General and synthetic methods

General and Synthetic Methods Volume 8 A Specialist Periodical Report General and Synthetic Methods Volume 8 A Revi...

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General and Synthetic Methods Volume 8

A Specialist Periodical Report

General and Synthetic Methods Volume 8

A Review of the Literature Published during 1983

Senior Reporter

G. Pattenden, Deparfment of Chemistry, University of Nottingharn Reporters J. M. Clough, ICI Plant Protection Division, Jealott3 MIA Berkshire K. Cooper, Hizer Central Research, Sandwich, Kent S. G. Davies, University of Oxford S. C. Eyley, Fisons p.l.c., Loughborough, Leicestershire C. R. A. Godfrey, lCl Plant Protection, Jealott's Hi14 Berksbire P. F. Gordon, lCl Organics Division, Mancbester L. M. Harwood, University of Oxford D. W. Knight, University of Nottingham T. W. Lee, University of Bristol S. G. Lister, Wellcome Research Laboratories, Beckenham, Kent K. E. B. Parkes, University of Nottingham G. M. Robertson, University of Nottingham S. E. Thomas, University of Oxford P. Whittle, Pfizer Central Research, Sandwich, Kent

The Royal Society of Chemistry Burlington House, London WIV OBN

ISBN 0-85186-894-0 ISSN 0141-2140 Copyright 01986 The Royal Society of Chemistry All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from the Royal Society of Chemistry

Printed in Great Britain by Adlard & Son Ltd, Dorking

Introduction

This report on General and Synthetic Methods covers the literature published between January and December 1983. The aim of the Reports has been to provide a summary and assessment of reactions and methods in organic chemistry which are new (or useful variants of existing ones) and appear sufficiently general to be useful in synthesis. Interconversions between all the major functional groups are covered in five chapters (Chapters 1-5), and the applications of organometallic compounds in synthesis are treated in Chapter 6, Two further chapters deal with developments in the synthesis of saturated carbocycles (Chapter 7) and saturated heterocycles (Chapter 8) and the final chapter provides a summary of ‘Highlights in Total Synthesis of Natural Products’. A list of reviews on General and Synthetic Methods is collected at the end of the Report. Future volumes in this series will be produced from camera-ready copy of manuscripts. July 1985

G. PATTENDEN

Contents Chapter 1 Saturated and Unsaturated Hydrocarbons By J. M. Clough and C. R. A. Godfrey 1 2 3 4 5 6 7 8

Saturated Hydrocarbons Olefinic Hydrocarbons Conjugated 1,3-Dienes Non-conjugated Dienes Allenic Hydrocarbons Acetylenic Hydrocarbons Enynes and Diynes Polyenes

Chapter 2 Aldehydes and Ketones By S. C. Eyley 1 Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones

1 1

6 57 65 69 72 75 79 84 84 84 87 89 93 98

2 Synthesis of Functionalized Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substituted Aldehydes and Ketones Dicarbonyl Compounds

02 102 109 117

3 Protection and Deprotection of Aldehydes and Ketones

120

4 Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reactions Conjugate Addition Reactions

123 123 126 128

Chapter 3 Carboxylic Acids and Derivatives By D. W. Knight 1 Carboxylic Acids General Synthesis Acid Chlorides and Anhydrides

131 131 131 134

...

Contents

Vlll

Diacids Hy droxy-acids Keto-acids Unsaturated Acids Protection and Deprotection Decarboxylation

134 136 138 139 142 142

2 Esters Esterification General Synthesis Diesters Hydroxy-esters Keto-esters Unsaturated Esters Thioesters

144 144 145 148 151 155 160 167

3 Lactones P-Lactones Butyrolactones a-Methylenebutyrolactones Butenolides and Phthalides Tetronic acids Valerolactones Macrolides

168 168 168 175 177 181 181

4 Carboxylic Acid Amides Synthesis Reactions Thioamides Peptide Bond Formation

185 185 187 189 190

5 Amino-acids Synthesis Dehydroamino-acids AsymmetricHydrogenation Protection and Deprotection

192 192 194 196 196

Chapter 4 Alcohols, Halogeno-compounds, and Ethers By L. M. ffarwood 1 Alcohols Preparation by Addition to Alkenes Preparation by Reduction of Carbonyl Compounds ChemoselectiveCarbonyl Reductions Stereoselective Carbonyl Reductions Asymmetric Carbonyl Reductions Enzymic Asymmetric Carbonyl Reductions

183

200 200 200 204 204 206 207 210

Contents

ix Preparation by Nucleophilic Addition Allylic Alchols Homoallylic Alcohols Other Unsaturated Alcohols Diols General Methods of Preparation Allylic Alcohols Homoallylic and Other Unsaturated Alcohols Diols Protection and Deprotection Reactions of Alcohols Oxidation Hydrogenolysis and Deoxygenation Halogenation Chiral Auxilliaries Other Reactions

211 213 215 218 219 219 221 221 223 224 226 226 227 228 229 229

2 HalogenoCompounds Preparation Reactions

230 230 232

3 Ethers 4 Thiols and Thioethers 5 Macrocyclic Polyethers

234 237 239

Chapter 5 Amines, Nitriles, and Other Nitrogenconta ining FunctionaI G roups By S. G. Lister 1 Amines Primary Amines Secondary Amines Tertiary Amines

2 3 4 5 6 7 8 9 10 11 12 13 14 15

Enamines Allylamines, Homoallylamines, and Alkynylamines Amino-alcohols Amino-aldehydesand Amino-ketones Amides and Thioamides Nitriles and Isocyanides Nitro- and Nitroso-compounds Hydrazines Hydroxylaminesand Hydroxamic Acids Imines, Iminium Salts, and Related Compounds Oximes Carbodi-imides Azides and Diazo-compounds Azo- and Azoxy-compounds

245 245 245 254 262 264 268 270 279 280 283 294 300 300 301 304 305 306 308

Contents

X

16 Isocyanates, Thiocyanates, Isothiocyanates, and Selenocy anates 17 Nitrones 18 Nitrates and Nitrites

Chapter 6 Organometallics in Synthesis Part I The Transition Elements By S. G.Davies and S. E. Jhomas 1 2 3 4 5

Introduction Reduction Oxidation Isomerizations and Rearrangements Carbon-CarbonBond Formation via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling Reactions via Carbonylation and Related Reactions 6 Synthesis of Heterocycles 7 Miscellaneous Reactions

Part II Main Group Elements By/? E Gordon 1 Group1

Selective Lithiation Synthetic Equivalents Sulphur-stabilized Anions and Dianions Miscellaneous Reactions

309 309 311 312 312 312 312 314 317 318 318 323 328 333 335 337 338 338

338 342 344 346

2 Group11 Magnesium Zinc and Mercury

348 348 351

3 Group111 Boron Aluminium

353 353 358

4 GroupIV Silicon Tin

360 360 367

5 GroupV Phosphorus

369 369

6 GroupVI Sulphur Selenium Tellurium

373 373 378 380

Contents

xi

Chapter 7 Saturated Carbocyclic Ring Synthesis By 7: V: Lee

381

1 Three-memberedRings 2 Four-membered Rings 3 Five-memberedRings Fused Five-membered Rings Naturally Occurring Fused Cyclopentanoids

381 382 384 387 390

4 Six-memberedRings Diels-Alder Reactions Intramolecular Diels-Alder Reactions Other Six-membered Ring Syntheses Steroids

391 391 394 395 399

5 Seven-membered,Medium, and Large Rings 6 Ring Expansion Methods 7 Spiro-ringCompounds

400 402 404

Chapter 8 Saturated Heterocyclic Ring Synthesis By K Cooper and P. J. Whiftle 1 Oxygen-containingHeterocycles

Oxiranes Four-membered Rings Five-membered Rings Tetrahydrofur ans Dihy drofurans Five-membered Rings with More than One Oxygen Atom Six-membered Rings Tetrahydropyrans Dihy dropyrans [5 .n]-Spiroacetals Six-membered Rings with More than One Oxygen Atom Seven- and Eight-membered Rings 2 Sulphur-containingHeterocycles 3 Heterocycles ContainingMore than One Heteroatom Nitrogen- and Oxygen-containing Rings Three-membered Rings Five-membered Rings Six- and Eight-membered Rings Oxygen and Sulphur-, and Nitrogen and Sulphur-containing Rings

407

407 407 410 412 412 418 424 425 425 426 434 439 441 443 448 448 448 448 450 453

xii

Contents 4 Nitrogen-containingHeterocycles Three-memberedRings Four-memberedRings Five-memberedRings Containing One Nitrogen Atom Five-membered Rings Containing More than One Nitrogen Atom Six-membered Rings Containing More than One Nitrogen Atom Medium Ring Nitrogen Heterocycles Rings Containing One Nitrogen Atom Rings Containing More than One Nitrogen Atom

454 454 456 457 472 480 483 483 487

5 19-Lactams,Penicillins, Cephalosporinsand Related Compounds 488

Chapter9 Highlights in Total Synthesis of Natural Products By K E 6.Parkes and G.Pattenden

497

Introduction Terpenes Steroids Anthracyclinones 5 Alkaloids 6 Prostaglandins and Leukotrienes 7 Spiroacetals 8 Pseudomonic Acids 9 Sugars 10 Macrolides and Ionophores 11 Other Natural Products

497 497 507 508

Reviews on General and Synthetic Methods By G. Pattenden and G.M. Robertson

541

1 2 3 4

1 2 3 4

Olefins Aldehydes and Ketones Carboxylic Acids Alcohols, Halogeno-compounds, and Ethers 5 Nitrogen-containingFunctional Groups 6 Organometallics General Transition Elements Boron and Thallium 7 Ring Synthesis 8 Heterocycles 9 Electrochemical Methods 10 Photochemical Methods

511

522 524 527 529 532 537

541 541 542 542 542 542 542 542 543 543 543 544 544

...

Contents

Xlll

11 12 13 14

Peptide Synthesis Asymmetric Synthesis General Miscellaneous

Author Index

545 545 546 547 548

1 Saturated and Unsaturated Hydrocarbons BY J. M. CLOUGH AND C. R. A. GODFREY

1 Saturated Hydrocarbons

Many new methods for the preparation of alkanes via reductive removal of functional groups have been reported during the year. A preparatively useful method for the conversion of carboxylic acids into alkanes has been developed by Barton and his co-workers. Primary, secondary, and tertiary carboxylic esters (1) RC02H

i .ii

R

Ao,Q S

iii or

IV

RH

(1) Reagents: i, (COCI),; ii,

@ ; iii, Bun,SnH; iv, Bu'SH HO

S

derived from thiohydroxamic acids such as N-hydroxypyridine-2-thione undergo efficient radical chain decarboxylation to the corresponding nor-alkanes on treatment with either tri-n-butyltin hydride or t-butylmercaptan. Under these mild reaction conditions, ketones, olefins, and normal carboxylic esters remain unchanged. Decarboxylation of carboxylic acids can also be effected using sodium persulphate and a catalytic amount of silver nitrate. Unstabilized alkyl radicals from aliphatic acids afford alkanes or, in the presence of copper(I1) salts, alkenes.2 By contrast, arylacetic acids give benzylic radicals, and these dimerize to give 1,2-diarylethanes in moderate yield^.^ Williams and Moore have reported that the reduction of a variety of heterocyclic thiones to the corresponding methylene compounds occurs readily on heating with an excess of tri-n-butyltin hydride and a radical initiator (e.g. Scheme l).4Conversion of the cyclic thiocarbonate (2) into the 1,3-dioxolane ( 3 ) is noteworthy in that the Corey-Winter reaction does not take place under the reaction conditions. The desulphurization of thiols and thioketones to alkanes D. H. R. Barton, D. Crich, and W. B. Motherwell, J . Chem. Soc., Chem. Commun., 1983,939;D. H. R. Barton and G . Kretzschmar, Terruhedron Lett., 1983, 24, 5889. W. E. Fristad, M. A. Fry, and J. A. Klang, J . Org. Chem., 1983,48, 3575. W. E. Fristad and J. A. Klang, Tetrahedron Lett., 1983, 24,2219. D. K.Williams and J. L. Moore, Tetrahedron Lett., 1983, 24, 339.

1

General and Synthetic Methods

2

0 6un3Sn H , A 1 BN

0-

Bun3SnH, A1 BN

*

do (3)

Scheme 1

and alkenes using sodium triethylborohydride and iron(I1) chloride is improved by adsorption of the borohydride onto a l ~ r n i n aMoreover, .~ this heterogeneous reaction occurs at room temperature and products are easily isolated by simple filtration. A variety of benzylic di- and tri-arylmethyl mercaptans react with stoicheiometric amounts of [Fe3(C0)12]or [co2(CO),] under phase-transfer conditions to give the corresponding hydrocarbons in good yields.6 Monosubstituted thiiranes are reduced to alkanes on treatment with Raney nickel in ethanol at -4O"C, conditions under which olefinic bonds are ~naffected.~ On irradiation, solutions of diselena[3.3]cyclophanes in HMPA are transformed cleanly into the corresponding cyclophanes (e.g. Scheme 2) .,

h v , HMPA

Scheme 2

Treatment of (hydroxymethy1)diphenylphosphine oxides (4) with P214in carbon disulphide at room temperature affords excellent yields of the alkyldiphenylphosphineoxides (5) with no trace of the corresponding iodide^.^

it* ( 4 )R', R2 = a l k y l

'

(5)

H. Alper, S. Ripley, and T. L. Prince, J. Org. Chem., 1983,48,250. H. Alper, F. Sibtain, and J. Heveling, Tetrahedron Lett., 1983, 24,5329. J. R. Schauder, J. N. Denis, and A. Krief, Tetrahedron Lett., 1983,24,1657. H. Higuchi, M. Kugimiya, T. Otsubo, Y. Sakata, and S. Misumi, Tetrahedron Lett., 1983,24, 2593. M. Yamashita, K. Tsunekawa, M. Sugiura, T. Oshikawa, and S. Inokawa, Chem. Lett., 1983, 1673.

Saturated and Unsaturated Hydrocarbons

3

Suzuki and his co-workers have shown that benzyl alcohols are smoothly deoxygenated on treatment with P214in boiling benzene. The reaction works well even with sterically hindered secondary benzyl alcohols, as illustrated in

Scheme 3

Scheme 3.1° Extending this work, the same group has reported that a mixture of LiA1H4 and P214offers a mild alternative to conventional methods for the deoxygenation of aromatic ketones (e.g. Scheme 4). l1 Halogens , esters, and olefinic bonds are not affected by these reaction conditions.

Q

Q Scheme 4

Ueno and his co-workers have described conditions under which tosylates, including those derived from primary alcohols, undergo efficient radical deoxygenation to give hydrocarbons.12 A noteworthy example is the selective removal of the tosyl group from the diol derivative (6) which takes place without the need to protect the free hydroxy-group. OH Bun3SnH, N a I

OTs

+ HO@ 56 "lo

20 ' l o

Several reports describing the use of lithium triethylborohydride for the reduction of alkyl halides, especially alkyl fluorides, have been published during the year. l 3 Catalytic amounts of silver perchlorate markedly accelerate the reduction H. Suzuki, H. Tani, H. Kubota, N. Sato, J. Tsuji, and A. Osuka, Chem. Lett., 1983,247. H. Suzuki, R. Masuda, H. Kubota, and A. Osuka, Chem. Lett., 1983, 909. l2 Y. Ueno, C . Tanaka, and M. Okawara, Chem. Lett., 1983, 795. l3 S. Krishnamurthy and H. C. Brown,J. Org. Chem., 1983,48,3085;S. Brandange, 0.Dahlman, and J. Olund, Acta Chem. Scand., Ser. B, 1983,37, 141. lo

l1

4


of 1,l-dibromocyclopropanes to the corresponding monobromides by LiAlH4.l4 This catalyst also facilitates the reduction of tertiary or sterically hindered alkyl bromides which are normally resistant to LiA1H4. gem-Bromochlorocyclopropanes react with a mixture of diethyl phosphonate and triethylamine to give the corresponding chlorocyclopropanes exclusively, and (trichloromethy1)benzene is reduced to (dichloromethy1)benzene in a yield of 86% under the same ~0nditions.l~ Photostimulated reduction of either cyclohexyl chloride or bromide with LiA1H4 in the presence of di-t-butyl peroxide gives cyclohexane in good yield. Vinyl bromides are converted into olefins under these conditions, but yields are only moderate.16 a-Halogenocarbonyl compounds are smoothly dehalogenated on treatment with sodium hydrogen telluride, generated in situ from tellurium and NaBH4 in ethan01.l~ a-Nitrohydrazones (7),readily prepared from the corresponding nitroalcohois (8), are cleanly reduced to the hydrazones (9) on treatment with LiAlH4. However, the reaction fails for nitrohydrazones (7) in which R2 and R3 are both hydrogen atoms.18

. . R2 R3

(8)

(7)

(9)

Reagents: i, Na,Cr,O,; ii, NH,NHTs; iii: LiA1H4

Dimeric products often encountered during the reduction of nitroalkenes to the corresponding nitroalkanes with NaBH4 can be avoided by carrying out the reaction at 25°C in the presence of silica gel, in a mixture of chloroform and propan-2-01.l~ Reasonable yields of alkanes can be obtained by electrohydrogenation of both alkenes and alkynes using a nickel-plated cathode coated with Raney nickel powder.20However, many other functional groups are also reduced under these conditions. Alper and Heveling have reported the first examples of organometallic phasetransfer catalysis under acidic conditions.*l For example, hydrogenation of 9,9'bifluorenylidene (10) or diarylethylenes occurs on treatment with [Co,(CO),] or [CO~(CO)~(PBU and ~ ) ~tetrafluoroboric ] acid under phase-transfer conditions. Anthracene, however, is not reduced. The solvated ion pair [(CSH17)3NMe][RhCI4]- catalyses the hydrogenation of a variety of unsaturated compour,ds under phase-transfer conditions.22Even aromatic substrates may be +

N. Shimizu, K. Watanabe, and Y . Tsuno, Chem. Lett., 1983, 1877. T. Hirao, S. Kohno. Y. Ohshiro, and T. Agawa, Bull. Chem. Soc. Jpn., 1983, 56, 1881. l6 A. L. J. Beckwith and Swee Hock Goh, J . Chern. SOC.,Chem. Cornmun., 1983, 907. A. Osuka and H. Suzuki, Chem. Lett., 1983, 119. l8 G. Rosini, R. Ballini, and V. Zanotti, Synthesis, 1983, 137. l5 A . K. Sinhababu and R. T. Borchardt, Tetruhedron Lett., 1983,24,227. 20T.Chiba, M. Okimoto, H . Nagai, andY. Takata, Bull. Chem. SOC.Jpn., 1983, 56, 719. H . Alper and J. Heveling, J. Chem. SOC., Chem. Commun., 1983, 365. 22 J. Hum, I. Amer, A. Zoran, and Y. Sasson, Tetrahedron Lett., 1983, 24,4139. l4 l5


5

(10) Reagents: i , C12H25C6H4S03Na+, C,H6, 50% HBF,, [Co2(CO),]

reduced to the corresponding alkanes at room temperature and under a pressure of 2 atm of hydrogen, but reaction rates are sensitive to steric effects. Reactive halides such as benzyl bromide undergo homo-coupling on treatment with titanocene methylene-zinc halide complexes of the type [Cp,TiCH,.ZnX,] (X=Cl or I).23 Reetz and Westermann have reported that treatment of lithium alkoxides of the type (11) with a 1:l mixture of MeTiC1, and Me,TiCl, at -40°C affords the methylated products (12), which are potentially useful as synthetic tetra-

/

OMe

OMe (11)

Me

OMe (12) R’, R 2 = alkyl Reagents: i, R2Li; ii, MeTiC1, : Me2TiC1, (1: 1)

hydrocannabinoid interrnediate~.~~ Undesirable Wagner-Meerwein rearrangements or retro-Friedel-Crafts reactions are not observed under these reaction conditions. By contrast, gem-dimethylation of the optically active disubstituted cyclopentanone (13) using Me2TiC12affords a mixture of racemic cuparene (14) n

23 24

J. J. Eisch and A. Piotrowski, Tetrahedron Lett., 1983,24,2043. M. T. Reetz and J. Westermann, J . Org. Chem., 1983, 48, 254.

6


and the olefin (15), products which can be accounted for in terms of intermediate carbonium ions.25 2 Olefinic Hydrocarbons

Although the extremely hindered olefin tetra-t-butylethylene has still not been synthesized, the closely related compounds ( 16),26(17), (18), and (19)27have been prepared and characterized, and some of these are potential precursors of tetrat-butylethylene itself.

House and his co-workers have synthesized further examples of strained enones, either by elimination or by intramolecular Wadsworth-Emmons reactions. 2-Phenylbicyclo[3.3.l]non-l-en-3-one (20) is stable when protected from oxygen, or nucleophiles such as water.28By contrast, the bicyclo[3.2.l]octane species (21) and (22) could only be generated as transient intermediates which

l>o

( Me0I2P

T NaOHor

ob cEt3N --

NaOMe I

0

(22)

I

OS02Me

were trapped with nucleophiles or, in the case of (22), as a cycloadduct with f~ranA . ~ simple ~ two-step preparation of bicyclo[3.3.0]oct-l-en-3-onealso makes use of an intramolecular Wadsworth-Emmons reaction (potassium carbonate and 18-crown-6 in benzene at 60°C) to close the second ring.30 G. H. Posner and T. P. Kogan, J . Chem. SOC., Chem. Commun., 1983, 1481. T. Loerzer, R. Gerke, and W . Luttke, Tetrahedron Lett., 1983,24, 5861. 27 A. Krebs, W. Born, B. Kaletta, W.-U. Nickel, and W. Riiger, Tetrahedron Lett., 1983,24,4821. 28 H. 0. House, R. J . Outcalt. J. L. Haack. and D. VanDerveer, 1. Org. Chem., 1983,48,1654. 29 M.0. House, J. L. Haack, W. C . McDaniel, and D. VanDerveer, J . Org. Chem., 1983, 48, 1643. 30 P. A. Aristoff, Synth. Commun., 1983,13,145. 25

26


7

Bicyclo[5.1.l]non-l(8)-ene (23) has been synthesized by Ramberg-Backlund reactions using each of the stereoisomericbromosulphones (24) and (25) (Scheme 5 ) . No competing 1,2-dehydrobromination is observed.31Although isolable, the

(24)

(23) Scheme 5

olefin (23) shows the usual high reactivity towards oxygen, acids, and dienes. Another way of constructing bridgehead olefinsis via intramolecular Diels-Alder reactions, but high temperatures are usually required. Shea and Gilman have now shown that, in the presence of stoicheiometric amounts of diethylaluminium chloride, these reactions take place smoothly at room temperature. A particularly impressive example is the reaction shown in Scheme 6 which gives a 70% yield of the bridgehead olefin within 5 minutes.32

0 Scheme 6

Marshall and Flynn have reported that trans-hydroxymethylcycloalkenes [e.g. (26)] of known absolute configuration and high optical purity can be prepared by the Sharpless kinetic resolution procedure. The (+)-(R)-trans-cycloalkene (26) was converted in six steps into (+)-(R)-[lo. 101-betweenanene (27) with better than 90% optical purity (Scheme 7).33 f+

steps

(27) Reagents: i, TiCl,, Li; ii, H2,Pt-C

Scheme 7 K. B. Becker and M. P. Labhart, Hefv.Chim. Acta, 1983,66, 1090. K. J. Shea and J. W. Gilman, Tetrahedron Lett., 1983,24,657. 33 J. A. Marshall and K. E. Flynn, J . Am. Chem. SOC., 1983, 105,3360. 32


8

The low-valent titanocene species generated by reducing [Cp,TiCl2] with sodium naphthalenide is a highly efficient and almost stereospecific catalyst for the isomerization of simple non-functionalized terminal alkenes to (15)2 - a l k e n e ~The . ~ ~transformation is complete within minutes at room temperature and internal olefinic bonds of either configuration are inert under the reaction conditions. Hex-1-ene is rapidly converted into a stereoisomeric mixture of hex2-enes on treatment with a catalytic amount of the stable and commercially available complex [OsHBr(CO)(PPh,),] in toluene at 150°C.35 Partial hydrogenation of acetylenes to olefins is often accomplished using the Lindlar catalyst. A systematic study with nine metal ions has now shown that the chemoselectivity for semihydrogenation, especially for monosubstituted acetylenes, is significantly and reproducibly improved when the catalyst is modified with manganese(I1) Suzuki and his co-workers have described two new systems for the partial reduction of acetylenes to (2)-olefins at room temperature. The first, a catalytic amount of palladium chloride in polyethylene glycol and dichloromethane, allows diphenylacetylene to be hydrogenated to (2)-stilbene at atmospheric pressure , but over-reduction appears to be a problem.37Much better selectivity is achieved with the second system in which NaBH, replaces hydrogen.3sSimple 1,3-dienes can be hydrogenated specifically to olefins at -78 "C using allyl(hydrido)platinum(II) complexes as catalysts.39 Oxiranes are conveniently deoxygenated to give olefins using hydrogen iodide generated in situ from toluene-4-sulphonic acid and sodium iodide in acetonitrile. The transformation is complete within minutes at room t e m p e r a t ~ r e . ~ ~ Vinyl sulphones are reduced to the corresponding olefins in high yield and with retention of configuration on treatment with alkyl Grignard reagents and nickel or palladium catalysts in THF at room temperature (e.g. Scheme 8).41Coupling

99.5'10 (21-isomer Reagents: i, Bu"MgC1, [Pd(acac),], DABCO

Scheme 8

products between the sulphone and Grignard reagent are only formed to a small extent (generally 96 :4) diastereoselectivity . Successive oxidation and base-catalysed p-elimination then furnishes homoallylic alcohols with greater than 90% enantiomeric S. K. Pate1 and I. Paterson, Tetrahedron Lett., 1983,24, 1315. Hiyama, M. Obayashi, and M. Sawahata, Tetrahedron Lett., 1983, 24,4113. 190 T. Hayashi, M. Konishi, and M. Kumada, J. Org. Chem., 1983,48,281. 188

189 T.


53

excess (Scheme 9O).l9l The synthesis of both (R)- and (S)-alcohols is possible using this procedure, since (R,R)-and (S,S)-forms of the acetals are both readily available. Allylic chromium species, complexed with chiral bidentate auxiliaries R

R

H

ii , iii

(134) Reagents: i, CH,=CHCH,SiMe,,

TiCl,, Ti(PrlO),; ii, PCC; iii, KOH

Scheme 90

such as lithium ephedrinate, react with aldehydes to give optically active homoallylic alcohols with modest enantiomeric excesses. 19* The borane (135), which is easily prepared in an optically pure form from (+)-a-pinene, readily condenses with aldehydes at -78°C to provide, after oxidative work-up, optically active secondary homoallylic alcohols with excellent enantiomeric purities (Scheme 91)

I

(135 1

R

Reagents: i, RCHO; ii, NaOH, H,02

Scheme 91

Bulky allylboronates of the type (136) bearing polar heteroatomic substituents at the a-position react with aldehydes to give substituted allylic alcohols with predominantly the (Z)-configuration.194

Y

pii
9 : 11 are easily prepared by conventional Horner reactions with aldehydes and lithiated allyldipheny lphosphine oxide. Block and his co-workers have reported that under basic conditions the products of the free-radical addition of bromomethanesulphonyl bromide to olefins undergo both elimination of hydrogen bromide and Ramberg-Backlund reaction to give 1,3-dienes (e.g. Scheme 105).*19A variety of dienes, including types which Br

(R

= n - C 5H11)

I

Br

99

(€

- isomer

Reagents: i, BrCH,SO,Br, hv; ii, Et,N; iii, KOBu'

Scheme 105

are not readily accessible by other routes, may be prepared from appropriate olefins, often with a high degree of stereocontrol. Scheme 106 illustrates some of the transformations that can be performed. trans-2,5-Disubstituted-3-sulpholenes such as (152) can be prepared by regiospecific and stereoselective dialkylation of 3-sulpholene provided the labile anionic species are generated in the presence of an alkyl iodide so that they are trapped before undergoing ring-opening. The products can be converted either *18

219

J. Ukai, Y. Ikeda, N . Ikeda, and H. Yamamoto, Tetrahedron Lett., 1983,24,4029. E. Block and M. Aslam, J. Am. Chem. Soc., 1983, 105, 6164; E. Block, M. Aslam. V. Eswarakrishnan, and A. Wall, ibid., p. 6165.


61

56%

(3-

Scheme 106

G

into ( E ,E)-dienes by heating with a base in a protic solvent, or into mixtures of the two possible (E,2)-dienes by reductive desulphonylation (e.g. Scheme 107).220 -(CH2)6Me

0

--( CH2)6Me

i,ii,i,L

502

502 (152) (+11'/0

T ( C H 2 ) g M e

\

+

cis-isomer)

r /

(CH2I6Me

Reagents: i, LiN(SiMe,),; ii, Me(CH&I; iii, MeI; iv, K,CO,, EtOH; v, LiAlH,

Scheme 107

Derivatives of vitamin D3 have been prepared using methodology of this kind.221 Scheme 108 illustrates a related synthesis of (E,E)-1,3-dienes in which a high degree of stereocontrol originates from selective alkylation at the less hindered

(153)

(CH2)70H

96 - 3'10 ( Z, E - i so mer

r

liv

1

f--

- so2

Reagents: i, BunLi; ii, I(CH2),0THP; iii, TsOH; iv, 600 "C,

CCI.

50 ms

Scheme 108 220 221

S. Yamada, H. Ohsawa, T. Suzuki, and H. Takayama, Chem. Left., 1983, 1003. S. Yamada, T. Suzuki, H. Takayama, K. Miyamoto, I. Matsunaga. and Y. Nawata, J. Org. Chem., 1983, 48, 3483.

62


face of the Diels-Alder adduct (153).222The product in the example shown, (E,E)-dodeca-8,10-dieno17is a pheromone from the codling moth. If trimethylsilyl chloride 222 or ketones or aldehydes 223 are used as electrophiles in place of alkyl iodides, thermolysis gives l-trimethylsilyl-173-dienes or 2,4-dien1-01s respectively. Scheme 109 shows an example of a novel regiospecific pentannulation sequence .224 In an intermolecular variant of this process, cyclododecanone SOZPh

rn

KOH,

KOH,

a

Scheme 109

reacts with methyl phenyl sulphone and potassium t-butoxide to give (E)3-methylenecyclododecene . Reaction between a$-unsaturated aldehydes or ketones and an organocopper reagent derived from buta-173-dien-2-ylmagnesium chloride is regiospecific with respect to both reactants: only 173-dienes derived from 174-addition are formed.225Both examples shown in Scheme 110 gave isolated yields of greater

Reagents: i

,

y , CuBr.Me,S MgCl

Scheme 110

than 80%. p-Quinones and a,/?-unsaturated aldehydes and ketones undergo pentadienylation without competing Diels-Alder reaction on treatment with penta-2,4-dienyltrimethylstannaneand a Lewis acid (e.g. Scheme 111).226

Reagents: i. , ,

SnMe,, Lewis acid

Scheme 111 222 223 224 22s

226

R. Bloch and J. Abecassis, Tetrahedron Lett., 1983, 24, 1247. R. Bloch, D. Hassan, and X. Mandard, Tetrahedron Lett., 1983,24,4691. C. Fehr, Helv. Chim. Acia, 1983, 66,2519. K. J. Shea and P. Q. Pham, Tetrahedron Lett., 1983,24,1003. Y. Naruta, N. Nagai, Y. Arita, and K. Maruyama, Chem. Lett., 1983, 1683.


63

Corey and Albright have described a new procedure for the homologation of sensitive aldehydes to ( E ,E)-2,4-dienals containing four extra carbon atoms.*17 On treatment with [Mo(CO),] and bis(trimethylsilyl)acetamide, allylic acetates smoothly eliminate the elements of acetic acid to give 1,3-dienes, generally as regio- and stereo-isomeric mixtures where possible. The transformation is most useful where elimination can take place in only one direction (e.g. Scheme 112).228

iii

A

C

0

2

M

e

w

C (

0

2

M

e

f , € ):(f,Z1 = 5: 1

Reagents: i, 4-C1C,H,S(0)CH,COzMe, piperidine; ii, Ac,O, DMAP; iii, [Mo(CO),], BSA

Scheme 112

The reagent (154), prepared by addition of diethyl trimethylsilyl phosphite to acrylonitrile undergoes successive Peterson and Wittig reactions with aidehydes or ketones in one pot to give 2-cyanobuta-1,3-dienes (e.g. Scheme 113).l19

2 isomers, 94:6

(154) Reagents: i, 2LDA; ii, 2Me,CHCHO

Scheme 113

Substituted methoxyallenes (155), which are easily prepared from methoxyallene itself isomerize to the corresponding methoxy-l,3-dienes (156) on treatment with pyridinium tol~ene-4-sulphonate.~~~ OMe

+ 111 R

&-, R

(155)

(156) > 8 3 % ( €)-isomer

Reagents: i, Bu"Li; ii, RCH,X (X=Br or I); iii, TsOH.py

E. J. Corey and J. 0. Albright, J . Org. Chem., 1983,48,2114. B. M. Trost, M. Lautens, and B. Peterson, Tetrahedron Lett., 1983,24,4525. 229 M. Nakano and Y . Okamoto, Synthesis, 1983,917. 230 A. Kucerovy, K. Neuenschwander, and S. M. Weinreb, Synth. Commun., 1983,13, 875.

227

228

64


A variety of 1,3-dienes which are substituted with halogens and sulphur or selenium can be prepared regiospecifically from 1,4-dichlorobut-2-yne by addition-elimination sequences such as those shown in Scheme 114.231 SPh

1

I

cL

\

SPh

Cl Reagents: i, PhSC1; ii, Al/Hg; iii, DBU

Scheme 114

Buta-l,3-diene-l,4-bis-sulphonium 232 and -phosphonium 233 salts, as well as the stable and crystalline 1,3-dienes (157),234have been prepared for the first time.

(157) n = O , l , o r 2 ; R = C H z P h or But

Convenient syntheses of the alkylidenebutenolides (158) and (159) ,235 and new ~ ~ a,P-unsaturated ~ ketene approaches to a variety of 1,3-dienyl ~ u l p h i d e sand diphenylthioacetals 237 have been reported. A (Z,Z)-1,3-diene has been purified for the first time by urea inclusion.238 R

Do

(158) R = M e or Ph

(159) n = 3,4,5,or9

A. J. Bridges and J. W. Fischer, Tetrahedron Lett., 1983, 24, 445. P. J. Duggan. J. L. Leng, D. R. Marshall, and C. J. M. Stirling,J. Chem. Sac., Perkin Trans.1,1983, 933. 233 H.-J. Cristau, G. Duc, and H. Christol, Synthesis, 1983, 374. 234 L. E. Overman, C. B. Petty, T. Ban, and G. T. Huang, J . Am. Chem. SOC., 1983,105,6335. 235 R. W. Saalfrank, P. Schierling, and P. Schatzlein, Chem. Ber., 1983,116, 1463; R. W. Saalfrank, P. Schierling, and W. Hafner, ibid., p. 3482. 236 K. S. Kyler and D. S. Watt, J . Am. Chem. Soc., 1983, 105, 619; T. Nishio, T. Tokunaga, and Y. Omote, Chem. Ind. (London), 1983, 243; R. H. Everhardus, R. Grafing, and L. Brandsma, Synthesis, 1983, 623; M. Reglier, 0. Ruel, R. Lome, and S. A. Julia, ibid., p. 624. 237 0. G . Kulinkovich, I. G. Tishchenko, N. A . Roslik, and I. V. Reznikov, Synthesis, 1983, 383. 238 C. E. Bishop and G. W. Morrow, J . Org. Chem., 1983,48, 657.

231 232


65

4 Non-conjugated Dienes

Shea and his co-workers have reported that bridgehead divinylbicycloalkanes undergo spontaneous [3,3]-sigmatropic rearrangement at or below room temperature to give bridgehead dienes such as (160) with (E,E)-geometry with respect to the larger ring.239Another research team has independently prepared the diene (160) via a closely related pathway.240

L

(160) Reagent: i, 2Ph3P= CH,

Negishi and Miller have shown that 1-trimethylsilyloct-1-yne undergoes ;egiospecific allylzincation on treatment with allylzinc bromide. The products, after iodinolysis, are two stereoisomeric 1,4-dienes which can be converted into substituted cyclopentenones (Scheme 115).241 Allylzincation of internal SiMe3 1

Reagents: i, CH,=CHCH2ZnBr; ii, I,; iii, disiamylborane; iv, NaOH, H,Oz; v, CrO,; vi, MeLi; vii, 2Bu'Li; viii, CO, Et,N, 1 equiv. [Pd(PPh,),]

Scheme 115

acetylenes is more difficult, but takes place on treatment with diallylzinc in the presence of a zirconium catalyst. When allylic alkoxides are heated with the reagent (161)) successive displacement of fluoride ion, sigmatropic rearrangement, and dehydrosulphenylation take place to give good yields of 2-methoxycarbonyl-l,6dienes contaminated K. J. Shea, A. C. Greeley, S. Nguyen, P. D. Beauchamp, and S. Wise, Tetrahedron Lett., 1983,24, 4173. 240 P. Warner, I-Shan Chu, and W. Boulanger, Tetrahedron Lett., 1983, 24, 4165. 241 E. Negishi and J. A . Miller, J . Am. Chem. SOC., 1983, 105, 6761.

239

66


with less than 12% of the isomeric conjugated dienes (e.g. Scheme 116).242 The reagent (161) is prepared in five steps from 1,l,l-trifluoroacetone.

d-"" '6 KH

Me0

9: 1

SOPh

(1611

Scheme 116

Despite earlier suggestions to the contrary, neat mixtures of alk-2-ynol chlorides and cyclopentadiene undergo clean Diels-Alder cycloaddition at 0 "Cto give, after methanolysis, methyl norbornadiene-2-carboxylates (78434%) (Scheme 117).243

C02Me

R = M e , Ph, or But Reagents: i, Cyclopentadiene; ii, MeOH, NaHCO,

Scheme 117

Pentadienylboranes, generated in situ from pentadienyl anions, react at the 3-position with aldehydes and ketones to give non-conjugated products exclusively (Scheme 118).244

OH

Reagents: i, BunLi; ii, BunLi, KOBu'; iii, Ph,BBr; iv, R'R2CO; v, NaOH

Scheme 118 J.-M. Vatele, Tetrahedron Lett., 1983, 24, 1239. E. Bauml and H. Mayr, J. Org. Chem., 1983,48,2600. 244 M. G . Hutchings, W. E. Paget, and K. Smith, J. Chem. Res. (S), 1983, 31. 242 243

67


Cutting and Parsons have reported five examples of a new silicon-mediated rearrangement of epoxides (Scheme 119).245Catalysis by Lewis acids other than tin(I1) chloride fails. R' SnClb

R2 *OH

R2

26

-L 5 %

R1,R2 = H or alkyl

Scheme 119

Allylic chlorides and bromides undergo reductive coupling at room temperature on treatment with stoicheiometric amounts of [CoCl(PPh,),] .246 Although mixtures of regioisomeric 1,5-dienes are formed, the geometry of the allylic double bond is preserved during coupling (e.g. Scheme 120).

R

R

R

63 '10

R=

L

.

16 '10

+

0

9O I O Reagent: i, [CoCl(PPh,),]

Scheme 120

On treatment with TiC14, vinylketene methyl silyl acetals undergo homocoupling to give high yields of 1,5-dienes, probably via bis-allylic dititanium complexes.247With favourable substitution patterns, the product of y, y-coupling, which always predominates, is formed almost exclusively (e.g. Scheme 121). OSiMe3

I

+

M e 0 2 C A 7 p C02Me

96:4 Scheme 121 I. Cutting and P. J. Parsons, J . Chem. Soc., Chem. Commun., 1983, 1435. D. Momose, K. Iguchi. T. Sugiyama, and Y. Yamada, Tetrahedron Lett., 1983, 24, 921. 247 K. Hirai and 1. Ojima, Tetrahedron Lett., 1983, 24, 785. 24s

246

68


Overman and Renaldo have shown that 2-alkyl-1,S-dienes with an electronwithdrawing group at the 3-position (162) reliably undergo Cope rearrangement (64-94% yields) at only 40°C under the influence of palladium(iI) catalysts.248By contrast, under similar reaction conditions, 5-alkyl-l,5-dienes with an electronwithdrawing group at the 3-position (163) undergo a novel rearrangement to give moderate yields (21-53%) of cyclohexenes ( 164).249

Ee R

c a t . [ Pd CI 2( MeCN 12 1

(162)

R

R (163) R = a l k y L ; E = C 0 2 R , C O R , o r CN

(164)

The functionalized dienes (165) dimerize regio- and stereo-specifically to give cyclo-octadienes (166) in the presence of nickel(0) catalysts.*jO [ N i ( a c a c 1 2 1 . EtZAIOEt,PPh3

-

-X X = C02Me or OSiMe3

1

mx I

or “i(cod121

(165)

(166)

[2,3 :5,6]Dicyclobuta-p-benzoquinone(167), a crystalline solid, is the most strained annelated p-benzoquinone to have been made so far.251(E,E)-Cycloundeca-l,5-diene (168), a distillable liquid, has been prepared for the first time,252

(167)

(168)

and evidence for the transient existence of ( E ,E)-cyclonona-l,5-diene has been presented. 2s3 L. E. Overman and A. F. Renaldo, Tetrahedron Lett., 1983,24,3757. L. E. Overman and A. F. Renaldo, Tetrahedron Lett., 1983, 24,2235. 250 P. Brun, A. Tenaglia, and B. Waegell, Tetrahedron Lett., 1983,24, 385. 251 Y . Kanao, M. Iyoda, and M. Oda, Tetrahedron Lett., 1983, 24, 1727. 252 G. Haufe, Synthesis, 1983, 235. 253 A. C . Connell and G. H. Whitham, J . Chem. SOC., Perkin Trans. I, 1983, 995.

248

249


69

5 Allenic Hydrocarbons Buchwald and Grubbs have described an experimentally simple approach to di-, tri-, and tetra-substituted allenes.254In the example shown in Scheme 122, treatment of the titanacyclobutane (169) with 1,l-diphenylallene (170) leads to the metallacycle (17 1) in quantitative yield; subsequent reaction with cyclopentanone affords the allene (172).

32 . ..

-L

[&m3 N

Li

Me

+

1'. Reagents: i, BunLi; ii, BR3; iii, MeI; iv, NaOH, H202

Scheme 11

substituted boranes were not investigated as an extension of the method to nonsymmetrical ketones. Another approach utilizing ate-complexes, this time derived from 172-dimethoxyethenyl-lithium , generates aldehydes after a Lewis acid-induced rearrangement (Scheme 12).74 Investigations of the conveniently hOyOMe

iii

R ' $ M e

Br

R 3-8

iv

R L

H

O

R2B Li

+

Reagents: i, BunLi; ii, BR,; iii, BF3.Et20;iv, H30+

Scheme 12

stored and handled dimesitylborane have shown this to be a highly regioselective reagent for the hydroboration of alkynes, apparently responding to steric effects.75Alkenes react very slowly with this borane, again offering increased chemoselectivity . Phosphorus ylides have been used for the preparation of selected phosphine-stabilized mono-organoboranes, useful reagents in the synthesis of aldehydes and ketones (Scheme 13).76 The aryl borinate derivative employed offers a reasonable compromise between high reactivity and low tendency for disproportionation. Migration of the less highly substituted alkyl group in a-diazo-/3-hydroxy-esters has been reported with a variety of metal catalysts, including Wilkinson's catalyst, and palladium and cobalt chlorides , giving a regioselective homologation of ketones under neutral conditions [equation (5)].77 The reaction was developed for application to a regioselective ring expansion. An asymmetric, stereospecific pinacol rearrangement promoted at low temperatures by triethylaluminium offers a route to a-vinyl or a-aryl ketones with high optical purity.78The starting J. Koshino, T. Sugawara, T. Yogo, and A. Suzuki, Synth. Commun., 1983,13,1149. A . Pelter, S. Singaram, and H. Brown, Tetrahedron Lett., 1983,24, 1433. 76 H. J. Bestmann and T. Roder, Angew. Chem., Int. Ed. Engl., 1983,22,782. 77 K. Nagao, M. Chiba, and S.-W. Kim, Synthesis, 1983,197. 78 K. Suzuki, E. Katayama, and G.-I. Tsuchihashi, Tetrahedron Lett., 1983, 24,4997. 74

75

Aldehydes and Ketones

-

95

i.ii

R’APPh3

RlnBH2.PPh3

liv R2

R2

+

+

MePPhg

I

-

Reagents: i, BH,.THF; ii, A; iii, 2,4,6-Me3C&OH; iv, R2CH=CR3R4, MeI; v, C1,CHOMe; vi, LiOCEt,; vii, NaOH, H 2 0 2

Scheme 13

diol derivative is however required to be chiral, the optical -activitybeing maintained in the transformation [equation (6)]. The conversion of epoxides into ketones has been achieved under electrolytic conditions for the generation of the acid catalyst req~ired.’~ Lithium, sodium, and magnesium perchlorates were the most efficient electrolytes found.

~e

3Et3Al

- CH2Cl2

OH

MeOzSO 79

H

-78

O C

(6)

H

k2

K. Uneyama, A. Isimura, K. Fujii, and S. Torii, Tetrahedron Lett., 1983, 24,2857.

96


Further developments in the regioselectivity of dipolar additions of nitrile oxides to olefins have mapped out the preparative applications of isoxazolines for the diastereospecific synthesis of 2-substituted aldols.80,81 Raney-nickel and boric acid are recommended components in the reduction of the heterocycle to the aldol.*l Photolysis of the heterocycle and pentacarbonyliron in methanol fragments the ring to give two carbonyl products, as if from a retro-aldol reaction (Scheme 14).82 A substituent is necessary at the 5-position. The reaction

Reagents: i, hv, MeOH, [Fe(CO),]

Scheme 14

highlights an interesting synthetic relationship between the products and likely starting materials for the formation of the heterocycle, and extends the utility of C-alkylations of isoxazolidines. Aldehydic morpholino-enamines have been prepared by a nett formylation of substituted acetic acids by 4-(methoxymethylene)morpholinium methyl sulphate [equation (7)] .83 The reaction was also used to prepare l-dimethylamino2 LiNPr'Z

+ OMe R2N4 (7)

NR2

= NMe2,

n

1-alkenes. Trimethylsilyl trifluoromethylsulphonate is a convenient reagent for the preparation of N-silylated enamines from a aminonitrile derivatives [equation (8)i -84 S. F. Martin and B. Dupre, Tetrahedron Lett., 1983,24, 1337. D. P. Curran, J . Am. Chem. SOC., 1983,105,5826. s2 M. Nitta and T. Kobayashi, Chem. Lett., 1983, 51. 83 R. Knorr, P. Low, and P. Hassel, Synthesis, 1983,785. g4 H. Ahlbrecht and E.-0. Duber, Synthesis, 1983,56.

97

Aldehydes and Ketones R’HN

-

CN

R’ NSiMe3

Me+ i 0 SO2 C F3

R

2

3

+

R2’$

Et3N

R3

Me3SiCN

(81

R3

Improved conditions for the reductive conversion of nitro-alkenes into ketones have been disclosed (Scheme 15), using electrochemical reduction at a lead cathode in solutions containing perchloric Work-up with either aqueous

0 Reagents: i, R2CH2N02;ii, CH2Cl,, dioxan, HC104, (Pb) 4e; iii, NH,OH.HCl, AcONa; iv, H,O, HCHO; v, MeOH, H,SO,, (Pt) 4e; vi, Raney Ni, EtOH, H,O, NaH,PO,; vii, hydrolysis

Scheme 15

formaldehyde or hydroxylamine gives the ketone or oxime, respectively. Reduction has also been reported on electrolysis over a platinum cathode in methanolic sulphuric acid, giving the oxime,86 and on treatment with Raney-nickel and sodium hypophosphite at pH 5 , giving the ketone.*’

R’

R3

-

OMe iii ,i\

AcO

R2

R1

OMe R2

0 Reagents: i, Anode, MeOH, AcOH, Et,N+ p-MeC,H,SO,-; ii, NaBH,, MeOH; iii,p-MeOC,H,SO,Cl; iv, Me,CO, H 2 0

Scheme 16 S. Torii, H. Tanaka, and T. Katoh, Chem. Lett., 1983,607. T. Shono, H. Hamaguchi, H. Mikami, H. Nogusa, and S. Kashimura, 1. Org. Chern., 1983,48,2103. 87 D. Monti, P. Gramatica, G. Speranza, and P. Manitto, Tetrahedron Lett., 1983,24, 417.

86

98


Methods for 1,Ztranspositions of the carbonyl group have been reviewed in an article covering early terpenoid and steroid work, but mainly more recent methods based on sulphur, on boron, and on silicon.88A method for 1,4-carbonyl transposition has been reported using anodic y-methoxylation of dienol acetates as the key step (Scheme 16).89 Cyclic Ketones.-The Nazarov cyclization of divinyl ketones and their precursors to give cyclopentenones has been reviewed.90Iron(m) chloride has been found to induce this cyclization for /3-silyl-substituteddivinyl ketones with control over the regiochemistry of the double bond in the product.91Steric factors associated with remote substituents can control the stereochemical sense of cyclization, and the necessity for stoicheiometric amounts of water to be present in the reaction medium was d e m ~ n s t r a t e dLewis . ~ ~ acids mediate the intramolecular acylation of vinylsilanes to form cycloalkanones, an approach in which the precise product obtained depends markedly on the substitution pattern on the double bond.93,94 The synthesis of ketones via intramolecular cyclization of a sulphur-stabilized carbanion into an amide on an o-aminothiophenol template has been extended to prepare medium (8-12 membered) ring ketones (Scheme 17).95Esters may be

1

ii.iii

iv

0-

\

Reagents: i , Br(CH,),+,COCI; ii, ButOK, high dilution; iii, NaIO,; iv, LiNPr',; v, Al/Hg

Scheme 17 V. V. Kane, V. Singh, A. Martin, and D . L. Doyle, Tetrahedron, 1983, 39, 345. T. Shono and S. Kashimura, J . Org. Chem., 1983,48,1939. C. Santelli-Rouvier and M. Santelli, Synthesis, 1983, 429. 91 T. K. Jones and S. E . Denmark, Helv. Chim. Acta, 1983,66,2377. 92 T . K. Jones and S. E . Denmark, Helv. Chim. Acta, 1983,66,2397. 93 K. Mikami, N . Kishi, and T. Nakai, Tetrahedron Lett., 1983,24,795. 94 E . Nakamura, K. Fukuzaki, and I. Kuwajima, J . Chem. SOC.,Chem. Commun., 1983,499. 95 Y . Ohtsuka and T. Oishi, Chem. Pharm. Bull., 1983,31, 454. 88

89


99

substrates for acyclic ketone synthesis by this method if sulphones or sulphoxides stabilize the anion.96 Reduction of titanium(Ir1) chloride by lithium aluminium hydride forms a reagent which reductively couples keto-esters to form cycl~alkanones.~~ Small, medium, and large rings can be formed, and the method has been utilized to close the nine-membered ring in a synthesis of isocaryophyllene [equation (9)].98 The

cyclization substrate was that designed for a synthesis of caryophyllene, but during the course of the ring formation double-bond inversion occurred. [3 4Phenylt hio) buta- 1,3-dienyl]triphenylphosphonium chloride has been developed as a reagent for the annulation of P-keto-esters to cyclohexenones (Scheme 18).99The method complements the Robinson annulation in that the sequences give relatively transposed products.

2c1-

Reagents: i, K,CO,; ii, base, DMF; iii, TiCl,, AcOH; iv, base

Scheme 18

Hindered enones take part in classical Robinson annulation sequences with difficulty. However, the reaction may be induced at very high pressure.lm Reaction of @unsaturated aldehydes, including cycloalkene carboxaldehydes, with (3-ethoxycarbonyl-2-oxopropylidene)triphenylphosphorane affords cyclohexenones in moderate yield.lo1 The highly regioselective rhodium-catalysed insertion of diazo-P-keto-esters to form 3-alkylcyclopentanones has been extended to provide an enantioselective Y. Ohtsuka and T. Oishi, Chem. Pharm. Bull., 1983,31,443. J. E. McMurry and D. D. Miller, J . Am. Chem. Soc., 1983, 105, 1660. 98 J. E. McMurry and D . D . Miller, Tetrahedron Lett., 1983, 24, 1885. 99 R. J. Pariza and P. L. Fuchs, J . Org. Chem., 1983,48, 2304. loo W. G . Dauben and R. A. Bunce, J . Org. Chem., 1983,48, 4642. lol K. M. Pietrusiewicz, J . Monkiewicz, and R. Bodalski, J . Org. Chem., 1983,48,788. 97

100


cyclization by the expedient of using esters of chiral alcohols derived from camphor [equation (lo)]. lo2 Optical resolution of 3-methylcycloalkanones has

R

been reported using chiral 176-bis-(o-halogenylphenyl)-1 ,6-diphenylhexa-2,4diyne-l,6-diols (4) as complexing agents. lo3

Synthetic methods for the construction of cyclopentanone derivatives continue to benefit from improved carbonylation procedures. Stereoselectivity studies of intramolecular alkyne-alkene-octacarbonyldicobalt cyclizations have appeared , the results aiding the preparation of intermediates for the synthesis of dl-coriolin [equation (ll)].Io4 Alkyne hexacarbonyldicobalt complexes interact with 2,5-

dihydrofurans to give functionalized cyclopentenone derivatives directly, although the range of substituents allowable remains to be determined [equation (12)1.105

lo*

lo3 lo4 Io5

D. F. Taber and K. Raman, J . Am. Chem. SOC., 1983,-105,5935, F. Toda, K. Tanaka, T. Omata, K. Nakamura, and T. Oshima, J . Am. Chem. SOC., 1983,105,5151. C. Exon and P. Magnus, J . Am. Chem. SOC., 1983,105,2477. D. C. Biilington, Tetrahedron Lett., 1983, 24, 2905.


101

Allylzinc reagents have been found to be among the few species known so far to be capable of carbometallation of terminal alkynes and, with greater regiochemical control, silylacetylenes. The vinyl iodides formed on work-up with iodine can undergo either a stoicheiometric palladium-mediated cyclization with carbon monoxide or base-induced cyclization of a derived terminal carboxylic acid to give cyclopentanoid products (Scheme 19). Investigations of nucleophilic additions of

-

R

SiMe3

SiMe3

i,ii

R-E-

SiMe3

iv - v i

qH-

R

SiMe3

R

SiMe,

vii ,viii

8

0

Reagents: i, H,C=CHCH,ZnBr; ii, I,; iii, CO, Et,N, [Pd(PPh,),]; iv, Sia,BH; v, H,O,, NaOH; vi, Cr0,; vii, MeLi; viii, Bu'Li

Scheme 19

carbanions to 1,3-diene tricarbonyliron complexes indicate the possibility of a general synthesis of 3-substituted cyclopentanones via cyclization of the acyliron intermediates (Scheme 20) .lo7

$

CHO

-

i . i i ( $

CN

\ Fe(CO13

F -

0

i,ii

Fe(C013

CN

Reagents: i, Me,C(CN)Li; ii, H+

Scheme 20

Solvolysis of homoallylic brosylates with hydrogen peroxide offers a new route to medium-ring ketones via a two-carbon ring expansion [equation (13)].'08

OH E.-I. Negishi and J. A. Miller, J . Am. Chem. SOC., 1983, 105, 6761. M. F. Semmelhack, J. W. Herndon, and J. P. Springer, 1.Am. Chem. SOC., 1983, 105,2497 lO8 R. C. Ronald and T. S. Lillie, J . Am. Chem. Soc., 1983,105, 5709. Io7


102

Macrocyclic ketones have been obtained from a three-carbon ring expansion of bromo-lactones of form ( 5 ) or the derived sulphones (Scheme 21).lo9The reaction

0 I

C

a R

\

OH

iv , ii

/i

Reagents: i, HBr, hv, petrol; ii, MeCO,H, BF,.Et,O; iii, Li, BrCH,CH,Br; iv, PhSH, AIBN; v, LiNPr',; vi, Al/Hg

Scheme 21

of related sulphonyl ketones affords penta-annulated products, which are also intermediates to large-ring ketones, e.g. muscone.l10 2 Synthesis of Functionalized Aldehydes and Ketones

Unsaturated Aldehydes and Ketones.-Dehydrogenation of aldehydes to the a$unsaturated derivative may be carried out using silver trifluoromethanesulphonate and a tertiary amine base, preferably N-methylmorpholine, catalysed by [PdCl,(PhCN),] .ll1 The method is applicable to ketones if stannous trifluoromethanesulphonate and N-ethylpiperidine are used. Direct dehydrogenation of 2-alkylcyclopentanones with cupric bromide is of interest in the preparation of prostanoid intermediates.ll* Rhodium trichloride catalyses the rearrangement of 2-methylenecyclopentanone to the endocyclic isomer.113 Oxidation of aldehyde trimethylsilyl enol ethers with lead(1v) acetate gives the enal when the starting material bears two /?-carbon sub~tituents.~'~ With other substitution patterns, or in the presence of potassium acetate and acetic acid, the product is the a-acetoxy-derivative. Ketone enolates 115 and their silyl enol C. Fehr, Helv. Chim. Acta, 1983,66, 2512. C. Fehr, Helv. Chim.Acta, 1983, 66,2519. l l 1 T. Mukaiyama, M. Ohshima, and T. Nakatsuka, Chem. Lett., 1983,1207. 112 D. D. Miller, K. B. Moorthy, and A. Hamada, Tetrahedron Lett., 1983,24,555. 113 B. W. Disanayaka and A. C . Weedon, Synthesis, 1983,952. 114 G. M. Rubottom, R. Marrero, and J. M. Gruber, Tetrahedron, 1983,39,861. I. Shimizu, I. Minami, and J. Tsuji, Tefrahedron Lett., 1983,24, 1797.

103


ethers 116 are dehydrogenated to enones via palladium-catalysed decomposition of their allyl enol carbonates. In the presence of tributyltin methoxide, the reaction may be extended to enol acetates [equation (14)].117 OAc

0

+

MeOSnBu3

4-

c02

+

(14)

AcOMe

Photolytically generated singlet oxygen has been reported as a reagent for the oxidation of a variety of simple cyclic olefins to the corresponding enones.l18The method was also shown to be applicable to acyclic olefins, and could be carried out on the mole scale. The activation of iodosobenzene with boron trifluoride etherate provides a reagent combination useful for the oxidation of 2-substituted allyl silanes to 2-(methy1ene)aldehydes [equation (191.119 PhI-0

R

BF3.Et20 -dioxan

(151

R H

The addition of alkenyl copper reagents and organocuprates to acyl halides to form enones is catalysed by palladium(0) complexes.120The catalyst appears to ,C02C

4 i ,ii ,i ,iii

0

H 2 Ph

ivl

1'

0

Reagents: i, KOH; ii, ButPh,SiC1, imidazole; iii, (COCI),; iv, Bu,SnH, AIBN; v, CO, cat. [BzClPdIIP W 2 1

Scheme 22 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Left., 1983, 24, 5635. '1 J. Tsuji, I. Minami, and I. Shimizu, Tetruhedron Lett., 1983, 24, 5639. 11* E. D. Mihelich and D. J. Eickhoff, J . Org. Chem., 1983,48,4135. M. Ochiai, E. Fujita, M. Arimoto, and H. Yamaguchi, Tetrahedron Left., 1983, 24, 777. 120 N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett.. 1983, 24, 5081. lI6

104


reduce significantly further reactions of the product enones. Stereo-definition in the copper reagent is retained. A similar coupling occurs between an acyl halide and a tin derivative of benzyl acrylate and has been used to prepare precursors to the macrolide antibiotic pyrenophorin (Scheme 22).I2l Dithioacetals have been used as the equivalent of an alkenyl anion in a connective approach to the synthesis of enones (Scheme 23).12*In conjunction with alkyl iodides, a zinccopper couple promotes the acylation of alkenes by acid chlorides, in an aliphatic Friedel-Crafts-type reaction. 123

- '1 i.ii

PhS-SPh

PhS

SPh

OH

.

i iii

PhS

SPh

liv SPh Reagents: i, BunLi; ii, RICH,Br; iii, R2CHO; iv, p-MeC,H,SO,H; v, NaIO,

Scheme 23

Conditions for the use of 3-(dimethy1amino)acrolein derivatives for vinylogous Vilsmeier formylations of aromatic substrates have been determined. 124 Michael addition of organolithium reagents to enamino-ketones results in the formation of enones in improved yield when the reaction is carried out in hydrocarbon solvents.125Reduced basicity of the lithium reagent is a major factor controlling the success of this route to enones. Factors influencing stereoselectivity in the conjugate addition-elimination reaction of cuprates withp-alkylthioenones include the reaction temperature and choice of ethereal solvent.126Reaction of (E)-substrates occurs with predominant retention of configuration in tetrahydrofuran solvent systems, whereas under diethyl ethereal conditions the stereochemistry is reversed. The nitro-group controls regiochemistry in a sequence for the preparation of a-methylene-ketones via a hydroxymethylation under weakly basic conditions (Scheme 24). 127 In condensations of a-silylketimines with carbonyl compounds to form enones, silicon controls both the site of deprotonation of the imine and the stereochemisJ. W. Labadie and J. K. Stille, Tetrahedron Lett., 1983, 24,4283. J. Durman, J. Elliott, A . B. McElroy, and S . Warren, Tetrahedron Lett., 1983, 24, 3927. Iz3 T. Shono, I. Nishiguchi, M. Sasaki, H. Ikeda, and M. Kurita, J . Org. Chem., 1983,48,2503. F.-W. Ullrich and E . Breitmaier, Synthesis, 1983, 641. 12s T. Mukaiyama and T. Ohsumi, Chem. Lett., 1983,875. 126 R. K. Dieter and L. A . Silks, J. Org. Chem., 1983, 48,2786. lZ7 N. Ono, H. Miyake, M. Fujii, and A, Kaji, Tetrahedron Lett., 1983, 24, 3477.

12*

105


0

0

liii

Reagents: i, HCHO, cat. PPh,, PriOH; ii, Ac,O, py; iii, Bu,SnH, AIBN; iv, DBU

Scheme 24

try of the elimination step [equation (16)]. 128 The reaction gives substantial amounts of the less readily available (2)-isomer of the enone, and has been applied in the synthesis of retinal analogues. Improved conditions for the pre-

R2 Me35

0 (16)

I?'*

R

R

paration of unsaturated ketones by Horner-Wittig reactions of diethyl 2-0x0alkanephosphonates with aldehydes have been developed, using highly concentrated aqueous solutions of potassium carbonate in the absence of an organic solvent. 129 In contrast to esters, orthoesters react with alkynylborates in the presence of titanium(1v) chloride, giving, after the usual alkaline peroxide oxidation, a,/?unsaturated ketones [equation (17)].130 The result of nucleophilic addition to the

allenyl thioacetal S-oxides (6) depends on the reagent employed (Scheme 25) .131 The control offered allows considerable scope for the preparation of a wide range of enone derivatives. A. A. Croteau and J. Termini, Tetrahedron Lett., 1983, 24,2481. J. Villieras and M. Rambaud, Synthesis, 1983, 300. 130 S. Hara, H. Dojo, and A. Suzuki, Chem. Lett., 1983, 285. 131 I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983, 1209. 12*

129


106

i.ii

H

O

R2

A

\\\

0

II kc=(,,

R'

R2

... 111

~

R'

SPh

H

(6)

R'

vi X = OEt or SPh

R2

CHO

SPh

SPh

OH

SPh Reagents: i, 2Bu"Li; ii, 2PhSCl; iii, MeLi; iv, Me,CuLi; v, NaX; vi, HgCl,, H,O, MeCN

Scheme 25

A new unsaturated lithium reagent , prepared from (a-ethoxybutenyl)tributyltin, shows promise for the preparation of propenyl ketones (Scheme 26).132Zinc salts of enol ether anions couple with alkenyl (and aryl) halides when

iii

OH Reagents: i, BunLi; ii, R1K2CO;iii, H,O+

Scheme 26

catalysed by a palladium(0) species, forming enol ether derivatives of enones (Scheme 27).133Allenyl ethers react under similar conditions, to achieve an acryloylation of an alkenyl halide. Polyenic enol ethers of enals have been formed iv. ii, iii

1

Reagents: i, Bu'Li; ii, ZnC1,; iii, PdO, PPh3, R1R2C= CHI; iv, BunLi; v, H 3 0 +

Scheme 27 132 133

J.-P. Quintard, B. Elissondo, and M. Pereyre, J. Org. Chem., 1983,48, 1559. C. E. Russell and L. S. Hegedus, J . Am. Chem. Soc., 1983,105, 943.


107

by homologation of enals with (alkoxymethy1)phosphonate reagents.134Predominant (E)-stereoselectivity in the newly formed double bond was noted. l-tButylthio-3-methoxy-1-alkenes show intriguing potential as reagents for the preparation of unsaturated carbonyl compounds. The site of deprotonation of the (2)-isomer is highly base-dependent. n-Butyl-lithium in conjunction with potassium t-butoxide metallates at the 1-position, whereas the 2-lithio-derivative is the product of deprotonation by s-b~tyl-lithium.'~~ In contrast, the (E)-isomer forms the allylic anion.136All these anions have complementary properties in strategies for the design of syntheses of enones (Scheme 28). 0 R1+H

R' MQsBu' Me0 R'

R2

SBu'

AJ R'

Me0

.

iii iv

Me0

I

SBu'

I

Reagents: i, KOBut, Bu"Li; ii, BusLi; ii, LiNPr',; iv, RI; v, hydrolysis

Scheme 28

A deconjugated enone is the product from acylation of the zirconacene complex of isoprene with The reaction is highly regioselective for the 1-position of the diene, and works for a,@-unsaturated esters, giving the a,@,@', y' -unsaturated ketone [equation (18)]. Deconjugation occurs on debromination of a-bromo-a,@-unsaturated cyclic ketones with diethyl phosphte. 138

Tributyltin enolates are alkylated by 1-bromo-1-alkenes with retention of configuration in the presence of palladium chloride complexes [equation (19)].139 Y . Vo-Quang, D. Carniato, L. Vo-Quang, and F . Le Goffic,J. Chem. SOC., Chem. Commun., 1983, 1505. 13s C. Bibang Bi Ekogha, 0. Ruel, and S . A. Julia, Tetrahedron Lett., 1983,24,4825. 136 0 .Ruel, C. Bibang Bi Ekogha, and S . A. Julia, Tetrahedron Lett., 1983,24,4829. 137 M. Akita, H. Yasuda, and A. Nakamura, Chem. Lett., 1983, 217. 138 T. Hirao, T. Masunaga, K.-I. Hayashi, Y. Ohshiro, and T. Agawa, TetrahedronLett., 1983,24,399. 139 M. Kosugi, I. Hagiwara, and T. Migita, Chem. Lett., 1983, 839.

lM


108

The same metals appear in a method for the coupling of allylic halides, stannanes, and carbon monoxide [equation (20)] a-Alkenylated ketones also result from a reductive rearrangement of alkynyl hal0h~drins.I~~ Unfortunately, under the

reaction conditions further reduction occurs, necessitating reoxidation to obtain the ketone (Scheme 29). The stereochemistry required by the rearrangement process is that observed in the major product from addition of alkynyl carbanions

L

iii

0li1 R

Reagents: i, LiAlH, or DIBAL; ii, H+; iii, CrO,, py

Scheme 29

to a-halogeno-ketones. Base-induced fragmentation of 3-sulphonylcyclobutanols can be induced to afford p-methylene-ketones if potassium hydride is employed as base [equation (21)].142

OH

141

14*

F. K. Sheffy and J. K . Stille, J . Am. Chem. Soc., 1983, 105, 7173. P. A. Wender, D. A. Holt, and S. M. Sieburth, J. Am. Chem. SOC.,1983, 105, 3348. T. Takeda, K. Ando, and T. Fujiwara, Chem. Left., 1983, 1285.


109

Alkynyl boranes, prepared from alkynyl carbanions and boron trifluoride etherate, react with tertiary amides at low temperatures in THF to give acetylenic ketones. 143 Boron tribromide catalysis makes the hydroboration of 1-bromoalkynes by thexylchloroborane proceed at a synthetically useful rate (Scheme 30).14 The product is the equivalent of an acylating agent for alkynyl anions. CL

l+,B(

+

-

ii

i

.SMe2

H

Br-e-R’

Br

R’

OPri

hR’

Br

I

iii

OPr’

Reagents: i, cat. BBr,; ii, NaOPr’; iii, LiC=CR2; iv, NaOH, H202

Scheme 30

Thiolesters acylate trimethylsilylacetylenes rapidly in the presence of silver tetrafluoroborate to give the corresponding acetylenic ketone. 145 Stereospecificitesin the synthesis of chiral ynones from optically active terminal alkynes and acid chlorides via Lewis acid- and palladium-catalysed acylations have been assessed.146 a-Substituted Aldehydes and Ketones.-The acylation-rearrangement of nitrones offers a new method for the a-oxygenation of aldehydes and ketones (Scheme 31).147The m-chloroperbenzoic acid oxidation of silyl enol ethers is the key to recent syntheses of the terpene lactones actinidiolide and aeginetolide (7) [equation (22)].148 Boron trifluoride etherate-catalysed rearrangement of ate complexes formed from 1,2-dimethoxyethenyl-lithium and trialkylboranes leads to borane intermediates which may be oxidized to methoxymethyl ketones (Scheme 32; cf. Scheme 12).149 M. Yamaguchi, T. Waseda, and I. Hirao, Chem. Lett., 1983,35. H. C. Brown, N. G . Bhat, and D. Basavaiah, Synthesis, 1983,885. 145 Y. Kawanami, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1983,24,5131. 146 G. Giacomelli, C. Rosini, A. M. Caporusso, and F. Palla, J . Org. Chem., 1983,48,4887. 14’ C. H. Cummins and R. M. Coates, J . Org. Chem., 1983,48, 2070. 14* G . M. Rubottom and H. D. Juve, J . Org. Chem., 1983,48, 422. 149 J. Koshino, T. Sugawara, T. Yogo, and A. Suzuki, Chem. Lett., 1983, 933.

143 144

110


0-

no H

I H

111

H

0

li \o

hNx H

Reagents: i, Bu'NHOH, TsOH, Na,SO,, CH,Cl,; ii, RCOCl; iii, H,O, AcOH, AcONa

Scheme 31

OSiMe3

ArC03H

(7)

iiv OMe

Na+

Reagents: i, Bu"Li; ii, BR,; iii, BF3.Et20;iv, NaOMe, MeOH; v , H,02

Scheme 32

The trapping of acyl anions with carbonyl compounds continues to be a general method explored for the synthesis of a-hydroxy-ketones. The uses of the anions derived from N-t-butylhydrazones of aldehydes 150and from the addition of alkylR. M. Adlington, J. E. Baldwin, J. C. Bottaro, and M. W. D. Perry,J. Chem. SOC., Chem. Commun., 1983, 1040.


111

lithium reagents to carbon monoxide 151-153 have been described. Trimethylsilyl ethers of cyanohydrins react with Grignard reagents to form acy10ins.l~~ The reaction requires only small excesses of the Grignard reagent, but is unsatisfactory with alkyl-lithium reagents. Regioselective Lewis acid-mediated a-t-alkylation of acyloins represents a further method for the preparation of highly substituted a-hydroxy-ketones [equation (23)].155

High enantioselectivity has been observed in the protonation of the enediolate derived from benzoin by (2R,3R) 0,O-dipivaloyltartaric acid at low temperatures. 156 An efficient 1,3-asymrnetric induction in the reduction of P-keto-sulphoxides using either sodium borohydride 157 or lithium aluminium hydride 158 leads to carbonyl-protected a-hydroxy-aldehydes(Scheme 33). The two diastereoisomers 0-

0: \

1

og-Ar A r = p -c&i~Me

R2

SR’

R1 = Me or Ar

lii !*

SR

R2

SR

Reagents: i, NaH, R2C02Et;ii, NaBH, or LiAIH4; iii, A q O , py; iv, Cu2CI2,AcOH

Scheme 33

formed have been separated by chromatography or by crystallization158or the substrates may be prepared in optically active form at sulphur by starting the sequence with the resolved formaldehyde dithioacetal S-oxide.15’ The enantioselective preparation of a-hydroxy-aldehydes having a tertiary chiral centre D. Seyferth, R. M. Weinstein, and W.-L. Wang, J. Org. Chem., 1983, 48, 1144. D. Seyferth, R. M. Weinstein, W.-L. Wang, and R. Hui, Tetrahedron Lett., 1983,24, 4907. 153 R. M. Weinstein, W.-L. Wang, and D. Seyferth, J. Org. Chem., 1983, 48, 3367. ls4 L. R . Krepski, S . M. Heilrnann, and J. K. Rasmussen, Tetrahedron Lett., 1983,24,4075. 155 M. T. Reetz and H . Heimbach, Chem. Ber., 1983,116,3702. lS6 L. Duharnel and J.-C. Launay, Tetrahedron Lett., 1983,24,4209. 157 K. Ogura, M. Fujita, T. Inaba, K. Takahashi, and H. Jida, Tetrahedron Lett., 1983,24,503.

15* Is*


112

starting from aminals derived from (S)-2-(anilinomethyl)pyrrolidine has been extended to the synthesis of chiral a-benzyloxy-aldehydes (Scheme 34) .159 The reaction was applied in a synthesis of exo-( +)-brevicomin.

- (h i -iv

o p P h

vi

V

Ph

Ph

i

HO

.OxCH0 R H Reagents: i, DIBAL; ii, MeOH; iii, RMgBr; iv, NH,Cl; v, NaH, PhCH,Br; vi, 2% HCl, H 2 0 OMe

R

R

Scheme 34

In a sequence which is equivalent to the epoxidation of an enone, the adduct between the platinum complex (8) and (E)-but-Zenal reacts with trifluoroacetic acid to form the oxirane (9) with high stereoselectivity, a result of significance if the reaction can be made catalytic [equation (24)].la Modest asymmetric induc-

’

+

P ‘lt’ Ph3P

-

0

Ph3P

OHC-

0‘

OHC,

H

(24)

OH?\+ 0

tion occurs in the cyclodextrin-catalysed epoxidation of trans-chalcones.161 2,3Epoxycyclohexanonesof very high optical purity result from resolution via complexation with the optically active diyne (4; X=C1).162 Addition reactions of trimethylsilyl enol ethers and ethoxycarbonylnitrene, formed in situ by thermolysis of ethyl azidoformate, have been found to be selective, giving N-ethoxycarbonyl-a-amino-ketones [equation (25)].163 Optically Me3SiO

+

R l h , R2

-% A

N3C02Et

NHCOzEt

R1

(25)

R2

G . Guanti, E. Narisano, L. Banfi, and C. Scolastico, Tetrahedron Lett., 1983,24,817. M. Asami and T. Mukaiyama, Chem. Lett., 1983, 93. M. J. Broadhurst, J. M. Brown, and R. A. John, Angew. Chem., Znt. Ed. Engl., 1983,22,47. 161 S. Banfi, S. Colonna, and S. Julia, Synth. Commun., 1983,13, 1049. K. Tanaka and F. Toda, J . Chem. SOC., Chem. Commun., 1983,1513. la S. Lociuro, L. Pellacani, and P. A. Tardella, Tetrahedron Lett., 1983,24,593.

lS8

159


113

active N-(t-butoxycarbony1)-a-amino-aldehydeshave been prepared in the past by reduction of amino-acid derivatives. Reduction of the (N-methoxy-Nmethy1)amides using lithium aluminium hydride is reported to give the aldehyde with high optical activity. The lithium salts of N-protected (acyl, alkoxycarbonyl, or arylsulphonyl)chiral a-amino-acids serve as precursors for the synthesis of a-amino-ketones. The carboxylates react with alkyl-lithium and Grignard reagents with very little ra~emizati0n.l~~ Trifluoroacetyl nitrate, prepared in situ from ammonium nitrate and trifluoroacetic anhydride, is an excellent nitrating agent , capable of converting enol acetates regiospecifically into a-nitro-ketones.166The reagent is powerful enough to nitrate tetrasubstituted enol derivatives, providing a method for the preparation of 2-alkyl-2-nitro-alkanones. Replacement of the nitro-group of a-nitro-ketones by hydrogen may be accomplished by treatment of their tosylhydrazoneswith lithium aluminium hydride The use of the corresponding deuteride affords the regiospecifically a-deuteriated product. 168 N-Bromosuccinimide was a suitable reagent for the cleavage of the tosylhydrazone without loss of the isotopic label. P-Phosphono-enamines are intermediates in a convenient route to formyl alkanephosphonates (Scheme 35).169 The method relies on the acidity of alkane

R2

1

iii R *

+H

liv

Reagents: i , BunLi;ii, DMF; iii, H,O; iv, H 3 0 +

Scheme 35

phosphonates and the reaction of the conjugate base with dimethylformamide. a-Phosphono-vinyl sulphides may be converted into (alky1thio)methylketones by reaction with aldehydes in the presence of a thiolate (Scheme 36).170 The reaction was only exemplified using benzaldehydes. J.-A. Fehrentz and B. Castro, Synthesis, 1983,676. C. G . Knudsen and H. Rapoport, J . Org. Chem., 1983,48,2260. 166 P. Dampawan and W. W. Zajac, Synthesis, 1983,545. 167 G . Rosini, R. Ballini, and V. Zanotti, Synthesis, 1983, 137. la G . Rosini and R. Ballini, Synthesis, 1983,228. 169 E. E. Aboujaoude, N. Collignon, and P. Savignac, Synthesis, 1983,634. 170 M. Mikoiajczyk, P. Kielbasinski, and S. Grzejszczak, Synthesis, 1983,332.

165

114 0

II

(EtO)2PW

-

General and Synthetic Methodr 0

0

II

I

( Et

o)2pY-cI SMe

Ar

k\5R

II

(Eto)2pY / liii I1

SMe

At-

-

v ii

0

II

iv. v

$SR SMe

0

(Et0)2PFSR

SMe

Reagents: i , MeSC1; ii, Et,N; iii, RSH, NaOEt, EtOH; iv, NaH; v, ArCHO; vi, RSNa, ArCHO; vii, TiCl,, H 2 0 , MeCN

Scheme 36

Methyl methylthiosulphonate has been shown to be a superior reagent for the a-methylthiolation of enolates of cyclic ketones. 171 Comparison was made with literature methods using either dimethyl disulphide or methyl sulphenyl chloride. A convenient method for the preparation of the thiosulphonate was also described. Cyclic a-diazo-ketones react with phenylsulphenyl chloride to afford a-chloro-a-(pheny1thio)-cycloalkanones7 which are dehydrochlorinated to the enone under basic conditions.17* The reaction also proceeds with terminal diazoketones the products undergoing ready Friedel-Crafts alkylation of benzene to afford a-phenyl-a-(pheny1thio)-ketones [equation (26)]. Conditions have been

L,N -~

R

PhSCl

R%Cl

SnClL PhHb

R%Ph

SPh

(26) SPh

defined for the efficient conversion of a-chloroaldimines into a-sulphenylated aldimines.173 Oxalic acid in a two-phase (water-dichloromethane) system was recommended for hydrolysis to the sulphenylated aldehyde. Carbanion-accelerated Claisen rearrangements of ally1 enol ethers of a-sulphonyl-ketones have been shown to be highly stereoselective as observed in the thermal reaction [equation (27)] The products are in accord with a chairArS02

NaH

__t

yo),

ArS02

\ -K H

(27) I

I

D. Scholz, Synthesis, 1983, 944. M. A. McKervey and P. Ratananukul, Tetrahedron Lett., 1983, 24,117. 173 N. De Kimpe, R. VerhC, L. De Buyck, and N. Schamp, Synthesis, 1983,632. 174 S . E. Denmark and M. A. Harmata, J . Org. Chem., 1983,48,3369.

172


115

like transition state. Rearrangement of a$-epoxy-sulphones in the presence of boron trifluoride etherate gives rise to (presumed) a-sulphonyl-aldehydes (Scheme 37). 175 The corresponding enamines were isolated after treatment of the reaction mixture with a secondary amine.

I

jl

TO1 0 2 s

H

.

A Ar

H

T0102S

lii Ar

NR1R2

> H- ( -

T0102S

+

Reagents: i, PhCH,NEt,, C1-, NaOH, H,O, MeCN, ArCHO; ii, BF3.Et,0, CH,Cl,; iii, R1R2NH

Scheme 37

Addition of a selenosulphonate to an acetylene forms synthetically versatile sulphones which may be converted to, inter aha, a-sulphonyl-ketones. 176 The a-(phenylse1eno)vinyl-sulphones may be converted either into the unprotected P-keto-sulphone by aqueous perchloric acid, or into the acetal under basic conditions (Scheme 38). R1-E-R2

Rj_(024r

,A_ PhSe

R2

- Rgo

/ 0

PhSe

R2

lo iii ,

R2

Reagents: i, PhSeS0,Ar; ii, m-ClC6H,CO3H; iii. (CH,OH),, KOH; iv, HClO,, H,O

Scheme 38

Addition of bromine to a-ethoxyvinyl ketones followed by acidic hydrolysis constitutes a simple route to brornomethyl-l,2-diketone~.'~~ An investigation of the properties of the lithium salt of dichloromethyl phenyl sulphoxide has A. A. M. Houwen-Claassen, J. W. McFarland, B. H. M. Lammerink, L. Thijs, and B, Zwanenburg, Synthesis, 1983, 628. 176 T. G. Back, S. Collins, and R. G. Kerr, J. Org. Chem., 1983,48, 3077. N. K. Hamer, J . Chem. SOC.,Perkin Trans. 1, 1983, 61. 175

5

116


revealed its use in the preparation of dichloroketones from aldehydes [equation (28)].178 The addition of chlorine to a,p-unsaturated ketones in tetrahydrofuran -0 RCHO

+

CL

zvk, j, OH

Li --+

Phi-+ CL

-L R

(28)

CHCl2

,SPh

-0

+

at low temperatures has been found to involve incorporation of the solvent [equation (29)].179The reaction is regiospecific, and leads to the a-chloro-/3alkoxy-ketone.

A convenient preparation of bromoacetaldehyde has been published, giving the conditions necessary for the successful ozonolysis of 1,4-dibromobut-2-ene.180 The ozonide was reduced by triphenylphosphine. Uses of the aldehyde as an electrophile in a variety of reactions were also described. In a complementary paper, 1-bromo-2-methoxyvinyl-lithium has been used as a bromoacetaldehyde

[ A] AR' - - -

anion equivalent (Scheme 39). 18* d6r

Me0

HO

ii

-

-

Br

Me0

Br

Me0

iii

& ' R2

R'

R2

8r

0

Br

Reagents: i, BunLi, -8o"C, Et,O; ii, R1R2CO;iii, HCl, H,O

Scheme 39

Examples of the use of sodium hydrogen telluride for the dehalogenation of a-halogeno-ketones have appeared. 182 The method described is mild and high yielding. a-Bromo-ketones act as precursors to silyl enol ethers via debromination using either trimethylsilyltributyltin in the presence of a palladium(0) catalyst [equation (30)] 183 or lithium di-isopropylamide followed by trimethylsilyl

V. Reutrakul and K. Herunsalee, Tetrahedron Letr., 1983, 24,527. M. Bertrand, J.-P. Dulcere, J. Rodriguez, and J.-P. Zahra, Tetrahedron Lett., 1983, 24, 1967. G. A. Kraus and P. Gottschalk, J. Org. Chern.,.1983,48,2111. 181 R. H. Smithers, J . Org. Chern., 1983, 48, 2095. 182 A. Osuka and H. Suzuki, Chern. Lett., 1983,119. M. Kosugi, T. Ohya, and T. Migita, Bull. Chern. SOC.Jpn., 1983, 56, 3539.

178

179


117

ch10ride.l~~ In the latter case, hydrolysis in place of silylation leads to the expected ketone in good yield. The use of zinc in combination with trimethylsilyl chloride for the reduction of a-chloro-ketones to silyl enol ethers has been extended to the preparation of difluoro-enol ethers from chlorodifluoromethyl ketones. lXsThe introduction of fluorine a- to a carbonyl group has been achieved by anodic oxidation of enol acetates in the presence of an acid fluoride salt of triethylamine ls6 and by the use of acetyl hypofluorite as a fluorinating agent for 1,3-dicarbonyl compounds. Ig7 Thermolysis of the adducts formed between aldehydes and the lithium salt of fluoromethyl phenyl sulphoxide leads to fluoromethyl ketones [cf. equation (28)].ls8 Dicarbonyl Compounds.-Coupling of acyl chlorides with vinylstannanes to give enones is catalysed by palladium(I1) salts. The use of vinyl substrates bearing a-methoxy substituents leads to monoprotected a-diketones from which the diketone may be released by acid.lX9Nafion-H has been recommended as a catalyst for the cleavage of a-keto-acetals to the dicarbonyl compound. 190 Nitroaldol reactions with a-keto-aldehydes or their hemiacetals lead to 1,Zdiketones after elimination of the nitrite group [equation (31)]. 191 a-Amino-acids are the

The starting point for a route to 1,2-diketones via isoxazolinones (Scheme 40).192 method is applicable to the synthesis of a - k e t o - a ~ i d s . ' ~ ~ ~ ' ~ ~ Synthetic applications of 3-alkoxyacroleins as equivalents of malondialdehyde have been described. 19s Magnesium salts of cyclic thioureas act as efficient carriers of carbon dioxide for the a-carboxylation of ketones. 196 Acylation of the lithium enolate of trimethylsilyl acetate affords excellent yields of p-keto-acids after the very mild hydrolysis necessary for silyl Methyl ketones were isolated in very good J.-E. Dubois, C. Lion, and J.-Y. Dugast, Tetrahedron Lett., 1983, 24, 4207. M. Yamana, T. Ishihara, and T . Ando, Tetrahedron Lett., 1983, 24,507. lX6 E. Laurent, R. Tardivel, and H. Thiebault, Tetrahedron Lett., 1983,24, 903. 0. Lerman and S. Rozen, J . Org. Chem., 1983,48,724. lax V. Reutrakul and V. Rukachaisirikul, Tetrahedron Lett., 1983, 24, 725. J. A. Soderquist and W. W.-H. Leong, Tetrahedron Lett., 1983, 24, 2361. K. S. Petrakis and J. Fried, Synthesis, 1983, 891. 191 K. S. Petrakis, G. Batu, and J. Fried, Tetrahedron Lett., 1983, 24, 3063. 192 J. Leyendecker, U. Niewohner, and W. Steglich, Tetrahedron Lett., 1983,24,2375. 193 C. Klein, G. Schulz, and W. Steglich, Leibigs Ann. Chem., 1983, 1623. 194 C. Klein, G. Schulz, and W. Steglich, Leibigs Ann. Chem., 1983, 1638. 195 J. Maddaluno and J . d'Angelo, Tetrahedron Lett., 1983, 24, 895. 196 N. Matsumura, N. Asai, and S. Yoneda, J . Chem. SOC., Chem. Commun., 1983, 1487. 197 P. J. Cowan and M. W. Rathke, Synth. Commun., 1983,13,183.

184

118


Nxo

H

CF3

Reagents: i, (CF,CO),O; ii, NEt,, CH=CHCO,Bu';

iii, R'MgX or R'Li; iv, HC0,H; v, H,Oi

Scheme 40

yield on slightly more vigorous hydrolysis. 13-Keto-estersare formed in high yield when methyl cyanoformate reacts with regioselectively preformed lithium ketone en01ates.l~~ This electrophile may be used for the direct preparation of nonenolizable keto-esters. A variety of carboxylate derivatives, including dialkylformamides, acyl chlorides, and alkyl carbonates react with P-lithioenamines to form P-ketoaldehydes, -ketones, and -esters , respectively, in excellent yield, after hydrolysis of the enaminone intermediates.199 A range of enaminone derivatives has also been prepared through condensation of enol silyl ethers with oxime mesylates in the presence of organoaluminium reagents (Scheme 41) .200 Ethylaluminium chlorides were the preferred Lewis acids for the induction of the Beckmann rearrangement. ,OS02Me

+

m-

YR OS i Me3

Reagent: i, Et2A1Cl

Scheme 41 L. N. Mander and S. P. Sethi, Tetrahedron Lett., 1983, 24, 5425. L. Duhamel, J.-M. Poirier, and N. Tedga, J . Chem. Res. (S), 1983, 222. *O0 Y. Matsumura, J. Fujiwara, K. Maruoka, and H. Yamamoto, 1. Am. Chem. SOC., 1983,105,6312. lg8

Iw


119

The alkylation of silyl enolates by phenylthioalkyl chlorides has been extended to a-phenylthio-a-chloro-esters 201 and -ketones,2o2leading to synthetic routes to 1,6dicarbonyl derivatives (Scheme 42). y-Keto-aldehydes,-ketones, -esters, and OSiMe3

R

1

4

/

-k

0 R = OMe, a l k y l , or a r y l

R2

R

R1

R2

0

liii

Reagents: i , ZnBr, or TiCI,; ii, NaIO,, MeOH; iii, Raney Ni

Scheme 42

-nitriles result from the reductive coupling of acid anhydrides with activated alkenes [equation (32)].203 The procedure uses chemical or electrochemical

(R’C0120

4-

R2Jz

.

e‘. v i t . hv 812

R

1

q

Z

(32)

R2

z = CHO, CORG,

C O ~ ,Ror~ CN

reduction whilst irradiating in the presence of vitamin BIZ.Other cobalt complexes may be used, serving to modify the reduction potential required for reaction to be observed. Combination of two known reactions, the ready palladium-catalysed allylation of potassium enoxyborates and the mercury(I1)formic acid-mediated hydrolysis of vinyl chlorides to ketones, offers another approach to the synthesis of 1,4- and 1,5-diketones (Scheme 43).204 The ozonolytic cleavage of cyclic enones may be convenient on the very small scale, but with larger amounts care has to be taken with regard to build-up of ozonide intermediates. An ozonide decomposition which may be carried out concomitantly with the ozonolysis has been developed, using basic hydrogen peroxide in the presence of a phase-transfer catalyst [equation (33)].2u5 An added 201

2M ,03 204 ,05

I. Fleming and J. Iqbal, Tetrahedron Lett.. 1983. 24, 327, L. Duhamel, J. Chauvin, and C. Goument, Tetrahedron Lett., 1983, 24.2095. R. Scheffold and R. Orlinski, J. Am. Chem. Soc., 1983,105,7200. E.-I. Negishi, F.-T. Luo, A. J. Pecora, and A. Silveira, J. Org. Chem., 1983,48,2427. J. A. Cella, Synth. Commun., 1983, 13,93.


120

I

I

R2

R2

liv

ti,ii

0

R* Reagents: i, KH or KN(SiMe,),; ii, BEt,; iii, ClCH,CH= HCOzH

C(Cl)Me, [Pd(PPh,),]; iv, Hg(OAc),,

Scheme 43

0

benefit is the extraction of the product acid from the dichloromethane phase throughout the oxidation. Investigations of metal-assisted cleavage of silyloxycyclopropanes indicate that silver(1) and copper(I1) tetrafluoroborates lead to symmetrical 1,6-diketones, with deposition of the metal [equation (34)].206

3 Protection and Deprotection of Aldehydes and Ketones Aldehydes and ketones are readily converted into their 1,3-dioxolanes by reaction with a slight excess of ethylene glycol in the presence of trimethylsilyl chloride ,*07 or by bis(trimethylsily1oxy)ethane in the presence of electrochemically generated acid.208Mixed acetals may be prepared without the formation of mixtures by acetoxymercuration of a vinyl ether in the presence of a slight excess of an alcohol.20YDemercuration was effected in basic solution by either sodium borohydride or sodium trithiocarbonate. Copper salts may also be used to I. Ryu, M. Ando, A. Ogawa, S. Murai, and N. Sonoda, J . A m . Chem. SOC.,1983, 105,7192 *a7 T. H. Chan, M. A. Brook, and T. Chaly, Synthesis, 1983, 203. 208 S . Torri and T. Inokuchi, Chem. Lett., 1983, 1349. 2y R. K. Boeckman and C. J . Flann, Tetrahedron Lett., 1983,24,4923. 2rm


121

catalyse the addition of an alcohol or a carboxylic acid to a vinyl ether.210 By maintaining reaction temperatures at ca. 20"C, unsymmetrical acetal derivatives may be prepared. A polystyrene resin-bound diol has been described for the isolation of aldehydes and ketones from mixtures, and as a protecting group for carbonyl compounds during other transformations whilst attached to the resin.211Loadings were of the order of 1 mmole of the carbonyl compound per gram of resin. An interesting observation indicates that cyclohexa-l,6dione forms the monoacetal in ca. 80% yield on acetalization with butane-174-diol, a higher yield of a monoprotected derivative than with many diols.212 Titanium(r1) chloride shows excellent activity in the conversion of aldehydes and ketones into thioacetals with alkyl thiols and d i t h i ~ l s and , ~ ~ ring-opens ~ y-lactols to hydroxy-aldehydes protected as the ethylene d i t h i ~ a c e t a lBis(di.~~~ isobutylaluminium)ethane-1,2-dithiolate converts acetals into ethylenedithioacetals whereas ketones do not react, offering a useful selectivity.215 Cyanohydrin anions are produced from cyanide ion and carbonyl compounds under phase-transfer catalysis by 18-cr0wn-6.~~~ The anions may be trapped in situ by acid chlorides, anhydrides, or alkylating agents. Cyanohydrin ethers may also be formed by treatment of acetals with trimethylsilyl cyanide.217Following the conversions of acetals into cyanohydrin ethers by trimethylsilyl cyanide, the (potentially explosive!) azido-ethers may be prepared in similar fashion from the silyl azide when catalysed by tin(1v) chloride.218 Iron(m) chloride is an effective catalyst for the conversion of a variety of aldehydes into geminal d i a c e t a t e ~ . ~ ~ ~ Trimethylsilyl chloride in combination with acetic anhydride furnishes enol acetates from saturated and conjugated ketones.220Regio- and stereo-selective syntheses of enol boranes enable the selective preparation of enol silyl ethers, as N-trimethylsilylimidazole is an efficient reagent for the exchange of silicon for boron [equation (35)].221 Rhodium-catalysed isomerization of /?-trimethylsilyl

M. Tordeux, R. Dorme, and C. Wakselman, Synth. Commun., 1983, 13,629. P. Hodge and J. Waterhouse, J . Chem. SOC., Perkin Trans. 1, 1983, 2319. 212 J. A . Hyatt, J . Org. Chem., 1983, 48, 129. 213 V. Kumar and S. Dev, Tetrahedron Lett., 1983, 24, 1289. 214 P. C. Bulman-Page, R. A. Roberts, and L. A. Paquette, Tetrahedron Lett., 1983,24,3555. 215 T. Satoh, S. Uwaya, and K. Yamakawa, Chem. Lett., 1983, 667. 216 R. Chhevert, R. Plante, and N. Voyer, Synth. Commun., 1983, 13, 403. 217 S. Kirchmeyer, A. Mertens, M. Arvanaghi, and G. A. Olah, Synthesis, 1983, 498. 218 S. IGrchmeyer, A. Mertens, and G. A . Olah, Synthesis, 1983. 500. 219 K. S. Kochhar, B. S. Bal, R. P. Deshpande, S . N. Rajadhyaksha, and H. W. Pinnick, J . Org. Chem., 1983,48,1765. 220 P. K. Chowdhury, R. P. Sharma, and J . N. Barua, Tetrahedron Lett., 1983,24, 3383. 221 J. Hooz and J. Oudenes, Tetrahedron Lett., 1983, 24, 5695. 210

211

122


alcohols offers an additional regioselective route to silyl enol ethers.222

N-Phenyltrifluoromethanesulphonimideis an efficient reagent for the conversion of regiospecifically generated enolates into enol t r i f l a t e ~ . ~ ~ ~ Further examples of the in situ protection of aldehydes as aldimines have been described, allowing for example the selective methylenation of a ketone in the presence of an aldehyde.224 The N-t-butylaldiminewas cleaved during chromatographic isolation of the products. Girard reagents have been used in conjunction with silica gel for the selective in situ protection of carbonyl groups.225More reactive or less hindered carbonyl groups were selectively protected in competitive reduction studies. Titanium tetrakis(dialky1amides)show discrimination in chemoselective blocking of carbonyl groups, enabling Grignard and aldol reactions to be induced at ketonic centres in the presence of aldehydes.226 Shortest possible reaction times, using tetrahydrofuran as solvent and diethyl ether as the recrystallization solvent, have been recommended for the preparation of the sensitive-tosylhydrazones of aldehydes.227 Titanium(1v) chloride, particularly in combination with lithium iodide,228and dimethylboron and diphenylboron bromides 229 have been recommended for the cleavage of acetals and ketals to the parent carbonyl compounds. The two-phase system formic acid-pentane hydrolyses 3-alkenylacetals at room temperature with minimal isomerization to the conjugated enal.230The isomerism may be effected at elevated temperatures. The method has been applied to the formation of 3-alkynylaldehydes. The electrochemical deprotection of thioacetals has been extended to substrates bearing a /3-phosphonium Such thioacetals have considerable potential as d3 reagents for the preparation of enones. Tributyltin fluoride may be used as a selective reagent for the cleavage of silyl enol ethers.232The rate of cleavage is reduced with increasing steric congestion around the double bond. The reaction was catalysed by palladium salts, which however did not appear to contribute significantly to the observed chemospecificity. Triethylammonium c h l o r o ~ h r o m a t eand ~ ~ ~bispyridinesilver ~ e r m a n g a n a t e ~ ~ ~ are further reagents for the oxidative regeneration of carbonyl compounds from oximes. Copper(r1) chloride in aqueous methanolic tetrahydrofuran at room temperature hydrolyses tosylhydrazones to ketones, conditions which esters survive.235 222 I.

Matsuda, S. Sato, and Y. Izumi, Tetrahedron Lett., 1983,24,2787. J. E. McMurry and W. J. Scott, Tetrahedron Lett., 1983,24, 979. 224 G. P. Zecchini, M. P. Paradisi, and I. Torrini, Tetrahedron, 1983,39,270!9. 22s T. Chihara, E. Waniguchi, T. Wakabayashi, and K. Taya, Chem. Lett., 1983, 1647. 226 M. T. Reetz, B. Wenderoth, and R. Peter, J . Chem. SOC., Chem. Commun., 1983,406. 227 S . H. Bertz and G. Dabbagh, J . Org. Chem., 1983,48,116. u8 G. Balme and J. Gort, J . Org. Chem., 1983,48, 3336. 229 Y. Quindon, H. E. Morton, and C. Yoakim, Tetrahedron Lett., 1983,24,3969. w, F. Barbot and P. Miginiac, Synthesis, 1983, 651. Dl H. J. Cristau, B. Chabaud, and C. Niangoran, J . Org. Chem., 1983,48,1527. 23* H. Urabe, Y. Takano, and I. Kuwajima, J . Am. Chem. SOC., 1983,105,5703. 233 C. Gundo Rao, A. S. Radhakrishna,€3. Bali Singh, and S. P. Bhatnagar, Synthesis, 1983, 808. 234 H. Firouzabadi and A. Sardarian, Synth. Commun., 1983, 13, 863. 235 0. Attanasi, M. Grossi, and F. Serra-Zanetti,J . Chem. Res. (S), 1983, 322.

123


4 Reactions of Aldehydes and Ketones Reactions of Eno1ates.-A two-part review of the syntheticuses of silyl enol ethers has appeared, covering their preparation and reactions,236and the chemistry of silyloxybutadienes,including their [4 21 cycloaddition reactions.237 In the alkylation of silyl enol ethers with a-heteroatom-substituted alkyl chlorides the electrophile has been activated by trimethylsilyl iodide or trifluoromethanesulphonate, improving the specificity of halide displacement [equation (36)].238The related alkylations with adducts from vinyl ethers and

+

I R2

Y=ORorSR

phenylsulphenylchloride or phenylselenenyl chloride proceed when catalysed by zinc chloride.239The reaction has been extended to the adducts of simple alkenes, but only in the case of the sulphur adducts, attempted carboselenenylation leading to a-selenenyl-ketones by attack at selenium (Scheme 44). $ R‘ \ y

SePh

y

‘CI

ii

Y = O orCH2

Y

I

I

iii

R2YS R1o R A ‘’O

Reagents: i, PhSC1; ii, PhSeC1; iii, R3C(=CH2)OSiMe3;ZnBr,

Scheme 44

Palladium(I1)-phosphine catalysed allylations of ketone derivativescontinue to be explored, including the rearrangement of allyl carbonates, prepared by trapping enolates with allyl chloroformates (Scheme 45) .240 Extending this to enolates of allyl P-keto-carboxylates as substrates forms a simple method for the regioselective synthesis of a,a-diallyl-ket~nes.~~~ Silyl enol ethers 242 and enol Brownbridge, Synthesis, 1983, 1. P. Brownbridge, Synthesis, 1983, 85. 238 A. Hosomi, Y. Sakata, and H. Sakurai, Chem. Lett., 1983, 405. 239 R. P. Alexander and I. Paterson, Tetrahedron Lett., 1983, 24, 5911. 240 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24, 1793. 241 I. Shimizu, Y. Ohashi, and J. Tsuji, Tetrahedron Lett., 1983, 24,3865. 242 J. Tsuji, I. Minami, and I. Shimizu, Chem. Len., 1983, 1325.

u6 P. 237

124


Reagents: i, CICO,CH,CH= CH,; ii, Pd,(dba),.CHC13, PPh3;iii, PdO, PPh,, ROCOCH,CH= iv, PdO, dppe, ROCOCH,CH=CH,, Bu,SnOMe

CH,;

Scheme 45

acetates,243the latter in the presence of tributyltin methoxide as base, are also substrates for the reaction. The combination of the tin alkoxide and a palladium(I1)-phosphine catalyst is also capable of coupling enol acetates and aryl bromides to form a-aryl-ketones [equation (37)].244 Counter-cation effects have OAc

(37)

4- PhBr

R1%

cat. BugSnOMe [PdCl2( Ar3P121

R I h P h

R2

R2

been noted to be important for the effective palladium-catalysed allylation of enolates by allylic carboxylates. In particular , zinc enolates and lithium enolates in the presence of triethylborane show high regioselectivity and high product yields.245 Ketone enol ethers undergo an ene reaction with formaldehyde and trimethylaluminium, offering a possible method for sequential reactions at the aand a'-positions of a ketone (Scheme 46) .246 Silver(1)-promoted decomposition of RO

i

ii

Rl+R2

OH

R l f i R 2

OH

Reagents: i, Me,Al, HCHO, CHCl,; ii, e.g. R=SiMe,: F-, E+

Scheme 46 J. Tsuji, I. Minami, and I. Shimizu, Tetrahedron Lett., 1983, 24, 4713. M. Kosugi, I. Hagiwara, T. Sumiya, and T. Migita, J. Chem. SOC., Chem. Commun., 1983, 344. 245 E.-I. Negishi and R. A. John, J . Org. Chem., 1983, 48, 4098. 246 B. B. Snider and G. B. Phillips, J. Org. Chem., 1983, 48, 2789.

243

244

125


peroxydisulphate is a convenient initiator for the alkylation of water-soluble ketones with lipophilic alkenes [equation (38)].247

Using 2-methylcyclohexanone as a substrate, kinetic enolate formation is preferred on treatment with potassium hydride followed by triethylborane, whereas the thermodynarnicall-y more stable enolate is the product using potassium hexamethyldisilazide in place of the h ~ d r i d e Bromomagnesium .~~~ di-isopropylamide and trimethylsilyl chloride form an excellent reagent cornbination for the conversion of cyclic ketones into their thermodynamically more stable silyl enol ethers.249 The sodium salt of the monoanion from t-butyl acetothioacetate may be alkylated as anticipated, but more importantly the dianion derived from the anion and butyl-lithium shows good regioselectivity in its reactions with electrophiles provided that 1,2-dimethoxyethane is used as the solvent for the reaction (Scheme 47) .250 The use of sulphonium salts as electrophiles for the C-alkylation of p-dicar-

Reagents: i, BuSNa; ii, NaH, MeOCH,CH,OMe; iii, RlX; iv, BunLi; v, R2X; vi, R1R2C0

Scheme 47

bony1 compounds may prove to have advantages for the introduction of primary alkyl groups into compounds prone to O - a l k y l a t i ~ n . ~ ~ ~ Methods for the alkylation of aldehydes and ketones via nitrogen derivatives have been reviewed.252Reactions of enarnines are described, and reactions of metallated imine, oxime, and hydrazone derivatives are compared with equivalent enolate cases. A. Citterio, F. Ferrario, and S. De Bernardinis, J. Chern. Res. (S), 1983. 310. E.-I. Negishi and S. Chatterjee, Tetrahedron Lett., 1983, 24, 1341. 249 M. E. Krafft and R. A. Holton, Tetrahedron Lett., 1983. 24, 1345. 250 P. M. Booth, C. M. J. Fox, and S. V. Ley, Tetrahedron Lett., 1983, 24, 5143. 251 M. E. Garst and B. J . McBride, J. Org. Chern., 1983,48, 1362. 252 J. K. Whitesell and M. A . Whitesell, Synthesis, 1983, 517.

247

248

126


Aldol Reactions.-An

example of a cross-aldol reaction between aldehydes has been demonstrated using tin(I1) e n o l a t e ~2-Bromo-2-methylpropanal .~~ was used as the precursor to the enolate, the a-branched structure precluding elimination of water from the aldol product to give the enal. Rapid generation of the enolate by metallic tin reduction lessens the self-condensation of the nucleophilic aldehyde component. This reductive method has been used for the generation of the tin(I1) enolate from m e t h y l g l y ~ x a l which , ~ ~ ~ takes part in reactions with aldehydes to give predominantly the syn-isomers of the aldol products [equation (39)].The tin(I1) enolate of 1,3-dibenzyloxypropanone,generated by the tin(I1) RCHO,

R

(39)

OH

H

trifluoromethanesulphonate-N-ethylpiperidine method, undergoes aldol reactions with ketones to provide anti-isomers of aldols, a reaction of significance in syntheses of carbohydrate-related compounds [equation (40)] .255 0

ii0

Sn (OSO2Me12

RO

OR

Et

K ~ o ~ M ~ w

C02Me RO

OR

(40)

R = CH2Ph

Silyl enol ethers react with tributyltin(1v)fluoride and a palladium(I1)catalyst to give the stannyl enolates which readily take part in aldol reactions with aldehydes.z6 The fluoride reacts selectively with less hindered silyl enol ethers, enabling a chemoselective aldol reaction to be carried out on protected diketones [equation (41)]. Tin(1v) chloride converts silyl enol ethers into a-trichlorostannyl-

J.-I. Kato and T. Mukaiyama, Chem. Lett., 1983, 1727. T. Mukaiyama, R. Tsuzuki, and J.-I. Kato, Chem. Lett., 1983, 1825. 255 R. W. Stevens and T. Mukaiyama, Chem. Lett., 1983, 595. 256 H. Urabe and I. Kuwajima, Tetrahedron Lett., 1983,24,5001.

253

254


127

ketones,257which participate in highly erythro-selective aldol reactions with aldehydes at low temperature.258Equivalent reactions have been reported for titanium(1v) chloride .259,260 Titanocene enolates of methyl ketones may be formed by the specific methylenation of acyl chlorides, under conditions where isomerization of the enolate is not observed (Scheme 48; cf. Scheme 3).261Standard aldol reactions could be employed with this enol derivative. 9 T i Cl C p2

/

Cp= C5H5-

R

A

Reagents: i, 0°C; ii, RCOCl; iii, RlCHO; iv, H30t

Scheme 48

Aldol reactions of lithium enolates show increased yields in the presence of cerium(m) chloride, the stereochemistry of the product reflecting the geometry of the enolate generated initially.262 Chiral aldehydes show high diastereofacial preferences in their Lewis acidmediated reactions with silyl enol ethers.263 Further details have appeared on the fluoride-catalysed aldol reactions between silyl enol ethers and carbonyl compounds, generating either tetra-alkylamm ~ n i u m *or ~ ~ tris(dialky1amino)sulphonium e n o l a t e ~ as ~ ~ intermediates. ~ Condensations promoted by tetra-alkoxysilanes in the presence of fluoride ions lead to the unsaturated carbonyl compounds through elimination from the aldol product .266 Silyl enol ethers may be induced to participate in erythro-selective aldol-type reactions with acetals, a method suitable for effective cross-condensations [equation (42)].267 OSi Me3

h

w

+

R

Me+i OSO2CF3

(42)

(Me012CHR

w

E. Nakamura and I. Kuwajima, Chem. Lett., 1983, 59. E. Nakamura and 1. Kuwajima, Tetrahedron Lett., 1983,24, 3347. 259 E. Nakamura, J.-I. Shimida, Y. Horiguchi, and I. Kuwajima, Tetrahedron Lett., 1983, 24, 3341. 2M) E. Nakamura and I. Kuwajima, Tetrahedron Lett., 1983,24,3343. 261 J. R. Stille and R. H. Grubbs, J . Am. Chem. SOC., 1983, 105, 1664. 262 T. Imamoto, T. Kusumoto, and M. Yokoyama, Tetrahedron Lett., 1983,24, 5233. 263 C. H. Heathcock and L. A. Flippin, J . Am. Chem. SOC., 1983,105,1667. 2M E. Nakamura, M. Shimizu, I. Kuwajima, J. Sakata, K. Yokoyama, and R. Noyori, J. Org. Chem., 1983, 48, 932. 265 R. Noyori, I. Nishida, and J. Sakata, J . Am. Chem. SOC., 1983, 105,1598. 266 C. Chuit, R. J. P. Corriu, and C. Reye, Synthesis, 1983, 294. 267 H. Sakurai, K. Sasaki, and A. Hosomi, Bull. Chem. SOC.Jpn., 1983,56,3195. 257 258


128

Condensations between aldehydes and silyl enol ethers have been carried out under neutral conditions by dint of using pressures approaching 10 kbar.26sA preference is observed for the oppposite stereoselectivity compared with the titanium(1v) chloride-catalysed reaction. Enaminosilanes have been subjected to aldol reaction conditions using boron trifluoride catalysts , and shown to give products of erythro-selective kinetic reaction [equation (43)].269 Me@ NR'

TiClL

+

RCHO

(43)

CH2Cl2, -78O C

Moderate enantioselectivity has been observed in the aldol-type condensations of chiral a-sulphinyl-hydraz~nes.~~~ Induced chirality at the P-position was retained through the reductive desulphurization (Scheme 49). Me2NN

01

Me2"

0i.ii

R'

A

Ar = p -C6HLMe

,l%st~r

R2

4

OH

i

iii

OH

OH

Reagents: i , BunLi; ii, R2CHO; iii, Na/Hg, NaH2P04,MeOH; iv, CuC1, Scheme 49

Conjugate Addition Reactions.-p-Dicarbonyl and 0-silylated ketene a ~ e t a l sundergo ~ ~ * conjugate addition to enones under neutral conditions at 15 kbar pressure. At such pressures steric factors are reduced, enabling reaction to proceed with higher degrees of substitution on the reactants than is possible with the thermal or Lewis acid-catalysed reactions [equation (44)].

0

2a Y. Yamamoto, K. Maruyama, and K. Matsumoto, J . 269 W. Ando and H. Tsumaki, Chem. Lett., 1983, 1409.

Am. Chem. SOC., 1983, 105, 6963.

L. Colombo, C. Gennari, G. Poli, C. Scolastico, R. Annunziata, M. Cinquini, andF. Cozzi,J. Chem. SOC., Chem. Commun., 1983,403. 271 W. G. Dauben and J. M. Gerdes, Tetrahedron Lett., 1983,24,3841. 272 R. A. Bunce, M. F. Schlecht, W. G. Dauben, and C. H. Heathcock, Tetrahedron Lett., 1983, 24, 4943.

270

129


The efficiency of ligand transfer from cuprates is dependent on the choice of copper(1) salt employed to prepare the reagent. Comparisons of the iodide and the isocyanate provide some evidence for the latter giving rise to ‘higher order’ cuprates, with altered r e a ~ t i v i t i e s .Additions ~~~ of the higher-order cuprate R2Cu(CN)Li2to a$- and P,P-disubstituted unsaturated esters can lead to saturated ketones by 1,2- followed by 1,4-additions [equation (45)].274Such cuprates,

nor +

- nR

R2Cu(CN)Li2

(45)

0

R

O

when complexed to boron trifluoride, add in conjugate fashion to alkyl cyclopropyl ketones to form the y-alkylated product [equation (46)] .275

Enantioselective conjugate additions of mixed cuprates incorporating a chiral ligand derived from L-prolinol have been observed to be improved when the reaction is carried out at higher Enantioselectivity is also highly dependent on small structural changes in the ligand (Scheme 50). The N-methyl

fi - pF% - MeoR i , iii

ii , iii

Ph

HO

*

Me

O

Y

s But

0

Reagents: i, Me,CuMgBr; ii, Me,CuLi; iii, PhhKPh

Scheme 50

derivative gave high chemical and optical yields in the conjugate addition of a methyl group from magnesium cuprates. 4-t-Butylthio-derivatives induced greatest asymmetry in methylation by copper-lithium reagents.277 Chiral oxazolidines derived from a,P-unsaturated aldehydes and ephedrine react with methylcopper 278 and with lithium dialkylcuprates 279 to provide optically active /3-substituted aldehydes [equation (47)]. H Me

+lq$ R:CuLi+ * or

R’

R ~ C U

.‘JJ R’

(47)

0

B. H. Lipshutz, J. A. Kozlowski, and R. S . Wilhelm, J . Org. Chem., 1983, 48, 546. B. H. Lipshutz, Tetrahedron Lett., 1983, 24, 127. 275 C . Moiskowski, S. Manna, and J. R . Falck, Tetrahedron Lett., 1983, 24, 5521. 276 F. Leyendecker, F. Jesser, and D. Laucher, Tetrahedron Lett., 1983,24,3513. 277 F. Leyendecker and D. Laucher, Tetrahedron Lett., 1983, 24, 3517. 278 M. Huche, J. Aubouet, G. Pourcelot, and J. Berlan, Tetrahedron Lett., 1983, 24, 585. 279 P. Mangeney, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1983,24,373. 273

274

130


Diarylzinc compounds will participate in conjugate addition reactions with enones in the presence of nickel acetylacetonate, and may be prepared conveniently by sonication of the aryl bromide, lithium wire, and zinc bromide in an ethereal solvent.280The same transformation may be achieved, this time using aryl iodides, when catalysed by palladium(I1) salts in formic acid containing triethylamine [equation (48)] .281

Mercuration of ketone hydrazones forms precursors for acetoxy-radicals which will add in conjugate fashion to activated olefins (Scheme 51).282The intermedi-

ti

liv

0 R’

0

II,,

Reagents: i, H,NNH,; ii, HgO, Hg(OAc),; iii, KC1; iv, NaBH,, CH,=CHCOMe

Scheme 51

ate organometallic reagent need not be isolated, enabling this coupling reaction to be carried out in one reaction vessel.

J.-L. Luche, C. Petrier, J.-P. Lansard, and A. E. Greene, J. Org. Chem., 1983,48, 3837. Cacchi and A. Arcadi, J. Org. Chem., 1983,48,4236. B2 B. Giese and U. Erfort, Chem. Ber., 1983, 116,1240. B 1 S.

3 Carboxylic Acids and Derivatives BY D.W. KNIGHT

1 Carboxylic Acids

General Synthesis.-One-carbon homologations of alkyl halides to carboxylic acids can be readily achieved using the phenylthio methyl ether (1) (Scheme 1).l Among many other uses, reagent (1) and its phenylsulphonyl analogue can also be employed in one-carbon extensions of ketones to a-acetoxy-acids (2). Onecarbon homologations of non-enolizable aldehydes have also been carried out using the amino-nitrile (3) (Scheme 2).2The a-silyl derivative (4) must be used when the aldehyde contains an a-proton and, although the yields for both methods are variable, the sequence could find use in suitable cases. Similar reactions between (3) and benzoic acid esters ( 5 ) lead to a-keto-amides (6). SPh

.1

I,

Jones

A!l)/,i i , Jones

R'y:bo:"

R-qH

R

(2)

Scheme 1

CN

CN (31

Scheme 2

Me3SiYNMePh---ArC02R

CN

(4)

(5)

NMePh

(6I

T. Mandai, K. Hara, T. Nakajima, M. Kawada, and J. Otera, Tetrahedron Lett., 1983, 24, 4993. K. Takahashi, K. Shibasaki, K. Ogura, and H. Iida, J . Org. Chem., 1983,48,3566; Chem. Lett., 1983, 859; K. Takahashi, T. Masuda, K. Ogura, and H. Iida, Synthesis, 1983, 1043.

131


132

Reductive alkylations of Meldrum’s acid by carbonyl compounds in the presence of a borane-amine complex results in an overall two-carbon homologation to carboxylic acids, after acid hydrolysis (Scheme 3) . 3 This simple-looking method gives yields in the range 52-94%. R1>o

{:x 0

0

R2 0

0 Scheme 3

Alper’s group4has developed a much milder set of conditions for the hydrocarboxylation of olefins, [(7)+(8)], consisting of a catalyst system of PdC12-CuC12HC1-H20 under one atmosphere of CO and O2at room temperature. Yields are excellent, and high regioselectivities can be obtained in reactions with unsymmetrical olefins. In related work, it has been briefly demonstrated that strained olefins can undergo simultaneous Pdo-catalysed addition of vinyl, aryl, or benzyl bromides and carbon monoxide [e.g. (9)+( lo)] .5 Octacarbonyldicobalt is used as the catalyst in carboxylations of ammonium salts (11) which yield acids (12) in 7 0 4 5 % yields in a process which can be regarded as a reverse of the Curtius degradation.6 Stability to aqueous base (5M NaOH) and light are substrate requirements for this reaction.

(10)

C02 H (14 1

Although alkyl-mercury species , RHgX, add efficiently to many electrondeficient olefins, such reactions with crotonic esters are not satisfactory. A solution to this limitation is to use the Knoevenagel adducts (13) and to complete the sequence by acid hydr~lysis.~ Overall conversions of RCHO into the twocarbon homologues (14) are in the range 20-50%, although rather brutal conditions (80% H2S04,A) are used in the final step. A systematic study of conjugate additions by the alkyl-copper species RCu.BF3.Bu3Pto unsaturated esters (15) D. M. Hrubowchak and F. X. Smith, Tetrahedron Lett., 1983,24,4951. H. Alper, J . B. Woell, B. Despeyroux, and D. J. H. Smith, J . Chem. SOC., Chem. Commun., 1983, 1270. M. Catellani, G. P. Chiusoli, and C. Peloso, Tetrahedron Lett., 1983, 24, 813. J.-J. Brunet, C. Sidot, and P . Caubere, J . Org. Chem., 1983,48, 1919. B. Giese, H. Harnisch, and S. Lechhein, Synthesis, 1983, 733.

Carboxylic Acids and Derivatives

133

containing a chiral alcohol residue (R*) has resulted in syntheses of P,Pdisubstituted acids (16) with 292% enantiomeric excesses.*Crucially, the chiral alcohol R*must contain a large neo-pentyl ether substituent if high optical yields are to be realized and, although only a few examples have been studied, the method appears to have considerable potential. Full details have been presented for the synthesis of (Z?)-(17), or (S)-sodium [2-2H,2-3H]acetate.9

An unusual and simple oxidation method for converting aryl alcohols or aryl aldehydes into aryl acids, ArC02H, consists of treating the former with sodium hydride and pyrazole in THF under oxygen or air at room temperature.1° Yields are good ( 6 6 9 9 % ) but the method is clearly limited to non-enolizable substrates. The original Ogata method for the a-chlorination of aliphatic acids (Clz02-C1S03H cat.) is not particularly effective when applied to long-chain fatty acids but by substituting TCNQ for oxygen yields are much improved.ll a-Chloroand a-bromo-acids can be obtained in ca. 80% yields from the corresponding a-amino-acids by diazotization in the presence of 48 : 52 (w/w) HF :pyridine and KC1 or KBr.120The sequence is not effective for the preparation of a-iodo-acids, although a related procedure can be used for the synthesis of a- or p-fluoroesters. 12b a-Trifluoromethyl-carboxylic acids are obtainable from simple orthoesters by reaction with trifluoromethanesulphenyl chloride, CF3SC1.l3 Ester and lactone cleavage with Me3SiI is not always successful when the reagent is generated in situ from Me3SiC1 and NaI; in such cases, a mixture of C13SiMeand NaI in acetonitrile may prove effe~t1ve.l~ A triphasic system consisting of poly(ethy1ene glycol) grafted onto polystyrene copolymers-C6H660% aq. KOH has been found to be almost as effective as the usual KOH in aqueous alcohol method for ester saponification. l5 a-N, N-Dialkylamino-ketones can be cleaved by hydrogen peroxide (Scheme 4).16Yields of carboxylic acids are a W. Oppolzer, R. Moretti, T. Godel, A. Meunier, and H. Loher, TetrahedronLett., 1983,24,4971; W. Oppolzer, R. Pitteloud, G. Bernardinelli, and K. Boettig, ibid., P. 4975. See alsoK. Soai, A. Ookawa, and Y. Nohara, Synth. Commun., 1983, 13,27. K. Kobayashi, P. K. Jodhav, T. M. Zydowsky, and H. G. Floss, J . Org. Chem., 1983,48,3510. See also J. D. Rozzell Jr., and S . A. Benner, ibid., p. 1190. lo S. Ohta, T. Tachi, and M. Okamoto, Synthesis, 1983, 291. l 1 R. J. Crawford, J . Org. Chem., 1983, 48, 1364. l2 (a) G. A. Olah, J. Shih, and G. K. S . Prakash, Helv. Chim. Acm, 1983,66,1028; ( b ) S. Hamman and C. G. Beguin, Tetrahedron Lett., 1983, 24, 57. l3 W. L. Mendelson, J.-H. Liu, L. B. Killmer, Jr., and S. H. Levinson, J . Org. Chem., 1983,48,298. l4 G. A. Olah, A. Husain, B. P. Singh, and A. K. Mehrotra, J . Org. Chem., 1983,48, 3667. l5 Y. Kimura and S . L. Regen, Synth. Commun., 1983, 13, 443. l6 D. Wenkert, K. M. Eliasson, and D. Rudisill, J . Chem. SOC.,Chem. Commun., 1983, 392.

134


high given that the substrate is otherwise stable to prolonged exposure to 30% H202.

Scheme 4

Acid Chlorides and Anhydrides.-Details of the preparation of polymer-bound PC15have been given.*’The reagent offers the advantage of a very simple work-up procedure, i.e. filtration and evaporation of the reaction solvent (1’2dichloroethane) , in the conversion RCO,H-RCOCl. The same transformation can also be carried out effectively using polymer-supported phosphines and cc14. l8 Symmetrical acid anhydrides can be easily obtained from the parent acids in ca. 80% yield using the formamidium chloride (18).l9 Alternatively, acid chlorides can be converted into symmetrical anhydrides under phase-transfer conditions (toluene-20% aq. NaOH-Bun4NC1) in 6 6 9 0 % yields.20 Diacids.-Fujisawa’s group has further extended its studies on the reactions between Grignard reagents and p-lactones to include condensations between bisGrignard reagents (19) and P-propiolactone. Yields of diacids (20) in this sixcarbon homologation procedure are in the range 60-68% .21 Hydroperoxides (21), derived from cyclic silyl e n d ethers, undergo cleavage and dimerization on MgBr

+ Me2NC=NMe2

(CHZ),

CI

MgBr

I

CI-

CO 2H

I

I

I

(CH2)n+ 4 Li 2CuC14

I

COZH

treatment with FeS04 resulting in a straightforward synthesis of long-chain a,odiacids (22) (53-72%).22 The reactions presumably proceed via the radical (23); when CU(OAC)~ is used in conjunction with FeS04, the dimerization step is suppressed and, instead, o-unsaturated acids (24) are isolated in 4 6 7 7 % yield. Both procedures appear to be milder than many existing methods for achieving such conversions, and should be applicable to more complex substrates.

G. Cainelli, M. Contento, F. Manescalchi, L. Plessi, and M . Panunzio, Synthesis, 1983, 306. C. R. Harrison, P. Hodge, B. J. Hunt, E. Khoshdel, and G. Richardson, J . Org. Chem., 1983,48, 3721. l9 T. Fujisawa, K. Tajima, and T. Sato, Bull. Chem. SOC. Jpn., 1983, 56,3529. 2o F. Roulleau, D. Plusquellec, and E . Brown, Tetrahedron Lett., 1983,24,4195. 21 T . Fujisawa, T. Sato, T. Kawara, and H. Tago, Bull. Chem. SOC.Jpn., 1983, 56,345. I. Saito, R. Nagata, K. Yuba, and T. Matsuura, Tetrahedron Left., 1983,24, 4439. l7

l8


135

(21)

(22)

(23)

(24)

The preparation of chiral compounds continues to be an area of great activity and examples will be found throughout this and other chapters in this Report. Of relevance to this section is a definition of the structural requirements for efficient asymmetric hydrolyses of dimethyl glutarates, when catalysed by pig liver e s t e r a ~ eThis . ~ ~ method can produce excellent results, such as the conversion of the hydroxyglutarate (25) into the half-ester (26) in virtually 100% optical yield. Copper-catalysed Michael additions by Grignard reagents (RMgX) to the sugar derivative (27) show a notable diversity of stereoselection.24When R is aryl or t-butyl, degradation of the initial adducts leads to diacids (28), whereas when R is ethyl or isopropyl addition occurs from the opposite face of (27) leading, after degradation, to the diacids (29). Optical yields throughout are excellent, and the method can also be used to obtain chiral butyrolactones [e.g. (30)]. Two research

K - Hh

MeOzC

COzMe

MeOzC

(coZEt

COzH

(26 1

(25)

/ /

\

=

R ,'

Et or Pr'

\

I.' C02 H

0< T H

H

COzH (31 1

dH

0

\y1

H

p:o*H

HOz C

H70:& HO2C

(28)

(29)

(30)

P. Mohr, N. Waespe-SarEevit, C. Tamm, K. Gawronska, and J. K. Gawronski, Helv. Chim. Actu, 1983, 66, 2501; W. K. Wilson, S. B . Baca, Y. J. Barber, T. J. Scallen, and C. J. Morrow, J. Org. Chem., 1983,48, 3960. 24 I. W. Lawston and T. D. Inch, J . Chem. Soc., Perkin Trans. 1, 1983, 2629.

23

136


groups have reported preparations of some potentially useful additions to the ‘chiral pool’, [e.g. (31)], starting from L-malic acid.25 Hydroxy-acids.-Almost all of the notable work reported in this area during 1983 has been directed towards enantioselective syntheses. Under appropriate conditions, the organometallic species R2Zn or RTi(OPr’)3 add to the (R)glyceraldehyde derivative (32) with stereoselectivities of S90% .26 Subsequent benzylation and degradation of the initial adducts (33) affords largely the (S)-abenzyloxy-acids (34) Three separate syntheses of (2S, 3R)-verrucarinic acid (35) have been developed; 27 chirality was introduced either by enantioselective ester hydrolysi~.~~ Sharpless epoxidation, or asymmetric hydroboration using dilongifolylborane.

--+

An’”

HOzC

R

H O Z C A O H II

Asymmetric condensations between enolates and aldehydes feature in three different approaches to chiral P-hydroxy-acids. The trianion (36) derived from (R)-N-acetyl-a-phenylglycinol reacts with aldehydes to give, after hydrolysis, the acids (39) of 297% enantiomeric purity after one recrystallization.28 Similar

(361

(391

(371

J. S. Bajwa and M. J. Miller,J. Org. Chem., 1983,48, 1114;J. D. Aebi, M. A. Sutter, D. Wasmuth, and D. Seebach, Liebigs Ann. Chem., 1983, 2114. 26 J . Mulzer and A . Angermann, Tetrahedron Lett., 1983, 24, 2843. 27 P. Herold, P. Mohr, and C. Tamm, Helv. Chim. Acta, 1983,66,744. 28 M. Braun and R. Devant, Angew. Chem., Int. Ed. Engl., 1983, 22, 788.

25


Me0

137

+ isomer

(40)

Scheme 5

condensations using the chiral sulphoxide (37) lead to acids (39) with 24-48% enantiomeric excesses.29In a somewhat different approach, reactions between bivalent tin enolates derived from the thiazolidine-2-thione (38) and aldehydes in the presence of a diamine ligand derived from (S)-proline result in products having optical purities of ca. 90% .30 An approach to chiral p-hydroxy-acids which does not involve carbanions is by [1,3]-dipolar additions between olefins and the nitrile oxide (40), derived from the glyceraldehyde (32) (Scheme 5 ) .31 Although the diastereoselectivities in this step are poor or non-existent, the resulting isomeric isoxazolines are readily separable by chromatography, and so the overall method could be worthwhile in appropriate cases. Closely related [1,3]dipolar additions using the nitrile oxide (41) (Scheme 6) lead to cis-hydroxy-acids . ~ ~ yields are good but after degradation of the initially formed h e t e r ~ c y c l eOverall the conditions used in the degradation steps (H,Raney nickel followed by H5106)clearly impose some constraints on the method.

Scheme 6

A further example of the subtle effects which can be encountered in enzymemediated reactions has been found during an asymmetric synthesis of L-carnitine (44) (Scheme 7),33an amino-acid involved in the metabolism and transport of long-chain fatty acids. Reduction of the ethyl ester of acetoacetate (42) by yeast gives the (S)-isomer of (43) in 55% enantiomeric excess, whereas reduction of the n-octyl ester of (42) occurs at the same rate but gives (R)-(43) with 90% e.e.! R. Annunziatia, M. Cinquini, A. Gilardi, and F. Cozzi, Synthesis, 1983, 1016. N. Iwasawa and T. Mukaiyama, Chem. Lett., 1983,297. 31 A. P. Kozikowski, Y . Kitagawa, and J. P. Springer, J. Chem. SOC., Chem. Commun., 1983, 1460. 32 A. P. Kozikowski and M. Adamczyk, J. Org. Chem., 1983,48,366. 33 B. Zhou, A . S. Gopalan, F. VanMiddlesworth, W. Shieh, andC. J. Sih, J. Am. Chem. SOC.,1983,105, 5925.

29 30


138

(42)

(43) Scheme 7

(44)

Large-scale Baeyer-Villiger oxidations are often difficult and potentially dangerous to carry out; thus a recently developed procedure using 30% H202, together with acetic and maleic anhydrides, should find wide application in the preparation of w-hydroxy-acids from cyclic ketones.34 Keto-acids.-A one-pot procedure for the conversion of a-amino-acids (45) into a-keto-acids (46) proceeds via the derived 2-trifluoromethyl-3-oxazolin-5ones.35fl-Keto-acids can be efficiently prepared by acylation of the enolate of trimethylsilyl acetate with acid chlorides: the lability of the silyl ester group is crucial allowing isolation of the keto-acids before decarb~xylation.~~ An alterna-

tive approach to aroylacetic acids is to carboxylate acetophenones using the reagent (47), which can be obtained from DBU.37 Copper-catalysed additions of ethyl diazoacetate to enol ethers (48), followed by saponification, provides the cyclopropane acids (49) which are convertible into y-keto-acids (50) simply by brief treatment with hot, aqueous methanol.38 Yields throughout are excellent and the only significant drawback would seem to be the regioselectivity of attack by the carbenoid species in the first step, in cases involving complex substrates. y-Keto-acids (52) can also be obtained readily by treatment of terminal acetylenes (51) with Me1 and CO in the presence of cobalt and ruthenium ~ a r b o n y l sPreviously .~~ reported work showed that such reactions when catalysed only by [co,(co)8] lead instead to butenolides. An alternative set of conditions for the oxidative cleavage of enones [e.g. (53)454)] has been developed which consists of ozonolysis at -78°C in CHzClz,

I. Bidd, D. J. Kelly, P. M. Ottley, 0. I. Paynter, D. J. Simmonds, and M. C . Whiting,]. Chem. SOC., Perkin Trans. 1, 1983, 1369. 35 C. Klein, G. Schulz, and W. Steglich, Liebigs Ann. Chem., 1983, 1623, 1638. 36 P. J. Cowan and M. W. Rathke, Synth. Commun., 1983,13, 183. 37 N. Matsumura, T. Ohba, and S. Yoneda, Chem. Lett., 1983, 317. 38 H. Kunz and M. Lindig, Chem. Ber., 1983, 116,220. 39 11. Alper and J.-F. Petrignani, J . Chem. SOC., Chem. Commun., 1983, 1154. 3,4

139

Carboxylic A c i h and Derivatives MeOy,

+

M e o RF C 0 2 H

6

R\lfVco2H 0

R (481

(491

(50)

followed by oxidation with 30% H202and aq. NaOH under phase-transfer conditions.40 Unsaturated Acids.-A few preliminary results suggest that aza-Claisen rearrangements involving (L)-valinol derivatives [e.g. (%)] could provide a useful entry into optically active acids [e.g. (56)] (Scheme 8).41The enantiomer of (56) is formed to an extent of 13% and, although the method has only been tested on very simple substrates, it may turn out that even higher optical yields will be realized in rearrangements of more complex substrates.

155 “c ___j

(561

(55)

Scheme 8

y-Brominations of a,/?-unsaturated acids using N-bromosuccinimide are often unsatisfactory, in contrast to similar brominations of the corresponding esters. If the y-bromo-acid is required, then the final ester hydrolysis step can be problematical in this approach. A solution to this is to employ water sensitive trimethylsilyl esters, allowing the conversion [(57)+(58)] to be effected, generally in good overall yields.42 Metallation of terminal allenes (59) by t-butyl-lithium followed by conversion into the tri-isobutylaluminate derivatives, and finally carboxylation affords the acetylenic acids (60) in ca. 70% yields, virtually uncontaminated by the corresponding allenic acids, which are formed as major products when the Zithiurn allenes are directly ~arboxylated.~~ These two methods are thus complementary J. A. Cella, Synth. Commun., 1983, 13, 93. M. J. Kurth and 0. H. W. Decker, Tetrahedron Lett., 1983,24, 4535. 42 M. Bellassould, F. Habbachi, and M. Gaudemar, Synthesis, 1983,745. 43 G. Hahn and G. Zweifel, Synthesis, 1983, 883. 41

140


(57)

(59)

(58)

(60)

\

and provide one solution to the perennial problem of acetylene-allene equilibration. y, 6-Acetylenic acids (63) can be prepared by TiC1,-catalysed additions of alkynyl-silanes (61) to unsaturated acyl cyanides (62) followed by aqueous hydrolysis (Scheme 9); overall yields are reasonable .44

(61 1

(62)

(63) Scheme 9

Cobalt-catalysed carbonylations of aryl bromides [(64)+(65)] using one atmosphere of carbon monoxide can be carried out under phase-transfer conditions provided that the mixture is irradiated with a sunlamp.45Yields of the aryl carboxylates (65) are usually in excess of 90%; the method is also effective for the carboxylation of cycloalkenyl bromides and bromostyrene and for the preparation of lactones and lactams in examples where an appropriate nucleophile (OH or NH2)is present as an ortho substituent of the aryl bromide. Benzylic halides (66) can also be carbonylated under phase-transfer conditions, but using [Fe(CO)5]as catalyst; returns of the arylacetic acids (67) in this apparently simple method are in the range 31-75% .46 Alternative approaches to arylacetic acids ArBr

(64)

__f

ArCOzNa

(65)

Ar-X

(66)

ArnCO,H

(67)

involve rearrangements of acetals of a-halogenoalkyl aryl ketones cataiysed by Lewis or of the unprotected ketones, in the presence of HC(OEt), and l'l(N03)3.47b Phase-transfer catalysed carbonylations are also featured in a method for the overall isomerization of trans- to cis-cinnamic acids, involving bromination of the former followed by decarboxylative debromination, to give the cis-bromo-styrene (68), and finally PTC-carbonylation (Scheme lo) .48 Overall yields are in the range 28--47% (cf. ref. 45).

(68 1 Scheme 10 A. Jellar, J.-P. Zahra, and M. Santelli, Tetrahedron Lett,, 1983,24, 1395. .I.-J. Brunet, C. Sidot, and P. Caubere, J . Org. Chem., 1983, 48, 1166. 46 G. Tanguy, B. Weinberger, and H. des Abbayes, Tetrahedron Lett., 1983,24,4005. 47 ( a ) G. Castaldi, A. Belli, F. Uggeri, and C. Giordano, J. Org. Chem., 1983,48,4658; ( b )K. Fujii, K. Nakao, and T. Yamauchi, Synthesis, 1983, 444. 48 V. Galamb and H. Alper, Tetrahedron Lett., 1983, 24,2965.

44 45


141

A Japanese group has given full details of its studies on the metallation reactions of the benzene-tricarbonylchromium complexes (69); treatment of the intermediate lithiated complexes with COz provides a useful entry to various substituted benzoic acids and quenching with methyl chloroformate yields the corresponding methyl Significantly, the regioselectivity of metallation can be controlled by adjusting the size of the oxygen substitutent ‘R’; when this is small [e.g. (69; R=Me)], metallation at position 2 is favoured by chelation control, but when R is large steric shielding results in attack at position 4. 1-Substituted-2-naphthoic acids (71) can be prepared in 32-84% yields by displacement of the 1-methoxy-group in the oxazoline derivative (70) using organometallic species, followed by hydrolysis of the heterocycle .50 The methoxygroup is sufficiently labile that it is even displaced by the di-isopropylamide group of LDA, a reagent not usually noted for its nucleophilicity. Starting materials for the possible extension of this work, i.e. 1-hydroxy-2-naphthoic acids (73), are , ’ . \

I

I

\ I

OMe ( 69)

(70)

(71)

(73)

( 74 1

R

(72)

usually prepared by Kolbe-Schmitt carboxylation of the corresponding 1-naphthoxides. However, the method is not without its practical difficulties, which has led to the development of an alternative approach involving treatment of 1-hydroxynaphthalenes (72) with Stiles reagent, magnesium methyl carbonate, in DMF at 180°C under ca. 34 atm of n i t r ~ g e n .Yields ~’ of acids (73) are virtually quantitative in the examples quoted. In a tenacious piece of work, a Japanese group has prepared all nineteen possible deuteriated benzoic acids (74) .52 The compounds, which will doubtless be of use in various mechanistic and biosynthetic studies, were mainly prepared by Br/D exchange using Raney Cu-A1 alloy in 10% NaOD-D20.

M. Vemura, N. Nishikawa, K. Take, M. Ohnishi, K. Hirotsu, T. Higuchi, and Y. Hayashi, J . Org. Chem., 1983,48,2349. 50 A . I. Meyers and K. A. Lutomski, Synthesis, 1983, 105. 51 L. A. Cate, Synthesis, 1983, 385. s2 M. Tashiro, K. Nakayama, and G. Fukata, J . Chem. SOC.,Perkin Trans. 1, 1983, 2315.

49


142

Protection and Deprotection.-A total synthesis of a major metabolite of PGDz features the use of the Wittig reagent (75) in which a carboxylic acid function is masked using methodology recently brought to prominence by C ~ r e y The .~~ closely related 2,4,10-trioxa-3-adamantyl group can similarly be used, as shown by the successful preparation of Grignard reagents (76; This latter moiety is obtained by treatment of the corresponding nitrile with cyclohexane1,3,5-triol and hydrogen chloride, a standard method for the preparation of such heterocycles. A drawback with both protecting groups is the requirement of sequential acid hydrolysis and base saponification for their removal, which may

na

Ph3P

11

(75)

(76)

rather limit their utility in multi-functional syntheses. Diacids and hydroxy-acids, as well as a number of other bifunctional compounds, can be temporarily protected as the silylene derivatives, prepared using divinylo~ysilanes.~~ This serves to emphasize that one of the easiest ways briefly to protect the acidic proton in carboxylic acids is by conversion into the water-labile trimethylsilyl ester 2"5 .36742,

Decarboxy1ation.-Simple alkanoic acids can be decarboxylated to give the corresponding alkanes by treatment with silver nitrate (catalytic amount) and sodium persulphate in hot, aqueous a c e t ~ n i t r i l eThe . ~ ~ method, which probably proceeds via radical intermediates and involves AgI1species, appears to be quick and straightforward although yields are only moderate; when applied to arylacetic acids, 1,Zdiarylethanes are produced (ca. 50%). In an extension of previous work, it has been found that aliphatic esters derived from N-hydroxypyridine-Zthione can be efficiently decarboxylated via a radical chain reaction in the presence of either Bun3SnHor B u ~ S HWhen , ~ ~ such esters are heated with carbon tetrachloride , the corresponding alkyl chlorides are produced, again probably via a radical chain mechanism, in 70-95% yield, implying that this method is a viable alternative to the classical Hunsdiecker reaction.58The latter reaction is not usually applicable to the synthesis of alkyl fluorides; however, such transformations can be effected by treatment of a carboxylic acid with xenon difluoride-hydrogen fluoride in methylene chloride at room t e m p e r a t ~ r eThe .~~ method works well in many cases (54-84% yields) but is limited (e.g. it fails in the cases of hydroxy- and benzoic acids) not the least because of the need for a tame inorganic chemist to supply the XeF2.The Cristol-Firth modification of the E. J. Corey and K. Shimoji, J . Am. Chem. SOC., 1983,105, 1662. G . Voss and H. Gerlach, Helv. Chim. Acta, 1983, 66,2294. 55 Y. Kita, H. Yasuda, Y. Sigiyama, F. Fukata, J. Haruta, and Y. Tamura, Tetrahedron Lett., 1983,24, 1273. s6 W. E. Fristad, M. A. Fry, and J. A. Klang, J . Org. Chem., 1983,48, 3575; W. E. Fristad and J. A. Klang, Tetrahedron Lett., 1983,24,2219. s7 D. H. R. Barton, D. Crich, and W. B. Motherwell, J . Chem. SOC., Chem. Commun., 1983,939. s8 D. H. R. Barton, D. Crich, and W. B. Motherwell, Tetrahedron Lett.,1983,24,4979. 59 T. B. Patrick, K. K. Johri, and D. H. White, J . Org. Chem., 1983, 48, 4158. 53 54


143

Hunsdiecker reaction has been successfully applied to the mercury(I1) salts of nicotinic acid, to give 3-halogenopyridines via ipso-halogenation A detailed study of the steric course in dehydrative decarboxylations of P-hydroxy-acids has revealed that whereas the erythro-isomers generally give only (E)-olefins, the threo-isomers lead to either ( E ) -or (Z)-olefins, depending on the substituents present (Scheme 11). Furthermore, when R1=alkyl and R2=Ph, mixtures of the two isomers are produced; a reasonable rationale of these observations is presented.

> 98"Ia

> 98 ' l a

A1

thre o

R' = A r or OR R2 = AIkyl

R' = Ar

R2=

e - r i c h Ar

Scheme -11

A popular method for the direct decarboxylation of P-keto-esters [(77)- (78)] is to heat the latter in wet DMSO (Krapcho's method). A procedure that may well supersede this involves treatment of the keto-ester with the sodium or potassium salt of propane-l,2-diol in propane-1,2-diol at 6&85 "C for 15-30 rnin6*Yields are often, but not always, in excess of 95%. Ethylene glycol or glycerol can be used in place of propanediol; significantly, the method requires both shorter reaction times and lower temperatures than those used in the DMSO procedure. The synthetic utility of the initial adducts formed from p-keto-ester enolates and similar species and cationic cycloalkadienyl-iron complexes can be diminished owing to difficulties in decarboxylation. One solution to this problem is to use

C02Me

(80)

(81)

(82)

(83)

2-(trimethylsily1)ethyl esters, which lead to adducts such as (79), decarboxylation of which is achieved simply by treatment with fluoride.63 S. Vemura, S. Tanaka, M. Okano, and M. Hamana, J . Org. Chem., 1983,48, 3297. J. Mulzer and 0. Lammer, Angew. Chem., Int. Ed. Engl., 1983,22, 628. 62 R . Aneja, W. M. Hollis, A. P. Davies, and G. Eaton, Tetrahedron Lett., 1983, 24, 4641. 63 M. Chandler, P. J. Parsons, and E. Mincione, Tetrahedron Lett., 1983, 24, 5781.


144

The classical copper-quinoline method has been successfully applied to the decarboxylation of (2)-a-acetylamino-unsaturatedacids (80), leading to primary (E)-enamides (81) in 50-77% yields.64When pyridine is used as solvent, the lower temperature allows the isolation of significant amounts of the corresponding (2)-isomers. Hindered halogeno-esters [e.g. (82)] can be efficiently degraded to styrenes (83) by thermolysis in HMPA at 140°Cor, more slowly, by refluxing in pyrrolidine .6s 2 Esters Esterificati0n.-A review of methods for esterification and thioester formation has been published.66Further additions to the already extensive list of coupling reagents suitable for ester formation include the oxalic acid-derived homologue of 1,l’-carbonyldi-imidazole ,67 2-chlor0-3,5-dinitropyridine,~~ and 1,l’dimethyl~tannocene.~~ Each reagent could be advantageous in appropriate circumstances. A very simple method for esterfication is to treat a mixture of an acid and an alcohol (excess) with chlorotrimethylsilane.70This mild procedure affords esters in 73-98% yield and can also be used to prepare ketals from ketones. Carboxylic acids react with alkyl chloroformates in the presence of triethylamine and 4-dimethylaminopyridine (DMAP; catalyst) to give alkyl carboxylates rapidly and cleanly (>90% yield usually), in yet another mild esterification p r ~ c e d u r e However, .~~ during a total synthesis of Trichoverrol B, the (2,E)dienoic acid fragment was coupled to a central alcohol unit without isomerization by using the mixed anhydride formed with pivaloyl chloride and the sodium salt of the as the usual ‘mild’procedures involving catalytic amounts of DMAP resulted in extensive isomerization of the dienoic acid, possibly because of reversible Michael additions by this base catalyst. A new route to t-butyl esters involves brief treatment of a carboxylic acid with DMF di-t-butyl acetal at 80°C in benzene or toluene.73Although a number of DMF acetals have been used in esterifications in the past, the method has apparently not been previously applied to t-butyl esters. A full recipe has been given for the preparation of polystyrene-bound diphenylphosphine which, in conjunction with diethyl azodicarboxylate, can be used to form esters from one equivalent each of an acid and an alcohol at ambient temperature in THF with yields of 64-99%.74 Esters can also be formed by the alkylation of acids with one equivalent of an alkyl bromide in the presence of mercuric oxide and H F or HBF,; yields vary between 34 and 79%.7s Schmidt and A. Lieberknecht, Angew. Chem., Int. Ed. Engl., 1983,22, 550. J. L. Belletire and D. R. Walley, Tetrahedron Lett., 1983, 24, 1475. 66 A. Arrieta, T. Garcia, J. M. Lago, and C. Palomo, Synth. Commun., 1983,13, 471. b7 S. Murata, Chem. Lett., 1983, 1819. S. Takimoto, N. Abe, Y. Kodera, and H. Ohto, Bull. Chem. SOC. Jpn., 1983,56,639. 69 T. Mukaiyama, J. Ichikawa, and M. Asami, Chem. Lett., 1983, 683. 70 M. A. Brook and T. H. Chan, Synthesis, 1983, 201. 71 S. Kim, Y. C. Kim, and J. I. Lee, Tetrahedron Lett., 1983,24,3365. 72 W. R. Roush and A. P. Spada, Tetrahedron Lett., 1983, 24,3693. 73 U. Widmer, Synthesis, 1983, 135. 74 R. A. Amos, K.W. Emblidge, and N. Havens, J . Org. Chem., 1983,48,3598. 75 J. Barluenga, L. Alonso-Cires, P. J. Campos, and G. Asensio, Synthesis, 1983,649.

61 U . 65

145


General Synthesis.-The p-tolylsulphone (85) has been found to be superior to the corresponding methylsulphone for the one-carbon homologation of alkyl halides (84) into esters (86).76Phase-transfer conditions are used in the alkylation step and the resulting intermediates are converted into the esters (86) by sequential oxidation, using hydrogen peroxide, and acidic methanolysis. Furthermore, condensations of (85) with aromatic aldehydes can be used to prepare a-methoxyarylacetates. RX

-csMe

+

so;! p-tol (85)

( 84)

-COtEt

Bu"MeCu(CN)LiZ

\

(88)

(87)

I I

'y

RC02Me

a@-Unsaturatedesters, in contrast to similar ketones, are usually ineffective as Michael acceptors in reactions with the common cuprate reagents, R2CuLi. It has now been found that such additions can be achieved by using higher-order, mixed cuprates having a stoicheiometry of R2C~(CN)Li2.77 The method works well with P-substituted esters [e.g. (87)] and also in the cases of a$-disubstituted substrates (e.g. tiglates), provided that these are esterified with a very bulky t-butyldiphenylsilyl group. In order to avoid wastage of a potentially valuable ligand, R, mixed cuprates [e.g. (SS)] can be used; thus, ethyl crotonate (87) is converted into ester (89) in 86% yield with only 4.5% of the alternative product arising from transfer of the methyl ligand being produced. An alternative strategy for effecting the same overall transformation is to use the known conjugate addition-trapping sequence of unsaturated keto-phosphoranes (90), followed by oxidative degradation (NaOC1) and esterification (CH2N2) (Scheme 12).78 Overall yields are very good, and the method can be applied to relatively sensitive substrates such as terpenoids. Potassium enolates of simple esters and amides

0

RixcO*M

R'

R2

( 90)

Scheme 12 76 l7

K. Ogura, N. Yahata, K. Hashizume, K. Tsuyama, K. Takahashi, and H. Iida, Chem. Lett., 1983,767. B. H. Lipshutz, Tetrahedron Lett., 1983,24, 127. M. P. Cooke, Jr., J . Org. Chem., 1983,48, 744.

146


undergo efficient Michael additions to vinyl sulphones, providing yet another method for ester h o m ~ l o g a t i o n . ~ ~ One or two tertiary alkyl groups can be incorporated into the a-position of esters by treatment of trimethylsilyl ketene acetals with tertiary halides in the presence of zinc chloride (Scheme 13).*OUnderstandably, yields are variable but probably compare well with alternative routes to such highly substituted compounds.

Scheme 13

Generally, the method of choice for the production of reactive carbenoid intermediates from diazoacetates is to use a rhodium(I1) carbonyl catalyst. However, when generated in this way, these species are not effective in cyclopropanation reactions of electron-deficient olefins, such as a,P-unsaturated esters. This limitation can be overcome by the use of various nickel catalysts or by using Pd(OAc)2.81Thus, treatment of ethyl diazoacetate and methyl acrylate in hot benzene with this catalyst affords cyclopropane (91) in 85% yield; returns are poorer when the olefin is more highly substituted. Variations in the regioselectivity of cyclopropanation reactions between ethyl diazoacetate and various dienes and trienes as a function of the nature of the catalyst have also been investigated.s2 Carbonylation of 1,l-dibromocyclopropanes (92) with tetracarbonylnickel in hot DMF in the presence of an alcohol (R30H) leads to cyclopropane carboxylates (93) in 4 6 7 8 % yields.83If an appropriately positioned alcohol group is present, lactones [e.g. (94)] can be prepared by this method. As cyclopropanes (92) are usually formed from an olefin and

0

P. R. Hamann and P. L. Fuchs, J . Org. Chem., 1983,48,914. M. T. Reetz, K. Schwellnus, F. Hubner, W. Massa, and R. E. Schmidt, Chem. Ber., 1983,116,3708. M. W. Majchrzak, A . Kotelko, and J . B. Lambert, Synthesis, 1983,469. A . J. Anciaux, A . Demonceau, A . F. Noels, R. Warin, A . J. Hubert, and P. TeyssiC, Tetrahedron, 1983, 39,2169. 83 T. Hirao, Y. Harano, Y . Yamana, Y. Ohshiro, and T. Agawa, Tetrahedron Lett., 1983,24,1255.

79

8o

147


dibromocarbene, this method represents an alternative to one-step cyclopropanation reactions involving diazoacetate. Enolates of cyclopropane carboxylates (95) can be successfully generated using LDA, although good yields of the dqlkylated products (96) are only realized with reactive electrophiles such as methyl iodide or allylic halides.84 Previous work by Sharpless et al. has been developed into a general method for . ~ ~ the ether cannot the oxidation of benzyl ethers into benzoates by R u O ~Clearly, contain other functions, such as isolated phenyl groups,86which are also oxidized by this reagent. A method for the synthesis of a-bromo-esters, outlined in Scheme 14, looks to be especially suitable for large-scale preparation^.^^ The final decarboxylation step is considerably facilitated by the addition of catalytic amounts of lithium carbonate. @-Iodo-esters[e.g. (97)] are formed on brief treatment of the corresponding a,@-unsaturated acids with Me3SiI;88 this reaction thus could represent a

i, ii

R~ : : 2 "

TCO'" C02Et

COZEt

iii

, R/ycoz Br

Reagents: i, 1 equiv. KOH, EtOH; ii, Br,, AcOH; iii, A, THF, Li2C03

Scheme 14

limitation in the ester dealkylation method using the latter reagent, although reversal of the addition should not be difficult. Isolable titanium homoenolates (98) can be obtained from cyclopropanone acetals and condense with aldehydes to give y-chloro-esters (99).89 The intermediate hydroxy-esters can only be isolated in low yields. Recipes have been provided for the preparation of a variety of substituted aryloxy-acetic acid esters (100; X=SCN, NCS, N3, OR).90 CI

R'

RZ

OSiMe3 (101)

I

NR2 (102)

I. Reichelt and H.-U. Reissig, Chem. Ber., 1983, 116, 3895. P. F. Schuda, M. B . Cichowicz, and M. R. Heimann, Tetrahedron Lett., 1983,24,3829. 86 A. K. Chakraborti and U. R. Ghatak, Synthesis, 1983,746. 87 0. P. Goel and U . Krolls, Tetrahedron Lett., 1983,24, 163. T. Azuhata and Y. Okamoto, Synthesis, 1983,461. E. Nakamura and I. Kuwajima, J . Am. Chem. Soc., 1983, 105,651. 9o J. L. Colin and B . Loubinoux, Synthesis, 1983, 568.

84 85

6

148


Ester (and lactone) silyl enolates (101) undergo zinc chloride--catalysedalkylations with dialkylaminomethylethers leading to the Mannich-type adducts (102) in 59-90% yields.91Dienolates can be used, reaction occurring at the y-position. These adducts are useful as precursors to a-methylene-esters and lactones; indeed, when applied to 6-valerolactone, the scheme leads directly to the a-methylene derivative. Silyl enolates (101) can also be alkylated by a-chloroethers (104) obtained from vinyl ethers (103) by the addition of phenylsulphenyl chloride; again dienolates react at the y-positions.92 Carbocyclic analogues of (105) can also be prepared from cycloalkenes by this route. Good to excellent asymmetric inductions have been achieved in alkylations of enolates obtained from esters of (+)-camphor derivatives; these results can be explained in terms of steric shielding and cation c~mplexation.~~ Diestem.-In extensions of previous studies, Trost and Hung have found that reactions between aryl-substituted allylic carbonates (106) or (107) and dimethyl sodiomalonate are completely regioselective when a tungsten carbonyl catalyst is used, and lead exclusively to the more hindered isomer (108) (Scheme 15).94The use of carbonate as leaving group rather than the more usual acetate was necessary because of the former’s greater reactivity in this respect. Malonate enolates also show a marked preference for attack at the more hindered site in molybdenum-catalysed reactions with tertiary allylic acetates [e.g. (109)+ (l10)];95 however, other related nucleophiles tend to add predominantly at the primary centre. A further example of regioselective attack by malonate is in alkylations of enol thi0ethe1-s.~~ Such SN2displacements [(ill)+(112)] seem to be general for other soft nucleophiles related to malonate, resulting in a method of considerable potential. A similar propensity for SN2attack by soft nucleophiles has been observed in reactions between a-bromomethyl-esters (113) and keto-ester enolates (114) which lead largely or exclusively to the Necic acid synthons (115).97 Malonates and related keto-esters and 1’3-diones can be forced to undergo

T. Oida, S . Tanimoto, H. Ikehira, and M. Okano, Bull. Chem. SOC.Jpn., 1983,56,645. R. P. Alexander and I. Paterson, Tetrahedron Lett., 1983,24,5911; S . K. Pate1 and I. Paterson, ibid., p. 1315. 93 G. Helmchen, A . Selim, D. Dorsch, and I. Taufer, Tetrahedron Lett., 1983, 24, 3213. 94 B . M. Trost and M.-H. Hung, J . Am. Chem. Soc., 1983,105,7757. See also T. Hayashi, T. Hagihara, M. Konishi, and M. Kumada, ibid., p. 7767. 95 B. M. Trost and M. Lautens, J . Am. Chem. SOC., 1982,105,3343. % B. M. Trost and A. C. Lavoie, J . Am. Chem. SOC., 1983, 105,5075. 97 F. Ameer, S . E. Drewes, N. D. Emslie, P. T. Kaye, and R. L. Mann, J. Chem. SOC., Perkin Trans. 1, 1983, 2293. For other examples of Neck acid syntheses, see R. S . Glass and M. Shanklin, Synth. Commun., 1983, 13, 545.

91

92

149

Carboxylic Acids and Derivatives Ar

wOC02 Me (106)

1

or

OC02Me (107)

I

(108)

Scheme 15

(11 3)

Michael additions to P,P-disubstituted enones and other sterically hindered substrates by the application of high pressure (ca. 15 kbar).98Such conditions can also be used to effect Michael additions of 0-silyl enolates to enones without the need to add a Lewis acid. Clearly, such a procedure has considerable potential for the synthesis of very acid- or base-sensitive compounds but does have the drawbacks of small reaction scale and/or the availability of suitable apparatus. Simple ester enolates add to 4-bromocrotonate, presumably via a conjugate addition-intramolecular cyclization sequence, to give substituted cyclopropanes in 3 7 4 2 % yield (Scheme 16).99A somewhat similar method for the preparation of cyclopropane-1,1-dicarboxylates from vinyl selenones and malonate enolates has also been devised. loo

W. G . Dauben and J. M. Gerdes, Tetrahedron Len., 1983,24,3841; R. A . Bunce, M. F. Schlecht, W. G . Dauben, and C. H. Heathcock, ibid., p. 4943. 99 P. Prempree, S. Radviroongit, and Y . Thebtaranonth, J. Org. Chem., 1983,48, 3553. loo I. Kuwajima, R. Ando, and T. Sugaware, Tetrahedron Lett., 1983,24,4429. 98

150


Scheme 16

A further application of chiral pyrrolidines derived from proline in asymmetric synthesis is in condensations of the enamine (116) with arylidene malonates (117) which give the expected products (118) with >90% diastereoselectivity and >SO% enantiomeric enrichment. lol

The propensity of cyclopropane-1,l-dicarboxylates to act as Michael acceptors has been exploited in a synthesis of the substituted phenols (119) (Scheme 17).lo2 Although yields of (119) are high, the overall conversions are low and the reaction conditions appear to be in need of optimization. An unusual 1,2-ester transposition has been observed when succinates (120) are treated with potassium hydride in glyme.'03 Although the products (121) are formed in high yield presumably via a cyclopropane alkoxide, the method is probably limited to examples where R2is an electron-withdrawing group such as C02Me or CN.

Scheme 17

Ph

%

C02Me

R2

(120)

&

Ph

VMe C02Me

R2

( 121 1

A double hydroesterification of terminal acetylenes leading to maleates (122) has been described (Scheme 18).lO4Yields are generally 70-89% for simple S. J. Blarer and D. Seebach, Chem. Ber., 1983, 116,2250, 3086. G. Sartori, F. Bigi, G. Casiraghi, and G. Casnati, Tetrahedron, 1983,39, 1761. lo3 J. S. Tou and A. A. Schleppnik, J. Org. Chem., 1983,48, 753. lo4 H. Alper, B. Despeyroux, and J. B. Woell, Tetrahedron Left., 1983,24,5691.

lo*

151


acetylenes; when carried out with methyl alkynes, (E)-monoesters (123) are obtained [cf. (7)- (8); ref. 41. Succinates can be prepared by alkylations of the

(122 1 Reagents: i, PdCl,, CuCI,, HCl, O,, CO (1 atm), MeOH, 20°C

Scheme 18

Reformatsky reagent derived from t-butyl bromoacetate with a-bromoacetates in DMSO. lo5 Similar reactions involving y-bromo-crotonates proceed in an SN2 manner leading to hexenedioates (124). Dianions derived from alkanedioates can be oxidatively coupled intramolecularly , using CuX2, but only when the resulting carbocycles are three- or six-membered [(125) and (126) respectively]. lo6 Acetoxymercurations of cyclopropanes in the presence of fumarates can be used to prepare variously substituted succinates (Scheme 19).lo7 Olefins other than fumarates can also be used successfully; overall yields for these manipulatively simple reactions are between 41 and 75%.

a

CO2 Me C02Me

(I26)

Reagents: i, Hg(OAc),, AcOH; ii, NaBH,

Scheme 19

Hydroxy-esters.-As in previous years, the main developments in this area have been in diastereoselective and asymmetric synthesis. a-Keto-esters derived from (-)-8-phenylmenthol are reduced by K(OBU')~BHin THF to give hydroxy-esters (128) with enantiomeric enrichments of up to 9O%.losPresumably, the phenyl substituent acts as a steric s ~ r e e nlargely ~ , ~ ~preventing attack from one side of the keto-ester group [cf. (127)]. This type of ester seems to have considerable synthetic potential as it has been demonstrated that other nucleophiles such as Grignard reagentslog and alkyl stannaneslo9can also react with (127) to give substituted F. Orsini and F. Pelizzoni, Synth. Commun., 1983, 13, 523. S. K. Chung and L. B. Dunn, Jr., J . Org. Chem., 1983,48, 1125. B. Giese and W. Zwick, Chem. Ber., 1983, 116,1264. lo* J. K. Whitesell, D. Deyo, and A. Bhattacharya, J . Chem. Soc., Chem. Commun., 1983,802. lO9 Y. Yamamoto, N. Maeda, and K. Maruyama, J . Chem. Soc., Chem. Commun., 1983,774.

lO5

152


cr-hydroxy-esters with 85-90% enantiomeric enrichments. Tri-n-butylallylstannanes react with isopropyl glyoxylate to give largely (90%) the erythro-isomer [e.g. (129)] in contrast to the corresponding 9-BBN derivative which gives a 3:l mixture in which the threo-isomer predominates. When the same allyl stannane is reacted with the menthyl glyoxalate (127; R=H), the resulting hydroxy-ester can be converted into verrucarinolactone (130), a fragment of verrucarin A, with 91% enantiomeric enrichment, after recrystallization. The erythro-hydroxy-ester (129) can also be obtained with 98% selectivity by a [2,3]-Wittig-type rearrangement of aza-enolates derived from the dihydro-oxazine (131), followed by alcoholysis of the resulting isomeric oxazine (132).'1° As mentioned above, condensations between allyl boranes and glyoxalates give predominantly threo-crhydroxy-esters. Similar reactions with pyruvate derivatives of very bulky phenols

(127)

(128 1

(1 29)

4 I 1

n

A

OH (132)

(e.g. 2,6-di-t-butyl-4-methylphenol) lead exclusively to the threo-isomers [e.g.

(133)]."' Methyl benzoylformate (134) condenses with the chiral allyl silane (135) under standard conditions to give the expected product (136) with 91% enantiomeric enrichment.''* The generality of this approach has not been defined and it may perhaps be limited to examples in which both reactants carry bulky subst ituen ts . 0 P hA C O * M e

(134) 4

+ SiMe,

(133)

@YPh H

Ph

(136)

(135 1 110 K.

Mikami, K. Fujimoto, and T. Nakai, Tetrahedron Lett., 1983, 24,513. 111 Y. Yamamoto, T. Komatsu, and K. Maruyama, J . Chem. SOC.,Chem. Commun., 1983, 191. T. Hayashi, M. Konishi, and M. Kumada, J . Org. Chem., 1983,48,281.


153

A full report has been given describing optimum conditions for lead tetraacetate oxidations of ester trimethylsilyl enolates to a-acetoxy-esters.ll3 The method is also suitable for oxidations of lactone enolates; yields are often very good. The classical Reformatsky route to P-hydroxy-esters can sometimes be improved by the use of highly reactive zinc-graphite in place of the more conventional metals. 114 An alternative preparation of P-hydroxy-esters involves Lewis acid-promoted condensations between ketones and silyl ketene acetals (ester silyl enolates). The steric limitations of this reaction have now been defined; for example, the approach fails when the ketone is doubly a-branched, as in the case of di-isopropyl ketone.’15 Enolates derived from the heterocyclic amides (137) condense with aldehydes, R2CH0, to give only the erythro-p-hydroxy-esters (138) after oxidation at sulphur and cleavage by methoxide. 116 Yields of the initial condensation products are 45435% but returns from the last two steps are not detailed. In an extension of work previously discussed,30 condensations between the tin(I1) enolate of 3-acetylthiazolidine-2-thione (38) and a-keto-esters in the presence of a diamine ligand derived from (S)-proline produce derivatives (139) with >95% enantiomeric enrichrnent.ll7 A number of additions to the ever increasing list of enantioselective reductions which can be carried out using Baker’s yeast have been reported this year. The potassium salts of /!I-keto-acidsare reduced by the yeast to give hydroxy-esters (140) in chemical yields of 38-59% after esterification and chromatography. 11* Optical yields are essentially quantitative and the method looks to be a distinct improvement of the established approach to esters (140) which involves similar reductions of P-keto-esters. However, reductions of P-keto-esters containing perfluoroalkyl groups have been carried out using Baker’s yeast to give the corresponding P-hydroxy-esters in >90% optical ~ i e 1 d s . Two l ~ ~ isolated examples of yeast reductions worthy of note are those of ethyl a-formylpropionate, leading to hydroxy-propionate (141) with 6 0 - 6 5 %

G. M. Rubottom, J. M. Gruber, R. Marrero, H. D. Juve, Jr., and C. W. Kim, J . Org. Chem., 1983, 48, 4940. 114 G . P. Boldrini, D. Savoia, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J . Org. Chem., 1983, 48, 4108. 115 G. Wenke, E. N. Jacobsen, G. E. Totten, A. C. Karydas, andY. E. Rhodes, Synth. Commun., 1983; 13, 449. 116 F. Babudri, L. DiNunno, and S. Florio, Tetrahedron Lett., 1983,24,3883. See also C. H . Heathcock and J. Lampe, J . Org. Chem., 1983, 48, 4330. R. W. Stevens and T. Mukaiyama, Chem. Lett., 1983,1799. 11* M. Hirama, M. Shimizu, and M. Iwashita, J . Chem. SOC., Chem. Commun., 1983, 599. T. Kitazume and N. Ishikawa, Chem. Lett., 1983, 237.

113

154


enantiomeric enrichment,I2Oand of 3-ketotetrahydrothiophene carboxylate to give, after Raney nickel desulphurization, methyl (S)-3-hydroxy-pentanoate (142).

+ OH

H

C02Me

R &C02Me

H

0

a

HCO;, Et

Alkylations of enolates derived from acetonides (143) by methyl iodide give the a$-dihydroxy-ester derivatives (144) largely or exclusively with the stereochemistry indicated, but, by contrast, condensation of (143; R=Me) and acetone leads to the opposite arrangement (145).122Further work is needed to define fully the possibly considerable potential of this method. An alternative approach to chiral a#-dihydroxy-esters has been briefly examined and is exemplified by the condensation between the benzyloxy-ester (146) and acetaldehyde which leads, after hydrogenolysis, to the (R,R)-erythro-isomer (147) containing 4 0 % of the corresponding threo-isomer.123 Alkoxymercurations of certain S-hydroxy-y-alkyl-a$-unsaturated esters proceed with high diastereoselectivitiesto give the aldol-typeproduct (148).124 Good diastereoselectivities have also been observed in condensations between p-alanine derivatives

H LOB"

(147)

(146)

(148)

OR2

_-_

+ R' CH'O (14 9

C O ~ R ~ (150)

*R

I

Y

co2R~

OH (151

M. F. Ziiger, F. Giorannini, and D. Seebach, Angew. Chem., Int. Ed. Engl., 1983,22, 1012. R. W. Hoffmann and W. Ladner, Chem. Ber., 1983,116,1631. ( a ) W. Ladner, Chem. Ber., 1983, 116, 3413; ( b ) T. Schubert, F. Kunisch, and P. Welzel, Tetrahedron, 1983, 39, 221 1. 123 J. d'Angelo, 0. Pagks, J. Maddaluno, F. Dumas, and G . Revial, Tetrahedron Letr., 1983,24,5869. lZ4 S . Thaisrivongs and D. Seebach. J . A m . Chem. SOC.. 1983,105,7407.

120 121


155

(150) and alkoxy-aldehydes (149). After quaternization of the amino-group and base-induced elimination, the unsaturated dihydroxy-esters (151) are obtained, largely as the isomers shown.125 Keto-esters.-A number of routes to keto-esters have been developed which may be superior to established methods in certain circumstances. The enolate of the a-aminocrotonate derivative (152), obtained using LDA or KDA, undergoes alkylationslargely or exclusively at the y-position to give a-keto-esters (153) after acid hydrolysis.126Alternatively, a-keto-esters (154) can be simply prepared by condensations between alkyl-cadmiums, R2Cd, and ethyl cyanoformate, NCC02Et,in the presence of zinc chloride; yields, however, are not particularly good (2&-66%). 127 Anions (155) derived from the O-trimethylsilyl cyanohydrin of methyl glyoxalate, on alkylation with allylic or benzylic halides (only!) followed by treatment with acetic anhydride, afford enol acetates (156) of a-ketoesters in ca. 70% yield.128Diketo-esters (157), useful as precursors to pyrroles etc., can be readily derived from conjugate additions of methyl a-nitroacetate to NMe Ph

n

0 RK C 0 2 E 1 (154)

OTMS

(155)

OAc (156 1

0 (157)

vinyl ketones in the presence of triethylamine followed by treatment with methoxide and ozonolysis.129 A popular method for the preparation of P-keto-esters is by condensations of ketone enolates with dialkyl carbonates [i.e. (158)+ (159)]. However, the procedure is not without its limitations and hence an alternative has been developed in which methyl cyanoformate is used as the electrophile.130The key features of this method, which is only successful when lithium enolates of ketones are used, are that the condensations can be performed at -78°C and that there is no need for acidification during work-up. Yields are comparable with the dialkyl carbonate procedure (65-96%) and the method can also be employed to prepare nonenolizable B-keto-esters by direct C-acylation [e.g. (160)- (161)l. A less direct

L. Banfi, L. Colombo, C. Gennari, and C. Scolastico,J. Chem. Soc., Chem. Commun., 1983, 1112. H. Ahlbrecht and H. Simon, Synthesis, 1983,58. lZ7 Y. Akiyama, T. Kawasaki, and M. Sakamoto, Chem. Lett., 1983,1231. 128 T. Mukaiyama, T. Oriyama, and M. Murakami, Chem. Lett., 1983,985. 129 W. J . Thompson and C. A. Buhr, J . Org. Chem., 1983, 48, 2769. L. N. Mander and S. P. Sethi, Tetrahedron Lett., 1983,24,5425.

125

126

156

General and Synthetic Methods OTMS

but nevertheless efficient approach to P-keto-esters (163) involves acylation by diethyl carbonate of the vinyl-lithium species (162), obtained from the corresponding bromide using n-butyl-1ithi~m.l~~ The known adducts (165) formed from diazoacetate enolates (164) and ketones can be rearranged by treatment with catalytic amounts of rhodium(I1) acetate in pentane to provide yet another route top-keto-esters ( 163).132 Clearly, this approach is only useful when there is a large difference in the migratory aptitudes of the substituents R1 and R2;in such cases, yields are often excellent. The Blaise reaction, a relative of the Reformatsky

OH

4

reaction in which /3-keto-esters are obtained by condensations of zinc enolates of esters with nitriles, is little used, mainly because yields are generally poor. Improved conditions have now been developed which could make this a viable method in some cases.133 In an extension of Weiler's method for P-keto-ester homologation, a Dutch group has found that dianions derived from the unsaturated keto-esters (166) react regioselectivity with electrophiles such as alkyl halides, aldehydes, and ketones, to give the deconjugated homologues (167) in excellent ~ i e 1 d s .Vinylic l~~ and allylic halides can be efficiently formylated by treatment with carbon monoxide in the presence of tri-n-butyltin hydride and a palladium(0) catalyst;135for example, the methyl enol ether of y-chloroacetoacetate is converted into the useful aldehydo-ester (168) in 86% yield. L. Duhamel, J.-M. Poirier, and N. Tedga, J . Chem Res. ( S ) , 1983, 222. K. Nagao, M. Chiba, and S.-W. Kim, Synthesis, 1983, 197. 133 S. M. Hannick and Y. Kishi, J . Org. Chem., 1983,48,3833. 134 J. A. M. van den Goorbergh and A . van der Gen, R e d : J . R. Neth. Chem. SOC., 1983,102,393. 135 V. P. Baillargeon and J . K. Stille, J. Am. Chem. SOC., 1983, 105, 7175.

131

13*

157


E (166)

(168)

(167)

Sodium enolates of B-keto-esters can be C-alkylated using sulphonium salts [e.g. Me3S+BF4-]136 and fluorinated by methyl hypofluorite, AcOF, obtained

from CFC13,fluorine, and sodium acetate.137 a-Amidoethylations of P-keto-esters can be effected by condensations of the latter with aziridines, in the presence of triethylamine. 138 The a-phenylthio-acetate (170) reacts cleanly with 0-silyl enolates of ketones (169) in the presence of zinc bromide to provide a general and efficient route to y-keto-esters (171; R3=SPh) .139 Subsequent desulphurization using nickel affords keto-esters (171; R3=H) while oxidative elimination of the phenylthio-group leads to the unsaturated esters (172). Simple y-keto-esters (174) can also be

0

R’+COz

Me R2 (172 1

obtained from 2,5-dimethoxydihydrofurans(173), readily prepared from the corresponding 2-substituted furans, following dealkylation of the acetal function with one equivalent of iodotrimethylsilane. 140 When three equivalents of the silane are used, dealkylation of the ester function also occurs, resulting in the formation of 4-substituted but-2-enolides. Dichloro-bicyclo[4.1 .O]heptanes (175) are cleaved on treatment with methanolic methoxide to give the cyclohexane carboxylates (176). 141 0

M. E. Garst and B. J . McBride, J. Org. Chem., 1983,48, 1362. 0. Lerman and S. Rozen, J . Org. Chem., 1983,48,724. See also S. T. Purrington and W. A . Jones, ibid., p. 761. 13* H. Stamm and J. Budny, J. Chem. Res. ( S ) , 1983, 54. 13y T. V. Lee and J. 0. Okonkwo, Tetrahedron Lett., 1983,24,323; I. Fleming and J . Iqbal, ibid., p. 327. lJn B. L. Feringa and W. Dannenberg, Synth. Commun., 1983,13,509. 141 M. G. Banwell, J. Chem. SOC., Chem. Commun., 1983.1453.

136 13’


158

(175)

(176)

A useful route to vinyl ketones, developed by Stille’s group, is by palladiumcatalysed couplings of acid chlorides and vinyl stannanes. This method has been applied to a synthesis of the pyrenophorin precursor (179) using the pentanoyl chloride (177) and P-stannyl acrylate (178); 142 the stereochemistry of the acrylate is retained. An alternative pyrenophorin precursor (181) has been obtained from diketo-ester (180) in a sequence which features protection of the dione function as an isoxazole during manipulation of the distal double bond (Scheme 20).143

(180)

(181)

Scheme 20

In a continuation of studies on the applications in asymmetric synthesis of chiral hydrazone enolates derived from the N-amino-pyrrolidines ‘SAMP’ and ‘RAMP’, Ender’s group has found that such enolates undergo Michael additions to unsaturated esters leading to 8-keto-esters with 296% enantiomeric enrichment and in 4 5 4 2 % overall yield (Scheme 21).’# It is not difficult to foresee many applications of this method in the future, particularly in view of the relative simplicity and probable generality of the approach, the availability of both enantiomers of the final product in a predictable way [e.g. ‘SAMP’ hydrazones lead to the (R)-isomers as shown, and vice versa], and the fact that the chiral ligand can be recovered and recycled. Many standard Michael reactions can be

Scheme 21 J. W. Labadie and J. K. Stille, Tetrahedron Lett., 1983,24,4283. See also S. Yokota, M. Nishida, and 0. Mitsunobu, Bull. Chem. SOC.Jpn., 1983,56,. 1803. 143 P. G. Baraldi, A. Bareo, S. Benetti, F. Moroder, G. P. Pollini, and D. Simoni, J . Org. Chem., 1983, 48, 1297. D. Enders and K. Papadopoulos, Tetrahedron Lett., 1983,24,4967. 142

159


carried out by heating the reactants together with caesium fluoride and a tetraalkoxysilane;145this method could be useful in certain cases. Enolates of a-trimethylsilyl acetates generally react with enones in a [1,2] fashion to give dieno ates following a Peterson reaction. However, the bulkier diphenylmethyl derivative (182) adds to enones in a Michael sense when HMPA is a co-solvent to provide, for example, yet another synthesis of methyl jasmonate (Scheme 22).146 i,ii,iii

CO2Et

0 (182 1 Reagents: i, HMPA, THF; ii, B r

m ; iii, KF, MeOH

Scheme 22

The useful homo-Michael acceptor (183) undergoes nucleophilic ring opening by the iron complex Na2Fe(C0)4.qdioxan in the presence of carbon monoxide to give a complex, which can be converted into a number of useful derivatives (Scheme 23) ;147 all overall yields are in the order of 65% . Carbonylation of simple butyrolactones (184) at 50 atm and 140°C using [Co,(CO),] as catalyst and HSiEt2Me as trapping agent provides the masked formyl-esters (185) in high yield.

h

C

02 Et

o

R02c-fco2Et

~

c

oEt z

C02Et

CO2Et

CO,Et

Scheme 23

(186 1

(187 1

J. Boyer, R. J. P. Corriu, R. Perz, andC. Reye, Tetrahedron, 1983,39,117; R. J. P. Corriu, R. Perz, and C. Reye, ibid., p. 999. 146 W. Oppolzer, M. Guo, and K. Baettig, Helv. Chim. Acra, 1983, 66,2140. 14' W. H. Tamblyn and R. E. Waltermire, Tetrahedron Lett., 1983, 24, 2803. N. Chatani, S . Murai, and N. Sonoda, J . Am. Chem. Soc., 1983,105,1370.

145

160


+

L i2CuC Ic,

Br(CH*),,C02Et

O@(CH2),+zC02Et H30

+

Scheme 24

The adducts (186), formed from a-nitro-cycloalkanones and methyl vinyl ketone are cleaved by treatment with methanolic sodium methoxide at 0°C to give the keto-esters (287) in 53-93% yield. 149 Simple a-alkyl-cycloalkanones can also be ring-opened to give keto-esters by reactions with oxygen and iron(rI1) chloride in C6HG-MeOHat 60°C; yields, however, are ~ a r i a b 1 e . The l ~ ~ useful Grignard reagent derived from the ethylene acetal of 3-bromopropanal can be coupled efficiently to primary o-bromo-esters on addition of Li2CuC14to provide o-formyl-esters in ca. 80% yield after acid hydrolysis (Scheme 24).151 Unsaturated Esters.-Standard Wadsworth-Emmons reactions between a-phosphonoacetates and aldehydes leading to (E)-@unsaturated esters can be simply and efficiently performed using aqueous potassium carbonate or bicarbonate as base.152Similar transformations can also be effected by utilizing the tellurium ylides (188; R=Me or Bun).153Although these reagents are unlikely to SLi

+ -

R 2Te CHCOzEt

replace the much better known phosphorus analogues in such olefinations, they could find use in the corresponding reactions with ketones as, in these cases, yields of a$-unsaturated esters are quite respectable. The known route to largely (E)-unsaturated esters (190) involving condensations between aldehydes and dianion (189) has been improved by using either triethyl phosphite or hexamethylphosphorus triamide as desulphurizing agents in the final step; 154 overall yields are in the range 68-90%. Exclusively (2)-2-t-butyl-cinnamates can be obtained in 11-62% yields by the sequence outlined in Scheme 25.155It is a very well established principle quoted in all text-books that such Wadsworth-Emmons reactions always lead to the more thermodynamically stable olefin. In a notable piece of perception, Still and Gennari have deduced that the less stable isomer should be obtained if (a) elimination in the initial adduct is faster than adduct equilibration and (b) the counter-cation has a minimal complexational ability. 156 To satisfy these criteria, electron-withdrawing trifluoroethyl groups are incorporated into the phosphonate group and the condensations are carried out using W. Huggenberg and M. Hesse, Helv. Chim. Acta; 1983,66,1519. Ito and M. Matsumoto, J . Org. Chern., 1983,48, 1133. 151 R. A. Volkmann, J. T. Davis, and C. N. Meltz, J . Org. Chern., 1983,48, 1767. 152 J. Villieras and M. Rambaud, Synthesis, 1983, 300. lS3 A. Osuka, Y. Mori, H. Shimizu, and H. Suzuki, Tetrahedron Lett., 1983,24,2599. ls4 S . Matui, K. Tanaka, and A. Kaji, Synthesis, 1983, 127. 155 E. Schaumann and S.' Fittkau, Synthesis, 1983, 449. 156 W. C . Still and C. Gennari, Tetrahedron Len., 1983,24,4405. 149

150 S.

161


potassium enolates in the presence of 18-crown-6. In this way, a,P-unsaturated esters are obtained with stereoselectivities of between 4: 1 and 50:1 in favour of the (2)-isomers (Scheme 26). The method is also very effective for the homologation of aldehydes into the (2)-a-methyl derivatives (191), by using the corresponding a-methyl-phosphonoacetate. M e s ~ c oEt2 MeS

tlo:11.176 For example, treatment of ester (219)with (2)-lithium dipropenylcuprate leads very largely to the adduct (220) via a Felkin-type addition anti- to the polar allylic methoxy-group in (219) rather than by co-ordination-directed attack involving the latter substituent .

Reactions between cyclohexadienyl-iron complexes [e.g. (221)] and simple ester enolates, as well as other relatively reactive nucleophiles, in the presence of carbon monoxide lead to substituted cyclohexenes after trapping of the intermediate acyl-iron complex with an electrophile (Scheme 31).177Although as yet few examples of the procedure have been reported, it would appear to have considerable synthetic potential. Three groups 178 have independently investigated the substantial influence of a-alkoxy-groups on the stereochemical outcome of simple Ireland-Claisen ester enolate rearrangements. For example, a 10.2:1 selectivity was observed in favour of isomer (223)when the a-methoxy-ester (222; M. Gaudemar, Tetrahedron Lett., 1983,24,2749. W. R. Roush and B. M. Lesur, Tetrahedron Lett., 1983,24, 2231. 177 M. F. Semmelhack, J. W. Herndon, and J. P. Springer, J . Am. Chem. Soc., 1983, 105,2497. 17s S. D. Burke, W. F. Fobare, and G. J. Pacofsky, J. Org. Chem., 1983,48,5221; J. Kallmerten and T. J. Gould, Tetrahedron Lett., 1983, 24, 5177; T. Sato, E. Tajima, and T. Fujisawa, ibid., p. 729. 175

176

General and Synthetic Methodr

166

R=Me) was subjected to the rearrangement; benzyloxy and MEMO groups were found to be less effective in terms of stereochemical control. In contrast to esters and ketones, but in common with amides and thioamides, dithiopropionates give rise to a preponderence of (2)-lithio-enolates on treatment with lithium di-isopropylamide; subsequent S-allylation and thio-Claisen rearrangement can be used to prepare erythro-esters [e.g. (224)], with diastereoselectivitiesof up to 87: 13

Fe (CO), (221 1 Reagents: i, CO, -78 "C; ii, Me1

Scheme 31

Full details for the preparation of the isolable 5-phosphoranylidene levulinate (225) have been published; the compound reacts cleanly with aldehydes to provide unsaturated keto-esters (226) in 70-90% yields.180 Useful WadsworthEmmons substrates [e.g. (227)] may be obtained by EtAlC1,-catalysed ene reactions between 2-phosphonoacrylates and olefins. 2,4-Dienoates (229), largely as the (E,E)-isomers, have been obtained from aldehydes (228) by a two-carbon homologation involving sequential condensation with methyl a-arylsulphinyl acetate, acetylation, and finally treatment with the 0-silyl enolate of N-trimethylsilylacetamide and [Mo(CO)~];the full potential of the method has not been fully defined.lS2Trienoates [e.g. (230)] and tetraenoates [e.g. (231)] have been obtained by palladium-catalysed couplings of buta-l,3-dienes with one or two equivalents respectively of a fl-bromopropenoate. 183 The brevity and simplicity of the method compensate for the usually lowish yields. Allenic esters (232) can be prepared by chromium(n)-induced debrominations of the corresponding 6-bromo-2-en-4-ynoates.184

P. Beslin, P. Metzner, Y. VallCe, and J. Vialle, Tetrahedron Lett., 1983,24,3617. R . C. Ronald and C. J. Wheeler, J. Org. Chem., 1983,48, 138. lB1B. B. Snider and G . B. Phillips, J . Org. Chem., 1983,48,3685. lB2B. M. Trost, M. Lautens, and B. Peterson, Tetrahedron Lett., 1983,24, 4525. IB3W. Fischetti, K. T. Mak, F. G. Stakem, J.-I. Kim, A. L. Rheingold, and R. F. Heck, J. Org. Chem., 1983,48,948. B. LeDoussal, A. Le Coq, A. Gorgues, and A. Meyer, Tetrahedron, 1983,39,2185. 179

180

167


Thioesters.-A useful review, containing some 200 references, has been published on the synthesis of dithiocarboxylic acids and estersls5(see also ref. 66). Thioesters can be readily obtained by reactions between 3-acylthiazolidine2-thiones [cf. (38)] and thiols in the presence of triethylamine.ls6 Generally, yields are very good but the by-product, thiazolidine-2-thione, has to be removed by chromatography. The sodium salt of thiosaccharin has been employed in an ‘odourless’ route to thioesters in which the alkylthiol is generated in situ; subsequent coupling with an acid chloride gives the thioester in ca. 90% yield.ls7 Perchloric acid has been found to be superior to hydrogen chloride for the hydrolysis of a-chlorovinyl sulphides to thioesters in the presence of thiophenol.188S-Aryl thiobenzoates can be obtained in 80-94% yields by Ullman-type couplings of aryl iodides with copper salts of thiobenzoates in hot HMPA .lS9 Acetylenic alcohols (233) undergo [2,3]-sigmatropic rearrangements on treatment with phenylsulphenyl chloride to give allenes (234) which, when simply warmed in ether, rearrange to the unsaturated thioesters (235; R’, R2#H), presumably via a sila-Pummerer mechanism.’” During a synthesis of bufadienolides, a new route to y-hydroxy-a,P-unsaturatedthioesters has been used, an outline of which is given in Scheme 32.1g1Presumably, the last step involves a process reminiscent of a Pummerer rearrangement.

(233 1

( 234 1

(235)

S. R. Ramadas, P. S. Srinivasan, J. Ramachandran, and V. V. S . K. Sastry, Synthesis, 1983,605. K. Soai, H. Hayashi, and A. Ookawa, J . Chem. Res. ( S ) , 1983, 20. 187 H. Yamada, H. Kinoshita, K. Inomata, and H. Kotake, Buff. Chem. SOC.Jpn., 1983, 56,949. V. Reutrakul and P. Pooehaivatananon, Tetrahedron Lett., 1983,24,535. 189 A. Osuka, N. Ohmasa, Y. Uno, and H. Suzuki, Synthesis, 1983, 68. lW I. Cutting and P. J. Parsons, Tetrahedron Lett., 1983,24, 4463. 191 P. E. Bauer, K. S. Kyler, and D. S. Watt, J . Org. Chem., 1983,48,34, lX3


168

Reagents: i. BuSLi;ii, R1R2CO;iii, O2

Scheme 32

Enolates derived from dithioesters are soft nucleophiles judging from the observations that such species add in a Michael fashion to enones 192 andP-vinyl$lactones ly3 (Scheme 33). Yields from such additions are variable, partly because of the tendency for reaction at sulphur as well as at carbon, which results in the formation of dithioketene acetals as by-products. The synthetic utility of these reactions may be enhanced by new procedures for the conversion of a variety of thiocarbonyls into carbonyls by reaction with either N-nitrosopiperidine or N-nitroso-N-methylaniline in 4M-HC1-CH2C12.194

0

A

R'

s

SMe

S

Scheme 33

3 Lactones

P-Lactones.-Enolates (236) derived from p-lactones add in a largely or completely stereoselective manner to dimethyl maleate to give the a-substituted lactones (237).ly5 Butyro1actones.-Considerable degrees of regioselectivity have been achieved in oxidations of simple 2,2-disubstituted butane-l,4-diols to butyrolactones [e.g. P. Metzner and R. Rakotonirina, Tetrahedron Lett., 1983, 24, 4203. Fujisawa, T. Itoh, and T. Sato, Chem. Lett., 1983, 1901. Iy4 K. A . Jmgensen, M. T. M. El-Wassimy, and S.-0. Lawesson, Tetrahedron. 1983, 39, 469. 195 J . Mulzer, A. Chucholowski, 0.Lammer, I. Jibril, and G. Huttner,J. Chem. SOC.,Chem. Commun., 1983, 869.

192

193 T.

Carboxylic Acids and Derivatives R'

169

G' -.

nu

K

.

NPr',

Reagents: i, MeSO,H, MeOH, Hg(OAc),; ii, h-ClC6H,CO3H, BF,

Scheme 34

(238)- (239)] using mixtures of bromine and nickel(I1) alkanoates. lY6 An efficient and highly diastereoselective approach to 3-methyl-4-alkylbutyrolactones is via a three-carbon extension of aldehydes using titanium enolates of O-allylic carbamates (Scheme 34).197 An interesting and seemingly facile preparation of 4-substituted and 3,4-disubstituted butyrolactones is by Hg'I-mediated cyclopropane cleavages in the presence of an internal nucleophile (Scheme 35).198 The method can be highly stereoselective and is applicable to the synthesis of other ring systems. Similarly substituted butyrolactones have also been obtained, but with a high degree of cis stereoselectivity, by radical-mediated cyclizations of ally1 trichloracetates [(240)+ (241)] triggered by CuCl in acetonitrile at 140°C.199 The initial products (241) are completely dechlorinated in a separate step using

"0

W

C

O

Z

N

a

-

Scheme 35

M. P. Doyle, R. L. Dow, V. Baheri, and W. J. Patrie, J. Org. Chem., 1983,48,476. See also T . Kageyama, S. Kawahara, K. Kitamura, Y. Ueno, and M . Okawara, Chem. Lett., 1983, 1097; Y. Tamaru, Y. Yamada, K. Inoue, Y. Yamamoto, and Z. Yoshida, 1.Org. Chem., 1983, 48,1286; Y. Ishii, K. Osakada, T . Ikariya, M . Saburi, and S. Yoshikawa, Tetrahedron Lett., 1983, 24, 2677. 197 D . Hoppe and A. Bronneke, Tetrahedron Lett., 1983,24, 1687. 198 D. B. Collum, F. Mohamadi, and J. S. Hallock, J . A m . Chem. SOC., 1983, 105, 6882. See also Y. Yokoyama and M. Yunokihara, Chem. Lett., 1983, 1245. 199 H. Nagashima, H. Wakamatsu, K. Itoh, Y. Tomo, and J. Tsuji, Tetrahedron Lett., 1983.24, 2395.


170

R’

(2421

(2431

tri-n-butyltin hydride. Only the threo-adduct (242) is obtained when the corresponding butyrolactone 0-silyl enolate is condensed with acetaldehyde using TIC4 as catalyst; similar reactions with other aldehydes have yet to be reported.2004,4Disubstituted lactones (243) can be prepared in 50-70% yield using SnC14catalysed additions of ethyl a-chloro-cr-arylthioacetate to olefins.201 During an approach to naturally occurring lignans, a new dianion (244) derived from mercaptosuccinic acid has been used to obtain butyrolactones (245) by condensation with aryl aldehydes; yields are in excess of 50% .202 An apparently better route to the related 4-arylparaconic acids (246) is by condensations between aromatic aldehydes and succinic anhydride using a ZnCl2.Et3Ncomplex as catalyst .*03 C02 Me

-

C02Me

ArCHO

M e 5 4

0

A simple route to a-hydroxy-butyrolactones (248) involves condensations between metallated cyanohydrin derivatives (247) and monosubstituted epoxides.2a Yields are high throughout, and the intermediate (1-ethoxy)ethoxylactones can also be isolated. Related P-hydroxy-butyrolactones (249) are obtainable in 61-99% yields by condensations between trimethylsilyl ester enolates and b r o m~a ceta ld ehyde.Crucial ~ ~ ~ to the success of this method is the use of readily hydrolysable silyl esters (other esters fail or give low yields) and the K. Yamamoto and Y. Tomo, Chem. Lett., 1983,531. M. Wada, T. Shigehisa, H. Kitani, and K. Akiba, Tetrahedron Lett., 1983, 24, 1715. 202 A. Pelter, R, S. Ward, P. Collins, R., Venkateswarlu, and I. T. Kay, TetrahedronLett., 1983,24,523. 203 J. M. Lawlor and M. B. McNamee, Tetrahedron Lett., 1983, 24,2211. *04 G. A. Garcia, H. Munoz, and J. Tamariz, Synth. Commun., 1983, 13, 569. 205 G. A . Kraus and P. Gottschalk, J. Org. Chem., 1983,48,5356.

M’

201

171


development of a convenient preparation of anhydrous bromoacetaldehyde. Excellent diastereoselectivities have been observed in iodolactonizations of the 3-hydroxy-4-enoic acids (250; R', R2=H or Me), leading to the P-hydroxy-

OH R2

(250)

(251) R

R

I

(252)

YH 1

(253)

+co2Me OH (254)

butyrolactones (251) .206 Perhaps not surprisingly, cis-dihydroxylations of butenolides (252) by KMn0,-dicyclohexano-18-crown-6also proceed with very high diastereoselectivitieswhen the y-substituent is very large (e.g. R=Ph3C0 or Ph2MeSiO), to give the dihydroxy-butyrolactones (253) in 50-60% yields.207 When the substituent is much smaller (e.g. R=Bu"), the selectivity is only ca. 3:l in favour of (253). More remarkable is the finding that similar hydroxylations of (E)-y-hydroxy-a$-unsaturated esters [e.g. (254)], using OsO, and N-methylmorpholine N-oxide, give only trans-dihydroxy-butyrolactones[e.g. (255)] whereas the corresponding (2)-esters give rise exclusively to cis-dihydroxy-lactones [e.g. (256)].208 A reasonable rationale of these results is given which may well be of predictive value.

2M

A. R. Chamberlin, M. Dezube, P. Dussault, andM. C . McMills,]. Am. Chem. SOC., 1983,205,581Y. T. Mukaiyama, F. Tabuse, and K. Suzuki, Chem. Lett., 1983, 173. G . Stork and M. Khan, Tetrahedron Lett., 1983,24,3951.

172


i*

0Me

L

H

HP - H6?o ii, iii

OMe

Reagents: i , p-MeC,H,S03H; ii, H,O+; iii, PCC

Scheme 36

A neat application of an acid-catalysed intramolecular Michael addition forms the basis of a new method for the annelation of butyrolactones (Scheme 36).209 This single example suggests that this type of cyclization could well be exploited in other syntheses. Another, currently fashionable, cyclization procedure employs free radicals as key intermediates. An illustration of this is a new procedure for the construction of annelated butyrolactones from crotonyl esters of /3-hydroxyselenides (Scheme 37) .210 Unfortunately, the method is not effective when applied to the corresponding acrylate esters. More established methods have been used to exploit the availability of dienylacetic acids [e.g. (257)]63 in stereoselective syntheses of fused [e.g. (258)] and 3,4-disubstituted [e.g. (259)] butyrolactones .211

as> ac, SePh

ii)

0

j

&o I

H

Reagents: i, MeCH=CHCO,Ag; ii, Ph,SnH

Scheme 37 CHO

CHO ( 257 1

(258)

(259)

G. Stork and K. S. Atwal, Tetrahedron Lett., 1983, 24, 3819. D. L. J. Clive and P. L. Beaulieu, J . Chem. Soc., Chem. Commun., 1983,307. 211 A. J. Pearson, T. Ray, I. C. Richards, J. CIardy, and L. Silveira, Tetrahedron Lett., 1983,24,5827. 209

*lo


173

trans-Hydroxy-lactones [e.g. (261)] can easily be obtained from bicyclic diacids [e.g. (260)] by treatment with commercial bleach.*l2 This procedure, which is

reminiscent of halogenolactonization, does not afford lactones directly from similar monocyclic or acyclic olefinic acids, but rather the corresponding transdihydroxy-derivatives. Total syntheses of Aeginetolide (262) and the related butenolides Dihydroactinidiolide and Actinidiolide have been reported.213The key steps consist of oxidation of an appropriate cyclohexanone silyl enol ether to give an a-hydroxycyclohexanone followed by acetylation and closure of the lactone ring by an intramolecular condensation.

4co*H C02H

H*co*H

- -0

'0

(2601

(261 1

(262)

The glyoxylic acid derivative (263) reacts with 1,3-dienes in the presence of an acid catalyst (MeS03H) to give cx-acylamino-y-alkenyl-butyrolactones (264) as major products while the expected Diels-Alder adducts arising from the intermediate acyliminium species are produced in much lower yields Simple alkylations of (S)-P-amino-butyrolactone derivatives, readily available from (L)-aspartic acid, give largely the trans-homologues (265) .*I5 Chiral annelated butyrolactones (267) have been obtained with enantiomeric enrichments of 58-88% by reduction of imides (266) derived from (R)-2-amino2-phenylethanol; *16 the carbocyclic ring size is between three and six carbons in the examples examined. One of Mukaiyama's lactonization reagents, 2-chlorol-methylpyridinium iodide, has been found to be very effective in the preparation of strained trans-fused butyrolactones [e.g. (268)] from the corresponding trans-yhydroxy-acids.217

J. B. Hendrickson and V. Singh, Tetrahedron Lett., 1983,24,431. G. M. Rubottom and H. D. Juve, Jr., 1. Urg. Chem., 1983,48,422. 214 D. Ben-Ishai and S. Hirsch, Tetrahedron Lett., 1983, 24, 955. 215 G. J. McGarvey, R. N. Hiner, Y. Matsubara, and T. Oh, Tetrahedron Lett., 1983, 24,2733. 216 T. Mukaiyama, H. Yamashita, and M. Asami, Chem. Lett., 1983,385. 217 L. Strekowski, M. Visnick, and M. A . Battiste, Synthesis, 1983, 493.

212

*13


174

Details of the preparation of bis-lactones [e.g. (269)] from glyoxal and dimethylketene acetals have been given.218New procedures for the construction of spiro-butyrolactones [e.g. (270) and (271)] have been developed using the well established cyclopropanol+ cyclobutanone ring expansion method originally reported by Trost, and have been applied to a total synthesis of Plumericin (272).219

Qo (270)

A promising new route to (E)-alkylidene-butyrolactones(Scheme 38) has in the key step an intramolecular trapping of an epoxy-silane by a carboxylic acid group.220Oddly, the intermediate hydroxy-silane does not undergo direct basecatalysed syn-elimination to give the corresponding (2)-isomers. The method is also effective in the preparation of alkylidene-tetrahydrofurans. OH

R

Reagents: I, m-ClC,H,CO,H; ii, Ac@; iii, F-

Scheme 38

Tetraethoxyallene acts as the synthetic equivalent of a malonate ester dianion in condensations with a,o-diacid chlorides which lead to the ylidene-lactones C. G. Bakker, J. W. Scheeren, and R. J. F. Nivard, R e d : J . R . Neth. Chem. SOC., 1983,102,96. B. M. Trost and M. K.-T. Mao, J . Am. Chem. SOC.,1983,105,6753; B. M. Trost, J. M. Balkovec, and' M. K.-T. Mao, ibid., p. 6755. 220 F.-T. Luo and E. Negishi, J . Org. Chem., 1983,48, 5144.

*19


175

[(273) ; n =2 4 1 .221 The known a-amino-acid derivatives (274) can be simply converted into the potential protease suicide substrates (275) by treatment with an N-halogenosuccinimide .222

a-Methylenebutyro1actones.-Ban's group has summarized its work on the preparation of lactones and lactams by Pd"-catalysed carbonylation of vinyl halides containing a hydroxy or secondary amine group respectively.223Among other uses,45,48 such transformations [(276)-+(277)] provide a useful entry into four-, five, and six-membered a-methylene-lactones. Oxidations of ally1 silanes [e.g. (278)] using iodosobenzene and BF,.Et,O provides a new entry into enals (279), further oxidation of which by sodium chlorite leads to a-methylenebutyrolactones (280) in reasonable overall yields.224Simply by positioning the acetoxygroup 6- to the silyl group, the method can also be used to prepare a-methylenevalerolactones (281). y-Substituted lactones (280) are also available by Pdo-catalysed cyclizations of chloroformates (282), derived from homoallylic alcohols and phosgene.225

173-Dipolaradditions between the nitrile oxide (283) and cis-olefins followed by hydrogenolysis lead to the butane-174-diols(284) which can be converted into lactones (285) following methenyl,ation, deprotection, and oxidation.z26

222 223

R. W. Saalfrank and W. Rost, Angew. Chem., Int. Ed. Engl., 1983,22, 321. M. J. Sofia, P. K. Chakravarty, and J. A . Katzenellenbogen, J. Org. Chem., 1983,48,3318. M. Mori, Y. Washioka, T. Urayama, K. Yoshiura, K. Chiba, and Y. Ban, J . Org. Chem., 1983,48, 4058.

M. Ochiai, E., Fujita, M. Arimoto, and H. Yamaguchi, Tetrahedron Len., 1983, 24, 777. 225 F. Henin and J.-P. Pete, Tetrahedron Lett., 1983, 24,4687. 226 A. P. Kozikowski and A . K. Ghosh, Tetrahedron Lett., 1983,24,2623.

224

176


Although reasonably efficient, the method is limited to olefinic substituents (R) that are not affected by the Raney nickel hydrogenolysis conditions required; problems of regioselectivity may also arise in reactions beginning wtih an unsymmetrical olefin. A full report has been published on an alternative but nonstereoselective route to p, y-disubstituted-a-methylenebutyrolactones [cf. (285)] by distillation of mixtures of cyclopropanecarboxylates (286) and Me3SiI.227 The cyclopropanes (286) are constructed using carbene additions to olefins, so again there are considerable restrictions on the types of substituent (R1, R2)that can be used. In another full report is detailed the preparation of butyrolactones (287) by condensations between a-acetoxy-aldehydes and the enolate of ethyl a-phenylthiopropanoate .228 Oxidation at sulphur followed by thermolysis of cis(287) leads to the a-methylene derivatives (288) whereas similar treatment of the trans-isomers gives largely lactones (288) along with some of the corresponding butenolides. Hydrolysis of the acetoxy-group prior to oxidation gives rise to the cc-rresponding /3-hydroxy-a-methylene-butyrolactones.The stable iron salts (289) act as vinyl cation equivalents in condensations with /3-keto-ester enolates, leading largely to the trans-disubstituted lactones (290) following reduction, acidcatalysed elimination of ethanol, and d e m e t a l l a t i ~ nUnder . ~ ~ ~ the present conditions, the method is only really efficient when R=Me.

In an extension of previous work, it has been shown that condensations between anions derived from phenylthiomethacrylates and aldehydes or ketones represent an efficient and general approach to a-phenylthiomethylene-butyrolactones (291).230Another total synthesis of (+)-Avenaciolide (292) has been achieved starting from a-phenylthi0-,8-vinylbutenolide.~~~ a-Methylenebutyrolactones (293) can be efficiently deconjugated to give (E)/(Z)-mixtures of butyrolactones (294) by irradiation at 254 nm in 227 H.

Saimoto, K. Nishio, H. Yamamoto, M. Shinoda, T. Hiyama, and H. Nozaki, Bull. Chem. SOC., Jpn., 1983, 56, 3093. 228 P. Barbier and C . Benezra, 1. Org. Chem., 1983,48,2705. 229 T. C. T. Chang and M. Rosenblum, Tetrahedron Lett., 1983,24,695. 2x1M. Kitaoka, Y. Takahashi, H. Kosugi, and H. Uda, Chem. Left., 1983,1065. D l F. %do, Y. Tooyama, Y . Noda, and A. Yoshikoshi, Chem. Lett., 1983,881. zz F. HCnin, R. Mortezaei, and J.-P. Pete, Synthesis, 1983, 1019.


177

SPh

(291

(292 1

(294)

(293)

Butenolides and Phthalides.-Radical-mediated cyclizations210are featured in a new method for the preparation of a wide variety of /?-substituted butenolides (Scheme 39).233'Double' cyclization is also possible [e.g. (295)+ (296)], and when applied to allylic ethers [e.g. (297)], trans-substituted butyrolactones [e.g. (298)] are obtained stereoselectively and in good overall yield. Another new route to /?-substituted butenolides, developed during a total synthesis of the clerodane diterpene insect antifeedant Ajugarin 1,involves conjugate addition of metallated sulphones to an appropriate acetylenic acid ester followed by deprotection and desulphurization (Scheme 40).234Overall yields are ca. 45% but distinct advantages are the availability of the starting materials and the relative simplicity of the procedure. Metallated sulphones have also been used to prepare butenolides by sequential alkylations with an alkyl halide and sodium iodoacetate; in this case elimination of the sulphone group provides the olefinic bond (Scheme 41).235y-Substituted derivatives can also be obtained from aryl methyl sulphones by a similar sequence involving sequential condensations with an aldehyde and ICH2C02Na. Bc3SnH

R\

-*b0/VCI I

Scheme 39

G. Stork and R. Mook, Jr., J. Am. Chem. SOC., 1983,105,3720; G. Stork, R. Mook, Jr., S. A. Biller, and S. D. Rychnovsky, ibid., p. 3741. 234 S. V. Ley, N. S . Simpkins, and A. J. Whittle, J. Chem. SOC., Chem. Commun., 1983,503. 235 K. Tanaka, K. Ootake, K. Imai, N. Tanaka, and A, Kaji, Chem. Lett., 1983,633. 233

178


A novel and reasonably efficient route to a,y-disubstituted butenolides (301) consists of conversion of the unsaturated sulphones (299) into vinyl stannanes (300) by sequential treatment with Bun3SnLiand an aldehyde, R2CHO; the sequence is then completed by tin-lithium exchange, carboxylation, and acidcatalysed ring closure.236The related butenolides (303) can be obtained from (302), formed from the cyclopentadiene-maleic anhydride Diels-Alder adduct and RlMgX, following alkylation [LDA; R2X]and retro-Diels-Alder reaction.237 Dealkylation of 2-methoxyfuran by Me,SiI in the presence of the enone (304) leads to the butenolide (305).238This single example suggests that such an approach could have a wider application. a-Silylfurans can also serve as butenolide precursors following oxidation with AcOOH as outlined in Scheme

Scheme 40

M. Ochiai, T. Ukita, and E. Fujita, Tetrahedron Lett 1983,24, 4025. P. Canonne, M. Akssira, and G. Lemay, Tetrahedron Lett., 1983,24,1929. z3a G. A. Kraus and P. Gottschalk, Tetrahedron Lett., 1983,24,2727.

236

237

179


42.239It seems likely that more complex butenolides could be prepared by this met hod.

n=lor 2 I I

Scheme 42

P-Lithio-acrylates have been used as key intermediates in rather inefficient but very brief syntheses of the natural butenolides Lepichlorin (306) 240 and Umbelactone (307) .241 Metallation of the N, N-diethylamide of 2-furylacrylic acid by LTMP takes place at the P-acrylate position rather than at the more usual 5-position of the furan to give anion (308), condensation of which with ketones leads directly ,to butenolides (309).242A related species can be generated from pyrrolidine (310) using LDA as base; again condensation with aldehydes or ketones gives butenolides of general formula (311) .243P-Amino-as well asp-thioderivatives of butenolides [(312); X=NR or S] can be easily obtained from the corresponding P-halogenobutenolides by an addition-elimination sequence with secondary amines or sodium thiolates as nucleophiles respectively.244

D. Goldsmith, D. Liotta, M. Saindane, L. Waykole, and P. Bowen, Tetrahedron Lett., 1983, 24, 5835. **D. Caine and V. C. Ukachukwa, Tetrahedron Lett., 1983, 24, 3959. 241 D. Caine, A. S. Frobese, and V. C. Ukachukwa, J . Org. Chem., 1983,48,740. 242 R . R. Schmidt and R. Hirsenkorn, Tetrahedron, 1983,39, 2043. 243 R. R. Schmidt, J. Kast, and H. Speer, Synthesis, 1983, 725. 244 F. Farina, M. V. Martin, F. Sanchez, M. C. Maestro, and M. R. Martin, Synthesis, 1983, 397.

239

7

180


A promising route to chiral butenolides and tetronic acids (Scheme 43) relies on asymmetric Sharpless epoxidations to provide optically active intermediates and has been applied to a total synthesis of ( - ) - V e r t i n ~ l i d e . ~ ~ ~ OH OH OH R

0

Symmetrical acetylenes can be carbonylated at relatively high temperatures and pressures in the presence of a rhodium carbonyl catalyst and an alcohol (R20H)to give good to excellent yields of the alkoxy-butenolides (313).*%Not surprisingly, unsymmetrical acetylenes lead to mixtures of both possible products. A new route to ylidenebutenolides (316) is by condensation between enolizable 1,2-diones (314) and the vinylidenephosphorane (315) .247 The approach seems to be widely applicable and yields are usually good to excellent.

(313 1

(314)

(315)

(316)

A full report has been published on an efficient and general route to 3-hydroxyphthalides and hence phthalides themselves, in which a key step is the temporary protection of the aldehyde group of an o-bromobenzaldehyde by hemiaminal formation (Scheme 44) A related procedure involving chiral oxazolines formally derived from o-bromobenzoic acids has been used to prepare OR

OR

OR

Br

OLi Reagents: i, N-Lithiomorpholine; ii, BunLi, -78 "C, CO,, H 3 0 + ;iii, NaBH,

Scheme 44 J. E. Wrobel and B. Ganem, J . Org. Chem., 1983,48,3761. 246 T. Mise, P. Hong, and H. Yamazaki, J . Org. Chem., 1983,48, 238. 247 R. W. Saalfrank, P. Schierling, and P. Schatzlein, Chem. Ber., 1983,116, 1463; R. W. Saalfrank, P. Schierling, and W. Hafner, ibid., p. 3482. 248 A. K. Sinhababu and R. T. Borchardt, J . Org. Chem., 1983,48,2356.

245


181

3,3-disubstituted phthalides with enantiomeric enrichments of 20-25% .249 Much higher enrichments (40-80%) can, however, be obtained by reactions between the corresponding o-keto-oxazolines and Grignard reagents. Further examples have been given of the preparation of 3-arylphthalides by Diels-Alder reactions between cyclohexa-l,3-dienes and 4-aryl-4-hydroxybut-2-ynoates.2so Tetronic Acids.-The Dieckmann route to 3-acyltetronic acids has been significantly improved (Scheme 45).2s1 The key features are the use of dianions derived fromp-keto-thioesters, Masamune's transesterification procedure, and the use of fluoride as base in the ring-closure step. The approach has been successfully applied to a synthesis of (S)-carlosic acid by using (S)-dimethyl malate in the transesterification step. 0-Alkyl-tetronic acids can be obtained from 4-hydroxybut-2-ynoates or the corresponding orthoesters using Hg-Nafion-H.2s2

'0--0

Reagents: i, NaH, Bu"Li, DME, RlX; ii, R*CH(OH)CO,Me, Ag02CCF3;iii, Bun,NF

Scheme 45

Valero1actones.-Dye-sensitized photo-oxygenation of cyclohexane-l,2-diones (317; R=alkenyl or alkynyl) gives the 8-keto-acids (318) in very high yields; conversion into the &substituted valerolactones (319) is then straightforward (NaBH,; H,O+).253 Examples of the synthesis of chiral valerolactones reported this year include those of (I?)-( +)-5hexadecanolide (320), a pheromone isolated from the oriental hornet ,254 and the potential erythronolide A precursors (321) and (322).255A stereoselective synthesis of the (4RS,6SR)-mevalonolactone derivative (323) has also been developed .256 A. 1. Meyers, M. A. Hanagan, L. M. Trefonas, and R. J. Baker, Tetrahedron, 1983, 39,1991. P. A . Harland and P. Hodge, Synthesis, 1983,419. 251 P. M. Booth, C. M. J. Fox, and S. V. Ley, Tetrahedron Lett., 1983, 24, 5143. 252 H . Saimoto, M. Shinoda, S. Matsubara, K. Oshima, T. Hiyama, and H. Nozaki, Bull. Chem. SOC. Jpn., 1983,56, 3088. 253 M. Utaka, H. Kuriki, T. Sakai, and A. Takeda, Chem. Lett., 1983,911. 254 S. Servi, Tetrahedron Lett., 1983, 24, 2023. 255 I. Paterson, S. K. Patel, and J. R. Porter, Tetrahedron Lett., 1983, 24, 3395. 256 H. Ferres, I. K. Hatton, L. J. A . Jennings, A . W. R. Tyrrell, and D. J. Williams, Tetrahedron Lett., 1983,24,3769.

249

2so


182

During efforts towards the total synthesis of Quassinoids, the intramolecular Michael addition [(324)+ (325)] has been found effective for the formation of a valerolactone unit. 257 The cyclization was performed using Me3SiI and may proceed via the corresponding ,&iodo-silyl enol ether: other, more conventional Reformatsky-type conditions failed to produce the required lactone. Readily available 2-bromoallyl boronates react with aldehydes to give excellent yields of the (2)-homoallylic alcohols (326). One synthetic utility of these compounds is in the formation of unsaturated valerolactones (327) by carbonylation using [Ni(CO),] .258 Pummerer rearrangement of readily available a-phenylsulphinyl-valerolactone leads to the good Michael acceptor (328). Subsequent reaction with a range of appropriate nucleophiles followed by oxidative elimination of the phenylsulphenyl group gives the ,&substituted unsaturated lactones (329); yields are good throughout .259 A straightforward synthesis of a-methylenevalerolactones (331) is by condensation between the methallyl alcohol dianion (330) and mono-substituted epoxides followed by oxidation of the allylic alcohol function.260 Overall yields are in the range 13-61%. S-Alkoxycarbonylmethylene-valerolactones can be obtained by Wittig reactions between certain phosphoranes derived from a-halogenoesters and glutaric anhydride.261 r

0 Me3SiI %

M. Voyle, N. K. Dunlap, D. S . Watt, and 0. P. Anderson, J . Org. Chem., 1983,48, 3242. R. W. Hoffrnann and B. Landmann, Tetrahedron Lett., 1983,24,3209. 259 M. Kato, A. Ouchi, and A. Yoshikoshi, Chem. Lett., 1983, 1511. 260 R. M. Carlson and L. L. White, Synth. Commun., 1983, 13, 237. 261 S. Tsuboi, H. Fukurnoto, and A, Takeda, Chem. Lett., 1983, 1219. 257

258


183

Macro1ides.-A new and potentially very valuable technique for macrolide formation consists of heating a suspension of a potassium salt of an w-bromo-acid in toluene with a small amount of the phase-transfer catalyst Bun4NBr.262 Yields of macrolides are >90% in the simple examples examined at apparent concentrations of up to 0.1M. A full account has been given of the ‘template’ approach to

RNH

(332)

NHR

0 ( 333 1

macrolides from w-hydroxy-acids and Bun2Sn0.263 Overall, the method is essentially one of double-activation, and has been used in a very brief synthesis of the naturally occurring ion carrier Enterobactin (333), in 23% isolated yield, by ‘trimerization’ of the /3-lactone (332).264 A feature of work in this area during the past year, however, has been the emphasis placed on macrolide formation by C 4 rather than C 4 bond formation. Polymer-bound palladium has been used to effect ring closures of vinyl epoxides (334) to give macrolides (335) in yields of 70437% at concentrations of 0.1--0.5M.265 The method is limited to bis-sulphones but is applicable to very large rings (e.g. 27-membered). More conventional palladium(0) catalysts have been used in a synthesis of antibiotic A26771B (337), which involves cyclization of the allylic acetate (336).266This key step could well find use elsewhere as a y-keto-a,P-unsaturated lactone unit is commonly found in such compounds. A number of classical C 4 bond-forming reactions have also been employed in Y. Kimura and S. L. Regen, J. Org. Chem., 1983,48,1533. K . Steliou and M.-A. Poupart, J. Am. Chem. SOC., 1983,105, 7130. 264 A. Shanzer and J. Libman, J. Chem. SOC., Chem. Commun., 1983,846. 265 B. M. Trost and R. W. Warner, J . Am. Chem. SOC., 1983, 105,5940. 266 B. M. Trost and S. J. Brickner, J. Am. Chem. SOC., 1983, 105,568.

262 263


184

0

0

(334)

(335) 0

(336)

( 337 1

macrolide formation. Synthesis of (S,S)-( +)-Grahamimycin A (338) has been achieved by an intramolecular pinacol-type coupling of an a,o-dialdehyde using Zn/Cu-TiCl,, followed by oxidation.267A Lewis acid-catalysed intramolecular Diels-Alder reaction has been used to prepare the sensitive bridgehead olefin (340) from the acrylate (339) in 85% yield,268and recently described ketenylidene phosphoranes are key intermediates in another version of the intramolecular Wittig-type approach to macrolides (Scheme 46) .269 Although yields are usually good, in this latter method, high dilution conditions are required. Reasonable yields ofp-keto-macrolides (342) can be realized by cyclization of thep-keto-ester dianions (341).”O The method has been used to prepare 14-16-membered lactones as well as a 26-membered example containing one ck-double bond. 9-27Membered lactones have been prepared by photolysis of w-methylsulphenyl Yields are in the range 36--80% at fairly esters of N-hydr~xyalkylphthalides.~~~ high dilutions (2.9-7.0 mM in acetone).

267

268

269

*’O

D. Ghiringhelli, Tetrahedron Lett., 1983, 24, 287. K. J. Shea and J. W. Gilman, Tetrahedron Lett., 1983,24,657. H. J. Bestmann and R. Schobert, Angew. Chem., Int. Ed. Engl., 1983, 22, 780. R. J. Sims, S. A . Tischler, and L. Weiler, Tetrahedron Lett., 1983, 24,253. M. Wada, H . Nakai, K. Aoe, K. Kotera, Y. Sato, Y. Hatanaka, andY. Kanaoka, Tetrahedron,1983, 39, 1273.


185

Scheme 46

( 342 1

(343)

I No2

0 ( 346 1

(347)

(348 1

Two examples of a four-atom ring expansion method for converting a-nitrocycloalkanones into macrolides [(343)+ (344)] have been described.272The mildness of the conditions used suggests that this method may have further potential. a-Methoxy-hydroperoxides formed by olefin ozonolysis in methanol undergo a Criegee rearrangement, complementary to the Baeyer-Villiger rearrangement, on treatment with trifluoroacetic anhydride to give esters or lac tone^.^^^ Using this method, the enol ether (345) can be converted into caprolactone (346), and the bicyclodecene (347) affords the macrolide (348).

4 Carboxylic Acid Amides Synthesis.-Some new methods for amide bond formation from acids and amines have been added to the already vast number. The use of P214as coupling agent is very efficient and may offer advantages in cases involving unreactive acids or a m i n e ~An . ~ alternative, ~~ very mild procedure consists of reactions between acid chlorides and N-silylamines .275 An alternative method for the oxidation of a-amino-nitriles to amides is by passage of oxygen through a solution of the former in 50% aqueous NaOH and DMSO containing B z E ~ ~ N CClearly ~ . * ~ the ~ method is limited to non-enolizable K. Kostova and M. Hesse, Helv. Chim. Acta, 1983, 66, 741. S. L. Schreiber and W.-F. Liew, Tetrahedron Lett., 1983, 24, 2363. 274 H. Suzuki, J. Tsuji, Y. Hiroi, N. Sato, and A. Osuka, Chem. Lett., 1983, 449. 275 J. R. Bowser, P. J. Williams, and K. Kurz, J . Org. Chem., 1983, 48, 4111. 276 F. Yuste, A. E. Origel, and L. J. Brefia, Synthesis, 1983, 109.

272

273

186


products such as benzamides. Such Strecker intermediates can also be hydrolysed to a-amino-amides using solid-state catalysis; some refinements of this method have been reported.277Hemiaminals derived from an aldehyde and morpholine can be oxidized to the corresponding amides by reaction with bromobenzene and a palladium(I1) catalyst; yields are in the range 50-90%.278 a-Hydroxy-amides can be obtained in >80% yields, except in cases of severe steric hindrance, by a modification of the Passerini reaction involving condensations between aldehydes or ketones and the titanium imine (349), derived from methyl isocyanide and TiC14 (Scheme 47).279 Chiral P-hydroxy-amides (351) of unknown absolute configuration, have been obtained in 6 6 9 9 % e.e. by condensations between the magnesium enolate of amide (350) and aldehydes, followed by desulphurization (Na-Hg) .280 The corresponding lithium enolates give much lower optical yields of the opposite configuration. o-Stannoxy-amides (352; n =&3) can be obtained from the corresponding lactones and Me3SnNEt, and, on acidification, provide excellent overall yields of the w-hydroxy-amides (353).281Coupling of the salt (352;n=3) with ally1 bromide or benzoyl chloride leads to the ether (354) or the benzoate (355) respectively.

OH

OTiCIj

( 3 4 91

Scheme 47 0 H+

4

Me3 Sn0-CONEt2

(350)

(352)

H 0 -CONEtZ

(353)

I

1

RCHO

\)I HO -0-CONEt2 /

R

(351)

Ph CO 2-CONEt

(354)

( 3 5 51

The dianion (357) derived from 3-hydroxy-5-methylisoxazole(356) represents a protected form of the hypothetical acetoacetamide dianion related to Weiler’s acetoacetate d i a n i ~ n and , ~ ~as~ such reacts with electrophiles at the 5-methyl group to provide homologues (358) in variable yields, hydrogenolysis of which leads to P-keto-amides (359) (Scheme 48).282Related keto-amides (361) can also R. Sola, J. Brugidou, J. Taillades, and A. Commeyras, Tetrahedron Lett., 1983, 24, 1501. Y. Tamaru, Y. Yamada, and Z. Yoshida, Synthesis, 1983, 474. 279 M. Schiess and D. Seebach, Helv. Chim. Acta, 1983,66, 1618. 280 R. Annunziata, M. Cinquini, F. Cozzi, F. Montanari, and A. Restelli, J. Chem. SOC., Chem. Commun., 1983, 1139. 281 A. Ricci, M. N. Romanelli, M. Taddei, G. Seconi, and A. Shanzer, Synthesis, 1983, 319. 282 T. A. Oster and T. M. Harris, J. Org. Chem., 1983,48, 4307. 277

278


187

be assembled by treatment of phosphoranes (360), readily obtained from phosphorylides and an acid chloride, with phenyl isocyanate, followed by hydrolysis.283Various methods for the oxidation of N,N-disubstituted P-ketoamides to the corresponding or$-diketo-derivatives (362) have been developed.284

(356)

(357)

(358)

(3591

Scheme 48

Further examples of the excellent stereoselectivities which are often observed in Eschenmoser amide-acetal Claisen rearrangements have been reported.2g5 Reactions.-Primary amides can be activated by conversion into N-acylpyrroles using readily available dichlorodimethoxybutane.286Subsequent displacement of the pyrrole by primary or secondary amines proceeds smoothly to give secondary or tertiary amides respectively (Scheme 49). This method will be particularly useful with base-sensitive substrates and can also be used to prepare methyl esters from the initial amides by reaction of the intermediate pyrroles with NaOMe. Mono-N-alkylation of primary amides [(363)+ (364)] can also be achieved using monosubstituted olefins and Hg(N03)2.287 Yields are variable (17-99%), but when it works well the method looks to be very attractive and simple to perform. Secondary amides are efficiently O-alkylated to give imides (365) by alkyldiphenylsulphonium salts, RPh2S+BF4-,which, although less reactive than the more commonly encountered oxonium salts, have the advantage that ‘R’ groups other than methyl or ethyl can be used.288Similar treatment of tertiary amides leads to the imidate salts corresponding to (365). Me0

OMe

Scheme 49 283 H. J. Bestmann and K. Kumar, Chem. Ber., 1983, 116,2708. 2&1 W.-D. Malmberg, J. Voss, and S. Weinschneider, Liebigs Ann.

Chem., 1983, 1694. C. H. Heathcock and B. L. Finkelstein, J . Chem. SOC.,Chem. Commun., 1983,919; E. H. Smith and N. D. Tyrrell, ibid., p. 285. 286 S. D. Lee, M. A. Brook, and T. M. Chan, Tetrahedron Lett., 1983,24, 1569. 287 J. Barluenga, C. Jimknez, C. Najera, and M. Yus, J . Chem. SOC., Perkin Trans. 1, 1983, 591. 2R8 M. Julia and H. Mestdagh, Tetrahedron, 1983, 39, 433.

285


188

OR

A further example of very high stereoselectivity in hydride reductions is that of P-keto-amides [e.g. (366)] which, on treatment with zinc borohydride in ether at -78 "C,give virtually pure erythro-P-hydroxy-amides [e.g. (367)] in very high yields.289Some useful regioselectivities of attack by nucleophiles onto N , N diethylsorbamide (368) have been reported .290 Thus, simple Grignard reagents effect mainly [1,4]-additions whereas lithium dialkylcuprates add in a [1,6] manner. The subtle effects that counter-cations can have on the course of anionmediated reactions is further demonstrated in the case of dianions obtained from the cyclohexene carboxamide (369) .291 Whereas the dilithium derivative gives mixtures of isomers, addition of MgBr2 prior to the electrophile gives largely or exclusively the traris-l,4-disubstituted cyclohexenes (370). N- Allyl-amides (372) can be obtained by Wittig-Horner reactions of dianions derived from phosphine oxides (371).292Addition of a symmetrical ketone gives only one diastereoisomer of the intermediate P-hydroxy-phosphine oxide and only two diastereomers are obtained after reaction with acetaldehyde: stereochemical control over the methyl group a- to nitrogen is thus complete.

(366 1

(368 1

(367)

L

(369)

(370)

(371)

(372)

A useful overview of the salient features of directed metallations in secondary and tertiary benzamides has been given.293o-Lithiated benzamides (373) can be converted into anthranilamides (374) in 31-71 % yields by sequential reactions with tosyl azide and sodium borohydride .294 This procedure, which overall provides a source of NH2+,can also be used to aminate other lithiated species. When Y. Jto and M. Yamaguchi, Tetrahedron Lett., 1983, 24, 5385. F. Barbot, A. Kadib-Elban, and Ph. Miginiac, Tetrahedron Lett., 1983,24, 5089. 291 P. Beak, J . E. Hunter, and Y. M. Jun, J. Am. Chem. SOC., 1983,105,6350. 292 D. Cavalla and S. Warren, Tetrahedron Lett., 1983, 24,295. 2y3 P. Beak, A . Tse, J. Hawkins, C.-W. Chen, and S. Mills, Tetrahedron, 1983, 39, 1983. See also M. Iwao, K. K. Mahalanabis, M. Watanabe, S. 0. DeSilva, and V. Snieckus, ibid., p. 1955. 294 J . N. Reed and V. Snieckus, Tetrahedron Lett., 1983, 24,3795. 28y

290


189

two ortho-positions in a benzamide are open to metallation, the more reactive site can be blocked by silylation allowing metallation and electrophilic substitution to be carried out at the less reactive position; subsequent desilylation can be effected by C S F . Thus, ~ ~ ~ the 3-methoxybenzamide (375) can be converted into the homologues (376) in a five-step sequence. However, silyl groups are not always suitable for the protection of phenol functions during such metallations, as 0-C migration can occur. For example, treatment of O-trimethylsilylbenzamide (377) with BusLi at -78 "C followed by warming to room temperature gives the C-silyl derivative (378) .296

OMe ( 373 1

(377)

OMe

(374)

( 37 5 )

( 376 1

(378)

( 3 7 91

(380)

An S-+C shift of a dialkylamino-group has been observed when o-carboxysulphonamides (379) are reacted with thionyl chloride leading to the benzamides (380) in virtually quantitative yields.297A simple method for the conversion of amides into their a-nitro-derivatives has been reported.298Subsequent treatment with a potassium hypohalite leads to the corresponding a-halogeno-a-nitroamides. Thioamides.-Aldonitrones (381) are converted into thioamides (382) in 67-75% yields on heating in benzene with 1,l'-thiocarbonyl-di-imidazole or t r i a ~ o l e The . ~ ~ Willgerodt-Kindler ~ procedure for the conversion of aromatic

ArCHO ( 3 8 31

+ ArCNMqZ (384)

aldehydes (383) into thioamides (384) or of acetophenones into phenylthioacetamides can be problematical when volatile amines are used, R. J. Mills and V. Snieckus, J . Org. Chem., 1983,48, 1565. R. J. Billedeau, M. P. Sibi, and V. Snieckus, Tetrahedron Lett., 1983, 24, 4515. 297 K . Hovius, A. Wagenaar, and J. B. F. N. Engberts, Tetrahedron Left., 1983,24,3137 298 H. Feuer, C . S. Panda, L. Hou, and H. S. Bevinakatti, Synthesis, 1983, 187. 299 D. N. Harpp and J. G. MacDonald, Tetrahedron Lett., 1983,24, 4927.

295

2q6

190


because of the relatively high temperatures required (ca. 200 "C). Such drawbacks can be simply overcome by using the corresponding amine hydrochloride^.^^ Procedures for carrying out thio-Claisen rearrangements (Scheme 50) have been described in detail.301Diastereoselectivities, although variable, are often excellent especially when secondary thioamides are used, although in these examples yields are lower (40-50%). Ketene S, N-acetals (385), derived from the corresponding thioamide under standard conditions (LDA, TMSCl), condense with benzaldehyde in the presence of Bun4NFor TiC14 to give largely the ery thro-P-hydroxy-t hioamides (386).302 Most types of thioamides (387) are converted into amides (388) in 72-98% yield simply by treatment with rn-chloroperbenzoic acid in methylene chloride at room temperature.303

i

R2

R Reagents: i, BunLi, R*CH=CHCH,X

(X=Cl, Br, or OTs); ii, A , THF

Scheme 50

SSiMe,

S

0

ll

II

R1CNR2R3 ---f R'CNR2R3

NMe2

Peptide Bond Formation.-Mostly analogues and homologues of established coupling reagents have been reported this year, some of which have particular features which may make their use advantageous in certain circumstances. Dibenzotriazole carbonate offers the advantage that the by-product, 1-hydroxybenzotriazole can be removed by washing with 1% aqueous sodium bicarbonate.304Bis-succinimides derived from oxalic acid can be used to activate carboxylic acid groups prior to coupling with unprotected a-amino-acids in aqueous a c e t ~ n i t r i l e Other . ~ ~ ~ related coupling agents which can also be used in ester and thioester synthesis are oxazolinyl phosphates306 and N, N'carbonyldibenzoisoxazolinone.307 Carboxylic acid groups can also be activated by esterification with o-hydroxybenzaldehyde oxime; couplings are then carried out under neutral conditions.308All the foregoing methods are virtually or comp300 301

J. 0. Amupitan, Synthesis, 1983, 730.

Y. Tamaru, Y. Furukawa, M. Mizutani, D. Kitao, and Z. Yoshida, J . Org. Chem., 1983,48, 3631. C. Goasdoue, N. Goasdoue, and M. Gaudemar, Tetrahedron Lett., 1983,24,4001. 303 K. S. Kochhar, P. A. Cottrell, and H. W. Pinnick, Tetrahedron Lett., 1983, 24, 1323. 304 M. Veda, H. Oikawa, and T. Teshirogi, Synthesis, 1983,908. See also M. Furukawa, N. Hokama, and T. Okawara, ibid., p. 42. 305 K. Takeda, I. Sawada, A. Suzuki, and H. Ogura, Tetrahedron Lett., 1983,24,4451. 306 T. Kunieda, T. Higuchi, Y. Abe, and M. Hirobe, Tetrahedron, 1983,39,3253. 307 M. Ueda, H. Oikawa, N. Kawaharasaki, and Y. Imai, Bull. Chem. SOC.Jpn., 1983,56,2485. 30*

191


letely free of racemization. Racemization and urethane formation are sometimes serious drawbacks when mixed anhydrides are used as activated intermediates in peptide coupling. These can often be minimized if N-methylpiperidine is used as base during anhydride formation from chloroformates.3090- or p-Aminobenzoic acids can be efficiently incorporatedinto peptides without protection of the less nucleophilic aromatic aminogroup.310 Na-Fmoc protecting groups are particularly useful because of their extreme ease of removal by secondary amines; unfortunately deprotection can occur prematurely by reaction with the incoming amino-group during peptide bond formation. This can be avoided by using very reactive perfluorophenyl esters of W-Fmoc a-amino-acids; couplings with a-amino-esters are then very clean and rapid. 311 Solid-state peptide synthesis can be performed using polystyrene-bound p-nitrobenzophenone oxime groups to form an ester linkage to the first Na-protected - cr - amin ~- a cid This . ~ ~ ~method may offer some advantages in the final removal step of the completed peptide. Alternatively, such solid-state syntheses can be carried out using a 4-(2-chloropropionyl)phenylacetamidomethyl resin which is photolabile at A=350 nm.313 A new concept for the elaboration of peptides, which could potentially be used for automated synthesis, is outlined in Scheme 51.314 Photolysis of 5-azido-3,4oxadiazoles (389), derived in six steps from Na-protected cr-amino-acids,gives the acyl cyanides (390) which are trapped in situ by an unprotected amino-derivative of another 1,3,4-oxadiazole. The process can then be continued by addition of an azido-group to the 5-position of the heterocyle followed by photolysis and trapping, and so on.

(3891

(390)

R’

R*

Scheme 51 1. Hayachi and K. Shimizu, Bull. Chem. SOC.,Jpn., 1983, 56, 3197. F. M. F. Chen, R. Steinauer, and N. L. Benoiton, J . Org. Chem., 1983,48,2939. 310 F. H. C . Stewart, A w t . J . Chem., 1983,36,1629,2511. 311 L. Kisfaludy and I. Schon, Synthesis, 1983, 325. 312 S. H. Nakagawa and E. T. Kaiser, J . Org. Chem., 1983,48,678. 313 F.-S. Tjoeng and G. A. Heavner, J . Org. Chem., 1983,48,355. 314 P. N. Confalone and R. B. Woodward, J . Am. Chem. SOC., 1983,105,902.

3w

192


5 Amino-acids Synthesis.-A broad review of new naturally occurring amino-acids has been published which contains a discussion of some synthetic approaches to these compounds.315Schollkopf has summarized his group's work on the synthesis of chiral amino-acids by reactions between various electrophiles and metallated bislactim ethers,316and has further demonstrated the utility of this approach in syntheses of (R)-a-methyl-S-alkylcysteine methyl esters, (R)-isovaline, ( R ) serine analogues, and chiral ,8-fl~oro-a-amino-acids.~~~ A full report has been published concerning the preparation of chiral a-amino-acid analogues (392) by alkylations of enolates derived from Schiff's bases (391) .318 Chemical yields are good but optical yields are variable. Analogues (392) have also been prepared in 4 6 8 5 % e.e. by closely related procedures starting with the a-D-galactose-(L)alanine adduct (393) ,319 or with Schiff's bases derived from hydroxypinanone~.~'" In the latter case, enantiomeric enrichments are between 15 and 90%.

TheP- and y-iodo-a-amino-esters (394; n = l or 2) can be coupled to lithium dialkylcuprates to provide derivatives (395) in 42-89% yields without r a c e m i z a t i ~ nThese . ~ ~ ~ reactions are especially notable in the case of (394; n = l ) , which usually undergoes only E2 elimination of hydrogen iodide when treated with nucleophiles. Complete Walden inversion occurs when trifluoromethanesulphonates (396) of chiral a-hydroxy-esters are treated with primary or secondary amines to give a-amino-esters (397).322This procedure will be of value as the direct alkylation or arylation of a-amino-esters has many limitations and similar displacements involving poorer leaving groups are usually accompanied by extensive racemization. I. Wagner and H. Musso, Angew. Chem., Int. Ed. Engl., 1983, 22, 816. U. Schollkopf, Tetrahedron, 1983, 39,2085; Pure Appl. Chem., 1983,55,1799. 317 U. Groth and U. Schollkopf, Synthesis, 1983,37,673; U. Schollkopf and R. Lonsky, ibid., p. 675; U. Schollkopf, U. Groth, M.-R. Gull, and J. Nozulak, Liebigs Ann. Chem., 1983, 1133. 315

316

M. Kolb and J. Barth, Liebigs Ann. Chem., 1983, 1668. I. Hoppe, U. Schollkopf, and R. Tolle, Synthesis, 1983, 789. 320 J. A. Bajgrowicz, B. Cossec, Ch. Pigikre, R. Jaquier, and Ph. Viallefort, Tetrahedron Lett., 1983,24, 3721. 321 A. Bernardini, A. El Hallaoui, K. Jacquier, Ch. Pigiere, Ph. Viallefont, and J. Bajgrowicz, Tetrahedron Lett., 1983, 24, 3717. See also R. M. Adlington, J. E. Baldwin, A. Basak, and R. P. Kozyrod, J . Chem. Soc., Chem. Commun., 1983,944. 322 F. Effenberger, U. Burkard, and J. Willfahrt, Angew. Chem., Znt. Ed. Engl., 1983, 22, 65. 318 319

193


C02Me

(394)

(396)

@t2H

-

(397)

t Scheme 52

The principle of 'self-reproduction of chirality' is illustrated in Scheme 52 in a synthesis of (S)-proline analogues.323The stereochemistry of the original optical centre in (S)-proline completely controls the orientation of a second chiral centre formed by condensation with pivalaldehyde. Enolization then destroys optical activity at the original site but electrophilic attack is directed to the re-face by the newly created second site. High diastereoselectivity is also observed at the third potentially chiral carbon formed when the enolate is condensed with unsymmetrical ketones. The (2S,3S,4R)-aminopentanoicacid (399), the central connecting unit in Bleomycin A2, has been obtained in extremely high optical yield by acylation of the enolate of oxazolidinone (398) with Na-Boc-(D)-alanine anhydride followed by zinc borohydride reduction289and hydrolysis (Scheme 53) .324 OH

BocNH

+ ( 398 1

Scheme 53

Essentially complete enzymic resolution of N-acetylphenylalanine methyl esters has been achieved on a preparative scale using a commercially available serine protease; the enzyme catalyses hydrolysis of the (Qmethyl ester only.325 D. Seebach, M. Boes, R. Naef, and W. B. Schweizer, J. Am. Chem. SOC., 1983, 105,5390. R. M. DiPardo and M. G. Bock, Tetrahedron Lett., 1983, 24, 4805. 325 J. M. Roper and D . P. Bauer, Synthesis, 1983,1041, See also K. Bernauer, R. Deschenaux, and T . Taura, Helv. Chim. Acta, 1983,66,2049; Y . Tachibana, M. Ando, and H. Kuzuhara, Bull. Chem. SOC.Jpn., 1983, 56, 3652.

323 324

194


Further work on the uses of aziridine-2-carboxylic acid derivatives in the synthesis of a-amino-acids has resulted in new routes to threo-3-methyl-(~)-cysteine,3,3dimethylcystine, and cystine itself .326 cis-2-Amino- and cis-2-cyano-aziridines can be converted into P-fl~oro-a-amino-acids~~~ using Olah’s reagent [pyridiniumpoly(hydrogen fluoride)] ,327 the former leading selectively to the threo-isomers. An efficient new route to racemic N-Boc-Coronamic acids (400; R=H, alkyl, or Ph), which are related to a structural feature of the bacterial toxin Coronatine, is by addition of a diazoalkane to dehydroalanine followed by thermolysis (90°C in toluene) and base hydrolysis.328a-Methoxylation of protected a-amino-acids can be achieved electrochemically in methanol containing sodium chloride .329 P-Amino-acid derivatives (403)91are obtained in 42-95% yield by condensations between ketene silyl acetals (402) and either O-benzyloximes (401; R1=H orMe)330or N,N,N-trialkyl-hexahydrotria~ines;~~~ yields are between 20 and 95%.

C02H

R ( 40 0)

+

R’]

4NHBo~

NOB~ (4011

-

.j=(oTMs

R3

OR^ (4021

R2 R3

R$”(

CO, R 4 NHOBz

(403)

The more soluble p,p’-diphenyl analogue of Lawesson’s reagent has been found to be very effective for the conversion of protected a-amino-amides into the corresponding t h i ~ a r n i d e sDuring . ~ ~ ~ a preparation of the dipeptide sweetening agent aspartame and of thioaspartame, Lawesson’s reagent itself was used first as a coupling reagent and subsequently in its more usual role as a thiation reagent .333 Aspartic acid is the starting material for syntheses of L-serine stereospecifically labelled at C-3 with deuterium, the key step being a Baeyer-Villiger oxidation,334 and of L-glutamic acid also specifically labelled at C-3 with deuterium and nonstereospecifically with tritium at C-4; a Wolff rearrangement with retention of stereochemistry forms the key step in the latter

Dehydroamino-acids.-Phosphonates (404) can be obtained from glycine using conventional methods and undergo typical Wadsworth-Emmons reactions with aldehydes to give dehydroamino-acid derivatives (405) .336Alcoholysisof azlactones (406) derived from an aldehyde and hippuric acid also leads to unsaturated amino-esters (405) .337 The reactions are stereoselective; thus the (E)-isomer of K. Nakajima, H. Oda, and K. Okawa, Bull. Chem. SOC. Jpn., 1983,56,520; K . Nakajima and K. Okawa, ibid., p. 1565; T. Wakamiya, K . Fukase, K. Shimbo, and T. Shiba, ibid., p. 1559. 327 A. I. Ayi and R. Guedj, J . Chem. SOC., Perkin Trans. 1, 1983,2045. 328 M. Suzuki, E. E. Gooch, and C. H. Stammer, Tetrahedron Lett., 1983,24, 3839. 329 T. Shono, Y. Matsumura, and K. Inoue, J . Org. Chem., 1983,48, 1388. 330 K. Ikeda, K. Achiwa, and M. Sekiya, Tetrahedron Lett., 1983,24, 4707. 331 K. Ikeda, K. Achiwa, and M. Sekiya, Tetrahedron Lett., 1983,24, 913. 332 G. Lajoie, F. Lepine, L. Maziak, and B. Belleau, Tetrahedron Lett., 1983,24, 3815. 333 B. Yde, I. Thomsen, M. Thorsen, K. Clauson, and S . - 0 . Lawesson, Tetrahedron, 1983,39, 4121. 334 D. Gani and D. W. Young, J . Chem. SOC.,Perkin Trans. 1, 1983,2393. 335 S. J. Field and D. W. Young, J. Chem. SOC., Perkin Trans. I , 1983, 2387. 336 R. Kober and W. Steglich, Leibigs Ann. Chem., 1983, 599. 337 C . Cativiela, M. D. Diaz dc Villegas, J. A. Mayoral, and E. Melendez, Synthesis, 1983, 899.

326

195


azlactones (406) can be converted into esters (407), and, although this work has only dealt with azlactones derived from thiophenecarboxaldehydes, the route should be more generally applicable. 0

I

(404)

(405)

Ph (406)

R4

(407)

Aryl bromides can be coupled with N-acetyldehydroalanine in the presence of Pd(OAc), and a tertiary amine to give a-acetamidocinnamic acids in 25-75% yields.338P-Hydroxy-a-acylamino-esters are smoothly and stereospecifically dehydrated by (diethy1amino)sulphur trifluoride (DAST) , the threo-isomers leading to (2)-unsaturated a-amino-esters whereas the erythro-isomers afford only the corresponding (E)-isomers .339 Dehydration of N-hydroxy-N-acetyl-aamino-esters can be quickly and easily achieved using tosyl chloride and triethylamine to give largely (E)-a-acetamido-unsaturated esters.340 Peptides containing a central dehydroamino-acid residue can be obtained by simultaneous coupling of two a-amino-acids with N-carboxy-a-dehydroaminoacid anhydrides (Scheme 54).341This attractive looking method can clearly also be used to incorporate terminal unsaturated amino-acid residues.

TFAA,

R*

0

R4

Scheme 54 M. Cutolo, V. Frandanese, F. Naso, and 0. Sciacovelli, Tetrahedron Lett., 1983, 24, 4603. 339 L. Somekh and A . Shanzer, J. Org. Chem., 1983,48, 907. 340 T. Kolasa, Synthesis, 1983, 539. 341 C. Shin, T. Yamada, and Y. Yonezawa, Tetrahedron Lett., 1983, 24,2175. 338

196


Asymmetric Hydrogenation.-A brief but useful review of this topic has been published.342A chiral ligand derived from an (S)-2,2’-diaminobiphenyl has been found which, in conjunction with rhodium(I), catalyses the hydrogenation of a-acetamidoacrylic acid to give N-acetyl-(R)-alanine in up to 81% optical yield.343 Further, but not always impressive, examples of asymmetric hydrogenations of dehydro-dipeptides by chiral Rhl-diphosphine complexes have been reported .344 In general, rhodium(1)-based catalysts are not capable of effecting the hydrogenation of tetrasubstituted a-acylamino-a$-unsaturated esters. Such reductions can however be effected very easily by using iridium-derived catalysts although optical yields are as yet rather Protection and Deprotection.-Ally1 esters can be effective in carboxylic acid protection during peptide synthesis as they are .stable to hydrolysis under conditions acidic enough to remove Boc and Z groups and are themselves cleaved under essentially neutral conditions by [ (Ph3P)3RhCl].346 2-Bromoethyl ester blocking groups have been successfully employed in glycopeptide synthesis.”’ The usual method of removal (conversion into the iodoethyl derivative and zinc reduction) does not affect Z protecting groups or sensitive O-glycoside bonds. Dithiane-based Dim esters (4O8), prepared by Al( OPr’)3-catalysed transesterification of the corresponding methyl esters, are relatively acid stable but can be readily removed by oxidation to the sulphoxide/sulphone derivatives, using hydrogen peroxide and ammonium molybdate, followed by exposure to mildly basic conditions of pH Related methodology has previously been used in amino-group protection; one significant drawback associated with Dim derivatives in general is the group’s incompatibility with cysteine residues. Another amino-protecting group which can be used in the masking of carboxylic acids is the 9-fluorenylmethyl (Fm) function.349Again, removal is under very mild basic conditions by treatment with a secondary amine .311 A preliminary report concerning CAM esters [(409); carboxyamido methyl] suggests that these groups could provide yet another general method of acid protection. Prepared by reaction

(4081

(4091

W. S. Knowles,Acc. Chem. Res., 1983,16,106. See also P. Pine and G. Consiglio, PureAppl. Chem., 1983,559, 1781. 343 A. Vehara, T. Kubota, and R. Tsuchiya, Chem. Lett., 1983, 441. 344 M. Yatagai, M. Zama, T. Yamagishi, and M. Hida, Chem. Left., 1983, 1203. 345 L. A. Oro, J. A . Cabeza, C. Catwiela, M. D. Diaz de Villegas, and E. Melendez, J . Chem. Soc., Chem. Commun.. 1983, 1383. 346 H. Waldmann and H. Kunz, Liebigs Ann. Chem., 1983, 1712. 347 M. Buchholz and H. Kunz, Liebigs Ann. Chem., 1983, 1859. 348 H . Kunz and H. Waldmann, Angew. Chem., Znt. Ed. Engl., 1983. 22, 62. 349 H. Kessler and R. Siegmeier, Tetrahedron Lett., 1983, 24, 281.

342


197

between the caesium salts of Na-protected-amino-acids and a-chloroacetamide, the function remains intact while Boc, Z, and Fmoc groups are removed under the usual conditions and is itself cleaved by mild aqueous base, without affecting the foregoing groups.”O Anhydrous toluene-p-sulphonic acid and toluene-psulphonyl chloride in ethanol is reported to be a useful mixture for the esterification of a-amino-acids such as tryptophan which are rather resistant to such derivatization under other more usual condition^.^^' Yet another reagent for the preparation of Na-Boc derivatives of a-amino-acids is t-butyl benzotriazol-l-yl carbonate.3552 (For a complete list, consult the current Fluka catalogue.) An easily handled, stable crystalline solid, the compound is especially suited to those in a hurry as reaction times are less than thirty minutes. The benzotriazolylcarbonyl (Btc) group itself can be used to block amino-functions during peptide coupling and is easily removed by acid hydrolysis.353An exceptionally acid-labile amino-protecting group is the t-Bumeoc moiety (410); kinetic studies have shown that it is removed 4000X faster than Na-Boc functions in 80% aqueous acetic acid.354Procedures for the preparation of Na-2,2,2trichloroethoxycarbonyl (Na-Troc) and Na-Fmoc derivatives of amino-acids using activated carbonates derived from N-hydroxysuccinimide look to be useful additions to existing methodology.3ssN-Alkylation of Na-Fmoc-a-amino-acids can be achieved by formation of oxazolidinone derivatives (411) using an aldehyde,

R2CH0, and tosic acid followed by reduction with t r i et hyl ~i l ane.The ~~~products (412) are obtained with 99%) enantiomeric excess are possible if the potassium salts (13) are used in place of the esters.36 An improved experimental procedure for asymmetric reduction of trifluoromethyl and methyl ketones uses a large excess of yeast in a small volume of water in the absence of added sugar.37The simpler work-up necessary results in a reduction of manipulative losses. Baker's Yeast has been used in a simple synthesis of (2S,SS)-hexanediol from 2,Shexanedione in 57% yield.38Fungal reduction with Curvularia lunata or Mortierella rammanniana of racemic bicyclo[3.2.0]hept-2-en-6-one(14) results in reduction of only one enantiomer to give 6-endo-( 1S,5R ,6S)-bicyclo[3.2 .O] hept-2-en-6-01 (15) and optically active starting material. 39

(14)

(recovered 1

(15)

Preparation by Nlrcleophilic Addition.-(Di-isopropoxymethylsily1)-methylmagnesium chloride (16) has been developed40 as a synthetic equivalent to the hydroxymethyl anion via transition-metal catalysed coupling with halides followed by deprotection with hydrogen peroxide-fluoride. A second hydroxymethyl anion equivalent, t-butoxymethyl-lithium (17) , has been reported by C ~ r e y .The ~ l reagent is prepared in a two-stage procedure by generation of the anion with s-butyl-lithium-potassium t-butoxide followed by metal exchange with

( Pri 0 12MeSiCH2MgCL

(16)

'HOCH;

=>

But OCHzLi (17)

R. W. Hoffmann and W. Ladner, Chem. Ber., 1983,116,1631. M. F. Zuger, F. Giovannini, and D . Seebach, Angew. Chem., lnt. Ed. Engl., 1483, ICJL?. 35 B. Zhou, A. S . Gopalan, F. Van Middlesworth, W.-R. Shieh, and C . J. Sih, J . Am. Chem. Soc., 1983, 105, 5925. 36 M. Hirama, M. Shimizu, and M. Iwashita, J . Chem. Soc., Chem. Commun., 1983, 599. 37 M. Bucciarelli, A. Forni, I. Moretti, and G. Torre, Synthesis, 1983,897. 38 J. K . Lieser, Synth. Commun., 1983,765. 39 M. J. Dawson, G. C. Lawrence, G. Lilley, M. Todd, D. Noble, S . M. Green, S. M. Roberts, T. W. Wallace, R. F. Newton, M. C. Carter, P.Hallett, J. Paton, D. P. Reynolds, and S . Young, J . Chem. SOC., Perkin Trans. 1, 1983, 2119. K. Tamao, N. Ishida, and M. Kumada, J . Org. Chem., 1983,48,2120. 41 E. J. Corey and T . M. Eckrich, Tetrahedron Lett., 1983,24,3165. 33

3

8


212

lithium bromide. The bis-anion (18) generated from 2-methylbenzyl alcohol reacts in the expected manner with aldehyde^.^^

u-Hydroxy-ketones have been prepared by the addition of Grignard reagents to 0-trimethylsilylated cyanohydrins (Scheme 17).43 Less Grignard reagent is OSiMe3 R1-+CN

i,ii

OH R1+=

R2

R2

0 R3

Reagents: i, R3MgX, Et,O, r.t., 2 h; ii, H,O+

Scheme 17

necessary and the yields of adducts are higher than in the usual procedure with cyanohydrins themselves. Terminal epoxides are converted regiospecifically into primary alcohols via reaction with organotin compounds (Scheme 18).44 This reaction has been applied particularly to the preparation of a-amino-alcohols.

R / O O

Reagents: i, Me,SnX, CH,C12;ii, CH2(C02H)2,Et,O

Scheme 18

The addition of cuprates to sterically unbiased /?,y-epoxy-alcohols [e.g. (19)] has been shown to favour C-2 attack (Scheme 19).4s OH

RZCuLi ___)

- 25 OC (19)

Bzow OH R major product

Scheme 19 M. Braun and E . Ringer, Tetrahedron Lett., 1983,24,1233. 43 L. R. Kepsi, S. M. Heilmann, and J. K. Rasmussen, Tetrahedron Lett., 1983, 24,4075. 44 M. Fiorenza, A. Ricci, M. Taddei, and D. T a w , Synthesis, 1983, 64U. 45 M. A. Tius and A. H. Fauq, J . Org. Chem., 1983,48,4131.

42

Alcohols, Halogeno-compounds, and Ethers

213

2,2,2-Trichloro-alcoholsare formed by the addition of electrolytically generated trichloromethyl anion to aldehydes.M An improvement upon the Henry nitroaldol reaction (which suffers from the tendency of nitro-compounds to alkylate on oxygen instead of carbon) has been r ep~ r t ed.~’ The reaction is carried out with the materials adsorbed on to activity I alumina in the absence of solvent. Using this technique high yields of 2-nitro-alkanols have been achieved. Samarium di-iodide has been shown to promote the addition of aryl and alkenyl bromides to aldehydes,48and aryl and alkenyl chromium compounds add selectively to aldehydes in the presence of ketones and cyanides (Scheme 20).49

OH

OH Reagents: i , RX (R=aryl or alkenyl, X=Br or I), CrCl,, DMF, 25°C

Scheme 20

Reetz and co-workers have published procedures whereby 1,2-, 1,3-, and 1,4asymmetric induction can be maximized in the nucleophilic addition to chiral benzyloxy-aldehydes, via chelation control (Scheme 21).50951In the case of 2-benzyloxypropanal (20) use of methyltitanium(w) chloride favours the erythro-product , but use of methyltitanium(rv) isopropoxide reverses the stereochemical outcome. Two procedures are described for 3-benzyloxyaldehydes (21). The first uses methyltitanium(1v) chloride, and the second involves precomplexation with titanium(1v) chloride followed by addition of allysilanes or di-n-butylzinc. In all cases the stereoselectivities are >90%. The prechelation technique when applied to 4-benzyloxypentanal (22) gives a diastereoisomer ratio of 85 : 15. Diethylzinc in the presence of bis- [(-)-camphorquinone-a-dioximato]palladiurn(~~) yields (-)-benzyl alcohols with moderate enantiomeric excess on reaction with aromatic aldehyde^.^^ Allylic Alcohols. The (2)-1-cyanoalkenyl anion (23) adds to ketones and aldehydes to give /3-cyano-allylic alcohols in good yield (Scheme 22).53 Aryl ytterbium halides have been shown to yield allylic alcohols with a&unsaturated 46 47

49

51 52

53

T. Shono, S. Kashimura, K. Ishikazi, and 0. Ishige, Chem. Lett., 1983, 1311. G. Rosini, R. Ballini, and P. Sorrenti, Synthesis, 1983, 1014. J. Souppe, L. Danon, J. L. Nancy, and H. B. Kagan, J . Organomet. Chem., 1983,250,227. K. Takai, K. Kimura, and T. Kuroda, Tetrahedron Lett., 1983,24, 5281. M. T. Reetz, K. Kesseleler, S. Schmidtberger, B. Wendroth, and R . Steinbach, Angew. Chem., Znr. Ed. Engl., 1983, 989. M. T. Reetz and A. Jung, J . Am. Chem. SOC., 1983,105,4833. N. Ogumi, T. Omi, Y. Yamamoto, and A . Nakamura, Chem. Lett., 1983,841. Y. Sat0 and K. Hitomi, J . Chem. SOC.,Chem. Commun., 1983, 170.

214

-

BrO

i

, b C H O

H (


s 1-(20)

I

BzO

OH

BzO

OBz OH

OBz H minor

H

OH

major

OBz

iv

CHO

+

(22)

+ H

OBz

H

OH

+

H

OBz

HO

H

85

15

Reagents: i, MeTiCl,, CH2C12,-78°C; ii, MeTi(OPri),, CHC12, -78°C; iii, either MeTiC1, or Tic&, followed by CH,=CHCH,SnMe3 or Bun,Zn; iv, TiCl,; v, Me,Zn, -95°C

Scheme 21

215


(23) Reagents: i, Bun4N+F-,THF, -15°C; ii, R2R3CO;iii, H30+

Scheme 22

iii

OH

Br

R Reagents: i, LiSnBu,, THF, -78°C; ii, Ph,P, CBr4, Na2S03,CH,Cl,; iii, m-ClC,H,CO,H

Scheme 23

aldehydes,54and y-bromo-allylic alcohols have been prepared from a,p-unsaturated aldehydes via halogenostannanes (Scheme 23) .s5 Allylic alcohols have been produced by the Reformatsky reaction of p-dimethylaminopropionates with a-alkoxy-aldehydes followed by elimination (Scheme 24).s6

R3*CH0

anti (major p r o d u c t )

SY n

Reagents: i, THF, -78°C; ii, MeI, MeOH, 0°C; iii, DBU, Me,CO, r.t.

Scheme 24

Homoallylic Alcohols. The addition of ethoxymethyl-substituted alkyl stannanes to carbonyl compounds has been demonstrated to yield homoallylic alcohols possessing a cis-double bond regardless of the stereo- or regio-chemistry of the initial stannane (Scheme 25) .57 Selective synthesis of branched or linear homo54

55

56 ST

K. Yokoo, Y. Yamanaka, T. Fugawa, H. Tuniguchi, and Y. Fujiwara, Chem. Lett., 1983, 1301. M. Shibasaki, H. Suzuki, Y . Torisawa, and S . Ikegami, Chem. Lett., 1983, 1303. L. Banfi, L. Colombo, C. Gennari, and C. Scholastico,J. Chem. SOC.,Chem. Commun., 1983,1112. Y. Naruta and K. Maruyama, J . Chem. SOC., Chern. Commun., 1983, 1264.

216

General and Synthetic Methods Et O ' y " SnMq

OH PhCHO

Ph A

______)

O

E

t

SnC14 , -78'C

J

Scheme 25 RZBSePh I

II

+

PhSe-

-

R

1

iii, iv

R iii,iv

R +

f--

PhSe/J-4

OH

R'y-R OH

Reagents: i, LDA, THF, -78°C; ii, R,B, -78--0"C, 1h; iii, RICHO, -78°C; iv, H,O; v, R3B, -78°Cr.t., 24 h

Scheme 26

allylic alcohols is possible via the reaction of aldehydes with an allylic boraneselenium system.58Choice of reaction conditions determines the nature of product obtained (Scheme 26). The pentadienylborane system (24) reacts with ketones at the central carbon giving the thermodynamically less stable alcohols (25).59 Zinc-graphite and potassium-graphite lamellar inclusion complexes have been combined with allylic halides resulting in homoallylic alcohols after reaction with carbonyl compounds.60Japanese workers have found that simultaneous addition

58 59

Y. Yamamoto, Y. Saito, and K . Maruyama, J . Org. Chem., 1983,48, 5408. M. G . Hutchings, W. E. Paget, and K. Smith, J . Chem. Res. (S), 1983, 31. G . P. Boldrini, D. Savoia, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J . Org. Chem., 1983, 48, 4108.


217

of aromatic aldehydes and ally1 halides to a suspension of manganese in refluxing THF containing iodine can give good yields of alcohols.61By similar simultaneous addition of cinnamyl chloride and benzaldehyde to magnesium, 1,2-diphenyl-but3-en-1-01 has been prepared.62 This is the first description of the successful generation and use of a cinnamyl Grignard reagent. Ally1 boronates (26) are reported to add to aldehydes to give the y-adducts (27) with a high preference for

X

X

(26)

(27)

X = Br, C I , SEt , or OMe

Z-configuration of the double bond.63The reaction of (a-ethoxycarbonyl vinyl)d e m o n ~ t r a t e dhigh ~ ~ diastereofacial selectivity in the tin(1v) chlride-mediated 27) .@The reactions are high yielding, and stereoisomerically pure allylic alcohols

R’

OEt

111

tE, , ,R

A-

R2

c--

OH R3

Reagents: i , R’CuYLi, Et,O, -78°C; ii, R2R3CO;iii, aq. NH,Cl

Scheme 27

are obtained with ketones and epoxides. An allenoate intermediate has been proposed to explain the stereochemical outcome with ketones. Heathcock has d e r n ~ n s t r a t e dhigh ~ ~ diastereofacial selectivity in the tin(1v) chloride-mediated reaction of allysilanes with chiral a- and P-alkoxy-aldehydes (Scheme 28), thus 62

6; 65

T. Hiyama, M. Sawahata, and M. Obayashi, Chem. Lett., 1983,1237. J. M. Coxon, G. W . Simpson, P. J. Steel, and V . C . Trenerry, Tetrahedron Lett., 1983, 24. 1427. R. W. Hoffmann and B. Landmann, Tetrahedron Lett., 1983,24, 3209. J. P. Marino and R. J. Linderman, J . Org. Chem., 1983, 48, 4621. S. Kigooka and C. H. Heathcock, Tetrahedron Lett., 1983, 24, 4765.

218

General and Synthetic Methods OBz

OBz

CH 'O R=H R = Me

B

z

O

35 45

1 1

A CHO

10 Reagents: i, SnC14,Me$

1

Y R Scheme 28

complementing the work of Reet~.~O> 51 Other Lewis acids result in loss of stereoselectivity in this case. In an attempted enantioselective synthesis of homoallylic alcohols, allylic halides and aldehydes were combined in the presence of chromium(I1) chloride and a chiral auxiliary.&However, only low enantiomeric excesses were observed. Some measure of success has been achieved in the Lewis acid-catalysed reaction of optically active diallylbis-(2-phenylbutyl)tin with aldehydes67when enantiomeric excesses of up to 82% were recorded.

Other Unsaturated Alcohols. Lithiated derivatives of butynyl carbonates, on sequential addition of titanium isopropoxide and a ketone, provide diastereomerically pure a-allenyl alcohols (Scheme 29) .68 a-Allenyl alcohols are Me

Me

Reagents: i, BunLi, Et,O, -78°C; ii, Ti(OPrl),, -78°C; iii, R1R2C0

Scheme 29

the major products from the reaction of 1-lithio-1-phenylthioallene(28) with ketones.69Propargyl alcohols are also formed as minor products. High yields of propargyl alcohols are obtained from the reaction of 3-lithio-1-methoxy1-trimethylsilylpropyne(29) with ketones70(Vol. 6, p. 165). 6 67

69 'O

B. Cazes, C . Vernikre, and J. Gore, Synth. Commun., 1983, 73. J. Otera, Y . Kawasaki, H. Mizuno, and Y. Shimizu, Chem. Lett., 1983, 1529. D. Hoppe and C . Riemenschneider, Angew. Chem., Znt. Ed. Engl., 1983, 54. A. J . Bridges and R. D. Thomas, J . Chem. SOC.,Chem. Commun., 1983,485. I. Kuwajima, S. Sugahara, and J. Enda, Tetrahedron Lett., 1983, 24, 1061.

A Ecoh oIs, Halogen o-compounds, and Ethers

219

PhS

OMe

);.=

Li

TMS

(28)

(291

Diols. Sequential treatment of chlorohydrins with n-butyl-lithium and lithium naphthalenide gives an organolithium species which reacts with carbonyl comA diastereoselective synthesis of 1,2-diols has been pounds to produce 1,2-di0ls.~l reported72using the chiral alkoxy-acetate (30). With acetaldehyde as the electrophile the major product has the erythro-configuration (Scheme 30).

erythro

(30)

10 : 1

threo

Reagents: i, Pr,NLi; ii, MeCHO, -120°C; iii, H,, Pd(OH),

Scheme 30

General Methods of Preparation. *-A2-Isoxazolines, prepared by 1,3-dipolar addition of nitriles to olefins, can be hydrogenolysed by Raney-nickel, and the resultant product hydrolysed to give P-hydro~y-ketones.~~ This strategy provides an alternative route to the aldol condensation for obtaining /3-hydroxy-ketones, and has been used in the synthesis of furanone precursor^.^^ In the field of sugar chemistry, a deoxygenative [ 1,2]-hydride shift has been utilized to convert cis-diol monotosylates into inverted secondary alcohols (Scheme 31) .75 Snider has used

DMSO-THF

HO OTs Scheme 31

two sequential ene reactions in an annelation procedure which produces hydroxydecalins from methylenecyclohexane and a$-unsaturated ketones (Scheme 32a) (see Vol. 6, p. 166).76More work by Snider and c o - ~ o r k e r shas ~ ~ demonstrated the utility of reacting enol ethers with formaldehyde in the presence of *Any alcohol preparation which is in fact removal of a protecting group will be listed under Protection and Deprotection. 71 J. Barluenga, J . Flbrez, and M. Yus, J . Chem. SOC. Perkin Trans. 1, 1983, 3019. 72 J. d'Angelo, 0. Pagks, J. Maddaluno, F. Dumas, and C . Revial, Tetrahedron Lett., 1983, 24,5869. 73 D. P. Curran, J . A m . Chem. SOC., 1983,105,5826. 74 S. H. Anderson, K. K. Sharma, and K. G. Torssell, Tetrahedron, 1983,39,2241. 75 F. Hansske and M. J . Robins, J . A m . Chem. SOC., 1983, 105,6736. 76 B. B. Snider and E. A. Deutsch, J. Org. Chem., 1983,48, 1822. 77 B. B. Snider and G. B. Phillips, J. Org. Chem.,1983,48, 2789.


220

a

li

J @OH

Hoho R

b

Me

Reagents: i , HCHO, Me,Al, CH,CIZ,0°C; ii, H,O

Scheme 32

organoaluminium compounds (Scheme 32b). An improved procedure for hydrolysing alkyl bromides to alcohols has been reported;78use of mercury(I1) oxide and fluoroboric acid reduces the amount of elimination which may occur giving alcohols in 67-95% yield. Studies using endo-tricyclo.[5.2.1.02,6]decanehave enabled bridgehead hydroxylation to be carried out using rn-chloroperbenzoic acid to give the alcohol (31) in 77% yield79(Vol. 1, p. 156). Zinc-trimethylsilyl

chloride has been shown to act as a mild reducing system for converting epoxides to alcohols; with an unsymmetrical epoxide the alcohol with less a-substitution is the major product. Carboxylate salts have been shown to undergo copper(1)mediated addition to cyclic allylic epoxides giving monoesters of syn-diols.81This 78

79

*O *l

J. Barluenga, L. Alonso-Cires, P. J. Campos, and G. Asensio, Synthesis, 1983, 53 N. Takaishi, Y . Fujikura, and Y . Inamoto, Synthesis, 1983, 293. Y . D. Vankar, P. S. Arya, and C . T. Rao, Synthesis, 1983,869. J. P. Marino and J. C. J a h , Tetrahedron Lett., 1983, 24, 441.


221

reaction is limited to cyclic compounds where the double bond is constrained in a cisoid relationship to the epoxide. Work by Pelter and co-workers with methyldimesitylboranes2 has demonstrated its use for preparing homologous alcohols from halides. Alcohols labelled with 1 7 0 have been prepared by the action of 1 7 0 gas on trialkylboranes followed by decomposition with acid.83 Organosilicon fluorides can be cleaved oxidatively to alcohols with a combination of peracid, dimethylformamide, and potassium

Allylic Alcohols. Cyclopentadiene has been used to protect the double bond of a$-unsaturated ketones prior to reaction with Grignard reagents;85 reverse Diels-Alder reaction then liberates the double bond providing efficient access to isopropenyl alcohols (Scheme 33). Tertiary allylic alcohols may be prepared by

lii Reagents: i , Cyclopentadiene, heat; ii, MeMgI; iii, 550°C

Scheme 33

isomerization of primary 3,3-disubstituted alcohols with bis(trimethylsily1) peroxide in the presence of [VO(acac),] catalystVs6 This complements the ready, acidcatalysed tertiary to primary alcohol isomerization. A novel oxidatively assisted hydrolysis of allylic iodides to rearranged allylic alcohols has been reported (Scheme 34);s7the key feature of the process is the [2,3]-sigmatropic rearrangement of an allylic iodoso-compound to an allylic hypoiodite. Tin(1v) chloride. mediated rearrangement of the epoxide (32) occurs in moderate yields to give allylic alcohols (33);88a four-membered 0x0-tin intermediate has been implicated.

Homoally lic and Other Unsaturated Alcohols. Cyclopentenols have been prepared via intramolecular photo-oxetane formation from unsaturated P-ketoA. Pelter, B. Singaram, L. Williams, and J. W. Wilson, Tetrahedron Lett., 1983,623; A . P. Pelter, L. Williams, and J. W. Wilson, ibid., p. 627. 83 G . W. Kabalka, T. J. Reed, and S. A . Kunda, Synthesis, 1983,737. K. Tamao, T. Kakui, M. Akita, T. Iwahara, R. Kanatani, J. Yoshida, and M. Kumada, Tetrahedron, 1983, 39, 983. 85 R. Bloch, Tetrahedron, 1983, 39, 639. 86 S. Matsubara, K. Takai, and H. Nozaki, Tetrahedron Lett., 1983, 24, 3741. 87 S. Yamamoto, H. Itani, T . Tsuji, and W . Nagata, J . A m . Chem. SOC., 1983,105,2908. 88 I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983, 1435.

82

222

General and Synthetic Methods R’

r

R1

R

3

0 x

I

L

I

+

R’

R2

R3+OH

.

R1

R3+(

R2

*Ao

Reagents: i, m-ClC6H,C03H, EtOAc or CH,Cl,, aq. Na2C03

Scheme 34

R’

R1

Si Me3 R2+OH

esters (Scheme 35).89The erythrolthreo selectivity of the [2,3]-Wittig rearrangement of crotyl propargyl ethers (Figure 5 ) has been shown to be dependent upon the terminal substituent of the acetylene.w W. S. Johnson has described the use of acetal templates derived from chiral diols for the asymmetric synthesis of homoallylic91and propargylic alcohols.92The strategy (Scheme 36) permits the preparation of these alcohols in good overall yield with enantiomeric excesses of up to 92%.

HO Reagents: i, hv; ii, NaH ( 3 equiv.), benzene, reflux

Scheme 35 89 91

92

T. H. Kim, Y. Hayase, and S. Isoe, Chem. Lett., 1983, 1421. K. Mikami, K. Azuma, and T. Nakai, Chem. Lett., 1983, 1379. W. S. Johnson and J. D. Elliott, J. Am. Chem. SOC., 1983, 105,2088. W. S. Johnson and J. D. Elliott, J . Am. Chem. Soc., 1983, 105,2904.


223

N , X erythro

X

TMS

threo

-

100 100 90

Me H

10

F 0 7

N , X

X

TMS Me H

R

73

27

1

99 99

1 Figure 5

R

R1

H H H Reagents: i, R'TMS, TiCl,, CH2Cl,, -78°C; ii, MeOH; iii, PCC; iv, KOH, MeOH

Scheme 36

Diols. A sequence has been described93which converts allylic alcohols into 3-amino-1,2-diols. A polymer-supported diol (34) has been prepared,94finding use in the isolation of carbonyl compounds and as a protecting group. Samarium di-iodide has been shown to mediate the reductive dimerization of aldehydes and ketones to form p i n a c o l ~Similarly, .~~ pyridyl glycols (35) have been prepared in a OH

93 94 95

G . Cardillo, M. Orena, and S. Sandri, J . Chem. SOC., Chem. Commun., 1983,1489. P. Hodge and J. Waterhouse, J . Chem. SOC.,Perkin Trans. 1, 1983, 2319. J. L. Namy, J. Souppe, and H. B. Kagan, Tetrahedron Lett., 1983,765.


224

'one-pot' process which is promoted by aqueous titanium(II1) chloride.96(R)-Butl-ene-3,4-diol (36), a valuable intermediate for the synthesis of optically active compounds, has been prepared97in 20% overall yield with 92% enantiomeric excess from (2K,3R)-tartaric acid.

OH OH

(35)

(36)

Protection and Deprotection.-Primary and secondary alcohols may be converted into their methoxymethyl (MOM) ethers using trimethylsilyl iodide and dimeth~xymethane.~~ Tertiary alcohols are converted into the iodides. The methoxymethyl group has proven useful in the protection of uracil residues in oligoribonucleotide synthesis.w Primary alcohols have been protected as their t-butyldiphenylsilyl (TBDPS) ethers in the presence of polyvinylpyridine.looThe advantage of this technique is the non-aqueous work-up procedure which simply requires removal of reagents by filtration and evaporation of the filtrate. Primary hydroxy-groups may be preferentially protected in the presence of secondary hydroxyls by sequential alternative addition of t-butyldimethylsilyl chloride (TBDMS chloride) and silver nitrate in THF.lolTBDMS ethers of tertiary and sensitive alcohols can be prepared by the use of 15 kbar pressure at room temperature. lo2 0-Benzoylation of carbohydrate derivatives is sometimes complicated by migration of the benzoyl group, but phase-transfer catalysis in the presence of additional sodium salts has been shown to minimize such side reactions.lo3 Benzoyl trifluoromethanesulphonate has proven to be an efficient benzoylating agent for hindered alcohols'@' although acetals and epoxides are decomposed. Benzylation of alcohols has been carried out in neutral, non-polar media using potassium exchanged Y-type zeolite resin in refluxing hexane.lo5 Olah has describedlo6the use of a polymeric perfluorinated sulphonic acid resin for the preparation of tetrahydropyranyl (THP) ethers (cf. Vol. 6, p. 175). It was found necessary to add the dihydropyran slowly to the alcohol and resin to avoid decomposition, but following this procedure yields were nearly quantitative with A. Clerici and 0. Porta, Tetrahedron, 1983,39, 1239. D. A. Howes, M. H. Brookes, D. Coates, B. T. Golding, and A. T. Hudson, J . Chem. Res. (S), 1983, 9. 98 G. A. Olah, A. Hussain, and S. C. Narang, Synthesis, 1983, 896. 99 H. Takaku, S. Ueda, and T. Ito, Tetrahedron Lett., 1983, 24, 5363. lMG. Cardillo, M. Orena, S. Sandri, and C. Tomasini, Chem. Ind. (London), 1983, 643. lol K. K. Ogilvie and G. H. Hakimelahi, Carbohydr. Res., 1983, 115, 240. lo2 W. G. Dauben, R. A. Bunce, J. M. Gerdes, K. E. Henegar, A. F. Cunningham, andT. B. Ottoboni, Tetrahedron Lett., 1983, 24, 5709. lo3 W. Szeza, Carbohydr. Res., 1983, 115, 240. lO4 M. Koreeda and L. Brown, J . Chem. SOC., Chem. Commun., 1983,1113. lo5 M. Onaka, M. Kawai, and Y . Kumi, Chem. Lett., 1983,1101. lo6 G. A. Olah, A. Husain, and B. P. Singh, Synthesis, 1983, 897. 96

97


225

most alcohols except for tertiary alcohols, which eliminated. The THP ethers were obtained by filtration of the reaction mixture. Phenyl ethers have been prepared using 2-0~0-1,3-propanedisulphonates (37) which have the advantage of non-acidity and lack of toxicity. lo7 Kinetic acetalization with p-methoxy-

phenylmethyl ethers and DDQ has been used to protect 1,2- and 1,3-diols.lo8This neutral procedure has the additional advantage of giving largely one epimer of the newly formed acetal (Scheme 37). OH

OH

11

--Me

OC Ph

39

1 V

71 '10 Reagents: i, MeO(C6H,)CH20Me, DDQ, CH2C12

Scheme 37

Ether cleavage reactions which have appeared in the literature up to 1981have been reviewed. lo9 Selective demethylation of rnethoxyanthraquinones using boron trifluoride is possible due to the formation of internally chelated boron enolates. llo Modified boron halides have received much attention as selective deprotecting agents. Dimethylboron bromide deprotects acetals MEM, MOM, and methylthiomethyl (MTM) ethers.lll 2-Chloro-l,3,2-dithioboralancleaves MOM ethers, acetonides, and benzylidene acetals but does not affect benzyl, IM lO8

lo9 110

F. Ogura, H. Yamaguchi, T. Otsubo, T. Nakano, andT. Saito, Bull. Chem. SOC.Jpn., 1983,56,1257. Y. Oikawa, T. Nish, and 0. Yonemitsu, Tetrahedron Lett., 1983,24, 4037. M. V. Bhatt and S . U. Kulkarni, Synthesis, 1983,249. P. N. Preston, T. Winwick, and J. 0. Morley, J . Chem. SOC., Perkin Trans. 1, 1983, 1439. Y. Guindon, C, Yoakim, and H. E. Morton, Tetrahedron Lett., 1983,24, 2969, 3969.

226


THP, TBDMS, or TBDPS ethers or methylene acetals.l12Aliphatic MTM ethers are cleaved by trityl fluoroborate 113 and also by trimethylsilyl chloride-acetic anhydride,l14the latter system also cleaving methyl ethers. Pyridinium toluene-psulphonate in butan-2-one or t-butyl alcohol efficiently deprotects allylic MEM and MOM ethers. 115 A solution of titanium(1v) chloride in methylene chloride buffered with solid sodium bicarbonate has been shown to cleave MOM ethers.l16 Trimethylsilyl bromide, although usually too unreactive to cleave ethers, will do so on catalysis with iodine monobromide. 117 Trimethylsilyl chloride-iodine monochloride cleaves only benzyl and tertiary alkyl ethers. Trichloromethylsilane with sodium iodide has been used to cleave ethers, being more reactive than a combination of trimethylsilyl chloride and sodium iodide. 11* Ionexchange resins suspended in methanol efficiently cleave THP ethers lO6, 119 and are particularly useful for acid-sensitive alcohols119(Vol. 4, p. 154). Another mild means of cleaving THP ethers uses sodium periodate-sodium iodide in acetic acid.12*Benzyl ethers have been shown to be oxidized to benzoates by ozone121or ruthenium tetroxide122and thence to alcohols, although the degree of additional functionality which may be present is limited. Reactions of Alcohols.-Oxidation. Work has continued at an undiminished rate to produce mild and selective oxidants. Pyridinium chlorochromate has been used to oxidize 2-nitro-alcohols without promoting reverse aldol cleavage. 123 N-Chlorosuccinimide complexed with dimethyl selenide (38)124and periodinane (39)125have both proven useful in the oxidation of primary alcohols to aldehydes. Me

I I

Se-Me

CI

Sodium bromite oxidizes secondary alcohols , but primary alcohols give esters. 126 The oxidation of secondary alcohols with potassium permanganate is more efficient if ultrasound is applied to the reaction mixture,127but primary alcohols give R. Williams and S. Sakdarat, Tetrahedron Lett., 1983, 24, 3965. P. K. Chowdhury, R. P. Sharma, and J. N. Baruah, Tetrahedron Lett., 1983,4485. N. C. Baruah, R. P. Sharma, and J. N. Baruah, Tetrahedron Left., 1983,24,1189. 115 H. Monti, G. LCandri, M. Klos-Ringuet, and C. Corriol, Synth. Commun., 1983, 1021. 116 N. Morishima, S. Kato, S. Kanemitsu, and S. Zen, Chem. Lett., 1983, 1189. 117 E. C. Friedrich and G. De Lucca, J . Org. Chem., 1983,48, 1678. G. A. Olah, A. Hasain, B. P. Singh, and A. K. Mehrotra, J . Org. Chem., 1983, 48,3667. 119 B. TanBcs, F. Kling, I. Mucha and J. MBrton, Acta Chim. Acad. Sci. Hung., 1983, 112, 233. 120 S. Das, R. N. Baruah, R. P. Sharma, and J. N. Baruah, Chem. Znd. (London), 1983,80. M. Hirama and M. Shimizu, Synth. Commun., 1983,781. lZ2P. F. Schuda, M. B. Cichowicz, and M. R. Heimann, Tetrahedron Lett., 1983,3829. lZ3G. Rosini and R. Ballini, Synthesis, 1983, 543. lZ4K. Takaki, M. Yasumura, and K. Negoro, J . Org. Chem., 1983,48, 54. lzs D. B. Dess and J. C . Martin, J . Org. Chem., 1983,48,4155. lZ6T. Kageyama, Synthesis, 1983, 815. lZ7J. Yamawaki, S. Sumi, T. Ando, and T., Hanafusa, Chem. Lett., 1983, 379.

112 D. 113


227

limited success. A combination of chromium trioxide and trimethylsilyl chloride is a versatile oxidizing system for secondary alcohols,12*as is pyridinium dichromate and bis(trimethylsily1)peroxide. 129 Potassium dichromate in the presence of Adogen-464 provides a neutral system for acid-sensitive substrates. 130 Polystyrene-bound phenylseleninic acid has been found to oxidize secondary alcohols. 131 Selenium dioxide in catalytic quantities selectively oxidizes benzylic alcohols in the presence of bis-(p-methoxypheny1)selenoxide as a co-oxidant .132 Other reagent systems which selectively oxidize benzylic or allylic alcohols are cerium(1v) ammonium n i t r a t e - c h a r ~ o a l ,cerium(Iv) ~~~ triethylammonium nitrate ,134 ruthenium(n) chloride-bis(trimethylsily1) peroxide ,129 barium manganate,135 and tetra-n-butylammonium c h l o r o c h r ~ m a t e ,although ~~~ the latter reagent when used in a 6 :1ratio with the substrate can be used to oxidize primary alcohols as well. Selective oxidation of primary alcohols to aldehydes in the presence of secondary alcohols is possible using the electrochemically generated nitroxyl species (40) ,13' whereas selective oxidation of secondary alcohols in the

42 I

0 '

presence of primary alcohols may be carried out using a vanadium(1v) catalyst with t-butyl hydroperoxide as the regenerating agent .13* Diols have been oxidized to lactones using palladium(I1)-catalysed aryl bromide oxidation,139sodium bromite ,140 pyridinium chlorochromate on celite ,141 ruthenium complexes with benzylidene acetone as a hydrogen acceptor ,142 and bromine-nickel(I1) carboxylate^.'^^ In the latter two cases the oxidation is regioselective, the least sterically hindered hydroxyl being oxidized (Scheme 38).

Hy drogenolysis and Deoxygenation. A review of deoxygenation techniques has appeared in the literature. 144 A general method for deoxygenation of secondary J. M. Aizpurua and C. Palomo, Tetrahedron Lett., 1983,24,4367. S. Kanemoto, K. Oshima, S. Matsubara, K. Takai, andH. Nozaki, TetrahedronLett., 1983,24,2185. N. R. Natale and D. A. Quincy, Synth. Commun., 1983, 817. R. T. Taylor and L. A. Flood, J . Org. Chem., 1983,48, 5160, 13* F. Ogura, T. Otsuko, K. Ariyoshi, and H. Yamaguchi, Chem. Lett., 1983,1833. 133 Y. Hatanaka, T. Imamoto, and M. Yokoyama, Tetrahedron Lett., 1983, 24, 2399. 134 H. Firouzabadi and N. Iranpoor, Synth. Commun., 1983, 1143. 135 H. Firouzabadi and Z. Mostavivipoor, Bull. Chem. SOC. Jpn., 1983, 56, 914. 136 E. Santianello, F. Milani, and R. Casati, Synthesis, 1983, 749. 13' M. F. Semmelhack, C. S. Chou, and D. A. Cortes, J . Am. Chem. SOC., 1983,105,4492. 138 K. Kaneda, Y. Kawanishi, K. Jitsukawa, and S . Teranishi, Tetrahedron Lett., 1983,24, 5009. 139 Y. Tamaru, Y. Yamada, K. Inoue, Y. Yamamoto, and Z . Yoshida, J . Org. Chem., 1983,48,1286. T. Kageyama, S. Kawahara, K. Kitamura, Y. Ueno, and M. Okawara, Chem. Lett., 1983,1097. 141 T. K. Chakraborty, V. Bushan, and S . Chandrasekaran, Indian J . Chem., Sect. A , 1983, 22, 9. 142 Y. Ishii, K. Osakada, T. Ikariya, M. Saburi, and S. Yoshikawa, Tetrahedron Lett., 1983,24,2677. 143 M. P. Doyle, R. L. Dow, V. Bagheri, and W. J. Patrie, J . Org. Chem., 1983,48,476. lUW. Hartwig, Tetrahedron, 1983, 39, 2609.

1B

129


228

R

R

R

major

minor

Reagents: i, (Ref. 142) Ru cat., benzyiideneacetone (2 equiv.), Et,N, toluene, reflux; ii, (ref. 143) Br,, (RC02)*Ni,MeCN

Scheme 38

alcohols via their phenylthiocarbonate esters has been reported14j and a similar technique has been applied in a synthesis of isoclovene. 146 Tri-n-butyltin hydride reduction of tosylates has also been used to accomplish this transformation. 147 Alkylbenzenes have been obtained from benzyl alcohols in one step by refluxing in benzene with diphosphorus t e t r a i ~ d i d e and ' ~ ~ 1,2-diols are deoxygenated to olefins using trimethylsilyl chloride-sodium iodide in acetonitrile. 149

Halogenation. A review covering the nucleophilic replacement of the hydroxygroups with halogens via oxyphosphonium intermediates has been published. 150 Alkyl iodides have been obtained from alcohols in good yields using a combination of sodium hydride, sodium iodide, and trimethylsilyl phosphate in the absence of solvent. lS1 Polymer-bonded phosphorus reagents of structure (41)

/R

Resin-CHZ-N

R

=PBr,

( PCI,)

'

(411

have found use in the preparation of alkyl bromides and ch10rides.l~~ The phosphorus by-products remain bonded to the resin and may be regenerated. Simple 1,2-diols are converted into chlorohydrins using triphenylphosphine-t-butyl h y p ~ c h l o r i t e 'and ~ ~ qu-diols are converted into iodohydrins with diphosphorus tetraiodide in carbon dis~1phide.l~~ In the latter case a primary hydroxy-group is selectively replaced if possible. A continuous extraction process has been described 15j for more efficient preparation of halogenohydrins from a,u-diols. 145 146

14* 149

I5O I5l 152 153

ls4 155

M. J. Robins, J. S. Wilson, and F. Hansske, J . Am. Chem. Soc., 1983,105, 4059. D. Kellner and H. J. E. Loewenthal, Tetrahedron Lett., 1983,24,3397. Y. Ueno, C . Tanaka, and M. Okawara, Chem. Lett., 1983, 795. H. Suzuki, H. Tani, H. Kubota, N. Sato, J. Tsuji, and A . Osuka, Chem. Lett., 1983, 247. J. C. Sarma, N. C. Barua, R. P. Shanna, and J. N. Barua, Tetrahedron, 1983,39,2843. B. R. Castro, Org. Renct., 1983, 29, 1. T. Imamoto, T. Matsumoto, T. Kusumoto, and M. Yokoyama, Synthesis, 1983, 460. G. Cainelli, M. Contento, F. Manescalchi, L. Pessi, and M. Panunzio, Synthesis, 1983, 306. C. N. Barry and S. A . Evans, J . Org. Chem., 1983, 48,2825. W. Buijs, P. Van Elburg, and A. Van der Gen, Synth. Commun., 1983, 387. F. Camps, J. M. Casamor, J. Coll, A. Guerrero, and M. Riba, Org. Prep. Proced. Znt., 1983,15,63.


229

Chiral Auxilliaries. The asymmetric reduction of carbonyl compounds via chiral boranes26and chiral acetates32and the asymmetric alkylation of carbonyl compounds via their chiral a c e t a l ~ ~ have l > ~ *already been discussed in this chapter. Optically active 1,6-bis-(o-chlorophenyl)-l,6-diphenylhexa-2,4-diyne-l,6-diol (42) may be used to resolve 3-methylcyclohexanones, 5-methyl-y-butyrolacand 2,3-epoxycyclohexanones 157 by complexation and recrystallization.

P

h

w

OH

P

h

OH

(42)

The neryl ether (43) derived from (R)-binaphthol has been cyclized in the presence of various aluminium compounds with good enantioface differentiation to yield (R)-limonene with enantiomeric excesses of up to 77% (Scheme 39).158

(43) Scheme 39

Other Reactions. A review of alcohol dehydration reactions has been published. 159 An improvement on the Mitsonubo reaction for alcohol inversion has been reported which uses in situ generated caesium acetate to displace the mesylate group, permitting easier n.m.r. analysis of the product (Vol. 6 , p. 178). Primary amides can be N-alkylated by alcohols in moderate yield using a ruthenium(rr) catalyst. 161 3-Stannyl alcohols, on treatment with boron trifluorideacetic acid complex, cyclize to cyclopropanes, in marked contrast to the silyl derivatives, which p-eliminate. 162 Allylic alcohols may be coupled with Grignard reagents via the iminium species (44) (Scheme 40).163Such reaction is possible F. Toda, K. Tanaka, T. Omata, K. Namura, and T. Oshima, J . Am. Chem. Sac., 1983,105,5151. K. Tanaka and F. Toda, J . Chem. SOC., Chem. Commun., 1983, 1513. 158 S. Sakane, T. Fujiwara, K. Maruoka, and H. Yamamoto, J . Am. Chem. Soc., 1983, 105,6154. 159 G. H. Foxley, Educ. Chem., 1983, 20, 185. J . W . Huffman and R. C. Desai, Synrh. Commun., 1983, 553. 161 Y. Watanabe, T. Ohta, and Y . Tsuji, Bull. Chem. Soc. Jpn., 1983, 56, 2647. 162 I. Fleming and C . J. Urch, Tetrahedron Lett., 1983,24,4591. 163 T. Fujisawa, S. Iida, H. Yukizaki, and T. Sato, Tetrahedron Lett., 1983,24, 5745.

lS6 Is’


230

iii R’

R’

R3

(minor product)

(major product)

Reagents: i, l-Chloro-2-methyl-N,N-tetramethylenepropenylamine; ii, R4MgX, CuI, THF, HMPA

Scheme 40

even in the presence of cyanide, carboxylic ester, ketones, or halide functionalities. Allylic alcohols have also been coupled with aldehydes in the presence of triphenylphosphine and a palladium(I1) catalyst in a Wittig-type olefination. The 2-methylene-4-phenylthio-alcohol (45) is a useful precursor to various ter-

OH

(45)

penes.165Triphenylbismuth acetate has been shown to react with 1,n-diols (n=2S), converting one of the hydroxy-groups into a phenoxy-group.160 Tertiary alcohols react very slowly if at all, and in cyclic systems axial hydroxy-groups are converted preferentially. 1,6Diols are conveniently cyclodehydrated to tetrahydrofurans by the action of trimethylsilyl chloride in DMSO. 167 2 Halogeno Compounds

Preparation.-Reviews of the preparation of alkyl halides from alcohols150and the synthesis of dihalides from unsaturated compounds using purified enzymes168 have been published. A novel, one-step method for conversion of alcohols into 164 165

166

167

M. Moreno-Manas and A. Trius, Bull. Chem. SOC. Jpn., 1983,56,2154. T. Mandai, M. Kawada, and J. Otera, J . Org. Chem., 1983,48,5183. S . David and A. Thieffy, J . Org. Chem.. 1983.48, 441. D. F. Wad and N. D. Ungur, Synthesis, 1983,217. S. L. Neidleman and J. Geigert, Trends Biotechnol., 1983,1,21.

23 1


bromides or iodides has used a reactive halide, such as ally1 bromide or methyl iodide, with 1,l-carbonyldi-imidazolein a~etonitri1e.l~~ A general method of synthesis of primary alkyl chlorides has been reported involving the DMFcatalysed decarboxylation of alkyl chloroformates (Scheme 41). 170 Primary alkyl

-

0 RO

RCI

+ MezNCHO -k

C02

Scheme 41

iodides have been prepared from terminal olefins by bis(cyclopentadieny1)zinc chloride-catalysed addition of dialkylmagnesium halides followed by displacement of the metal with iodine.1712-Vinyl iodides and bromides may be obtained from terminal acetylenes via halogenoboration with 9-BBN bromide followed by acid treatment of the a d d u ~ tReaction . ~ ~ ~ of the initial adduct with an equivalent of the lithium acetylide yields 2-1-alkynyl-2-halogenoalkenes (Scheme 42)

R'C-CH

-

;f 11

Br

H

Br

\vI \

- iv

R2

Reagents: i, 9-BBN bromide, CHCl,, 0°C; ii, LiC=CR2, pentane, -78°C; iii, I,, -78°C-r.t.; H 2 0 7 ,aq. NaOH; v, AcOH

iv, 30%

Scheme 42

The same research group has reported a similar sequence of reactions using 1-chloroacetylenes. 174 Work with E-vinyl boronic acids has that reaction with sodium bromide and N-chlorosuccinimide yields 2-vinyl bromides by means T. Kamijo, H. Harada, and K. Iizuka, Chem. Pharm. Bull., 1983,31,4189. R. Richter and B. Tucker, J . Org. Chem.,1983,48,2625. 171 U. M. Dzhemilev, 0. S. Vostrikova, and R. M. Sultanov, Izv. Akad. Nauk S.S.S.R. Ser. Khim., 1983,2625 (Chem. Abstr., 1983,98,160304d). 172 S. Hara, H. Dojo, S. Takinami, and A. Suzuki, Tetrahedron Lett., 1983,24, 731. 173 S. Hara, Y . Satoh, H. Ishiguro, and A. Suzuki, Tetrahedron Lett., 1983, 24, 735. 174 S. Hara, T. Kato, and A. Suzuki, Synthesis, 1983, 1005. 175 G. W. Kabalba, K. A. R. Sastry, F. F. Knapp, and P. C. Srivastava, Synth. Commun., 1983, i027. 170


232

of an addition-elimination sequence. The preparation of vinyl iodides from

hydrazones has been improved by using a guanidine base, anhydrous conditions, and an inverse addition procedure. 176 Cylopropyl ketones are cleaved in good yield by diphosphorus tetraiodide in acetone to produce 3-iodo-ketones. 177 Epoxides may be converted into 1,2-chlorides using triphenylphosphine in refluxing carbon tetrachloride for extended periods,l’* and to 1,Zdibromides under mild conditions using a dioxodibromomolybdenum(vI)-acetonitrile complex. 179 A convenient synthesis of 1,l-dichloroalkenes has been reported which utilizes the addition of the anion derived from cr-dichloromethyltrimethylsilane to aldehydes (Scheme 43).180 In the first stage low-temperature quenching is crucial for success.

Me3S

OH Reagents:

, Bu*Li or LDA, THF,

DNHI X

X

Scheme 5

249

Amines, Nitriles, and Other Nitrogen-containing Functional Groups C02 H

CO2H

I

I

I

'

R@OH

R@NH2

Reagents: i, NH,, NH4C1, H20, 180°C (bomb)

Scheme 6

-.>

R Y o Cl

&

R82: 20:1 over kinetic product), which can be readily silylated to give the silyl enol ether, a reaction which contrasts sharply with that of lithium di-isopropylamide .39 Not surprisingly the majority of papers that deal with organomagnesium compounds relate to their use as conventional Grignard reagents. In recent years the trend in this area has been towards reagents capable of reacting in a specific sense and 1983 proved to be no exception. In the total synthesis of (+)methylpseudomonate from carbohydrates, a Grignard reagent from (55) has been used to open the epoxide (56).40 The reaction is characterized by the regiospecificity of the nucleophilic ring-opening of the epoxide to (57), the specific formation of the E-double bond, and the formation of the normal, unrearranged Grignard reagent. High stereocontrol is also seen in the addition of methylmagnesium iodide to propiolic acid to give 2-3-iodoacrylic acid in conditions only slightly different to those used to prepare butenolides from propiolic acid .41 In common with lithium reagents, magnesium reagents can promote asymmetric inductions via the agency of a chiral auxiliary or chiral solvent. For

0

s-

OH

II

S-CONMe 1

2

&CON R *

Me2

I

To I

(581

(59)

P. E. Eaton and P. G. Jobe, Synthesis, 1983, 796. M. E. Krafft and R. A . Holton, Tetrahedron Lett.,1983,24,1345. J. Beau, S. Aburaki, J . Pougny, and P. Sinay, J . A m . Chem. SOC.,1983,105,621. 41 M. E. Jung, J. A. Hagenah, and Z. Long-Mei, Tetrahedron Idett.,1983,24, 3973. 38

39

Organometallics in Synthesis

349

example, very high levels of asymmetric induction are possible during the condensation of the chiral sulphoxides (58) with aldehydes (RCHO) using t-butylmagnesium bromide as base.42After reductive cleavage of the sulphoxide group the P-hydroxy-amides (59) are obtained in good yield. A similar highly enantioselective synthesis is observed during the addition of Grignard reagents to keto-esters of 8-phenylmenthol, resulting in good yields, both chemical and optical, of tertiary alcohols.43A slightly different approach has been used in Grignard crosscoupling reactions leading to optically active alkenes where the chiral auxiliary is in the ~ a t a l y s t .In~ both > ~ ~cases the chiral catalyst is a nickel salt containing chiral phosphorus ligands. Continuing in the same vein, transition-metal catalysts have been used in the synthesis of the alkenes and butadienes shown in Scheme 5. In two cases nickel

R

R

R2 iii R z A r

(Ref. 48)

d

RMg X

Ar Ar

Reagents: i ,

7

; iii.

OP(OEt)?

Ar

RlxB; R

; ii, ArI-X

-

R’

Scheme 5

catalysts with phosphorus ligands are ~ ~ e dand, in~ the ~ third , ~ an ~ iron catalyst (FeDBM), is found to be an excellent promoter of the cross-coupling reaction.48 This year several syntheses of alkenes from Grignard reagents have been reported, a further example here being the preparation of terminal alkenes from acyl chlorides as shown in Scheme 6.49Best results are obtained when ether is used R’

RCOC~ i.ii

\C/OMgBr

~

R2’

.. .

R’

Ill

‘CH2Li

Reagents: i, CH2N,; ii, R2MgBr, MgBr,; iii, Li

Scheme 6 45R. Annunziata, M. Cinquini, F. Cozzi, F. Montanari, and A . Restelli, J . Chem. SOC., Chem. Commun., 1983, 1138. 43 J. K. Whitesell, D . Deyo, and A. Bhattacharya, J . Chem. SOC., Chem. Commun., 1983, 802. 44 G. Consiglio, F. Morandini, and 0. Piccolo, J . Chem. SOC., Chem. Commun., 1983, 112. 45 T. Hayashi, M. Konishi, M. Fukushima, K. Kanehira, T. Hioki, and M. Kumada, J . Org. Chem., 1983,48,2195. C. Sahlberg, A . Quader, and A . Claesson, Tetrahedron Lett., 1983,24,5137. 47 E. Wenkert, J. B. Fernandes, E. L. Michelotti, and C. S. Swindell, Synthesis, 1983,701. G. A . Molander, B . J. Rahn, D. C . Shubert, and S. E. Bonde, Tetrahedron Lett., 1983,24,5449. 49 J . Barluenga, M. Yus, J. M. Concellon, and P. Bernad, J . Org. Chem., 1984, 48, 3116.

350


as solvent for the addition of the Grignard reagent, and then THF is added as co-solvent for the final lithiation reaction. In the preparation of the pentacycloundecane (60) two sequential Grignard additions to the corresponding diketone (61) provide access to the desired product in good yield.50The silylated compound (Me,SiCH,HgCl) is the preferred reagent, and the method is found to be far superior to the classical Wittig reaction.

Grignard reagents are very effective in the synthesis of a-hydroxy-ketones (62) from readily available silylated cyanohydrins (63) ,sl whereas ketones have been prepared from carboxylic acids and Grignard reagents using the chloroenamine (64) as a condensation agent.52The Grignard reagent actually attacks the intermediate (65), formed in situ from the carboxylic acid and the chloroenamine. The same reagent (64) and ally1 alcohols give an intermediate which provides excellent yields of cross-coupled aikenes upon treatment with Grignard reagents.53 A notable feature in this reaction is the high level of regiocontrol during the attack of the Grignard reagent at the a-position for PhCH2CH2MgBrand at the y-position for aryl Grignard reagents. 0

d

CI

OTMS

In the preparation of Grignard reagents from 3-halogenoethers it is imperative that highly reactive magnesium metal is used in the formation of the Grignard reagent to prevent competing cyclopropane formation.s4New Grignard reagents are fairly rare; however, the Grignard reagent (66) is an example of a new versatile nucleophilic hydroxymethylating agent for organic halides (RX) .55 Alkylation of (66) with an alkyl, aryl, or heteroaryl halide in the presence of a metal catalyst (Pd, Ni, Cu) gives compound (67), which readily oxidizes to alcohols (68). Finally, the magnesium complex (69; X=MgBr) is an efficient fixation agent for carbon dioxide, and the carboxylate complex (69; A. P. Marchand and R . Kaya, J . Org. Chem., 1983,48,5392. L. R. Krepski, S. M. Heilmann, and J . K. Rasmussen, Tetrahedron Lee., 1983,24,4075. 52 T. Fujisawa, T. Mori, K. Higuchi, and T. Sato, Chem. Lett., 1983, 1791. 53 T. Fujisawa, S. Iida, H. Yukizaki, and T. Sato, Tetrahedron Lett., 1983, 24, 5745. 54 T. P. Burns and R. D . Rieke, J . Org. Chem., 1983,48,4141. 55 K. Tamao, N. Ishida, and M. Kumada, J . Org. Chem., 1983,48,2120. 51

351

Organornetallies in Synthesis

X = C02MgBr) so formed transfers the carboxy-group to ketones (R1COCH2R2) to give the corresponding a-carboxy-ketone~.~~

(Pri0)2MeSiCHtMgCI

(Pri0I2McSiCHZR

RCH20H

X-N

N-X \ I (CHZ),

Zinc and Mercury.-Once again activity in the zinc area has been of a low order; however, two papers have appeared providing details of some useful synthetic transformations involving organozinc compounds. In the first , a novel synthesis of a,,&unsaturated cyclopentenones via allylzincation of silylalkynes (Scheme 7)

n- C6H,

n - C 6 H 13 e S i M e 3

n- C6H,3-CEC-SiMe3

&

P

OH l ii

CO,H Reagents: i , CH2=CHCH2ZnBr, I*; ii, [O]; iii, MeLi; iv, BuLi

Scheme 7

is reported.57 Interestingly, the presence of the silicon group in the alkyne is essential since no carbometallation is found to occur in its absence. In the second paper organozinc compounds (RlZnX) were found to react with acyl chlorides (PdPR3, cat.), providing a very general and convenient route to ketones.58 Danishefsky and his co-workers have been active in the field of mercury-based reagents and have developed a synthesis of S-coniceine (70) from the alkene (71) via intramolecular ureidomercuration. Reductive coupling to give (72) followed by two simple steps results in the formation of d - ~ o n i c e i n eThe . ~ ~ same authors ha:e also used a mercury-catalysed cyclization and reductive coupling reaction of the acrylanilide (73) to generate the tricycle (74).60 Similarly, mercuric acetate N. Matsumura, N. As&, and S. Yoneda, J . Chem. SOC., Chem. Commun., 1983,1487. E.-i. Negishi and J. A. Miller, J . Am. Chem. SOC., 1983, 105, 6761. 58 E.4. Negishi, V. Bagheri, S. Chatterjee,F. Luo, J. A. Miller, and A . T. Stoll, TetrahedronLen., 1983, 24, 5181. 59 S. Danishefsky, E. Taniyama, and R. R. Webb, jun., Tetrahedron Lett., 1983, 24, 11. S. Danishefsky and E. Taniyama, Tetrahedron Lett., 1983,24,15. s6 57

352


facilitates ring closure of p-lactams (75),yielding the lactam (76) after bromination. The preceding cyclizations all rely upon conventional mercury cyclizing reagents; however, mercury(n) trifluoromethanesulphonate-amine complex is a new cyclization reagent promoting the cyclization of various farnesol derivatives in good yield and with high selectivity.62

Cbz (71 1

(70)

(72)

R (73) H

0

H

”

Two papers concerned with the coupling ofp-acetamido-radicals, generated by reduction of the corresponding organomercurials, both involve their addition to electron-deficient alkenes. Kozikowski sees the products (77; R=H) as useful building blocks for alkaloid constr~ction,~~ and Henning converts (77; R=C1) into proline derivatives as described below .@

Two useful-looking general syntheses also rely upon the intermediacy of meradd the elements of mercuric chloride across curials. 4-Hydroxyalk-2-yn-1-ones the triple bond to give vinylmercurials (78; R=Me) in a reaction which is claimed to represent the first example of syn-addition of mercuric chloride.65Vinyl mercurials (78) can then be dehydrated to 3-mercurialfurans, which carbonylate to give 3-furylcarbonyl compounds. One drawback of this mercuration reaction appears to be its sensitivity to substituent effects, since anti- as well as synaddition occurs in some cases, e.g. when R1=R2=Me, or R=OMe. A M. L. Phillips, R. BonjoukSan, N. D. Jones, A. H. Hunt, and T. K. Elzey, Tetrahedron Len., 1983, 24,335. 62 M. Nishizawa, H. Takenaka, H. Nishide, and Y. Hayashi, Tetrahedron Lett., 1983, 24, 2581. 63 A. P. Kozikowski and J. Scripko, Tetrahedron Lett., 1983,24,2051. R. Henning and H. Urbach, Tetrahedron Lett., 1983,24,5343. 65 R. C. Larock and C. Liu, J . Org. Chem., 1983,48,2151. 61


353

benzoyloxy-mercuration-demercuration reaction has been used to good effect in a new strategy for the synthesis of aldol-type products, since the diastereoselective construction of certain carbon skeletons bearing alternate OR and alkyl substituents, e.g. (79), by classical aldol reaction can still be problematical.66 Thus, the alternative reaction sequence is by the a-alkylation of/3-hydroxy-esters, followed by a two-carbon chain extension (via Wittig olefination) and culminating in the benzoyloxymercuration, e.g. (79)-+(80). Me

(781

(791

Me

(801

3 Group I11

Boron.-Several papers have appeared relating to asymmetric hydroborations and therefore further extending the scope of this useful reaction. For example, the boron reagents prepared from borane and the chiral amino-alcohols (S)valin01~~" and (81)67breduce ketones in high chemical and optical yields, and particularly the amino-alcohol (81), which is claimed to give enantiomeric excesses (e.e.'s) of 94-100% accompanied by chemical yields of -100%. The chiral borane-amine complexes (82) also reduce ketones to the corresponding chiral both enantiomers of the alcohol can be formed separately depending upon the enantiomer of 2,2'-dihydroxy-6,6'-dimethylbiphenyl( R or S ) used. In a similar fashion the borane (83) reduces aryl-a-halogenoalkyl ketones to the corresponding halohydrins in very high optical and chemical yields, although the aliphatic analogues give a somewhat lower yield.69Likewise hydroboration of certain a-chiral olefins and ketones with highly hindered boranes also shows high s e l e ~ t i v i t yIn . ~this ~ case disiamyl- and dicyclohexyl-borane both show selectivity exceeding that of 9-BBN in the reduction of a-chiral olefins such as (84; X=CH2) and attaining greater than 98% epimeric purity for the very sterically hindered bis-trans-2-methylcyclohexylboranereagent. Interestingly, the reduction of the related ketones (84; X=O) proceeds with high selectivity but in an opposite sense to 9-BBN and, perhaps surprisingly, to trialkylborohydrides; the latter have previously been reported to reduce cyclohexanones in the same sense as dialkylborohydrides. 9-BBN and thexylborane have also been used with good results in the diastereoselective synthesis of threo-diols (85) from secondary allylic alcohols (86).'l Diastereoselectivities vary between 8:1and 15:1,and furthermore S. Thaisrivongs and D. Seebach, J . Am. Chem. SOC., 1983,105,7407. (a)S . Itsuno, A. Hirao, S. Nakahama, and N. Yamazaki, J . Chem. SOC., Perkin Trans. 1, 1983,1673; ( b ) S. Itsuno, K. Ito, A. Hirao, and S. Nakahama, J. Chem. SOC.,Chem. Commun., 1983,469. H. Suda, S. Kanoh, N. Umeda, T. Nakajo, and M. Motoi, Tetrahedron Left., 1983, 24, 1513. H. C. Brown and G. G. Pai, J . Org. Chem., 1983,48, 1784. 70 M. M. Midland and Y. C. Kwon, J . Am. Chem. SOC., 1983, 105,3725. 71 W. C. S till and J. C. Barrish, J . Am. Chem. SOC.,1983,105,2487.

67

@

@

354


9-BBN is found to be most suitable when the alkene is at the terminal position, whereas thexylborane works better for trisubstituted olefins.

0 0 \ /

H/B‘NR’ (81 1

R2R3

(83 1

(82)

Me

OH

( 8 41

Me

OMc

OH (87 1

(85)

Boronates have featured in a number of useful transformations this year. For instance, the boronic esters (87) react with the lithium reagent [LiCH(OMe)SPh] to give, after treatment with mercuric chloride, the boronate ester (88), which may then be oxidized to the corresponding aldehyde (RCH0).72Since (87) can be readily obtained by selective hydroboration of an alkene, the overall sequence provides a convenient new method for introducing a formyl group into alkenes in a regio- and stereo-controlled manner. Another boronic ester homologation occurs with 99% enantioselectivity, and is demonstrated in the synthesis of the pheromone (3S,4S)-4-methylheptan-3-01(Scheme 8) .73 The addition of zinc chloride is critical for both high selectivity and high chemical yield. Similar methodology has been applied to the synthesis of em-Brevicomin. Allylboronates are present as intermediates in three useful syntheses all involving the production of stereo-defined homoallylic alcohols. The allylboronate (89), formed by reaction between (90) and an alkenyl-lithium followed by rearrangement, reacts at the y-position with aldehydes (RCHO) to give the homoiii,iv

‘0

R‘

;I

Reagents: i, LiCHCl,; ii, ZnC1,; iii, R’MgBr; iv, H,O,

Scheme 8 7* H. 73 D.

C. Brown and T. Imai, J . Am. Chem. Soc., 1983,105,6285. S. Matteson and K. M. Sadhu, J . Am. Chem. SOC.,1983, 105, 2077.

~

v\fc OH

OH


355

allylic alcohols (91).74Similarly, the allylboronate (92) gives high yields of the 2-alkene (93) ,75 and the allylboronate (94) reacts in a highly diastereoselective fashion with the chiral aldehyde (95) to give (96), which can then be converted in two steps into a D-fucose d e r i ~ a t i v eIn . ~ an ~ analogous reaction the allylborane (97) reacts at the y-position with pyruvates to yield the threo-alcohol (98).77

(90

(92 1

(91

w8 B N bH (96)

(97)

(98)

Branched- and straight-chain homoallylic alcohols are obtained from the same allylborane system simply by altering the reaction conditions; the key to the method is the use of the selenylallylborane (99)) which readily rearranges to the borane Once formed the borane (100) can be trapped with aldehydes to give linear homoallylic alcohols or alternatively isomerized to the borane (101)) which can then be trapped by aldehydes to yield branched-chain homoallylic alcohols. The whole reaction sequence depends on the relatively slow (compared with conventional allylboranes) iosomerization (loo)-+( 101). An unusually slow thermal isomerization of alkyldihalogenoboranes also allows for a highly regiospecific and stereospecific synthesis, in this case) of alkyldihalogenoborane~.'~ It has been found that 3-hexylboranes, e.g. (102)) isomerize 22 R kePh Pr- CH- Et PhSc

R

(99)

R

(100)

m6RzSePh

(101 1

I

BCL,SMe (102

P. G. M. Wuts, P. A. Thompson, and G. R. Callan, J . Org. Chem., 1983,48,5398. R. W. Hoffmann and B. Landmann, Tetrahedron Lett., 1983,24,3209. 76 W. R. Roush, D. J. Harris, and B. M. Lesur, Tetrahedron Lett., 1983,24,2227. TI Y. Yamamoto, T. Komatsu, and K. Marayama, J . Chem. SOC., Chem. Commun., 1983,191. 78 Y. Yamamoto, Y. Saito, and K. Maruyama, J . Org. Chem., 1983,48,5408. 79 H. C. Brown and U . S. Racherla, J . Org. Chem., 1983,48,1389. 74

75

356


times slower than the corresponding 9-BBN derivative, which was previously the only 3-hexylborane to be resistant to thermal isomerization. Thus hydroboration of labile olefins where isomerism is undesirable now seems feasible using, HBC12.SMeas hydroborating reagent. Several papers have been published pertaining to the boronation of alkynes and the various useful synthetic reactions arising from the organoboron intermediates so obtained. Some of these papers are highlighted in Scheme 9.

X = Br

(Ref.83) -x=~iorar xi i

R-c-c-x iv, v

But

Br

R

I R’

X X

= I or

Br

Reagents: I , Catecholborane; ii, cis-ICH= CHR’; iii, trans-ICH= CHR1; iv, BuLi; v, BF3.0Et2; 0 vi, ; vii, N-0; viii, LiAIH,; I X , X B Q ; x, AcOH; xi, LiC-CR1; xii, R? RI R’

A

Pelter and his group have released a number of interesting papers concerning the use of the bulky dimesitylboron group in organic synthesis. Dimesitylborane (103), a readily available, solid, stable borane, is reported to be an extremely selective reagent for regioselective hydroboration of unsymmetrical alkenes and alkynes; being sensitive to steric factors, it tends to attack at the least hindered so G. Cassani, P. Massardo, and P. Piccardi, Tetrahedron Lett., 1983,24,2513.

( a ) M. Yamaguchi and I. Hirao, Tetrahedron Lett., 1983, 24, 391; ( b ) ibid., p. 1719. (a) S. Hara, H. Dojo, S. Takinami, and A. Suzuki, Tetrahedron Lett., 1983,24,731; ( 6 ) S. Hara, Y. Satoh, H . Ishiguro, and A. Suzuki, ibid., p. 735. 83 S. Hara, T. Kao, and A. Suzuki, Synthesis, 1983, 1005. 84 H. C. Brown, N. G. Bhat, and D. Basavaiah, Synthesis, 1983,885. 81

82


357

part of the molecule.8saFurthermore, the bulky dimesitylboron group favours the formation of a-carbanions, by deprotonation. These anions can then be alkylated and oxidized to give alcohols [equation (l)]and condensed with ketones and aldehydes to give alkenes in a boron equivalent of the Wittig reaction [equation (2)] .8sLd Heteroatom-substituted derivatives (104) are also prepared easily and some deprotonate readily to give synthetically useful anions,8se as does the alkylborane (105) to give the anion (106), which then reacts regio- and stereospecifically at the y-position to give trans-vinylboranes .8sf The latter can be oxidized to give aldehydes. Mes 28H2MR

Mcs 2BH

(104)M = Si, Sn,Pb, S, or Hg

(103)

M~S,BCH,-

M e s 2 8 e

Mes2-6 (105 1

(106)

-

M ~ ~ ~ B C H ~ % M ~ S R~ B C RCHOH H~

- R2

3

R'

Li

+

Me2BCR' R2

+

R3R4C0

(11

Simple boron reagents are capable of promoting a number of useful functional group interchanges as evidenced by their further use this year. Trimethylamineborane is a useful reagent for the N-acylation or N-alkylation of amines by carboxylic acids,86whereas the borolane (107) cleaves the carbon-oxygen bond in methoxyethoxymethyl ethers (MEM)in high yield even at -78 "C.% Similarly dimethylboron and diphenylboron cleave MEM,MOM,and MTM ethers as well

(109)

(108

(107)

OH I *SOPh

C02Me I

But Mc2Si0

(a) A. Pelter, S . Singaram, and H. Brown, Tetrahedron Left., 1983, 24, 1433; ( b ) A. Pelter, L. Williams, and J. W. Wilson, ibid., p. 627; (c) A. Pelter, B. Singaram, and J. W. Wilson, ibid., p. 635; A. Pelter, B . Singaram, L. Williams, and J. W. Wilson, ibid., p. 623; ( e )M. V. Garad, A. Pelter, B . Singaram, and J. W. Wilson, ibid., p. 637; (f) A. Pelter, B . Singaram, and J. W. Wilson, ibid., p. 631. 86 G . Trapani, A. Reho, and A. Latrofa, Synthesis, 1983, 1013.

85

(cf)

358


as a c e t a l ~and , ~ ~diphenylboron ~ bromide cleaves aliphatic, aromatic, and cyclic ethers efficiently.876 The elegant work carried out on boron enolates in the past few years has been continued this year and is exemplified by the directed aldol condensations of the boron enolates (108) and (109) to give the racemic ester (110) and the chiral ester (ill), respectively, in high yield.88The ester (110) is used in the synthesis of (4RS, 6S,7S)-serricormine. Aluminium.-Not surprisingly, fewer references have been found for aluminium reagents than for the corresponding boron reagents. Nevertheless, several very useful transformations may be accomplished using organoaluminium compounds as the following demonstrates. Ethylaluminium dichloride (EtAlCl,) in toluene causes the ‘cyclic ketone (112) to undergo a cyclocontraction-spiroannulation reaction to give the bicycle (113), thus representing a stereoselective approach to s p i ro ~ y cle s The .~~ choice of solvent is important in giving a clean reaction and’ thereby avoiding formation of (114). In a related reaction dimethylaluminium chloride (Me2A1C1) initiates cyclization of the dienone (115) to provide the trans-fused hydrindenone (116) in 50% yield, a reaction with obvious implications.% The same reagent also catalyses two sequential ene reactions between aJ-unsaturated carbonyl compounds and alkylidenecycloalkenes (117) to yield bicyclic alcohols (118), albeit in rather variable yieldsg1 OH

0

H (116)

B s’

(117)

(I181

Lithium aluminium hydride promotes a facile reductive rearrangement of the alkynylhalohydrins (119) to give a-alkenylhydroxy-compounds (120), via a cyclic aluminium intermediate, and thence the corresponding keto-compounds after ~xidation.~, Reductive cleavage of the chiral acetals (121), also using an aluminium hydride (R,AlH), results in the formation of chiral alcohols (122).93 Since acetals (121) can be obtained readily from ketones (R1R2CO)and the chiral (a) D . R . Williams and S. Sakdarat, Tetrahedron Lett., 1983,24,3965; ( b ) Y. Qindon, H. E. Morton, and C. Yoakim, Tetrahedron Lett., 1983, 24, 3969; (c) ibid., p. 2969. R. Barker and J. A . Devlin, J . Chem. SOC., Chem. Commun., 1983,147. 89 B. M. Trost and B. R. Adams, J . Am. Chem. Soc., 1983, 105,4849. B. B . Snider and T. C. Kirk, J. Am. Chem. SOC., 1983,105,2364. 91 B. B . Snider and E. A . Deutsch, J . Org. Chem., 1983,48,1822. 92 P. A. Wender, D. A . Holt, and S. M.Sieburth, J . Am. Chem. SOC., 1983,105,3348. 93 A . Mori, J . Fujiwara, K. Maruoka, and H. Yamamoto, Tetrahedron Lett., 1983,24, 4581. 87

Organornetallies in Synthesis

359

auxiliary (121a) this reaction represents a convenient method for the asymmetric reduction of ketones. Similarly, achiral trialkylaluminium reagents (R3A1) attack 2,3-epoxy-alcohols (123) to provide a-chiral aldehydes (124) after a periodate OH

_-C=CR

I,,

R2

OH

RZTC=C, (1201

OH

R

(121a)

(1 19)

H

OH

(121)

OH

(123 1

(122)

I1 2 4 )

treatment.94 In contrast, in the enantioselective ortho-hydroxyalkylation of phenols, the aluminium reagent is the source of the chirality as depicted in Scheme

x

X

x

Scheme 10

Trialkylaluminium, formaldehyde, and the enol ether (125) react to form the adduct (126) .% Interestingly, the reaction shows high threo-selectivity (9&95%) regardless of the isomer of the enol ether (125) used. Finally, in this section, tristrimethylsilylaluminium effects the chemoselective and stereocontrolled umpolung of aryl and vinyl halides (Ni or Pd catalyst) yielding the corresponding silyl derivatives, e.g. (127)-+( 128) and (129)-+( 130).97

(125)

(126)

(127)

SiMe, I

W. R.Roush, M. A . Adam, and S. M. Peseckis, Tetrahedron Lett., 1983,24,1377. F. Biga, G. Casiraghi, G. Casnati, G. Sartori, and L. Zetta, J . Chem. SOC., Chem. Commun., 1983, 1210. % B. B. Snider and G. B. Phillips, J . Org. Chem., 1983,48,2789. 97 B. M. Trost and J . 4 . Yoshida, Tetrahedron Lett., 1983,24,4895.

9.1

95


360 4 GroupIV

Silicon.-Allylsilanes are versatile intermediates as evidenced by the large volume of literature published in recent years concerned with their use in synthetic chemistry. Consequently new syntheses of allylsilanes are useful additions in this area, and this is so for the two papers detailed below. In the first, various allylsilanes have been synthesized in high yield from the corresponding allylic phosphonates and the reagent combination PhMe2Si-A1Et2.98The method is flexible so that the same reagent can be used to prepare vinylsilanes from enolphosphonates. Tertiary allylic acetates also give allylsilanes; however, unlike the previous method the silyl groups are introduced y- to the leaving acetate group. In this way, stereo-defined cyclohexanes (131a) and (131b) have been prepared in high yield, thus extending the scope of this general reaction.99

mx

9

H SiMe3

Ph

(131 1 a; X = SiMe2Ph,Y = Me

(132 1

b; X = Me, Y = SiMe,Ph

Once again a number of useful enantioselective syntheses involving allylsilanes have been reported. For example, with Lewis acid catalysis the optically active cyclic allylsilanes shown in Scheme 11react with ethylene oxide and aldehydes to

Reagents: i , HSiMeCl,, [PdCl,{(R)-(S)-PPFA}]; ii, EtOH, NEt,; iii, MeLi; it, TiCl,, RCHO

0

v , TiCI4,

Scheme 11

give the corresponding hydroxyalkyl-cyclopentenes and -cyclohexenes in good yields.100In an analogous fashion the allylsilane (132) reacts with aldehydes to yield homoallylic alcohols with high enantioselectivity.lOOIn contrast, the achiral 98

99 loo

Y . Okudo, M. Sato, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1983, 24,2015. I. Fleming and N. K. Terrett, Tetrahedron Left., 1983, 24, 4151. ( a )T. Hayashi, K . Kabeta, T. Yamamoto, K. Tamao, and M. Kumada, Tetrahedron Lett., 1983,24, 5661; ( b ) T. Hayashi, M. Konishi, and M. Kumada, J . Org. Chem., 1983, 48, 281.


361

silanes allyl- and methallyl-trimethylsilane attack the chiral alkoxy-aldehydes (133) and (134) to give chiral homoallylic alcohols (135) and (136), respectively. lol For a-alkoxy-aldehydes, e.g. (133), diastereofacial preference is excellent with isomer ratios of >35 :1attainable, althoughp-alkoxy-aldehydes show a somewhat inferior selectivity (7-12: 1).A more remote asymmetric induction than that just described is seen in the protodesilylation of the allylsilanes (137) resulting in the formation of alcohols (138).lo2 Interestingly, when the acetates corresponding to (137) are used the opposite stereochemistry is produced at the new chiral centre.

x:::

PhCH20&

CHO OH

(133)

(134)

R

(135)

Mt,

OH (136)

(137)

R (138)

The synthesis of several homoallylic alcohols has already been described above; however, further evidence for the utility of allylsilanes in the preparation of homoallylic alcohols is apparent in the highly erythro-selective reaction between E-crotyl- and E-cinnamyl-trimethylsilanesand various aldehydes. lo3 Unfortunately the selectivity is relatively poor for the 2-isomers. In a new siliconmediated rearrangement of epoxides, allyl alcohols (140) are formed from allylsilanes (139).'04 Surprisingly, none of the isomer (141) is formed in this reaction.

(139)

(140 1

(141 1

In a quite different reaction of allylsilanes, the silyl enamine (142) condenses with various enamines to give m-aminophenols; the presence of the silyl group in (142) ensures a selective cross-condensation reaction and avoids self-condensations. l o 5 ~ The , structure of the m-aminophenol that is formed depends upon the S.-i. Kiyooka and C. H. Heathcock, Tetrahedron Lett., 1983,24,4765. S. R. Wilson and M. F. Price, Tetrahedron Lett., 1983, 24,569. lo3 T. Hayashi, K. Kabeta, I. Hamachi, and M. Kumada, Tetrahedron Lett., 1983, 24, 2865. I. Cutting and P. J. Parsons, J . Chem. SOC., Chem. Commun., 1983,1435. 1°5 (a) T. H. Chan and G . J. Kang, Tetrahedron Left., 1983,24, 3187; ( b ) ibid., p. 3051. lol

lM


362

nature of the enamine used to react with (142); if acyclic enamines (143) are used then rn-aminophenols (144) are formed, whereas if cyclic enamines [143; R1R2=(CH2)"; n=2 or 31 are co-reactants then m-aminophenols (145) are formed in preference. However, for cyclic enamines derived from medium-ring cyclic ketones [143; R1R2=(CH2)9]the balance is tipped back in favour of rn-aminophenols [144; R1R2=(CH,),]. The latter compounds have also been resolved into optical isomers.

Me,Si

(142)

&OH

Me

C0,Mc (143 1

OH

(144)

(145 1

Vinylsilanes are yet another class of valuable synthetic intermediates and examples of their use abound in the literature. This year, for example, a novel, general synthesis of four- to six-membered carbocyclic rings has been achieved via intramolecular acylation of n-trimethylsilyl-n-alkenoyl chlorides, where n=4 or 5 .Io6 Another intramolecular acylation of vinylsilanes provides a new synthesis of various cyclopentenones. lo7 The route is versatile, allowing the preparation of cyclopentenones (146) from vinylsilanes (147), and can also be used for the construction of spirocyclopentenones. In this context, the spiro-compound (148) is prepared readily from the vinylsilane (149), thus providing a rapid construction of a trichothecane-type carbon framework.

The cleavage of carbon-silicon bonds by fluoride ion is a well recognized reaction though not always a clean procedure, especially for the cleavage of the C-Si bond in vinylsilanes. It now seems that the presence of one or two phenyl rings on the silicon atom, i.e. PhMe2Sior Ph,MeSi, greatly facilitates the cleavage lo6

lCn

K. Mikami, N. Kishi, and T. Nakai, Tetrahedron Lett., 1983,24,795. E . Nakamura, K. Fukuzaki, and I. Kuwajima, J. Chem. SOC., Chem. Commun., 1983, 499.

363


reaction (with Bu,NF) and a clean reaction and good yields of desilylated alkenes are obtained.los In the same vein, the C-Si bond in the 2-unsaturated nitrile (150) is cleaved readily and the anion so generated can be trapped with carbonyl compounds to give hydroxynitriles (151) with complete retention of configuration.lo9 CN

CN

OH

(150)

(151)

Trimethyl-(2-nitroviny1)silane reacts with organometallic compounds regioselectively to yield useful looking trimethyl-(1-nitromethylalky1)silanes in excellent yields.l'* This is therefore claimed to be the first example of reactivity umpolung of 1-alkenylsilanes. The vinylsilane (152) is yet another useful intermediate since it acts as a single synthon for both the (E)-P-formylvinyl cation and anion depending on how the bromine atom is replaced in the alkylation reaction.lll Such alkylation results in the vinylsilane (153), which can then be converted into the a,P-unsaturated aldehyde (154) by standard synthetic manipulation. a$-Unsaturated compounds (155) are also formed after a BF3,0Et2-induced Pearrangement of epoxysilanes (156), which are in turn obtained from the vinylsilanes (157).'lk a different type of rearrangement occurs when the vinylsilanes (157) are treated with catalytic amounts of NaH in HMPA.112bIn this case a 1,3 silyl group shift occurs from carbon to oxygen, representing the first case of a rearrangement of silicon from an sp2 carbon to oxygen. THPOCRiMe,

H

Br

THPOCH,

R

\=\

(153)

R2

0

CHO

X

H

(152 1

R'

SiMe,

R'

HO

R

(154)

SiR,

HO

H. Oda, M. Sato, Y. Morizawa, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1983, 24, 2877. Y. Sat0 and K. Hitomi, J . Chem. SOC., Chem. Commun., 1983,170. I l 0 T. Hayama, S. Tomoda, Y. Takeuchi, and Y . Nomura, Tetrahedron Lett., 1983, 24,2795. l l 1 R. B. Miller and M. I. Al-Hassan, Tetrahedron Lett., 1983, 24,2055. 11* (a)F. Sato, Y. Tanaka, and H. Kanbara,J . Chem. SOC.,Chem. Commun., 1983,1024; (b) F. Sato, Y. Tanaka, and M. Sato, ibid., p. 165. lo8

364


New or improved routes to vinylsilanes are always welcome. Thus, direct ) ~catalyst, ] results in the hydrosilylation of methyl acrylate, using [ C O ~ ( C Oas formation of methyl (E)-3-silylacrylates in high yield and is a far superior method to the low-yielding route from prop-2-yn-1-01.113 Hydromagnesiation of l-alkynylsilanes by isobutylmagnesium bromide (cat. [Cp2TiC12])followed by treatment of the Grignard compound with alkyl iodide-copper provides excellent yields of 2-1,2-dialkylvinylsilanes. 114The sequence has been used in a very simple two-step construction of dihydrojasmone. Alternatively, the alkynylsilane Me3SiC=CBr reacts with copper acetylides to furnish the l-trimethylsilyl-l,3diynes (158), which can then be desilylated (F-) to yield terminal a 1 k ~ n e s . lIf~ ~ (158) is reduced with lithium di-isobutyl-n-butylaluminium hydride, then stereodefined 2-enynes (159) are obtained, and a further reduction with di-isobutylaluminium hydride yields the dienes (160).1156 The silyl group therefore allows appreciable discrimination between the adjacent carbon-carbon triple bonds.

R R

H

i“

HO”

(161 1

1

Me

(162 1

The formation of chiral propargylic alcohols, as described below, further demonstrates the varied chemistry possible with l-silylalkynes. 1-Trimethylsilylalkynes(R1C=CSiMe3, R1=Me or SiMe3)react with chiral acetals (161), giving chiral propargylic ethers (162) from which the alcohol can be liberated simply by treatment with alcoholic KOH. 116 Chemical yields are excellent and enantiomeric excesses of the propargyl alcohols are generally very high. In contrast, the chiral synthesis of the propargyl silane shown in Scheme 12 requires a chiral catalyst for asymmetric induction.117 Once formed the propargyl silane can be converted into chiral allenes and chiral silanes. Organosilicon reagents of the type R3SiXare capable of a wide variety of useful functional group interchanges such as dealkylation, cyanidation, azidation, etc. K. Takeshita, Y . Seki, K. Kawamoto, S. Murai, and N. Sonoda, J . Chem. SOC., Chem. Commun., 1983, 1193. 114 F. Sato, H. Watanabe, Y. Tanaka, T. Yamaji, and M. Sato, Tetrahedron Lett., 1983, 1041. 115 (a)J. A. Miller and G. Zweifel, Synthesis, 1983, 128; ( b ) J. A. Miller and G. Zweifel, J . Am. Chem. Soc., 1983, 105, 1383. 116 W. S . Johnson, E. Elliott, and J. D. Elliott, J . Am. Chem. SOC., 1983, 105, 2904. 117 T. Hayashi, Y . Okamoto, and M. Kumada, Tetrahedron Lett., 1983,24, 807. 113


365 ,SiMt3

PhCEC-Br

+

i P m h-CEC-C,&Ph

Mc3siybBr

Ph

H‘

Ph

But

1

/

Fc70%).' Corey et al. have shown that P-peroxy-mercurials, generated by peroxy-mercuration of olefins, afford epoxides ( 5 ) on reduction with sodium borohydride. The reaction is thought to go via P-peroxy-radicals.lOTrisubstituted olefins react with iodine-pyridinium dichromate under anhydrous conditions at room temperature to give epoxides via the corresponding iodohydrins, which can be isolated with shorter reaction times (see Scheme 1).l1 Y. Tsunokawa, S. Iwasaki, and S. Okuda, Chem. Pharm. Bull., 1983,31,4578.

' F. Camps, J. Coll, A . Messeguer, and F. Pujol, Chem. Lett., 1983, 971.

T. Hiyama and M. Obayashi, Tetrahedron Lett., 1983,24,395. K. Takai, K. Oshima, and H. Nozaki, Bull. Chem. SOC.Jpn., 1983,56, 3791. E. J. Corey, G. Schmidt, and K. Shimoji, Tetrahedron Lett., 1983,24, 3169. R. Antonioletti, M. D'Auria, A . De Mico, G. Piancatelli,and A. Scettri, Tetrahedron, 1983,39,1765.

409

Saturated Heterocyclic Ring Synthesis

" R2

R3

d [

OH H

B

R

A

-

R'

0

R f i R 3

Reagents: i, Bu'Me,SiOOH, Hg(02CCF3)2,-90°C; ii, NaBH,, H,O, O'C, iii, I,, PDC

Scheme 1

1,2-Diols can be converted directly into epoxides with carbon tetrachloridetriphenylphosphine-potassium carbonate, probably via l,Zchlorohydrins, in variable yield depending on the substitution pattern. l2 a-Halogeno-ketones react with acetonyl- and allyl-tin in the presence of a palladium(I1) catalyst to give epoxides (6) generally in good yield (65%). The reaction is also applicable to the synthesis of oxetanes and tetrahydrofurans. l3

Sulphur ylides are commonly used to epoxidize ketones, and more recently non-stabilized arsonium ylides have been used in a similar manner. This method has now been extended to the synthesis of the vinyl epoxides (8) from the stabilized allylic arsonium ylides (7) in high yield.14 The vinyl epoxides (10) can also be synthesized from aldehydes by the addition of the organotin reagent from 1-chloro-3-iodopropene and tin(11) chloride, followed by treatment of the intermediates (9) with methoxide. The yields are moderate (50%) and the reaction shows cis-stereoselectivity .l5 Finally, full details on the useful conversion of ketones or aldehydes into a&epoxytrimethylsilanes using chloromethyl(trimethylsilyl)lithium have now appeared.l6 C. N. Barry and S. A. Evans, jun., Tetrahedron Lett., 1983,24, 661, I. Pri-Barr, P. S. Pearlman, and J. K. Stille, J . Org. Chem., 1983: 48, 4629. l4 J. B. Ousset, C. Mioskowski, and G . Solladie, Tetrahedron Lett., 1983, 24, 4419. J. Auge and S . David, Tetrahedron Lett., 1983, 24, 4009. l6 C. Burford, F. Cooke, G . Roy, and P. Magnus, Tetrahedron, 1983,39, 867.

12

l3

410


..

R2

.----.. (7)

I R'

+

CICH-CHCHZI

SnC12

- wMeO-

+ DMF OSnCL2I

R

(9)

(10)

Four-membered Rings.-Variations on cycloadditions continue to be popular for the formation of the oxetane ring system. Thus, the deactivated ketene acetals (11) add to carbonyl compounds under high pressure (12 kbar) at much greater

R"'FR3

OMe

+

R2

(11 1

OMe

Rd

R2 OMe

rates than at atmospheric presssure.17 When the reaction is carried out with benzaldehyde, trans-oxetanes predominate , again in contrast to atmosphericpressure conditions where the cis-form predominates. Photochemical cycloaddition of aryl carbonyl compounds with vinyloxy compounds has been investigated by two groups of workers this year. Ruotsalainen and Karki have shown that aryl aldehydes (12) add to vinyl acetate giving mixtures of oxetanols where the 3-isomer predominates,ls whereas Shimizu and co-workers have demonstrated that benzophenone adds to trimethylsilylenol ethers, giving the oxetanes (13) in generally high yield (>80%). l9 R. W. M. Aben and H. W. Scheeren, Tetrahedron Lett., 1983,24,4613. H. Ruotsalainen and T. Karki, Acta Chem. Scand., Ser. B, 1983,37, 151. 19 N. Shimizu, S. Yamaoka, and Y. Tsuno, Bull. Chem. SOC.Jpn., 1983, 56, 3853.

17

18

Saturated Heterocyclic Ring Synthesis 0

+

Ar A H (12)

-

411

hV

(OAC

P

Ar

O

A

C

2

7

,R~

R* 0 PhA

CHR~ P

h

+

R1AOSiMe3

R1

i, h v

P

ii a MeOH, K2CO3

Ph

OH Ph (13)

or p-TsOH, MeOH

3-Hydroxyoxetane itself can be readily prepared from epichlorohydrin as outlined in Scheme 2.20The method is particularly suitable for large-scale synthesis.

-

OH

lii A

c

O

T

C

L

f-111

OH

OEt Reagents: i , AcOH; ii, CH,=CMe(OEt),

H + ; iii, NaOH

Scheme 2

The benzyl ethers (14) are deprotonated using the hindered base lithio-2,4dimethylpiperate, and undergo intramolecular attack at the epoxide leading to oxetanes, tetrahydrofurans, and tetrahydropyrans in high yield; the formation of oxetanes is particularly favoured.21 Full details on the direct conversion of ketones into oxetanes using S-methyl-S(sodiomethyl)-N-(4-tolylsulphonyl)sulphoxime,developed by Welch et al., have now appeared,22and a similar reaction using trimethylsulphoxonium methylide (15) as the methylene transfer agent has been reported.23Thus treatment of epoxides with one equivalent of (15) leads to the oxetanes (16), and treatment of ketones with two equivalents of (15) also leads to (16). K. Baum, P.T. Berkowitz, V. Grakauskas, and T. G . Archibald, J . Org. Chem., 1983, 48, 2953. D . R. Williams and J . Grote, J . Org. Chem., 1983, 48, 134. 22 S. C. Welch, A . S. C . Prakasa Rao, J. T. Lyon, and J.-M. Assercq, J . Am. Chem. SOC., 1983,105,252. 23 K. Okuma, Y. Tanaka, S. Kaji, and H. Ohta, J . Urg. Chem., 1983,48, 5133.

2o


412

(14) n =0- 2

A review of the synthesis and properties of 1,2-dioxetanes has been published during 1983.24 Five-membered Rings.-Tetrahydrofurans. Although a well used method for tetrahydrofuran ring formation, new variations on the intramolecular ether formation still appear. For example, the acyl-lithium reagents (17), generated in situ by the addition of alkyl-lithiums to carbon monoxide, add to 5-chloropentan2-one to afford the acyl tetrahydrofurans (18) in high yield.25In a similar type of reaction the addition of 4-chloro-2-lithiobut-1-ene to aldehydes or ketones leads

RLi

+

+

lLi Rh ii,iii)

I

CO

R

(17)

(18) 80 -95’/0

Reagents: i, THF, E t 2 0 , pentane (4:4:1); ii, MeCOCH,CH,Cl; iii, -110 to 47°C

(19) Reagents: i, MeLi,THF, -78°C; ii, RIRZCO;iii, NH,Cl, -78°C; iv, HMPA, -78°C to r.t.; v, KH, THF 24 25

W. Adam and G . Cilento, Angew. Chem., Int. Ed. Engl., 1983, 22, 529. R. M. Weinstein, W.-L. Wang, and D. Seyferth, J . Org. Chem., 1983,48,3367

413


to 3-methylenetetrahydrofurans (19) in moderate yields (51--63%) .26 The mixture triphenylphosphine-t-butyl hypochlorite-potassium carbonate is a useful complement to the triphenylphosphine-carbon tetrachloride method for the preparation of tetrahydrofurans from 1,4-diols.” The tribromides (21), which were reported previously to cyclize to tetrahydrofurans, are prepared much more readily by the bromination of the cyclopropyl ketones (20). The tribromides (21) were then cyclized to give methoxy- or cyano-tetrahydrofurans, again by intramolecular ether formation.28 Br I

Ar

dBr Ar%

Ar

Me0

Reagents: i, Br,, CC1,; ii, NaOH, MeOH, H 2 0 ; iii, NaCN, MeOH

The allylic alcohols (22) when treated with a PdO catalyst in carbon tetrachloride are converted into oxaphosphonium compounds which then give the (x-al1yl)palladium complexes (23). The chloride anion, formed in situ, cleaves the triethylsilyloxy-group, generating an alkoxide anion which then undergoes intramolecular displacement to afford tetrahydrofurans (see Scheme 3) .29 A further use of alkoxide opening of (n-ally1)palladium complexes has been described by Stork and P ~ i r i e rwhere , ~ ~ the optically pure allylic benzoates (24) and (26) afford the tetrahydrofurans (25) and (27) respectively, with high chirality transfer, in the presence of PdO catalyst. The primary tosylates (28) are reduced using a tri-n-butyltin hydride-sodium hydride mixture, generating a radical which is captured by the double bond to give tetrahydrofurans or tetrahydropyrroles in high yield.31 Similarly the a-halogenosulphones (29) reductively cyclize under the same conditions to give tetra hydro fur an^,^^ and the ease with which the latter reaction proceeds is in E. Piers and V. Karunaratne, J . Org. Chem., 1983,48, 1774. C. N. Barry and S. A. Evans, jun., J . Org. Chern., 1983,48,2825. 28 M. Takahashi, N. Takeshi, K. Myojoh, H. Sano, and T. Morisawa, J . Heterocycl. Chern., 1983, 20, 209. 29 S. A. Stanton, S. W. Felman, C . S. Parkhurst, and S. A . Godleski, J . Am. Chem. SOC., 1983, 105, 1964. 30 G. Stork and J. M. Pokier, J . Am. Chem. Soc., 1983,105, 1073. 31 Y. Ueno, C. Tanaka, and M. Okawara, Chem. Lett., 1983,795. 32 Y. Ueno, R. K. Khare, and M. Okawara, J . Chem. SOC., Perkin Trans. 1, 1983, 2637.

26

27

414


m

OSiEt3 OH

H

Scheme 3

HO [ Pd ( PP h3),.]

0 (241

Et3N. MeCN

(26)

(25)

(27)

Bu3SnH,

NaH

*d

azobisisobutyron i t r i Le

DME

(28)

R = H or Ph

X = O or NTs

y,f R

p -To ISO2

R’ (29)


415

direct contrast with the ease of nucleophilic substitution of halogen in a-halogenosulphones . Intramolecular opening of epoxides features in two approaches to tetrahydrofurans reported this year. In the first the trimethylsilyl olefinic alcohols (30) are epoxidized with rn-chloroperbenzoic acid and the resulting epoxides treated with potassium hydride to give a-alkylidenetetrahydrofurans(31) via sequential epoxide opening and ~yn-elimination.~~ In the second method the epoxides (34), which are generated by addition of the stabilized carbanions (33) to the iodolactone (32), cyclize in situ to give mixtures of 2- and E-a-alkylidenetetrahydr~furans.~~ The 2-compounds predominate when X is an oxygenbased stabilizing group. The known cycloaddition of 3-oxidopyrilium ylides to olefins to give tetrahydrofurans has been extended by Sammes and his group. They have found that

iKH

(30) I

I (31)

(32)

x (34) R

2

+

X

YLi + ( 3 3 ) R = H or Me

R ' S ' . / O H

X = PhSO2 ,PhzPO, COZR1, or CN 33

F.-T. Luo and E. Negishi, J . Org. Chem., 1983,48,5144. Batmangherlich,A. H. Davidson, and G . Procter, Tetrahedron Left., 1983,24,2889.

41 S .

f

416


the ylides add to electron-rich and strained olefins, not only under thermal conditions but also at room temperature in the presence of base. For example the 3-oxidopyrilium ylide (35) adds to ethyl vinyl ether to give the tetrahydrofuran (36).35 The method has also been applied to a series of potential herbicides demonstrating the feasibility of the intramolecular variant (Scheme 4).36In a OEt

b or tertiary base

AcO

R

+ /

OEt (36)

(35)

AcO

qo Scheme 4

+

(38) R3

35 36

J

P. G. Sammes and L. J. Street, J . Chem. SOC.,Perkin Trans. 1 , 1983,1261. P. G. Sammes, L. J. Street, and P. Kirby, J . Chem. Soc., Perkin Trans. 1, 1983,2729.


417

similar type of reaction, originally investigated by Biichi, the cycloaddition of the pyrones (37) giving tricycles containing a tetrahydrofuran ring has been reported. 37 The intramolecular Diels-Alder reaction of the alkenyl oxazole-Scarbarnates (38) proceeds cleanly to give tetrahydrofuropyrrolidines (39), in contrast to the intermolecular reaction which affords p y r i d i n e ~ . ~ ~ The treatment of dibromocyclopropane ethers with methyl-lithium is known to give tetrahydrofurans via intramolecular carbene insertion: this reaction has now been extended to the conversion of cyclopropyl acetals (40) into tetrah y drofurans. 39

R1

-

R2

MeLi

-78

OC

Br Br

(40)

A new method for the synthesis of tetrahydrofurans and tetrahydropyrans involving the oxidative cyclization of olefinic alcohols has been reported this year. Thus, treatment of the olefins (41) with DDQ in methylene chloride affords tetrahydrofurans or tetrahydropyrans depending on the substitution pattern, the reaction only working for E-olefins.40

R'O

/

R2= H

DDQ.CHzCI2

/

R' 0

x = -+OM 6R2 (41)

M. E. Garst, B. J . McBride, and J. G. Douglass 111, Tetrahedron Left., 1983, 24, 1675. S. Shimada and T. Tojo, Chem. Pharm. Bull., 1983, 31,4247. 39 J. Arct, L. Skattebol, and Y. Stenstrom, Acta Chem. Scand., Ser. B, 1983, 37, 681. 4o Y. Oikawa, K. Horita, and 0. Yonemitsu, Heterocycles, 1983, 20, 135.

37

38

418


1,6-Dioxaspir0[4,4]nonanesoccur in many natural products and a delightfully efficient method for their synthesis has been published. It entails the deprotonation of acetone N , N-dimethylhydrazone and treatment with an epoxide followed by a second treatment with base and epoxide to give the diols (42) which then cyclize to give the spirotetrahydrofurans (43) in excellent overall yield (5082%) .41 The availability of chiral epoxides allows optically active compounds to be synthesized. Furofurans are also featured in several natural products and a synthesis of perhydrofurofurans (44) via the well used iodolactonization sequence has been reported.42

OLi

OH

OH (42)

H

(44) Reagents: i, Bu"Li; ii, -15°C

0

; iii, RZ,i/o;

(43)

iv, Amberlite 1R 120A, THF, A; v , I,, NaHCO,, MeCN,

Dihydrofurans.The Lewis acid-catalysed reaction of a-(t-buty1thio)-a-chloroacetone with the olefins (45) affords 2,3-dihydrofurans in moderate yield (45%) accompanied by varying amounts of the ene products (46).43The reaction has also been applied to the synthesis of y-butyrolactones as shown in Scheme 5. a-Hydroxy-l,3-diketones are known to undergo acid-catalysed cyclodehydration to give furanones, and Curran and Singleton have now published a new entry into a'-hydroxydiketone equivalents via nitrile oxide cycloaddition to enol ethers.44The adducts (47) are reduced with Raney nickel and cyclized in the presence of acid to afford the dihydrofurans (48). The method has been applied to the synthesis of bullatenone (49). Bullatenone and geiparvarin have been synthesized by another general procedure for the synthesis of dihydrofurans reported by Raphael and Jackson.45The procedure involves the hydration of the acetylenic ketones (51) which are conveniently prepared by palladium-assisted coupling of acetylenes with the acid bromide (50). The resulting enamines (52) cyclize on treatment with acid to give dihydrofurans, where (53) was converted in a few steps into geiparvarin (54). D. Enders, W. Dahmen, E. Dederichs, and P. Weuster, Synth. Commun., 1983, 13, 1235. M. Jalali, G . Boussac, and J.-Y. Lallemand, Tetrahedron Lett., 1983,24, 4307. 43 M. Wada, T. Shigehisa, H. Kitani, and K. Akiba, Tetrahedron Lett., 1983,24,1715. 44 D. P. Curran and D. H. Singleton, Tetrahedron Lett., 1983,24,2079. 45 R. F. W. Jackson and R. A. Raphael, Tetrahedron Lett., 1983,24,2117.

41

42

419


+

(45)

R’$TR2

Buts

0

ArS

CL

+

-

R1

SnC14

R1 Scheme 5

+

HO

(471 70 - 98 ‘lo

(48) 50- 71 ‘10

OEt +(OH

R2 R3

Ph

Me

The 3-metalloenaminegenerated by deprotonation of the enamine (55) adds to ketones or aldehydes to give adducts in moderate to good yield (40-78%), which can then be transformed into either dihydrofurans (56) by thermolysis or tetrahydrofurans (57) by solvolytic cyclization.46 Enamines also feature in an unusual photocoupling reaction: the irradiation of enamines of amines in the presence of cobalt trisacetoacetate affords the aminodihydrofurans (58) in variable yield (42-75%) depending on the structure of the amine or enamine.47Di-iminodihydrofurans (61), a class of compounds 46 47

H. Ahlbrecht and H. Simon, Synthesis, 1983, 61. T. Sato and K. Watanabe, Chem. Lett., 1983, 1499.


420

Reagents: i, [Pd(PPh,),Cl,], Et,N, CuI; ii, Et,NH; iii, AcOH, H20

.I -... 111

R' OH

- qph

'NPh

R2

C02Me

(55)

R2

Me02C

Me02C Me0%2: (57)

(56)

Reagents: i, LDA, -78°C; ii, K1R2CO;iii, CF,CO,H, -+O"C;iv, A; v, H2S04,MeOH

R3

/I/RL '

R' N' R2

\

hv

or

[Co(acac131, M e C ND3 : &

R3

R'

N '

R2

/

O N/R

/I/RL

1

R2

(58)

1

421


R1

(60)

(59)

R’ 0

A

N2J-Lo*E1

+

(62)

R3

which were previously unknown, can be prepared by the addition of isocyanides to the acylketeneimines (60), which are prepared by thermolysis of the diazoketones (59) in the presence of triphenylphosphane imides.@The thermolysis of ethyl diazopyruvate in the presence of enol ethers affords 2,3dihydrourans (62) in variable yield ( 3 6 7 9 % ) depending on the structure of the enol ether, but complete regio- and stereo-specificity is observed and the reaction also succeeds with ketene a c e t a l ~ . ~ ~ It is known that o-allyl-substituted phenols (63) can be converted into 2,3dihydrobenzofurans by reaction with thallium(m) acetate and subsequent reaction of the organothalium intermediate. It has now been reported that simply by using thallium(m) nitrate the reaction proceeds in one step, giving the benzofurans (64) as mixtures of isomers.50The yields of 2,3-dihydrobenzofurans (65) from the Nick1 reaction have been substantially improved by using the lithiophenolate in toluene rather than the sodio-derivative in mefhan01,~land the L. Capuano, P. Morsdorf, and H. Scheidt, Chem. Ber., 1983,116,741. M. E. Alonso, P. Jano, M. I. Hernandez, R. S. Greenberg, and E. Wenkert, J . Org. Chem., 1983,48, 3047. M. L. Forcellese, C. Alfonsi, S. Calvitti, and E. Mincione, Heterocycles, 1983, 20, 1559. 51 F. Bigi, G. Casiraghi, G. Casnati, and G. Sartori, Tetrahedron, 1983,39,169. 49


422 R

(64)R' =Me or NO2

(63)

R (65)

synthesis of benzofurans by the six-electron cyclization of phenyl vinyl ethers has been reviewed.52 The acetylene compounds (67) cyclize in the presence of a catalytic amount of potassium hydride in DMSO to afford 2-metho~y-2,5-dihydrofurans.~~ The

LO A

=c 5 0 %

EtO

R’ R30>=

0

- .+R2

ii 3 0 - 8 5 %

- 0

OH

Reagents: i, H,SO,, MeOH; ii, Hg, Nafion H; iii, CF,CO,H, Hg(OAc),

Scheme 6 55

H. Saimoto, M. Shinoda, S. Matsubara, K. Oshima, T. Hiyama, and H. Nozaki, Bull. Chem. SOC., Jpn., 1983, 56, 3088.


424

Five-memberedRings with More than One OxygenAtom. The photo-oxygenation of diarylcyclopropanes (71) in the presence of 9,lO-dicyanoanthracene leads to 3,5-diaryl-l,2-dioxolanes as mixtures of isomers but in generally excellent yields (>85%). Yields only fall when the oxidation potentials of the cyclopropanes are high (typically >0.9 V).s61,2-Dioxolanes are also readily prepared in good yield by the silver ion-assisted cyclization of the peroxybromides (73), which are generated by intermolecular alkylation of t-butyl hydroperoxide by the dibromide (72).57The procedure offers a much safer alternative to the use of hydrogen peroxide on the dibromides (72), and can be extended to the synthesis

A

Ar’

A‘fiAr2

0-0

\Ar2

(71) DCA = d icyan oant hracene

‘CH2Br

R

Br

4

( C H 2In

-C H

Br

0 0

(72)

of 1,2-dioxanes. Full details on the preparation of 1,2-dioxolanes by the Lewis acid-catalysed reaction of ozonides with olefins have appeared.s8

COzH

I

(74)

Q

I

*-Me “O H

i

(75) .. ...

1

11, 111

iv, v

(76) Reagents: i, Bu‘CHO, H+; ii, LDA; iii, I(CH,),CMe,

/o-

; iv, LiAlH,; v, H+

0-

Scheme 7 56

57 5*

K. Mizuno, N. Kamiyama, and Y. Otsuji, Chern. Lett., 1983, 477. N. A. Porter and J. C. Mitchell, Tetrahedron Lett., 1983, 24, 543. M. Yoshida, M. Miura, M. Nojima, and S . Kusabayashi, J . Am. Chern. SOC., 1983,105,6279.


425

An increasing number of total syntheses of natural products containing 1,3dioxolanes have appeared, usually relying on intramolecular acetal formation as the ring-forming step. One example has been selected to illustrate these reactions, where the principle of ‘self-reproduction of chirality’ is beautifully demonstrated by the total synthesis of R-( +)-frontalin (76) from S-( +)-lactic acid. Initially the chirality of the acid (74) is transferred to the t-butyl-bearing carbon of the 173-dioxolane(75),and then transferred back in the alkylation step (Scheme 7).59 Six-membered Rings.-Tetrahydropyrans. The intramolecular cyclization of the chloroformate (78), generated by reaction of the y,S-unsaturated alcohol (77) with phosgene, gives the tetrahydropyran (79) in 57% yield under Lewis acid catalysis.‘j0

CH2CL2 ,O°C

SiMe3

SiMe3

(77)

( 7 8)

(79)

The 6,8-dioxabicyclo[3.2. lloctane (81) is readily prepared by intramolecular alkylation of the acetal (80). Two selective reductions of the bicycle (81) then afford the tetrahydropyran (S2).61A more general but rather unusual synthesis of SOZPh

I

H

H

(80)

1

Bu”Li

+OH H

i , N a ,Et OH,TH F

H

,I

702Ph

Q--H ,/OMS

ii, AIC13, LiALH4

OMS

(81)

(82) 59

R. Naef and D. Seebach, Liebigs Ann. Chem., 1983, 1930. K. Isaac, P. Kocienski, and S. Campbell, J . Chem. SOC., Chem. Commun., 1983,249. Y . Masaki, Y. Serizawa, K . Nagata, and S. Kaji, Chem. Lett., 1983. 1601.

426


tetrahydrofurans, contained in the 6,8-dioxabicyclo[3.2. lloctane ring system, has been published during this reporting period. Thus, base-catalysed oxygenation of the dibromides of 2,6-disubstituted cyclohexanones (83) affords the tetrahydropyranyl carbolactones (84) in generally good yield;62the regiochemistry of the reaction in the case of non-symmetrical ketones is said to be under investigation.

I

MeOH, NaOH, 02

The intramolecular Diels-Alder reaction in molecules which contain an ester linkage are beset with difficulties, but Boeckman and Flan have shown that the mixed acetal equivalent (85) behaves well in thermal reactions so that cyclohexane-fused tetrahydropyrans are readily prepared by thermolysis of (85) in yields of 70% or more with no accompanying elimination of methanol.63

Dihydropyrans. In an extension to the previously reported synthesis of dihydr opyrone spiroacetals, Crimmins and Bankaitis have developed a synthesis of 2,3-dihydropyrones from 1-methoxy-but-1-en-3-yne (86).@Thus, deprotonation of (86) and addition to aldehydes followed by acid-catalysed ring closure of the adducts gives the dihydropyrones (87) in 40-80% yields. A preliminary communication on the general preparation of dihydropyrans annelated to cyclopentadienes has appeared. The method was primarily aimed at a short synthesis of virbutinal(88) as shown in Scheme 8, but can be applied to a range of dihydropyrans (89). 65 M. TJtaka, H. Makino, Y . Oota, S. Tsuboi, and A . Takeda, Tetrahedron Lett., 1983,24, 2567. R. K. Boeckman, jun. and C . J. Flann, Tetrahedron Lett., 1983,24,5035. 64 M. T. Crimmins and D. M. Bankaitis, Tetrahedron Lett., 1983, 24, 5303. h5 J.-L. Brayer, J.-P. Alazard, and C. Thal, J . Chem. SOC., Chem. Commun., 1983,257. 62 63

427


b

R R

(86)

(87)

ivl /*

R

FCHO

Reagents: i, BunLi; ii, RCHO; iii, p-TsOH, THF, H20,30% HClO,; iv, 30% HClO,, O'C, 20 min; v, 30% HClO,

The use of the hetero-Diels-Alder reaction to construct the dihydropyran ring system has again featured heavily in this year's literature. a,P-Unsaturated carbonyl compounds are known to undergo the hetero-Diels-Alder reaction as the 4n component but often require extreme conditions. Yamauchi and his group have discovered that the introduction of an electron-withdrawing group at the a-position allows the reaction with vinyl ethers to proceed at room temperature in .

I

- ... 111

HO

OH

f!, '0 H

(88) Reagents: i , Na; ii, MeCH(Br)CO,Et; iii, LiAlH,; iv, Me,NCH(OMe),; v, NaOH, (CO,H),, pH 4; vi, benzene, (CO,H),, A; vii, DDQ

Scheme 8

428


excellent yield (>96%) .66 Where the cr,,&nsaturated carbonyl compound (90) is non-symmetrical the reaction is selective for the dihydropyran (91) where R3=Me over R3=OEt or Ph, and selective for (91) where R3=Ph over R3=OEt. The triacyl compounds (92; R=H) also react only very slowly with enol ethers (reaction times of typically 200 h). It has been found that the acylated compound (92;

R’0

+

eR4 - $PR4 R2

0

0R’

(91)

(90)

R=Ac) reacts much faster (ca. 8 h) quantitatively to give dihydropyrans, and a chiral acyl group such as camphanoyl leads to asymmetric induction of around 50% e.e.67 Danishefsky and his group have continued their studies on the hetero-DielsAlder reaction and have reported on several important developments. The first was the discovery that [Eu(fod),] functions well as the Lewis acid catalyst for the reaction and that for the first time the dihydropyran intermediates (93) could be isolated, and then stereoselectively converted into the dihydropyrans (94) or tetrahydropyrans (95).68From this observation they showed that using a catalyst

A

OMe

66 67

M. Yamauchi, S. Katayama, 0. Baba, and T . Watanabe, J . Chem. SOC. Chem. Commun., 1983,281. L.-F. Tietze and K.-H. Glusenkamp, Angew. Chem., Int. Ed. Engl., 1983, 22,887. M. Bednarski and S . Danishefsky, J . Am. Chem. SOC.,1983,105, 3716.


429

which bears a chiral ligand, e.g. Eu[3-(heptafluoropropylhydroxymethylene)-dcamphor at^]^, [Eu(hfc),], some chiral induction is observed in the reaction. Higher inductions are seen with more bulky groups on the diene component and when the reaction is carried out at lower temperatures (Scheme 9).69By including an 1-menthyl group as R1 there is a significant interaction between the menthyl group and the [Eu(hfc),] catalyst (i. e. better than additive) giving enantioselectivities of up to 13:1 in the tetrahydropyrans (96) .70 MQSio$

R3

Y3

M e $ : D 0 ~ P h

+

R2

ii

O p ,R3. P h

I_)

R2 I

OR’

bR1

(96)

liii R3

on=ph

R2

&?I

Reagents: i, PhCHO, [Eu(hfc),], CDCl,, r.t.; ii, TFA; iii, Et,N, MeOH

Scheme 9

The hetero-Diels-Alder reaction of 1-hydroxy-4-aminobutadienes with carbonyl compounds usually gives a-aminodihydropyrans. However ,by increasing the electron-donating ability of the hydroxy-group, for example by conversion into the t-butyldimethylsilyl ether, the reaction shows the opposite regiochemistry , as shown in Scheme 172,3-Tricarbonyl compounds (97) are efficient dienophiles in the hetero-Diels-Alder reaction, giving a variety of spirodihydropyrans (98) in variable yield (32-87%), when the diene is electron

Scheme 10 69

M. Bednarski, C. Maring, and S. Danishefsky, Tetrahedron Lett., 1983,24,3451.

70 M. Bednarski and S. Danishefsky, J. Am. Chem. SOC., 1983,105, 6968. 71 R. R. Schmidt and A. Wagner, J. Am. Chem. SOC., 1983,24,4661. 7i

R. R. Schmidt and K. Vogt, Synthesis, 1983,799.

430


x={D,

{-“o, -NH

{ - -0 Ox

The viability of a quasi intramolecular Diels-Alder reaction has been addressed by Snider and his co-workers. Reaction of the alcohols with Lewis acid forms the aluminate (99) which directs the dienophile and increases the stereoand regio-selectivity of the reaction depending on the substitution pattern to give the dihydropyrans (100).73

R ’ y o H

9 R2

(1001

As an extension to the synthesis of cycloalkenes from bromodienes, Heck et al. have studied the palladium-catalysed cyclization of bromodialkenyl ethers (101).74The cyclization occurs at the least substituted end of the double bond, preferentially giving five-membered rings if possible; however, five-, six-, and seven-membered oxygen heterocycles are available by this method. 73 74

B. B . Snider, G . B. Philips, and R. Cordova, J . Org. Chem., 1983, 48, 3003. L. Shi, C. K. Narula, K. T. Mak, L. Kao, Y. Xu, and R. F. Heck, J . Org. Chem., 1983,48,3894.


431

The epoxidation of the 2-furancarbinols (102) under Sharpless conditions affords the 3,4-dihydropyrans (103) in moderate yield (45-70%), and is reported to be more convenient than previously reported oxidations since a neutral sideproduct is given.75

A reinvestigation of the synthesis of the benzoxepines (105) by reaction of the ketones (104) with methoxymethylsulphonium ylide, originally published some time ago ,76a has shown that the side-product chromans, occasionally encountered during the original reaction, can be made the main Thus, treatment of the benzoxepines (105) with TFA gives the corresponding chromans in excellent yield.

(104)

As part of a programme directed towards the total synthesis of the antibiotic frenolicin, Semmelhack and Zask have developed a general synthesis of b e n ~ o p y r a n s .The ~ ~ method entails the palladium-catalysed intramolecular alkoxycarbonylation of the olefinic alcohols (106), giving selectively the pyrans T.-L. Ho and S. G. Sapp, Synth. Commun., 1983,13,207. (a) P. Bravo, C. Ticozzi, C. Fronza, R . Bernadi, and D. Maggi, Gazz. Chim. Itul., 1979,109,137; ( b ) F. M. Dean and M. A. Jones, Tetrahedron Lett., 1983,24,2495. 77 M. F. Semmelhack and A. Zask, J . Am. Chem. SOC., 1983,105,2034.

75

76

432


(107) with a cis-arrangement of substituents. The olefinic alcohols (108) oxidatively cyclize in the presence of four equivalents of ceric ammonium nitrate to give the naphthoquinones (109) as a mixture of hydroxyl isomers.78

OMe R1

OMe (108)

0

R'

0

OH

(109)

Ketenes are well known to undergo [2+2] cycloaddition reactions but they are also capable of undergoing [4+2] cycloadditions as the dienophile either at the carbon-carbon double bond or at the carbonyl group. Both of these additions have been put to use as methods for the synthesis of 2-pyranones via dihydropyrans. Thus, the cycloaddition of ketenes with @-unsaturated ketones (110) affords 2-pyranones after reduction of the intermediate dihydropyrans where R1= halogen,79and the reaction of ketenes with the dienes (111) affords R3 R~

R*

1

i , (111)

(110). 8OoC

I

1t3n

Zn, A c O H

R' = halogen

: &R

R3

: : YR

R3 R R4

h

o

R4 (110)

( 1111

T. A . Chorn, R. G. F. Giles, I. R. Green, and P. R. K. Mitchell,J . Chem. SOC., Perkin Trans. I, 1983, 1249. l9 W. T. Brady and M. 0. Agho, J. Org. Chem., 1983,48,5337.


433

2-pyranones after double-bond rearrangement of the intermediate dihydropyrans.8*Dichloroketenes also add to enaminones to afford 2-pyranones in variable yield and the method has been applied to the synthesis of a range of benzoxepine analogues (see Scheme 11).*l

Ct

+o

NR2

CI

'

0

Scheme 11

2-Pyrones can also be prepared by the enol-lactonization of the /3, y-unsaturated-S-keto-esters (113) in the presence of TFA/TFAA.82The keto-esters (113) can be readily prepared by the conjugated addition of ester anions to P-methylthio-a,/3-enmes (112) followed by acidic hydrolysis, and thus the method allows the systematic variation of the substitution pattern of the final product.

T FA

+

R2&

TFAA

W. T. Brady and M. 0. Agho, J . Heterocycl. Chem., 1983,20,501. G . Menozzi, L. Mosti, and P. Schenone, J. Heterocycl. Chem., 1983, 20,539. ** R. K. Dieter and J. R. Fishpaugh, J . Org. Chem., 1983,48,4439. 8o R1

R'

434


Methylthio-, ethylthio-, and benzylthio-diphenylcyclopropeniumsalts (114) react with five- and six-membered cyclic 1,3-diketones in the presence of triethylamine at room temperature to give annelated 2-alkylthio-2H-pyrans (1 15) in good to excellent yields (60-90%).83

[S.n]Spiroacetals. A large number of natural products with a wide variety of biological actions, such as the insecticidal avermectins and milbemycins, and the avian toxins talaromycin A and B, incorporate a spiroacetal ring system and this has stimulated great interest amongst organic chemists. The majority of methods have had as the key spiroacetal-forming step either a keto-diol cyclization or a related reaction. A few examples from this year's literature have been selected highlighting the ingenuity used in the construction of the precursors to the cyclization step. In the first example the precursor is prepared by bis-alkylation of 1,3-dithian giving the protected keto-alcohol(ll6) in four steps. Deprotection and cyclization occur in one step to give exclusively the required spiroacetal(117), which was then transformed into talaromycin B.84

1

i,HgCIz,H20, MeCN ii, MezC(OMe12

OH

Talaromycin B 83

- HoT(117)

H. Yoshida, M. Nakajima, T. Ogata, and K. Matsumoto, Hererocycles, 1983, 20, 1013. S. L. Schreiber and T. J. Sommer, Tetrahedron Lea., 1983,24,4781.


435

The P-diketone (119), prepared by acylation of the ketone (118), cyclizes in a cascading fashion to form the spiroacetal (120) as a mixture of epimers at C-L8’

Ph

(118)

(119) /HBFL

aq., E t 2 0

0

Two groups have independently approached the spiroacetal portion of the avermectins by broadly similar approaches, which involve the addition of an acetylide to a lactone followed by internal acetalization. In both cases the starting materials were optically pure and cyclization gave one isomer only. Thus, Hannessian et al. have synthesized the spiroacetal unit of avermectin Bl a aglycon by addition of the acetylene (122) to the lactone (121) followed by partial reduction and cyclization,86whereas Baker and his group added the acetylene (124) to the lactone (123) and, after complete reduction of the acetylene, cyclized the product to the spiroacetal (125).*’ In a more general synthesis of spiroacetals the enyne (126) has been developed as a synthon for the formylacetone dianion (128). The lithio-derivative of (126) adds to lactones to give adducts which can be converted into the spiroacetals (127) as outlined in Scheme 12, where the two-step procedure usually gives better yields.88 Danishefsky has applied the Lewis acid-catalysed hetero-Diels-Alder reaction to a synthesis of w-hydroxyalkyl dihydropyrans which then cyclize to give spiroacetals in the presence of alumina or by intramolecular oxymercuration 85

86 8’

D. R. Williams and B. A. Barner, Tetrahedron Lett., 1983,24, 427. S. Hannessian, A . Ugolini, and M. Therien, J . Org. Chem., 1983, 48, 4427. R. Baker, R. H. 0. Boyes, D . M. P. Broom, J. A. Devlin, an&C. J. Swain, J . Chem. SOC., Chem. Commun., 1983,829. M. T. Crimmins and D. M. Bankaitis, Tetrahedron Lett., 1983,24, 4551.

15


436

sioT +

Ph 2But

OCH2Ph

(121)

(124)

(123)

HO

$7

I

vii

- ix

v,vi

f p h f i o T > y H

OSiBu' Ph2

I

OSi But Ph2

(125) Reagents: i, BunLi, -78°C; ii, H,, Pd/BaSO,; iii, BF3-Et20;iv, Bu,NF, THF; v, BunLi;vi, MeOH, H+; vii, H,, Pd/C, 1 h; viii, H+; ix, HS, Pd/C, 18 h

followed by reduction as shown in Scheme 13.89In the final example which involves a keto-diol or related ring closure Kocienski and Yeates have reported on a short entry to spiroacetals using the addition of the organocuprate (129) to epoxides and subsequent cyclization.90 89

S. J. Danishefsky and W. H. Pearson, J. Org. Chem., 1983,48,3865.

* P. Kocienski and C. Yeates, Tetrahedron Lett., 1983, 24, 3905.


437

xr i ,ii

R’

0

M 0 )”yOH (/+e (CH’

R2

R’

liv

n

OMe

+d

0-

0-

(128)

(126)

Reagents: i, (126); ii, Bu”Li; iii, K2C03, MeOH; iv, 30% HClO,, CH2Cl,

Scheme 12

The formation of cyclic ethers by intramolecular hydrogen abstraction of oxyradicals is well precedented and two reports have appeared this year applying this method to the spiroacetal ring system. Thus, irradiation of the hypoiodites (130) gives the spirostan sapogenins (131) in 80% yield, where the reaction is

(CH2),,0Si But Me2

+

. .. RCHO

‘J“

+

-/ iiii 0

Et3SiO iv

Reagents: i, (Yb(fod),]; ii, Pd(OAc),; iii, A1,03; iv, DIBAL; v , Hg(OAc),; vi, NaBH,

Scheme 13

R

-


438 . ..

iii , iv

I , II

4

(129)

% OH

Reagents: i, Bu'Li; ii, CuI; iii, L O T H P ; iv, H+

thought to proceed via a seven-membered cyclic transition The second method involves the unusual acid-catalysed rearrangement of the tetrahydropyranyl ether (132) to the ether (133), which is then oxidatively cyclized via its hypoiodite to give the spiroacetal (134) after acid treatment.92

lhv

(132)

R' I

(133)

1

i, 12, HgO ii,TFA

OCH2CCI3 (134) C. G. Francisco, R. Freire, R. Hernandez, M. C. Medina, and E. Suhrez, Tetrahedron Lett., 1983,24, 4621. 92 I. T. Kay and E. G. Williams, Tetrahedron Lett., 1983,24,5915.

91


439

Finally in this section, Ireland's group, in a synthesis of the antibiotic methymycin, have synthesized spiroacetals via hetero-Diels-Alder reactions as shown in Scheme 14.93

(major isomer) Scheme 14

Six-membered Rings with More than One Oxygen Atom. The addition of singlet oxygen to the functionalized dienes (135) proceeds smoothly at -78°C to give endoperoxides which can be further manipulated under mild conditions to give keto- or hydroxy-endoperoxides.94

1 R2

R' = OSiMe3,R2=OMe

'02,-782

0

R' (135)

OMe

R2

THF. 0 . 0 0 5 M HCI

I

R1= H R2 = OSiMe3 THF, 0.005M HCI

OH

I

Two groups have published procedures for the synthesis of zoapatenol analogues containing the 1,6dioxolane ring system. The first procedure used a transacetalization followed by an intramolecular 0-alkylation to form the dioxolane ring (see Scheme 15),95and the second constructed the dioxolane ring by R. E. Ireland, J. P. Daub, G . S . Mandel, and N. S . Mandel, J . Org. Chem., 1983,48,1303, 1312. E. L. Clennan and R. P. L'Esperance, Tetrahedron Left., 1983,24,4291. 95 J. B. Jiang, M. J. Urbanski, and Z . G. Hajos, J . Org. Chem., 1983,48,2001.

93

94


440

1

i , KOH, M e O H

ii, HCI, Me2CO

Zoapatanol

analogues

f--

Ph -0

Scheme 15

intramolecular acid-catalysed ring closure of the epoxy-alcohol (136), itself prepared by an epoxide opening.96

Z o a p a t a n o l analogues

-

c02me QoI0\OH

0

The research group of Jefford has developed a synthesis of 1,3,4-trioxanes by the reaction of 1,Zdioxetanes with ketones or aldehydes. The method involves the acid-catalysed reaction of the dioxetanes (137) with aldehydes, giving variable yields of the trioxanes (138);97the reaction also works for 1,4-endopero~ides.’~ Further work has shown that the intermediate zwitterions from the photooxygenation of enol ethers can be captured in situ by aldehydes giving the 1,2,4trioxanes (139).99 Jefford et al. have also published a method for the synthesis of the previously unknown 1,2,4-trioxan-5-ones (140) in good yields by the reaction of peroxyesters with ketones or aldehydes in the presence of trimethylsilyl triflate at -78 “C.loo M. C. Wani, B. R. Vishmuvajjala, W. E. Swain, jun., D. H. Rector, C. E. Cook, V. Petrow, J. R. Reel, K. M. Allen, and S. G. Levine, J . Med. Chem., 1983, 26, 426. 97 C. W. Jefford, J . Boukouvalas, and S. Kohmoto, Helv. Chim. Acta, 1983, 66, 2615. 98 C. W. Jefford, D. Jaggi, J. Boukouvalas, and S. Kohmoto, J. Am. Chem. SOC., 1983,105, 6497. 99 C. W. Jefford, S. Kohmoto, J. Boukouvalas, and U. Burger, J . Am. Chem. Soc., 1983, 105,6498. loo C. W. Jefford, J.-C. Rossier, and G . D. Richardson, J . Chem. SOC., Chem. Commun., 1983, 1064. 96


441 R3

p-?, ArO

Rl

+?

Am berli te

+

R3CH0

&:

0

resin

ArO

R2

(137)

R'

R2

R1 MeCHO

'0 2

_I_)

~

R

R (138)

R3

R3

OMe (139)

Quite independently Schmid and Hofheinz have completed a total synthesis of the naturally occurring antimalarial qinghaousu (143), in which the key 1,2,4trioxane-forming step was the cyclization of the presumed hydroperoxide ketone (142) formed by the singlet oxygenation of the olefin (141) in the presence of methanol. lol 0-OSiMe3

0

OSiMe3

0

0

Me0

/

HO2C

lo2 +

-H -H

MeOH

HCO2H

HOO, Me0

___I)

-H

Me0 HO2C

0 (141 1

(142)

(143)

Seven- and Eight-membered Rings.-The intramolecular TiC1,-catalysed aldol condensation of silyl enol ethers with acetals has been applied to the synthesis of six-, seven-, and even eight-membered rings without the need for high-dilution techniques. The reaction only works with TiC14and is thought to proceed via a titanium template effect giving moderate to good yields of the heterocycles as outlined in Scheme 16.1°2 lol lCn

G. Schrnid and W. Hofheinz, J . Am. Chem. SOC., 1983,105,624. G. S. Cockerill and P. Kocienski, J . Chem. SOC., Chem. Commun., 1983,705.


442

OSi PhMe2

iL

O v 0

3

1

OSi PhMe2

Reagents: i , TiCl,, CH,CI,, -78°C

Scheme 16

The [2+2] cycloaddition of alkenes to the benzofuran (144) affords adducts which undergo retro-aldol reactions giving benzoxepinones (145) in moderate overall yield (typically 50%).lo3

‘Ac (145) lo3

J. H. M. Hill and S. T. Reid, J . Chem. SOC., Chem. Commun., 1983,501.

443


. ..

LL

Q-x x (146) X = Br or CL

liii (148)

(147)

Reagents: i, CHX,, NaOH; ii, A ; iii, LIAlH,, Et,O, 25°C; iv, LiAlH,, THF, 40°C

The ring expansion of 1,4-benzodioxine by carbene insertion and rearrangement affords the dihalogenoalkenes (146) which are immediately reduced either partially, to the previously unknown halogenobenzodioxepines (147) or fully to the again previously unknown benzodioxepine (148) .lo4 Finally in this section, a range of the extremely unusual pentaoxacyclo-octanes (150) have been prepared in a general method whereby the ozonides (149) are treated with ketones in the presence of chlorosulphonic acid and acidic hydrogen peroxide. lo5

20

OC

(149)

(150)

2 Sulphur-containing Heterocycles In a series of papers on thromboxane A2analogues, the total syntheses of (&)- and (+)-thiathromboxane (151) and (&)-dithiathromboxane (152) have been reported, using the known intramolecular displacement reaction to form the thietane ring.lo6 Further studies on the cycloaddition of thiocarbonyl ylides to dipolarophiles by Huisgen’s group have revealed that the yields in this series of reactions can be considerably improved by generating the ylide in situ. lCnThus 2,2-diphenyl-l,3,4lo4

G. Guillaumet, G. Coudert, and B. Loubinoux, Angew. Chem., Int. Ed. Engl., 1983,22,64. Miura, A. Ikegami, M. Nojima, S. Kusabayashi, K. J. McCullough, and M. D. Walkinshaw, J . Chem. Soc., Perkin Trans. 1, 1983,1657. S. Ohuchida, N. Hamanaka, and M. Hayashi, Tetrahedron, 1983,39,4263,4269,4273. L. Xingya and R. Huisgen, Tetrahedron Lett., 1983, 24,4181; R. Huisgen and L. Xingya, Heterocycles, 1983, 20, 2363.

lo5 M.

lW

444


-

SAC I

01=/\/\C02Me MsO

NaoMe

I

I

OAc (151)

MeOzC

S’ I

OBz i , NaOMe ii,NaOH,THF

thiadiazolide extrudes nitrogen at -45 “C, giving the thiocarbonyl ylihz (153), which adds to a range of dipolarophiles in situ, e.g. with substitutedalkenes giving tetrahydrothiophenes (Scheme 17). The scope of the synthesis of tetra-

- xsl Ph

PhxC=S

CH2N2

-78OC

Ph N=N

Scheme 17


445

hydrothiophenes (154) by the reaction of a$-unsaturated carbonyl compounds with sodium polysulphide has been studied and the authors have concluded that only 1,3-diaryl-a,,t?--unsaturatedketones (chalcones) give the reaction, although when the reaction is successful yields are good (>63%).Io8

The t-butylthioacrylonitrile (155) undergoes cycloaddition reactions with electron-deficient dienophiles as a 4n-component to give either tetrahydrothiophenes (156) or 2,3-dihydrothiophene (157).lo9The reaction is accompanied by the loss of the t-butyl group as isobutylene, and the yields are variable.

/

(156) X = 0 or NPh C02Me

NC

I

C02Me C02Me

(157)

a-Thiol-aldehydes (159) are known to react with vinylphosphonium salts or vinylphosphonates to give 2,5-dihydrothiophenes, but the thiol-aldehydes have not been readily available. However, a-thiol-carboxylic acids are known, and a convenient synthesis of thiol-aldehydes has now been developed from the acids (158), involving the DIBAL reduction of oxathiolanes, which are readily prepared from (158)."O In a broadly similar approach to ring construction, the 3-thiatestosterone analogue (162) was prepared by intramolecular Wittig reaction of the intermediate (161) generated by addition of triphenylphosphonium methylide to the disulphide (160). ll1

lo9

M. G . Reinecke, D . W. Morton, and D. Delmazza, Synthesis, 1983, 160. D. Dopp and H. Libera, Tetrahedron Lett., 1983, 24,885. J. M. McIntosh and M. A. Siddiqui, Can. J . Chem., 1983, 61, 1872. G. A. Flynn, .I. Org. Chem., 1983,48, 4125.

-

General and Synthetic Methods R2

DlBAL

R~+CHO

Toluene -78OC

SH (159)

Ph3P-CH=CH2

1

i, Ph3P=CH2 ii,HCt

OSi But Me.

(161)

K+ But d.DMSO OSiBu‘ Me2

The regiochemistry of thiocarbonyl Diels-Alder reactions with dienes to give dihydrothiapyranshas been studied by Vedejs and his group with reference to the substituent R (see Scheme 18).”*They have found that path ‘a’is preferred when R is an electron-donating group, whereas path ‘b’ is the preferred pathway when 112

E. Vedejs, D. A. Perry, K. N. Houk, and N. G. Rondan, J. Am. Chem. SOC., 1983,105,6999.

447

Saturated Heterocyclic Ring Synthesis R’

-A ‘a‘

+

R

R

/ i R

2

R

R2

qR2 R’ = OMe or H

R2 = OSiBufMe2

Scheme 18

R is electron withdrawing. These results agree with a similar study carried out by Baldwin and Lopez who generated the required thioaldehydes by thermolysis of thiosulphinates, and interestingly they found that the Diels-Alder reaction can be carried out intramolecularly to give the dihydrothiopyran (163).113

(163)

The known synthesis of dihydropyran S-oxides by the cycloaddition of dienes with sulphines can be carried out with complete asymmetric induction when using a chiral ~u1phine.l~~ Thus the camphor or sulphoximino sulphines react with 2,3dimethylbutadiene to give exclusively the adducts (164).

113

‘14

J. E. Baldwin and R . C. G. Lopez, Tetrahedron, 1983,39,1487. P. A. T. W. Porskamp, R. C. Haltiwanger, and B. Zwanenburg, Tetrahedron Lett., 1983,24,2035.


448

3 Heterocycles Containing More than One Heteroatom

Nitrogen- and Oxygen-containingRings.-Three-membered Rings. The synthesis of N-sulphonyloxaziridines by peracid epoxidation of sulphonimines has been modified to give, after fractional crystallization, optically pure oxaziridines The method entails treating the sulphonimines (165) with (+)-peroxycamphoric acid at low temperature under basic conditions.

(165)

-6O0C,CHZCI2,M e O H , p H S - I 0 , 3 h

I+)- p e r o x y c a m p h o r i c acid

Five-memberedRings. A new synthesis of nitrones, the well known isoxazolidine intermediates, has been reported whereby hydroxylamines are oxidized and a,,P-unsaturated catalytically in the presence of palladium metal at 100°C,116 sulphones have been shown to be suitable olefin partners in the cycloaddition reaction with nitrones, giving 4-sulphonylisoxazolidines.117 Allylic thiocarbamidates, which are easily prepared from the corresponding alcohols by treatment with isothiocyanate, undergo bromocyclization to give, exclusively, 2-0x0-oxazolines (166) in high overall yield. 118 N-Sulphonyl-2-0~0SMe

R’

(166) Reagents: i, NaH; ii, MeNCS; iii, MeI; iv, Br(collidine),ClO,; v, aq. Na2CO3

oxazolines (168) can be prepared by the base-mediated cyclization of the sulphamides prepared from the chlorosulphonyl isocyanate adducts (167) Two new cycloaddition reactions to form oxazolidin-6ones have been reported this year. Thus, a-bromoisobutyramides on treatment with sodium hydride give the dipoles (169), which add to dimethylformamide giving the oxazolidones (170) M. Bucciarelli, A . Forni, S. Marcaccioli, I. Moretti, and G . Torre, Tetrahedron, 1983, 39, 187. S.-I. Murahashi, H. Mitsui, T. Watanabe, and S . Zenki, Tetrahedron Lett., 1983,24, 1049. 11’ P. D . Croce, C. L. Rosa, R. Stradi, and M. Ballabio, J. Heterocycl. Chem., 1983,20, 519. 118 S. Knapp and D . V. Patel, J. Am. Chem. Soc., 1983, 105, 6985. J.-L. Montero, G . Dewynter, B. Agoh, B. Delaunay, and J.-L. Imbach, Tetrahedron Lett., 1983,24, 3091. 115 116

-


RNH2

X- 0 y N ~ s o 2 c 1

0 (167)

x

-

449

O)fNH\50*NHR 0

A t 3 N

n O KNso2NHR 0 (168)

in good yield, and the authors have shown that azetidinones or 1,2,3-triazolones also provide a source of the dipoles (169). 120 In the other method diphenylketenes were added to S, S-dimethyl-N-acylsulphiliminesto give adducts which were then reduced directly to give the oxazolidinones (171).

N=N

(171) 120 I2l

P. Scrimin, F. D’Angeli, A. C. Veronese, and V. Baioni, Tetrahedron Lett., 1983,24, 4473. D. M. Ketcha, M. Abou-Gharbia, F. X. Smith, and D. Swern, Tetrahedron Lett., 1983,24,2811.

450


The 1,2,5-oxadiazole 2-oxide (172) undergoes two sequential nitrone-olefin cycloadditions to give the azadioxabicyclo[3.3.O]octanes (174) ,where the initially formed adduct (173) eliminates ethyl cyanoformate to form the second nitrone.122

Six- and Eight-membered Rings. Gilchrist and his co-workers have published further details on the synthesis of 5,6-dihydro-4H-l,2-oxazines from a-nitrostyrenes, and have extended the scope of this hetero-Diels-Alder reaction by Thus, treatment of the using more electrophilic vinyl nitroso-c~mpounds.~~~,~~~ halogeno-oximes (175) with base in the presence of olefins affords the dihydrooxazines (176), presumably by capture of the vinyl nitroso intermediates.

"'x:

+ NOH

NO

-

RL

(175) R1 = H, Me or OEt

0 R3

(176)

Benzylic alcohols and dialkylanilines each undergo oxidation with Mn02, but when these functional groups are present in the same molecule in an ortho-relationship, MnO, oxidation gives the benzoxazines (177) in generally T. Schimizu, Y . Hayashi, and K. Teramura, J . Org. Chem., 1983,48, 3053. E. Davies, T. L. Gilchrist, and T. G. Roberts, J . Chem. Soc., Perkin Trans. I , 1983, 1275. 124 T. L. Gilchrist and T. G . Roberts, J . Chem. Soc., Perkin Trans. 1 , 1983,1283. lzz

123 D .


45 1

high yield Reinhoudt et al. have also published a synthesis of benzoxazines (178), by adapting a method they had published previously.126

I

I

I

R"YO

Rl")

Two methods for the annelation of a 1,4-0xazinones have been compared using the amino-alcohols (179) as starting materials (Scheme 19).lZ7 The classical approach, i.e. acylation of the amine followed by 0-alkylation, gave poor yields

I

a

OH

83,

" R

iv, v

7

0 Reagents: i, CICH,COCI, base; ii, NaH, DMSO; iii, -0; v, NaOH, MeCN; vi, BF,.OEt,, CH,Cl,

iv,p-HO,CC,H,SO,N,,

DBU, MeCN;

Scheme 19 lz5 F.

lZ7

Kienzle, Tetrahedron Lett., 1983, 24, 2213. W. Verboom, B. G. van Dijk, and D. N. Reinhoudt, Tetrahedron Lett., 1983, 24, 3923. D. E. McClure, P. K. Lumma, B. H. Arison, J. H. Jones, and J. J. Baldwin,J. Org. Chem., 1983,48, 2675.


452

(route ‘a’)whereas the ketocarbene addition (route ‘b’) gave overall yields of 50% or better. The 5-aza-2-oxabicyclo[2.2.llheptanes (180) have been prepared in good to excellent yield (56-93%) by the intramolecular Mitsunobu reaction of 4-hydroxyproline analogues,128 and the 2,4-diaza-9-oxabicyclo[3.3. llnonanes (181) were prepared by treatment of glutaraldehyde with ureas under aqueous conditions, a reaction which had previously only given polymers. 129

”, DEAD, PPh3

f

0’

P

6’

J2”

Several examples of the rare 1,4,5-benzodioxazocine ring system have been synthesized by modification of methodology developed for the analogous 1,5,6benzodioxazocines as outlined in Scheme 20. 130 0

Ph

Ph

1

iv,v

% ’ ’R R2

-N

/O

Ph Reagents: i, BrCH,CH,OH; ii, PBr,; iii, a c o \ N O - K + ;

co’

iv, NH2NH2.H20,EtOH; v, HCl

Scheme 20 M. M. Bowers-Nemia and M. M. Joullie, Heterocycles, 1983,20, 817. H. Matsuda, A. Ninagawa, A. Baba, and K. Sato, Tetrahedron Lett., 1983,24,789. I3O E. J. Browne, L. M. Engelhardt, and A. H. White, Aust. J . Chem. 1983,36,2555.

lz8 lz9


453

Oxygen and Sulphur-, and Nitrogen and Sulphur-containing Rings.-The synthesis of a series of dihydrobenzoxathiines (182), potential antihypertensive agents, has been described by Tegeler et al. and is based on the intramolecular displacement of halide by a1k0xide.I~~ The reaction was found to give the best yields when carried out in diglyme with the sodioalkoxide.

,+

Me0

diglyme

CI

,

Me0

HO

Cl (182)

The dihydropyrimidine thione derivatives (184) have in the past proved to be useful intermediates for the synthesis of various 1,3-thiazines.13*They have now been shown to give dioxothiazolidines (183) or oxothiazolines (185) depending on the substrate used, so that reaction of (184) with a-halogenocarboxylic acids gives (183), whereas reaction with a-halogenoketones gives (185). Thiazolines (n= 1)

(183)

(1 84 )

(185)

can also be prepared by acid-catalysed cyclization of the thioureas (186), which are prepared by addition of amines to i ~ ot hi ocyana t es.The ~~~reaction also Me0 Me0W

N

H (CH2)n

I

OH

i

Me0

Me0T N Y W

J/

(CH2)n

I

(116) OH iv

Me0

Me0

Me0 M e

o

T

'f

N /NHR

Reagents: i, RNCS, benzene, A; ii, MeI; iii, MeOH, KOH; iv, EtOH, HC1 Scheme 21 J. J. Tegeler, H. H. Ong, and J. A. Profitt, 1. Heterocycl. Chem., 1983, 20, 867. H. Singh, P. Singh, and K. Deep, Tetrahedron, 1983, 39, 1655. 133 F. Fiilop, M. S. El-Gharib, A. Sohajda, G . Bernath, J. Kobar, and G. Dombi, Heterocycles, 1983,20, 1325. 131

132


454

succeeds for 1,3-thiazinesand the thiocarbamides can also be converted into 1,3oxazo-compounds (187) as outlined in Scheme 21. A convenient synthesis of the previously unknown dihydro-173-thiazin-4-ones (188) has been described where isothiazolonesare ring-expandedby reaction with rarbenes generated from diazo-compounds and a rhodium catalyst.134

(188)

Dihydro-1,4-thiazines (190) on the other hand can be prepared by the isomer,~~~ ization of N-vinylaziridines (189) in the presence of potassium t h i ~ c y a n a t eand benzo-174-thiazines(191) are available from the reaction of N-allylanilines with sulphur dichloride.136

___)

DME,

A (190)

R' SCL 2 ___.)

-HCI

4 Nitrogen-containingHeterocycles Three-membered Rings.-172,3-Trisubstituted aziridines (195) have been prepared by the reaction of phenyldiazomethane with imines (192) in the presence of zinc iodide. 137 cis-Aziridines are formed exclusively, probably via the intermediacy of (193) and (194). Attempts to obtain other aziridine derivatives using aliphatic diazo-compounds were unsuccesstul. Aza-1-bicyclobutanes (197) were D. Crow, I. Gosney, and R. A. Ormiston, J . Chem. SOC., Chem. Commun.,1983,643. Y. Gelas-Mialhe, E. Touraud, and R. Vessiere, Heterocycles, 1983, 20, 2391. 136 M. Muhlstadt, K. Hollman, and R. Widera, Tetrahedron Lett., 1983,24,3203. 137 R. Bartnik and G. Mloston, Synthesis, 1983, 924.

134 W.

135


Ar

R'

455

i,Znl2

---+

>N--RZ

ii, PhCH=N2

(192) (193 1

Ph

A\'

I

N

I

R2

readily obtained by photolysis of carbamates (196),138and a one-step synthesis of an aziridino-mitosene analogue (199), involving an intramolecular Darzens-type

Ph

RIR K hv

0

(196)

phJ$ N (197) R = Ph , 77 'lo R = E t , 40°/o

reaction, has been reported starting from 2-(N-phenylformimidoyl)indole (198)

% 0 2 , . Br

L

Br

-

I

075

NPh

'C02Me

(198) 13*

139

(199) 60 '10

R. Bartnik, Z. Cebulska, and A. Laurent, Tetrahedron Lett., 1983,24, 4197. R. M. Cory and B. M. Ritchie, J . Chem. SOC., Chem. Commun., 1983, 1244.

456


Full details have appeared of the formation of a-cyanoaziridines by cyanation of a-halogenoketimines,14 and further studies of the reaction of 2-azido-alcohols with trialkyl phosphites to produce aziridines have been reported.141 Four-membered Rings.-A one-pot synthesis of 2-aryl-N-arenesulphonylazetidines (202) has been described starting from N-arenesulphonylimines (200) and dimethylsulphoxonium methylide (201). 142 Reaction of (201) with benzylideneaniline, however, failed to give any azetidine product. 0 Ar1-CH=N-S-Ar2

-

Me

II II 0

+

2

DMSO

\! /+\

N2,r.t.

Me CH2 (201)

(200)

A ! p 2 A r 2

(202)21-47 '10

Dilithio-derivatives of oximes (203) have been shown to react with aldimines (204) to produce 2-hydroxyaminoazetidines (205) as a mixture of isomers in generally good yields,143and the 1-hydroxyazetidines (208) have been prepared i , 2 BunLi ,THF, O°C

R3-CH2

ii, ArCH=NR1(20LI

)cN-OH

R2

~

iii, NHbCI , H20

p;:

H

R2

( 2 0 5 ) 55-

(203)

81 '10

by reductive cyclization of the 0-protected oxime tosylates (206).14 In the absence of 0-protection, facile cyclization to produce the isoxazolidine (207) occurs. NHOR

NaCNBH3

H R=H,R1=Me

CH20Ts

(206)

(207)

1

R = CHZPh

Pd/C.H:

'YH (208)

N. De Kimpe, P. Sulman, R. VerhC, L. De Buyck, and N. Schamp, J . Org. Chem., 1983,48,4320. A. Willeit, E. P. Muller, and P. Peringer, Helv. Chim. Actu, 1983, 66,2467. 142 U. K. Nadir and V. K. Koul, Synthesis, 1983,554. 143 M. Bellassoued, R. Chtara, F. Dandoize, and M. Gaudemar, Synthesis, 1983,951. M. L. M. Penning, D . Kuiper, and D. N. Reinhoudt, Tetrahedron Lett., 1983, 24,825. 141


457

Five-membered Rings Containing One Nitrogen Atom.-Two reviews relevant to the synthesis of five- and six-membered nitrogen heterocycles have appeared this year. Stella has described the synthetic potential of homolytic heterocyclizations of N-chloroalkenylamines145 and Mariano in a review of electron-transfer mechanisms in photochemical transformations of iminium salts, also describes synthetic applications of such processes. 146 A major interest this year has been the generation and trapping of nonstabilized azomethine ylides and related 1,3-dipolar nitrogen ylides to produce pyrrolidines. Roussi and co-workers have generated the ylide (210) by base treatment of trimethylamine N-oxide (209)7147 and Padwa et al. have prepared the related species (211) by treatment of a-cyanoaminosilane (212) with silver flu01ide.l~~Cycloadditions with substituted alkenes to form pyrrolidines (213) Me

I

N -Me

Me-

J-

0 (2091 i, L D A , -78

OC

1

i i , unactivated alkene

AgF, MeCN

aelectron - deficient

[CH2=!-CH]

alkene

1

(210) R = M e

NCCHzNCH2SiMe3

I

CH2Ph

(212)

(211 I R = CH2Ph

"H"' N

I

R (213)

proceed in moderate to good yields and are stereospecific, but surprisingly the two ylides (210) and (211) differ markedly in their reactivity: (210) is trapped by unactivated alkenes such as hex-1-ene or cyclohexene, whereas 211) only reacts with electron-deficient alkenes. L. Stella, Angew. Chem., Int. Ed. Engl., 1983, 22,337. S . Mariano, Acc. Chem. Res., 1983, 16, 130. 14' R. Beugelmans, G. Negron, and G. Roussi, J . Chem. SOC., Chem. Commun. 1983, 31. 148 A. Padwa and Y.-Y. Chen, Tetrahedron Lett., 1983, 24, 3447. 145

146 P.

458


The fluoride ion-induced desilylation reaction of immonium salts has been extended in several novel ways as a route to substituted pyrrolidines. Padwa et al. have shown that the reaction can be applied to immonium salts derived from amides, thioamides, and vinylogous amides to provide access to reactive azomethine ylides in generally good ~ i e 1 d s .The l ~ ~ lactam (216), for example, was produced in 75% overall yield from the enamide (214) via the cycloadduct (215). 0

- b+ OMe

i, Me1

NHCH2ph

ii. MejSiCH2OTf

y C H 2 S i Me3

I CHzPh

(214)

1

CH2=CHC02Me

CsF

0

OMe

COzMe

\

CH2Ph

(215)

0

% I

CHZPh

(216) 75'10 overall

Two other research groups have also reported on the generation of thioimidate methylides and related species. Vedejs and West, in an extension of their earlier work, have shown that pyrrolines (218) are produced in higher yields from the thioimidate precursors (217) than from the analogous imidates,150 and Living-

(217 1 149

(218)

-1, 6 6 % n = 2,61

A. Padwa, G. Haffmanns, and M. Tomas, Tetrahedron Lett., 1983,24,4303. Vedejs and F. G. West, J . Org. Chem., 1983,48,4773.

150 E.


459

house and Smith have reported an efficient synthesis of pyrrolidine derivatives (220) and (222) by the acyl fluoride-mediated generation and trapping of N-acylimidate methylides (219) and (221) (Scheme 22).1517152 Although inter-

Me+iCH2NC

Me3SiANA

!-.

SEt

1. (221)

'"I

iii

I

76 Yo

(222)

Reagents: i, C,H,,,NH, CuCl; ii, PhCOF; iii, dimethyl fumarate; iv, EtSH, [Cu(acac),]; v, p-02NCbHdCOF

Scheme 22

molecular trapping of these ylides with unactivated dipolarophileswas unsuccessful, the tricyclic aminal(223) could be prepared by intramolecular cycloaddition with an unactivated alkene.151 Further details have appeared of the formation and trapping of azomethine ylides derived from N-(benzylidene)trimethylsilylmethylamine and acyl 15*

152

T. Livinghouse and R . Smith, J . Chem. Soc., Chem. Commun., 1983,210. R. Smith and T. Livinghouse, J . Org. Chem., 1983,48, 1554.

460


Q& .*

PhCOF __+

N-

N

I Me

Si Me3

Me

(223) 90°/o

chlorides,153and a route to N-unsubstituted pyrrolidines (224) has also been re~0rted.l~~ Me3S i 0 S 02CF3 (cat.I

X

CsF (cat .I

Me3SiCH2-

N=CHPh

$Ph

XCH=CHY

I

H

(224)

Azomethine ylides have also been generated by photochemically induced desilylation: irradiation of the iminium perchlorates (225) and (227) in the presence of dimethyl acetylenedicarboxylateled to smooth formation ( 7 6 7 5 % ) of the spirocyclic amines (226) and (228).155A brief review of new applications of dipolar cycloaddition chemistry in heterocyclic synthesis has appeared.156

(&;> Clod

Me

OZCBU' _______) hDMAD, v ( h>280nm) MeCN

SiEtg

(225) n = 1 (227) n = 2

(cH+ MeO2C CO2Me (226) n = 1 (228) n = 2

K. Achiwa, T. Motoyama, and M. Sekiya, Chem. Pharm. Bull., 1983,31,3939. K. Achiwa and M. Sekiya, Heterocycles, 1983,20,167. lS5 S . F. Chen, J. W. Ullrich, and P. S. Mariano, J . Am. Chem. SOC.,1983,105,6160. 156 A. Padwa, Y.-Y. Chen, K. F. Koehler, and M. Tomas, Bull. SOC. Chim. Belg., 1983,92,811.

ls3

154

461


Pyrroline (230) has been produced stereospecifically from the imine (229) by 1,5-electrocyclization,157and the synthetic equivalent of an intramolecular

Ar-

Q

AT

,N,CHC02Me

,OMe

(229) AT = 2 - naphthyl

HR

HI.

Ar

H

C02Me

cycloaddition between a diene and a nitrene has been accomplished in the twostep synthesis of azatricyclodecenones(232) from azidopropylcyclohexadienones (231).158

R (231)

&Me

Me 0 (232)R = Me 79% R = But 97%

The pyrrolidone (234) has been prepared in quantitative yield from the acylated hydroxylamine derivative (233) in what is claimed to be the first example of an intramolecular ene reaction of an i ~ i n e . ~ ~ ~

0G

M

I

CH2C02Et

(233)

e

0&--o&

II

CHCO2Et

I

CH2C02Et

(234)lOO%

R. Grigg and H. Q. N. Gunaratne, Tetrahedron Lett., 1983,24,1201. lsa A. G. Schultz, J. P. Dittami, S. 0. Myong, and C.-K. Sha, J . Am. Chem. Soc., 1983,105,3273. 159 K. Koch, J.-M. Lin, and F. Fowler, Tetrahedron Lett., 1983, 24, 1581. 15'

462


Overman and his co-workers have published further details of their investigations of the synthetic applications of cationic aza-Cope rearrangements. These include a general synthesis of polysubstituted 3-acylpyrrolidines via a tandem cationic aza-Cope rearrangement-Mannich cyclizationlWand the use of the ringenlarging pyrrolidine annelation reaction in the synthesis of the pentacyclic and trans-3a-aryl-4Aspidosperma alkaloids,161 ~is-3a-aryloctahydroindoles~~~ oxodecahydrocyclohepta[b]pyrroles. 163 Further studies of acyliminium ion cyclizations have been reported by Speckamp and co-workers. Formation of the isomeric pyrrolizidines (236) from the hydroxy-lactam (235) has been shown to

Ar

Ar

(235)

It

-aWAr 0

II

OCHO AT

H

( 2 3 6 1 1:l mixture

proceed stereoselectively via a 2-aza-Cope N-acyliminium ring closure1@and acid-catalysed intramolecular reactions of a-acyliminium ions with ally1 and propargyl silanes have been shown to give bridgehead nitrogen bicyclic compounds regioselectively and in high yields ( 7 6 9 0 % ) (Scheme 23) .165

II n=l

0

n =3

0 Scheme 23 L. E. Overman, M.-a. Kakimoto, M. E. Okazaki, and G. P. Meier, J . Am. Chem. Soc., 1983,105, 6622. 161 L. E. Overman, M. Sworin, and R. M. Burk, J . Org. Chem., 1983,48,2685. 162 L. E. Overman, L. T. Mendelson, and E. J. Jacobsen, J. Am. Chem. SOC., 1983,105,6629. L. E. Overman, E. J. Jacobsen, and R. J. Doedens, J . Org. Chem., 1983,48,3393. lW H. Ent, H. de Koning, and W. N. Speckamp, Tetrahedron Lett., 1983,24,2109. lU H. Hiemstra and W. N . Speckamp, Tetrahedron Len., 1983,24, 1407.


463

The pyrrolizidine alkaloids (-)-hastanecine (238)166and (+)-heliotridine (240)167have been synthesized by routes involving stereoselective acyliminium ion cyclizations of hydroxy-lactams (237) and (239) respectively. PhCH-,0

HCO;

O ' -

'

HO

MeS02CI NEt3

0' (239)

An efficient preparation of the tricyclic system (243) has been reported, starting from the N-chlorocyclobutylamine (241), by silver ion-inducedring expansion and Pictet-Spengler cyclization of the intermediate iminium salt (242). 168 Several procedures for the formation of five-membered nitrogen heterocycles by intramolecular addition of a nitrogen nucleophile to an unactivated double bond have been reported. Kametani and co-workers have published further details of their sulphenocycloaminationroute to the pyrrolizidine skeleton 169 and in addition, Danishefsky and co-workers have reported the synthesis of the D. J. Hart and T.-K. Yang, J . Chem. SOC.,Chem. Commun., 1983,135. A. R. Chamberlin and J. Y. L. Chung, J . Am. Chem. SOC., 1983, 105,3653. la F. M. Schell and A. N. Smith, Tetrahedron Lett., 1983,24,1883. 169 T. Ohsawa, M. Ihara, K. Fukumoto, and T. Kametani, J . Org. Chem., 1983,48,3644

16'


464

___)

Benzene

Me0

(241 1

( 2 4 3 ) 67%

A1 BN

'Cbr ( 2 4 5 ) 7 0 % overall

NHCbz ( 244 1

yc*HgOAc

NaBH(0Me 13 Me02CCH=CH2

\

~

C02Me

\

Cbz

Cbz

(246) 64

HMe

0

R

( 2 4 9 ) R = a - H , 34OlO

( 2 5 0 ) R = P - H , 11%

overall


465

substituted pyrrolidines (245) and (246) from the carbamate (244) by ureidoallylation and ureidomercuration procedures respe~tively;'~~, 171 synthesis of benzoindolizidinone (248) from the acrylanilide (247) was unsuccessful. Closure to give the five-membered products (249) and (250) was the preferred reaction pathway, as was the case with the analogous palladium-mediated cyclizations.17* A regiospecific (5- or 6-exo-trig) cyclization of alkenic amines (251) to produce alkenyl-pyrrolidinesor -piperidines (252) has been reported,173and disubstituted R'

-(CH2)nNHR3

AgN03 Or

i, HgCl2 ii.NaBH4

R2

I

R3

(251) n = l o r 2

(252) 35-95 *lo

proline derivatives (253) have been prepared in moderate overall yields by a stereoselective route involving reductive coupling of acetamidomercurials with (Scheme 24). The proline derivative (253; n=2) electron-deficient a l k e n e ~ l175~ ~ .

(CHzD

n = 1 or2

H ( C H q F C O 2 H

-

/

NHCOMe

( C H i 'HgCl

I COMe (CH21n T > C N

iii

+

NHCOMe

COMe

I

(CHT>--CN

(253) Reagents: i, Hg(NO,),, MeCN; ii, NaCl; iii, CH,=C(CI)CN, NaBH,; iv, NaH; v, 5N-HCl

Scheme 24

has also been prepared by a ring contraction of the appropriate a-chloro1a~tam.l~~ A general route to five- and six-membered nitrogen heterocycles involving olefinic cyclizations promoted by Beckmann rearrangement of oxime sulphoR. R. Webb and S. Danishefsky, Tetrahedron Lett., 1983,24, 1357. S. Danishefsky, E. Taniyama, and R. R. Webb, Tetrahedron Lett., 1983,24,11. S . Danishefsky and E. Taniyama, Tetrahedron Lett., 1983,24, 15. 173 S. Arseniyadis and J. Gore, Tetrahedron Lett., 1983, 24, 3997. 174 R. Henning and H. Urbach, Tetrahedron Lett., 1983, 24,5343. 175 R. Henning, H. Urbach, and E. F. Paulus, Tetrahedron Lett., 1983,24,5347. 176 R. Henning and H. Urbach, Tetrahedron Lett., 1983,24,5339. 170 171


466

nates has been described, as exemplified by the formation of the pyrroline (255) and the tetrahydropyridine (257) from precursors (254) and (256) re~pective1y.l~~ R‘

P

SnCIL

R2 “OMS

( 2 5 5 ) 80 - 8 8 %

(7

Et2AICI

OlBAH

The reaction proceeds at low temperature in aprotic solvents with only one equivalent of Lewis acid. Aliphatic and aromatic ketones, either cyclic or acyclic, can be used as starting materials and the products are easily predictable since synlanti equilibration of the oximes does not occur under the mild reaction conditions. 5-Aryl-2-pyrrolidones (259) have been prepared by Beckmann fragmentation in the Wolff-Kishner reduction of the piperidones (258),17*and several base-

CN

R = H o r OH

Me

I

Ar

Me

R

R

t

HzNNH2,KOH 190°C

Me

Ar

I

*‘Pl

Me

Me

Me

OH (258) In

(259)

S. Sakane, Y. Matsumura, Y. Yamamura, Y. Ishida, K. Maruoka, and H. Yamamoto,J. Am. Chem.

SOC.,1983,105, 672. 178 J. Bosch, M. Moral, and M. Rubralta, Heterocycles, 1983, 509.

467


catalysed procedures for the synthesis of five-membered nitrogen heterocycles, based upon C-N bond formation by intramolecular reaction of a nitrogen nucleophile have been reported. The pyrrolizidine (261) and the indolizidines (262) and (263) have been prepared by a one-pot 'crisscross annelation' pro-

(260)

NHC0CF3

(262)

+ (263)

a q . HCI

MeOH

0

66 '10

1

NaCNBH3

H

(26314-(262) 9 : 1

cedure from the amido-diketones (260) ,179 and the cyclic unsaturated amino-acid derivatives (265) and (266) have been produced by a route involving anodic oxidation of ornithine and lysine derivatives (264).I8O The cis-octahydroindolone (268) has been prepared from the lactone (267) as part of a reaction sequence which may be useful as a general route to the cis179 T. 180 T.

16

Ohnuma, M. Tabe, K. Shiiya, and Y. Ban, -TetrahedronLett., 1983, 24,4249. Shono, Y . Matsumura, and K. Inoue, J . Chem. SOC., Chem. Commun., 1983,1169,

468

General and Synthetic Metho&

r

1

-2e

I

HNJ ( c H ~ I~ ~ C 0 2 M e C02Me

-2e

MeDH.EtiNOTs

[I! C02Me

CO2Me

C02Me

1

1

i ,MeOH,H+ ii,NHbCI,A

MeOH,NaCI

,'"H:;k::;Me I I

HN

C02Me

COzMe

\

MeOH, H+

C02Me ( 2 6 5 ) n = 0,36 ' / o overall n = 1 , 4 9 % overall

I

C02Me ( 2 6 6 ) n = O a 5 2 '/a overall n = 1 ' 4 3 Ol0 overall

3-aryloctahydroindole nucleus,181and the synthesis of mesembrine (269) from enone (270) has also been reported.182 Base-catalysed cyclization of stilbene carboxamides (271) has led to benzylphthalimidines (272) in high yieldP3 and an improved procedure for the Blaise reaction, followed by in situ intramolecular alkylation of the initial adduct, provides a useful route to pyrrolidine derivatives, as illustrated by the preparation of the saxitoxin intermediate (274) from the cyano-mesylate (273).ls4 The N-acetylindoline (276) has been synthesized in moderate yield by intramolecular electrophilic amination of the carbanion derived from the 0-methylhydroxylamine (275).18s The synthesis of steroidal pyrrolidine derivatives by remote functionalization initiated by phosphoramidate radicals has been described.186 Pyrrolidones (278), P. W. Jeffs, R. Redfearn, and J . Wolfram, J . Org. Chem., 1983,48,3861. I. H. Sanchez, J. de J. Soria, M. I. Larraza, and H. J. Flores, Tetrahedron Lett., 1983,24, 551. E. Napolitano, R. Fiaschi, and A. Marsili, Tetrahedron Lett., 1983,24,1319. lM S. M. Hannick and Y. Kishi, J . Org. Chem., 1983,48,3833. la5B. J. Kokko and P. Beak, Tetrahedron Lett., 1983,24,561. C. Betancor, J . I. Concepcion, R. Hernandez, J . A. Salazar, and E. Suarez, J . Org. Chem., 1983,48, 4430. la*

lE2


469

MeNH2

R,R = 0

0

0

N

I H Me (268) R,R=O

H

(267 1

(269) R = H

0

NMe

Me0 OMe

I

0 (271 1

OMe

i,Zn, BrCH2C02Me ii, K 2 C O 3 , DMF

(274) 69%

(273) i , MeLi ii, BunLi

iv. p y , MeCOCl

(275)

QQ I

W N H O M e

COMe (276) 42%


470

for example were produced in quantitative yield from the phosphoramidates (277), and the phosphoryl moiety could be easily removed to give the N-unsubstituted compound (279).

Further details have appeared of the regiospecific formation of iminium salts of bicyclic nitrogen heterocycles by distillation of the appropriate carboxyalkyl lactams from soda lime,Ig7and Shono et al. have described a novel zinc-promoted alkylation of iminium salts, the intramolecular version of which provides a useful synthesis of five- and six-membered nitrogen heterocycles, (Scheme 25). lS8

MeomN+ Zn

Me0

('

CH I -2 In1

Me0 Me0

MeCN

n =3,45% n =4,4201~

0 - 3 ~ ~ 4 Scheme 25

Several saturated nitrogen heterocycles, e.g. (281), have been produced in varying yields by photocatalytic cyclization of diamines (280) ,lg9 and a procedure

J. M. McIntosh, L. Z. Pillon, S. 0. Acquaah, J . R. Green, andG. S. White, Can.J . Chem., 1983,61, 2016. T. Shono, H. Hamaguchi, M. Sasaki, S. Fujita, and K. Nagami, J . Org. Chem., 1983,48,1621. 189 S.4. Nishimoto, B. Ohtani, T. Yoshikawa, and T. Kagiya, J . Am. Chem. Soc., 1983,105,7180.

lg]


471

for the cyclization of aminoalkenes (282) to pyrrolines (283) or piperidines (284) under catalytic 'Wacker process' conditions has also been reported.lgO

66 (284)

:

34

7 5 % combined yield

Pyrolysis of the Meldrum's acid derivative (285) gives rise to the dihydropyrrol3-one (286) in good yield,19*and further details have appeared of the acidcatalysed thermolytic rearrangement of dicyclopropyl ketimines to give cyclopropyl pyrrolines. 192 0

II

C

0 x 0 600 O C ___)

Torr

(285)

-

1

(286) 6Ooh 1x1B. Pugin and L. M. Venanzi, J . A m . Chem. Soc., 1983,105,6877. 191 H. J. Gordon, J. C. Martin, and H. McNab, J . Chem. SOC., Chem. Commun., 1983,957. 192 H . H. Wasserman and R. P. Dion, Tetrahedron Lett., 1983,24,3409.

472


Five-memberedRings Containing More than One Nitrogen Atom.-Activation of the thiazoline (287) by addition of boron trifluoride greatly enhances the reactivity of the imine moiety towards nucleophilic attack and enables a useful yield of (288), an intermediate in the synthesis of biotin, to be achieved.193(+)- and (-)-

Tryptoquivaline G have been prepared by a route which involves as a key step the biomimetic double cyclization of the intermediate (289) to the imidazoindole spirolactone ring systems (290) and (291).lW

Six-membered Rings Containing One Nitrogen Atom.-The synthesis of 2,6disubstituted piperidines, oxanes, and thianes has been reviewed.195Several reports of the synthesis of six-membered nitrogen heterocycles by utilizing the lg3

194

R. A. Volkmann, J. T. Davis, and C. N. Meltz, J. Am. Chem. SOC., 1983,105,5946. M. Nakagawa, M. Taniguchi, M. Sodeoka, M. Ito, K. Yamaguchi, and T. Hino,J. Am. Chem. SOC., 1983, 105, 3709. V. Baliah, R. Jeyaraman, and L. Chandrasekaran, Chem. Rev., 1983,83,379.

473


Diels-Alder reaction have appeared but most of these have been extensions or applications of known methodology. A review of Diels-Alder reactions of azadienes has appeared,196and Cheng et al. have published further details of the preparation and intramolecular Diels-Alder reaction of N-acyl-1-azadienes to produce piperidine derivatives.197 Intramolecular cyclization .of an o-quinone methide N-alkylamine has been used as the key step in a formal total synthesis of g e p h y r o t o ~ i n and , ~ ~ ~Weinreb and co-workers, as an extension of their earlier work on the intramolecular imino Diels-Alder reaction, have synthesized the 2oo and cryptopleurine.200 quinolizidine alkaloids epil~pininel~~> The preparation of the hydroisoquinolines(293) and (294) from the azatrienes (292) has been investigated.201 With one exception, combined yields of (293) and (294) were good (7&80%) but although cyclization to give the cis-product (293)

was preferred, the degree of stereoselectivitywas generally low. In an alternative procedure, a potentially general route to cis-hydroisoquinolines (296) has been reported, based upon amino-Claisen rearrangement of the zwitterionic N-vinylisoquinuclidenes (295).202

& +i

1

C02R

I

C

___)

I

'Rl

H

R2

I

H (296) D. L. Boger, Tetrahedron, 1983,39,2869. Y.-S. Cheng, A. T. Lupo, jun., and F. W. Fowler, J. Am. Chem. SOC.,1983,105,7696. lg8 Y. Ito, E. Nakajo, M. Nakatsuka, and T. Saegusa, Tetrahedron Lett., 1983,24,2881. 199 M. L. Bremmer and S. M. Weinreb, Tetrahedron Lett., 1983,24,261. M. L. Bremmer, N. A. Khatri, and S. M. Weinreb, J. Org. Chem., 1983,48,3661. 201 S . F. Martin, S. A. Williamson, R. P. Gist, and K. M. Smith, J. Org. Chem., 1983, 48,5170. 2m F.-A. Kunng, J.-M. Gu, S. Chao, Y . Chen, and P. S. Mariano, J. Org. Chem., 1983,48,4262. 197


474

Further studies on the regioselectivity of the photochemical cycloaddition of enamine-carbaldehydes and alkenes to produce 174-dihydropyridineshave also been reported.2o3 The intramolecular Mannich reaction has been utilized in two biomimetic syntheses: quinolizidinesand indolizidines (298) have been prepared from amine acetals (297)7204and acid treatment of amino-nitrile (299) gave the

-

R2

R 2R1 C=CH C0 Me

H N(CH 2)" C H (OE t 1

(297) n = 3 o r 4

I I R'

MeCO C H 2 C N H( C H 2 ) n C H ( OE t l2

I2M

- HCL

H

(

C

T

R2 R1 ( 2 9 8 ) 15-60°/o

azabicyclononanes (300), intermediates in the formation of ladybug alkaloids (301).205

CPh A ___)

10% HCI, MeOH

(299)

L

1

0 0

-

R

(301)

R

(300) R = H , 90°/o R = CcjH11,9O0/o R = Me,

m3 L. F. Tietze, A. Bergmann, and K. Bruggemann, Tetrahedron Lett., 1983,24, 3579. miF. D . King, Tetrahedron Lett., 1983,24,3281. 205

D. H. G. Medina, D . S. Grierson, and H.-P. Husson, Tetrahedron Lett., 1983,24,2099.


475

Formation of six-membered nitrogen heterocycles by acyliminium ion-initiated cyclizations continues to be a major interest. Overman et al. have reported the formation of tetrahydropyridines by intramolecular reaction of vinylsilanes with iminium ions in an endocyclic sense [(302)+(303)] .206 Thus, products (305) were produced from the amines (304) via cationic aza-Cope rearrangement and cyclization with complete regiocontrol of the double bond position.

I

R1

( 3 0 4 ) R’ = a l k y l or aryl R2 = H or h e x y l

1

R~CHO, MeCN C S A

R2

0I

R’

-I

L

Kano et al. have described the synthesis of the phenyldecahydroisoquinoline (307) from the carbamate (306) via an N-acyliminium ion-induced polyolefinic heterocycli~ation.~~~ As an extension of known methodology this same research

H

(306)

(307)

group has also reported the synthesis of oxazolo[4,3-a]tetrahydroisoquinolinesby intramolecular cyclization of a-oxa-acyliminium ions ,208, *09 and Hadley et al. have prepared the cyclized products (310) by a route involving a high-yielding, singlestep conversion of the dicarboxylic acid precursors (308) into the imides (309).210 L. E. Overman, T. C. Malone, and G. P. Meier, J. Am. Chem. Soc., 1983,105,6993. S . Kano, T. Yokomatsu, Y . Yuasa, and S. Shibuya, Tetrahedron Lett., 1983,24,1813. S . Kano, Y. Yuasa, T. Yokomatsu, and S. Shibuya, J . Org. Chem., 1983,48, 3835. 209 S. Kano, Y. Yuasa, T. Yokomatsu, and S. Shibuya, Chem. Lett., 1983, 1475. 210 M . S. Hadley, F. D . King, and R. T. Martin, Tetrahedron Lett., 1983,24,91.

476


+

H02C-X-Y-CH2C02H

(308) X - Y

HzNCH2CH=CH2

=-CH2-O-,-CHz-S180-230°C

i A

i,NaBHL, H

I

(310) 50 -

OCHO 6 2 '/* overall

(309 1

Okita et al. have described a synthesis of (+)-lupinine and (+)-epilupinine which is based upon the formation of cyclized products (312) by intramolecular C-alkylation, possibly via the intermediacy of the acyliminium ion (311).211

(CH2)n

0

i , anodic oxidation, MeOH

* coNHR Br Br

I

li

i + RNH2

( 3 8 8 ) 23 - 84 "ie Reagents: i, KOH pulv., CH2C12,Bun4N+Br-

Scheme 29

Kametani and his co-workers have published details of their synthesis of /?-lactams by the sulpheno-cycloamination procedure ,259 and further studies of the diethyl azodicarboxylate-triphenylphosphine-mediatedcyclization of /3-hydroxyamide derivatives to produce P-lactams have been described. Miller et aE. have developed an efficient route to N-hydroxy-2-azetidinonesby cyclization of the appropriate 0-acylated amino-acid hydroxamate and subsequent deprotection,260and the same group has also investigated analogous cyclizations of serylaminomalonates (390) and related compounds.261In this case treatment of the hydroxyamide (390) with DEAD-triphenylphosphine or formation of the dianion of /3-chloroamide (391) resulted in cyclization to the p-lactam (392), but cyclization of the monoanion of (391) gave the pyrrolidinone (389). Townsend et al. have reported full details of similar cyclization studies in connection with the synthesis of (-)-3-aminonocardicinic acid.262 R. M. Adlington, A . G. M. Barrett, P. Quayle, A . Walker, and M. J. Betts, J . Chem. SOC., Perkin Trans. I , 1983, 605. 258 A . Commerson and G. Ponsinet, Tetrahedron Lett., 1983,24, 3725. 259 M. Ihara, Y. Haga, M. Yonekura, T. Ohsawa, K. Fukumoto and T. Kametani, J . Am. Chem. SOC., 1983, 105, 7345. 2@ M. J . Miller, A, Biswas, and M. A . Krook, Tetrahedron, 1983,39,2571. 261 M. J. Miller and P. G. Mattingly, Tetrahedron, 1983,39, 2563. 262 C. A. Townsend, A . M. Brown, and L. T. Nguyen, J . Am. Chem. SOC., 1983,105,919. 257


492 Me

Me& 0

CO2Et CO2Et

H

X=OH

DEAD, PPh3

C H ( C 0 2 E t 12

C H ( C 0 2 E t 12

(390);X = OH (391);X = C L

(392) X=Cl 2 LDA

The cephem (394) has been prepared from the diacid (393) by a double cyclization using benzotriazol-l-yloxytris(dimethy1amino)phosphonium hexafluorophosphate (BOP) as the condensing agent .263 The use of dicyclohexylcarbodi-imide gave only a 20% yield of (394). Several reports have appeared this year from different research groups of the synthesis of 2-0x0- or 2-thioxo-penams and their conversion into 2-hetero-substituted penems. Ghosez and co-workers have reported a general route to 2-0x0, Me

H

(393) 0

lSOp

(394) 80°/0 263

J.-C. RozC, J.-P. Pradere, G. Duguay, A. Guevel, H. Quiniou, and S. Poignant, Can. J. Chem., 1983, 61, 1169.

493


2-thioxo-, and 2-imino-penams (396) from a single precursor (399, which is readily prepared from penicillin G (Scheme 30) .264 Hydrogenolysis and methyla-

i

C02R2 (395) R' = CH2Ph or But R2 = CH2Ph or p - N O ~ C G H ~ C H ~

( 3 9 6 ) X = O,S,or NMe 2O-59%

Reagents: i, COCi,, NEt,; CSCl,, NEt,; or MeN =CBr,, NEt,

Scheme 30

tion then gave the corresponding 2-hetero-substituted penems. Girijavallabhan et al. have synthesized the optically active 6 4 l-hydroxyethyl) analogue of (396; X=S) by an essentially identical but have also described a more convenient stereospecific synthesis of thioxopenam (398) by base-catalysed cyclization of the dithiocarbamate (397).266Leanza et al. have achieved the same ring closure by starting with the phenoxythiocarbonyl analogue of (397).267

PH

S

II

I 7 Li N(TMS12

JH

J3s-c-N+N ____)

-76

0

C02R

OC

J

0

Q

S

CO2R

(3971 R = a l l y [

(398) 76.10

In an extension of their earlier work, Cooke et al. have now reported a one-pot conversion of the 4-allysulphinylazetidinones (399) into the corresponding penems (401), presumably via the intermediacy of 2-thiacephems (400).268A 0

$

0 C02PNB

C02PNB ( 399 1

(400)

( 4 0 1 ) R = M e ,4 8 % R = Ph , I 8 '/o

M. Cossement, J. Marchand-Brynaert, S. Bogdan, and L. Ghosez, TetrahedronLett., 1983,24,2563. V. M. Girijavallabhan, A. K. Ganguly, P. Pinto, and R. Versace, TetrahedronLett., 1983,24,3179. V. M. Girijavallabhan, A. K. Ganguly, P. Pinto, and R. Versace, J. Chem. SOC., Chem. Commun., 1983, 908. W. J. Leanza, F. DiNinno, D. A. Muthard, R. R. Wilkening, K. J. Wildonger, R. W. Ratcliffe, and B. G. Christensen, Tetrahedron, 1983,39,2505. 268 M. D. Cooke, K. W. Moore, B. C. Ross, and S . E. Turner, Tetrahedron Lett., 1983,24,3373.

264 265


494

report from Perrone et al. describing their studies of the synthesis of penems by desulphurization of 2-thiacephems has also appeared.269 The carbene insertion reaction has been utilized in the synthesis of several novel penicillin and cephalosporin analogues. A new route to the isopenam sulphone (403) has been described, via rhodium-catalysed decomposition of the a-sulphonyl diazoester (402) ,270 and Kametani and co-workers have

PhH,8O0C

k02 C H2Ph

(402)

(403)9 5 %

prepared 2-carboxylated penicillin and cephalosporin derivatives by utilizing an initial S-1-C-2 bond cleavage step brought about by reaction of penicillin derivatives with a - d i a z o m a l ~ n a t e s . ~The ~ ~ ’ ~same ~ ~ research group has also prepared the eight-membered cis-oxa-p-lactams (406) by addition of the carbene derived from p-nitrobenzyl a-diazozacetate (405) to the ,!?-face of penicillin derivatives (404) followed by ring expansion.273

(406)2 2 - 27 */o E. Perrone, M. Alpegiani, A . Bedeschi, M. Foglio, and G . Franceschi, Tetrahedron Lett., 1983, 24, 1631. 270 J . Brennan, and I. L. Pinto, Tetrahedron Lett., 1983, 24, 4731. 271 T. Kametani, N. Kanaya, T. Mochizuki, and T. Honda, Heterocycles, 1983,20,455. 272 T. Kametani, N. Kanaya, T. Mochizuki, and T. Honda, Heterocycles, 1983, 20, 435. 273 T. Kametani, N. Kanaya, T. Mochizuki, and T. Honda, Tetrahedron Lett., 1983,24, 221. 269


495

Two other routes to related ring-expanded oxa-/3-lactams have also been reported. The seven-membered systems (410) and (411) have been synthesized from the monocyclic azetidinones (408) and (409) by routes which utilize the total carbon-oxygen skeleton of benzyl clavulanate (407),274 and full details have

C(OMe) CH2CHO

(408)

OMe C 0 2 C H2Ph

(410)46%

appeared of the synthesis of l-oxacepham and l-oxahomocepham systems by free-radical cyclization of alkenyl- and alkynyl-substituted a~etidinones.”~ Stoodley and co-workers have reported full details of the synthesis of an iso-

(412) 274 275

( 4 1 3 ) 20%

G. Brooks and E. Hunt, J . Chem. SOC.,Perkin Trans. 1, 1983, 115. M. D. Bachi, F. Frolow, and C. Hoornaert, J . Org. Chem., 1983,48,1841.

General and Synthetic Methodr

496

clavam-3-carboxylate,276 and Philips et al. have prepared some 3-oxa5-carbacephamanaloguesby mercuric acetate-assistedintramolecularcyclization of 4-allylazetidinone-l-alcohols.2n Cyclization of the phosphoramidate (412) has given the novel bicyclic/3-lactam (413) in modest yield,278and Baldwin et al. have prepared the y-lactam analogues (414) and (415) of carbapenicillanic acid and penicillanic acid respectively (Scheme 31).279

i,CH2=CHC02Me

C02Me

.c

ii.Hz.Ra-Ni

iii, MeOH,

0

A

COZMe

1

1

-m

PhOCH2CONH

0 O

E

3

COzK

i02CH2Ph

(414)

- p3 i , CH2N2 ii,NaOH

COZH

Scheme 31

J. Brennan, G. Richardson, and R. Stoodley, J . Chem. SOC., Perkin Trans. 1, 1983,649. M. L. Philips, R. Bonjouklian, N. D. Jones, A. H. Hunt, and T. K. Elzey, Tetrahedron Len., 1983, 24, 335. 27* G. Just, D . Dugat, and W.-Y. Liu, Can. J . Chem., 1983, 61, 1730. 279 J. E. Baldwin, M. F. Chan, G. Gallacher, P. Monk, and K. Prout, J . Chem. SOC., Chem. Commun., 1983, 250.

276

9 Highlights in Total Synthesis of Natural Products BY K. E. B. PARKES AND G. PATTENDEN

1 Introduction This Report is similar in style, format, selectivity, and subjectivity to the previous chapter in the series.

2 Terpenes

Cobalt-mediated carbon-to-carbon bond-formingreactions have featured prominently in a number of elegant natural product syntheses in the past decade. Now Exon and Magnusl have shown that the well known formation of cyclopentenones by reaction between a strained alkene and an alkyne-octacarbonyldicobalt complex can be effected in an intramolecular sense [viz. (1)+(2)], to provide the key bicyclic interdediate (2) in an efficient formal synthesis of coriolin (3). In two alternative new approaches to coriolin, published during 1983, Wender et al. have used their now well documented arene-lefin photocyclization approach, i. e. (4)-+(5), and Koreeda et al. have employed the interesting dianion (6) from 3-isobutoxycyclopent-2-enonein a reaction with 3-iodo-2,2-dimethylpropanal, followed by addition of MOM chloride, to set up the central intermediate (7). A particularly fascinatingroute to the triquinane ring system found in hirsutene (9) is that based on rearrangement by homoenolization of the intermediate (8) (Scheme 1) in the presence of potassium t-b~toxide.~ Little et aL5 have also described a neat approach to hirsutene which uses intramolecular diyl trapping by an unactivated diylophile, viz. (lo), to set up the tricycle. Greene et aL6 have published full details of their total synthesis of hirsutic acid (11) , which fully demonstrates the effectiveness of chloroketene-diazoalkane annelation in the construction of five-membered rings (Scheme 2). This useful annelation procedure has also been used by Paquette and Annis7 to produce the diquinane segment (12) in their synthesis of pentalenene (15), a metabolite of Streptomyces griseochromogenes. The third ring in these authors’ synthesis of C. Exon and P. Magnus, J . Am. Chem. SOC., 1983,105,2477. P. A . Wender and J. J. Howbert, Tetrahedron Len., 1983,24,5325. M. Koreeda and S. G. Mislankar, J . Am. Chem. SOC., 1983,105,7203. B. A. Dawson, A. K. Ghosh, J. L. Jurlina, and J. B. Stothers,J . Chem. Soc., Chem. Commun., 1983, 204. R. D. Little, R. G. Higby, and K. D. Moeller, J . Org. Chem., 1983,48,3139. A. E. Greene, M. Luche, and J. Deprts, J . Am. Chem. SOC., 1983,105,2435. L. A. Paquette and G. D. Annis, J . Am. Chem. SOC., 1983,105,7358.

497

498


O

t

0

t

'H OH

I

0Bui (6)

*-%O

OH

OBu'

(7)

OTMS

Reagents: i, LDA, Me,SiCl; ii, CH212,Zn, Ag; iii, NaOH, MeOH; iv, NaNH,, MeI; v, Bu'O-, Bu'OH

Scheme 1

Highlights in Total Synthesis of Natural Products

499

Cl

"""&

IV,

.1

I,III,VI

Meozc\&&-o H

Cl

M eOzC v

a3 .,

-- e* HOzC,,

H

H

O (11)

Reagents: i, Cl,C=C=O;

ii, Me,CuLi, iii, CH,N,; iv, NaBH,; v, Cr(ClO,),; vi, Zn, AcOH

Scheme 2

H

(13)

(15) Reagents: i, Cl,C=C=O;

ii, CH,N,

Scheme 3

17


500

0

0

A

(16)

pentalenene was added by SnC1,-catalysed cyclization of the enal(13), leading to (14), which was then converted into pentalenene (15) and its methyl epimer (Scheme 3). The capnellane family of sesquiterpenes found in the soft coral Capnella imbricata continues to attract attention from the synthetic chemist. Thus, Mehta et a1.* have shown that thermolysis, under flash vacuum pyrolysis conditions, of the adduct (17) obtained via the Diels-Alder adduct (16) of methylcyclopentadiene isomers andp-benzoquinone, leads to the tricyclic dione (18) in 60% yield. Several steps then gave A9912-capnellene(19). In the same year, Birch and Pattenden9 have provided full details of the first synthesis of the novel 5,8-fused ring system found in precapnelladiene (22) ,which co-occurswith A9>12-capnellene

in C. irnbricata. The authors’ synthesis uses a highly stereoselective intramolecular photocycloaddition reaction from the enol benzoate (20), followed by retroaldolization to (21), to set up the unusual biocyclic carbon framework found in precapnelladiene. Two groups of researchers have described a new approach to the synthesis of the tetracyclic lactone quadrone (27), based on an intramolecular Diels-Alder

* G . Mehta, D. S. Reddy, and A. N. Murty, J . Chem. SOC., Chem. Commun., 1983, 824; for another synthesis of capnellene see: R. D. Little, G. L. Carroll, and J. L. Petersen, J . Am. Chem. SOC.,1983, 105, 928. A. M. Birch and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1, 1983, 1913.

501


(24)

(27)

reaction, viz. (23)+(24).l0>l1The two syntheses differ only in the manner in which the adduct (24) was next converted into (25),and then into the tricyclic acid (26), an intermediate used by Danishefsky et al. in their first synthesis of quadrone. In an entirely different approach to quadrone (27), Takeda et a l l 2 have applied solvolytic rearrangement of the substituted bicyclo[4.2.0]octano1(28) followed by cyclopentenone annelation to set up the tricyclic acid intermediate (26),

I II

(28)

J

The useful, but comparatively little exploited, intramolecular Michael reaction has featured in new approaches to the novel ring systems found in clovene (29) l3 and in cedrene (30) l4 published this year, and an interesting approach to a-acoraR . H. Schlessinger,J. L. Wood, A. J. Poss, R. A. Nugent, and W. H. Parsons, J. Org. Chem., 1983, 48, 1146. l1 J. W. Dewanckele, F. Zutterman, and M. Vandewalle, Tetrahedron, 1983,39,3235. l2 K. Takeda, Y. Shimono, and E. Yoshii, J. Am. Chem. SOC., 1983,105,563; see also: S. Burke, C . W. Murtiashaw, and J . A. Oplinger, Tetrahedron Lett., 1983,24, 2949. l3 P. G. Baraldi, A. Barco, S. Benetti, G. P. Pollani, and D. Simoni, Tetrahedron Lett., 1983,24,5669. l4 M. Horton and G. Pattenden, Tetrahedron Lett., 1983, 24,2125.

lo


502

=a O

H

0

(30)

diene (33) has as its basis the intramolecular photocycloaddition of the chlorodienone (31), leading to largely (32), followed by reductive cleavage using Li-NH3.

The synthesis of complex polycyclic molecules using intramolecular photocycloaddition followed by fragmentation is also well illustrated in a new synthesis of zizaene (35) starting from the enol acetate (34).16 0

0

(34)

ls,W. Oppolzer, F. Zutterman, and K. Battig, Helv. Chim. Actu, 1983, 66, 522. l6 A. J. Barker and G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 1983, 1901.

.1


503

An interesting synthesis of bulnesene (38), which features intramolecular cycloaddition involving the 3-oxidopyrylium species (37) generated from the corresponding pyranulose acetate (36), has been published by Sammes et al. l7 The

A

150 *C*

Ac 0

(37)

(36)

J.

0

same general strategy was also employed to develop new syntheses of the terpenes cryptofauronol (39) and valeranone (40).

a 0

I

I

The Diels-Alder reaction remains one of the most useful and subtle methods for elaborating all types of terpene ring systems. This feature is illustrated this year with approaches to the drimane sesquiterpenes, e.g. warburganal (41) ,I8 and

17

l8

P. G. Sammes and L. J. Street, J . Chem. SOC., Chem. Commun., 1983, 666. D. M. Hollinshead, S. C . Howell, S. V. Ley, M. Mahon, N. M. Ratcliffe, and P. A. Worthington, J . Chem. SOC., Perkin Tram. 1, 1983, 1579.


504

in an enantioselective synthesis of (-)-P-salltalene dienophile (42).19

(43) using the chiral

Intramolecular reductive coupling of the wester carbonyl compound (44)using Tiois accompanied by E-2-isomerization about the double bond, to produce the ketone precursor (45) of the medium-ring sesquiterpene isocaryophyllene (46) .*O

(44)

1

C02Et

Germacrone (48),a constituent of Geranium macrorhizum, although possessing a labile E,E-1,5-diene system, has been synthesized by a route based on intramolecular alkylation of the carbanion generated from the protected cyanohydrin (47).21 The more elaborately substituted germacrane eucan-

(47)

i, p - T S A ii, NaOH

W. Oppolzer and C. Chapuis, Tetrahedron Lett., 1983, 24, 4665. J E. McMurry and D. D. Miller, Tetrahedron Lett.. 1983. 24, 1885. 21 T. Takahashi, K. Kitamura, H. Nemoto, J. Tsuji, and 1. Miura, Tetrahedron Lett., 1983,24,3489.

l9


505

nabinolide (51) has been synthesized by a beautifully neat sequence involving oxy-Cope ring expansion of (49) to (50) in the presence of KN(TMS):! at 85 "C as a

OH

OMe (49)

OMe

(50)

key step.22 Still and his c o - w o r k e r ~have ~ ~ also outlined a synthesis of the cembranoid anti-tumour agent asperidiol (54)which uses the diastereoselective macrocyclization of the aldehydo-allylic bromide (52) in the presence of Cr" to produce the diastereoisomer (53) of the macrocycle. Kato et al.24 have also

/br

0-

(52)

(541 W. C. Still, S. Murata, G. Revial, and K. Yoshihara, J . Am. Chem. SOC., 1983, 105, 625. W. C. Still and D. Mobilio, J . Org. Chem., 1983,48,4785. 24 M. Akoi, Y. Tooyama, T. Uyehara, and T. Kato, Tetrahedron Lett., 1983,24,2267.

22

506


described a synthesis of asperdiol starting from the ally1 alcohol (56) prepared via intramolecular cyclization of the acid chloride. (55).

i , SnCL4

E 51

TI,

L l C l , LlZCO3

111,

LIALHI,

>

+(54)

(56)

Me02 C

(59)

?\

H


507

Lombardo and ManderZ5have now extended their elegant synthetic investigations amongst the gibberellin plant hormones, and have outlined a neat synthesis of gibberellin A38methyl ester (63). Their synthesis is based on elaboration of the previously described intermediate (57) to the aldehyde (58),followed by a novel intramolecular Michael reaction, viz. (59)+(60) and intramolecular aldol cyclization, viz. (61)+(62). Other notable achievements amongst the total synthesis of terpenes published in 1983 are the synthesis of the insect anti-feedant ajugarin I (64) ,26 a biogenetictype synthesis of aphidicolin (65) ,27 and synthesis of the biogenetically interesting sesquiterpenes eremolactone (66) and isoeremolactone (67).28+29 0

0

0

3 Steroids The possibilities for the intramolecular variant of the Diels-Alder reaction in the regio- and stereo-controlled synthesis of complex polycycles seem endless. Thus, this year Kametani and his c o - w ~ r k e rhave s ~ ~ demonstrated how the reaction can L. Lombardo and L. N. Mander, J. Org. Chem., 1983,48,2298. S. V. Ley, N . S. Simpkins, and A. J. Whittle, J. Chem. SOC.,Chem. Commun., 1983, 503. 27 E. E. van Tamelen, S. R. Zawacky, R. K. Russell, and J. G . Carlson, J. A m . Chem. SOC., 1983,105, 142. 28 R. Ramage, 0. J. R. Owen, and I. A. Southwell, Tetrahedron Lett., 1983,24, 4487. M. Asaoka, K. Ishibashi, N. Yanagida, and H . Takei, Tetrahedron Lett., 1983,24,5127. 30 T. Kametani, Y. Suzuki, H. Furuyama, and T . Honda, J. Org. Chem., 1983,48, 31. 25

26

18


508

be employed to set up the tricycle (68) for elaboration to androstane-2,17-dione (69). Johnson et aL31have described further details of their novel biomimetic polyene cyclization approach to steroids using the allylsilane residue as an appropriate terminator. Thus, treatment of (70) with SnC14in pentane at 0°C (15 min) then at 15°C for 5 min afforded a mixture of (71) and (72) in a useful combined yield of 45%.

R’

RZ

(71) R1 = OCH2CH20H, R 2 = H (72) R 1 = H, R 2 = OCHzCHzOH

4 Anthracyclinones Stoodley and his c o - ~ o r k e r shave ~ ~ outlined a new strategy for elaborating anthracyclines in which the 6a,7- and 10,lOa-bondsare constructed via a DielsAlder reaction. Thus, Diels-Alder reaction between the diene (74) and the oxirane (73) was found to give the adduct (75) with high diastereocontrol. In a sixstep sequence the adduct (75) was then converted into (+)-demethoxy31

32

W. S. Johnson, Y.-Q. Chen, and M. S . Kellogg, J . Am. Chem. SOC.,1983,105, 6653. R. C. Gupta, P. A. Harland, and R. J. Stoodley, J . Chem. SOC., Chem. Commun., 1983, 754.


509

a+ A;;; OSi Me3

0

0

0 (73)

0

AcOCH,

, I

OAc

(74)

Qy-$J-y 0

OH

0

OH

0

\

6

\

1

O+

(76)

Sugar

(75)

OH

daunomycinone, the aglycone of 4-demethoxydaunomycin (76). The diastereoselection observed in the Diels-Alder reaction between (73) and (74) is particularly interesting and important, since chiral dienes have not previously enjoyed a good reputation of diastereodifferentiation in [4+2] cycloaddition reactions. Sequential intramolecular Michael reaction followed by aldolization from the dione-ester (77) in the presence of [2.2.2]-KH cryptate, leading to (78), provides

Me0

(77)

OH

0 (78)


510

the basis of a new biomimetic route to aklavinone (79), the aglycone of aclacinomycin A .33 A synthesis of a-citromycinone (82), one of the rarest anthracyclinones produced in fermentation broth of Streptomyces purpurescens, has been accomplished by Swenton et al.34The author’s synthesis uses the addition of the vinyl-lithium reagent, produced from (80), to (81), followed by hydrolysis and deprotection to elaborate the tetracycle.

1

I

Bu‘MeZSiO

OMe

OR

(81)

(80) OMe OH

F\

OH

A/

H

BCL3)

OH

H>

I

OMe 0

OH

OH

OH

0 (82)

Boeckmann and his co-workers 35 have provided further illustrations of the use of the Diels-Alder strategy between naphthoquinones (83) and the bicycle (84) for elaborating anthracyclinones, by achieving a new total synthesis of daunomycinone (86) and of adriamycinone (87). An approach to

mco~ GR isomers

I

Me0

0

0

(85) 33 34

35

Me0

0

OH

OH

(86) R = H (87) R = OH

K. Maruyama, H. Uno, and Y . Naruta, Chem. Lett., 1983, 1767. D. K. Anderson, C. E. Coburn, A. P. Haag, and J. S . Swenton, Tetrahedron Lett., 1983,24, 1329. R. K. Boeckmann and S. H . Cheon, J . Am. Chem. SOC., 1983, 105,4112.


511

11-deoxydaunomycinoneand daunomycinone (86) described by Rao et al.36 starts from the ketone (88) and involves sequential Friedel-Crafts alkylation, i. e. (88)+(89), and acylation, i.e. (90)+(91) and (92)-+(93), reactions.

Br

(89)Br

(88)

JI 4

4- \ \

/

OMe

\

OMe

OM e

(91)

OMe

(90)

(89)++ OMe

OH

OMe

OH

5 Alkaloids

The Diels-Alder reaction continues to feature prominently in alkaloid synthesis. Thus, Magnus et al.37 have published the full details of their indole 2,3quinodimethane strategy for the synthesis of (f)-aspidospermidine (lOl), and have also applied the methodology to the synthesis of (+)-kopsanone In the latter synthesis, the Diels-Alder reaction is applied to the imine (94), leading to the tetracyclic intermediate (95). Removal of the carbonate protecting group and re-acylation then gave the sulphoxide (96), which could be cyclized to (97) in a Pummerer-type reaction in the presence of trifluroacetic acid anhydride. Allylation of (97) [to (98)] then set-up the molecule for a second intramolecular DielsAlder reaction producing (99), which was converted into (+)-kopsanone (100) in six further steps. Another Diels-Alder reaction, this time between the 1,4-diarylbutadiene(102) and maleimide, provided the cornerstone of a synthesis of the slime mould 36 3’ 38

A. V. R. Rao, K. B. Reddy, and A. R. Mehendale, J . Chem. SOC., Chem. Commun., 1983,564. T. Gallagher and P. Magnus, J . Am. Chem. SOC., 1983,105,2086. T. Gallagher, P. Magnus, and J. C. Huffman, J . Am. Chem. SOC., 1983,105,4750.

512


Ts

TS

(94)

(95)

0

6-jp N

I TS

N J:

&-dH ‘-a

N

I

Ts

(97)

(96)

0

0

Q-Q PhS-

PhS--

QT! I

TS

(98)

-

I

Ts

(99)


513

metabolite arcyriaflavin B (104) .39 Aromatization of the newly formed cyclohexene ring of (103) using dichlorodicyano-p-benzoquinonefollowed by elaboration of the carbazole residues by nitrene insertion reactions and deprotection, then

I-/

/ H

\ /

\ /

H

OH

H

gave the natural product. A nitrene insertion reaction, viz. (105)+( 106), has also provided a key step in a synthesis of methoxatin (107), a co-enzyme present in methylotropic bacteria.40

39

I. Hughes and R. A. Raphael, Tetrahedron Lett., 1983,24,1441. A. R. MacKenzie, C. J. Moody, and C. W. Rees, J . Chem. SOC., Chem. Commun., 1983, 1372.


514

Japanese workers have used the o-iminoquinonemethine (109) as a central intermediate in a synthesis of the tricycle ( l l l ) , a known precursor of the frog neuropoison gephyrotoxin (112) .41 Thus, treatment of the ammonium bromide (108) with caesium fluoride led to the transient intermediate (109), which gave (110) by an intramolecular Diels-Alder reaction. The synthesis of (111) from (110) was then completed by way of a two-step catalytic hydrogenation sequence.

HO

Me@ 0

$?

N-SiMe3

Br -

OMe ( 108 1

H HO

OMe

(109)

Ho41 OMe

(111)

( 1 10)

4 J(

H

Weinreb and his c o - ~ o r k e r have s ~ ~ published full details of their use of acylimine dienophiles in Diels-Alder cycloadditions, with a synthesis of (+)-epilupinine (113). They have also provided a new application of this methodology in a synthesis of (+)-cryptopleunne (114). 41 42

Y . Ito, E. Nakajo, M. Nakatsuka, and T. Saegusa, Tetrahedron Lett., 1983,24,2881. M. L. Bremmer, N. A. Khatri, and S. M. Weinreb, J . Org. Chem., 1983, 48, 3661.


515

OMe Me0

0 (11 3)

0

Me0 (114)

The intramolecular cyclization (116)+( 117) of a formamide ylide prepared by sequential methylation and fluoride ion-induced desilylation of (115), formed the final step of a new short route to the physostigmine alkaloid (k)-eserethole (117).43The high yield (70%) of this step is particularly impressive. Me

Me (116)

1

1,3-Dipolar cycloaddition was also used in a synthesis of a-isosparteine (121), whereby the tetracycle (120) was elaborated by treatment of 4H-pyran with the nitrone (118) leading to (119), which was then hydrogenated catalytically.MIn addition, Oppolzer et aZ.45have now published full details of their nitrone-based strategy to the clavine alkaloids, e.g. (122). Overman and his co-workersM have applied their ‘ring enlarging pyrrolidine annelation’ sequence to a synthesis of the aspidosperma alkaloid (+)16-methoxytabersonine (129). The key intermediate (126) was prepared by R. Smith and T. Livingstone, J . Org. Chem., 1983,48,1554. H. Oinuma, S. Dan, and H. Kakisawa, J . Chem. SOC., Chem. Commun., 1983,654. 45 W. Opyolzer, J. I . Grayson, H. Wegmann, and M. Urrea, Tetrahedron, 1983,39,3695. 46 L. E. Overman, M. Sworin, and R. M. Burk, J. Org. Chem., 1983,48,2685. 43

44

516


methylenation and deprotection of the tricyclic amide (125) which itself was derived from the reaction between (124) and the acyl anion equivalent (123). Treatment of (126) with paraformaldehyde under mildly dehydrating conditions resulted in rearrangement, via (127) and (128), to give the complete aspidosperma ring system (128), which required only methoxycarbonylation to complete the synthesis of methoxytabersonine (129). A full paper on Overman’s synthesis of the related (+)-crimine (130) was also published during 1983.47 The synthesis of the pyrrolizidine family of alkaloids has been a particularly active area during the period of this Report. Noteworthy have been enantiospecific syntheses of (+)-heliotridine (131) from S-malic and of (132), an ant venom, whereby the chirality was introduced by the ubiquitous Sharpless epoxidation procedure.49 In a synthesis of (+)-supinidine (135), the lithiodihydropyrrolidine (133) was used as the pivotal intermediate, allowing the introduction of a four-carbon chain to give (134) .50 The pyrrolidine (134) was then deprotected and cyclized to (?)-supinidine (135), in one-pot by treatment with L. E. Overman, L. T. Mendelson, and E. J. Jacobsen, J. Am. Chem. SOC., 1983, 105, 6629. A. R . Chamberlin and J. Y . L. Chung, J. Am. Chem. SOC., 1983,105, 3653. 49 S. Takano, S. Otaki, and K. Ogasawara, J. Chem. SOC., Chem. Commun., 1983, 1172. T. L. Macdonald and B. A . Narayanan, J . Org. Chem., 1983,48, 1129.

47

48


/d""

OSiMe3

MeO

\

NH

I

+ .,

co28u'

(123 1

8

517

COzMe

+

/

+

i

(124)

9""'"'"" OMe

(125 1

r

OMe

J

0 Me (126)

(128)

(129)

C02Me

methyl-lithium. Novel lithiation methodology has also been used in a recent synthesis of the potent anti-leukaemic alkaloid (k)-sesbanine (139) .51 Treatment of nicotinamide (136) with lithium tetramethylpiperidide was found to give the 4-lithio-derivative (137), which was successfully trapped with cyclopent-3-enone. 51

M. Iwao and T. Kuraishi, Tetrahedron Lett., 1984, 24, 2649.

518


Lactonization and reduction then gave (138), the substrate for a further lithiation to introduce the last required carbon atom. Sesbanine (139) was then prepared from (138) in a further four steps.

I

I

COzMe

COzMe

(132)

@0

NPrI2

(133)

/OH

b

f--

C

I

C

I

COz Me (134)

0, 1

(137)

QCO2H f-

The mercury(I1)-catalysed Ritter reaction has provided the basis of a most impressive one-pot synthesis of some Aristotelia alkaloids.52Thus, (+)-makomakine (142) was obtained in 17% yield from the reaction of indol-3-yl-acetonitrile (141) with (-)-P-pinene (140) in the presence of mercury(I1) nitrate, followed by reductive work-up. Similarly, (+)-a-pinene led to (+)-hobartine (143) in 11%yield, the lack of enantiospecificityin this case being due to the fact that the cyclization can occur at both ends of the allylic mercurial intermediate (144). Stevens et al. have prepared karachine (146) in 66% yield, by a one-pot double annelation of berberine (145).53 52

53

R. V. Stevens and P. M. Kenney, J . Chem. SOC.,Chem. Commun., 1983,384. R . V. Stevens and J . R. Pruitt, J . Chem. SOC., Chem. Commun., 1983,1425.


519

H

H

'H (143)

(144)

Biomimicry has provided the inspiration for an enantiospecific synthesis of the fungal metabolite (+)-tryptoquivaline G (150). Thus, treatment of the indole (147) , prepared from L-tryptophan methyl ester, with N-bromosuccinimide gave the bromide (148), which was then cyclized without isolation to (149). The synthesis was then completed by deprotection and oxidation.54 ~ published the results of their extensive studies on the Kuehne et u E . ~ have synthesis of minovincine (152) via a presumed biosynthetic precursor , 19-oxosecodine (151). 54

M. Nakagawa, M. Taniguchi, M. Sodeoka, M. Ito, K. Yamaguchi, and T. Hino,]. Am. Chem. SOC.,

55

1983, 105, 3709. M. E. Kuehne and W. G . Early, Tetrahedron, 1983,39,3707, 3715.


520

. . O w 0

OvO

Finally in this section, a short synthesis of a known precursor (155) of 7-methoxymitose (156) has been published.56 Thus, photolysis of the aminoquinone (153), and the retention of the irradiated solution on silica for a few days before chromatography, produced (154) as a 5:4 mixture of diastereomers in a combined yield of 72%. Both isomers then formally lose t-butyl formate on treatment with trifluoroacetic acid, giving (155). 56

M. Akiba, S. Ikuta, and T. Takada, J . Chem. SOC., Chem. Commun., 1983,817.


ov

H CO ;!CH 2 CC I 3

NHCOzCHzCCI3 (147)

0 t--

0 ( 1 50)

521

522


6 Prostaglandins and Leukotrienes Noyori and his co-workers have outlined a modification to their route to PGEl, published last year, which uses as a key operation the tandem organocopper conjugate addition/nitro-olefin Michael trapping of the resulting enolate intermediate, identified in Scheme 4.57A synthesis of PGE2described by Fuchs et u E . ~ ~

I

OSiMe2But

Scheme 4

is 'enantioconvergent' in that it uses both enantiomers of the alcohol (157) to make the single enantiomer (158) needed to construct the prostanoid intermediate (159) by reaction with (160) and (161). OH I

N M q >02Ph

y e 2

(ySPh(y *. i i

i, (160)

+

5 11

' , 6SiMe2But

I I

( 1 57)

c ; ; 2 ) 3 c 0 2 M e

I

OSiMe2But

(158) L-if

C5H11

0si Me

Bu'

(159)

I -C02Me

I

(161)

0s i Me 2B ut (160)

The Glaxo group has summarized its work on new total synthesis of PGA2, PGI,,and PGD2.5M1 Leukotriene B5(165), which originates from eicosapentaenoic acid rather than arachidonic acid, is of interest in connection with understanding the basis of the

*coma

i - V )

o

T

o

AcO' (162)

(163)

T. Tanaka, T. Toru, N. Okamura, A. Hazato, S. Sugiura, K. Manabe, S. Kurozumi, M. Suzuki, T. Kawagishi, and R. Noyori, Tetrahedron Lett., 1983,24,4103. 58 R. E. Donaldson, J. C . Saddler, S. Bym, A. T.McKenzie, and P. L. Fuchs, J. Org. Chem., 1983,48, 2167. 59 R. F. Newton, D. P. Reynolds, J. Davies, P. B. Kay, S . M. Roberts, and T. W. Wallace, J . Chem. SOC.,Perkin Trans. 1, 1983, 683. 6o A . D. Baxter, S. M. Roberts, F. Scheinmann, B. J. Wakefield, and R. F. Newton, J . Chern. SOC., Chem. Commun., 1983, 932. 61 E. W. Collington, C. J. Wallis, and I. Waterhouse, Tetrahedron Lett., 1983,24, 3125. 5'


523 H

PPh3 I-

vii

OH

- xii

Illv=v

(165) Reagents: i, Zn/Hg, HC1; ii, DBU; iii, LiOH; iv, H,, Pd/C; v, PDC; vi, Sharpless epoxidation; vii, Lindlar hydrogenation; viii, Collins reagent; ix, MeOCMe2(CH,),CH= PPh,; x, AcOH, H 2 0 , THF; xi, PPh,, I,, DIPA, imidazole; xii, PPh,; xiii, (163); iv, KOPr'; xv, OH-

Scheme 5

cardiovascular protective effect of dietary fish lipids. Previously LTB5 has only been obtained in minute amount (a few micrograms). Now Corey et a1.62have developed a synthesis of the leukotriene, which starts from the known lactone (162) and proceeds via the phosphonium salt intermediate (164) (Scheme 5). A new synthesis of LTB4 (168) using the chiral intermediates (166) and (167) employed in earlier synthesis emphasizes that the intermediates can be made very effectively from non-carbohydrate precursors!63

HO C02H

62 63

E. J. Corey, S. G . Pyne, and W. Su, Tetrahedron Lett., 1983,24,4883. C. Fuganti, S. Servi, and C. Zirotti, Tetrahedron Lett., 1983, 24, 5285.

524

General and Synthetic Methods 7 Spiroacetals

Interest in the synthesis of spiroacetals has intensified greatly in recent years with the recognition that this structural unit is found in a number of important antibiotics, as well as in insect pheromones. In what looks to be the most economic synthesis of (k)-endo-brevicomin (170), a sex attractant of the female Western pine beetle, Cohen et al.(j4have simply treated the acrolein dimer (169) with three equivalents of ethyl-lithium in the presence of TMEDA, and worked-up with methyl iodide followed by aqueous acid, to secure (170) in 69% yield.65

Y

-0,

OLi

An interesting synthesis of lineatin (172), a pheromone of the ambrosia beetle Trypodendrom lineatum, has, as its key feature an intramolecular [2+2] cycloaddition of the ene-allene (171).66Synthetic work by Mori and his has firmly established the stereochemistry of (+)-lineatin as (lR,4S,5R,7R).

=? A

490

OC

Q

5

O

--w 0

(171)

T. Cohen and M. Bhupathy, Tetrahedron Lett., 1983,24,4163. For other syntheses of brevicomin see: R. J. Ferrier and P. Prasit, J . Chem. SOC., Perkin Trans. 1, 1983, 1645; N. N. Joshi, V. R. Mamdapur, and M. S. Chadha, ibid., p. 2963. 66 L. Skattebol and Y . Stenstrom, Tetrahedron Lett., 1983, 24, 3021. 67 K. Mori, T. Uematsu, M. Minobe, and K. Yanagi, Tetrahedron, 1983, 39, 1735.

65

525


The acid-catalysed rearrangement of the tetrahydropyranyl ether (173) in the presence of boron trifluoride, leading to (174), constitutes the basis of a new and attractive approach to the pheromone component (175) of the female olive fly

(173)

1

b

H OCH2CC13

woH

OH

(175)

Dacus oleae.@ The talaromycins A and B are toxins isolated from the fungus Talaromyces stipitatus. In a synthesis of talaromycin B (178) the anomeric effect was used to control all four chiral centres of (177) in the cyclization of (1715).~~

OH HgC12 MeCN

OH (177) (178)

R = OH R = Me

The conversion of the furano-carbinol (179) to the pyranone (180)-in the presence of rn-chloroperbenzoic acid constitutes the basis of a short synthesis of the spiroacetal carbinol (181) used by Ireland in his synthesis of the antibiotic In yet another spiroacetal synthesis, the anion (182) was tirandarny~in.~~

69

'O

I. T. Kay and E. G . Williams, Tetrahedron Lett., 1983,24, 5915. S. L. Schreiber and T. J. Sommer, Tetrahedron Lett., 1983,24,4781. P. DeShong, S. Ramesh, and J. J. Perez, J . Org. Chem., 1983,48, 2117.

526


OBZ

(180)

527


employed in a Wittig-Horner reaction to form a mixture of enol ethers, which were then cyclized with acid to give (183), a pheromone from Paravespula vulgaris.71 The spiroacetal segment of avermectin B1, has been synthesized from the two fragments (184) and (185) derived from D-glucose and S-malic acid. Reduction of the intermediate (186) then gave an olefin which could be cyclized to give the optically pure spiroacetal (187).72

8 Pseudomonic Acids French workers have described a neat total synthesis of methyl pseudomonate C (193) using carbohydrate precursors .73 Their synthesis was based on regiospecific ring opening of the epoxide (188) derived from D-xylose using the allylic anion of (189), which itself was produced from D-glucose. The copper-catalysed ring opening of (188) first afforded (190), which was then converted into the acetonide. Selective tosylation of (191a) then afforded (191b), which with Ph I

+

o&

OSiMe, But

(188)

(189 1

OH

(191) a; R = O H b; R =OTS C;

R =CN

potassium cyanide gave (191c), the precursor of the ketone (192). This ketone was finally converted into methyl pseudomonate C (193), as shown in Scheme 6. have also described a synthesis of methyl pseudomonate C Fleet and his from carbohydrates. Thus, L-arabinose served as a precursor to the side chain (194), and D-arabinose was used to prepare the chiral allylic alcohol (195). Two S. V. Ley and B. Lygo, Tetrahedron Lett., 1984, 25, 113. S. Hanessian, A. Ugolini, and M. Thesien, J. Org. Chem., 1983,48,4427. 73 J.-M. Beau, S. Aburaki, J.-R. Pougny, and P. Sinay, J. Am. Chem. SOC., 1983,105, 621. 74 G. W. J. Fleet andT. K. M. Shing, TetrahedronLett., 1983,24,3657; G .W. J. Fleet, M. J. Gough, and T. K. M. Shing, ibid., p. 3661. 71

72


528

-Y 0

I

OH

(192)

I

i-v

OH

OH

(193)

Reagents: i, MeC( =NSiMe3)0SiMe3; I(CH,),CO,Me

ii, EtO,CFHPO(OEt),;

iii, H 30+; iv, NaOH; v,

Scheme 6

e'~CoNMe t

Claisen

I'

Qo

I'

CONH?

0s i P h *But

J

i .(196)

'CO,Et

ii, H+

OH

+I J (193)

Scheme 7

529


Claisen amide acetal rearrangements served to transfer chirality twice from oxygen to the ring in the steps ultimately used to synthesize the pseudomonate (Scheme 7). 9 Sugars The period under review has witnessed a significant interest in the synthesis of less common sugars. this perhaps reflecting a realization of the importance of the sugar moiety to the activity of anthracyclinones as anti-tumour agents. Grethe’s group has published syntheses of the epoxide (196) a known precursor of L-daunosamine (197), by one-carbon extension of ~ - a r a b i n o s eand , ~ ~also by a non-carbohydrate-based route in which chirality is introduced by asymmetric hydroboration with (-)-di-3-pinanylborane (198) .76

(196)

OH

(198)

(197)

A particularly short and high-yielding route to a protected (+ )-daunosamine involved the addition of the nitrone (200), derived from the ester (199), to ethyl vinyl ether which was found to give (201) diastereospecifically . Catalytic hydrogenation of the adduct in acidic methanol, using Pearlman’s catalyst, and acetylation then gave the protected (2)-daunosamine (202) in 58% overall yield.77

(200)

(201)

J

OMe

G. Grethe, T. Mitt, T. H. Williams, and M. R. UskokoviC, J . Org. Chem., 1983,48, 5309. G. Grethe, J. Sereno, T. H. Williams, and M. R. UskokoviC. J . Org. Chem., 1983, 48, 5315. 77 P. DeShong and J. M. Leginus, J . Am. Chem. SOC., 1983, 105, 1686. 75

76

530

General and Synthetic Methoak

Iodo-cyclization of the trichloromethyl imidate ester of allylic alcohols has provided a convenient way of introducing the vicinal cis-amino-alcohol functionality common to many anthracyclinone sugars. Thus, reaction of the sodium salt of the allylic alcohol (204), which is readily available by known chemistry from L-rhamnose (203), with trichloroacetonitrile gave the imidate ester (205), which cyclized to the oxazoline (206) when treated with the iodonium salt (207). Dehalogenation and hydrolysis then produced N-acetylristosamine (208) .78 The daunosamine derivative (210) was prepared similarly from the epimeric alcohol (209) made by Mitsunobu inversion of (204).79

(205)

(204)

cc 13 I

+ c10I;-

O w e I ( 206 1 OMe

OMe

OH

(209)

Danishefsky et al. have now applied their pyrone-forming Diels-Alder reaction of aldehydes to the synthesis of the amino-octose lincosamine (215), which as its methylthioglycoside forms the saccharide portion of the antibiotic lincomycin. Boron trifluoride-catalysed Diels-Alder reaction between the diene (211) and crotonaldehyde gave the expected endo-product (212), which was converted into the pyranose (213) by reduction and treatment with rn-chloroperbenzoic acid in methanol. Functionalization of the 1-propenyl side chain to lincosamine (215) H. W. Pauls and B. Fraser-Reid, J. Org. Chem., 1983,48, 1392. H. W. Pauls and B. Fraser-Reid, J. Chem. SOC., Chem. Commun., 1983, 1031. 8o E. R. Larson and S . Danishefsky, J . Am. Chem. SOC., 1983,105, 6715. 78

79

531


I

,o

(212 1

was achieved via the bromohydrin (214), which was obtained diastereospecifically on treatment with N-bromosuccinimide in aqueous acetic acid. Also of note in the area of sugar synthesis is the elaboration of the potent aminoglycoside antibiotic apramycin (216) from the previously synthesized neamine (217).81

OH

HO+NH~ ( 217 1 81

OH

K. Tatsuta, K. Akimoto, H. Takahashi, and T. Hamatsu, Tetrahedron Lett., 1983,24,4868.


532 10 Macrolides and Ionophores

A major synthetic achievement published during 1983 was the synthesis by Meyers and his thirteen co-workers of 3 mg of the anti-tumour macrocycle (-)maysine (226), which used a convergent approach from the three fragments (218), (219), and (222).82Thus, the cuprate derived from (218) was coupled to the allylic bromide (219), to give the achiral portion of the molecule (220). The epoxide portion (222), which contains all but one of the chiral centres, was prepared from Cl

Me

C\

Me

COz H

H

S-(+)-3-hydroxy-2-methylpropionic acid (221), and coupled to the vinyl-lithium reagent from (220) to give a 1:l mixture of epimers at the C-10 hydroxyl-group, which was separated after methylation and desilyation to (223). Oxidation and acylation of the nitrogen centre in (223) then gave the aldehydo-phosphonate (224), which underwent cyclization to give (225) in the presence of potassium t-butoxide. Deprotection and formation of the cyclic urethane by treatment with phosgene and ammonia at -78°C completed the synthesis. 82

A . I. Meyers, K. A. Babiak, A. L. Campbell, D. L. Comins, M. P. Fleming, R. Henning, M. Heuschmann, J . P. Hudspeth, J . M. Kane, P. J. Reider, D. M. Roland, K. Shimizu, K. Tomioka, and R. D. Walkup, J. Am. Chem. SOC., 1983, 105, 5015.


533

II

P(OEt 12

M

/

e

0

\

4 Me

/

/

e

OEE SE t SEt

M

\ eo

'%

/

,,Me D

O

OEE SE t SE t

I I

OMe

(225)

OMe

(224)

OMe (226)

An interesting synthesis of the antibiotic S, S-( +)-grahamimycin (229) used the titanium-induced pinacol cyclization of the dialdehyde (227). Oxidation of (228) then gave material identical to the natural product except in the sense of optical rotation; this permitted the assignment of the R, R-configuration to natural grahamirny~in.~~ A tin template effect has been used to prepare the iron carrier enterobactin (233). Thus, refluxing the protected anhydro-serine (230) in chloroform in the presence of the cyclic tin compound (231) led to the trimer (232), which only required deprotection and acylation to complete the synthesis. It is believed that the cyclization proceeds by multiple insertion of the p-lactone into the cyclic tin 83

D. Ghiringhelli, Tetrahedron Lett., 1983, 24, 287.


534

0 0

0 W 0


535

compound followed by expulsion of the trimer and regeneration of the template.84 Stork’s group has published a simplification of their original synthesis of cytochalasin B (236), in which the key Diels-Alder step is performed as an intramolecular reaction, viz. (234)+(235), and the synthesis is completed by elaboration of the allylic alcohol moiety in the cyclohexane ring.85

@

A. Shanzer and J. Libman, J . Chem. SOC., Chem. Commun., 1983,846. G. Stork and E. Nakamura, J . Am. Chem. SOC., 1983,105, 5510.

536


Considerable interest has been shown in the synthesis of boromycin (237), routes to the C-3-C-17, and the C-1-C-17 segments being published by Hanessian et al.86 and by White et al.87 respectively. The ionophore antibiotic X-14547A (243), which is of particular interest because of its ability to transport both univalent and bivalent cations, has been synthesized by a convergent approach in which the fragments (239) and (242) are

HO .

H

coupled together using a Julia reaction. The pyran-aldehyde (239) was prepared in sixteen steps from 1,6-anhydro-P-~-glucose(238), and the sulphone (242) was derived from the addition of the lithio-pyrrole (241) to the lactone (240).88 Me

Me

Ft

Me

Me

86

S. Hanessian, D . Delorme, P. C. Tyler, G . Demailly, and Y . Chapleur, Can. J . Chem., 1983,61,634. J. D . White, M. A. Avery, S. C . Choudhry, 0. P. Dhingra, M-c. Kang, and A . J. Whittle, J . Am. Chem. SOC., 1983,105,6517. M. P. Edwards, S. V. Ley, S. G . Lister, and B. D . Palmer,J. Chem. SOC., Chem. Commun., 1983,630.

537


Ireland et aLS9have published the full details of their synthesis of the nonselective ion carrier and antibiotic lasalocid A (244), and have also used a closely related approach to prepare its enantiomer.90 11 Other Natural Products Tabtoxin (247) ,produced by the infecting agent Pseudomonas tabaci, is the toxin . described ~ ~ responsible for wildfire disease in tobacco plants. Baldwin et ~ 1 have the first synthesis of the toxin, which uses the Diels-Alder reaction between benzyl nitrosoformate and the cyclohexadiene (245) to produce the adduct (246) whose C -N and C -0 bonds define the relative stereochemistryat C-2 and C-5 in (247). The sensitive p-lactam ring in the toxin, which undergoes a facile intramolecular transacylation to the stable, inactive isotabtoxin (248) (tl,*pH 7, 24 h at 25"C), was closed in the final stages of the synthesis. CO;! Et

b +

C02Et

0

II

___)

N 'COzCH2Ph

P&

N

'C02

CH2Ph

(245)

I

0

C02H

4

'$---COzCH, Ph

R. E. Ireland, R. C. Anderson, R. Badoud, B. J. Fitzsimmons, G. J. McGarvey, S. Thaisrivongs, and C. S. Wilcox, J. Am. Chem. SOC., 1983,105,1988. 9o R. E. Ireland, L. Courtney, and B. J. Fitzsimmons, J. Org. Chem., 1983, 48, 5186. 91 J. E. Baldwin, P. D. Bailey, G. Gallacher, K. A. Singleton, andP. M. Wallace,J. Chem. SOC., Chem. Commun., 1983, 1049. 89


538

COz C H2 CC I 3

Me0

I

I

Boc iv - v i

(250) Reagents: i, Cl3CCHZO,CC1,NEt,, CHzC1,; ii, Me,O+BF,-; iii, PhC1, A; iv, BF,.OEt,; v, AcC1, DMAP, CH,Cl,; vi, NaBH3CN, AcOH, 50°C; vii, NaOH, THF; viii, C$,OH, DCC; ix, Zn, AcOH; x, DMAP, py

Scheme 8


539

Wassermann and his c o - w o r k e r ~have ~ ? ~now ~ completed total syntheses of two members, i.e. (+)-verbaxenine (249) and (2)-chaenorhine (250), of the polyamine family of alkaloids. Their strategy is based on successive ring expansions of smaller lactam systems, and is illustrated in Scheme 8 for (&)-chaenorphine. Since the publication that compactin (251), a fungal metabolite of Penicillium brevicompactum, is a potent inhibitor of rat liver microsomal 3-hydroxy3-methylglutaryl CoA reductase, the rate-controlling enzyme in cholesterol biosynthesis, the molecule and its close relative mevinolin (252) have been the subjects of intense synthetic activity. During 1983 no less than three total syntheses of compactin and one of mevinolin were and several research groups have outlined approaches to the salient structural features found in these important molecules.98 There have been many outstanding examples of the chiral syntheses of natural products from carbohydrates published in the past few years. One particularly outstanding example however, is the short and efficient synthesis of (-)-shikimic acid (257) described by Fleet and his co-workers,w which uses the readily available mesylate (253) from D-mannose as starting material. Displacement of the mesylate with the phosphonate anion (254) first leads to the protected alcohol

(253)

(251) R = H

(252) R = Me 0 OH

OH

II

H. H. Wassermann and R. P. Robinson, Tetrahedron Lett., 1983,24,3669. H . H. Wassermann, R. P. Robinson, and C. G. Carter, J . Am. Chem. SOC., 1983, 105, 1697. 94 P. A. Grieco, R. E. Zelle, R. Lis, and J. Finn, J . Am. Chem. SOC., 1983, 105, 1403. 95 C. Hsu, N. Wang, L. H. Latimer, and C. J. Sih, J. Am. Chem. Soc.,1983,105,593. % N. N. Girotra and N. L. Wendler, Tetrahedron Lett., 1983, 24,3687. (n M. Hirama and M. Iwashita, Tetrahedron Lett., 1983, 24, 1811. 98 E.g. E. A . Deutsch and B. B. Snider, Tetrahedron Lett., 1983, 24, 3701. G. W. J. Fleet and T. K. M. Shing, J . Chem. SOC., Chem. Commun., 1983,849.

93

19

540

General and Synthetic Methoak

(255), which is then deprotected and deprotonated to produce the ring-opened intermediate (256). Intramolecular olefination, followed by deprotection, then completes this neat synthesis of shikimic acid. Other interesting natural products whose syntheses have been achieved during the period of the Report include the Laurencia-derived cyclic ethers (258) and (259),'O0 the fungal metabolite cryptosporiopsin (260) ,lol and the intriguing 1,6methano[ 101annulene (261) from the sponge Pleraplysilla spinifera. Io2

Br

(259)

HO

CI (260)

A. B. Holmes, C. L. D. Jennings-White, andD. A. Kendrick, J . Chem. SOC.,Chem. Commun., 1983, 415. Io1 G. B. Henderson and R. A. Hill, J . Chem. SOC.,Perkin Trans. 1, 1983,2595. I M J . A. Marshall and R . E. Conrow, J . Am. Chem. SOC., 1983,105, 5679. loo

Reviews on General Synthetic Methods COMPILED BY G. PATTENDEN AND G. M. ROBERTSON

1 Olefins

E. Block, ‘Olefin Synthesis by Deoxygenation of Vicinal Diols’, Org. React., 1984, 30, 457. W. J. Stec, ‘Wadsworth-Emmons Reaction Revisited’, Acc. Chem. Res., 1983, 16, 411. J. E. McMurry, ‘Titanium-Induced Dicarbonyl-Coupling Reactions’, Acc. Chem. Res., 1983, 16, 405. K. J. Ivin, ‘Olefin Metathesis’ Academic Press, New York, 1983. B. Giese, ‘Formation of CC Bonds by Addition of Free Radicals to Alkenes’, Angew. Chem., Int. Ed. Engl., 1983, 22, 753. W. Smadja, ‘ElectrophilicAddition to Allenic Derivatives: Chemo-, Regio-, and Stereochemistry and Mechanisms’, Chem. Rev., 1983, 83, 263.

2 Aldehydes and Ketones P. Brownbridge, ‘Silyl Enol Ethers in Synthesis-Part 1’,Synthesis, 1983,l; Part 11, ibid., p. 85. D. G. Morris, ‘Carbonyl Group Transpositions’, Chem. SOC.Rev., 1982,11,397. V. V. Kane, V. Singh, A. Martin, and D. L. Doyle, ‘The Chemistry of 1,2Carbonyl Transpositions’, Tetrahedron, 1983, 39, 345. J. K. Whitesell and M. A. Whitesell, ‘Alkylation of Ketones and Aldehydes via their Nitrogen Derivatives’, Synthesis, 1983, 517. D. J. Ager, ‘Silicon-containing Carbonyl Equivalents’, Chem. SOC.Rev., 1982, 11, 493. J. D. Albright, ‘Reactions of Acyl Anion Equivalents Derived from Cyanohydrins, Protected Cyanohydrins, and a-Dialkylaminonitriles’, Tetrahedron, 1983, 39, 3207. N. H. Werstiuk, ‘Homoenolate Anions and Homoenolate Anion Equivalents. Mechanistic Aspects and Synthetic Applications’, Tetrahedron, 1983, 39, 205. G. Consiglio and P. Pino, ‘Asymmetric Hydroformylation’, Top. Curr. Chem., 1982, 105, 77.

3 Carboxylic Acids A. J. L. Cooper, J. Z . Ginos, and A. Meister, ‘Synthesis and Properties of the a-Keto Acids’, Chem. Rev., 1983, 83, 321. S. R. Ramadas, P. S. Srinivasan, J. Ramachandran and V. V. S. K. Sastry, ‘Methods of Synthesis of Dithiocarboxylic Acids and Esters’, Synthesis, 1983, 605.

541

542

General and Synthetic Methods 4 Alcohols, Halogeno-compounds,and Ethers

W. Hartwig, ‘Modern Methods for the Radical Deoxygenation of Alcohols’, Tetrahedron, 1983, 39, 2609. B. R. Castro, ‘Replacement of Alcoholic Hydroxyl Groups by Halogens and Other Nucleophiles via Oxyphosphonium Intermediates’ , Org. React. , 1983, 29, 1. M. V. Mavrov, ‘Advances in the Chemistry of a-Haloallenes’,Russ. Chem. Rev., 1982, 51, 887. R. E. Bands, ‘Preparation, Properties and Industrial Applications of Organofluorine Compounds’, Wiley , New Jersey, 1982. M. V. Bhatt and S. U. Kulkarni, ‘Cleavage of Ethers’, Synthesis, 1983, 249.

5 Nitrogen-containingFunctional Groups R. B. Cheikh, R. Chaabouni, A. Laurent, P. Mison, and A. Nafti, ‘Synthesis of Primary Allylic Amines’, Synthesis, 1983, 685. M. B. Gasc, A. Lattes, and J. J. Perie, ‘Amination of Alkenes’, Tetrahedron, 1983, 39, 703. P. W. Hickmott , ‘Enamines: Recent Advances in Synthetic Spectroscopic, Mechanistic, and Stereochemical Aspects-11’ , Tetrahedron, 1982, 38, 3363. T. L. Gilchrist, ‘Nitroso-alkenes and Nitroso-alkynes’, Chem. SOC. Rev., 1983, 12, 53. J. 2. Witczak, ‘Synthesis and Preparative Applications of Monosaccharide Thiocyanates’ , Heterocycles, 1983, 20, 1435. V. G. Granik, ‘Advances in the Chemistry of Amidines’, Russ. Chem. Rev., 1983, 52, 377.

6 Organometallics General ‘Organometallic Chemistry Directed Toward Organic Synthesis’, ed. J. Tirouflet and M. Schlosser , Pure Appl. Chem., 1983,55, (11). D. W. Macomber, W. P. Hart, and M. D. Rausch, ‘Functionally Substituted Cyclopentadienyl Metal Compounds’, Adv. Organomet. Chem., 1983, 21, 1.

Transition Elements ‘Transition Metals in Organic Synthesis’, ed. R. Scheffold, Wiley-Interscience, New York, 1984. J.-E. Backvall, ‘Palladium in Some Selective Oxidation Reactions’, Acc. Chem. Res., 1983, 16, 335. B. Weidmann and D. Seebach, ‘Organometallic Compounds of Titanium and Zirconium as Selective Nucleophilic Reagents in Organic Synthesis’, Angew. Chem., Int. Ed. Engl., 1983,22, 31.

Reviews on General Synthetic Methods

543

M. T. Reetz, ‘Organotitanium Reagents in Organic Synthesis. A Simple Means to Adjust Reactivity and Selectivity of Carbanions’, Top. Curr. Chem., 1982,106, 3. R. S. Dickson, ‘Organometallic Chemistry of Rhodium and Iridium’, Academic Press, New York, 1983. D. Astruc, ‘Organo-Iron Complexes of Aromatic Compounds. Applications in Synthesis’, Tetrahedron, 1983,39,4027.

Boron and Thallium A. Suzuki, ‘Some Aspects of Organic Synthesis Using Organoborates’, Top. Curr. Chem., 1983, 112, 67. ‘Synthetic Reagents, Volume 5, Thallium(m) Acetate and Trifluoroacetate; Ammonia; Iodine Monochloride’, ed. J. S. Pizey , Wiley-Interscience, New York, 1983. 7 Ring Synthesis C. Santelli-Rouvier and M. Santelli, ‘The Nazarov Cyclization’, Synthesis, 1983, 429. R. J. Ferrier and P. Prasit, ‘Routes to Prostaglandins from Sugars’, Pure Appl. Chem., 1983, 55, 565. V. A. Mironov, A. D. Federovich, and A. A. Akhrem, ‘Synthetic Methods for Cyclohexa-1,3-dienes’, Russ. Chem. Rev., 1983, 51, 43. R. W. Alder, ‘Medium-Ring Bicyclic Compounds and Intrabridgehead Chemistry’, Acc. Chem. Res., 1983, 16, 321. L. N. Mander, ‘New Strategies for the Construction of Highly Functionalised Organic Molecules: Applications to CI9 Gibberellin Synthesis’, Acc. Chem. Res., 1983, 16, 48. J. Redpath and F. J. Zeelen, ‘Stereoselective Synthesis of Steroid Side-chains’, Chem. SOC.Rev., 1983,12,75. 8 Heterocycles A. S. Rao, S. K. Paknikar, and J. G. Kirtane, ‘Recent Advances in the Preparation and Synthetic Applications of Oxiranes’, Tetrahedron, 1983, 39, 2323. J. K. Crandall, and M. Apparu, ‘Base-Promoted Isomerizations of Epoxides’, Org. React., 1983, 29, 345. E. G. Lewars, ‘Oxirenes’, Chem. Rev., 1983, 83, 519. G. A. Iacobucci and J. G. Sweeney, ‘The Chemistry of Anthocyanins, Anthocyanidins and Related Flavylium Salts’, Tetrahedron, 1983, 39, 3005. G. L’abbe, ‘Some Ring Transformation Reactions of Sulphur-Containing Heterocycles’, Tetrahedron, 1982, 38, 3537. B. Iddon, ‘Cycloaddition, Ring-Opening and Other Novel Reactions of Thiophenes’, Heterocycles, 1983, 20, 1127. L. H. Klemm, ‘Synthesis of Tetracyclic and Pentacyclic Condensed Thiophene Systems’, Adv. Heterocycl. Chem., 1982, 32, 127.


544

M. P. Sammes and A. R. Katritzky, ‘The 2H- and 3H- Pyrroles’, Adv. Heterocycl. Chem., 1982, 32, 234. S. M. Weinreb and R. R. Staib, ‘Synthetic Aspects of Diels-Alder Cycloadditions with Heterodienophiles’, Tetrahedron, 1982, 38, 3087. D. L. Boger, ‘Diels-Alder Reactions of Azadienes’, Tetrahedron, 1983,39,2869. I. Hermecz and Z. Meszaros, ‘Chemistry of Pyrido[ 1,2-a]pyrimidines’, Adv. Heterocycl. Chem., 1983, 33,242. A. Albert, ‘Annelation of a Pyrimidine Ring to an Existing Ring’, Adv. Heterocycl. Chem., 1982, 32, 3. V. K. Majectic and G. R. Newkome, ‘Pyridinophanes, Pyridinocrowns, and Pyridocryptands’, Top. Curr. Chem., 1982, 106, 79. V. Ballah, R. Jeyaraman, and L. Chandrasekaran, ‘Synthesis of 2,6-Disubstituted Piperidines, Oxanes and Thianes’, Chem. Rev., 1983, 83,379. R. Rastogi and S. Sharma, ‘2-Aminobenzimidazoles in Organic Synthesis’, Synthesis, 1983, 861. S.-J. Lee and J. M. Cook, ‘Synthesis of Azaphenalenes’, Heterocycles, 1983,20, 87. B. Robinson, ‘The Fischer Indole Synthesis’, Wiley-Interscience, New York, 1982. W. W. Paudler and R. M. Sheets, ‘Recent Developments in Naphthyridine Chemistry’, Adv. Heterocycl. Chem., 1983, 33, 147. J. P. Freeman, ‘A4-Isoxazolines(2,3-Dihydroisoxazoles)’,Chem. Rev., 1983,83, 241. F. Kurzer, ‘1,2,4-Thiadiazoles’, Adv. Heterocycl. Chem., 1982, 32, 286. M. H. Elnagdi, H. A. Elfahham, and G. E. H. Elgemeie, ‘Utility of a$Unsaturated Nitriles in Heterocyclic Synthesis’, Heterocycles, 1983, 20, 519. 9 Electrochemical Methods M. M. Baizer and H. Lund, ‘Organic Electrochemistry’, 2nd Ed., Marcel Dekker, New York, 1983. J. S. Swenton, ‘Quinone Bis- and Monoketals via Electrochemical Oxidation. Versatile Intermediates for Organic Synthesis’, Acc. Chem. Res., 1983,16,74. 10 Photochemical Methods

G. G. Wubbels, ‘Catalysis of Photochemical Reactions’, Acc. Chem. Res., 1983, 16, 285. W. H. Laarhoven, ‘Photochemical Cyclizations and Intramolecular Cycloadditions of Conjugated Arylolefins’, Recl.: J. R . Neth. Chem. SOC.,1983,102,185. P. S. Marian, ‘The Photochemistry of Iminium Salts and Related Heteroaromatic Systems’, Tetrahedron, 1983,39.3845. F. B. Mallory and C. W. Mallory, ‘Photocyclization of Stilbenes and Related Molecules’, Org. React., 1983, 30, 1. H. Rau, ‘Asymmetric Photochemistry in Solutions’, Chem. Rev., 1983, 83, 535. M. A. Fox, ‘Organic Heterogeneous Photocatalysis: Chemical Conversions Sensitized by Irradiated Semiconductors’, Acc. Chem. Res., 1983, 16, 314.


545

R. G. Salomon, ‘Homogeneous Metal-Catalysis in Organic Photochemistry’ , Tetrahedron, 1983, 39,485. W. H. Laarhoven, ‘Photochemical Cyclizations and Intramolecular Cycloadditions of Conjugated Arylolefins. Part 2: Photocyclizations without Dehydrogenation and Photocycloadditions’, Rec. : J . R. Neth. Chem. SOC., 1983,102,241. A. G. Schultz, ‘Photochemical Six-Electron Heterocyclization Reactions’, Acc. Chem. Res., 1983, 16,210. S. T. Reid, ‘The Photochemistry of Oxygen- and Sulphur-Containing Heterocycles’, Adv. Heterocycl. Chem., 1983, 33, 1.

11 Peptide Synthesis V. N. R. Pillai, ‘New Perspectives in Polymer-Supported Peptide Synthesis’, Top. Curr. Chem., 1982, 106,119. S. V. Vurov and M. P. Smirnova, ‘Protection of the Amino Group in Peptide Synthesis’, Russ. Chem. Rev., 1982, 51, 902.

12 Asymmetric Synthesis K. B. Sharpless, C. H. Behrens, T. Katsuki, A. W. M. Lee, V. S. Martin, M. Takatani, S. M. Viti, F. J. Walker, and S. S. Woodward, ‘Stereo- and Regioselective Openings of Chiral 2,3-Epoxy Alcohols. Versatile Routes to Optically Pure Natural Products and Drugs. Unusual Kinetic Resolutions’, Pure Appl. Chem., 1983,55, 589. H. Haubenstock, ‘Asymmetric Reductions with Chiral Complex Aluminium Hydrides and Tricoordinate Aluminium Reagents’, Top. Stereochem., 1983, 14,213. M. Nakazaki , ‘The Synthesis and Stereochemistry of Chiral Organic Molecules with High Symmetry’, Top Stereochem., 1984, 15, 199. S. Hanessian, ‘Synthetic Design with Chiral Templates’, Pergamon Press, Elmsford, N.Y. , 1983. E. I. Klabunovskii, ‘Advances in Enantioselective Hydrogenation in the Presence of Chiral Complexes of Rhodium, Palladium, and Cobalt’, Russ. Chem. Rev., 1982, 51,630. S. W. Knowles, ‘Asymmetric Hydrogenation’, Acc. Chem. Res., 1983, 16, 106. H. G. Floss and M.-D. Tsai, ‘Stereochemistry of Biological Reactions at Proprochiral Centres’, Top. Stereochem., 1984, 15, 253. T. Hayashi and M. Kumada, ‘Asymmetric Synthesis Catalysed by TransitionMetal Complexes with Functionalised Chiral Ferrocenylphosphine Ligands’, Acc. Chem. Res., 1982, 15,395. S. Masamune and W. Choy, ‘Advances in Stereochemical Control: The 1,2- and 1,3-Diol Systems’, Aldrichimica Acta, 1982, 15, 47. G. Quinkert and H. Stark, ‘Stereoselective Synthesis of Enantiomerically Pure Natural Products’, Angew. Chem., Int. Ed. Engl., 1983, 22, 637.

546


C. H. Behrens, ‘New Transformations of 2,3-Epoxy Alcohols and Related Derivatives. Easy Routes to Homochiral Substances’,Aldrichimica Acta, 1983, 16, 67. 13 General ‘The Total Synthesis of Natural Products, Volume 5, Sesquiterpenes’, ed. J. ApSimon, Wiley-Interscience, New York, 1983. R. B. Bates and C. A. Ogle, ‘Carbanion Chemistry’, Springer-Verlag,New York, 1983. L. Rossa and F. Vogtle, ‘Synthesis of Medio- and Macrocyclic Compounds by HiLh Dilution Principle Techniques’, Top. Curr. Chem., 1983, 113, 1. P. Caubkre, ‘Complex Reducing Agents (CRA’s) - Versatile, Novel Ways of Using Sodium Hydride in Organic Synthesis. [New Synthetic Methods (39)], Angew. Chem., Int. Ed. Engl., 1983, 22, 599. D. Ginsburg, ‘The Role of Secondary Orbital Interactions in Control of Organic Reactions’, Tetrahedron, 1983, 39, 2095. S. Warren, ‘Organic Synthesis: The Disconnection Approach’, Wiley , New Jersey, 1982. E. Stahl, ‘A Quarter Century of Thin-Layer Chromatography - An Interim Report’, Angew. Chem., Int. Ed. Engl., 1983, 22, 507. P. J. Strong and M. R. White, ‘Triflic Acid and its Derivatives’, Aldrichimica Acta, 1983, 16, 15. J. Ackroyd and F. Scheinmann, ‘The Synthesis of Leukotrienes: A New Class of Biologically Active Compounds Including SRS-A’, Chem. SOC. Rev., 1982,11, 321. R. H. Green and P. F. Lambeth, ‘Leukotrienes’, Tetrahedron, 1983, 39, 1687. P. Cmagne, J. Elguero, and R. Gallo, ‘The Present Use and the Possibilities of Phase Transfer Catalysis in Drug Synthesis’, Heterocycles, 1983, 20, 1379. U. E. Wiersum, ‘Flash Vacuum Thermolysis, A Versatile Method in Organic Chemistry. Part 11, Fragmentation Patterns in Specific Classes’, Recl.: J . R. Neth. Chem. SOC., 1982, 101, 365. F. Minisci, A. Citterio, and C. Giordano, ‘Electron-Transfer Processes: Peroxydisulphate, a Useful and Versatile Reagent in Organic Chemistry’,Acc. Chem. Res., 1983, 16,27. R. M. Adlington and A. G. M. Barrett, ‘Recent Applications of the Shapiro Reaction’, Acc. Chem. Res., 1983, 16, 55. T. H. Black, ‘The Preparation and Reactions of Diazomethane’, Aldrichimica Acta, 1983, 16, 3. L. Stella, ‘Homolytic Cyclization of N-Chloroalkenylamines [New Synthetic Methods (38)]’, Angew. Chem., Int. Ed. Engl., 1983, 22, 337. A. Zamoiski, A. Banaszek, and G. Grynkiewicz, ‘The Synthesis of Sugars from Non-Carbohydrate Substrates’, Adv. Carbohydr. Chem. Biochem., 1982, 40, 1. G . M. Whitesides and C.-H. Wong, ‘Enzymes as Catalysts in Organic Synthesis’, Aldrichimica Acta, 1983, 16, 27. J. Retey and J. A. Robinson, ‘Stereospecificity in Organic Chemistry and Enzymology’, Volume 13, Verlag Chemie, Deerfield Beach, FL. , 1982.


547

14 Miscellaneous

S. A. Narang, ‘DNA Synthesis’, Tetrahedron, 1983,39,3. H. J. Sigel, ‘Lithium Halocarbenoids. Carbanions of High Synthetic Versatility’, Top. Curr. Chem., 1982, 106,55. A. P. Croft and R. A. Bartsch, ‘Synthesis of Chemically Modified Cyclodextrins’,

Tetrahedron, 1983, 39, 1417. G. (3. Yakobson and N. E . Akhmetora, ‘Alkali Metal Fluorides in Organic Synthesis’, Synthesis, 1983, 169. K. B. Beckers, ‘Synthesis of Stilbenes’, Synthesis, 1983, 341. W. H. Okamura, ‘Pericyclic Reactions of Vinylallenes: From Calciferols to Retinoids and Drimanes’, Acc. Chem. Res., 1983, 16, 81. B. B. Jarvis and E. P. Mazzola, ‘Macrocyclic and Other Novel Trichothecenes: Their Structure, Synthesis and Biological Significance’, Acc. Chem. Res., 1982, 15, 388. H.-J. Timpe and A. V. El’tsov, ‘Pseudoazulenes’, Adv. Heterocycl. Chem., 1983, 33, 185. E . F. V. Scriven, ‘4-Dialkylminopyridines: Super Acylation and Alkylation Catalysts’, Chem. Soc. Rev., 1983, 12, 129.

Author Index

Abe, N., 144 Abe, Y., 190 Abecassis, J . , 62 Aben, R. W. M., 410 Abou-Gharbia, M., 449 Aboujaoude, E. E., 113 Aburaki, S., 348, 527 Acevedo, 0. L., 487 Achiwa, K., 194,460 Acquaah, S. 0 ., 470 Acs, T., 485 Adam, G., 302,478 Adam, M. A. 359 Adam, W., 412 Adamczyk, M., 137,291 Adams, B. R., 38,358,405 Adkins, R. L., 86 Adlington, R. M., 110, 192, 308,345,491 Aebi, J. D., 136, 340 Aebischer, B., 298 Afzali, A , , 235 Agawa, T., 4, 51, 107, 146 Ager, D. J., 90,344 Aggarwal, S. K . , 280 Agho, M. O., 432,433 Agoh, B., 448 Agosta, W. C., 303 Ahlbrecht, H., 96,155,419 Ahn, K. H., 232 Aizpurua, J. M., 84,227 Akiba, K., 170,373, 418 Akiba, M., 520 Akimoto, K., 531 Akita, M., 8,50, 107,221, 317,326 Akita, T., 198 Akiyama, S., 239 Akiyama, Y., 155 Akkemann, S., 382 Akoi, M . , 505 Akssira, M., 43, 178 Alabori, S., 239 Alazard, J.-P., 426 Albaugh-Robertson, P., 162 Albright, J. D., 91, 289 Albright, J. O., 63 Alder, R. W., 483 Alexakis, A., 32, 58, 59,103, 129,233,333,404 Alexander, R. P., 123, 148 Alfonsi, C., 421 Al-Hassan, M. I., 47, 90,363 Allen, K. M., 440

Allmann, R., 489 Alneri, E., 407 Alonso, M. E., 421 Alonso-Cires, L., 144,220 Alpegiani, M., 494 Alper, H., 2 , 4 , 41, 86, 132, 138, 140,150,237, 335,488 Alvarez, A., 407 Alverez, M.. 264 Alvernhe, G., 480 Amaratunga, W . , 88 Ameer, F., 148 Amer, I., 4 Ammanamanchi, K., 247,339 Amos, R. A., 144 Amupitan, J . O., 190, 282 Anciaux, A. J., 146 Anderson, D. K., 510 Anderson, J. S .,295 Anderson, K. W. 367 Anderson, 0. P., 182 Anderson, R. C., 537 Anderson, S. H., 219 Ando, K., 51, 108 Ando, M., 120,193, 256,477 Ando, R., 149,379,382 Ando, T., 10,20, 21,84, 117, 226,293,372 Ando, W., 128,301 Andrews, D. R., 401 Andrieux, J . , 302,478 Andriollo, A , , 8 Aneja, R., 143 Angeletti, E., 11, 371 Angermann, A , , 136 Angus, R. O., 393 Annis, G. D., 334, 391, 488, 497 Annunziata, R., 128,137, 186, 341,349 Anton, D. R., 10, 233 Antonioletti, R., 408 Aoe, K., 184 Aquadro, R. E., 204 Arai, I., 197 Araki, Y., 394 Arase, A., 76 Arcadi, A . , 130 Archibald, T. G . , 411 Arct, J . , 417 Arimoto, M., 33,103, 175 Arison, B. H., 197,451 Aristoff, P. A., 6, 388 Arita, Y . , 62

548

Ariyoshi, K., 86,227 Armstrong, R. J . , 399 Arrhenius, P., 398 Arrieta, A., 144, 283, 307 Arseniyadis, S., 50, 344, 465 Arvanaghi, M., 121,247,290, 293,307, 366 Arya, P. S . , 220 Arzoumanian, H., 232 Asai, N., 117, 351 Asami, K., 324 Asami, M., 112, 144, 173, 382 Asaoka, M., 507 Asato, A. E., 83 Asensio, G., 144,220, 261 Ashcroft, P. L., 298 Aslam, M., 60 Assercq, J.-M., 411 Atherton, E., 198 Attanasi, O., 122, 283 Attia, A., 253 Atwal, K. S., 172 Aubouet, J . , 129 Auge, J . , 409 Avery, M. A., 536 Awad, S. B., 407 Ayaguchi, Y., 8 Ayi, A. I., 194 Ayyangar, N. R., 245 Aznar, F., 265, 267, 302 Azuhata, T., 147 Azuma, K., 222 Baba, A., 452 Baba, O., 428 Baba, T., 93 Babiak, K. A., 532 Babin, P., 388 Babler, J. H., 206 Baboulene, M., 199, 269 Babudri, F., 153 Baca, S. B., 135 Bachi, M. D., 495 Back, T. G., 115 Backvall, J. E., 268, 315,321 Badot, O., 274 Badoud, R., 537 Baettig, K., 159 Bauml, E., 66 Bagheri, V., 89,169,227, 333, 351 Bailey, P. D., 276, 537 Baillargeon, V. P., 93, 156, 234,333

Author Index Baioni, V., 449 Baird, G . J., 324, 325 Baizer, M. M., 87 Bajgrowicz, J. A., 192 Bajwa, B. S . , 311 Bajwa, J. S . , 136 Baker, R., 85, 435 Baker, R. J . , 181 Baker, W. R., 260 Bakker, C. G., 174 Bal, B. S . , 121 Balabane, M., 268 Baldwin, J. E., 110, 192, 276, 294,308,447, 496, 537 Baldwin, J. J . , 451 Baliah, V., 472 Bali Singh, B., 122 Balkovec, J . M., 163, 174,405 Ballabio, M., 448 Ballesteros, P., 41 Ballini, R., 4, 113, 213,226, 235,298 Balme, G., 122 Bamezai, S., 295 Ban, T., 64, 393 Ban, Y . , 175,467,476,485 Bandy, J . A . , 325 Banfi, L., 112,155,215 Banfi, S . , 112,206,407 Bankaitis, D. M., 426, 435 Banks, B. J., 276 Banwell, M. G., 157 Baraldi, P. G., 158, 265, 501 Barbarella, G., 388 Barber, Y. J . , 135 Barbier, P., 176 Barbot, F., 122, 188 Barco, A., 158, 501 Barker, A. J . , 502 Barker, R.,358 Barlos, K . , 198 Barluenga, J., 18, 144, 187, 219,220,261,262,265,267, 282, 302,549 Barner, B. A,, 435 Barnes, J. F., 298 Barr, N., 336 Barrett, A. G. M . , 276, 345, 489,491 Barriere, J. C., 384 Barrish, J . C., 200, 353 Barrow, M. J., 298 Barry, C. N., 228, 409,413 Barth, J . , 192 Barthels, R., 198 Bartlett, P. A . , 53 Bartnik, R., 454, 455 Barton, D. H. R., 1,23, 87, 142,232,251 Bartsch, H. 289 Bartsch, R . A . , 232,241,243 Baruah, J. N., 8, 121,226, 228 Baruah, N. C., 226,228 Baruah, R. N., 8,226

549 Basak, A., 192,387 Basavaiah, D., 75, 109,356 Bashiardes, G., 23,232 Batmangherlich, S., 415 Battig, K., 404, 502 Battiste, M. A . , 173 Batu, G., 117 Bauer, D. P., 193 Bauer, L. J . , 244 Bauer, P. E., 167, 344 Baum, K., 411 Baxter, A. D., 522 Bayod, M., 267 Bayon, A. M., 261 Baze, M. E., 72 Beak, P., 188,261,264, 391, 468 Beau, J.-M., 348, 527 Beauchamp, P. D., 65 Beaulieu, P. L., 172, 378 Beaumont, D., 253 Becker, A. M., 247 Becker, K. B., 7 Becker, P. N., 316 Beckwith, A. L. J., 4,232, 389,490 Bedeschi, A., 494 Bednarski, M., 428,429 Beebe, T. R., 86 Beeley, N. R. A., 296 Beeman, D., 13 Beguin, C. G., 133 Behnke, M., 56 Behr, A , , 285 Bell, A. P., 239 Bell, T. W., 244 Bellassoued, M., 139, 301,456 Belleau, B., 194 Belletire, J. L., 11, 12, 144 Belli, A., 140 BelluS, D., 236 BeMiller, J. N., 283 Benetti, S., 158, 501 Benezra, C., 176 Ben-Ishai, D., 173 Benneche, T., 235 Benner, S. A., 133 Bennetau, B., 366 Benoiton, N. L., 191 Bergbreiter, D. E . , 269, 303 Berger, G. D., 487 Bergman, R. G., 316 Bergmann, A , , 474 Berkowitz, P. T., 411 Berlan, J., 129 Bernad, P., 18,349 Bernadi, R., 431 Bernardinelli, G., 133 Bernardini, A . , 192 Bernath, G., 453 Bernauer, K., 193 Bernet, B., 272 Bernheim, M., 75,270 Berryhill, S. R., 334

Bertani, R., 8 Berthet, M., 243 Berti, C., 301 Bertrand, M . , 116, 235 Bertz, S. H., 122 Beslin, P., 166 Besselievre , R . , 288 Bestmann, H. J., 72,94,184 187 Betancor, C., 468 Betts, M. J., 345,489,491 Beugelmans, R., 457 Bevinakatti, H. S . , 189, 298 Bhat, N. G., 75, 109,356 Bhat, S. V., 311 Bhatnagar, S. P., 122, 253 Bhatt, M. V . , 225 Bhattacharya, A., 151,349 Bhupathy, M., 524 Bibang Bi Ekogha, C., 33, 107, 342 Bickelhaupt, F., 382 Bidd, I . , 138 Bigi, F., 150,359,421 Billedeau, R. J., 189 Biller, S. A., 177 Billington, D. C., 100 Bills, L. J . , 241 Biloski, A. J., 300 Binger, P., 386 Bioul, J. P., 285 Birch, A. M., 500 Bishop, C . E., 64 Bishop, P. M . , 400 Biswas, A., 491 Blanchard, M., 391 Blandy, C., 306 Blarer, S. J., 150 Bloch, R., 34,62, 221,376 Block, E., 60 Blum, J . , 4 Bluthe, N., 56 Boardman, L. D., 30, 384 Boaventura, M., 406 Boche, G., 75,270 Bock, M. G., 193,279 Bodarski, R., 39,99, 398 309 Boden, N., Boeckmann, R. K., jun., 120, 394,396,426,510 Bolcskei, H., 485 Bonnemann, H., 86 Boes, M . , 193,340 Boettig, K., 133 Bogardus, C. C., 86 Bogdan, S . , 493 Boger, D. L., 302,473 Boldrini, G. P., 153,216,245 Bonde, S. E., 16,349 Bonin, M . , 288 Bonjouklian, R., 352,496 Booth, P. M., 125,181 Borchardt, R. T., 4, 180,297 Bordeleau, L., 378

550 Born, W., 6 Bosch, J., 466 Bosch, R. J. 381 Bosma, R. H. A., 57,287 Bottaro, J . C., 110,308 Boukouvalas, J., 440 Boulanger , W., 65 Boussac, G. 418 Bowen, P., 179 Bowers-Nemia, M . M . , 452 Bowser, J. R., 185,280 Boyer, J., 159 Boyes, R. H. O., 435 Bradbury, R . , 298 Bradshaw, J . S., 234,239 Brady, W . T . , 432,433 Branchaud, B. P., 303 Brandange, S., 3 Brandsma, L., 64,238,265, 347 Braun, M., 136,212 Braverman, S . , 375 Bravo, P., 431 Brayer, J . - L . , 426 Breitmaier, E., 104 Bremmer, M. L., 302,473,514 Breiia, L. J . , 185 Brennan, J., 494,496 Brickner, S. J . , 183 Bridges, A . J., 36, 64,218, 344,374 Bringmann, G., 283 Brinkman, A . , 386 Broadhurst, M. J . , 112 Bronneke, A . , 169 Brook, M. A . , 120,144,187, 282,365 Brookes, M. H., 224 Brookhart, M., 319,381 Brooks, G., 495 Broom, D. M. P., 435 Brown, A. M., 491 Brown, D. W., 288 Brown, E., 134 Brown, H . , 94, 357 Brown, H. C., 3,53,75,91, 109,200,232,353,354,355 356 Brown, J . M., 112 Brown, K. C., 295 Brown, L., 224 Brown, P. J . , 374 Brown, P. R., 239 Brown, R. F. C., 247 Brownbridge, P., 123,162 Browne, E. J., 452 Bruggemann, K., 474 Brugidou, J . , 186 Brun, P . , 68 Brunet, J.-J., 132, 140 Brunner, H . , 319,381 Bucciarelli, M., 211, 448 Buchholz, M . , 196 Buchwald, S. L., 69

General and Synthetic Methods Buckley, T.F.,111, 479 Budny, J., 157 Buchi, G., 56 Butikofer, P.-A., 82 Buhr, C. A . , 155 Buijs, W., 228 Bulman-Page, P. C., 121 Bunce, R. A . , 99, 128,149, 224,396 Burbaum, B. W., 394 Burford, C., 409 Burger, U., 440 Burk, R. M., 462, 515 Burkard, U., 192 Burke, S., 501 Burke, S . D., 165,394 Burks J . , 376 Burns, T. P., 350 Burton, D. J., 20,371,372 Bushan, V . , 227 Bushby, R. J., 309 Buss, A. D., 12,370 Butula, I., 197 Byrboth, B., 163 Byrn, S., 340,522 Cabeza, J . A . , 196,312 Cacchi, S., 130,476 Caine, D., 179 Cainelli, G., 134, 228, 245, 384 Caldwell, C. G., 393 Callan, G. R., 355 Calverley, M . J . , 261 Calvitti, S., 421 Cambie, R. C., 309 Campbell, A. L., 532 Campbell, S., 425 Campos, P. J . , 144, 220 Camps, F., 228, 408 Canonne, P., 43, 178 Caporusso, A. M . , 109 Capuano, L., 421 Cardillo, G., 223,224,270 Carini, D. J., 387 Cariou, M . , 291 Carlson, J. G., 400, 507 Carlson, R. M . , 44, 182 Carman, M . , 197 Carniato, D., 107 Carpino, L. A., 197 Carr, R. V. C., 376, 392 Carroll, G. L., 500 Carruthers, W., 335,477 Carson, J . F., 197 Carter, C. G., 487,539 Carter, M. C., 211 Carturan, G., 8 Casadei , M. A. , 303 Casamor, J. M . , 228 Casares, A . M., 56, 57 Casati, R . , 85, 227 Cascaval, A . , 264 Casiraghi, G., 150, 359, 421 Casnati, G., 150, 359, 421

Cassani, G., 59,233,356 Castaldi, G., 140 Castedo, L., 300 Castro, B., 113,197,279 Castro, B. R., 228 Cate, L. A. 141 Catellani, M . , 132 Cativiela, C., 194, 196, 312 Caubere, P., 132, 140 Caubi&re,P., 204 Cava, M. P., 285 Cavalla, D., 50,188,281,370 Cazeau, P., 274 Cazes, B., 53,218 Cebulska, Z . , 455 e ef elin, P., 233 CBlkrier, J. P . , 45, 163, 266 Cella, J. A . , 119, 139 Cenini, S., 309 Cha, J. K . , 201 Chabaud, B . , 122,371 Chackalamannil, S., 397 Chadha, M. S., 524 Chakraborti, A. K., 147 Chakraborty, T. K., 227 Chakravarty, P. K., 175 Chaly, T., 120, 365 Chamberlin, A. R., 171,463, 516 Champney , B ., 8 6 Chan, D. M. T., 388 Chan, M. F., 496 Chan, T. H., 120, 144, 187, 208,282,361,365,366,382 Chandler, M . , 143 Chandrasekaran, L., 472 Chandrasekaran, S., 227,245 Chandrasekharan, J., 200 Chang, H., 197 Chang, T. C. T., 176,319 Chao, S . , 473 Chapleur, Y . , 536 Chapman, D .,56 Chapuis, C . , 504 Charles, G., 262 Charusin, V. N., 253 Chatani, N., 26,93, 159 Chatterjee, A . , 280 Chatterjee, S., 24,89,125, 333,351 Chatzhosifidis, I., 284 Chauhan, S.M. S . , 300 Chauvin, J . , 199 Chawla, H. P. S . , 8 Chen, B., 269 Chen, C. H., 81 Chen, C.-W., 188,264,391 Chen, F. M. F., 191 Chen, S. F., 304, 460 Chen, Y . , 473 Chen, Y.-Q., 399,508 Chen, Y.-Y., 367,457,460 Chhevert, R . , 121,239,287, 290

Author Index Cheng, C. H., 197 Cheng, Y.-S., 473 Cheon, S. H., 510 Chianelli, D., 237 Chiba, K., 175 Chiba, M., 94, 156 Chiba, T., 4 Chida, Y., 254 Chihara, T., 122 Chiharu, M . , 254 Chikashita, H., 285 Chiriac, C. I., 280, 283 Chiusoli, G . P., 132 Choi, V. M. F., 290,366 Chong, J. M., 368 Chorn, T. A., 432 Chou, C. S . , 85,227 Chou, T.-S. 88 Choudhry, S. C., 536 Choukroun, R., 306 Chowdhury, P. K., 121,226 Choy, E., 394 Choy, W., 394 Christ, W. J., 201 Christensen, B. G., 493 Christensen, J. J . , 239 Christol, H., 64, 393 Chtara, R., 301,456 Chu, D. T. W., 86,373 Chuang, C. P. 389 Chucholowski, A,, 168,340 Chuit, C., 32, 127 Chung, J. Y. L., 463,516 Chung, S. K., 151,381 Cichowicz, M. B., 147,226 Cilento, G., 412 Cinquini, M., 128, 137, 186, 341,349 Citterio, A . , 125 Claesson, A , , 58,69, 349 Clardy, J., 172 Clark, L. D., 309 Clauson, K . , 194 Clennan, E. L., 439 Cleophax, J., 384 Clerici, A., 224 Clive, D. L. J., 172,378 Coates, D., 224 Coates, P. M . , 204 Coates, R. M . , 109 Coburn, C. E . , 510 Cockerill, G. S., 400,441 Cohen, T., 524 Colin, J. L., 147 Coll, J., 228, 408 Collignon, N., 113 Collington, E. W., 522 Collins, P., 170 Collins, S., 115 Collum, D. B., 169 Colombo, L., 128,155,215, 341 Colombo, R., 197 Colonna, S., 112,206, 407

55 1 Comins, D. L., 532 CommerGon, A., 491 Commeyras, A., 186 ConceUbn, J. M . , 18,349 Concepcion, J . I. , 468 Confalone, P. N., 191 Conia, J. M . , 406 Connell, A. C., 68 Conrow, R. E . , 540 Consiglio, G . , 18, 196, 236, 321,349 Contento, M . , 134,228 Cook, C. E., 440 Cooke, F., 409 Cooke, M. D., 493 Cooke, M. P., jun., 145 Cooper, C. S . , 300 Cordopatis, P., 198 Cordova, R., 430 Corey, E. J., 63,76, 142,204, 211, 342,365, 377, 389,408, 523 CornClis, A., 237, 296 Cornish, C. A., 370 Corriol, C., 226 Corriu, R. J. P., 32,127, 159 Cortes, D. A., 85,227 Cortes, S . , 262 Cory, R. M., 455 Cossec, B., 192 Cossement, M . , 493 Cossy, J., 376 Cottrell, D. A., 190, 282 Coudert, G., 443 Courtney, L., 537 Cousse, H., 235 Cowan, P. J., 117,138 Cox, D. G., 20, 371 Coxon, J. M . , 217 Cozens, A. J . , 259,309 Cozzi, F., 128,137,186,341, 349 Crabtree R. H,, 10,233, 312 Cram, D. J . , 243,244 Craven, B. M., 394 Crawford, R. J . , 133 Cremner , G., 296 Crich, D., 1, 142 Crimmins, M. T., 426,435 Cristan, H.-J., 64,122, 371, 393 Croce, P. D., 448 Croft, A. P . , 232 Crombie, L., 487 Crosby , J . ,298 Croteau, A. A., 31, 105 Crouse, G . D., 392 Crow, W. D., 454 Csehi, A., 197,204 Cumming, S. A., 335,477 Cummins, C. H., 109 Cunningham, A. F., 224 Cupps, T. L., 291 Curran, D. P., 96, 219,418

Cutolo, M . , 195,266 Cutting, I., 67,72, 105, 167, 221,238,361,375 Cuvigny, T., 57,313, 376 Czech, A., 243 Czech, B., 241,243 Czyzewska, E., 70 Dabbagh, G., 122 Dabbas, N., 309 Dahlman, O., 3 Dahmen, W., 418 Dampawan, P., 113, 298 Dan, S., 515 Dandoize, F., 456 Danelli, R., 384 D’Angeli, F., 449 d’Angelo, J., 117, 219, 391 Danheiser, R. L., 382, 387 Danishefsky, S., 272, 351, 378, 397,428,429,465, 530 Danishefsky, S. J., 436 Dannenberg, W., 43,157 Danon, L., 213 Danopoulos, A. A., 309 Dao, T. V., 204 Darzoide, F., 301 Das, S . , 226 Dashan, L., 339 Daub, J. P . , 439 Dauben, W. G., 99, 128, 149, 224, 356 D’Auria, M . , 408 Dauzonne, D., 295 Daves, G. D., 332 David, S., 230, 409 Davidson, A. H., 415 Davies, A. P., 143 Davies, D. E., 299, 450 Davies, H. M. L., 164 Davies, J., 522 Davies, S. G., 236,312,324, 325,327 Davies, F. A., 407 Davis, J. T., 92, 160,329, 394, 472 Davis, M. W., 312 Davis, W. A., 285 Dawson, B. A., 390,497 Dawson, M. J., 211 Dean, F. M., 431 Debaerdemaeker, T., 489 De Bernardinis, S . , 125 De Buyck, L., 114, 262,303, 456 de Castro Dantas, T. N., 269 De Cicco, G. J., 83 Decker, 0. H. W., 139 De Clerq, P. J . , 394 Dederichs, E., 418 Deep, K . , 453 Degani, I . , 237 Deitsch, E. A., 394 dc Jong, R. L. P., 347


552 Dekerk, J. P., 308 Deketele, M . , 308 De Kimpe, N., 114,262,303, 456 de Koning, H., 462 De las Heras, F. G., 283 Delaumeny, J. M., 251 Delaunay , B .,448 Delmas, M . , 12 Delmazza, D., 445 Delorme, D., 536 Delpuech, J. J., 249 De Luca, 0 . D., 204 De Lucca, G., 226 Dedmailly, G., 536 Demerseman, P., 294 De Mico, A . , 408 Demonceau, A., 146 Denis, J. N., 2, 232 Denmark, S. E., 98,114,387 Denny, M., 83 Depaye, N., 237 Deprks, J.-P., 315, 390,497 Derome, A. E., 294 des Abbayes, H., 140 Desai, R. C., 229 Deschenaux, R . , 193 Deshayes, C., 300 DeShong, P., 525,529 Deshpande, R. P . , 121 Deshpande, S. R., 295 De Silva, D., 483 De Silva, S. O., 188,478 Desmond, R., 57 Desobry, V., 322 de Souza, N. J., 311 Despeyroux, B., 132, 150 Desportes, S. H., 294 Dess, D. B., 85,226 Deutsch, E. A . , 219, 358,398, 539 Dev, S . , 8, 121, 377 Devant, R., 136 devi Manandhar, M., 379 Devlin, J. A,, 358, 435 De Vos, M. J., 372 Dewanckele, J. W., 501 Dewynter, G., 448 Deyo, D., 151,349 Deziel, R ., 378 Dezube, M . , 171 Dhaon, M. K., 199 Dhawan, B ., 244 Dhingra, 0. P., 536 Diaz de Villegas, M. D., 194, 196,312 Dieter, J. W . , 377 Dieter, R. K., 104, 377,433 Di Giamberardino, T., 379 Dillon, J. L., 382 Di Ninno, F., 493 Di Nunno, L., 153 Dion, R. P . , 471 Di Pardo, R. M., 193,279

Di Rienzo, B .,303 Disanayaka, B. W., 102 Dittami, 3. P . , 461 Dodsworth, D. J., 478 Doedens, R. J., 304,462 Dopp, D., 289,445 Dojo, H., 22,34,105,231, 356 Dombi, G., 453 Donaldson, R. E ., 340,522 Doney, J. J., 81 Dorlhene, A . , 296 Dorme, R., 121 Dorsch, D., 148 Douglass, J. G., 111, 417 Doutheau, A., 385 Dow, R. L., 169,227 Doyle, D. L., 98 Doyle, M. P., 164, 169,227, 311 Doyle, T. W . , 303 Draper, R . W., 307 Dreiding, A. S . , 402 Drewes, S. E . , 148 Drovin, J., 406 Duar, T., 375 Dubey, S. K . , 271 Dubodin, F., 274 Dubois, J.-E., 117 Duc, G., 64,393 Diiber, E.-O., 96 Duffley, R. P., 274 Duflos, A., 235 Dugast, J.-Y., 117 Dugat, D., 496 Duggan, M. E., 373 Duggan, P . J., 64 Duguay, G . , 492 Duhamel, L . , 111, 118, 119, 156,265 Duhl-Emswiler, B. A., 476 Dulcere, J.-P., 116, 235 Dumas, F., 154, 219 Dumont, W . , 379 Dunlap, N. K., 182 Dunn, L. B., jun., 151,381 Dunogues, J . , 366, 388 du Penhoat, C. H . , 376 Dupre, B., 96 Durman, J., 31, 104, 162,377 Dussault, P., 171 Duthaler, R. O., 295 Dyke, S. F., 336 Dzhemilev, U. M., 231 Earl, R. A., 336 Early, W. G., 519 Easton, C. J . , 490 Eaton, G., 143 Eaton, P. E., 348 Ebihara, R., 295 Ebine, S., 239 Echegoyen, L., 243 Eckrich, T. M., 211,342 Edwards, M. P., 536

Effenberger, F., 192 Eguchi, S . , 302,484, 485 Ehrmann, E. U . , 478 Eickhoff, D. J., 37, 103 Eilbracht, P., 313 Einhorn, J., 294 Eisch, J. J . , 5 , 326 El-Gharib, M . S., 453 El Hallaoui, A . , 192 Eliasson, K. M., 133 Elissondo, B ., 106,235,368 Elliott, E., 364 Elliott, J., 31, 104, 377 Elliott, J. D., 53, 73, 222, 290, 364,366 Elliott, R., 73 Elsevier, C. J., 328 El-Wassimy, M. T. M . , 168 Elzey, T. K., 352,496 Emblidge, R. W., 144 Emde, H., 26 Emslie, N. D., 148 Enda, J., 76,218, 422 Enders, D., 158,340,418 Endo, Y.,259 Engberts, J. B. F. N., 189 Engelhardt, L. M., 452 Ennen, B., 15 Ent, H., 462 Erden, I . , 404 Erfort, U . , 130 Erhardt, P. W., 261 Ermolenko, M. S . , 88, 380 Eswarakrishnan, V., 60 Eugster, C. H., 82 Evans, S. A . , jun., 228,409, 413 Everhardus, R. H., 64,238 Exon, C., 100,333,390, 497 Fabre, J.-L., 8,57, 313, 376 Faith, W. C., 482 Falck, J. R., 129 Farcasin, D., 316 Farina, F., 179,266 Fauq, A . H., 212 Fedij, V., 344 Fehlhaber, H. W., 311 Fehr, C., 62, 102, 404 Fehrentz, J.-A., 113,279 Felix, A. S , ,283 Felman, S. W., 335,413 Fenwick, A . , 489 Ferguson, G., 302 Fernandes, J. B., 329, 349 Fernandez, F. J., 305 Fernandez-Resa, P . , 283 Feringa, B. L., 43,157 Ferraboschi, P., 296 Ferrario, F., 125 Ferres, H., 181 Ferrier, R. J., 524 Feuer, H., 189,298 Feustel, M . , 78

553

Author Index Fiandanese, V., 88, 266 Fiaschi, R., 468 Field, L. D., 284, 365 Field, S. J., 194 Fife, W. K . , 287, 366 Finck, M. S . , 90 Fink, D. M., 387 Finkelstein, B. L., 187 Finn, J . , 539 Fiorenza, M., 212,238,272, 291 Firouzabadi, H . , 84,85, 122, 227,235,237,308 Fischer, J. W., 64, 374 Fischetti, W., 81, 166 Fisher, K. J., 302 Fishpaugh, J. R., 433 Fittkau, S., 160 Fitzsimmons, B. J . , 537 Flann, C. J., 120,426 Fleet, G. W. J . , 397,527, 539 Fleming, I . , 119,157,229,360, 368,373 Fleming, M. P., 532 Flippin, L. A . , 127 Flood, L. A , , 227 Flores, H. J., 468, 484 Flbrez, J., 219 Florio, S., 153 Floss, H. G ., 133 Floyd, A. J . , 288 Fludzinski, P., 20, 164 Flynn, G. A . , 27,445 Flynn, K . E . , 7 Fobare, W. F., 165 Fochi, R., 237 Foglio, M . , 494 Forcellese, M. L., 421 Forni, A . , 211, 448 Fourrey, J.-L., 23, 232 Fowler, F. W., 50, 461,473 Fox, C. M. J., 125,181 Foxley, G. H., 229 Franceschi, G., 494 Francisco, C. G., 438 Frandanese, V., 195 Fraser-Reid, B., 270,530 Frkhet, J. M. J., 88 Freerksen, R. W., 86 Freidinger, R. M., 197 Freire, R., 438 Frejd, T., 328 Freyberger, G., 384 Fried, J., 117 Friedrich, E. C . , 226 Fringuella, F., 391 Fristad, W. E., 1, 142 Frobese, A. S., 179 Frolow, F., 495 Fronza, C., 431 Froussios, K., 197 Fry, M. A . , 1,142 Fuchs, P. L., 39, 99, 146, 340, 347,371,397,522

Fulop, F., 453 Fuentes, L. M., 257, 342 Fuganti, C., 523 Fugawa, T., 215 Fuhr, B., 487 Fuji, K., 343 Fujii, K., 95, 140 Fujii, M., 104, 164 Fujikura, Y . , 220 Fujimoto, K., 152 Fujimoto, Y . , 235 Fujisawa, T., 87,88,89, 134, 165,168,204,208, 229, 304, 350 Fujita, E., 9,28, 33, 103, 175, 178,343, 376 Fujita, M., 111 Fujita, S., 470 Fujita, T., 237 Fujita, Y . , 385 Fujiwara, J . , 44, 118, 209,258, 275,358,398 Fujiwara, T., 51,108,229 Fujiwara, Y . , 215 Fukasawa, H., 9 Fukase, K., 194 Fukata, F., 142 Fukata, G., 141 Fukui, M., 206 Fukumoto, H . , 182 Fukumoto, K . , 463,491 Fukushma, M . , 331,349 Fukutani, Y . ,258 Fukuzaki, K., 37,98,362,405 Fukuzawa, S . , 10,200, 235, 387 Fung, A . P . , 284,365 Furukawa, M . , 190 Furukawa, Y . , 190,302, 485 Furusawa, F., 82 Furuyama, H., 394, 507 Fustero, S . , 262 Gadwood, R. C., 402 Galamb, V., 41, 140 Gallacher, G., 276, 496, 537 Gallagher, T., 511 Galli, R., 78 Galvez, C., 295 Ganboa, I., 283 Gandour, R. D., 243 Ganem, B., 180,250,300,345 Ganguly, A. K., 493 Gani, D., 194 Gamer, G. A . , 302 Garad, M. V., 357 Garcia, G. A . , 170 Garcia, T . , 144 Garigipati, R. S . , 55, 269, 271, 378 Garner, P., 391 Garst, M. E., 125, 157, 398, 417 Gartiser, T., 249

Gasc, M. B. , 245 Gaset, A . , 12 Gasparrini, F., 238 Gaudemar, M . , 139,165, 190, 301,456 Gawronska, K., 135 Gawronski, J . K., 135 Gebhard, J. S., 234 Gehrig, K . , 308 Geigert, J., 230 Gelas-Mialhe, Y . , 454 Gelin, S., 300 Gellert , E., 479 Genet, J.-P., 268 Gennari, C., 40,128, 155,160, 215,341, 370 George, J .,245 Georgiadis, G. M., 9 Gerdes, J. M., 128, 149,224 Gerke, R., 6 Gerlach, H., 142 Gero, S. D., 251,384 Gerstmans, A , , 237 Gervais, D., 306 Ghatak, U. R., 147 Ghiringhelli, D., 184, 533 Ghosez, L., 493 Ghosh, A . K., 43,175,390, 497 Giacomelli, G., 109 Giattini, P. G., 283 Giese, B., 92,130, 132,151 Gilard, A . , 137

Gilbert, J. C., 72,90,265 Gilchrist, T. L., 299, 450 Giles, R. G . F., 432 Gilman, J. W., 7, 184 Giordano, C., 140 Giordano, L. A . , 90 Giovannini, F., 154, 211 Giovannoli, M., 238 Girijavallabhan, V. M., 493 Girotra, N. N., 539 Gist, R. P . , 473 Glass, R. S., 148 Glusenkamp, K.-H., 428 Goasdoue, C., 190 Goasdoue, N., 190 Godel, T., 133 Godleski, S. A , , 335, 413,477 Godoy , J., 85 Godts, F., 283 Goel, 0. P., 147 Gogte, V. N., 287 Goh, S. H., 232 Gokel, G. W., 243 Gold, V., 239 Golding , B . T., 224 Goldsmith, D., 179 Goli, D. M., 243 Gonzales, A . , 295 Gooch, E. E., 194 Gopalan, A. A . , 137,211 Gordon, H. J., 45,471

554 Gor6, J., 50,53,56,122,218, 385, 465 Goren, Z., 233 Gorgues, A , , 166 Gosney, I . , 454 Gotoh, Y . , 208 Gottschalk, P., 116, 170, 178 Gough, M. J . , 527 Gould, T. J., 55, 165 Goument, C., 119 Govindan, C. K., 302 Govindan, S. V., 387 Grafing, R ., 64 Grafing, R . , 238 Grakauskas, V., 411 Gramatica, P., 97 Granados, R . , 264,284 Gravel, D . , 378 Grayson, J. I . , 261, 515 Greeley, A. C., 65 Green, I. R . , 432 Green, J. R . , 470 Green, S. M . , 211 Greenberg, R. S . , 421 Greenblatt, J., 239 Greene, A. E., 130, 315, 390, 402,497 Greene, E. W., 393 Greenlee, W. J . , 290, 366 Grethe, G., 529 Gribble, G. W . , 205, 283 Grieco, P. A . , 391, 539 Grierson, D. S . , 288, 342,474, 480 Grigg, R . , 302,304,461 Grossi, M., 122 Grote, J . , 411 Groth, U., 192 Grubbs, R. H., 69, 127, 325 Gruber, J. M., 102,153 Grynkiewicz, G., 283 Grzejszczak, S . , 113 Gu, J.-M., 473 Guanti, G., 112 Guedj, R . , 194 Guerrero, A., 228 Guerrier, L., 342, 480 Guevel, A., 492 Guillaumet, G.,443 Guindon, Y . ,225 Guittet, E., 238 Gull, M.-R., 192 Gunaratne, H. Q. N., 304,461 Gundo Rao, C., 122 Guo, M . , 159 Gupta, R. C., 508 Gutowski, D. A . , 243 Gutsche, C. D., 244 Gyoung, Y. S . , 205 Haack, J. L . , 6 Haag, A. P., 510 Habata, Y . ,239 Habbachi, F., 139

General and Synthetic Methods Hacksell, U., 332 Hadley, M. S . , 475 Haffmanns, G., 303,304,458 Hafner, W., 64, 180 Haga, Y , ,491 Hagenah, J. A . , 46,348 Hagihara, T., 18, 148, 331 Hagiwara, I . , 51,107,124,331 Hahn, G., 77,139 Haines, A. H . , 242 Hajos, Z . G., 439 Hakimelahi, G. H., 224 Hakushi, T., 239 Halazy, S., 379 Hall, C . D., 239 Hallett, P . , 211 Hallock, J . S., 169 Halls, T. D. J., 391 Haltiwanger, R. C., 447 Hamachi, I., 361 Hamada, A., 37,102 Hamaguchi, H . , 97,470 Hamana, M., 143 Hamanaka, N . , 443 Hamann, P. R., 146,347 Hamatsu, T., 531 Hamer, N. K . , 115 Hamman, S., 133 Hammer, B., 319, 381 Hammond, P. J . , 239 Hanafusa, T., 10, 84, 226,293 Hanagan, M. A., 181 Hanessian, S . , 435, 527,536 Hangauer, D. G., 290,366 Hannick, S. M., 156,266,468 Hansske, F., 219, 228 Hara, K . , 24,131, 318,374 Hara, S . , 22,23, 34,105, 231, 356 Harada, H.; 231 Harada, T., 71, 291 Harakal, M. E., 407 Harano, Y., 146 Harding, M. M., 298 Harland, P. A . , 181, 508 Harmata, M. A., 114 Harnisch, H., 132 Harpp, D. N., 189 Harris, D. J . , 355 Harris, R. B., 197 Harris, T. M., 186, 282, 345 Harrison, C. R . , 134,280 Hart, D. J., 252,389,463,476 Hartling, S., 288 Hartwig, W., 227 Haruta, J . , 142 Harvey, R . G., 289 Hasain, A . , 226 Hasebe, M., 487 Hashimoto, K . , 317 Hashizume, K . , 145 Hashizume, T., 239 Hassan, D . , 62, 376 Hassel, P., 96, 264

Hata, K . , 317 Hatanaka, Y . , 85,184,227 Hatton, I. K., 181 Hattori, K . , 256, 477 Hatzigrigoriu, E., 293 Haubenstock, H., 207 Haufe, G., 68 Hauptmann, S . , 307 Havama, N., 59 Havashi, T., 52 Havens, N . , 144 Hawkins, J., 188 Hayachi, I., 191 Hayama, N., 233 Hayama, T., 296,363 Hayami, H., 29 Hayase, Y ., 222, 406 Hayashi, H., 167,237 Hayashi, K . , 51, 107 Hayashi, M., 443 Hayashi, T., 18,79,148,152, 331,343,349,360,361,364 Hayashi, Y . , 141, 327, 352, 400,450 Hazato, A., 297,522 Heacock, D. J., 335,477 Heath, W. F., 198 Heathcock, C. H., 127, 128, 149,153,187,217, 361 Heavner, G. A . , 191 Hebblethwaite, E. M., 334, 488 Hebert, E . , 91 Heck, R. F., 81,166, 386,430 Hedge, S., 204 Hegedus, L. S . , 32,106,233, 331 Heilmann, S. M., 27, 111,212, 289,350 Heimann, M. R., 147,226 Heimbach, H., 111 Heissler , D . , 393 Helgeson, R. C., 243 Helmchen, G., 148 Henderson, G. B., 540 Hendrickson, J. B., 173 Henegar, K. E., 224 Henin, F . , 44, 175,176 Henning, R., 352,465,532 Henzen, A. V., 25,370 Heo, G. S . , 241 Hernandez, M. I., 421 Hernandez, R.,438,468 Herndon, J. W., 101, 165, 321 Herold, P., 136 Hershberger, S. S., 16 Herunsalee, K., 21. 116, 345 HervC du Penhoat, C., 57,313 Hesse, M., 160, 185,298,404 Heuschmann, M., 532 Heveling, J., 2, 4, 237 Hevesi, L., 379 Iiewson, A. T., 390 Hida, M., 196

Author Index Hidai, M . , 317 Hiemstra, H., 462 Higby, R. G., 497 Higuchi, H., 2 Higuchi, K., 88, 350 Higuchi, T., 141, 190 Hii, P. S., 86 Hill, J. H. M., 442 Hill, R. A . , 540 Hillard, R. L., 336 Himbert, G., 78 Himmelsbach, R. J., 87 Hiner, R. N., 173 Hinkle, J. S., 197 Hino, T., 472,519 Hioki, T., 331, 349 Hipes, P. G., 241 Hirai, K., 67, 161 Hirama, M., 153,211,226,539 Hiranuma, H., 393 Hirao, A . , 207, 208, 353 Hirao, I., 74,109, 356, 371 Hirao, T., 4,51, 107,146 Hirobe, M . , 190 Hiroi, K., 375 Hiroi, Y . , 185,280 Hirotsu, K., 141 Hirsch, S., 173 Hirsenkorn, R., 179 Hitomi, K., 213,290, 363 Hiyama, T., 45,48,52,176, 181,217,265,346, 366,408, 422,423 Ho, C . D., 71 Ho, L.-K., 17 Ho, T.-L., 431 Hobbs, F. W., jun., 347 Hodge, P.,121,134, 181,223, 280 Hodge Markgraf, J., 393 Hodgkisson, I., 242 Hodgson, S. T., 334, 488 Hoffmann, H. M. R., 164 Hoffmann, R. W., 53, 154, 182,211,217,355 Hofheinz, W., 441 Hojo, M., 204,205 Hokama, N., 190 Hollenstein, R., 298 Hollinshead, D. M., 334, 488, 503 Hollis, W. M., 143 Hollman, K . , 454 Holman, N. J., 236,327 Holmes, A . B., 540 Holmes, D. R . , 298 Holt, D. A . , 54, 108,358 Holton, R. A., 25,125,348 Holtz, W. J., 287 Honda, T . , 394, 494,507 Honda, Y . , 242 Hong, C. Y., 232 Hong, P., 180 Hoornaert, C., 495

555 Hooz, J., 25, 121 Hoppe, D., 71,169,218 Hoppe, I., 192 Hori, I . , 79, 343 Horiguchi, Y . , 127 Horiie, T., 290 Horita, K., 417 Horler, H., 92 Horn, K. A., 387 Horton, M., 501 Hoshi, M . , 76 Hoshino, M., 11,233, 237 Hosokawa, T., 314,315 Hosomi, A . , 22, 55, 123, 127, 232, 346, 394 Hou, L., 189,298 Houk, K. N., 446 House, H. O., 6 Houwen-Claassen, A. A. M., 115,268 Hovius, K., 189 Howbert, J. J. , 390, 497 Howell, S. C., 503 Howes, D. A., 224 Hrubiec, R. T., 270 Hrubowchak, D. M., 132 Hsiao, C.-N., 343 Hsu, C., 539 Huang, G. T., 64,393 Huang, S.-B., 88 Hubert, A. J., 146 Huche, M., 129 Hudlicky, T., 387, 391 Hudson, A. T., 224 Hudspeth, J. P . , 532 Hiibner, F . , 146 Huffman, J. C., 511 Huffman, J. W., 229 Huggenberg, W., 160,298 Hughes, I . , 513 Hui, R., 111,342 Huisgen, R.,443 Hung, M.-H., 148, 319 Hunt, A . H., 352, 496 Hunt, B. J., 134,280 Hunt, E., 495 Hunt, P. G., 162 Hunter, J. E., 188 Husain, A . , 133,224, 365 Husain, S., 296 Husk, G. R., 319,381 Husson, H.-P., 288,342, 474, 480 Hutchings, M. G., 66, 216 Huttner, G., 168, 340 Huynh, C., 69,347 Hwu, J. R., 86, 376, 387, 399 Hyatt, J . A . , 121 Hyun, J. L., 83 Hyun, M. H., 254 Ibrahim, B. E . , 302 Ichikawa, J., 144 Iddon, B., 485

Tden, R . , 487 Iguchi, H., 394 Iguchi, K., 67, 328 Ihara, M., 463 491 Iida, H., 87, 111, 131, 145, 278,282,287 Iida, K., 324 Iida, S., 88,229, 350 Iizuka, K., 231 Ikariya, T., 169, 227 Ikeda, H.. 35,104 Ikeda, I., 243 Ikeda, K., 194 Ikeda, M., 383 Ikeda, N., 60, 324 Ikeda, T., 242 Ikeda, Y . , 60,324 Ikegami, A., 443 Ikegami, S., 9,215 Jkehira, H., 148,238, 301 Ikenaga, K., 17 Jksander, G. M., 302 Ikuta, S., 520 Ila, H . , 163, 377 Jmada, Y . , 315 Imai, K., 42,177 lmai, T., 91, 354 Imai, Y . , 190 Imaizumi, M., 283 Imamoto, T., 85,127,227, 228,283 Imbach, J.-L., 448 Inaba, M., 22,232, 346 Inaba, S . , 89,233 Inaba, T., 111 Inai, M., 198 Inamoto, N., 13,14,371,380 Inamoto, Y . , 220 Inch, T. D., 135 Ingold, C. F., 84 Inokawa, S., 2 Inokuchi, T., 120, 382 Inomata, K., 91, 167,237 Inoue, K., 84,169,194,227, 467,478 Inoue, M., 290 Inoue, S . , 82 Inoue, T., 204, 205 Inoue, Y . , 239 Iqbal, J., 119, 157, 373 Iranpoor, N., 85,227 Ireland, R. E., 439, 537 Isaac, K., 425 Ishag, C. Y . , 302 I-Shan Chu, 65 Ishibashi, K., 507 Ishida, N . , 47, 211, 350 Ishida, Y . , 49,254,256. 365, 404,466 Ishido, Y , , 379 Ishiguro, H., 23,231,356 Ishihara, T., 20,21,117, 372 Ishii, A . , 380 Ishii, T., 13,14, 371

556 Ishii, Y., 169, 227 Ishikawa, N., 153 Ishikawa, Y., 243 Ishikazi, K., 213 Isimura, A . , 95 Isobe, K., 327 Isoe , S., 222,406 Itahara, T., 295 Itani, H., 47, 221 Ito, K., 207, 353 Ito, M., 472,519 Ito, M. M., 302 Ito, S., 160 Ito, T., 224 Ito, Y . , 188,206,473,514 Itoh, K., 54, 169, 170,284, 285, 365 Itoh, T., 168 Itsuno, S . , 207, 208, 353 Iwahara, T., 221 Iwao, M., 188,478,517 Iwasaki, S . , 408 Iwasawa, N., 137 Iwashita, M., 153,211, 539 Iwata, K., 487 Iyer, P. S., 307, 366 Iyoda, M., 68, 82,239 Izatt. R. M . , 239 Izawa, Y., 8, 11 Izumi, T., 204, 205 Izumi, Y., 26, 122,287, 318 Jabri, N . , 32, 58, 59, 103, 333 Jackson, D. A . , 402 Jackson, R. F. W., 418 Jacobs, S. A . , 289 Jacobsen, E. J., 304, 462, 516 Jacobsen, E. N . , 153 Jacquier, R . , 192 Jadhav, P. K., 53 JaCn, J. C., 220 Jalali, M., 418 James, B. R., 386 Jano, P., 421 Janout, V., 233 Januszkiewicz, K., 86 Jeffery-Luong, T., 80 Jefford, C. W., 440 Jeffs, F. W . , 468 Jelittc, R . , 313 Jellal, A . , 73, 140, 293 Jennings, L. J. A . , 181 Jennings-White, C. L. D., 540 Jesser, F . , 129, 324 Jeyaraman, R., 472 Jiang, J. B . , 439 Jibril, I., 168. 340 Jih Ru Hwu, 22 Jimknez, C., 187,282 Jitsukawa, K., 47, 85, 227 Jobe, P. G., 348 Jodhav, P. K., 133 J~rgensen,K. A , , 168 John, R. A . , 112, 124

General and Synthetic Methods Johne, S . , 288 Johnson, A . T., 398 Johnson, D. M., 294 Johnson, R. P., 393 Johnson, W. S . , 53, 73, 222, 290,364, 366,399, 508 John, K. K., 142 Jones, B. A , , 234, 239 Jones, D. N., 374 Jones, J. H . , 451 Jones. M. A . . 431 Jones, N. D., 352,496 Jones, R. C. F., 487 Jones, R. L., 76 Jones, T. K., 98,387 Jones, W. A . , 157 Josel, H.-F., 239 Joshi, N. N . , 524 Joucla, M. F . , 300 Joullie, M. M., 452 Joyce, C. J., 298 Julia, M., 8, 57, 187,304, 313, 376 Julia, S . , 112, 206, 238, 407 Julia, S. A . , 33, 64,107, 342 Jun, Y. M., 188 Jung, A . , 213 Jung, M. E., 46, 283, 348, 365 Jung. S.-H., 253 Jungk, S. J., 243 Junjappa, H., 163, 377 Jurczak, J., 242, 303 Jurlina, J . L., 390, 497 Just, G., 496 Juve, H. D., jun., 109, 153, 173 Kabalka, G. W., 221, 231 Kabat, M. M., 319 Kabeta, K., 360,361 Kadib-Elban, A , , 188 Karki, T., 410 Kagan, H. B., 213,223 Kageyama, M., 394 Kageyama, T., 85,169,226, 227 Kagiya, T., 470 Kahn, M . , 201 Kahne, D. E., 312 Kaifer, A , , 243 Kaiser, E. T., 191 Kaji, A . , 40,42. 104, 160,164 177,346 Kaji, S., 411, 425 Kakimoto, M.-a., 462 Kakisawa, H., 515 Kakui, T., 221 Kaletta, B., 6 Kalkote, U. R., 245 Kallmerten, J., 55, 165 Kametani, T., 394, 463, 491, 494,507 Kameyama. M., 263

Kamijo, T., 231 Kamitori, Y . , 204, 205 Kamiyama, N., 424 Kanai, K.-i., 252, 476 Kanao, Y, , 68 Kanaoka, Y . , 184 Kanatani, R., 221 Kanaya, N., 494 Kanazawa, T., 275 Kanbara, H., 34, 363 Kandil, F . , 239 Kane, J. M., 532 Kane, V. V., 98 Kaneda, K., 47, 85,227 Kanehira, K., 331, 349 Kaneko, T., 303 Kanemasa, S . , 393 Kanemitsu, S., 226 Kanemoto, S . , 29,85,227 Kang, G. J., 361 Kang, J., 76 Kang, M.-c., 536 Kang, S. I . , 241 Kano, S., 475,484 Kanoh, S., 208,353 Kao, L., 430 Kao, T., 356 Kapnang, H . , 262 Karanewsky, D. S., 373 Karunaratne, V., 48, 413 Karydas, A. C., 153 Kashimura, S., 36, 86,97, 98, 213 Kast, J., 179 Kataoka, H., 319 Katayama, E., 94 Katayama, S . , 428 Katayama, T., 243 Kato, J.-I., 126 Kato, M., 182 Kato, S., 226 Kato, T., 23, 34, 231,505 Katoh, T., 97, 305 Katritzky, A . R., 259, 302, 309 Katsuki, T., 75, 109 Katsuro, Y., 18, 331 Katzenellenbogen, J. A . , 162, 175 Kauffmann, T., 15 Kawabata, N., 238 Kawada, M., 24, 131, 230, 318, 374,393 Kawagishi, T., 297, 522 Kawahara, S . , 169, 227 Kawaharasaki, N., 190 Kawai, M., 224 Kawakami, Y . , 58,233 Kawamoto, K., 46, 364 Kawanami, Y., 75,109 Kawanishi, Y . , 85, 227 Kawanisi, M., 81 Kawara, T., 134 Kawasaki, K., 295 Kawasaki, T., 155

Author Index Kawasaki, Y., 218 Kawashima, T., 13, 14, 371 Kawate, T., 10, 293 Kay, I. T., 170, 438,525 Kay, P. B., 522 Kaya, R., 350 Kaye, P. T., 148 Keim, W., 285 Keinan, E., 77,314 Kellner, D., 228 Kellogg, M. S . , 399, 508 Kelly, D. J., 138 Kelly, W. J., 298 Kende, A. S., 20, 164 Kendrick, D. A , , 540 Kenney, P. M., 518 Kepsi, L. R., 212 Kerr, R. G., 115 Kervagoret, J., 479 Kesseler, K., 213 Kessler, H., 196 Ketcha, D. M., 449 Keve, T., 485 Khalafi-nejad, A . , 235 Khan, M., 171,374 Khare, R. K., 413 Khatri, N. A . , 302, 473, 514 Khoshdel, E., 134,280 Khuong-Huu, Q., 479 Kibayashi, C., 278 Kido, F., 176 Kido, M., 383 Kiehl, G., 489 Kielbasinski, P . , 113 Kienzle, F . , 264, 451 Kikui, T., 243 Kikukawa, K., 17 Killmer, L. B., jun., 133 Kim, B., 204 Kim, C.-W., 88,153, 347 Kim, J.-I., 81, 166 Kim, S., 88, 144, 197, 232 Kim, S.-W., 94,156 Kim, T. H., 222,406 Kim, Y. C., 144 Kim, Y. J., 232 Kim, Y . H., 482 Kimura, K., 48,213 Kimura, Y . , 133,183,286 King, F. D., 474, 475 Kini, A . , 83 Kinney, W. A., 392 Kinoshita, H., 91,167, 237 Kinsman, R. G., 288 Kirby, P., 416 Kirchmeyer, S . , 121,290, 306, 366 Kirisawa, M., 489 Kirk, T. C., 358,388 Kirson, I., 314 Kirszensztejn, P., 286 Kirtane, J. G . , 407 Kisfaludy, L., 191 Kishi, N., 37, 98, 362

557 Kishi, Y., 156, 201,266,468 Kiso, Y., 198 Kita, Y., 142 Kitagawa, K., 198 Kitagawa, Y . , 137 Kitamura, K., 169,227,401, 504 Kitani, H., 170,373,418 Kitao, D., 190 Kitaoka, M., 176 Kitayama, R., 375 Kitazume, T., 153 Kitsuki, T., 242 Kiyooka, S.-i., 217, 361 Klang, J. A . , 1, 142 Klaus, A . J., 308 Kleefeld, G., 487 Kleijn, H., 80 Klein, C., 117,138 Klein, H., 384 Kling, F., 226 Klingstedt, T., 328 Klop, W., 265 Klos-Ringuet , M ., 226 Klumpp, G. W . , 343 Knapczyk, J., 197 Knapp, F. F., 231 Knapp, S . , 270,448 Knaus, E. E., 271 Knochel, P., 296 Knor, R.,96,264 Knowles, W. S., 196, 312 Knudsen, C. G., 113, 279 Kobar, J., 453 Kobayashi, H., 243 Kobayashi, K., 45, 133, 265, 346 Kobayashi, T., 96, 285 Kobayashi, Y., 324 Kober, R., 194 Koch, K., 50,461 Kochetkov, N. K., 88,380 Kochhar, K. S . , 121,190,282 Kochi, J. K., 407 Kocienski, P., 400, 425, 436, 441 Kodera, Y.,144 Kodomari, M . , 309 Koehler, K. F., 460 Koga, K., 308 Koga, T., 266 Kogan, T. P., 6 Kohmoto, S . , 440 Kohn, H., 253, 262 Kohno, S., 4 Kojima, T., 263 Kokko, B. J., 261,468 Kolasa, T., 195, 266 Kolb, M., 192 Kolovos, M., 197 Komatsu, T., 152, 355 Konar, S. K., 272 Kondo, Y . ,74 Konig, J., 300

Konishi, M., 52, 148, 152,331, 349,360 Kontoleon, B. D., 90 Koreeda, M., 224, 388, 497 Kornblum, N., 298 Koshino, J., 94, 109 Koskinen, A . , 288 Kostova, K., 185 Kosugi, H., 176 Kosugi, M . , 26. 51, 107, 116, 124,263,331 Kotake, H., 91,167,237 Kotelko, A . , 146, 483 Kotera, K., 184 Koul, V. K., 456 Koyama, K., 381 Kozerski, L., 262 Kozikowski, A . P., 43, 137, 175,291,352 Kozlowski, J. A . , 129, 233 Kozluk, T., 303 Kozyrod, R. P., 192 Krafft, M. E., 25, 125,348 Kraus, G. A., 116,170,178, 487 Krauss, J. C . , 291 Krawczyk, S. H., 487 Krebs, A . , 6 Krentzien, H., 232 Krepski, L. R., 27, 111,289, 350 Kretzschmar, G., 1 Krief, A., 2 , 232, 372,379, 393 Krishnamurthy, S . , 3, 232 Krolikiewicz, K., 287, 366 Krolls, U., 147 Krook, M. A . , 491 Krowczynski, A . , 262 Kruithof, K. J. H., 343 Kubota, H., 3,228 Kubota, T., 196 Kucerovy, A . , 63 Kuehne, M. E., 519 Kugimiya, M., 2 Kuiper , D ., 456 Kulicki, W . , 303 Kulinkovich, 0. G., 64 Kulkami, S. U., 225 Kulp, S. S . , 86 Kulp, T., 387 Kumada, M., 18,47, 52,148, 152, 211,221,331, 349,350, 360,361,364 Kumar, K., 72, 187 Kumar, N., 479 Kumar, V., 121, 377 Kumari, K. S . , 245 Kumi, Y . ,224 Kunai, A . , 296 Kunda, S. A . , 221 Kundig, E. P., 322 Kunesch, G., 249 Kunieda, T., 190 Kunisch, F., 154

558 Kunng, F.-A.,473 Kunz, H., 138, 196,198 Kunzer, H., 284 Kuraishi, T., 517 Kuriki, H., 181 Kurita, J., 487 Kurita, M., 35, 104 Kurita, Y., 89, 304 Kuroda, T . , 48,213 Kurozumi, S . , 297, 522 Kurth, M. J., 139 Kurz, K., 185,280 Kurz, M. E., 296 Kusabayashi, S . , 424, 443 Kusano, Y., 241 Kusumoto, T . , 127, 228 Kuwajima, I., 37,76,98,122, 126,127,147,149, 218,338, 362,368,379,382,493,405, 422 Kuzikowski, A , , 400 Kuzuhara, H., 193 Kuzuoaka, T., 309 Kvarnstrom, I . , 257 Kwon, Y . C., 353 Kyba, E. P., 268 Kyler, K. S., 64, 86,167, 344 Labadie, J . W., 89, 104, 158, 333,369 L’Abbe, G., 283,308 Labhart, M. P., 7 Ladner, W . , 154,211 Lago, J . M., 144,307 Laguzza, B. C., 76 Lai, R., 232 Lajoie, G., 194 Lallemand, J.-Y., 418 Lambert, J. B., 146,381,483 Lammer, O., 143,168, 340 Lammerink, B. H. M., 14, 115,268 Lammertsma, K., 247 Lampe, J . , 153 Landmann, B., 53, 182, 217, 355 Lansard, J.-P., 130,402 Lantos, I . , 198 Lapatsanis, L., 197 Larcheveque, M., 161,293, 346 Larock, R. C., 16, 352 Larraza, M. I . , 468, 484 Larson, E. G., 381 Larson, E. R., 272,530 Laszol, P., 237,296 Latimer, L. H., 539 Latrofa, A , , 262, 357 Lattes, A . , 199,245, 269 Lau, C. K. 406 Laucher, D., 129,324 Lauer, M., 243 Laughton, C. A . , 236, 327 Launay, J.-C., 111

General and Synthetic Methods Laur, J., 197 Laurent, A . , 268,455,480 Laurent, E., 117 Lautens, M., 50, 63, 148,166, 319 Laval, J. P., 269 Lavoie, A . C., 148,330 Lawesson, S.-O., 168,194 Lawlor, J. M., 170 Lawrence, G. C., 211 Lawston, I . W., 135 LCandri, G., 226 Leanza, W. J., 493 Le Bigot, Y., 12 Lechhein, S . , 132 Le Coq, A . , 166 LeDoussal, B., 166 Lee, D. G., 84 Lee, J. I . , 88, 144 Lee, N. J., 482 Lee, S. D., 187,282 Lee, T.-J., 287 Lee, T. V., 157,373 Leginus, J. M., 529 Le Goffic, F., 107 le Guillanton, G., 291 Lehmkuhl, H., 18 Leiden, T. M., 387 Lein, G. M., 244 Lemay, G., 43,178 Lemieux, E., 287 Lemke, T. L., 303 Leng, J . L., 64 Lennon, P . , 386 Leonard, N. J., 307 Leong, W. W.-H., 117,333 Lepine, F., 194 LePoire, D. M., 311 Lerch, U., 300 Lerman, O., 117, 157 L’Esperance, R. P., 439 Lesur, B. M., 165, 355 Levine, J. A , , 244 Levine, S. G., 440 Levinson, S. H., 133 Ley, S. V., 28,41,90,125, 177,181,334,345, 488,503, 507,527,536 Leyendecker, F., 129,324 Leyendecker, J., 117 Lhommet, G . , 45,163,266 Libera, H., 289,445 Libman, J., 183,535 Lieberknecht, A . , 24, 144 Lieser, J. K., 211 Liew, W.-F., 185 Lillie, T. S., 101 Lin, J.-M., 50, 461 Lin, Y., 317 Linderman, R. J., 162, 217, 268, 371 Lindig, M., 138 Linstrumelle, G., 69,80, 347 Lion, C . , 117

Liotta, D., 179 Lipshutz, B. H., 129,145,233, 323 Liquori, A , , 301 Lis, R., 539 Lister, S. G., 536 Little, R. D., 87, 497,500 Liu, C., 352 Liu, H.-J., 17 Liu, J.-H., 133 Liu, R. S. H., 83 Liu, W.-Y., 496 Liu, Y., 241 Livinghouse, T., 367,459, 515 Liz, R., 265,267, 302 Ljubit, M., 197 Lociuro, S., 112, 279 Loher, H., 133 Loeppky, R. N., 300 Loerzer, T., 6 Low, P., 96 Loewenthal, H. J. E., 228 Lombardo, L., 507 Long-Mei, Z., 46,283, 348, 365 Lonsky, R., 192 Lopez, F. J . , 484 Lopez, R. C. G., 447 Lopez-Calahorra, F., 264 Lopusinski, A . , 197 Lorne, R., 64,238 Loubinoux, B., 147,443 Lounasmaa, M., 288 Louw, R., 238 Low, P., 264 Lown, J. W., 300 Lu, L. D.-L., 279 Lu, X . , 317 Luche, J.-L., 130,402 Luche, M.-J., 315,390,497 Luscher, I . F., 198 Liittke, W., 6 Lugade, A. G., 245 Lumma, P. K., 451 LUO,F.-T., 30, 89, 119,174, 331,333,351,415 Lupo, A. T., jun., 473 Lutomski, K. A., 141 Luttringer, J.-P., 489 Lygo, B., 527 Lyon, J. T., 411 Mabon, G., 291 McArthur, C. R., 198 McBride, B. J., 125, 157, 398, 417 McClure, D. E., 451 McComsey, D. F . , 476 McCullough, K . J .,443 McDaniel, W. C., 6 MacDonald, J. G., 189, 394 MacDonald, R., 197 Macdonald, T. L., 516 McElroy, A . B. , 31,104,377

Author Index McFarland, J. W., 115,268 McGarvey, G., 90 McGarvey, G. J., 173,537 McGee, M. J., 86 Machida, H., 11,233 McIntosh, J. M., 445, 470 Mack, K. T., 386 McKean, D. R., 27, 86,238, 365 MacKenzie, A. R., 513 McKenzie, A. T., 340,522 McKervey, M. A . , 114,373 McKillop, A , , 294 MacLean, D. B . , 257,478 McMills, M. C., 171 McMurry, J. E., 27,99, 122, 314, 330,398, 504 McNab, H., 45, 471 McNamee, M. B., 170 MacPherson, D. T., 390 Maddaluno, J . , 117, 154, 219 Madyastha, K. M., 264 Maeda, H., 243 Maeda, N., 54,151,367 Maekawa, T., 372 Maestro, M. C . , 179 Mafunda, B. G., 233,404 Maggi, D., 431 Magnus, P., 100,333, 390, 409,497,511 Mahalanabis, K. K., 188, 478 Mahon, M., 503 Maigrot, N., 91 Mais, F.-J., 487 Majchrzak, M. W., 146, 483 Majetich, G., 56, 57 Mak, K. T., 81, 166,430 Makino, H., 426 Malacria, M., 56 Malherbe, R.,236 Malhotra, N., 280 Malmberg, W.-D., 187 Malone, T. C., 49,475 Mamdapur, V. R.,524 Mametsuka, H., 10 Manabe, K., 297,522 Manabe, O., 241,242,243 Mandai, T . , 24,131,230, 318, 374,393 Mandal, A. N., 280 Mandard, X., 62, 376 Mandel, G. S., 439 Mandel, N. S . , 439 Mander, L. N., 118, 115,507 Manescalchi, F., 134, 228 Manfredini, S., 265 Mangeney, P., 129 Manitto, P., 97 Mann, G., 307 Mann, R. L., 148 Manna, S., 129 Manoharan, T. S., 264 Mansour, E. M. E., 197 Mao, M. K.-T., 163, 174,405

559 Marcaccioli, S., 448 Marchand, A . P., 350 Marchand-Brynaert, J . , 493 Marchese, G., 88 Margarethd, P., 303 Mariano, P. S., 304,457, 460, 473 Maring, C., 429 Marino, G., 316 Marino, J. P., 162,217,220 Marrero, R., 102, 153 Marsden, R., 478 Marshall, D. R., 64 Marshall, J. A . , 7, 540 Marsili, A., 468 Marston, C. R., 243 Martelli, G., 384 Martin, A . , 98 Martin, H.-D., 487 Martin, J. C., 45,85,226, 471 Martin, M., 308 Martin, M. R., 179 Martin, M. V., 179,266 Martin, R. T., 475 Martin, S., 20, 346 Martin, S. F., 96,473 Martinez, J., 197 Miirton, J . , 226 Maruoka, K., 44,49, 118,209, 229,254,256,258,275, 358, 365, 398,404,466, 477 Maruyama, K., 54, 62, 128, 151,152,215,216, 355,367, 510 Maryanoff, B. E., 13, 476 Masaki, Y . , 425 Masamune, S . , 394 Masana, J., 407 Mashima, K . , 324 Mason, R., 12, 370 Masroua, A . , 480 Massa, W., 146 Massardo, P., 59,233, 356 Massner, A . , 382 Masters, N. F., 327 Masida, R., 3,204, 205 Masuda, T., 131 Masuda, Y., 76 Masui, M., 85 Masunaga, T., 51,107 Mathur, H. H., 295 Matsubara, S., 46, 85, 181, 221,227,423 Matsubara, Y . , 173 Matsuda, H., 452 Matsuda, I., 26, 122,287,318 Matsuda, T., 17 Matsuda, Y., 79, 343 Matsuhashi, Y . , 82 Matsumoto, H., 238 Matsumoto, K . , 54, 128, 367, 434 Matsumoto, M., 160 Matsumoto, T., 228

Matsumura, N., 117, 138, 351 Matsumura, Y., 44,49,86, 118,194,256,275, 404,466, 467,477,478 Matsunaga, I., 61 Matsuura, T., 57, 134 Matsuzaki, M., 287 Matteson, D. S . , 354 Mattingly, P. G., 491 Matui, S., 40, 160,346 Mat-Zin, A. R., 487 Mauleon, D., 284 Maverick, E. F., 244 Mayer, R., 12 Mayoral, J. A . , 194 Mayr, H., 66,384 Maziak, L., 194 Meanwell, N. A . , 374 Medina, D. H. G., 474 Medina, M. C., 438 Mehendale, A. R.,511 Mehrotra, A. K., 133,226,365 Mehrotra, S . , 295 Mehta, G., 500 Meier, G. P., 49, 462, 475 Meijer, J . , 80 Meinhart, J. D., 335, 477 Melendez, E., 194,196,312 Melhado, L. L., 307 Melis, S . , 264 Meltz, C. N., 92, 160, 329, 472 Mendelson, L. T. , 462, 516 Mendelson, W . L., 133, 198 Menozzi, G., 292, 433 Merrifield, R. B., 198 Mertens, A . , 121,247,290, 306,366 Messeguer, A . , 408 Mestdagh, H., 187,304 Metzger, J . , 232 Metzner, P., 166, 168 Meunier, A., 133 Meyer, A . , 166 Meyer, E., 252 Meyers, A . I., 87, 141, 181, 257,268,303,342,371,532 Michelot, D., 16 Michelotti, E. L., 329, 349 Midland, M. M., 353 Miginiac, P., 122,188 Migita, T., 26, 51, 107, 116, 124,263, 331 Mihelich, E. D., 37, 103 Mijngheer, R.,394 Mikami, H., 97 Mikami, K., 37,98, 152,222, 362 Mikolajczyk, M., 113 Milani, F., 85, 227 Milias, G., 197 Miller, D. D., 37, 99,102,398, 504 Miller, J . A . , 65, 76,78, 89, 101, 333,351,364, 386

560 Miller, M. D., 393 Miller, M. J., 136. 491 Miller, R. B., 47,90,363 Miller, R. D., 27, 86,233,238, 365 Miller, S. I . , 393 Mills, R. J., 189, 340 Mills, S . , 188 Milner, J . , 298 Minami, I . , 38,39,102,103, 123,124,315 Minami, T., 241,242, 371, 385 Mincione, E., 143,421 Minguillon, C., 284 Minobe, M., 524 Minuti, L., 391 Mioskowski, C . , 409 Mirao, I . , 385 Mirbach, M. F . , 93 Mirbach, M. J . , 93 Mise, T., 180 Misiti, D., 238 Mislankar, S. G., 388, 497 Mison, P . , 268 Misumi, S . , 2 Mitani, M., 381 Mitchell, J. C . , 424 Mitchell, P. R. K., 432 Mitsui, H., 309, 448 Mitsunobu, O., 158 Mitt, T., 529 Miura, I,, 504 Miura, M., 424, 443 Miyake, H., 104, 164 Miyake, M., 489 Miyamoto, K . , 61 Miyamoto, O., 82 Miyano, S . , 279 Miyaura, N., 407 Miyazaki, M., 285 Miyazaki, T., 254,256, 477 Mizuno, H., 218 Mizuno, K., 239,424 Mizuta, Y . ,317 Mizutani, M., 190 Mlochowski, J., 241 Mloston, G., 454 Mobbs, B. E., 236,327 Mobilio, D., 401, 505 Mochizuki, T., 494 Moeller, K. D., 497 Morsdorf, P., 421 Mohacsi, E., 235 Mohamadi, F., 169 Mohanraj, S . , 330 Mohr, P., 135, 136 Moiskowski, C., 129 Mol, J. C., 57, 287 Molander, G. A., 16, 349 Molinari, H., 206, 407 Momose, D., 67,85, 328 Mompon, B., 296 Monk, P., 496 Monkiewicz, J., 39, 99, 398

General and Synthetic Methods Monni, F., 264 Monsan, P . , 199 Montanari, F., 186, 349 Montanucci, M., 237 Monte, W. T., 87 Montero, J.-L., 448 Montgomery, A. M., 294 Monti, D., 97 Monti, H., 226 Moody, C. J., 513 Mook, R., jun., 41,177 Moore, J. A , , 243 Moore, J. L., 1 Moore, K. W., 493 Moorthy, K. B., 37, 102 Moracci, F. M., 303 Moral, M., 466 Moran, J. R . , 244 Morandini, F., 18,236, 321, 349 Moreno-Mafias, M., 230 Morera, E., 283 Moretti, I., 211, 448 Moretti, R., 133 Mori, A . , 209,358 Mori, I., 366 Mori, K., 209, 524 Mori, M., 175 Mori, T., 87, 88,204,350 Mori, Y . , 40, 160, 380 Morisawa, T., 413 Morishima. N., 226 Morizawa, Y . , 29, 363 Morley, J. O . , 225 Moroder, F . , 158 Morrow, C. J . , 135 Morrow, G. W., 64 Mortezaei, R., 176 Morton, D. W., 445 Morton, H. E., 122, 225,358, 406 Morton, J. A . , 55,269 Mostafavipoor, Z . , 84, 227, 308 Mosti, L., 292, 433 Motherwell, W. B., 1, 87,142, 25 1 Motohashi, S . , 235 Motoi, M., 208, 353 Motoyama, T., 460 Mouko-Mpegna, D., 235 Moulines, F., 274 Mouzin, G . ,235 Mucha, I., 226 Muhlstadt, M., 454 Muller, E. P . , 456 Muller, J . , 197 Muller, P., 85 Mugrage, B. B., 400 Mukaiyama, T., 31, 34, 46, 102,104,112,126, 137,144, 153,155,171,173, 203, 315, 382 Muller-Starke, H., 284

Mulzer, J., 136,143, 168, 340 Munoz, H., 170 Murahashi, S.-I., 263,309, 314, 315, 448 Murai, S . , 26,46, 93,120, 159, 364 Murakami, M., 46, 155 Murakami, Y . , 300 Muramatsu, T., 197 Murata, S . , 144,505 Murata, Y . ,91 Muratake, H., 485 Murayama, E., 393 Murtiashaw, C. W., 501 Murty, A. N., 500 Musso, H., 192 Muthard, D. A , , 493 Myojoh, K . , 413 Myong, S. O., 461 Myrboh, B., 377 '

Naderi, M., 237 Nadir, U. K., 456 Naef, R., 193,340,425 Nafti, A., 268 Nagai, H., 4 Nagai, N., 62 Nagakura, I . , 406 Nagami, K., 470 Nagao, K., 94, 156 Nagasaki, M., 485 Nagashima, H., 169 Nagasuna, K . , 8,317 Nagata, K., 425 Nagata, R., 57, 134 Nagata, W . , 47,221 Ngjera, C., 187,282 Nakagawa, M., 472,519 Nakagawa, S. H., 191 Nakahama, S . , 207,208,353 Nakai, H., 184 Nakai, K . , 262 Nakai, T., 37,98, 152,222, 362,385 Nakajima, K., 194 Nakajima, M., 434 Nakajima, T., 24, 131, 374 Nakajo, E., 473, 514 Nakajo, T., 208, 353 Nakamizo, N., 482 Nakamura, A . , 8, 50, 107,213, 317,324,326 Nakamura, E., 37,98, 127, 147, 362,368,394, 403,405, 535 Nakamura, H., 244 Nakamura, K., 100 Nakamura, T., 243 Nakanishi, H., 232 Nakano, M., 63,287 Nakano, T., 225 Nakao, K . , 140 Nakashima, K., 239 Nakashita, Y., 298,404

Author Index Nakata, T., 206 Nakatsuji, S., 239 Nakatsuji, Y., 243 Nakatsuka, M., 473, 514 Nakatsuka, T., 31, 102, 315 Nakayama, J., 11,233,237 Nakayama, K., 141 Nakazaki, M., 242 Nakazono, Y . , 81 Namie, M. W., 12 Namuta, K., 229 Namy, J . L., 213,223 Napier, J. J., 394 Napolitano, E., 468 Narang, S. C., 224,284,365 Narasimhan, N. S., 247, 339 Narayanan, B. A , , 262,516 Narayanan, K., 16 Narisano, E., 112 Naritomi, T., 54 Narula, A. P. S . , 8 Narula, C . K., 386, 430 Naruta, Y . , 62,215, 367, 510 Nasipuri, D., 272 Naso, F., 195,266 Natale, N. R., 84, 227 Natile, G., 238 Natsume, M . , 485 Natu, A. A., 287 Nawata, Y., 61 Negishi, E.-i., 24, 30, 65, 89, 101, 119, 124, 125, 174, 331, 333,351, 384,386,415 Negoro, K., 86,226 Negron, G . , 457 Neidleman, S. l., 230 Nemlin, J., 479 Nemoto, H., 401,504 Netzel, M. A . , 344 Neuenschwander, K . , 63 Neuenschwander, M., 78 New, J . S., 252 Newcomb, M., 303 Newkome, G. R., 239, 243 Newton, R. F., 211,522 Nguyen, L. T., 491 Nguyen, S . , 65 Niangoran, C., 122,371 Nicholas, K. M . , 78, 328 Nickel, W.-U., 6 Niessner, M . , 75, 270 Niewohner, U., 117 Nikam, S. S., 71 Nikrad, P. V., 245 Ninagawa, A . , 452 Nish, T., 225 Nishida, I . , 127 Nishida, M . , 158 Nishida, R., 478 Nishida, S., 285 Nishide, H., 352,400 Nishiguchi, I . , 35, 104 Nishikawa, N., 141 Nishimoto, S . 4 , 470

561 Nishimura, K . , 266 Nishimura, S., 253 Nishio, K., 176 Nishio, T., 64 Nishiyama, H., 54. 284, 365 Nishiyama, K., 247, 366 Nishizawa, M . , 352, 400 Nitta, M., 96 Nivard, R. J. F., 174 No, K. H., 244 Nobayashi, Y., 74 Noble, D., 211 Noda, Y . , 176 Noels, A . F., 146 Nogami, Y., 266 Nogusa, € I . , 97 Nohara, Y., 133 Nojima, M . , 424, 443 Nokami, J . , 87, 318 Nomoto, T., 8 Nomura, K., 284 Nomura, Y., 296,302,363 Nonnenmacher, A . , 12 Nordberg, R. E., 321 Normant, J. F., 20, 32,58, 59, 103, 129,233, 333, 346, 404 Nose, M., 82 Nott, M. W . , 253 Noureldin, N. A , , 84 Noyori, R., 127, 297, 522 Nozaki, H., 29, 46, 48, 85, 176, 181. 221.227, 290, 360, 363, 366,408,422, 423 Nozaki, Y . , 71 Nozulak, J., 192 Nugent, R. A., 394, 501 Nugent, W. A . , 347 Nunez, O., 478 Nunez, W., 86 Nunomoto, S., 58, 233 Nutaitis, C. F . , 205 Nystrom, J. E., 268 Oae, S . , 308 Obase, H., 482 Obayashi, M., 52, 217, 290, 366,408 Ochiai, H., 93 Ochiai, M., 9,28, 33, 103, 175, 178, 376 Oda, H., 194,363 Oda, M., 68, 82 Oehlschlager, A. C., 70 Olund, J., 3 O’Fee, R. P . , 264 Oftring, A . , 487 Ogasawara, K., 516 Ogata, T., 434 Ogawa, A., 120 Ogilvie, K. K., 224 Ogumi, N., 213 Ogura, F., 30, 86, 225,227 Ogura, H., 190

Ogura, K., 87, 111, 131, 145, 282,287,402 Oh, T., 173 Ohashi, Y., 123 Ohba, T., 138 Ohira, N., 30 Ohmasa, N ., 167 Ohmori, Y., 239 Ohnishi, M., 141 Ohno, K., 383 Ohnuma, T., 467, 485 Ohsawa, H., 61 Ohsawa, T., 463,491 Ohshima, M., 31,102, 315 Ohshiro, Y., 4, 51, 107, 146 Ohsumi, T., 34, 104 Ohta, H., 411 Ohta, S . , 133 Ohta, T., 229, 282, 314 Ohtani, B., 470 Ohto, H., 144 Ohtsuka, H., 206 Ohtsuka, Y . , 98, 99 Ohuchida, S., 443 Ohya, T., 26, 116 Oi, R., 382 Oida, T., 148, 238 Oikawa, H., 190 Oikawa, Y . , 225, 417 Oinuma, H., 515 Oishi, T., 79,98, 99,206, 343 Ojima, I . , 67, 161 Okada, H., 287 Okahara, M . , 243 Okamoto, M . , 133 Okamoto, T., 259 Okamoto, Y., 63, 147, 242, 287,364 Okamura, N., 297, 522 Okano, K., 262 Okano, M., 143,148,238,309, 387 Okano, T., 302, 484, 485 Okawa, K., 194 Okawara, M., 3,31, 85, 169, 227,228, 413 Okawara, T., 190 Okazaki, M. E., 462 Okazaki, R., 380 Okimoto, M., 4 Okita, H., 476 Okon, A . V., 198 Okonkwo, J. O., 157,373 Okruszek, A . , 238 Oku, A., 71 Okubo, M., 308 Okuda, S., 408 Okuda, Y., 29,360 Okum, A . , 291 Okuma, K., 411 Olah, G. A., 121, 133,224, 226, 247,284,290, 293, 306, 307,365,366 Olano, B . , 262

General and Synthetic Methods Omata, T., 100, 229 Omi, T., 213 Omote, Y . , 64 Onaka, M., 224 Ong, H. H., 453 Ono, A . , 245 Ono, N . , 104, 164 Onozuka, J., 402 Ookawa, A . , 133, 167, 237 Oota, Y . , 426 Ootake, K., 42, 177 Oplinger, J. A . , 501 Oppolzer, W., 133, 159, 261, 404, 502,504, 515 Orena, M., 223,224, 270 Origel, A. E., 185 Oriyama, T., 46, 155 Orlinski, R., 119 Ormiston, R. A . , 454 Ornstein, P. L., 402 Oro, L. A . , 196, 312 Orsini, F., 151 Orta, G., 283 Osaka, K., 393 Osaka, N., 284, 365 Osakada, K . , 169,227 Osborne, S . , 487 O’Shea, D. M., 389 Oshikawa, T., 2 Oshima, K . , 29, 85, 181,227, 360, 363,408, 423 Oshima, M., 237 Oshima, T . , 100, 229 Oshumi, T., 245 Oster, T. A., 186,282,345 Osuka, A . , 3 , 4 , 11,40, 116, 160,167,185,228, 280,285, 309, 380 Otaki, S., 516 Otera, J., 24, 131, 218,230, 374,393 Otsubo, T., 2,30, 86,225 Otsuji, Y . , 239, 424 Otsuka, T., 227 Ottley, P. M., 138 Ottoboni, T. B., 224 Ouchi, A . , 182 Ouchi, M., 239 Oudenes, J., 25, 121 Ousset , J . B ., 409 Outcalt, R. J., 6 Overman, L. E., 49,64,68, 304, 317,393, 398, 462,475, 515,516 Owen, 0. J. R., 507 Oya, E., 237 Ozaki, S . , 85 Pacofsky, G. J., 165 Padmanabhan, S., 78,328 Padwa, A . , 304,367,394,457, 458,460 Pagb, O., 154,219 Paget, W. E., 66,216

Pai, G. G., 353 Paknikar, S. K . , 407 Palla, F., 109 Palma, P., 283 Palmer, B. D., 536 Palmieri, G., 238, 476 Palomo, C., 84,144, 227,283, 307 Pancrazi, A . , 479 Panda, C. S . , 189,298 Pandit, U . K . , 262 Pandit, V. S., 287 Panunzio, M., 134,228,384 Papadopoulos, K., 158,340 Papaioannou, D., 198 Papini, A . , 238, 291 Paquette, L. A . , 41, 121,376, 387, 391,392,401,497 Paradisi, M. P., 122 Paraskewas, S. M., 309 Parish, E. J., 84 Pariza, R. J., 39,99,371, 397 Park, K. B., 205 Parker, D . , 233 Parker, K. A . , 264 Parkhurst, C. S., 335, 413 Parnell, C. A . , 336 Parson, P. J., 67, 72, 105, 143, 167,221,238,361, 375 Parsons, W. H., 394,501 Parvez, M., 302 Pascard, C., 296 Patel, D. V . , 270, 448 Patel, R. C., 309 Patel, S . K., 52, 148, 181 Paterson, I . , 52, 123, 148, 181 Paton, J., 211 Paton, R. M., 298 Patrick, T. B., 142 Patrie, W. J., 169, 227 Pattenden, G., 49, 389,500, 501,502 Pauls, H. W., 270, 530 Paulus, E. F., 465 Paynter, 0. I., 138 Pearce, C. J . , 204 Pearlman, P. S., 369, 409 Pearson, A. J., 172 Pearson, J. R., 400 Pearson, W. H., 247, 280,436 Pecora, A. J., 119 Pelizzoni, F., 151 Pellacani, L., 112, 279 Peloso, C., 132 Pelter, A . , 15, 23, 92, 94, 170, 200,221, 357 Pennetreau, P., 296 Pennings, M. L. M., 456 Peretz, M., 77 Pereyre, M., 106,368 Perez, J. J., 525 Perie, J. J., 245 Peringer, P. , 456 Perlmutter, H. D., 13

Perlow, P. S . , 197 Perri, R. B., 283 Perriot, P., 161,293,346 Perrone, E., 494 Perry, D . A . , 446 Perry, M. W. D., 110, 308 Perz, R., 159 Peseckis, S. M., 359 Pessi, L., 228 Pete, J.-P., 44, 175, 176 Peter, R., 122, 337 Petersen, J. L., 500 Peterson, B., 63, 166 Petit, Y . , 161,293,346 Petrakis, K. S . , 117 Petrier, C., 130, 402 PCtrignani, J.-F., 138,232 Petrow, V . , 440 Petty, C. B., 64,393 Peyton, A. L., 300 Pfister, J. R., 247 Pham, P. Q., 62,233 Phan, X . T., 282 Phillippe, M., 251 Phillips, G. B., 124, 166,219, 359,430 Phillips, M. L., 352, 496 Phu, T. N., 93 Pia-Calcagno, M., 478 Piancatelli, G., 408 Piccardi, P., 59, 233,356 Piccolo, O., 18,236,321, 349 Pickering, R. A . , 311 Piers, E., 48,368, 406,413 Pietraszkiewicz, M., 242, 303 Pietrusiewicz, K. M., 39, 99, 398 Pigikre, Ch., 192 Pilar Vazquez, M., 300 Pillon, L. Z., 470 Pine, P., 196 Pinnick, H. W., 121, 190,282 Pinto, I. L., 494 Pinto, P., 493 Piotrowski, A . , 5, 326 Piper, I. M., 257 Piras, P. P., 264 Pirkle, W. H., 253, 254 Pirrung, M. C., 22 Pitacco, G., 388 Pitteloud, R., 133 Pizzo, F., 391 Pizzotti, M., 309 Plante, R., 121,239,290 Plat, M. M., 302,478 Plessi, L., 134 Plieninger, H., 12 Plusquellec, D., 134 Poignant, S . , 492 Pokier, J.-M., 118, 156, 265, 336,413 Poli, G., 128, 341 Pollini, G. P., 158, 501 Poncini, L., 235

Author Index Ponsinet, G., 491 Poochaivatananon, P., 22,167 Porskamp, P. A. T. W., 14, 447 Porta, F., 309 Porta, O., 224 Porter, J. R., 181 Porter, N. A., 424 Posner, G. H., 6 Poss, A. J., 394, 501 Potts, K. T., 265 Pougny, J.-R., 348, 527 Poupart, M.-A., 183 Pourcelot, G., 129 Powner, T. H., 394 Pradere, J.-P., 492 Prakasa Rao, A. S. C., 411 Prakash, G. K. S., 133,307 Prasit, P., 524 Prempree, P., 149 Preston, P. N., 225 Pri-Bar, I., 369, 409 Price, D ., 485 Price, M. F., 361 Price, T., 334 Prince, T. L., 2 Procter, G., 415 Proffitt, J. A., 453 Prout, K., 325,496 Pruitt, J. R., 518 Puckett, W. E., 239 Pugin, B., 302,314, 471 Pujol, F . , 408 Purrington, S. T., 157 Pyne, S. G., 204, 365,389,523 Quader, A., 58, 69, 349 Quayle, P., 345,491 Quesada, A. M., 478 Quessy, S. N., 336 Quincy, D. A., 84,227 Quindon, Y., 122, 358 Quiniou, H., 492 Quinn, N. R., 234 Quintard, J.-P., 106,235,368 Raban, M., 239 Rabe, J., 164 Racherla, U. S., 355 Radhakrishna, A. S., 122,253 Radner, F., 295 Radviroongit, S., 149 Rahn, B. J., 16, 349 Rajadhyaksha, S. N., 121 Rajaram, J., 8 Rakotonirina, R., 168 Ramadas, S. R., 167 Ramachandran, J., 167 Ramachandran, P. V., 295 Ramage, R., 507 Raman, K., 100,386 Rambaud, M., 32,105, 160 Ramesh, S., 525 Rand, C. L., 30,384

563 Ranganathan , D . ,295 Ranganathan, S., 295 Ranu, B. C., 391 Rao, A. S., 407 Rao, A. V. R., 511 Rao, C. G., 253 Rao, C. T., 220 Rao, V. B., 85 Raphael, R. A., 418,513 Rapoport, H., 113,279,479 Rasmussen, J. K., 27, 111, 212,289,350 Ratananukul., P., 114,373 Ratcliffe, N. M., 503 Ratcliffe, R. W.,493 Rathke, M. W., 117, 138 \ Ravasi, M., 296 Ravenscroft, P. D ., 85 Ray, T., 172 Raychaudhuri, S. R., 280 Razdan, R. K., 274 Rector, D. H., 440 Reddy, D. B., 387 Reddy, D. S., 500 Reddy, K. B., 511 Reden, J., 311 Redfearn, R., 468 Reed, J. N., 188,247,339 Reed, L. A., 111,394 Reed, T. J., 221 Reel, J. R., 440 Rees, C. W., 300,513 Reetz, M. T., 5, 111, 122, 146, 213,284,323,337 Reeves, P. C., 286 Regan, A. C., 340 Regen, S. L., 133,183,204, 286 Reglier, M., 64,238 Regondi, V., 237 Reho, A., 262,357 Reichelt, I., 147 Reid, S. T., 442, 483 Reider, P. J., 532 Reif, L., 296 Reinecke, M. G., 445 Reinhardt, G., 83 Reinhoudt, D. N., 451,456 Reinking, P., 86 Reissig, H.-U., 147 Reitz, A. B., 13 Renaldo, A. F., 68, 317,398 Renger, B., 298 Renzulli, L. A., 90 Restelli, A., 186,349 Reuman, M., 87 Reutrakul, V., 21,22, 116, 117,167,345 Revial, G., 154,219,391,505 Revol, J. M., 391 Rey , M., 402 ReyC, C., 32,127, 159 Reynolds, D. P., 211,522 Reznikov, I. V., 64

Rheingold, A. L., 81, 166 Rhodes, Y. E., 153 Riba, M., 228 Riccim A., 186,212,238,272, 291 Ricci , M. , 407 Rich, D. H., 199 Richards, I. C., 172 Richardson, G., 134,280,496 Richardson, G. D., 440 Richaud, M. G., 45,163,266 Richter, R., 231, 305 Richter, W. J., 386 Rickards, R. W., 247 Rieke, R. D., 89,233,350 Riemenschneider, C., 71,218 Rieu, J.-P., 235 Riguera, R., 300 Ringer, E . , 212 Riordan', P. D., 294 Ripley, S., 2 Rist, G., 236 Ritchie, B, M., 455 Ritter, A. R., 294 Roberts, B. W., 41 Roberts, D. H., 389 Roberts, R. A., 41, 121 Roberts, S. M., 211,522 Roberts, T. G., 450 Robertson, G. M., 49,389 Robins, M. J., 219,228 Robinson, R. P., 487, 539 Rodes, R., 265 Rodriguez, J., 116,235 Roder, T., 94 Rohe, D. M. M., 86 Roland, D. M., 532 Romanelli, M. N., 186 Ronald, R. C., 101,166 Rondan, N. G., 446 Ronzini, L., 88 Roper, J. M., 193 Rosa, C. L., 448 Rosenblum, 176,319,334,386 Roshan-Ali, Y . , 288 Rosini, C., 109 Rosini, G., 4,113,213,226, 298 Roslik, N. A., 64 Rosowsky, A., 198 Ross, B. C., 493 Rosier, J.-C., 440 Rossini, S., 384 Rost, W., 175 Roulleau, F . , 134 Roush, W. R., 144,165,355, 359 Rousseau, G., 381 Roussi, G., 457 Roy, G., 409 Royer ,J., 342,480 Royer, R., 294,295 Roie, J.-C., 492 Rozen, S., 117,157

General and Synthetic Methods Rozzell, J. D., jun., 133 Rubottom, G. M., 88, 102, 109,153,173,347 Rubralta, M . , 466 Rudisill, D., 133 Ruediger, E. H., 406 Ruger, W., 6 Ruel, O., 33,64, 107,238, 342 Riimmele, O . , 487 Ruffini, A. J., 265 Rukachaisirikul, V., 21, 117, 345 Ruotsalainen, H., 410 Russell, C. E., 32, 106, 233, 331 Russell, M. A., 276 Russell, R. K., 400, 507 Russo,C., 388 Rutledge, P. S . , 309 Rychnovsky, S. D., 177 Rys, P., 308 Ryu, I . , 120 Saalfrank, R. W., 64,175,180 Saburi, M., 169,227 Saccomano, N. A . , 384 Saddler, J. C., 340, 522 Sadhu, K. M., 354 Saednya, A . , 283 Saegusa, T., 473, 514 Sahai, M., 314 Sahlherg, C., 58, 69, 349 Saimoto, H., 176, 181,422, 423 Saindane, M., 179 Saito, I., 57, 134 Saito, M., 394 Saito, T., 225 Saito, Y., 216, 355 Sakai, T., 181 Sakakibara, T., 379 Sakamoto, H . , 239 Sakamoto, M., 155 Sakamoto, T., 74 Sakan, K., 394 Sakane, S . , 49,229,256,398, 404,466,477 Sakata, J . , 127 Sakata, Y., 2,55, 123 Sakdarat, S . , 226, 358 Sakuraba, H., 232 Sakurai, H., 22, 55, 123,127, 232,346,394 Sakuta, K., 54,284, 365 Salanski, P., 242 Salas, M., 264 Salazar, J. A., 468 Salomon, R . G., 312 Samaddar, A. K., 272 Sammes, P. G., 416, 478,503 Sanchez, F., 179,266 Sanchez, I. H . , 468, 484 Shnchez-Delgado, R. A . , 8 Sander, J . , 15

Sandri, S . , 223,224,270 Sano, H., 258, 413 Santaniello, E., 85,227,296 Santelli, M . , 73,98, 140,293, 387 Santelli-Rouvier, C., 98, 387 Sapp, S. G., 431 Sard, H., 274,382 Sardarian, A , , 122, 237 Sarma, J. C., 228 Sarma, K., 239 Sartoretti, J., 385 Sartori, G., 150,359,421 Sarussi, S. J . , 206 Sasaki, H., 245 Sa ki, J., 394 Sazki, K . , 127,296,394 Sasaki, M., 35, 104,470 Sasaki, T., 302, 484,485 Sasakura, C., 300 Sasatani, S., 254, 365 Sasson, Y . , 4 Sastry, K. A. R., 231 Sastry, V. V. S. K., 167 Sato, F., 29, 34,324, 363,364 Sato, K., 82,452 Sato, M., 29,239, 324,360, 363,364 Sato, N., 3,185,228, 280 Sato, R. I . , 394 Sato, S . , 26, 122,318, 375 Sato, T., 87,88, 89, 134, 165, 168,204,208,229, 304,350, 419 Sato, Y . , 162, 184, 213,290, 363 Satoh, J. Y . , 284 Satoh, T., 121 Satoh, Y . , 23,231, 356 Satomi, M., 235 Sauerwald, M., 323 Saus, A , , 93 Sauvetre, R., 20, 346 Savignac, P., 113 Savoia, D., 153,216 Sawada, H., 30,384 Sawada, I., 190 Sawada, S . , 387 Sawahata, M . , 52,217 Sawyer, J. S., 262 Scallen, T. J., 135 Scettri, A . , 408 Schatzlein, P., 64, 180 Schallenberg, J . , 252 Schamp, N., 114,262, 303, 456 Schaper, W., 72 Schauder, J. R., 2 Schaumann, E., 160 Scheeren, H. W., 410 Scheeren, J. W., 174 Scheffold, R., 119 Scheidt, H . , 421 Scheinmann, F., 522 Schell, F. M., 463

Schenone, P., 292,433 Schierling, P . , 64, 180 Schiess, M., 186 Schlecht, M. F., 128,149 Schleppnik, A . A . , 150 Schlessinger, R. H., 394, 501 Schleyer, P. von R., 265 Schmid, C. R. , 86,285 Schmid, G., 441 Schmidt, G., 408 Schmidt, H., 303 Schmidt, R. E., 146 Schmidt, R. R., 179,429 Schmidt, U., 24, 144 Schmidtberger, S . , 213 Schmitz, R. F., 343 Schneider, C. H., 198 Schneider, S., 283 Schobert, R., 184 Schollkopf, U., 192 Schon, I., 191,197, 204 Schonauer, K., 89,371 Scholz, D., 19, 114 Schreiber, S. L., 185, 434,525 Schroder, C., 303 Schroder, G., 239 Schubert, T., 154 Schuda, P. F., 147,226 Schull, V . , 41 Schultz, A. G., 422, 461 Schulz, G., 117, 138 Schwarz, O., 289 Schweizer, W. B., 193, 340 Schwellnus, K . , 146 Schwichtenberg, E., 487 Sciacovelli, O., 195, 266 Scolastico, C., 112, 128, 155, 215,341 Scott, A . D., 84 Scott, F., 233,404 Scott, L. T., 83 Scott, W. J., 27, 122 Scrimin, P., 449 Scripko, J . , 352 Scrivanti, A . , 8 Seconi, G., 186 Seebach, D., 136,150, 154, 186,193,211,296, 340, 353, 425 Seetz, J. W. F. L., 382 Seki, Y . , 46,364 Sekiya, M., 194,262,460 Selikson, S. J . , 86 Selim, A . , 148 Selve, C., 249 Selway, K. N., 303 Semeria, D., 251 Semmelhack, M. F., 85, 86, 101,165,227,285, 321, 326, 431 Senda, S . , 209 Seoane, C., 305 Sepiol, J . , 249 Sepulchre, A.-M., 251

565

Author Index Serajul Hague, M., 394 Sereno, J., 529 Serizawa, Y . , 425 Serratosa, F., 236 Serra-Zanetti, F., 122, 283 Servi, S., 181, 523 Sethi, S. P., 118, 155 Seyferth, D., 111, 342,412 Sghibartz, M., 239 Sha, C.-K., 461 Shadday, J., 86 Shanklin, M . , 148 Shannon, P. J., 282 Shanzer, A , , 183,186, 195,535 Sharma, K. K., 219 Sharma, K. S., 245 Sharma, R. P., 8, 121,226, 228 Sharma, V. K., 245 Sharpless, K. B., 279 Shea, K. J., 7, 62, 65, 184,233 Shechter, H., 343 Shedrinsky, A . , 394 Sheffy, F. K., 17, 108, 163, 234,369 Sheppard, R . C., 198 Sher, M. P., 293 Sheridan, R. S., 302 Sheth, J. P., 387 Shi, L., 430 Shiba, T., 194 Shibasaki, K . , 131, 282 Shibasaki, M., 9. 215 Shibuya, S . , 475, 484 Shieh, W.-R., 137,211 Shigehisa, T., 170,373, 418 Shih, J . , 133 Shiiya, K., 467 Shimada, J., 37,403 Shimada, K., 238 Shimada, S . , 417 Shimao, I . , 308 Shimazu, M., 394 Shimbo, K., 194 . Shimida, J.-I., 127 Shimizu, H., 11, 40, 160, 380 Shimizu, I., 38,39, 102,103, 123, 124, 315 Shimizu, K., 191, 532 Shimizu, M., 127,153, 211, 226 Shimizu, N., 4, 410 Shimizu, T., 450 Shimizu, Y . , 218 Shimoji, K., 142,377,408 Shimono, Y , ,501 Shimuzu, H., 309 Shin, C., 195 Shing, T. K. M . , 397,527, 539 Shinkai, H., 243 Shinkai, S., 241,242, 243 Shinoda, M . , 176,181,423 Shinokazi, H., 283 Shinozaki, K., 199

Shiraiwa, M., 74 Shishiyama, Y . , 290 Shono, T., 35,36, 86,97, 98, 104, 194,213,275,467,470, 478 Short, R. P., 391 Shubert, D. C., 16, 349 Shudo, K., 259 Sibi, M. P., 189, 339 Sibtain, F., 2, 237 Siddiqui, M. A . , 445 Sidot, C., 132, 140 Sieburth, S. M., 54, 108, 358 Siefert, K., 288 Siegmeier, R., 196 Sigiyama, Y . , 142 Shi, C . J., 137,211, 539 Silks, L. A., 104 Sillitoe, A., 298 Silveira, A , , 119 Silveira, L., 172 Silvestri, M. S . , 397 Simchen, G., 26 Simmonds, D. J . , 138 Simmons, D. P., 322 Simmons, K. A . , 253 Simon, E. S., 251 Simon, H., 155, 419 Simonet, J . , 291 Simoni, D., 158,265, 501 Simpkins, N. S . , 28, 41, 90, 177,345,507 Simpson, G. W., 217 Sims, R. J., 184 Sinay , P . , 348, 527 Sindona, G., 301 Singaram, B., 15, 23, 92,221, 357 Singaram, S . , 94, 200 Singh, B. B., 253 Singh, B. P . , 133, 224,226, 365 Singh, H., 280,453 Singh, H. K . , 298 Singh, P., 453 Singh, R. P . , 245 Singh, V . , 98, 173 Singleton, D. H., 418 Singleton, K. A . , 276, 537 Sinhababu, A. K., 4, 180,297 Skarzewski, J., 241 Skattebol, L., 383, 417, 524 Skinner, I. A . , 164 Slougui, N., 381 Smaardijk, A. A., 373 Smith, A. N., 463 Smith, C . , 242 Smith, D. J. H., 132,335,488 Smith, E. H., 187 Smith, F. X., 132, 449 Smith, H. K., iun., 27 Smith, J. C., 90 Smith, J . G., 234 Smith, J. K., 303

Smith, K . , 66,216 Smith, K. M., 473 Smith, M. B., 270 Smith, R., 367,459,515 Smithers, R. H., 116, 343 Snider, B. B . , 124, 166,219, 358,359,388,394, 398, 430, 482, 539 Snieckus, V., 188,189,247, 339,340,478 Snowden, R. L., 387 Soai, K., 133,167, 237 Sodeoka, M . , 472,519 Soderquist, J. A . , 32, 117,333, 369 Sofia, M. J., 175 Sofuku, H., 238 Sohajda, A., 453 Sola, R., 186 Solladie, G., 409 Somekh, L., 195 Sommer, T. J., 434,525 Son, B . , 241 Sonoda, N., 26, 46,93, 120, 159,364 Sonoda, T., 87 Sonveaux, E., 243 Sorenson, E. M., 404 Soria, J. de J . , 468, 484 Sorrenti, P . , 213, 298 Sotigu, F., 264 Soto, J. L., 305 Souppe, J . , 213,223 Southwell, I. A . , 507 Spada, A. P., 144 Speckamp, W. N., 462 Speer, H., 179 Speranza, G., 97 Spessard, G. O., 294 Speziale, V . , 199,269 Springer, J. P . , 101, 137, 165, 321,397,401 Spunta, G., 384 Sridharan, V., 304 Srinivasan, P. S . , 167 Srivastava, P. C., 231 Stampfli, U.. 78 Stakem, F. G., 81, 166 Stamm, H., 157 Stammer, C. H., 194 Stanton, S. A , , 335,413 Staunton, J., 340 Steel, P. J . , 217 Steglich, W., 117,138,194 Stehouwer, P. M., 328 Steigel, A . , 487 Steinauer, R.,191 Steinbach, R., 213 Steliou, K., 183 Stella, L., 457 Stenstrom, Y., 383,417, 524 Stevens, J . B., 262 Stevens, R. V . , 518 Stevens, R. W., 126, 153

566 Stevenson, P. J., 302 Stewart, F. H. C., 191 Still, B . , 387 Still, W. C., 40, 160,200,353, 370,401,505 Stille, J. K., 17, 89,93, 104, 108, 156,158,163, 234,333, 369,409 Stille, J. R., 127, 325 Stirling, C. J. M., 64 Stiver, S., 305 Stoll, A. T., 89,333,351 Stone, W. E., 367 Stoodley, R. J., 496, 508 Stork, G., 41, 171, 172,177, 201,293,312,336,384,394, 413,535 Storr, R. J., 237 Stothers, J. B., 390, 497 Stradi, R., 448 Strande, P., 235 Strange, G. A., 309 Street, L. J., 416, 503 Streith, J., 489 Strekowski, L., 173 Strickland, S. M., 394 Su, W., 523 SuBrez, E., 438,468 Suda, H., 208,353 Sugahara, S., 76,218,422 Sugawara, T., 94,109,149, 379,382 Sugiura, M., 2 Sugiura, S., 297, 522 Sugiyama, T., 67, 328 Sukata, K., 286 Sulman, P., 262,456 Sultanov, R. M., 231 Sumi, S., 84,226 Sumiya, T . , 124, 331 Sunbhanich, M., 253 Surya Prakash, G. K . , 293,366 Suschitzky, H., 485 Sutherland, J. K., 400 Sutter, M. A., 136 Suzuki, A., 22,23,34,93,94, 105, 109,190,231, 356 Suzuki, H., 3,4,11,40,116, 160,167,185,215,228,280, 285,309,380 Suzuki, K., 94,171,203,262 Suzuki, M., 194,297, 522 Suzuki, N., 8 Suzuki, T . , 61,93, 254 Suzuki, Y., 254,394, 507 Sviridov, A. F . , 88, 380 Swain, C. J., 85, 435 Swain, W. E., jun., 440 Swee Hok Goh, 4 Swenton, J. S., 510 Swern, D . , 449 Swindell, C. S., 329,349 Swonn, M . , 462,515 Szantay, C . , 485

General and Synthetic Methods Szarek, W. A., 257 Szeza, W., 224 Szirtes, T., 204 Szymanski, J., 303 Tabe, M., 467,485 Taber, D. F., 100,386 Tabusa, F., 171,203 Tachi, 133, Tachibana, Y., 193 Taddei, M., 186,212,238,272, 291 Tagaki, K., 233 Tagliavini, E., 153, 216 Tago, H., 134 Taillades, J., 186 Tajima, E., 165 Tajima, K., 134 Yajima, M . , 283 Takada, T., 520 Takagi, K., 59 Takahashi, H., 254,531 Takahashi, K., 87,111,131, 145,282,287 Takahashi, M., 383, 413 Takahashi, T . , 308,319,401, 485,504 Takahashi, T. T., 284 Takahashi, Y., 176 Takai, H., 482 Takai, K., 46,48, 85,213,221, 227, 408 Takainami, S., 356 Takaishi, N., 220 Takaki, K., 86,226 Takaku, H., 224 Takano, K., 259 'Takano, S., 516 Takano, Y., 112,338 Takaoka, T., 283 Takata, Y., 4 Takayama, H., 61 Take, K., 141,327 Takeda, A., 181,182,426 Takeda, K . , 190,501 Takeda, T., 51,108 Takei, H., 507 Takenaka, H., 352,400 Takenaka, S., 371,385 Takeshi, N., 413 Takeshita, H., 10 Takeshita, K., 46,364 Takeuchi, H., 259 Takeuchi, M., 11 Takeuchi, R., 245 Takeuchi, S . , 162 Takeuchi, Y . , 296,302,363 Takikawa, Y., 238 Takimoto, S., 144 Takinami, S., 22,231 Takizawa, S., 238 Tam, J. P., 198 Tamagawa, M., 300

Tamao, K., 47,211,221,350, 360 Tamariz, J., 170 Tamaru, Y., 84,93, 169, 186, 190,227 Tamblyn, W. H., 159, 204 Tamm, C., 135,136 Tamura, Y . , 142, 383 Tanabe, H., 238 Tanacs, B . , 226 Tanaka, C., 3,228,413 Tanaka, H., 97,305 Tanaka, K., 40,42,100,112, 160, 177,229,290, 346 Tanaka, M., 278 Tanaka, N., 42,177,247,366 Tanaka, R., 307 Tanaka, S., 82,143 Tanaka, T., 206,297,522 Tanaka, Y., 29,34,232, 363, 364, 411 Tanguy, G., 140 Tani, H., 3, 228 Taniguchi, M., 472, 519 Tanimoto, S., 148,238,301 Taniyma, E., 351,465 Tantratrat, T., 296 Tarbin, J. A., 294 Tardella, P. A., 112, 279 Tardivel, R., 117 Tashiro, M., 141,242 Tassi, D., 212, 272 Taticchi, A., 391 Tatsumi, T., 317 Tatsumo, T., 235 Tatsuta, K., 531 Taufer, I., 148 Taura, T., 193 Taya, K., 122 Taylor, E. C., 164 Taylor, G., 302 Taylor, R. T., 227 Tedga, N., 118,156,265 Tegeler, J. J., 453 Tenaglia, A , , 68 Teramura, K . , 450 Teranishi, S., 47, 85,227,482 Terao, Y., 262 Terasaki, S., 245 Termini, J., 31, 105 Terpstra, J. W., 164, 311 Terrett, N. K., 360 Teshirogi, T., 190 Testaferri, L . , 237, 330 TeyssiC, P., 146 Tezuka, H., 387 Thaisrivongs, S., 154,353,537 Thal, C . , 426 Thebtaranonth, Y . , 149 Theodoropoulos, D., 198 Therien, M., 435, 527 Thianpatanagui, S., 304 Thiebault, H., 117 Thieffy, A , , 230

Author Index Thies, R. W. 406 Thijs, L., 115,268 Thomas, D. G., 252 Thomas, E. E., 394 Thomas, R. D., 36,218, 344 Thompson, D .,286 Thompson, P. A., 355 Thompson, W. J., 155 Thomsen, I . , 194 Thorsen, M., 194 Tice, C. M . , 250 Tickner, A. M., 198 Ticozzi, C., 431 Tiecco, M., 237, 330 Tietze, L.-F., 428,474 Timmers, D., 319, 381 Tingoli, M., 237, 330 Tischler, S. A . , 184 Tishchenko, I. G., 64 Titus, G. R., 265 Tius, M. A , , 212 Tjoeng, F.-S., 191 Tober, D., 479 Toda, F., 100,112,229,290 Todd, M., 211 Tolle, R., 192 Toh, N., 266 Toi, N., 302, 485 Tojo, T., 417 Tokunaga, T., 64 Tokutake, N., 489 Tol, R., 382 Tomas, M., 304,458,460 Tomasik, W., 300 Tomasini, C., 224 Tominaga, H., 317 Tomioka, H., 11 Tomioka, K., 532 Tomo, Y., 169 Tomoda, S . , 296,302, 363 Tooyama, Y., 176,505 Topalsavoglou, N., 93 Tordeux, M., 121 Torii, S., 95, 97, 120,305, 382 Torisawa, Y., 215 Torre, G., 211,448 Torregrosa, J. L., 269 Torrini, I., 122 Torssell, K. G., 219 Toru, T., 297, 522 Toshimitsu, A., 235,309, 387 Totten, G. E., 153 Tou, J. S., 150 Tour, J. M., 30, 384 Touraud, E., 454 Townsend, C. A . , 491 Townsend, L. B., 291,487 Tran Huu Dau, E., 296 Trapani, G . , 262, 357 Trecoske, M. A . , 90 Trefonas, L. M., 181 Trenerry, V. C., 217 Trippett, S., 339 Trius, A ., 230

567 Trivedi, G. K., 295 Trombini, C . , 153,216 Trost, B. M., 38, 50,63, 148, 163,166,174,183,247,280, 319,330,358,359, 376, 388, 393,394,402, 405 Trudell, M. L., 164 Trueblood, K. N., 244 Tschamber, T., 489 Tse, A . , 188 Tsien, Y.-L., 18 Tsubata, K . , 478 Tsuboi, S., 182,426 Tsuchihashi, G., 94,402 Tsuchiya, K., 243 Tsuchiya, R., 196 Tsuchiya, T . , 253, 487 Tsuge, O., 393 Tsuge, S., 87 Tsui, J., 401 Tsuji, J., 3,38, 39,102, 103, 123,124,169,185, 228,280, 315,319, 504 Tsuji, T., 47,221 Tsuji, Y., 229,245,282 Tsukanaka, T., 8 Tsumaki, H., 128, 301 Tsumiyama, T., 263 Tsumo, T., 243 Tsunekawa, K., 2 Tsuno, Y., 4,410 Tsunokawa, Y . ,408 Tsuruoka, Y., 245 Tsuyama, K., 145 Tsuzuki, R., 126 Tucker, B., 231, 305 Tucker, J. R., 319,381 Tueting, D., 89, 333, 369 Tumey, M. L., 27 Tundo, P., 11,371 Tuniguchi, H., 215 Turner, S. E., 493 Turowski, E. C., 344 Tyler, P. C., 536 Tyrrell, A. W. R., 181 Tyrrell, N. D., 187 Uccella, N., 301 Uchida, Y., 317 Uchino, T., 383 Uchiyama, H., 324 Uchiyama, M., 93 Uda, H., 176 Uberhardt, T., 204 Ueda, K., 242 Ueda, M., 190,343 Ueda, S . , 224 Uehara, H., 88 Uematsu, T., 524 Uemura, M., 327 Uemura, S . , 10,200, 235,309 Ueno, Y., 3,31, 85,169, 227, 228,413 Ueshima, T., 85

Uggeri, F., 140 Ugolini, A., 435, 527 Ukachukwa, V. C., 179 Ukai, J., 60, 324 Ukita, T., 9,28, 178,376 Ullah, S., 296 Ullrich, F.-W., 104 Ullrich, J. W., 304, 460 Ulrich, H., 305 Umani-Ronchi, A . , 153,216, 245 Umeda, N., 208,353 Umezawa, S . , 253 Undheim, K., 235 Uneyama, K., 95 Ungur, N. D., 230 Uno, H . , 510 Uno, Y., 167 Urabe, H., 122, 126, 338,368 Urayama, T., 175 Urbach, H., 352,465 Urbanski, M. J . , 439 Urch, C. J., 229,368 Urrea, M., 261, 515 Urso, F., 335, 488 UskokoviC, M. R., 529 Utaka, M., 181,426 Utimoto, K., 290 Uwaya, S., 121 Uyehara, T., 505 Vagberg, J . , 321 Valeds, J. A . , 305 Valencia, N., 8 Valentin, E., 388 VallCe, Y., 166 Van Asch, A., 283 van den Aardweg, G. C. N., 57, 287 van den Goorbergh, J. A. M., 156 van der Gen, A., 25,156,228, 370 van der Leij, M., 14 Van der Plas, H. C., 253 Van Derveer, D., 6 Vandewalle, M., 501 van Dijk, B. G., 451 Van Elburg, P., 228 Vankar, Y. D., 220 Van Middlesworth, F., 137, 211 van Noort, P. C. M., 238 van Rijn, P. E., 265 Van Royen, L. A., 394 van Schaik, T. A. M., 25,370 van Tamelen, E. E., 387,399, 400,507 Van Wallendael, S . , 477 Varma, R. K., 253 Vasdella, A., 272 Vasella, A., 298 Vatele, J.-M., 66, 164 Veda, M., 190

568 Vedejs, E., 446, 458 Vehara, A . , 196 Veki, M . , 199 Vemura, M . , 141 Vemura, S., 143, 387 Venanzi, L. M., 302,314,471 Venkateswarlu, R., 170 Venturello, C., 407 Venturello, P., 11, 371 Verboom, W., 451 VerhC, R., 114,262,303,456 Verkruijsse, H. D., 265 Vermeer, P . , 80,328 Vermeeren, H. P. W., 238 Vernikre, C., 53,218 Veronese, A . C., 449 Versace, R., 493 Vessal, B., 237 Vessiere, R., 454 Vialle, J., 166 Viallefont, Ph., 192 Vidaluc, J. L., 199 Villieras, J., 32, 105, 160 Vishmuvajjala, B. R., 440 Visnick, M., 173 Viswanathan, M . , 234 Viti, S. M . , 279 Vlad, D. F., 230 Voelter, W., 197 Vogel, D. E . , 56 Vogt, K., 429 Vogtle, F . , 239 Volkmann, R. A . , 92, 160, 329,472 Vollhardt, K. P. C., 336 Vo-Quang, L., 107 Vo-Quang, Y . , 107 Vorbruggen, H., 287, 366 Voss, G., 142 Voss, J., 187 Vostrikova, 0. S., 231 Voyer, N., 121,287, 290 Voyle, M., 182 Vuilhorgne, M., 384 Wada, F . , 17, 393 Wada, M., 170,184,373,418 Wada, T., 393 Wade, J. D., 198 Waegell;B., 68 Waespe-SarEeviL, N., 135 Wagenaar, A . , 189 Wagner, A . , 429 Wagner, I., 192 Waigh, R . D . , 253 Wakabayashi, S . , 87 Wakabayashi, T., 122 Wakabayashi, Y . , 208, 290 Wakamatsu, H., 169 Wakamatsu, T., 476 Wakamiya, T., 194 Wakefield, B. J., 522 Wakselman, C., 121 Waldmann, H., 196

General and Synthetic Methods Walker, A . , 345,491 Walkinshaw, M. D., 443 Walkup, R. D., 532 Wall, A . , 60 Wallace, I. H. M . , 382 Wallace, P. M . , 276, 537 Wallace, T. W., 211, 522 Wallendael, S. V., 335 Walley, D. R., 11, 144 Wallis, C. J . , 522 Waltermire, R. E., 159 Wamhoff, H., 303 Wang, B. C., 400 Wang, D., 208,366 Wang, K. K., 71 Wang, N., 539 Wang, W.-L., 111,342,412 Wani, M . C., 440 Waniguchi, E., 122 Ward, R. S . , 170 Warin, R., 146 Warner, P., 65 Warner, R. W., 183, 319 Warren, S., 12, 31, 50, 104, 162,188,237,281, 370, 377 Wartski, L., 293 Waseda, T., 74, 109 Washioka, Y . , 175 Wasmuth, D., 136 Wassermann, H. H., 471, 487, 539 Watanabe, H., 29, 364 Watanabe, K., 4,419 Watanabe, M., 188, 478 Watanabe, N., 309 Watanabe, T., 309,428, 448 Watanabe, Y . , 229,245,282 Waterhouse, I., 522 Waterhouse, J., 121,223 Watt, D. S . , 64, 86, 167, 182, 344 Waykole, L., 179 Weatherford, W. D., 86 Webb, M. W., 86 Webb, R. R., jun., 351, 378, 465 Weber. E., 239 Weber, G . , 307 Weber, T., 340 Weedon, A. C., 102,164 Weerasooriya, U., 90,265 Wegmann, H., 261,515 Wei-Hwa Leong, W., 32,369 Weiler, L . , 184, 399 Weinberger, B., 140 Weingold, D. H., 204 Weinkam, R. J., 300 Weinreb, S . M., 55,63,269, 271,302,378,473, 514 Weinschneider, S . , 187 Weinstein, R. M . , 111, 342, 412 Weisser, J., 285 Welch, C. J., 254

Welch, S. C., 411 Wells, G. J., 387 Welvart, Z . , 91 Welzel, P., 154 Wender, P. A . , 54, 108,358, 390, 497 Wenderoth, B., 122,213, 337 Wendler, N. L., 539 Wenger, C., 13 Wenke, G., 153 Wenkert, D., 133 Wenkert, E., 329, 349, 391, 421 Werstiuk, N. H., 92 West, F. G., 458 Westermann, J., 5 Westmijze, H., 80, 328 Weuster, P . , 418 Wheaton, G. A . , 372 Wheeler, C. J., 166 White, A. H., 452 White, D. H., 142 White, G. S., 470 White, J. D., 536 White, L. L., 44, 182 Whitesell, J. K., 125, 151, 349 Whitesell, M. A . , 125, 268 Whitham, G. H., 68 Whiting, M. C., 138 Whittle, A . J., 41, 177, 507, 536 Wicha, J . , 319 Widdowson, D. A . , 327 Widera, R., 454 Widmer, U . , 144 Wieschollek, R., 15 Wilbur, D. S . , 367 Wilcox, C. S . , 537 Wilde, H., 307 Wildonger, K. J., 493 Wilhelm, R. S., 129 Wilkening, R. R., 493 Willeit, A . , 456 Willfahrt, J., 192 Williams, D. J., 181, 276 Williams, D. R., 1, 226, 303, 358,411,435 Williams, E. G . , 438, 525 Williams, G. D., 319, 381 Williams, J. R., 197 Williams, L., 221, 357 Williams, P. J., 185, 280 Williams, R. V., 376, 392 Williams, T. H., 529 Williamson, S. A . , 473 Willner, I., 233 Wilson, I. B . , 197 Wilson, J. S., 228 Wilson, J. W., 15,23,92,221, 357 Wilson, S. R., 9, 361,394 Wilson, W. K., 135 Winkler, J. D., 384 Winwick, T., 225

569

Author Index Wise, D. S . , 291 Wise, S . , 65 Witt, W., 239 Woell, J. B., 132, 150 Wolfe, S., 84 Wolff, A., 489 Wolff, G . , 489 Wolff, S., 303 Wolfram, J., 468 Wong, H., 303 Wong, J . , 41 Wood, J. L., 394,501 Wood, R. D., 345 Woodgate, P . D., 309 Woodward, R. B., 191 Worster, P. M., 198 Worthington, P. A . , 503 Wright, J. E., 198 Wrobel, J. E., 180 Wroble, R. R., 86 Wulff, W. D., 394 Wuts, P. G. M . , 355 Wymann, W. E., 247 Wynberg, H., 373 Xingya, L., 443 xo, z . , 400 Xu, Y., 430 Yadav, L. D. S., 31 Yaginuma, F., 245 Yahata, N., 87, 145 Yamabe, K., 307 Yamada, H . , 167,237 Yamada, S., 61 Yamada, T., 195 Yamada, Y., 67,84,85,93, 169, 186,227, 328 Yamagishi, T., 196 Yamaguchi, H., 30,33, 86, 103,175,225,227 Yamaguchi, K., 472,519 Yamaguchi, M., 74, 75, 109, 188,206,356 Yamaguchi, R., 81 Yamahira, A . , 239 Yamaji, T., 29, 364 Yamakawa, K . , 121 Yamamoto, H . , 44, 49, 60, 118,176,209,229,254,256, 258,275, 324,358, 365, 398, 404,466,477 Yamamoto, K . , 170, 242 Yamamoto, S . , 47, 221 Yamamoto, T., 360

Yamamoto, Y., 54, 84,128, 151,152,169,213,216,227, 355,367,381 Yamamura, Y., 49,256, 404, 466 Yamana, M., 20, 21,117 Yamana, Y., 146 Yamanaka, H., 74 Yamanaka, Y., 215 Yamanouchi, T., 371,385 Yamaoka, S., 410 Yamashita, H., 173, 382 Yamashita, M., 2,402 Yamashita, Y., 58, 233 Yamauchi, M . , 428 Yamauchi, T., 140 Yamawaki, J . , 10,84,226,293 Yamazaki, H . , 180 Yamazaki, N., 208, 353 Yamazaki, Y., 93 Yan, T. H., 387 Yanagi, K., 524 Yanagi, Y., 296 Yanagida, M., 79, 343 Yanagida, N., 507 Yanaura, S., 254 Yang, D. C., 394 Yang, S., 232 Yang, T.-K.,252,463 Yano, Y., 237 Yashunsky, D. V., 88,380 Yasuda, H., 8, 50, 107, 142, 317, 324, 326 Yasumura, M., 86, 226 Yatagai, M., 196 Yates, P., 305 Yates, S . W., 86 Yatsu, I., 237 Yde, B., 194 Yeates, C., 436 Yevich, Y. P., 252 Yoakim, C., 122,225,358 Yogo, T., 94,109 Yokomatsu, T., 475,484 Yokoo, K., 215 Yokota, S . , 158 Yokoyama, K., 127 Yokoyama, M., 85,127,227, 228,283 Yokoyama, T.-a., 291 Yokoyama, Y., 169,300 Yoneda, S . , 117,138,351 Yonekura, M., 491 Yonemitsu, O., 225, 417 Yonezawa, Y., 195 Yoon, N. M., 205

Yoshida, H . , 434 Yoshida, J., 50,221,238,359 Yoshida, K., 391 Yoshida, M., 424 Yoshida, Y . , 285 Yoshida, Z., 84,93,169,186, 190,227 Yoshihara, K., 505 Yoshii, E., 501 Yoshikawa, S., 169,227 Yoshikawa, T., 470 Yoshikoshi, A . , 176, 182 Yoshimura, N., 263 Yoshinaga, M., 239 Yoshitomi, S . , 309 Yoshiura, K., 175 Young, C . G., 386 Young, D. W., 194 Young, S . , 211 Yuasa, Y., 475,484 Yuba, K., 57,134 Yue, S., 487 Yukizaki, H., 229, 350 Yunokihara, M., 169 Yus, M., 18,187,219,282, 349 Yuste, F., 185 Zahra, J.-P., 73,116,140,293 Zajac, W. W., jun., 113, 298 Zaks, W. J., 393 Zama, M., 196 Zanotti, V . , 4, 113 Zard, S. Z., 87, 251 Zask, A . , 326, 431 Zawacky, S. R., 400,507 Zayed, S . M. A . D., 253 Zbiral, E, 89, 371 Zecchini, G. P., 122 Zelle, R. E., 539 Zen, S . , 226 Zeng, L.-M., 46, 283,348,365 Zenki, S.-i., 309, 448 Zetta, L., 359 Zhou, B., 137,211 Zirotti, C., 523 Zoran, A., 4 Zore, B., 197 Zuger, M. F., 154,211 Zutterman, F., 393,404, 501, 502 Zwanenburg, B., 14, 115,268, 447 Zweifel, G., 76, 77, 78, 139, 364 Zwick, W., 151 Zydowsky, T. M., 133

General and synthetic methods

General and synthetic methods

General and synthetic methods., Volume 3