasmid M13m~18.2~9 The successful introduction of the dimer was demonstrated by the activity of an endonuclease specific for its recognition and removal. A Dewar pyrimidinone photoproduct of d(TpT) (173) is formed quantitatively upon photolysis of an aqueous solution of the (6-4) photoproduct of d(TpT) (174) using a medium-pressure mercury arc lamp.250 Spectroscopic data suggest that the conformation of (173) more closely resembles that of B-form d(TpT) than does that of (174). NTreatment of S'-Q-dimethoxytri tyl-2'-deoxythymidine-3'-(2-cyanoethyl)-N, diisopropylphosphoramidite with phosphoryl chloride and 1E-1,2, 4-triazole affords (175) which may be inserted into an oligodeoxynucleotide by standard synthetic methods and subsequently treated with aziridine to give a residue of type (1 76). When the oligonucleotide containing (176) is annealed to its complementary strand, cross-linking occurs, and in the study reported, (177) was formed. By studying the substrate behavior of (177) and similar duplexes with Klenow fragment ( E . coli DNA polymerase I, large fragment) and T4 and T7 DNA polymerases, it was established that Klenow polymerase does not require DNA strand separation for enzymic activity, while the exonuclease site requires that four or more base pairs of primer strand must melt for exonucleolytic removal of nucleotides from the primer terminus.251 The T4 and T7 enzymes required that two and three base pairs should melt, respectively, for exonucleolytic removal of nucleotides. The distance of the primer terminus from the cross-linked base pair required for each polymerase to show activity was also defined. Using a biotinylated oligonucleotide annealed to the complementary sequence of a longer template strand, it was shown that in the presence of avidin the Klenow polymerase and exonuclease functions displayed different requirements for the position of the primer terminus with respect to the

257

6: Nucleotides and Nucleic Acids

r””

HN

-0 JH 0 - P - N H I H 0”

-0

9.B 9. 0-

0-P-0 N

-0

/ \

R1

R2

( 1 7 9 ) R1=Me;R2=CH2CH;!NMe2 n ( 18 0 ) R’ = H ; R2 = CH2CH2N-0

(181) *B = CytToL

(182) n = 1

(183) n

2 or 3

258

Organophosphorus Chemistry

avidin-biotin-complexed base, emphasizing their physical separation in solution and differing substrate structural requirements. By using normal phosphoramidite synthesis and employing a 5'-amino-2', 5'dideoxynucleoside derivative in place of the regular 2-deoxynucleoside derivative, the methods of solid phase oligodeoxyribonucleotide synthesis can be used to introduce phosphoramidate links as in (178) ad libitum into a given ~ e q u e n c e . ~ 5 ~ These links are cleaved specifically in 80 % acetic acid, affording a means of specific directed chemical cleavage. If, however, oligodeoxyribonucleotide synthesis is performed using H-phosphonate methodology with subsequent oxidative coupling to diamines, aminoalkylphosphoramidate links such as (179) and (180) are formed.253 Oligonucleotides containing these links are resistant to nucleases, and the links themselves are hydrolyzed to phosphodiester links to formic acid. Oligonucleotides which contain only aminoalkyl phosphoramidate links (positively charged at slightly acid pH) can form duplexes with complementary oligodeoxyribonucleotides containing only phosphodiester links, but the stability of the duplex is lessened by increasing ionic strength - the reverse of normal - due to destabilization between the oppositely charged strands. If phosphodiester and aminoalkylphosphoramidatelinks are alternated along an oligonucleotide strand, the backbone is virtually electroneutral and the duplex stability independent of ionic strength. While proper base-pairing is a prerequisite for complex formation, the extra dimension in control of duplex stability which these 'cationic oligonucleotides' appear to afford offers tantalizing prospects for the design of oligonucleotide probes. Displacement of successive diisopropylamine residues from a protected deoxynucleoside 3'-phosphorodiamidi te, firstly by another nucleoside and secondly by 4chlorobenzylmercaptan, followed by oxidation of the resultant dinucleosidyl phosphorothioite with sulphur, has been used to generate the phosphorodithioate (1811, which was converted to its 3'-(2-cyanoethyl)-N, N-diisopropylphosphoramidite and used to prepare deoxycytidylate oligomers containing phosphorodithioate l i n k ~ . * 5In ~ oligomers containing mixed phosphodiester and phosphorodithioate diester links, exonucleases (spleen and snake venom phosphodiesterases) could not degrade the chain past the phosphorodithioate links, suggesting that they might be used to protect oligonucleotides from degradation. The oligonucleotide d(C)28 containing only phosphorothioate internucleotidic links (prepared chemically as a diastereoisomeric mixture) is a remarkably powerful linear competitive inhibitor of HIV reverse transcriptase, with a Ki value more than two orders of magnitude lower than that of all-phosphodiester d(C)28.255 Other d(C)28 analogues with cumulative runs of nine phosphorothioate links at the beginning, middle, and end of the sequence gave intermediate Ki values. Unfortunately, the all-phosphorothiate d(C)28 showed substantial inhibition also of DNA polymerases a and y, and may thus be cytotoxic.

6: Nucleotides und Nucleic Acids

259

Treatment of the (l3p) or (Sp) isomer of 5'-Q-monomethoxytrityl-2'deoxythymidine-3'-~-[4-nitrophenyl]methanephosphonate with 3'-Q-acetyl-2'deoxythymidine and t-butylmagnesium chloride in pyridine affords the methane phosphonate (182) in a reaction which proceeds stereospecifically with inversion at phosphorus, although traces of the stereoisomers of the coupled product are formed, probably due to exchange racemization of the starting material by the released nitrophenolate.256 Detritylation of (182) followed by repetition of the condensation has allowed all-lXp or all-sp oligo(deoxy thymidine methanephosphonates (183) to be constructed. Spectroscopic studies of the deprotected all-Ep (183, n = 3) suggest that its conformation closely resembles that of d[(Tp)3T], but a much reduced molecular ellipticity (which could result from solvation differences) was observed for the allSp diastereoisomer. Oligonucleoside methanephosphonates (non-stereoregular) prepared by previously described solid-phase procedures using 3'-(methanephosphonic imidazolide) or 3'-(N, N-diisopropylmethanephosphonamidite) monomer units, have been derivatized either at 5'-terminal phosphate or at cytosine bases to attach 1, 2-diaminoethane moieties, which were then treated with EDTA anhydride to introduce EDTA.257 While this derivatization decreased the stability of duplexes formed with complementary sequences, specific hydroxylradical-mediated scission took place on complementary oligonucleotides in the region of the oligomer binding site and, in the presence of Fe2+ ions and DTT, more efficiently so with DNA than with RNA. Unfortunately, the EDTA-derivatized oligomers also undergo rapid autodegradation under these conditions, apparently with release of the EDTA moiety rather than methanephosphonate cleavage. The effects of ionic strength on the stability of the duplexes formed between oligonucleoside methanephosphonates (or oligodeoxyribonucleotides containing some methanephosphonate links) and their complementary sequences have been studied258 At low ionic strength methanephosphonate substitution for phosphodiester links increased the stability of the hybrids, while at higher ionic strength it diminished it. The use of antisense oligonucleotides for the inhibition of mRNA translation, HIV replication, etc., continues to excite much interest. The mechanism of translation arrest via hybrid formation appears to be the digestion by ribonuclease H of the tract of mRNA strand which is hybridized to the anti-sense oligodeoxyribonucleotide or analogue thereof.259 In a comparative study of the inhibition of rabbit globin mRNA translation in cell-free systems by antisense a-and poligodeoxyribonucleotides and by a-oligonucleotides containing phosphorothioate links, 17-mer sequences of the P-oligodeoxyribonucleotides with or without phosphorothioate links present targeted to the coding region of P-globin mRNA, suppressed translation but the a-oligomers did not, possibly because the aDNA/mRNA hybrids did not elicit RNase H activity.260 The presence of phosphorothioate links increased the activity, possibly by conferring increased

260

Organophosphorus Chemistry

resistance to nucleases. A less powerful but non-specific inhibition of protein synthesis was exhibited by the phosphorothioa te-containing P-oligonucleotides, but not by the phosphate-linked containing p- or a-oligonucleotides. The presence of a cumulative tract of about five (or more) phosphorothioate links at each end of the sequence conferred increased activity on an otherwise phospha te-linked oligonucleotide. Broadly similar results have been seen in the inhibition of HIV replication by antisense oligodeoxyribonucleotides containing phosphodiester links261 compared with sequences containing phosphorothioate or phosphoramidate (n-butylamidate, morpholidate or piperazidate) links?62 methylphosphonate links,263 and oligo[(2'-Q-methyl)ribonucleosidephosphorothioatesl .264 In most of these studies, 15-mers or 20-mers were used, and the phosphorothioates, phosphoramidates and methylphosphonates displayed a comparable activity at concentrations in the micromolar range which was generally appreciably better than that shown by the all-phosphodiester oligomers. Introduction of only a few modified links had little or no effect. A degree of inhibition by modified and unmodified homooligomers was also observed, suggesting that inhibition by more than one mechanism may be operative. The stabilities of duplexes formed by a number of oligodeoxyribonucleotides containing all-methyl phosphotriester links with their complementary sequences have been compared using UV hyperchromicity data.265 The 'melting temperatur6.s' were higher for duplexes formed with deoxyribopolymers than for those formed with ribopolymers, the differences between these (and other data involved in comparable studies involving ethylphosphotriesters and methanephosphonates) being rationalized on the basis of steric and stereoelectronic effects. Decadeoxyribonucleotides containing a single ethylphosphotriester or phosphorothioate link of defined stereochemistry between the deoxyadenosine residues in the restriction sequence of Eco R I [d(GGGAATTCCC)]have been prepared via phosphoramidite methodology.266 The diastereoisomers of the 5'-dimethoxytritylated decamers Q-ethylated at the thiophosphate link were separable by h.p.l.c., after which deethylation with ammonia afforded the pure isomers. The absolute stereochemistries could be assigned using snake venom phosphodiesterase, and by interrelation involving oxidative ( H 2 0 2 ) conversion of the ethylated thiophosphate to the ethyl phosphotriester. The decamer duplex containing l?p-phosphorothioate was specifically cleaved by Eco RI endonuclease, while the sp-diastereoisomer and the ethyl phosphotriester isomers were not, indicating that the stereochemistry at the phosphate group immediately downstream of the cleavage site is critical in determining the susceptibility of the substrate. The chemical synthesis of oligoribonucleotides containing vicinal 2') 5'- and 3', 5'-phosphodiester links, which are found at the branching site of 'lariat' mRNA during mRNA splicing, has been re~iewed.26~ The synthesis of a substantial number of triribonucleoside diphosphatcs (184) has been reported; analogues of (184:

6: Nucleotides and Nucleic Acids

26 1

B1=Ade, B2=B3=Ura)with deoxythymidine replacing uridine, with ara-adenosine replacing adenosine, and with 3'-UMP forming a phosphodiester link with the 5'-OH group of adenosine, were also prepared.26* Generally, either the 5'-monomethoxytritylated ribonucleoside (B1 residue) was condensed with the 2,3'-0. Q-bis(TBDMS)-ribonucleoside5'-me thy1 (or cyanoethy1)diisopropylphosphoramidite(s) of the B2 and 8 3 residues, or the 2',3'-Q Q-bis(TBDMS)ribonucleoside(s) (B2 and B3 residues) were allowed to react with N6-benzoyl-5'-@ monomethoxytrityladenosine-2') 3'-bis[(methyl or cyanoethy1)diisopropylphosphoramidite] in one-flask procedures, isomeric products being separated by reversed phase h.p.1.c. after depro tection. The conformational properties of these compounds have been examined using a variety of spectroscopy techniques: the purine ring B1 stacks with the base B2, but the base 83 is free of interaction with its neighbours.269 In another synthesis of (184: B1 = Ade, 8 2 = Gua, B3 = Ura), the internucleotidic phosphate links were introduced separately using H-phosphonate chemistry in an otherwise conventional pr0cedure.2~0 Either link could be introduced first, but the unblocked phosphodiester was formed in each case prior to the introduction of the second link to minimize transesterification and positional isomerization. In more elaborate syntheses, larger tracts of the branch point have been prepared, e.g. ApN2'PC (N = A, C, U or G ) by a method which started with the 3'pu

protected dinucleosidyl phosphotriester of ApN, introducing the 3'-5'-link via 11phosphonate chemistry and the 2'-5'- link using phosphoramidite ~hemistry2~1 and CpUpA2'PGPU by a block coupling procedure involving phosphoramidite and 3'PUpc phosphotriester coupling stages.272 These syntheses are exemplary in the use they make of protecting groups, and also afford new insights, such as the finding that a neighboring 3'-phosphodiester increases the acid lability of a 2'-Q-pixyl group by some 40- 75-fold, allowing its regiospecific removal without significant loss of other acid-labile protecting groups.271 These branched oligonucleotides have been thoroughly characterized and subjected to intense conformational ~ t u d y z ~ lbut -3 a definitive answer as to why all lariat RNA introns have adenosine as the branch point nucleotide remains elusive.273 '2-5 A' (pppA(;Z')pA(Z')pA)continues to attract attention. A synthesis of 'core trimer' (A(2')pA(Z')pA)using 3'-Q-tetrahydropyran-2-y1protected adenosine and standard phosphotriester chemistry has been described,274as have three different core trimer accounts of the synthesis of cordycepin (3'-deoxyadenosine)-containing using phosphotriester methodology and different combinations of protecting gr0ups.2~5Similarly, p(3'dA) (2')pA(2')p(3'dA)has been prepared and found to bind to ribonuclease L only 2 - 3 times less effectively than its pA(2')pA(2')pA parent.276 The corresponding 5'-triphosphate was ten times less effective than '2 - 5 A' as an activator of the endonuclease. Other novel related species include analogues of core

Organophosphorus Chemistry

262

I

OH 0-

-0 (184)

(185) R =O(CH2),0CH2 Ade - 9 or OCHKH-0-CH Ade-9 -1 I CH2OH CH2OH

B'=

Ade; B2=Ura;B3=Ura,Gua B2 = Gua ; B3= Gua,Ura,Cyt B2 = Cyt ; B 3 = Cyt ; Gua B 1 = Gua; B 2 = B3= Ura

OH (186) R' = H ; R2.R3=C(OMe)(CH2)14Me or R 2 = H ; R 3 = CO(CH;!)1&le or R2 = CO(CH2)14Me ; R3 = H

or R1 =

R2,R3=C (OMe) (CH,),,Me 144 - mer

l

l

l

l

l

11 -mer

l

l

l

l

l

D

~

139 - mer n

'

I

l

1

1

1

1

1

16 - mer

I OL i gonuc t eot ide (189) X = Nucleophilic group on enzyme

14-mer

6: Nuclrotides and Nucleic Acids

263

trimer (185) in which the third adenosine residue is replaced by an 'open-ring' adenosine analogue, which was prepared by standard methods and showed increased resistance to phosphodies tera~es,2~7 and analogues (186) in which a strongly lipophilic moiety is attached to the 3'-residue of core trimer (or of its 5'-phosphate).278 The palmitate-derived termini were obtained by condensation of the &-diol terminus of the (otherwise protected) phosphotriester synthetic intermediate with trimethyl orthopalmitate, and the terminal phosphate introduced subsequently via 2-cyanoethoxydichlorophosphine.Following infection of human T (H9) cells with HIV, the level of '2 - 5 A' and the associate RNase L activity appear to increase strongly, resulting in degradation of HIV transcripts, and then to drop to latent values when the cells begin to release HIV.279 The time during which the viral transcripts are degraded is extended by AZT. It thus appears that agents stimulating 2 - 5 A production could afford a novel approach to treatment of HIV infection. The non-enzymic template-directed synthesis of informational macromolecules has been reviewed.280 Much of the work in this area has involved nucleoside 5'-phosphorimidazolides, and the effectiveness of different divalent metal ions in promoting oligomerization of these species has been examined.281 Lead ions were the most effective catalysts giving oligomers up to hexamer length in 35 - 55 % yield, with 2' - 5' internucleotidic links formed predominantly. Little or no oligomerization was seen using the 5'-phosphorimidazolides of sugar-modified adenosine analogues (2'-deoxyadenosine, cordycepin, ara-adenosine, aristeromycin, neplanocin A): a ribosyl system appears to be prerequisite. In an attempt to oligomerize 9-(2-deoxy-6-~-(1-imidazolo)phosphono-~-~-r~~~-hexopyranosyl~adenine (187), no oligomer was obtained, but a high yield of the 4',6'-cyclic phosphate was formed, demonstrating that the pyranose ring is sufficiently flexible for cyclophosphate formation to occur.282 This, with other relevant findings, has prompted the suggestion that only ribo- and arabino-nucleotides may be derivatized to 5'-phosphorimidazolides which s terically disfavor cyclophosphate formation and thus permit oligomer formation, and may thus have been 'selected for' as units for prebiotic oligonucleotide formation, with the other potential candidates having been eliminated by preferential cyclophosphate formation. However, some bisphosphoimidazolides of 'open ring' analogues of adenosine and guanosine are reportedly capable of undergoing oligomerization in the presence of complementary polynucleotide templates.283 The oligomerization of uridine- and guanosine -5'phospho-2-methylimidazolideson poly (C, A) random copolymers has been ~tudied.28~ Analysis of the oligo (G, U) species formed showed that species up to at least tridecamer length were obtained, but that the efficiency of incorporation of uridylate residues was far lower than that of cytidylate residues and unaffected by increasing the proportion of uridine 5'-phospho-(2-methyl)imidazolidein the

264

Orgat?oy hosphorus Choni s t y

substrates. It thus appears that RNA templates containing runs of consecutive adenylate residues would be unsuitable in a chemical self-replicating system.

4.2 Enzymatic synthesis. The refinement of the Polymerase Chain Reaction (PCR) described last year132 has been eagerly exploited, and a deluge of papers has followed detailing various aspects of its application. Therrnus uquuticus (Taq) DNA polymerase, upon which the PCR depends, was designated 'Molecule of the Year' (1989) by the journal Science. Not surprisingly, the Tuq DNA polymerase gene has been isolated, characterized, and expressed in E . coli.285 Its encoded amino acid sequence shows significant similarity to that of E . coli DNA polymerase I. The fidelity of in vifro DNA synthesis catalyzed by Taq polymerase has been investigated using a DNA substrate in which the 3'-terminal base of the primer strand was cytosine, mispaired with adenine on the template, and it was shown that the enzyme lacks detectable exonucleolytic proofreading ability.286 The frequency of commission of base substitution errors (one in 9,000 nucleotides polymerized) and frameshift errors (one in 41,000 polymerizations) is modest, under the normal polymerization conditions. It has been reported that changing the buffer system normally employed for the PCR reaction to that conventionally used for reverse transcriptase-catalyzed reactions significantly increases the efficiency of the Tuq polymerase-catalyzed pr0cess.28~ Also, the inclusion of 7-deaza-2I-dGTP at a concentration three times that of dGTP in PCR reactions is advantageous: the incorporation of 7-deazaguanine precludes Hoogsteen (but not Watson-Crick) pairing, thus suppressing the formation of very stable hairpin loop structures which can otherwise cause complications.288 However, the complete replacement of dGTP by 7-deaza-dGTP slows the PCR to an unacceptable extent. In an improved method of photofootprinting yeast genes in vivo, the products of multiple rounds of annealing and extension in Tuq polymerase PCR on UV-irradiated yeast DNA are compared with those formed on non-irradiated DNA: the UV-induced lesions represent stop sites for the polymerase reaction, and the positions at which they are formed (and suppression of their formation due to protein binding) can thus be monitored.289 The use of Tuq polymerase is advantageous since the higher temperature of the reaction eliminates effects due to secondary structure, while PCR cycling permits the gel bands representing DNA molecules resulting from photodamage to be amplified. A general procedure for the in vitvo preparation and specific mutagenesis of DNA fragments has been detailed.290 The end-labelled DNA fragments formed can be used for footprinting assays, sequencing reactions, or the production and analysis of paused RNA polymerase transcription complexes. By using an extendable primer containing a mismatch site, mutagenesis using the PCR is easily performed: the second round of replication generates full duplex DNA containing the fully mutated

6: Nuclwtides trrid Nuclric Acids

26.5

site close to one terminus.290 The site of mutation can be relocated by hybridization to a second PCR-generated fragment containing the complement of the original mutated site located at its other terminus, annealing and gap-filling. PCR-mediated gene synthesis has been described, the chemically synthesized genes of horse and tuna cytochrome c being amplified using the two 5'-end oligonucleotides of each gene as p r i m e r ~ . ~ gBy l using primers from DNA sequences flanking hypervariable minisatellite loci in human DNA, a number of minisatellite loci up to 5 - 10 kilobases long can be coamplified and detected to give a reproducible and characteristic DNA 'fingerprint' from nanogram quantities of starting DNA.292 Using this technique, the derivation of DNA fingerprints from only a few cells, or even only one, appears possible. A method designed to detect recombinant fragments utilizes two primers, each complementary to one end of the recombinant gene sequence it is desired to detect.293 Only the recombinant gene, if formed, is amplified exponentially for detection as in the normal PCR: for non-recombinant sequences the number of copies due to primed synthesis will also increase, but linearly. This permits considerable sensi tivity of detection of the desired recombinant gene. As noted above, Tuq polymerase does not possess a proofreading function. If presented with a template-and two primers, one of which is perfectly paired and the other of which possesses a mismatch, the binding and elongation of the perfectly paired primer is strongly favoured in conditions of low stringency. By performing competitive oligonucleotide priming with two differentially labelled primers, one mismatched and one matched, together with a third primer to define the other end of the amplified sequence, PCR amplification and analysis to determine which labelled primer was utilized permits the identity of the complementary base on the template at the match/mismatch site to be identified.294 This permits the detection of single base differences in DNA. The same essential principle, cast in slightly different terms and using slightly different methodology (coamplification of two gene segments, each using a different pair of primers: the presence of a 3'-terminal mismatch in one member of a pair of primers means that the relevant gene segment is no longer amplified) has been described in terms of a method for analysis of any point mutation in DNA, and termed the 'Amplification Refractory Mutation System' (ARMS).*95 In a method for direct detection of point mutation by mismatch analysis, both wild-type (end-labelled) and mutant sequences are amplified by PCR, separated and allowed to anneal to form a mixture of perfect hybrids and hybrids with point mismatches.296 Treatment with a single-strandspecific modifying agent (e.g. hydroxylamine for cytosine, osmium tetroxide for thymine) followed by piperidine cleaves the chain at the mismatch site, thus indicating the site of mutation. By using primers which have previously been 5'end-labelled with biotin in PCR amplification, permitting the elongated primers to hybridize to a labelled probe in solution, and collecting the hybrids formed

266

Organophosphorus Chemistry

quantitatively by passage over an avidin matrix, the efficiency of PCR amplification can be quantitated.297 The efficiency is found to be close to 100 % at low template concentrations, but drops as template concentration increases. In a labour-saving method of gene synthesis, a gene for the HIV-transactivator protein TAT was prepared from two long oligomers (effectively two long bits of one strand) and three small complementary oligomers (three small bits of the other strand).*98 The annealed mixture (188) was ligated into a gapped plasmid, and transformed into a cell line (HeLa) in which in vivo gap repair completed the work of synthesis and ligation and the gene was shown to be expressed. The amount of synthetic work was cut almost in half. 5,6-Dihydro-dTTP has been found to be a substrate for Klenow fragment, but not for T4 DNA polymerase or avian myeloblastosis virus reverse transcriptase (AMV-RT), while 5, 6-dihydroxy-dTTP ('thymidine glycol triphosphate') was not a substrate for any of these enzymes.*99 Sequencing gel analysis indicates that d i h y d r o - d l T is readily incorporated opposite most single adenine sites, but that pausing occurs at cumulative template adenine sites, suggesting that sequential incorporation of dihydro-dTTP molecules produces disorder at the primer terminus. The kinetics of insertion and primer extension by Klenow fragment and DNA polymerase I using Q2-methyl-,eth yl-, or isopropyl-dTTP (prepared from their nucleosides by kination using wheat shoot phosphotransferase, followed by the carbonylbis(imidazo1e)/pyrophosphate procedure) or @-methyl-dTTP as substrates, have been compared on several different types of template.300 The Q2-alkyl-dTTP species underwent ready incorporation, with 02-isopropyl-dl'TP the most readily utilized, with efficiency approaching that of dTTP. Q4-Methyl-dTTP was inserted opposite adenine more readily than Q2-methyl-dTTP. The Q-alkylthymine/adenine base pair does not appear to confer major structural distortion at a primer terminus, since dGTP was readily incorporated opposite cytosine at the next site adjacent. In an elegant series of investigations involving primer template duplexes of varying length with a matched or mismatched 3'-terminus on the primer strand, the kinetic mechanism whereby Klenow fragment replicates DNA with high fidelity has been elucidated.301 In a first, discriminatory, stage the rate of phosphodiester bond formation is greatly reduced for the insertion of incorrect nucleotides. The discriminatory contribution due to selective dNTP binding to the enzyme is relatively smaller. Once the phosphodiester bond is formed, a conformational change slows the dissociation of the incorrectly matched products from the enzyme, giving the exonuclease function more time to edit the mismatch (the exonuclease is not itself discriminatory between correctly and incorrectly paired nucleotides). Finally, the enzyme adds the next correct dNTP substrate to a mismatched terminus very slowly compared to a correctly matched terminus. Attempts have been made to correlate the thermodynamics of me1ting processes in a template-primer duplex with matched or mismatched primer 3'-terminus with the kinetics of elongation at

6: Nucleotides and Nucleic Acids

267

the terminus by DNA polymerase a from Dro~ophiIa.3~~ The discrepancies found (discrimination by the enzyme in terms of correct versus incorrect pairing is far higher than that which would be anticipated simply on the basis of the energetics of base melting) led the experimenters to suggest that the binding site cleft of the enzyme may fit snugly with exclusion of water to amplify the base pair free energy differences . 5-Fluoro-dCTP (the triphospha te was formed from the chemicallysynthesized monophosphate using NMP kinase, NDP kinase, pyruvate kinase, ATP and PEP) can be copolymerized with dGTP using poly [d(G-C)] template, primer, and Klenow fragment, to give poly[d(G-f5C)] which, in the presence of 5adenosylmethionine, bound to Hha I methylase causing time-dependent first-order inactivation.303 Gel filtration, digestion, and other data suggest the 5-fluorodeoxycytidylate residue acts as a mechanism-based inhibitor, with a covalent enzyme-nucleic acid complex of putative structure (189) being formed. DNA in which thymine bases are completely replaced by either 5-iOdO- or 5-bromo-2'deoxyuridine have been synthesized on an M13 template, and the sites at which damage occurred following UV irradiation at 300 nm found to be strongly sequence dependent, specifically analogue-related, and similar for both nucleoside analog~es.~m The degree of damage is thought to be related to the distance between C-5 of the pyrimidine ring carrying the halogen atom, and H-2 of the sugar ring, and sequence-related variations in microstructure cause this parameter to alter, with smaller distances correlating with higher damage. Klenow fragment has also been used to incorporate biotinyl-11-dUTP (i.e. dUTP with biotin attached via an eleven atom linker to the 5-position of the uracil ring) into DNA to effect the non-isotopic labelling of DNA probes cloned in M13 for fingerprinting human genomic DNA305, and to incorporate digoxigenin-tagged dUTP into DNA probes which were detected, after hybridization, by enzyme-linked immunoassay.306 Succinylfluorescein-labelled dideoxynucleoside triphosphates, e.g. (1901, such as are used in a fluorescence-labelled DNA sequencing method described last year,*32 have been found to be good substrates for terminal deoxynucleotidyl transferase, and may thus be used to prepare DNA with a fluorescent tag at the 3'-terminus.307 This method has been used to tag synthetic oligonucleotides, blunt-ended DNA, and DNA fragments formed during Maxam-Gilbert sequencing. Terminal deoxynucleotidyl transferase has also been used to add one or two residues of 1, N6-ethenoadenylate at the 3'-terminus of an oligodeoxyribonucleotide complementary to the Shine-Dalgarno region of 16s rRNA in E. coli, which was also derivatized at its 5'-end (via enzymic phosphoryla tion, coupling to ethylenediamine using EDC, and treatment with FDNB) to form its 242, 4-dinitropheny1)aminoethylphosphoramidate.308 Electron microscopy of the complex formed by the 30 S ribosomal subunit of E . coli, the doubly tagged oligodeoxyribonucleotide, and antibodies specific to the ethenoadenosine and dini trophenyl moieties permitted the

268

Organophosphorus Chemistry

localization of the Shine-Dalgarno sequence on the subunit, and thence, with other data, a model of mRNA orientation on the 30 S subunit to be proposed. Large quantities of hybridization probes can be prepared from small amounts of DNA by 'filter priming': the DNA fragment is immobilized on a nylon filter using UV light and used as template to prepare radioactive probes in a random primed labelling reaction.309 The probes are removed from the filter by heating, purified and used, while the filter-bound DNA may be re-used. More than 20 repeating sequence DNA molecules containing phosphorothioate links have been prepared using the corresponding deoxynucleoside 5'-(1thio)triphosphates and DNA polymerase I with appropriate tem~lates.3~0 Necessarily, this implies that all the phosphorothioate links were of (Rp) stereochemistry. The presence of phosphoro thioate groups 5'- to pyrimidine residues destabilized the duplexes formed by these oligonucleotide analogues to a greater extent than phosphorothioates 5'- to purine residues, although both caused destabilization relative to the corresponding unmodified duplexes. Also, phosphorothioate 5'- to purine residues promoted the formation of triplexes, while phosphorothioate 5'- to pyrimidine residues destabilized them. The resistance of phosphorothioate-containing duplexes to digestion by pancreatic DNase I did not correlate with phosphorothioate content, and it has been suggested that phosphorothioate groups cause small conformational changes and may reveal new sets of conformational polymorphisms. The enzymatic incorporation of dGTPaS into a recombination sequence to place it at the normal site of cleavage by Int recombinase has been found to block the second cleavage process associated with recombination [the (Ep) isomer of the link formed was tentatively identified as the inhibitory diastereoisomer] permitting recombination to be halted at the Holliday-structure In vitro transcription intermediate, which was identified ele~trophoretically.3~1 with ribonucleoside 5'4 l-thio)triphosphates has been used to form pre-mRNA analogues of the small intron of a rabbit P-globin gene and its flanking exon sequences.312 In the transcripts prepared using ATPaS, normal splicing by a HeLa cell nuclear extract was inhibited, but a new product was formed by cleavage three nucleotides upstream of the normal 3'-splice site. The mechanism of misplacement of the splicing site by phosphorothioate blockage of the normal cleavage site is not clear. The amplification by PCR of a DNA segment containing a functional RNA promoter together with an insert (probe sequence) under its control affords double stranded products which are suitable templates for transcription by DNA-dependent RNA polymerase.313 The RNA transcripts obtained are then useful for in situ RNA-RNA hybridization. By in vitro transcription of synthetic DNA templates, RNA hairpin sequences of 16-mer to 22-mer length containing homopolymer loops of 3 to 9 nucleotides, consisting of adenosine, cytidine or uridine residues have been prepared, and their thermal stabilities determined.314 The stability varied with loop

6: Nucleotides and Nucleic Acids

269

size, being maximal for loops of 4 or 5 nucleotides, but was almost independent of loop composition. (It is noteworthy that in transcribing DNA templates containing (dA)g or (dT)9 sequences, substantial amounts of transcripts were formed which were longer than expected: evidently slippage, which was shown to be templatedependent, can occur at (dA)9 or (dT)9 sequences during transcription.) Similarly, RNA hairpins containing 4 nucleotides in the loop and a bulge (i.e. unpaired) nucleotide in the stem have been prepared, and the destabilization of the hairpin due to the presence of the bulge nucleotide (which was found to be sequencedependent) determined from melting ~tudies.3~5 The ability of T7 RNA polymerase to go from a double stranded promoter region to a single stranded template two nucleotides beyond the initiation site, and subsequently to make a single stranded to double stranded transition, permits the incorporation of mutagenic oligonucleotides into the coding strand, and direct transcription of the partially mismatched template then affords mutant RNA molecules.3~~ Using T7 RNA polymerase, 4-thio-UTP, 5-bromo-UTP, and a plasmid engineered to contain a T7 promoter and the complete precursor tRNAPhe sequence, pre-tRNAsphe containing 4-thiouridine or 5-bromouridine in place of uridine residues were prepared and found to be substrates for endonuclease and yeast tRNA ligase, and formed covalent cross-links to the ligase upon UV-irradiation.317 Location of the cross-link positions permitted a model for the in vivo splicing of yeast pre-tRNA to be developed. Arabino- and xylo-nucleotide units have been introduced into oligoribonucleotides using T4 RNA ligase and chemically-synthesized substrates of general formula A(5’)ppN (where N is the modified nucleoside).3’8 T4 RNA Ligase has also been used to ligate half-molecules of yeast tRNAAla to afford the tRNA analogue in which inosine-34 was replaced by adenosine or guanosine.3’9 The general procedure employed has been outlined in previous Reports. The modified tRNA retained its alanineaccepting ability, but the ability of the charged tRNA to incorporate alanine into proteins was diminished. The binding of phage R17 coat protein to its RNA binding site is known to depend on a unique hairpin structure containing four essential single-stranded nucleotides, with additional specificity believed to be due to four or five ionic contacts between internucleotidic phosphate links and protein. By transcription of synthetic DNA using T7 RNA polymerase and a single NTPaS species in different transcription mixes, eleven sequence variants of the R17 coat protein binding site with varying patterns of thiophospha te substitution have been generated and evaluated for coat protein binding function to determine which sites of thiophosphate substitution alter the binding affinity.320 Four such sites were identified, and it is believed that the internucleotidic links at these positions form direct contacts with the coat protein. By initiation of mouse mammary tumour virus (MMTV) RNA chains, in preparations of isolated nuclei from cultured rat hepatoma cells containing stably integrated MMTV provirus, using ATPPS, GTPPS

270

Organophosphorus Chem istly

or UTQS, followed by separation of the transcripts using mercurated Sepharose chromatography and analysis of the starting sites of transcription using a nuclease protection assay, it has been shown that while, in the presence of Mg2+ ions, initiation using GTPPS at a specific template site is dominant, some chains are also initiated with ATPPS or UTPPS at closely adjacent ~ i t e s . 3In~ the ~ presence of Mn2+ ions, however, initiation using GTPPS becomes exclusive, at a site 40 nucleotides further downstream! Evidently divalent ions can play a role in specifying the start site for transcription in vitro. Oligonucleotide-directed mutagenesis can be performed by direct transfection of host bacteria with molecules of recombinant phage which are duplex apart from a single stranded tract, plus the mutagenic oligonucleotide which (except for the designed mismatch at the mutation site) is complementary to part of the single stranded segment.322 Annealing occurs with gap-filling in v i m (cf. ref. 298) after which mutant phage are formed, the yield of mutations being substantially improved if the mutagenic oligonucleotide contains two phosphorothioate links (formed by chemical synthesis) immediately adjacent to its 5'-terminus. It has been found that a number of DNA polymerases, viz.Taq polymerase, polymerase a from chick embryo, polymerase p from rat, AMV reverse transcriptase, and polymerase I from Saccharornyces cerevisiae, can all add a single deoxyribonucleotide residue (preferentially dATP) to the 3'-terminus of a bluntended DNA substrate - i.e. without any coding information from a template strand.323 While the significance of the reaction is unclear, it might prove useful as a method for 3'-terminal labelling. RNA Polymerase I1 from wheat germ can add ATP to the 3'-terminus of ApU to form ApUpA, or UTP to UpA forming UpApU, but analogues of UpA containing Q-phosphonylmethyl links were poor acceptors for UTP, while similar analogues of ApU were inactive as ~ r i m e r s . 3 ~ ~ Finally, synthesis of oligonucleotides by degradation! Homologues of oligouridylate have been prepared by successive digestion of RNA with RNase Ti and RNase U2, followed by deamination, to afford oligouridylate sequences with 3'terminal purine nucleotides, which were subjected to enzymic dephosphorylation, periodate oxidation and p-elimination of the terminal residue, and a second dephosphorylation step.325 This afforded ( U P ) ~ U species (n = 1 - 71, which were separated chromatographically.

27 1

6: Nuc1twtide.s und Nucleic Acids

Me

4-0gp30Y=/ H H

(190)

0

II

R NH(CH2)eO-P-0-

I

-0

0

0

0

P-0-

P-0-

P-O-(dCyd-5')

II

II

I

-0

I

-0

II I

-0

(191) R = CF3CO (192) R = Sepharose

Rib- 5'- P (1 93)

Orgunophosphorus Chcmistly

212

5. Other Studies 5.1 Affinitv Separation - Treatment of dCTP with carbonylbis(imidazo1e) followed by N-trifluoroacetyl-6-aminohexyl phosphate affords (191), which was deacetylated and coupled via its aminoalkyl group to CNBr-Sepharose, affording a p4 (dC) affinity column (192).326 This column gave a one-step, 19,000-fold purification to homogeneity of deoxycy tidine kinase from a crude ammonium sulphate fraction of Lactobacillus acidophilus R-26 extract, with 60 % recovery, a striking instance of the power of affinity chromatography. Elution from the column was performed with dCTP, which is a powerful end-product inhibitor for the enzyme and serves to stabilize it. The bulk of the novel work in affinity separation has again involved oligonucleotides. Using a support derivatized with thymidine attached via a urethane linkage (introduced using tolylene diisocyanate, as reported previously), an l&mer was synthesized using normal solid phase cyanoethyl phosphoramidite chemistry, and deprotected using ammonia without cleavage from the column, to afford the immobilized unprotected oligodeoxyribonucleotide, which was used to screen mRNA for complementary sequences.327 Similar direct synthesis of the oligodeoxyribonucleotide on the surface of the solid support to be used as the affinity column was practised in synthesis of a 51-mer which was attached to the The immobilized 51-mer was surface of Teflon via a C-25 hydrocarbon ~pacer.3~8 then annealed to its complementary (coding) strand and the resulting duplex permitted 60-fold purification (to apparent homogeneity) of transcription factor TF IIIA from S. cerevisiae. An attempt to perform this purification using the same sequence attached to CNBr-Sepharose had failed, due to non-specific binding by TF IIIA and other contaminant proteins: the low nonspecific absorption on Teflon due to its inertness, coupled with a high ligand concentration per unit bed volume (resulting in small column and eluate volumes) commend the use of Teflon columns in procedures of this type. An oligodeoxyribonucleotide bearing a 3-mercaptopropyl moiety attached to a 5'-terminal phosphate group has been coupled to tresyl-activated Sepharose 4B (or, better, epoxy-activated Sepharose 6B), and thus immobilized via a thioether linkage.329 The complementary sequence was then annealed to the immobilized strand and the 20-mer duplex (which contained the d(GAAIITC) restriction sequence) was used to purify restriction endonuclease Eco RI to ca. 80 % homogeneity. Single-stranded DNA immobilized on cellulose was used in the final stage of purification of a DNA helicase from Xenopus laevis ovaries, giving 140-fold purification and quantitative recovery of enzymic activity.330 'Dynabeads TM' are polystyrene beads of uniform diameter (4.5 pm) with a magnetite core, derivatized to bear different functional groups on the surface. Different methods of attachment of DNA to these beads (which can be isolated using

6: Nuc1eofide.y und N u c h k Acids

273

a magnet) have been evaluated, including attachment to diazotized derivatized Dynabeads TM CNBr-activated hydroxy-group-bearing Dynabeads TM etc.33I The highest yields of coupled DNA were obtained by attaching 5'-phosphorylated DNA to amino-group-bearing DynabeadsTMusing EDC in imidazole buffer, but the aminated beads also exhibited high non-specific binding. Probably the best, if more cumbersome, method consists in attaching ethylenediamine to 5'-phosphorylated DNA using EDC, and then coupling this, in turn, to DynabeadsTM derivatized to bear carboxy groups (which exhibit low non-specific binding). The binding of a variety of deoxyribo- and ribo-, homo- and copolynucleotide complementary duplexes to agarose-linked homopolynucleotides has been evaluated, to determine the specificity of recognition of complementary base pairs in triple helix formation under physiological conditions.332 The full range of conceivable base triplets was studied, to determine which triplets can and cannot form - i.e. to establish a third strand binding code. Besides the requirements for a cluster of purine bases in one strand, and for third-strand cytosine bases to be protonated, the allowable base triplets were found to be: A.A.T/U; U.A.T/U; G.G.C; C+G.C;I.A.T/U and I.G.C. Macroporous silica gel with poly(9-vinyladenine) either coated or immobilized on the surface has been reported to give practically useful h.p.1.c. columns for the separation of nucleotides, displaying base-selective recognition ability.333

5.2 Affinitv labelling - Some new variants on old labels have been prepared and utilized. Alkaline hydrolysis of 8-azido-CAMPaffords 8-azidoadenosine-3'monophosphate, which is 5'-phosphorylated (and simultaneously labelled) using T4 ATI' to give 8-azidoadenosine-3', 5'polynucleotide kinase and [@'%'I bis(phosphate).33* This has been used for the photoaffinity labelling of bovine pancreatic ribonuclease A. Curiously, it was also reported that the prephotolyzed nucleotide could label the enzyme in the dark, a finding which seems inconsistent with the normally accepted mechanism of photochemical generation of a reactive nitrene of relatively short lifetime, and merits further study. 8-Azido-dATP has been used for the photoaffinity labelling of terminal deoxynucleotidyl transferase, in which both a and p subunits of the enzyme became labelled.335 Treatment of 8-azido-ATP with dansyl chloride in bicarbonate buffer at pH 9.8 affords 2'-Qdansyl8-azido-ATP, as indicated by 'H n.m.r. data in comparison with appropriate standards, and this fluorescent photoaffinity agent has been used for the labelling of adenylate kinase from rabbit muscle,336 and of the catalytic subunit of CAMPdependent protein k i n a ~ e . 3 38-Azido-AMP, ~ -ADP, and -ATP have been treated with 2, 4, 6-trinitrobenzenesulphonicacid in bicarbonate buffer to form their respective 2', 3'-0-(2, 4, 6-trinitrophenyl) derivatives which are superfluorescent (i.e. exhibiting

274

Organophosphorus Chem istiy

a large increase in fluorescence during hydrolysis of the polyphosphate chain) and efficient photoaffinity probes of the catalytic and regulatory sites of Ca2+ - ATPase from sarcoplasmic reticulum.338 8-Azidoadenosine 3', 5'-bis(phosphate) (see above) has also been ligated into the 3'-end of truncated yeast tRNAPhe molecules using RNA ligase, to replace either A73 or A76 by 8-azidoadenosine.339 Where A73 was replaced, the -CCA terminus was restored using the specific nucleotidyltransferase. The replacement of A76 by 8-azidoadenosine blocked aminoacylation of the modified tRNA, but replacement at A73 did not. Neither substitution hindered binding of the tRNA to the P site of the E . coti ribosome in the presence of poly(U), and, upon photocrosslinking, protein L27 of the 50s ribosomal subunit was labelled exclusively in each case. When N-acetylphenylalanyl-(&azido-A73) tRNA was bound to the p site and irradiated, a different labelling pattern was seen, suggesting that the aminoacyl moiety may influence the proper placing of the 3'-end of tRNA in the P site. Photolabelling with 2-azido-(a-32P)ADPhas been used to map nucleotide-binding sites in the ADP/ATP carrier of beef heart mitochondria.340 Analogues of '2-5 A' in which 2-azidoadenosine or 8-azidoadenosine replace the adenosine residues have been prepared by using 2-azido-ATP and 8-azido-ATP, respectively, as substrates for 2 - 5 A synthetase from rabbit reticulocyte lysates.341 The 8-azidoadenosine-containinganalogue bound to RNase L with similar affinity to 2 - 5 A in a competitive binding assay, and both analogues activated RNase L to cleave rRNA at nanomolar concentrations. However, in photoaffinity labelling studies the 2-azidoadenosine-containinganalogue labelled only a 185 kDa polypeptide, while the 8-azidoadenosine-containinganalogue labelled no fewer than six, although protection experiments indicated that the photoprobes bound specifically to the 2 - 5 A binding site. Treatment of AMP with aziridine gives 1 42-aminoethy1)-AMP,which upon Dimroth rearrangement to @-(Z-aminoethyl)AMP at pH 11 followed by reaction with 4-azido-2,3,5,6-tetrafluoropyridine affords Nb-(N-[(4-azido-3,5,6trifluoro)pyridin-2-y1]-2aminoethylJAMP(193) a new photoactivatable AMP analogue.x2 With horse liver alcohol dehydrogenase, (193) acts as a competitive inhibitor of NAD+ binding, and upon irradiation it appears to bind covalently at the AMP-binding subsite of the NAD+-bindingsite. Treatment of N-[3-(1251)iodo-4azidophenylpropionyl]-~-(2'-thiopyridyl)cysteine with Coenzyme A affords (1941,a photolabelling derivative of Coenzyme A, which was found to label exclusively a 30 kDa protein of beef heart mi tochondrial ADP/ATP carrier upon irradiation.343 While no yields were quoted for the preparation of (194), it seems likely that the thiol groups of Coenzyme A or the pyridine-2-thiol displaced could interact with the azidoaryl group to reduce the efficiency of the preparation. 3'(2')-Q-(4Benzoylbenzoy1)ATP has been used for photoaffinity labelling of the active site of myosin, in which Ser-324 was found to be the residue principally labelled,

275

6: Nucleotides and Nucleic Acids

O-+c / H

(195) n = 1.2 or 3

(197) n = 2.3,or 4 ;Nuc = Ado (198) n = 2 or 3 ; Nuc = Gua

(196) n = 3

d? -A -A qN 0 II

(."

0 II

SCH;, COCOCHzBr

8-P-0-P-0

HO OH

HO OH (199) n = 2 or 3

(200)

'-0gp307!Yde 0

dRib

276

Organophosphorus Chemistry

apparently by insertion of the benzophenone C-0unit into a C-H bond at Ca or Cp of the amino acid.344 Affinity labels containing aromatic aldehydes (195) and (1961, prepared by published procedures, have been incubated with the DNA polymerase-primase complex from yeast, and then reduced with sodium borohydride to attach the analogues irreversibly at a lysine residue.345 Subsequent addition of [cx-~*P]ATP as substrate means that if the labelled complex is catalytically competent to form phosphodiester links, autocatalytic radiolabelling of the enzyme results. While no labelling was in fact observed for (195, n = 11, the p48 and p58 subunits of DNA primase were labelled to varying extents when (195, n = 2 or 3) or (196) were employed. If the radioactive RNA primer was instead first attached to the complex covalently after the enzymatic reaction, if DNA synthesis was uncoupled, both the primase and polymerase were labelled, but if DNA synthesis had been permitted to occur first, only the polymerase was labelled. The use of pyridoxal 5'-oligophospho5'-nucleoside species seems to be increasing dramatically: pyridoxal-5'-diphospho-5'adenosine (197; n = 2) has been used for the affinity labelling of yeast hexokinase P 11,346 aldose reductase from human psoas muscle34' and rho (p) pr0tein3~8while the corresponding tri- and tetraphospho compounds (197; n = 3 or 4) inactivate phosphorylase kinase, binding notably at an ATP-binding site on the y-subunit>49 and (197; n = 4) inactivates pyridoxal kinase, again apparently via binding at an ATPbinding site.350 The guanosine analogues (198) are affinity labels for the ras oncogene product p21, in which they bind at a guanine nucleotide binding site.351 In all cases, the aldehyde condenses with the E - N H ~ group of a lysine residue in or adjacent to the binding site, labelling being rendered irreversible by reduction of the Schiff base, usually, with borohydride. The syntheses of species (197) and (198) have been outlined in previous Reports. Other aldehydic affinity labels which have been employed belong to the much utilized class of periodate-oxidized ribonucleotides: periodate-oxidized GDP and GTP have been used to label elongation factor Tu from Therrnus therrnophilus,352 and periodate-oxidized NADPH to label the cytosolic and membrane components of the respiratory burst oxidase of human neutrophils, in which it appears to attach covalently to a residue at the NADPH binding site, to inactivate the enzyme.353 Perioda te-oxidized tRNA*la forms a cross-link to alanyltRNA synthetase, which is rendered irreversible (as are the cross-links formed in the last two studies) by reduction with cyanoborohydride.39 Attachment of the oxidized tRNA occurs mainly at Lys-73, and investigations with a mutant enzyme in which Lys-73 was replaced by Gln suggest that the Lys-73 is important for the aminoacylation of tRNA*la which occurs following alanyladenylate synthesis. Among alkylating affinity labels, 8-[(4-bromo-2,3-dioxobutyl) thiol ADP and ATP (199; n = 2 or 3), formed by successive treatments of the corresponding 8bromoadenosine phosphates with lithium hydrosulphide and 1, 4-dibromobutanedione, have been used to label pyruvate kinase from rabbit muscle.355

6: Nucleotides and Nuclric Acids

277

Inactivation occurred in a biphasic manner, being faster for (199; n = 3) than for (199; n = 2). A binding site distinct from the active site became labelled also. Treatment of I, s6-etheno-ADP with alkali followed by carbon disulphide affords 1, N6-etheno2-thio-ADP, which on alkylation with I, 4-dibromobutanedione gives 2-[(4-bromo-2, 3-dioxobutyl)thio]-l, N6-etheno-ADP (200).356 This fluorescent affinity label exhibited similar behaviour to (199; n = 2 or 3) with pyruvate kinase from rabbit muscle, in a study in which the non-essential modified residue, and also the residue modified with consequent loss of enzymic activity, were identified. The apparent suicide inactivation of Klenow fragment by adenosine 2', 3'-epoxide-5'-triphosphate (201) has been investigated.357 Using a synthetic DNA template-primer of defined sequence, (201) appeared to become incorporated at the 3'-end of the primer, but, instead of forming a covalent cross-link to the enzyme, the intact epoxy-terminated template primer dissociated very slowly from the enzyme, resulting in tight-binding inhibition and suppression of polymerase activity. The exonuclease function of Klenow fragment remained fully functional. When is 'affinity labelling' not affinity labelling? This is a nice example! 5.3 SequencinrZ and Cleavage Studies - Single-stranded DNA for sequencing can conveniently be produced using the PCR.358 Two primers defining the ends of the tract of DNA to be sequenced are employed in the incubation mix as in the regular PCR amplification, but one is used in large (say, 100-fold) excess. Initially, exponential amplification of the double-stranded DNA defined by the primer termini occurs, until the primer present in lesser quantity is exhausted. Thereafter, PCR cycles give a linear increment of single strands of the DNA primed by the primer present in excess. This simple but ingenious procedure permits the amplification for sequencing of single-copy sequences from genomic DNA. Moreover, if at the end of this 'asymmetric synthesis' a labelled primer complementary to the strand formed in excess is added, together with the elongation/ termination mix of dNTP and 2', 3'-dideoxy-NTP species usually employed in sequencing via dideoxytermination, Taq DNA polymerase performs the primer extension and termination reactions to generate the arrays of strand lengths separated on sequencing gels without prior need for purification.359 Taq DNA polymerase is highly convenient for manual and automated DNA sequencing since it is fast and highly processive, i t has no significant 3'-exonuclease activity (as noted above), it is active over a wide range of temperature (sequencing procedures at 70 - 750 are described), it accepts 7-deaza-GTP as substrate, resulting in the elimination of strong secondary structure in G-C rich sequences and the resulting band compressions which can complicate sequencing, and it is more stable than sequenase, and also cheaper!3s9/3h0 Sequenase is, however, widely used, and the addition of DMSO to sequencing reactions for the dideoxy termination sequencing of PCR amplified DNA using sequenase also tends to suppress formation of

278

Organophosphorus Chemistry

secondary structure, alleviating problems due to re-annealing of template strands and giving higher intensity of bands against background on the sequencing gels.361 Tuq DNA Polymerase has been found to incorporate the 6p)-diastereoisomer of dNTPaS species into DNA as efficiently as the corresponding dNTP species, permitting direct sequencing of PCR-amplified DNA fragments via the thiophosphate sequencing te~hnique.36~ Four separate polymerizations are performed, each in the presence of three dNTP species and one dNTPaS species, a different one in each polymerization. Octadecamer primers were used, with denaturation at 95 - 9 6 O between cycles. By using one 5'-phosphorylated primer and one 5'-nonphosphorylated primer, kinasing with [ Y - ~ ~ATP P ] at the conclusion of amplification labelled only the 5'-non-phosphorylated strands. Subsequent treatment with 2-iodoethanol or (better) 2,3-epoxy-l-propanol effects partial random degradation at the thiophosphate links, the alkylation at phosphorothioate sulphur being the ratedetermining step, after which polyacrylamide gel electrophoresis and autoradiography reveal the sequence. Continuous on-line DNA sequencing using primers containing multiple fluorophores has been described. In one technique, a 19-mer primer containing two residues of (202) was prepared using phosphoramidite methodology, and then treated with fluorescein isothiocyanate to label the side chains of the (202) residues with the fluorophore.363 The modified primer was a suitable substrate for elongation in a dideoxy sequencing protocol using Klenow fragment and 7-deazadGTP to suppress band compression. Following electrophoresis, sequencing gels were read with a scanning fluorescence detector. In another method, in vifro amplification was performed using one fluorescently labelled primer and one unlabelled primer.364 The fragments for sequencing were generated either by dideoxy termination or by a solid phase chemical degradative method, and on-line analysis of the gel separation performed using a fluorescent DNA sequencer. Sequencing of biotin-labelled DNA in which gel bands are revealed using a streptavidin-alkaline phosphatase conjugate and colorimetric detection has also been de~cribed:36~ the biotin may be introduced by restriction enzyme cleavage of the DNA to be sequenced to leave overlapping ends which are backfilled with dGTP, dATP and biotin-11-dUTP using Klenow fragment, or by more direct chemical introduction. Then, either Maxam-Gilbert sequencing was performed, or biotinylated oligodeoxyribonucleotide primers were employed in the phosphorothioate sequencing protocol described above. The use of pyrrolidine in place of piperidine to effect cleavage in Maxam-Gilbert sequencing has been evaluated: piperidine can be used as precursor in the synthesis of phenylcyclidine ('Angel Dust'), and is now a controlled substance in the U.S.366 Short single-stranded DNA fragments containing the sequence d(GCGAAAGC) have been found to form an extraordinarily stable (even in 7 M urea) structure, likely a mini-hairpin, which caused them to move anomalously fast on denaturing polyacrylamide gels, and it

6: Nucleotides and Nucleic Acids

279

has been suggested that this sequence, and any others giving comparably stable structures, may not have been analyzed correctly by gel sequencing, and may have afforded erroneous data in published sequences.367 A new dimension in site-specific cleavage reagents has been achieved by linking a ribonuclease to an oligodeoxyribonucleotide. The species (203), an oligomer linked via its 5'-terminal phosphate to an activated disulphide, was treated with an analogue of S peptide (the first 20 residues of ribonuclease A) in which lysine-1 had been replaced by cysteine, and disulphide exchange occurred with displacement of pyridine-2-thiol.368 This S peptide-oligonucleotide conjugate was then combined with S protein (ribonuclease A lacking the S peptide), to form a hybrid enzyme (204) which cleaved a 62-residue single stranded RNA target site selectively 2: a single UpA sequence. Ribonuclease S (i.e. S peptide plus S protein, lacking the conjugated oligonucleotide) cleaved the RNA target strand at eleven sites for comparison. Above 370 the S peptide-oligonucleotide conjugate dissociated from the S protein and the efficiency and specificity of cleavage were lost. The (l3p) and (Sp)-diastereoisoiners of d[ApAp(s)ApA] (where p(S) denotes a phosphorothioate link) have been prepared using methoxydiisopropylphosphoramidite methodology, separating the dias tereoisomers of the fully protected tetramers by h.p.1.c. prior to deblocking, and tested as substrates for a number of deoxyribonucleases.369 While both (IXp) and (Sp) phosphorothioate groups were resistant to hydrolysis by staphylococcal nuclease and DNases I and 11, spleen phosphodiesterase hydrolyzed the (Sp) diastereoisomer [but not the (Rp) diastereoisomer] very slowly. In some cases, the presence of the phosphorothioate also caused suppression of the rate of hydrolysis of neighboring phosphate groups. 'Class I' AP endonucleases cleave DNA at AP, i.e. apurinic or apyrimidinic, sites by a process of p-elimination, in which a 3'-terminal 2, 3-dideoxy-2, 3-didehydro sugar remnant is formed as the 3'-phosphate is eliminated. It has been proposed that these enzymes should be designated AP lyases, with the term AP endonuclease being reserved for those enzymes which hydrolyze the C3'-0-P link 5'- to AP sites (previously styled 'Class 11' AP e n d ~ n u c l e a s e s ) .The ~ ~ ~unsaturated sugar remnant left at the 3'-terminus, following P-elimination by AP lyases, is a Michael acceptor, and the addition of thiol compounds containing anionic groups (e.g. thioglycolate) to these termini can be followed by gel electrophoresis, permitting the distinction to be made between p-eliminative and hydrolytic ~ l e a v a g e . 3Thiol ~ ~ addition in this way also prevents 6-elimination, and thus the presence or absence of thiols in the medium in which AP endonuclease activity is studied may influence the results observed, and thus the interpretation of the mode of enzymatic activity. Indeed, it is suggested that thiols may influence the pathways followed by repair processes at AP sites in DNA in viva A bovine AP endonuclease has been investigated and found to display fairly broad specificity in its recognition of 'AP' sites, cleaving synthetic substrates with ethylene glycol, propane-1, 3-dio1, or tetrahydrofuran at the 'abasic'

280

Orgunoph osphorus Chemistrq’

0 II

R S -0-P-0-

[ d ( T T C G C G G T G G T G G C )]

I -0

( 2 0 4 ) R = R Nase S-S-

O d(Tp),-dT-O-CH2CONH

C ( Me)[CH20-P-

II

SCH2CONH(OP)12

I

-0 ( 2 0 6 ) O P a s in ( 2 0 5 )

0 II

d ( Tp),d T -0 -P-SCH,CON I

H (OP)

-0 ( 2 0 7 ) O P a s in ( 2 0 5 ) 0 H II (OP NH COC H2 N- P -0

I

- [d ( A AT T G T T AT C C G C T C AC A A T T)]

-0

(208) O P a s in ( 2 0 5 )

6: Nuclrotidrs und Nuclei, Acids

28 1

site 5'- to the lesion to leave a 3'-hydroxy terminus.372 Partial depurination of d(ApA) affords the isomers d(SpA) and d(ApS) (S = depurinated sugar, i.e. deoxyribose) which have been evaluated as substrates for endo- and e x ~ n u c l e a s e s . ~ ~ ~ Snake venom phosphodiesterase readily cleaved d(SpA) to release dAMP, but did not hydrolyze d(ApS); calf spleen phosphodiesterase (rather slowly), and nucleases P1, Sl, and mung bean nuclease all hydrolyzed d(ApS), but not d(SpA). Derivatization of the aldehydic groups of these molecules with methoxyamine did not alter these observations, and experiments using d(SpTpC) as substrate for the above enzymes gave results consistent with those for d(SpA) and d(ApS). Following UV irradiation of d(TpTpT), the two cis-syn cyclobutane dimercontaining isomeric products d(T

TpT) and d(TpT

T) have been isolated by h.p.1.c. and tested as substrates for n ~ c l e a s e s . 3The ~ ~ exonucleases snake venom and spleen phosphodiesterases could not cleave the intradimer phosphodiester links when these were located at the 3'- or 5'- end of the trimers, respectively, but otherwise displayed their normal activity. Of the various other nucleases investigated, only nuclease P 1 was abIe to cleave an intradimer link, in d(T

TpT) (but not in its isomer), to form dTod(pTpT). T4 Polynucleotide kinase was found unable to phosphorylate d(T

T) or the 6-4'[pyrimidine-Zt-one1pyrimidine photoproduct (174),or d(T

TpT),but could phosphorylate d(TpT

T) at the same rate as d ( T ~ T p T ) . 3 ~This 5 permitted the d(TpT

T)species isolated from irradiated poly (dA). poly (dT) after digestion with snake venom phosphodiesterase and alkaline phosphatase to be quantitated at the femtomole level. Comparative studies showed that the rate of dimer formation in natural DNA was four times the rate in poly(dA). poly (dT), while analysis using nuclease P 1 to identify the residue found 5' to the thymine dimer lesions gave a ratio for pyrimidine: purine of 6:1, indicating that tripyrimidine sequences in DNA are hotspots for UV-induced damage. An ingenious method involving the kinetics of repair of mutant plasmids within UV-irradiated E . cali has been used to determine whether excision repair initiated by T4 endonuclease V and Uvr ABC excinuclease and monomerization of dimers by photolyase occurs via a processive (i.e. the enzyme scans along DNA for damaged sites without dissociation) or distributive (binding and repair of damage sites occurs only when they are encountered by random 3-dimensional diffusion) m e ~ h a n i s m . 3 ~In 6 the processive mechanism the accumulation of fully repaired plasmids is linear with time, and in the distributive mechanism it rises steadily following an initial lag phase. T4 Endonuclease V and Uvr ABC excinuclease appeared to follow a processive mechanism and photolyase a distributive mechanism. Poly [d(A-T)] containing a few [a-32P, uracil-3HIdUMP residues has been prepared using [cc-3*P, uracil-3HldUTP as a substrate for Klenow fragment, and then treated successively with uracil N-glycosylase and T4 UV endonuclease V to afford polydeoxyribonucleotide chains with deoxyribose 5-[32Pl phosphate residues at the

282

Organophosphoms Chemistry

3’-termini.377 Further treatment with sodium periodate afforded also [32Plphosphoglycolaldehyde residues as the 3’-termini. Endonuclease IV from E. coli was found able to remove phosphoglycolaldehyde, phosphate, and deoxyribose-5-phosphate from the ?-termini of DNA, and also dideoxyribose-5-phosphate, generated by ~ 3’-repair diesterase from yeast, identified and p-elimination at AP ~ i t e s . 3A~ DNA purified using synthetic DNA with a 3’-phosphoglycolaldehydeterminus, can remove the same ?-termini as E . coli endonuclease IV, above, and also serves as the major repair enzyme for AP sites, cleaving by hydrolysis on the 5’-side to give a 3’-0H terrninus?’g i.e. functioning as an AP endonuclease according to the proposed classification.370 Exonuclease V from S. cerevisiae degrades single-stranded DNA processively, preferentially from an 5’-phosphorylated terminus, to form dinucleotides of general formula d(pNlpN2), as revealed by studies with synthetic oligo- and polyn~cleotides.3~9 Only the last three or four residues remain undegraded. The absence of a 5’-terminal phosphate causes poorer binding of the substrate, and the initial release of a mixture of dinucleoside monophosphates and trinucleoside diphosphates. The solid-phase phosphoramidite method, using sulphur oxidation of the phosphite intermediates as appropriate, has been used to prepare (Ep) and (Sp) - d[T3p(S)T5],-d[T4p(S)T4],and -d[T5p(S)T31. The diastereoisomers were separated by h.p.l.c., their absolute configuration established using snake venom phosphodiesterase, and their substrate behaviour with respect to cleavage by DNA topoisomerase I from E . coli examined and found to depend markedly on the position and stereochemistry of the phosphorothioate link.380 While for the hydrolysis of (dT)B, the smallest acceptable substrate, cleavage to give (dT)4 is dominant, no (dT)5 product was formed from any of the phosphorothioate analogues, and, while there was no consistent pattern of preferred stereochemistry at phosphorus in the substrate, the thiophosphorylated species which were cleaved fastest relative to their diastereoisomers were not cleaved at the phosphorothiate link. Basic polypeptides have been found to accelerate the hydrolysis of RNA, the greatest catalytic effect among the species studied being found for poly (Leu-Lys) which accelerates the rate of hydrolysis of ApAp by about 150-fold at pH 8.3g1 Since the rate of hydrolysis of adenosine-2‘, 3’-monophosphate to 2’-AMP and 3’-AMP is only increased five-fold, the principal effect is on the initial cyclization step. In the presence of oligo (A), poly (Leu-Lys) adopts P-sheet structure, in which the distance along the p strand between two consecutive positively charged side chains is ca. 6.5 A, closely matching the 6.2 A distance separating two phosphate groups in single-stranded helical poly (A). The formation of p sheet structure is not seen in the absence of oligo (A) and is presumed due to electrostatic interaction: the same interaction may promote the increased cyclization at phosphate, at least in part. The catalytic effect is decreasedvby increasing ionic strength, consistent with the requirement of complex formation for catalysis. No catalytic activity is observed

6: Nucleotides and Nucleic Acids

283

with d(pA)s in place of oligo (A). The specificity of tRNA hydrolysis catalyzed by lead (11) ions has been studied in substrates of modified structure, and under varying conditions of pH, temperature, and urea ~oncentration.38~ Normally hydrolysis is predominant in the D-loop, but none is observed in an isolated 5’-half molecule of tRNAPhe, indicating that a T-D loop interaction is critical for hydrolysis, and studies in intact but modified tRNA suggest that a U5g-C60 sequence in the T loop is also required for efficient specific cutting. Sequence-specific cleavage of nucleic acids, especially by chemically reactive complementarily addressed oligonucleotide sequences, continues to command much interest. The sequence d(T*T3CT&T4CT), in which the 5’-residue T* is deoxythymidine derivatized to carry an EDTA moiety, is complementary to an 18-mer polypurine sequence which occurs only once in the 48.5 kbp (kilobase pairs) of the genome of bacteriophage h, and treatment of h with this sequence at pH 7, together with ferrous ions, spermine, and DTT to initiate strand cleavage, effects cleavage at the target sequence with 25 ‘30efficiency, without detectable cleavage at secondary sites (although detectable cleavage at part-complementary secondary sites can be observed with longer incubation times at lower temperatures).383 Evidently directed cleavage via triple helix formation involving T.A.T and C+.G.C base triplets is occurring (the oligomer binds by Hoogsteen pairing in the major groove of the DNA parallel to the polypurine strand), a technique which may prove very valuable in directed segmentation of large DNA molecules, for instance in sequencing the human genome. In conceptually related s t ~ d i e s , 3(dT)s ~ ~ has been linked at its 3’- or 5’- terminus to 1, 10-phenanthroline, with or without the presence of an acridine derivative attached at the other terminus to stabilize duplexes by intercalation, forming, e.g., (205) [assembled by joining 3-Qdimethoxytrityl-2, 2-dimethyl-3hydroxypropyl (4-chloropheny1)phosphate to protected octadeoxythymidylate by phosphotriester coupling, detri tylation, thiophosphorylation using bis(2cyanoethy1)-N, N-diisopropylphosphoramidite followed by oxidation with sulphur, deprotection and alkylation using N5-(iodoacetyl)-5-amino-l, 10-phenanthrolinel, and (206) (assembled by 3’-Qalkylation o f 5’-Q-dimethoxytrityl-2’-deoxythymidine with DBU and methyl bromoacetate, condensation of the product with 2-amino-2methylpropane-1, 3-dio1, thiophosphorylation as above to form the protected bis(thiophosphate), coupling to the 3‘-end of protected heptadeoxythymidylate, and deblocking followed by 5-alkylation, again as above) and (207). Using a 27-mer single-stranded DNA target containing a (dA)8 sequence, cleavage induced by 3-mercaptopropionate was observed in hybrid-stabilizing conditions at both ends of the (dA)g sequence, probably via triplex formation with two OP-bearing (dT)g strands hybridized in antiparallel fashion. With a 27-mer duplex as target, cleavage sites were observed on both strands, consistent with the OP-bearing (dT)s strand becoming hybridized to the (dA)8 (dT)8 sequence parallel to the (dA)s strand, in

284

Organophosphorus Chemistry

accord with the previous study. In studies using a-(dT)s with 1, 10-phenanthroline attached at the 5’-terminus and P-(dT)8 with 1, 10-phenanthroline attached at the 3’-terminus, in each case via alkylated thiophosphate, and the 27-mer singlestranded DNA target with (dA)s sequence, cleavage by (OP)-a-(dT)s with copper ions and P-mercaptopropionate occurred at the 5’-end of the (dA)8 sequence, indicating that the a-DNA. P-DNA hybrid was parallel-stranded.385 However, using an RNA target containing (rA)g or (rA)lo target sequences, (OP)-a-(dT)g elicited cleavage only at the ?-end of the target sequence, indicating that the a-DNA. P-RNA hybrid was antiparallel-stranded. With OP-P-(dT)s, antiparallel-stranded helix formation was observed irrespective of whether the target P-sequence was (dA)s or (rA)8. In footprinting studies on the sequence-specific recognition of the major groove of DNA via triple helix formation, a 32-mer oligodeoxyribonucleotide containing homopurine (A/G mixed sequence) 11-mer and 10-mer tracts separated by a deoxythymidine residue was used, together with its complementary sequence, and the protection from cleavage by 1, 10-phenanthroline/Cu+ afforded by 11-mer and 10-mer homopyrimidine sequences complementary to the homopurine tracts was determined.386 Triple helix forma tion with parallel orientation of the homopyrimidine oligomers to the polypurine tracts occurred, and was found to suppress cleavage, although cleavage occurred at the A.T base pair between the two triple helical tracts, and also at the duplex segments adjacent to the triple helices. The asymmetry of the cleavage patterns on opposite strands of the duplex indicated that 1, 10-phenanthroline-Cu+bound in the minor groove of the duplex. The kinetic mechanism of the nuclease activity of 1, 10-phenanthroline-copper has been investigated, and found to be an obligatory ordered mechanism, in which the tetrahedral cuprous complex (Or12 Cu+ is the species which binds to DNA, and is responsible for sequence-dependen t activity, probably via non-intercalative binding in the minor gr0ove.38~It is formed in solution by reduction of (OP)2 Cu2+ prior to binding: the reduction of DNA-(OP)2 Cu2+ is too slow to be consistent with a main pathway intermediate. Instead DNA-(OP)2 Cu+ is formed and oxidized by hydrogen peroxide to give an intermediate copper-oxo complex and subsequent strand scission. The specific binding of 1, 10 -phenanthroline to a DNA structural lesion has been demonstrated by preparing 12-mer duplexes of identical structure except for a single deoxycytidine bulging out (i.e. non-hybridized) in differing positions on one of the strands.388 1, 10-Phenanthroline-copper bound specifically at the lesiongenerated intercalation site causing cleavage in the non-lesion strand over a sequence of three residues, implying that the actual agent causing cleavage was diffusible. Analysis of the locations of the cleavage sites again indicated that (0P)fCu+ binds in the minor groove in B-DNA. The effects of sequence variation on the characteristics of cleavage by (OP)2-Cu+have been examined using a series of 11-mer duplexes, one strand being 5’-d(CCCTPyPuPyCCCC)-3’and the other its complement, in which the purine bases in the central triplet were varied.389 While

6: Nucleotides and Nucleic Acids

285

the duplex (PyPuPy = TAT) was cleaved preferentially, the product termini formed (3'-phosphoglycolate from 4'-attack or 3'-phospho-5-methylfuranone degrading to 3'-phosphate plus methylenefuranone from 1'-attack) varied markedly depending on which residue was attacked. A guanine base in either of the first two base pairs of the central triplet inhibited the binding of (OP)2-Cu+,which was proposed, again, to occur in the minor groove via partial intercalation. The sequence-specific scission of RNA by 1, 10-phenanthroline linked to a 21-mer oligodeoxyribonucleotidevia a phosphoramidate group (208) at its 5'-terminus has been investigated.390 In the presence of Cu2+ ions and 3-mercaptopropionate, the 81-mer RNA target was cleaved specifically over a sequence corresponding to the position of the 5'-terminus of (208) in the DNA-RNA hybrid, plus or minus three residues. This may have been due to the diffusibility of the oxidative species formed: the phenanthroline ring did not suppress normal hybridization, since the hybrid was susceptible to cleavage by RNase H. The kinetics and characteristics of cleavage of DNA and RNA backbones using I, 10-phenanthroline and copper ions appear very similar. (OP)2Cu+ and DNase I have been utilized as sequence-dependent but non-nucleotidespecific cleavage agents to investigate the influence of flanking sequences and fragment length on digestion.391 Using 18-mer oligodeoxyribonucleotide duplexes and restriction fragments containing the same sequence but 10-fold longer, it was shown that cleavage by these conformationally sensitive agents alters in response to variation in sequence, but is unaffected by changes in fragment length. The construction of a sequence-specific DNA-cleaving protein has been achieved by attaching Gly-Gly-His (the consensus site for the copper-binding domain of serum albumin) to the amino-terminus of the DNA binding domain of Hin recombinase to give a 55-residue hybrid protein.392 This was shown by footprinting to bind to four H i n sites on a DNA target at micromolar concentrations, and to degrade the DNA backbone at one of the sites in the presence of cupric ions, hydrogen peroxide and sodium ascorbate. Cleavage occurred at only two base pairs, suggesting that a non-diffusible oxidant may have been generated, and , from the asymmetric cleavage pattern, from the minor groove, to give 3'- and 5'- phosphate termini. Structural variation (cf. ref. 390, above) may have precluded cleavage at the other Hin sites. Sequence-specific cleavage of DNA by N-bromoacetyldistamycin has also been ~ t u d i e d . 3 ~Using 3 a 167-base pair DNA restriction fragment as target, binding occurred at four A-T-rich sites, each five base pairs in length, but cleavage occurred at only one site, adenine in the sequence GTTTA, apparently by alkylation at N-3 of the base, leaving 3'- and 5'-phosphate termini after treatment with piperidine. A metal-chelating trica tionic porphyrin has been found to mediate strand scission in DNA in the presence of cupric ions, DTT, and hydrogen peroxide, in a process believed to involve initial intercalation.394 Photocleavage of singlestranded DNA occurs upon irradiation in the presence of the dimethyldiazaperopyrenium dication, with predominant scission at guanine base residues to leave a

286

Organophosphorus Chernistly

3'-phosphate terminus.395 Cleavage is enhanced by treatment with piperidine, suggesting that irradiation results initially in modification at guanine residues, giving alkali-labile sites. An ethidium derivative has been linked to an octadeoxyribonucleotide to give (209), which was capable of cutting at a target sequence in a complementary 14-mer oligodeoxyribonucleotide upon laser irradiation.396 Again alkali-labile sites were also formed, and after piperidine treatment the total addressed cleavage of the target was about 40 %. Synthetic oligodeoxyribonucleotides have been used to investigate the sequence-specificity of interaction of the bicyclo[7.3.01dodecadienediyne-containing neocarzinostatin (NCS) chromophore, which was shown to cleave DNA preferentially at thymine and adenine bases (N2) in the sequence d(GN1N2) (N1# G; N2 = T or A).3g7 Probably, the naphthoate moiety of the chromophore intercalates at GNI and this, together with an electrostatic interaction between an amino sugar moiety of the chromophore and DNA, serve to locate the bicyclododecadienediyne adjacent to the C-5' position of the deoxythymidine or deoxyadenosine residues attacked. At some sequences a similar binding mode can generate an abasic lesion at the deoxycytidine residue on the opposite strand also, forming a double-stranded lesion. Using d(AGCGAGCG) (with C7 tritiated both in base and sugar as target, and enzymic digestion followed by h.p.1.c. to characterize the products of its attack by NCS, both the carboxylate and lactone forms of 2-deoxyribonic acid were identified.398 Without enzymic cleavage, cytosine is lost, but the phosphodiester links replain intact. In the mechanism proposed, the NCS chromophore removes the hydrogen atom at C-1' to form a free radical which reacts with oxygen to give (210). Subsequent reduction of the corresponding hydroperoxide would give an oxyanion to expel the base, forming (211), the observed product. Analysis of the c l e a v i p site termini generated in restriction fragments by treatment with NCS to give double-stranded lesions, followcd by cleavage with putrescine or endonuclease IV to generatt double-stranded breaks, gave results consistent with the previous studies: generation of an AP site on one strand, with a closely opposed break with 3'-phosphate and 5'-aldehyde termini, two positions upstream from the base opposite the AP site.399 Evidently NCS attacks two residues on opposite edges of the minor groove of DNA. In anaerobic conditions the free radical generated at C-5' of deoxythymidine residues in DNA treated with NCS reacts with the cellular radiosensitizer misonidazole, resulting in strand cleavage with formation of 3'-formyl phosphate terminus, and tracer work with oxygen-18 has demonstrated that the formyl oxygen is derived from the nitro group of misonidazole.400 In the putative mechanism, reaction of the C-5' radical with misonidazole generates the nitroxide radical adduct (212) which fragments with loss of the nitroso compound to form the formyl phosphate terminus and the C-4' radical (2131, which in turn fragments to give thymine, sugar fragments, and a 5'-phosphate terminus. A synthetic cyclodecaenediyne related to the calicheamicine-speramicin class of

287

6: N u c l e o t i h and Nucleic Acids

0

p(

H I1 NHCOCH2CH2 N-P-0-

AATACTCT )]

I

-0 Et

Ph

b,

P4 0

-0

/’

\

0

Ti: 0‘p”/O

-0’

0-

O

-o/

\

O \

0

O\

\

(210)

\o -0’

0

\ pl’/

\o -o/’

\

0-CHO

+ 0

‘i

(212) N, C H2 C HOH CH2 OMe

R =

Q

-ghY O\ 4 0

-0

0 p\

0,

288

Orgunop hosp horus Chemistry

antibiotics has been prepared and shown to cause clean scission of double-stranded The reaction products were not identified, DNA in the absence of however. While the degradation of DNA in vitro by bleomycin - Fe2+ has been firmly associated with the generation of base propenal species, it is now reported that a small amount of 8-hydroxyguanine is also formed in the DNA, in a dose-dependent manner.402 Curiously, using bleomycin - Fe2+ with Ehrlich ascites cells in culture, no base propenal or 8-hydroxyguanine formation could be demonstrated, even in conditions of quantitative cell kill. The green complex of bleomycin A2 and cobalt (111) causes photoinduced strand scission in DNA on aerobic irradiation with h > 300 nm.4038 404 Using d(CGCTTTAAAGCG) as substrate, cytosine was formed as a major product with degradation occurring preferentially at C3 and Cii, but no cytosine ~ treatment propenal or phosphoglycolate-termina ted (214) were d e t e ~ t e d . 4Instead, of the product with alkali afforded (215), suggesting that (216) had been formed. The formation of base propenal is thought to be associated normally with intermediate formation of a 4'-hydroperoxide: the green cobalt bleomycin complexes are thought to contain hydroperoxide, however, and to perform efficient hydroxylation at C-4', rather than generation of a C-4I-radical leading to 4'-hydroperoxide formation. In other accounts of chemical DNA cleavage, si te-specific oxidation at polyguanosine tracts by cupric ions and hydrogen peroxide has been reported in a reaction which did not produce abasic sites and was unaffected by superoxide dismuta~e,~O5 photohydrolysis by 4-diazoniumanilides of L-leucine, L-ornithine, and L-5carboxyspermine has been described,406 and photochemical cleavage by nitrobenzamides linked via a polyniethylene chain to 9-aminoacridine and irradiated at h > 300 nm has been observed.407 Of a number of agents of this last acridine was found to be the class synthesized, 9-[ [6-(4-nitrobenzamido)hexyl]amino] most effective, showing predominant cleavage at guanine and thymine base residues which was enhanced by treatment with piperidine. Mechanistic schemes were proposed in which the triplet state of the nitro group abstracts a hydrogen atom from C-l', C-3' or C-4', and addition of the resultant radical to the nitroxide radical generates an adduct [e.g. (217) via attack at C-4'1 which can fragment with loss of base and subsequent p-elimination to give chain cleavage. Irradiation of supercoiled either alone DNA at 420 nm in the presence of 9-amino-6-azido-2-methoxyacridine, or tethered by an octamethylene link to 9-aminoacridine, results in single-strand cleavage and formation of covalent adducts.408 Cleavage is predominant at thymine positions and appears (from electrophoretic evidence) to form 5'-phosphate termini, but the mode of action is uncertain. The bidacridine) was used in photofootprinting experiments to determine the binding site of RNA polymerase on promoter DNA. The 13-mer RNA sequence pppGGGCCGAAACGUA catalyzes the specific self-cleavage of a 41-mer oligoribonucleotide in the presence of magnesium ions.*09

289

6: Nucleotides and Nuclric Acids

CYt

Gua

R

-0

-0

( 2 1 4 ) R =CH,COO(215) R

=$OH

0

f-\

Gua414

0

(220)

290

Organophosp horns Chemistry

The two sequences correspond to those in the 'hammerhead' structure of the virusoid of lucerne transient streak virus, which undergoes self-cleavage. The 13-mer is the smallest ribozyme reported hitherto. By examining the effect of singlebase changes both in the substrate RNA and in the active site of the 'L-21 Sca I RNA' ribozyme (derived from Tetvahyrnena theymuphila) itself, it has been shown that the rate of cleavage by the ribozyme (acting as an endoribonuclease) can be increased up to 100-fold by the presence of a base mismatch within the three nucleotides preceding the cleavage site.410 The progressive destabilization of the ribozymesubstrate complex by mismatches, or by the addition of chaotropic reagents (urea or formamide), or by decreasing metal dication concentration, appears first to increase the rate of cleavage to an optimum value, and subsequently to depress it. The 359-mer minus strand of the satellite RNA of tobacco ringspot virus has been found to contain a 50-residue catalytic RNA sequence and a 14-residue substrate RNA sequence which together form a catalytic complex which does not conform to the 'hammerhead' model or any other previously characterized for ribozyme catalysis.411 The values of Kcat, KM, optimum temperature and activation energy obtained for cleavage of the substrate indicate that the catalytic centre of this ribozyme is the most efficient described to date. During the self-splicing reaction of precursor rRNA in T. therrnophila, the intervening sequence (IVS) becomes cyclized to form a 414-nucleotide circle (cIVS), and the kinetics of the reversal of this cyclization by covalent addition of oligoribonucleotides (CU), (n = 1,2 or 31, UCU,412and also dCrU, rCdU, dCdT and water413 in the presence of varying concentrations of Mg2+ have been measured. The results suggested that the oligonucleotide and Mg2+bind in separate steps, and that the reverse cyclization, which is effectively independent of oligomer length, may involve the binding of a weakly held Mg*+ ion.412 Evaluating the dinucleoside monophosphates as potential substrates for opening cIVS indicated that the 2-hydroxy group of the 5'-residue appeared to be required for substrate binding, while that of the 3'-residue was required for Mg2+ binding.413 Both the energy and entropy of activation required for opening of cIVS were found to be large and positive, possibly indicating that cIVS undergoes partial unfolding during formation of the transition state. A model of the transition state (218) involving Mg*+ ions bridging between sugar 2'- and 3'-oxygen atoms and equatorial oxygens to trigonal bipyramidal phosphorus has been proposed.41 In a method of analysis of RNA splicing, an oligodeoxyribonucleotide complementary to the exon sequence (or sequences) upstream of a known 5'-splice site is hybridized to the RNA, and the RNA strand of the hybrid(s) cleaved with RNase H.414 A second primer, labelled with phosphorus -32, and complementary to an exon sequence downstream of a 3'-splice site, is then hybridized to the cleaved RNA, and primer extension performed using reverse transcriptase, a process terminated by the site(s) of RNase H-catalyzed cleavage. The length($ of the

6: Nucleotides and Nucleic Acids

29 1

products indicate the distances between, and identities of, the splice site utilized, while comparison of results obtained with pre-spliced and spliced RNA permit the length and sequence of the intron to be determined.

5.4 Post-Svnthetic Modification - A substantial study of the use of 1-ethyl-343dimethy1amine)propylcarbodiimide (EDC) as an agent for the derivatization of oligo- and polynucleotide phosphomonoester groups in aqueous solution has been reported, and protocols described which permit the preparation of phosphodiesters and phosphoramidates of oligodeoxyribonucleotides at 3'- and /or 5'-terminal phosphate groups, and in oligoribonucleotides at 5'-terminal phosphate, in good yields.415 Derivatization at pH 2 5.5 at 40 C in the presence of high magnesium ion concentrations was recommended, since in these conditions side reactions at bases are largely suppressed, and acid conditions increase the reactivity of EDC, probably via protonation of the tertiary amine increasing electrophilicity of the carbodiimide (219). An alternative method to introducing, e g , a polydeoxyadenylate tail onto DNA without the use of terminal deoxynucleotidyl transferase consists in 5'-phosphorylation of an appropriately tailed oligodeoxyribonucleotide, e.g. d(AATTCCCGGGAlo), using T4 polynucleotide kinase, followed by annealing to d(CCCGGG) to create a hybrid containing an overlap end identical to that formed by restriction of DNA with Eco RL4I6 This hybrid is in turn annealed with Eco RIrestricted DNA and ligated to it adding, in effect, the hexamer duplex plus decadeoxyadenylate tail. A novel methylating agent (220) has been prepared in which N-methyl-Nnitrosourea(MNU) is linked, in effect, to methidium chloride, and shown to cause formation of piperidine-labile N7-methylguanine adducts in DNA.417 Methylation by (220), which appears to occur via non-sequence-specific intercalation followed by hydrolytic generation of the nondiffusible alkylating agent, is enhanced by increased ionic strength, while that by MNU, which methylates preferentially at oligo(G) residues at sequences, is not. The formation of Q~-methyl-2'-deoxyguanosine specific guanine bases in a 17-mer DNA target by methylation using MNU has been quantitated using h.p.l.c., and was found to be subs tantially greater for positions 2 and 3 in a -GGG- run than for position 1 or for an isolated G base, but only when the target was double stranded.4'8 Evidently secondary structure has a major influence on the extent of alkylation. Single-stranded M13mp18 phage DNA has been methylated with dimethylsulphate, and then treated with alkali, causing ringopening of 7-methylguanine to form 2, 6-diamino-4-hydroxy-5-~-methylformamidopyrimidine residues.419 Methylation of the DNA reduced its efficiency in acting as template for in vitro DNA synthesis by Klenow fragment, apparently due to methylation at adenine and cytosine rather than guanine bases, but ring-opening of the methylated guanine bases blocked synthesis further. [6-I5N] Adenine has

292

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been prepared chemically, and incorporated enzymatically into [6-15N]2'deoxyadenosine, which was converted to its protected phosphoramidite, which in turn was used to prepare a self-complementary 12-mer containing the recognition site of Eco RI methylase with [6-I5N] adenine a t the position of methylation.420 Following methylation by the enzyme, degradation and mass spectrometric analysis, all the isotopic label was shown to remain at the N6-position of adenine, implying a mechanism of direct methyl transfer to N6 of adenine, rather than to N*with subsequent Dimroth rearrangement. The modification of prime bases in tRNA molecules with diethylpyrocarbonate largely prevents the recognition of the altered tRNA by the enzyme ATP/CTP: tRNA nucleotidyltransferase, so that catalyzed exchange of the 3'-terminal adenylate with 5'-[32Pl adenylate from [a-32Pl ATP no longer occurs.421 The modified purines interfering with recognition cluster predominantly at the corner of the molecule where the D- and T-loops are juxtaposed. Modification of the uracil bases by hydrazine has relatively little effect. 4-Diazobenzoylbiocytin (221) has been introduced as a new biotinylating agent for DNA, and is used at pH 9 to label, presumably, guanine bases at C-8.422 5'-Phosphorylated nucleosides and polynucleotides have been labelled with fluorophores by coupling ethylenediamine or poly (L-lysine) to the terminal phosphate via phosphoramidate formation, followed by derivatization with the Oligodeoxyribonucleotides fluorophore: dansyl chloride or fluore~camine.~~3 containing phosphorothioate internucleotidic links can be labelled with fluorophores in situ after separation on a polyacrylamide gel by incubation with monobromobimane solution, and detected by destaining and viewing.424 Using oligonucleotides containing phosphorothioate links of known chirality, no difference in labelling was observed between (Rp) and (Sp) diastereoisomers, and no labelling occurred in the absence of phosphorothioate links. The d[Tp(S)T] derivative (221), which was prepared as a model compound, was reasonably stable at pH 3 - 7, but increasingly unstable at higher pH values. The efficiency of labelling decreased in longer oligomers. Post-synthetic treatment of oligodeoxyribonucleotides of varying length, each containing a single thymine base, with osmium tetroxide, has been used to introduce a single thymine glycol !esion into oligomer sequences with > 90 % effi~iency.~25These sequences were annealed to a complementary 14-mer primer and the resultant hybrids used to assess the ability of DNA polymerases to bypass the lesion. This was shown to vary with template length, sequence context, and the presence or absence of a 3'-5'-exonuclease function. Oligodeoxyribonucleotides of differing length but containing a central d(GG?TGG) sequence have been irradiated to form thymine photodimers at the central sequence and then tested as substrates for T4 endonuclease V, with or without prior annealing to their complementary sequences.426 The enzyme, which cleaves pyrimidine photodimers and the

293

6: Nucleotides and Nucleic Acids

JH

JHr HO

0-P-0

s

OH Me

i

Me $+Me

DNA

0

t

Protein

0

(221)

I

-

d Rib 5'- P P P

(224) n = 2 ( 2 2 5 ) n = 1 or 3 Me I

0

H H ~ N ( C H ~ ) , - S - S S - (CH2)2-N

II - P-0 - [oligodeoxyribonucleot ide-5'1 I

294

Organophosphorns Chemistry

3'-phosphodiester linkage of the apyrimidinic site required a far higher concentration of single-stranded substrates in order to display significant cleavage than it did of the corresponding duplexes. The formation of bipyrimidine photoproducts in DNA irradiated with a high intensity of UV light has been found to be less than that observed at lower intensity: the higher intensity light causes promotion of low-lying excited states to higher excited states, resulting in ionization and loss of base and formation of decomposition fragments, while the proportion of dimers formed via low-lying excited states is reduced.427 The y-irradiation of nitrous oxide-saturated aqueous solutions containing nucleohistone leads to protein-DNA cross-linking. Acid hydrolysis of the conjugate followed by silylation and g.c.-m.s. analysis indicates that a thymine-tyrosine cross-link (222) is formed, probably by abstraction of hydrogen from the methyl group of thymine by hydroxyl radical, followed by attack on tyrosine and subsequent loss of a hydrogen atom.428 Assay of the formation of 8-hydroxyguanine in nuclear and mitochondria1 DNA of rat liver upon exposure to various prooxidants (alloxan, with or without calcium or ferric ions; ferric ions alone; y-irradiation) shows that substantially more 8-hydroxyguanine is formed in mtDNA than in nuclear DNA, possibly due to high oxygen concentrations, inefficient DNA repair, or the absence of histones.429 It has been conjectured that this may explain the high mutation rate of mtDNA. Chemical aspects of complementarily addressed modification of nucleic acids have been reviewed, with emphasis on the Russian approach using 2-chloroethylaminoarylated oligonucleotide deriva tives430 Using oligo(cytidy1ate) species attached in phosphorbearing 4-(~-2-chloroethyl-~-methylamino)benzylamine amidate linkage to the 5'-terminal phosphate as addressed reagent, and oligo(dG), either single-stranded or in a duplex, as target, the pH optimum for alkylation of the guanine bases of the target strand in the duplex was found to be lower (pH 4.5) than that for single-stranded oligo(dG) (pH 5.5).431 The lower pH optimum lies close to the pKa of cytidine, and was interpreted as meaning that addressed modification of the duplex occurs via triplex formation, with C+.G.Cbase triplets being formed. If, in addition to the alkylating addressed oligodeoxyribonucleotide of the type described above, a second oligodeoxyribonucleotide complementary to the DNA sequence immediately adjacent to the target sequence for the alkylating strand, and in addition derivatized at the 5'- (or, better, 5'- and 3'-) phosphate(s) with an N-hydroxyethylphenazinium ligand [see, e.g. (22311 is also present, alkylation at the target strand is significantly increased.432 The phenazinium-bearing strand plays an 'effector' role, increasing both the extent and specificity of the addressed alkylation, and this effect is further increased if two phenazinium moieties are attached. In these studies it should be noted that the concentrations of the alkylating and effector strands were much higher than those of the target strands. Treatment of (EJ-5-(3-aminoprop-l -enyl)-2'-dUTP with the N-hydroxysuccinimide ester of 3-methylthiopropionic acid affords (2241, which can be

6: Nucleotides and Nucleic Acids

295

incorporated into a primer template DNA complex using Klenow fragment.433 Upon activation using cyanogen bromide at pH 5.5 and 250 C, methylation occurs predominantly at a guanine base on the strand complementary to that incorporating (224), two residues to the 5'-side of the position of (224) on the opposing strand, as evidenced by the position of cleavage of the methylated strand following piperidine treatment. The cleavage yield was estimated densitometrically as 9 %. Using analogues (225) of (224) with different lengths of side chain did not increase cleavage yield or specificity. This procedure thus permits non-enzymatic sequence-specific methyl transfer to DNA to be performed. 4, 5', 8-Trimethylpsoralen has been derivatized to form the phosphoramidite (226), which was incorporated as the 5'-terminus of a protected oligodeoxyribonucleotide by standard synthetic methods, and then unblocked.434 Hybridization to a complementary 21-mer followed by irradiation gave a photo-crosslinked doublestranded DNA fragment with high efficiency. Since photo-crosslinking (involving photoaddition to the 5, 6-double bonds of two thymine bases) could only occur between a 5'-d(TpA) segment on the psoralen-bearing strand and the complementary d(TpA) on the opposing strand, the high degree of crosslinking indicates efficient hybridization to the target strand. Experiments on the DNA sequence specificity of photocrosslinking by 4, 5', 8-trimethylpsoralen indicate that while 5'-d(TpA) sites are preferred for crosslinking, the rate of reaction can vary three- to four-fold depending on the adjacent base sequences.435 In an investigation of the specificity of site-directed psoralen addition to RNA, a 5'-kinased oligodeoxyribonucleotide was coupled, using EDC, to 1, 6-diamino-3, 4-dithiahexane to give (227), which was reduced with DTT and used to displace pyridine -2-thiol from trimethylpsoralen linked via a spacer to an activated disulphide to give, finally, the psoralen attached via a reducible disulphide link to the 5'-terminal phosphoramidate attached to the oligonucleotidc.436 Upon hybridization to a complementary RNA strand to form a duplex containing a non-paired base about five nucleotides from the 5'-end of the oligodeoxyribonucleotide strand, affording an intercalation site for the psoralen, efficient photoadduction to specific uracil bases on the RNA strand could be effected. Subsequent reduction of the disulphide left the psoralen attached to the RNA strand. 4'-Hydroxymethyl-4, 5', 8-trimethylpsoralen (HMT) affords cis-syn photodimers formed between the psoralen 4'-5' furan double bond and the 5, 6double bond of the thymine base, on photoadduction to DNA. Subsequent enzymatic hydrolysis releases a mixture of diastereoisomers arising by addition having taken place to the 3'-face (228) or the 5'- face (229) c f tbe thymine base: for calf thymus DNA the ratio of diastereoisomers formed is (228):(229)= 66:34.437 Various DNA-binding drugs, such as cis-platin, distamycin A, and the steroidal dication dipyrandium, have been found to alter this ratio to increase the proportion of (229) in each case, probably by perturbing the structures of the sites at which HMT

Organophosphorus Chemistly

296

( 2 2 9 ) mirror image of ( 2 2 8 )

Me (230)

H

Me (232) x=O; or & = I ; n = 2 , 4 or 6 ; z varies

6: Nucleotides and Nucleic Acids

297

intercalates, prior to photoadduction. Following formation of a photocrosslink between HMT and the thymine bases of the duplex d(GGGTACCC), base-catalyzed reversal of the cross-link has been observed under denaturing alkaline conditions (pH 10.1,3 M urea, 60 O C ) to afford only the pyrone-side monoadducted oligonucleotides, the furan-side adducts having been cleaved.438 This is of interest since photoreversal of psoralen photocrosslinking gives mainly furan-side monoadducts. A mechanism of cleavage has been suggested in which hydrolysis of the pyrone-side adduct, a phenolic lactone, gives (230) + (2311, with subsequent re-closure of the lactone ring. Evidently psoralen-adducted DNA should not be placed in alkaline denaturing conditions if crosslinking is to be maintained. Others have noted the same behaviour and exploited it by hybridizing a 19-mer containing a furan-side psoralen monoadduct with a complementary 56-mer target sequence, irradiating to form the pyrone-side crosslink at the target site, and then performing base-catalyzed reversal to leave the pyrone-side psoralen monoadduct at the target site.439 Angelicin (isopsoralen) species produce uncrosslinked monoadducts upon irradiation with double-stranded DNA, and 4, 5'-dimethylangelicin linked by polyamine or poly(ethy1ene oxide) spacer arms to biotin has been used to label DNA with biotin in this way.440 Better results were obtained using polyamine spacer arms, possibly due to enhanced interaction by electrostatic attraction between the polycation and the sugar-phospha te backbone. 4'-[~-(~-Aminoalkyl)laminomethyl-4, 5', 8-trimethylpsoralens have been attached using EDC to the 5'-phosphate termini of 5'-nucleotidylated oligonucleoside methylphosphonates giving species of general structure (232), with sequences complementary to rabbit globin mRNA.441 Upon irradiation, these species formed crosslinks specifically to their target sequences on the mRNA, with (232; x = 1, n = 2) giving the highest amount of crosslinking. The extent of crosslinking was also governed by the length and sequence in (232), and occurred much more readily when the psoralen was located opposite uracil on the mRNA strand than when opposite cytosine. In another study, (232; x = 1, n = 2) of appropriate complementary sequence was crosslinked readily to either the coding or the non-coding single strands of synthetic DNA containing a T7 RNA polymerase promoter sequence, but not to the DNA duplex.442 Crosslinking to the template strand inhibited transcription by T7 RNA polymerase; in the previous study crosslinking to the globin mRNA inhibited its translation.441 Together, these results suggest possible means of controlling gene expression in viva Microscale spectroscopic techniques have been used to show the structure of a previously uncharacterized adduct formed by reaction of mitomycin C with guanine bases in DNA to be (2331.443 5.5. Metal Complexes - On stirring two equivalents of [(trpn) Co (H20)2]3+ [trpn = tris(aminopropyl)amine] with the disodium salt of AMP in water for six

Organophosphoms Chemistry

298

0

DMTrO

I SMe

(236) R’ = DMTr; B = Thy or R ’ = P i x y l ; B = C y t Bz; R2 = 2,4- dichlorophenyl (237) A S (236) but R Z = H

6: Nucleotides and Nucleic Acids

299

hours at 25O C, quantitative hydrolysis occurs to release adenosine and form ([(trpn)Co]2P04}3+,in which all four phosphate oxygens are bound to cobalt.444 With one equivalent of [(trpn) Co (H20)2]3+, a complex is formed with AMP in which both anionic oxygens are coordinated to cobalt; addition of the second equivalent is thought to form (234) transiently, with subsequent expulsion of adenosine affording the observed products. By heating at neutral p H in the presence of Mn2+ ions at temperatures above 500 C, ATP can be used to phosphorylate the hydroxy groups of serine and tyrosine non-enzymatically.445 Calcium ions can substitute for Mn2+ ions, albeit less effectively, but Mg*+ ions are ineffective. The reaction can be used to prepare radiolabelled phosphoserine - or phosphotyrosinecontaining pep tides. The crystal and molecular structure of cis-(Pt(NH3)2[d(pGpG)])/the principal adduct formed by reaction of cis-dichlorodiamminoplatinum (11) (DDP) with DNA, has been determined.446 The conformation in the dinucleotide appears to be largely dictated by the requirements of platinum coordination. A mathematical analysis of the kinetics of adduct formation between cis-DDP-type complexes and consecutive guanine bases in DNA suggests that the phosphate group lying 5'- to the guanine base at which initial adduction occurs is kinetically significant.447 The kinetics of reaction of GMP with cis-DDP and cis-dichloroethylenediamineplatinum(11) have been monitored using IH n.m.r. spectroscopy, and suggest initial formation of a mono(GMP) complex coordinated to platinum via N-7 of the guanine ring, which subsequently undergoes further platination to form a GMP-bridged diplatinum (11, 11) species with one platinum coordinated at N-1 and one at N-7, or reacts with a second GMP molecule to form a bis(GMP)-Pt(I1)complex, with the metal 8 cis-DDP-type drugs which have been coordinated at N-7 of each b a ~ e . 4 ~Novel described include an analogue of cis-dichloroethylenediamineplatinum (11) in which one nitrogen atom of ethylenediamine is joined, via a trimethylene or hexamethylene linker, to the nitrogen atom of acridine orange (an inter~alator)$*~ ( C=H 4,5 ~ )or , N6H ) ~J and bidplatinurn) complexes of type { [ C ~ S - P ~ C ~ ~ ( N H ~ ) I ~ N H ~(n in which each platinum atom is coordinated by one amino group of an alkanediamine.450 In interactions with DNA the intercalator-bearing complex bound covalently with the acridine ring becoming intercalated one or two base pairs distant from the site of binding449 while the bidplatinurn) complexes bound to confer increased resistance to digestion of the DNA by restriction endonucieases compared with that conferred by reaction with cis-DDP.45o The nonamer d(TCTCGTCTC) has been treated with monofunctional platinum compounds {PtCl[NH2(CH2)2NH(CH2)2NH21 }Cl and [PtCl(NH3)3]Clto form the corresponding ~~~ monoadducts and then hybridized to the complementary n ~ n a r n e r .Monoadduction by each drug was found to cause considerable destabilization of the duplex by comparison with the non-adducted hybrid, comparable to that seen with bifunctional platinum compounds, and i t is therefore thought that the principal

300

Organophosphorus Chemistry

distortion and destabilization of DNA structure by bifunctional platinum drugs occurs in the first platination step. The metal ion-coordinating proper ties of tubercidin (7-deazaadenosine) 5'-monophosphate have been compared with those of 5'-AMP and I, @-etheno-5'AMP.452 The stability constants of 1:1 complexes formed between the nucleotides and a range of divalent metal cations were determined, in conditions in which selfassociation is negligible. 7-Deaza-AMP showed stability constants expected for sole coordination of the metal ion to phosphate, while some AMP complexes showed increased stability due to macrochelate formation, being additionally coordinated to N-7 of adenine. The 1, N6-ethenoadenine structure presents a pseudophenanthroline binding site, and 1, N6-etheno-AMP complexes of transition metal dications were strongly stabilized by backbinding of the phosphate-coordinated metal ion to the ethenoadenine moiety. The complexation of nucleotides by Mn2+, Co2+ and Ni2+ ions has been studied polarographically, and in the case of coordination by Ni2+, complexation to base could be distinguished from complexation to ~~~ phosphate by the splitting of polarographic waves in base c ~ m p l e x a t i o n .The interaction of the vanadyl (V02+) ion with nucleotides has been studied spectrophotometrically at pH 4.9, and found to involve only the phosphate group(s), without involvement of the nucleoside moieties.454 At high pH values some interaction with the deprotona ted sugar hydroxy groups in ribonucleotides is observed. A comparative study of the c.d. spectra of Zn*+ complexes of A(5')p4A and a number of its methylene- and substi tuted-methylenephosphonate-containing analogues has been made.455 In the laser Raman spectra of the py-bidentate Cr(II1)ATP and Co(II1) (NH3)4-ATP complexes, the lines corresponding to the phosphate stretching vibrations were broad and intense compared with those in ATP and Mg(I1)-ATP, possibly because the tight binding of Cr3+ and C03+ to the triphosphate chain and not to the base alters the spectroscopic vibrational selectivity.456 The complexation of Mo(V1) and W(V1) to nucleoside 5'-monophosphates in aqueous solution has been studied by 31P n.m.r. spectroscopy, inter alia.457 In the p H range 2 - 4, a single, non-labile complex appears to be formed in each case, possibly a polynuclear structure involving five metal atoms and two nucleotides in which exclusively bidentate participation of the phosphate groups occurs. A correction has been published458 to the structure of a 4, 7-diphenyl-1, 10phenanthroline-derived ligand in a ru thcnium (11) complex described in last year's Report [see structure (193) in ref. 1321. The amendment, involving positional substitution on the phenyl rings, in no way compromises the essential results reported. A series of mixed-ligand complexes of Ru(II), in which the ligands used were 2, 2'-bipyridyl, 1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, 5-nitro-1, 10-phenanthroline, 4, 5-diazafluoren-9-one, and 9,lO-phenanthrenequinonediimine, has been prepared a n d the isotherms and spectroscopic characteristics of binding to DNA were measured.459 All except ruthenium

6: Nuclwtides und Nucleic Acids

30 1

tris(bipyridy1) appeared to intercalate, with strong intercalators exhibiting enantioselectivity, and complexes containing phenanthrenequinonediimine showing particularly strong intercalating activity. While a correlation was observed between hydrophobicity and DNA-binding affinity, the critical factor in determining affinity appeared to be complementarity of shape of the complex to DNA. Tris(4, 7diphenylphenanthro1ine)rhodium (111) binds to duplex DNA near the base of cruciform structures, and, upon irradiation, cleaves both strands.460 The cleavage sites in viral and plasmid DNA molecules map consistently to positions of known cruciform structure, the complex presumably recognizing specific elements of asymmetry associated with the structure. Bis(phenanthro1ine) (9, lo-phenanthrenequin0nediimine)rhodium (111) cleaves double-stranded DNA, upon irradiation, selectively at 5'-Py-Pu-3' steps, particularly d(CCAG) seq~ences.~61 The single site cleavage characteristics suggest that diffusible species are not generated, while the asymmetry of cleavage suggests that cleavage occurs from the major groove of the helix. It is thought that in B-DNA, propellor twisting at 5'-Py-Pu-3' sequences results in steric interference between the cross-strand purine bases in the minor groove, causing the major groove to open and creating a site at which the 9, 10phenanthrenequinonediimine ring of the complex can intercalate without steric hindrance between the neighboring bases and the phenanthroline rings: complementarity of fit dictates the sequence-selective binding and cleavage. Bis(9, 10-phenanthrenequinonediimine)(bipyridy1)rhodium (111) also cleaves DNA in a similar manner but in essentially sequence-neutral fashion, a phenanthrenequinonediimine ring being able to intercalate from the major groove at any sequence, without concomitant steric hindrance to the other ligands. Both rhodium (111) complexes cause the release of bases and formation of 3'- and 5'-phosphate termini at the point of cleavage, suggesting that the sugar is the site of attack. 6 . Analytical Techniaues and Phvsical Methods

A mixture of cetyltrimethylainmonium bromide and ammonium sulphate has been recommended for effecting the quantitative precipitation, free of sugar and protein, of short oligonucleotides which prove refractory to precipitation with ethano1.462 The mixed-mode chromatography of nucleic acids has been reviewed,463 and articles on reversed-phase h.p.1.c. for the purification of synthetic oligodeoxy465 in which column packing of large pore size (150 A) and small ribonucleotides,4~~ particle diameter (5 nm) grafted with monochloroalkylating agents of a long (CIS) alkyl chain was recommended for the large-scale preparation of oligodeoxyribonucleotides up to 50-mer length,464 and on anion-exchange h.p.1.c. directed to the same purpose465t466 have appeared. Anion-exchange h.p.1.c. using hyperbolic sodium chloride concentration gradients for elution permits the separation by chain

302

Orgartophosphorus C h mistry

length of oligoribonucleotides up to 30 residues long: it is claimed that the concentration of sodium chloride required to effect elution can be used to determine chain length.467 Linear gradients permitted separation of oligoribonucleotides of up to decamer length. Reversed-phase h.p.1.c. has been found effective for the In the procedure purification of oligodeoxyribonucleoside methyl-pho~phonates.~6* described, these compounds were initially chromatographed before removal of a 5'-trityl blocking group, to remove failure sequences, and re-chromatographed after detritylation. High performance capillary gel electrophoresis using polyacrylamide gels in narrow-bore (diameter up to 200 pm) fused silica tubing capillaries and high electric fields (typically 400 V cm-*)permits the resolution to baseline of picomole quantities of oligodeoxyribonucleotides [e.g. a (dA)48-60mixture] in less than eight minutes.469 While the quantities which can be applied are necessarily small, microgram quantities of material can be purified in a single run in less than 30 minutes. The resolving power is equivalent to five million plates per metre! The technique appears ideal for the rapid separation of modest quantities of oligonucleotides. In a series of papers Cantor and his colleagues47()and others471 have delineated the methodology for, and parameters affecting, the high-resolution separation and size determination of large DNA molecules using pulsed-field gel electrophoresis. Topics considered inc!ude the generation of size standards using oligomers of bacteriophage DNA, the effects of agarose (resolution improves slightly in small pore gels) and temperature, pulse time, electric field strength and electrode configuration, and the influence of DNA topology on separation. The effects of the same parameters on the mobility in agarose gels of DNA molecules during field inversion gel electrophoresis (FIGE) have been determined, and its use in the Pulsed homoanalysis and mapping of vaccinia virus DNA dem0nstrated.4~~ geneous orthogonal field gel electrophoresis (PHOGE) has also been described, as a technique capable of resolving DNA molecules of megabase-pair size.473 The resolution seen with orthogonal field alternation gel electrophoresis (OFAGE) probably combines the separatory mechanisms utilized in FIGE and PHOGE systems. In zone-interference gel electrophoresis, the migration of a macromolecular complex in rapid dynamic equilibrium is measured as a function of the interacting ligand concentration in a surrounding The technique affords a rapid method for determining the dissociation constant of the complex, and has been used to study weak complexes formed between proteins and nucleic acids. Recommendations for the definitions and nomenclature of nucleic acid structural parameters, arising from discussions at an EMBO Workshop on DNA Curvature and Bending, have been published.475 While this chapter generally omits report of X-ray diffraction studies of nucleotides and oligo- and polynucleotides, the disclosure of the cocrystal structure of an editing complex of Klenow fragment with DNA demands mention for the fascinating insights it affords

6: Nuclrotides and Nucleic Acids

303

into the strand separation of duplex DNA by the protein and the likely catalytic mechanism of phosphodiester hydrolysis in the exonuclease reacti0n.~~6 Applications of two-dimensional n.m.r. spectroscopy in determining the conformations of nucleic acids in solution have been reviewed.477 3IP-N.m.r. spectroscopy has been applied to determine the 'visibility' or otherwise of adenine nucleotides in rat liver m i t o ~ h o n d r i a ~- ~the 8 suggestion that organelle compartmentation could compromise the n.m.r. visibility of nucleotides was reported last year.132 It transpired that intra- and extramitochondrial nucleotides could be differentiated by addition of the chelator trans-1 , 2-diaminocyclohexane-N, N, N', N'-tetraacetic acid, and TI relaxation time values for magnesium-bound matrix nucleotides were determined, together with factors (temperature, ionic strength, presence/absence of Mg2+) affecting Ti values. Mi tochondrial ATP is n.m.r.-visible in isolated mitochondria in vitro, and can be quantitated, giving values in good agreement with those determined biochemically, but matrix ADP, while detectable, is not easy to quantitate. The influence of sulphate ions (used to promote crystallization) and pH on the attachment of ATP to its two binding sites on yeast 3-phosphoglycerate kinase, and the affinity of magnesium ions for the bound ATP ~ 9 chemical shifts of molecules, have been examined by 3IP n.m.r. ~ p e c t r o s c o p y . ~The bound ATP and ADP proved independent of pH in the range 6.4 - 9.0, suggesting that the nucleotides are well sequestered from the bulk solution. Measurements of the effects of paramagnetic nuclei Mn2+ and Co2+ on spin relaxation rates of the 31P nuclei of bound ADP and ATP were also made: the relaxation rates in the Enzyme. Mn2+. nucleotide complexes were exchange-limited, affording no structural information, but those in the corresponding cobalt complexes were not, yielding distances between the cobalt and phosphorus nuclei commensurate with direct coordination between Co2+ and the phosphate groups.480 Comparable studies have been performed on complexes of pig muscle adenylate kinase with ATP, GTP, GDP and AMP in the presence of Co2+and Mn2+i0ns.~8' Again, results with Co2+ gave structural data indicating direct coordination of the metal ion to Pp and P, of ATP and GTP, and to Pp of GDP, in the enzyme complexes. 31P N.m.r. magnetization transfer measurements have been made to determine the flux between ATP and orthophosphate during steady-state isometric muscle contraction of the rat hind limb,482and in reactions catalyzed by phosphoglycerate kinase and glyceraldehyde-3phosphate dehydrogenase in anaerobic yeast cells.483 The origins of sequence-specific variations in the 31P n.m.r. chemical shifts of the internucleotidic links in DNA have been investigated using shift/sequence data obtained for a number of oligodeoxyribonucleotide duplexes, in which signals were assigned using 2-D n.m.r. or by site-specific labelling of the phosphate groups with oxygen-17.484 In duplex B-DNA, the shifts correlate fairly well with some aspects of the Dickerson-Calladine sum function for variation in the helical twist of the oligomers. The 31P shift perturbations appear predominantly dependent on changes

304

Orgunoph osp h orus Chemistty

in the P-0 and C - 0 backbone torsional angles consequent on variation in the local helical structure, and both 31P chemical shifts and J ~ 3 l - pcoupling constants suggest that the variations in backbone torsional angles can be greater at the end of the duplex than in the centre. Since the helical structure shows a degree of sequencespecific variation, the 3IP chemical shift is dependent on both sequence and position within a duplex. Homo- and heteronuclear 2 0 n.m.r. and also 3IP n.m.r. spectroscopy have been used to determine conformation and conformational transitions in 13-mer oligodeoxyribonucleotide duplexes which were complementary except for a deoxycytidine485 or deoxyadenosine486 'bulge' (i.e. opposing unpaired C or A bases) site in each strand. The extra cytosine bases equilibrated between looped-out conformations at low temperature and stacked conformations at higher temperature?85 while the extra adenosine stacked (below the melting temperature) with the flanking base pair to form a wedge-like insert.486 In each case significant perturbation in the phosphodiester backbone was also found to occur in regions external to the bulge site. In conformational studies on abasic sites in DNA duplexes, the duplexes d(CATGAGTAC). d(GTACXCATG)(where X is the abasic site, either an acylic 1, 3-propanyl or 1, 2-ethanyl link in place of the nucleoside) have been investigated using 'H and 3'P n.m.r. spectroscopy, and the deoxyadenosine moiety opposite the abasic lesion found to stack into the helix in each case.487 The perturbation in conformation of the phosphodiester backbone torsion angles neighbouring the abasic sites varied somewhat from those in a similar duplex with a furan ring as the abasic site. In the duplex d(CGCACGC>.d(GCGDGCG),in which D is a natural abasic site, i.e. a 2-deoxyribose moiety, the aldehydic carbon of the sugar has been labelled with oxygen-17 either by dissolving the duplex in I70-enriched water, or by removal of uracil from d(GCGUGCG) using uracil-DNA glycosylase in [170]-water followed by annealing to the complementary strand in the same solvent.488 Both methods gave identical 1 7 0 n.m.r. spectra, in which the aldehydic oxygen signal had about 1 % of the intensity of the signals due to the hydroxyl oxygens of the hemiacetal diastereoisomers. This figure suggests that the aldehyde content of the abasic site of the duplex is little affected by its geometry: the lessened reactivity of abasic sites in double stranded DNA relative to single-stranded DNA is probably due to steric restriction to access by base to the acidic protons lying a to the aldehydic group. Conformational changes in the phosphate-sugar backbones of calf thymus DNA and in poly(rA).poly(rU), upon intercalation by ethidium, quinacrine, and daunomycin, have been monitored using 31P n.m.r. spectroscopy.489 Perturbation due to intercalation results in gradual downfield shift of the 31P signals in DNA, and in the appearance of a new downfield signal in the RNA duplex. Multinuclear studies, including 3IP n.m.r., of a number of oligodeoxyribonucleotide sequences forming hairpin structures, have shown that unusual phosphate torsion angles may be found in the stem, as dictated by the loop ~equence.~90 Atypical phosphate shifts may occur up- or downfield. Also, the stacking arrangement in the

6: Nuc1rotidr.s wid Nucleic .4cids

305

loop depends on the last (i.e. nearest) base pair in the stem: evidently loop conformation and dynamics are sensitive to small changes in loop and adjacent stem sequences. N.m.r. ('H and 31P) and c.d. studies of the hairpin-loop-forming sequence d[(CG)5Td(CG)5]indicate a B-helical stem at low salt concentration with the 2'-deoxythymidine sugars mainly in 2'-cndo conformation, and a Z-helical stem in high salt, with the 2'-deoxythymidine sugars biased towards 3'-endo conformation.491 A spin-labelled 2-deoxythymidiiic analogue has been incorporated, via chemical synthesis employing (235), at a central position in oligo(dT); into the stem sequence and the central loop position of an oligodeoxyribonucleotidecontaining a (dT)5 hairpin loop; and into a self-complementary concatenated sequence.492 The e.p.r. spectra obtained from the probe in its different molecular environments were characteristic in line shape and/or correlation time, with restriction of local motion giving lower correlation times, and may thus be useful as 'dynamic signatures' of DNA structures. Circular dichroism (c.d.1 spectroscopy indicates that the hexamminecobalt (111) complex effects a &DNA-+ Z-DNA+ Y-DNA conformational transition in poly[d(G-C)l and poly[d(G-msC)].493 The Y-DNA form is characterized by an unusual c.d. spectrum (high positive ellipticity at 225 - 300 nm and complete absence of negative ellipticity) and appears, from its being recognized by an anti-Z-DNA antibody, to have a left-handed Z-DNA-like conformation. In laser Raman spectroscopic analysis of crystals of d[(CG)3] and d(CGCGTG) (which form Z-DNA duplexes, the latter containing G.T mismatches) the Raman bands corresponding to phosphodiester group vibrations and known to be sensitive to DNA backbone conformation were similar for both compounds, showing that the G.T mismatches d o not significantly perturb the Z-DNA backbone.494 In solution, the Raman bands of both hexamers resemble those of B-DNA, but normal phosphodiester geometry appears to obtain for only six of the ter. phosphodiester groups in the G.T mismatch hexamer duplex, the remaining four (thought to be near the mismatch site) having apparently modified geometry and giving rise to an extra band. Resonance Raman spectroscopy has been used to investigate the interactions of the Cu2+,Ni2+ and C$+ complexes of tetrakis(4-N-methylpyridy1)porpyhrin4+ with poly[d(G-C)l, poly[d(A-T)] and calf thymus and salmon DNA.495 The Cu2+ and Ni2+ complexes were known to intercalate at G-C sites, and bands originating in the N-methylpyridinium groups were found to show small shifts due to coulombic interaction with the negatively charged phosphodiesters of the nucleic acids. By covalent attachment of fluorescein (as donor) and rhodamine (as acceptor) to the 5'-termini of complementary oligodcoxyribonucleotides, hybridization can be measured by non-radiative fluorescence resonance energy transfer (FRET) from fluorescein to rhodamine: as hybridization occurs, the emission intensity of fluorescein falls while that of rhodamine rises.496 Correction must be made for

306

Organophosphorus Chemistry

substantial quenching in fluorescein emission intensity by the unlabelled complementary strand. The transfer efficiency of FRET at 50 C in this system decreases rapidly with increasing oligonucleotide length (from 50 % for 8-mers to 4 % for 16-mers, or the inverse sixth power of the interchromophoric distance, assuming double-helical DNA), and its use for studying hybridization of longer oligomers thus appears limited. However, it can be used to study hybridization of two labelled oligomers to a single unlabelled complementary strand (the labelled 3'- and 5'-termini of the oligomers were four bases apart) and to study intercalation (using acridine orange as intercalator/donor to a rhodamine acceptor) and may prove useful in studying the kinetics of hybridization in matched yersus mismatched strands, for instance. Guanosine and deoxyguanosine nucleotides can conveniently be detected fluorimetrically following reaction with phenylglyoxal at pH 4.0.497 The other common nucleotides do not react to form fluorophores under the same conditions. The detection limit of guanosine nucleotides is in the range of 0.1 nmol m1-1. Continuous flow FAB-m.s. spectra of 5'-GMP, 5'-AMP and 5'-IMP and variously their alkali metal, alkaline earth and transition metal complexes have 9 ~ parent molecular been obtained using low concentration of matrix in ~ a t e r . ~Both ions and characteristic fragmentations patterns were observed for all compounds, and it may prove possible to identify the likely binding sites of the metal ions on the nucleotides from the fragment ion patterns. Using FAB-tandem m.s., massanalyzed ion kinetic energy spectra of dfTpU) and d(UpT) indicated that the 5'-pyrimidine base was characteristically eliminated first, and consistent results were This preferred also obtained with d(CpT) and 5'-Q-dimetho~ytrityl-[d(Tp(S)U)I.~~9 cleavage of the 5'-glycosidic bond in principle offers a method for sequencing pyrimidine dideoxynucleosidyl phosphates. When the fully-protected deoxynucleoside 3'-S-methyl-Q-Z, 4-dichlorophenylphosphorothioates(236) are exposed to 9.5 KeV xenon bombardment in liquid matrices during FAB-m.s., selective removal of the protecting groups occurs.500 Matrix-substrate interaction in the energized condensed phase (glycerol or 3-aminopropane-1, 2-diol matrix) promotes solvolytic removal of the 2, 4-dichlorophenyl group giving S-methylphosphorothioatediesters which, on desorption into the gas phase, give identical metastable ion kinetic energy spectra in the negative ion mode to those obtained from the triethylammonium salts of (236). If 3-mercaptopropane-1, 2-diol is present in the solvation sphere of (236) in the condensed phase, competitive demethylation can also occur. In the positive ion mode, selective loss of the pixy1 or dimethoxytrityl cations occurs from (236). These observations afford a timely reminder that the matrices used for FAB-m.s. are by no means chemically inert in the experimental conditions employed, and may offer food for thought (or rationalization) if one's attempted FAB-m.s. characterization of intermediates in oligonucleotide synthesis elicits results other than those anticipated!

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32 1

6: Nuclmides urid Nucleic. A c i h 469. 470. 471. 472. 473. 474. 475. 476. 477. 478. 479. 480. 481. 482. 483. 484. 485. 486. 487. 488. 489. 490. 491. 492.

A S . Cohen, D.R. Najarian, A. 1’~1ulus, A. Guttmann, J.A. Smith, and B.L. Karger, Proc. Natl. Acad. Sci. USA, 1988,85,9660. M.K. Mathew, C.L. Smith, and C.R. Cantor, Biochemistrv, 1988, ?7,9204; idem, 1988,27,9210; C.R. Cantor, A. Gaal, and C.L. Smith, 1988,27, 1988,27, 9222. 9216; M.K. Mathew, C.-F. Ilui, C.L. Smith, a n d C.R. Cantor, B.W. Birren, E. Lai, S.M. Clark, L. I-Iood, and M.I. Simon, Nucleic Acids Res., 1988,16.7563. C.J. Bostock, Nucleic Acids R c s , 1988, Ih,4239. I. Bancroft and C.P. Wolk, Nucleic Acids Res., 1 9 8 8 , s 7405. J.P. Abrahams, B. Kraal, and L. Bosch, Nucleic Acids Res., 1988,16, 10099. R.E. Dickerson Nucleic Acids Res., 1989,17, 1797. P.S. Freemont, J.M. Friedman, L.S. Beese, M.R. Sanderson, and T.A. Steitz, Proc. Natl. Acad. Sci. USA, 1988,135, 8924. R.V. Hosur, G. Govil, and H.T. Miles, M a m . Reson. Chem., 1988, 26, 927. S.M. Hutson, D. Berkich, G.D. Williams, K.F. LaNoue, and R.W. Briggs, Biochemistrv, 1989,28, 4325. B.D. Ray and B.D.N. Rao, Biochemistry, 1988, 27, 5574. B.D. Ray and B.D.N. Rao, Biocliemistrv, 1988,27, 5579. B.D. Ray, P. Rosch, and U.D.N. Rno, 13iochemistrv, 1988,27, 8669. K.M. Brindle, M.J. Blackledge, R.A.J. Challiss, and G.K. Radda, Biochemistrv, 1989, 4887. K.M. Brindle, Biochemistrv, 1988,27, 6.187. D.G. Gorenstein, S.A. Schroccler, J.M. Fu, J.T. Metz, V. Roongta, and C.R. Jones, Biochemistrv, 1988,27, 7223. M.W. Kalnik, D.G. Norman, M.G. Zagorski, P.F. Swann, and D.J. Patel, Biochemistrv, 1989,28, 294. M.W. Kalnik, D.G. Norman, P.F. Sivann, and D.J. Patel, J. Biol. Chem., 1989, 3702. M.W. Kalnik, C.-N. Chang, F. Johnson, A.1’. Grollman, and D.J. Patel, Biochemistrv, 1989,28, 3373. J.A. Wilde, P.H. Bolton, A. Mazumder, M. Manoharan, and J.A. Gerlt, I. Am. Chem. SOC.,1989,lTJ 1894. D.G. Gorenstein and K. Lai, ~iochemistrv,1989, 28, 2804. J.R. Williamson and S.G. Boxer, Giochcmistrv, 1989, 28, 2819, 2831. S.K. Wolk, C.C. Hardin, M.W. Germann, J.H. van de Sande, and I. Tinoco Jr., Biochemistrv, 1988,27, 6960. A. Spaltenstein, B.H. Robinson, and P.G. Hopkins, J. Am. Chem. SOC.,1989, 111,2303. T.J. Thomas and T. Thomas, Nucleic Acids Res., 1989,17, 3795. J.M. Benevides, A.H.-J. Wang, G.A. van der Marel, J.H. van Boom, and G.J. Thomas Jr., Biochemistry, 1989, 28, 304. J.H. Schneider, J. Odo, and K. Nal
m.,

m.,

a

_____

493. 494. 495. 496. 497. 498. 499.

500.

m., u.,

a

7 YIides and Related Compounds BY B. J. WALKER

1

Introduction

Important publications on the mechanism of the Wittig reaction continue to appear. An understanding of most facets of the mechanism has probably now been achieved and a substantive review of all aspects of the Wittig reaction has appeared.10 Developments in synthetic methods include the use of ylide-anions (both carbon and nitr0:Cl.n) as alternatives to ylides in synthesis.

2 MethvleneDhosphoraneS 2.1 Prepuation and Structure,- Another ab initio M.O. study of a range of simple phosphorus ylides (1) has been reported.1 Comparisons are made with analogous nitrogen compounds and charge distributions, P-C rotational barriers, and bonding parameters are extensively analysed. The bonding in the diphosphacyclobutadienes ( 2 ) and (3) has been investigated by photoelectron spectroscopy and the spectra obtained interpreted on the basis of SCF-MO calculations.2 The EI and CI mass spectra of a large number of fluorinated phosphorus and arsenic ylides (e.g. 4) have been reported.3 A variety of ylides (e.g. 5) of arsenic, antimony and bismuth have the reaction of diazo compounds been prepared under mild conditions &v with the appropriate three valent ~ r g a n o m e t a l l o i d . ~ Schmidbaur's group continues to produce new ylide structures, for example ( 6 ) . 5 The lithiated ( 8 ) has been prepared directly from the parent aza-ylide aminophosphonium salt (7) by treatment with two molar equivalents of butyllithium.6 Reactions of (8) with alkyl or acyl halides give the corresponding substituted aminophosphonium salts and hence provide a new Phosphorus compounds ( 9 ) synthesis of primary amines (Scheme 1). containing a linear P-B bond chain have been synthesised.7 2.2 Reactions of MethvlenephosDhoraneS 2 2 . 1 Aid.- The reactions of phosphorus ylides, PO-activated carbanions and iminophosphoranes have been incorporated into CAMEO, an interactive computer program for the mechanistic evaluation of organic reac tions.8 The chemistry and synthetic applications of phosphorus and arsenic ylides and PO-stabilised carbanions have been reviewed.9

323

7: Hides and Related Compounds

Ph2P\ CH2-C

Ph3 X =C ( SO 2 Ph ) 2

,PPh2

\\

PMePh2

( 5 ) X = As, Sb, Bi

Ph3$-NH2B;

-

(6 1

ii

Ph3P=NLi

(8)

(7) Reagents : i , 2 x BunL i , THF

;

ii, excess RX

Scheme 1

Me

Ph

I+ -

Me -P

I

1

-BH2

Me

9

I+

-

Ph \

-,( - BH2)"Ph

(9) n = 0 , 1 , 2

I+ P-BH3 I

Ph

Ph36-NHR

X-

324

Organophosphorus Chemistry

Maryanoff and Reitz have published a monumentous review of the current views on all aspects of the Wittig and related reactions.1 0 Maryanoff's most recent results derive from a detailed n.m.r. rate study of the reaction of 2,2-dimethylpropanal with tributylbutylidenephosphorane.1 1 At -55OC oxaphosphetanes ( 1 0 ) and (11) are formed but little or no decomposition to alkene takes place. At this temperature "stereochemical drift" from cis-(10) to t r a n s - ( l l ) oxaphosphetane occurs. In a similar experiment at -15OC no cis-oxaphosphetane can be observed and decomposition of this intermediate to trans-alkene (presumably via initial "stereochemical drift") readily takes place. These results indicate that ''stereochemical drift" (presumably via a reverse Wittig reaction) occurs much more rapidly than collapse to alkene. The sensitivity of this process to substrate structure is indicated by the absence of significant "stereochemical drift" in similar reactions with secondary aldehydes. Vedejs and his coworkers have published a number of significant papers. One report extends the evidence that reversibility plays a much smaller role in determining olefin stereochemistry than had been previously assumed.12 The Wittig reactions of the ethylidene ylides (12 to 15) with aliphatic aldehydes have been studied both directly and by independently generating the oxaphosphetane intermediates in each case. In all but one case (that of cis-oxaphosphetane (16)) the oxaphosphetane intermediates decompose with no detectable reversal or loss of stereospecificity. Except for (16), in all the cases studied the stereochemistry of alkene appears to be under kinetic control, even when the (E)-alkene is the preferred product. Another report is a comprehensive assessment of the role of P-substituents in controlling As might be expected it is stereochemistry in the Wittig reaction.13 conclusive and a model of clarity in spite of having to deal with a topic which has been the subject of many, and often contradictory, publications by other authors. The way in which the interplay of 1,2- and 1,3-steric interactions in the transition state for reactive ylides determines which diastereomeric oxaphosphetane will be favoured, and how this arises from the unusual circumstance (in organic chemistry) of having a rigid sp3 hybridised reacting centre, is clearly explained. Models for Wittig reactions of semi-stabilised ylides (early transition state with distorted square planar phosphorus) and stabilised ylides (very late transition state with oxaphosphetane-like interactions) are described. In addition the paper contains a very useful list of mechanistic generalisations for the Wittig reaction. Finally Vedejs has provided, from a 13C n.m.r. study, the first direct evidence that the oxaphosphetane structure ( 1 7 ) is preferred over the alternative ( 1 8 ) . 1 4 The implications of this for the Wittig reaction mechanism are discussed.

325

7: Ylides and Related Compounds

Et

I

E*.

P=CHMe

**

Et' (12) R' = R 2= Et (13) R ' =Ph,R2=Et (14) R' = R 2 =Ph

RCH=CHCH2SiMe3

+

RCH-CH=CH2

I

(20)

+

Ph3PCH2 I

N a N ( TMS12

I-

c

THF

Ph, P =C H I (22)

O,CH20Me

r-f

P-0

I

326

Organophosphorus Chemistiy

The stereochemistry of the olefination of aldehydes with allylic phosphonium ylides has been investigated and methods have been developed for highly stereoselective synthesis of both ( E ) - and (Z) alkenes.15 The results are explained on the basis of Vedejs' recently proposed model. The use of tri(2-methylpheny1)phosphonium ylide (19), rather than the triphenyl analogue, in reactions with aldehydes has been shown to give much greater (Z)-selectivity in the formation of (20).16 By careful choice of reaction conditions the extent of formation of the normally unwanted product ( 2 1 ) can also be substantially reduced. ( Z ) - 1 - I o d o - l alkenes have been prepared stereoselectively and in good yield by the Wittig reaction of iodomethylene ylide (22) under salt-free conditions.17 Similar reactions of the corresponding chloro- and bromomethylene ylides A comparison of the stereochemistry of the show poor stereoselectivity. stilbenes ( 2 3 ) , formed by Wittig reactions of 4-substituted benzylidene ylides with O-protected salicylaldehyde, with that of the same stilbenes obtained by the alternative Wittig reaction of 2-alkoxybenzylidene ylides has shown the variation to be relatively small.18 A study comparing, under a range of conditions, diene synthesis by the two alternative Wittig routes, allylic ylide-saturated aldehyde (route 1) and reactive ylide-a,P-unsaturated aldehyde (route 2), has been reported.19 For the system chosen (Scheme 2 ) the reactive ylide-a,P-unsaturated aldehyde route is clearly preferred in that the stereochemistry of the new double bond can be controlled more easily and there is little or no isomerisation of the double bond already present in the aldehyde. A route to symmetrically substituted polyenes containing an odd or even number of double bonds has been reported (Scheme 3).20 The Wittig reactions of ylides derived from treatment of cycloalkylidenemethyltriphenylphosphonium salts (24) with butyllithium have been reported.21 The products of these reactions were allenes (25) and alkenylcyclohexenes (26) depending on the nature of ( 2 4 ) and the ratio of base to salt used. The ylide (27) has been successfully used as an equivalent of the P-acylvinyl anion ( 3 0 ) to prepare a variety of substituted enones, e.g. ( 2 8 ) and ( 2 9 ) , via both Wittig reactions and additions to activated alkenes (Scheme 4).22 Mono- or di-olefination of 2,5furandicarbaldehyde (31) is possible through the Wittig reaction by simple 3-Ethoxycarbonyl-2-aza-l,3modification of the molar ratio of reagents.23 dienes (33) and the carboxyimide (34) have been prepared by the Wittigtype reactions of the phospha-h5-azenes (32) with aldehydes and phenyl isocyanate, respectively.24 Sat0 has reported a new route to allylic sulphides through the reaction of a -sulphenyl aldehydes (35) with phosphonium ylides or phosphonate carbanions.25 Similar reactions have been used to achieve a two-carbon

7: Ylides and Related Compounds

321

+

Ph,P=CH(CH,),OH

( € 1 - MeCH,CH=CHCHO

(Route 1 )

Ph3P=CH CH=CH CH2 Me

+

HO(CH2 16 CHO

( Route 2 )

M~CH~(CH=CH)~(CHZ)~OH Scheme 2

2 R(CH=CH),CHO

+

+

+

BU~PCH~(CH=CH), C H ~ P B U ~ 2 Br-

R ( C H=C H)2r+y

Reagents : i , NaOMe or KOBut, EtOH or

D M F , 50

-

Scheme 3

100 'C

328

Orguiioph osl)h orus Chemistry

n w =C =C

(C

(25)

i , Bu"Li

OSiMe2 But

HR

+

i , ii

h , P h 3

&R

\ iii. ii

OH

0

Reagents : i. RCHO

;

ii. Bun4NF; iii.

!I RCHO. Me3SiOSCF3 0

Scheme 4

329

7: Ylides and Related Cornpourids

EtOzC,

O H C G C H O R'

PPh3

EtOzC

>".,

R'

\\

NPh

(33)

R',

(34)

,SPh

P h3P =C X Y

C R'

SPh X

or

(Et012P(0)CLi X Y

'CHO

(35)

MeOCH2SPh

-

R

R

1

CHO

SPh iii,iv

- qx V

R

R

0

\

0

Reagents: i , RCHO; i i , McS02C1, E t 3 N ; i i i , Ph3P=CR'COX

i v , ButOK; v . CF3C02HnH20.CH2CI2

Scheme 5

0 II -

or (EtOIZPCR'COX;

330

Organophosphorus Chemistry

elongation as part of a three-carbon elongation method to synthesise various y-keto carbonyl derivatives (Scheme 5).26 The products and stereochemistry of the Wittig reaction of benzylidenetriphenylarsorane with benzaldehyde and ethanal have been studied by IH n.m.r. both in the presence of lithium salts and under salt-free condi tions.27 Olefination of aldehydes with the arsonium ylide generated i n situ from the arsonium salt (36) provides a highly stereoselective synthesis of conjugated, unsaturated isobutylamides (37) in good to excellent yield.2 The method was used to synthesise the naturally occurring insecticide pellitorine (37, R=CH3( CH2)4, n=l). A novel tri-n-butylarsine-catalysed olefination reaction has been used to synthesise a range of a,P-unsaturated esters and ketones in good yield (Scheme 6).29 It is suggested that the reaction proceeds a Wittig reaction of an intermediate arsonium ylide and that the arsine is regenerated through deoxygenation by the phosphite present. Reactions of arsonium ylides with carbonyl compounds can provide alkenes or epoxides depending mainly on the nature of the ylide. Predominantly (E)-2,3-epoxy-3-arylpropanols (38) have been prepared in excellent yield by the reaction of 2-hydroxyethyltriphenylarsonium bromide with aromatic aldehydes under phase transfer conditions using solid (3,3- D i i s o p r o p o x y p r o p y l ) potassium hydroxide as the base.30 triphenylarsonium ylide (39) can be considered as a P-formylvinyl anion (41) equivalent. The ylide (39) has been prepared and, through its reaction with aldehydes, used in this way to prepare a variety of y - h y d r o x y - e n a l s (40) (Scheme 7).31 2J.2 K e t o n e s . - A 3 1 P n.m.r.-based kinetic investigation of the Wittig reaction of isopropylidenetriphenylphosphorane with benzophenone provides the first example where both formation and decomposition of the oxaphosphetane intermediate can be monitored in the same reaction.3 2 Base treatment of the salt (42) gives cis- and trans-bicyclo[5.2.0]non2-enes (43) rather than the bridgehead alkenes which would be the product A new synthesis of 4of a simple intramolecular Wittig reaction.33 substituted vinyl glycines (46) in moderate to excellent yield is provided by olefination reactions involving the previously unreported oxime-stabilised ylide ( 4 4 ) or the analogous phosphonate anion ( 4 5 ) (Scheme 8).34 The reactions of acenaphthylene-l,2-quinone monoxime (47) with esterstabilised and keto-stabilised phosphonium ylides have been investigated and low yields of Wittig products obtained (Scheme 9).35 A new method for the benzannelation of indoles relies on a Wittig reaction of (48) to construct the carbon skeleton.36 The reactions of phosphaallene ylides ( 4 9 ) with a diketones and 1,2-hydroxyketones have been used to synthesise 5 alkylidene-2(5H)-furanones (50) and 2(5H)-furanones (51), respectively.37

*

7: Ylides and Related Compounds

R(CH=CH),,CHO

RCHO

+

+

BrCH2X

33 1

KZC03

t

Ph3AsCH2CONHBui Br-

+

(Ph0)3P

.CH$N -L-c

-

R(CH=CH),+,CONHBU'

RCH=CHX

+

(PhO)3P(O)

Reagents : i , Bun3As(catalyst),K2C03, THF.CH3CN. r.t.

Scheme 6

ArCHO

+

Ph3dsCH2CHzOH 6r-

THF, H20

ArCH-,CHCH20H \ 0

(38)

R e a g e n t s : i I R C H O ; ii, T F A , C H C l 3 ; iii, E t 3 N 4 E t 2 0

Scheme 7

332

Organophosphoms Chem istly

u

cro;

R'n C 0 2 Me

__c

x + f T QNOMe Me

NH2

(46)

(44)X=Ph36

(45 X = (MeO)?P(0) R e a g e n t s : i , R'R'CO;

ii. Z n . HCOZH

Scheme 8

(47)

1

iii

\

Reagents : i , Ph3P=CHC02Me; ii, Ph3P=CHCOMe

;

iii,

0:

CH=PP CH=PP h3 h3

Scheme 9

7: Hides and Related Compounds

+

333

/

Ac

Me

Ac

Ph

(49)

(50)

R3

R3

R’2 P = C R 2 R 3

I X

-k

R4COCH2R5

R4

X=F

F

(52) (53)

334

Orgut i ophosphorus Clit w i isriy

There have been a number of reports of the synthesis and Wittig reactions of P-halogenoylides (52).38339 The P-fluoroylides (52; X=F) react with aldehydes and ketones to give isolable 2-fluorooxaphosphetanes (53).39 Heating ( 5 3 ) leads to the formation of allyl-(54) or vinyl-(55) phosphonates depending on the nature of the substituents on the ylide and carbonyl compounds. The reactions and synthetic potential of ylide-anions (56) continue to be investigated, with differing results in some cases. What is not in doubt is the increased nucleophilic reactivity of these reagents compared to that of the corresponding ylides. Cristau's group has shown40 that the ylide anion ( 5 7 , R=H) gives alkenes in excellent yields on reaction with the sterically hindered fenchone and ditertiarybutylketone, whereas the parent ylide ( 5 6, R = H ) is unreactive. However, the ylide-anion (57, R=COPh), derived from a keto-stabilised ylide, is generally unreactive even to aldehydes. This last result is in conflict with another report that ylide-anions ( 5 8 ) derived from stabilised ylides react readily with aldehydes and even ketones to give high yields of alkenes.41 Ylide-anions are especially advantageous in reactions with ketones (where stabilised ylides often give no reaction or low yields) and can be used even when the ketone is enolisable (see Reference 42). Stabilised ylides (59), carrying only two phenyl substituents on phosphorus, have been shown to be much more reactive in Wittig reactions than similar ylides (60) derived from triphenylphosphine, although still somewhat less reactive than the ylide-anions ( 5 8 ) . The ylide-anions ( 5 7 , R=H) also react with esters and amides to give Wittig products, although the yields of alkene are often reduced by acylation (Scheme 10) and other competing reacti0ns.~3 Enolisable carbonyl compounds do not form alkenes, although in these cases the acylation reaction takes place in the presence of excess ylide. This may have some bearing on the apparently contradictory resuIts4l 142 concerning whether or not enolisable ketones and aldehydes react with ylide-anions to 2-Hydroxyalkyldiphenylphosphine phenylimides (62) and form alkenes. oxides (63) have been prepared diastereoselectively by the reaction of ametallated phosphine imides (61) with a l d e h ~ d e s . 4 ~ 3 Ylides Coor-ed to MeThe "phospha-Wittig" reaction has been reported for the first time.45 The phosphonate-stabilised phosphide (65) (prepared by base treatment of the tungsten complex (64)) reacts with carbonyl compounds to give phosphaallene complexes (66). 4 M i s c u e o u s ReactioOxygen v e r ~ ucarbon ~ alkylation of j3oxido arsenic and phosphorus ylides by alkyl halides has been ~ t u d i e d . ~ 6As might be expected alkyl substituents on the ylide carbon severely inhibit Calkylation. An n.m.r. study of the acylation of the stabilised ylide (67) at low temperature has yielded surprising results.47 The 0-acylated salt (6 8)

7: Yliu'es and Related Compounds

/.

335

CHX

Ph2P ; -

\\

Li+

CHX

(58) X

COMe, C02Me, CN

(59)

(60)

+ /CH3 Ph2 p,

0 II

X-

CH2COR

RCY

0 Ph2PMe

+

/R H2C=C, Me

R = Ph,PhCH=CH X = OEt, NMe2 Reagents: i , 2 h , - 5 5 * C i 1 3 h .

+

2 1 O C ;

ii,HX.H20

Scheme 10

NPh M+ II ,PPh2

RCH

yii

RIS/PPh2 -A

H R'

OH

( 6 2 ) X=NPh (63) X=O

.

336

Organophosphorus C/i(miistry

0

11 H (Et 0)2P-P-R I

(64)

(66 1

(65)

-

Me

I

Ph3P=CC02Et

+

0

R%OCI

II

Me \

-10 'C

/

c=c

\

'Ph;

(67)

OCR2 CL-

OEt

(68)

Me + I Ph 3P-C-CO2Et

+

/

2 Et3N

Ph3PCH2 R' X -

I

CORZ CI-

Ph3P=C, COR'

R'COZ

( 70)

5.u3 -

R

(71)

(73)

-

CI

I

ii i

Bu3P=C(COPh)'

Reagents

i.

+ co,

&R

, M e 3 S i C L , l50.C.

t PhC=CHCOPh

PhCECCOPh

4 0 h ; ii.

0 (72)

@: Ph

(741

Scheme 11

; iii. M e 3 S i C l ,150'C

is initially formed and this rearranges to the C-acylated product ( 6 9 ) at room temperature. Acylation of phosphoranes carrying a -hydrogen atoms gives the acylated ylide but only with a maximum yield of 50% due to transylidation. This problem has now been overcome for stabilised ylides by treating the corresponding phosphonium salt (70) with acylating agent in the presence of two molar equivalent of base; excellent yields of the synthetically useful P-ketomethylenetriphenylphosphoranes are ~ b t a i n e d8. ~ Prolonged heating of the P-keto phosphorane (71) in a sealed tube with the trapping agents ( 7 2 ) and ( 7 4 ) gives low yields of ( 7 3 ) and ( 7 5 ) , respectively (Scheme 11).49 The results lead the authors to suggest that cycloalkynones (76) are intermediates in the reaction. This was supported by the formation of (78) in high yield on heating the phosphorane (77) in the absence of trapping agents. New syntheses of the 2,2'-biindolyls ( 7 9 ) , 1,2-diindoIylethenes ( 8 0 ) , 1,2-dibenzofurylethene (81) (Scheme l2)50 and 2-alkenylindoles5 from intra- and intermolecular Wittig reactions have been reported. The regioselectivity of the Wittig-type reaction of methoxycarbonylmethylenetriphenylphosphorane with a number of symmetrically substituted maleic anhydrides has been investigated.52 In the case of methoxy substituents the carbonyl group adjacent to the methoxy group is exclusively attacked to give (82). The reactions of reactive, semi-stabilised and stabilised ylides with 5(4H)-oxazolones (83) give a range of products including methyleneoxazoles ( 8 4 ) , 5-oxazole acetates ( 8 5 ) and ylides ( 8 6 ) , depending on the nature of the 5(4H)-oxazolone and the ylide.53 A new route to protected a-aminoacids involving the reaction of phosphonium ylides with N-(diphenylmethy1ene)oxamate esters has been reported (Scheme 13) and used to prepare a range of examples.54 A similar procedure involving the reaction of oxamic esters ( 8 7 ) derived from aminonitriles provides a route to protected dehydrodipetides (88) (Scheme 14).55 The hydrazones ( 8 9 ) have been obtained in good yields by the reaction of methoxycarbonylmethylene ylides with conjugated azoalkanes.5 6 A simple, general one-pot synthesis of halo enol lactones (92) is available from bromination of the ylides (90), presumably via the 1-bromo derivative ( 9 1 ) .57 A one-pot, stereospecific synthesis of the t r a n s - f l u o r o v i n y l i c epoxides (93) has been achieved in remarkably good yield by the reaction of isopropylidene ylide with, consecutively, trifluoroacetic anhydride, methylenetriphenylarsorane and an aldehyde (Scheme 15).5 8 Iminophosphoranes are being increasingly used in synthesis. The (tripheny1phosphinimido)hydrazone (94) has been reported to react with both cyclic ( 9 5 ) and acyclic acid anhydrides to give 5-substituted-lH-l,2,4Excellent yields of iminolactam triazoles ( 9 6 ) in variable yield.59

*

Organophosphoms Chemistry

338

(80) X=NR (81) X = O

Reagent : i , ButOK

Scheme 12

+

“‘$0 R

0

Ph3P=CHC02Me

-

CHC02Me MeoQ R

0 (82)

7: Ylidrs u t d Related Compounds

Ph3P=CHR4

339

-

+ (83)

H

C ‘’

R4

+

Ph3PO

(84)

1

Ph3P=CR’R2

+

P h 2 C = N C 0 C 0 2 But

Ph2C=N-C-CO,Bu‘

II

CR’R~

lii Ph;! C H NH C H C 0 2 B u t

1 CHR’ ~2 Reagents: i, toluene

;

ii. excess NaBH3CN

Scheme 13

Organophosphorns Chemist?

340

0 CHR'

0

R e a g e n t s : i, Ph3P=CHR1;

R'

ii, H B r , t o l u e n e

S c h e m e 14

341

7: Ylides and Related Compounds

Me

+

Ph ,P=CHCO,Me

i

R' N=NC=CHR

Me

I

R'NHN=C-C=CHC02Me

I

+

Ph3P

R2

(89)

( 90)n =1,2

(91)

R e a g e n t s : i . (CF3CO)20; ii. Ph3As=CH2;

iii, RCHO

S c h e m e 15

342

Organophosphorus Chemistry

t

&NxN3

Ph3P

0

0

Reagents: i . L D A . THF; ii, CR3CO$O; iii. ( E t 0 ) 3 P

Scheme 16

343

7: Ylides and Related Compounds

derivatives ( 9 8 ) have been obtained by treatment of the azides (97) with triphenylphosphine.60 A new synthesis of oxazoles in moderate to good yield is available from the reaction of a-azidoketones with triethyl phosphite (Scheme 16).61 The reactions of iminophosphoranes with organic isocyanates, carbon dioxide and carbon disulphide have been used to prepare a wide range of nitrogen heterocycles. Examples include the synthesis of [ 1,2,4]triazolo[5,1-c]-[ 1,2,4]-triazines ( 9 9 ) , 2H-[ 1,2,4]triazino[4,3b]-[ 1,2,4,5] tetrazine derivatives ( 100),62 2-pyridinecarboxylates ( 1 0 11, pyrazolo[3,4-b]pyridines ( 1 0 2 ) and (103),63 benzopyrimidine derivatives (Scheme 17),64 and various tricyclic compounds (Scheme 18).65 Routes to 1-aroyl-4H-imidazo[ 1,5-a]benzimidazoles (105) and 1-arylimino2-arylcarbamoyl-2,3-dihydro-lH-imidaza[ 1,5-a]-benzimidazoles (107) from the iminophosphoranes ( 1 0 4 ) and ( 1 0 6 ) , respectively, have been dev eloped.66 A detailed structural and theoretical study of the adducts ( 1 0 9 ) , obtained from the reactions of the iminophosphorane ( 1 0 8 ) with aliphatic isocyanates, has led the authors to suggest the charge distribution shown.67 The multifunctional nature of (Z)-/3-enamino-X5-phosphazenes ( 1 10) has been demonstrated by a study of their reactions with a variety of electrophilic reagents (Scheme 19).68 Reaction of the metallated N-acyl-Asphosphazenes ( 1 11) with aryl cyanides gives imino-15-phosphazenes ( 1 12) (Scheme 2O).69 In certain cases (e.g. 113) heating these products leads to the formation of rearranged phosphine oxides (e.g. 114). The formation of 2-anilinoalkyldiphenylphosphine phenylimides ( 1 1 6 ) by the reaction of metallated derivatives of alkyldiphenylphosphine imides ( 1 15) with imines is highly diastereoselective (Scheme 2l).70 The compounds (116) can be readily and stereospecifically converted into the corresponding phosphine oxides ( 1 1 7 ) . Attempts to prepare ( 1 1 7 ) directly from phosphine oxide carbanions gave poor diastereoselectivity. Telluroaldehydes have been generated and trapped for the first time act i v at ed by the re ac ti o n of be n z y 1i de ne tr i p h e n y 1p h o sp h or a ne with tellurium (a method analogous to that previously used to prepare selenoaldehydes) (Scheme 22).71 A wide range of reactive ylides have been converted into the adducts ( 1 1 8 ) by reaction with borane.72 On heating, ( 1 1 8 ) rearrange to triphenylphosphine-monoalkylborane adducts (11 9 ) which undergo the expected hydroboration reactions with alkenes. A new route to phosphaalkenes ( 1 2 1 ) is available from the reaction of phosphinomethylenetriphenylphosphoranes (120) with Lewis acids.73 In the case of (120, R2=NPr$) the compounds (121) can be isolated and in one case an X-ray structure was obtained. However, similar reactions of (120, R2=But) lead to the dimers (122). "

"

344

Orgm ophosphorus Chemistry

zNx; -

Me ‘N

RNCO

N

I

1

N

N=PPh,

It

RNH

CHPh

imx Me

Ph

NHR

C02 Et

RNH

Ph

(101)

(102) X = C O M e , N 0 2

CONHR’

N=PPh,

liii R e a g e n t s : i , R2NCO; ii, COz; iii, C S 2

Scheme 17

Me

N \ m : Ph

H

(103) X = COMe ,NO2

7: Ylides rind Relutrd Cornpourids

345

CO;!Et i , ii

CjQJ Me

Me

__c

N=PPh3

I

NHAr

R e a g e n t s : i, C S 2 ; ii. 17OoC

;

iii. ArNCS

Scheme 18

346

Orgaizophosp horns Chernistly

N=PPh,

(109)

Me

(108) X =

hN\

N

z

If

iii, iv. v

Reagents : i . CLCO2Et , ii, ~ r , E2 t 3 N

;

iii. R ~ ;X i v , B u L i , THF

Scheme 19

" , ~~0

347

7: Ylides and Related Compounds

I

Jii

Reagents : i , L D A , T H F ,

- 70 ' C

;

ii. ArCN

Scheme 20

(113)

Reagents: i,LDA, THF,

- 30'C

;

ii,R2CH=NPh,-

70 'C

Scheme 21

;

iii .H20

;

iv.CO2, THF,

-

70 ' C

348

Organophosphorus Chemistry

.

Reagents : i, 105 “C, 12 h , toluene ; ii Ph3P=CHPh;

iii ,

mZ

Scheme 2 2

/

Ph,P=C

R’

‘P(NPri2 ) R2 ( 120) RZ=NPri2

1

2 BF3.Et20

R +

Ph3 P-C

/

+P N Pr

*

X

-

(122 1

(121)

0 II ( PhO), P - C H - N H

b

R’

(123 1

>

R2

CR’ Ar

R3

7: Ylides and Related Compounds

349

3 ReartiQaS of PhosDhonate Anions An investigation of substituent effects in the phosphonates (123) and their carbanions, by 13C, 1H and 31P n.m.r., has been rep0rted.7~ Arylidenecyclopropanes (124) have been prepared by WadsworthEmmons reactions of the corresponding cyclopropylphosphonates.~5 Phosphonate-based olefination has been used to synthesise a - m e thylene monosubstituted 6-lactones (126)76 and a ,p -unsaturated hydrazones (128)77 from the phosphonates (125) and (127), respectively. Olefinations of aldehydes with the phosphonate (129) have been studied under a variety of conditions.78 It was possible to obtain (Z)-alkenes highly stereoselectively from reactions of aliphatic aldehydes and these results were applied to a key step in a synthesis of the diterpenoid (&)-isolinaridiol. A variety of 3s u b s t i t u t e d - 2 - p h o s p h o m e t h y l acrylates (1 3 0 ) have been prepared as mixtures of ( E ) - and (2)-isomers by a sequence involving addition of phosphorus nucleophiles to vinylphosphonates followed by olefination reactions of the products (Scheme 23).79 Reactions of the lithium salt of the dienylphosphonate (132) with aldehydes have proved useful in the stereoselective synthesis of (E,E,E)-trienes but attempts to apply this to the synthesis of the triene (133) from the ketone (131) gave only poor However, excellent yields and substantial stereoselectivity were yields .80 obtained from the latter reaction by the use of the potassium salt of (132). The olefination procedure developed by Warren, involving the isolation of j3hydroxyalkylphosphine oxides followed by decomposition induced by a sodium base, has been applied to reactions of the phosphonate (134).81 This procedure gave a much higher yield of alkene than the direct olefination procedure. The structure of the previously unidentified product of the reaction of k-strophanthidin and cyanomethylphosphonate carbanion under protic conditions has been shown to be (135) by 2-D n.m.r. spectroscopy.82 a-Silyl-a-thiomethylphosphonates (e.g. 136) are among a range of derivatives which have been prepared from the (methy1thio)methyl1.1 -Difluoro-3 -alkenephosphonates have been phosphonate carbanion.83 prepared by alkylation of [(diethoxyphosphinyl)difluoromethyl]zinc bromide (137) with allylic halides.84 The regiochemistry is determined by steric factors. The phosphonylphosphinyl dianion (139) has been generated by base-treatment of the corresponding monoanion (138). 8 5 The dianion (139) is readily monoalkylated to give ( 1 4 0 ) and the site of alkylation provides evidence that the dianion is involved (Scheme 24). The factors controlling stereoselectivity in the carbanionic claisen rearrangement of chiral phosphonates (141 ) have been investigated.86 The degree of stereoselectivity depends on both the nature of the counterion associated with the carbanion and the size of the substituent on nitrogen in (141).

350

Organophosphorus Chemistry

Na H

R 3CH0

THF

0

II (Et0)2PCHCH=N-NMe2 (127)

+ YD

l

H

O

\

Reagents : i , NaOMe , MeOH ; ii, (

C02Me

8 MeOI2PKC02Me

(130) ;

iii, RCHO

CH2

Scheme 23

qt

-

+

KH .THF, HMPA

Me

C02 E t

Me

35 1

7: Ylides and Related Compounds

,SiMe3 (Et012PCH \ SMe

-

0

It

(EtOI2PCF, ZnBr

+

0 I1

(EtO), PCF2 CHRCH=CR'R2

CuBr

R' R2C=CHCHRX

o

I1

+

(EtO), PCF, CR' R2CH=CHR

(137)

0

j0 ,OPr'

II

(P~'o),P, CH?'

'CH~R

Reagents : i , NaH,THF. 20.C

-

;

ii, B u n L i , THF,

-

$0 ,OPr

0 II

iii, i v

,,

(Pr'O)*P, GH

78'C

Scheme 2 4

;

iii. R X

;

i v , H20

CH,

Orguriophosphorus Chemi s t y

352

Me

Me

Me

04

MeN

C02H

(145) 0

II

(Et0)2PCH2COCH2COSBut

But S

C

Reagents: i , N a H , T H F , O ° C ; ii.-CHO,

O

C

H

THF, O'C

(146)

Scheme 2 5

2

C

O

z

353

7: Ylidrs and Related Compounds

With a lithium counterion and a tertiary diastereoselectivity of 94:6 can be obtained.

alkyl

group

on

nitrogen

. .

Selected ADDlicatiQILS in SvnP h o sp h o r u s -b a se d d 4.1 C a r o t ~ JoI i d R e 1a t e d C om D ou n Qs. olefination continues to be the method of choice in retinoid synthesis. Examples include the use of phosphonate-based olefination in the synthesis of 16,16,16-trifluororetinal (142).87 Attempts to prepare the trienyl ester ( 1 4 4 ) by phosphonate-based olefination of the ketone ( 1 4 3) were unsuccessful.88 The results from model reactions suggest that the failure of this reaction is due to steric factors. The yellow slime mould pigment fuligorubin A (145) has been efficiently synthesised using a phosphonateolefination of the polyene aldehyde (146) as a key step (Scheme 25).89 The all trans-isomer ( 1 4 7 ) of parinaric acid specifically deuterated at all vinyl positions has been prepared using the Wittig reaction to couple a dienyl ylide with an appropriate a,P-unsaturated aldehyde.90 4

L e u k o t r i e m Prostaglandins and R&&d C o m D o u n d s . - Examples of the use of the Wittig reaction in the synthesis of compounds related to arachidonic acid include an efficient synthesis of methyl arachidonate ( 1 4 8 ) by a three-carbon homologation sequence involving (3,3-diisopropoxypropy1)triphenylphosphorane (149).91 Both diastereomers of trioxilin B3 ( 1 5 0 ) , hydroxylation products of the diastereomeric 10-hydroxy-l l ,12epoxyeicosatrienoic acids,92 and five stereoisomers of the trio1 ( 1 5 1 ) , an arachidonic acid metabolite,93 have been prepared using established Wittig methods. (2)-Hepoxilin A3 ( 1 5 2 ) , a biologically active metabolite of arachidonic acid, has been synthesised using a strategy involving arsonium ylides to construct the carbon skeleton and to introduce the epoxide functional group (Scheme 26).94 The ylide ( 1 5 3 ) has been used in the stereocontrolled total synthesis of various ( 7 E , 9 E . 1l Z , 142)-5,6-dihydroxy7,9,11,14-icosatetraenoic acid (5,6-diHETE) methyl esters (e.g. 154).95 Examples of the use of Wittig methods in leukotriene synthesis include the preparation of 13,13-difluoroleukotriene B4 ( 1 5 9 9 6 and the synthesis of ( + ) - L T B 4 ( 1 5 9 ) and homo-LTB4 ( 1 6 0 ) by the reaction of the ylide ( 1 5 6 ) with the aldehydes ( 1 5 7 ) and ( 1 5 8 ) , respectively.97 The dihydro-LTB4 metabolite (161) and its C-12 epi-analogue have been prepared by a Wittig reaction of the ylide (162) (derived from L-glutamic acid) and the aldehyde (163) (derived from 2-deoxy-D-ribose).98 Examples of standard uses of Wittig reactions to prepare prostaglandin analogues include a synthesis of PGF2..99

Organophosphorus Chemistry

354

D

D

D

D

D

D

D

D

ph3p-Y0 OPr i

(149)

HO

H'

C02Me

I

-

OH

IV

Reagents: i , Ph3As=

CHCH2CH(OPri)2. THF,- 40 ' C

i v , But PhzAs =CHCHzCH=CH

C02Me

;

ii ,Si02,H2S04;iii. S i 0 2 , Et2O

C5H11, T H F l HMPA,

Scheme 2 6

ii ,iii

- 40 "C

355

7: Ylides and Related Compounds

m*'

Ph3P

\ SiMe3

OH

OH COz H

(157)n=l (158)n = 2

F

r

(159)n = 3 (160)n = 4

COZ H

OHC

P CSH11 P

h

3

356

Orgunophosph oms Chemistry

4.3

w e s and R e b t e d -ds.The total synthesis of amphoteronolide B (166) and amphotericin B (167) has been reported in a series of papers by Nicolaou's group.100 The method uses the phosphonatebased olefination of (164) with (165) to form the basic carbon skeleton A which is cyclised by an intramolecular phosphonate-based olefination. Wittig reaction of the ylide ( 1 6 8 ) is a key step in the synthesis of the cytotoxic macrocycle riccardin C (169).101

4.4 P h e r m . - Synthetic applications of phosphonate-based olefination to insect pheromones include the preparation of a juvenile hormone I11 fluorinated analogue.102

4.5 Miscellaneous Reactions.- Stereoselective syntheses of ( E ) - and (Z)(170) and (E)-(171) have been achieved by Wittig reactions of protected Dribofuranose and D-mannofuranose under different conditions of temperature and solvent.103 Wittig reactions of 2-acylimino-2-deoxy-4,6-0ethylidene glucose ( 1 72 ) with reactive ylides give the chiral glycerol derivatives ( 1 7 3 ) rather than the expected products (174).104 It is suggested that the formation of (173) is- due to the initial formation of the aldehyde (175) via a retroaldol reaction initiated by the highly basic ylides; similar reactions with the less basic semi-stabilised and stabilised ylides both give (174). Reactions of phosphonate carbanions have been used to synthesise the Olefinations of 1,4-furanoside isosteres of various natural phosphates. (176) with diphosphonate carbanions have been used as key steps in the synthesis of ( 1 7 7 ) and ( 1 7 8 ) , isosteres of 2 - ( R ) - 3 - c a r b o x y - 3 h y d r o x ypr opan e - 1 - p h o s p h a t e . 105 A cadmium reagent, predominantly (179), has been used to introduce the 1,l-difluoromethylphosphonate group in a synthesis of the L-glycerol-3-phosphate isostere ( 1 8 0 ) . l o 6 The phosphonate isostere (183) of AZT 5'-phosphate has been synthesised by the reaction of methylphosphonate carbanion ( 1 82) with the nucleosidic oxetane (181) as a key step.107 Intramolecular olefination of the phosphonates (184) and (186) has been used as the final step in syntheses of (d-jolkinolides (e.g. 185)lOg and the antitumour, antibiotic asperlin (187),109 respectively. In the latter case this confirms the stereochemistry of asperlin as (6S,7R). A new synthesis of (E)-a,P-unsaturated macrocyclic lactones by intramolecular Wittig reaction of a-aldehydoalkoxycarbonylmethylene ylides (189) has been reported.110 Compounds ( 1 8 9 ) are conveniently obtained by the reaction of triphenylphosphoranylideneketene (188) with the appropriate (free or protected) w-hydroxyalkanals.

357

7: Ylides and Related Compounds

OR

Me

HO

HO

OR

R=H (167) R = (166)

$H=PPh,

Me0

Q

HO OH

o n C02 Me (168)

(169)

Orgar I op hosph orus Chemisrly

358

H

OH

t",x

OTr ( ~ ) ( 1 7 0 )R'=C02Me.R2=H (Z)(170) R 1= H, R 2 = C02Me

r

( X = P h or C 0 2 R )

X NHCOR (174)

7: Ylides and Related Compounds

3 59

0

HO\x

II

(EtO),PCF,

CdBr

(177) X = H (178) X = F

(179)

0 - P CF,CH,

I

CH(OH)CH,OH

(180)

0

A-.. .

0 II

0

II

OCOCHMeP(OEt),

Na H

DME

(184)

0 II

OH

PO3 H

Me

-

Orgunoph osph orus Chemistiy

360

1

Base

R =

Reagents : i , L D A . THF

;

ii , HF, MeCN

Scheme 27

7: Ylides and Related Compounds

36 1

XHO

0

+

BunLi

I

II

(MeO)* PCHN,

THF,

- 7 8 ‘C 0 H

11

P(OMe)

,

0 0 II

(EtO), P CH,CO CH,

(199)

2 NaH

_____c

THF,HCHO

C02 H

k

2

H

Organophosphorus Chemistry

362

OH

0

A

/

/

#

OH

(207)

C02Me

(2091

(208)

+

R’= alkyl

Ph,P=N<

R2

(210)

1

1

i , R1= B r

ii

(3\

/

RZ

R’

(211)

(212)

Scheme 28

7: Hides and Reluted Compounds

363

The Wadsworth-Emmons reaction of the aldehyde ( 1 9 0 ) with the complex phosphonate (191) has been used to construct the C i o - C i 1 double bond in a convergent synthesis of lacrimin A ( 1 9 2 ) (Scheme 27).111 Phosphonate-based olefination has been extensively used in the synthesis of cytohalasans (e.g. 193), a group of biologically active fungal metabolites.112 The phosphonate (194) has been used to construct a triene function which ultimately forms the tricyclic structure through an intramolecular Diel's Alder reaction. 14,15-Dehydroforskolin (196) has been prepared by the base-induced reaction of the aldehyde ( 1 9 5 ) with dimethyl Under certain conditions the phosphonate d i a z o m e th y l p h o s p h o n a t e . 1 13 (197) can be isolated and this provides evidence for the involvement of the Wadsworth-Emmons intermediate (198) in the reaction. The phosphonate (200) has been prepared from diethyl 2-oxopropanephosphonate (199) by a long procedure and used in an olefination reaction with formaldehyde to prepare (+)-sarkomycin (201) in 9% overall yield from ( 1 9 9 ) . 1 1 4 2-(1Alkenyl)-2-imidazolines (203) have been prepared by the reaction of ketones with the 2-imidazoline substituted ethylphosphonate carbanion ( 2 0 2 ) 1 1 5 after attempts to prepare ( 2 0 3 ) by reactions of carbonyl compounds with non-phosphorus containing carbanions failed. The Wittig reaction has been used to construct the side-chain in a synthesis of (-)-sirenin (208), a water mold sperm-attacking hormone.1 1 6 The intermediate (206) was generated, without competing formation of the structural isomer ( 2 0 7 ) , by reaction of the ylide ( 2 0 5 ) with ( 2 0 4 ) under salt-free conditions in DME. Standard Wittig methods have been used to construct the side-chain in an enantioselective synthesis of ( + ) - ( 7 E , 9Z) methyl trisporate (209) and its (9E)-isomer.117 The reaction of triphenyl(viny1imino)phosphorane derivatives ( 2 1 0 ) with tropones provides a convenient synthesis of l-aza-azulenes ( 2 1 1 ) and ( 2 1 2 ) in either one or two steps (Scheme 28).118 The mechanism of the one-step reaction was investigated using deuterium-labelled tropane derivatives. REFERENCES

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J.P. Bazureau, D. Person and M. Le Corre, Tetrahedron Lett., 1989, 3 0 , 3065. D. Person and M. Le Corre, Tetrahedron Lett., 1989, 30, 3069.

56.

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Y. Shen, Q. Liao and W. Qiu, J.

59.

L. Bruche, L. Garanti and G. Zecchi, J. Chem. Research(S), 1989, 16.

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Chem. SOC., Chem. Commun., 1988, 1309.

H. Takeuchi, S-i. Yanagida, T. Ozaki, S. Hagiwara and S. Eguchi, J. Org. Chem., 1989, 54, 431.

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P. Molina, M. Alajarin and A. Vidal, J. Chem. SOC., Perkin Trans 1. 1989, 247.

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Organophosphorus Chemistly

366 65.

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66.

P. Molina, M. Alajarin, C. Lopez-Leonardo, I. Madrid, C. Foces-Foces and F.H. Cano,

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P. Molina, M. Alajarin, C.L. Leonardo, R.M. Claramunt, M. de la C. Foces-Foces, F.H.

Tetrahedron, 1989, 45, 1823. Cano, J. Catalan, J.L.G. de Paz and J. Elguero, J. Am. Chem. SOC., 1989, 111, 355. 68.

J. Barluenga, F. Lopez, F. Palacios, F.H. Can0 and M. de la C. Foces-Foces, J. Chem.

SOC.,Perkin Trans.1, 1988, 2329. 69.

J. Barluenga, M. Ferrero, F. Lopez and F. Palacios, J. Chem. SOC.,Perkin Trans.1,

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71.

G. Erker and R. Hock, Angew. Chem., Int. Ed. Engl., 1989, 28, 179.

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1989, 615.

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S.J. Smith, H. Zimmer, E. Fluck and P. Fischer, Phosphorus Sulfur, 1988, 35, 105.

75.

R.T. Lewis and W.B. Mothenvell, Tetrahedron Lett., 1988, 29, 5033.

76.

G. Falsonne and U. Wingen, Tetrahedron Lett., 1989, 30, 675.

77.

R.E. Dolle, W.P. Armstrong, A.N. Shaw and R. Novelli, Tetrahedron Lett., 1988, 29,

78.

E. Piers and J.S.M. Wai, J. Chem. SOC.,Chem. Commun., 1988, 1245.

79.

W.R. Schoen and W.H. Parsons, Tetrahedron Lett., 1988, 29, 5201.

6349.

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A.P. Craven, H.J. Dyke and E.J. Thomas, Tetrahedron, 1989, 45, 2417.

81.

R.T. Lewis, W.B. Mothenvell and M. Shipman, J. Chem. SOC.,Chem. Commun., 1988, 948.

82.

W. Kreiser, G. Bartels, S. Bathe-Burmeister, L. Ernst and U. Stache, Liebigs Ann.

Chem., 1989, 315. 83.

M. Mikolajczyk and P. Balczewski, Synthesis, 1989, 101.

84.

D.J. Burton and L.G. Sprague, J. Org. Chern., 1989, 54, 613.

85.

M.H.B. Stowell, J.F. Witte and R.W. McClard, Tetrahedron Lett., 1989, 35, 411.

86.

S.E. Denmark, G. Rajendra and J.E. Marlin, Tetrahedron Lett., 1989, 30, 2469.

87.

Y. Hanzawa, M. Suzuki and Y. Kobayashi, Tetrahedron Lett., 1989, 30, 571.

88.

C.Y. Robinson, W.J. Brouillette and D.D. Muccio, J. Org. Chem., 1989, 54, 1992.

89.

S.V. Ley, S.C. Smith and P.R. Woodward, Tetrahedron Lett., 1988, 29, 5829.

90.

M.M. Goerger and B.S. Hudson, J. Org. Chem., 1988, 53, 3148.

91.

J. Viala and M. Santelli, J. Org. Chem.. 1988, 53, 6121.

92.

S. Lumin, P. Yadagiri and J.R. Falck, Tetrahedron Lett., 1988, 29, 4237.

93.

P. Yadagiri, D-S. Shin and J.R. Falck, Tetrahedron Lett., 1988, 29. 5497.

94.

P. Chabert, C. Mioskowski and J.R. Falck, Tetrahedron Lett., 1989, 3 0 , 2545.

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J.C. Nicolaou, J.Y. Ramphal, J.M. Palazon and R.A. Spanevello, Angew. Chem., Int.

Ed. Engl., 1989, 28, 587. 96.

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29, 5665.

7: Ylides and Related Compouds 97.

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1989, 30, 429. 100.

K.C. Nicolaou, T.K. Chakraborty, Y . Ogawa, R.A. Daines, N.S. Simpkins and G.T. Furst, J. Am. Chem. SOC., 1988, 110, 4660; K.C. Nicolaou, R.A. Daines, J. Uenishi, W.S. Li, D.P. Papahatjis and T.K. Chakraborty, J. Am. Chem. Soc., 1988, 110, 4672; K.C. Nicolaou, R.A. Daines, T.K. Chakraborty and Y . Ogawa, J. Am. Chem. SOC., 1988, 110, 4685; K.C. Nicolaou, R.A. Daines, Y . Ogawa and T.K. Chakraborty, J. Am. Chem. SOC., 1988, 110, 4696.

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Tetrahedron Lett., 1988, 2 9 , 5039.

1989, 45, 269.

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E.J. Thomas and J.W.F. Whitehead, J. Chem. SOC., Perkin Trans.1, 1989, 499; i b i d , 507; R. Sauter, E.J. Thomas and J.P. Watts, J. Chem. Soc., Perkin Trans.], 1989, 519;

H. Dyke, P.G. Steel and E.J. Thomas, J. Chem. SOC., Perkin Trans.1, 1989, 525. 113.

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1143.

8 Phosphazenes BY C. W. ALLEN Introduction This chapter covers the literature of phosph(v)azenes. Activity in this area continues unabated with an increase of interest in acyclic materials being noted over the past few years. While there have not been any general reviews published in the past year, the collected papers from the 5th International Symposium of Inorganic Ring Systems (Amherst, MA 1988) have appeared.’ Main group ring systems and polymers are featured in a recent volume of Inorganic Syntheses.2 As in previous years, highly focused reviews will be cited in the appropriate sections below. 1.

Acvclic Phosphazenes Interest continues to be shown in acyclic phosphazenes (phosphazo derivatives, phosphine imines, phosphoranimines). Reviews include a comprehensive survey of the chemistry (synthesis, structure, bonding and spectroscopy) of transition metal complexes of pho~phoranimines~, a survey of recent uses of Ph2P(=NSiMe3)NSiMe, as a precursor to transition metal containing inorganic heterocycles4 (section 5) and various aspects of the Staudinger reaction.’ MO calculations at the SCF level on oxyphosphorus nitride isomers indicate that ONP is the most stable species.6 Computer assisted evaluation of mechanistic pathways has been extended to include the azaWittig r e a ~ t i o n . ~Solid state powder 31P NMR studies of show that most shielded Ph,PNAr(Ar=Ph, ,o, g, pCH,C,H,) component of the 31Ptensor is along the phosphorus-nitrogen bond axis. The field gradients have been modeled using & initio MO calculations and the 31P-14Ndipolar coupling constant can be used to measure bond lengths.’ The first stable phosphorus-nitrogen triple bond [P=NAr+][AlCl,-] (Ar=2,4,6(Me3C),C6H,) has been prepared from aluminum chloride and ClP=NAr. The selenium oxidation of (Me3C),PP=NAr ultimately gives (Me,C)zP(Se)SePNAr which on the basis of structural data and MO calculations is proposed to be a donor acceptor complex 2.

369 of the type [ (Me,C),PSe,] [ P=NAr] .lo The ever popular Staudinger reaction continues to be the most common route to acyclic phosphazenes.' This year many of the preparations are the initial part of a sequence involving subsequent transformations and consequently will be mentioned below in the discussion of reactions of acyclic phosphqzenes. The reaction of phenylazide with allyldiphenylphosphine gives the expected phosphazene which undergoes a facile double bond shift to Ph,P(=NPh) CHCH,. l 1 Benzopyran-4-one azides are easily converted to the triphenylphosphazo derivatives upon reaction ... with triphenylphosphine.'L Several inorganic iminophosphoranes have been reported this year. Reactions of the azidoborane, (Me,Si),NB (CMe,)N, with phosphines lead to the (bory1imino)phosphoranes l(R,=(Me,Si),N,R,=Me, R3=Me,Ph, 13 R2,,=Me3SiE=(E=CH,N) ; R1=Ph, R,=R,=Me,N) . Bis(dipheny1phosphino)methane is oxidized with trimethylsilylazide to give the monophosphazene Ph,PCH,PPh, (=NSiMe,) which exists in four isomeric forms resulting from phosphorus-nitrogen bond rotation.l 4 The analogous reaction of (Ph)(Me)(R)P (R=alkyl, cycloalkyl) gives high yields of (Ph) (Me)(R)P=NSiMe,. l5 Triethylphosphite reacts with dialkylphosphoric acid azides to yield (RO)2 P ( 0 )N=P (OR) l6 The cumulative sulfur-nitrogen phosphorus-nitrogen derivative Me2S(0)=NPPh2=NSiMe, has been prepared using trimethylsilyl azide and the appropriate ph0~phine.l~The reaction of 1,lbis(dipheny1phosphino)-ferrocene with trimethylsilyazide gives (C,H,PPh,=NSiMe,) ,Fe. l8 The novel organometallic azides CpFe(CO),SiRR'N, (Cp=q5C,H,; R=Me, R1=H, Me, Cl; R=C1, R1=H, C1) are converted to CpFe(CO),SiRRIN=PMe, upon reaction with trimethylphosphine. Reactions of phosphosphines with the diazo functionality can lead to phosphazides as seen in the trapping of 2 with triphenylphosphine yielding 3.2o The attack of triphenylphosphine on the exocyclic imino group of 5-imino2-phenyl-thiadiazolidin-3-one gives Ph,P=NC ( S ) NHC (0) NHPh.21 Addition reactions of low coordinate phosphorus compounds have proved to be an interesting route to novel acyclic phosphazenes. Phosphino carbenes, R2PCSiMe3, exhibit typical multiple bond behavior in 2+3 cycloaddition reactions with trimethylsilylazide. The cycloadduct easily rearranges to the 22 diazo derivatives R2P(=NSiMe,) C(=N2)SiMe,. The addition of the

,.

Organophosphoms Chemistry

370

x=N2

YN-N ON I

R

CH=N-N=

PPh3

N&H \ I N=N

NR’

\p4

Me3C\

/ \

Me3C

M e 3 C -C=P

zN

i\

- N-PCMe3

(4)

NR’

II R,NP-N’ I Cl

NR,

NR,

NR’

II I

\N-PNR, ‘P’ NR,

CL

(7)

SiMe3 (12)

r (Me3SiI2NP

1

SiMe3

S i Me3

Ph

37 1

8: Phosphazenes

phosphaalkyne, Me,C=P, to phosph(III)azenes, gives a three membered ring containing an exocyclic phosph(v)azene ( 4 ) which isomerizes to a four membered a~adiphosphetine.'~ An extensive study of the reactivity of photochemically generated (from RR'PN,) RR'PN with low coordinate phosphorus centers has lead to the preparation of several new phosphazenes.24 When several iminophosphanes, RttP=NRtft,were used as trapping agents the tricoordinate species RRtPN=P(Rt*)=NRtt' were obtained. By way of contrast, (Me3Si),NP=NSiMe3 reacted to form the diazadiphosphetidine 5 (R=iPr, R'=SiMe,, X=--)which could be derivatized with tosylazide on sulfur to yield 5 (X, TosN= and X, S). The use of 6 as a trapping agent leads to R2N(MeC)P(=NCMe3)N=PNR,. Addition reactions of CC1, to the diazadiphosphetidines, 7 , were also reported. When R=iPr and R'=SiMe3, the open chain species R,NP=NP(=NR') (C1)NR2 is formed at low temperature and can either add another equivalent of CC1, to yield R,NP(CCl,)ClP(=NRI) (C1)NR2 or dimerize to the diphosphazene 8 . The corresponding reaction of 7 (R=R'=SiMe3) leads to the open chain analog but it rearranges to 9 . The various reactions observed allow formulation of mechanistic processes for these reactions.24 The reaction of RP=NR with the low coordinate boron-nitrogen derivative RB=NR (all R=CMe3) is proposed to go through the intermediary of 10 on its way to the final product 11 (E=NR). The proposed intermediate can be trapped by oxidation to 11 (E=O).25 The oxidation R,NP=C(R) CH=CHR (R=SiMe3) with Me,SiN, gives 12. A structural isomer of 12, 13, is obtained from the cycloaddition reaction of Me,SiCrCH with R,NP (=NR)=CHR.25 Deprotonation of aminophosphorus derivatives can also lead to the phosphorusnitrogen double bond. The reaction of ArNHP(=CSiMe3)2 (Ar=phenyl, a-Naphthyl) with butyl lithium leads to the phosphazene anion, ArN=P (=CSiMe,) 27 Treatment of Ph,PNH;Brwith butyl lithium gives Ph,P=NLi which reacts with alkylhalides o r acyl halides to give Ph,P=NR(R=alkyl, C(0) Ph) .28 Dissolution of the phosphonium salts (R2N)zP(NH,)NHCH,CH2NR1Rz+ in a sodium/liquid ammonia solution Patents f o r the leads to (R2N)2P(=NH)NHCH,CH2CH,NR1R2i . 2 9 production of (Phz(R)P=),Nix- from the reactions of alkylhalides with the in situ generated (Ph,P),N- anion are a~ailable~"~'. The Kirsanov reaction also continues to be used to generate phosphazenes. The reaction of PC1, with (RO)2P (0) NH, proceeds

,.

372

Organophosphorus Chemistry

with rearrangement to give (RO),PCl=NP (0) Cl,. 32 Three patents the reaction of NH4C1 for the preparation of Cl,P(O)N=PCl, with PCl, followed by treatment with, among other reagents, SO, have appeared.33-35 Direct synthesis of longer chain acyclic phosphazenes, [ XPPh, (NPPh,) ,XI+ have been reported. The reaction of 1 4 with chlorine gives the species with X=C1 which undergoes ammonlysis to X=NH,. Bromination in alcoholic solvents gives the species with X=OR. The reaction of Ph,P (=NSiMe,) NSiMe, with Ph,PC1 gives [ Ph,P ( PPh2N),PPh2PPh2]+C1-.36 Inorganic syntheses preparations of [N(PC1,) ,] SbC127, [ C1Ph2P=NPMeC12] d 7 , Me,SiN=P (X)Me, (X=Br, OCH2CF3) 38 and Me,S iN=P (OCH,CF,) MePhm have been reported. Reactions of acyclic phosphazenes continue to attract considerable attention. Reactions in which the phosphazene is transformed will be considered first followed by those in which the phosphazene unit stays intact. This year the azaWittig of iminophosphoranes (usually prepared by the Staudinger reaction) has received considerable attention. The with aldehydes gives reaction of R'CH=C(CO,Et)N=PPh,R R'CH=C(CO,Et) N=CHR2.39 Aza-Wittig reactions followed by an annulation process have provided new routes to several heterocyclic systems.40-48 The aza-Wittig reaction of 2- (Ph,P=N) C6H4CONHR with organic isocyanides, CO, and CS, followed by subsequent cyclization through the adjacent NH function leads to quinazolines (15). Benzimidazoquinazolines are accesible a similar route.40 The aza-Wittig reaction of Ph,P=NSiMe, with the ester carbonyl of 0- (RCO,) C6H4C(0) C1 and the intramolecular elimination of Me3SiC1 affords a route to benzoxazinones (16). 4 1 The analogous reaction of RC0,CHMeC (0) C1 followed by thermolysis leads to RC0,CHMeCN. 41 Internal condensation reactions of the triphenylphosphazo (Ph,PN) moiety with an ortho-hydrazine unit in 1,2,4-triazoles gives triazinotetrazines (17).42 The adjacent placement of the Ph,PN function and an imine allow an aza-Wittig reaction followed by electrocyclic ring closure to give pyrimidines. Thus 5-triphenylphosphaza-4-formoyl pyrazoles react with isocyanates, CO, and CS, to yield species such as 18 (X=NPh, S, Pyrazolopyridinium salts arise from the reactions of 0) acylchlorides and triazolopyramidines are available from analogous reactions.43 Several pyridine syntheses utilize the aza-wittig process. Thermolysis of molecules with vicinal

.',

373

8: Phosphazenes

(15)

X

R'

I

Me,Siy,IP=NSiMe3 R-E-CHSiMe,

I

Y (20)

374

Organophosphorus Chemistry

aldehyde and Ph,PN units leads to pyridine~.~,The reactions of iminophosphoranes with isothiocyanates provide conjugated carbodiimides which undergo electrocyclic ring closure to pyrimidines.45 Pyrazolopyridines are also available from iminophosphoranes and isocyanates 46 Iminophosphorane substituted indoles can be converted to polycyclic systems with pyridines or pyrimidines fused to the indole by using the aza-Wittig reaction followed by ring closure.46 The intramolecular aza-Wittig reaction of a Ph,PN unit with a carbonyl function leads to a dienimine intermediate in the ergosterol acetate synthesis.47 Tetrahydrobenzofurans with a Ph,PN substituent can undergo 4+2 cycloaddition reactions leaving the phosphazene undisturbed or can be converted to carbodiimides which are ultimately transformed to isoureas or more complex quinazolines.48 The aza-Cope rearrangement of PhP (X) (CH,CH=CH,) N=CCR' (X=O,S ) has been shown to go through an imminophosphine intermediate, PhP (X)=NCRR'CH,CH=CH,, which can be trapped by the addition of alcohols across the phosphorusnitrogen bond.49 The reactions of the aziridine derivative, (C,H,N) (NR'),P=NR' with R,PC15' or Me3SiCls1lead to the cyclic phosphonium salts 19 (X=R,P or Ac respectively). The reactions of carboxylic acids with (ArNH),P=NAr give the phosphonium carboxylate, ( ArNH),P+RCO,'. 52 The reaction of (EtO),P=NCR1R2R3 with water gives (EtO),P ( 0 )NHCR1R'R3 and with 53 p-toluenesulfonic acid to give the tosylate salt of NH2CR1R2R3. The hydrolysis of the phosphazene unit in ArC(O)C(=N-N=Ph3) leads to hydrazones which can undergo intramolecular cycli~ation.~~ A novel synthesis of a transition metal imide is seen in the reactions of Ph3P=NC6H4N=PPh3with OReCl,L, to give Cl3L,Re=NC,H,,N=ReL$l3. 55 Numerous reactions have also been reported in which the phosphazene unit is unchanged during reactions at other sites in the molecule. The wide range of these reactions demonstrates the ability to carry out chemical modification of the phosphaze containing moiety before applying any of the reactions discussed above. Addition reactions of the silylated imino(methy1ene) phosphorane, Me,Si) ,NP (=NSiMe,) =CHSiMe,, with chlorophosphines all occur across the phosphorus-carbon bond to yield derivatives of the type (Me,Si),NP(Cl) (=NSiMe3)CHSiMe3RR'(R=R'=Ph, NMe,; R=Cl, The chlorophosphine derivative undergoes internal R'=Ph)

.

.

8: Phosphazenes

375

cyclization to 2 0 (E=P, X=C1, R=Ph, Y = * * ) . Analogous additions of amines and alcohols also occur across the phosphorus-carbon bond and one of the products, (Me3Si),NP (OCH2CF3)( CH,SiMe3)=NSiMe,, undergoes an elimination/dimerization process to give 2 0 (E=P,R=X=CH,SiMe,,Y=Me3SiN=). Addition of methyl lithium across the phosphorus-carbon bond followed by quenching with chlorosilanes yields (Me,Si) ,NP(Me) [HC(SiMe3)SiMe,X]=NSiMe, (X=Me, Cl) and in the case of X=C1 internal cyclization occurs to yield 2 0 (E=Si, R=Y=X=Me).56 Treatment of Me3SiN=P(OCH,CF3)Me2 with butyl lithium followed by the addition of various electrophiles yields the series OEt , Br) When Me3SiN=PMe(OCH,CF,) CH,R (R=Me, CH,Ph , CH=CH,, C (0) carbonyl containing species are used as electrophiles followed by quenching with Me3SiC1, the silylethers, Me3SiN=PMe(OCH,CF,) CH,C (OSiMe,)RR' 57 The addition of bromine to (Me,Si),NPR(CH=CH,) gives the 2-vinylphosphanimines, Me3SiN=PR( CH=CH2)Br (R=Ph, CH=CH,, Me) in which the bromine atom can be displaced by a trifluoroethoxide ion.58 The reactions of a-anions of phosphine imines, RCHPPh,=NR'- , with aldehydes proceeds with diastereoselectivity to give R2 CH (OH)CHRPPh,=NPhS9 and with nitriles to give Ar (NH,) C=C(R) PPh2=NR'.60 The reactions of Ph,P=NSiMe, with nonmetal chlorides give the new triphenylphosphazo derivatives (Ph,P=N)"E (n=2, E=S02, SO, CS : n=l , E=SO,Cl) " The reactions of .Me2SiBr2with alkyl and aryl phosphazenes, RR1R2P=NSiMe3, give the dimer 21 unless steric demands result in the monomer, RR'R'P=NSiMe,Br .62 The introduction of an allyloxy substituent onto Cl,P=NP(O) C1, using ROCH,CH=CH, (R=Na, Me,Si) gives C1,P (0) N=P (OCH2CH=CH2) C1, at low temperatures which rapidly undergoes a thermally induced phosphazene-phosphazene N (CH,CH=CH,) P (0) C1, and rearrangement to give traces of C1,P (0) Cl,] as the main product.63 The corresponding reaction HN [ P (0)

.

.

.

,

,

with pyrrolidine gives (pyr),P (0) NP (pyr) and [ (pyr),P (0)3 ,NH (pyr=C,H,N) 64 The morpholinophosphazide, (Mor),PN,Ar (Mor=C,H8N0, Ar=2,4,6-C6H2(NO?),) can be alkylated by the triethyloxonium cation to give (Mor),PN,N (Et)Ar+ in which the N, unit stays intact.65 Although still of interest, there are fewer reports of the interaction of transition metal complexes and organometallic derivatives with acyclic phosphazenes this

.

376

Organophosphorus Chemistry

year. The reactions of Me,S(O)=NPPh,=NSiMe, with transition metal chlorides gives the series Me2S(0)=NPPh2=NR[R=CpTiC12, VOCl,, Cp*TaCl, (Cp*= 05-C,Me5)1. Structural data (section 7) of materials show a short SN bond in each case.17 The reaction of CpTiC1, and Me,SiN=PPh,CH,PPh, gives CpTiCl,N=PPh,CH,PPh, l 4 The salt, (Cl,PNPCl,) C1 , reacts with MoNCl, to give C15MoNPC1,NPC1, in solution which is in equilibrium with its salt form (cl,PNPCl,) 'MoNC1,- in the solid state.& Tetraphenyl imidophosphate, [Ph2P(0)],NH, can act as a bidentate ligand (through oxygen). In six-coordinate complexes of titanium (IV) fluorides, the ligand can be either in the neutral or anionic, [Ph2P(0)2N-],form with the later showing phosphazene character.67 The thio analog [ Ph,P ( S ) 3 ,NH forms gold complexes of the ligand in its anionic form.68 A few miscellaneous applications of acyclic phosphazenes including the use of Cl,PNPCl,PCl,+PCl,- in the preparation of poly (siloxanes) free of OH groups,69 alkyl , cycloalkyl and phenyl phosphazo derivatives of mitomycin as potential anticancer and antibacterial agents,70 N-alkyl-N,2,2dimethylvinyliminophosphates as antibacterial agents7' and triaryl-N-carbamato phosphazenes as diuretics and for lowering plasma renin activity and for increasing cardiac contractilityn have been reported. Other examples of reactions of acyclic phosphazenes or of acyclic phosphazenes as substituents on inorganic rings can be found in sections

.

3-6.

CvcloDhosphazenes Focused reviews of various aspects of cyclophosphazene chemistry including the relation of exocyclic substituents to polymerizability and synthetic transformations of organometallic and bioactive phosphazenesn, a summary of variables involved in the synthesis of bicyclic phosphazenes from aminocyclotetraphosphazenes,74 synthesis of cyclic organophosphazenes, (R,PN),-,, by the thermolysis of phosphoraniminesE, polyamine derivatives of N,P,Cl, with emphasis on medicinally significant materials76 and polymers with cyclophosphaz ene substituents in medic ina1 chemis tryn have appeared. A brief comparison of phosphorus-nitrogen bond lengths relative to phosphorus-oxygen systems leads to the suggestion 3.

8: Phosphazenes

377

of some multliple bond character in the former.78 Ab initio MO calculations on (NPX2)3 (X=F,H) show that while geometric aspects can be described without d orbitals, they (3d) are required to properly describe the electronic structure. The A system, while highly polarized, does contain elements of both the delocalized (Craig and Paddock) and three-centered (Dewar) models which have previously been invoked for these molecules.79 Raman vibrational data have been obtained for (NPX,), (X=F,Cl) under high pressure. The behavior of various normal modes differ significantly in the two systems and is correlated to the electron withdrawing (X=F) or donating (X=Cl) character of the substituent .80 Raman and near-infrared reflectance studies of N3P,C1, stabilized collodial alumina dispersions suggest that hydrogen bonding between the solvent and the phosphazene along with phosphazene binding to the alumina surface occurs.81 Photo-degration and photo-cross linking reactions of poly[bis(4-benzolyphenoxy)]phosphazene can be quenched by energy transfer to hexakis(2-napthoxy) cyclotriphosphazene." Several NMR investigations of cyclophosphazenes have been reported. Line broadening in the 31 P NMR spectra suggest absorption of N,P,C1,83 and Nip, (OCH,CF,) onto colloidal alumina. The temperature dependance of the 31 84.85 P and 13C" NMR spectra of N3P3Ph6-,Cl,(n=2,4,6) and a wide range of spirocyclic derivatives , N,P3Ph2C1,[ X (CH,) "Y] , show significant variations which, in favorable cases, allow for resolution of overlapping peaks. Non-equivalence of methylene protons in the spirocyclic rings was observed in the 'H NMR spectra and was related to conformational properties of the The 31P data were subjected to a dual exocyclic ring." substituent parameter analysis generating (within the limits of validity of this model) values for uR and u I . The former, while significant, was relatively unchanged and the later showed wide variability." An analysis of the 31Pchemical shift data for polyamine derivatives of N3P,C1, indicate that the data is transferable from one molecule to a new system. Parameters include a basic shift for each structural type and an increment related to the bond angle at p h o ~ p h o r u s . ~ ~ Systematics in the NMR spectra of bicyclic phosphazenes have been disc~ssed.~' The ESR spectrum of a phosphazene with a nitroxide spin label, 2 2 , shows only a singlet due to spinspin exchange. The Curie-Weiss law is obeyed indicating no

68'

378

Organophosphoms Chernistry

antiferromagnetic spin exchange.88 Dipole moment determinations show that N3P,(OC,H,-p-X) (X=H, C1) have the same phenoxy conformation and that the solution conformation differs from that obtained in the solid state (sect. 7).89 Extension of these measurements to a wide range of aryloxy and the P-Naphthyloxy derivatives and analysis by vector addition of component bond moments show that differences arise due to rotation about the phosphorus-oxygen bond.90 New basicity data has been reported for various amino substituted cyclotrimers and tetramers Separation of bicyclic cyclotetraphosphazenes by HPLC has been achieved.74 The reactions of (NPC1,) 3 , 4 and N,P, (NHEt),C1, with excess pyrrolidine lead to the known pyrrolidine derivatives and the amidinum salt CH3(C,H,N)C=NH*HC1 the formation of which was shown to be promoted by the phosphazene." The complexities of the reactions of polyamines with N3P,C1, continue to be of interest. The addition of N3P3C1, to spermidine under high dilution conditions leads to 23 (X=C1) in which both spiro(2,2) and ansa (2,4) bridging is achieved by the same amine. Reaction of 23(X=C1) with diaminopropane leads to 23 (X,=NH(CH,),NH) in which spirocycle formation occurs at the remaining =PC1, center. The remaining chlorine atom resists substit~tion.~'The high dilution addition of N3P3C1, to NH, (CH,),NH ( CH,) ,NH (CH,),NH2 gives 24 : which is the commonly obtained structure, as a minor product and the dispiransa derivative 25(n=2) as the major product. The analogous reaction of NH, (CH,) ,NH (CH,),NH (CH,),NH, gives only the dispiransa structure, 25 (n=4).92 The reactions of dioxodiamines, NH, (CH,). O (CH,)"0(CH,) ,,NH, (m=n=2: m=3, n=2 ; m=3, n=4) with N3P3C1, lead to the ansa derivative, 26, or under phase transfer conditions, the spirocyclic derivative, 27 .93 Addition of N3P3C1, to the trioxodiamine, NH, (CH,) 3O(CH,),O (CH,),O (CH,)3NH, results in formation of the ansa derivative analogous to 2 6 while reverse addition gives the spiro derivative analogous to 27.94 The kinetics of three diamine-N3P,C1, reactions have been followed by 31P NMR spectroscopy. The reaction of NH,(CH,),NH, leading to the spirocyclic derivative is the fastest with activation parameters similar to those of methylamine. The use of NH, (CH,) ,NH, leads to the bino derivative, N3P3C1,NH(CH,),NHN3P,C1,, at a slower rate with parameters

."

379

8: Phosphazenes

I

I

,N-l

N “,

P N@ N‘

(5H2In

II,Nl

I

CI P

(C H2I3

I

c I*P %N’

P ‘CI

H

L i (THF), I

(29)

C p -Fe

-Cp

Cp-Fe-Cp (31)

380

Organophosphorus Chemistry

similar to dimethylamine (larger AH’, less negative AS’). The aminomethylether, NH, ( CH,) ,O (CH,) ,NH, gives an ansa derivative similar to 26 and in this case the intermediate, N3P3C1,NH(CH,) 3O (CH,) (CH,) ,NH,, is observed. The rates are much slower with both AH’ and AS’ being increased over the other diamines.% A series of monospiro derivatives N,P,Ph,Cl, [ X (CH,) ,,Y3 (X=Y=O, NH, n=2-4 : X=O , Y=NH , n=2-4 : X=Y=NMe, n=2,3; X=NH, Y=NMe, n=2,3; X=O, Y=NMe, n=2) has been prepared for NMR studies (vida ante) .85 The cytotoxic effects of some new aziridinylcyclophosphazenes have been reported.96 Inorganic syntheses preparations of N,P,Az,Cl,-, (Az = aziridine: n=l, 2 (cis, trans, gem), 3 (gem)) 9 7 , N3P3Az2(NHMe), (cis, trans, gem)97, N,P4AznCl8-, (n-1, 2 (trans-2,6, cis-2,6, trans-2,4, gem, cis-2,4), n=3 (2,2,6 and cis-2,6-trans mixture, cis-2,4-transtrans-2,6-N,P, (NHEt)$lgQ8, 2,6 6)97, trans-2,6-N,P4Az2 (NHMe) and the bicyclic and 2,4-N,P4 (NHCMe,) 2C16,98N,P, (NHCMe,) compounds N,P, (NMe,) (NHEt)NEt98 and N,P, (NHEt),NEt9’ have been reported. The reactions of the sodium salt of propargyl alcohol gives rise to the series N,P3Cl6-,, (OCH,CeCH), (n=l-6) in which non-geminal regioselectivity and trans stereoselectivity is exhibited at the bis stage of substitution. Significant amounts of the geminal tris, but not tetrakis, derivative are observed. The phenoxy derivatives, N3P,(OPh)6-,, ( OCH2C=CH),, (n=l,2) can be obtained from the propargyloxy precursors.99 Persubstituted derivatives of N,P,Cl,OCH=CH, are available with -OCH2CF3, -0Me and -NMe2 substituents. The exhaustive dimethylaminolysis of 2,4-N,P3C14(OCH=CH,) followed by NMR (lH and 31P) analysis shows a slight excess of the & over trans isomer.loo The synthesis of N,P3 (OC6H,-p-R) (R=Et, CMe,, OMe, SMe, NMe2) and N,P, ( OCHpCH) can be effectively accomplished using the appropriate thallium oxyanions lo’ Further studies on the remarkable geminal to non-geminal isomerization upon with oxyanions have been derivitization of 2,2-N3P,C1,(NH,) reported. The use of OCH,CF,- gives both rearranged and unrearranged products while for OR- (R=Et, n-Pr, n-Bu) only rearranged materials were isolated. On the other hand, the pyridine induced reactions of the alcohols ROH(R=Me, Et, Pr, i-Pr) show no rearrangement nor did the reactions of 2,2N3P,C1, (NHCMe,) or 2,2 ’ -N3P,C1, (NH2)N=PPh, with oxyanions.

697,

898,

,, ,

.

8: Phosphazenes

38 1

Solvent effects have also been explored. In the tetrameric series 2,2-N,P4C1,(NH2), gives 2,2 and 2,6-N4P4(0Me),(NH2), while no rearrangement occurs in the reaction of the 2,6 isomer.lo2 The derivatives, N3P3[ 0 ( CH,CH,O) ,,,C6H4N=NC6H,X]6 (X=H, m=0-3 ; X=OMe, m=0-3), have been prepared and one (X=OMe, m=2) exhibits liquid crystal behavior. ‘03 The protected gylceral phosphazenes 2 8 (R=R’=H, Me; R=H, R1=OMe)lo4as well as the aryloxy ester, N3P3( OC,H,CO,Et) ,lo5 have been reported. The sulfonates , N3P3C1,0R (R=C,H,SO,Na , SO,C,H,ONa) as well as N3P3( OC,H40C2H,0Me) 50C2H4S03Nahave been prepared. lo7 Several mixed phenoxy and aminophenoxy derivatives of N3P3C16with various substituents on the phenoxy and aminophenoxy functions have been patented. lo’ Hydroxyethyl methacryl derivatives continue to be of interest. A preliminary examination of the preparation and phosphazene-phosphazane rearrangement of C (Me)=CH2lo0as well as the preparation of N,P,Cl,OCH,CH,OC (0) mixed substituent tetramers containing the same substit~ent’~~ have appeared. The use of zinc oxide to promote the reaction of hydroxethyl methacrylate with N3P3C1, has been noted. ’lo Patents for 4-maleimidophenoxy”’ and hydroxymethylphenoxy”’ phosphazenes are available. The reactions of N3P3C1, with hydr~quinone”~’~’~ and re~orcinal”~ give rise to the 1,4 and 1,3 bridging diols, N,P3C1,0C,H,0N,P3~1, respectively. Oligomeric materials, N3P,C1, [ OC,H40N3P3C1,] nOC6H,0N3P3C1, and a 2,4 dibridged compound, N3P3C1,[OC,H,0]2N3P,C14 ( 2 9 ) , are also available from hydroquinone.‘13 An inorganic syntheses preparation of N3P3C1,0CH=CH, has appeared.’15 The fall off in the number of papers dealing with organometallic reactions of cyclophosphazenes noted last year has continued. A comprehensive study of the reactions of trimethylaluminum with N3P3C16 leading to N3P3C1,-,Men(n=1-6) has been reported. At the stage of disubstitution, a geminal/nongeminal mixture is obtained but only geminal products are obtained at higher degrees of substitution. A ring opening reaction, leading to (Me3P=NPMe2=NPMe2NH2) ‘Cl-, is competitive with the substitution reactions.’16 The copper phosphine catalyzed reaction of i-C,H7MgC1 with N3P3C16 followed by addition of aldehydes on ketones to the intermediate anionic phosphazene gives the novel alcohols, 2,2’N3P3C1,( C3H7)CR1R20H. ‘17 As opposed to enolate anions, the sodium

382

Organophosphorus Chemistry

salts of diethylmalonate and diethylmethylmalonate react with N3P3C1, by attack at the carbon, not oxygen, end of the nucleophile. The malonate derivative easily decomposes via tautomerization to a ylid having the =(NH) P=CR, unit. '18 Treatment of the transannular phosphazene [ N3P3F,Cp2Fe]( Cp=n5C5Hs) with LiBEt,H gives 3 0 thus suggesting the coordination of cations to endocyclic nitrogen centers in phosphazene Thermolysis of [N3P3(OPh),CP2Fe] gives the cyclic anions. '19 hexamer 31.120 Inorganic syntheses preparations of N3P3C15CH2SiMe3 and 2,2 -N3P3C1,(Me)CH,SiMe, are available. Reactions at exocyclic positions of cyclophosphazene derivatives allow for construction of substituents that are not available by direct reactions. Treatment of the ester function in N3P3(OC,H,CO,Et) with potassium tert-butoxide leads to the free carboxylic acid which can be converted to the acid chloride and n-butylamide by use of thionyl chloride and nbutylamine respectively.lo5 Hydrolytic deprotection in acid media of protected glyceral phosphazenes ( 2 8 ) gives N3P3[OCH2CH(OH)CH20H]6.'04 The Wittig reaction of N,P,(OC,H,CHO) and stabilized phosphonium yields to the styrene derivatives N,P3 (OC,H,CH=C (R)X) (R=C02R' , R ' =Me, Ph , X=H, Br , Me) .122 Exposure of N,P, (OCH2CH20CH2CH20Me)to y-irradiation was studied to model cross linking behavior of the corresponding polymer.lZ3 Oxidative coupling of N3P3(OPh),OCH,C=CH leads to the interesting diactylene N3P3( OPh),OCH,C=C-C=CCH20N3P3(OPh) .99 Radical addition polymerization of the olefinic centers in N3P3C150CH=CHz115 and the hydroxy-4 -vinylbiphenyl derivatives, N3P3X,0C6H,C,H,-p-CH=CH2 (X=F,C1) , 124 gives high molecular weight polymers with the latter showing increased thermal stability over the corresponding materials without the phosphazene. The same rate of polymerization was observed in the chloro- and fluorophosphazene vinylbiphenyl monomers indicating a lack of significant perturbation of the olefin by the phosphazene.124 A preliminary communication of the radical addition homopolymerization and copolymerization (with methyl methacrylate) of N3P3C1,0CH,CH20C ( 0 )C (Me)=CH, has appeared.loo Analogous polymerization of the tetramers, N,P, (OR) [ OCH,CH,OC ( 0 )C (Me)=CH2] gives cross 1inked solids in which the relationship of mechanical properties to the nature of the substituent R has been examined.lo9 A preliminary communication concerning the radical polymerization and

,

,

383

8: Phosphazenes

copolymerization of 2,2 -N,P3C1, (i-C,H,) CH (OH)C,H,CH=CH, as well as of the methacyloyl esters of 2 , 2 I -N,P3C1, ( i-C3H,) CH (OH)CH, is A detailed study of the copolymerization of available.'I7 both 3- and 4-(l-methylethenyl)phenylpentafluorocyclotr~phosphazene, N,P,F,C,H,C (CH,) =CH,, with styrene and methyl methacrylate has been conducted. Reactivity ratios and Alfrey-Price parameters for the styrene system show that the major electronic interaction of the arene and phosphazene rings is a polar a-electron withdrawing effect. The mechanism for the methyl methacrylate copolymerization showed major contributions from penultimate effects. The applications potential of cyclophosphazenes is apparent from the large number of patents and applications oriented studies which have appeared this year. The use of phosphazenes as flame retardants continues to represent the area of greatest activity. A comprehensive structure-activity study of the oxygen index, and thermogravimetric characteristics of several cyclo- and cyclolinear phosphazenes shows that flame retarding efficiency is in the following order NPCl,>NP (OR,)Cl>NP (OR,),>NP (OR,) (OR)>NP (OPh)Cl>NP(OR) (R,=CH,(CF,),H, n=2,4,6; R=alkyl) .126 Similar studies on bromaryloxy phosphazene treated rayon fiberlZ7 and chloroethoxyphosphazene containing phenolic foams128have been reported. Other substituents for flame retardant cyclophosphazenes include aminoaryloxy ,lo8 4-maleimidophenoxyI'11 hydfoxymethylphenoxy''2 and a l k ~ x y "groups. ~ Amido phosphazenes have been used to impart flame retardency to cellulose fibers.130-133 Variations in the process in order to improve retention on washing have been studied.13'-133

,

A m i d o p h o ~ p h a z e n e s ' ~ ~ and - ' ~ ~aminophenoxyphosphazenes13s"~have

been used as curing agents for expoxy resins and various thermal and mechanical properties have been measured. Composites and laminates can be constructed from Nadimid~',~ and 4-maleirnidopheno~y'~~ phosphazenes. Silicone release films C ( CH,) =CH,] have been prepared. 139 derived from N3P3[ OCH,CH,OC (0) Fluoroalkoxy140and mixed phenoxy-fluor~alkoxy'~~ cyclophosphazenes have proven to be suitable materials for rotary pump lubricants. Hexaethoxycyclotriphosphazene has been used as a plasticizer for PVC membranes.',, Cyclophosphazenes have been employed as catalysts in the Primary amino polymerization of siloxanes.1 4 3 n 1 4 4

Orgunophosphorus Chmistry

384

cyclophosphazene derivatives are useful in controlling the premature vulcanization of methylvinylsiloxane units by H,PtCl,. 145 Ziegler-Natta catalysts for use in the stereospecific polymerization of olefins can be modified by the addition of N,P,(ECH,CF,), (E=O14,, S'47)

.

Cvclophospha(thia)zenes Reports of new phosphia(thia)zene chemistry this year are largely restricted to systems containing two and three coordinate sulfur centers. The donor properties of the 1,5(PPh,) ,N,S, ring system (32) have been explored.148 The nitrogen centers act as Lewis bases in the 1:l adducts with BCl,, Me' and H ' . X-ray data shows a shortening of the Preliminary sulfur-sulfur bond and lengthening of the phosphorus-nitrogen bond. Dimethyl and diprotic adducts are mixtures of the two regioisomers where the adjacent nitrogen (1,3) and cross ring (1,5) nitrogen centers act as donor sites. Ab initio calculations show that the two regio isomers are similar in energy. In the 32-Pt(PPh3), complex, v2 sulfur-sulfur ligand to metal bonding is observed.148 The 1,3-(PPh,)N4S2 ligand (33) also exhibits Lewis base behavior giving 1:l adducts with BX,(X=F,Cl) , SnCl,, H+ and Me+ in which the nitrogen atom between the phosphorus and sulfur atoms is the reactive site. Ab initio calculations on 1,3-(PH,),N,S, suggest that the regioselectivity is due to electrostatic effects and allow for rationalization of the conformational changes and electronic spectral shifts which occur on adduct formation.'49 Interest continues in cyclothiazenes with exocyclic phosphazene moieties. The reaction of Ph,P=NS,N, with various amines gives the ring expanded product 1,5- (Ph,P=N) ,S,N, in good yields.150 Unsymmetrically disubstituted cyclotetrathiazenes, 1,5(Ph,P=N) [ (MeC6H4),Ph,-,P=N J S4N4 (n=l,2) are obtained from the reaction of S,N, with mixtures of the two phosphines in que~ti0n.l~'The reaction of SC1, with Me,SiN=PPh,NP=C (PH)N ( SiMe,) leads to 34 which undergoes dechlorination with SbC13 to the two coordinate sulfur cyclophospha(thia)zene radical, [NPPh2NCPhNS]'. The esr data for the radical shows that the spin is distributed over the PNS region of the ring.'52 The reaction of SCl, with 14 leads to the cyclotetraphospha(thia)zene 35 which undergoes an analogous reductive dechlorination upon treatment with SbPh, to 4.

,

8: Phosphazenes

Ph,P//

385

CI

N ‘PPh,

N’

I

\N

+s

“/

s’

I

CI (34)

(35)

2

R

N

\

Ph

N4

PPh,

I

y”y’ YXP,

I “*,AR. R“0’

O ‘R

R

N ‘

N//C\N

I ,PXY

YXP,

ry2 Ph,P=N

N’

II CR

386

Organophosphorus Chemistry

give [Ph,P,N,S]* as the major product.153 A minor product, the spirocyclic material 36 is also obtained in the reduction.154 The esr spectrum of [Ph,P,N,S]* is temperature dependant due to conformational changes and provides the first evidence for conformational rigidity in a cyclophosphazene.153 An inorganic synthesis preparation of 37 (E=S, R=C1, X=Y=Ph) is available.lS5 Complexes of the anionic ligand [NP(NH,) ,],NSO,(37: E=S, R=O, 0, X=Y=NH,) having the formulae Cr$*9H,O and ML,*8H,O (L = the phospha(thia)zene anion; M=Co, Nil have been reported. It has been proposed that coordination occurs through an oxygen atom in the chromium complex and through a nitrogen atom adjacent to the sulfur atom in the ML,-8H2O complexes.156 Other, related, materials may be found in section 5. Miscellaneous Phosphazene Containincr Rinq Systems. Phosphatriazenes (azaphosphorins, triazaphosphinimes) which are formally related to symmetrical triazines by replacement of a =CR unit with a =PR, unit continue to receive renewed attention. The reactions of 38 (R=R1=CF3,X=Y=F) with N-lithiocyclosilazanes provides several systems with linked phosphatrizine and cyclosilazane rings as in derivatives of (Me,SiNH), where either one or two nitrogen centers has a phosphatriazene substituent. In other systems, the lability of the anionic cyclotrisilazane results in the formation of (R=n-Bu) cyclodisilazane substituents e.g. - F i w S i R , F 1 The reaction with and -N (SiMe,F)SiMezy SiMe, S,iMe,-hSiMe,. (LiNHSiR'),NH (R'=ipr) give spirocyclic materials derived from ring closure at phosphorus by the -NHSiR,'NHSiR,'NH- unit. If 38 (R=R'=CF,, X=Y=Cl) is allowed to react with (LiNCMe,),SiMe,, the spirocyclic derivative from closure of the - (CMe,) SiMe,N (CMe,) - unit is observed.lS7 The structural parameters for 38 (R=R'=CF3, X=Y=NC2H4)which is available from the reaction of aziridine with the appropriate dichloro phosphatriazene, have been compared to various Dipole moment studies show cyclophosphazene derivatives.'51 that the coordination of SbC1, in the 1:l adducts with the series 38 (R=R1=CC1,, X=Y=Cl, X=Y=Ph; R=R1=CF3,Y=Ph; R=Ph, R'=CCl,, X=Y=Cl) 'occurs at the nitrogen atom in the CNC fragment.159 The reaction of PhC (=NSiMe3)N ( SiMe3) with PhPCIZ 5.

,

3 87

8: Phosphazenes

gives a derivative in which two phosphatriazene, 38 (R=R'=NMe,, X=Ph) , units are linked by a -PPh-PPh- bridge.160 A bicyclic cyclotetramer, 39, was obtained in the reaction of PhPCl, with The reaction of R'C(Cl)=NNHPh with [Me,NC(NH,),JC1.la (RO)(CR' 0)PNCO gives 4 0 , the hydrolysis of which leads to 4 0 Inorganic syntheses preparations of with a =P(OR) OH center.16' 37 (R=Ph, X=Y=Cl, X=Ph, Y=Cl, X=Y=Ph; R=Me,N, X=Y=Cl) are available.162 Metallocyclic species based on transition or main group metals and metalloids are of interest. The reaction of Me,SiN=PPh,CH,PPh,=NS iMe, with GeC1, gives Cl,keN=PPh,CH,PPh,=h Replacement of the chlorine atoms by azides followed by a Staudinger reaction with Ph2PCH2PPh2gives the spirocyclic derivative, G&[N=PPh,CH,PPh,=h],. The reactions of transition metal halides or oxides with Ph,PCH,PPh,=NSiMe, gives a series of metallocycles, 4 1 [X=M(COD), M=Rh, Ir; X=Rh(CO),; X=M(CO),, M=Mo, W; X=ReO,(OSiMe,)]. Some analogous complexes derived 164 The from Ph,AsCH,PPh,=NSiMe, have also been reported. Ph,PCH,PPh2=NSiMe3 ligand can also act as a neutral donor with retention of the SiMe, functionality to give 42.16,' '64 The phospha(vanda) zenes 37 (E=V, R=C12, X=Y=CF,) is obtained from The the reaction of (CF3),P(Cl) =NSiMe, with Me,SiN=VCl,. '61 cyclotetraphospha(thiatungsta)zenes,43 (X=F, Cl),isobtained from the reaction of Me,S(N=PPh,NSiMe,), with WX, (X=F, C1) . l M Elimination of Me3SiF in the reaction of Fe (CSH4PPh2=NSiMe3) with WF, gives a cyclic derivative of ferrocene where the two cyclopentadienyl rings are bridged by the -PPh,=NWF,N=PPhmoiety.

.

,

6.

.

Poly (phosphazenes)

This section is devoted to polymers containing open-chain phosphazenes. Cyclolinear and cyclomatrix phosphazenes are covered in section 3 . Reviews covering the following topics have appeared: the relationship between exocyclic groups and ring opening polymerization of substituted cyclotriphosphazenesn, substituents on poly (phosphazenes) with potential biological activityn, preparation and properties of ,'61 poly (organophosphazenes) conducting poly (phosphazenes) derived from reactions of poly(dichlorophosphazene), (NPCl,),, and the use of these materials in biology and medicinelm, synthesis of poly(organophosphazenes) from thermolysis of

Organophosphorus Chemistry

388

Ph, N-P+ N

MeZS4 II N ,

I

P=N ph,

Si Me3

(43)

(42)

Ph,

7-c N‘ CI,Au \

I

,WXY

/

S-PPhz

(44)

Ph,

389

8: Phosphazenes

phosphoraniminesE, mesophases in poly (phosphazenes)169, compounding of poly(phosphazenes) for military applications (e.g. flame resistance, low temperature flexibility and solvent resistance)1 7 0 , poly (phosphazenes) as low surface energy171and flame retardant17' inorganic polymers and a brief summary of poly(phosphazenes) in the context of advanced inorganic polymers. lTJ There is continued interest in the synthesis of poly(phosphazenes) from small molecule precursors. The use of ionic sulfates as catalysts in the solution polymerization N,P3C1, has been patented. 1740175 The effect Of N,P,Cl, On N3P3C1, polymerization is complicated, initially inducing acceleration of polymerization while at higher conversions a retardation is observed.176 Ambient temperature plasma polymerization of N3P,C1, gives high molecular weight (NPCl,), as well as The ring opening polymerization phosphazene oligomers behavior of 2,21-N,P3C14(CH2SiMe3)R (R=Et, i-Pr, n-Bu, t-Bu, neopentyl, Ph) was compared to the non-silylated analogs, 2,2'N3P,C1, (Me)R. The presence of the trimethysily group favored polymerization while sterically demanding cosubstituents such as t-butyl and neopentyl retarded polymerization. Under certain conditions, carbon-silicon bond cleavage can also occur leading to polymers in which the -CH2SiMe3 group is An inorganic synthesis transformed to a methyl group.17' preparation involving the ring opening polymerization of 2,2lN,P3C1, ( CHzSiMe3)CH3 has also appeared.lZ1 A novel ring opening polymerization of a fully substituted phosphazene trimer occurs if the transannular bridged ferrocenylphosphazene, N3P3(OCHZCF3),[ (q5-C5H,),Fe] is heated in the presence of a catalytic amount of N3P3C1,. If the trifluoethoxy groups are replaced by the more sterically demanding phenoxy moiety only ring expansion products are observed (section 3) .lZo The first poly (metallaphosphazenes), [ N=MC13N=PPh2N=PPh2] ,, (M=Mo, W) have been prepared by ring opening polymerization of 37 (E=Mo, W; R=Cl,, X=Y=Ph). The new polymers, which have modest molecular weights, are thermally and hydrolytically stable.179 Inorganic syntheses preparations of (NPRRl) (R=R1=Me;R=Me, R'=Ph) &y thermolysis of phosphoranimines have appeared. Phosphorus nitride or phosphorus oxynitride can be transformed to Li,PN,O which in turn is thermally decomposed to Li,PN,.la0

.

390

Orgutioph osphorus Chemistry

The synthesis of poly(ph0sphazene) derivatives by single or multistep reactions of poly(phosphazene) precursors continues to represent the major pathway to new members of this class of materials. The reaction of an oxyanion with (NPCl,), is the most common synthetic procedure in this area. Protected glyceral poly(phosphazenes) analogous to the cyclic homologs, 2 8 , have been prepared and may be crosslinked by exposure to y-irradiation. Acidic deprotection yields the free glyceral substituted polymers which undergo slow hydrolysis. The deprotected polymers can be crosslinked using adipoly chloride or hexamethylene diisocyanate to form materials which form hydrogels upon uptake of water.lo4 The oxyanion route also provides the series, { NP [ 0( CH,CH,O) ,,,C,H,N=NC,H,X] ) , (X=H, m=0-3 ; X=OMe, m=0-3 ) of which certain members (X=OMe, m=2,3) are thermotropic liquid crystals.lo3 Mixed substituent trifluoroethoxy poly(phosphazenes) containing either cyclopentadienylethoxy or dicyclopentadienyldiethoxy cosubstituents undergo crosslinking Diels-Alder dimerization which is, in part, reversible. The crosslinking can be blocked by addition of maleic anhydride.la' Inorganic Syntheses preparations of [ NP (CH,SiMe,) (Me)(NP(OCH,CF,) ] , and [ NPMe, (NP(OCH,CF,) ,) ,] , are available. Phosphazene polyelectrolytes of the type [ NP (OR) (0(CH,),S03Na) , (R=MeO(CH,) ,O , Me0 (CH,),O ( CH,) ,O) have been prepared by the sequential reaction of (NPCl,), with Crown ether containing NaO (CH,),SO,Na and RONa.'06"07 poly(phosphazenes) , [NP(O(CH2),R)2], (n=3,6; R=16-crown-5) and their sodium salts have prepared. Patents describing the preparations of a wide variety poly(ph0sphazenes) have appeared. These include: phosphazenes with oligoether side chains which can be employed to trap transition metal cations or function as catalysts for organic reactionsla3, derivatives derived from the displacement of OCH,CH, by OCH,CH,OMela, systems arising from partial displacement of 2-methoxyethoxy groups by 2-aminoethoxy groups which were subsequently amidated by propionyl chloride and mixed with LiC10, to give solid electrolyte^'^^"^, displacement of the CH2CF3 unit in y reactions with OCH,CF, substituents by ethyl groups & Grignard preparation of [NP(O(CH,CH,0)o.5Me) 1.62(O(CH2CH20)6.5(CH2)3S03Li)0.381n which can be

,

,

'"

8: Phosphazenes

39 1

used as gas separation or ion exchange membranes'= and 189 polymers from partial replacement of OCH2CF3 by OCH,CH,OH. Thallium aryloxides such as TlOC,H,-p-R(R=Et, t-Bu, OMe, SMe, NMe,) are useful reagents for the synthesis of [NP(OC,H,-p101 R)2]n The carboxylic acid containing poly(phosphazene), [ NP (OC,H,CO,H) ,] ,, which is obtained by base hydrolysis of a corresponding ester does not undergo crosslinking upon exposure to y-irradiation. Treatment with sodium carbonate gives the sodium carboxylates which are water soluble and form crosslinked hydrogels with polyvalent cations.lo* Hydrogels are also formed by y-irradiation induced crosslinking of [ NP (OCH,CH,OCH,CH,OCH,) ,] ,,Iz3. A patent describing poly(phosphazene) synthesis by exchange of -OCH,CF, by -0Ph substituents is available.I9O Mixed substituent, [NP(OR)x(NHMe)Z-x]n (R=OCH,CF,, OPh) , polymers obtained by sequential reactions of (NPCl,), with the oxyanion and methylamine are cross linked by exposure to y-irradiation to give semipermeable membranes.19' Hydrolysis of mixed substituent, [NP(NHEt),(OEt) polymers induces partial substitution by hydroxide. These materials are soluble in water at low temperature and reversibly form gels with increasing temperature.19* A careful study of the hydrolysis of [NP(OCH2CF3) ,In shows introduction of 5-7% hydroxy substitution. The strongly acidic materials are believed to exist in the hydroxyphosphazene rather than the NH- , fo m . 193 Sulfonation of the phenyl oxyphosphazene, =P (0) groups in [NP(OPh),], by SO3 gives the water soluble, partially sulfonated, materials which can be converted to the sulfonyl chlorides by reaction with SOC1,. The reaction of the sulfonyl chloride with glycine leads to the -OC6H4SOZNHCH2C02H function which undergoes decarboxylation to the -OC,H,SO,NHCH, function.194 A graft copolymer involving poly (phosphazenes) has been prepared by treatment of poly(bis(4-methy1phenoxy)phosphazene with N-vinyl-2-pyrrolidone in an aqueous Cu(NO,), The slow hydrolysis of solution followed by y-irradiation.'91 poly(phosphazenes) with amino and ester substituents has been utilized to provide slow release of unstable anticancer agents which can be physically incorporated into the polymers. 196 Investigations of physical properties of various poly(ph0sphazenes)are of continuing interest with a major focus being on phase changes. Single crystals of [NP(OC6H4-~-F),], in

.

392

Orgurioyhosp horus Chm i s t y

bulk films have been studied by electron microscopy and diffraction techniques which yield lattice constant data. 197 Twinned crystals of the same polymer are obtained by cooling from the thermotropic state of room temperature. The room temperature structure is a three-dimensional orthorhombic Crystal structure data along with glass transition system.19’ temperatures (Tg) and transition to the mesophase temperature (T1),m.p. and degradation temperatures have been reported for several partially crystalline poly(phosphazenes) containing Ph, OC6H4-p-X (X=H, Br, C1, I, Me, Ph) , 2-naphthyl, Me and OMe substituents. Thermotropic (T1) and polymorphic behavior vary widely with substituent and rates of temperature changes. NMR spectroscopy is rapidly becoming a major tool for evaluation of solid state properties of poly(ph0sphazenes). Solid state, MAS, 13C and 31PNMR has been used to study phase transitions and change in chain conformation in [NP(OC,H4-~including the first MAS-NMR study of a phosphazene Et)‘3 mesophase transition.201 Below the mesophase transition, the 31 P spectra show three chemical shifts of the backbone in the crystalline, interfacial and amorphous phases.201 A comparison of the aforementioned ethylphenoxy and the corresponding tbutylphenoxy system shows a similar phase transition behavior with the bulky effect of the t-butyl group being manifested in a higher Tg value.‘02 Room temperature 31PMAS NMR spectra of [ NP (OC6H4-m-CH,)‘1 show at least two different morphological domains. ‘03 Similar studies on [ NP (OCH,CF,) 2] confirm the existence of two distant crystalline and amphorous regions below T(l), the ratio of which can be quantified, and a highly The use of ‘H NMR mobile two-dimensional phase above T(1) .‘04 gives preliminary data on water catalyzed polymerization and crosslinking of (NPC1,) n . 203 A NMR and dielectric spectroscopy study of the liquid crystalline [NP(OCnH2,,),], (n=1-12) polymers allows for an examination of side chain reorientation and shows that the motion becomes independent of the main chain for n>4 .‘05 Evidence for stabilization of collodial (MEEP)83J206, dispersions of alumina by [ NP (OR)‘1 [ R=C2H40C2HCOCH3 CH,CF,206] has been obtained from 31PNMR spectroscopy. A recent area of intense activity is the use of cationic complexes of poly(phosphazenes) with Lewis base substituents (usually polyethers) as a basic component of solid, thin film, polyelectrolytes. General issues such as Salt selection, Tg,

’*

8: Ph osphazen es

393

and measurement temperature involved in fast ion conductivity of poly(ph0sphazenes) with polyoxyethylene and polyoxypropylene side chains have been discussed.,07 A significant effort continues on the use of MEEP (vide ante) based systems. Lithium MEEP salts derived by reactions of LiCF3S03 or LiC10, have useful and stable conductivity for two months and in combination with TiS, produces cells which can attain a high current efficiency 208'209 The cell shows polarization during transfer of Li+ from TiS, and evidence for incomplete reoxidation following reduction was obtained.209 The dimensional stability of LiCF,SO, MEEP complexes is improved, without loss of conductivity, by y radiation induced crosslinking.'" Detailed ',Na NMR, electrical conductivity and DSC studies have been reported for the MEEP NaCF,SO, complex. The material exhibits properties typical of an amphorous ionic conducting polymer. Motional narrowing of the NMR spectrum above Tg was observed and line width data reflect localized motion.211 A new clpss of cation conductors based on [ NP (OR) ( OC2H4S03Na) ( R=C2H,0C2H40Me, C2H40Me) have been studied. 106,107,212 Electrical conductivity studies show poor conductivity probably due to sulfate sodium ion pairing. lo7 The conductivity can be substantively improved by the addition of 2,2,2 cryptand.212 Other new conductivity studies have been conducted on [ NP (OC,H,OC,H,OMe) [ ( OC,H4NR,R1 ) +X-J n, lo7 poly (phosphazenes) with pendant 16-crown-5-ethersI mixed 2methoxyethoxy/2-aminoethyoxy poly(phosphazenes) which have been amidated and complexed with LiC104'"'213 and mixed 2methoxyethoxy/Li benzoates.214 The electrical properties (dc conductivity, temperature dependance of total conductivity, etc) of [NP(OC,H,OPh),], and its AgSO,CF, complexes have been examined.215 Doping of [NP(oc~H~-x) ,I , (X=SMe, NMe,) with I, has been reported with the latter polymer being the most highly conducting phosphazene polymer yet reported. lo' The redox properties of the ferrocenyl poly(phosphazenes), [ N3P3 ( OCHZCF,15C5H4FeC5H5I n and [ N3P3F4 ( C5H41ZFe1n [ N3P3( OCH2CF3J Li (C,H4),Fe ] have been examined using cyclic voltametry and related techniques. An unexpected enhancement of the rate of charge transport in bridged ferrocene substituted materials (see 31 for a cyclic analog) relative to the pendant ferrocene substituted systems was observed.216

.

394

Organophosphorus Chsnistry

Other physical studies have also been persued. The ssparation characteristics of poly(phosphazene) membranes are of interest. The separation properties of [NP(OPh),In membranes are diffusion (size related) controlled for atmospheric and hydrocarbon gases while transport of CO,, H2S and SO, are sorption controlled.217 Studies of various poly(ph0sphazene) membranes show that the highest gas permeability was observed for [NP(NHPr) (NEt,) 3 , while [NP(OC6H41-Cl)2 ] , exhibited the highest 0, to N, selectivity.218Membranes from [ NP (OR),] (R=Ph, CH2CF3)have been used to separate components of aqueous alcohol solutons.219 The membrane forming properties of related materials derived from [NP(OR),(NHCH3,,], polymers which were crosslinked by exposure to y-irradiation were Membranes containing [ NP (OCH,CF,) 2 ] and layers of examined.19’ supporting crystalline polymers can be fabricated to hollow fiber membranes for oxygen enhancement.220 Photodegradation and photo crosslinking events for poly[bis(4-benzoylphenoxy)phosphazene] are related to the first excited triplet state of the benzophenone unit and can be quenched with naphthalene or naphthoxycyclophosphazenes.79 IR and SIMS studies show that UV irradiation of [NP(OC,H,-p-ipr),], films generates hydroperoxides on the tertiary carbon of the isopropyl group.221 Thermal and mechanical properties such as abrasion or tear resistance and long term thermal stability of poly(ph0sphazene) fluoroelastomers (fluoroalkoxy copolymers) have been compared to fluorosilicone rubber with the phsophazene having superior performance in the first two catagories.222 Crosslinked poly (phosphazenes) with penta(oxyeth1ene) side chains show catalytic activity in the synthesis of polyamides.223 Numerous applications of poly(phosphazenes), in addition to those noted in detailabove, have been reported. These include: flame retardency in polypropylene224or polyarylene and polyester fibers,22s hydrophobic moldings226, coatings for gel capsules227and rubber like adhesives for semiconductor assemblies.228 Protective layers of PN or PNO for semiconductor devices also have been reported.229 7. Molecular Structure of PhosDhazenes. The following structures have been determined by X-ray diffraction. All distances are in picometers and angles in degrees.

8: Phosphazenes

395

Compound [ P=NR]AlC1, R=2,4 ,6- (Me3C),C6H, (Me3C),P (Se)SePNR R=2 ,4 ,6- (Me,C)3c6Hz

Ref

Comments PN 147.5(8) LPNR 177.0(7)

9

PN 149.3(1)fiNR 169.l(n) Bidentate -PSe2 binding to PNR

10

Me,S (6)=NPPh,=NTi (Cp)Cl,

PN 162.9(3), P=N 159.5(2) LNPN 116.6 (1)

17

Me,S (0) =NPPh2=NV(0) C1,

PN 163.3(3), P=N 160.8(3) LNPN 116.9 (2)

17

Me2S(0) =NPPh,=NTa (C,Me,) C1,

PN 161.5 (4) , P=N 159.6(3) , L NPN 119.7(2)

( Me2CH),NP=NP (NR,) (tmp)=NSMe, P ( I11 ) =N 155.8 ( 3 ) R=ipr; tmp=tetramethylpiperdine P(V)=N 152.6(3) P-N 164.6(3), 167.1(3)

RP (=NR') =NSMe, R=2 ,4, 6-Me3C6H2 R'=2,4 ,6-( CMe,) 3C6H2

,

PpP ( =NR1) =C ( SiMe,) R =2,4 ,6- (CMe,),C6H,

P=N 154.9, 153.3 L N=P=N 135.2

17 24

230

P=N 155.2

230

L N=P=C 129.9

11 (E=NR; R=CMe,)

P=N (exo) 151.2 (2) PN(endo) 170.9(2), 171. (2) L NPN 79.7

25

[ Ph2PPPh,=NPPh2=NPPh2PPh2] + C1 8H20

PN 157.6(6) -158.4 (6) P=NP 136.7 (4), 138 7 (4) LNPN 119.0(3) PN,, 161.9 "P=@ 168.4 Short interior N=N

36

[ (Morph),P=NNN (Et)Ar]Br, morph=morpholino Ar=2 ,4 ,6- (N,) ,C6H,

-

65

[ C13PNPC13] MoNC1,

disordered

66

44

PN 159.4, 158.7(5)

68

First genuine ansa (2,4 231 bridge) ; PN,,, 157.2 (2), 157.7(2), 160.2(3); PN,,, 161.6(3) ;LNPN 116.0(2) (at substtuted P) , 119.3 (2) 26

27

(m=2, n=2)

(m=2, N = 2 )

Macroansa; PN,,, 156.5 (4)159.1(5) ; PN,,, 161.0(4), 160.4 (5); one endo N out of plane

232

macrospiro; PN,,, 154 - 9(3)162.3(3): PN,,, 161.6(3): planar P,N,

232

Organophosphorus Chemistry

396 COmDOUnd

Ref

Comments macrospro : PNed long at substituted P 160.4(5), 161.5(6), others normal 154.9(5)-157.1(6) PN,,, 162.4 (5), 162.3 (6) LNPN 119.4, 120.4

233

PN 157.5(5); PO 157.9(5) 89 LPNP 122.5(3);LNPN 117.4(3) Phenoxy conf. different at one P (OC10h7)6 0-Naphthyloxyl N3P3

PN 158(1) : PO 158(1) LPNP 120(1) L NPN 119(1) Slight deviation from planarity second ring of C10H7over P,N,

90

PN 156.9 (4)-158.9 (3)

113

157.0 (4)-158.6 (3)

N3P3 and C, rings nearly perpendicular N3P,C1,0C6H,,0N3P3C1,

independent determination

114

45

P(Me)N 159.2(2) : P(C1,)N

234

155.0-(2), 156.2(2);

P,N, rings in cis position PN(Li) 167.4(6), 162.6(5) : LNP(B)N 112.7(3) ; considerable deviation from planarity

30

119

34

PN 163.5(4), 162.0(4)

152

35

PN 157.3 (8)-163.2 (7) L NPN 118 0 ( 4 ) - 12 1 .5 ( 4 ) boat conformation

153

33

.

Me+CF3S0,-

PNMe lengthened on adduct formation (168), other PN unchanged: both P displaced to same side of ring

149

PN (moving from SN,) 161(2), 154 158(2) ; L NPN 121.3;1 PNP 132(3)

36

PN, 157.3(4)-163.1(5)

46

235

L NPN 118.8(2)-119.2(3) P,SN,

distorted tub

47

(M+=Na)

PN (mean) 160.3 (5) PN,,, (mean) 165.9 (5) PN long in PNS unit

236

47

(M+=K)

160.0 (3)-162.8 (3) P N ,, PNexo162.9 (4)-169.9 ( 3 ) PN long in PNS unit

236

397

8: Phosphazenes

Ref

Comments

ComDound

159.3(7) , 159.5(6) 162.9(7), 163.3(7) LNPN 1 1 5 . 6 ( 4 ) , 1 1 6 . 7 ( 4 )

PN

39

38 (R'=cF~: X=Y=C,H,N)

37 (E=V; R=C1,;X=Y=CF3)

PN,,, 1 6 3 . 5 (2) 158 PN,,, 1 6 1 . 9 ( 2 ) Compared to cyclophosphazenes PN (in PNP) 1 5 9 . 5 ( 3 ) PN (in PNV) 1 6 1 . 2 ( 4 ) LPNP 1 2 1 . 3 , L PNV 1 2 9 . 0 ( 3 ) Puckered ring with alternating short and long bonds ( 1 5 5 . 4 ( 1 0 ) 1 6 5 . 9 ( 1 4 ) ) ; long PN bonds in PNW

43

160

165

166

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a),

u,

1838. 236. V.I. Soko, L.

Ya Medvedeva, M.A. Porai-Koshits, E.N. Beresnev and I.A. Rozanov, Russ. J. Inorq. Chem. [Encrl. Transl.), 1988, 3 3 , 947.

Author Index

I n t h i s i n d e x t h e number g i v e n i n p a r e n t h e s i s i s t h e C h a p t e r number o f t h e c i t a t i o n and t h i s i s f o l l o w e d b y t h e r e f e r e n c e number or numbers o f t h e r e l e v a n t c i t a t i o n s w i t h i n t h a t Chapter

Abaev, V.T. ( 1 ) 234 Abbas, S.A. ( 6 ) 145 Abd-Ellah, I. ( 1 ) 182 Abdou, W.M. ( 5 ) 224 Abe, N. ( 1 ) 9 8 A b e l l , A.D. ( 7 ) 4 7 , 57 Abelson, J . ( 6 ) 317 A b i c h t , H.P. (1) 58; ( 3 ) 38 A b r a h a m , J . P . ( 6 ) 474 Aciego, R.M.D. ( 7 ) 103 Adachi, Y. ( 6 ) 109 Ad&, W. (1) 118 Adamek, C. ( 1 ) 37 Adamiak, R.W. ( 6 ) 44 Adamic, K . J . ( 8 ) 211 Adamov, A.V. ( 1 ) 157, 170; ( 2 ) 1 2 , 13 Adams, S.E. ( 6 ) 298 A f s h a r , C. ( 6 ) 123 Agrawal, S. ( 6 ) 261-263, 496 Ahluwalia, G. ( 6 ) 2 3 Ahmad, A. ( 1 ) 236 Ahmad, M.M. (1) 227 ( 5 ) 123 Ahmad, W.-Y. Ahmed, K . J . ( 6 ) 449 Aimene, A. ( 1 ) 9 3 Akasaka, K. (1) 119 Akashi, M. ( 6 ) 333 Akhmetkanova, F.M. ( 5 ) 13 Akimova, G.S. ( 1 ) 209 Akinaga, K. ( 1 ) 245; ( 7 ) 33 Aksinenko, A.Yu. ( 2 ) 4 5 , 46; ( 5 ) 175 Aksinenko, W.A. ( 2 ) 6 Aksnes, G. ( 5 ) 233 Akutagawa, K. ( 4 ) 97 Aladzhova, I.G. ( 5 ) 70 A l a j a r i n , M. ( 7 ) 6 2 , 6 4 , 6 6 , 67; ( 8 ) 4 0 , 42

A l b a r e l l a , J . P . ( 6 ) 440 A l b e r t , G. ( 1 ) 206 A l b e r t i , M. ( 8 ) 177 A l ' b i t s k a y a , V.M. ( 5 ) 229 A l b r e c h t , S. ( 8 ) 1 6 Alcock, N.W. ( 1 ) 4 7 , 83, 334 Aldenhoven, H. ( 1 ) 33 Aleksandrova, L.A. ( 6 ) 127 Alekseeva, S.G. ( 8 ) 223 Alewood, P.F. ( 5 ) 186 A l e x i e v , V.D. ( 1 ) 317 A l ' f o n s o v , V.A. ( 4 ) 1 4 , 15, 4 2 , 43; ( 5 ) 138, 169 Al-Juaid, S.S. ( 1 ) 162 A l l c o c k , H.R. ( 8 ) 73, 103-105, 119-121, 123, 167, 178, 191, 210, 216 A l l e n , C.A. (8) 219 A l l e n , C.W. ( 8 ) 100, 115, 125 A l l e n , D . J . ( 6 ) 189, 251 A l l e n , D.W. ( 1 ) 219 A l l e n , L.C. ( 7 ) 1 A l l s p a c h , T. ( 1 ) 292 A l m a s y , A. ( 3 ) 15 Almond, H.R., j u n . ( 7 ) 11 Alnaimi, I.S. (5) 206 A l o u i , M. ( 7 ) 109 Alster, D. ( 6 ) 276 A l t h o f f , U. (1) 269 Altmeyer, 0. ( 1 ) 258 A l v e s , A.M. ( 4 ) 58; ( 6 ) 190 Ames, B.N. ( 6 ) 429 Ammosov, A.D. ( 6 ) 152 Amrani, Y. (1) 132 An, S.-H. ( 6 ) 150 Anders, E. (1) 232, 233 Anderson, D.M. ( 1 ) 2 3

Anderson, J . D . ( 6 ) 92 Anderson, M.W. ( 7 ) 115 Ando, T. ( 5 ) 10, 11 A n d r i a n a r i s o n , M. ( 1 ) 4 2 , 44, 284 A n d r o s i t s , B. ( 1 ) 355; (3) 1 4 Andrus, A. ( 6 ) 172 Ang, H.G. ( 1 ) 305 Angelov, C.M. ( 1 ) 222; ( 5 ) 154, 155, 226 Angelov, Kh. ( 5 ) 153 Annen, U. (1) 292 A n s e l l , G.B. ( 1 ) 6 5 Anslyn, E. ( 6 ) 1 4 Anson, M.S. ( 4 ) 53; (5) 54 Ansorge, W. ( 6 ) 364 A n t e u n i s , M.J.O. ( 7 ) 27 A n t i p i n , M.Yu. (1) 267, 276, 303, 304, 306; ( 3 ) 18; ( 4 ) 8 6 , 8 7 ; ( 7 ) 46; ( 8 ) 6 5 , 158, 230 Antipova, V.V. ( 1 ) 158, 170 Antkowiak, W.Z. ( 6 ) 44 Anzai, M. ( 8 ) 109 A o t a n i , S. ( 8 ) 227 A p i t z , J. ( 3 ) 9 Appel, R . (1) 257, 266, 281, 329, 358; ( 8 ) 27 A p p e l t , A. ( 1 ) 6 0 A r a k i , S. (5) 1 6 Arata, Y. ( 6 ) 367 Arbuzov, B.A. ( 1 ) 147, 148, 199, 347-350; (5) 21, 58, 6 0 , 61 A r c h a v l i s , A. ( 1 ) 54 A r c h i e , W.C. ( 2 ) 39 Argues, A. ( 7 ) 63; (8) 43, 45 A r i f , A.M. ( 1 ) 316

Author Index Armstrong, W.P. ( 7 ) 77 Arndt, U. ( 1 ) 39 Arni, R. ( 6 ) 16 Arnold, L.D. ( 1 ) 111; ( 6 ) 178

Arnold, 2. ( 4 ) 9 Arnoldi, A. ( 1 ) 244 Arshinova, R.P. ( 1 ) 199; ( 5 ) 21

Artyushin, 0.1. ( 1 ) 4 , 125, 149

Arzoumanian, H. ( 4 ) 79 Aseeva, R.K. ( 8 ) 128 Ashizawa, T. ( 8 ) 70 Ashley, G.W. ( 6 ) 124 Asseline, U. ( 4 ) 6 1 ; ( 6 ) 194-196

Assil, H.I. ( 1 ) 111 Astrina, V.I. ( 8 ) 118 Atherton, D. ( 6 ) 2 Atkinson, T. ( 6 ) 327 Atrazheva, E.D. ( 6 ) 127 Attanasi, O . A . ( 7 ) 56 Aubert, T. ( 8 ) 44 Audisio, G . ( 8 ) 224 Auer, M. ( 6 ) 153 August, E.M. ( 6 ) 21 Avens, L.R. ( 1 ) 152-154 Avila, L.Z. ( 5 ) 238 Axelrod, J . D . ( 6 ) 289 Aymami, J. ( 6 ) 233 Aymie, M. ( 6 ) 334 Baba, Y. ( 6 ) 110 Babaev, O.A. ( 8 ) 128 Babbitt, P.C. ( 6 ) 133 Babkin, Yu.A. ( 3 ) 1 Baboir, B.M. ( 6 ) 353 Baboulhe, M. ( 5 ) 5 5 , 77 Baccolini, G. ( 1 ) 78-80; ( 2 ) 3 5 ; ( 4 ) 44

Baceiredo, A. ( 1 ) 144, 145; ( 3 ) 3 4 ; ( 4 ) 100, 1 0 1 ; ( 8 ) 22

Bader, A . ( 1 ) 66 Badri, M. ( 5 ) 62 Baechler, R.D. ( 8 ) 11 Bailly, V. ( 6 ) 370, 371 Baker, B.F. ( 6 ) 393 Baker, J. ( 1 ) 132 Baklanov, M.A. ( 1 ) 165 Balczowski, P. ( 5 ) 135 Baldini, G. ( 6 ) 247 Balegroune, F. ( 1 ) 1 2 , 196

Balgobin, N. ( 6 ) 270, 271, 273

Ball, J.M. ( 1 ) 223 Ball, R.G. ( 1 ) 81 Balueva, A.S.. (1) 1 4 7 , 220, 221

407 Balzarini, J. ( 6 ) 2 2 , 29, 94

Banaszczyk, M. ( 6 ) 444 Bancroft, I. ( 6 ) 473 Bandanyan, Sh.0. ( 5 ) 228 Bandoli, G . ( 8 ) 8 9 , 90 Banks, M.R. ( 4 ) 99 Bannwarth, W. ( 4 ) 5 9 ; ( 6 ) 1 9 1 , 252

Bansal, R.K. ( 1 ) 211; ( 4 ) 12

Bao, J. ( 5 ) 204; ( 6 ) 319 Baran, E.J. ( 6 ) 454 Barangulova, R.N. ( 2 ) 28 Baranova, L.V. ( 6 ) 160 Baranskii, V . A . ( 5 ) 236 Barbier, B. ( 6 ) 381 Barbier, C. ( 6 ) 196 Barbin, P. ( 8 ) 41 Bardkova, E. ( 6 ) 178 Barion, D. (1) 307; ( 4 ) 8 4 ; ( 8 ) 23

Barluenga, J. (1) 357; ( 3 ) 12; ( 7 ) 24, 44, 68-70; ( 8 ) 3 9 , 5 9 , 60 Barnett, R.W. ( 6 ) 159 Barone, A.D. ( 6 ) 157 Barrans, J. ( 2 ) 2 5 , 26 Barrie, S.E. ( 6 ) 151 Barron, A.R. ( 1 ) 46, 295 Bartels, G . ( 7 ) 82 Bartlett, P.A. ( 5 ) 161, 242 Bartlett, R.A. ( 1 ) 261, 299, 301 Barton, J . K . ( 6 ) 458-461 Bartsch, R . ( 1 ) 342, 343 Bashuk, O.S. ( 6 ) 186 Basile, L.A. ( 6 ) 458 Bass, W . J . ( 6 ) 437 Bassegyan, S.K. ( 1 ) 91 Basyanina, L.K. ( 4 ) 47 Bates, G.S. ( 1 ) 17 Bathe-Burmeister, S . ( 7 ) 82 Bats, J . W . ( 1 ) 124; ( 4 ) 102 Batta, G. ( 8 ) 12 Batyeva, E.S. ( 4 ) 14-16, 2 2 , 42, 4 3 ; ( 5 ) 169 Baudin, G. ( 5 ) 34 Baudler, M. ( 1 ) 2 6 , 3 4 , 36-39 Bauer, B.F. ( 1 ) 198; ( 6 ) 175 Bauer, G.A. ( 6 ) 379 Baxter, S.G. ( 1 ) 322 Bay, E. ( 1 ) 101 Bayer, E. (1) 66 Bayomi, S.M.M. ( 6 ) 73 Bazhina, Yu.N. ( 6 ) 432 Bazile, D. ( 6 ) 197

Bazin, H. ( 6 ) 126 Bazureau, J.P. ( 7 ) 54 Beardsley, G.P. ( 6 ) 227, 228, 425

Beaucage, S.L. ( 6 ) 157, 172

Becher, J. ( 8 ) 43 Becker, W. ( 1 ) 201, 321 Bednarski, M.D. ( 6 ) 149 Beese, L.S. ( 6 ) 476 Behr, J . P . ( 6 ) 406 Beigelman, L.N. ( 6 ) 67 Beijer, B. ( 6 ) 225 Bekker, A.R. ( 5 ) 48, 4 9 , 170

Belekhov, V.V. (5) 120, 163

Bellan, J. ( 1 ) 255; ( 4 ) 9 5 ; ( 5 ) 95

Belostotskaya, I.S. ( 2 ) 3 2 , 33

Belt, H . 4 . ( 1 ) 70 Belykh, O.A. ( 5 ) 219, 227 Benac, B.L. ( 1 ) 48 Benbow, R.M. ( 6 ) 330 Bendiashvili, T.M. ( 8 ) 223

Benevides, J.M. ( 6 ) 494 Bengtstrom, M. ( 6 ) 297 Benham, V. ( 6 ) 498 Benimetskaya, L.Z. ( 6 ) 396

Benkovic, P. ( 6 ) 301 Benkovic, S . J . ( 6 ) 7 4 , 189, 251, 301, 357

Benmaarouf-Khallaayoun,

z.

( 5 ) 77

Bennett, J . L .

( 8 ) 123,

2 10

Bennett, S.M. ( 6 ) 65 Bennett-Slavin, L.L. ( 6 ) 448

Bensley, D.M. ( 1 ) 22 Bent, E.G. ( 4 ) 2 9 , 30 Bentley, D.R. ( 6 ) 296 Bentrude, W.G. ( 4 ) 9 7 , 9 8 ; ( 6 ) 9 4 , 101, 102

Benzorari, M.D. ( 8 ) 112 Berdnik, I.V. ( 5 ) 110 Berdnikov, E.A. ( 5 ) 223 BGrC, A. ( 6 ) 395 Beres, J. ( 6 ) 94 Beresnev, E.N. ( 8 ) 236 Bergbreiter, D.E. ( 1 ) 14 Bergen, J.J. ( 2 ) 15 Bergman, R.G. ( 1 ) 138 Bergstrom, D.E. ( 6 ) 55 Berkich, D. ( 6 ) 478 Berman, H.M. ( 6 ) 75 Bernadou, J. ( 6 ) 8 2 , 83 Berner, S . ( 4 ) 4 6 ; ( 6 ) 45 Bertani, R. ( 8 ) 122

408 Berton, A. ( 8 ) 122 B e r t r a n d , G. ( 1 ) 144, 145, 308; ( 3 ) 34; ( 4 ) 100, 101; ( 8 ) 22, 24 B e r t r a n d , M . J . ( 6 ) 498 Bespal'ko, G.K. ( 5 ) 129 Bestari, K.T. ( 8 ) 153 Bestmann, H.-J. (1) 216; ( 7 ) 37, 72, 110 B e t h e l l , R.C. ( 6 ) 116 B e t z , P. ( 1 ) 296 Bevilacqua, P.C. ( 6 ) 413 B e z o r a r i , M.D. ( 8 ) 108 B i c k n e l l , A.J. ( 7 ) 34 Biedenbach, B. ( 1 ) 291, 296 B i h a t s i - K a r s a i , E. ( 7 ) 101 Binger, P. ( 1 ) 288, 291, 296 B i n s t e d , N. ( 1 ) 317 B i r r e n , B.W. ( 6 ) 471 B i s c h o f b e r g e r , N. ( 6 ) 230 B i t t n e r , S. ( 1 ) 115 Bixner, D . I . ( 6 ) 7 3 Bjoerk, F. ( 8 ) 222 Blackburn, G.M. ( 5 ) 127; ( 6 ) 155; ( 7 ) 105 Blackledge, M . J . ( 6 ) 482 Blake, K.R. ( 6 ) 257, 441, 442 Blanks, R. ( 6 ) 329 Blaser, D. ( 1 ) 44 B l a t c h l y , R.A. ( 6 ) 74 Bleeke, J . R . (4) 35 B l i n , N. ( 6 ) 306 Block, E. ( 1 ) 6 ; ( 3 ) 3 Blohm, M. ( 8 ) 11 Blotny, G. ( 5 ) 15 Bodalski, R. (3) 10 Boeck, A. ( 8 ) 69 Boehshar, M. ( 5 ) 25 Boese, R. ( 1 ) 27, 44, 8 6 , 259, 260 Boeshe, J. ( 8 ) 24 Bogachev, V.S. ( 6 ) 8 Boganova, N.V. ( 1 ) 20; ( 4 ) 18 Bohle, D.S. ( 1 ) 274 Bohra, R. ( 1 ) 35 Boikova, M.A. (1) 243 Boisdon, M.T. ( 2 ) 24-26 Boiteux, S. (6) 419 Boldeskul, I . E . ( 1 ) 103, 267; ( 4 ) 21; ( 7 ) 38; ( 8 ) 65, 158 B o l i t t , V. (1) 247 Bolm, C. (1) 7, 77; ( 5 ) 23 Bolognesi, A. ( 8 ) 221 Bolotova, O.P. ( 2 ) 10 Bolton, P.H. ( 6 ) 488

Orgunophosp horus Chemistry Bondarenko, N.A. ( 1 ) 231 Bongartz, J.-P. ( 5 ) 123 Bonnet, J.P. ( 8 ) 76, 8 7 , 92 Bookharn, J . L . (1) 73; ( 3 ) 20 Boorman, P.M. (1) 223 B o o s a l i s , M.-S. ( 6 ) 302 Borisenko, A.A. ( 1 ) 189 Borisov, E.V. ( 8 ) 6 Borisov, G. ( 8 ) 168 Borowiecka, J. ( 5 ) 40 Borowy-Borowski, H. (6) 222 B o r t o l u s , P. ( 8 ) 8 2 , 221 Bosch, L. ( 6 ) 474 B o s c h e l l i , D.H. ( 6 ) 17 Bose, R.N. ( 6 ) 448 Boske, J . ( 1 ) 308 Bostock, C . J . ( 6 ) 472 Bosyakov, Yu.G. ( 3 ) 11 Bottka, S. ( 6 ) 96-98 Boucheron, J . A . ( 6 ) 418 Boulay, F. ( 6 ) 340 Bovin, A.N. (1) 128; ( 5 ) 2, 234 Bowler, B.E. ( 6 ) 449 Boxer, S.G. (6) 490 Boyd, B.A. ( 4 ) 82; ( 8 ) 26 Boyd, D.R. ( 5 ) 209 Brack, A. ( 6 ) 381 Braddock, M. ( 6 ) 298 Bradley, D.C. ( 1 ) 140 Brandi, A. (1) 133; ( 3 ) 7 Brandolin, G. ( 6 ) 340 Brandt, K . ( 8 ) 96, 113 Brandt, P.F. ( 1 ) 69 Brankamp, R.G. ( 6 ) 435 Brankovan, V. ( 6 ) 21 Bratenko, M.K. (1) 207 Braun, R . ( 2 ) 14 B r a u n s t e i n , P. (1) 12 Breau, L. ( 7 ) 52 Rreenbaum, S.G. ( 8 ) 211 Brel', V.K. ( 5 ) 38, 152 Brennan, D . J . (8) 121, 178 Breslow, R. ( 6 ) 14 Bressan, M. ( 1 ) 9 Breuer, E. ( 5 ) 139, 215, 216, 232 B r i g g s , R.W. ( 6 ) 478 B r i l l , W.K.-D. ( 4 ) 70, 72; ( 6 ) 49, 50 B r i n d l e , K.M. ( 6 ) 482, 483 Broder, S. ( 6 ) 23, 255 Broeders, N.L.H.L. ( 6 ) 31, 32 Brondum, K. ( 8 ) 43 Bronson, J..J. (6) 60 Broom, A.D. ( 6 ) 71-73

Broos, R . (7) 27 B r o u i l l e t t e , W . J . ( 7 ) 88 B r o v a r e t s , V.S. (1) 239, 240 Brow, M.A.D. ( 6 ) 288, 359 Brown, D.E. ( 8 ) 100, 115, 125, 193 Brown, J . M . ( 1 ) 9 , 83 Brownbridge, P. ( 5 ) 50 Broxterman, H . J . G . ( 6 ) 146, 239 Broyde, S. ( 6 ) 27 Brozda, D. ( 6 ) 276 Bruche, L. ( 7 ) 59 Brumbaugh, J . A . ( 6 ) 363 Brune, H.-A. (1) 11, 21 Brunner, J. ( 6 ) 246 Bruzik, K.S. ( 5 ) 240 Bryce, M.R. ( 1 ) 227 Brzecheffa, L. (6) 9 5 Buchardt, 0. ( 6 ) 407, 408 Buchheit, D . J . ( 6 ) 150 Buchko, G.W. ( 6 ) 25 Buck, H.M. ( 2 ) 7 , 8; ( 5 ) 237; ( 6 ) 30-32, 265 Budesinsky, M. ( 1 ) 8 8 ; (4) 9 Budzikiewicz, H. (1) 37 Buergi, H.B. ( 5 ) 22 Bugner, D.E. (1) 224 Bujacz, G. ( 3 ) 18 Bukowska, D. ( 5 ) 65 Bulgarevich, S.L. (8) 159 B u l l , H.G. ( 5 ) 184 Bulychev, N.V. ( 6 ) 396 Bumber, A.A. ( 1 ) 234 Bungardt, D. ( 1 ) 8 6 , 260 Bunke, D. ( 1 ) 171; ( 4 ) 37; ( 5 ) 202 Buono, G. (1) 54, 194; ( 2 ) 5; ( 4 ) 79 Burangulova, R.N. (1) 209 Burford, N. ( 1 ) 324-327; (4) 91 Burgada, R . ( 5 ) 132 Burger, K. ( 6 ) 18 Burgers, P.M.J. ( 6 ) 379 Burkhardt, J. ( 8 ) 69 Burkhouse, D.W. ( 5 ) 164 Burmistrov, S.Yu. ( 4 ) 47 Burnaeva, L.A. ( 1 ) 209; ( 2 ) 27, 28, 30, 31 Burrans, J. ( 2 ) 24 Burrows, C . J . ( 6 ) 114 Burschka, C. ( 1 ) 198 Burton, D . J . ( 5 ) 125, 126; ( 7 ) 8 4 Burton, G. (7) 34 Burtseva, N.L. ( 1 ) 243 Busch, R.D. (5) 184 Busch, T. (1) 328; (4) 92 Buslaev, Yu.A. ( 8 ) 67,

Author Ijidex

409 223

142

Busygin, I . G . ( 5 ) 211 Butin, B.M. ( 1 ) 72 Butsugan, Y. ( 5 ) 16 Buvashkina, N . I . ( 5 ) 146 Buwalde, P.L. ( 8 ) 117 Buzykin, B.I. ( 5 ) 230 Byrne, L.T. (1) 61 Cabal, M.P. ( 7 ) 99 Cabioch, J.-L. ( 1 ) 270 Cai, G.L. ( 6 ) 24 Caine, D. ( 3 ) 30 Cairns, S.M. ( 4 ) 9 7 , 9 8 ; ( 6 ) 102

Camerini-Oterio, R.D.

(6)

164

Cameron, D.G. ( 5 ) 174 Cameron, T.S. ( 1 ) 324, 325; ( 4 ) 3 1 , 9 1 ; ( 8 ) 233 Caminade, A.M. (5) 62 Camp, D. (1) 109, 110, 112; ( 2 ) 1 7 , 18 Camps, F. ( 7 ) 102 Cann, P.A. ( 6 ) 308 Cano, F.H. ( 7 ) 6 3 , 66-68 Cantor, C.R. ( 6 ) 470 Cao, W. ( 7 ) 9 Capdevila, J. ( 7 ) 98 Capobianco, M. ( 5 ) 8 7 ; ( 6 ) 237 Capuano, L. ( 7 ) 50 Cardullo, R.A. ( 6 ) 496 Caregg, P.J. ( 6 ) 37 Carenza, M. ( 8 ) 195 Carlson, E. ( 6 ) 440 Carmichael, D. ( 1 ) 343 Carneiro, T.M.G. ( 1 ) 12 Carter, K.C. ( 8 ) 100 Carughi, M. ( 1 ) 244 Caruthers, M.H. ( 4 ) 6 5 , 70-72, 7 6 ; ( 6 ) 48-50, 157, 200, 254 Casellato, U. ( 8 ) 8 9 , 90 Caskey, C.T. ( 6 ) 294 Castaldi, G. ( 5 ) 147 Castera, P. ( 8 ) 7 6 , 9 3 , 231, 232 Castro, M.M.C.A. ( 6 ) 457 Catalan, J. ( 7 ) 67 Catalano, C.E. ( 6 ) 357 Cavell, R.G. ( 1 ) 8 1 , 1 1 6 ; ( 8 ) 1 4 , 163, 164 Cazenave, C. ( 6 ) 260 Cech, D. ( 6 ) 2 6 , 8 6 , 8 7 , 206 Cech, T.R. ( 6 ) 410 Cedergren, R . J . ( 4 ) 6 7 ; ( 6 ) 199 Cefelin, P. ( 8 ) 168, 183,

Cen, W. (5) 125 Chabert, P. ( 7 ) 3 1 , 94 Chabre, M. ( 6 ) 118 Chaddha, M. ( 6 ) 170, 182 Chadnaya, I . A . (1) 13 Chaiz, C. ( 6 ) 179 Chakraborty, T.K. ( 7 ) 100 Challiss, R . A . J . ( 6 ) 482 Chambers, J . W . ( 5 ) 191 Chambers, R.D. ( 7 ) 106 Chambers, R.W. ( 6 ) 222 Chand, P. ( 1 ) 314 Chang, C.-N. ( 6 ) 372, 487 Chang, H. ( 5 ) 86 Chang, P.-I. ( 6 ) 247 Charrier, C . ( 1 ) 24 Charubala, R. ( 6 ) 5 , 275-277

Chassignol, M. ( 4 ) 6 0 ; ( 6 ) 192, 193, 384

Chattopadhyaya, J . ( 6 ) 4 6 , 126, 244, 270-273 (1) 1 8 5 , 186 Chavez, F. ( 6 ) 300 Chavis, C. ( 6 ) 318 Chekhlov, A . N . ( 1 ) 193; ( 2 ) 45, 46; ( 5 ) 152, 175, 234 Chellamani, A. ( 1 ) 117 Chen, C.-S. ( 5 ) 31 Chen, C.B. ( 6 ) 390 Chen, K. ( 8 ) 106, 107, 212 Cheng, Y.-C. ( 6 ) 7 2 , 73 Chen-Yang, Y.W. ( 8 ) 99 Cheong, C. ( 6 ) 302 Chepakova, L.A. ( 5 ) 38 Cherezova, E.N. ( 5 ) 199 Cherkasov, R.A. ( 2 ) 3 4 ; ( 5 ) 7 3 , 222, 223, 225 Cherkasova, O.A. ( 5 ) 199 Chern, J.-W. (1) 96 Chernega, A.N. (1) 267, 276, 303, 304, 306; ( 4 ) 86, 87, 89; ( 8 ) 65, 1 5 8 , 230 Chernov, P.P. ( 1 ) 348 Chernyuk, I.N. ( 1 ) 207 Chiche, L. ( 7 ) 6 , 4 0 , 4 2 ; ( 8 ) 28

Chauzov, V.A.

Chichester-Hicks, S.V. ( 8 ) 101, 201, 202

Chien, W.S. ( 8 ) 99 Chin, J. ( 6 ) 444 Chistokletov, V.N. ( 1 ) 200; ( 2 ) 28, 3 1 ; ( 8 ) 161 Chivers, T. ( 8 ) 148, 149, 155 Chladek, S . ( 6 ) 243

Chojnowski, J. ( 1 ) 68 Chou, S.-H. ( 6 ) 201 Choukrad, M. ( 4 ) 79 Chow, K. ( 7 ) 99 Christodoulou, C. ( 4 ) 6 8 ; ( 6 ) 209

Christov, V.Ch. ( 5 ) 155 Chuan, H. ( 6 ) 1 1 9 , 336, 337

Chung, J . R . ( 8 ) 99 Chung, Y. ( 8 ) 181 Churchich, J.E. ( 6 ) 350 Civeira, M.P. ( 6 ) 261-263 Claramunt, R.M. ( 7 ) 6 7 ; ( 8 ) 42

Clark, G.R. ( 1 ) 274 Clark, J . M . ( 6 ) 323, 425 Clark, S.M. ( 6 ) 471 Classon, B. (1) 97 Clayden, N . J . ( 1 ) 317 Clegg, W.

( 1 ) 316

Clin, 8. ( 8 ) 41 Clough, S.B. ( 8 ) 181 Coan, C. ( 6 ) 120 Cocks, S. ( 5 ) 76 Coenen, A . J . J . M . ( 6 ) 31 Coggio, W.D. ( 8 ) 119 Cohen, A.S. ( 6 ) 469 Cohen, J.S. ( 6 ) 255, 260 Cohen, S . ( 6 ) 164 Cohrs, M.P. ( 6 ) 250 Colemann, M.S. ( 6 ) 335 Coll, M. ( 6 ) 233 Collignon, N. ( 5 ) 221 Collington, E.W. ( 3 ) 32 Colman, R.F. ( 6 ) 355, 356 Colonna, F.P. ( 5 ) 8 7 ; ( 6 ) 237

Colquhoun, I.J. (1) 7 3 , 127; ( 5 ) 200

Combs, P.L. ( 5 ) 184 Connelly, M.C. ( 6 ) 23 Conway, N.E. ( 6 ) 424 Cook, A.G. ( 6 ) 140 Cook, N. ( 5 ) 19 Cook, S.L. ( 1 ) 317 Cooke, A.M. ( 5 ) 33 Cooney, D.A. ( 6 ) 2 3 , 125 Cooper, M.K. ( 1 ) 84 Corbel, B. ( 5 ) 194, 195 Cordes, A.W. ( 8 ) 152-154, 235

Corriu, R.J.P. (5) 68 Cortay, J.-C. ( 6 ) 156 Cosstick, R. ( 4 ) 7 4 ; ( 6 ) 35

Costisella, B. (5) 108, 134

Couret, C. ( 1 ) 255, 283, 284; ( 4 ) 95

Cowart, M. ( 6 ) 251 Cowie, J.M.G. ( 8 ) 182,

410 207

Cowley, A.H. ( 1 ) 4 8 , 49, 289, 290, 295, 297, 316

Cozzone, A.J. ( 6 ) 156 Cramer, F. ( 5 ) 5 ; ( 6 ) 34 Craven, A.P. ( 7 ) 80 Crey, A.E. ( 8 ) 219 Cribbs, L.V. ( 1 ) 152-154 Crich, D. ( 1 ) 1 0 6 ; ( 2 ) 16 Cristau, H.-J. ( 1 ) 215, 237; ( 7 ) 6 , 4 0 , 42, 43; ( 8 ) 28 Critch, D. ( 3 ) 35 Critchfield, J.M. ( 6 ) 100 Crofts, P.C. ( 1 ) 184 Cropper, P.E. ( 1 ) 219 Cros, P. ( 1 ) 194 Crosby, R.C. ( 8 ) 203 Cross, R.L. ( 6 ) 346, 348 Cruickshank, K.A. ( 6 ) 188 Csaky, A.G. ( 7 ) 23 Cullis, P.M. ( 6 ) 136 Cummings, D.G. ( 8 ) 217, 219 Cummins, J.H. ( 5 ) 232 Curnutte, J.T. ( 6 ) 353 Curtis, R.D. ( 8 ) 8 Curtze, J. ( 1 ) 206 Cushman, C.D. ( 6 ) 441 Cvekl, A. ( 6 ) 324 Czajka, M. ( 5 ) 65 Czekanski, T. ( 5 ) 108

Dabkowski, W. ( 5 ) 5 ; ( 6 ) 34

Dahl, 0. ( 6 ) 46 Dahlhoff, W.V. ( 1 ) 174 Daimon, M. ( 8 ) 133 Daines, R . A . ( 7 ) 100 Dalbon, P. ( 6 ) 340 Dalpozzo, R. ( 2 ) 35 Damha, M.J. ( 6 ) 226, 268, 269

Dangyan, Yu.M. ( 5 ) 228 Daniels, L.M. ( 2 ) 4 2 ; ( 4 ) 28

Danilova, 0.1. ( 5 ) 21 Danishefsky, S.J. ( 7 ) 99 Danopoulos, A.A. ( 1 ) 53 Dantzig, J.A. ( 6 ) 112 Daolio, S . ( 8 ) 221 Dargatz, M. ( 1 ) 71 Dartmann, M. ( 4 ) 92 Darzynkiewicz, E. ( 6 ) 18-20, 143

Datema, R. ( 6 ) 126 Dattagupta, N. ( 6 ) 440 Dauben, W.G. ( 1 ) 2 ; ( 3 ) 6 , 16

Davelaar, E. ( 4 ) 54 Davidson, J. ( 5 ) 184

Organophosphorus Chemistly Davies, K.E. ( 6 ) 309 Davies, L.C. ( 6 ) 151 Davies, R.W. ( 6 ) 159 Davis, A.M. ( 6 ) 1 2 , 13 Davis, W.M. ( 1 ) 7 ; ( 5 ) 23 Day, R.A. ( 2 ) 41 de Almeida, S.G. ( 6 ) 450 DeBear, J.S. ( 6 ) 165 DeBoer, J.L. ( 8 ) 234 Debouzy, J.-C. ( 6 ) 79 Decamp, D.L. ( 6 ) 355, 356 de Clercq, E. ( 6 ) 2 2 , 29, 63, 9 4 , 220, 238 Declercq, J.-P. ( 1 ) 255, 284; ( 4 ) 95 Deeter, J.B. (5) 191 Degnan, I.A. ( 1 ) 47 DeGroot, K. ( 8 ) 196 Degtyarev, A.N. ( 5 ) 234 Dehmlow, E.V. ( 5 ) 92 Dehnicke, K. ( 8 ) 3 , 66 DeJaeger, R. ( 8 ) 63 De Keijzer, A.E.H. ( 2 ) 7 , 8 ; ( 5 ) 237 Delian, A. ( 1 ) 85 Dellinger, D.J. ( 6 ) 200 Delmas, M. ( 5 ) 62 Delpech, B. ( 7 ) 113 Dgmarcq, M.C. ( 5 ) 42 Dembek, A.A. ( 8 ) 210 Dembek, P. ( 6 ) 44 DembiAski, R. ( 4 ) 1 9 ; ( 5 ) 4345 Dembkowski, L. ( 5 ) 176 Demir, T. ( 5 ) 212 Demple, B. ( 6 ) 377, 378 Demura, Y. ( 1 ) 212 Denis, J.-M. ( 1 ) 270 Denisenko, V.I. ( 5 ) 228 Denmark, S.E. ( 5 ) 245; ( 7 ) 86 de Paz, J.L.G. ( 7 ) 67 Depezay, J.-C. ( 7 ) 97 DePillis, G.D. ( 6 ) 303 Dergan, J.J. ( 1 ) 108 de Riese-Meyer, L. ( 1 ) 36 Dervan, P.B. ( 6 ) 231, 383, 392, 393, 433 Desgr&, J. ( 6 ) 89 Deubelly, B. ( 1 ) 59, 60 Deutsch, J. ( 6 ) 164 Deutsch, W.F. ( 8 ) 84-86 de Vaumas, R. ( 1 ) 315 de Vroom, E. ( 4 ) 7 7 ; ( 5 ) 8 8 ; ( 6 ) 4 1 , 53, 239 Dhaher, S.M. ( 1 ) 162 Dhathathreyan, K.S. ( 8 ) 9 8 , 148 Dhawan, B. ( 3 ) 2 ; ( 5 ) 159, 217 Dianova, E.N. ( 1 ) 347-350 Dias, H.V.R. ( 1 ) 261,

299, 301, 302

Dickerson, R.E. ( 6 ) 475 Dicko, A. ( 5 ) 55 Diel, B.N. ( 1 ) 25 Diel, P.J. ( 5 ) 172, 173, 182

Dieter, M. ( 8 ) 21 Dietl, S . ( 1 ) 346; ( 4 ) 85 Dikshit, A. ( 6 ) 170, 182 Dillon, K.B. ( 1 ) 102 Dimukhametov, M.N. ( 5 ) 197

Dinehart, W.J. ( 6 ) 173, 439

Ding, W. ( 7 ) 9 Dingwall, J.G. ( 4 ) 8 ; ( 5 ) 182

Dinya, Z. ( 8 ) 12 Dixon, G.H. ( 6 ) 287 Dixon, R.M. ( 6 ) 154 Dizdaroglu, M. ( 6 ) 428 Dobson, C.M. ( 1 ) 317 Dodds, D.R. ( 6 ) 157 Dodge, J.A. ( 8 ) 120 Dodonov, V.A. ( 2 ) 10 Dobler, C. ( 4 ) 80 Dogadina, A.V. ( 5 ) 119, 219, 227

Doi, J.T. ( 5 ) 241 Dolinnaya, N.G. ( 6 ) 28 Dolle, R.E. ( 7 ) 7 7 ; ( 8 ) 47

Dollinger, D.L. ( 6 ) 88 Domanico, P.L. ( 6 ) 380 Dombroski, A.J. ( 6 ) 348 Domiguez, C. ( 7 ) 23 Dominici, P. ( 6 ) 350 Donaldson, A.J. ( 4 ) 35 Donini, P. ( 6 ) 156 Donogues, J. ( 8 ) 41 Dontsov, A.A. ( 8 ) 145 Dooley, S . ( 6 ) 306 Dorow, R.L. ( 5 ) 245 Dorr, R.T. ( 6 ) 76 Dotz, K.H. ( 1 ) 353 Dotzer, R. ( 1 ) 216 Doviken, L. ( 6 ) 421 Drach, B.S. ( 1 ) 239, 240 Drake, P.L. ( 6 ) 189 Drandarevski, C. ( 1 ) 206 Drapailo, A.B. ( 1 ) 303, 304; ( 4 ) 87

Dreef, C.E. ( 4 ) 5 0 , 5 1 , 7 7 ; ( 5 ) 32; ( 6 ) 41

Dreef-Tromp, C.M. ( 6 ) 241, 242

Dreiling, C.E. ( 6 ) 108 Drescher, M. ( 5 ) 101 Drescher, S. ( 7 ) 50 Drew, M.G.B. ( 1 ) 336 Drewello, T. ( 1 ) 292 Driess, M. ( 1 ) 28, 29

Author Index Driller, H. ( 6 ) 216-218 Drummond, R. ( 6 ) 285 DuBois, D . A . ( 1 ) 331; ( 8 ) 56

Dubourg, A. ( 1 ) 255, 284; ( 4 ) 95

Duckworth, P.A. ( 1 ) 84 Duc Le Van, ( 3 ) 9 Dudzikiewicz, H. ( 1 ) 39 Duesler, E.N. (1) 45 Dulog, L. ( 8 ) 88 Dummler, M. ( 1 ) 93 Du Mont, W.-W. ( 1 ) 127; ( 5 ) 200

Duncan, I.B. ( 6 ) 64 Dunn, B.S. ( 8 ) 121, 178 Duplaa, A.M. ( 6 ) 221 Dupraz, B. ( 6 ) 79 Dupuis, A. ( 6 ) 118 Durand, M. ( 6 ) 196 Dureault, A. ( 7 ) 97 DUS, D. ( 8 ) 96 Duthu, B. ( 5 ) 27 Dutta, C. ( 6 ) 416 Dvorak, D. ( 4 ) 9 Dvorakova, H. ( 6 ) 62 Dyatkina, N.B. ( 6 ) 7 , 127 Dyke, H . J . ( 7 ) 8 0 , 112 Dyker, H. ( 1 ) 106; ( 2 ) 1 6 ; ( 3 ) 35

Eaborn, C. ( 1 ) 162 Eadie, J.S. ( 6 ) 174 Ebel, ,J.P. ( 6 ) 382 Eberle, M.K. ( 6 ) 95 Ebright, Y. ( 6 ) 468 Eccleston, J.F. ( 6 ) 99 Eckes, H.-L. ( 4 ) 1 0 ; ( 5 ) 99

Eckstein, F. ( 4 ) 55; ( 6 ) 100, 135, 321, 362, 369 Edelmann, F.T. (1) 250, 294; ( 8 ) 4 , 18 Edge, M.D. ( 4 ) 58; ( 6 ) 190 Edmundson, R.S. ( 5 ) 66, 6 7 , 75 Edwards, P.G. ( 1 ) 53 Edwards, R.M. ( 6 ) 298 Efremov, Yu.Ya. (1) 175, 176, 181; ( 4 ) 42 Egholm, M. ( 6 ) 407 Eguchi, S. ( 7 ) 6 0 , 61 Ehle, M. ( 1 ) 332 Ehlenbeck, O.C. ( 6 ) 314 Ehrenfreund, J. ( 4 ) 8 Eitel, M. ( 7 ) 51 Ekerdt, J.G. ( 5 ) 3 Ekiel, I. ( 6 ) 20, 143 El Bakili, A. ( 8 ) 7 6 , 9 3 , 94, 232, 233

41 1 Elder, J.S. ( 7 ) 34 El-Din, G.N. ( 1 ) 336 Elguero, J. ( 7 ) 6 7 ; ( 8 ) 42

Elias, A . J .

( 4 ) 26; ( 8 )

27

150, 151

Elie, C . J . J .

( 4 ) 5 0 , 51,

6 9 ; ( 5 ) 32

Eliseeva, G.D. ( 5 ) 236 Eller, K. ( 1 ) 292 Elliott, J. ( 3 ) 24 Elliott, R. ( 6 ) 159 El-Maghrabi, M.R. ( 6 ) 140 El-Ouatib, R. ( 1 ) 253 Elov, A.A. ( 6 ) 236 Elzanowska, H. ( 6 ) 453 Elzinga, M. ( 6 ) 344 Emanuilidi, S.E. ( 1 ) 234 Emma, J.E. ( 8 ) 72 Enchev, D.D. (1) 222; ( 5 ) 153, 154, 226

Engelhardt, L.M. ( 1 ) 61 Engels, J. ( 6 ) 158 Englisch, U. ( 4 ) 57; ( 6 ) 434

Enikeev, K.M. (1) 179 Enjalbert, R. ( 8 ) 231, 232

Eperon, I.C. ( 6 ) 312 Epishina, T.A. ( 1 ) 191-193; ( 5 ) 8 , 37 ( 5 ) 102 ( 1 ) 147, 148, 220, 221 Erba, E. ( 7 ) 53 Erfle, H. ( 6 ) 159, 364 Ericson, A.C. ( 6 ) 126 Eriks, K. ( 1 ) 129 Erker, G. ( 7 ) 71 Erlich, H.A. ( 6 ) 358 Ernst, L. ( 6 ) 6 9 ; ( 7 ) 82 Ernst, M.F. ( 1 ) 5 Ershov, V.V. ( 2 ) 32, 33 Erster, S.H. ( 6 ) 414 Erzhanov, K.B. (1) 72 Escudie, J. (1) 255, 283, 284; ( 4 ) 95 Esposito, F. ( 6 ) 435 Etemad-Moghadham, G. ( 1 ) 253 Eudy, N.H. ( 8 ) 72 Euerby, M.R. ( 5 ) 53 Evans, J. (1) 317 Evans, M.J. ( 6 ) 498 Evans, P.L. ( 1 ) 83 Evans, R.K. ( 6 ) 335 Evans, S . A . , jun. ( 1 ) 107; ( 2 ) 19 Ewing, A.G. ( 8 ) 216 Exarhos, G.J. ( 8 ) 8 0 , 8 1 , 8 3 , 206

Epstein, W.W. Erastov, O.A.

Facchin, B. ( 8 ) 221 Facchin, G. ( 8 ) 122 Fairhurst, S.A. ( 1 ) 227 Fait, J.F. (1) 223 Fakhrutdinova, G.Kh. ( 2 ) Fakhrutdinova, R.A.

(1)

175, 176

Faktor, M.M. ( 1 ) 140 Falck, J . R . ( 1 ) 247; ( 7 ) 92-94, 98

Falsonne, G. ( 7 ) 76 Farag, R. ( 1 ) 182 Farnier, M. ( 8 ) 44 Farrance, I . K . ( 6 ) 174 Farrell, N.P. ( 6 ) 450 Farrell, T.P. ( 6 ) 394 Farschtschi, N. ( 4 ) 7 3 ; ( 6 ) 51

Fassbender, F. (8) 48 Faucher, J.P. ( 8 ) 7 6 , 9 3 , 232

Faure, B. ( 1 ) 54 Fausnaugh, J. ( 6 ) 468 Fawzi, R. ( 3 ) 39 Fearon, K. ( 4 ) 56 Federova, O.S. ( 6 ) 431, 432

Fedorov, S.G. ( 8 ) 126 Feher, M. ( 1 ) 34, 39 Feng, X. ( 1 ) 301 Fentiman, A.F. ( 5 ) 196 Fernandez, E. ( 8 ) 68 Ferrar, W. ( 8 ) 193 Ferrero, M. ( 7 ) 24, 6 9 ; ( 8 ) 3 9 , 60

Ferris, J.P. ( 6 ) 103 Ferris, K.F. ( 8 ) 7 9 , 8 1 , 8 3 , 206

Feshchenko, N.G. ( 1 ) 202-204;

( 8 ) 52

Fest, D. ( 1 ) 309 Feuerstein, J. ( 6 ) 139 Fiddler, S . ( 3 ) 30 Fife, T.H. ( 5 ) 64 Fild, M. ( 1 ) 171; ( 4 ) 36, 37; ( 5 ) 116, 201, 202

Filin, L.G. ( 8 ) 128 Filippone, P. ( 7 ) 56 Filonenko, L.P. ( 5 ) 129; ( 8 ) 50

Fincham, J.K. ( 8 ) 102 Finn, L.A. ( 6 ) 414 Firca, J . R . ( 6 ) 157 Fischer, P. ( 5 ) 149; ( 6 ) 114; ( 7 ) 74

Fischer, R. ( 5 ) 201, 203 Fisher, E.F. ( 6 ) 157 Fitzpatrick, R . J . ( 8 ) 123 Flamigni, L. ( 8 ) 82 Fleischer, H. ( 1 ) 41, 318, 319

Organophosphorns Chemistry

412

Fliess, A. ( 6 ) 235 Flores, C. ( 6 ) 496 Fluck, E. ( 1 ) 359; ( 2 ) 1 4 ; ( 4 ) 40, 4 1 ; ( 5 ) 149, 150; ( 7 ) 2 , 7 4 Flynn, P. ( 6 ) 201 Flynn, T.G. ( 6 ) 347

Foces-Foces, M. de la C. ( 7 ) 6 3 , 66-68;

( 8 ) 45

Foldesi, A. ( 6 ) 244, 270, 271

Foiani, M. ( 6 ) 345 Fokin, A.V. ( 1 ) 185, 186 Fokin, E.A. ( 2 ) 45, 46 Fontanella, J.J. ( 8 ) 211 Fonte, M. ( 1 ) 237 Foo, T. (1) 138 Foresti, E. ( 1 ) 79 Foucaud, A. ( 1 ) 333 Fowler, A.V. ( 6 ) 2 Fraile, M.N. ( 8 ) 68 Francke, R. (1) 9 5 ; ( 2 ) 4 ; ( 5 ) 130, 131

Francl, M.M. ( 7 ) 1 Franqois, J.-C. ( 6 ) 384-386

Frankhauser, P. ( 1 ) 29 Franz, J.E. ( 4 ) 1 1 ; (5) 183; ( 8 ) 48

Frazao, C.M. ( 1 ) 75 Frederick, C.A. ( 6 ) 233 Freeman, S. ( 3 ) 3 7 ; (5) 243, 246; ( 6 ) 140

Freemont, P.S. ( 6 ) 476 Frendewey, D.A. ( 6 ) 414 Fresco, J.R. ( 6 ) 332 Fresneda, P.M. ( 7 ) 6 3 , 6 5 ; ( 8 ) 46

Frey, S.E. ( 6 ) 138 Fridland, A. ( 6 ) 23 Friedman, J.M. ( 6 ) 476 Friedman, P. ( 8 ) 79 Friedrich, D.M. ( 8 ) 7 9 , 8 1 , 8 3 , 206

Friend, R.H. ( 1 ) 227 Frigo, D.M. ( 1 ) 140 Fritz, G. ( 1 ) 4 1 , 318, 319

Fritz, H.-J. (6) 322 Fromm, E. ( 6 ) 332 Fronczek, F.R. ( 1 ) 5 7 , 64 Frost, J.W. ( 5 ) 238 Fryzuk, M.D. (1) 17 Fu, G. ( 7 ) 3 Fu, J.M. ( 6 ) 484 Fujikawa, K. ( 8 ) 129 Fujimoto, T. ( 3 ) 29 Fukui, M. ( 6 ) 5 6 ; ( 7 ) 107 Fukui, T. ( 6 ) 349, 35 Fukukawa, K. ( 6 ) 78 Fukushima, J. ( 8 ) 228 Fulde, M. ( 1 ) 124; ( 4

102

Fulop, V. ( 1 ) 122 Funhoff, A.S. ( 1 ) 2 ; ( 3 ) 6 , 16

Funukawa, Y. ( 8 ) 229 Furman, R.E. ( 6 ) 99 Furst, G.T. ( 7 ) 100 Furukawa, I. (1) 98 Furukawa, M. ( 8 ) 111, 174, 175

Furuta, H. ( 6 ) 80 Furuta, M. ( 4 ) 6 4 ; ( 6 ) 169

Fustero, S . ( 1 ) 357; ( 3 ) 12

Fyles, J. ( 6 ) 291 Gaal, A. ( 6 ) 470 Gadebusch, H. ( 5 ) 184 Gaedcke, A. ( 5 ) 214 Gaffney, B.L. ( 6 ) 223 Gafurov, E.K. ( 4 ) 45 Gagnor, C. ( 6 ) 248 Gait, M.J. ( 4 ) 6 8 ; ( 6 ) 209

Gajda, T. ( 6 ) 101 Gajewski, E. ( 6 ) 428 Galiaskarova, R.T. ( 1 ) 348, 349

Galishev, V.A. ( 8 ) 161 Gallo, R. ( 8 ) 224 Galy, J. ( 8 ) 231, 232 Ganapathiappan, S. ( 8 ) 106, 107, 212

Ganoub, N.A.F. ( 5 ) 224 Garanti, L. ( 7 ) 59 Garbesi, A. ( 5 ) 8 7 ; ( 6 ) 237

Garin, J. ( 6 ) 118 Garrett, D.S. ( 6 ) 250 Garrossian, M. ( 5 ) 102 Gaset, A. ( 5 ) 62 Gasparyan, G.Ts. ( 1 ) 9 1 , 92

Gatrone, R.C. ( 3 ) 40 Gaur, R.K. ( 6 ) 185 Gazizov, T.Kh. ( 4 ) 3 4 , 45 Gdaniec, Z. ( 6 ) 44 Gebel, W. ( 5 ) 203 Gebura, M. ( 8 ) 191 Gehrke, C.W. ( 6 ) 89 Gelas, P. ( 6 ) 83 Gelb, M.H. ( 4 ) 56 Geleria, M. ( 8 ) 194 Gelfand, D.H. ( 6 ) 285, 359

Gelmi, M.L. ( 7 ) 53 Geluk, A. ( 6 ) 242 Genet, J.P. ( 1 ) 7 6 ; ( 4 ) 4 ; ( 5 ) 165

Genkina, G.K. ( 5 ) 70

Geraldes, C.F.G.C.

(6)

457

Gerlt, J.A. ( 6 ) 488 Germann, M.W. ( 6 ) 491 Ghazzouli, I. ( 6 ) 21 Ghilardi, C . A . ( 1 ) 136 Giannelli, F. ( 6 ) 296 Giannis, A . ( 7 ) 104 Gibbons, W.A. ( 5 ) 53 Gibbs, R.A. ( 6 ) 294 Gibson, D. ( 5 ) 232; ( 6 ) 446

Gibson, K.J. ( 6 ) 251 Giegi, R. ( 6 ) 382 Giering, W.P. ( 1 ) 129 Gierstae, R. ( 5 ) 233 Gigg, R. ( 5 ) 33 Gildea, B. ( 6 ) 214 Gillam, S. ( 6 ) 327 Gilljam, G. ( 6 ) 126 Gil'manova, G.Kh. ( 5 ) 61 Gilyarov, V.A. ( 5 ) 5 1 ; ( 8 ) 32

Ginell, S.L. ( 6 ) 123 Ginestar, E. ( 6 ) 318 Giolando, D.M. ( 1 ) 49 Giordano, C. ( 5 ) 147 Giranda, V.L. ( 6 ) 75 Gish, G. ( 6 ) 362 Glanzer, B.I. ( 5 ) 34 Glaser, E. (1) 66 Gleiter, R. ( 7 ) 2 Glemarec, C. ( 6 ) 273 Gleria, M. ( 8 ) 8 2 , 8 9 , 9 0 , 122, 221

Glidewell, C. ( 7 ) 4 Glitz, D.G. ( 6 ) 308 Gloede, J. ( 2 ) 1 ; ( 4 ) 2 Gnevashev, S.G. ( 1 ) 199 Gnuchev, N.V. ( 6 ) 455 Goddard, J.D. ( 5 ) 19 Godovsky, Yu.K. ( 8 ) 169 Goedemoed, J.H. ( 8 ) 196 Goerger, M.M. ( 7 ) 90 Goeva, L.V. ( 8 ) 156 Gold, B. ( 6 ) 417 Goldberg, I.H. ( 6 ) 388, 397, 398, 400

Goldberg, Yu. ( 1 ) 230 Goldberger, W. ( 1 ) 93 Goldblum, A. ( 5 ) 139, 215, 216, 232

Gol'din, G.S. ( 8 ) 126 Goldman, Y.E. ( 6 ) 112 Golina, S.I. ( 8 ) 176 Golokhov, D.B. ( 1 ) 103; ( 2 ) 2 1 ; ( 4 ) 21; ( 5 ) 136

Golokhov, D.V. ( 7 ) 38 Gomelya, N.D. ( 1 ) 202-204 Gomez, M.A. ( 8 ) 200-202 Gonbeau, D. ( 1 ) 270 Gong, P. ( 6 ) 319

Author Index Gontar', A.F. ( 5 ) 175 Gonzalez, F.J. ( 1 ) 357; ( 3 ) 12

Gonzalez, M.S.P. ( 7 ) 103 Goodchild, J. ( 6 ) 261-263 Goodhart, P.J. ( 6 ) 137 Goodman, M.F. ( 6 ) 300, 302

Goody, R.S. ( 6 ) 139, 153 Gorbunov, Yu.A. ( 6 ) 161 Gorenstein, D.G. ( 4 ) 7 3 ; ( 6 ) 5 1 , 484, 489

Gorshkov, A.V. ( 8 ) 145 Gorshunov, I.Yu. ( 4 ) 1 6 , 22

Goryunov, E.I. ( 5 ) 7 Gosselin, G. ( 6 ) 29, 43 Goswami, N. ( 6 ) 448 Goti, A. ( 1 ) 133; ( 3 ) 7 Goto, T. ( 6 ) 77 Gottikh, M.B. ( 6 ) 236, 415

Gottsegen, A. ( 7 ) 101 Gough, G.R. ( 6 ) 165 Gouyette, C . ( 6 ) 79 Gouygou, M. ( 1 ) 253, 255; ( 4 ) 95

Govil, G. ( 6 ) 477 Goyer, C . ( 6 ) 20 Graaskamp, J.M. ( 8 ) 121 Grabowski, E.J.J. ( 1 ) 108, 130; ( 2 ) 15

Grachev, M.M. ( 4 ) 47 Graczyk, P. ( 3 ) 18 Graden, A.B. ( 7 ) 11 Graham, A. ( 6 ) 295 Grandas, A. ( 4 ) 7 1 ; ( 6 ) 254

Grandjean, D. (1) 1 2 , 196 Granier, M. ( 3 ) 34 Grassi, A. ( 8 ) 8 9 , 90 Gratfeuil, M. ( 8 ) 76 Gravier-Pelletier, C . ( 7 ) 97

Gray, G.A. ( 1 ) 334 Greaves, G.N. ( 1 ) 317 Gree, R. ( 1 ) 210 Green, M. ( 6 ) 447 Green, P.M. ( 6 ) 296 Grenz, D. ( 1 ) 39 Gresser, M.J. ( 6 ) 117 Griengl, H. ( 6 ) 63 Griffiths, A.D. ( 6 ) 312 Grishaev, M.P. ( 6 ) 152 Grobe, J. ( 1 ) 269; ( 3 ) 9 Grochowski, E. ( 1 ) 114 Groebe, D.R. ( 6 ) 314, 315 Groger, G. ( 6 ) 1 Grollman, A.P. ( 6 ) 372, 487

Gromova, E.S. ( 6 ) 236 Grone, D.L. ( 6 ) 363

413 Gross, H. ( 5 ) 108 Grosshans, C.A. ( 6 ) 410 Grove, D.M. ( 1 ) 351 Groves, J.T. ( 6 ) 394 Grutzmacher, H. ( 1 ) 144; ( 4 ) 8 3 , 100; ( 7 ) 7 3 ; ( 8 ) 22 Gruskin, E.A. ( 6 ) 376 Gryaznova, T.V. ( 1 ) 178-181 Gudat, D. ( 1 ) 320; ( 2 ) 4 3 ; ( 4 ) 2 7 , 9 0 ; ( 8 ) 25 Gunduz, N. ( 8 ) 64 Guerch, G. ( 8 ) 7 6 , 91, 92 Guerra, F.I. ( 6 ) 79 Guth, W. ( 4 ) 92 Guga, P. ( 6 ) 54 Guilard, R. ( 8 ) 44 Guillaume, H.A. ( 5 ) 56, 57 Guistian, R. ( 8 ) 193 Guneratne, R. ( 5 ) 125 Gupta, K.C. ( 6 ) 185 Gurarii, L.I. ( 5 ) 58-61 Gurskaya, A.V. ( 8 ) 128 Gusarova, N.K. ( 1 ) 82 Gusev, A.I. ( 8 ) 114 Gushchin, A.V. ( 2 ) 10 Gushurst, A.J. ( 3 ) 27; (7) 8; (8) 7 Guttmann, A. ( 6 ) 469 Guy, A. ( 6 ) 221 Guy, P.M. ( 6 ) 113 Gwara, J. ( 5 ) 43 Gyllensten, U.B. ( 6 ) 358

Habben, C.D. ( 1 ) 309 Haber, D. ( 6 ) 1 8 , 20, 143 Habibi, D. ( 1 ) 87 Habus, I. ( 1 ) 195 Hacklin, H. ( 1 ) 177 Hackney, M.L.J. ( 1 ) 69 Haddon, R.C. ( 8 ) 101, 201, 202

Haegele, G. (5) 160, 214 Haelters, J.P. ( 5 ) 194, 195

Haenel, J. ( 1 ) 156, 168, 169; ( 2 ) 11

Hafner, W. ( 7 ) 37 Hagaman, E.W. ( 3 ) 19 Hagan, W . J . , jun. ( 6 ) 103 Hagen, M.D. ( 6 ) 243 Hagi, T. ( 5 ) 124 Hagiwara, S . ( 7 ) 61 Haley, B.E. ( 6 ) 341 Hall, A.D. ( 6 ) 12 Hall, C.D. ( 2 ) 40 Hall, D. ( 3 ) 24 Hall, M.J. ( 6 ) 64 Hall, R.G. ( 4 ) 8

Hall, S.W. ( 1 ) 289, 290, 295, 297

Halmann, M. (1) 173 Halterman, R.L. ( 1 ) 7 ; ( 5 ) 23

Haltiwanger, R.C. ( 1 ) 6 9 ; ( 4 ) 29, 30

Hamada, Y. ( 5 ) 85 Hamamoto, S. ( 4 ) 6 4 ; ( 6 ) 169

Hambley, T.W. ( 1 ) 84 Hamlin, J.P. ( 6 ) 108 Hammer, V. ( 7 ) 50 Hammerschmidt, F. ( 5 ) 178-180

Hamoir, G. ( 6 ) 238 Hampel, A. ( 6 ) 411 Hampel, K. ( 6 ) 310 Hamper, B.C. ( 7 ) 48 Hampton, A. ( 6 ) 123 Han, J.S. ( 1 ) 164 Han, Y.-H. ( 6 ) 399 Hanafusa, T. ( 2 ) 23; ( 7 ) 32

Hanaya, T. ( 5 ) 122 Hanazawa, Y. ( 7 ) 96 Handa, Y. ( 3 ) 22 Handke, W. ( 5 ) 116, 201 Hani, R. ( 8 ) 75 Hanika, G. ( 1 ) 298, 300 Hanisch, M. ( 7 ) 50 Hanna, M.M. ( 6 ) 317 Hansen, J. ( 6 ) 126 Hanssgen, D. ( 1 ) 33 Hanus, V. ( 1 ) 88 Hanzawa, Y. ( 7 ) 87 Happ, E. ( 6 ) 243 Haq, W. ( 5 ) 89 Hara, E. ( 7 ) 118 Hara, T. ( 8 ) 130 Harada, M. ( 8 ) 146, 147 Haraguchi, K. ( 6 ) 56; ( 7 ) 107

Harakawa, K. ( 8 ) 134, 136 Hardin, C.C. ( 6 ) 491 Harel, P. ( 6 ) 221 Harger, M.J.P. ( 3 ) 37; ( 5 ) 243, 244, 246

Harms, K. ( 1 ) 353 Harrap, K.R. ( 6 ) 151 Harris, G. ( 6 ) 124 Harris, P.J. ( 8 ) 116 Harris, R.J. ( 1 ) 106; ( 2 ) 16

Harris, R.L.N. (5) 106 Hartmann, G.R. ( 6 ) 345 Harusawa, S . ( 5 ) 84 Hasemann, L. ( 1 ) 118 Hashimoto, S. ( 1 ) 98 Hassan, F.S.M. ( 1 ) 134 Hassler, K. ( 1 ) 56 Hata, T. ( 4 ) 6 6 ; ( 5 ) 7 1 ;

Orgunnphosp horus Chemistry

414 ( 6 ) 47, 142, 166, 210, 240 Hattori, S. ( 6 ) 351 Haw, J . E . ( 8 ) 203 Hawkins, A.F. ( 6 ) 245 Hayakawa, Y. ( 6 ) 267, 349 Hayashi, M. ( 6 ) 333 Hayashi, T. ( 1 ) 1 0 ; ( 5 ) 168 Hayden, W. ( 6 ) 63 Hayes, J.A. ( 6 ) 165 Healy, M.D. ( 1 ) 46 Hearst, J.E. ( 6 ) 438 Hecht, S.M. ( 6 ) 3 3 , 247, 404 Heckler, T.G. ( 6 ) 247 Heckmann, G. ( 1 ) 359 Heil, B. ( 1 ) 132 Heimer, E.P. ( 6 ) 64 Heine, J. ( 1 ) 9 5 ; ( 5 ) 12 Heine, P. ( 5 ) 203 Heinemenn, U. ( 6 ) 16 Heinicke, J. ( 1 ) 344 Heitz, M.-P. ( 1 ) 100 HClche, C. ( 6 ) 196, 260, 384-386, 395 Helfman, D.M. ( 6 ) 414 Helgesson, G. ( 1 ) 228 He-Line, W. ( 1 ) 333 Hendrick, K. ( 1 ) 84 Hendrikkson, J.B. ( 1 ) 249 Hendriksen, D.E. ( 1 ) 65 Henkel, T. ( 8 ) 4 , 165 Henner, W.D. ( 6 ) 372 Henriksen, U. ( 6 ) 408 Hensel, R. ( 1 ) 127; ( 5 ) 200 Heptinstall, L.E. ( 6 ) 295 Herdering, W. ( 6 ) 215, 220 Herdewijn, P. ( 6 ) 22, 163 Hernandez Cano, F. ( 8 ) 45 Herrera, F.J.L. ( 7 ) 103 Herrmann, E. ( 8 ) 1 6 , 177 Her&, M. ( 6 ) 79 Hess, N.J. ( 8 ) 80 Hesse, M. ( 1 ) 63 Heubel, J. ( 8 ) 63 Heuer, L. ( 1 ) 159 Hewitt, D. ( 5 ) 210 Hey, E. ( 1 ) 43 Higginbottom, R. ( 1 ) 184 Higgins, S.J. ( 1 ) 134 Higuchi, R. ( 6 ) 290 Higuchi, T. ( 1 ) 282 Hildenbrand, K. ( 6 ) 85 Hill, A.F. ( 1 ) 293 Hill, A . R . , jun. ( 6 ) 282 Hill, K. ( 6 ) 354 Hiller, W. ( 3 ) 39 Himelsbach, F. ( 6 ) 5 , 275

Hingerty, B.E. ( 6 ) 27 Hingorani, V.N. ( 6 ) 121, 138

Hinkle, R.J. ( 1 ) 213 Hinman, A.S. ( 1 ) 223 Hiramura, Y. ( 7 ) 25 Hirao, I. ( 6 ) 367 Hiraoka, W. ( 6 ) 84 Hirose, H. ( 8 ) 109 Hirotsu, K. ( 1 ) 282 Hirst, M.C. ( 6 ) 309 Histand, G. ( 6 ) 253 Hitchcock, M.J.M. ( 6 ) 21 Hitchcock, P.B. (1) 23, 3 5 , 162, 278, 342, 343

Hixson, S.S. ( 6 ) 334, 339 Ho, Y.-K. ( 6 ) 121, 138 Hoa Tran Huy, N. (1) 356 Hobbs, J.B. ( 6 ) 132 Hock, R. ( 7 ) 71 Hodges, R.R. ( 6 ) 424 Hohlmaier, J. ( 6 ) 322 Hojo, M. ( 1 ) 10 Holand, S . ( 1 ) 312; ( 4 ) 38

Holderich, W. ( 1 ) 63 Holland, D. ( 4 ) 5 8 ; ( 6 ) 190

Hollander, F.J. ( 1 ) 138 Hollis, L.S. ( 6 ) 449 Holmes, R.R. ( 2 ) 41 Holmes, W.M. ( 6 ) 175 Holt, M.S. ( 1 ) 334 Hol:, A. ( 5 ) 9 7 , 107; ( 6 ) 5 8 , 6 1 , 6 2 , 324 Holzl, W. ( 1 ) 352 Honda, K. ( 4 ) 75 Hong, (2.1. ( 6 ) 150 Honjo, M. ( 5 ) 1 1 1 ; ( 6 ) 6 4 , 109 Hood, L. ( 6 ) 157, 471 Hoogerhout, P. ( 4 ) 50, 69 Hopkins, P.B. ( 6 ) 492 Hoppe, J. ( 6 ) 340 Horie, N. ( 6 ) 90 Horie, Y. ( 5 ) 124 Horiguchi, A. ( 7 ) 116 Horiki, K. ( 5 ) 89 Horn, T. ( 6 ) 176 Hornes, E. ( 6 ) 331 Horska, K. ( 6 ) 324 Horvath, S.J. ( 6 ) 157 Hoshi, M. ( 8 ) 197 Hoshino, M. ( 6 ) 351 Hossain, M.G. ( 1 ) 236 Hosseini, M.W. ( 6 ) 115, 116 Hostomsky, Z. ( 6 ) 178 Hosur, R.V. ( 6 ) 477 Hotoda, H. ( 4 ) 6 6 ; ( 5 ) 7 1 ; ( 6 ) 4 7 , 166, 240 Houalla, D. ( 5 ) 27

Houlgrave, C.W. ( 6 ) 399 Howard, J.A.K. ( 1 ) 293 Hoy, N.H.T. ( 1 ) 335 Hruska, F.E. ( 6 ) 25 Hu, B. ( 5 ) 47 Huang, C.-H. ( 6 ) 103 Huang, D.-L. ( 6 ) 14 Huang, G. ( 5 ) 117 Huang, J. ( 5 ) 109 Huang, Y.-Z. ( 7 ) 28-30 Huber, B. ( 1 ) 298, 300 Hudson, B.S. ( 7 ) 90 Hudson, H.R. ( 5 ) 174 Hudson, R.F. ( 4 ) 99 Hugel-Le Goff, C. ( 1 ) 271 Hughes, D.L. ( 1 ) 108; ( 2 ) 15

Hui, C.-F. ( 6 ) 470 Hung, J . T . ( 1 ) 314 Hunkapiller, M.W. ( 6 ) 157 Hunkapiller, T. ( 6 ) 157 Huser, D.L. ( 5 ) 191 HUSS, S. ( 6 ) 43 Hussain, L.A. ( 4 ) 26 Hussoin, M.S. ( 1 ) 249 Hutson, S.M. ( 6 ) 478 Huy, N.H.T. ( 1 ) 313 Huynh-Dinh, T. ( 6 ) 7 9 , 187

Hyodo, N. ( 5 ) 6 Hyun, J.L. ( 4 ) 32 Ibrahim, E. ( 1 ) 182; ( 5 ) 206

Ide, H. ( 6 ) 299 Ideses, R. ( 7 ) 19 Ido, H. ( 7 ) 16 Igau, A . (1) 144, 145; ( 4 ) 100, 101; ( 8 ) 22 Ignateva, S.N. ( 1 ) 148 Ignatov, M.E. ( 8 ) 67 Igolen, J. ( 6 ) 187 Igueld, S . ( 5 ) 55 Ihn, W. ( 5 ) 24 Iigo, M. ( 6 ) 238 Iino, Y. ( 7 ) 118 Iizuka, T. ( 8 ) 130 Ikeda, S . ( 6 ) 326 Ikeda, T. ( 8 ) 133 Ikehara, M. ( 5 ) 8 1 ; ( 6 ) 171, 184, 205

Ikeuchi, T. ( 6 ) 263 Il'in, E.G. ( 8 ) 6 7 , 142 Il'ina, L.F. (2) 30 Il'yasov, R.N. ( 1 ) 72 Imai, K. ( 6 ) 7 7 , 207, 211 Imai, S . ( 6 ) 91 Imamoto, T. ( 1 ) 104; ( 7 ) 7

Imamura, S. ( 6 ) 78 Imbach, J.-L. ( 6 ) 29, 43,

415

Author Index 197, 248, 318

Imoto, H. (3) 26; (4) 81 Inamoto, N. (1) 252, 254, 263, 264, 282; (4) 94; (8) 49 Inanaga, J. (3) 22 Inaoka, T. (6) 426 Inazawa, K. (7) 96 Indzhikyan, M.G. (1) 91, 92, 205 Inglese, J. (6) 74 Innis, M.A. (6) 288, 359 Inokawa, S. (5) 122 Inone, K. (8) 124 Inoue, T. (6) 316 Ionin, B.I. (1) 165; (5) 119, 148, 152, 163, 219, 227 Iovel, I. (1) 230 Ironside, M.D. (3) 28 Isaacs, N.S. (1) 336 Ishida, M. (6) 426 Ishido, Y. (6) 274 Ishihara, H. (5) 41 Ishihara, T. (5) 10, 11 Ishii, M. (7) 16 Ishmaeva, E.A. (1) 285-287 Ishmuratov, A.S. (5) 72 Ismaev, I.E. (5) 197 Isoe, S. (7) 108 Isono, J. (6) 91 Issartel, J.-P. (6) 118 Issleib, K. (1) 146, 272 Iteyen, B.J. (8) 210 Itkes, A.V. (6) 277 Ito, Y. (1) 10; (5) 168; (8) 175 Ito, Z. (8) 174 Itoh, S. (8) 134 Ivanov, A.N. (1) 191-193; (5) 8, 37 Ivanov, S.A. (4) 24, 25 Ivanova, N.A. (8) 159 Ivanova, V.N. (5) 230 Ivanova, Ya.A. (8) 127 Ivanovskaya, M.G. (6) 236, 415 Ivarie, R. (6) 174 Iverson, B.L. (6) 392, 433 Ives, D.H. (6) 326 Iwahara, M. (1) 8 Iwai, H. (8) 130 Iwai, N. (6) 456 Iwai, S. (6) 208, 212 Iwasake, M. (6) 497 Iwase, R. (6) 142, 210 Iyengar, B.S. (6) 76

Jackson, L.A. (8) 116

Jackson, S.A. (5) 98 Jacob, P. (4) 17 Jacobsen, G.B. (1) 134 Jacobsen, G.E. (1) 61 Jacobson, M.D. (6) 27 Jacquier, R. (5) 166 Jager, L. (5) 203 Jager, A. (6) 33 Jagner, S. (1) 228 Jahngen, E.G.E. (6) 113 Jahngen, J.H. (6) 113 Jain, J.K. (1) 211 Janca, J. (8) 177 Janecki, T. (3) 10 Janik, J.F. (1) 45 Janke, F. (3) 15 Janout, V. (8) 168, 183, 223

Jaouhari, R. (7) 106 Jardine, A.M. (5) 78 Jastorff, B. (5) 26, 28 Jaudet, E. (5) 221 Jaworska, M. (6) 256 Jayaraman, K. (6) 291 Jazwinski, J. (6) 395 Jedlinski, Z. (8) 96 Jeffreys, A.J. (6) 292 Jeffries, A.C. (6) 409 Jegorov, A. (1) 88 Jekel, A.P. (8) 113 Jenkins, C.L.D. (5) 106 Jenkins, I.D. (1) 109, 110, 112; (2) 17, 18 Jennings, W.B. (5) 209 Jensen, M.A. (6) 307 Jeppesen, C. (6) 407, 408 Jessup, J.S. (8) 219 Jin, Y. (6) 20, 143, 319 Jinkerson, D.L. (8) 75 Jiricny, J. (6) 462 Johansson, N.G. (6) 126 John, A. (8) 16 Johns, D.G. (6) 23, 125 Johns, R.B. (5) 56, 57, 186 Johnson, A.W. (6) 377, 378 Johnson, F. (6) 487 Johnson, I.D. (6) 298 Johnson, M.A. (6) 23 Johnson, 0. (5) 66 Jones, B.K. (6) 173, 439 Jones, D.W. (5) 66 Jones, N.D. (5) 191 Jones, P.G. (8) 68 Jones, R.A. (1) 48, 49, 290; (6) 223 Jones, R.C.F. (7) 115 Jorgensen, W.L. (3) 27; (7) 8; (8) 7 Josey, J.A. (4) 49 Jost, J.-P. (6) 462

Jowett, I.C. (5) 50 Joyce, G.F. (6) 280, 284, 316

Juby, C.D. (4) 78; (6) 229

Juge, S. (1) 76; (4) 4; (5) 165

Jujimoto, M. (8) 225 Jung, G. (5) 187 Jutzi, P. (1) 142, 143, 256

Kabachnik, M.I. (2) 47; (5) 7, 70

Kabachnik, M.M. (1) 13; (4) 39

Kachovskaya, L.S. (1) 276, 286

Kadel, J. (1) 360 Kadoura, J. (7) 6; (8) 28 Kadyrev, A.A. (5) 113 Kadyrov, R.A. (1) 199 Kai, M. (6) 497 Kajiwara, M. (8) 134, 173, 218, 227, 229

Kajtar-Peredy, M. (7) 101 Kakihana, M. (7) 15 Kakoschke, C. (6) 69 Kal'chenko, V.I. (2) 29 Kalinov, S.M. (1) 94; (5) 121

Kalnik, M.W. (6) 485-487 Kalsheker, N. (6) 295 Kalyanova, R.M. (5) 70 Kamaike, K. (6) 274 Kamalov, R.M. (5) 73 KamiAski, R. (4) 19; (5) 44

Kamiyama, S. (8) 111 Kamo, J. (8) 220 Kanaan, M. (5) 132 Kaneko, M. (8) 129 Kang, G.J. (6) 125 Kang, H.-S. (5) 143 Kansal, V.K. (6) 9, 187 Kappen, L.S. (6) 398, 400 Kappler, F. (6) 123 Karaghiosoff, K. (1) 183; ( 4 ) 12; (8) 160 Karaman, R. (5) 139, 215, 216, 232

Karara, A. (7) 98 Karasawa, Y. (8) 146 Karasik, A.A. (1) 147 Karataeva, F.Kh. (2) 34 Karger, B.L. (6) 469 Kargin, Yu.M. (3) 1 Karikh, K. (6) 341 Karpeiskii, M.Ya. (6) 67, 277

Karpen, J.W. (6) 100

Orgunophosphorus Chem isoy

416

Karpova, G.G. (6) 430 Karpyshev, N.N. (6) 157, 161

Karsch, H.H.

(1) 59, 60, 280, 298, 300 Kartasheva, O.N. (6) 277 Kasai, H. (6) 402 Kasai, M. (8) 70 Kashemirov, B.A. (5) 162, 231 Kass, V. (3) 39 Kastrup, R.V. (1) 65 Kasykhin, L.F. (8) 65 Kataoka, H. (6) 401 Kataoka, S. (6) 91 Kato, S. (5) 41 Kato, T. (3) 5 Katsarava, R.D. (8) 223 Katsumura, S. (7) 108 Katsuta, M. (8) 174, 175 Katsyubova, S.A. (4) 14; (5) 138 Katti, K.V. (1) 116; (8) 14, 163, 164 Katti, S.B. (5) 89 Katzhendler, J. (6) 164 Kaukorat, T. (4) 5 Kawada, T. (6) 91 Kawagoe, K.-I. (7) 96 Kawakami, M. (3) 31 Kawakami, T. (8) 109 Kawakita, M. (6) 351 Kawamoto, H. (5) 122 Kawasaki, T. (7) 36 Kawase, Y. (6) 212 Kawashima, M. (4) 64; (6) 169 Kawashima, T. (8) 49 Kawazoe, Y. (6) 402 Kayser, M.M. (7) 52 Kazankova, M.A. (1) 4, 125, 149, 166 Kazantsev, A . V . (4) 45 Kazymov, A.V. (1) 243 Kean, J . M . (6) 441 Keglevich, G. (1) 355; (3) 14, 15; (5) 14 Kehne, A . (6) 215 Keitel, I. (5) 134 Keith, G. (6) 89 Keller, K. (1) 250; (8) 165 Kelley, J.A. (6) 125 Kelman, D . J . (6) 423 Kenyon, G.L. (6) 133, 134 Kettani, A.E.-C. (6) 82 Keyte, J. (6) 292 Khabou, A. (8) 66 Khachatryan, R.A. (1) 205 Khafizova, G.S. (2) 30 Khailova, A.N. (5) 18 Khairullin, V.K. (5) 145

Khandker, M.N. (1) 236 Kharadze, D . P . (8) 223 Kharitonov, V.G. (1) 238; (7) 46

Kharshan, M.A. (5) 18 Khaskin, B.A. (5) 72 Khasnis, D.V. (2) 44 Khawli, L.A. (5) 123 Khodak, A.A. (5) 51; (8)

44, 360; (8) 157

32

Khokhlov, P.S. (5) 162, 231

Kholodyazhnyi, 0.1. (1) 267

Khusainova, D.R. Khusainova, N.G.

(3) 1

(5) 223,

225

Khusnutdinova, E.K. (2)

Knight, J . G . (3) 32 Knoch, F. (1) 329; (8) 27 Knorre, D.G. (6) 431, 432 Knowles, J . R . (6) 140 141

KO, Y.K. (5) 86 Kobayashi, C. (6) 343 Kobayashi, K. (3) 5; 143, 144

27, 30, 31

Kibardin, A.M.

Kitayama, M. (8) 110 Kitts, P.A. (6) 311 Klabunde, K.J. (5) 3 Klaus, H. (6) 219 Klaus, M.M. (6) 227 Klaus, W. (6) 153 Klebanskii, E.O. (1) 306 Klepa, T.I. (8) 71 Klingebiel, U. (1) 42,

(1)

178- 181

Kiebasinski, K. (7) 114 Kierzek, R . (4) 65; (6) 202, 412, 413 Kihara, T. (8) 49 Kihler, H. (5) 203 Kiji, J. (1) 8 Kikuchi, K. (6) 232 Kilic, E. (8) 64 Kilic, Z. (8) 64 Kim, C . (8) 55, 103 Kim, D.Y. (5) 100, 133 Kim, H.-S. (6) 293 Kim, H.-Y. (6) 125 Kim, S. (1) 99; (5) 86, 249; (7) 22 Kim, T.H. (5) 128, 133 Kim, T.V. (1) 241 Kimura, A. (7) 108 Kimura, K. ( 5 ) 192 Kimura, S. (5) 111 Kimura, T. (5) 248 Kind, J. (6) 206 King, T.J. (5) 67, 75 Kingsman, A. J. (6) 298 Kingsman, S.M. (6) 298 Kinoyan, F.S. (1) 205 Kirchmeier, R . L . (5) 204 Kireev, V.V. (8) 118, 205 Kirilov, M. (5) 154, 226 Kirisits, A . J . (6) 150 Kirk, D.N. (6) 144 Kirpotin, D.B. (6) 467 Kirsanov, A.V. (8) 61 Kirshenbaum, M.R. (6) 460 Kisarova, L.I. (1) 234 Kise, M. (5) 192, 193 Kiseleva, E.I. (1) 241 Kiso, Y. (5) 248 Kitahara, T. (7) 116 Kitami, J. (8) 197 Kitamura, T. (5) 25

Kobayashi, S. (6) 264 Kobayashi, T. (7) 118 Kobayashi, Y. ( 7 ) 87, 96; (8) 215

Kobzev, V.F. (6) 160 Kocienski, P. (7) 111 Koenig, H. (8) 152 Koenin, -. J. (6) 86, 87 Koenig, M. (1) 253, 255; (4) 95

Kogan, V.A. (8) 159 Kohda, K. (6) 402 Koidan, G.N. (1) 172, 187 Koizumi, T. (5) 124 Kojima, M. (8) 198, 199 Kolasa, T. (1) 113 Kolba, E. (8) 19 Koleck, M.P. (6) 165 Kolesnikova, G.G. (1) 13 Kolle, P. (1) 30, 31, 32 Kolobushkina, L . I . (6) 67 Kolodiazhnyi, 0.1. (1) 103; (2) 21, 22; (4) 21; (5) 136; (7) 38, 39 Kolotilo, M.V. (8) 158, 159 Komarov, E.V. (5) 120 Komarova, N . I . (6) 40 Komissarov, V.Yu. (1) 125, 248 Komissarova, N.L. (2) 32 Komiyama, M. (6) 104-107 Kon, Y. (8) 136 Konakahara, T. (6) 417 Kondrat'eva, N.O. (6) 455 Konig, S. (1) 300 Konishi, H. (1) 8 Kono, K. (8) 70 Konomoto, K. (1) 246 Konovalova, I . V . (1) 209; (2) 27, 28, 30, 3 1 Koole, L.H. (2) 7 ; (5) 237; (6) 30-32, 265

417

Author Index Kopylov, V.M. ( 8 ) 145 Kopytin, A.V. ( 8 ) 142 Korenchenko, O.V. ( 2 ) 46 Korkin, A.A. ( 2 ) 6 ; ( 4 ) 48; ( 8 ) 6

Kormachev, V.V. ( 1 ) 167 Kornuta, P.P. ( 8 ) 158, 159

Korolev, O.S. ( 5 ) 222 Korshak, U.V. ( 8 ) 168 Koshida, R . ( 6 ) 126 Koshkin, A.A. ( 6 ) 396 Koster, R. ( 1 ) 27 Kostina, V.G. ( 8 ) 52 Kostka, K. ( 5 ) 94 Kotova, E.V. ( 8 ) 126 Kountz, P.D. ( 6 ) 140 Kouril, M. ( 8 ) 177 Kovacs, T. ( 6 ) 122 Kovalenko, L.V. ( 5 ) 146 Kovyazin, V.A. ( 8 ) 145 Kowal, C.D. ( 6 ) 76 Kowalski, M.H. ( 1 ) 213 Kowlaski, J. ( 1 ) 68 Koyama, H. ( 1 ) 225 Koziolkiewicz, M. ( 6 ) 266 Kozionov, A.L. ( 6 ) 396 Kozlara, A. ( 8 ) 53 Kraaijkamp, J . G . ( 1 ) 351 Kraal, B. ( 6 ) 474 Kraemer, K.H. ( 6 ) 405 Kraevskii, A.A. ( 6 ) 127 Kramer, B. ( 1 ) 251; ( 4 ) 93

Kramer, W. ( 6 ) 322 Krannich, L.K. ( 1 ) 151 Krasil'nikova, E.A. ( 5 ) 110

Krauch, T. (5) 239 Kravtsova, S.F. ( 8 ) 126 Krawczyk, E. ( 5 ) 45 Krawetz, S.A. ( 6 ) 287 Krebs, B. ( 4 ) 92 Krech, F. ( 1 ) 146 Kreiser, W. ( 7 ) 82 Kreitmeier, P. ( 1 ) 279 Kretschmann, M. ( 5 ) 203 Kreuzfeld, H.-J. ( 4 ) 80 Krieger, L. ( 1 ) 266 Krishnamurthy, S.S. ( 4 ) 3 1 ; ( 8 ) 7 4 , 98

Krivchun, M.N. ( 1 ) 165 Krolevets, A.A. ( 1 ) 157, 158, 170; ( 2 ) 1 2 , 13

Kroos, R. ( 1 ) 142, 143 Kruger, C. ( 1 ) 296, 300 Kruger, W. ( 1 ) 160 Krummel, B. ( 6 ) 290 Kruse, L . I . ( 8 ) 47 Kryuchenkova, L.V. ( 8 ) 127

Krzyzosiak, W.J.

( 6 ) 382

Ku, B. ( 4 ) 7 ; ( 5 ) 185 Kuchino, Y. ( 6 ) 9 0 , 279 Kuchmeier, R.L. ( 5 ) 125 Kuchta, R.D. ( 6 ) 301 Kudryavtsev, A . A . (1) 242; ( 8 ) 29

Kugler, M. ( 5 ) 187 Kuhm, P. ( 4 ) 4 0 , 41 Kuhne, U. ( 1 ) 146 Kuijpers, W.H.A. ( 6 ) 31 Kukhar, V.P. ( 1 ) 267; ( 4 ) 6 ; ( 5 ) 167, 177; ( 8 ) 65

Kukhareva, T.S. ( 2 ) 3 3 ; (5) 170 Kumar, C.V. ( 6 ) 459 Kumaravel, S.S. ( 4 ) 31 Kumarev, V.P. ( 6 ) 160 Kunimoto, K. ( 5 ) 192 Kunkel, T.A. ( 6 ) 286 Kuo, K.C. ( 6 ) 89 Kurihara, T. ( 5 ) 84 Kuroboshi, M. ( 5 ) 10, 11

Kurozawa, Y. ( 6 ) 456 Kusano, T. ( 5 ) 9 Kusmierek, J.T. ( 6 ) 300 Kutny, R. ( 6 ) 2 Kutyavin, I . V . ( 6 ) 432 Kutyrev, A.A. ( 5 ) 1, 80 Kutyrev, G.A. ( 5 ) 222 Kuwabara, M.D. ( 6 ) 8 4 , 387, 391

Kuyl-Yeheskiely, E. ( 4 ) 5 2 ; ( 6 ) 241, 242

Kuz'min, V . I . ( 5 ) 18 Kuznedelov, K.D. ( 6 ) 160 Kuznetsova, S.A. ( 6 ) 236 Kwok, F. ( 6 ) 350 Kwon, S . ( 8 ) 104, 105, 123, 191

Labadi, I. ( 6 ) 18 Labarre, J.F. ( 8 ) 7 6 , 8 7 , 91-95,

231-233

Lacey, J.C., j u n . ( 6 ) 245 Lacombe, S . ( 1 ) 270 LaDine, J . R . ( 6 ) 346, 348 Laguna, A. ( 8 ) 68 Laguna, M. ( 8 ) 68 Lai, E. ( 6 ) 471 Lai, K. ( 6 ) 489 Laibinis, P.E. ( 1 ) 46 Laible, R . C . ( 8 ) 170 Lambert, R.W. ( 6 ) 64 Lammertsma, K. ( 1 ) 314 Lamond, A . I . ( 6 ) 225 Landgraf, B. ( 4 ) 17 Laneman, S.A. (1) 5 7 , 64 Lang, H. ( 1 ) 3 Langen, P. ( 6 ) 7 Langermans, H.A. ( 6 ) 31 Lanin, A.G. ( 5 ) 205

Lanneau, G.F. ( 5 ) 68 LaNoue, K.F. ( 6 ) 478 Lapinska, ?I(.8 ) 180 Lappert, M.F. (1) 2 3 , 35 Larpent, C . ( 1 ) 8 9 , 9 0 , 131; ( 3 ) 8

Larsen, T.A. ( 6 ) 387 Lasater, L.S. ( 6 ) 308 Latimer, L.J.P. ( 6 ) 310 Latscha, H.P. ( 1 ) 190; ( 4 ) 33 Lattman, M. ( 2 ) 44 Laval, J. ( 6 ) 419 Lavery, R. ( 6 ) 385 Law, R. ( 6 ) 391 Lawyer, F.C. ( 6 ) 285 Lazhko, E.I. ( 1 ) 149 Lazukina, L . A . ( 4 ) 6 ; ( 5 ) 177

Leader, H. ( 5 ) 139, 215, 216, 232

Leander, J.D. ( 5 ) 191 Lebedenko, E.N. ( 6 ) 183 Lebedev, A.V. ( 6 ) 396 Lebedeva, O.E. ( 5 ) 222 Leblanc, J . C . ( 1 ) 262 Lebleu, B. ( 6 ) 248 Leclercq, D. ( 5 ) 68 Lecomte, L. ( 1 ) 132 Le Corre, M. ( 7 ) 5 4 , 55 Lee, B.L. ( 6 ) 442 Lee, H.-Y. ( 1 ) 96 Lee, J.S. ( 6 ) 310 Lee, K.K. (1) 305 Lee, P.H. ( 1 ) 9 9 ; ( 5 ) 249; ( 7 ) 22

Lee, S.-G. ( 4 ) 97 Lee, S.H. ( 6 ) 397 Lee, T . A . ( 1 ) 9 9 ; (5) 249 Lee, T.R. ( 6 ) 400 Lefeber, A.W.M. ( 4 ) 5 2 ; ( 6 ) 241

Le Floch, P. ( 1 ) 354 Legocki, J. ( 5 ) 65 Le Goffic, F. ( 6 ) 342 Lehart, W. ( 8 ) 193 Lehmann, C . ( 4 ) 6 8 ; ( 6 ) 209

Lehn, J.-M.

( 6 ) 1 1 5 , 116,

395

Leibnitz, P. ( 1 ) 1 6 8 ; ( 2 ) 11

Leifeng, C . ( 2 ) 36 Leissring, E. (1) 272 Lekschas, J. ( 6 ) 2 6 , 206 Lemaitre, M. ( 6 ) 248 Le Merrer, Y. ( 7 ) 97 Lemmen, P. ( 4 ) 17 Lemoine, P. ( 1 ) 339 Lensink, C . ( 2 ) 42, 4 3 ; ( 4 ) 2 7 , 2 8 ; ( 8 ) 148 ( 4 ) 1 1 ; ( 5 ) 183

Leo, G.C.

Organophosph oms CIiemisty

418

Leone, R. ( 1 ) 130 Leonetti, J.P. ( 6 ) 248 Leonil, J. ( 6 ) 342 Lermontov, S.A. ( 5 ) 4 Lesnikowski, Z.J. ( 6 ) 5 4 , 256

Lessinger, L. ( 6 ) 123 Leta, S . ( 1 ) 65 Letai, A.G. ( 6 ) 332 Letsinger, R.L. ( 6 ) 253 Lett, R. ( 7 ) 113 Leuer, M. ( 1 ) 163 Leung, W.-P. ( 1 ) 3 5 , 61 Le Van, D. ( 1 ) 269 Levin, B.V. ( 8 ) 142 Levin, D. ( 3 ) 23 Levin, J.D. ( 6 ) 377 Levina, A.S. ( 6 ) 40, 186, 432

Levy, J.N. ( 5 ) 141 Levy, M.J. ( 6 ) 33 Lewis, R.T. ( 5 ) 103; ( 7 ) 7 5 , 81

Ley, S.V. ( 7 ) 89 Li, L.-P. ( 5 ) 74 Li, S . ( 5 ) 235 Li, S.W. ( 6 ) 341 Li, W. ( 6 ) 319 Li, W.S. ( 7 ) 100 Li, Z. ( 5 ) 47 Liao, P.M.-C. ( 6 ) 437 Liao, Q. ( 7 ) 58 Liao, X. ( 5 ) 104, 235 Liblong, S.W. ( 8 ) 148, 149

Liedtke, A. ( 1 ) 268 Liguori, A. ( 6 ) 499, 500 Lilga, K.T. ( 6 ) 423 Limy S . ( 6 ) 355 Lin, G. ( 5 ) 29 Lin, J. ( 6 ) 336 Lin, S.-B. ( 6 ) 257 Lin, T.-S. ( 6 ) 21, 2 4 , 129

Lincoln, J. ( 1 ) 102 Linden, A. ( 1 ) 324, 325; ( 4 ) 31, 9 1 ; ( 8 ) 233 Linder, E. ( 3 ) 39 Lindner, A.J. ( 6 ) 345 Lindner, E. (1) 19, 66 Linti, G. ( 1 ) 32 Liorber, B.G. ( 5 ) 230 Lipka, P. ( 5 ) 40 Lipman, R. ( 6 ) 443 Lippard, S.J. ( 6 ) 446, 449 Lippert, J. ( 8 ) 193 Lithei, G. ( 8 ) 12 Litvinov, G.N. ( 1 ) 148 Litvinov, I.A. ( 1 ) 147, 180, 181, 348; ( 5 ) 58, 5 9 , 6 1 , 151

Liu, H. ( 6 ) 148 Liu, H.-J. ( 5 ) 82 Liu, H.-Y. ( 1 ) 129 Liu, L. ( 6 ) 148 Liu, S. ( 6 ) 117 Liu, Y.-C. ( 5 ) 31 Liu, Z. ( 1 ) 97 Liuzzi, M. ( 6 ) 373-375 Livantsov, M.V. ( 1 ) 2 0 , 235; ( 4 ) 18

Llinas, J.R. ( 2 ) 5 Lloyd, D. (7) 4 Lloyd, R.S. ( 6 ) 376 Lobanov, D.N. ( 2 ) 47 LoBrutto, R. ( 6 ) 137 Loeffler, W. ( 5 ) 187 Lonnberg, H. ( 6 ) 1 0 , 1 8 , 19

Logunov, A.P. ( 3 ) 11 Logusch, E.W. ( 4 ) 1 1 ; ( 5 ) 183

Loiseau, P. ( 2 ) 37 Lomakin, A.I. ( 6 ) 161 Lomonosov, A.V. ( 8 ) 126 Long, E.C. ( 6 ) 461 Lopez, F. ( 7 ) 44, 68-70; ( 8 ) 5 9 , 60

Lopez-Leonardo, C. (7) 6 6 , 67

topusihski, A. ( 5 ) 46 Lora, S. ( 8 ) 195 Loreau, N. ( 6 ) 260 Losse, G. ( 6 ) 167 Lowe, G. ( 5 ) 8 3 ; ( 6 ) 116, 154

Lowther, N. ( 2 ) 40 Lu, X. ( 5 ) 109 Lucas, A., I11 ( 8 ) 137 Lucchini, G. ( 6 ) 345 Luczak, L. ( 5 ) 46 Ludwig, J. ( 4 ) 5 5 ; ( 6 ) 135

Liicke, M. ( 8 ) 179 Lukashev, N.V. ( 1 ) 4 , 125, 149

Lukevics, E. ( 1 ) 230 Lumin, S . ( 7 ) 9 2 , 98 Lunardi, J. ( 6 ) 118 Lund, V. ( 6 ) 331 Lundmark, P.J. ( 1 ) 223 Luo, Y. ( 5 ) 104 Luss, H.R. ( 5 ) 19 Lutsenko, I.F. ( 1 ) 4 , 1 3 , 2 0 , 125, 149, 166, 189, 235; ( 4 ) 1 8 , 39 Luzikov, Yu.N. ( 1 ) 4 Lyons, C . ( 6 ) 347

Ma, Q. ( 6 ) 133, 134 Ma, Y.-X. ( 4 ) 7 2 ; ( 6 ) 50 Maata, E.C. ( 8 ) 55

MacArthur, D.M. ( 8 ) 208, 209

McAtee, R.E. ( 8 ) 219 McBride, L.J. ( 6 ) 157 McCaffrey, R.R. ( 8 ) 217, 219

McClard, R.W. ( 5 ) 9 8 , 218; ( 7 ) 85

McConlogue, L. ( 6 ) 288 McCray, J.A. ( 6 ) 111 McDonald, J.F. ( 4 ) 1 1 ; ( 5 ) 183

Macedo, A.M. ( 6 ) 305 McFadden, H.G. ( 5 ) 106 McFarlane, H.C.E. ( 1 ) 55 McFarlane, W. ( 1 ) 5 5 , 7 3 , 127; ( 3 ) 2 0 ; ( 5 ) 200

McGeary, C.A.. ( 1 ) 162 McGhee, W.D. ( 1 ) 138 McGuckin, M.R. ( 5 ) 209 McGuigan, C. ( 4 ) 53 McGuiness, B.F. ( 6 ) 443 McIntosh, D.B. ( 6 ) 338 Mack, D.P. ( 6 ) 392 McKenna, C.E. ( 5 ) 123, 141

McKenna, E.G. (7) 41 McLaren, K.L. ( 5 ) 242 McLaughlin, L.W. ( 6 ) 214, 235, 329, 424, 463

McLennan, A.G. ( 6 ) 155 McNamara, W.F. ( 1 ) 45 McPartlin, M. ( 1 ) 4 7 , 84 McQuigan, C. ( 5 ) 54 Madaule, Y. ( 2 ) 37 Madden, T.J. ( 1 ) 342 Maddox, M.L. ( 2 ) 20 Mading, P. ( 1 ) 120 Madrid, I. ( 7 ) 66 Maeda, H. ( 1 ) 217, 218, 246; ( 7 ) 49

Maekawa, T. ( 5 ) 11 Maerkl, G. ( 1 ) 265, 279, 345, 346, 352; ( 4 ) 85

Magano, J. ( 7 ) 23 Magill, J.H. ( 8 ) 198, 199, 205

Mahmood, R. ( 6 ) 344 Mahmood, T. ( 5 ) 204 Mahran, M.R. ( 5 ) 224 Maidanovich, N.K. ( 8 ) 7 1 Maier, L. ( 5 ) 172, 173, 182

Maigrot, N. ( 1 ) 24 Maikuma, S. ( 4 ) 75 Majoral, J.P. ( 1 ) 308, 323; ( 5 ) 6 2 ; ( 8 ) 24

Majors, J. ( 6 ) 289 Majumdar, C. ( 6 ) 255 Makarov, G.M. ( 5 ) 73 Makhaev, V.D. ( 1 ) 193 Makhaeve, G.F. ( 5 ) 234

419

Author Index Makino, K. ( 6 ) 464 Malavaud, C . ( 2 ) 24-26 Malisch, W. ( 8 ) 19 Malone, J.F. ( 5 ) 209 Malysheva, S.F. (1) 82 Mamaev, S.V. ( 6 ) 432 Mancini, W.R. ( 6 ) 129 Mang, M.J. ( 8 ) 119 Manners, I. ( 8 ) 119, 120 Manoharan, M. ( 6 ) 488 Mansuri, M.M. ( 6 ) 21 Mantei, N. ( 6 ) 159 Marchenko, A.P. ( 1 ) 172, 187, 242; ( 5 ) 129; ( 8 ) 29, 5 0 , 51 Marciniec, B. ( 1 ) 67 Marciniec, T. ( 6 ) 382 Marecek, J.F. ( 6 ) 114 Margolis, S.A. ( 6 ) 428 Marinetti, A. ( 1 ) 135, 275, 315; ( 7 ) 45 Markham, A.F. ( 6 ) 295 Markiewicz, W.T. ( 6 ) 157, 202 Markmann, J. ( 7 ) 37 Markovskii, L.N. (1) 276, 285-287, 304, 306; ( 2 ) 29; ( 4 ) 8 6 , 8 7 , 89 Markus, F. ( 1 ) 232, 233 Marky, L.A. ( 6 ) 223 Marlin, J.E. ( 7 ) 86 Marshall, W.S. ( 4 ) 7 1 ; ( 6 ) 254 Marsico, J.W. ( 8 ) 72 Marth, C.F. ( 7 ) 12-14 Martin, D. ( 1 ) 123 Martin, G.S. ( 6 ) 445 Martin, J . A . ( 6 ) 64 Martin, J.C. ( 6 ) 21, 57, 60 Martin, R.F. ( 6 ) 304 Martin, S.F. ( 4 ) 49 Martoglio, B. ( 6 ) 246 Martynov, I.V. ( 1 ) 158, 170, 191-193; ( 2 ) 12, 1 3 , 45, 46; ( 5 ) 4 , 8 , 37, 38, 152, 175, 234 Marumoto, R. ( 6 ) 232 Maruyama, I. ( 8 ) 174, 175 Maruyama, T. ( 5 ) 111; ( 6 ) 66, 109 Maryanoff, B.E. ( 7 ) 10, 11 Masaki, M. ( 6 ) 56; ( 7 ) 107 Masnyk, T.W. ( 6 ) 427 Masojidkova, M. ( 6 ) 58, 62 Masse, G. ( 5 ) 9 0 , 208 Massoud, S.S. ( 6 ) 452 Mastryukova, T.A. ( 5 ) 70 Masuda, N. ( 6 ) 210

Masuda, S. ( 3 ) 5 Masui, M. (1) 217, 218, 246; ( 7 ) 49

Masuko, T. ( 8 ) 197, 198 Matern, E. ( 1 ) 318, 319 Mathew, M.K. ( 6 ) 470 Mathey, F. ( 1 ) 24, 135, 271, 275, 312, 313, 315, 335, 337, 338, 354, 356; ( 4 ) 38; ( 7 ) 45 Mathieu, R. (1) 137 Mathieu, S . (1) 330; ( 5 ) 198 Mathur, K.B. ( 5 ) 89 Mathur, S . ( 1 ) 211 Mato, K. ( 8 ) 143 Matreux, J. ( 8 ) 19 Matrosov, E.I. ( 2 ) 47 Matrosova, N.V. ( 2 ) 47 Matsuda, A. ( 6 ) 90, 303 Matsuki, T. ( 5 ) 30; ( 8 ) 184-187, 189, 190, 213, 214, 226 Matsumoto, J. ( 8 ) 54 Matsumoto, M. ( 1 ) 226 Matsumoto, T. ( 6 ) 464 Matsura, N. ( 1 ) 16 Matsushita, T. ( 1 ) 1 Matsuura, T. ( 3 ) 31; ( 6 ) 403, 404 Matsuzaki, J.-I. ( 6 ) 166 Matsuzawa, S. ( 8 ) 192, 215 Matt, D. ( 1 ) 1 2 , 196 Matta, K.L. ( 6 ) 145 Matteucci, M.D. ( 6 ) 157, 230 Maurizot, J.C. ( 6 ) 196 Maury, G. ( 6 ) 318 Mavrin, V.Yu. ( 4 ) 1 3 ; ( 5 ) 118, 140 Maynard, S.J. ( 8 ) 203 Mazieres, M.-R. ( 1 ) 323 Mazumder, A. ( 6 ) 488 Mazzah, A. ( 8 ) 63 Mazzarelli, J. ( 6 ) 235 Meares, C.F. ( 6 ) 404 Mebel, A . M . ( 4 ) 4 8 ; ( 8 ) 6 Medeiros, A.C. ( 6 ) 305 Medvedeva, L.Ya. ( 8 ) 156, 236 Meetsma, A. ( 8 ) 113 Megera, I.V. ( 1 ) 208 Meguro, H. ( 1 ) 119 Mehrotra, K. ( 5 ) 17 Meidine, M.F. ( 1 ) 278, 342, 343 Meier, H. ( 4 ) 1 0 ; ( 5 ) 99 Meijboom, N. ( 1 ) 1 5 , 50-52 Meindl, K. ( 1 ) 300

Meine, G. (1) 259 Meisetsu, K. ( 8 ) 135 Meller, A. ( 1 ) 309 Mellin, T.N. ( 5 ) 184 Mendelman, L. ( 6 ) 300 Mercier, F. ( 1 ) 271 Merion, M. ( 6 ) 466 Meshitsuka, S. ( 6 ) 456 Meshoyrer, R. ( 6 ) 459 Messeguer, A. ( 7 ) 102 Mestre, F. ( 7 ) 97 Metcalfe, S. ( 7 ) 4 Metschies, T. ( 5 ) 26, 28 Metz, J.T. ( 6 ) 484 Meunier, B. ( 6 ) 8 2 , 83 Meunier-Piret, J. ( 1 ) 71 Meyer, M. ( 1 ) 4 2 , 360; ( 8 ) 157

Meyer, U. ( 1 ) 256 Mezzina, E. (1) 78-80; ( 2 ) 35; ( 4 ) 44

Micas-Languin, D. Michael, J.P. ( 5 ) Michalska, M. ( 5 ) Michalski, J. ( 3 )

( 7 ) 97 250 40 4; (4) 1 9 ; ( 5 ) 5 , 43, 44, 46; ( 6 ) 34 Michel, L. ( 6 ) 118 Middendorf, L.R. ( 6 ) 363 Midollini, S. ( 1 ) 136 Mielewczyk, S . ( 6 ) 44 Mikhailov, G.Yu. ( 1 ) 166 Mikhailov, L.E. ( 1 ) 234 Mikhailov, S.N. ( 6 ) 6 7 , 277 Mikhailov, Yu.B. ( 1 ) 179, 180 Mikita, T. ( 6 ) 227, 228 Mikityuk, A.D. ( 5 ) 231 Miklos, P. ( 3 ) 15 Mikolajczyk, M. ( 3 ) 1 8 ; ( 5 ) 135; ( 7 ) 8 3 , 114 Milashvili, M.V. ( 8 ) 176 Milecki, J. ( 6 ) 44 Miles, H.T. ( 6 ) 477 Milhaud, P.G. ( 6 ) 248 Millard, J.T. ( 6 ) 437 Miller, B.W. ( 6 ) 144 Miller, M . J . ( 1 ) 113 Miller, P.S. ( 6 ) 257, 441, 442 Milliaresi, E.E. ( 5 ) 18 Milligan, J.F. ( 6 ) 320 Mills, J . L . ( 1 ) 152-154 Min, S . ( 5 ) 41 Minami, T. (1) 245; ( 7 ) 21, 33 Minegar, R.L. ( 6 ) 440 Minkwitz, R. ( 1 ) 268 Minto, F. ( 8 ) 82, 195, 221 Minton, K.W. ( 6 ) 427

Organophosphorus Chemistry

420

Mintz, E.A. ( 1 ) 22 Mioskowski, C . ( 1 ) 100, 247; ( 7 ) 31, 94

Misra, K. ( 6 ) 170, 180, 182

Misra, P.K. ( 5 ) 89 Mitani, M. ( 5 ) 35 Mitchell, T.N. ( 1 ) 70 Miura, K. ( 6 ) 142, 367 Miyamoto, T. ( 8 ) 54 Miyasaka, T. ( 6 ) 56; ( 7 ) 107

Miyata, H. ( 6 ) 333 Miyauchi, N. ( 6 ) 333 Miyazawa, T. ( 6 ) 90 Mizokuchi, M. ( 6 ) 110 Mkrtchyan, G.A. (1) 205 Mlotkowska, B. ( 5 ) 36 Modak, A.S. ( 5 ) 125 Moderhack, D. ( 8 ) 20 Modro, A.M. ( 5 ) 220 Modro, T.A. ( 5 ) 7 6 , 7 8 , 7 9 , 220

Moehler, H. ( 8 ) 88 Moelling, K. ( 6 ) 126 Mohammadi, V. ( 1 ) 87 Moiseev, G.P. ( 6 ) 277 Moiseev, V.I. ( 8 ) 114 Molaire, T. ( 8 ) 193 Molina, P. ( 7 ) 62-67; ( 8 ) 40, 42, 43, 45, 46

Molko, D. ( 6 ) 179 Moneti, S. ( 1 ) 136 Moni, S . ( 8 ) 110 Monin, E.A. ( 1 ) 189 Montandon, A.J. ( 6 ) 296 Montello, D. ( 1 ) 137 Montenay-Garestier, T. ( 6 ) 385, 395

Montoneri, E. ( 8 ) 8 9 , 9 0 , 194

Montury, M. ( 5 ) 55 Moody, H.M. ( 6 ) 31 Mori, K. ( 7 ) 106 Mori, S . ( 8 ) 139, 140, 141

Moriguchi, K. (5) 39 Morii, T. ( 6 ) 403, 404 Morikawa, S. ( 1 ) 139 Morimoto, M. ( 8 ) 70 Morisawa, H. ( 6 ) 264 Morita, I. ( 5 ) 192, 193 Morita, T. ( 5 ) 35 Morito, E. ( 8 ) 235 Morjana, N.A. ( 6 ) 347 Morr, M. ( 6 ) 69 Morrow, J.R. ( 5 ) 63 Morvan, F. ( 6 ) 197 Morvillo, A. ( 1 ) 9 Moschidis, M.C. ( 5 ) 96 Mose, C . ( 1 ) 262 Moser, H.E. ( 6 ) 383

Mosh, S.A. ( 1 ) 235 Moskva, V.V. ( 4 ) 1 3 ; ( 5 ) 1 , 8 0 , 118, 140

Moss, T. ( 6 ) 416 Mosset, P. ( 1 ) 210 Motherwell, W.B. ( 5 ) 103; ( 7 ) 7 5 , 81

Motorin, Yu.A. ( 6 ) 467 Mouysset, G. ( 5 ) 95 Movshovich, D.Ya. ( 8 ) 159 Moyer, J.D. ( 6 ) 125 Muaki, S . ( 6 ) 264 Muccio, D.D. ( 7 ) 88 Muhlegger, K. ( 4 ) 4 6 ; ( 6 ) 45

Mueller, E. (5) 22 Mueller, N.M. ( 8 ) 66 Muller, W.E.G. ( 6 ) 279 Muisch, E.G.B. ( 8 ) 71 Mukherjee, B.L.P. ( 8 ) 13 Mukmenev, E.T. ( 5 ) 58-61 Mukmeneva, N.A. ( 5 ) 199 Mulder, N.H. ( 8 ) 97 Mulero, J.J. ( 6 ) 421 Muller, A. ( 1 ) 142; ( 5 ) 213

Muller, G. ( 1 ) 27, 59, 60, 7 4 , 7 5 , 273, 298, 300; ( 7 ) 5

Muller, H. ( 1 ) 105 Muller, U. ( 1 ) 229 Munster, P. ( 7 ) 104 Muntendam, H.J. ( 4 ) 69 Murai, T. ( 5 ) 41 Murakami, A. ( 6 ) 441 Muramatsu, T. ( 6 ) 90 Murashov, D.A. ( 8 ) 114 Murata, M. ( 5 ) 85 Murray, A.W. ( 3 ) 28 Murray, V. ( 6 ) 304 Musin, R.Z. ( 1 ) 175, 176; ( 4 ) 1 6 , 42

Musker, W.K. ( 5 ) 241 Mutoh, K. ( 8 ) 144 Myambo, K.B. ( 6 ) 285, 359 Mylona, A. ( 7 ) 18 Mynott, R. ( 1 ) 174, 291, 296

Nagahara, Nagai, K. Nagai, M. Nagao, F. Nagareda,

S. ( 6 ) 464 ( 5 ) 16 ( 6 ) 211 ( 3 ) 21 K. ( 2 ) 23; ( 7 )

32

Nagase, S. ( 1 ) 282 Nagata, R. ( 3 ) 31 Nagaya, F. (5) 16 Najarian, D.R. ( 6 ) 469 Nakahira, H. ( 5 ) 30 Nakajima, T. ( 3 ) 5

Nakamaye, K.L. ( 6 ) 362 Nakamoto, K. ( 6 ) 495 Nakanaga, T. ( 8 ) 188 Nakanishi, K. ( 6 ) 443 Nakano, M. ( 8 ) 124 Nakashima, H. ( 6 ) 264 Nakatsuji, Y. ( 6 ) 464 Nakayama, K. ( 6 ) 207 Nakayama, M. ( 7 ) 21 Naoi, M. ( 4 ) 81 Narahara, T. ( 8 ) 138 Naraoka, T. ( 6 ) 367 Narayanaswamy, P.Y. ( 8 ) 98

Narkiewicz, D. ( 5 ) 65 Narukami, T. ( 5 ) 248 Nash, H.A. ( 6 ) 311 Natchev, I.A. ( 1 ) 200; ( 5 ) 144, 156-158, 181, 188, 189; ( 6 ) 70

Naumov, V.A. (1) 147, 180, 181, 348; ( 5 ) 58, 151

Navech, J. (1) 330; ( 5 ) 198

Nazari, G.A. ( 8 ) 208, 209 Nazrnutdinova, V.N. ( 4 ) 42 Nazur, H. ( 8 ) 64 Nechaev, A. ( 6 ) 150 Neckers, L.M. ( 6 ) 260 Neenan, T.X. ( 8 ) 191 N;?gre,D. ( 6 ) 156 Negrebetskii, V.V. ( 2 ) 29 Neidlein, R. ( 1 ) 2 ; ( 3 ) 6 , 16

Neilson, R.H. ( 1 ) 331; ( 8 ) 1 3 , 38, 56-58, 75

Nelson, J.H. ( 1 ) 8 5 , 334 Nesrneyanov, N.A. ( 1 ) 238; ( 7 ) 46

Neumann, J.-M. ( 6 ) 79 Neumann, R. ( 6 ) 292 Neumuller, B. ( 1 ) 359; (7) 2

Neuner, P. ( 6 ) 225 Newborn, J.S. ( 6 ) 147 Newman, H. ( 8 ) 72 Newton, C.R. ( 6 ) 295 Nguyen, H.T. ( 6 ) 427 Nguyen, P.-N. ( 6 ) 294 Nickson, T.E. ( 5 ) 114 Nicoghosian, K. ( 4 ) 6 7 ; ( 6 ) 199

Nicolaides, D. ( 7 ) 35 Nicolaou, J.C. ( 7 ) 95 Nicolaou, K.C. ( 6 ) 401; ( 7 ) 100

Niece, R.L. ( 6 ) 2 Niecke, E. ( 1 ) 163, 251, 258, 307, 308, 310, 311, 320; ( 4 ) 84, 88, 90, 9 2 , 93; ( 8 ) 9 , 1 0 ,

42 1

Author Index 23-25

Niedermann, H.-P.

( A ) 10;

( 5 ) 99

Nuber, B. ( 1 ) 346; ( 4 ) 85 Nunn, C.M. ( 1 ) 48, 49, 289, 290, 295

Niederprum, N. ( 1 ) 259 Nief, F. ( 1 ) 337, 338 Nieger, M. (1) 33, 163,

Nuretdinova, O.N. ( 5 ) 69 Nurtdinov, S.Kh. ( 1 ) 175,

251, 257, 258, 308, 310, 311, 320; ( 4 ) 8 8 , 9 0 , 9 3 ; ( 8 ) 9 , 1 0 , 24, 25, 48 Nielsen, J. ( 4 ) 7 0 , 7 1 , 7 6 ; ( 6 ) 46, 48, 4 9 , 254 Nielsen, P.E. ( 6 ) 407, 408 Nielson, R.H. ( 4 ) 8 2 ; ( 8 ) 26 Niemann, B. (1) 257 Niewiarowski, W. ( 6 ) 54 Nifant'ev, E.E. ( 2 ) 33; ( 4 ) 47; ( 5 ) 1 8 , 4 8 , 4 9 , 170 Niitsu, T. ( 1 ) 254, 264, 282; ( 4 ) 94 Nikitin, E.V. ( 3 ) 1 Nikitina, G.S. ( 8 ) 126 Nikokavouras, J. ( 7 ) 18 Nikonov, G.N. ( 1 ) 147, 148 Nishikawa, T. ( 8 ) 111 Nishimura, S . ( 6 ) 90 Nishimura, Y. ( 6 ) 367 Nitta, M. ( 7 ) 118 Niven, M.L. ( 5 ) 79 Nixon, J.F. ( 1 ) 278, 342, 343 Nizamov, I.S. ( 4 ) 1 4 , 1 5 ; ( 5 ) 138, 169 Nizamutdinov, F.Kh. ( 1 ) 248 Nobel, D. ( 1 ) 196 Noble, N.J. ( 5 ) 33 Nogradi, M. ( 7 ) 101 Noguchi, T. ( 8 ) 174 Noltemeyer, M. ( 8 ) 4 , 1 7 , 36, 166 Nonaka, Y. (7) 36 Nord, L.D. ( 6 ) 282 Norman, A.D. ( 1 ) 25, 6 9 , 150; ( 4 ) 29, 30 Norman, D.G. ( 6 ) 485, 486 Norman, N.C. ( 1 ) 316 Nose, T. ( 6 ) 456 Noth, H. ( 1 ) 30-32 Novelli, R. ( 7 ) 77 Novikova, V.G. ( 5 ) 69 Novikova, Z.S. ( 1 ) 1 3 , 189; ( 4 ) 39 Novozhilov, S.Yu. ( 6 ) 396 Nowacka-Krukowska, H. ( 5 ) 65 Nowell, I.W. ( 1 ) 219 Nozaki, H. ( 7 ) 25, 26

Nussbaum, A.L. ( 6 ) 227 Nyangulu, J . M . ( 5 ) 82 Nyilas, A. ( 6 ) 244

176

Oakley, R.T. ( 8 ) 152-154, 235

Obayashi, T. ( 6 ) 403 Oberhammer, H. (1) 360 Obertelli, D. (1) 227 Ocando, E. ( 1 ) 308; ( 8 ) 24

Ochoki, J. ( 5 ) 94 O'Connor, T.R. ( 6 ) 419 Oda, D. ( 7 ) 15 Odagaki, Y. ( 1 ) 282 O'Day, C.L. ( 6 ) 249 Odo, J. ( 6 ) 495 Odorisio, P.A. ( 4 ) 32 Oe, S. ( 8 ) 130 Oehler, E. ( 5 ) 143 Oehlert, W. ( 1 ) 26 Otvos, L. ( 6 ) 9 4 , 122 Ofori-Okai, G. ( 1 ) 6 ; ( 3 ) 3

O'Gara, J.F. (8) 208, 209 Ogasawara, T. ( 5 ) 30 Ogawa, T. ( 6 ) 402 Ogawa, Y. ( 6 ) 8 0 , 401; ( 7 ) 100

Ogilvie, K.K. ( 4 ) 67, 7 8 ; ( 6 ) 65, 162, 181, 199, 203, 226, 229, 268, 269 Ogita, T. ( 6 ) 141 Oh, D.Y. ( 4 ) 7 ; ( 5 ) 100, 128, 133, 185 O'Hagan, D. ( 7 ) 106 Ohara, K. ( 8 ) 215 Ohashi, M. ( 8 ) 109 Ohashi, S . ( 6 ) 110 Ohkura, Y. ( 6 ) 497 Ohmayer, A. ( 6 ) 322 Ohmi, N . ( 6 ) 351 Ohmori, H. ( 1 ) 217, 218, 246; ( 7 ) 49 Ohms, G. ( 1 ) 168, 169; ( 2 ) 11 Ohshiro, H. ( 6 ) 456 Ohta, H. ( 1 ) 214 Ohta, K. ( 3 ) 29 Ohtsuka, E. ( 6 ) 208, 212, 426 Ohtsuki, M. ( 4 ) 6 2 ; ( 6 ) 39, 204 Oivanen, M. ( 6 ) 1 0 , 19 Ojo, I.A.O. ( 5 ) 174

Okada, Y. ( 1 ) 245; ( 7 ) 33 Okamoto, T. ( 8 ) 129 Okamoto, Y. ( 5 ) 9 Okano, T. ( 1 ) 8 Okawa, K. ( 8 ) 226 Okazaki, H. ( 7 ) 26 Okhlobustin, 0.Yu. ( 1 ) 234

Okruszek, A. ( 6 ) 54 Okuma, K. ( 1 ) 214 Oleinik, V.A. ( 1 ) 172, 187

Oliveira, C.R.G. ( 6 ) 120 Ollmann, R . J . ( 1 ) 2 Ollmann, R.R., jun. ( 3 ) 6 , 16 O l m s , P. ( 8 ) 165

Olmstead, M.M. ( 4 ) 23 Olson, H.M. ( 6 ) 308 Omarov, T.T. (1) 72 Omelanzcuk, J. ( 4 ) 97 0110,A. ( 6 ) 420 Ono, M. ( 8 ) 138 Ono, T. ( 8 ) 192 Onoe, M. ( 6 ) 110 Onoue, K. ( 3 ) 21 Onysko, P.P. ( 1 ) 241 Oominato, H. ( 8 ) 175 Oosting, G.E. ( 8 ) 117 Oota, S . ( 1 ) 212 Opiela, S. ( 1 ) 37 Orchinnikov, V.V. ( 2 ) 34 Oretskaya, T.S. ( 6 ) 28 Organ, G.J. ( 1 ) 84 Orgel, L.E. ( 6 ) 282, 284 Orita, M. ( 6 ) 205 Oritani, T. ( 7 ) 117 Orlandini, A. ( 1 ) 136 Orlofskii, A.F. ( 6 ) 467 Ornstein, P.L. ( 5 ) 190, 191

Orpen, A.G. (1) 316 Orr, R.M. ( 6 ) 151 Orui, H. (1) 119 Oshiki, T. ( 1 ) 104; ( 7 ) 7 Oshikima, T. ( 4 ) 81 Osterman, D.G. ( 6 ) 303 Oswald, A.A. ( 1 ) 65 Otera, J. ( 7 ) 2 5 , 26 Otsuka, Y. ( 8 ) 133 Ouazzani, F. ( 5 ) 166 Ousset, T.B. ( 7 ) 31 Ouzounis, D. ( 1 ) 37, 38 Ovakimyan, M.Zh. ( 1 ) 9 1 , 92

Ovodova, O.V. ( 5 ) 21 Ovrutskii, D.G. ( 5 ) 80 Owen, M . J . ( 8 ) 1?1 Ozaki, H. ( 4 ) 75 Ozaki, S. ( 5 ) 6, 30, 35 Ozaki, T. ( 7 ) 61

Orgunophosphorus Chernistly

422

Paces, V. (6) 178 Pachuta, J.B. (6) 108 Padyukova, N.Sh. (6) 67 Paetzold, P. (8) 25 Pagara, C. (8) 221 Pagniez, G. (8) 33 Paine, R . T . (1) 30, 31, 45

Pak, Y.S. (8) 211 Pakulski, M. (1) 316 Palacios, F. (1) 357; (3) 12; (7) 24, 44, 68-70; (8) 39, 59, 60 Palazon, J.M. (7) 95 Palczewski, P. (7) 83 Palissa, M. (6) 86, 87 Palladino, M.A. (6) 332 Palrna, G. (8) 195 Panevin, A.S. (8) 161 Panosyan, G.A. (1) 92; (5) 228 Paoletti, C. (6) 197 Paoletti, J. (6) 197 Papageorgiou, G. (7) 35 Papahatjis, D.P. (7) 100 Papasergio, R . I . (1) 61 Papkov, V.S. (8) 169 Pappalardo, G.C. (8) 89, 90 I Parekh, A. (1) 84 Parish, R.V. (1) 87 Parkanyi, L. (1) 122 Parkes, H.G. (8) 84, 86 Parks, J.-W. (6) 429 Parsons, W.H. (5) 105, 184; (7) 79 Partridge, L.Z. (5) 53 Parvez, M. (8) 119 Paschal, J.W. (5) 191 Paschalidis, C. (1) 74; (7) 5 Pashkevich, K . I . (5) 211 Passirnount, N. (8) 34, 35 Pastor, S.D. (4) 32 Patchett, A.A. (5) 184 Patel, D . J . (6) 485-487 Paterson, M.C. (6) 373-375 Patin, H. (1) 89, 90, 131; (3) 8 Patonay, T. (8) 12 Patonay-Peli, E. (8) 12 Patsanovskii, 1.1. (1) 285-287 Patterson, W.L. (6) 440 Patt-Siebel, U. (8) 66 Paul, W. (1) 273 Pauli, J. (8) 67 Paulus, A. (6) 469 Pautard-Cooper, A . (1) 107; (2) 19 Paver, F. (8) 4

Pavlov, V.A. (5) 230 Payard, M. (5) 95 Payne, A.W. (5) 19 Payne, J.S. (2) 41 Payne, R.C. (6) 247 Payne, S. (5) 33 Pearsall, M.A. (1) 316 Pegoraro, M. (8) 224 Pein, C.D. (6) 26 Pelczer, I. (6) 97 Pellerin, B. (1) 270 Pellow, R.C. (7) 1 Pena, S . D . J . (6) 305 Peng, W.-J. (4) 35 Penk, M. (1) 142 Penn, G. (6) 63 Perales, A. (1) 137 Perich, J.W. (5) 56, 57 Perly, B. (8) 94, 95 Person, D. (7) 54, 55 Peter, M.E. (6) 352 Peters, J. (5) 160 Peterson, M.G. (6) 360 Petnehizy, I. (3) 15; (5) 14

Petrignani, J.-F. (4) 79 Petrov, A.A. (5) 119, 120, 219, 227; (8) 161

Petrovskii, P.V. (1) 91, 92, 157, 238; (5) 7; (7) 46 Petrusska, J. (6) 302 Pezzin, G. (8) 195 Pfister-Guillouzo, G. (1) 270 Pflaum, S. (1) 345 Pfleiderer, B. (1) 66 Pfleiderer, W. (6) 5, 275-277 Pharn, P. (5) 123 Phillips, I . G . (1) 8 1 Pianka, M. (5) 174 Pieles, U. (4) 57; (6) 434 Pieper, W. (5) 214 Piers, E. (7) 78 Pietrusiewicz, K.M. (1) 133; (3) 7, 33, 36 Pilar, M. (8) 45 Pilgram, K.H. (5) 52 Pilkis, S.J. (6) 140 Pinchuk, A.M. (1) 172, 187, 242; (5) 129; (8) 29, 50, 51, 61 Pindur, U. (7) 51 Pingoud, A. (6) 235 Platt, A.W.G. (1) 197 Platt, T. (6) 348 Plenat, F. (7) 40, 42 Plenio, H. (8) 4 Plevani, P. (6) 345 Plumet, J. (7) 23

Pocar, D. (7) 53 Podlaha, J. (1) 88 Podolyanko, V.A. (5) 70 Podsiadlo, S. (8) 180 Podust, L.M. (6) 431 Podyrninogin, M.A. (6) 432 Poglotti, A.L., jun. (6) 420

Polborn, K. (1) 32 Poll, E.H.A. (6) 330 Pollock, R.M. (5) 15 Pomerantz, M. (1) 115 Pony R.T. (6) 162, 181, 203, 287

Ponomarchuk, M.P. (8) 65 Ponomarev, D.A. (5) 229 Popkova, T.N. (5) 170 Popov, A.G. (1) 157, 158, 170; (2) 12, 13

Poppe, M. (1) 358 Porai-Koshits, M.A.

(8)

114, 236

Porshnev, Yu.N. (5) 51; (8) 32

Potapov, V.K. (6) 236 Potin, P. (8) 33-35 Potter, B.V.L. (5) 33, 83, 232; (6) 312

Povirk, L.F. (6) 399 Povolotskii, M.I. (1) 276, 306; (4) 86, 87

Povsic, T.J. (6) 231 Powell, D. (6) 17 Powell, H.R. (1) 47 Powell, S.J. (6) 295 Power, J.M. (1) 49, 289 Power, P.P. (1) 261, 299, 301, 302; (4) 23

Power, W.P. (8) 8 Pozdeev, O.E. (5) 61 Pracejus, H. (4) 80 Prechtl, F. (1) 118 Predvoditelev, D.A. (5) 48, 49

Prescott, M. (6) 155 Pressova, M. (6) 157, 278 Preu, L. (8) 20 Price, R . J . (1) 317 Pringle, P.G. (1) 197 Prishchenko, A . A . (1) 20, 235; (4) 18

Pritzkow, H. (1) 28, 29, 190; ( 4 ) 33, 83; (7) 73

Prock, A. (1) 129 Prokof'eva, T.I. (2) 32 Prokopenko, V.P. (1) 241 Proskurina, M.V. (5) 13 Prout, T.R. ( 4 ) 29 Provotorova, N.P. (8) 183 Prusoff, W.H. (6) 21 Pudovik, A.N. (1) 178-181, 209; (2) 27,

Author Index 28, 30, 31, 34; ( 4 ) 14-16, 22, 34, 42, 4 3 ; ( 5 ) 7 3 , 145, 169, 222, 223, 225 Pudovik, D.A. ( 4 ) 42, 43 Puech, F. ( 6 ) 29 Pujari, M.P. ( 5 ) 64 Purgstaller, K. ( 5 ) 251 Pushin, A.N. ( 2 ) 45; ( 5 ) 38, 175 Pyle, A.M. ( 6 ) 459, 461

423 Reardon, J.E. ( 6 ) 128 Reber, G. ( 1 ) 7 4 , 7 5 , 105; ( 7 ) 5

Rebrova, O.A. ( 1 ) 238 Recknagel, A. ( 1 ) 294 Reddy, P. ( 6 ) 428 Redmore, D. ( 3 ) 2 ; ( 5 ) 159, 217

Reed, G.H. ( 6 ) 137 Reedijk, J. ( 6 ) 451 Reese, C.B. ( 4 ) 6 2 ; ( 6 ) 204

Qiu, M. ( 6 ) 319 Qiu, W. ( 7 ) 58 Quaedflieg, P.J.L.M. ( 6 ) 31, 32

Quartin, R.S. ( 6 ) 258 Raab, K.M. ( 1 ) 265 Radda, G.K. ( 6 ) 482 Rademacher, P. ( 4 ) 92 Radtke, J. ( 6 ) 306 Radzikowski, C. ( 8 ) 96 Rahamin, E. ( 6 ) 164 Raharinirina, A. ( 1 ) 283 Rahman, M.M. ( 1 ) 129 Rahn, J.A. ( 1 ) 85, 334 Raitarskaya, M.V. ( 1 ) 231 Rajendra, G. ( 7 ) 86 Raju, N. ( 6 ) 68 Rakhmankulov, D.L. ( 5 ) 13 Rakhmatullina, T.N. ( 1 ) 82

Ramachandran, K. ( 8 ) 115 RarnalhocOrtigao, F. ( 6 ) 1 Ramarijaona, 0. ( 1 ) 253 Ramphal, J.Y. ( 7 ) 95 Ramsey, A.A. ( 1 ) 206 Ranaivonjatovo, H. ( 1 ) 284

Rao, B.D.N. ( 6 ) 479, 480, 48 1

Rao, M.N.S.

( 4 ) 26; ( 8 ) 150, 151, 155 Rapp, C. ( 5 ) 187 Rappaport, H.P. ( 6 ) 213 Rashid, A. ( 7 ) 105 Raston, C.L. ( 1 ) 43, 61 Rathunde, K.A. ( 7 ) 20 Ratsep, P.C. ( 6 ) 130 Rattay, W. ( 1 ) 30 Raushel, F.M. ( 6 ) 147 Raveney, F.J. ( 5 ) 212 Ray, B.D. ( 6 ) 479-481 Rayner, B. ( 6 ) 248 Raza, Z . (1) 195 Razadkina, E.N. ( 5 ) 48, 49 Reamer, R.A. ( 1 ) 108; ( 2 ) 15

Reese, R.L. ( 8 ) 203 Regan, A.C. ( 6 ) 13 Regberg, T. ( 6 ) 38 Regitz, M. (1) 277, 288, 291, 292, 296, 332; ( 4 ) 96 Rehmann, J.P. ( 6 ) 459 Reichenbach, N.L. ( 6 ) 341 Reichert, F. ( 1 ) 310, 311; ( 4 ) 8 8 ; ( 8 ) 9 , 10 Reid, B. ( 6 ) 201 Reid, D.H. ( 5 ) 250 Reid, G.P. ( 6 ) 111 Reisacher, H.4. ( 1 ) 280 Reitz, A.B. ( 7 ) 1 0 , 11 Rekik, L.L. ( 2 ) 37 Remaud, G . ( 6 ) 4 6 , 271-273 Remers, W.A. ( 6 ) 76 Renger, B. ( 5 ) 112 Rensch, B. (1) 71 Repkova, M.N. ( 6 ) 40 Reutov, O.A. (1) 238; ( 7 ) 46 Revankar, G.R. ( 6 ) 92 Revel, M. ( 1 ) 330; ( 5 ) 198 Revenko, G.P. ( 3 ) 11 Reynolds, M.A. ( 6 ) 134 Ribeill, Y. ( 1 ) 215; ( 7 ) 40, 42, 43 Ribot, S.A. ( 4 ) 54 Ricard, L. ( 1 ) 24, 313, 315, 337, 356 Ricca, G. ( 8 ) 194 Rich, J. ( 6 ) 233 Richardson, F.C. ( 6 ) 418 Richardson, J.F. ( 8 ) 149 Richter, C. ( 6 ) 429 Richterich, P. ( 6 ) 365 Rickard, C.E.F. ( 1 ) 274 Rickert, P.G. ( 3 ) 40 Rickwood, D. ( 6 ) 331 Riding, G.H. ( 8 ) 120, 123, 216 Rieck, C. ( 5 ) 116 Ried, W. ( 1 ) 124; ( 4 ) 102 Riede, J. (1) 6 0 , 273, 298 Riedel, R. ( 5 ) 149, 150

Riesel, L. ( i ) 156, 168, 169; ( 2 ) 1 1 ; ( 8 ) 67

Riffel, H. ( 4 ) 41 Rill, R.L. ( 6 ) 389 Ringel, I. ( 6 ) 164 Ripperger, H. ( 5 ) 247 Rizzo, V. ( 6 ) 332 Roberts, R.M.G. ( 1 ) 340, 34 1 Robins, R.K. ( 6 ) 6 8 , 9 2 , 130, 282

Robinson, B.H. ( 6 ) 492 Robinson, C.Y. ( 7 ) 88 Robinson, E.A. ( 8 ) 78

ROCCO, K. ( 8 ) 11 Roddick, D.M. (1) 5 Rodebaugh, R.K. ( 4 ) 32 Roder, T. ( 7 ) 72 Roduit, J.P. ( 6 ) 65 Roelen, H.C.P.F. ( 5 ) 8 8 ; ( 6 ) 53

Rosch, P. ( 6 ) 153, 481 Roeschenthaler, G.-V. ( 1 ) 9 5 , 141, 177; ( 2 ) 4 ; ( 5 ) 1 2 , 130, 131 Roesky, H.W. ( I ) 183, 250, 294; ( 8 ) 4 , 1 7 , 1 8 , 36, 160, 165, 166, 179 Roesser, J.R. ( 6 ) 247 Rokhlin, E.M. ( 5 ) 113 Rol'nik, L.Z. ( 5 ) 13 Romakhin, A.S. ( 3 ) 1 Rornanenko, V.D. ( 1 ) 276, 285-287, 303, 304, 306; ( 4 ) 8 6 , 8 7 , 8 9 ; ( 8 ) 230 Romby, P. ( 6 ) 382 Roongta, V. ( 6 ) 484 Roper, W.R. ( 1 ) 274 Roques, C. ( 1 ) 323 Rose, B.G. ( 5 ) 250 Rosenberg, I. ( 5 ) 9 7 , 107; ( 6 ) 58, 324 Rosenthal, A. ( 6 ) 364 Rosenwirth, B. ( 6 ) 63 Rosette, C. ( 6 ) 313 Rossomando, E.F. ( 6 ) 113 Rostovskaya, M.F. ( 1 ) 9 4 ; ( 5 ) 121 Rothenberg, J.M. ( 6 ) 422 Roumestant, M.L. ( 5 ) 166 Roussis, V. ( 4 ) 3 ; ( 5 ) 142 Roy, A.K. ( 8 ) 57 Roy, P.D. ( 1 ) 130 Royan, B.W. ( 1 ) 324-327; ( 4 ) 91 Rozanov, I.A. ( 8 ) 114, 156, 236 Rozek, M. ( 6 ) 202 Ruban, A.V. ( 1 ) 303, 304; ( 4 ) 86, 8 7 , 8 9 ; ( 8 ) 230

424

Ruban, L . V . ( 8 ) 128 Rudnitskaya, L.S. ( 1 ) 185, 186

Rudomino, M.V. (1) 231 Rudyi, R . A . ( 2 ) 29 Ruggeri, R. ( 7 ) 12 Rukavishnikov, M.Yu. ( 6 ) 152

Rumyantseva, Z.G. ( 8 ) 142 Ruoho, A . E . ( 6 ) 343 Rupp, C. ( 4 ) 17 Rusakov, V.A. ( 8 ) 126 Rusch, J . W . ( 8 ) 97 Ruth, J.L. ( 6 ) 363 Rutherford, M. ( 5 ) 209 Rutkovskii, E.K. ( 8 ) 52 RU-Yu, C . ( 2 ) 36 Ryabov, B.V. ( 5 ) 148 Ryazantsev, E.N. ( 5 ) 229 Rybalkina, L.E. ( 8 ) 159 Rybasova, G.I. ( 8 ) 176 Ryder, U. ( 6 ) 225 Rzepa, H.S. ( 5 ) 20

Samuelsson, B. ( 1 ) 97 Sancar, A. ( 6 ) 224 Sanchez, F.4. ( 7 ) 102 Sanchez, M. ( 1 ) 323 Sanderson, B . J . S . ( 6 ) 372 Sanderson, M.R. ( 6 ) 476 Sandhoff, K. ( 7 ) 104 Santelli, M. ( 7 ) 91 Santeusanio, S . ( 7 ) 56 Santi, D.V. ( 6 ) 303, 420 Saraceno, R.A. ( 8 ) 216 Sarfati, S.R. ( 6 ) 9 Sarin, P.S. ( 6 ) 261-263 Sartorelli, A.C. ( 6 ) 24 Sasaki, M. ( 5 ) 39 Sasaki, S . ( 1 ) 254, 263; ( 4 ) 94

Sasakura, T. ( 8 ) 131-133 Satge, J. ( 1 ) 283, 284 Sato, F. ( 6 ) 84 Sato, H. ( 4 ) 6 3 ; ( 6 ) 168 Sato, K. ( 8 ) 143 Sato, R. ( 8 ) 130 Sato, T. (1) 252; (7) 25, 26

Saal, D. ( 6 ) 233 Saalfrank, R.W. ( 7 ) 37 Sadaghianizadeh,K. ( 8 ) 182

Sadana, K.L. ( 6 ) 25 Saegusa, K. ( 7 ) 15 Saegusa, T. ( 1 ) 139 Saenger, W. ( 6 ) 16 Safina, Yu.G. ( 2 ) 34 Sagripanti, J.-L. ( 6 ) 405 Saiki, N. ( 8 ) 184-187, 189, 190, 213, 214, 226

Saiki, R.K. ( 6 ) 285, 290 St. Louis, R. ( 6 ) 498 Saison-Behmoaras, T. ( 6 ) 384-386

Saito, H. ( 8 ) 3 0 , 31 Saito, I. ( 3 ) 3 1 ; ( 6 ) 403, 404

Saito, Y. ( 8 ) 70 Sakai, K. ( 1 ) 246 Sakamaki, Y. ( 8 ) 192 Sakamoto, M. ( 7 ) 36 Sakatsume, 0 . ( 4 ) 6 2 ; ( 6 ) 3 9 , 204 Saket, B.M.

221

Sawada, M. ( 2 ) 23; ( 7 ) 32 Sawai, H. ( 6 ) 281 Sawamura, M. ( 5 ) 168 Sazonova, M.G. ( 8 ) 142 Scalfi-Happ, C. ( 6 ) 243 Schachenmann, A. ( 6 ) 246 Schaeffer, R. ( 4 ) 30 Schaus, J.M. ( 5 ) 191 Scheide, G.M. ( 8 ) 57 Scheller, D. ( 1 ) 120 Schiebel, H.-M. ( 1 ) 160 Schieven, G. ( 6 ) 445 Schilling, M.B. ( 6 ) 136 Schimel, P.R. ( 6 ) 354 Schliselfeld, L. ( 6 ) 150 Schmid, R. ( 6 ) 331 Schmidbaur, H. ( 1 ) 7 4 , 7 5 , 105; ( 7 ) 5

Schmidpeter, A. ( 1 ) 4 0 , (5) 209

Sal'keeva, L.K. ( 4 ) 45 Salunkhe, M. ( 6 ) 253 Saluz, H. ( 6 ) 462 Saman, D. ( 4 ) 9 Sambe, J.C. ( 8 ) 181 Samons, R.D. ( 6 ) 137 Samoshin, V.V. ( 8 ) 128 Sampedro, M.N. ( 7 ) 103 Sampson, N.S. ( 5 ) 161 Samuels, W.D. ( 8 ) 8 1 , 8 3 , 206

Satoh, K. ( 8 ) 144 Sau, A.C. ( 8 ) 98 Sauerbier, C. ( 5 ) 92 Sauter, R. ( 7 ) 112 Savignac, P. ( 5 ) 9 3 , 137,

183, 351; ( 4 ) 1 2 ; ( 8 ) 3 6 , 3 7 , 160, 162 Schmidt, A.H. ( 1 ) 93 Schmidt, D. ( 4 ) 5 9 ; ( 6 ) 191 Schmidt, H. ( 1 ) 272; ( 4 ) 27 Schmidt, M. ( 2 ) 43 Schmitt, G. ( 1 ) 190; ( 4 ) 33 Schmuck, A . ( 2 ) 2 Schmutzler, R. ( 1 )

159-161, 201, 321; ( 4 ) 5 Schneider, J.H. ( 6 ) 495 Schnurr, W. ( 1 ) 277 Schobert, R. ( 7 ) 110 Schoeller, W.W. ( 1 ) 311, 328; ( 4 ) 9 2 ; ( 8 ) 10 Schoen, W.R. ( 5 ) 105, 1 8 4 ; ( 7 ) 79 Scholtissek, S . ( 6 ) 235 Scholz, G. ( 1 ) 26, 3 4 ; ( 6 ) 350 Scholz, M. (1) 250 Scholz, U. ( 1 ) 183; ( 8 ) 160 Schomburg, D. ( 1 ) 171, 321; ( 4 ) 37; ( 5 ) 202 Schopferer, M. ( 1 ) 190; ( 4 ) 33 Schott, H. ( 6 ) 325 Schrader, T. ( 5 ) 171 Schramm, V.L. ( 6 ) 7 5 , 88 Schriver, D . F . ( 8 ) 106 Schroder, H.C. ( 6 ) 279 Schroeder, S.A. ( 6 ) 484 Schrumpf, F. ( 8 ) 17 Schubert, D.M. ( 1 ) 25 Schubert, F. ( 6 ) 86 Schulte, P. ( 1 ) 329; ( 8 ) 27 Schulte-Frohlinde, D. ( 6 ) 85 Schultz, C. (5) 26, 28 Schultz, P.G. ( 6 ) 368 Schumann, W. ( 1 ) 66 Schwager, C. ( 6 ) 364 Schwartz, A.W. ( 6 ) 283 Schwarz, H. ( 1 ) 292 Schwarzmann, M. ( 1 ) 63 Schweizer, B. (5) 239 Scriven, E . F . V . ( 8 ) 5 Sebesta, K. ( 6 ) 324 Seebregts, C.J. ( 6 ) 338 Seela, F. ( 6 ) 215-220, 2 35 Segi, M. ( 3 ) 5 Seidel, G. ( 1 ) 27 Sekine, M. ( 4 ) 6 6 ; ( 5 ) 7 1 ; ( 6 ) 47, 142, 166, 177, 210, 240 Seliger, H . ( 4 ) 4 6 ; ( 6 ) 1 , 45 Semi, S . ( 8 ) 109 Semmelhack, M.F. ( 6 ) 17 Sendyurev, M.V. ( 1 ) 165 Sentemov, V.V. ( 5 ) 110 Seppelt, K. (2) 2 Sera, T. ( 6 ) 403 Serhadli, 0. ( 1 ) 127; ( 5 ) 200 Severint, F. ( 8 ) 224 Seyden-Penne, J. ( 3 ) 17

Author Index Shabarova, Z.A.

( 6 ) 28, 236, 415 Shadid, B. ( 4 ) 54 Shagvaleev, F.Sh. ( 1 ) 176 Shah, J. ( 6 ) 291 Shani, A. ( 7 ) 19 Shapiro, R. ( 6 ) 27 Shapirov, S.M. ( 5 ) 151 Shapley, J . R . ( 5 ) 3 Sharatin, V.V. ( 2 ) 9 Sharky, V. ( 6 ) 17 Sharma, D. (1) 211 Sharma, M. ( 6 ) 423 Sharma, P. ( 6 ) 185 Sharpless, K.B. (1) 7 , 7 7 ; ( 5 ) 23 Shavanov, S.S. (1) 248 Shaw, A.N. ( 7 ) 77 Shaw, B.L. (1) 134 Shaw, J . C . ( 8 ) 125 Shaw, R.A. ( 5 ) 207, 212; ( 8 ) 84-86, 102 Shay, R.H. ( 1 ) 25 Shcherbina, T.M. ( 5 ) 70 Shegvaleev, F.Sh. ( 5 ) 110 Sheldrick, G.M. (1) 42, 47; ( 8 ) 4 , 165 Sheldrick, W.S. (1) 183; ( 2 ) 4 ; ( 8 ) 160 Sheluchenko, O.D. ( 5 ) 72 Shen, Y. ( 1 ) 155; ( 7 ) 3 , 58 Sheng, Q. ( 5 ) 47 Sheppard, R.N. ( 5 ) 20 Sherman, S.E. ( 6 ) 446 Shevchenko, I . V . ( 1 ) 267 Shevchuk, M . I . (1) 207 Shi, L. ( 7 ) 28-30 Shi, Y. ( 6 ) 366, 438 Shibahara, S . ( 6 ) 264 Shigematsu, H. ( 8 ) 175 Shikita, S. ( 7 ) 21 Shilling, F.C. ( 8 ) 200 Shimidzu, T. ( 4 ) 75 Shimokura, M. ( 5 ) 248 Shin, D.-S. ( 1 ) 247; ( 7 ) 93 Shing, T.K.M. ( 7 ) 109 Shiori, T. ( 5 ) 85 Shipman, M. ( 7 ) 81 Shishido, Y. ( 4 ) 6 4 ; ( 6 ) 169 Shkodin, A.M. ( 5 ) 70 Shneider, M.A. ( 5 ) 163 Shockman, G.D. ( 6 ) 88 Shono, T. (1) 1 Shrago, E. ( 6 ) 343 Shreeve, J.M. ( 5 ) 125, 204 Shriver, D.F. ( 8 ) 107, 210, 212 Shtepanek, A.S. ( 8 ) 61

42 5 Shtokman, M . I . ( 6 ) 396 Shum, P.W. ( 6 ) 55 Shumyantseva, V.V. ( 6 ) 131

Shuto, S. ( 6 ) 78 Shymanska, M. ( 1 ) 230 Siabalis, N. (1) 281 Sicicinger, A. (1) 19 Sicsic, S . ( 6 ) 342 Sidky, M.M. ( 5 ) 224 Siebert, W. (1) 28, 29 Sigel, G.A. ( 4 ) 23 Sigel, H. ( 6 ) 452 Sigman, D.S. ( 6 ) 387, 390, 391

Sihler, R. ( 1 ) 11 Sijuwade, T. ( 6 ) 20, 143 Sillett, G.J.D. (1) 343 Silver, J. ( 1 ) 340, 341 Simon, E.S. ( 6 ) 149 Simon, M . I . ( 6 ) 471 Simpkins, N.S. ( 7 ) 100 Sinden, R.R. ( 6 ) 435 Sindona, G. ( 6 ) 499, 500 Singer, B. ( 6 ) 300 Singh, A.N. ( 6 ) 147 Singh, M.S. ( 5 ) 17 Singh, R.K. ( 6 ) 170, 180, 182

Singman, C.N. Sinitsa, A.D.

( 6 ) 253 (1) 241;

( 8 ) 71

Sin'ko, N.L. ( 8 ) 126 Sinning, H. (1) 229 Sinou, D. (1) 132 Sinyashin, O.G. ( 4 ) 1 6 , 22

Sippel', I.Ya. ( 5 ) 223, 2 25

Siriwardane, U. ( 2 ) 44 Skelton, B.W. (I) 43, 61 Skiles, R.D. ( 5 ) 52 Skoblikova, L . I . ( 5 ) 162 Skopek, T.R. ( 6 ) 418 Skov, K.A. ( 6 ) 450 Skowrohska, A. ( 4 ) 1 9 ; ( 5 ) 43-45

Skrzypczynski, Z. ( 3 ) 4 Slama-Schwok, A. ( 6 ) 395 Sliedregt, L.A.J.M. (6) 239

Slonim, I.Ya. ( 8 ) 223 Slusher, R.M. ( 6 ) 72 Smallridge, M . J . ( 7 ) 115 Smee, D.F. ( 6 ) 68 Smith, A . J . ( 6 ) 2 Smith, C.L. ( 6 ) 470 Smith, D.J. ( 1 ) 317 Smith, J.A. ( 6 ) 469 Smith, J.C. ( 6 ) 295 Smith, J . D . (1) 162 Smith, M. ( 6 ) 327

Smith, R.M. ( 6 ) 353 Smith, S.C. ( 7 ) 88 Smith, S.J. ( 7 ) 74 Smithers, G.W. ( 6 ) 137 Smithies, 0 . ( 6 ) 293 Smolii, O.B. ( 1 ) 239, 240 Smrt, J. ( 6 ) 131, 178, 278

Snyatkova, E.V.

(1) 13 ( 7 ) 21 Sobol, R.W., jun. ( 6 ) 341 Soderlund, H. ( 6 ) 297 Soko, V . I . ( 8 ) 236 Sokol, V . I . ( 8 ) 114 Sokolov, M.P. ( 5 ) 230 Sokolov, V.A. ( 2 ) 45, 46 Sokolov, V.B. (1) 191-193; ( 5 ) 8 , 3 7 , 175 Sokolov, V.V. (5) 227 Sokolova, N.I. ( 6 ) 28 Sokol'skaya, I . R . ( 8 ) 205 Soldatova, I . A . ( 2 ) 33 Solodenko, V.A. ( 5 ) 167 Solov'iev, V.N. ( 5 ) 234 Sommadossi, J.-P. ( 6 ) 21 Sonderikhin, A . I . ( 5 ) 119 Sonenberg, N . ( 6 ) 20 Song, A. ( 5 ) 115 Sonnenberg, U. (1) 86 Sonveaux, E. ( 6 ) 238 Sopchik, A.E. ( 4 ) 97; ( 6 ) 101, 102 Sosnov, A.V. (5) 146 Sosnovsky, G. ( 5 ) 251 Sournies, F. ( 8 ) 7 6 , 9 3 , 94, 232, 233 Sowers, L.C. ( 6 ) 302 Spacciapoli, P. ( 6 ) 421 Spaltenstein, A. ( 6 ) 492 Spanevello, R.A. ( 7 ) 95 Spangler, C.W. ( 7 ) 20 Spaniol, T.P. (1) 293 Spector, T. ( 6 ) 128 Speier, G. (1) 122 Speirs, R.A. ( 5 ) 250 Spek, A.L. ( 8 ) 234 Spengler, S.J. ( 6 ) 300 Speziale, V. ( 5 ) 77 Spielmann, H.P. ( 6 ) 438 Spitzer, S. ( 6 ) 369 Sprague, L.G. ( 5 ) 126; ( 7 ) 84 Springer, J.P. ( 5 ) 184 Sprinzl, M. ( 6 ) 352 Sproat, B.S. ( 6 ) 225, 364 Sredin, Yu.G. ( 6 ) 160 Srivastava, D.K. ( 1 ) 151 Stabinsky, Z. ( 6 ) 157 Stache, U. ( 7 ) 82 Stalke, D. (1) 42, 250, 294; ( 8 ) 4 , 165 Stallcup, M.R. ( 6 ) 321 so,

s.

\

Organophosphorus Chemistry

426

Stamatov, S.D. ( 4 ) 24, 25 Stang, N . ( 6 ) 167 Stang, P.J. ( 1 ) 213; ( 5 ) 25

Stanhope, B. ( 3 ) 30 Stanley, G.G. ( 1 ) 57, 64 Starrett, J.E., jun. ( 6 ) 21

Stawinski, J. ( 6 ) 6 , 37, 38, 4 2 , 43, 52 ( 5 ) 240; (6) 54, 256, 266 Steel, P.G. ( 7 ) 112 Steenbergen, A. ( 8 ) 117 Steenken, S. ( 6 ) 81 Stegermann, J. ( 6 ) 364 Steglich, W. ( 5 ) 171; ( 7 ) 104 Steigelmann, 0. ( 1 ) 273 Steil, H. ( 6 ) 1 Stein, C.A. ( 6 ) 255, 260 Stein, S. ( 6 ) 468 Steinrnetz, M. ( 1 ) 273 Steitz, T.A. ( 6 ) 476 Stenberg, B. ( 8 ) 222 Stepanova, Yu.2. ( 1 ) 285-287 Stephanidou-Stephanatou, J. ( 7 ) 35 Stepinski, J. ( 6 ) 20, 143 Stepowska, H. ( 1 ) 114 Sterzycki, R.J. ( 6 ) 21 Stock, J.A. ( 6 ) 151 Stockwell, D.L. ( 6 ) 188 Stoffel, S . ( 6 ) 285 Stone, C . ( 1 ) 17 Stone, F.G.A. ( 1 ) 293 Stork, G. ( 7 ) 17 Stowell, M.H.B. ( 5 ) 218; ( 7 ) 85 Strahle, J. ( 8 ) 3 Strazewski, P. ( 6 ) 234 Strepikheev, Yu.A. ( 5 ) 231 Strobel, S.A. ( 6 ) 383 Stroemberg, R. ( 6 ) 6 , 36-38, 42, 43 Struchkov, Yu.T. ( 1 ) 180, 267, 276, 303, 304, 306; ( 2 ) 47; ( 3 ) 1 8 ; ( 4 ) 86, 8 7 ; ( 5 ) 151; ( 7 ) 46; ( 8 ) 6 5 , 158, 230 Stryer, L. ( 6 ) 100 Stubbe, J. ( 6 ) 124 Studnev, Yu.N. ( 1 ) 185, 186 Stupik, P.D. ( 1 ) 46 Sturtz, G . ( 5 ) 90, 194, 195, 208 Su, D. ( 5 ) 125 Suades, J. ( 1 ) 137

Stec, W . J .

Subasingh, C. ( 6 ) 260 Subramanian, R. ( 6 ) 420 Suda, N. ( 8 ) 192 Suga, S. ( 3 ) 5 Sugawar, K. ( 8 ) 138 Sugeta, H. ( 6 ) 456 Suggs, J.W. ( 6 ) 437 Sugimoto, N . ( 6 ) 412, 413 Sugiyama, H. (6) 403, 404 Sugiyama, M. ( 5 ) 193 Suhadolnik, R . J . ( 6 ) 341 Suhs, K. ( 7 ) 72 Sukharukova, N . A . ( 5 ) 236 Sumiyama, T. ( 6 ) 110 Summers, C. ( 6 ) 295 Sumner-Smith, M. ( 6 ) 159 Sun, D. ( 6 ) 261 Sun, J. ( 6 ) 385 Sun, W.-C. ( 6 ) 113 Sundquist, W.I. ( 6 ) 449 Sunjic, V. ( 1 ) 195 Suresh, R. ( 1 ) 117 Surratt, C.K. ( 6 ) 247 Sussangkarn, S.J. ( 1 ) 22 Su-Tsai, S.-M. ( 6 ) 138 Suzuki, H. ( 1 ) 16 Suzuki, M. ( 7 ) 87 Suzuki, T. ( 6 ) 402 Svara, J. ( 7 ) 2 Svyat'skaya, T.N. ( 5 ) 70 Swaminathan, K.S. ( 5 ) 34 Swann, P.F. ( 6 ) 485, 486 Swarat, K. ( 8 ) 18 Swenberg, J.A. ( 6 ) 418 Swenson, R.P. ( 6 ) 326 Symes, J. ( 5 ) 79 Symons, R.H. ( 6 ) 409 Syundyukova, V.Kh. ( 1 ) 128; ( 5 ) 2

Syvanen, A.-C. ( 6 ) 297 Szameitat, J. ( 1 ) 293 Szilagyi, L. ( 8 ) 12 Szollosy, A. ( 3 ) 15 Taba, K.M. (1) 174 Tabuchi, H. ( 5 ) 16 Tabyaoni, B. ( 8 ) 44 Tachon, C. ( 1 ) 253 Tada, N . ( 3 ) 21 Tada, S . ( 5 ) 192 Tada, Y. ( 8 ) 188 Tafeenko, V.A. ( 1 ) 149 Tagaya, M. ( 6 ) 349, 351 Tahara, S.M. ( 6 ) 20, 143 Taira, K. ( 6 ) 15 Tajbakhsh-Jadidi, M. ( 1 ) 184

Takagi, M. ( 8 ) 124 Takahashi, A. ( 8 ) 138 Takahashi, K. ( 1 ) 212; ( 8 ) 135, 136

Takahashi, S. ( 7 ) 117 Takahashi, Y. ( 8 ) 134 Takai, Y. ( 2 ) 23; ( 7 ) 32 Takaki, M. ( 4 ) 64; ( 6 ) 169

Takakis, I.M. ( 7 ) 18 Takaku, H. ( 4 ) 62-64; ( 6 ) 39, 168, 169, 204, 207, 211 Takamuku, S. ( 5 ) 9 Takanami, T. ( 1 ) 217 Takeuchi, H. ( 7 ) 6 0 , 61 Takeuchi, T. ( 6 ) 464 Takeuchi, Y. ( 5 ) 124 Takita, S . ( 1 ) 188; ( 8 ) 30, 31 Takle, A. ( 7 ) 111 Taktakishvili, M.O. ( 6 ) 183 Tam, L. ( 6 ) 379 Tamaoka, M. ( 1 ) 218 Tamura, J.K. ( 6 ) 346 Tamura, R. ( 7 ) 15 Tamura, S. ( 8 ) 133 Tan, W. ( 1 ) 333 Tan, Z.-K. ( 4 ) 68; ( 6 ) 209 Tanaka, H. ( 6 ) 56; ( 7 ) 107; ( 8 ) 200-202 Tanaka, J . C . ( 6 ) 99 Tanaka, M. ( 1 ) 1 Tanaka, S. ( 3 ) 29 Tanaka, T. ( 5 ) 8 1 ; ( 6 ) 171, 184, 205 Tang, J.-Y. ( 4 ) 7 2 ; ( 6 ) 50 Tang, J.Y. ( 4 ) 6 5 ; ( 6 ) 157 Tangour, B. ( 2 ) 24, 25, 26

Tanigaki, T. ( 8 ) 124 Tanigami, T. ( 8 ) 192 Taniyama, Y. ( 6 ) 232 Tanner, N.K. ( 6 ) 317 Tao, X. ( 5 ) 109 Tarusova, N.B. ( 6 ) 7 , 455 Taub, D. ( 5 ) 184 Taylor, G.E. ( 5 ) 127; ( 6 ) 155

Taylor, J.-S.

( 6 ) 249,

2 50

Teare, J. ( 6 ) 436 Tebbe, K.-F. ( 1 ) 34 Temeriusz, A. ( 6 ) 20 Tenhunen, J. ( 6 ) 297 Teoule, R. ( 6 ) 179, 221 Terov, A.A. ( 5 ) 148 Teulade, M.P. ( 5 ) 93, 137, 221

Thederahn, T.B. ( 6 ) 387 Thelin, M. ( 6 ) 42, 52 Thivierge, J. ( 6 ) 388

Author Index

Thoma, R.J. ( 4 ) 8 2 ; ( 8 ) 26

Thomas, E.J. ( 7 ) 8 0 , 112 Thomas, G.J., jun. ( 6 ) 6 4 , 494

Thomas, R.D. ( 6 ) 245 Thomas, R.L. ( 6 ) 145 Thomas,

T.

( 6 ) 493

Thomas, T.J. ( 6 ) 493 Thornton-Pett, M. ( 1 ) 7 3 , 134

Thorton, A.H. ( 6 ) 262 Thuong, N.T. ( 4 ) 6 0 , 6 1 ; ( 6 ) 192-196, 260, 384, 385 Thurlow, D.L. ( 6 ) 421 Tikhonenkova, E. ( 8 ) 126 Tikhonina, N.A. ( 5 ) 5 1 ; ( 8 ) 32 Tikuoka, R. ( 6 ) 16 Timoteev, V.P. ( 6 ) 455 Tindall, K.R. ( 6 ) 286 Tinoco, I., jun. ( 6 ) 302, 49 1 Tirakyan, M.R. ( 5 ) 228 Tiriliomis, A. ( 1 ) 353 Tisnes, P. ( 2 ) 37 Tisne-Versailles, J. ( 5 ) 95 Tittelbach, F. ( 1 ) 123; ( 8 ) 21 Tocik, 2 . ( 6 ) 178 Todesco, P.E. ( 1 ) 78-80; ( 4 ) 44 Toke, L. ( 1 ) 355; ( 3 ) 1 4 , 1 5 ; ( 5 ) 14 Tokoroyama, T. ( 7 ) 16 Tolstikov, G.A. ( 1 ) 248 Tomasz, J. ( 6 ) 96-98, 130 Tomasz, M. ( 6 ) 443 Tomcufcik, A.S. ( 8 ) 72 Tomita, N. ( 8 ) 220 Tomka, M. ( 6 ) 413 Tonelli, A.E. ( 8 ) 200-202 Topal, M.D. ( 6 ) 224 Topolski, M. ( 5 ) 176 Torgasheva, N . A . ( 5 ) 72 Torreilles, E. ( 1 ) 237; ( 7 ) 6 ; ( 8 ) 28 Torrence, P.F. ( 6 ) 276 Torres, M.R. ( 1 ) 137 Toth, G. ( 3 ) 15 Toth, I. ( 1 ) 132 Toulm;, J.J. ( 6 ) 260 TOUS,G.I. ( 6 ) 468 Toyota, K. (1) 282 Tracey, A.S. ( 6 ) 117 Trainor, G.L. ( 6 ) 307 Tregear, G.W. ( 5 ) 56, 57 Trent, J.O. ( 7 ) 47, 57 Trentham, D.R. ( 6 ) 111, 112

427 Tresselt, D. ( 5 ) 24 Tribolet, R. ( 6 ) 452, 460 Trinquier, G. ( 4 ) 101 Trinquier, J. ( 1 ) 145 Trishin, Yu.G. ( 2 ) 28, 31; ( 8 ) 161

Tritz, R. ( 6 ) 411 Trivunin, V.S. ( 1 ) 175 Trofimov, B.A. ( 1 ) 82 Trogler, W.C. ( 5 ) 63 Tromp, C.M. ( 4 ) 52 Trostyanskaya, I.G. ( 1 ) 166

Trushin, Yu.G. ( 1 ) 209 Tsai, M.-D. ( 5 ) 29 Tsao, J. ( 6 ) 468 Tse-Dinh, Y.-C. ( 6 ) 380 Tsivunin, V.S. ( 1 ) 176 Ts'o, P.O.P. ( 6 ) 257 Tsubokawa, M. ( 8 ) 140, 141

Tsuda, M. ( 5 ) 192, 193 Tsuda, T. ( 1 ) 139 Tsuhako, M. ( 6 ) 110 Tsukamoto, M. ( 7 ) 16 Tsumaki, H. ( 1 ) 16 Tsuno, K. ( 6 ) 80 Tsvetkov, E.N. ( 1 ) 128, 231; ( 2 ) 6 ; ( 4 ) 4 8 ; ( 5 ) 2 , 234 Tsygankov, A.Yu. ( 6 ) 467 Tsytovich, A.V. ( 6 ) 28 Tuinman, R.J. ( 5 ) 32 Tumanov, Yu.V. ( 6 ) 152 Tur, D.R. ( 8 ) 168, 183 Turnbull, K. ( 8 ) 5 Turner, D.H. ( 6 ) 412, 413 Turro, N.J. ( 6 ) 459 Twiss, P. ( 1 ) 61 Tyeklar, Z. ( 1 ) 122 Tyka, R. ( 5 ) 160 Tyler, B.M. ( 6 ) 366 Tyrtysh, T.V. ( 6 ) 455 Tyuganova, M.V. ( 8 ) 127

Uccella, N. ( 6 ) 499, 500 Uchida, M. ( 8 ) 220 Uchida, Y. ( 3 ) 21 Uebel, R. ( 5 ) 203 Ueda, C. ( 7 ) 49 Ueda, T. ( 6 ) 7 2 , 7 3 , 7 8 , 90

Uenishi, J. ( 7 ) 100 Ueno, Y. ( 5 ) 7 1 ; ( 6 ) 240 Uesugi, S . ( 5 ) 8 1 ; ( 6 ) 171, 205

Ugi, I. ( 4 ) 17 Uhlenbeck, O.C. ( 6 ) 315, 320

Uhlmann, E. ( 6 ) 158, 275 Umeno, M. ( 1 ) 188; ( 8 )

30, 31

Underwood, G.R. ( 6 ) 27 Unteregger, G. ( 6 ) 306 Urbaniak, W. ( 1 ) 67 Urdea, M.S. ( 6 ) 176 Urman, Ya.G. ( 8 ) 223 Urretavizcaya, G. ( 6 ) 454 Ushkov, V.A. ( 8 ) 128 Usman, N. ( 4 ) 67, 7 8 ; ( 6 ) 162, 199, 226, 229

Usmanova, L.N. ( 4 ) 34 Uzanski, B. ( 6 ) 54 Uziel, J. ( 5 ) 165 Uznanski, B. ( 6 ) 266 Vaahs, T. ( 1 ) 318, 319 Vaghefi, M.M. ( 6 ) 68, 130 Vahldiek, M. ( 4 ) 36 Valerio, R.M. ( 5 ) 186 Valiant, M.E. ( 5 ) 184 Van Aerschot, A. ( 6 ) 163 van Boom, J . H . ( 4 ) 50-52, 6 9 , 7 7 ; ( 5 ) 32, 8 8 ; ( 6 ) 41, 53, 146, 239, 241, 242, 451, 494 van de Grampel, J.C. ( 8 ) 7 7 , 9 7 , 113, 117, 234 van den Elst, H . ( 4 ) 6 9 , 7 7 ; ( 6 ) 41, 451 Vanderhaeghe, H. ( 6 ) 163

van der Hofstad, W.J.M. ( 5 ) 237

van der Huizer, A.A.

(8)

97

van der Marel, G.A. ( 4 ) 50-52, 6 9 , 7 7 ; ( 5 ) 32, 8 8 ; ( 6 ) 4 1 , 53, 146, 239, 241, 242, 494 van der Plas, H.C. ( 4 ) 54 van der Wal, S.J. ( 6 ) 31, 32 van de Sande, J.H. ( 6 ) 453, 491 Van Doorn, J.A. (1) 1 5 , 5 0 , 51, 52

van Garderen, C.J. ( 6 ) 45 1

van Genderen, M.H.P. ( 6 ) 30-32,

265

Van Haastert, P.J.M. ( 6 ) 93

van Van Van Van

Houte, L.P.A. ( 6 ) 451 Houten, B. ( 6 ) 224 Koten, G. ( 1 ) 351 Ments-Cohen, M. ( 6 )

93

Varasi, M. ( 2 ) 20 Vasella, A. ( 5 ) 34 Vasileva, T.V. (1) 167 Vasyanina, L.K. ( 2 ) 33 Vasyanina, M.A. ( 5 ) 145

Orgunophosph oms Chemimy

428

Vather, S.M. ( 5 ) 78 Veal, J.M. ( 6 ) 389 Vedejs, E. ( 7 ) 12-14 Vederas, J.C. ( 1 ) 111 Venyaminova, A.G. ( 6 ) 40 Verduym, R. ( 4 ) 51 Verfiirth, U. ( 4 ) 17 Verheyden, J.P.H. ( 6 ) 57 Verjovski-Almeida, S . ( 6 ) 120

Verkade, J.G. ( 2 ) 42, 43; ( 4 ) 27, 28

Verly, W.G. ( 6 ) 370, 371 Verma, L. ( 6 ) 27 Vermes, B. ( 7 ) 101 Verna, C. ( 6 ) 447 Veszpremi, T. ( 7 ) 2 Viala, J. ( 7 ) 91 Viallefont, P. ( 5 ) 166 Vicentini, A.M. ( 6 ) 159 Vidal, A. ( 7 ) 62, 6 4 ; ( 8 ) 4 0 , 42

Viduad, L. ( 8 ) 95 Vignais, P.V. ( 6 ) 118, 340

Vinader, M.V. ( 7 ) 6 3 ; ( 8 ) 43, 45

Vinogradova, S.V. ( 8 ) 168, 183

Visscher, J. ( 6 ) 283 Vizel, A.O. ( 5 ) 151 Vollenkle, H. ( 5 ) 180 Vogt, R. ( 1 ) 161 Voigt, J.M. ( 6 ) 224 Vol'eva, V.B. ( 2 ) 32 Volfson, A.D. ( 6 ) 467 Volkov, E.M. ( 6 ) 236 Von Allworden, U. ( 1 ) 141 von Janta-Lipinski, M. ( 6 ) 7 , 127

Vonk, C.R. ( 4 ) 54 Voronkov, M.G. ( 1 ) 82 Vosberg, H.-P. ( 6 ) 362 Voss, H. ( 6 ) 364 Vovk, M.V. ( 5 ) 205 Vrudhala, V.M. ( 6 ) 123 Vyalykh, E.P. (1) 82 Vyle, J.S. ( 4 ) 7 4 ; ( 6 ) 35 Vysotskii, V.I. ( 1 ) 94; ( 5 ) 121

Wachtler, U. ( 8 ) 19 Wada, M. ( 1 ) 1 Wada, T. ( 4 ) 66; ( 6 ) 47 Wagner, A. ( 1 ) 100 Wagner, 0 . ( 1 ) 332 Wai, J.S.M. ( 7 ) 78 Walder, J.A. ( 6 ) 259 Walder, R.Y. ( 6 ) 259 Walker, B.J. ( 3 ) 1 3 ; ( 7 ) 41, 42

Walker, D.M. (4) 1 1 ; ( 5 ) 183

Walker, J.W. ( 6 ) 111, 112 Walker, K.A.M. ( 2 ) 20 Wall, R. ( 6 ) 391 Wallace, P. ( 3 ) 25 Wallace, S.S. ( 6 ) 299 Wallbridge, M.G.H. ( 1 ) 47 Wallis, C.J. ( 3 ) 32 Wamhoff, H. ( 8 ) 48 Wang, A.H.-J. ( 6 ) 233, 446, 494

Wang, Wang, Wang, Wang,

C.K. ( 6 ) 328 D. ( 6 ) 198, 319 H. ( 1 ) 278, 342 J.H. ( 6 ) 119, 336,

337

Wang, W. ( 7 ) 29, 30 Wang, Y. ( 7 ) 29 Warren, S . ( 3 ) 23-25, 32 Warren, W. ( 6 ) 466 Wartalowska-Graczyk, M. (5) 36

Washington, L.D. ( 6 ) 321 Wasielewski, C. ( 5 ) 176 Wasylishen, R.E. ( 8 ) 8 Watanabe, K. ( 6 ) 367 Watanabe, T. ( 4 ) 6 3 ; ( 6 ) 168

Watanabe, Y. ( 5 ) 6 , 30, 35

Waters, K.E. ( 8 ) 58 Watkins, C.L. ( 1 ) 151; ( 6 ) 245

Watkins, D.A. ( 5 ) 207 Watson, J.E.V. ( 6 ) 309 Watson, W.H. ( 4 ) 82 Watterson, A.C. ( 8 ) 181 Watts, J.P. ( 7 ) 112 Weatherford, D.A. ( 1 ) 14 Webb, M.R. ( 6 ) 139 Webb, R.R., I1 ( 6 ) 59, 60 Weber, L. ( 1 ) 8 6 , 259, 260

Weferling, N. ( 1 ) 121 Wegner, P. ( 1 ) 19 Wei, H. ( 5 ) 117 Wei, S. ( 5 ) 115 Weichmann, H. ( 1 ) 7 1 ; ( 3 ) 38

Weier, H.-U. ( 6 ) 313 Weil, E.D. ( 8 ) 172 Weil, P.A. ( 6 ) 328 Weinfeld, M. ( 6 ) 373-375 Weissberger, B. ( 5 ) 184 Weissman, S.A. ( 1 ) 322 Weisz, M. ( 6 ) 164 Wells, A.S. ( 1 ) 340, 341 Wen, X. ( 7 ) 28 Wenger, R. ( 6 ) 279 Werner, H. (1) 273 Werner, W. ( 5 ) 24

Werz, U. ( 1 ) 1 1 , 21 West, C.R. ( 6 ) 150 Westerhausen, M. ( 1 ) 45 Westheimer, F.H. ( 2 ) 38, 39

Westman, E. ( 6 ) 42 Wetmur, J.G. ( 6 ) 258 Wettermark, U.G. ( 8 ) 57 Whang, E.E. ( 6 ) 449 Wheatley, P.J. ( 2 ) 3 White, A.H. ( 1 ) 43, 61 White, J.M. ( 5 ) 3 White, P.S. ( 1 ) 326 Whitehead, J.W.F. ( 7 ) 112 Whitesides, G.M. ( 6 ) 149 Whittington, B.I. ( 7 ) 47 Wiaterek, C. ( 1 ) 36 Wieber, M. ( 1 ) 198 Wieczorek, M.W. ( 3 ) 18 Wiemer, D.F. ( 4 ) 3 ; ( 5 ) 142

Wiewiorowski, M. ( 6 ) 382 Wife, R.L. ( 1 ) 50 Wilchek, M. ( 6 ) 422 Wilde, J.A. ( 6 ) 488 Wilk, A. ( 6 ) 54 Williams, A. ( 5 ) 244; ( 6 ) 1 2 , 13

Williams, G.D. ( 6 ) 478 Williams, K.R. ( 6 ) 2 Williams, L.D. ( 6 ) 388 Williams, M.S. ( 6 ) 129 Williamson, J.R. ( 6 ) 490 Willis, R.C. ( 6 ) 130 Wilson, A. ( 8 ) 170 Wilson, S.H. ( 6 ) 255 Wilson, V. ( 6 ) 292 Wilting, T. ( 8 ) 97 Wimmer, T. ( 1 ) 105 Wing, R.M. ( 6 ) 447 Wingeleth, D.E. ( 1 ) 150 Wingen, U. ( 7 ) 76 Wingert, H. ( 5 ) 25 Winship, P.R. ( 6 ) 361 Winter, H. ( 8 ) 234 Winter, J.N. (1) 227 Wintersgill, M.C. ( 8 ) 211 Wippler, J. ( 6 ) 322 Wirkner, U. ( 6 ) 364 Wisian-Neilson, P. ( 8 ) 38, 57

Wisniewski, W. ( 3 ) 36 Witek, S. ( 5 ) 108 Witt, M. ( 8 ) 4 , 36, 165 Witte, J.F. ( 5 ) 218; ( 7 ) 85

Wittig, G. ( 2 ) 3 Wittman-Liebold, B. ( 6 ) 352

Wolcott, R.A. ( 1 ) 154 Woldegiorgis, G. ( 6 ) 343 Wolf, D.E. ( 6 ) 496

Author Index

429

Wolf, J. (1) 273 Wolf, J.-G. ( 2 ) 37 Wolf, R. ( 5 ) 27 Wolfes, H. ( 6 ) 235 Wolfsberger, W. ( 1 ) 6 2 , 164; ( 8 ) 1 5 , 62 473 491 ( 6 ) 436 191 75 126; ( 4 ) 20 Woodward, P.R. ( 7 ) 89 Woollins, J.D. ( 1 ) 126; ( 4 ) 20 Wos, J.A. ( 6 ) 60 Wosnick, M.A. ( 6 ) 159 Wower, J. ( 6 ) 334, 339 Wrackmeyer, B. ( 1 ) 27 Wray, V. ( 1 ) 160 Wright, T.C. ( 1 ) 48 Wu, J.C. ( 6 ) 303, 337 Wu, R. ( 6 ) 319 Wu, T. ( 6 ) 181, 203 wu, Y. ( 7 ) 3 Wulvik, E.A. ( 5 ) 233 Wurdeman, R.L. ( 6 ) 417 Wurthwein, E.4. ( 1 ) 269

Wolk, C.P. ( 6 ) Wolk, S.K. ( 6 ) Wollenzien, P. Wong, D.T. ( 5 ) Wood, C.E. ( 8 ) Wood, P.T. ( 1 )

Xi, S.-K. ( 1 ) 115; ( 2 ) 42, 43; ( 4 ) 27, 28

Xin, Y. ( 1 ) 155 Xu, C . ( 6 ) 247 xu, x. ( 7 ) 3 Xu, Y. ( 5 ) 117; ( 7 ) 3 XU, Y.-Z. ( 4 ) 68; ( 6 ) 209 Yadagiri, P. ( 7 ) 9 2 , 9 3 , 98

Yaguchi, A. ( 8 ) 110, 139 Yahiro, S. ( 1 ) 245; ( 7 ) 33

Yaklakov, M.G. Yakovlev, G . I . Yamada, K. ( 5 ) Yamada, S . ( 8 ) Yamada, Y. ( 5 )

( 8 ) 118 ( 6 ) 277 16 188 81; ( 6 )

171, 184

Yamaguchi, M. ( 3 ) 22; ( 6 )

21

Yamamoto, N. ( 6 ) 264 Yamamoto, S. ( 1 ) 214 Yamamoto, T. ( 8 ) 134-136 Yamamoto, Y. ( 6 ) 110 Yamana, K. ( 4 ) 75 Yamana, M. ( 5 ) 11 Yamashita, K. ( 7 ) 117 Yamashita, M. ( 3 ) 26; ( 4 ) 81

Yamashoji, Y. ( 1 ) 1 Yamataka, H. ( 2 ) 23; ( 7 ) 32

Yamaura, K. ( 8 ) 192 Yamazoe, 0 . ( 8 ) 131, 133 Yamoto, s. ( 4 ) 75 Yanagawa, H. ( 6 ) 80 Yanagi, K. ( 5 ) 39 Yanagida, S . ( 7 ) 61 Yang, C. ( 6 ) 400 Yang, I.-Y. ( 6 ) 72 Yang, J. ( 7 ) 28 Yang, S.W. ( 1 ) 314 Yankovskaya, V.L. ( 5 ) 234 Yarkova, E.G. ( 2 ) 30; (5) 222

Yashima, E. ( 6 ) 333 Yastrebov, S.I. ( 6 ) 161 Yates, J.T. ( 5 ) 3 Ye, M.-C. ( 5 ) 74 Ye, W. ( 5 ) 104 Yeung, A.T. ( 6 ) 173, 439 Yokota, S. ( 1 ) 225 Yokoyama, S. ( 6 ) 90 Yoneda, R. ( 5 ) 84 Yonekura, S. ( 6 ) 497 Yonetake, K. ( 8 ) 197 Yoneyama, M. ( 8 ) 109 Yoon, C. ( 6 ) 391 Yoshifuji, M. ( 1 ) 252, 254, 263, 264, 282; ( 4 ) 94 Yoshihashi, K. ( 8 ) 109 Young, S.G. ( 8 ) 205 Yount, R.G. ( 6 ) 344 Yoza, N. ( 6 ) 110 Yuan, G . ( 5 ) 235 Yuan, W. ( 4 ) 56 Yudelevich, V.I. ( 5 ) 120, 163 Yufit, D.S. ( 2 ) 47 Yurchenko, R.I. ( 8 ) 71

333

Yamaizumi, Z. ( 6 ) 90 Yamaji, N. ( 6 ) 91 Yamakage, S. ( 6 ) 3 9 , 274 Yamamoto, A. ( 1 ) 10 Yamamoto, H. ( 5 ) 122 Yamamoto, I. ( 3 ) 29; ( 7 )

Zablocka, M. ( 3 ) 33, 36 Zabotina, E.Ya. ( 1 ) 347, 350

Zagorski, M.G. ( 6 ) 485

Zain, R. ( 6 ) 52 Zakharov, L.S. ( 5 ) 7 Zal'tsman, I.S. ( 1 ) 242; ( 8 ) 29, 50, 51

Zamecnik, P.C. ( 6 ) 261, 262, 263, 496

Zarytova, V.F. ( 6 ) 186, 431, 432

Zasorina, V.A. ( 8 ) 61 Zaug, A.J. ( 6 ) 410 Zavadskii, K.S. ( 1 ) 189 Zavorin, S.I. ( 5 ) 4 Zawadzki, S. ( 5 ) 91 Zbiral, E. ( 5 ) 101, 143 Zecchi, G. ( 7 ) 59 Zeigler, T. ( 8 ) 149 Zelenev, Yu.V. ( 8 ) 205 Zellner, K. ( 1 ) 60 Zhai, C. ( 5 ) 7 4 , 115 Zhang, J. (5) 117 Zhang, P. ( 7 ) 9 Zhang-Keck, Z. ( 6 ) 321 Zhao, J. ( 1 ) 155 Zhao, K. ( 7 ) 17 Zhao, Y. ( 5 ) 115 Zhao, Y.-F. ( 5 ) 74 Zheng, D.H. ( 1 ) 140 Zheng, K. ( 6 ) 319 Zhou, X.-X. ( 6 ) 272 Zhu, J. ( 5 ) 109 Zhuzhlikova, S.T. ( 7 ) 46 Ziebell, G. ( 5 ) 24 Ziegler, M.L. ( 1 ) 127, 346; ( 4 ) 8 5 ; ( 5 ) 200

Zielonacka-Lis, E. ( 6 ) 11 Ziemer, B. ( 1 ) 168; ( 2 ) 11

Zieske, L.R. ( 6 ) 465 Ziessel, R. (1) 18 Zimin, M.G. ( 5 ) 73 Zimmer, H. ( 5 ) 164; ( 7 ) 74

Zimmer, M. ( 8 ) 166 Zimmermann, J. ( 6 ) 364 Zimmermann, R.A. ( 6 ) 334, 339

Zirzow, K.-H. ( 1 ) 40 Zlotskii, S.S. ( 5 ) 13 Zolk, R. ( 1 ) 273 Zsolnai, L. ( 1 ) 3 Zubieta, J. ( 1 ) 6 ; ( 3 ) 3 Zuccarello, G. ( 6 ) 401 Zuckermann, R.N. ( 6 ) 368 Zugliani, C . ( 6 ) 246 Zurawinski, M. ( 7 ) 114 Zurrniihlen, F. ( 4 ) 96 Zwierzak, A. ( 8 ) 53 Zykova, T.V. ( 1 ) 176; ( 5 ) 110