Terpenoids and Steroids: Volume 9 (SPR Terpenoids and Steroids (RSC))

Terpenoids and Steroids

Volume 9

A Specialist Periodical Report

Terpenoids and Steroids Volume 9 A Review of the Literature Published between September 1977 and Augltst 1978

Senior Reporter J. R. Hanson, School of Molecular Sciences, University of Sussex Reporters

G. Britton, University of Liverpool J. D. Connolly, University of Glasgow

D. N. Kirk, Westfield College, London B. A. Marples, University of Technology, Loughborough

T. Money, University of British Columbia, Vancouver, Canada R. B. Yeats, Bishop's University, Lennoxville, Quebec, Canada

The Chemical Society Burlington House, London, W I V OBN

British Library Cataloguing in Publication Data Terpenoids and steroids. (Chemical Society. Specialist periodical reports). VOl. 9 1. Terpenes 2. Steroids I. Hanson, James Ralph 11. Series 547’.71 QD416 74-615720 ISBN 0-85186-650-6 ISSN 0300-5992

Copyright @ 1979 The Chemical Society

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 Chemical Society

Set in Times on Linotron and printed offset by J. W. Arrowsmith Ltd., Bristol, England Made in Great Britain

In trod uction

The terpenoids and steroids have continued to provide a fascinating amount of chemistry. The increasing use of high-field 'H n.m.r. and I3C n.m.r. data in structural elucidation, whilst leading to a diminution of natural product chemistry, has substantially increased the total number of known terpenoids. However, it sometimes seems that although the spectroscopic data can be readily interpreted in terms of the suggested structure for a natural product the data do not always prove the structure to the exclusion of others. There is an ever-present need for unambiguous chemical correlation with known structures of proven absolute stereochemistry. Marine and insect sources have continued to provide novel structural types whilst phytochemical surveys of the Compositae and Labiatae have yielded many new terpenoids. The value of 13Cn.m.r. methods in biosynthetic studies, particularly utilizing 13C-13C coupling patterns for defining the manner of folding of prenyl chains, has been exemplified in a number of studies. More recently there have been reports of the application of 2H n.m.r. to the elucidation of the stereochemistry of terpenoid biosynthesis and of 2H-'3C n.m.r. studies in distinguishing between plausible hydrogen rearrangements. During the year the synthetic challenge created by the sesquiterpenoids has been met with a number of elegant syntheses whilst the steroids have remained valuable substrates for examining the scope of physical methods and of new reactions. Considerable information has now accrued on detailed steroid conformations and the application of this to the comparison of steroid reactivities is an interesting area.

J. R. HANSON

Contents

Part I Terpenoids

3

Chapter 1 Monoterpenoids By R. B. Yeats 1 Introduction

3

2 Physical Measurements: X-Ray Crystallography;Chirality X- Ray Crystallography 2,6-Dimethyloctanes Naturally Occurring Halogenated Monoterpenoids Chrysanthemyl Derivatives and Pyrethrins Cyclopentanes, Iridoids, Monoterpenoid Alkaloids p- Menthanes m-Menthanes Cycloheptanes Bicycle[ 2,2,1Iheptanes Bicyclo[3,1,l]heptanes Cannabinoids and other Phenolic Monoterpenoids Miscellaneous Spectral and other Physical Data Absolute Configuration, Optical Purity, Asymmetric Synthesis, Resolution Chromatography

5 5 5 5

6 6 7 8 8 8 9 10 11 11 12 15

3 General Synthetic Reactions

16

4 Biogenesis, Occurrence, Chemotaxonomy, and Biological Activity Biogenesis Essential Oils and Chemotaxonomy Pyrethroids and Related Insecticides

24 24 26 28

5 Acyclic Monoterpenoids Terpenoid Synthesis from Isoprene 2,6-Dimethyloctanes Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives vii

29 29 32 39

...

Terpenoids and Steroids

Vlll

6 Naturally Occurring Halogenated Monoterpenoids

42

7 Monocyclic Monoterpenoids

45 45 45 50 58 59 60 61 61

Cyclobutane Cyclopentanes, Iridoids p-Menthanes 0-Menthanes rn- Menthanes Tetrame thylcyclohexanes Dimethylethylcyclohexanes Cycloheptanes 8 Bicyclic Monoterpenoids Bicyclo[3,1,O]hexanes Bicyclo[2,2,llheptanes Bicyclo[3,1,llheptanes Bicyclo[4,1,O]heptanes

62 62 63 69 73

9 Furanoid and Pyranoid Monoterpenoids

75

10 Cannabinoids and other Phenolic Monoterpenoids

77

Chapter 2 Sesquiterpenoids By T. Money

81

1 Farnesane

81

2 Mono- and Bi-cyclofarnesanes

85

3 Bisabolane

90

4 Sesquipinane (Bergamotane), Sesquicamphane

93

5 Cuparane, Trichothecane, Laurane

96

6 Chamigrane

101

7 Carotane, Acorane, Cedrane

103

8 Amorphane efc.

108

9 Himachalane, Longipinane, Longicamphane, Longifolane

110

10 Hnmulane, Caryophyllane, Protoilludane, Illudane, Marasmane, Hirsutane, etc.

112

11 Germacrane

119

12 Eudesmane (Selinane)

124

13 Eremophilane etc.

138

14 Vetivane, Vetispirane

143

15 Guaiane, Pseudoguaiane, Valerenane

148

Contents

ix

16 Aromadendrane

156

17 Miscellaneous

157

Chapter 3 Diterpenoids By J. R. Hanson

160

1 Introduction

160

2 Bicyclic Diterpenoids

161 161 164

Labdanes Clerodanes

3 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids

4 Tetracyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tetracyclic Diterpenoids Gibberellins Grayanotoxins Diterpenoid Alkaloids

167 167 170 171 171 174 174 175 175

5 Macrocyclic Diterpenoids and their Cyclization Products

176

6 Miscellaneous Diterpenoids

179

7 Diterpenoid Total Synthesis

182

Chapter 4 Triterpenoids By J. D. Connolly

186

1 Squalene Group

186

2 Fusidane-Lanostane Group

188

3 Dammarane-Euphane Group Tetranortriterpenoids Quassinoids

193 196 200

4 Lupane Group

20 1

5 Oleanane Group

203

6 Ursane Group

212

7 Hopane Group

214

8 Stictane Group

217

9 Miscellaneous

217

Terpenoids and Steroids

X

Chapter 5 Carotenoids and Polyterpenoids By G. Britton

218

1 Carotenoids Reviews New Structures and Stereochemistry Bicyclic Carotenoids Monocyclic Carotenoids Acyclic Carotenoids Apocarotenoids Degraded Carotenoids Synthesis and Reactions Carote noids Retinoids Other Degraded Carotenoids Carotenoid-Protein Complexes Physical Methods Separation and Assay N.M.R. Spectroscopy Electronic Absorption Spectroscopy Resonance Raman Spectroscopy X - Ray Structures Linezr Dichroism Miscellaneous Spectroscopy and Physical Chemistry Photoreceptor Pigments Biosynthesis and Metabolism Stereochemistry Pathways Inhibition and Regulation Metabolism in Animals Retinoids Ionones

218 218 218 218 222 222 223 223 224 224 23 1 234 237 237 237 238 238 239 239 240 240 242 242 243 244 246 246 247 247

2 Polyterpenoids and Quinones

247 247 249 249 25 1

Polyterpenoids Isoprenylated Quinones Chemistry Biosynthesis

Part I1 Steroids Chapter 1 Physical Methods By D. N. Kirk

255

1 Structure and Conformation

255

2 N.M.R. Spectroscopy

258

xi

Contents 3 Chiroptical Phenomena

260

4 Mass Spectrometry

262

5 Miscellaneous Physical Properties

263

6 Analytical Methods Immunoassay of Steroids Chromatography

265 265 267

Chapter 2 Steroid Reactions and Partial Synthesis By B. A. Marples Section A : Steroid Reactions

269

1 Alcohols and their Derivatives, Halides, and Epoxides Substitution, Solvolysis, and Elimination Oxidation and Reduction Epoxide Formation and Ring Opening Ethers, Esters, and Related Derivatives of Alcohols

269 269 27 1 272 273

2 Unsaturated Compounds Electrophilic Addition Other Addition Reactions Other Reactions of Unsaturated Steroids Aromatic Compounds

275 275 278 279 280

3 Carbonyl Compounds Reduction 0ther Reactions Reactions involving Enols or Enolic Derivatives Oximes and Related Derivatives

282 282 283 285 288

4 Compounds of Nitrogen

289

5 Molecular Rearrangements Backbone Rearrangements Miscellaneous Rearrangements

29 1 29 1 294

6 Photochemical Reactions

298

Section B : Partial Syntheses 7 Cholestane Derivatives and Analogues

303

8 Vitamin D and its Metabolites

310

9 Pregnanes

313

10 Androstanes and Oestranes

318

11 Cardenolides and Bufadienolides

320

12 Cyclo-steroids and Seco-steroids

322

Terpenoids and Steroids

xii

13 Heterocyclic Steroids

323

14 Microbiological Transformations

325

15 Miscellaneous Syntheses

327

Errata

329

Author Index

331

Part I TERPENOI DS

1 Monoterpenoids BY

R. B. YEATS

1 Introduction This year's Report surveys the literature' up to August 1978, subject to its availability in Europe2 by early November 1978. A few additional papers of particular significance which were published between August and December 1978 have been included for added ~ l a r i t y Further .~ changes for this Report concern halogenated mon~terpenoids~ and the consolidation of monoterpenoid X-ray crystallographic structure determinations into a separate section. The X-ray analysis of monoterpenoids has been increasing ~ignificantly.~ Unfortunately it is not always possible to identify such structure determinations in earlier Reports.6 Since previous Reports' and lists' of X-ray structure determinations were or i n a c c ~ r a t e ,it~ * seems ~ timely to include in this

See Vol. 8, p. 3, ref. 1 for details of the literature coverage; 137 titles have been searched this year, page-by-page, to yield approximately 2200 monoterpenoid-related papers; 1586 provide the core upon which this Report is based. Compared to last year (Vol. 8, p. 3, ref. 2), 135 papers may be computer-retrieved from the Essential Oils Section of Chemical Abstracts from September 1977 to August 1978, whereas a total of 217 papers are retrievable under essential oils in all sections of Chemical Abstracts during this period. This Report is dedicated to Sir Derek Barton, F.R.S., in honour of his 60th birthday. The kind hospitality and helpful encouragement extended by Sir Derek at the Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, France, during the preparation of this manuscript is acknowledged with gratitude. Literature available only as a Chemical Abstract after September 1st 1978 is not, however, included. ' Naturally occurring halogenated monoterpenoids have been placed in a new section this year. Since many of them are now known to be cyclic compounds, it is no longer logical to classify them in the acyclic section. Non-naturally occurring halogenated monoterpenoids, however, continue to be reported in their respective sections. Volumes 6,7, and 8 report 3,11, and 10 papers respectively, with a further 35 papers published this year. Examples where X-ray determinations are not identified include p-menth-l(7)-ene-trans-2,8-diol (Vol. 2, p. 32, ref. 126) and bruceol (Vol. 7, p. 49, ref. 461). P. P. Williams, Cryst. Structure Comm., 1973,2,1S, For example, 2~~,4a-dibromo-lO~-pinan-3-one, has not been included previously in these Reports. Vol. 5, pp. 206,207; for example, P-thujaplicin, J. E. Derry and T. A. Hamor, J.C.S. Perkin 11,1972, 694, is excluded from this list. 'Molecular Structures and Dimensions; Bibliography 1935-1969, General Organic Crystal Structures', ed. 0. Kennard and D. G. Watson, International Union of Crystallography, N.V.A. Oosthoek's Uitgevers Mij Utrecht, 1970; thirteen out of thirty-two compounds listed under monoterpenes are non-monoterpenoid. In contrast, thujic acid p-bromophenacyl ester" is not listed as a monoterpenoid. l o R. E. Davis and A. Tulinsky, J. Arner. Chern. SOC.,1966,88,4583.

3

4

Terpenoids a n d Steroids

new section references to all monoterpenoid X-ray crystal structure determinations which have been reported in the literature to date.” Authors are reminded of a request made earlier (Vol. 8, p . 4 ) concerning sending reprints of monoterpenoid-related papers automatically to this Reporter to assist the prompt compilation of future Reports.’ The restricted space available for these Reports unfortunately does not allow the discussion of a number of topics of interest to monoterpenoid chemists; useful reviews of such topics include monoterpenoid alkaloids,12 carbazole alkaloid^,'^ isoprenoids and alkaloids of tobacco,14 naturally occurring plant c o u m a r i n ~the ,~~ biosynthesis of aromatic hemiterpenes,16 and recent developments in the field of naturally occurring aroma components. l 7 The poor quality of the Chemical Abstracts” makes it difficult to assess the significance of a number of reviews of potential industrial interest.” A volume in the ‘Methodicum Chimicum’ series includes a very brief discussion of some monoterpenoids.20 Three useful reference works have been p ~ b l i s h e d . ~ ’ Some - ~ ~ acyclic monoterpenoids containing one chiral centre are included in lists relating the sign of optical rotation (no numerical values are given) and absolute stereochemistry with the method of structural correlation; unfortunately the literature has only been covered to 1971.21In contrast, Klein and Rojahn22have included literature references to October 1976 in the literature report which accompanies their wall-chart of monoterpenoid configurations. In an otherwise excellent and most useful work, attention is drawn to four misprinted formulae [(+)-trans-myrtanol, (-)-piperitenone epoxide, (+)-piperitone epoxide, and (-)-junionone] and the omission of the iridoids, the naturally occurring halogenated monoterpenoids, and some well-known cycloheptane monoterpenoids. It is always difficult to be all-inclusive ; however, a significant number of monoterpenoids appear in only one or the other of these works.21,22The graphic assembly of formulae22 from Dragoco also illustrates the array of inconsistent nomenclature practices which Most of these X-ray structure determinations have been published during the period covered by these Reports; for the sake of completeness, 25 papers earlier than 1969 are included. This Reporter would welcome hearing of structure determinations which have been omitted, so that they may be included in future Reports. I’ G. A. Cordell in ‘The Alkaloids, Chemistry, and Physiology’,ed. (the late) R. H. F. Manske, Vol. 16, Academic Press, New York, 1977, Chapter 8, p. 431. l 3 D. P. Chakraborty, Fortschr. Chem. org. Naturstoffe,1977, 34, 299. 14 C. R. Enzell, I. Wahlberg, and A. J. Aasen, Fortschr, Chem. org. Naturstoffe, 1977, 34, 1. l5 R. D. H. Murray, Fortschr. Chem. org. Naturstoffe, 1978, 35, 199. l 6 M. F. Grundon, Tetrahedron, 1978, 34, 143. l7 G. Ohloff, Fortschr. Chem. org. Naturstoffe,1978, 35, 431. l 8 Further to earlier criticism (Vol. 4, p. 3; Vol. 8, pp. 3, 4) of Chemical Abstracts, five examples of duplicate abstracts have appeared this year; e.g. Volume 6 has been abstracted again, Chem. Abs., 1977,87,168 257; cf. Chem. Abs., 1977,86,72 919. ( a )A. Nuerrenbach, Chem. LaborBerr., 1977,28,171 (Chem. A h . , 1978,88,121 390); ( b ) T .D. R. Manning, Rep. N.Z., Dep. Sci. Ind. Res., Chem. Din, 1977, C.D. 2256 (Chem. Abs., 1978, 88, 121 394); ( c )T. Nishida, Y. Fujita, and K. Itoi, Sekiyu GakkaiShi, 1977,20,689 (Chem. Abs., 1978, 88, 7065); ( d ) H. Hikino, ibid., 1977, 20, 728 (Chem. Abs., 1978, 88, 7068). *” ‘Methodicum Chimicum’, Vol. 11, pt. 3, ‘Steroids, Terpenes, and Alkaloids’, ed. F. Korte and M. Goto, Academic Press, New York, 1978, p. 44: S. Hayashi, ‘Monoterpenoids and Sesquiterpenoids’. J. Jacques, C. Gros, and S. Bourcier, ‘Absolute Configurations of 6000 Selected Compounds with One Asymmetric Carbon Atom’, Vol. 4 of the series ‘Stereochemistry: Fundamentals and Methods’, ed. H. B. Kagan, Thieme Verlag, Stuttgart, 1977. W. Rojahn and E. Klein, ‘Die Konfigurationen der Monoterpenoide’, Dragoco, Holzminden, Germany, 1977; see p. 73 and refs. 144 and 658 for related comments.

’’

5

Monoterpenoids

have grown up with the literature [e.g. thujone (isothujone), A4-carene (car-2ene), inconsistent o -menthane nomenclature, 2,6-dimethylocten-1 -diol-(3,8) (cf. 3,7-dimethyloct-7-en- 1,6-diol), myrcenol us. myrcen-8-01]. Surely the time has come to,adopt a standardized monoterpenoid nomenclature. Few of the recently published reference books covering natural products provide the chemist, within a single volume, with most of the detail which is frequently required, uiz. names, structure, physical data, together with references to occurrence, structure determination, and synthesis. The revised edition of Karrer,23aand its first ~ u p p l e m e n t , ’do ~ ~provide this detail in their comprehensive coverage of plant products. This strength makes these volumes indispensable, despite the delay in covering the literature, uit. to 1956,23“and 1957-6123b respectively. Newly isolated monoterpenoids now occupy a class of their own in the first supplement, although some cycloheptane monoterpenoids (e.g. pdolabrin), quinones (e.g. /3 -thujaplicinol), and tetrahydrocannabinol (the formula is incorrect) are listed ~ e p a r a t e l y . ’ ~ ~

2 Physical Measurements: X-Ray Crystallography; Chirality X-Ray Crystallography.--In addition to 43 new structure determinations reported this year, the list of X-ray structure determinations of monoterpenoids (and closely related compounds falling within the scope of these Reports) which follows includes compounds reported directly in earlier volumes (to which references are made); original literature references are given for all other structures, whether newly reported7*’*’’or not.6 The literature has been covered from 1946 to August 1978. 2,6-Dimethyloctanes. Geranylamine h y d r ~ c h l o r i d e . ~ ~ Naturally Occurring Halogenated Monoterpenoids. (3R,4S,7S)-trans,trans-3,7Dimethyl-l,8,8-tribromo-3,4,7-trichloro-octa-1,5-diene (Vol. 7, p. 18, ref. 200) ; violacene 2 (1;X = Cl) (Vol. 7, p. 19, ref. 209); costatol (Vol. 8, p. 31, ref. 301); costatone (Vol. 8, p. 31, ref. 302); a reassigned structure for violacene (2);25 chondrocolactone (3);26 (lR,2S,4S,5R)-l,4-dibromo-5-chloro-2E-chlorovinyl1,5-dimethylcyclohexane (1; X = Br);27 and (lS,2S,4R,5S)-2-bromo-lEbromovinyl-4,5-dichloro-l,5-dimethylcyclohexane (4).27 Br

(1)

L1

(2)

(3)

(4)

( a ) W. Karrer, ‘Konstitution und Vorkommen der organischen Pflanzenstoffe (exklusive Alkaloide)’, 2nd edn., Birkhauser Verlag, Basel, Switzerland, 1976; ( b )W. Karrer, E. Cherbuliez, and C. H. Eugster, ‘Konstitution und Vorkommen der orgmischen Pflanzenstoffe (exklusive Alkaloide)’, Erganzungsband 1, Birkhauser Verlag, Basel; Switzerland, 1977. 24 D. W. J. Cruickshank and G. A. Jeffrey, Acta Cryst., 1954, 7 , 646. ” D. van Engen, J. Clardy, E. Kho-Wiseman, P. Crews, M. D. Higgs, and D. J. Faulkner, Tetrahedron Letters, 1978, 29. 26 F. X. Woolard, R. E. Moore, D. Van Engen, and J. Clardy, Tetrahedron Letters, 1978, 2367. ” A. G . Gonzblez, J. M. Arteaga, J. D. Martin, M. L. Rodriguez, J. Fayos, and M. Martinez-Ripolli, Phytochemistry, 1978, 17, 947.

23

6

Terpenoids and Steroids

Chrysanthernyl Derivatives and Pyrethrins. ( 1R,3R) - ( + )-trans- Chrysanthemic acid p-bromoanilide (Vol. 7, p. 20, ref. 2 13);28(4s)-2-(prop-2’-enyl)rethron-4yl(lR,3R)-trans-chrysanthemate 6-bromo-2,4-dinitrophenylhydrazone (Vol. 4, p. 20, ref. 115 incorrectly refers to the X-ray study of six pyrethrins)286(Vol. 5, p. 15, ref. 102);28‘ a- cyano-3-phenoxybenzyl ci~-3-(2’,2’-dibromovinyl)2,2-dimethylcyclopropanecarboxylate;29 cis- 3 -phenoxybenzyl 3-(2’,2’di~romovinyl)-2,2-dimethylcyclopropanecarboxylate (Vol. 7, p. 10, ref. 1f9); and cis-3-phenoxybenzyl 3-(2’,2’-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (Vol. 7, p. 10, ref. 119). Cyclopentanes, Irridoids, Monoterpenoid Alkaloids. ( - )-Bromodihydroumbellulone (5);30 ( - )-isoiridomyrmecin (6);3’ ( + )-iridomyrmecin (7) at -150 0C;316*32 loganin penta-acetate r:,onomethyl ether the rubidium salt dihydrate of monotropein (8; R = H);34(-)-sarracenin (Vol. 7, p. 27, ref. 269); ( -)-1-0-acetylxylomollin;34” (*)-gentiolactone (9);35 ( - )-jasminin aglucone ethyl ether;3h tecomanine meth~perchlorate;~’ alkaloid C m e t h i ~ d i d eand ; ~ ~nitropolyzonamine (10) per~hlorate.~’

@ @ H

(8)

H

(9)

(10)

( a ) The X-ray analysis of the p-bromophenacyl ester of (lR,3R)-(+)-rran~-chrysanthemic ester is reported as a personal communication from G. Ferguson in the following; ( 6 ) M. J. Begley, L. Crombie, D. J. Simmonds, and D. A. Whiting, J.C.S. Chem. Comm., 1972,1276 (Vol. 5,p. 206); (c) J.C.S. Perkin I, 1974,1230. 29 J. D. Owen, J.C.S. Chem. Comm., 1974,859;see Vol. 7,p. 10,ref. 118 for the full paper. 30 H. E. Smith, R. T. Gray, T. J. Shaffner, and P. G. Lenhert, J. Org. Chem., 1969,34,136. 31 ( a ) B.P. Schoenborn and J. F. McConnell, Acta Cryst., 1962,15,779; ( 6 )J. F. McConnell, A. McL. Mathieson, and B. P. Schoenborn, Tetrahedron Letters, 1962,445.The structure depicted in the former for isoiridomyrmecin is incorrect. 32 J. F. McConnell, A. McL. Mathieson, and B. P. Schoenborn, Acta Cryst., 1964,17,472. 33 P. J. Lentz, jun. and M. G. Rossmann, J.C.S. Chem. Comm., 1969,1269; P.J. Lentz, jun., Diss. Abs. Internat. ( B ) , 1971,32,715 (Vol. 5 , p. 206). 34 N. Masaki, M. Hirabayashi, K. Fuji, K. Osaki, and H. Inouye, Tetrahedron Letters, 1967,2367. 34aM.Nakane, C. R. Hutchinson, D. Van. Engen, and J. Clardy, J. Amer. Chem. SOC.,1978,100,7079; see also ref. 462. 35 I. H.Suhr, P. Arends, and B. Jensen, Phytochemistry, 1978,17, 135. 36 A. Shimada and M. Fukuyo, Abstracts of the 22nd Japan Chemical Society Meeting, 1969,60,as reported in Vol. 3,p. 28,ref. 141;Vol. 3,formula (105)lacks an 0-P-Glu group at C-1 (cf Vol. 6, p. 26). 37 (a) G. Jones, G. Ferguson, and W. C. Marsh, J.C.S. Chem. Comm., 1971, 994 (Vol. 5, p. 206 incorrectly refers to p. 944);cf. Vol. 7,p. 28;( b ) G. Ferguson and W. C. Marsh, J.C.S. Perkin 11, 28

1975,1124. 38

R. W.Miller and A. T. McPhail, J. Chem. Res. ( M ) , 1978,901;(10)is a stereochemical revision of the structure reported previously (Vol. 6,p. 13).

7

Monoterpenoids

p-Menthanes. (-)-Men thyl trimethylammonium iodide ;39 (-)-men thyl 4 -bromo2-nitroben~oate;~' (+)-isomenthy1 p -brom~phenylcarbamate;~~ the (-)menthoxyacetamide of (+)-trans-2- (0-bromophenyl)cyclohexylamine;42 (-)menthyl phenylgly~xylate;~~ (-)-menthy1 p-brom~phenylglyoxylate;~~ (-)menthyl (-)-p-iodobenzenes~lphinate;~~ (lR,3R,4S)-(-)-menthyl S-methyl (S),-phenylphosph~nothioate;~~ (lR,3R,4S)-(-)-menthyl methyl (R),-phenylp h ~ s p h o n a t e ; ~trans-dichlorobis(dimethylneomenthylphosphine)nickel(~~);~~ ~ trans -dichloro bis(dime th ylneomen thylp hosphine)palladium(11) ;49 trans dichlorobis(dimethylmenthylphosphine)palladium(~~) ;49 (+)-a-naphthylphenyl(4R,8R)- (+) -p-men th- 1-en-9-01 p-iodobenzo1-men thoxymethoxysilane ate;" the diol (11);52(+)-cis-carvone t r i b r ~ m i d e 2,4-dibrom0menthone;~~ ;~~

(11)

syn - and anti-pulegone toluene-p-sulphonylhydrazones;54" (+)-[(4S)carvone]Rh'(C,H,) ; 5 5 Fe(C0)3-pulegone racerni~,'~"*~ l a e ~ o - ,and ~~~'~ E. J. Gabe and D. F. Grant, Acta Cryst., 1962, 15, 1074; for earlier crystallographic data on this compound, (-)-menthylamine hydrochloride, and (-)-menthylamine hydrobromide, see D. F. Grant and D. Rogers, ibid., 1954,7, 301. An earlier paper, uiz. I. W. Ramsay and D. Rogers, ibid., 1952, 5, 268, records data on a-I-menthol. 40*A.Itai, Y. Iitaka, U. Nagai, and Y. Kamo, Acta Cryst., 1976, B32, 1553. " G. Kartha, K. T. Go, A. K. Bose, and M. S. Tibbetts, J.C.S. Perkin ZZ, 1976, 717. '' T. G. Cochran, A. Weber, A. C. Huitric, A. Camerman, and L. H. Jensen, J. Org. Chem., 1976,41, 1640. 43 R. Parthasarathy, J. Ohrt, A. Horeau, J. P. Vigneron, and H. B. Kagan, Tetrahedron, 1970,26,4705 (Vol. 5, p. 206). '' J. M. Ohrt and R. Parthasarathy, Acta Cryst., 1969, A25, S198; J. Cryst. Mo:. Structure, 1975,5,359. 45 E. B. Fleischer, M. Axelrod, M. Green, and K. Mislow, J. Arner. Chem. SOC.,1964,86, 3395. 46 J. Donohue, N. Mandel, W. B. Farnham, R. K. Murray, jun., K. Mislow, and H. P. Benschop, J. Amer. Chem. Soc., 1971, 93, 3792. Vol. 5, p. 206 incorrectly refers to a thiolate. 47 W. B. Farnham, K. Mislow, N. Mandel, and J. Donohue, J.C.S. Chem. Comm., 1972, 120. 48 K. Kan, Y. Kai, N. Yasuoka, and N. Kasai, Bull. Chem. SOC.Japan, 1977, 50, 1051. 49 K. Kan, K. Miki, Y. Kai, N. Yasuoka, and N. Kasai, Bull. Chem. SOC. Japan, 1978,51, 733. J. A. Kanters and A. M. van Veen, Cryst. Structure Comm., 1973, 2, 261; for an earlier crystallographic study of the racemic compound, see J.-P. Vidal, J.-L. Galignt, and J. Falgueirettes, Compt. rend., 1970, 270, C, 690 (Vol. 5 , p. 206). 5 1 J. F. Blount, B. A. Pawson, and G. Saucy, J.C.S. Chem. Comm., 1969, 715; the formula of (4R,8R)-p-menth-l -en-9-d is depicted incorrectly in this paper. " W. E. Scott and G. F. Richards, J. Org. Chem., 1971,36, 63; W. E. Scott, Diss. Abs. Znternat. ( B ) , 1970, 31, 157 (Vol. 5, p. 206 incorrectly refers to p. 170). 53 R. W. Schevitz and M. G. Rossmann, J.C.S. Chem. Comm., 1969,711; R. W. Schevitz, Diss. Abs. Znternat. ( B ) ,1971,31,4533 (Vol. 5, p. 206). 54 J. A. Wunderlich and W. N. Lipscomb, Tetrahedron, 1960, 11, 219. 54a J. F. Blount, and reported in W. G. Dauben, G. T. Rivers, and W. T. Zimmerman, J. Amer. Chem. Soc., 1977, 99, 3414 and G. T. Rivers, Diss. Abs. Znternat. (B), 1978, 38, 3700. This WBS first reported in Vol. 7 , p. 34, ref. 341; however, the chirality at C-1 has not been stated. 5 5 W. Winter, B. Koppenhofer, and V. Schurig, J. Organometallic Chem., 1978,150, 145. 56 E. Koerner von Gustorf, F.-W. Grevels, C. Kriiger, G. Olbrich, F. Mark, D . Schulz, and R. Wagner, 2. Naturforsch., 1972, 27b, 392 (Vol. 5, p. 206). 57 ( a ) Vol. 7, p. 29, ref. 287; ( b )J. Kroon, P. R. E. van Gurp, H. A. J. Oonk, F. Baert, and R. Fouret, Acta Cryst., 1976, B32, 2561; (c) F. Baert, M. Foulon, and R. Fouret, 3rd European Crystallographic Meeting, 6th-10th September 1976, Zurich, Switzerland, Collected Abstracts, p. 215; ( d ) F. Baert, R. Fouret, H. A. J. Oonk, and J. Kroon, Acta Cryst., 1978, B34, 222. 39

8

Terpenoids and Steroids

m i x e d - ~ r y s t a carvoxime; l ~ ~ ~ ~ ~ optically race mi^,^^^^^" and solid-solution of benzoylcarvoxime; diplatinum tetra(dithi0cumate) ;" dibromodehydrobispulegone;60 monobromoisodehydrobispulegone;61and the monoterpenoid-related tri-o -thymitide and some clathrates.62 m-Menthanes. 3,CY -Dimethyls t yrene-[Fe (C0),l2 Cycluheptanes. Thujic acid p-bromophenacyl ester;1° p-thujaplicin;" 3,5,7- tribromohinokitiol;63" 3,7-dibrornohinokiti01;~~~ 5,7-dibromohinokiti01;~~~ yt hu j aplicin ;64 and the di-isopropyldi tropolonofuran u tahin .64a*65 Bicyclo[2,2, llheptanes. (+)-Camphor;"" ( - )-," (+)-,"" and (f)-camphoroxime;"* (+)-3-bromocamphor (Vol. 2, p. 38);6" (+)-8-bromocamphor (Vol. 8, p. 49, ref. 439); endo-3,9-dibromocamphor;70 3-exo,9,9-tribromocamphor [Vol. 7, p. 37, ref. 372; formula (179) should have an exo-3-bromo-group]; (+)-3-endo, 9,9-tribromocamphor (Vol. 8, p. 50, ref. 442); (+)-camphor-3-carboxylic acid;70" (+)-3-p-bromobenzylidenecamphor;71 (+)-" and (*)-o-chlorophenylirnin~carnphor;~~~ (f)-trans-r-camphanic acid (Vol. 3, p. 67, ref. 293); (+)-3-diazocamphor (Vol. 3, p. 62, ref. 269); (-)-2-exo-bromo-2-endo-nitro~ a m p h a n e ;(+)-lO-bromo-2-exo ~~ -chloro-2-endo - n i t r o s ~ c a m p h a n e ; 2-exo~~ bromo-2-endo- nitr~fenchane;~' 6-endo- b r o m o i s ~ f e n c h o n e(-)-1,7-dibromo;~~ 3,3,4-trimethylnorbornan-2-one (Vol. 8, p. 49, ref. 440); 1,7-dibromo-4dibromomethyl-3,3-dimethylnorbornan-2-one (Vol. 8, p. 50, ref. 441); 2-endoF. Baert, J.-P. Mornon, and P. Herpin, Compt. rend., 1971, 273, C , 231. J. P. Fackler, jun., J. Amer. Chem. SOC., 1972, 94, 1009 (Vol. 5, p. 206). 6o A. Perales, S. Martinez-Carrera, and S. Garcia-Blanco, Acta Cryst., 1969, B25, 1817. 61 S. Martinez-Carrera and J. M. Franco, Acta Cryst., 1972, A28, S20; J. M. Franco, S. MartinezCarrera, and S. Garcia-Blanco, ibid., 1974, B30,415. The incorrect nomenclature used in this paper was later corrected; see Vol. 7, p. 29, ref. 288. See also ref. 525. 62 S. Brunie and G. Tsoucaris, Cryst. Structure Comm., 1974, 3, 481; S. Brunie, A. Navaza, and .G. Tsoucaris, Acta Cryst., 1975, A31, S127; D. J. Williams and D. Lawton, Tetrahedron Letters, 1975,111. 62n F. H. Herbstein and M. G. Reisner, J.C.S. Chem. Comm., 1972, 1077; see formula (166). S. It& Y. Fukazawa, and Y. Iitaka, Tetrahedron Letters, ( a )1972,741; ( b )1972,745. The authors use the name hinokitiol in preference to (3-thujaplicin. 64 ( a ) A.-C. Wiehager, B. Karlsson, and A.-M. Pilotti, 2nd European Crystallographic Meeting, 26th-29th August 1974, Heszetely, Hungary, Collected Abstracts, p. 573; ( b ) Vol. 8, p. 48, ref. 423. b5 B. Karlsson. A.-M. Pilotti, and A.-C. Wiehager, Acta Cryst., 1976, B32, 3118. 66 H. A. J. Oonk, Ph.D. Thesis, Utrecht, 1965. 67 F. Baert and R. Fouret, Acta Cryst., 1978, B34, 2546. '* F. Baert, R. Fouret, and C. Gors, 4th European Crystallographic Meeting, 30th August-3rd September 1977, Oxford, England, Abstracts B, p. 522. 69 F. H. Allen and D. Rogers, J. Chem. SOC.( B ) , 1971,632. For earlier reports, see F. H. Allen and D. Rogers, J.C.S. Chem. Comm., 1966, 837 and M. G. Northolt and J. H. Palm, Rec. Trav. chim., 1966,85,143.An earlier paper also reports X-ray data for a-chloro- and a-cyano-camphor; viz. E. H. Wiebenga and C. J. Krom, ibid., 1946, 65, 663. 70 K. L. Brown and D. Hall, Cryst. Structure Comm., 1973, 2, 659. 70aA.Baptista, Anais Acad. brasil. Cienc., 1977,48, 223 (Chem. Abs., 1977,87, 125 684). 71 J. J. Bonnet and U. Jeannin, Krist. und Tech., 1973,8, 133 (Chem. Abs., 1973,79,71 146). 7 2 (a) F. Baert, M. Foulon, and R. Fouret, Cryst. Structure Comm., 1975,4,61;( b )M. Foulon, F. Baert, and R. Fouret, ref. 57c, p. 279. 73 D. A. Brueckner, T. A. Hamor, J. Monteath Robertson, and G. A. Sim, J. Chem. SOC., 1962,799. 74 G. Ferguson, C. J. Fritchie, J. Monteath Robertson, and G. A. Sim, J. Chem. Soc., 1961, 1976. 75 C. RCrat, Compt. rend., 1968, 266, C , 612; for an earlier report, see J. Berthou, Y. Brunel, A. Laurent, A. Rassat, and C. Rerat, ibid., 1967, 264, C , 292 (Vol. 5 , p. 207). 76 P. P. Williams, Chem. and Ind., 1964, 1583; Acta Cryst., 1969, B25, 409. 58

"

Monoterpenoids

9

bromo-6-exo(dimethylaminomethyl)fenchane hydr~bromide;~’ anhydrobromonitrocamphane ( (-)-camphene-8-carboxylic acid;79 (+)-iso-

camphenilanic acid p -bromophenacyl ester;79a(k)-carbocamphenilone;” syn 2,2’-bifenchylidene E at -120 O C ; ” l-biapocamphane;82 N- (S)-phenylalaninato[(+)-hydroxymethylidenecamphorato]copper(~~);’~bis-(3-nitrocamphorato)-(2-methylpyridine)copper(11);84 A-( +)ss9-truns-tris-[(+)-3-acetylcamphorato]chromium(~~~);~~ (1R,2S,3S,aR)- 3 -(ahydroxybenzyl)-l,7,7-trimethylbicyclo[2,2,1]heptan-2-ol;86 (1R,3S,aR)- 3-(ahydroxybenzy1)-l,7,7trimethylbicyclo[2,2,1]heptan-2-one;s7(2R)-(-)- 2- [(lS’,2R’)- 1’,3’-dithian-2’yl]isoborneol l’-oxide;88 and 2,2,5-endo,6-exo,8,9,10-heptachlorobornane.89 Many papers (e.g.see Vol. 5,p. 207) have confirmed the absolute configuration of (+)-3-endo -bromocamphor-9-sulphonic acid;” likewise a number of papers have established the absolute configuration of (+)-camphor-10-sulphonic acid as various For the isoalbene S-benzylthioether (189; X = SCH,Ph) (endo2,6-dimethyl-4-benzylthiotricyclo[5,2,1 ,02*6]dec-3-ene)see ref. 611b.

Bicyclo [3,1, llheptunes. 2a,4a- Dibromo- lop -pinan-3-0ne;~ (-)-cis-pinocarveyl p-nitrobenzoate (Vol. 5, p. 36, ref. 269); the cyclic sulphite of lop( a )G. Reck, 2.Chem., 1969,9,30; ( b )L. Kutschabsky and G. Reck, J. prukt. Chem., 1971,312,896 (Vol. 5, p. 207). 78 G. L. Dwivedi and R. C. Srivastava, Actu Cryst., 1972, B28, 2567. 79 P. C. Moews, J. R. Knox, and W. R. Vaughan, J. Amer. Chem. Soc., 1978,100,260;see Vol. 8, p. 49, ref. 438 for a preliminary publication. For further discussion of this compound, (184; X = H,H; Y = E-CHCHO,H), see p. 66. 79a J. M. Midgley, W. B. Whalley, G. Buchbauer, G. W. Hana, H. Koch, P. J. Roberts, and G. Ferguson, J.C.S. Perkin I, 1978, 1312; see formula (183; X = exo-COZCHzCOC6H4Br-p). 80 B&ee, J. P. Seymour, and A. W. Burgstahler, J.C.S. Chem. Comm., 1974,235; for the full paper, see Vol. 8, p. 49, ref. 437. 81 T. Pilati and M. Simonetta, J.C.S. Perkin II, 1977, 1435. 82 R. A. Alden, J. Kraut, and T. G. Traylor, J. Amer. Chem. Soc., 1968,90, 74. 83 L. Casella, M. Gullotti, A. Pasini, G. Ciani, M. Manassero, and A. Sironi, Znorg. Chim. Acru, 1978, 26, L1. Personal communication from the authors indicates that the last two lines of the fourth paragraph should read ‘agreement indices are R = 0.045 and Rw = 0.055 for the correct enantiomorph and R = 0.050 and Rw = 0.061 for the other’. 84 G. Dessy and V. Fares, Cryst. Structure Comm., 1977,6, 583. 85 W. Dew. Horrocks, jun., D. L. Johnston, and D. MacInnes, J. Amer. Chem. Soc., 1970, 92, 7620 (Vol. 5, p. 207). 86 R. L. Harlow and S. H. Simonsen, Cryst. Structure Comm., 1976,5, 791. 87 R. L. Harlow and S. H. Simonsen, Cryst. Structure Comm., 1976, 5,471. 88 R. F. Bryan, F. A. Carey, 0.D. Dailey, jun., R. J. Maher, and R. W. Miller, J. Org. Chem., 1978,43, 90. 89 K. J. Palmer, R. Y. Wong, R. E. Lundin, S. Khalifa, and J. E. Casida, J. Amer. Chem. SOC.,1975,97, 408. 90 J. A. Wunderlich, Acru Cryst., 1967, 23, 846 (Vol. 5, p. 207). 91 For example, see G. R. Brubaker and L. E. Webb, J. Amer. Chem. SOC., 1969, 91, 7199; C. Couldwell, K. Prout, D. Robey, R. Taylor, and F. J. C. Rossotti, Actu Cryst., 1978, B34, 1491. 77

10

Terpenoids and Steroids

~ i n a n e - 2 , 3 a - d i o l ; ~ ~3-(N-methylaminomethyl)pinane hydr~bromide;~~ 3 - (N,N-dimethy laminomethy1)pin-2 ( 10)-ene hydro bromide ;94 (-) -bromoderivative of paeoniflorin (Vol. 3, p. 71, ref. 308); (+)-bis-(T-pineny1)nickel (Vol. 3, p. 71, ref. 310; Vol. 6, p. 41, ref. 307); (+)-Fe(CC)3-pinocarvone complex;56 the phosphetan (-)-(13) which is synthesized from (-)-a-pinene

(13)

and MePC12-AlC13;95 (-)-(lS,5S)-6,6-dimethyl-2-[(2'S)-3',3',3'-trichloro-2'hydroxypropyl]bicyclo[3,1,l]hept-2-ene tosylate ester (cf Vol. 8, p. 54);96 3c h l o r ~ n o p i n o n e ; ~and ~ " 3-brom0nopinone.~~" Cannabinoids and other Phenolic Monoterpenoids. (-)-Bruce01 (14; X = OH, Y = H);97 (-)-bromobruceol (14; X = OH, Y = Br);98 (*)-dibromodeoxybruceol (15; X = Br);97 an acetylcitran [Vol. 7, p. 48, formula (255)]99 and the corresponding f ~ r m y l c i t r a ndibromocannabicyclol(16);'oo ;~~ murrayazoline ( 17);'01 cyclocymopol monomethyl ether acetate (Vol. 7, p. 48, ref. 454); xanthochymol (Vol. 8, p. 60, ref. 536) and the related isoxanthochymol di-p-bromobenzenesulphonate;lo2 ~annabinol;"~~annabidiol;"~6P-hydroxy-A1-THC-DMF complex at -165 0C;'05A'-tetrahydrocannabinolic acid B (Vol. 6 , p. 49, ref. 362); cannabispiran;lo6and the synthetic cannabinoid derivative 8,5a-trans-5a,9a-cisM. J. Brice, J. M. Coxon, E. Dansted, M. P. Hartshorn, and W. T. Robinson, J.C.S. Chem. Comm., 1969, 356. For related discussion of this compound, see Vol. 8, p. 9 (cf. Vol. 1, p. 43). 93 G. Reck and L. Kutschabsky, Acta Cryst., 1970, B26, 578. 94 L. Kutschabsky, 2. Chem., 1969,9, 31; for the full paper see ref. 77b. 95 E. Vilkas, M. Vilkas, D. Joniaux, and C. Pascard-Billy, J.C.S. Chem. Comm., 1978, 125. y6 M. J. Begley, G. B. Gill, and B. Wallace, J.C.S. Perkin I, 1978, 93; see formula (209) for the parent alcohol. 96aY.Barrans, Compt. rend., 1964, 259, 796. 97 M. J. Begley, L. Crombie, D. A. Slack, and D. A. Whiting, J.C.S. Chem. Comm., 1976, 140; J.C.S. Perkin f, 1977,2402. In the latter there is a discrepancy between the crystallographic models and the formulae which are used; the absolute configuration was not determined, however. 98 A. M. Duffield, P. R. Jefferies, E. N. Maslen, and A. I. M. Rae, Tetrahedron, 1963, 19, 593. 99 M. J. Begley, L. Crombie, R. W. King, D. A. Slack, and D. A. Whiting, J.C.S. Chem. Comm., 1976, 138; J.C.S. Perkin I, 1977, 2393. In the latter, formulae (4) and (5) are misprinted. loo M. J. Begley, D. G. Clarke, L. Crombie, and D. A. Whiting, J.C.S. Chem. Comm., 1970,1547; W. M. Bandaranayake, M. J. Begley, B. 0. Brown, D. G. Clarke, L. Crombie, and D. A. Whiting, J.C.S. Perkin I, 1974, 998. lo' J. Bordner, D. P. Chakraborty, B. K. Chowdhury, S. N. Ganguli, K. C. Das, and B. Weinstein, Experientia, 1972,28,1406.See ref. 100 and Vol. 5, p. 45 for related chemistry. In the latter, formula (255) lacks a methyl group at C-4 and its name is spelled incorrectly; it should be murrayazolidine. C. G. Karanjgoakar, A. V. Rama Rao, K. Venkataraman, S. S. Yemul, and K. J. Palmer, Tetrahedron Letters, 1973, 4977. See, however, ref. 705. T. Ottersen, E. Rosenqvist, C. E. Turner, and F. S. El-Feraly, Acta Cnem. Scand., 1977, B31,781. ( a )P. G. Jones, L. Falvello, 0. Kennard, G. M. Sheldrick, and R. Mechoulam, Actu Cryst., 1977, B33, 3211; (6) T. Ottersen, E. Rosenqvist, C. E. Turner, and F. S. El-Feraly, Acta Chem. Scand., 1977, B31, 807. l o 5 T. Ottersen and E. Rosenqvist, Acta Chem. Scand., 1977, B31, 749. lo6 Vol. 7, p. 49, ref. 667; F. S. El-Feraly, M. A. Elsohly, E. G. Boeren, C. E. Turner, T. Ottersen, and A. Aasen, Tetrahedron, 1977,33, 2373. y2

11

Monoterpenoids 0

(16)

(17)

1,8-dimethyl-5a-isopropyl-5a,6,7,8,9,9a-hexahydrodibenzofuran-3-ol (Vol. 6, p. 49, ref. 363). Miscellaneous. Mustelan

1,l-dioxide (Vol. 7, p. 8, ref.

88);

trans-

[PtCl(CH2=C-CMe=CH2)(PPh3)2];'07 trans- [Pt(CH,=C-CMe=CH,) (C_=C-CMe=CH,)(PPh3)2];'07 2,7-dirnethyloctane-2,7-diol tetrahydrate;'" trans -2,7-dimethylocta-2,4,6- triene- 1:4,5 :8-diolide.

O9

Spectral and other Physical Data.-The 1: 1 adduct camphor-[Eu(dpm),] illustrates a simple balanced linear regression method for obtaining the equilibrium constant (K)for adduct formation and the limiting chemical shifts, corresponding to complete complexation, for each methyl group; K values determined from data for each methyl group agree very closely.'1o A useful method for preparing small quantities of anhydrous n.m.r. solvents has been published."' A twodimensional Fourier-transformation technique for correlating 'H and 13Cchemical shifts, based upon long-range spin-spin coupling, may be used to identify gem -dimethyl groups (e.g. menthone, camphor) by observing the 'H spectra arising from modulated 13C signals.'12 The assignment of 13C resonances by off-resonance decoupling may be improved by scaling down the proton-carbon splittings to optimum values (e.g.the C-3 triplet and C-4 doublet components for c a m p h ~ r ) . ' '13C ~ N.m.r. data are reported for some monoterpenoid 1,3-dithians 107 108 109 110 111 '12

A. Furlani, M. V. Russo, A. C. Villa, A. G. Manfredotti, andC. Guastini, J.C.S. Dalton, 1977,2154. G. A. Jeffrey and D. Mastropaolo, Acta Cryst., 1978, B34,552. A. Colombo and G. Allegra, Acta Cryst., 1966, 21, 124. 3.. Bouquant and J. Chuche, Bull. Soc. chim. France, 1977,959. J. B. Alper, Analyt. Chem., 1978, 50, 381. G.Bodenhausen and R. Freeman, J. Amer. Chem. Soc., 1978, 100, 320. R. Freeman and G. A. Morris, .L Magn. Resonance, 1978,29, 173.

12

Terpenoids and Steroids

[citral, citronellal, perillaldehyde, myrtenal, menthone, isopulegone, and carvone (18)], 1,3-dithiolans [citronellal, menthone, isopulegone, (IS)], and dithiol

Michael-adducts [isopulegone, (1 S)]. '14 y-Shift correlations are of value in assigning hydroxy- and bromo-substituent group stereochemistry adjacent to axial methyl or gem-dimethyl groups in substituted c y c l ~ h e x a n e s . ~Further '~ n.m.r. data are reported below in the discussion o n absolute configuration and optical purity, as well as in individual sections. Some monoterpenoid stereoisomers (e.g. the pinenes, geraniols, borneols, and menthols) are readily distinguished by ion kinetic energy spectroscopy.116 Further discussion of c.d. calibration using (+)-camphor-10-sulphonic acid has been published (cf. Vol. 8, p. 5).'17 A c.d. investigation of charge-transfer complexes between chiral donors and tetracyanoethylene, dichlorodicyanoquinone, and Vitamin K, includes data on monoterpenoids [e.g. (-)fenchone, (+)-camphor, (+)-3-endo-bromocamphor, (-)-a-pinene, (-)menthol]; n + T * and T + T * transitions were also investigated in a vapour-phase and solvent-dependent c.d. study of, inter alia, (+)-pulegone, (-)-carvone [(4R)(18)], (-)-fenchone, and (+)-camphene-l-carboxaldehyde."8 Further papers in this section report intramolecular hydrogen-bonding in 2-arylaminomethylenecycloalkanones (menthone, carvomenthone, camphor),l'' the effect of chlorinated solvents on the stability constants of hydrogen-bonded complexes between pyrrole and, inter alia, fenchone,12' and a correlation of half-wave oxidation potentials with the pK, values of the corresponding conjugate acids (e.g. 3 -endo-cyano~amphor).~*~

Absolute Configuration, Optical Purity, Asymmetric Synthesis, Resolution.Reviews of interest in this section concern methods of determining absolute

A. Hoppmann, P. Weyerstahl, and W. Zummack, Annaien, 1977, 1547. P. Crews and E. Kho-Wiseman, Tetrahedron Letters, 1978, 2483; see ref. 426 for an application. ' I 6 S . Eguchi, K. Nagai, M. Nakayama, and S . Hayashi, Shitsuryo Bunseki, 1976,24,295 (Chem. Abs., 1977,87, 135 984). G . C. Chen and J. T. Yang, Analyt. Letters, 1977, 10, 1195. ' 1 8 M. Houtan, Diss.Abs. Internat. ( B ) , 1978, 38, 5381. 'I9 V. N. Gogte, C. I. Jose, A. G . Namjoshi, Y. D. Vankar, and B. D. Tilak, Indian J. Chem., 1977,15B, 778. '*" J. Monteau, H. Huser, M. Guerin, and M. Gomel; ( a )J. Chem. Res. ( S ) , 1978,256; ( b )J. Chem. Res. ( M ) ,1978, 3217. The former implies that camphor is used in this study but the latter only refers to fenchone. 12' J. M. Kern and P. Federlin, Tetrahedron, 1978, 34, 661.

13

Monoterpenoids

configurations, 122 discriminating interactions between chiral strategies in optical resolutions,124and asymmetric Yamaguchi has extended the use of [Eu(fod),] with Mosher’s reagent esters (cf. Vol. 8, p. 4), to the determination of absolute configuration and enantiomeric purity of primary alcohols which are chiral at the adjacent carbon. However, methoxy peak separation for (4R,8R)-(+)-p-menth-l-en-9-01 does not allow enantiomeric purity determination.126The determination of absolute configuration and of stereoisomeric composition for enantiomeric (cf. ref. 126b) and diastereomeric (cf.Vol. 8, p. 4)secondary alcohols profits from better resolution ’ ~ ~ for determining the absolute configuration of in the 19Fn.m.r. ~ p e c t r u m . Rules secondary alcohols (e.g. menthol) by observing 13C n.m.r. glycosidation shifts have been proposed (cf. Vol. 8, p. 40).’** In contrast, Horeau has developed a simple kinetic method for determining the enantiomeric purity and absolute configuration of chiral secondary alcohols (e.g. menthol) based upon enantioselective esterification with a -phenylbutyric anhydride of known enantiomeric purity. 129 Cholesteric phase formation on adding small amounts (<1 mg) of chiral molecules to nematic has been used to determine absolute configurations of molecules possessing one asymmetric carbon atom (uia i.r. rotatory dispersion); the sign of the R-Cotton effect correlates well with absolute configurations [e.g. carvone (IS), pulegone, limonene] expressed in ligand volume priority.’30h For the determination of the enantiomeric composition of some chiral acidic monoterpenoids, see the chromatography section below. The optical purity of chiral lactones [e.g. (19)] follows from ‘H n.m.r. observation, in the presence of tris[trifluoromethylhydroxymethylene-(-)camphorato]europium(~~~), of the diols derived from treatment with methyl-

A 122

123 124 125 126

127

128 129 130

‘Stereochemistry: Fundamentals and Methods’, ed. H. B. Kagan, Thieme Verlag, Stuttgart, 1977; ( a ) Volume 1: ‘Determination of Configurations by Spectrophotometric Methods’; (b) Volume 2: ‘Determination of Configurations by Dipole Moments, CD, or ORD’; (c) Volume 3: ‘Determination of Configurations by Chemical Methods’. D. P. Craig and D. P. Mellor, Fortschr. Chem. Forsch., 1976, 63, 1. S. H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 1977, 33, 2725. D. Valentine, jun. and J. W. Scott, Synthesis, 1978, 329. ( a ) F. Yasuhara and S. Yamaguchi, Tetrahedron Letters, 1977, 4085; ( 6 ) an earlier paper, S. Yamaguchi, F. Yasuhara, and K. Kabuto, Tetrahedron, 1976, 32, 1363, concerning secondary alcohols, was inadvertently omitted from these Reports. A. J. Van de Wal, E. M. Merckx, G. L. Lemikre, T. A. Van Osselaer, J. A. Lepoivre, and F. C. chim. belges, 1978,87, 545. Alderweireldt, Bull. SOC. S. Seo, Y. Tomita, K. Tori, and Y. Yoshimura, J. Amer. Chem. Soc., 1978,100, 3331. A. Schoofs and A. Horeau, Tetrahedron Letters, 1977, 3259; cf. Vol. 8, p. 8, ref. 70. ( a ) E.-H. Korte, B. Schrader, and S. Bualek, J. Chem. Res. ( S ) , 1978, 236; see also E.-H. Korte, B. Schrader, S. Bualek, and H.-J. Krabbe, Angew. Chem. Internat. Edn., 1977, 16, 790; (b) H.-J. Krabbe, H. Heggemeier, B. Schrader, and E.-H. Korte, ibid., 1977,16,791; J. Chem. Res. ( S ) , 1978,238.

14

Terpenoids and Steroids

1 i t h i ~ m . l ~The ' enantiomeric compositions of oxaziridines derived from camphor132may be determined133by 'H n.m.r. in the presence of 2,2,2-trifluoro1-arylethanols, extending an earlier ~ u g g e s t i o n ; these ' ~ ~ papers also report an enzymic synthesis of (R)- (-) -2,2 2 -trifluoro- 1 -a-naph thyle thanol (76 YO optical and asymmetric induction in oxaziridine formation using ( S ) - ( + ) monoperoxycamphoric The latter may be compared with results obtained using rn-chloroperoxybenzoicacid where in the presence of (R)-(-)-menthol the degree of asymmetric induction in oxaziridine formation is much less than in the presence of (S)-(+)-2,2,2-trifluoro-l -phenylethan~l.'~~ Asymmetric epoxidation of alkenes using H 2 0 2and the dehydrating agent (20; x = 2, Y = CO) is only marginally better than with monoperoxycamphoric acid

(20)

(however, cf. Vol. 8, p. 7);136in contrast, epoxidation with t-butyl hydroperoxide in the presence of chiral vanadium or molybdenum complexes, e.g. bis-[(+)-3trifluoroacetylcamphorato]dioxomolybdenum, proceeds with no asymmetric indu~tion.'~'An extension of previous work (Vol. 6, p. 6; Vol. 7, p. 4; Vol. 8, p. 7) is double asymmetric induction which uses a chiral NAD(P)H model system to reduce (R)-(-)-menthy1 ben~oy1formate.l~~ This has also been reduced with NaBH,-chiral phase-transfer catalyst although asymmetric induction was not Further examples of always consistent with the Prelog rule (cf. Vol. 8, p. asymmetric homogeneous rhodium hydrogenation c a t a l y ~ t s illustrate ~ ~ ~ ~ ' ~the ~ potential of using chiral bidentate ligands.141 Hydroboration-oxidation of cisalkenes with monoisopinocampheylborane (IPCBH2) and with di-isopinocampheylborane (IPC2BH),both derived from (+)-pinene, yields alcohols of opposite stereochemistry in -20% and 295% optical yields The preparation of IPCBH2 has been optimized.'43The simple to IPCBH2 turns out to be a relatively long and time-consuming process;143gmethods of synthesis have proceeded through treatment of the complex Et3N-IPCBH2143b*c 131 132

133 134 135 136

137 138 139 140

141 142

143

I. J. Jakovac and J. B. Jones, J.C.S. Chem. Comm., 1978,722. For another (uncited) report of these oxaziridines as well as those derived from (-)-menthylamine, see D. Mostowicz and C. Belzecki, J. Org. Chem., 1977, 42, 3917. A. Forni, I. Moretti, and G. Torre, Tetrahedron Letters, 1978, 2941. W. H. Pirkle and P. L. Rinaldi, J. Org. Chem., 1977, 42, 3217. A. Forni, I. Moretti, and G. Torre, J.C.S. Chem. Comm., 1977, 731. J. Rebek: S. Wolf, and A. Mossman, J. Org. Chem., 1978, 43, 180. C. Dobler and E. Hoft, 2. Chem., 1978,18, 218. A. Ohno, T. Kimura, S. G . Kim, H. Yamamoto, S. Oka, and Y. Ohnishi, Bioorg. Chem., 1977,6,21. R. Kinishi, Y. Nakajima, J. Oda, and Y. Inouye, Agric. and Biol. Chem. (Japan), 1978,42, 869. G. Paiaro and L. Pandolfo, Gazzetta, 1977,107,467. M. Fiorini, F. Marcati, and G. M. Giongo, J. Mol. Catalysis, 1978, 4, 125. A. K. Mandal and N. M. Yoon, J. Organometallic Chem., 1978,156,183; cf. Vol. 8, p. 6, ref. 4 4 and Vol. 8, p. 7, ref. 47. ( a ) Vol. 8, p. 7, ref. 47; (b) Vol. 8, p. 6, ref. 44; (c) Vol. 8, p. 6, ref. 45; ( d ) H. C . Brown and A. K. Mandal, Synthesis, 1978, 146; ( e ) Vol. 8, p. 7, ref. 48; (f) B. Singaram and J. R. Schwier, J. Organometallic Chem., 1978, 156, C1; ( g ) H . C. Brown, J. R. Schwier, and B. Singaram, J. Org. Chem., 1 9 7 8 , 4 3 , 4 3 9 5 .

Monoterpenoids

15

with BH3,THF1436or better with BF3,Et20in pentane to the rapid preparation of IPC2BH143a*e which is converted into a crystalline bis-adduct with N,N,N',N'-tetramethylethylenediamine'43ffrom which optically pure IPCBH2is liberated on treating with BF3,Et20 in THF. 143g Palladium(I1)-catalysed asymmetric oxidative cyclization of 2-allylphenols is achieved in the presence of (-)-P-pinene; similar optical yields (12%) are observed with bisracetoxy-(10,2, 3-q-pinene)palladium(11)]~ a t a 1 y s i s . The l ~ ~ full paper of an earlier report of Damino-acid synthesis (Vol. 7, p. 4) demonstrates the superior chiral directing ability. of Schiff bases derived from (lS,2S,SS)-(-)-2-hydroxypinan-3-0ne'~~ over those derived from (-)-menthone. 146 Enantioselective carbenoid cyclopropanation (Vol. 8, p. 7) has been described in Regioselectivity to terminal double bonds in some conjugated olefins with up to 88% enantioselect i ~ i t y ' ~has ~ "not been improved upon with the use of additional monoterpenoidcobalt mechanistic details and control of enantioselectivity have also been In contrast, the decomposition of chiral diazoacetates [e.g. (+)-bornyl, (-)-menthy11 by CuCl proceeds with low asymmetric induction. 148 Further examples of asymmetric reactions involving chiral monoterpenoids include the formation of chiral /3 -keto-sulphoxides from (-)-menthy1 carboxylates,I4' synthesis of diastereomeric tetrahedral molybdenum complexes,15othe enantioselective hydrosilylation of ketone^,"^ and the preparation of the chiral 1-amino-2-phenylethylphosphonic Interesting examples of optical resolutions include the use of dicarbonylrhodium(1) 3-trifluoroacetyl-( lR)-camphorate for g.1.c. separation of chiral 01efins'~~ and of dimeric nickel(I1) bis-(3-trifluoroacetyl-lR -camphorate) for an improved separation of chiral epoxides (cf. Vol. 8, p. 8).154The resolution of (R/S)-pantoic acid with chiral amines derived from a- and p-pinene (Vol. 7, p. 43, ref. 420) may signal their more widespread use.1551,3-Dithian 1-oxide has been Chromatography.-G.1.c. papers of interest include the separation of monoterpenoid hydrocarbons on modified graphitized carbon the separation of

14' 146 147

T. Hosakawa, S. Miyagi, S.-I. Murahashi, and A. Sonoda, J.C.S. Chem. Comm., 1978, 687. Unfortunately the authors name this catalyst bis[acetoxy-(7,1,2-~-pinene)palladium(11);other poorly numbered compounds are recorded in ref. 22. T. Oguri, N. Kawai, T. Shioiri, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1978,26,803. T. Oguri, T. Shioiri, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1977,25,2287. ( a )A.Nakamura, A. Konishi, Y. Tatsuno, and S. Otsuka, J. Amer. Chem. SOC.,1978,100,3443; (b) A. Nakamura, A. Konishi, R. Tsujitani, M. Kudo, and S . Otsuka, ibid., 1978,100,3449.For earlier reports see (c) A. Nakamura, Pure A p p l . Chem., 1978,50,37;( d )Vol. 8,p. 7;( e ) Y. Tatsuno, A. Konishi, A. Nakamura, and S . Otsuka, J.C.S. Chem. Comm., 1974,588, which was inadvertently

148

149

"'

omitted from an earlier Report. P. E. Krieger and J. A. Landgrebe, J. Org. Chem., 1978,43,4447. N. Kunieda, H. Motoki, and M. Kinoshita, Chem. Letters, 1978,713. H.Brunner and J. Doppelberger, Chem. Ber., 1978,111,673. M . Capka, Coll. Czech. Chem. Comm., 1977,42,3410.The asymmetric hydrosilylation of alkenes is reported in ref. 49. A. Kotynski and W. J. Stec, J. Chem. Res. ( S ) , 1978,41. V.Schurig, Angew. Chem. Internat. Edn., 1977,16,110;this paper was inadvertently omitted from last year's Report. V. Schurig and W. Burkle, Angew. Chem. Internat. Edn., 1978,17,132. J. Paust, S. Pfohl, W. Reif, and W. Schmidt, Annalen, 1978,1024. A. Di Corcia, A. Liberti, C. Sambucini, and R. Samperi, J. Chromatog., 1978,152,63.

Terpenoids and Steroids

16

menthol isomers,157and further work by Scheffer et al. on the prefractionation of monoterpenoids by liquid-solid column chromatography before g.1.c. separation.15' H.p.1.c. resolution of chiral acids [e.g. ( 3-RS)-dihydrocitronellic acid, (3-RS)-7-methoxycitronellic acid] is now reported via (R)-(+)-1-(1'-naphthy1)ethylamide derivatives (cf. Vol. 8, p. 22).159

3 General Synthetic Reactions Some useful reviews'" which discuss applications from, or are of value to, monoterpenoid chemistry concern recent applications of the retro-Diels-Alder reaction in organic synthesis,161the Claisen rearrangement,'62 intramolecular ene reactions,163the Prins chiral insect pheromones (synthesis, absolute configuration, and optical p ~ r i t y ) , ' ' ~ the synthesis of monoterpenoids using the Wittig reaction,Ih6the introduction of fluorine into organic organoselenium chemistry,168bromination using 2,4,4,6-tetrabromocyclohexa-2,5-dienone (in Japanese),169titanium tetrachloride in organic 4-dialkylaminopyridines as acylation catalysts,171the use of insoluble polymer supports in organic selective reactions with organoaluminium and organic reactions on a 1 ~ m i n a . ICorey ~~ has expanded computer-assisted synthetic analysis to include stereoselective olefin synthesis. 175 As the search for new synthetic methods continues, there has been a substantial increase in the number of papers reporting the use of monoterpenoids as model compounds. Some of the more significant examples of such synthetic methods provide the basis for the following discussion. The ene reaction (of, for example, the pinenes) with P h S 0 2 N S 0 has been d e ~ c r i b e d , 'and ~ ~ the cyclization-induced [3,3] sigmatropic rearrangement of allylic carbamates (e.g. linalyl N,N-dimethylcarbamate) catalysed by mercuric H. Thieme and R. Benecke, Zentralbl. Pharm., Pharmakother. Laboratoriumsdiagn., 1977,116,139. J. J. C. Scheffer, A. Koedam, M. Th. I . W. Schiisler, and A. Baerheim Svendsen, Chromatographia, 1977, 10, 669 and references therein. l S 9 ( a ) B. J. Bergot, R. J. Anderson, D. A. Schooley, and C. A. Henrick, J. Chromatog., 1978,155,97; ( b ) C. A. Henrick, R. J. Anderson, G. B. Staal, and G . F. Ludvik, J. Agric. Food Chem., 1978,26, 542. 160 Recent reviews of interest to organic chemists are listed as a new regular feature in Journal of Organic Chemistry. For reviews published in 1977, see J. Org. Chem., 1978,43,3085; a second list covering the first half of 1978 has appeared recently, uir. ibid., 1978, 43, 4397. 161 J. L. Ripoll, A. Rouessac, and F. Rouessac, Tetrahedron, 1978, 34, 19. I h 2 G. B. Bennett, Synthesis, 1977, 589. W. Oppolzer and V. Snieckus, Angew. Chem. Internat. Edn., 1978, 17, 476. 164 D. R. Adams and S. P. Bhatnagar, Synthesis, 1977, 661. 16' R. Rossi, Synthesis, 1978, 413. M. S. Bathia, Riechst., Aromen, Kosmet., 1977, 27, 205. M. Schlosser, Tetrahedron, 1978, 34, 3. "* D. L. J. Clive, Tetrahedron, 1978, 34, 1049. 169 T. Kato, I. Ichinose, and T. Hosogai, J. Synth. Org. Chem., Japan, 1977, 35, 491. 170 T. Mukaiyama, Angew. Chem. Internat. Edn., 1977, 16,817. 171 G. Hofle, W. Steglich, and H. Vorbruggen, Angew. Chem. Internat. Edn., 1978, 17,569. ( a ) C. C. Leznoff, Accounts Chem. Res., 1978, 11, 327; (b) P. Hodge, Chem. in Britain, 1978, 14, 237. 1 7 3 H. Yamamoto and H. Nozaki, Angew. Chem. Internat. Edn., 1978,17, 169. ' 7 4 G. H. Posner, Angew. Chem. Internat. Edn., 1978, 17,487. '71 E. J. Corey and A. K. Long, J. Org. Chem., 1978,43,2208. 176 G. Deleris, J. Kowalski, J. Dunogues, and R. Calas, Tetrahedron Letters, 1977, 421 1; see also refs. 216. 498.

Is7

Is8

Monoterpenoids

17

trifluoroacetate avoids skeletal rearrangement in the 60% overall conversion of linalool into geraniol and nerol(7 : 3).17' The [3,3] sigmatropic rearrangement of allylic thionocarbamates to allylic thiolcarbamates (Vol. 8, p. 25) has been used further to synthesize acids and esters (e.g. geranic esters E :2 / 3 : 1)via mercurycatalysed cleavage of a,a -bis-sulphenylated derivatives; alkylation of the corThe responding a -monosulphenylated derivative leads similarly to rearrangement of unsaturated cyclohexenones [e.g. carvone (1S)], catalysed by RhC1,,3H20 (cf. Vol. 8, p. 9) results in aromatization; corresponding imines behave ~ i m i 1 a r l y .Whereas l~~ simple allylic alcohols rearrange in high yield to the corresponding aldehydes and ketones using [(cod)1r(PMePh2),]PF6, rearrangement of nerol is poor.18oA simple 1,2-carbonyl transposition (e.g. menthone to carvomenthone) results from an epoxidation-LiAlH, reduction-chromic acid oxidation sequence on enol silyl ethers (cf.Vol. 8, p. 53).181 Although the investigation of oxidative methods continues, it is apparent that Swern's'82 is usually the method of choice for the oxidation of alcohols to aldehydes and ketones (e.g. the borneols, 182b geranio1'82c) in high to essentially quantitative yields (cfiVol. 8, p. 10). Other methods include the use of barium manganate (the borneo1s),lg3 oxidation of alkoxymagnesium bromides using N-chlorosuccinimide, rn -chloroperbenzoic acid, diacetoxyiodobenzene (e.g. menthol), or, best of all, 1,l'-(azodicarbony1)dipiperidine [geraniol yields citral (96'/0)].'~~The oxidation of monoterpenoid allylic alcohols using 2,3-dichloro5,6-dicyano- 1,4-benzoquinone has been d e ~ c r i b e d . 'The ~ ~ failure to oxidize unsaturated silyl ethers with N-bromosuccinimide contrasts with results (Vol. 7, p. 6) on the corresponding tributylstannyl ethers, despite acceptable yields with saturated silyl ethers.lS6The economical vicinal cis-hydroxylation of alkenes (e.g. citronellyl acetate) using Et4N' OAc--t-butyl peroxide in acetone, catalysed by osmium tetroxide, has been the corresponding regiospecific vicinal cis -oxyamination has been achieved in pyridine or CH2C12(e.g. citronellyl methyl ether) by treatment with trioxo(t-alkylimido)osmium(vIII) leading to carbonnitrogen bond formation at the least-substituted carbon atom.188Allylic methyl oxidation of acetals and tetrahydropyranyl ethers using S e 0 2in pyridine has been L. E. Overman, C. B. Campbell, and F. M. Knoll, J. Amer. Chem. Soc., 1978, 100, 4822. T. Nakai, T. Mimura, and T. Kurokawa, Tetrahedron Letters, 1978, 2895. 179 P. A. Grieco and N. Marinovic, Tetrahedron Letters, 1978, 2545. ''O D. Baudry, M. Ephritikhine, and H. Felkin, Nouueau J. Chim., 1978, 2, 355. ''I W. E. Fristad, T. R. Bailey, and L. A. Paquette, J. Org. Chem., 1978, 43, 1620. '" ( a ) S. L. Huang, K. Omura, and D. Swern, Synthesis, 1978, 297; ( 6 ) K. Omura and D. Swern, Tetrahedron, 1978,34,1651; (c) A. J. Mancuso, S.-L. Huang, andD. Swern, J. Org. Chem., 1978,43, 2480. l B 3 H. Firouzabadi and E. Ghaderi, Tetrahedron Letters, 1978, 839; the borneols [a mixture of (+)-borne01 and (-)-isoborneol was used] and camphor each lack the C-10 methyl group in this paper. lB4 K. Narasaka, A. Morikawa, K. Saigo, and T. Mukaiyama, Bull. Chem. Soc. Japan, 1977,50,2773; for related oxidations from these workers, see Vol. 7, p. 6. lS5 J.-I. Iwamura, Nippon Kagaku Kaishi, 1978,846;for related work on saturated alcohols, see Vol. 4, p. 6 and Vol. 8, p. 10. lB6 H. W. Pinnick and N. H. Lajis, J. Org. Chem., 1978, 43, 371. K. Akashi, R. E. Palermo, and K. B. Sharpless, J. Org. Chem., 1978, 43, 2063. ''' D. W. Patrick, L. K. Truesdale, S. A. Biller, and K. B. Sharpless, J. Org. Chem., 1978,43,2628. Two closely related papers (no monoterpenoid examples) report major improvements in this process, viz. E. Herranz and K. B. Sharpless, ibid., 1978,43,2544; E. Herranz, S. A. Biller, and K. B. Sharpless, J. Amer. Chem. SOC.,1978,100, 3596. 177

'71

Terpenoids and Steroids

18

examined.ls9 Enolates may be converted directly into a -hydroxy-ketones (e.g. 3 -endo -hydroxycamphor) using M O O ~ - ~ ~ - H M P A ; thermal '~' intermediate fragmentation may lead to some camphorquin~ne,~~' which is also a major by-product in attempted conversion of thiocamphor into camphor using benzeneseleninic anhydride as reagent. 19' The highly regioselective addition of phenylselenenic acid ['PhSeOH', or more probably PhSeOSePh or PhSeOSe(O)Ph, generated in situ from PhSe02H and PhSeSePh] followed by treatment with t-butyl hydroperoxide results in a one-pot synthesis of rearranged allylic alcohols (e.g. 8-methoxy-2,6-dimethyloct-3-en-2-ol from citronellyl methyl ether).192The same paper also explores the catalytic effectiveness of various seleninic acids (0-nitro- and 2,4-dinitro-phenylseleninic acids are the most effective) in olefin (e.g. citronellyl methyl ether) epclxidation using 30% H 2 0 2in the presence of anhydrous MgS04. Regioselectivity studies on geraniol differ somewhat from those reported earlier (Vol. 8, p. ll).'92 Photochemical co-oxygenation of alkenes and acetaldehyde with moltx-ular oxygen produces epoxides (e.g. from a- and B-pinene) effectively and with reported regioselectivity (1,2-epoxy-p-menth-8-enefrom limonene; 98'/0);'~~t-pentyl hydropero~ide-Mo(C0)~ has been used for epoxidizing silicon-containing alkenes (e.g. 9-trimethyl~ilyl-p-rnenth-l-ene).'~~ Methods for deoxygenating epoxides using Me~(OPh)J-BF,,Et,O-MeCN (epoxycitronellyl methyl ether)lQ5and (EtO),P(O)Te Na' [limonene diepoxide yields 1,2-epoxy-p-menth-8-ene (76'/0)]'~~have been reported; in the latter, the reagent may be generated continuously in situ using a catalytic amount of tellurium. 196 NaOH-modified alumina favours the rearrangement of epoxides to allylic alcohols.'97 Allylic alcohols are the almost exclusive products of the rapid reduction of a$-unsaturated ketones [e.g. (4R)(-)- (18), pulegone (21), piperitone] using

(21)

NaBH4-CeC13,6H20-Me0H;'98 like the parent 9-BBN, B-(1,2-dimethylpropyl)-9-borabicycl0[3,3,1 Jnonane also produces allylic alcohols exclusively from qp-enals (e.g. ~ i t r a l )The . ~ ~full ~ paper on the exclusive reduction of the lS9

I9O lgl 19*

193 194

195 196

'91

19' 199

F. Camps, J. Coll, and A. Parente, Synthesis, 1978, 215. E. Vedejs, D. A. Engler, and J. E. Telschow, J. Org. Chem., 1978, 43, 188. D. H. R. Barton, N. J. Cussans, and S. V. Ley, J.C.S. Chem. Comm., 1978, 393. T. Hori and K. B. Sharpless, J. Org. Chem., 1978, 43, 1689. H. Kropf and M. R. Yazdanbakhch, Synthesis, 1977,711. I. A. Gailyunas, E. M. Tsyrlina, N. I. Solov'eva, N. G. Komalenkova, and V. P. Yur'ev, J. Gen. Chem. (U.S.S.R.),1977,47,2188. However, see ref. 181; this compound is incorrectly named in the paper. K. Yamada, S. Goto, H. Nagase, Y. Kyotani, and Y. Hirata, J. Org. Chem., 1978,43,2076. D. L. J. Clive and S. M. Menchen, J.C.S. Chem. Comm., 1977,658. V. S. Joshi and S. Dev, Tetrahedron, 1977, 33, 2955; for further discussion, see the bicyclo[3,1 ,l]heptane and the bicyclo[4,1,0]heptane sections. J.-L. Luche, L. Rodriguez-Hahn, and P. Crabbb, J.C.S. Chem. Comm., 1978,601. M. M. Midland and A. Tramontano, J. Org. Chem., 1978, 43, 1470. This reagent is probably most valuable for the preferred reduction of aldehydes in the presence of ketones.

Monoterpenoids

19

olefinic double bond of a,P -unsaturated carbonyl compounds [e.g. (18)]reports improved yields using Naz[Fe(C0)4]-Fe(CO)5-HOAc-dioxancompared with Na[HFez(C0)8];200 trialkylammonium formate-Pd/C also performs this reaction efficiently [citral to citronella1 (910 / ~ ) ] . 2 0 ' Reductions (e.g. of camphor) with various magnesium hydrides give predictable stereochemical results.202Azodicarboxylate may be used to reduce carbon-carbon double bonds in cyclic .~~~ catalytic hydroperoxides (e.g. ascaridole to d i h y d r o a s c a r i d ~ l e ) Selective genations Include reduction of a,@-unsaturated ketones to saturated ketones [e.g. (18) to dihydrocarvone] using K3C~(CN)5204 or [ R h ( b i ~ y ) ~ion20s ]+ as catalyst, and the exocyclic double bond reduction in limonene over Ni-P.*06 Electroreductive syntheses involve the conversion of P -hydroxy-sulphone groups derived from lactones [e.g. (19)] or aldehydes (e.g. citronellal) into vinyl groups2o7 and the similar conversion of @ -hydroxy-sulphides derived from ketones (e.g. menthone).208 Electroreduction of the corresponding y-hydroxy-sulphide mesylates (22; R = H or Me), which are readily obtained from citral, provides an efficient route to the cyclopropanes (23; R = H or Me) respectively.209A less efficient a,@-unsaturated aldehyde-cyclopropane conversion involves Birch reduction of (22; R = H) to (23; R = H).210Interestingly, no cyclopropanes [e.g. (23; R = Me)] result from Simmons-Smith reaction when citral reacts with

CH212-Zn-Me3A1.207b Alicyl esters (e.g. bornyl acetate) are reduced to alkanes in reasonable yields (quantitatively for tertiary esters) using Na-HMPA-Bu'OH.211 200

J. P. Collman, R. G. Finke, P. L. Matlock, R. Wahren, R. G. Komoto, and J. I. Brauman, J. Amer. Chem. SOC.,1978,100, 11 19; see Vol. 7, p. 7 for the earlier report. The authors also make a useful comparison with other methods for performing this reaction. 201 N. A. Cortese and R. F. Heck, J. Org. Chem., 1978,43, 3985. 202 E. C. Ashby, A. B. Goel, and J. J. Lin, Tetrahedron Letters, 1977, 3133; E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 1978,43, 1560, 1564; cf Vol. 7, p. 7 . 203 W. Adam and H. J. Eggelte, Angew. Chem. Internat. Edn., 1977, 16, 713. 204 G. S. R. Subba Rao, J. Rajaram, S. Rathnamala, and R. Sivaramakrishnan, Proc. Indian Acad. Sci., 1977,86A, 435. 205 G. Mestroni, R. Spogliarich, A. Camus, F. Martinelli, and G. Zassinovich, J. Organornetallic Chem., 1978,157,345;conditions for reduction to carvotanacetone, carvomenthone, or dihydrocarveol are also described. 206 K. Isogai, S. Ageishi, and H. Ojima, J. Synth. Org. Chem., Japan, 1977, 35, 750. 207 ( a )T. Shono, Y. Matsumura, and S. Kashimura, Chem. Letters, 1978,69; ( b )much better yields for methylenation of citral are obtained using CH212-Zn-Me3Al whereas for ketones (e.g. camphor) CH2Br2-Zn-TiC14 is preferred: K. Takai, Y. Hotta, K. Oshima, and H. Nozaki, Tetrahedron Letters, 1978,2417. 208 T. Shono, Y. Matsumura, S. Kashimura, and H. Kyutoku, Tetrahedron Letters, 1978, 2807. 2"9 T. Shono, Y. Matsumura, S. Kashimura, and H. Kyutoku, Tetrahedron Letters, 1978,1205; formula (11) is incorrect in this paper. 210 Y.-H. Chang, D. E. Campbell, and H. W. Pinnick, Tetrahedron Letters, 1977, 3337. * 1 1 H. Deshayes and J.-P. Pete, J.C.S. Chem. Comm., 1978, 567.

20

Terpenoids and Steroids

Reductive deoxygenation of alcohols using Ireland’s method212a has been improved for sterically hindered alcohols (e.g. LY -terpineol) by an improved synthesis of N,N,N’,N’-tetramethylphosphorodiamidates;212b straightforward modification of the method allows alkene and alkyl chloride formation [depending upon whether the alcohol is primary, secondary (e.g. menthol), or tertiary (e.g. cy -terpineol)] without affecting such acid-sensitive groups as a ~ e t a l s The .~~~ well-known reductive cleavage of enol phosphates212a(cf. Vol. 8, p. 45) to alkenes ( e , g . camphor to born-2-ene) has been improved by the use of titanium Reductive deoxygenation of tosylhydrazones [ e . g . pulegone (21)] may also be accomplished (cf. Vol. 6, p. 9; Vol. 7, p. 7) using NaBH4-HOAc, although in somewhat lower Allylic deuteriation [e.g. P-pinene, (4R)-(-)-(18), citronellyl methyl ether] results from ene reaction with TsN=S=O followed by retro-ene reaction after deuterium exchange of the derived acidic NH proton (cf. Vol. 7, p. 8).216The susceptibility of fenchone to hydride transfer without accompanying carbanion addition has been used in dehydrogenative aromatization (by deprotonation-hydride elimination) with fenchone and a catalytic amount of potassium fencholate; olefin formation is only possible with appreciably acidic C H A number of papers report enolate alkylation and related procedures. They include the regiospecific generation of lithioenamines from a$ -unsaturated imines [e.g. from (18)Jand subsequent alkylation as an alternative to reductive alkylation of enones,218reductive alkylation of epoxy-ketones (e.g. 1,6-epoxycarvone) using M ~ , C U L ~ - M ~ I - H M P the A , ~regioselective ~~ alkylation of diepoxides (e.g. limonene diepoxide), using R(CN)CuLi, at the least hindered oxiran,220and reductive a -methylsulphenylation in moderate yield of cyclic cy,P-unsaturated ketones [e.g. (IS)], via pseudoaxial attack, using dimethyl disulphide.221” Although attempts222 to improve upon reductive cy - phenylsulphenylation22’bof a,@-unsaturated ketones [e.g. (18)] by using diethylaluminium cyanide were unsuccessful and the intermediacy of the ,8 -cyanosilylenol ether offered no improvement in yield, treatment of the p-cyanosilylenol ether with methyl-lithium results in an effective net 1,4-addition of an acetyl anion equivalent to an enone.222Related work includes the conversion of aldehydes (e.g. citronellal) and ketones into their (Y -phenylseleno-derivatives via the silylenol ether and phenylselenenyl the quantitative tri’12

’13

’14 215 216

’” 218

‘I9

*” 221

222

223

( a )See Vol. 3, p. 312, ref. 126; ( b )H.-J. Liu, S. P. Lee, and W. H. Chan, Canad. J. Chem., 1977,55, 3797. H.-J. Liu, W. H. Chan, and S. P. Lee, Chem. Letters, 1978, 923. S. C. Welch and M. E. Walters, J. Org. Chem., 1978, 43, 2715. R.0. Hutchins and N. R. Natale, J. Org. Chem., 1978, 43, 2299. T. Hori, S. P. Singer, and K . B. Sharpless, J. Org. Chem., 1978, 43, 1456; for closely related ene reactions, see refs. 176, 498. M. T. Reetz and F. Eibach, Angew. Chem. Internat. Edn., 1978, 17,278. P. A . Wender and M. A. Eissenstat, J. Amer. Chem. SOC., 1978, 100, 292. R. P. Szajewski, J. Org. Chem., 1978,43, 1819; for similar work, see Vol. 2, p. 26. R.-D. Acker, Tetrahedron Letters, 1978, 2399. ( a )P. G. Gassman, D . P. Gilbert, and S. M. Cole, J. Org. Chem., 1977,42,3233;( 6 )for related work, see M. Samson, H. D e Wilde, and M. Vandewalle, Bull. SOC.chim. belges, 1977,86, 329. M. Samson and M. Vandewalle, Synth. Comm., 1978,8,231; no physical data are reported for the acetyl derivative and reference 3 of this paper is incorrect. I. Ryu, S. Murai, I. Niwa, and N. Sonoda, Synthesis, 1977, 874; facile cyclization of a-phenylselenocitronellal is also reported.

Monoterpenoids

21

phenylphosphine-catalysed 1,4-addition of phenyl trimethylsilyl selenide to a,@unsaturated ketones [e.g. (18 ) y 4and the highly regiospecific Markovnikoff addition of phenylselenenyl chloride to alkenes (e.g. a -terpineol, cis- and transrose oxides) at -50 0C.225Alkylation of allylic nitriles (e.g. geranyl and neryl nitriles) followed by reductive decyanation of the corresponding &?-unsaturated nitriles yields tetrasubstituted alkenes efficiently.z26The generation of vinyllithium reagents and subsequent trapping with electrophiles (including Vilsmeier formylation) has been described in detailzz7and a two-step procedure, consisting of anti-Markovnikoff thiophenol addition to monosubstituted alkenes (e.g. limonene) followed by lithium cleavage, effects regiospecific hydrolithiation to form alkyl-lithiums.228 The formation of .rr-allylpalladium complexes from ~~~= activates an allylic alkenes [e.g. (18),methyl geranate, @ - ~ i n e n e ] effectively C-H bond for subsequent allylic alkylation (aided by phosphorus ligands) with various synthetically useful n ~ c l e o p h i l e s ,e.g. ~ ~ anions ~ ~ * ~ from malonic acid (Vol. 6, p. 4 9 , P-keto-sulphides, P-keto-sulphoxides (Vol. 6, p. 9), and P-ketosulphones. Alkylative elimination involving thermal sulphenic acid elimination readily yields c,P-y,S-unsaturated esters (Vol. 6, p. 9), and prenylation with MeZC=CH-C=(COzMe)SO2Ph can be used to transform monoterpenoids into the corresponding sesquiterpenoids.2z9c Other prenylation procedures which have been reported include Lewis acid-catalysed reaction of Me3SiCMe2CH=CH2 with acetals and with ketones (regiospecific transposition of the allylic double bond is and the Bu:N’ F--catalysed reaction of Me3SiCHzCH=CMe2 with aldehydes and ketones (no double-bond transposition is observed);231however, Me3SiCHzCH=CMe2undergoes regiospecific transposition of the allylic double bond in the A1C13- or BF3,Etz0-catalysed monoallylic substitution, and also in the TiC14-catalysed diallylic substitution or conjugate addition-substitution, of a$-unsaturated a~etals.’~’3,3-Dimethylallyl(dipropy1)borane adds to aldehydes with double-bond and prenylation of dithians (e.g. from citronellal, citral, perillaldehyde, and myrtenal) has been reported using prenyl as well as prenylation of anions formed from senecioamides, with control over a- and y- prenylation depending

233

D. Liotta, P. B. Paty, J. Johnston, and G. Zirna, Tetrahedron Letters, 1978,5091. D. Liotta and G. Zima, Tetrahedron Letters, 1978,4977. J. A.Marshall and R. Bierenbaum, J. Org. Chem., 1977,42,3309. A. R. Chamberlin, J. E. Sternke, and F. T. Bond, J. Org. Chem., 1978,43, 147;in the case of camphor, reaction is best with the 2,4,6-tri-isopropylbenzenesulphonylhydrazone.For related work, see Vol. 6,p. 7;Vol. 7,p. 36.In the latter, reference to camphor was inadvertently omitted. See also ref. 635. C. G. Screttas and M. Micha-Screttas, J. Org. Chem., 1978,43,1064. ( a )B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton, andT. J. Dietsche, J. Amer. Chem. SOC., 1978, 100,3407;B.M.Trost, L. Weber, P. E. Strege, T. J. Fullerton, and T. J. Dietsche, ( b ) ibid., 1978, 100,3416; ( c ) 1978,100,3426. Unfortunately, inattention to detail in the numbering of compounds (lo),(12),and (13)in ref. 229c results in errors in relating the experimental section with the main text and in equations 3-9. A. Hosomi and H. Sakurai, Tetrahedron Letters, 1978,2589. A.Hosomi, A. Shirahata, and H. Sakurai, Tetrahedron Letters, 1978,3043. A.Hosomi, M. Endo, and H. Sakurai, Chem. Letters, 1978,499. B. M.Mikhailov, Yu. N. Bubnov, A. V. Tsyban, and M. Sh. Grigoryan, J. Organometallic Chem.,

234

A. Hoppmann and P. Weyerstahl, Tetrahedron, 1978,34,1723.

224

*”

226 227

’” ’”

230 231

232

1978,154,131.

22

Terpenoids and Steroids

upon the use of lithiated or cuprated species re~pectively.~~’ Regioselective y-alkylation of allylic alcohols (e.g. geraniol, linalool) to yield alkenes (stereoselectively in appropriate examples) may be accomplished by the action of N-methyl-N-phenylaminotributylphosphonium iodide on allyloxy-CuRLi The stereoselective elaboration of an acetylenic bond into the corresponding E-2-methylalkenylalane by regioselective addition of Me3Alzirconocene dichloride (C12ZrCp2),237followed by known functionalization, yields esters (e.g. ethyl geranate), alcohols (e.g. geraniol), carboxylic acids, and methyl ethers very effectively.237cThe straightforward carbanionic addition of a -phenylthioacetate to ketones and a$-unsaturated ketones [e.g. ( and the one-step synthesis of nitriles from ketones (e.g. 2-cyanocamphane from camphor) using tosylmethyl isocyanide have been cis -2-Ethoxyvinyl-lithium (prepared by hydrostannation of ethoxyacetylene) is a useful nucleophilic acetaldehyde equivalent for the chain extension of aldehydes (e.g. geranial) and ketones into a,P -unsaturated aldehydes.240Two groups241report a similar interconversion in modifications of the Wittig-Horner reaction; for example, the direct addition of the dianion of (EtO),P(0)CH2C02Hto aldehydes ~ ~ ~ ~ a,@ * and ketone^,^^^^'^ a reaction also reported s u b ~ e q u e n t l y , ~yields unsaturated carboxylic acids stereoselectively [e.g. geranic acid (E :2 / 4 : l)].241b The corresponding diethyl carboxylchloromethylphosphonate dianion yields, for example, a-chlorogeranic Alkenes (e.g. camphene) are readily prepared242by the BF3,Et20-catalysed elimination of secondary borate Terminal conjugated dienes may be prepared by Pd(OAc),-PPh,-catalysed elimination from ally1 phenyl ethers or allylic acetates [e.g. geranyl, neryl, and linalyl acetates to form similar mixtures of myrcene (60-74%), trans-ocimene (8-20°/0), and cis-ocimene (14-20Y0)],~~~ and the complex [(q-C5H5)Cr(N0)2]2 dehalogenates vic -dihalides (e.g. limonene tetrabromide) without affecting other halides (except for benzyl halides).245 235

236

237

238

239

241

242 243

244

J. A. Oakleaf, M. T . Thomas, A. Wu, and V. Snieckus, Tetrahedron Letters, 1978, 1645. For similar LY- and y-selectivity with a$-unsaturated acids and esters, see Vol. 7, p. 14. Y. Tanigawa, H. Ohta, A. Sonoda, and S.-I. Murahashi, J. Amer. Chem. SOC.,1978, 100,4610. ( a )D. E. Van Horn and E.-I. Negishi, J. Amer. Chem. SOC.,1978,100,2252;( b )E.-I. Negishi, N. Okukado, A. 0.King, D. E. Van Horn, and B. I. Spiegel, ibid., 1978,100,2254;( c )N. Okukado and E.-I. Negishi, Tetrahedron Letters, 1978, 2357. S. Yamagiwa, N. Hoshi, H. Sato, H. Kosugi, and H. Uda, J.C.S. Perkin I, 1978, 214. 0. H. Oldenziel, D. van Leusen, and A. M. van Leusen, J. Org. Chem., 1977,42, 3114. R. H. Wollenberg, K. F. Albizati, and R. Peries, J. Amer. Chem. SOC.,1977, 99, 7365. P. Savignac, M. Snoussi, and P. Coutrot, ( a ) Synth. Comm., 1978, 8, 19; (6) Synthesis, 1978, 133; L. Lombard0 and R. J. K. Taylor, (c) ibid., 1978, 131; ( d ) Synrh. Comm., 1978,8,463. M. P. Doyle, S. B. Williams, and C. C. McOsker, Synthesis, 1977, 717. Borate esters have recently been prepared in quantitative yields by reaction of alcohols [e.g. (-)-menthol] with BH3,SMez. See C. A.. Brown and S. Krishnamurthy, J. Org. Chem., 1978, 43, 273 1. J. Tsuji, T . Yamakawa, M. Kaito, and T. Mandai, Tetrahedron Letters, 1978, 2075. B. W. S. Kolthammer, P. Legzdins, and D. T . Martin, Tetrahedron Letters, 1978, 323.

* One questions the necessity for the rapid communication of the results in ref. 241d when they largely represent a minor modification of the authors’ earlier work with the corresponding trimethylsilyl in addition, some 20% of the paper is devoted to a discussion and comparison of the synthetic methods used (ref. 241b, and refs. 241c, 241d) to prepare (Et0)2P(O)CH2C02H. A perfectly acceptable published procedure exists for the preparation of the latter by hydrolysis of the corresponding ethyl ester, which is commercially available. In this Reporter’s opinion such proliferation of the literature is to be discouraged.

Monoterpenoids

23

In the area of functional group protection, pyridinium toluene-p-sulphonate (PTPS)is the catalyst of choice for the almost quantitative tetrahydropyranylation of alcohols [e.g. geraniol (99"/0),linalool (94%)] even in the presence of other acid-sensitive functional groups (e.g. acetals, epoxides); PTPS-catalysed hydrolysis is also virtually quantitative [e.g. geraniol (loo%), linalool (99"/0)].'"~ Primary (e.g. geraniol) and secondary alcohols may be protected as 2-tetrahydrothienyl ethers formed almost quantitatively by reaction with 2-tetrahydrothienyl diphenylacetate catalysed by toluene-p -sulphonic acid; cleavage with HgC12 (facile), HgC12-CaC03, AgN03-2,6-lutidine, and aqueous HOAc, but not MeOH, suggests selective deprotection in the presence of other commonly used protecting groups.247The use of t-butoxymethyl ethers (deprotection with aqueous CF,C02H) for protecting primary (e.g. geraniol, citronellol) and secondary alcohols has also been Benzeneseleninic anhydride has been used to advantage to regenerate aldehydes and ketones (e.g. fenchone) from 1,3-dithiolans and 1,3-dithian~,'"~a process also reported (e.g. menthone 1,3dithiolan) to occur by photochemical irradiation in oxygen.25o Further details of phase-transfer addition of dibromocarbene to a,@unsaturated esters and ketones [e.g. (18)]251and subsequent reductive monodebromination with tributyltin hydride (Vyl. 7, p. 34) have been p~blished;"~ Julia the use of solid NaOH-Et,NCH,Ph C1- for the solid-liquid phasetransfer catalytic generation of dichlorocarbene (addition to a -pinene and limonene). Dichlorocarbene also provides a mild and efficient method for the Beckmann fragmentation of anti-a-hydroxy-ketoximes into aldehydes (or ketones) and nitriles [e.g. 2-exo- hydroxy-3-hydroxyiminobornaneinto (24; X = CHO, Y = CN)].254Trimethylsilylcyclopropanes are synthesized by adding the

ylide Me3SiCH=SMe2, generated from methylthiomethyltrimethylsilane methiodide and Bu"Li, to a,@-unsaturatedketones [e.g. ( 18)].255

246

247

248

249 250 251 252

253 254 255

M. Miyashita, A. Yoshikoshi, and P. A. Grieco, J. Org. Chem., 1977, 42, 3772; for another application of this catalyst, see ref. 262. C. G. Kruse, E. K. Poels, F. L. Jonkers, and A. van der Gen, J. Org. Chem., 1978, 43, 3548; high selectivity for primary over tertiary alcohols is observed. The suggestion that similar reagents should be standard for the THF- and THP-protection of alcohols must be questioned in the light of the (unacknowledged) work reported in ref. 246. H. W. Pinnick and N. H. Lajis, J. Org. Chem., 1978, 43, 3964. D. H. R. Barton, N. J. Cussans, and S. V. Ley, J.C.S. Chem. Comm., 1977,751. T. T. Takahashi, C. Y. Nakamura, and J. Y. Satoh, J.C.S. Chem. Comm., 1977,680. L. K. Sydnes, Actu Chem. Scund., 1977, B31,823. L. K. Sydnes, Actu Chem. Scund., 1978, B32,47. S. Julia and A. Ginebreda, Synthesis, 1977, 682. J. N. Shah, Y. P. Mehta, and G. M. Shah, J. Org. Chem., 1978,43,2078. F. Cooke, P. Magnus, and G. L. Bundy, J.C.S. Chem. Comm., 1978,714.

24

Terpenoids and Steroids

Further papers of general synthetic interest include the full paper on the UO,Cl,-MeOH-catalysed photoreactions of enones (Vol. 7, p. 8),256chlorination of alcohols (e.g. menthol; poor yield) using C U C ~ , - P P ~ ~the , ~ ~use ’ of 5,5dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxan for monobromination of saturated aldehydes and ketones in high yield as well as a$-unsaturated ketones [e.g. pulegone (21)]regioselectively at the a’-carbon atom,258debromination of a -bromo-ketones with Fe2(C0)9-DMF-H20 (e.g. 3 -endo- bromocamphor to 3-exo-de~teriocamphor),~~~ conversion of ketones (e.g. camphor) into thioketones with the dimer of p-methoxyphenylthionophosphine sulphide,260 the mild transfer-nitration of alcohols (e.g. the borneols), without inversion, using N-nitrocollidinium tetrafluoroborate,261and the preparation of trimethylsilyl ethers (e.g. from citronellol) using bistrimethylsilyl etherz6, catalysed by the mildly acidic pyridinium toluene-p - ~ u l p h o n a t e . ~ ~ ~ 4 Biogenesis, Occurrence, Chemotaxonomy, and Biological Activity

Poulter has reviewed the evidence supporting an ionization-condensationelimination mechanism (Vol. 8,p. 24)in the prenyl-transfer reaction.263 (R)-(+)-Methyl p-tolyl sulphoxidz (synthesized in 100% optical purity by microbial oxidation of methyl p-tolyl sulphide using Mortierella isabellina) has been used to synthesize (3R)-(-)-mevalonolactone in 17% optical yield via a straightforward alkylation-sulphoxide removal sequence involving (R)-(+)-tbutyl a- (p-t~lyl)sulphinylacetate.~~~ Biogenesis.-Evidence supporting the hypothesis that 3-hydroxy-3-ethylglutarate and homomevalonate (or their metabolic equivalents) are intermediates in the biosynthesis of juvenile hormones in Manduca sexta has been published.265 The solvolytic behaviour of geranyl pyrophosphate (to yield geraniol :linalool/ 1:5 ) in the presence of Mg2+or Mn2’ 266 is consistent with the view263that two bivalent cations are required biochemically to ionize allylic pyrophosphates in initiating prenyl-transfer via an ionization-condensationelimination mechanism. The micro-organism Kluyveromyces lactis produces linalool and citronellol, with the yield of the latter increased by feeding with gerani01.’~~ Banthorpe has pointed out that interpretation of the results of feeding 256

257

258

259

260

261

262 263 264 265

266

267

T. Sato, S. Yoshiie, T. Imamura, K. Hasegawa, M. Miyahara, S. Yamamura, and 0. Ito, Buff. Chem. SOC.Japan, 1977, 50, 2714; for data on TiC14-MeOH photoreactions, see also Vol. 7, p. 33. S. Miyano, H. Watanabe, H. Ushiyama, Y. Yamada, and H. Hashimoto, Nippon Kagaku Kaishi, 1978, 138. R. Bloch, Synthesis, 1978,140; for pulegone bromination, the previously reported (Vol. 7, p. 8) enol silyl ether route is more efficient. R. Noyori, Y. Hayakawa, H. Takaya, S. Murai, R. Kobayashi, and N. Sonoda, J. Amer. Chem. SOC., 1978, 100, 1759; see also ref. 566. B. S. Pedersen, S. Scheibye, N. H. Nilsson, and S . - 0 . Lawesson, Buff.SOC.chim. befges, 1978,87, 223; the structural formula for thiocamphor is incorrect. G. A. Olah, S. C. Narang, R. L. Pearson, and C. A. Cupas, Synthesis, 1978,452. H. W. Pinnick, B. S. Bal, and N. H. Lajis, Tetrahedron Letters, 1978, 4261. C. D. Poulter and H. C. Rilling, Accounts Chem. Res., 1978,11, 307. E. Abushanab, D. Reed, F. Suzuki, and C. J. Sih, Tetrahedron Letters, 1978, 3415. ( a ) F. C. Baker and D. A. Schooley, J.C.S. Chem. Comm., 1978,292; ( b ) E. Lee, D. A. Schooley, M. S. Hall, and K. J. Judy, ibid., 1978, 290. D. N. Brems and H. C. Rilling, J. Amer. Chem. SOC., 1977, 99, 8351. F. Drawert and H. Barton, J. Agric. Food Chem., 1978, 2 6 , 7 6 5 .

Monoterpenoids

25

experiments may be complicated by seasonally dependent perturbations of biosynthetic pathways in higher plants (see also Vol. 8, p. 14).268In further experiments (see Vol. 8, p. 18)to elucidate the metabolic conversion of MVA into (+)-thuj-3-one in Tanacetum vulgare,268*269 evidence favours the sequence geraniol -+nerol -+cyclic monoterpenoids, geraniol being converted into nerol, without the intermediacy of linalool, in a redox process. Using (3RS)-[53H2]MVA, {(3R,4R)-[4- 3H1]MVA+ (3S,4S)- [4- 3H1]MVA}, or {(3R,4S)-[43H1]MVA + (3S,4R)-[4-3Hl]MVA} in admixture with (3RS)-[2-14C]MVA, it was shown that only the pro-(4R) hydrogen of MVA is incorporated into (+)-thuj-3-one (in vivo),and into geraniol and nerol using cell-free extracts which also incorporate both tritium atoms from [5-3H2]MVAinto geraniol but only one into nerol; in vivo, only one tritium atom was incorporated from [5-3H2]MVA into (+)-fhuj-3-0ne.’~~ A second paper268provides further evidence with in vivo winter feeding experiments using (1R)- and (1S)-[l-3Hl]geraniol, and (1R)- and (1S)-[l-3Hl]nerol, when it was shown that geraniol suffers stereospecific loss of the pro- (1S )- hydrogen atom on conversion into nerol which suffers no hydrogen loss at C-1 on further conversion into (+)-thuj-3-one. Non-winter feeding experiments in Tanacetum vulgare, and feeding experiments in Pinus pinaster (aand p- pinenes), Menthu piperita and Eucalyptus globulus (1&cineole), and Mentha spicata [carvone (18)],suggest that the straightforward redox conversion, geraniol + nerol, may be perturbed by a nerol + geraniol interconversion and/or C - 0 bond fission of pyrophosphate esters.268Some preliminary results on using tissue cultures of Tunacetum cinerariifolium for examining pyrethrin biosynthesis have been rep~rted.’’~Inouye has published furthur details of iridoid biosynthesis in Lamium amplexicaule, Deutzia crenata, and Galium spurium. Previously reported (and uncited - see Vol. 8, pp. 16, 17) data and the results of additional feeding experiments with [2-14C]MVA, 1l-[10-3H]hydroxyiridodial glucoside, and 7-[ 10-3H]deoxyloganic acid are consistent with his previous postulate (Vol. 8, pp. 16, 17) that the biosynthesis of asperuloside, deutzioside, ipolamiide, lamiide, lamioside, and scabroside may involve the biosynthetic sequence MVA ++ 10-hydroxygeraniol (or 1O-hydroxynerol) ++ iridodial (via 10-oxoneral ?) + iridodial glucoside, followed by further oxidative functionalization which may involve the oxidative sequence CH3 + CHZOH + C 0 2 R at C-1 1 but not the reverse reductive processes.271 Feeding experiments with Thymus vulgaris suggest that thymol may be biosynthesized by the aromatization of y-terpinene to p -cymene and subsequent hydr~xylation.~~’ Using cell suspensions from Mentha strains, pulegone ( 21)has been biotransformed into i s ~ m e n t h o n e . ’ ~Bornyl ~ pyrophosphate has been shown to be an intermediate in the biosynthesis of borneol from NPP using a Salvia officinalis enzyme preparation.274

268 269 270

27 1 272

273 274

D. V. Banthorpe, B. M. Modawi, I. Poots, and M. G . Rowan, Phytochemistry, 1978,17, 115. D. V. Banthorpe, 0. Ekundayo, and M. G. Rowan, Phytochemistry, 1978,17, 1111. M. M. Cashyap, J. S. H. Kueh, I. A . Mackenzie, and G. Pattenden, Phytochemistry, 1978,17, 544. H. Inouye, S. Ueda, and S. Uesato, Phytochernistry, 1977,16, 1669. A. J. Poulose and R. Croteau, Arch. Biochem. Biophys., 1978, 187, 307. D. Aviv and E. Galun, Planta Med., 1978, 33, 70. R. Croteau and F. Karp, Arch. Biochem. Biophys., 1977,184,77; for earlier work, see Vol. 8, p. 18.

26

Terpenoids and Steroids

Papers on the biosynthesis of monoterpenoid alkaloids lie outside the scope of this Report. Chemical communication in pine bark beetles has been reviewed;275related papers of interest include the inhibition of aggregation of Ips pini by ( S ) - ( - ) ipsen01~’~ and an examination of species-specific response differences of Ips species to ipsdienol e n a n t i o m e r ~ The . ~ ~ ~oviposition behaviour of the house longhorn beetle (Hylotrupes bajulus) is pheromone-stimulated by (-)-verbenone Neral and/or geranial are components of the and synergized by p -cyrnen-8-01.~~’ .~~~ mosquito sex pheromone of the parasitic wasp (Itoplectis ~ o n q u i s i t o r )The (Aedes aegypti) larvicide present in Tagetes minuta has been shown to be (5E)-0cimenone (25).”’

Essential Oils and Chemotaxonomy.-This section reviews the literature of the past year for essential oil analyses, but covers the past two years (see Vol. 8, p. 19) for phytochemical papers reporting variation of monoterpenoid content according to geographical, seasonal, and environmental factors, taxonomic and evolutionary implications, hybridization, and genetics of terpenoid development. For the previous report on Chemotaxonomy, see Vol. 7, p. 222. Further papers in a series on recent progress in essential oils have been published.2i0d Essential oil composition studies of interest concern Mentha rotundifolia [-85% piperitenone epoxide (26)],281Artemisia afra (cineole, artemisia ketone,

M. C. Birch, Amer. Scientist, 1978, 66, 409. M. C. Birch, D. M. Light, and K. Mori, Nature, 1977, 270,738. 277 J. P. Vitt, G. Ohloff, and R. F. Billings, Nature, 1978, 272, 817. 278 M. D. Higgs and D. A . Evans, Experientia, 1978, 34,46. 279 D. C. Robacker and L. B. Hendry, J. Chem. Ecol., 1977,3, 563. A . Maradufu, R. Lubega, and F. Dorn, Lloydia, 1978, 41, 181. 280a Recent reviews are B. M. Lawrence, Perfumer and Flavorist, 1978, 2(7), 44; 1978,3(2), 45; 1978, 3(3),46. For earlier reviews in this series, see B. M. Lawrence, ‘Essential Oils 1976-1977’, Allured Publishing Corp., Wheaton, Illinois, 1978. 281 S.4.Fujita, T. Nakano, and Y. Fujita, Nippon Nogei Kagaku Kaishi, 1977, 51, 699; an earlier analysis, R. H. Reitsema, J. Amer. Chem. Soc., 1956,78, 5022, reports significantly less (26). 275

276

Monoterpenoids

27

artemisia Chenopodium ambrosioides ( a ~ c a r i d o l e )and , ~ ~ ~Cymbopogon winterianus (Burmese type) (citronellal, c i t r ~ n e l l o l )Two .~~~ papers report, as natural products, trace amounts of karahanaenol(Z7; X = H,OH) in Cupressus s e m p e r v i r e n ~and ~ ~ ~/3 -pinene epoxide in Picea abies ;286 a third reports the presence of (+)-cis-sabinene hydrate (28) in a new chemical strain of Mentha candi~ans.~~’

Many papers report monoterpenoid analyses with geographical and seasonal variations. Geographical variations have been reported for Abies amabilis288and A. g r a n d i ~ Pinus , ~ ~ ~~ o n t o r t a and , ~ ~ Satureja ~ d o ~ g l a s i i Five . ~ ~ ~compositional types were identified for S. douglasii (cf. Vol. 7, p. 223)291nalthough environmental conditions, e.g. moisture stress, temperature, light, were also shown to influence monoterpenoid yield and composition.29’b~cThe effect of moisture stress on Pinus taeda has been and data on geographical monoterpenoid variations in Pinus p o n d e r ~ s aslash , ~ ~ pine,294 ~ and the Sitka spruce (Picea itche ens is)^^^ have appeared. Seasonal variations in the monoterpenoid content of essential oils from Salvia ~ c l a r e a Mentha , ~ ~ ~ j a p o n i ~ a , ’M. ~ ~ gentilis [( 1R,4S)(+)-4-hydroxyisomenthone (29) is a minor and a second ~ ~ been ~ ~ reported. chemotype of M. g e n t i l i ~have Further papers on new chemotypes include reports of two chemotypes of Achillea ageratum (one high in artemisia ketone and artemisyl acetate content

283

’“ 286 287

290

291

’” 293 294

295 296

297 298

J. Garnero, Parfums, Cosmet., Aromes, 1977, 16, 45; Chem. Abs., 1978, 88, 11 725 incorrectly assigns this work to M. Gavarry. G. S . Gupta and M. Behari, Indian Perfum., 1975, 18(2), 40; the delay between publication and abstracting (Chem. Abs., 1977,87, 122 623) is to be deplored. B. L. Kaul, D. K. Choudhary, and C. K. Atal, Indian J. Pharm., 1977, 39,42. J. Garnero, P. Buil, D. Joulain, and R. Tabacchi, Riuista Ital. Essenze-Profumi, Piante OfJic.,Aromi, Saponi, Cosmet., Aerosol., 1978,60,99. V. Heemann and W. Francke, Planta Med., 1977,32,342. D. Karasawa and S. Shimizu, Agric. and Biol. Chem. (Japan), 1978,42,433;the major component (85%) is (+)-trans-sabinene hydrate. E. von Rudloff and R. S. Hunt, Canad. J. Bot., 1977,55, 3087. D. J. Houkal, Diss. Abs. Internat. ( B ) , 1976, 37, 2592; see also Vol. 7, p. 222. G. I. Forrest, Comm. Eur. Communities, Rep. EUR, 1977, EUR 5885, p. 55 (Chem. Abs., 1978,88, 86 175). D. E. Lincoln and J. H. Langenheim, Biochem. System. Ecol., ( a ) 1976, 4, 237; ( 6 ) 1978, 6, 21; (c) J. Gershenzon, D. E. Lincoln, and J. H. Langenheim, ibid., 1978,6,33. A. R. Gilmore, J. Chem. Ecol., 1977,3,667. R. H. Smith, U.S. Dee. Agric., Tech. Bull., 1977, 1532, 1 (Chem. A b s , 1977, 87, 98798). C. R. Gansel and A. E. Squillace, Siluae Genet., 1976,25, 150; Chem. Abs., 1978,88,60 112 does not record the botanical name of this species. E. M. von Rudloff, Phytochemistry, 1978, 17, 127. T. Yoshida and T. Sawasaki, Nettai Nogyo, 1978, 21, 145 (Chem. Abs., 1978,89, 94 876). S.-I. Fujita, T. Nakano, and Y. Fujita, Nippon Nogei Kagaku Kaishi, 1977, 51,405. K. Umemoto and T. Nagasawa, Nippon NogeiKagaku Kaishi, ( a ) 1977,51,659;( b ) 1978,52,191.

28

Terpenoids and Steroids

and the other high in 1,8-cineole content),299a new strain of Chenopodium ambrosioides [high (-)-pinocarve01 (30) content],300 and a chemotype of Pinus

ponderosa which may prove to be resistant to the pine beetle Dendroctonus brevicomis because of its high limonene content.293A number of papers report studies on hybrids of Mentha species.3o1From a clone study of Picea d i e s , it has been suggested that the regulation of monoterpenoid biosynthesis (to high car-3-ene/terpinolene content, or to high limonenelp-phellandrene/pinene content) is controlled by a dominant-recessive allele pair of a single gene locus3o2 analogous to the genetic control of car-3-ene production in Pinus s y l ~ e s t r i s . ~ ~ ~

Pyrethroids and Related 1nsecticides.-A book of reviews was omitted from earlier The limited space available for this Report restricts the discussion of this year's pyrethroid literature.305 Papers of analytical interest include the g.c.-m.s. analysis of the six naturally occurring p y r e t h r i n ~ , ~g.c. ' ~ resolution307" and optical purity determination of synthetic allethronyl c h r y s a n t h e m a f e ~ ~and ~ ~ (' * ) - a l l e t h r ~ I o n e(a ~ ~synthesis ~~ of which has been published308),and h.p.1.c. analysis of the six naturally occurring 299 30" 301

302

303

304

305

3"6 307

308

R. Grandi, W. Messerotti, and U. M. Pagnoni, Phytochemistry, 1976, 15, 1770. K. Umemoto, Nippon Nogei Kagaku Kaishi, 1978, 52,149. ( a )A. G. Nikolaev, A. V. Dizdar, E. M. Pelyakh, Yu. S. Popov, and L. N. Chelovskaya, Izuest. Akad. NaukMold. S.S.R., Ser. biol. khim. Nauk, 1977, (6), 16 (Chem. Abs., 1978,88,166 844); ( b ) E. M. Pelyakh, V. I. Chobanu, A. G. Nikolaev, and Q. Z. Nguyen, ibid., 1976, (6), 16 (Chem. A h . , 1977, 86, 168 016); ( c ) A. G. Nikolaev, VIIth International Congress of Essential Oils, Kyoto, 7-11th October, 1977, Abstract No. 19 (Riuista Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1978, 60, 131); ( d ) T . Sacco and M. Gallino, Atti-Conv. Naz. Olli Essenz. Sui Deriv. Agrum., 1976,8-9, 82 (Chem. Abs., 1978,88,41 533). I. Esteban, F. Bergmann, H. R. Gregorius, and 0. Huhtinen, Silvae Genet., 1977, 25, 59 (Chem. Abs., 1978,88,60 213). R. Hiltunen, Ann. Acad. Sci. Fennicae, Ser. A#, 1976, 208, 1 (Chern. Abs., 1978,88, 86 184);see also Vol. 7, p. 224. 'Pyrethrum Flowers', ed. R. H. Nelson, 3rd edn., McLaughlin Gormley King Co., Minneapolis, U.S.A., 1975. Fortunately the keyword search for pyrethroids is relatively efficient and a significant proportion of this year's literature may be found in only two journals, viz. J. Agric. Food Chem. and Pesticide Sci. R. L. Holmstead and D. M. Soderlund, J. Assoc. Ofic. Analyt. Chemists, 1977, 60, 685. M. Horiba, H. Kitahara, and A. Murano, Agric. and Biol. Chem. (Japan), ( a ) 1978, 42, 671; ( 6 ) 1977,41, 2003. G. Piancatelli, A. Scettri, G. David, and M. D'Auria, Tetrahedron, 1978, 34, 2775.

Monoterpenoids

29

pyrethrin~~ and ' ~ of permethrin310 and some cyano-substituted The most active form of one of the latter (cypermethrin) has been shown to have the same S-configuration at the a -cyanobenzyl carbon atom312as that observed for decamethrin (Vol. 5, p. 16) and analogues.311Synthetic activity has been directed towards the synthesis of (lR)-cis-and (1R)-trans-permethrin labelled with 14Cat C-2 of the substituted vinyl group,313of permethrin metabolites314 and cyanosubstituted analogues,311of methyl-substituted cyclohexenylmethyl and cyclohexadienylmethyl c h r y ~ a n t h e m a t e s of , ~ ~pyrethrolone ~ and of substituted indanyl c h r y s a n t h e m a t e ~Pyrethroid .~~~ degradation studies include the photochemical decomposition of d e ~ a m e t h r i n ,~~ e' ~r m e f h r i nand , ~ ~kadeth~ rin320and the degradation of labelled321"and ~ n l a b e l l e dpermethrin ~~l~ in soil, on cotton leaves,322 in bean and in hens322band of cypermethrin in soi1.321 b.323 Other papers of interest concern decamethrin metabolism in permethrin metabolism in lactating cows,325and a discussion of structural and Structurebiological links between pyrethroids and DDT in new toxicity relationships and degradation of toxaphene components have also been

5 Acyclic Monoterpenoids

Terpenoid Synthesis from Isoprene.-Some prenylation procedures have been into prenyl reported An efficient conversion of prenyl acetate329has been described and the synthon (31; X = OH) (Vol. 7, p. 10) has D. Mourot, J. Boisseau, and G. Gayot, Analyt. Chim. A c f a , 1978, 97, 191. S. Lam and E. Grushka, ( a )J. Chromatog. Sci., 1977,15,234;( b )J. Chromatog., 1978,154,318; ( c ) E. J. Kikta, jun. and J. P. Shierling, ibid., 1978, 150, 229. 3 1 1 M. Elliott, N. F. Janes, D. A. Pulman, and D. M. Soderlund, Pesticide Sci., 1978, 9, 105. For an investigation of insecticidal activity, see M. Elliott, A. W. Farnham, N. F. Janes, and D. M. Soderlund, ibid., 1978, 9, 112. 312 K.-I. Aketa, N. Ohno, N. Itaya, I. Nakayama, and H. Yoshioka, Agric. and Biol. Chem. (Japan), 1978,42,895. 3 1 3 I. Nakatsuka, F. Shono, and A. Yoshitake, J. Labelled Compounds, 1977, 13, 561. 314 T. Unai and J. E. Casida, J. Agric. Food Chem., 1977,25, 979. "' F. Sugawara, T. Sugiyama, A. Kobayashi, and K. Yamashita, Agric. and Biol. Chem. (Japan), 1978, 42, 847. 316 K. Okada, M. Nozaki, Y. Takashima, N. Nakatani, Y. Nakatani, and M. Matsui, Agric. and Biol. Chem. (Japan), 1977,41,2205. 317 Y. Nakada, S. Muramatsu, M. Asai, S. Ohno, and Y. Yura, Agric. and Biol. Chem. (Japan), 1978,42, 1357; Y. Nakada, S. Ohno, M. Yoshimoto, and Y. Yura, ibid., p. 1365. 318 L. 0. Ruzo, R. L. Holmstead, and J. E. Casida, J. Agric. Food Chem., 1977, 25, 1385. 319 R. L. Holmstead, J. E. Casida, L. 0. Ruzo, and D. G. Fullmer, J. Agric. Food Chem., 1978,26,590. 320 K. Ohsawa and J. E. Casida, 175th A.C.S. Meeting, Annaheim, California, March 1978, Abstracts PEST, No. 53. 321 D. D. Kaufman, E. G. Jordan, and A. J. Kayser, 175th A.C.S. Meeting, Annaheim, California, March 1978, ( a ) Abstracts PEST, No. 48; ( b ) Abstracts PEST, No. 47. 322 L. C. Gaughan and J. E. Casida, ( a )J. Agric. Food Chem., 1978,26,525;( b ) 175th A.C.S. Meeting, Annaheim, California, March 1978, Abstracts PEST, No. 7. 323 T. R. Roberts and M. E. Standen, Pesticide Sci., 1977,8, 305. 324 L. 0. Ruzo, T. Unai, and J. E. Casida, J. Agric. Food Chem., 1978, 26, 918. 325 L. C. Gaughan, M. E. Ackerman, T. Unai, and J. E. Casida, J. Agric. Food Chem., 1978,26,613. 326 G. Holan, D. F. O'Keefe, C. Virgona, and R. Walser, Nature, 1978, 272, 734. 327 M. A. Saleh, W. V. Turner, and J. E. Casida, Science, 1977,198,1256;W. V. Turner, J. L. Engel, and J. E. Casida, J. Agric. Food Chem., 1977,25,1394;M. A. Saleh and J. E. Casida, ibid., 1978,26,583. 328 For an industrial synthesis from isoprene, see J. Levy and N. J. Christensen, U.S. P. 4 036 899 (Chem. Abs., 1977,87, 117 5 5 8 ) . 329 J. Horino, K. Moriguchi, and Y. Mitsuta, Jap. P. 95 606/1977 (Chem. Abs., 1978,88, 37 269).

309

310

30

Terpenoids and Steroids

been converted into the useful synthons (32) and (33).330The 2-isomer of (32) results from the stereoselective S02C12-inducedrearrangement of (3 1; X = OH) to the corresponding 2-8-chlorosulphone, followed by hydrolysis, whereas E(32) is obtained uia an oxidation-allylic transposition Pummerer PhS&

X rearrangement of (31; X = OAc) followed by a [1,2] shift yields (34) which after hydrolysis undergoes photochemical [1,3] migration to yield (33).3306 y Acetoxytiglicaldehyde is also readily available from (34).3306Julia and coworkers have reported (35; X = SMe or SPh),33’ (36),331Q(37; X = Y = SMe or SPh),33’band (38)3316as further useful synthons. PhS+ PhSO

Ethyl geranate has been prepared stereoselectively under phase-transfer conditions by prenylation of ethyl E-3-methyl-4-benzenesulphonylbut-2-enoate and d e s ~ l p h u r i z a t i o nBiomimetic .~~~ synthesis of (39) from dimethylallyl acetate and isopentenyl acetate (1:3) catalysed by LiC104-AcOH has been examined;333 the corresponding alcohol (40) is obtained efficiently from isopentenyl acetate by QOAc

:Iy:

OAc

reaction with an excess of 2-methylbut-3-en-2-01, catalysed by trifluoroacetic Base-catalysed reaction of prenyl chloride with 3-methylbut-2-enonitrile 330

331

332 333 334

P. J. R. Nederlof, M. J. Moolenaar, E. R. de Waard, and H. 0.Huisman, Tetrahedron,( a ) 1978,34, 447; ( b ) 1978,34,2205. For another synthesis of y-acetoxytiglicaldehyde, via nitroacetoxylation of isoprene, see P. A. Wehrli and B. Schaer, Synthesis, 1977,649. ( a )V. Ratovelomanana and S. Julia, Synth. Comm., 1978, 8, 87; ( b ) J.-C. Clinet and S. Julia, J. Chem. Res. ( S ) , 1978, 125. See also ref. 366. G. Cardillo, M. Contento, M. Panunzio, and A. Umani-Ronchi, Chem. and Ind., 1977, 873. M. Julia, C. Perez, and L. Saussine, J. Chem. Res. ( S ) , 1978, 268. M. Julia and L. Saussine, J. Chem. Res. ( S ) , 1978, 269.

Monoterpenoids

31

1have. been ~ unable ~ ~to produces a lavandulyl carbon Miginiac et ~ reproduce results reported previously (Vol. 7, p. 10) for the [(q5-C5H5),TiC12]catalysed addition of allylic Grignard reagents to isoprene337 and subsquent reaction with carbon dioxide or carbonyl compounds, in that allylic transposition accompanies the latter; further investigation seems warranted. The structure of the tail-to-tail isoprene-magnesium 2 : 1 adduct has been shown to be a 27membered m a c ~ o c y c l e . ~ ~ ~ Telomerization of isoprene using lithium and substituted dialkylamines (e.g. di-isopropylamine) yields (41) in addition to m ~ r c e n e Further . ~ ~ ~ details have been published on the effects of water (cf. Vol. 8, p. 21) and amine structure (cf. Vol. 7, p. 11) on the [NiC1,(PPh3),]-NaBH4-catalyseddimerization of iso~ r e n e . Regioselective ~~' head-to-head dimerization of isoprene occurs with, e.g., (FMePhSi), in the presence of [(PPh3),PdCl2] or [Pd(PPh3),] (cf. Vol. 7, p. 11),341 in contrast to a further report (Vol. 8, p. 20) of solvent-dependent predominant tail-to-tail dimerization {Pd[(Ph2PCH,),],-C0,} to (42),342nmonohydration of Compound (43) which is reported via diene protection with sulphur

is the major product of thermal decomposition of bis-(3,3-dimethylallyl)zinc, together with irregular monoterpenoid d i e n e ~ an ; ~almost ~ ~ identical product ratio results from CrCl3-LiA1H4-THF reductive dimerization of prenyl bromide.344Isoprene (in propylene carbonate) is cyclodimerized to limonene by the electrochemically generated [Fe(N0)2],345 and oxidized anodically in methanol to a complex mixture of methoxylated dimers and t r i r n e r ~ Hy.~~~ droxycitronellol has been synthesized via CuC1-catalysed coupling of 4-acetoxy1-chloro-2-methylbut-2-ene and 2-methylbut-3 -yn-2-01.~~~ Some further syntheses with C5units are discussed in the next section. 335 336 337

338

339

T. Miyakoshi, H. Omichi, and S . Saito, Nippon Kagaku Kaishi, 1978,1176. ( a ) F. Barbot and Ph. Miginiac, J. Organometallic Chem., 1978,145,269. For a full discussion of the non-catalysed addition of 3-methylbut-2-enylmagnesiumchloride to isoprene, see H. Lehmkuhl, D. Reinehr, K. Mehler, G. Schomburg, H. Kotter, D . Henneberg, and G. Schroth, Annalen, 1978,1449. H. Yasuda, Y. Nakano, K. Natsukawa, and H. Tani, Macromolecules, 1978,11,586. A. Murata, S. Tsuchiya, A. Konno, and H. Ikeda, Jap. P. 23 906/1978 (Chem. Abs., 1978,89,

42 395). 340

341

342

343 344

345 346 347

I. Mochida, K. Kitagawa, H. Fujitsu, and K. Takeshita, J. Catalysis, 1978,54,175. K.Tamao, S. Okazaki, and M. Kumada, J. Organometallic Chem., 1978,146,87. ( a )Y.Inoue, S . Sekiya, Y. Sasaki, and H. Hashimoto, J. Synth. Org. Chem.,Japan, 1978,36,328; (b) P. A. Ochsner, U.S. P. 4 066 710 (Chem. Abs., 1978,88,105 610). R. Benn, E. G. Hoffmann, H. Lehmkuhl, and H. Nehl, J. Organometallic Chem., 1976,146,103. Y. Okude, T. Hiyama, and H. Nozaki, Tetrahedron Letters, 1977,3829. E.Le Roy, F. Petit, J. Hennion, and J. Nicole, Tetrahedron Letters, 1978,2403. H. Baltes, E. Steckhan, a n d H . J. Schafer, Chem. Ber., 1978,111,1294. R.E.Close and J. M. Derfer, U.S. P. 4 056 573 (Chem. Abs., 1978,88,51 041).

32

Terpenoids and Steroids

2,6-Dimethyloctanes.-The lack of recent references (only one post- 1963) in a review of 7-hydroxycitronellal is to be deplored (cf.Vol. 3, p. 45;Vol. 5 , p. 14; Vol. 8, p. 25).348 The diol (44)has been isolated from Greek tobacco (cf. Vol. 8, p. 26) and synthesized in low yield by S e 0 2 allylic oxidation of l i n a l o 0 1 ; ~(44) ~ ~ (chirality

OH

(44)

unspecified) and the corresponding 2-isomer are also present as primary p-Dglucosides (betulalbuside A and B respectively) in Betula alba and Chaenomeles j a p o n i ~ a . ~3,7-Dimethylocta-1,6-diene-3,4-diol ~' ('cornusol') is a component of Cornus c o n t r o ~ e r s aand , ~ ~citronellyldiethylamine ~ has been isolated from Pelargonium gra veolens.3s2 The 'H n.m.r. spectra of isoprene and myrcene have been analysed in and 'H n.m.r. data on a number of bisulphite adducts of citral and citronella1 have been The existence of a steric interaction between an alkene double bond and a heteroatom in a S-position (e.g. 6-bromo-7-hydroxy-3,7-dimethyloct-2-ene, 7-bromo-6-hydroxy-2,6-dimethyloct-2-ene, 6,7-epoxy-3,7dimethyloct-2-ene) has been demonstrated from 13C n.m.r. data.3s5 (1R)- and (1S)-[l-3H,]geraniol and (1R)- and (1S)-[l-3Hl]nerol have been synthesized.268 Treatment of the pyrrolidenecarbodithioate (45) with excess

(45)

methyl iodide in HMPA in the presence of LiC0,-LiF at room temperature provides a mild and efficient procedure for the steroselective synthesis of the all-trans allo-ocimene uia an S-methylation-elimination process.356Syntheses have been of chiral citronellol, 7-methoxycitrone11o1, 7-methoxy348

349

350 351

352 353 354 355

356

G. T. Walker, Seifen, Ole, Fette, Wachse, 1977, 103, 432. D. Behr, I. Wahlberg, T. Nishida, and C. R. Enzell, Acra Chem. Scand., 1978, B32,228. R. Tschesche, F. Ciper, and E. Breitmaier, Chem. Ber., 1977, 110, 3111. T. Kurihara and M. Kikuchi, J. Pharm. SOC.Japan, 1978,98, 969. W. Rojahn and E. Klein, Dragoco Rep. (Ger. Edn.), 1977, 24, 150. R.K. Harris and A. V. Cunliffe, Org. Magn. Resonance, 1 9 7 7 , 9 , 4 8 3 . T. J. Johnson and R. A. Jones, Tetrahedron, 1978, 34, 547. M. E. van Dommelen, L. J. M. van de Ven, H. M. Buck, and J. W. de Haan, Rec. Trau. chim., 1977, 96, 295. T. Hayashi, A. Sakurai, and T. Oishi, Chem. Letters, 1977, 1483.

Monoterpenoids

33

citronellal, and citronellic acid of R or S configurations in high optical purity [e.g. ( R ) -(+)-7-methoxycitronellal, 99.5% enantiomeric purity] by known procedures (for related work, see Vol. 8, pp. 25,26). The paper also reports that the [a12for optically pure (R)-(+)-7-hydroxycitronellalshould be + 14.9" (CHCl,) (cf.Vol. 3, p. 45, ref. 205).'s9b (R)-(+)-Menthocitronello1 (46) of high, but unspecified, optical purity has been synthesized from the corresponding nitrile which is obtained from (-)-menthone via Beckmann rearrangement followed by known lactam cleavage using PC15.3s7Geraniol syntheses include cleavage of (47) with

Na,CO,-MeOH to yield methyl (E)-3-methyl-7-oxo-oct-2-enoate and straightforward elaboration via methyl g e ~ a n a t e , conversion ~'~ of 6-methylhept-5-en-lyne into the corresponding (E)-2-methylalkenylalane using Me3Al-C12ZrCp2 and reaction with formaldehyde via the derived ate and a straightforward conversion of N,N-dipropylgeranylamine (obtained from myrcenePr2NH-BuLi; cf. Vol. 8, p. 23) via geranyl chloride obtained by treatment with ethyl chlor~forrnate.~'~ Nerol was also obtained with high stereoselectivity using the same reaction sequence on the isoprene telomerization product N,N-dialkylnerylamine. This is a better alternative to the less selective amine-oxide rearrangement route (Vol. 5, p. 12; Vol. 7, p. 11).3s9The poor quality of the Chemical Abstract hides details of the preparation of (48) via dimethylcyclooctene pyrolysis and hydrof~rmylation.~~'

Diels-Alder reaction of itaconic anhydride with cyclopentadiene yields the adduct (49) which is converted into (50) (Scheme 1)for quantitative retro-DielsAlder thermolysis to racemic ipsenol (51),361reminiscent of the last steps of Mori's ipsenol synthesis (Vol. 6, pp. 18, 19). Both ipsenol (51) and the cor357 358 359

360

361

K. Derdzinski and A. Zabza, Bull. Acad. polon. Sci., Se'r. Sci. chim., 1977, 25, 529. K. Tsuzuki, H. Hashimoto, H. Shirahama, and T. Matsumoto, Chem. Letters, 1977, 1469. K. Takabe, T. Katagiri, and J. Tanaka, Chem. Letters, 1977, 1025. For related work where rearrangement occurs, see Vol. 4, p. 17. For the reverse conversion of geraniol to geranyl chloride without rearrangement, see Vol. 3, p. 38, ref. 186. A. J. De Jong, Ger. Offen. 2 704 547 (Chem. A h . , 1978, 88, 170 341); regrettably (48) has been named dihydromyrcenol (cf. Vol. 3, p. 15). J. Haslouin and F. Rouessac, Bull. SOC.chim. France, 1977, 1242.

34

Terpenoids and Steroids

(49)

A

liv, v

VI

t vii

t

(51) Reagents: i, NaBH4-DMF; ii, B u ~ A I H-80 , "C; iii, Bu'MgBr; iv, C S H ~ N H C ~ O ~ C I - C H 0 "C; ~C~~, V, BUbAlH, -80 "c;vi, Ph3PCH2-C&6, 8 0 "c;V i i , 4 5 0 "c

Scheme 1

responding ipsdienol have been synthesized by vinylcuprate addition to the corresponding ketones [e.g. (52)] followed by reduction; (52) is readily available by lithiation of allene and reaction with N,N-dimethyl-3-methylbut-2enamide.362The useful synthon (53; X = CHO), which is formed from the Claisen rearrangement product (53; X = C0,Me) of buta-2,3-dienyl dimethyl orthoacetate, provides short and efficient syntheses of ipsenol (51) and ipsd i e n 0 1 ; ~the ~ ~analogous known Claisen rearrangement of the but-2-enyl orthoester and conversion into a mixed anhydride is the basis for a synthesis of (*)-dihydrotagetone (54) via acylation of trimethylsilyl lithio-i~ovalerate.~~~

[2,3] Sigmatropic rearrangement of ( 5 5 ) , which is formed by thiophilic Grignard addition to the corresponding dithioester, followed by methylation and hydrolysis, yields the dihydromyrcenone (56; 25% yield).365Julia et al. have used the synthon (37; X = H, Y = PhSO) and a lithio-derivative of a protected cyanhydrin (cf. Vol. 8, p. 59) in a straightforward synthesis of the tagetones (57; A d : 2 / 5 5 : 45).366 362

363 364

365

366

J. C. Cline?.and G. Linstrumelle, Nouueau J. Chim., 1 9 7 7 , 1 , 3 7 3 ; for a related synthon (38) see ref. 331b. M. Bertrand and J. Viala, Tetrahedron Letters, 1978, 2575. R. Coufignal and J.-L. Moreau, Tetrahedron Letters, 1978, 3713. S. Masson, M. Saquet, and A. Thuillier, Tetrahedron, 1977, 33, 2949. Julia et al. reported a very similar sigmatropic rearrangement some time ago; see S. Julia, V. Tatovelomanana, and C. Huynh, Compt. rend., 1974, 218, C, 371 and Vol. 8, p. 32. E. Guittet and S. Julia, Tetrahedron Letters, 1978, 1155.

Monoterpenoids

35

Another ortho-ester Claisen rearrangement involves rearrangement of 3 3 dimethylhexa-2,5-diene-l-y1diethyl orthoacetate followed by Cope rearrangement in situ to yield ethyl 3,7-dimethylocta-3,7-dienoate(E :2/55 :45).367The conversion of 6-methylhept-5-en-l-yne into the corresponding (El-2-methylalkenylalane using Me,Al-Cl,ZrCp, has also been used in syntheses of ( E ) geranic acid and its ethyl The addition of dimethylallylcarbene to isoprene and 2-methylbut-l-ene yields ( 5 8 ; R = vinyl or ethyl, respectively); acid- and base-catalysed rearrangements of (58) may lead to regular and/or irregular monoterpenoid carbon Sodium-liquid ammonia treatment of (58; R = vinyl) yields the dihydromyrcene (59)whereas peracid oxidation followed by treatment with methanolic HCl yields, e.g., (60).3686 An interesting stereospecific hydrogen migration has been reported following the observation that N,N-diethylnerylamine and N,N-diethylgeranylamine rearrange to the corresponding trans-enamine of citronella1 (6 1; up to 90Y0) using [HCo(N,)-

OM

(PPh3)3]or cobalt octanoate-PPh3-Et3Al as catalysts. With the former Zieglertype catalyst containing chiral (including monoterpenoid) phosphines or diphosphines, up to 33% enantiomeric excess of 3R-or 3S-citronella1 can be obtained, enantioselectivity being both ligand- and temperature-dependent, and at the expense of isolated yields.369 Other syntheses of interest concern citral (via acetal pyrolysis; cf. Vol. 6 , p. 14; Vol. 7 , p. 15),370another report (Vol. 7, p. 17) of dehydrolinalool rearrangement to ~ i t r a 1 1,2-difluorolinalo01,~~~ ,~~~ 1,1,2-trifluorolinaloo1372and the related 7367

368 369

37" 371 372

Y. Fujita, T. Onishi, and T. Nishida, Synthesis, 1978,532. L. Crombie, P. J. Maddocks, and G. Pattenden, Tetrahedron Letters, ( a ) 1978,3479; ( b ) 1978,3483. H. Kumobayashi, S. Akutagawa, and S. Otsuka, J. Amer. Chem. SOC., 1978, 100, 3949; S. Akutagawa and H. Kumobayashi, Jap. P. 77 005/1977 (Chem. Abs., 1977,87,201 817). W. Leimgruber and D. H. Valentine, jun., U.S. P. 4 016 212 (Chem. Abs., 1977, 87, 136 042). P. Chabardes and E. Kuntz, Ger. Offen. 2 657 335 (Chem. Abs., 1977,87, 136 056). R. Sauvstre, D. Masure, C. Chuit, and J. F. Normant, Synthesis, 1978, 128.

Terpenoids and Steroids

36

methyl-3-trifluoromethylocta-1,6-dien-3-ol,373 (3RS,6R)-2,6-dimethyloct-7ene -2,3-diol ,374 and p -D-glucopyranosyl citronellyl phosphate. 375 Further work (Vol. 8, p. 26) has been published on geraniol and nerol . ~ ~ micro~ biotransformation using callus tissue from Cannabis ~ u t i v u The biological transformation products of g e r a n i 0 1 , ~l ~i n~a~l o 0 1 , ~and ~ ~ ~ner01,'~~ using Pseudomonas incognita have been analysed and metabolic pathways investigated.377b Geraniol and nerol metabolites may result from allylic C-3 methyl oxidation, C-2-C-3 dihydroxylation, and/or alcohol oxidation; linalool metabolites result from hydroxylation at the C-3 methyl group or the formation of (44).377b Attempts to mimic the formation of the chloroform-soluble (62)378failed

(62)

with a related phenolic diether analogue of monocarboxylic acid polyether antibiotics.379 The cyclization of 3,7-dimethylocta-1,6-diene [to e.g. (63; X = Y = H)] using A Bu"Li-TMEDA may occur via the polar equivalent of the ene kinetic analysis of the thermal rearrangement of linalyl trimethylsilyl ether confirms that the four diastereomeric products [ e . g (63; X = OSiMe,, Y = H)] are each formed by distinct intramolecular ene reactions although it has been ~'~ impossible to specify whether the transition states are endo or ~ x o . Thermolysis of dehydrolinalool to (64; X = OH) is a n a l o g o ~ s ; likewise ~~' with 3,7-dimethyloct-6-en-1- ~ n e . ~ 'The * full paper on the [2,3] sigmatropic rearrangement of geranyl o -nitrophenyl selenoxide followed by o -nitrobenzene seleninic acid-

% 373 374

375 376

377

378

379 38"

381 382

F. Camps, R. Canela, J. Coli, A. Messeguer, and A. Roca, Tetrahedron, 1978, 34, 2179. G . J . Cernigliaro and P. J . Kocienski, J. Org. Chem., 1977, 42, 3622; this compound is named incorrectly in this paper. L. L. Danilov, L. V. Volkova, and R. P. Evstigneeva, J. Gen. Chem. (U.S.S.R.),1977,47, 1948. H. Itokawa, K. Takeya, and S . Mihashi, Chem. and Pharm. Bull. (Japan),1977,25,1941;K. Takeya and H. Itokawa, ibid., p. 1947. J. Rama Devi and P. K. Bhattacharyya, Indian J. Biochem. Biophys., ( a ) 1977, 14, 288; ( 6 ) ibid., p. 359. For earlier linalool metabolic work with Pseudomonas, see Vol. 3, p. 10. The formation of (62) by exposing the corresponding geranyl acetate oxidation product to potassium ion was inadvertently omitted from a previous Report, R. E. Hackler, J. Org. Chem., 1975,40,2978. J. 0. Gardner and C. C . Beard, J. Medicin. Chem., 1978, 21,357. J. H. Edwards and F. J. McQuillin, J.C.S. Chem. Comm., 1977, 838. W. Pickenhagen, G. Ohloff, R. K. Russel, and W. D. Roth, Helv. Chim. Acta, 1978,61, 2249. B. B. Snider and T . A. Killinger, J. Org. Chem., 1978, 43, 2161.

Monoterpenoids

37

catalysed hydrogen peroxide epoxidation under buffered conditions (Vol. 8, p. 12) has been The well-known photochemical rearrangement of citral has been shown to be temperature-dependent; at elevated temperatures the major products are the formyl-migrated (65), with the cis-aldehyde p r e d ~ m i n a t i n g . Sensitized ~~~ photochemical rearrangement of the corresponding geranonitrile at 132 "C yields predominantly (66),a known acid-catalysed Beckmann fragmentation product of

(66)

(65)

a -fenchone ~ x i m e . ~Further ~' details of the Rose Bengal-sensitized photooxygenation of 2,6-dimethylocta-2,6-diene, which was reported earlier (Vol. 4, p. 14), have been published in a kinetic The full paper on the photochemical irradiation of citral in the presence of methanol and TiCl, (Vol. 6, p. 10) has been published.256The addition of photochemically generated free radicals to 3,7-dimethylocta-1,6-dieneoccurs selectively at the 6,7-double bond with bifunctional radical addends and at the 1,2-double bond with monofunctional radicals, analogous to earlier results (Vol. 7, p. 14) involving manganese(II1) acetate o x i d a t i o n ~ . ~ ~ ' Treatment of geraniol, nerol, linalool, and their acetates and phosphates with 85o/' phosphoric acid results in essentially similar mixtures of predominantly cyclic hydrocarbons ( a-terpinene, y -terpinene, isoterpinolene, limonene, p cymene, and p-menth-3-ene); the results are rationalized in terms of carbonium ion structures and stabilities with the interesting observations (i) that limonene can neither be derived from the a-terpinyl cation nor from (67), into which the

A (67)

a-terpinyl cation may be converted rapidly by a 1,2-hydride shift, (ii) that the a -terpinyl cation rearranges in preference to cyclization to bicyclic compounds, and (iii) that relatively slow deprotonation allows extensive intramolecular carbonium ion rearrangements to account for significant amounts of isoterpinolene and ~-menth-3-ene.~*' A second paper reports rearrangement in 3n3 384 3n5 386 387 388

T. Kametani, H. Nemoto, and K. Fukumoto, Bioorg. Chem., 1978,7,215. F. Barany, S. Wolff, and W. C. Agosta, J. Amer. Chem. SOC., 1978,,100, 1946. S.Wolff and W. C. Agosta, J. Org. Chem., 1978, 43, 3627. C. Tanielian and J. Chaineaux, J. Phorochem., 1978, 9, 19. J. H. Edwards, F. J. McQuillin, and M. Wood, J.C.S. Chem. Comm., 1978, 438. J. P.McCormick and D. L. Barton, Tetrahedron, 1978, 34, 325.

38

Terpenoids and Steroids

aqueous citric acid at pH 2.4; in addition to cyclization (to a-terpineol) and allylic rearrangement (e.g. to linalool), competitive hydration of the 6,7-double bond is observed (e.g. to yield 3,7-dimethyloct- l-ene-3,7-diol). The results suggest that, under the mild conditions used, a-terpineol formation from geraniol occurs via linalo01.~'~Citral cyclization in aqueous citric acid gives essentially identical results to those reported earlier (Vol. 8, p. 28).390 The predominant product of polyphosphoric acid cyclization of dehydrolinalool (cf. Vol. 1, p. 9) is dependent upon the amount of acid and upon the reaction temperature.391 The regioselective oxidation of 3,7-dimethyloctyl acetate, adsorbed on silica gel, with gaseous ozone at -78 "C as a function of substrate loading has been reported in full (without reference to the author's earlier communication; see Vol. 8, p. 29).392Cyclic hydroboration of myrcene with B2H6 followed by cyanidation (cf. Vol. 7, pp. 17, 18) yields (68) and (69) whereas reaction with thexylborane results predominantly in cyclic hydroboration [which leads to (68)] with some expected acyclic h y d r ~ b o r a t i o nFurther . ~ ~ ~ work with T-ally1 complexes (see also ref. 229) of myrcene (cf.Vol. 1, pp. 11, 12; Vol. 2, p. 10; Vol. 3, p. 13) includes alkylation with active methylene compounds (for related pinene alkylation see Vol. 6 , p. 45); C-1, C-2, (2-3' selectivity depends upon the metal (Pd or Ni), the phosphine ligand, and the alkylating agent (cf. Vol. 8, p. 29).394The effective 1,2-anti-Markovnikoff addition of sulphinic acids to the terminal double bond of myrcene has been accomplished using PdC1,-sulphinate salts followed by removal of the palladium from the v-allyl-palladium complex with dimethylglyoxime; surprisingly the terminal less-substituted alkene is formed selectively in contrast to the formation of (70) following prior extrusion of sulphur dioxide.395

(68)

(69)

(70)

Tsuji has observed that geranyl, neryl, and linalyl acetates undergo elimination to yield similar ratios of myrcene, cis -ocimene, and trans -0cimene using Pd(OAc)2Ph3P.396 The bisulphite adducts of citral have been characterized; interestingly, the 1: 2 citral: bisulphite adduct is (71), analogous to the structure of the piperitone 389 390

391 392

393 394

39s 396

R. L. Baxter, W. A . Laurie, and D. McHale, Tetrahedron, 1978, 34, 2195. D. McHale, W. A . Laurie, and R. L. Baxter, Rivista Ital. Essenze-Profumi, Piante Offic.,Aromi, Saponi, Cosmet., Aerosol., 1978, 60, 139 (VIIth International Congress of Essential Oils, Kyoto, October 7-11, 1977, Abstract No. 66). S.p.A. Anic, Belg. P. 852 918 (Chem. Abs., 1978,88, 152 426). A . L. J. Beckwith, C. L. Bodkin, and T. Duong, Austral. J. Chem., 1977, 30,2177. R. Murphy and R. H . Prager, J. Organometallic Chem., 1978,156, 133. R. Baker and R. J. Popplestone, Tetrahedron Letters, 1978, 3575; for related work see ref. 229. Y. Tamaru, M. Kagotani, and Z.-I. Yoshida, J.C.S. Chem. Comm., 1978,367; the formula for (70) is incorrect in the paper. J. Tsuji, personal communication. Some details of this work have been published; see ref. 244.

39

Monoterpenoids

sodium bisulphite addition compound reported earlier (Vol. 7, p. 34); reaction at the carbonyl group of (71) yields the 1 : 3 a d d u ~ t . ~ ~ ~ Other papers of interest in this section report addition of arylsulphenyl the mild regioselective conchlorides to ci~-2,6-dimethylocta-2,6-diene,~~~ version of the epoxide (72) into (73) using [Fez(C0)9],398 allylboration of ~ i t r a 1 , ~ ~ ~

(71)

(72)

(73)

conversion of myrcene into g e r a n y l a ~ e t o n e , cyclophane-monoterpenoid ~~~'~~~ inclusion C O ~ ~ O U ~ dimerization ~S,~'' of 2,6-dimethylocta-1,3,6-trieneusing nickel complexes,4o1 selective catalytic hydrogenations of ~ i t r a l , ~dehydro'~ linalo01,~'~ and gerani01,~'~and syntheses of 7-hydroxycitronellal.40s Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-Oxidosantolina triene (74) has been isolated from Arternisiu tridentutu together with (75), the diastereoisomer of a previously reported ester (Vol. 6 , p. 20; see Vol. 7, p. 21

397 398 399 400

401

402

403

404

405

G. M. Buchan and G. G. Cameron, J.C.S. Perkin I, 1978,783. K. Hayakawa and H. Schmid, Helv. Chim. Acta, 1977,60,1942. K. Takabe, G. H. Tang, H. Omura, T. Katagiri, and J. Tanaka, Chem. and Ind., 1977,768. Y. Ichikawa, M. Yamamoto, H. Tsuruta, K. Kato, T. Yamaji, E. Yoshisato, and T. Hiramatsu, Ger. Offen. 2 726 056 (Chem. Abs., 1978,88, 121 459). U. M. Dzhemilev, R. N. Fakhretdinov, and G. A. Tolstikov, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1977, 26,840. D. V. Sokol'skii, A. M. Pak, and M. A. Ginzburg, Doklady Akad. Nauk S.S.S.R., 1978,239,897; Vestnik Akad. Nauk Kaz. S.S.R., 1978, (4), 48; D. V. Sokol'skii, A. M. Pak, L. D. Rozmanova, and L. A. Sokolova, J. A p p l . Chem. (U.S.S.R.),1976, 49, 408; D. V. Sokol'skii, A. M. Pak, S. R. Konuspaev, M. A. Ginzburg, and L. D. Rozmanova, Trudy Inst. Org. Katal. Elektrokhim., Akad. Nauk Kaz. S.S.R., 1977, 14, 3 (Chem. Abs., 1978, 88, 89857); Y. Ichikawa, T. Yamaji, and T. Sawaki, Jap. P. 46 008/1977 (Chem. A h . , 1977,87, 136 052); P. S. Gradeff, Fr. P. 2 314 911 (Chem. Abs., 1977,87,136 055); R. S. De Simone and P. S. Gradeff, U.S. P. 4 029 709 (Chem. Abs., 1977,87, 184 727). D. V. Sokol'skii, A. M. Pak, 0.I. Kartonozhkina, I. N. Bratus, and A. A. Bakhtinov, J. A p p l . Chem. (U.S.S.R.),1977,50, 1769; D. V. Sokol'skii, A. M. Pak, and 0. I. Kartonozhkina, Zhur. org. Khim., 1978,14, 953. G. Takagi and S. Teratani, Jap. P. 91811/1977 (Chem. Abs., 1978, 88, 7119); Y. Ninagawa, Y. Ohmura, F. Nakahara, T. Nakamoto, and T. Kawaguchi, Jap. P. 131 506/1977 (Chern. Abs., 1978,88, 89 887). Y. Ichikawa and T. Yamaji, Jap. P. 25 70411977 (Chem. Abs., 1977, 87, 136 047), Jap. P. 25 708/1977 (Chem. Abs., 1977,87,136 046); Y. Ogino, Y. Saito, and K. Ito, Jap. P. 48 610/1977 (Chern. Abs., 1977,87, 136 053); E. N. Kiseleva, N. I. Chernousova, T. I. Filatova, K. I. Bogacheva, B. I. Lavrinenko, Z. I. Agarysheva, R. F. Shilina, and N. A. Smirnova, U.S.S.R. P. 571 472 (Chem. Abs., 1978, 88, 23 200).

40

Terpenoids and Steroids

for .a synthesis). Another source of Artemisia tridentata yielded, in addition to (74), the (3s)-diastereoisomer of (74) which may be converted into artemiseole (=arthole, Vol. 7, p. 20).406The isolation of (74) and (75) adds biosynthetic interest to the suggested generation of santolinyl monoterpenoids from chrysanthemyl alcohol (Vol. 7, p. 185) in that both (1R,3R)- and (1R73S)-chrysanthemo1 are now implicated. An application of 3,3-dimethylallyl(dipropyl)borane addition to aldehydes233 is the synthesis of the dihydroartemisia alcohol (76; X = H , Y = O H ) . The corresponding ketone (76; X,Y = 0)has been synthesized by three routes: (i) by [2,3] sigmatropic rearrangement of the lithio-cyanhydrin ether (77) and in situ loss of lithium cyanide (cf.Vol. 8, p. 59);407(ii) by Claisen rearrangement of (78), which is formed by dehydration of the corresponding ally1 N-acylamino-acid ester, hydrolysis, and oxidative cleavage;4o8and (iii) by the addition of prenylmagnesium bromide, with allylic transposition, to methyl dithioisovalerate, followed by methylation and hydrolysis.365This last method has also been applied to syntheses of artemisia ketone (79; X,Y = 0) and its non-conjugated isomer, isoartemisia ketone, starting with the corresponding unsaturated d i t h i o e ~ t e r s , ~ ~ ~ ~ syntheses of which have been competitive double allylic addition favoured the synthesis of (79; X,Y = 0) via base-catalysed isomerization of isoartemisia ketone.409a

(79)

(77)

The 3H-pyrazoles (80) can be regarded as isoprenoid thiovinylcarbene precursors; photochemical decomposition of (80) in ethyl prenyl sulphide yields (79; X = Y = SR), presumably via [2,3] sigmatropic rearrangement of (81), together with a minor [1,4] sigmatropic rearrangement product; with (80; R = p-tolyl) the SR

SR I

reaction is almost quantitative and [2,3] sigmatropic rearrangement is favoured 8: 1 over [1,4] sigmatropic rearrangement, resulting in a 65% isolated yield of 406

407 408 409

T. A. Noble and W. W. Epstein, Tetrahedron Letters, 1977,3933; formulae (1) and (3) of this paper lack a rnethylene group. This paper may be read usefully with that reporting the structure of artemiseole (227); see ref. 690. B. Cazes and S. Julia, Bull. SOC.chim. France, 1977,925. R . Lohmar and W. Steglich, Angew. Chem., 1978, 9 0 , 4 9 3 . P. Gosselin, S. Masson, and A. Thuillier, Tetrahedron Letters, ( a ) 1978, 2717; ( b ) 1978, 2715.

Monoterpenoids

41

artemisia ketone (79; X,Y = O).410Another synthesis of (79; X,Y = 0)involves straightforward manipulation of ethyl a~etoacetate.~" The utility of lithiated senecioamides as monoterpenoid synthons is illustrated by deconjugative a -prenylation (see Vol. 7, p. 14 for related work) and two-step reduction to lavandulol (82),235Another synthesis of the lavandulyl carbon skeleton has been reported earlier.335

v.-

HO

An undergraduate experiment on chrysanthemic acid synthesis has been p~blished.~ Oxidative '~ coupling of methyl acetoacetate with 2,5-dimethylhexa2,4-diene using manganese(II1)acetate yields-(83),photochemicalrearrangement of which leads to methyl cis- and trans-chrysanthemates after base treatment.413 Further reports on optimizing syntheses of chrysanthemic acid and some analogues have come from Krief's Isopropylidenetriphenylphosphorane addition to either diethyl fumarate or diethyl maleate yields trans-(84; R = Et, X = C02Et) with 100% stereoselectivity; partial hydrolysis, reduction, and oxidation yields the known and synthetically useful trans-(84; R = Et, X = CHO) (Vol. 8, pp. 33,34). Entry into the cis series [viz. cis-(84; R = Et, X = CHO)] was achieved by conversion of the trans-diester (84; R = Et, X = C02Et)into the cis-monoester (84; R = Me, X = C02H)via the

corresponding cis -anhydride.414The successful addition of phosphoranes to methyl trans-4-oxobutenoate (Vol. 8, p. 33) has now been shown to proceed via initial addition to the carbonyl group to yield a betaine which is essential to cyclopropane formation by further addition to the conjugate double bond; access to chrysanthemicester analogues is thus easy in a two-step one-pot A useful and industrially less dangerous alternative to the synthesis of chrysanthemic acid by diazoacetate addition to 2,5-dimethylhexa-2,4-dieneconsists of malonate addition to the corresponding monoepoxide to yield, after hydrolysis, 410 411

412 413 414

'15

M. Franck-Neumann and J. J . Lohmann, Tetrahedron Letters, 1978,3729. 0 .P. Vig, A. S. Sethi, M. L. Sharma, and S. D. Sharma, Indian J. Chem., 1977,15B, 951. P. F. Schatz, J. Chem. Educ., 1978, 55,468. K. Ohkata, T. Isako, and T. Hanafusa, Chem. and Ind., 1978, 274. M. J. Devos, J. N. Denis, and A. Krief, Tetrahedron Letters, 1978, 1847. M. J. Devos and A. Krief, 2nd I.U.P.A.C. International Symposium on Organic Synthesis, Jerusalem-Haifa, Israel, September 1978, Abstracts, p. 25; A. Krief, personal communication.

42

Terpenoids and Steroids

pyrocine (85),416another synthesis of which is a minor modification of an earlier synthesis (Vol. 8, p. 34), viz. Michael addition of 2-methylprop-1-enylmagnesium bromide to the butenolide (86).417SnC1,-catalysed allyloxymethyl chloride addition to methyl 4-methylpent-3-enoate, followed by ether cleavage and basecatalysed cyclization, yields the cis -chrysanthemate precursor (87);alternatively, addition of 2-bromoethyloxymethy1 chloride and base cyclization yields truns(84; R = Me, X = CH20CH2CH2Br)which on treatment with Zn-MeOH yields trans-(84; R = Me, X = CH20H).418 Further papers of interest in this section concern the decomposition of alkyl diazoacetates in 2,5-dimethylhexa-2,4-dienein the presence of chiral copper complexes (cf.Vol. 8, p. 33),419a revision of the 2-pyrazoline structures [viz. to (SS)] described in an early chrysanthemumdicarboxylic acid and

(85)

(86)

(87)

(88)

syntheses of me thy1 arylmet h yl 2,2 -dimethyl-3 - (2'-methylprop-1'-en y1)cyclop r o p y l p h o s p h o n a t e ~and ~ ~ ~the C9 compound salvan (2-isopropylhexa- 1,4Ediene).422

6 Naturally Occurring Halogenated Monoterpenoids Last year's Report (Vol. 8, p. 31) erroneously implies that the X-ray structure of costatolide has been determined. The past year has seen further advances in the isolation and characterization of new compounds, with most progress being in the area of cyclic halogenated monoterpenoids. The only new acyclic example is (89) from Aplysia l i r n a c i n ~ . ~ ~ ~

TC1 Br ,CH

416

417 418 419

420 421 422

423

'

M. J. Devos and A. Krief, Tetrahedron Letters, 1978, 1845. For similar work, see P. D. Klemmensen and H. Kolind-Andersen, Ger. Offen. 2 732 456 [Chem. A h . , 1978, 88, 136 190; formula (111)of this abstract lacks gem-dialkyl suhstituents]. S. Torii, H. Tanaka, and Y. Nagai, Bull. Chem. SOC.Japan, 1977,50, 2825. C. F. Garbers, M. S. Beukes, C. Ehlers, and M. J. McKenzie, Tetrahedron Letters, 1978, 77. ( a )T. Nagase, S. Nakamura, T. Aratani, and Y. Yoneyoshi, Jap. P. 25 755/1977 (Chem. A h . , 1977, 87, 136 048); (6) T. Aratani, Shokubai, 1977, 19, 327. H.-D. Scharf and J. Mattay, Chem. Ber., 1978, 111, 2206. J. J. Reid and R. S. Marmor, J. Org. Chem., 1978,43,999. S. D. Sharma and R. C. Aggarwal, Indian J. Chem., 1977,15B, 950. F. Imperato, L. Minale, and R. Riccio, Experientia, 1977, 33, 1273.

Monoterpenoids

43

Faulkner has now published full details of five new compounds reported last year from Plocamium cartilagineum ;the only modification is that one of them [Vol. 8, p. 31, formula (SS)] is now reported as (90)424in keeping with the reassigned structure of violacene (2).25An interesting, but not fully characterized, new minor component (91; X,X,X, = C1, C1, Br) adds novelty with an axial C-5 methyl

(91)

(90)

group.424A second report of new compounds from P. cartilagineum confirms2' the absolute configuration (1; X = Br) of a compound isolated previously by Faulkner [Vol. 8, p. 31, formula (89)l"""and reports one of only two known naturally occurring examples of a dimethylethylcyclohexane monoterpenoid with a bromovinyl side-chain (4).27The other is ochtodene (92; X = C1, Y = Br) which has been isolated from Ochtodes secundiramea together with ochtodiol (93) and chondrocole A (94),425awhose structure has now been reassigned (cf. Vol. 6, p. 47) as a result of the X-ray structure determination of chondrocolactone (3)from Chondrococcus hornemanni.26 The significance of a second report of new compounds from Ochtodes species cannot be assessed properly at present; 0. secundirumea is reported to yield (92; X = Br, Y = C1) and 0. crockeri to yield (95).4256Crews has published structural details of a number of compounds

(92)

(93)

(94)

(95)

isolated from Plocamium cartilagineum and P. violaceum (cf.Vol. 8, p. 31). The absolute stereochemistry of plocamene B is now established as (96) [and not as Vol. 6, p. 33, formula (1 5 l)];plocamene C is identical with violacene 2 (1 ;X = C1) [and not as Vol. 7, p. 20, formula (74) or Vol. 8, p. 31, formula (86)]; in view of the X-ray structure of violacene (2),25plocamene D must be the mirror image of that reported previously [Vol. 8, p. 31, formula (87)], viz. (97; X=Cl). Two new compounds are plocamene D' (97; X = Br) and plocamene E (98) which may be obtained from plocamene C (1; X = C1) by HBr elimination and isomerized into plocamene B (96).426Further new compounds are reported to be (99) from Australian P. curtilagil~eurn~~~ and mertensene (100)from P. mertensii, although Crews has expressed over the stereochemical assignment of the two 424 425

426

M. D. Higgs, D. J. Vanderah, and D. J. Faulkner, Tetrahedron, 1977, 33, 2775. 0. J. McConnell and W. Fenical, ( a ) J. Org. Chem., 1978, 43, 4238; (b) 175th A.C.S. Meeting, Annaheim, California, March 1978, Abstracts AGFD, No. 26. It is possible that (92; X = Br, Y = C1) is a misprint of (92; X = C1, Y = Br). P. Crews, E. Kho-Wiseman, and P. Montana, J. Org. Chem., 1978, 43, 116.

44

Terpenoids and Steroids

gem-substituted centres in (100) which is especially interesting in view of the similarity between the spectroscopic data presented for and the limited

(99)

c1

spectroscopic data presented for (91 ; X,X,X = C1, C1, Br);424 a third new compound (1; X = Br)427has already been reported (Vol. 8, p. 31).424,27A component (101) from Desmia (Chondrococcus) hornemanni which was omitted from earlier has now been synthesized together with (102) and perillyl bromide (103; R = CH,Br) by brominative cyclization of myrcene using 2,4,4,6-tetrabromocyclohexa-2,5 -dien- 1-one.428b

Further work (cf. Vol. 8, p. 30) has indicated the considerable geographic variation in the halogenated monoterpenoid content of P, c a r t i l u g i n e ~ m . ~ ~ ~ * ~ ~ Both plocamene B (96)and violacene (2) exhibit growth inhibition against mosquito and antibacterial activity against Staphylococcus aureus has been reported for ochtodene (92; X = C1, Y = Br).425u N.m.r. spectroscopy has been used extensively in the structural elucidation of halogenated monoterpenoids (e.g. refs. 424,426,427); two further papers which report useful data concern 13Cn.m.r. y-effects115and the differentiation of some brominated carbons from chlorinated carbons due to shortened 13C n.rn.r. spin-relaxation times and reduced values of nuclear Overhauser e n h a n ~ e m e n t . ~ ~ ’ 427

R. S . Norton, R. G . Warren, and R. J . Wells, Tetrahedron Letters, 1977, 3905.

429

(a) N. Ichikawa, Y. Naya, and S . Enomoto, 18th Symposium of Terpenes, Essential Oils, and Aromatic Chemistry, 1974, Abstracts, p. 67; (6) K. Yoshihara and Y. Hirose, Bull. Chem. SOC. Japan, 1978, 51, 6 5 3 . The formula for myrcene is misprinted in the latter. J. S . Mynderse and D. J. Faulkner, Phytochemistry, 1978, 17, 237.

43n

R. S . Norton, Tetrahedron, 1977, 33, 2577.

428

Monoterpenoids

45

7 Monocyclic Monoterpeaoids

Cyc1obutane.-A tricyclic acetal named lineatin has been isolated from the frass of the Douglas fir beetle Trypodendron lineatum ; structural elucidation and synthesis have not distinguished between (104) and (105).431

Mori has synthesized the natural (lR,2S)-(+)-grandisol (106) and its enantiomer in an improved synthesis reminiscent of that reported by Cargill and Wright (Vol. 6, p. 21) and based upon photochemical cycloaddition of ethylene to 3-ethoxycarbonylcyclopent-2-enone;optical purity measurements on the intermediate alcohols [e.g. (107)], using the n.m.r. shift reagent [Eu(facam)J, established an 80% optical purity for synthetic (106) with an optical rotation in agreement with that reported by Magnus (Vol. 7, p. 22).432The full paper on the Wenkert synthesis of racemic-(106) (Vol. 7, p. 22) has been Fragranol and grandisol derivatives [e.g. (108; 43%)] have been formed predominantly (72%) by treating 6,7-epoxygeranyl t-butyl sulphide with BuLi-1,2bis(dimethylamino)ethane,although the t-butylthio-group in (108) has prevented elaboration into f r a g r a n 0 1 . ~ ~ ~ SBu'

Cyclopentanes, 1ridoids.-The taxonomic significance of iridoids in Tubiflorue and the occurrence of secoiridoids in the G e n t i a n a ~ e a ehave ~ ~ ~been reviewed. Some papers of related synthetic interest have been discussed earlier -254.380-385 The dial (3R,8S)- (109), named dehydroiridodial, has been isolated from Actinidia polygama and synthesized from (-)-limonene via (4S,8S) -p- menth- 1en-9-01 of knowns1 absolute c ~ n f i g u r a t i o nthe ; ~ ~diastereoisomeric ~ chrysomelidial [(3S,8S)-(109)] (Vol. 8, p. 35) has been synthesized similarly from 431

432

433 434 435 436

437

J. G. MacConnell, J. H. Borden, R. M. Silverstein, and E. Stokkink, J. Chern. Ecol., 1977, 3, 549. K. Mori, Tetrahedron, 1978, 34, 915. E. Wenkert, D. A. Berges, and N. F. Golob, J. Arner. Chern. SOC.,1978,100, 1263. V. Rautenstrauch, J.C.S. Chern. Cornm., 1978, 519. R. Hegnauer and P. Kooiman, Plantu Med., 1978, 33, 1. W. G. van der Sluis and R. P. Labadie, Pharrn. Weekblad, 1978,113,21. K. Yoshihara, T. Sakai, and T. Sakan, Chern. Letters, 1978, 433.

46

Terpenoids and Steroids

( + ) - l i m ~ n e n and e ~ ~is~ now reported by Blum et al. as a single component from Gastrophysa ~ y a n e a . ~ ~ ~ From related synthetic work in which epiplagiolactone was synthesized from (4K,8R)-p-menth- 1-en-9-01, the ( S , S )- absolute configuration reported previously [Vol. 8, p. 35, formula (120)] for the C-4 epimeric plagiolactone from Plagiodera versicoloru confirms the close relationship to the co-occurring chrysomelidial [ ( 3 S , 8 S ) - (109)]438from which it was a minor product of autoxidatat i ~ nInterestingly . ~ ~ ~ no lactones were observed corresponding to those suggested439as minor products from Gastrophysa cyanea, uiz. (110) and the known (111) (Vol. 3, p. 26; Vol. 8, p. 35, ref. 324). Another oxygenated cyclopentane (112) from Turkish tobacco (cf. Vol. 6 , p. 27) is probably a nor-is~prenoid.~~'

(109)

(110)

(111)

(112)

Another report of the isolation441of the dolichodials and dolicholactone from Teucriurn rnarurn and their has appeared. The structure of nitropolyzonamine (10) has been revised (Vol. 6 , p. 13).38 Related synthetic work concerns the preparation of 2-isopropyl-5-methylc y ~ l o p e n t a n o n esyntheses ,~~~ of a number of chiral cyclopentanoid aldehydes and ketones and (113) (cf. Vol. 8, p, 38),443and a number of unsuccessful attempts to synthesize genipic

9 (113)

Popov has summarized the J1.9 coupling constants for a number of iridoids and examined the relationship of their values to the position and stereochemistry of substituents in the cyclopentane ring.445The correlation of absolute configuration 438 439

440 44 1

442 443

444 445

J. Meinwald and T. H. Jones, J. Amer. Chem. SOC.,1978,100, 1883. M. S. Blum, J. B. Wallace, R. M. Duffield, J. M. Brand, H. M. Fales, and E. A. Sokoloski, J. Chem. Ecol., 1978, 4 , 4 7 . T. Chuman, H. Kaneko, and M. Noguchi, Agric. and Biol. Chem. (Japan), 1978,42, 203. ( a ) C. Beaupin, J.-C. Rossi, J. Passet, R. Granger, and L. Peyron, Rivista Ztal. Essenze-Profumi, Aromi, Saponi, Cosmet., Aerosol., 1978, 60, 93; ( 6 ) C. Beaupin, R. Granger, J.-C. Piante Ofic., Rossi, J. Passet, and L. Peyron, ibid., 1977,59,369;the Chemical Abstract (Chem. Abs., 1978,88, 11 723) incorrectly reports this as the first isolation of these compounds from the plant kingdom. See Vol. 7, p. 23. B. S. Kulkarni and A. S. Rao, Org. Prep. Proced. Internat., 1978, 10,73. G . L. Lange, E. E. Neidert, W. J. Orrom, and D. J. Wallace, Canad. J. Chem., 1978,56, 1628. For related work, see M. Pesaro and J.-P. Bachmann, J.C.S. Chem. Comm., 1978,203; J. Kulesza and M. Sikora, Rivista Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet.,Aerosol., 1978,60, 141 (VIIth International Congress of Essential Oils, Kyoto, October 7-1 1,1977, Abstract No. 74). J. K. Whitesell and R. S. Matthews, J. Org. Chem., 1978, 43, 1650. S. S. Popov, Izuest. Khim. (Bulgaria),1976,9,459;the paper suggests that the structure of unedoside may be incorrect without reference to Rimpler's reassignment (Vol. 7, p. 24).

47

Monoterpenoids

of the valepotriates and c.d. data has been H.p.1.c. data on the v a l e p o t r i a t e ~and ~ ~ ~on iridoids from Gentiana species448have been reported. The isolation of ulmoside (114) from Eucommia ulmoides is of interest because of its p-isomaltose residue.449

A-@ HOCH

H

0-p-isomaltose

The isolation of three naturally occurring fulvoiridoids (Vol. 8, p. 38), uiz. cerbinal(l15; R' = C02Me, R2= CHO), cerberic acid (115; R' = C02Me, R2 = C02H),and cerberinic acid (115;R' = C02H,R2= CHO), from Cerbera manghas may reflect mild hydrolysis in viuo of co-occurring C16irid~ids.~"Other new Clo iridoid derivatives are pulchellosides 1451aand 114516 [(116) and its C-8 epimer respectively] from Verbena pulchella, the xylose-containing montinioside (117) from Montinia c a r y o p h y l l a ~ e aand , ~ ~four ~ isomeric pairs of novel allose-containing iridoid glycoside esters - named opulus iridoids I-IV [ 118; R1= H or Ac; R2= Ac (C-2', C-3' only), H (C-4' and/or C-6'), P-D-xylopyranosyl (C-4')] - frdm Viburnum 0 p u 1 u s . ~New ~ ~ valepotriates include acetoxyhydroxydidrovaltrate (119; R = Ac) and the previously unreported isovaleroxyhydroxydidrovaltrate (119; R = COCH2CHMe2)from Centranthus R'

m0 --

R2

HO' R'OCH,

446 447

448 449 4s0 451

452 453

0

OGlu

or

A . Konowal, G . Snatzke, and P. W. Thies, Tetrahedron, 1978,34, 253. G. Tittel and H. Wagner, J. Chromatog., 1978,148,459. 0.Sticher and B. Meier, Pharm. Acta Helv., 1978, 53,40. A . Bianco, C. Bonini, M. Guiso, C. Iavarone, and C. Trogolo, Gazzetta, 1978,108, 17. F. Abe, H. Okabe, and T. Yamauchi, Chem. and Pharm. Bull. (Japan), 1977,25, 3422. S. Milz and H. Rimpler, Tetrahedron Letters, ( a ) 1978, 895; ( b ) 1978, 3549. R. Dahlgren, S. R. Jensen, and B. J. Nielsen, Botan. Notiser, 1977, 130, 329. K. Bock, S. R. Jensen, B. J. Nielsen, and V. Norn, Phytochemistry, 1978, 17, 753.

48

Terpenoids and Steroids

ruber where they co-occur with the known (Vol. 7, p. 25) valtrate, didrovaltrate, and a c e ~ a l t r a t ewhose ~ ~ ~ structures, together with (119; R = COBu'), are depicted incorrectly in a second paper and in the corresponding Chemical 1 0-Deacetylasperulosidic acid and asperulosidic acid have been isolated as natural products from Rubia tinctorum and R . ~ e r e g r i n a ~(for ~ ~their " isolation as artefacts see ref. 456b), and monotropein methyl ester (8; R = Me) from Galium mo/l~go.~~~" Tietze et al. have described efforts to convert 7 - 0 - acetyl-loganin aglycone into loganin and the corresponding a- glucoside by standard glucosylation proced u r e ~ . ~ ~ ~ Acid-catalysed rearrangement of (120), a synthetic reduction product of lamiide, to (121) has been CHO

The secoiridoid (*)-gentiolactone (9) has been isolated from Gentiana p ~ r p u r e aand ~ ~the full paper on naucledal (Vol. 7, p. 26) includes data on its C-4 epimer (according to the iridoid numbering system used in these Reports; the authors have named this compound 3-epinaucledal) which accompanies naucledal on rearranging sweroside aglucone (122; R = H) in aqueous ~ y r i d i n e . ~ ' ~ (*)-Sweroside aglucone 0-methyl ether (122; R = Me) and secologanin 0methyl ether (123; R = Me) have been synthesized efficiently by Partridge et al. as an extension of their earlier work (Vol. 4, pp. 25,26) based upon the photoadduct of methyl diformylacetate and cyclohexa-1,4-diene (Scheme 2).460Secologanin (123; R = p-Glu) has been converted into the useful Cinchona alkaloid synthons dihydrorneroq~inene~~'" and r n e r ~ q u i n e n e ~via ~ ~ 'sodium cyanoborohydride reductive amination. In further bicyclo[3,3,0]octane synthetic work directed towards iridoids, the essential features of which have been reported previously (Vol. 8, p. 36; for related work, see also Vol. 8, pp. 37,38), Whitesell et al. have synthesized sarracenin (124), via Baeyer-Villiger oxidation of (125) followed by 4s4

45s 4s6

457

458 4sq 46"

461

N. Handjieva, S. Popov, and N. Marekov, Phytochemistry, 1978,17,561. For earlier reportsof (119; R = C O C H ~ C H M ~ Zsee ) , J. L. Laufer, B. Seckel, and J. Zwving, Pharm. Weekblad, 1970,105,609, and T. Adret, I. Iglesias, R. San Martin, and M. Torrent, Planta Med., 1975,27, 194. B. Eierrnann and P. T. A. Seym, Deut. Apoth.-Z., 1977,117,1204 (Chem.Abs., 1977,87,157 067). ( a ) A . Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Gazzetta, 1978, 108, 13; (6) H. Inouye, M. Okigawa, and N. Shirnokawa, Chem. and Pharm. Bull. (Japan), 1969,17,1949. ( a ) L.-F. Tietze, U . Niemeyer, and P. Marx, Tetrahedron Letters, 1977, 3441; (6) L.-F. Tietze and U. Niemeyer, Chem. Ber., 1978, 111, 2423; ( c ) L.-F. Tietze and P. Marx, ibid., 1978, 111, 2441 [formula (10) of this paper lacks a C-7 acetyl group]. A. Bianco, C. C. Bonini, M. Guiso, C. Iavarone, and C. Trogolo, Tetrahedron Letters, 1978,4829. J. Purdy and S. McLean, Canad. J. Chem., 1977,55,4233. C. R. Hutchinson, K. C. Mattes, M. Nakane, J. J. Partridge, and M. R. Uskokovic, Helv. Chim. Acta, 1978,61, 1221. R. T. Brown and J. Leonard, ( a ) Tetrahedron Letters, 1978, 1605; ( b )J.C.S. Chem. Comm., 1978, 725.

49

Monoterpenoids

ae. 4

OH

~e

HO

OMe

O H C G M e

OMe i v i , vii

viii-x

I;:g OR

OR (123)

(122)

Reagents: i, MeOH-H+; ii, OsO,; iii, HIO4, pH 5; iv, NaBH4-PriOH-H20, 0 OC; v, separation; vi, o-nitrophenylselenocyanate-PPh3-py; vii, H202; viii, OH--H,O-Pr'OH; ix, CH2N2; X,DCC-DMSO-PY-CF~CO~H

Scheme 2

o&2Me:

H

O*0 I

OH

H

(124)

(125)

(125a)

reduction and reductive ozonolysis, in a scheme readily adaptable to the synthesis of chiral and radiochemically labelled The C9 monoterpenoid alkaloid jasminidine (126) has been isolated from Syringa v ~ l g a r i s(+)-Acthidine .~~~ (127) is obtained by hydroxylamine treatment

(126) 462

463

(127)

(a) J. K. Whitesell, R. S. Matthews, and A. M. Helbling, J. Org. Chem., 1978, 43, 784; (b) J. K. Whitesell, R. S. Matthews, P. K. S. Wang, and A. M. Helbling, 175th A.C.S. Meeting, Annaheim, California, March 1978, Abstracts ORGN, No. 176. Details of an enantio-divergent route to the related xylornollin (125a)in the latter cannot be assessed at this time; formula (4)of this abstract is in error and the formula given for (-)-xylomollin [uiz.(125a)lrepresents a structural revision ( c f .Vol. 8, p. 39) subsequently confirmed by Hutchinson et ul.34a H. Ripperger, Phytochemistry, 1978,17, 1069.

Terpenoids and Steroids

50

of (128), the product of treating the acid chloride (129) with base, presumably via [ 1,5] sigmatropic hydrogen migration in the intermediate keten.464

(128)

(129)

p-Menthanes.-Reviews of CY - ~ h e l l a n d r e n e , ~/3 ~- ~ ’ h e l l a n d r e n eand , ~ ~carvone ~ (18) have been published. The trio1 (130) has been isolated from the micro-organism Fusicoccum amy g d ~ l ithe , ~acid ~ ~(131)from Cedrus deodara is probably a n o r - s e ~ q u i t e r p e n o i d , ~ ~ ~ the thymoquinol ether (132) is reported to occur in Blumea m e m b r a r ~ c e aand ,~~~

Bohlmann et al. have isolated many new thymol derivatives from a number of different species.471Doubts over the presence of a y-terpinene monoepoxide reported earlier (Vol. 5, p. 22) in Origanum heraczeoticum, and of its synthesis from y-terpinene by peracid epoxidation, have been ~ o n f i r m e d . ~ ’ ~ Further 13C n.m.r. data have been published on isomeric menthyl (cf.Vol. 7, pp. 5, 29) and carvomenthyl alcohols and some derivatives.473‘H N.m.r. data include [Eu(dpm),] methyl shift assignments in the menthols, the menthones, two carvomenthols, the isopulegols, the carveols, carvone, carvotanacetol, and carvotanacetone, together with the relevant and an analysis of 464

4h5 466

467 468 46q

470

471

472

473 474

J. D. Wuest, A. M. Madonik, and D. C. Gordon, J. Org. Chem., 1977,42,2111; this synthesis was inadvertently omitted from last year’s Report. B. Singaram and J. Verghese, Perfumer and Flavorist, 1978,2(7), 33. J. Verghese, Indian Perfumer, 1976, 18, 47 (Chem. Abs., 1977, 87, 201 776 incorrectly refers to 1975). B. Singaram and J. Verghese, Perfumer and Flavorist, 1977,2(3),47. C. G. Casinovi, G. Grandolini, L. Radics, and C. Rossi, Experientia, 1978, 34, 298. S. Krishnappa and S. Dev, Tetrahedron, 1978, 34, 594. K. P. Bokadia, S. K. Joshi, andM. M. Bokadia, Acta Cienc. Indica, 1976,2,239 (Chem. Abs., 1977, 87, 141 107). ( a ) F. Bohlmann and N. L. Van, Phytochernistry, 1977,16, 1765; (6)F. Bohlmann and C. Zdero, ibid., pp. 1773, 1854, ( c )F. Bohlmann, P. K. Mahanta, A. Suwita, A. Suwita, A. A. Natu, C. Zdero, W. Dorner, D. Ehlers, and M. Grenz, ibid., p. 1973; ( d )F. Bohlmann, P. K. Mahanta, J. Jakupovic, R. C. Rastogi, and A. A. Natu, ibid., 1978, 17, 1165. W. Rojahn and E. Klein, Dragoco Report (Ger. Edn.), 1977, 24, 172. J. Firl, G. Kresze, T. Bosch, and V. Arndt, Annalen, 1978, 87. T. Iida, S. Ibaraki, and M. Kikuchi, Agric. and Biol. Chem. (Japan), 1977,41,2471; see also Vol. 5, p. 3.

51

Monoterpenoids

p-menth-4-en-3-one and its carbonyl derivatives.475Using deuterium-labelled compounds, an unusual 1,2-elimination of water has been shown to be preceded by ring cleavage to the extent of 30% in the molecular ion of the (+)-dihydrocarveol (133; X = OH) but not apparently in that of its C-2 epimer or the corresponding c a r v o m e n t h o l ~ in ;~~ the ~ absence of physical data on the dihydrocarveols and the corresponding [ 1, 3 , 3 - 2 H 3 ] - ~ ~ m p ~however, ~ n d ~ , these results must be interpreted with caution since (+)-dihydrocarveol is depicted as (-)-neodihydrocarveo1(133; X = OH, C-2 epimer) and (133; X = OH) is named

(133)

(-)-dihydrocarveol. Other m.s. data concern p-menth-4-en-3-one and its carbonyl derivatives,475 and the monoterpenoid-related di-o -thymotide and t r i - o - t h y m ~ t i d e The . ~ ~ ~absorption and c.d. spectra of a- and P-phellandrene in solution (to 160 nm) and in the gas phase (to 135 nm) have been a n a l y ~ e dThe .~~~ i.r. 0 - H stretching frequencies of isopulegol and neoisopulegol have been assigned to specific hydrogen-bonded ~ o n f o r m a t i o n s Some . ~ ~ ~ thermophysical data for (-)-menthol vapour have been Fortunately the absolute configuration of (+)-carvone [(4S)-(18)] is in agreement with that derived by indirect chemical correlation ( ! ) . 5 5 Analytical data include a colorimetric method for determining thym01,~~l quantitative determination of (*)-trans-sobrerol by g . l . ~ . and , ~ ~the ~ g.1.c. determination of limonene and 1,8-cineole in oils of peppermint .483 The conversion of (3R)-(+)-citronella1 in to (-)-isopulegol is well known (Vol. 4, p. 28), although this and related (Vol. 7, p. 30) work is not cited in an examination of Lewis acid catalysis in which ZnBrz gives optimum results [70% yield, 94% (-).-isop~legol].~~~ Another 1,2-carbonyl transposition procedure (Scheme 3) converts menthone via the tosylhydrazone (134) into carvomenthone (135) although in lower yield ( 4 8 ' / 0 ) ~ ~than ~ the epoxysilane route reported 475

476

477 478 479 480 481

482 483

484

485

B. Singaram, G. N. Saraswathi, and J. Verghese, Indian J. Chem., 1977, 15B, 526; the name p-menth-3-en-5-one is used in this paper. R. Robbiani, H. Biihrer, H. Mandli, D. KovaEeviC, A. Fraefel, and J. Seibl, Org. Mass Spectrometry, 1978,13,275; carvone (18) is incorrectly identified in this paper also. G. M. Farias and B. D. Hosangadi, Indian J. Chem., 1977,15B, 997. K. P. Gross and 0. Schnepp, J. Chem. Phys., 1978,68, 2647; for related work, see Vol. 8, p. 5 . L. Ananthasubramanian and S. C. Bhattacharyya, J.C.S. Perkin ZZ, 1977, 1821. C. Becker, H. Reiss, and R. H. Heist, J. Chem. Phys., 1978,68, 3585. M. A. Korany, N. Abdel-Salam, and M. Abdel-Salam, J. Assoc. Ofic. Analyt. Chemists, 1978, 61, 169. J. L. Fibregas, Analyst, 1977, 102, 777. A. M. Humphrey, K. Goodhead, J. H. Greaves, W. S. Matthews, D. A. Moyler, R. G. Perry, J. Ridlington, R. A. Stocks, and,G. Watson, Analyst, 1978, 103, 375. Y.Nakatani and K. Kawashima, Synthesis, 1978, 147. T. Nakai and T. Mimura, 2nd I.U.P.A.C. International Symposium on Organic Synthesis, JerusalemHaifa, Israel, September, 1978, Abstracts, p. 6; T. Nakai, personal communication. For related eliminations, see ref. 54a; Vol. 7, p. 34; Vol. 8, p. 45.

Terpenoids and Steroids

52

Reagents: i, Bu"Li (2 equiv.), THF-TMEDA (2 : l ) , -50 to -30 "C; ii, MeSSMe (1 equiv.); iii, Bu"Li (1 equiv,); iv, room temperature, 5-20 h; v, H20; vi, HgCl2 (2-3 equiv.), MeCN-HzO (3 : l ) , reflux, 5 h

Scheme 3

earlier;'" intermediate carbanions such as (136) promise to be synthetically useful. A fourth paper directed towards the synthesis of (+)-8-phenylmenthyl acrylate, which is an efficient chiral director in Diels-Alder cycloaddition reactions (Vol. 7, p. 4), follows CuI-catalysed conjugate addition of phenylmagnesium + )-pulegone [ ( l R ) - (21)] by experimental bromide to the readily accessible (R)-( improvements on a previously reported 1,3-carbonyl-transpositionscheme (Vol. 5, p. 25).486Limonene has been converted into (137) via lead tetra-acetate acetate and the corresponding oxidation to (+)-8-hydroxy-p-menth-l-en-9-y1 (+)-uroterpenol followed by treatment with P ~ ( O A C ) ~Hydrolysis .~'~ of the 1,2-adduct of the lithio-derivative of methyl methylthiomethyl sulphoxide to 4-isopropylcyclohex-2-enone yields the non-naturally occurring (1 38).488

I

(137)

CHO I

(138)

Syntheses of the [ 1,3,3-2H3]dihydrocarvones,[ 1,3,3-2H3]neodihydrocarveol, [ 1,3,3-2H,]dihydrocarveol, [ 1,3,3-2H3]carvomenthol, and [ 1,3,3-2H3]ne~carvomenthol have been Further syntheses of interest concern [2-2H,]-(1R,2R,4R)-p-menthan-l-ol, [2-*H1][l-2Hl]neocarvomenthol, (lS,2S,4R)-p-menthan-l-01, [2-2Hl]-(2R,4R)-p-menth-1(7)-ene, and [2-*H,](2S,4R)-p-menth-l (7)-ene;489 the c a r v e y l a r n i n e ~ ; ~ stereospecific ~~ transformations of (+)-dihydrocarveyl tosylate (133; X = OTs) and (+)-neodihydrocarveyl tosylate into (lS,2R,4S)-, (1S,2S,4S)-, and (lR,2R,4R)-2-aminotrans-p- menthan-8-01 via a z i d o l y ~ i s ; and ~ ~ ' an extension of previously reported 486

487

488 489

49n 491

H. E. Ensley, C. A. Parnell, and E. J. Corey, J. Org. Chem., 1978,43,1610; for related work, see Vol. 7, p. 30 and Vol. 8, p. 40. M. Nomura, Y. Fujihara, and Y. Matsubara, Nippon Kagaku Kaishi, 1978, 1182. K. Ogura, M. Yamashita, and G.-I. Tsuchihashi, Tetrahedron Letters, 1978, 1303. P. Sundararaman and C. Djerassi, TetrahedronLetters, 1978, 2457. S . W. Markowicz and B. Bochwic, Polish J. Chem., 1978,52,671. 2.Chabudzinski, Z. Rykowski, and H. Orszanska, Polish J, Chem., 1978,52,767; formulae (13) and (16) of this paper lack azide groups.

Monoterpenoids

53

(Vol. 8, p. 40) work to synthesize the benzofuranone (139) and related compounds by acid ion-exchange resin rearrangement of the corresponding a l d e h ~ d o a c e t a t eLast . ~ ~ ~year’s Report omitted mention of the routine synthesis of ( 8 R ) - ( + ) -and (8S)-(+)-[9-2Hl]-a-terpineol via epoxide reduction (Vol. 8, p. 42, ref: 371) and syntheses of some deuteriated pulegones and pulegone tosylhydra~ones.~~~

(139)

Limonene is metabolized predominantly to (+)-perillic acid (103; R = C02H) by Pseudomonas incognita, presilmably via C-7 h y d r o ~ y l a t i o nwhich , ~ ~ ~ has also been reported in the conversion of a -terpineol into 7-hydroxy-cu -terpineol in further work (see Vol. 8, p. 26) on callus cultures of Nicotiana t a b a ~ u r nand ~ ~is~ also presumed to be involved to account for the isolation of oleuropeic acid (140) CO, H I

A OH

(140)

in further (see Vol. 7, p. 9) a -terpineol metabolic studies using P. a e r u g i n o ~ aA. ~ ~ ~ more thorough investigation of the microbial conversion of (-)-menthone by a Pseudomonas putida strain indicates that the new metabolite (3R,6S)-trans-(19) may be the precursor of the ring-opened metabolites reported earlier (Vol. 8, p. 42).495Noma has reported further work on the copversion of carvone (18) by P. ovalis (cf. Vol. 5 , p. 24; Vol. 6, p. 12),496and Candida cylindrusae has been used to resolve (*)-menthol via preferred valerate ester formation from the laevorotatory isomer.497 Double-bond isomerism by reversible ene reaction using sulphur dioxide may be interrupted in the presence of D20, which decomposes the intermediate allylic 492 493

494 495

496

497

K. J. Divakar, B. D. Kulkarni, and A. S. Rao, Indian J. Chem., 1977, 15B,849. T. Suga and T. Hirata, Rivista Ital. Essenze-Profumi, Piante Offic.,Aromi, Suponi, Cosmet., Aerosol., 1978, 60, 136 (VIIth International Congress of Essential Oils, Kyoto, October 7-11, 1977, Abstract No. 50). K. Tadasa, Agric. and Biol. Chem. (Japan), 1977,41, 2095. 0. Nakajima, R. Iriye, and T. Hayashi, Nippon Nogei Kuguku Kaishi, 1978, 52, 167. Y. Noma, Nippon Nogei Kagaku Kuishi, 1977, 51, 463; Y. Noma and C. Tatsumi, Riuistu Itul. Essenze-Profumi, Piante Ofic., Aromi, Suponi, Cosmet., Aerosol., 1978,60,136 (VIIth International Congress of Essential Oils, Kyoto, October 7-11, 1977, Abstract No. 51). M. Nakayama, Y. Yamaguchi, H. Machida, S. Iwasaki, A. Komatsu, and A. Shinoda, Jap. P. 51 09511977 (Chem. Abs., 1977,87, 136 054).

54

Terpenoids and Steroids

sulphinic acid (Vol. 8, p. 9), thus preventing [1,3] rearrangement, to label allylic positions with deuterium; (+)-p-menth-1-ene may be pentadeuteriated without r a c e m i ~ a t i o nA . ~previous ~~ report (Vol. 6, p. 29) on the Diels-Alder addition of butadiene to (-)-carvone [(4R)-(18)]did not mention the favourable influence of added A1Cl3 on the reaction yield nor that in its presence the only minor product corresponds to bringing the side-chain double bond of the major adduct into conjugation with the carbonyl group; the full paper has been published.499The structure of the a -phellandrene-maleic anhydride adduct has been confirmedSoo and the retro-Diels-Alder reaction of limonene using a CO, laser has been reported again (Vol. 3, p. 31).501Other observations relating to the fate of the a-terpineyl cation in 85% phosphoric acid are that a-terpineol and p-menth-len-4-01 give rise to no limonene but yield almost identical mixtures of hydrocarbons which may be derived from (67) or rearranged carbocations derivable therefrom.388In contrast, the rearrangement of 0-menthyl methylthiocarbamate by BF,,OEt, to cis- and trans-S-p-menthan-8-yl methylthiocarbamates may result from the predominant rearrangement of dihydro-(67) to the dihydro-cuterpineyl cation.5n2Other related papers report the generation of (141) from limonene in S02FC1-FS03H and its collapse to a-terpinene, a-phellandrene, and /3-phe1landrene5O3(although this route does not appear to be followed in 85% phosphoric further carbonium ion transformations (cf.Vol. 7, p. 31) over salicylic acid (a-phellandrene, p -phellandrene, and a - t e ~ p i n e n e ) , and ~ ' ~ the acid-catalysed ethanolysis of allylic alcohols (e.g. the p-menth-2-en-1-01s and the p i p e r i t o l ~ ) .Carvomenthone ~~~ (135) and carvenone (142) undergo dehydrogenation and rearrangement in SbF,-HF to yield (143)-(146) whereas menthone yields piperitone (147); the results can be rationalized on the basis of initial dication formation with protolysis occurring at a tertiary C-H bond p to a protonated carbonyl group.5o6 Photo-oxidation of limonene in pyridine in the presence of U02(0Ac)2,2H20 proceeds by anti-Markovnikoff addition of hydroxy-radical followed by reaction with molecular oxygen to yield ( 148)?07The identical photoreactions of methanol with pulegone (21) in the presence of TiCl, and U02C12(Vol. 7, p. 8) have now been reported in Sensitized photoaddition of methanol to carvone (18),508

498

499 500

501

502

503

504

505 506

507 508

D. Masilarnani and M. M. Rogic, J. Amer. Chem. SOC.,1978,100,4634.Acloselyrelateddeuteriation procedure using the reversible ene reaction of TsNS0216 has been used to produce [lO-ZH,]-(-)carvone from (4R)-(-)-(18). T. Harayarna, H . Cho, and Y. Inubushi, Chem. and Pharm. Bull. (Japan), 1977,25, 2273. B. Singararn and J. Verghese, J. Indian Chem. SOC.,1977, 54, 630. D . Garcia and P. M. Keehn, 175th A.C.S. Meeting, Annaheim, California, March 1978, Abstracts ORGN, No. 109. Y. Kinoshita, M. Misaka, S. Kubota, and H. Ishikawa, Agric. and Biol. Chem. (Japan), 1977, 41, 2357. I. I. Bardyshev, V. A . Barkhash, Z. V. Dubovenko, and V. I. Lysenkov, Zhur. org. Khim., 1978,14, 1 1 10. I. I. Bardyshev, L. A. Popova, E. F. Buinova, and B. G. Udarov, Vestsi Akad. Nauuk belarusk. S.S.R., Ser. khim. Navuk, 1977, (3), 58 (Chem. Abs., 1977, 87, 135 988); L. A . Popova, Tezisy Dokl. - Resp. Konf. Molodykh Uch. - Khim., Znd, 1977, 1, 58 (Chem. Abs., 1978, 89,90 226). J. Taskinen, Internat. Flavours Food Addit., 1976, 7 , 235; see also ref. 573. R. Jacquesy and J.-F. Patoiseau, Bull. SOC.chim. France, 1978, 2 5 5 . E. Murayarna and T. Sato, Tetrahedron Letters, 1977, 4079. B. Fraser-Reid, N. L. Holder, D . R. Hicks, and D. L. Walker, Canad. J. Chem., 1977, 55, 3978.

Monoterpenoids

55

(145)

(146)

(147)

( 148)

a further investigation of menthone photochemical transformation^,^^^ and nonselective proton transfer from p - cymene as the radical-cation half of an e x ~ i p l e x ~ ~ ' are described in other papers. The oxidation of a-terpinene to ascaridole (Vol. 7, p. 6) has been examined further; quantitative conversion occurs either photochemically using (hv-02SnC14-CH2C12,-90 "C) or in the dark using (02-liquid SO2, -70 "C) compared with Lewis acid-catalysed dark reactions which are less efficient (e.g. 0,-VOC1,CH2C12,67O/0).~"Oxymercuration-demercuration of CY -terpinene yields (149; X = OH; cis :truns/3 : 1); similarly a-phellandrene yields predominantly transcarvotanacetol (150) with minor amounts of (149; X = H; cis : truns/7 : l), whereas p-phellandrene yields predominantly (149; X = H; cis : trans/54 : 19), together with some p-menthane-1,3-diols in both The aerial oxidation of some p-menthadienes and p-cymene in dipolar aprotic solvents to p -methylLead acetophenone or 2-( p-methylphenyl)propan-2-01 has been tetra-acetate oxidation of methoxy-substituted p -cymenes occurs predominantly at the C-1 methyl group (e.g. to yield 4-isopropyl-3-methoxybenzyl peracid oxidation of menthylimines yields diastereoisomeric oxaziridines in high optical ~ i e 1 d s .The l ~ ~cis- and trans-isocarveols [cis- and trans-(15 l)], which are

c" c"" poH (149)

'09

'lo

'11 512

513

'14

(150)

(151)

R. K. Baslas, Indian Perfumer, 1976, 20, 131. P. J. Wagner and A. E. Puchalski, J. Amer. Chem. SOC.,1978,100,5948. R. K. Haynes, Austral. J. Chem., 1978, 31, 131. M. Bambagiotti A., S. A. Coran, and F. Vincieri, Rivista Ztal.,Essenze-Profumi,Piunte Offic.,Aromi, Saponi, Cosmet., Aerosol., 1978,60, 83. H. Iwamuro, T. Ohshio, and Y. Matsubara, Nippon Kaguku Kuishi, 1978,909. V. V. Dhekne and A. S. Rao, Synth. Comm., 1978,8,135.

56

Terpenoids and Steroids

obtained most efficiently from the respective limonene-1,2-epoxides by rearrangement using lithium di-isopropylamide, are rearranged allylically to perilla alcohol [(103; R = CH20H);up to 84%] uia PBr3 bromination, with rearrangement, and hydrolysis, as a viable alternative to the inefficient thermal rearrangement of derived esters and the complete absence of direct rearrangement of the parent alcohols. The corresponding perillaldehyde (103; R = CHO) may be obtained from [cis- and trans-(15l)]by oxidation-isomerization or directly from perillyl bromide (103; R = CH,Br) by treatment with 2-nitropropane and base; synthetically, trans-( 151) is the favoured starting material in these transf o r m a t i o n ~ .Catalysed ~’~ rearrangements of limonene- 1,2-epoxide by platinumgroup metals may yield carvenone (142) p r e d ~ m i n a n t l y ’although ~~ a more effective synthesis (92%) utilizes an exchange resin;517another exchange resin catalyses dihydrocarvone production (82’/0).’~~ Reaction of both limonene-1,2e p o x i d e ~ ’and ~ ~ the diepoxide519with amines518*s19 and with azidesl’ have been reported and a further paper on epoxide rearrangement over solid acids and bases (cf. Vol. 8, p. 43) concerns the corresponding saturated carvomenthene epoxide.s20 Lead tetra-acetate oxidation of the 4’-phenylsemicarbazone of 1,6epoxycarvone yields the oxadiazoline (152) which is thermolysed readily to 3-i~opropenylhept-5-ynal.~~’ Reductive cyclization of pulegone hydrochloride to (15 3) using Zn-HC1-Ac20 occurs uia pulegone (2 l).s22 Sodium borohydride reduction of enones [e.g. carvone (18), pulegone (21), piperitone (147)] in the presence of the lanthanide CeC13,6H20 or E I - ( N O ~ ) ~ , ~proceeds H ~ O almost exclusively by 1,2-addition to yield allylic alcohol^;^^^ further data on complex metal hydride reduction of carvone (18)and dihydrocarvone have been published (cf. Vol. 1, p. 30; Vol. 7, p. 7).524The reductive dimerization of (+)-pulegone [(lR)-(21)]has resulted in a number of recent papers (Vol. 2, p. 21; Vol. 4, p. 36; Vol. 6, p. 31); another now provides chemical evidence supporting the absolute configuration of the two series of ketols [e.g. (154)] and derivatives [uiz.allo- and iso- (cis- and trans-C-4’-methyl and C-2/C-3 respectively)] (cf.Vol. 7, p. 29).525 515

Y. Bessikre and F. Derguini-BoumCchal, J. Chem. Res. (S), 1977, 304. A more efficient synthesis (77%) of the cis-(151) only has been reported from the trans-l,2-epoxylimonene (Vol. 8, p. 43; ref. 384); last year’s Report erroneously implies otherwise. Line 11 should read (in part) ‘some expected arornatization is observed’ and not ‘the expected aromatization is observed’. For related work in the pinane series, see ref. 648. ’I6 T. Kurata, Yukagaku, 1978,27, 226. ’I7 N. E. Kologrivova, Z. V. Kamaeva, and L. A. Kheifits, Zhur. Vsesoyuz. Khim. obshch. im. D.I. Mendeleeva, 1977,22, 223 (Chem. Abs., 1977,87, 135 966). ”’ S. A. Kozhin, V. V. Zaitsev, and B. I. Ionin, J. Gen. Chem. (U.S.S.R.), 1978,48,177; the aminolysis of derived hydroxytosylates is also discussed. ’19 L. A. Mukhamedova, F. G. Nasybullina, and M. 1. Kudryavtseva, Bull. Acad. Sci. U.S.S.R., Div. Chem. Sci.,1977,26, 191 1. 520 K. Arata, S. Akutagawa, and K. Tanabe, Bull. Chem. SOC. Japan, 1978, 51,2289. ”’ G. A. MacAlpine and J. Warkentin, Canad. J. Chem., 1978,56, 308. ”’ E. Cros, I. Elphimoff-Felkin, and P. Sarda, Compt. rend., 1978, 286, C, 261. 523 J.-L. Luche, L. Rodriguez-Hahn, and P. Crabbt, J.C.S. Chem. Comm., 1978,601. The paper refers to carvone (18) reduction but the formulae depicted correspond to carvotanacetone and carvotanacetol. For additional complex metal hydride reduction data, see Vol. 1, p. 39, ref. 155. ’24 H. Rothbacher and F. Suteu, Chem.-Ztg., 1978,102, 61. E. FornC and J. Pascual, J.C.S. Perkin I, 1978, 288. It appears also that the X-ray structures of the allo-ketol, bishydropulegone, and the related dehydrobispulegone have been determined by D. Rogers et af.but never published (D. Rogers, personal communication; see also this reference and Vol. 7, p. 29, ref. 288).

”’

Monoterpenoids

57

(152)

(154)

(153)

Another use (cf. Vol. 5, p. 24) of chiral Rh(cod)(cyclohexylmethyl-o-anisylphosphine),BF, for asymmetric homogeneous hydrogenation is the highly selective reduction of piperitenone (155) to (-)-pulegone [(lS)-(21)] in up to 33% enantiomeric excess; slight modification of the ligand, however, produces the unusual observation of solvent-dependent selectivity to produce piperitone (147) p r e d ~ m i n a n t l y Selective .~~~ reductions of carvone (18) to dihydrocarvone using (CoC12,6H20-dimethylglyoxime)527 and of perillaldehyde (103; R = CHO) to shisool [(156; R = CH20H); cis: transll : 1 using Li-NH3-propan-2-01], shisoal [(156; R = CHO); cis : truns/3 : 1 using Li-NH3-propan-2-01 with inverse addiR I

(155)

(156)

tion], or p-menthan-7-01 [large-scale reaction (!) using Li-NH3-propan-2-01] have been reported.s28Further papers on p-cymene reduction to y-terpinene as the major product (using or calcium in liquid ammonia529b)have been published. Additional data on the thermal rearrangement of endo- cineole halohydrins and dihalides to halopinol derivatives (Vol. 8,p. 44) have been rep~rted.'~'In further attempts to synthesize 2,3-didehydro-l,8-~ineole, nitrosation of the endo- and exo-aminocineoles (157) results in a stereosyecificity not observed with dehydration of the corresponding alcohols (Vol. 8,p. 41); endo-(157) yields (158) and exo-(157) yields (159). The successful route to 2,3-didehydro-1,8cineole involves reduction of 2-hydroxyimino- 1,8-cineole with sodium bis-(2methoxyethoxy)aluminium hydride to the corresponding aziridine followed by nitrosation; interestingly, LiAlH, reduction of 2-hydroxyimino-l,8-cineoleis the most efficient route for the synthesis of ( 160).531" Bamford-Stevens reaction, s26

s27

528 s29

530

s31

J. Solodar, J. Org. Chem., 1978, 43, 1787. W. J. Ehmann, U.S.P. 4 020 108 (Chem. Abs., 1977,87, 136 044). For earlier reports of selective hydrogenation of carvone (18), see Vol. 4, p. 32; Vol. 7, p. 32. R. Murphy and R. Prager, Austral. J. Chem., 1978,31, 1629. V. V. Bazyl'chik and P. I. Fedorov, ( a )Zhur. obshchei Khim., 1978, 48, 674; ( b ) J. Appl. Chem. (U.S.S.R.), 1977,50, 1825; cf. Vol. 8, p. 44. J. Wolinsky, J. H. Thorstenson, and M. K. Vogel, J. Org. Chem., 1978, 43, 740. F. Bondavalli, A. Ranise, P. Schenone, and S. Lanteri, ( a )J.C.S. Perkin I, 1978, 804; ( b )personal communication.

58

Terpenoids and Steroids

under protic conditions, of the corresponding (+)-1,3,3-trimethy1-2-oxabicyclo[2,2,2]octan-6-one tosylhydrazone yields (159) plus some anhydro-( 159) and pinol. Under aprotic conditions the reaction is more complex, yielding substantial amounts of carbene-coupling Syntheses of alcohols and ketones derived from pinol have been r e p ~ r t e d . ’ ~ * Other papers related to p -menthanes concern the addition of chlorosulphonyl isocyanate to the exocyclic double bond of l i m ~ n e n ephenylselenenyl ,~~~ chloride addition to (Y -terpine01,~~’cyclization of a -phenylselenocitronellal,223cycloaddition of methylthiomaleic anhydride to (Y - ~ h e l l a n d r e n e ,HNCO ~ ~ ~ addition to a- and P-pinene (but not limonene) to yield a-terpineyl i ~ o c y a n a t e , ~ ~ ’ formation of (Y -terpineol n i t r o ~ o b r o m i d e , ’stereochemical ~~ assignment of (+)-dihydrocarvone oxime and (-)-carvoxime [of known X-ray structure ( !)57b*c],537 (-)-carvotanacetone synthesis via dehydrohalogenation of p-menth1-ene nitros~chloride,’~’menthol hydrosilylation in molten dodecylammonium p r ~ p i o n a t e , ’catalysed ~~ rearrangement of shisool (156; R = CH20H) into pmenth-3-en-7-01,’~’ arylation of p - ~ y m e n e , ~a ~reassignment ’ of the structure for the (-)-menthone-benzylideneacetophenone condensation reaction of limonene with recoil tritium atoms (to yield products from tritium incorporation and also radiolytic processes),542 2-isopropyl-5-methylphenoxyacetatocopper(I1) c~mplexes,’~’and copper(I1) chelate compounds with enaminoketones derived from (-)- hydroxyme thylenecarvone.544 o-Menthanes.-Bohlmann has isolated (161) and (162) from Piqueria triner~ia.~ ~ ’ reduction of o -cymol with calcium,546 The or in liquid ammonia in the presence of alcohols to yield o-mentha-1,4-diene (163) predominantly (together with o -mentha-3,6-diene, o -menth-1-ene, o-menth-2A. Siemieniuk, D. Mrozinska, and K. Piatkowski, Polish J. Chem., 1978, 52,727. G. Mehta, D. N. Dhar, and S. C. Suri, Indian J. Chem., 1978,16B, 87. s34 B. M. Trost and G. Lunn, J. Amer. Chem. SOC.,1977,99,7079. 535 T. Lesiak and W. Forys, Polish J. Chem., 1978, 52, 927. 536 C. P. Mathew and J. Verghese, J. Indian Chem. Soc., 1977,54,847. 537 B. Singaram and J. Verghese, Indian J. Chem., 1977,15B, 854. s38 B. Singaram, G. N. Saraswathi, and J. Verghese, Indian J. Chem., 1977,15B, 908. 539 J. Boyer, R. J. P. Corriu, R. Perz, and C. Reye, J. Organometallic Chem., 1978, 145, C31. s40 G. Vernin, C. Siv, and J. Metzger, Synthesis, 1977, 691. 541 G. L. Buchanan, Org. Magn. Resonance, 1978,11,45. s42 A. Cecchi, N. Taccetti, M. Bambagiotti A., S. A. Coran, and F. F. Vincieri, Radiochim. Acta, 1976, 23, 113. 543 J. Kratsmar-Smogrovic and V. Seressova, Chem. Zvesri, 1978, 32, 5 . ’*‘ G. V. Panova, V. M. Potapov, and N. K. Vikulova, Zhur. obshcheiKhim., 1978,48, 1611. F. Bohlmann and A. Suwita, Phytochemistry, 1978,17,560; (162) may have been reported already (Vol. 1, p. 35) although no direct comparison has been reported. 546 V. V. Bazyl’chik, P. I. Fedorov, and N. M. Ryabushikina, Zhur. org. Khim., 1978,14, 969.

532

s33

’‘’

59

Monoterpenoids

ene, and o- menth-6-ene) and the dehydration of cis- and trans-o-menthan-8-01s have been Other papers describing transformations involving the o -menthane carbon skeleton concern the tris(triphenylphosphine)ruthenium(II) dichloride-catalysedrearrangement of ally1 cyclohex-1-enylmethyl ether and the Claisen rearrangement to (164; R = CHO)548and oxyrnercuration-reduction of (164; R = Me).549

(161)

(162)

(163)

(164)

rn-Menthanes.-The ester (165; R = COPr’) has been isolated from Eupatorium species471cand from Senecio spe~ies,’’~ which have also yielded the ether (165; R = Me). I3CN.m.r. data have been recorded for (166).551The conformations of five rn -menthenols have been investigated using their i.r. hydroxy-group absorpt i ~ nIn. attempts553 ~ ~ ~ to rearrange 2a,3a-epoxycarane to (65)384by cyclopropylassisted epoxide ring opening in the presence of ZnBr2, rearrangement occurred predominantly to the non-naturally occurring rn -menthenone (167) and p cyrnene. No (65) was i~olated.”~ Catalytic dehydration of trans-rn-menthan-8-01 [to trans-rn-menth-8-ene/rn -menth-3(8)-ene or to rn -menth-2-ene/rn -menth3-ene pred~rninantly]”~and the hydration of five appropriately substituted rn -menthenols to similar proportions of cis- and trans-sylveterpin ( 168)555have been examined. Much of the work on sylvestrene nitrosochloride transf o r m a t i o n ~represents ~~~ minor modifications of work reported previously (Vol. 8, p. 46).

V. V. Bazyl’chik and E. A. Ionova, Zhur. org. Khim., 1978,14,538. J. M.Reuter and R. G. Salomon, J. Org. Chem., 1977,42,3360. 549 Y.Senda, S.-I. Kamiyama, and S. Imaizumi, J.C.S. Perkin I, 1978,530. 550 F. Bohlmann, K.-H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A. Suwita, D. Ehlers, N. L. Van, W.-R. Abraham, and A. A. Natu, Phytochemistry, 1977, 16, 965;this paper was inadvertently omitted from last year’s Report. This Reporter is unaware of any previous reports of naturally occurring (165;R = COPr’). 5s 1 K. Bachmann, Ph.D. Thesis, University of Zurich, 1977.For the X-ray structure of (166),see ref. 62a. 552 I. A. Shingel and I. V. Zen’ko, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1977,(5),99. 553 B.C. Clark, jun., T. C. Chafin, P. L. Lee, and G. L. K. Hunter, J. Org. Chem., 1978,43,519. 554 G . V. Deshchits and I. I. Bardyshev, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1977,

547

548

(4),111. 555

I. I. Bardyshev, I. V. Zen’ko, G. I. Voitekhovskaya, and N. G. Zimina, Vestsi Akad. Navuk belarusk.

556

S.S.R., Ser. khim. Navuk, 1977,(5),122. B. Singaram, G. N. Saraswathi, and J. Verghese, Indian J. Chem., 1977,15B,903.

60

Terpenoids and Steroids

Tetramethylcyc1ohexanes.-Aldehydo-esters (169; R = OAc, OH, or H) related to isoferulol have been isolated from Piqueria t r i n e r ~ i uand ~ ~the ~ structures of the furocoumarin ethers iselin and iliensin (Vol. 7, p. 35) have been revised and shown by synthesis to be derivatives of P-cyclolavandulol (170).557Cocker et ul.

have examined the sensitized photo-oxygenation and peracid oxidation of a pyronene (171) together with reductive and other manipulations of the oxidation products, with similar observations (after allowing for changed diene locus) to those made earlier for similar reactions in the P-pyronene series (Vol. 5, p. 28) except that PhC0,H-Et,O oxidation yields the less-substituted epoxide (172) presumably because in this case steric factors outweigh electronic Two-phase chromic acid oxidation of /3 -pyronene has been re-examined at lower temperatures than used by Cocker et al. (Vol. 5, p. 28) and has allowed the isolation of four additional products; unfortunately yields for them and for related cy -pyronene oxidation products have not been In 85% phosphoric acid, protonation of the isopropylidene double bond competes (-13%) with ionization of geraniol (but not nerol or linalool) resulting in cyclization to (173);388the formation of (174) as a minor product in the aqueous citric

acid-catalysed cyclization of geranyl acetate may involve similar protonation and ring closure with syn-addition of a molecule of water at C-3.389The telomer, N,N-diethylnerylamine, has been cyclized using BF3,Et20-HOAc to the mixture N,N -die thyl- ( a-cyclogeran y1)amine :N,N-die thyl- ( y -cyclogeranyl)amine/39 :60.560 Further papers of interest in this section concern allylb ~ r a t i o n , ’ diols ~ ~ and triols derived from P -cyclo~itral,~~’ sensitized photooxygenation of the ethyl ester of a-safranic acid followed by reduction and 557

”*

’59

S. K. Paknikar, J. Veeravalli, and J. K. Kirtany, Experientia, 1978, 34, 553. W. Cocker, K. J. Crowley, and K. Srinivasan, J.C.S. Perkin I, 1978, 159. J. de Pascual Teresa, I. Sanchez Bellido, M. R. Alberdi Albistegui, A . San Feliciano, and M. Grande Benito, Anales de Quim., 1978,74,470. J. Tanaka, Jap. P. 48 642/1977 (Chem.Abs., 1977,87,136 049). For further transformations of this telomer, see ref. 359. D. Behr, I. Wahioerg, and C. R. Enzell, Acra Chem. Scand., 1977, B31,793.

Monoterpenoids

61

~ e a r r a n g e m e n t , ~and ~ ~ alkylation of methylcyclohexa- 1,3-diene.563

l-(phenylsulphonylmethyl)-2,6,6-tri-

Dimethylethylcyc1ohexanes.-The two aldehydic and one alcoholic dimethylethylcyclohexane components of the boll weevil sex pheromone have been synthesized efficiently via ZnCl,-catalysed addition of ethyl vinyl ether to the ethyl acetal of 3,3-dimethylcyclohexanone.564

Cyc1oheptanes.-'H N.m.r. spectral data for beryllium bis-(a -isopropyltropolonate) have been The full paper on Noyori's syntheses of nezukone, a-thujaplicin, and p-thujaplicin or hinokitiol (175; R = Pr') has been Compound (175; R = Pr') has also been synthesized according to Scheme 4.567 Other syntheses of p-thujaplicin (175; R=Pr') have been

o+

o n o M e _

__* iii

\+

N Me

N Me

or Me

/"

C0,Me

'06 R

vi-viii

-

-

C0,Me (175) R=Pr' Reagents: i, Pr'MgBr; ii, m-ClC6H4C03H-CH2C12; iii, CHz=CHC02Me-THF; iv, MeI; v, NaHC03-HzO; vi, 10% aq. HCI; vii, IN aq. KOH; viii, copper chromite-quinoline, 230 "C

Scheme 4

reported. One of them involves reaction of the tricarbonyliron complex (176) with 2-diazopropane to yield the corresponding pyrazoline which readily loses nitrogen and undergoes alkaline P-ketone cleavage to yield (177); decom-

Fe(CO),

(176)

(177)

R. Kaiser and D. Lamparsky, Helv. Chim. Acta, 1978,61, 373. 563 S. Torii, K. Uneyama, and I. Kawahara, Bull. Chem. Suc. Japan, 1978,51,949. 564 J. P. de Souza and A. M. R. Goncalves, J. Org. Chem., 1978, 43, 2068. 565 A. Gryff-Keller and J. Terpinski, Roczniki Chem., 1977, 51, 2139. 566 H. Takaya, Y. Hayakawa, S. Makino, and R. Noyori, J. Amer. Chem. Soc., ( a ) 1978, 100, 1778; ( 6 ) ibid., 1978,100, 1765. See also ref. 259. For the earlier communication see Vol. 6, p. 33. "' Y. Tamura, T. Saito, H. Kiyokawa, L.-C. Chen, and H. Ishibashi, TetrahedronLetters, 1977,4075. 562

62

Terpenoids and Steroids

plexation, base conjugation, and introduction of the hydroxy-group by Noyori’s method566 transforms (177) into (175; R = Pri).568Another synthesis utilizes lithium-ammonia reduction of triethylsilyl 3-isopropylphenyl ether to (178) followed by anticipated dichlorocyclopropanation, hydrolysis, and epoxidation to give (179) which yields (175; R = P i ) on acid-catalysed elimination and hydrol ~ s i s . ’Essentially ~~ the same scheme from triethylsilyl 4-isopropylphenyl ether yields y-thujaplicin, although in an attempted synthesis of a -thujaplicin dichlorocyclopropanation of the dihydroaromatic silyl ether corresponding to (178) failed, presumably for steric reasons.569P-Dolabrin (175; R = CHMe= CH2) has also been synthesized568from (177) via oxidative tropone formation prior to decomplexation and known566hydroxylation; a second synthesis involves reaction of isopropylmagnesium bromide with (180; X = 0 , Y = OMe,OMe) and subsequent dehydration-deacetalization to (180; X = CMe2, Y = 0),the enolate

of which undergoes electrocyclic ring opening, silylation, oxidation, and hydrolysis to (175; R=CHMe=CH2).570 Further (cf. Vol. 8, p. 48) on karahanaenone (27; X = 0) formation by Zn-Cu couple dehalogenation of 1,3-dibrom0-3-methylbutan-2-onein the presence of isoprene shows an unusual reversal of selectivity on changing the solvent polarity, although yields remain low. In acetonitrile, karahanaenone (27; X = 0)is now the minor cycloheptenone and substituted cyclopentanone formation is when zinc is replaced by sodium iodide, formation of these products is almost completely suppressed in favour of substituted furan formation - see p. 77.s71b The charge distributions of protonated eucarvone and its boron trihalide adducts have been examined (there is more dienylic positive charge in the former)572aand the photoisomerization of the latter has been shown to be qualitatively similar to results with the former (Vol. 2, p. 36) although synthetic utility is limited because car-2-en-4-one,BX3 adducts readily yield carvacrol and carvone (

8 Bicyclic Monoterpenoids Bicyclo[3,1,O]hexanes.-Acid-catalysed ethanolysis (80% EtOH) of cissabinene hydrate (28) and its trans -isomer (of unspecified chiralities) yields 30% of p-menth-1-en-4-01;~’~ it would be of interest to know its optical purity in view of the reports that (+)-trans-sabinene hydrate may be isomerized to p-menth-l568 569 570

571 572

M. Franck-Neumann, F. Brion, and D. Martina, Tetrahedron Letters, 1978, 5033. T. L. Macdonald, J. Org. Chem., 1978,43, 3621. D. A. Evans, D. J. Hart, and P. M. Koelsch, J. Amer. Chem. SOC.,1978, 100,4593. H. M. R. Hoffmann and R. Chidgey, Tetrahedron Letters, ( a ) 1978,85; (b) 1978, 1001. R. F. Childs and Y.-C. Hor, Canad. J. Chem., ( a ) 1977,55, 3495; (b) 1977, 55, 3501.

Monoterpenoids

63

en-4-01 (4R :4S/3 : 7)573and acid-catalysed hydration of (+)-sabinene yields (+)-p-menth-l-en-4-01 stereospecifically (Vol. 3, p. 57). Attempts to use known thujone chemistry in synthesizing insect juvenile hormone analogues have been Umbellulone (18 l), together with the isomeric 2,4-transposed ketone, has been obtained by treating (182) with lithium dimethylcuprate and reaction of the enol lactones derived from the resultant keto-acid mixture with diethylmethanephosphonate anion.575

Bicyclo[2,2,l]heptanes.-Last year's Report incorrectly identifies vulgarole [Vol. 8, p. 49, line 21, formula (202; R = Ac) should be (208; R = Ac)]. A review of interest to this section concerns oxidation of bicyclic hydrocarbons using oxygen, hydroperoxides, peracids, and hydrogen The full paper on nojigiku alcohol has appeared;577the isolation of a new compound (132) has been referred to already.470 Recent X-ray crystal structure determinations have been reported earlier (see p. 8). A number of n.m.r. papers have been published. The 'H n.m.r. assignment of camphorimide has been made using [ E ~ ( d p m ) ~ ]and ' ~ ~long-range proton coupling constants have been measured for 3-endo,4-disubstituted the influence of substituents on 13C carbonyl chemical shifts in 4-substituted camphorquinones has been inve~tigated.~'~ A comparison of 'H n.m.r. chemical shift and relaxation rate data for complexes of (-)-borne01 with lanthanide shift reagents containing the ions Eu3+,Pr3+, La3+, and Gd3+ has revealed that the geometrical data for Gd3+ compiexes are incompatible with data from Eu3+or Pr3+c ~ r n p l e x e s ; ~an' ~examination of 'H and 13Cn.m.r. chemical shifts and signal broadening induced by four [ L n ( d ~ mJ )shift ~ reagents indicates that the metal binds to two sites on the carbonyl group of camphor.582The 13C n.m.r. signals 573

574

575

576

577 578 579

580

581 582

D. Karasawa, Shinshu Daigaku Nogakubu Kiyo, 1977, 14, 119 [Chem. Abs., 1978, 89, 24 543 incorrectly refers to (+)-trans-sabinene]. The enantiomeric composition was determined using tris-[3-trifluoroacetyl-(+)-camphorato]eur~pium(~~~). J. P. Kutney, J. Balsevich, R. Carruthers, A. Markus, M. J. McGrath, R. N. Young, and B. R. Worth, Bioorg. Chem., 1978,7,289. S. Benayache, C. FrCjaville, R. Jullien, and M. Wanat, Rivista Ital. Essenze-Profumi, Piante Offic., Aromi, Saponi, Comet., Aerosol., 1978, 60, 118. E. A. Lazurin, V. V. Voronenkov, and Yu.G . Osokin, Russ. Chem. Rev., 1977,46, 915. Y. Uchio, Bull. Chem. SOC. Japan, 1978,51,2342;see Vol. 6, p. 35 for the communication and Vol. 7, p. 38 for a synthesis. S. M. Verma and R. Prasad, Indian J. Chem., 1977,15B, 742. F. C. Brown, R. K. Fraser, R. W. Jemison, D. G. Morris, A. M. Murray, and J. D. Stephen, Austral. J. Chem., 1978, 31, 695; for a related paper, see ref. 613a. F. C. Brown, D. G . Morris, and A. M. Murray, Tetrahedron, 1978, 34, 1845; variations in i.r. stretching frequencies are also reported. D. H. Welti, M. Linder, and R. R. Ernst, J. Amer. Chem. SOC.,1978,100,403. B. H. S. LiCnard and A. J. Thompson, J.C.S. Perkin ZZ, 1977, 1390.

64

Terpenoids and Steroids

have been assigned for (-)-2-endo -dimethylphosphono-2-exo-thiomethylcamphane and a Karplus-type function derived for vicinal coupling constants in p h o ~ p h o n a t e s .Further ~ ~ ~ papers concern a I3C n.m.r. study of the two pinacols derived from ~ a m p h e n i l o n e an , ~ ~examination ~ of a -+ S effects produced by C-1 and C-4 triflate and ethoxy-groups in ~ a m p h e n e , ~and ~ ’ ‘H n.m.r. and 13C n.m.r. assignments of a series of 2-aryl-177,7-trimethylbicyclo[2,2,l]hept-2-ylcations derived from the corresponding exo -alcoh o l ~ Mass . ~ ~ spectral ~ fragmentations of chlorinated bornanes have been examined587 and further investigation (Vol. 5 , p. 3 l), using deuteriated compounds, of the cis-1,2-elimination of water from the molecular ions of borneol and isoborneol has shown that it is triggered by initial ring cleavage; the experimental results are inconsistent with an earlier proposal (Vol. 3, p. 59) involving non-classical carbonium ions.476C.d. data on Schiff -base condensation products of a c e t y l ~ a m p h o rhave ~ ~ ~ been published as well as for 9,9,9-trid e u t e r i o ~ a m p h o rfor , ~ ~a ~number of fenchone- and camphor-related ketones,590 and for electron donor-acceptor charge-complexes between iodine and camphor and iodine and c a m p h ~ r q u i n o n e . ~( ~ - )’ - B ~ r n e o l and ~ ~ ~(+)-camphor593 have been the subjects of theoretical c.d. studies. E.s.r. studies of nitryl radical mobility in camphor,594 of silyl, stannyl, and plumbyl radical addition to c a m p h o r q ~ i n o n eand , ~ ~of ~ cation-radicals generated from dehydrocamphor and d e h y d r o e p i ~ a m p h o have r ~ ~ ~been published. Other papers of a physical nature concern (&)-campheneself-diff u ~ i o nelectrical , ~ ~ ~ conductivity of plastic crystals of (*)-carnphoric anhydride, (*)-camphorquinone, and ( f ) - c a m p h o r ~ x i m e , ~ ~ ~ partition of isobornyl acetate between phenol and water,599and the synthesis, resolution, and olefactory properties of the exo- and endo-4-(2’-bornyl)-2methylcyclohexanones and of the exo- and endo -2-rnethyl-4-(5’,S76’-exo-trimethyl-2’-norbornyl)cyclohexanones.600 Pyrolysis of exo-(183; X = CD2NOMe2),601a which is obtained, without rearrangement, from optically pure (+)-isocamphenilanic acid of absolute 583 584 585

586

587 588

589

590 591 592

s93 594 595 596

597

598 599

6oo

‘”

J. Thiem and B. Meyer, Org. Magn. Resonance, 1978, 11, 50. J. B. Stothers and K. C. Teo, Org. Magn. Resonance, 1977, 9, 712. A. Garcia Martinez and M. Gornez Marin, Anales de Quim., 1978,74, 339. J. M. Coxon, P. J. Steel, J. M. Coddington,I. D. Rae,andA. J. Jones,Austral. J. Chem.,(a)1978,31, 1223; ( 6 )for related work, see ibid., 1977,30,2741. See also Vol. 6, p. 37 and later discussion in this section. H. Parlar, S. Nitz, A. Michna, and F. Korte, Z. Naturforsch., 1978, 33b, 915. H. P. Jensen, Acta Chem. Scand., 1978, A32, 149. W. L. Meyer, A. P. h b o , E. E. Ernstbrunner, M. R. Giddings, and J. Hudec, Tetrahedron Letters, 1978,1771. D. N. Kirk, J.C.S. Perkin I, 1977, 2122. H. G. Brittain and F. S. Richardson, J.C.S. Faraday II, 1978,74,115 1; for related work, see ref. 118. P. A. Snyder and W. C. Johnson, jun., J. Amer. Chem. Soc., 1978, 100,2939. J. Texter and E. S. Stevens, J. Chem. Phys., 1978,69, 1680. S. T. Kirillov and V. B. Stryukov, Russ. J. Phys. Chem., 1976, 50, 1746. A. Hudson, R. A. Jackson, and N. P. C. Simmons, J.C.S. Perkin II, 1977, 1633. J . Eloranta, E. Salo, and P. Malkonen, Finn. Chem. Letters, 1977, 217. N. T. Corke, N. C. Lockhart, R. S. Narang, and J. N. Sherwood, Mol. Crystals Liquid Crystals, 1978, 44,45. J. Swiatkiewicz and K. Pigon, Acta Phys. Polon., 1978, A53, 165 (Chem. Abs., 1978,89, 59 962). J. R. Alvarez Gonzalez and J . J. Niela Nieto, Anales de Quim., 1978, 74, 326. E. T. Theimer, T. Yoshida, and E. M. Klaiber, J. Agric. Food Chem., 1977,25, 1168. G. Buchbauer and H. Koch, ( a ) Chem. Ber., 1978, 111, 2533; ( h ) ibid., p. 2527.

Monoterpenoids

65

configuration [exo-(183; X = C02H)],yields [8,8-2H2]-(-)-camphene (184; X = H,H; Y = CD2);601a in the corresponding non-deuteriated series, (-)-camphene (184;X = H,H; Y = CH2)with [a]&!= -1 19.11' (benzene, c = 2.33)wasobtained A synthesis of [3-exo thus providing unambiguous proof of its 2Hl]camphor has been reported earlier.259The full paper on (+)-camphor synthesis by (+)-dihydrocarvone pyrolysis has appeared.602Another application of Nakai's 1,2-carbonyl-transposition scheme (cf. Scheme 3) is the conversion of camphor into epicamphor (46% yield).485Treatment of 3-endo- (p-t-butylpheny1)selenocamphorwith H 2 0 2under mild conditions yields camphorquinone (65'/0)~~~which has been used in a synthesis of tricyclenone (185) via BamfordStevens reaction of the appropriate acetal to~ylhydrazone.~?~ The known conversion of endo-(183; X = OAc) into endo-(184; X = 0; Y = H,OAc) is the

1

X

(183)

Y (1 84)

(185)

basis of a synthesis of (184; X = 0, Y = CH2).604Compound (186) has been converted into teresantalic acid (187) (Scheme 5).605A straightforward synthesis

(187)

(1 86)

Reagents: i, hv, acetone, 25 "C, 10 h; ii, NaH-HC0,Et-Et,O-EtOH, 25 "C, 4 2 h; iii, tosyl azideEt,N-CH,Cl,, 25 "C, 78 h; iv, hv, NaHC0,-THF-H,O, 25 "C, 45 min; v, LiNPr: (2.5 equiv.), THF, 50 "C, 1 h; vi, Bu"Li (1 equiv.), 50 "C, 1 h; vii, MeI, 25 "C, 16 h

Scheme 5

of camphenilanic acid [endo-(183; X = CO,H)], via (183; X = Br) and endo(183; X = CN), has been carried out from isocamphenilanic acid [exo-(183; X = C02H)],606an optical resolution of which has been r e p ~ r t e d ; ~reaction ~~'~~" of exo -( 183 ; X = C0,H) with 1,l'-carbonyldi-imidazole and LiAlH4 reduction provides access to exo-( 183; X = CH0).606Further synthetic work concerns ketopinoyl peroxides,6084-methylisocamphenilanic acid,609and attempts by '02

' 0 3 '04 605 '06 607

'08

'09

J. M. Conia and G . L. Lange, J. Org. Chem., 1978,43, 564. L. Borowiecki and M. Welniak, Roczniki Chem., 1977,51, 1751. N. H. Werstiuk and R. Taillefer, Canad.J. Chem., 1978, 56, 1134. S. A. Monti and S. D. Larsen, J. Org. Chem., 1978, 43, 2282. G. Buchbauer, Monatsh., 1978,109, 3. G. W. Hana and H. Koch, Arch. Pharm., 1978,311,498. Yu.A. Ol'dekop, N. A. Maier, A. A. Erdman,T. A. Rubakha, and I. A. Shingel, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1978, ( l ) , 118. G. Buchbauer and I. Schrnidmayer, Monatsh., 1978,109,751.

66

Terpenoids and Steroids

-

de Mayo and colleagues to synthesize 4-methylcamphordithioquinone (it is formed at 77 K but dimerizes on Kreiser and colleagues have reinvestigated the structure of albene (Vol. 3, p. 58; Vol. 5 , p. 34; there is a discrepancy between the formulae used) and established the structure as (188) by 13C n.m.r. analysis,611aby X-ray structure determination of the isoalbene (189; X = H)derivative (189; X = SCH2Ph),611b and by the synthesis of (-)-albene (188)from (+)-camphenilone [(184; X = H,H; Y = O ) - e n a n t i ~ m e r ] ~and " ~ of (*)-isoalbene (189; X = H) uia Diels-Alder reaction and conversion into (189; X = SCH2Ph).611c It seems reasonable that albene is a trisnorsesquiterpenoid.

Microbial oxidation of (+)-bornyl acetate (to 5-exo- and 5-endo-hydroxyborneol) using Helminthosporium satiuurn is more efficient and regiospecific than that reported previously (Vol. 8, p. 51) with the enantiomer, in contrast to the conversion of (+)- and (-)-bornyl acetate, using Fusarium culrnorurn, into 5 - exo - hydrox yborny 1 acetate .6 * The full paper on the rearrangement of cations derived from 2-endo-arylborneol in FS03H-S02C1F identifies additional cations (cf. Vol. 6, p. 37) and also confirms the SOC1,-pyridine-catalysed syn-dehydration of 2-endo-phenylb o r n e 0 1 . ~X-Ray ~ ~ ~ crystallographic data for (-)-camphene-8-carboxylic acid (184; X = H,H; Y = E - C H C 0 2 H ) have been interpreted as supporting the exo-methyl migration in the Nametkin rearrangement of camphene (184; X = H,H; Y = CH2).79The steric and inductive effects of substituent groups at C-4613a and other on the rates of base-catalysed exo- and endo-deuterium exchange in various bicyclo[2,2,l]heptan-2-ones have been examined. Photolysis of the spiro 2-oxo-2,5-dihydro-l,3,4-oxadiazolene derivatives prepared from (+)-camphor semicarbazone proceeds in cyclohexene by C0,extrusion to yield the cyclohex-2-enylhydrazone (44%) and, through cyclodimerization, the symmetrical camphor azine (53%) with only 3% of camphor arising via the alternative CO/N2 extrusion pathway.614Pb(OAc), oxidation of 610 611

'I2

614

N. Jacobsen, P. de Mayo, and A. C. Weedon, Nouveau J. Chim., 1978,2,331. ( a ) W. Kreiser, L. Janitschke, and L. Ernst, Tetrahed!on, 1978, 34, 131; (6) W. Kreiser, L. Janitschke, and W. S . Sheldrick, J.C.S. Chem. Comm., 1977, 269; ( c )W. Kreiser and L. Janitschke, Tetrahedron Letters, 1978,601. Full syntheticdetails for (-)-albene (188) have appeared recently, W. Kreiser and L. Janitschke, Chem. Ber., 1979, 112, 408, and for (+)-isoalbene (189; X = H ) ; see W. Kreiser, L. Janitschke, W. Voss, L. Ernst, and W. S . Sheldrick, Chem. Ber., 1979, 112,397. An unusual feature of (188) synthesis is an endo-Nametkin rearrangement; for example, cf. ref. 79 and Vol. 5, p. 31. M. S . Allen, N. Darby, P. Salisbury, and T. Money, Tetrahedron Letters, 1978, 2255. (a)F. C. Brown, E. Casadevall, P. Metzger, and D. G. Morris, J. Chem. Res. ( S ) , 1977,335; ( b ) N. H. Werstiuk, R. Taillefer, and S . Banerjee, Canad. J. Chem., 1978, 56, 1140, 1148. D. Daniil and H. Meier, Tetrahedron Letters, 1977, 3155.

Monoterpenoids

67

the 2-aminoindazole (20; x = 1, Y = NH2) to the corresponding 1,2,3-benzotriazine and photolysis yields (24; X = CN, Y = e t h ~ n y l ) . ~ Photolysis ~’ of the cyclic N-ethyl-(+)-camphoric imide produces predominantiy the two expected ring-expanded Norrish Type I1 bridged bicyclic keto-lactams together with some (190; X = CONHCHO) which may result from Norrish Type I cleavage.616The photochemical cleavage of homocamphor via an aldehyde or a keten pathway is solvent-dependent ; it is known that in Et20-cyclohexylamine only the amide results, whereas in THF-H20 the aldehyde (190; X = CH2CH2CHO)pathway predominates over the keten pathway by 30 : l.617 Oxidation of the known lactone (191; X=H,H) with Cr03 yields (191; X = 0),618 Chromyl acetate oxidations of exo- and endo-fenchyl acetates and of

(190)

(191)

fenchone have been investigated; fenchone is oxidized primarily to the 6-ketoderivative but the fenchyl acetates suffer oxidation at C-5 (keto- and exo-acetoxyproducts) in addition to oxidative conversion into diaceto~y-ketones.~’~ The manganese(II1) acetate oxidation of camphene has been reinvestigated more thoroughly (Vol. 6, p. 38) and extended to bornene which yields the lactones (192)-(194) and the C-2-epimer of (194); (194) is the major product from

v 0

(192)

(193)

(194)

camphene oxidation.620Additional oxidation papers concern ozonolysis of camphene (cleavage and Baeyer-Villiger products),621 peracid oxidation of camphorimines (to chiral oxaziridines),1327133 anodic Oxidation of isoborneol to (195),622mercuration of bornene with Hg0-HC104-NaC1 [to give (196) in addition to non-rearranged a d d u c t ~ ] , ~and ’ ~ oxymercuration-bromination of tricyclene to 2-bromotri~yclene.~~~ ‘I5 ‘I6

‘I7 ‘I9 620

621

‘’*

‘23 624

I. Ito, N. Oda, S.-I. Nagai, and Y. Kudo, Heterocycles, 1977,8, 319. Y. Kanaoka, H. Okajima, and Y. Hatanaka, Heterocycles, 1977, 8, 339. S. C. Critch and A . G. Fallis, Canad. J. Chem.. 1977, 55, 2845. Y. Hirose, M. Kuroiwa, M. Shibata, and A . Fujita, Chem. and Pharm. Bull. (Japan),1978,26,1003. J. Enqvist, Ann. Acad. Sci. Fennicae, Ser. A2, 1977,183, 1. K. Witkiewcz and Z. Chabudzinsky, Roczniki Chem., 1977,51,2155; for earlier papers in thisseries, see Vol. 8, pp. 43, 54, 57. J. Tanaka, K. Takabe, M. Kawakita, M. Ito, and T. Katagiri, Nippon Kagaku Kaishi, 1978, 284. P. S. Scholl, S. E. Lentsch, T. P. Steckel, and M. R. Van D e Mark, 170th A.C.S. Meeting, Chicago, August 1975, Abstracts ORGN, No. 73. This paper was inadvertently omitted from earlier Reports. E. V. Skorobogatova, L. N. Povelikina, and V. R. Kartashov, Zhur. org. Khim., 1978,14,663. S . N. Suryawanshi and U. R. Nayak, Tetrahedron Letters, 1978,465; for related work, see ref. 640.

68

Terpenoids and Steroids

(195)

(196)

Rassat has summarized some of his results on the stereochemistry of dissolvingmetal reduction of bicyclo[2,2,l]heptanones (cf.Vol. 2, p. 45).625Camphor is one of a number of ketones investigated in mechanistic studies of sodium borohydride reduction,626 lithium aluminium hydride and lithium alkoxyaluminium hydride and tri-isobutylaluminium-amine complex reductions;628 camphoric anhydride reduction with lithium aluminium hydride is included in a regioselectivity study of anhydride reduction.629The aluminium isopropoxide reduction of 10-halogeno-camphor results in (190; X = CH,CHO) via the endo10-bromoborneol but not via 10-chloroborneo1.630 The conjugate bases of camphoroxime and 2-nitrobornane undergo electrophile addition from the exo providing access to 2-exo-bromo-2-endon i t r ~ b o r n a n eand ~ ~ 2-endo -nitrobornane; nitration of camphoroxime to the nitrimine and 2,2-dinitrobornane, is also reported but attempts to obtain of 2-exo2-exo-nitrobornane were L ~ ~ s u c c ~ s Dehydrohalogenation s~u~.~~~ bromo-2-endo-nitrobornane (cf. Vol. 5 , p. 32, ref. 225) using AgSbF6 occurs selectively to 4-nitrocamphene in CH2C12 but yields 1-nitrocamphene :4nitrocamphene/7 : 3 in Dehalogenation of 3-exo- bromocamphor with AgSbF6-CH2C12 yields a mixture of lactones (presumably formed from 1,2,2-trimethylcyclohex-3-enylcarboxylicacid) in contrast to reaction with 3-endo-bromocamphor which yields 6-isopropenyl-6-methylcyclohex-2-enone analogously to rearrangement of 3-diazocamphor with HSbF6 in CH2C12 (presumably via exo -protonation), although tricyclocamphanone is formed with a catalytic amount of HSbF6.633The chemistry of o -nitrosocamphene (184; X = H,H; Y = CHNO), which has pronounced 1,4-dipolar character, has been investigated further (cf. Vol. 5, p. 32). Chromous chloride reduction of w nitrocamphene (184; X = H,H; Y = CHNO,) yields (197) presumably via (184; X = H,H; Y = CHNO); reaction of w-nitrocamphene (184; X = H,H; Y = C H N 0 2 )with fuming HBr followed by base yields the stable bridgehead nitrile oxide (198)which reacts with methanolic KOH to yield (199) via the presumed corresponding a,P -unsaturated n i t r o ~ o - d e r i v a t i v eThermal . ~ ~ ~ decomposition of the monoanion of the (2,4,6-tri-isopropylbenzene)sulphonylhydrazoneof camphor (to tricyclene via the carbene) occurs under milder conditions than with 625

626

627 628

629 630

631

632 633 634

A. Rassat, Pure Appl. Chem., 1977,49,1049. J.-C. Perlberger and P. Miiller, J. Amer. Chem. SOC.,1977,99,6316. K.E.Wiegers and S. G. Smith, J. Org. Chem., 1978,43,1126 T.Suzuki, M. Itoh, S. Ogawa, and Y . Takegami, Bull. Chem. SOC.Japan, 1978,51, 2664. M. M.Kayser and P. Morand, Canad. J. Chem., 1978,56,1524. N.Proth, Rev. Tech. Luxemb., 1976,68.195 (Chem. Abs., 1977,87,135 965). S. Ranganathan, H. Raman, and C. V. Srinivasan, Tetrahedron, 1978, 34, 3129.For reports of 2-endo-chloro-2-exo-nitrosobornane,74 see Vol. 6, p. 41,ref. 236. J.-P. BeguC, C. Pardo, and J. Sansoulet, J. Chem. Res. ( S ) , 1978,52. J.-P. BCguC, M. Charpentier-Morize, C. Pardo, and P. Sansoulet, Tetrahedron, 1978,34,293. S.Ranganathan, B. B. Singh, and C. S. Panda, Tetrahedron, 1977,33,2415.

Monoterpenoids

69

the camphort~sylhydrazone,~~~ the 3-em -deuterio analogue of which may be cleaved most effectively to the ketone, without enolization, using N-bromosuc~inimide.~~~ Other papers of interest in this section report an improved camphor ringexpansion via Lewis acid-catalysed benzyl diazoacetate addition,637further details of camphor cleavage to (24; X = C 0 2 H , Y = CHC1,) using CC14-KOHB u ' O H ~and ~ ~ of thio-Claisen rearrangements of allylic enethiolic ethers of t h i o ~ a m p h o rhypobromous ,~~~ acid cleavage of tricyclene [to (200; X = CHBr), (200; X = OH,CH2Br), and (200, X = OH,Me)],640acetalization of 2-exo,3-exo-

34

X

Br

d i h y d r ~ x y b o r n a n e ,reaction ~~~ (with Wagner-Meerwein rearrangement) of camphene with phenylselenenyl chloride,22s synthesis of aza-heterocyclic camphor derivatives,642 manganese(II1) acetate oxidation of N-vinylcamp h ~ r i m i d e , and ~ ~ ~ the synthesis of nitrogen mustards from hydroxymethylenecamphor and related compounds.644 Bicycle[3,l,l]heptanes.-Semi-empirical C N D 0 / 2 calculations on pinocamphone [truns-(201; X = O)], isopinocanqhone [cis-(201; X = O)], verbanone [truns-dihydro-(202; X = O)], and isoverbanone [cis-dihydro-(202; X = O)] are consistent with preferred boat conformation^.^^^ In a discussion of alkylation and 635

636

637

639

640

641

642 643 644 645

A. R. Chamberlin and F. T. Bond, J. Org. Chem., 1978, 43, 154; for the related dianion decomposition to vinyl-lithiums, see ref. 227. P. K. Freeman and J. R. Balyeat, J. Org. Chem., 1977,42, 3205. S. W. Baldwin and N. G. Landmesser, Synth. Comm., 1978, 8, 413; cf the poor results using a palladium-catalysed ring-expansion sequence reported in Vol. 8, p. 52, ref. 467. C. Y. Meyers and V. M. Kolb, J. Org. Chem., 1978, 43, 1985. D. Barillier, L. Morin, D. Paquer, P. Rioult, M. Vazeux, and C. G. Andrieu, Bull. SOC.chim. France, 1977,688; see Vol. 7, p. 40 for the preliminary communication. S. N. Suryawanshi and U. R. Nayak, Tetrahedron Letters, 1977,3595; for related work, see ref. 624. A. Bazbouz, H. Christol, J. Coste, and F. PlCnat, Bull. Suc. chim. France, 1978, 305. S. Seube, A.-M. Lamazoukre, and J. Sotiropoulos, J. Heterocyclic Chem., 1978, 15, 343. K. Yanagi and T. Nishiyama, Nippon Kaguku Kuishi, 1978,404. E. Mariani, A. Tasca, G. Bignardi, and P. Schenone, Farmuco, Ed. Sci.,1978, 33,612. J. Fournier, J. Chem. Res. ( S ) , 1977,320;for earlier conformational papers, see Vol. 2, p. 49; Vol. 5, p. 36; Vol. 6, p. 41.

70

Terpenoids a n d Steroids

Robinson ring annulation of nopinone, Thomas et al. have pointed out discrepancies between two previous assignments (Vol. 6, p. 41, ref. 304 and Vol. 7, p. 3, ref. 5) of the 13C n.m.r. for verbenone (202; X = 0),isoverbanone [cisdihydro-(202; X = O)], and cis- and trans-myrtanol [cis/trans-dihydro-(203; X = CH,0H)].64h Electron-impact mass-spectral fragmentation of epoxychrysanthenone (204) may occur by loss of CO, from a molecular ion via a lactonetype intermediate reminiscent of the known (Vol. 5, p. 27) photorearrangement product, filifolide A (205), although electron-impact rearrangement of (204) to (205) does not occur.647

(201)

(202)

(203)

(204)

(205)

Myrtenol (203; X = CH,OH) may be obtained most efficiently from the more stable secondary allylic alcohol (+)-trans-pinocarveol (30; enantiomer) via bromination with PBr3 to the rearranged bromide (203; X = CH,Br) [(30) :(203; X = CH,OH)/85 : 151; ester thermolysis and isomerization-oxidation were less effective; and the direct acid-catalysed isomerization was not Intramolecular cyclization of (206), which is readily synthesized via trifluoroacetic anhydride cyclization of 4-methylcyclohex-3-enylacetic acid to (186), affords (207) which is cleaved to (208; X = NH,) in a synthesis of (&)-a-

(206)

(207)

(208)

~ i n e n e . ~(-)-p ~ ' -Pinene is isomerized rapidly to (-)-a-pinene using potassium 3-aminopropylamide in 3-aminopropylamine, with essentially quantitative isomeric and optical conversion.65o The ~ y n t h e s i s 'of ~ ~ monoisopinocampheylborane (-100% optical purity) from (+)-a-pinene of lower optical purity143gand its conversion into (-)-isopinocampheol [(2R73R)-(201; X = H,OH)] of very high optical purity ([a]h5= -35.79'; benzene) has been The Organic Syntheses preparation of (+)-isopinocampheol from (-)-a -pinene of similar optical purity (Vol. 4, p. 56, ref. 267) gives a sample with [a]g= +32.8"in benzene. s -Trioxan and N-methylanilinium trifluoroacetate effects direct a methylenation of nopinone in high yield.651 646

647

648

649

Y. Bessiere, M. Bartheltmy, A. F. Thomas, W. Pickenhagen, and C. Starkemann, Nouveau J. Chim., 1978, 2, 365. S. Eguchi, Y. Uchio, A. Matsuo, M. Nakayama, and S. Hayashi, Chem. Letters, 1978, 1029. Y. Bessitre, E. Reca, F. Chatzopoulos-Ouar, and G. Boussac, J. Chem. Res. (S), 1977, 302; for related work in the p-menthane series, see ref. 515. S. D. Larsen and S. A. Monti, J. Amer. Chem. SOC.,1977,99,8015. C. A. Brown, Synthesis, 1978, 754. J.-L. Gras, Tetrahedron Letters, 1978, 2111.

Monoterpenoids

71

a -Pinene is metabolized by Pseudurnonas putida to acyclic unsaturated C,, acids in addition to degraded and of the four verbenols only (+)-transverbenol [trans-(202;X = H,OH)] is oxidized [to (+)-verbenone (202; X = O)] using cell-free callus from Cannabis ~ a t i v a . ~ ~ ~ The structure of the major FeC1,-catalysed ene adduct of chloral to (1S,5S)(-)-P-pinene (Vol. 8, p. 54)is (209).96Preferred ene reaction of PhS0,NSO with P-pinene has been used for the almost quantitative separation of a- and P - ~ i n e n e another ; ~ ~ ~ application of this reaction allows the conversion of a pinene into P -pinene via a triple allylic transposition sequence of ene-reaction, reduction, reductive silylation, and hydroly~is.'~~ Ene reactions of p -pinene under pressure have been observed (74-100% yields) at room temperature thus limiting, for example, retro-ene s i d e - r e a c t i o n ~ .The ~ ~ ~ full papers on a pinene/allo-ocimene pyrolysis (cf. Vol. 7, p. 12)654and on the thermal rearrangement of (208; X = H or Me) have been published (Vol. 4, pp. 61, 62);655 to yield only (210) in contrast to unpublished (208; X = H ) is observations of Frater who has reported the rearrangement of (210) to (208; X = H ) and the formation of p-menthadiene derivatives from (208; X = H or 0 - 1 . ~ ~ ~

(209)

(210)

The rearrangement of (+)-2a,3cr!-epoxypinane on alumina depends upon how the alumina is modified; on A1,03-NaOH, the major product is (-)-transpinocarveol (30; 93%) but on Al2O3-LiC1pinocamphone [trans-(201; X = O)] predominates. lg7 Rearrangement of the two 2,l O-epoxypinanes over A1203NaOH gives closely similar mixtures of trans-myrtanal, myrtenaI (203;X = CHO, enantiomer), (-)-trans-myrtanol, and (-)-myrtenol (203; X = CH,OH, enantiomer), although there is an inconsistency over the formula and the sign of the optical rotation used for (--)-myrten01~~~ (for example, see that used by Klein and Rojahn22). Hydroboration-oxidation of (+)-2a,3a-epoxypinan-4-one yields (2R)-(211):(2S)-(211)/70:30 via (212) with no effect of added LiBHq.657

652

653 654

655 656

657

N. J. Tudroszen, D. P. Kelly, and N.F. Millis, Biochem. J., 1977, 168, 315. J. A . Gladysz and Y. S. Yu, J.C.S. Chem. Comm., 1978, 599. K. J. Crowley and S. G . Traynor, Tetrahedron, 1978, 34,2783. Y. Bessiere, C. Grison, and G . Boussac, Tetrahedron, 1978, 34, 1957. G . Frater, 2nd International I.U.P.A.C. Symposium on Organic Synthesis, Jerusalem-Haifa, September 1978; personal communication. A . Uzarewicz and E. Segiet-Kujawa, Polish J. Chem., 1978, 52, 6 3 .

72

Terpenoids and Steroids

Hydroboration of (+)-verbenone (202; X = 0) and treatment with hydroxylamine-0-sulphonic acid results in a 65% yield of (+)-cis-8-pinene (213)658by elimination, with no resultant a r n i ~ ~ eDehydrated .~~’ neutral alumina may be used for the room-temperature concerted 172-eliminationfrom 10-pinanyl tosylate to yield 0-pinene (70%) and some a-pinene (14%) with little rearrangement to camphene.660The addition of diethyl NJV-dichlorophosphoroamidate to (-)-apinene yields (+)-(214)661and the structure of the adduct (-)-(13) from MePC12AlCl, addition to (-)-a-pinene has been confirmed by X-ray anal~sis.~’ The addition of HCNO to a- and P-pinene was reported earlier.535

(213)

(214)

Further papers in this section include additional reports of the thermal rearrangement of a-pinene662aand P-pinene,662b another report of salicylic acidcatalysed rearrangement of a- and P-pinene (see Vol. 3, p. 71),663epoxidation of a -pinene in the presence of molybdenyl a c e t y l a ~ e t o n a t e ,oxidation ~~~ of a pinene in the presence of polychelates of bis(aminopheno1s) and C O I ~ ,another ~~’ report of anodic oxidation of a- and p-pinene,666the full paper on B2H6-LiBH4 reduction of (+)-2a, l O - e p ~ x y p i n a n efurther , ~ ~ ~ details of chrysanthenone reduction (cf. Vol. 7, p. 43)668and of the conformations of lactams and derivatives obtained from Beckmann rearrangement of isopinocamphone oxime [cis-(201; X = NOH)] (cf.Vol. 6, p. 43),669the nitration of (-)-isopinocamphone [cis-(201; X = 0),enantiomer] with cerium(1v) ammonium nitrate [to yield (+)-2-nitropinocamphone together with fragmentation and rearrangement the A. Uzarewicz, E. Segiet-Kujawa, and I. Uzarewicz, Roczniki Chem., 1977, 51, 1537. Fluoroboric acid gives the same result. The cis- and trans-8-pinenes have not been named fully by Klein and Roj ahn .22 659 For the preparation of isopinocampheylamine by this method, see M. W. Rathke and A. Millard, Org. Synth., 1977,57, no. 2049 accepted for testing. 660 G. H. Posner, G. M. Gurria, and K. A. Babiak, J. Org. Chem., 1977,42,3173. 66 1 B. Olejniczak, K. Osowska, and A. Zwierzak, Tetrahedron, 1978, 34, 2051. A violent explosion during the preparation of this reagent has been reported recently; B. J. Walker, Chem. in Britain, 1979,15,65. 662 J. de Pascual Teresa, I. Sanchez Bellido, M. R. Alberdi Albistegui, A. San Feliciano, and M. Grande Benito, ( a ) Anales de Quim., 1978,74, 301; ( 6 ) ibid., p. 305. 663 I. I. Bardyshev, E. N. Manukov, and V. A. Chuiko, Vestsi A k a d . Navuk belarusk. S.S.R., Ser. khim. Nauuk, 1977, (6), 87. 664 A. M. Romanikhin, Izvest. Vyssh. Uchebn. Zaved., Khim. khim. Tekhnol., 1977, 20, 1807. 665 T. K. Popova and N. I. Popova, Izvest. Vyssh. Uchebn. Zaved., Khim. khim. Tekhnol., 1977, 20, 821. 666 M. Kasano, Y. Sakai, K. Yokoi, Y. Matsubara, and C. Yoshimura, Kinki Daigaku Rikogakubu Kenkyu Hokoku, 1977, (12), 93 (Chem. A h . , 1977,87, 184 699). See Vol. 4, p. 57 for the earlier report. Anodic oxidation of limonene is also discussed. 667 A. Uzarewicz and E. Segiet-Kujawa, Roczniki Chem., 1977, 51, 2147. Repetition of most of the previously reported (Vol. 6, p: 43) (and uncited) paper does not seem justified to this Reporter. 668 C. A. N. Catalan, D. J. Merep, and J. A. Retamar, Rivista Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1977,59,480. 669 C. Wawrzenczyk and A. Zabza, Bull. Acad. polon. Sci., Skr. Sci. chim., 1977, 25, 605. 670 J. de Pascual Teresa, I. Sanchez Bellido, B. Corrales, and M. Grande Benito, Anales de Quim., 1977, 73, 1377.

658

Monoterpenoids

73

and Wagner-Meerwein rearaminomethylation of verbenone (202; X = 0),671 rangements on adding phenylselenenyl chloride to Q - ~ i n e n e . ~ ~ ~

Bicyclo[4,l,0]heptanes.-3-Methoxy-4-iodocarane has been reported to explode violently on standing.672 13 C N.m.r. chemical shifts of a number of monoterpenoids of this class are included in a study of bicycl0[4,l,O]heptanes.~~~ A further paper in a series on enthalpies of combustion and formation concerns the 3 , 4 - e p o ~ y c a r a n e s . ~ ~ ~ (+)-Car-2-ene and (-)-car-2-ene of high optical purity have been synthesized from the respective (-)- and (+)-trans-caran-2-onesYvia the analogous and uncited tosylhydrazone/methyl-lithium route used by Cocker et al. for synthesizing (-)-cis-car-4-ene (Vol. 1, p, 47), thus providing access (Vol. 2, p. 29, ref. 108) Cocker et al. have from the readily available (+)- and (-)-dihydrocar~ones.~~’ synthesized norcaran-3-one (via dibromocarbene addition to 4,4-dimethoxycyclohexene and treatment with lithium dimethylcuprate) from which car-2-ene, car-3-eneYand car-3(10)-ene were prepared.676 In the carane series, the known dependence of epoxy-ring opening on steric factor^^^^^'^ and of the cyclopropane ring on electronic has been examined further using (215; X = H,H; Y = 0 ) ;(215; X = 0, Y = H,H), (215; X = H , H ; Y=H,OH), and (215; X=H,P-OH; Y=H,H). The direction of cyclopropane ring opening in ethereal HCl is governed by the influence of the carbonyl group but does not occur in the alcohol series; the electronic influence of an adjacent carbonyl group partly overcomes steric inhibition of nucleophilic attack in epoxide ring opening [e.g. (216) : (217)/7 : 1is obtained from (215; X = O , Y=H,H), cf. ref. 6 7 7 ~ 1whereas an adjacent hydroxy-group stereospecifically directs epoxide ring opening distant from it even when opposed by steric hindrance to nucleophilic attack [e.g. (218) is obtained from (215; X = H,H; Y = H , c x - O H ) ] . B2H6-LiBH4 ~~~ hydroboration of (+)3a,4a -epoxycarane yields (-)-(219) with minor amounts of (3R)-(+)-(220) or the diols (22 1) depending upon the mode of addition; (-)-3P,4p epoxycarane yields (222; 93%) and (3S)-(-)-(220) with no effect of the order of reagent addition.679A fourth paperlg7in a series discussing oxiran rearrangements over silica gel and alumina reports a decided preference for trans- A3,’o-caren-4-01 formation (63%) from (+)-3aY4aepoxycarane over sodium hydroxide-modified 671

672

673

674

675

676 677

678

679

H. Krieger, A. Kojo, and A. Oikarinen, Finn. Chem. Letters, 1978, 185. D. R. Dimmel, Chem. Eng. News, 1977,55(27), 38. T. 1. Pekhk, K. E. Kooskora, E. T. Lippmaa, V. I. Lisenkov, G. V. Deshchits, and I. I. Bardyshev, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk. 1977, (l),96. M. P. Kozina, V. A. Aleshina, G. L. Gal’chenko, G. V. Deshchits, and I. I. Bardyshev, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1977, (6), 94. For earlier papers, see Vol. 6, p. 45 and Vol. 7, p. 44. P. Brunetti, F. Fringuelli, and A. Taticchi, Gazzetta, 1977, 107, 433. W. Cocker, N. W. A. Geraghty, and D. H. Grayson, J.C.S. Perkin I, 1978, 1370. ( a ) E.g. for acid-catalysed cleavage, see Vol. 4, p. 64, ref. 305 and Vol. 7, p. 45, ref. 439a; ( 6 ) for LiAlH4 cleavage, see Vol. 7, p. 45, ref. 4396 and Vol. 8, p. 57, ref. 519; (c) e.g. see Vol. 2, p. 56, ref. 233. In Vol. 4, p. 64 the reference number on lines 3 and 5 should be 306 and not 305. B. A. Arbuzov, Z. G. Isaeva, and A. N. Karaseva, Proc. Acad. Sci. (U.S.S.R.), 1977, 237, 626. A. Uzarewicz, E. Zientek, and I. Uzarewicz, Polish J. Chem., 1978,52,389; cfi Vol. 8, p. 57. This paper, and earlier papers in the series, would be clearer with better formulae drawing and more use of formulae numbers in the text; in addition, the international numbering system of the caranes is not used.

74

Terpenoids and Steroids

(219)

(220)

(221)

(222)

alumina compared with alumina alone; alumina modification with sodium chloride gives results similar to those with silica gel (see references therein for the earlier work). 197 Another paper680a from Cocker's laboratory reports a reexamination of an earlier report6'Ob of treating (+)-carane-3&4a -diol with sulphuric acid; the major products are (223)-(226).680"

(223)

(224)

(225)

(226)

Further papers in this section include a straightforward synthesis of 4-methylcar-3-ene and some derivatives,681another report of cobalt-catalysed air oxidation of car-3-ene (cf. Vol. 7, p. 45),682 anodic oxidation of car-3-ene to yield 2,6,6-trimethylcyclohepta-2,4-dienol predominantly (together with some p menthane a further paper (cf.Vol. 8, p. 57) on dehydrogenation of car-3-ene over chromia and chromia-alumina the full paper on isomerization of 2,3- and 3,4-epoxycaranes over solid acids and bases,685 dimerization of (-)-cis-caran-4-one to 4-caranylidenecarane (mostly trunsoid) using the diamagnetic complex [THF,C12MgzTi]z,686(+)-car-3-ene nitroso680

"' 682

683

684

( a ) W. Cocker and D. H. Grayson, J.C.S. Perkin I, 1978, 155; ( 6 ) P. P. Pillay and J. L. Simonsen, J. Chem. SOC.,1928, 359. L. K. Novikova, 0. B. Skripnik, G. Sh. Bikbulatova, S. G. Vul'fson, 2. G . Isaeva, and A . N. Vereshchagin, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1978, 605. H. Sadowska, J. Kulesza, and J. Podlejski, Tlustcze, Srodki Piorace, Kosmet., 1976,21,393 (Chem. Abs., 1978, 88, 23 163); for an earlier report, see Vol. 7, p. 45. M. Kasano, K. Matsumoto, F. Hosogi, Y . Matsubara, and C. Yoshimura, Kinki Daigaicu Rikogakubu Kenkyu Hokoku, 1977, (12), 89; Chem. Abs., 1977,87,184 698 names this product poorly. V. Krishnasamy, Canad. J. Chem., 1978, 56, 1994. K. Arata, J. 0. Bledsoe, jun., and K. Tanabe, J. Org. Chem., 1978, 43, 1660; for the (unacknowledged) communication, see Vol. 8, p. 57. P. Sobota, C. Wawrzenczyk, and J. Utko, Bull. Acad. polon. Sci., Se'r. Sci. chim., 1977, 25, 957.

Monoterpenoids

75

and the rapid dealkylation of B-(4- isocaranyl)-9-borabicyclo[3,3,l]nonane with benzaldehyde.688

9 Furanoid and Pyranoid Monoterpenoids The occurrence and syntheses of rose oxides, dihydrorose oxides, rosefuran, and nerol oxides, together with related compounds, have been reviewed.689The structure of a cyclic monoterpenoid ether from Artemisia tridentata, which is related to the santolinyl monoterpenoids, has been confirmed (cf.Vol. 7, p. 20) as (227) and renamed artemiseole (cf. Vol. 8, p. 58 for an incorrect structural dedu~tion).~~' Interestingly, another new component of A. tridentata, the (3s)diastereoisomer of (74), with formic acid yields (227) in contrast to (74) which yields the acyclic aldehyde (228).690It is possible that some of the 31% of unidentified components in the essential oil of A . annua may correspond to these new The quinone (229) has been isolated from Lithospermum e~ythrol'hizon,~~~ and further details on the presence of aeginetolide in Aeginetia indica have been I

(227)

(228)

(229)

The full paper (Vol. 8, p. 58) on the biogenetic-type synthesis of the linalyl oxides has been published383and dihydro-ocimenoyl oxide (230) has been synthesized by the regiospecific reaction of 2-methylbutanal with the y-carbon atom of a,a-dimethylallyltrimethylsilanecatalysed by TiC14, presumably via cyclization of the corresponding y - ~ h l o r o - a l ~ o h oStraightforward l.~~~ syntheses of perillene (231; X = H,H) and egomaketone (231; X = 0)involve prenylation X

(230)

(231)

'"C. P. Mathew and J. Verghese, Indian J. Chem., 1977, lSB, 1081. '89

690 691

692

693

M. M. Midland, A. Tramontano, and S. A. Zderic, J. Organometallic Chem., 1978,156,203; cf. Vol. 8, p. 6. Y .R. Naves, Rivista Ital. Essenz-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1978,60, 265. T. A. Noble and W. W. Epstein, Tetrahedron Letters, 1977, 3931; see also ref. 406. E. V. Georgiev, N. S. Genov, R. D. Lazarova, and G. P. Gantchev, Rivista Ital. Essenre-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1978, 60, 302. 0. E. Krivoshchekova, S. A. Fedoreev, V. A. Denisenko, and 0. B. Maksimov, Chem. Natural Compounds, 1977,13,586. S . S . Dighe, S. V. Manerikar, and A. B. Kulkarni, Indian J. Chem., 1977, lSB, 546; see Vol. 6, p. 47 for the earlier report.

76

Terpenoids and Steroids

of 2-(3'-furyl)-1,3-dithianfollowed by appropriate d e ~ u l p h u r a t i o nIrradiation .~~~ of furan and 4-methylpentanal in the presence of methanesulphonic acid gives, after oxidation, a low yield (12%) of perillaketone [dihydro-(231; X = O)],""" the corresponding heterocyclic sulphur analogue of which is available from the efficient Pd(OA~)~-catalysed reaction of 3-bromothiophen with 4-methylpent-len-3-01.~" Prenylation of the lithio-enolate of 2-methylbut-2-enolide gives 40% of the y-prenylbutenolide which is readily reduced to rosefuran (232),696which is also reported to be obtained by Cu-Mg coupling of 2-bromo-3-methylfuran and prenyl The cis- and trans-rose oxides (233) have been prepared with little novelty via 5-hydroxycitronellol,6g*and more usefully (36% yield) by the one-step reaction of citronellol with N-iodosuccinimide in CC14.699 A stereocontrolled synthesis of (-)-cis-rose oxide [cis-(233)] from D-glucose via the Cerny

1

(232)

(233)

epoxide (234) is shown in Scheme 6.'" Another synthesis of the rose oxides (233) is based upon routine modifications of (235) which results from reaction of

aooo0 0 ocHo 0 CH ,OTr

CH,OAc

4

i ,

iii-vii

OAc OAc

OH

0

~

OMS

(234)

viii

1

cis-(233)

2

1

C H ,OTr

e ix-xi --

Me' Reagents: i, LiCuMez; ii, BF,,Et*O-Ac20; iii, Bu3SnSEt-SnC14; iv, NaOMe-MeOH; v, Raney Ni(W-4)-EtOH-NaBH4; vi, TrC1-py; vii, MsC1-py; viii, NaI-HMPA, 100 "C; ix, H2Pd/C; x, Arnberlist 15-MeOH; xi, pyridinium chlorochromate; xii, Me2C=PPh3

Scheme 6 694 695

b96 697

698

699 700

T. Kitamura, Y. Kawakami, T. Imagawa, and M. Kawanisi, Synth. Comm., 1977,7,521. Y. Tarnaru, Y. Yamada, and Z.-I. Yoshida, Tetrahedron Letters, 1977, 3365. D. R. Gedge and G. Pattenden, Tetrahedron Letters, 1977, 4443. A. Takeda and K. Nihama, Jap. P. 136 162/1977 (Chem. A h . , 1978,88,170 342). This synthesis is conceptually the same as that reported previously by A. Takeda et al. (Vol. 8, p. 59). J. S. Patel, H. H. Mathur, and S. C. Bhattacharyya, Indian J. Chem., 1978, 16B,188; for related work, see Vol. 1, p. 48; Vol. 3, p. 84; Vol. 7, p. 46. S. C. Taneja, K. L. Dhar, and C. K. Atal, J. Org. Chem., 1978,43,997. T. Ogawa, N. Takasaka, and M. Matsui, Carbohydrate Res., 1978,60, C4.

Monoterpenoids

77

(235)

formaldehyde with the telomer 2,6-dimethylo~ta-1,3,6-triene.~~~ The conformations of the rose oxides (233) and related compounds have been investigated by 13Cn.m.r.702The course of dehalogenation of 1,3-dibromo-3-methylbutan-2-one in the presence of isoprene is modified further (cf.p.62 and Vol. 8, p. 48) by using Cu-NaI, when cyclohept-4-enone and vinylcyclopentanone formation is suppressed in favour of (236) and the minor product (237), both of which may undergo [3,3] sigmatropic rearrangement to cyclohept-4-enones7 e.g. (237) to karahanaenone (27; X = O).5716 In a study of brominative (Br,-AgBF,) and acid-catalysed cyclization of homogeranic acid (cf. Vol. 4, p. 5 ) , it has been established that the trans -1actones are kinetically favoured over the thermodynamically favoured ~ i s - l a c t o n e s LY; ~-phenylselenylation ~~ of the lactones (238), oxidation, and thermal extrusion of benzenselenenic acid yields dihydroactinidiolide (239)703of which further details of related synthetic work have been

10 Cannabinoids and other Phenolic Monoterpenoids The structure of isoxanthochymol has been revised [to reposition a prenyl double bond into a terminal position in keeping with the structure of xanthochymol reported last year (Vol. 8, p. 60)]’”’ despite an earlier (incomplete) reportlo2of an X-ray structure determination. Further details (cf. Vol. 7, pp. 48, 49) of the chemistry and structures of (-)-bruceol (14; X = OH, Y = H),97 (*)-deoxybruce01,~~ chromenes and citrans produced from phloroacetophenone and phloroglucinaldehyde by citral c ~ n d e n s a t i o nand , ~ ~ rubranine9’ have been published; in a related paper the isolation of (-)-rubranhe from Aniba rosaeodora 701

702

703 704

T. Yamato and M. Nakamura, Rivistu Ital., Essenze-Profumi, Piante Ofic.,Aromi, Saponi, Cosmet., Aerosol., 1978, 60, 142 (VIIth International Congress of Essential Oils, Kyoto, October 7-11, 1977, Abstract No. 83). E. Kleinpeter, Ch. Duschek, and M. Muhlstadt, J. prukt. Chem., 1978, 320, 303. T. R. Hoye and M. J. Kurth, J. Org. Chem., 1978,43, 3693. K. Uneyama, M. Kuyama, and S. Torii, Bull. Chem. SOC.Japan, 1978,51,2108; cf. Vol. 7, p. 47. For related patents, see S. Torii, K. Uneyama, and M. Hisayama, Jap. P. 100 462/1977 (Chem. Abs., 1978, 88;23 198); S. Torii, K. Uneyama, I. Kawahara, and K. Ito, Jap. P. 106 846/1977 (Chem. A h . , 1978,88,89 888); K. Uneyama, G. Kuyama, and S. Torii, Jap. P. 106 859/1977 (Chem. Abs., 1978, 88, 121 458). S. C. Basa, P. Mahanty, and D. P. Das, Chem. and Ind., 1978, 166.

723

Terpenoids and Steroids

and a further examination of suggested biogenetic-type synthetic work (cf.Vol. 4, p. 75) has been Alliodorin (as its dimethyl ether) has been synthesized again .707 Tetrahydrocannabivarinic acid, cannabidivarinic acid, cannabichromevarinic acid, and cannabigerovarinic acid are the C-3" carboxylic acid derivatives of known propyl side-chain c a n n a b i n ~ i d sand , ~ ~others ~ are propyl homologues of cannabichromanone, cannabielsoin, and cannabielsoic acid B.709Turner et al. have reported an additional triol (240) from Cannabis s ~ t i v u . ~ ' ~

Several X-ray structure determinations have been reported earlier. 103-106 Cannabinoid analytical papers concerning cannabin01,'ll A1-THC,712*713 7h y d r ~ x y - A ' - T H C , and ~ ~ ~A1-tetrahydrocannabinol-7-oic and a further paper on the use of silyl ethers for g.c.-m.s. analysis of cannabinoid~~" have been published. M.S. fragmentation patterns of a number of cannabinoids and their pentyl side-chain homologues have been and metalloimmunoassay of A6-tetrahydrocannabinol-7-oicacid has been The synthons (241) condense718with olivetol, a useful synthesis of which has been p ~ b l i s h e d , to ~'~ yield A'-THC derivatives which do not undergo conversion into the A6-THC analogues in the presence of Two approaches to the synthesis of side-chain-hydroxylated tetrahydrocannabinoids involve the well706

707

708

709

710

7 1I 712

713 714 715 716

717

718

719

I. B. de Alleluia, R. B. Fo, 0. R. Gottlieb, E. G. Magalhaes, and R. Marques, Phytochemistry, 1978, 17, 517. 0. P. Vig, S. D. Sharma, N. K. Verma, and V. K. Handa, Indian J. Chem., 1977,15B, 988; cf.Vol. 7, p. 48. Y. Shoyama, H. Hirano, H. Makino, N. Umekita, and 1. Nishioka, Chem. and Pharm. Bull. (Japan), 1977,25,2306. The ~arboxy-'~C-labelledacids have also been synthesized; Y. Shoyama, H. Hirano, and I. Nishioka, J. Labelled Compounds, 1978, 14, 835. H. Grote and G. Spiteller, J. Chromatog., 1978, 154, 13. A. Elsohly, E. G. Boeren, and C. E. Turner, Lloydia, 1977,40,619(Proceedings of the 18th Annual Meeting of the American Society of Pharmacognosy; August 1977, Seattle, Washington). An accompanying triol was reported last year (Vol. 8, p. 61). P. J. Twitchett, P. L. Williams, and A. C. Moffat, J. Chromafog., 1978,149, 683. S . L. Kanter, L. E. Hollister, and K. 0.Loeffler, J. Chromatog., 1978,150,233; P. L. Williams, A. C. Moffat, and L. J. King, ibid., 1978,155,273; D. Rosenthal, T. M. Harvey, J. T. Bursey, D. R. Brine, and M. E. Wall, Biomed. Mass Spectrometry, 1978, 5 , 312; J. L. Valentine, P. J. Bryant, P. L. Gutshall, 0. H. M. Gan, P. D. Lovegreen, E. D. Thompson, and H. C. Niu, J. Pharm. Sci., 1977,66, 1263. J. Rosenfeld, Analyt. Letters, 1977, 10, 917. S . L. Kanter and L. 8.Hollister, J. Chromatog., 1978, 151, 225. D. J. Harvey, J. Chromatog., 1978,147, 291. T. B. Vree, J. Pharm. Sci., 1977,66, 1444. M. Cais, S. Dani, Y. Eden, 0. Gandolfi, M. Horn, E. E. Isaacs, Y. Josephy, Y. Saar, E. Slovin, and L. Snarsky, Nature, 1977,270,534. D. B. Uliss, G. R. Handrick, H. C. Dalzell, and R. K. Razdan, J. Amer. Chem. SOC.,1978,100,2929. A. Focella, S. Teitel, and A. Brossi, J. Org. Chem., 1977, 42, 3456.

Monoterpenoids

79

known condensation of p-mentha-2,8-dien- 1-01with C-5 -substituted resorcinols as the key step; one involves modifying an alkanoic ester ~ide-chain~~' and the other the elaboration of a 4'-( 1,3-dithian-l-y1) group.721Conversion of A1-3,4cis -THC into A6-3,4-trans-THCusing BBr3involves predominant epimerization at C-4.722Other papers of synthetic interest concern an improved synthesis of (f)-~annabichrornene,~'~ 1-a~acannabinoid,~'~1-ketocannabin~id,''~ 4 hydroxy~oumarin,~~~ and 4-hydroxythio~oumarin~~~ analogues, and the synthesis of A6-THC-C-4'-glucuronide727 which has also been isolated from mouse liver in V ~ V O . ~ ~ ~

The formation of O-glucuronides has been observed during in vivo cannabinol metabolism in the mouse and rat and compared with A'-THC and cannabidiol m&abolism (cf. Vol. 7, p. 51; Vol. 8. p. 63);729additional anticipated in vivo metabolites are reported in two further papers.73oAnother report of the microbiological oxidation of the pentyl side-chain of cannabinoids using Syncephalas trurn racernosurn (Vol. 7, p. 5 1) identifies 4",5"-bisnor-3"-hydroxycannabidiol as a major cannabidiol metabolite and includes data on Mycobacterium rhodochrous (which promotes terminal oxidation and acid degradation).731Microbial hydroxylation of (-)-A1-THC using Chaetomium globosum occurs in the side-chain (C-3") and at C-7.732 Two additional cannabidiol pyrolysis products have been identified [one is (242)733and the other corresponds to cannabidiol with the phenolic and pentyl 720 'I2*

722

723 724

728

729 730

'I3' 732

F. Lotz, U. Kraatz, and F. Korte, 2. Naturforsch., 1978, 33b, 349. C. G. Pitt, H. H. Seltzman, Y.Sayed, C. E. Twine, jun., and D. L. Williams, Tetrahedron Letters, 1978, 37. D. B. Uliss, G. R. Handrick, H. C. Dalzell, and R. K. Razdan, Tetrahedron, 1978,34, 1885. M. A. Elsohly, E. G. Boeren, and C. E. Turner, J. Heterocyclic Chem., 1978, 15,699. C.-M. Lee, R. J. Michaels, H. E. Zaugg, A. T. Dren, N. P. Plotnikoff, and P. R. Young, J. Medicin. Chem., 1977,20,1508. R. A. Archer, W. B. Blanchard, W. A. Day, D. W. Johnson, E. R. Lavagnino, C. W. Ryan, and J. E. Baldwin, J. Org. Chem., 1977,42, 2277. S . Y. Dike and J. R. Merchant, Bull. Chem. SOC. Japan, 1978,51,2145. 1977,99,6444; cf. Vol. 3, B. Yagen, S. Levy, R. Mechoulam, and Z. Ben-Zvi, J. Amer. Chem. SOC., p. 89. The numbering of the aromatic ring is incorrectly depicted in a previous Report [Vol. 2, p. 61, formula (332)l; the numbering of this ring is depicted correctly in formula (240). S.Levy, B. Yagan, and R. Mechoulam, Science, 1978,200, 1391. D. J. Harvey, B. R. Martin, and W. D. M. Paton, Biomed. Mass Spectrometry, 1977, 4, 364. W. Yisak, S. Agurell, J.-E. Lindgren, and M. Widman, J. Pharm. Pharmacol., 1978,30,462; W. A. Yisak, M. Widman, andS. Agurell, ibid., 1978, 30, 554. L. W. Robertson, S.-W. Koh, S. R. Huff,R. K.Malhotra, and A. Ghosh, Experientia, 1978,34,1020. R. M. Christie, R. W. Rickards, and W. P. Watson, Austral. J. Chem., 1978, 31, 1799.

Terpenoids a n d Steroids

80

I OH

(242)

HO (243)

groups interchanged, uiz. (243)733"],and the acid-catalysed degradation of A'THC has been examined further (cf. Vol. 6, p. 50).734

733

734

M. Luteyn, H. J. W. Spronck, and C. A. Salemink, ibid.,1978,97, 187; see Vol. 8, p. 63 for earlier work. E. R. Garrett, A. J. Gouyette, and H. Roseboom, J. Pharm. Sci., 1978,67, 27. ( a ) H. J. W. Spronck and C. A. Salemink, Rec. Truv. chim., 1978,97,185; ( b )J.

Sesqu iterpenoids BY T. MONEY

1 Farnesane

The use of a-alkoxystannanes in organic synthesis has been convincingly illustrated in a new synthesis of (2)-dendrolasin (4; R = H ) and (&)-9-hydroxydendrolasin (4; R = OH)' (Scheme 1). SnBu3

(--j i*iit(--f----o, CHO

-R

(2) 0-

I

(4; R = H)

(4; R = OH) Reagents: i, Bu3SnLi; ii, EtOCHClMe; iii, BuLi; iv, geranyl chloride; v, Li-NH3; vi,

H30+

Scheme 1

Further studies on the controlled oligomerization of isoprene (5) have shown that treatment with a nickel alkoxide catalyst provides trans-@-farnesene (6) in -60% yield.2

A new synthesis of grifolin (9), involving treatment of farnesyl chloride (8)with orcinol (7) in the presence of sodium, is reported to give a better yield than the various syntheses previously recorded for this compound3 (cf. Vol. 5 , p. 91). W. C. Still, J. Amer. Chem. SOC.,1978,100,1481. S.Akutagawa, T.Taketomi, H. Kumobayashi, K. Takayama, T. Someya, and S. Otsuka, Bull. Chem. SOC.Japan, 1978,51,1158. S. Yamada, F. Ono, T. Katagiri, and J. Tanaka, Synth. Comm., 1978,8,241.

81

Terpenoids and Steroids

82

Several new acyclic sesquiterpenoids have been reported during the past year: ,~ these include the a-farnesene derivative (10) (Peterauenia s c h u l t ~ i i )ageraborniol (1 1) (Ageratina aschenbornia),' eumorphinone (12), and cycloeumorphinone (13) (Eumorphia species).6

The elegant and fundamental investigations of Cornforth and his collaborators have previously shown that the biosynthesis of farnesyl pyrophosphate (16) involves condensation between C-1 of geranyl pyrophosphate (14)(G-P,) and the si,si face of isopentenyl pyrophosphate (15) (IPP). During this condensation process (Scheme 2 ) inversion of configuration occurs at C-1 of geranyl pyrophosphate (14) and a pro-E hydrogen (H") of isopentenyl pyrophosphate (15) (originally 2-pro-S of mevalonic acid) becomes located at the 4-pro-s position in farnesyl pyrophosphate (16). Recent investigations'**in this area have shown that the condensing enzyme (farnesyl synthetase; prenyl transferase) is able to condense diastereomeric pyrophosphates (1 8 ) and (19) with dimethylallyl pyrophosphate (17) or geranyl pyrophosphate (14) in a similar stereochemical fashion (cf. Scheme 3). Biosyntheticstudies on the phytoalexins (Vol. 8 , pp. 65,106) (cf.pp. 135,145), produced by diseased sweet potatoes have demonstrated that ipomeamorone (24) F. Bohlmann and A. Suwita, Phytochemistry, 1978,17,567.

' F.Bohlmann and L. Fiedler, Phytochemisfry, 1978,17,566.

' F. Bohlmann and C. Zdero, Phytochemisfry, 1978,17,1155. T. Koyama, K. Ogura, and S. Seto, J. Amer. Chem. SOC., 1977,99,1999. Cf C.D.Poulter, D. M. Satterwhite, and H. C. Rilling, J. Amer. Chem. SOC.,1976,98,3376.

Sesquiterpenoids

83

(16) Scheme 2

L

O

P

- A/++P

2 +2*+0p2

\

\

H

* H

*

op2

H

serves as a biosynthetic precursor of (4')- or 6-hydroxymyoporone" (25)9 (cf.Vol. 8, p. 65). L. T. Burka and L. Kuhnert, Phytochemistry, 1977,16,2022.

* Different uiz.:

numbering systems are presently used for farnesane sesquiterpenoids by various authors,

(1) farnesane

numbering,

12

and (2) IUPAC system,

I

In ref. 9 the former numbering system is used (cf. also ref. 1).

84

Terpenoids and Steroids

The proposed biosynthesis of two of the three insect juvenile hormones, JH I (32) and JH I1 (33), involves a modified biosynthetic scheme in which propionyl coenzyme A replaces acetyl coenzyme A to produce homomevalonic acid (27) (see Vol. 6, pp. 56, 186; Vol. 7, pp. 54, 199, Vol. 5, pp. 47, 174, 182; Biosynthesis" Vol. 5, p. 61, Vol, 3, p. 6). This compound and the normal terpenoid precursor, mevalonic acid, are then used to provide the homosesquiterpenoids JH I (32) and JH 11 (33) by the reaction sequences shown in Scheme 4 EtCOSCoA+ MeCOSCoA

--+

EtCOCH,COSCoA

1

2

(17) + 2( 15)

(32) (JHI) R 1 = R 2 = M e (33) (JH 11) R' = Me, R2 = H (34) (JH 111) R' = R2 = H Scheme 4

* 'Biosynthesis', ed. J. D. Bu'Lock (Specialist Periodical Reports), The Chemical Society, London, Vol. 3, 1975; Vol. 5 , 1977.

85

Sesquiterpenoids

[JH I11 (34), the third juvenile hormone, is of course produced from three molecules of mevalonic acid (35) in the normal way]. Recent studies have provided support for these schemes by demonstrating that 3-hydroxy-3-ethylglutaric [cf. (26)], homomevalonic (27), and mevalonic acid (35) can be synthesized by crude enzymes isolated from the corpora allata of Manduca sexta."

2 Mono- and Bi-cyclofarnesanes The isolation, structural elucidation, and total synthesis of insect pheromones continue to be a very active area of natural product research (cf. Vol. 8, pp. 66, 102). A recent paper" in this area describes the identification of ancistrodial(36) and ancistrofuran (37) as components of the defence secretion of termite soldiers (Ancistrotermes cauithorax).

(36)

(37)

Interest in the metabolites of marine organisms remains undiminished (see, e.g. Vol. 8, pp. 65,66,75,79,82,101,108).A detailed investigation of the terpenoid constituents of the Indo-Pacific sponge (Pseudaxinyssa pitys) has resulted in the isolation of several novel carbonimidic dichlorides (38)-(42).12-14 It has been ~

N =CCI,

H

O

W

N

-

,

c1 (39a,b) A','; (40a,b)

(41)

cis and trans N=CC12 cis and trans N=CC12

(42)

suggested13 that the unusual bicyclofarnesane framework of (38)-(41) [cf. pallescensin-A (47)] is formed by chloronium ion-initiated cyclization of the lo

l1 l2 l3 l4

( a ) E. Lee, D. A. Schooley, M. S. Hall, and K. J. Judy, J.C.S. Chem. Comm., 1978, 290; ( b )F. C. Baker and D. A. Schooley, ibid., p. 292. R. Baker, P. H. Briner, andD. A. Evans, J.C.S. Chem. Comm., 1978,410. S . J. Wratten and D. J. Faulkner, J. Amer. Chem. SOC.,1977,99,7367. S. J. Wratten, D. J. Faulkner, D. V. Engen, and J. Clardy, Tetrahedron Letters, 1978, 1391. S. J. Wratten and D. J. Faulkner, Tetrahedron Letters, 1978, 1395.

Terpenoids and Steroids

86

acyclic metabolite (42). The absolute configurations of pallescensin-1 (46), -2 (48), and -A (47) (cf. Vol. 5 , p. 92) have been established by total synthesis of (46) and (47) from ( R ) - (-)-cyclocitral (43)15(cf.Scheme 5).

\O'

(43)

(44)

(45)

Reagents: i, BuLi; ii, H,-5% Pd/C-EtOH; iii, A1Cl3-CH,CI,, -5 "C

Scheme 5

Zonarol(54) and isozonarol(55), fungitoxic constituents of brown seaweed (cf. Vol. 6, p. 94) have been synthesized from the ketol (49) by a reaction sequence (Scheme 6) in which the hydroquinone unit is attached to the bicyclofarnesane system by 1,4-addition of Grignard reagent to the enone (52).16 (It)-Puupehenone (62), an antibacterial component of a Hawaiian marine sponge (unknown genus), has been synthesized from farnesyl bromide (56) and the lithium salt of sesamol (57)" (cf.Scheme 7). Further examination of bark extracts of the East African tree Warburgia ugandensis ('Muziga' in Swahili) (Vol. 8, p. 66) has resulted in the isolation of muzigadial (63).'* The rearranged drimane skeleton assigned to muzigadial is based on spectroscopic evidence. It has also been shown that this compound has approximately the same antifeedant activity against army worms (Spodopteru species) as its co-metabolite warburganal (64) (Vol. 8, p. 66) and that both compounds exhibit potential antifungal, antiyeast , and plant-growth regulatory activity." (+)-Abscisic acid (ABA) (65), an important plant-growth regulator in higher plants, has been identified, for the first time, as an authentic metabolite of a fungus (Cercospora r o s i c ~ l a )Further . ~ ~ research on the constituents of bird's nest fungi (cf.Vol. 7, p. 95; Vol. 8, p. 111)has established that the bicyclofarnesane lactones (66a-c) are produced by still cultures of Mycocalia reticulata Petch.20 An l6

l7

l9 2o

T. Matsumoto and S. Usui, Chem. Letters, 1978, 105 S. C. Welch and A . S. C. P. Rao, J. Org. Chem., 1978,43, 1957. G . L. Trammell, Tetrahedron Letters, 1978, 1525. I. Kubo, I. Miura, M. J. Pettei, Y.-W. Lee, F. Pilkiewicz, and K. Nakanishi, Tetrahedron Letters, 1978,4553. G . Assante, L. Merlini, and G . Nasini, Experientia, 1977, 33, 1556. W. A . Ayer and S. Fung, Tetrahedron, 1977, 33,2771.

87

Sesquiterpenoids

(53) ix-xii/

:oJJH -

“

O

D OH

Reagents: i, N2H4-KOH-(CH20H),; ii, Cr0,-H,O+-Me,CO; iii, MeLi; iv, Me,SO, 155 “C; v, MCPBA-Na,HPO,-CHCI,; vi, LDA-THF; vii, CrO,,pyz-CHzC1,; viii, 2,5-dimethoxyphenylmagnesiumbromide; ix, Ac20; x, KOH-MeOH; xi, MeLi; xii, BUSH-HMPA, 150 “C

Scheme 6

independent investigationz1 has confirmed the previous assignmentz2of the absolute configuration of the fungal sesquiterpenoid cyclonerodiol (67) (cf.Vol. 7, p. 58). Related studiesz3on the incorporation of [2-14C]mevalonicacid into cyclonerodiol (67) have provided results in complete agreement with those previously publishedz4(Vol. 7, p. 194). Although the proposed biosyntheticroute to cyclonerodiol(67) and cyclonerotriol(68) involves farnesyl(l6) and nerolidyl (69) pyrophosphates as intermediates only the former compound has been incorporated into cyclonerodiol.z4However, support for the proposed biosynthetic route (cf. Vol. 7, p. 194) has besn provided by a recent study which has demonstrated that farnesyl and nerolidyl pyrophosphates can be converted into cyclonerodiol (67) by a cell-free extract derived from Gibberella f~jikuroi.’~ D. E. Cane and R. Iyengar, Tetrahedron Letters, 1977, 3511. J. R. Hanson, P. B. Hitchcock, and R. Nyfeler, J.C.S. Perkin I, 1975, 1586. 23 D. E. Cane and M.-S. Shiao, J. Amer. Chcm. SOC., 1978,100,3203. 24 R. Evans, J. R. Hanson, and R. Nyfeler, J.C.S. Perkin I, 1976,1214. ’’ D. E. Cane and R. Iyengar, J. Amer. Chem. SOC.,1978,100,3256. 21 22

Terpenoids and Steroids

88

k--iii

iv,v +

t vi,vii

(61) viiil

Reagents: i, Ac20-py; ii, BF3Et20-CH2C12; iii, KOH-MeOH; iv, naphthalene-2-sulphonic acidCH2Cl2; v, florid chromatography; vi, PC15-CH2C12; vii, H20-MeOH, A; viii, KOHMeOH-02

Scheme 7

f,"3 CHO

H.

CHO

HO

@

HO

89

Sesquiterpenoids

(66) a; R ' = R 2 = H b; R ' = O H , R 2 = H C; R ~ = R ~ = O H

(67) R = H (68) R = O H

Fermentation of Cochliobus miyabeanus in an atmosphere of N2 (79%), '*02 (10.5%), and I6O2 (10.5%) provides cochlioquinones-A (71a) and -B (71b)

containing two atoms of oxygen-18 (cf.Vol. 8, p. 67). Analysis of the mass spectra of the methyl ester (72) and lactone (73) derived from cochlioquinone-B (71b)has led to the conclusion that the two oxygen atoms of the 2-(2-hydroxypropyl)tetrahydropyran system in these compounds are derived from different oxygen This result is consistent with the intermediacy of a bis-epoxide [e.g. (70)] in the biosynthesis. 1

&: (70)

(71) a; R' = OAc, R2 = H, R3 = OH b; R1, R 2 = 0 , R 3 = H

@lo HO

HO (72) 26

:

(73)

L. Canonica, L. Colombo, C. Gennari, B. M. Ranzi, and C. Scolastico, J.C.S. Chem. Cornm., 1978, 679.

90

Terpenoids and Steroids

3 Bisabolane The previously reported biogenetic-type cyclization of nerol and geraniol to limonene using 2-fluoropyridinium salts has been extended to the sesquiterpenoid area.27Thus treatment of cis,truns-farnesol(77) with 2-fluoropyridinium (74), 2-fluorobenzothiazolium ( 7 3 , or 2-chlorobenzothiazolium (76) salts resulted in the formation of a-bisabolene (78) and y-bisabolene (79) in 55-75’/0 yield.

C3-Sr;r.p OH

(+) -Curcopheno1 (81), (-)-curcuquinone (82), and (-)-curcuhydroquinone (83)have been identified as antibacterial constituents of the Caribbean gorgonian Pseudopterogorgia rigidu.28Curcophenol (81) has also been synthesized in high yield from 2-hydroxy-4-methylacetophenone(go).**Further investigation of the essential oil of Cedrus deodora Loud. has resulted in the isolation and structural elucidation of two new acidic constituents, limonenecarboxylic acid (84) and deodardione (85).29The former compound (84) may arise by degradation of a bisabolane-type sesquiterpenoid while deodardione (85) could be produced by oxidation of the co-metabolite deodarone (86) (cf. Vol. 8, p. 67). The latter transformation can be accomplished in the l a b ~ r a t o r y . ~ ~ Recent studies have shown that the insect juvenile hormone analogues juvabione (87) and derivatives (88)-(90), produced by Abies alba, occur in 4R,l’R and 4R,l’S diastereomeric forms. It has been suggested that these sesquiterpenoids (cf. Vol. 8, p. 67) may be of value in chemosystematic studies of

Hp

J+j, 3 steps,

27

29

S. Kobayashi, M. Tsutsui, and T. Mukaiyama, Chem. Letters, 1977, 1169. F. J. McEnroe and W. Fenical, Tetrahedron, 1978, 34, 166. S. Krishnappa and S. Dev, Tetrahedron, 1978, 34, 599.

Sesquiterpenoids

91

&c02h

JJn ?H

0

\

Me0,C

a 0 qo A

Me0,C

(87)

the genus A b i e ~ . ~The ’ synthesis of (-)-a-bisabololone (99) and (+)-a-bisabolol (95) from diastereomeric epoxides derived from the appropriate enantiomer of limonene [cf. (91), (96), Scheme 81 has established the absolute configuration of (cf. Vol. 8, p. 69). these se~quiterpenoids~~ A general method for the synthesis of a,P-unsaturated aldehydes from vinylsilanes has been incorporated into a new synthetic route to (*)-nuciferal (102) (Scheme 9).32 Senedigitalene (103) and its derivatives (104) and (105) have been isolated from Senecio digitulifolius and their norbisabolane structures determined by spectroscopic means.33 J. F. Manville, K. Bock, and E. von Rudloff, Phytochemistry, 1977, 16, 1967. A. Kergomard and H. Veschambre, Tetrahedron, 1977, 33,2215. 32 K. Yamamoto, J. Yoshitake, N. T. Qui, and J. Tsuji, Chem. Letters, 1978, 859. ” F. Bohlmann and C. Zdero, Phytochemistry 1978,17,759. 30

31

Terpenoids and Steroids

92

(99)

T

iii-v

Reagents: i, H202-MeOH-MeCN; ii, Me2C=CHCH2MgCl; iii, KCN-EtOH-H20; iv, CH2=CMeCH2MgCl; v, KOH-MeOH

Scheme 8

Reagents: i, DIBAH; ii, MeLi; iii, MeI; iv, C12CHOMe-TiCI4

Scheme 9

93

Sesquiterpenoids

4 Sesquipinane (Bergamotane), Sesquicamphane Alternative syntheses of ( f ) - a - t r a n s - (114) and (*)-a-cis-bergamotene (115) from the known bicyclic keto-alkene (107) have been a c c o m p l i ~ h e dby ~ ~the routes outlined in Scheme 10 (cf. Vol. 1, p. 70 and Vol. 3, p. 105 for previous

1..

vi, or vii

/

OTMS

(110) R =

Me or Me2C=CHCH2CH2

k,xiii,x,xiv

(115)

l r e f . 34b

(114)

Reagents: i, (CF,C0)20; ii, Os04-N-methylmorpholine N-oxide-THF-HzO; iii, MsCl-Et,N; iv, Me3SiCI-Et~N-4-dimethylaminopyridine; v, LDA-THF; vi, MeI; vii, Me,C=CHCH,CHJ; viii, t-CSH1lOK-t-CSHIIOH:ix, NaNH,-dioxan; x, TsC1-py; xi, Bu',AlH-C,H,; xii, MeCOC0,H-H,O (pH 4.5);xiii, Ac20-4-dimethylaminopyridine; xiv, LiEt,BH

Scheme 10 34

( a ) S. D. Larsen and S. A. Monti, J. Amer. Chem. Soc., 1977,99,8015; ( b )T. W.Gibson and W. F. Erman, ibid., 1969,91,4771.

Terpenoids and Steroids

94

synthetic routes). Related investigations3’ have shown that the bicyclic ketoalkene (107) can also be used as an intermediate in a new synthesis of a-santalene (119) (Scheme 11). Another illustration of the use of naturally occurring mono-

Reagents: i, hv, Me2CO; ii, NaH-HC0,Et; iii, TsN3-Et3N; iv, hv, NaHC03-THF-HzO; v, LDA, then BuLi; vi, Me2C=CHCH2CH21; vii, LiAlH4-THF; viii, TsC1-py ; ix, LiBHEt3-THF

Scheme 11

terpenoids as starting materials in sesquiterpenoid synthesis has been provided by the recent synthesis of dihydroisosantalol (125) and tetrahydroisosantalol (126) from camphene (120)36(Scheme 12). The structure (131) previously assigned to albene, a trisnorsesquiterpenoid produced by Petasites alba, was based on spectroscopic evidence and supported by the synthesis of the tricyclic ketone (130) from (+)-camphenilone (127)37(cf. Vol. 5, p. 59). However, an independent synthesis of a compound having structure (131) and its non-identity with albene indicate that a revised structure is (cf.Vol. 8, p. 121). In a recent investigation, repetition and extension of the original synthetic work led to alternative exo-structures for the tricyclic ketone (129) and hence of albene (1 32).386The proposed cyclization of chloroalkene (128) to the exo- tricyclic ketone (129)38bis nonetheless surprising since this requires the occurrence of a 2,3-endo methyl shift. In view of the lower optical purity of albene obtained by this synthetic route it would seem reasonable to expect an alternative explanation for the cyclization of (128) to (129) (Scheme 13). Full details of a previously reported synthesis of (*)-sesquifenchene (133) have been published39 (cf.Vol. 4, p. 97; Vol. 6, p. 90; Vol. 7, p. 62). 35 36 37 38

39

S. A . Monti and S. D. Larsen, J. Org. Chem., 1978,43,2282. W. Rojahn, W. Bruhn, and E. Klein, Tetrahedron, 1978, 34, 1547. P. T. Lansbury m d R. M. Boden, retrahedron Letters, 1973, 5017. ( a ) W. Kreiser, L. Janischke, and W. S. Sheldrick, J.C.S. Chem. Comm., 1977, 269; ( b )W. Kreiser and J. Janischke, Tetrahedron Letters, 1978, 601. P. A . Grieco, C. S. kagonowski, S. D. Burke, M. Nishizawa, M. Miyashita, Y. Masaki, C.-L. J. Wang, and G. Majetich, J. Amer. Chem. SOC.,1977,99,4111.

95

Sesquiterpenoids

Reagents: i, CH20-HOAc; ii, Al(OPri)3-Me2CO; iii, Raney-Ni-H2; iv, NaOMe-ClCH2C02Et; v, KOH-H20-MeOH; vi, NaBH4

ec1 Scheme 12

cf. ref. 37 +

/

(128)

-.--:p (130)

Reagents: i, HC0,H; ii, (CF3CO),0-H202-H2S04; iii, Pb(OAc),

Scheme 13

Terpenoids and Steroids

96

5 Cuparane, Trichothecane, Laurane Further studies on the terpenoid constituents of liverworts (cf. pp. 100, 121, 145, 156) (cf.Vol. 8, pp. 75,99; Vol. 6, p. 63; Vol. 5, pp. 52,53) have resulted in the isolation of (+)-cuprenenol (134) and rosulantol (136) from Jungermannia r o s ~ l a n s The . ~ ~ structures of these compounds are based on spectroscopic evidence and chemical correlation with the co-metabolites, R- (+)-cuparene (135) and R- (+) -6-cuparenol (137) respectively. The absolute configuration of (+)-

HO (134)

(135)

cuprenenol (134) in J. rosulans is unusual since liverworts normally produce sesquiterpenoids enantiomeric to those found in higher plants. For example S-(-)-cuparene and S-(-)-8-cuparenol are liverwort constituents (cf. Vol. 5, p. 52; Vol. 6, p. 63") whereas R -(+)-cuparene is found in various higher plants. An iron carbonyl-promoted cyclocoupling reaction between 1,3-dibromo-3methylbutan-2-one (138) and 2-p-tolylpropene (139) has provided a simple alternative synthesis of (&)-a-cuparenone ( 140).t4' The extension of previous

(138)

(139)

(140)

investigations on the halogenated sesquiterpenoid constituents of various species of marine red alga,. (genus Laurencia) has resulted in the isolation of neolaurin40 41

A. Matsuo, I. Terada, M. Nakayama, and S . Hayashi, Tetrahedron Letters, 1977, 3821. Y.Hayakawa, F. Shimizu, and R. Noyori, Tetrahedron Letters, 1978,993.

* I n Vol. 6, p. 63 (and in the original reference) S-(-)-cuparene and S-(-)-&cupareno1 are erroneously described as R - ( - )-cuparene (77) and R- ( -)-d-cuparenol(78). t An alternative synthesis of this compound is described on p. 143.

Sesquiterpen oids

97

terol (141), isoaplysin (142), and the ether (143) from Laurencia okamurai collected in Japan4’ (cf. Vol. 1, pp. 74, 75; Vol. 8, p. 75).

Recent investigations have shown that @-addition of phenyl groups to a,@unsaturated cyclopentenones followed by a-alkylation of the intermediate enolate produces the thermodynamically less stable cis-2,3-disubstituted product.* This new procedure has led to an alternative synthesis of the cyclopentanone derivative (145)43 which had been previously as an intermediate in the synthesis of (*)-laurene (146).

Reagents: i, Me,CuLi; ii, MeI; iii, PhSCH,Li; iv, (PhCO),O; v, Li-NH,

Recent independent reports describe the syntheses of compounds (147)4sand (148),46 which could serve as intermediates in projected synthetic routes to verrucarol (149), a typical trichothecane sesquiterpenoid. Four mycotoxins

(151a-d), produced by Fusarium sulphureum grown on maize, have been identified as derivatives of 12,13-epoxytrichothec-9-ene( MO).~’ 42 43

44 45 46 4’7

M. Susuki and E. Kiirosawa, Tetrahedron Letters, 1978, 2503. G. Posner and C. Lentz, Tetrahedron Letters, 1977, 3215, 3211. J. E. McMurry and L. A. von Beroldingen, Tetrahedron, 1974, 30, 2027. E. W. Colvin, S. Malchenko, R. A. Raphael, and J. S. Roberts, J.C.S. Perkin I, 1978, 658. B. M. Trost and J. H. Rigby, J. Org. Chem., 1978, 43, 2938. P. S. Steyn, R. Vleggaar, C. J. Rabie, R. P. J. Kriek, and J. S. Harington, Phytochemistry, 1978,17, 949.

* The corresponding 0-alkyl addition/cY-alkylation process results in trans-stereochemistry.

98

Terpenoids and Steroids

(151) a; R 1 = R 2 = A c , R 3 = H b; R ' = R 2 = R 3 = A c C; R' = A c , R 2 = R 3 = H d; R ' = R 3 = H , R 2 = A c

Further studies on the biosynthesis of the trichothecane sesquiterpenoids (Vol. 8, p. 74)have shown that the coupling pattern in trichothecin (156) derived from [1,2-13C2]acetate is consistent with the previously established route to this compound (cf. Scheme 14) and excludes an alternative folding of the farnesyl pyrophosphate (153) precursor.48 The prodigious efforts of the late Professor S.

Q (152)

1 OR

(154)

I

(1 57) R = COCH=CHMe

OR (156) R = COCH=CHMe Scheme 14

M. Kupchan's group in the isolation and structural elucidation of biologically active sesquiterpenoids continue to find expression in the literature. A recent 48

B. Dockerill, J. R. Hanson, and M. Siverns, Phytochemistry, 1978, 17. 427.

Sesquiterpenoids

99

report from this group provides a complete description of structural studies on the potent antileukaemic compounds baccharin (158), baccharinol (159), isobaccharinol(160), and isobaccharin ( 161).49These compounds represent the first examples of trichothecanes isolated from a higher plant (Baccharis megupo tumica). It is also interesting to note that roridin D (162), a structurally similar fungal trichothecane, is devoid of antileukaemic activity.

(158) R’ = (R)-CH(OH)Me, R2 = H, R3= OH, 9,lO-epoxide (159) R’ = 6)-CH(OH)Me, R2= H, R3= OH, 9,lO-epoxide (160) R’ = (R)-CH(OH)Me, R2 = R3= OH (161) R’ = (S)-CH(OH)Me, R2= R3= OH (162) R1= CH(OH)Me, R2= R3= H

i

R‘ Full details of the X-ray crystallographic evidence which established the structure of a-pompene (syn. a-barbatene) (cf. Vol. 8, p. 75) have been published.” Recent investigations of the chemistry of the barbatenes (163) (cf.Vol. 8, p. 75; Vol. 6, p. 63; Vol. 5, p. 53) have shown that treatment with CF3C02H results in a series of Wagner-Meerwein rearrangements terminated by a 1,2-exomethyl shift to provide isobarbatene (164)” (Scheme 15). A full account of recent

+

Scheme 15 49

S. M. Kupchan, D. R. Streelman, B. B. Jarvis, R. G. Dailey, and A. T. Sneden, J. Org. Chem., 1977,

50

H.Nozaki, A. Matsuo, M. Nakayama, Y. Kushi, N. Kamijo, and S. Hayashi, Bull. Chem. SOC.Japan,

51

N. H. Andersen, C.-L. Tseng, A. Moore, and Y. Ohta. Tetrahedron. 1978,34,47.

42,4221.

1978,51,568,

Terpenoids and Steroids

100

studies on the sesquiterpenoid constitutents of various European liverworts and a summary of the evidence for the revised structure of a-bazzanene (165) (cf.Vol. 8,. p. 75) have been provided in a recent In general the sesquiterpenoids produced by liverworts [e.g. (-)-bisabolenes (166), (-)-a-alaskene (167), (-)longiborneol (168), (-)-longifolene (169), (-)-longipinenes (170), (-)longipinanol(l7l ) , (+)-yhimachalene [172), (-)-a-ylangene (173), (-)-sativene (174), and (+)-a-chamigrene (175)] are enantiomeric to those found in higher plants (cf. p. 96 and Vol. 8, p. 99). In addition it has been ~ u g g e s t e dthat ~~ (-)-P-barbatene (176) and (+)-anastreptene (177) (cf.p. 156) may be regarded as taxonomic markers for leafy liverworts (order Jungermanniales). Support for this suggestion has been provided by a related which demonstrated that thalloid liverworts of orders Metzgeriales and Marchantiales differ from the order Jungermanniales in that they do not produce (-)-P-barbatene (176) and (+)anastreptene (177).

OH

(173) H \

(176) ”

’3

(177)

N. H. Andersen, P. Bissonette, C.-B. Liu, B. Shunk, Y. Ohta, C.-L. W. Tseng, A. Moore, and S. Huneck, Phytochernistry, 1977,16, 1731. N. H. Andersen, Y. Ohta, C.-B. Liu, C. M. Kramer, K. Allison, and S. Huneck, Tetrahedron, 1977, 16, 1727.

Sesquiterpenoids

101

6 Chamigrane Halogenated sesquiterpenoids are now recognized as characteristic metabolites of marine algae. A recent investigation using mild isolation and purification conditions (cold solvent, inert atmosphere, rapid chromatography)has resulted in the identification of compound (178) as an unstable metabolite of the red alga Laurencia o b t ~ s aA . ~new ~ sesquiterpenoid isolated from Laurencia nipponica has been assigned the novel seco-chamigrane structure (181) on the basis of chemical and X-ray crystallographic evidence.55It has been suggested55that the biosynthesis of this compound involves ring cleavage of a bis-epoxide (179).

Br

Br

HO

Further investigation of the seaweed species Laurencia perforata has revealed the presence of two new metabolites, perforenone (185) and perforenone-C ( 183)56 (cf. Vol. 6, p. 65; Vol. 7, p. 70). These compounds are further examples of a comparatively new structural type of sesquiterpenoid whose carbon skeleton is presumably derived by rearrangement of a chamigrene precursor (cf. Vol. 6, p. 65; Vol. 7; p. 70). Structures (183) and (185) were established by chemical correlation with perforatone (182),* a previously reported constituent of L. perforata, and by the synthetic sequence57outlined in Scheme 16. The identification of the cis-diol(l90) as a component of the mixture produced by singlet oxygen oxidation of thujopsene (187) has been cited as evidence in favour of the dioxetan intermediate (188) previously proposed to account for the formation of the dicarbonyl product (189) (Scheme 17).58 "

A. G. Gonzalez, J. D. Martin, V. S. Martin, and M. Norte, Tetrahedron Letters, 1978, 2035.

'' T. Suzuki, A. Furusaki, N. Hashiba, and E. Kurosawa, Tetrahedron Letters, 1977,3731. 56

57

A. G. Gonzalez, J. Darias, and J. D. Martin, Tetrahedron Letters, 1977, 3375. A. G. Gonzalez, J. Darias, J. D. Martin, and M. A. Melian, Tetrahedron Letters, 1978,481. T. Takeshita, T. Hatsui, and I. Shimooda, Tetrahedron Letters, 1978,2889.

* N.m.r. evidence has resulted in a revision of the original a-stereochemistryof the bromine at C-7 (cf. Vol. 6, p. 65).

Terpenoids and Steroids

102

Br

HO

(183)

+ C-3 epirner

Reagents: i, Zn-HOAc; ii, K2C03-THF-H20; iii, DBN; iv, EtCOCH=CHMe-NaH; v, NaBH4; vi, Br,-CH,Cl,, -40 "C

Scheme 16

An efficient total synthesis of (+)-mayurone (197), (&)-thujopsene(187), and (+)-thujopsadiene (198) has been a c c ~ r n p l i s h e dby ~ ~a route in which diazoketones (191), (193), and (195) were subjected respectively to vinylogous Wolff rearrangement, photochemical Wolff rearrangement, and a known coppercatalysed intramolecular cyclopropanation reaction60'6*(Scheme 18). 59

"

S. J. Branca, R. L. Lock, and A. B. Smith, J. Org. Chem., 1977,42, 3165. ( a ) P. L. Anderson, Chem. Abs., 1968, 68, 3186; (b) K. Mori, M. Ohki, A. Kobayashi, and M. Matsui, Tetrahedron, 1970, 26, 2815. J. E. McMurry and L. C. Blaszczak, J. Org. Chem., 1974, 39,2217 (cf. Vol. 5 , p. 57).

Sesquiterpenoids

(1[6)

103

\

(195)

(194)

viii,ix

Reagents: i, [Cu(acac),]-C,H,,-MeOH; ii, NaOH-MeOH; iii, (COCI),-C,H,; iv, CH2N,; v, hv, MeOH; vi, Cu-CuSO4-C6H12; vii, SeO2; viii, MeMgI; ix, NH4CI-H20; x, MeLi

Scheme 18

7 Carotane, Acorane, Cedrane Several new synthetic routes to acorane sesquiterpenoids have been published during the past year (cf.Vol. 8, p. 76). In the first of these routes62spiroannulation of the pyrrolidine enamine (20 1) derived from cyclopentene aldehyde provided an enone (202) which was subsequently converted into (-)-acorenone (203) (Scheme 19). In an alternative synthetic route,64 Robinson annulation of the aldehyde (204) with methyl vinyl ketone provided a spiro-ketone (205) which served as a common intermediate in the synthesis of (-)-acorenone (203) and (-)-acorenone-B (211) (Scheme 20) (cf. Vol. 7; pp. 63, 64). To explain the conversion of (206) into (209), it has been suggested that the intermediate 1,2-borane borate (207) undergoes elimination followed by hydroboration. An elegant new approach65 to the spiro[4,5]decane system of the acorane sesquiterpenoids uses an intramolecular ene reaction to achieve the synthesis of epimeric spiro-esters (214) and (215), which can be converted into (*)-& acorenol (222), (*)-p-acoradiene (223), (&)-acorenone-B (21l), and (&)acorenone (203) (Scheme 21) (cfi Vol. 7, p. 64, 65; Vol. 5, pp. 53, 54). An 62

( a )G. L. Lange, W. J. Orrom, and D. J. Wallace, TetruhedronLetters, 1977,4679;(6) G. L. Lange, E.

E. Neidert, W. J. Orrom, andD. J. Wallace, Cunad. J. Chem., 1978, 56, 1628.

'' E. E. van Tamelen, G. M. Milne, M. I. Suffness, M. C. Rudler-Chauvin, R. J. Anderson, and R. S. Achini, J. Amer. Chem. SOC.,1970, 92, 7202. Pesaro and J.-P. Bachmann, J.C.S. Chem. Cornm., 1978,203. W. Oppolzer, K. K. Mahalanabis, and K. Battig, Helv. Chim. Actu, 1977, 60, 2388.

" M. 65

Terpenoids and Steroids

104

A

A (203)

(202)

Reagents: i, H2/Pd-C; ii, pyrrolidine-H+; iii, CH2=CHCOCH20Me-HOAc; iv, MeMgI; v, TSOH-C&j

Scheme 19

t

Q J

-

O H J - -Q. . v-VII

A

A

A

0

Reagents: i, MeCOCH=CH,; ii, MeLi; iii, BH,-THF; iv, H,O,-NaOH; v, Cr0,-H,O'Me2CO; vi, Br2-CH2C12; vii, LizC03-DMF; viii, TsOH-CH~CI~, 25 "C;ix, MeC03HCH2CI2; X, TsOH

Scheme 20

Sesquiterpenoids

105

C0,Et (215) v,vii,/

m-0

d

.O

iv-vil

OMe

xi,xii

A

C0,Et (220)

(217)

liii

li,xiii,xiv

mo A

OAc

C0,Et

k,xvi

w 0

A

A (223) Reagents: i, LiNC6H1 1Pr; ii, CH2=CHCH2CH2Br; iii, 290 "C; iv, Na2Cr207-HOAc-Ac20; v, MeLi; vi, ClCH,OMe; vii, Al,O,-py, 200 "C; viii, H,-[(Ph,P),RhCl]; ix, Pb(OAc),; x, T s O H - C ~ H ~xi, ; Sia2BH-H202; xii, Na2Cr207-H2S04; xiii, (PhS)2; xiv, LDA-MeI; xv, rn-CIC6H4C03H; xvi, 70 "c

Scheme 21

106

Terpenoids and Steroids

alternative route to the acorane framework involves cyclization of a monocyclic dienone (224) to epimeric spiro-enones (227) and (228)66 (Scheme 22). The stereochemistry of these products has been explained by stereoselective intramolecular hydride shifts in the postulated intermediates (225) and (226).66In addition the structure and stereochemistry of enones (228) and (227) have been confirmed by the three-step transformation^^^ to (k)-acorenone (203) and (&)-4epi-acorenone B (229) [cf. (21l)] respectively. Full details of the previously

GG< SnC14 +

Hm 0

reported (Vol. 7, p. 66) Diels-Alder approach to the synthesis of (*)-cedrol(232) and (*)-a-cedrene (233) have been published 67 (Scheme 23).

aH a H

kii (232)

H

Reagents: i, B,H,-Et,O; soc1,-py

ii, Cr0,-H';

iii, Me,SiCN-ZnI,; iv, LiAlH,; v, HNO,; vi, MeLi; vii,

Scheme 23 66 67

P. Naegeli, Tetrahedron Letters, 1978, 2127. E. G. Breitholle and A. G. Fallis, J. Org. Chem., 1978, 43, 1964.

Sesquiterpenoids

107

The regiospecific conversion of cycloalkanes into tertiary trifluoroacetates and esters of 1,2-diols by treatment with I?T [iodine tris(trifl~oroacetate)]~* has been applied to sesquiterpenoid~.~~ For example treatment of (8aH)-cedrane (234) with ITT followed by alkaline hydrolysis provides the ketone (237) in 78% yield while similar treatment of cedrol(232) results in the formation of 9-iodo-8cedrene (238) (70%), a-cedrene (233) (5%), and the ketone (237) ( 1 l Y 0 ) ~(cf. ~ Vol. 8, p. 77 for dry ozonation of cedryl acetate). It has been ~ u g g e s t e dthat ~~ these transformations involve initial conversion of cedrane (234) or cedrol(232) into a-cedrene (233) followed by formation of an iodonium ion intermediate

a fl Lfl I'ZT

a-cedrene (233)

via 8-triftuoroacetate?

H

a cedrol(232)

J

(234)

(235) H

H

(238)

(235). The structure and absolute configuration of aspterric acid (239), a carotane-type metabolite of Aspergillus terreus (IFO-6123), has been established by X-ray crystallographic analysis of its p-bromoben~oate.~~

(239) 68

69 70

J. Buddrus and H. Plettenberg, Angew. Chem. Internat. Edn., 1976, 15, 436. A. S. Narula, E. Trifilieff, L. Bang, and G. Ourisson, Tetrahedron Letters, 1977, 3959. Y. Tsuda, M. Kaneda, A. Tada, K. Nitta, Y. Yamamoto, and Y. Iitaka, J.C.S. Chem. Comm., 1978, 160.

108

Terpenoids and Steroids

8 Amorphane etc. (+)-a-Muurolene (240) and its 7-hydroxy- (241) and 7-acetoxy- (242) derivatives have been identified as constituents of a soft coral, Heteroxenia f u ~ c e s c e n s ~ ~ (cf. Vol. 8, pp. 65, 82). Six new muurolene derivatives (243)-(248) have been

(240) R = H (241) R = O H (242) R = O A c

(246)

(243) R = H (244) R = O H

(247)

(245)

(248)

isolated from the aerial parts of Verbesina occidentalis and their structures established by spectroscopic means.72 The partial resistance of cotton plants (Gossypiurn species) to insects may be associated with sesquiterpenoids such as gossypol(249) which are present in the pigment glands of the plant (cf.Vol. 7, p. 71; Vol. 6, p. 65). Other terpenoids such as hemigossypolone (250) and the C25 compounds helocide-13, (253), -H2 (254), -H3 (255), and -H4 (256) have recently been isolated from the glands of leaves, flower buds, and young bolls of G. h i r s u t ~ mIt . ~has ~ also been shown that heliocides-H, (254) and -H3 (255) are formed by Diels-Alder reaction of hemigossypolone (250) and myrcene (252)73a*b while heliocides-H1 (253) and -H4 (256) are formed in a similar way from hemigossypolone (250) and trans-p-ocimene (260).”= A related investigation by

HO

(249)

71

72 73

(250) R = H (251) R = M e

(252)

Y. Kashman, A. Rudi, and N. Gutman-Naveh, Tetrahedron, 1978,34, 1227. F. Bohlrnann and M. Lonitz, Phytochemistry, 1978,17,453. R. D. Stipanovic, A. A. Bell, D. H. O’Brien, and M. J. Lukefahr, ( a ) Tetrahedron Letterr, 1977,567 and references cited therein; ( b )Phytochemistry, 1978,17,151;( c )J. Agric. Food Chem., 1977,26, 115.

Sesq u iterpen oids

109

HO

R3

R'O

R4

(253) (254) (255) (256) (257) (258)

R' = R4 = R5= H, R2 = CH2CH=CMe2, R3=Me R' = R2= R4= R5= H, R3= (CH2)2CH=CMe2 R' = R2 = R3= R5 = H, R4= (CH2)2CH=CMe2 R' = R2 = R3= H, R4= Me, R5= CH2CH=CMe2 R4= R5= H, R' = R3= Me, R2 = CH2CH=CMe2 R2 = R3= H, R' = R4 = Me, R5 = CH2CH=CMe2

(259)

the same research group has revealed the presence of hemigossypolone 7-methyl ether (25l), heliocide-BJ (257) heliocide-B4 (258), and gossyrubilone (259) in young leaves or bolls of G. barbadense plants.74Lacinilene C methyl ether (267), another constituent of the cotton plant (cf.Vol. 6, p. 66), has been synthesiz6d7' by the simple sequence of reactions shown in Scheme 25. An interesting feature of

/

A

(265)

Reagents: i, NaBH4-Pr'OH; ii, SOC12-CsH6; iii, Br2-HOAc; iv, KCN-DMF; v, KOH-H202; vi, H2-Pd-KOH; vii, M ~ Z C H C H = C H ~ - A I C Iviii, ~ ; 30% Pd/C-decalin; k, (PhSe0)zOCH2C12 Scheme 25 74

A . A . Bell, R. D. Stipanovic, D. H. O'Brien, and P. A . Fryxell, Phytochemistry, 1978, 17, 1297.

'' P. W. Jeffs and D. G. Lynn, Tetrahedron Letters, 1978, 1617.

110

Terpenoids and Steroids

this synthesis is the fact that displacement of the chlorine atom in compound (262) could only be achieved in reasonable yield when an ortho-bromo-substituent was present [i. e. (263)l. The absolute configurations of ( +)-calamene (268) and ( + )-7-hydroxycalamenene (269), metabolites of Eremophila drummondii, have been established by X-ray crystallographic analysis.76These compounds are therefore enantiomeric to calamenenes previously found in other plants. Laevigatin (270), a constituent of the essential oil of Eupatorium laevigatum, has been assigned structure (270) on the basis of spectroscopic evidence and oxidation to.furanocadalene (271).77

(268) R = H (269) R = O H

9 Himachalane, Longipinane, Longicamphane, Longifolane Several new compounds isolated from various species of Stevia have been identified7' as acyloxy-derivatives (273)-(277) of the previously reported longipinane sesquiterpenoid vulgarone B (272) (Vol. 7, p. 75; Vol. 8, p. 87). In

(275)

(276)

(277)

R = COC(Me)=CHMe(cis), COC(Me)=CHMe(trans), COCH(Me)Et2, COCH=CMe2, or COC(Me)=CH2

addition the latter compound has also been identified as a constituent of Tanacetum tana~etioides.~' One of the recent highlights of sesquiterpenoid chemistry has been the publication of a new synthesis of longifolene (279).79A key feature 76 77

78 79

K. D. Croft, E. L. Ghisalberti, C. H. Hocart, P. R. Jefferies, C. L. Raston, and A. H. White, J.C.S. Perkin I, 1978, 1267. A. Braga de Oliveira, G. G. de Oliveira, F. Carazza, R. Braz Filho, C. T. Moreira Bacha, L. Bauer, G. A. de A. B. Silva, and N. C. S. Siqueira, Tetrahedron Letters, 1978, 2653. F. Bohlmann, A. Suwita, A. A. Natu, H. Czerson, and A. Suwita, Chem. Ber., 1977,110, 3572. W. Oppolzer and T. Godel, J. Amer. Chem. Soc., 1978,100, 2583.

111

Sesquiterpenoids

of the synthetic route (Scheme 26) is the use of an intramolecular photoadditionretroaldol sequence (de Mayo reaction) to obtain the required tricyclic intermediate (278).

OC0,CH ,Ph OCO,CH,Ph

, i i i

% 0 t

0

ii

0

vii,viii

0

0

(278)

(279)

Reagents: i, PhCH20COC1-py; ii, h v ; iii, H*-Pd/C-HOAc; iv, CH2=PPh3; v, Zn/Cu-CH212; vi, H2-Pt02-HOAc; vii, MeLi; viii, SOClz-py

Scheme 26

It has been demonstrated" that addition of Br2, C12, NOCl, IC1, ClN3, etc. to isolongifolene (280) yields 'abnormal' products (281)-(284) by rearrangement of an intermediate halogenonium ion (280a)." The absence of normal addition

(280a)

(281) X = C1 or Br

(282)

81

(283)

(284)

(a)Y. S. Yadav, H. P. S. Chawla, S. Dev, A . S. C.P. Rao, and U. R. Nayak, Tetrahedron, 1977,33, 2441; ( b ) Y. S. Yadav, H. P. S. Chawla, and S. Dev, ibid., 1978,34,475. Cf. S. Marmor and J. G. Maroski, J. Org. Chem., 1966, 31,4278.

112

Terpenoids and Steroids

products in these reactions has been explained by severe steric hindrance to the approach of the counter-ion at C-7.80aRelated investigationssob have shown that acetolysis of brolnoneoisolongifolene (285) provides a mixture in which a tertiary alcohol (286) and the known diene (287) are major components.

10 Humulane, Caryophyllane," Protoilludane, Illudane, Marasmane, Hirsutane, etc. Further research on terpenoid plant growth regulators has shown that crossconjugated dienones such as zerumbone (288), epoxyzerumbone (289), and santonin (290) display root-promoting activity whereas related compounds (291)-(293) devoid of this structural feature do not.82 Molecular mechanics

HoQ

(291)

(292)

(293)

calculations have demonstrated that the CT (296) and CC (297) conformations of humulene are significantly more stable than the 7T (294) and TC (295) conformations,83It is interesting to note that the AgN03-humulene complex also adopts the CT conformation (296).84 It has been suggesteds3 that the CT conformation (296) of humulene is involved in the biosynthesis of the illudoid group of sesquiterpenoids (protoilludane, illudane, etc.; cf. Vol. 8, p. 93) and that the hirsutane group could be derived by cyclization of the CC conformation

** R4

P. S. Kalsi, 0. S. Singh, and B. R. Chhabra, Phyfochemistry, 1978, 17, 576. H. Shirahama, E. Osawa, and T. Matsumoto, Tetrahedron Letters, 1978, 1987. A. T. McPhail and G. A. Sim, J. Chem. SOC.( B ) ,1966, 112.

* A fascinating group of diterpenoids isolated from soft coral have been Identified as isoprenylogues of caryophyllene or secocaryophyllene; cf D. J. Vanderah, P. A. Steudler, L. S. Ciereszko, F. J. Schmitz, J. D. Ekstrand, and D. van der Helm, J. Amer. Chem. SOC.,1977,99,5780; A. Groweiss and Y. Kashman, Tetrahedron Letters, 1978, 2205; cf. Chapter 3.

Sesquiterpenoids

113

rather than by rearrangement of a protoilludane intermediate (300)83(Scheme 27).

TT (294)

1 CT (296)

TC (295)

1

+ CC (297)

1

1

+ Hirsutanes

(302)

Scheme 27

Humulene biosynthesis probably involves the intermediacy of a monocyclic carbonium ion or its biological equivalent [cf. (303)] derived from truns,trunsfarnesyl pyrophosphate (16).A recent investigation based on this idea has shown that treatment of the (E,E)-mesylate (303; Z = OMS) with dimethylaluminium phenoxide provides humulene (304) in excelkent yield.85 The corresponding (2,E)-isomer, when treated with di-isobutylaluminium 2,6-dibutyl-4-methylphenoxide, is efficiently converted into germacrene (307) whereas the (E,E)isomer under these conditions provides a mixture (2 : 1) of humulene (304) and germacrene A (305).85 Monohydroboration-oxidation of caryophyllene

85

A. Itoh, H. Nozaki, and H. Yarnarnoto, Tetrahedron Letters, 1978,2903.

114

fi-p+p Terpenoids and Steroids

OP,

(16)

(303)

(304)

(308) and isocaryophyllene (311) has been shown to occur primarily at the trisubstituted and disubstituted double bonds respectively.86 A similar regiospecificity has been noted when these compounds are reduced with di-imide.86 In the case of caryophyllene the regiospecificity of the hydration and reduction processes may be associated with the enhanced reactivity of the strained trans-double bond while in isocaryophyllene the preferential steric environment for reaction at the exocyclic double bond could explain the observed results.86 ----, ii

(304) , I

(304)

+

(303) Z = O M s

Reagents: i, PhOAIMe,; ii,

-QOAiBui2 ,%Scheme 28

Attempts to devise a biogenetic-type synthesis of hirsutene (3 14) and derivatives (cf. Vol. 7, pp. 79,80) have recently culminated in the successful conversion of protoilludane epoxide (315) into hirsdten-8a -01 (3 16) and compounds (317)(3 19).87In contrast the diastereomeric epoxide (320) under the same conditions (BF3,Et20)provides the ketone (318) as the only product (Scheme 30). Thermal rearrangement of isovelleral(321) to pyrovellerofuran (322) has been cited as evidence supporting the postulated biosynthetic relationship between marasmane and vellerane sesquiterpenoids.88 The total synthesis of illudinine (333), illudalic acid (334), and illudacetalic acid (335) has been achieved 89 by the " 87

89

V. V. R. Rao and D . Devaprabhakara, Tetrahedron, 1978,34,2223. K. Hayano, Y. Ohfune, H. Shirahama, and T. Matsumoto, Tetrahedron Letters, 1978, 1991. J. Froborg and G. Magnusson, Tetrahedron, 1978, 34,2027. R. B. Woodward and T.-R.Hoye, J. Amer. Chem. SOC.,1978,100,8007.

115

Sesquiterpenoids

'OH (312)

(313) Reagents: i, (C6H11)2BH; ii, H202-NaOH; iii, N2H2CuS04-NH2NH2

Scheme 29

H

(314)

(319)

(320) Scheme 30

116

Terpenoids and Steroids

reaction sequence outlined in Scheme 31. During the course of these synthetic studies” the former structure (336) assigned to natural illudacetalic acid was revised and the new structure (335) confirmed by synthesis. The structure of calomelanolactone (337), a co-metabolite of pterosin Z (338) in Pityrogramma calomelanos (‘silver fern’), has been determined by X-ray crystallographic analy~is.’~ Lactarorufin C (342) (syn. isolactarorufin), a metabolite of the mushroom Lactarius rufus, has been assigned structure (342) on the basis of X-ray analysis of its p - b r o m ~ b e n z o a t e The . ~ ~ unusual ~~~ carbon skeleton (341) of this compound may be biosynthesized by rearrangement of a tricyclic intermediate (340) derived from cyclohumulene (339). Full details of the previously reported (Vol. 6, p. 73) synthesis of the secoilludane sequiterpenoid hypacrone (346) have been published.93 An interesting feature of the synthetic route is the use of a directed crossed aldol c ~ n d e n s a t i o n ~ ~ between the diketone (344) and the trimethylsilyl enol-ether (343) to produce the trans-isomer (345) of hypacrone (346).The absolute configuration of fomannosin (347) has finally been established by X-ray analysis of the camphanate ester derivative (348).95Full details of the biosynthesis of fomannosin (347) from [1,2-13C2]acetate(cf. Vol. 7, pp. 82, 196) have been p~blished.’~ The labelling pattern and 13C-13Ccouplings in fomannosin (347) are consistent with a biosynthetic route (Scheme 32) in which humulene (304) and an unspecified protoilludane derivative (349) serve as intermediates. These biosynthetic results, and the establishment of the R configuration at C-9 in fomannosin (347) have led to the suggestion that the cyclization of farnesyl pyrophosphate (16) involves addition of C-1 to the si,si face of the terminal double bond. Further studies by the Sussex group have shown that incorporation of [1,2-13C2]acetate into illudin-M (350) and -S (351) by the fungus Clitocybe illudens results in a labelling pattern which supports their derivation by rearrangement of a protoilludane intermediate (349).” Sesquiterpenoids based on the capnellane framework (352) have previously been isolated from soft coral (Capnella irnbricata) (cf. Vol. 5 , p. 70; Vol. 7, p. 81). Two new compounds isolated from this source have been identified as 90

91

92

y3 94 y5

96

9’

V. Bardouille, B. S. Mootoo, K. Hirotsu, and J. Clardy, Phytochemistry, 1978, 17, 275.

A. Konitz, M. Bogucka-Ledochowska, Z. Danter, A. Hempel, and E. Borowski, Tetrahedron Letters, 1977,3401. The isolation of vallerane-type sesquiterpenoids [cf. (322)] from various species of mushroom has previously been reported (Vol. 6, p. 74; Vol. 7, p. 7; Vol. 8, p. 93). Y. Hayashi, M. Nishizawa, and T. Sakan, Tetrahedron, 1977,33, 2513. Cfi T. Makaiyama, K. Narasaka, and K. Banno, J. Amer. Chem. SOC., 1974,96,7503. D. E. Cane, R. B. Nachbar, J. Clardy, and J. Finer, Tetrahedron Letters, 1977,4277. D. E . Cane and R. B. Nachbar, J. Amer. Chem. SOC.,1978,100,3208. A. P. W. Bradshaw, J. R. Hanson, and M. Siverns, J.C.S. Chem. Comm., 1978,303.

Sesquiterpenoids

117

/

+& \

\

C0,Me

Br

(328)

Br

(327)

(326)

~xIII-xv

-

v x ~ ~ , ~O &~ , ~

\

OCH

(329)

7’

HO

CO,R

(3:0)

OMe

@

R=Meh

\

C0,Me

OH

/

C0,Me

\

(331) XVI1I.XIX

\

OMe OMe

CO,H

CO,H

Reagents: i, ClCH2COCI-AIC13; ii, H2SO4, 100 “C; iii, MeI-KOBut; iv, Zn/Hg-HC1; v, Br2CHC13; vi, BuLi; vii, B(OMe)3; viii, HOAc; ix, H202; x, Me2S04-K2C03; xi, MgTHF; xii, ClC02Me; xiii, Cr03-HOAc; xiv, NaBH4-MeOH; xv, T s O H - C ~ H ~A;, xvi, Os04-Et20; xvii, NaI04-H204ioxan; xviii, NH40Ac-HOAc; xix, KOH-MeOH; xx, BBr3-CHzC12; xxi, HC(OMe)3-TsOH-MeOH

Scheme 31

Terpenoids and Steroids

118

*)q/

HO

\

/

(337)

(338)

(347) R = H

0


co-

OH

Sesquiterpenoids

119

(350) R = H (351)R = OH Scheme 32

A9''2'-capnellene (353)" and the corresponding tetrol (354)99on the basis of spectroscopic and chemical evidence. HOW

H

OH H

(352)

H

(353)

H

HO

(354)

11 Germacrane N.m.r. paramagnetic shifts induced by [Eu(dpm),], molecular mechanics calculations, and/or X-ray crystallographic data have been used to deduce the preferred conformation of agerol (355), agerol diepoxide (356),and ageratriol 98

99

E. Ayanoglu, T. Gebreyesus, C. M. Beechan, C. Djerassi, and M. Kaisin, Tetrahedron Letters, 1978, 1671. Y. M. Sheikh, C. Djerassi, J. C. Braekman, D. Daloze, M. Kaisin, B. Tursch, and R. Karlsson, Tetrahedron, 1977, 33, 2115.

120

Terpenoids and Steroids

*ep& (357).loo The latter compounds co-occur in Achillea ageratum. Their interconversion (Vol. 5, p. 71) and absolute configuration (Vol. 6, p. 75) have previously /

0

OH

(356)

(355)

(357)

been reported. Although the enantiomers of germacrone are, in theory, interconvertible by conformational inversion [cf. (358a) $ (358b)l recent investigations have shown that the barrier to inversion is sufficiently high to permit partial resolution of naturally occurring (*)-germacrone (358) via the corresponding alcohol (germacrol)."' [There is a previous report in the literature which indicates that germacrone can also be

/+=-

IUO 1

(358b)

(358a)

An extension of previous studies (Vol. 7, p. 81) on the synthesis of macrocyclic terpenoids from acyclic epoxyphenyl sulphides has resulted in the synthesis of (2E,6Z)(361) and ( 2 2 , 6 2 ) (362) stereoisomers of hedycaryol (Scheme 33).lo3

.ROH

1 ,

.. ...

/L 11,111

(359)

(360)

I

Reagents: i, Bu"Li-DABCO-THF; ii, Li-EtNH2-EtOH; iii, SiOz-AgN03 chromatography

Scheme 33 100

101

102

103

( a ) W. Messerotti, U. M. Pagnoni, R. Trave, R. Zanasi, G. D. Andreetti, G . Bocelli, P. Sgarabotto, J.C.S. Perkin 11, 1978,217; ( b )F. Bellesia, U. M. Pagnoni, A. Pinetti, and R. Trave, Guzzertu, 1978, 108, 39. R. K. Hill, M. G. Fracheboud, S. Sawada, R. M. Carlson, and S.-J. Yan, Tetrahedron Letters, 1978, 94:. F. Sorm, Pure A p p l . Chem. 1970,21,265. M. Kodama, S. Yokoo, H. Yamada, and S. Ito, Tetrahedron Letters, 1978, 3121.

121

Sesquiterpenoids

Costunolide-1,lO-epoxide (364) has been synthesized and subsequently converted into a mixture of santamarine (365a) and reynosin (365b) under a variety of reaction [cf.conversion of santonin into (365a)and (365b),p. 1281. A similar study has shown that treatment of herbolide B (366) with acidic reagents produces eudesmanolides (367) and (368)"' (Scheme 34). The general tendency

(363)

(365a) (365b)

(364)

Reagents: i, rn-ClC6H4C03H; ii, CHC13, 7 days; iii, silica gel; iv, BF3Et20, 30 min; v, AczOTsOH; vi, SOC12

Scheme 34

of liverworts to produce sesquiterpenoids enantiomeric to those found in higher plants (cf. p. 96) is again exemplified by the recent isolation of (-)-bicyclogermacrene (369) and (-)-a-gurjunene (370) from various species of Porella.lo6 Germacranolides [i.e. derivatives of the basic lactone structures (371) and (372)] possessing interesting biological activity (allergenic, fungitoxic, cytotoxic,

(369)

(370)

(371)

(372)

etc.) are common constituents of plants and their widespread occurrence is reflected in the annual output of papers concerned with their isolation and structural elucidation. Since last year's Report (Vol. 8, p. 94) the following new members of this group have been described: chromolaenide (373) (Chromolaena '04

lo' lo6

A. A. S. Rodrigues, M. Garcia, and J. A. Rabi, Phytochemistry, 1978, 17, 953. S. Sokoloff and R. Segal, Tetrahedron, 1977, 33, 2837. Y.Asakawa, M. Toyota, and T. Takemoto, Phytochemistry, 1978, 17,457.

122

Terpenoids and Steroids

g l ~ b e r r i m a ) , torotundin '~~ (374) (Tithonia rotundifolia,'08 eriofertopin (375) and 2- 0-acetyleriof ertopin (376) (Eriophy llum confertiflorum ),log 8 -desoxysalonitenolide (377), 1 lp,13-dihydro-8-desoxysalonitenolide(Platycarpha glom-

HO'

an

o-ko

0

(373)

(375) R = H (376) R = A c

(374)

(377)

erata),' l o peroxyferolide (378) (Liriodendron tulipifera,"l michelenolide (379) (Michelia compressa),' l2 costunolide derivatives (380)-(382) (Eupatorium specie^),"^ 14-acetoxydicomanolide (383) and 14-oxodicomanolide (384)

(381) R = H (382) R = A c F. Bohlmann and L. Fiedler, Chem. Ber., 1978,111,408. W. Herz and J. F. Blount, J. Org. Chem., 1978, 43, 1268. '09 S. M. Kupchan, J. W. Ashmore, and A. T. Sneden, Phytochemistry, 1977,16,1834. 'lo F. Bohlmann and C. Zdero, Phytochemistry, 1977,16, 1832. "' R. W. Doskotch, F. S. El-Feraly, E. H. Fairchild, and C.-T. Huang, J. Org. Chem., 1977,42,3614. 'I2 M. Ogura, G. A. Cordell, and N. R.Farnsworth, Phytochemistry, 1978,17,957. 'I3 F. Bohlmann, P. K. Mahanta, A. Suwita, Miss A. Suwita, A. A. Natu, C. Zdero, W. Dorner, D. Ehlers, and M. Grenz, Phytochemistry, 1977,16, 1973.

lo'

lo*

123

Sesquiterpenoids

(383) R = CH20Ac (384) R=CHO

(Dicoma a n ~ r n a l a ) ,8-desoxysalonitenolide ~'~ derivatives ( 3 8 5 a - d ) (Mikania species),115chromolaenolide derivatives (386)-(388) (Isocarpha species),l16 costunolide derivatives ( 3 8 9 a - e ) (Inula species),ll' 19-hydroxyglaucolide (390) (Erlangea remifolia),"* hirsutinolide derivatives (391a - e ) (South African Vernonia specie^),^'^ haageanolide (392) (Zinnia haageana),I2' and gallicin (393) (Artemisia maritima).I2'

(386) a; R' = OAc, R2 = H, R3= OH b; R' = OAc, R2 = H, R3 = OCOC(Me)=CHMe c; R'=H, R 2 = R 3 = O A c

QR

0

(387) 114 11s

116

117

118 119 120 121

(388a-6) R = COC(Me)=CH2, Pr', COC(Me)=CHMe, or COBu'

F. Bohlmann and N. Le Van, Phytochemistry, 1978,17,570. F. Bohlmann, A. A. Natu, and P. K. Mahanta, Phytochemistry, 1978, 17,483. F. Bohlmann, P. K. Mahanta, A. A. Natu, R. M. King, and H. Robinson, Phytochemistry, 1978,17, 471. F . Bohlmann, P. K. Mahanta, J. Jakupovic, R. C. Rastogi, and A. A. Natu, Phytochemistry, 1978,17, 1165. F. Bohlmann and H. Czerson, Phytochernistry, 1978,17, 1190. F. Bohlmann and R. C. Rastogi, Phytochemistry, 1978, 17,475. W . Kisiel, Phytochernistry, 1978, 17, 1059. A . G. Gonzalez, J. Bermejo, H. Mansilla, A. Galindo, J. M. Amaro, and G. M. Massanet, J.C.S. Perkin I, 1978, 1243.

124

Terpenoids and Steroids

( 3 8 9 a - e ) R = H, COEt, C03us, COBu', or COPr'

(391) a; R' = COC(Me)=CH2, R2 = Ac 0 b; R' = COC\, / R~ = I Me C; R' = COCH2(CH20H)=CH2, R2 = AC d: R1= COC(Me)=CH2, R2= H 0 e.; R' = COC'A, R2= H

I

Me

OH

Q (392)

o (393)

12 Eudesmane (Selinane) The racemic form of a new sesquiterpenoid, voleneol diacetate (394), has been identified as a constituent of the stem bark of Lepidotrichilia volensii Leroy.122 Several new eudesmane derivatives have been isolated from various species of Verbesina and their structures, (395)-(398), determined by spectroscopic methods. 123 Related investigations have shown that cuauhtemone (399) (Vol. 5, p. 74) and the eudesmane derivative (400) are metabolites of Pluchea foetida'24 while yselinen-8-one (401) occurs in the roots of Peteravena s c h ~ l t z i i . ' ~ ~

'** lZ3 lZ4

J. J. Hoffmann and J. R. Cole, J. Org. Chem., 1978,43, 1254. F. Bohlmann and M. Lonitz, Chem. Ber., 1978, 111, 254. F. Bohlmann and P. K. Mahanta, Phytochemistry, 1978,17, 1189. F. Bohlmann and A. Suwita, Phytochemistry, 1978,17, 567.

Sesquiterpenoids

125

(394)

O

b

P

h

(395) a; R ' = R ~ = H b; R1=OH, R 2 = H c ; R ' = H , R'=OH

rn I

O

O-Ph (396) R = Me or CHO

b

P

L

h

(398) R = H or OH

(397) R = H or OH

(399)

Terpenoid constituents of marine organisms continue to attract considerable attention* (cf.pp. 85, 86, 96, 101, 108, 116, 136, 156). Red algae of the genus Laurencia are recognized as common sources of these compounds. Recent independent reports have described X-ray crystallographic evidence for the structure and absolute configuration of l-bromo-4-hydroxy-7-chloroselinane (4O2)lz6 and heterocladol (4O3).lz7 These compounds are constituents of

Cl (402) lZ6 127

(403)

A. F. Rose, J. J. Sims, R. M. Wing, and G . M. Wiger, Tetrahedron Letters, 1978, 2533. R. Kazlauskas, P. T. Murphy, R. J. Wells, J. J. Daly, and W. E. Oberhansli, Ausrral. J. Chem., 1977, 30, 2679.

* Cf Vol. 8, pp. 65, 66,75, 79, 82, 101, 108.

Terpenoids and Steroids

126

Laurencia species found off the coast of Australia and it may be of biosynthetic significance that the bromoeudesmane derivative (403) co-occurs with (404) (cf. Vol. 8, p. 101). A new component of the Hawaiian marine alga Laurencia nidifica has been identified as (+)-selina-4,7(1l)-diene(405) on the basis of spectroscopic evidence."' Detailed chromatographic analysis of the sesquiterpenoid constituents of costus plant roots has revealed the presence of ar-costol(406), y-costol (407), y-costal (408), and the elemene derivative (409).'29

(407) R = CHZOH (408)R = C H O

Derivatives of dihydro-P-agarofuran (410) are characteristic metabolites of various genera of Celastraceae (Celastrus, Euonymus, Maytenus, Catha) (cf.Vol. 8 , p. 105) and recent reports describe the X-ray structural studies on malkanguniol (411) (Celastrus p a n i c u l a t ~ s ) ' ~and ~ alatamine (412) (Euonymus ala tus).' ' OAc

AcO

/ OAc

(410)

(412)

A synthesis* of 10-epijunenol(417) (cf.Vol. 8, p. 102) has been accomplished by photochemical cycloaddition of the cyclobutene ester (413) to piperitenone (414) followed by reductive cleavage of the phosphate ester (416)'32 (Scheme 35). H. H. Sun and K. L. Erickson, J. Org. Chem., 1978,43, 1613. B. Maurer and A. Grieder, Helv. Chim. Acta, 1977, 60, 2177. I3O H. Lotter, R. Bruning, and H. Wagner, Tetrahedron Letters, 1978, 3243. 13' K. Yamada, Y. Shizuri, and Y. Hirata, Tetrahedron, 1978, 34, 1915. 13' P. A. Wender and J. C. Lechleiter, J. Amer. Chem. SOC.,1978, 100,4321. * A similar route to cyclodeca-1,s-diene was reported in Vol. 8, p. 99. 12*

127

Sesquiterpenoids

a../ +b Pi-.

H

OH

OH

(EtO),OPO

Reagents: i, hv; ii, TsNHNHz; iii, NaH-toluene; iv, B2H6; v, BuLi-(EtO)zPOCl; vi, LiC1OH7THF, 0°C

Scheme 35

Modification of the synthetic strategy previously used'33a in the synthesis of (*)-occidentalol (cf. Vol. 8, p. 103) has resulted in a new synthesis of a-santonin (418) and its less stable P-epimer (419)'33b (Scheme 36). An extension of previous

+ i-vii

QCozH

__* viii

Q

/

OSEt SEt

q

OH

e-

0

I xii

-Y

(418) R' = H, R2= M e (419) R' = M e , R2 = H Reagents: i, Li-NH,-MeI; ii, LiAIH,; iii, Me,S-NCS--Et,N; iv, NaH-(EtO),POCH,Et; v, Li-NH,-EtOH; vi, Ph,P-NBS; vii, EtSCH,SOEt-BuLi; viii, HCIO,-H,O; ix, Pr',NLi-ICH,CO,Et ; x, Ag,CO,-celite; xi, Pr',NLi-MeI; xii, Pr',NLi; xiii, 0,-haematoporphyrin, kv

Scheme 36 133

J. A. Marshall and P. G. M. Wuts, ( a ) J. Org. Chem., 1977,42, 1794; (b) ibid., 1978,43, 1086.

128

Terpenoids and Steroids

studies on the conversion of a-santonin (418) into eudesmanolides (cf.Vol. 7, pp. 90-93) has led to the synthesis of vulgarin (423) and an alternative route to arglanine (425)'34 (Vol. 7, p. 91) (Scheme 37). A related study has shown that

n

0 R , x n , x i i i , x , x i

HO

HO-

(423)

0

SePh

0

0

(425)

(424)

Reagents: i, H2-Pd/SrCO,; ii, Br2; iii, -LiBr-DMF; iv, Al(OPri)3-PriOH; v, HCl-THF; vi, Cr03py;CH,Cl,; vii, (CH,OH),-TsOH-C,H,; viii, Os04-H,S4ioxan; ix, HOAc-H,O; x, Pr'2NLi-(PhSe)z; xi, 30% H202; xii, Hz-Pd/C; xiii, NaBH4

Scheme 37

vulgarin (423) can be converted into lp-hydroxyarbusculin A (426) (Scheme 37) and that the acetal-lactone (421) (cf.p. 150) can also serve as an intermediate in the synthesis of reynosin (365b), santamarine (365a) (cf.p. 121), and epoxysantamarine (428)13' (Scheme 38). The first total syntheses of (*)-ivangulin (429),'36 (*)-eriolangin (432),'37 (*)-eriolanin (431),'37and (*)-6-epieriolanin (430)13' have been achieved by the routes outlined in Schemes 39 and 40. A significant result of these investigations 134

13' 136

137

M. Ando, A. Akahane, and K. Takase, Bull. Chem. SOC.,Japan, 1978,51, 283. M. Ando and K. Takase, Tetrahedron, 1977, 33, 2785. P. A. Grieco, T. Oguri, C. L. J. Wang, and E. Williams, J. O r g Chem., 1977,42,4113. P. A. Grieco, T. Oguri, S. Gilman, and G. T. DeTitta, J. Amer. Chem. SOC.1978,100, 1617.

129

Sesquiterpenoids

was the discovery that 6-epieriolanin (430), which does not occur in nature, has greater antileukaemic and antitumour activity than the naturally occurring 1,lO-secoeudesmanolides eriolanin (431) and eriolangin (432). The absolute configurations of the 2,3 -secoeudesmane (elemane) sesquiterpenoids epishyobunone (433) and isoshyobunone (434) have been established by spectroscopic evidence and chemical correlation with shyobunone (435). 138*139 [Epishyobunone (433) was previously considered to be the C-2 epimer of shyobunone (cf.Vol. 4, p. 119; Vol. 7, p. 85)l.A new synthesis of isoshyobunone (134) from 6-ketocapronitrile has also been rep~rted.'~' The significant antitumour and cytotoxic properties of vernolepin (436) and, to a lesser extent, vernomenin (437) have stimulated general interest in the natural occurrence and total synthesis of 2,3-secoeudesmanolides or elemanolides (cf. Vol. 8, p. 111).Two new alternative multi-step syntheses of vernolepin (436) have recently been accomplished by independent research groups using the reaction sequences outlined in Schemes 4114' and 42.142 A total synthesis of (&)-ternisin (439) from the known acetal-ketone (438) (Scheme 43) and n.m.r. analysis at 250 MHz have confirmed the structure and established the stereochemistry of this An interesting new approach to the 2,3-secoeudesmanolide (elemanolide) framework has been sucessfully applied to the synthesis of saussurea lactone (442)144(cf. Vol. 8, p. 97).

vi,iii,vii,iv.v

*vi,iii-v

(365a)

(423)

,

(428)

Reagents: i, Br2; ii, Zn/Hg-HC1; iii, LiAlH(OBu1)3-THF; i v , Pr'zNLi-(PhSe)z; v, 30% H202; vi, Zn-HOAc; vii, m-ClC6H4C03H-CH2C12

Scheme 38 13*

139

140

14' 14*

143 144

G. Frater, Chimia (Switz.), 1975, 29, 528. M. Niwa, Y. Terada, M. Iguchi, and S. Yamamura, Chem. Letters, 1977, 1415, 1419. C. Alexandre and F. Rouessac, Bull. SOC.chim. France, 1977, 117. G. R. Kieczykowski and R. H. Schlessinger, J. Amer. Chem. SOC., 1978,100, 1938. M. Ishobe, H. Iio, T. Kawai, and T. Goto, ( a ) J. Amer. Chem. SOC., 1978,100,1940; (6)Tetrahedron Letters, 1977, 703. M. Nishizawa, P. A . Grieco, S. D. Burke, and W. Metz, J.C.S. Chem. Comm., 1978, 76. M. Ando, K. Tajima, and K. Takase, Chem. Letters, 1978, 617.

130

Terpenoids and Steroids

PhCH,?

PhCH 2

PhCH zO

1 0

vi,vii +

kXiV

xv.xvi

lxvii-xix I

Me0,C

H'

Reagents: i, Zn/Cu-CHzIZ,-EtzO; ii, PhCHzBr-NaH-DMSO; iii, 70% HC104; iv, TsNHNHzBF3,EtzO; v, Pr'zNLi; vi, ClzCHCOCl-NEt3; vii, Zn-HOAc; viii, (CH~OH)~-TSOHC6H6; ix, Li.NH3; x, Cr03,py-CHzClz; xi, rn-CIC6H4C03H (2 equivs.); xii, KzC03MeOH; xiii, MsCI-CHZClz; xiv, Li-NH3-Bu'OH; xv, AczO-Et3N; xvi, Li-EtNH2; xvii, 10% HCl-THF; xviii, dihydropyran-H+; xix, BuOOH-HO-; xx, Pr'ZNLi-HCHO; xxi, MsCI-py-CHzC12; xxii, MeOH-TsOH; xxiii, Cr03-H3Of-MezCO; xxiv, CHzN2-EtzO; XXV, DBU-C6H,j

Scheme 39

131

Sesquiterpenoids H?

H?

0

i-iv cf. Scheme 39

V-IX

____*

/

__+

0

o cf.x v - x x y

HO

w

o

mo

0

0''

Iiv

Go OR

R = SiMe2But biii-xx

CHO I

RO*o

0 .-

CHO

R = SiMe2Buf

0H

xxii,xxif

'

OR (431);R = COC(Me)=CH2 (432); R = COC(Me)=CHMe Reagents: i, Zn/Cu-CH212-EtzO; ii, 70% HC104-CH2C12; iii, TsNHNH2-BF3,Et20-C6H6; iv, Pr'2NLi-THF; v, Bu'Me2SiCl-DMF-imidazole; vi, C12CHCOCl-Et3N-C6H 14; vii, ZnHOAc; viii, 10% HCl-THF; ix, CgH5NH,Cr03Cl-CH2C12; x, Bu'OOH-THF-NaOH; xi, MeCONHBr-MeCO-H20, h v ; xii, Ag2O-DME; xiii, rn-ClC6H4C03H (4 equivs.)xv, Dowex 50W-X8(H+)-Me2COCH,Cl,; xiv, m-C~C6HIC03H-CH2C~,-Li2~~3; H20; xvi, B2H6-THF; xvii, SOCl*-py-C6H6; xviii, Pr'2NLi-THFXH20; xix, MsC1-pyCH,Cl,; xx, DBU-C6H,; xxi, Dowex 50W-X8(H+)-CHC13-HC0,H; xxii, [CH2=C(Me)CO]2O-THF-NEt3-4-dimethylaminopyridine; xxiii, Dowex l-X8(HOform)-MeOH, 0 "C

Scheme 40

132

Terpenoids and Steroids

(433)

q wo (434)

(435)

?

f/

0

H

, 0

(436)

0

0

H

OH

(437)

C0,Bu' xvii,xviiil

//

(OMe

Reagents: i, Pr'2NLi-HMPA; ii, H C E C C H ~ B ~iii,; BrCH2C02Et; iv, HgS04-H30+; v, K0Bu'Bu'OH; vi, (Me0)3CH-MeOH-TsOH; vii, Pr'2NLi; viii, LiAlH4; ix, CH2BrCHBrOMePhNMe2; x, NaI-Me2CO; xi, LiN(SiMe3)z;xii, 12-THF; xiii, Dibal; xiv, rnClC6H4C03H; xv, NaH-ClCH20Me; xvi, CH2CO~H2C02But;xvii, NaN02-HOAc; xviii, Ac,O, A; xix, PhSH-BF,,Et,O; xx, Ce(NH,),(NO,),; xxi, Cr0,-Me,CO-H,O'; xxii, Pr',NLi-CH,O-HMPA; xxiii, MsCl-py, A

Scheme 41

Sesquiterpenoids

133

,

CO E t

C0,Et

CO B u'

a a liii

//

//

,jv,v

0

/

:

H

,

CO E t

C02Bu'

C0,Bu'

O

, Et0,C

co 2

H a

7

C0,Bu'

C,H40Me

ix-xi

(436)

Reagents: i, CH2(C02But)z-TiC14-py-THF; ii, DBU-THF; iii, p-MeOC6H4SNa-THF; iv, mClC6H4C03H-CH2C12; v, (Me0)3P-EtOH, 60 "C; vi, rn-ClC6H4C03H-H20-CH2Cl*; vii, NaBH3CN-HMPA; viii, BH3-THF, -45 "C; ix, Amberlite IRA 400-MeOH, elution with TFA; x, Et2NH-CH20; xi, NaOAc-HOAc, 100 "C

Scheme 42

Lv-vi

4

(Continued on Page 134).

134

Terpenoids and Steroids

& 1

(Scheme 43 continued).

ivii

e xiv,xviii --

e2Bu'

H

0 (439)

0

O

O

Reagents: i, Pr'ZNLi-PhSeC1; ii, PrizNLi-HMPA-MezC=CHCH2Br; iii, 50% H202-THF; iv, Bu'OOH-Triton B; v, Li-NH,-NH,Cl-THF; vi, Ac,0-NEt3-4-dimethylaminopyridine; vii, 03-CHzC12, -78 "C, MezS work-up; viii, Cr03-H30'-MezCO; ix, CH2Nz; x, LiO-MeOH; xi, TsOH-C,H,; xii, Bu'Me,SiCl-DMF-imidazole; xiii, TsNHNH,; xiv, Pr'zNLi-THF; xv, LDA-THF-HMPA-MeI; xvi, O3-CHzCl2, -78 "C, NaBH4 work-up; xvii, o-N02C6H4SeCN-Bu3P-50% HzOz; xviii, Bu4NF-THF

Scheme 43

The crucial step in this reaction sequence (Scheme 44) involves ring cleavage of an intermediate epoxymesylate (441) derived from the keto-lactone (440)134[cf. (421), Scheme 371. One of the most potentially useful synthetic routes to

A1(OPri)z

1

I

.

Al(OPr')2

Reagents: i, LiAlH(OBu')3; ii, m-ClC6HdCO3H; iii, MsC1-py; iv, A1(OPri)3-PhMe, A, 3 days; v, KOH-EtOH; vi, TsOH-C~H~; vii, AczO-py; viii, Li-NH3; ix, Cr03-py-CHzClz

Scheme 44

vernolepin (436) and related dilactone 2,3-secoeudesmanolides involves functionalization of the angular methyl group in a suitable derivative of santonin (418). Preliminary investigations in this area have shown that the bromohydrin (444) derived from tetrahydrosantonin (433) can be oxidatively cyclized to a bromo-lactone (445) which is easily converted into the keto.-ester (446) (cf. Scheme 45)e145 M. Watanabe and A. Yoshikoshi, J.C.S. Chem. Comm., 1978, 748.

135

Sesquiterpenoids

i-iii

__*

H Br* O-+O

o

q

o

(444)

(443)

q. oq. "":, Piii

O

dViiSV

, H

0 (446)

0

0

0

Reagents: i, TsNHNH2; ii, Pr'ZNLi; iii, NBS-H20-DMSO; iv, hv, Pb(OAc)4; v, Cr03-HzS04; vi, Zn-HOAc; vii, m-ClC6H4C03H; viii, CH2N2

Scheme 45

Remote functionalization of the angular methyl group in santonin derivatives has also been accomplished using the Barton reaction. For example a key step in the previously reported 146 synthesis of the norsesquiterpenoid rishitin (450)from tetrahydro-a-santonin (443)involves photochemical transformation of the nitrite ester (447)to the oxime (448)(cf. Scheme 46). Rishitin (450)is a well known antifungal phytoalexin* produced by diseased potato tubers and recent studies

AcO (448)

(447)

lii-iv

Reagents: i, hv, C&6; ii, AqO-py; iii, MsC1-py; iv, collidine, A

Scheme 46 146

A . Murai, K. Nishizakura, N. Katsui, and T. Masamune, Bull. Chem. SOC.Japan, 1977,50,1201; cf. Vol. 8, ref. 1226.

* For a review of phytoalexins see ref. 147; also see Vol. 8, pp. 65, 106, 107.

136

Terpenoids and Steroids

have shown that when incubated with healthy tissues of white potato it is metabolized to the non-toxic hydroxy-derivatives (45 1)and (452)14' (cf. p. 139).

OH

(452)

A further example of the co-occurrence of germacranolides, eudesmanolides, 2,3-secoeudesmanolides(elemanolides),and guaianolides is provided in a recent paper which describes the isolation of compound (453),callitrisin (454), 1,2dihydrocallitrisin, callitrin ( 4 5 9 , columerallin (456) and 11,13-dihydrocolu-

(453)

(454)

\

0

(455)

(456)

merallin from the heartwood of Callitris columellaris (syn. C. glauca).149 Further evidence to support the structure of germazone (457) (Vol. 8, p. l l l ) , a minor component of zdravetz oil, has been provided in a recent paper.'''

A detailed investigation of the major sesquiterpenoid constituents of the red alga Laurencia subopposita (collected in S . California), has revealed the presence of compounds belonging to various structural groups, e.g. laurene (146), 714*

149

H. Grisebach and J. Ebel, Angew. Chem. Internat. Edn., 1978, 17, 635. A. Murai, N. Katsui, F. Yagihashi, T. Masarnune, Y. Ishiguri, and K. Tomiyama, J.C.S. Chem. Comm., 1977,670. D. G . Brecknell and R. M. Carman, Tetrahedron Letters, 1978, 73. E. Tsankova and I. Ognyanov, Tetrahedron, 1978, 34,603.

137

Sesquiterpenoids

hydroxylaurene (45 8), 10-bromo-7-hydroxylaurene (459), oplopanone (460) (Vol. 7, p. 72; Vol. 5 , p. 60; Vol. 3, p. 114), a germacrane diol (461), oppositol (462) and the related diols (463) (Vol. 5 , p. 77; Vol. 8, p. log), l-hydroxyallomadendrene (464), and allomadendrene alcohol (465).15' An elegant

(146) R = X = H (458) R = OH, X = H (459) R = OH, X = Br

(462)

(463)

(464)

(465)

seven step synthesis of (-)-valeranone (471) from (+)-carvomenthone (466) has been accomplished by the reaction sequence shown in Scheme 47.152

Q3u - i>ou iv-vi

HO'*-

/

vii -*

-.

I

OMe

Me0

0

Reagents: i, KOH-EtOH-MeO(CH2)2COCH2OMe;ii, KOH-EtOH; iii, LiAlH4; iv, Zn/Cuvii, MeOH-HCl-H20 CH212; v, Cr03-H2S04-Me2CO; vi, NH~NH~-KOH-(CH~OH)Z;

Scheme 47

The unusual termiticidal norsesquiterpenoid (*)-chamaecynone (476) has been synthesized (Scheme 48) in low yield. Diels-Alder reaction between the 15'

S. J. Wratten and D. J . Faulkner, J. Org. Chem., 1977,42, 3343. E. Wenkert, D. A. Berges, and N. F. Golob, J. Amer. Chem. Soc., 1978,100, 1263.

Terpenoids and Steroids

138

li-iii

Reagents: i, ( C H ~ S H ) ~ - B F ~ E ~ii,Z TsNHNHz-MeOH-CHC13; O; iii, NaBH3CN-TsOH-DMFsulpholane; iv, l l ( N 0 3 ) 3

Scheme 48

5-ethynyl-2-methylcyclohex-2-en-l-one (472) and diene (473) was followed by selective removal of the C-9 carbonyl group in the bicyclic intermediate ( 4 7 4 ) . l S 3 G.1.c. analysis of Virginia tobacco condensate has revealed that the noreudesmane compounds (477) and (478) are present to the extent of 0 . 1 % and 0.38% respectively.lS4

q & q OH

13 Eremophilane etc. Robinson annulation of the n-butylthiomethylene derivative (480) of (+)-2methyl-4-isopropenylcyclohexanone (479) with truns-pent-5-en-2-one has recently been shown to provide a mixture (-1 : 1) of (+)-nootkatone (481) and (-)-7-epinootkatone ( 4 8 2 ) . l s S In previous synthetic studies (Vol. 2, p. 108; Vol. 0

(479) R = H 2 (480) R = CHSBu" 153 154

15'

T. Harayama, H. Cho, and Y. Inubushi, Tetrahedron Letters, 1977,3273. E. Demole and P. Enggist, Helv. Chim. Acta, 1978, 61, 1335. Y . Takagi, Y. Nakahara, and M. Matsui, Tetrahedron,1978,34, 517.

Sesquiterpenoids

139

4, p. 129) the parent ketone (479) provided a 1: 9 ratio of these compounds. The structure of petasitin (484), a compound isolated from the dried flower stalks of Petasites japonica Maxim., has been deduced from spectroscopic data and by its synthesis from isopetasin (483).ls6

An investigation of the metabolism of sesquiterpenoid phyt~alexins'~'has shown that pepper or potato cell cultures can convert capsidiol(485) and rishitin (450) into their 13-hydroxy-derivati~es~~~ (cf.p. 136).Solavetivane derivatives-of this type have previously been isolated from flue-cured tobacco (Vol. 8, p. 107). New chemical and spectroscopic evidence has led to a revised configuration for the 3-hydroxy- or 3-acyloxy-substituent in furanofukinol (486) (Petasites juponica Maxim.) and the related esters (487) and (488), previously isolated from Farfugium hiberniflorum Kitam. '" OH

1

(485)

H

(486) R' = R2 = H (487) R' = COC(Me)=CHMe, R2= H (488)R' = COC(Me)=CHMe, R2 = Ac

Compounds (489)-(502) and (503)-(505) represent new eremophilane and , ' ~Lopholaena ~ species. metabolites isolated from various S e n e c i ~ ' ~ ~ Related papers by the same research group describe the structural elucidation of 55 new eremophilanes found in 27 Europys species162aand 23 similar compounds isolated from Othonna species.I6*' New dimeric eremophilane sesquiterpenoids, (506) and (507), have been ~ ~ eremophilene lactam identified as constitutents of Belfordia ~ a l i c i n a , 'and (508), the first eremophilane-type alkaloid, has been reported as a metabolite of Petasites hybridus.164 156

15' 15' 159

160

164

I. Takagi, Y. Tazuke, and K. Naya, Bull. Chem. SOC.Japan, 1977, 50, 3320. E. W. B. Ward, A. Stoessl, and J. B. Stothers, Phytochemistry, 1977, 16, 2024. K. Naya, Y. Makiyama, T. Matsuura, M. 11, H. Nagano, and T. Takahashi, Chem. Letters, 1978,301. F. Bohlmann and C. Zdero, ( a ) Phytochemistry, 1978,17, 1337; (bj ibid., 1978,17, 1161; ( c ) ibid., 1978,17,1333. F. Bohlmann, D. Ehlers, and C. Zdero, Phytochemistry, 1978, 17, 467. F. Bohlmann, C. Zdero, and P. K. Mahanta, Phytockemistry, 1977,16, 1769. F. Bohlmann and C. Zdero, ( a ) Phytochernistry, 1978,17,1135;( 6 )F. Bohlmann and K.-H. Knoll, ibid., 1978, 17,461. F. Bohlmann and N. Le Van, Phytochemistry, 1978,17, 1173. J. Jizba, Z. Samek, and L. NovotnL, Coll. Czech. Chem. Comm., 1977, 42, 2438.

Terpenoids and Steroids

140

(490) R = COCH=CHCHMe

(489) R = COC(Me)=CHMe and/or COCH=CMe2

I

CH~OAC

RO*-

(491) R = COCM=CHPr or COCH=CMe2

AcO OR

(492) R' = COCHMeEt R 2 = H 2or 0

(493) R = COC(Me)=CHMe

(494)

0::

(495) R = COCHMe2 or COC(Me)=CH2

OR

OR

OR

(496) R = COCHMe2 or COC(Me)=CH2

rn

R'O

OR2

(498) R = COCHMe2 or COC(Me)=CH2

(499) R1= Ac or H R2= COCH=CMe2, COCH2CHMe2, or H

(497) R = COCHMe2

14 1

Sesquiterpenoids

RO"

p q

RO'

.q& /

OAc

(501) R = COC(CH20H)=CHMe or COC(Me)=CHMe

(502) R = COCH=CMe2

(504) R = COC(Me)=CHMe

(503)

(505) R = COC(Me)=CHMe, COCH=CMe2, or COC(Me)=CH2

woommo mo I

I

0

\

H H

I

\

(506)

(507)

(508)

An alternative shorter synthetic route to (*)-ishwarane (512) (cf. Vol. 8, p. 118) has been achieved by using a carbene insertion reaction to construct the tetracyclic framework (Scheme 49).16'The first synthesis of (2)-ishwarone (5 18),

0

0

0

0

(511)

(512)

Reagents: i, MeZCuLi; ii, MeMgI; iii, SO% H2SO4; iv, CBr4-MeLi-Et20 ( - 7 . 5 4 "C)

Scheme 49 16'

R. M. Cory and F. R. McLaren, J.C.S. Chem. Comm., 1977, 587.

142

Terpenoids and Steroids

a congener of ishwarane (512), has been accomplished by a stereoselective sequence in which the tetracyclic framework was constructed by an intramolecular alkylation reaction (Scheme 50).166

Reagents: i, CBr,-Ph3P-Zn-CHzClz; ii, Bu"Li-THF, -78 "C; iii, CH,O; iv, HCl-Me,CO; v, HZPd/BaSO,-EtOH-quinoline; vi, MsC1-py ; vii, Bu'OK-Bu'OH; viii, Me,C(CH,OH),-H'; ix, N,CH(CO,Et),-copper bronze; x, LiAIH,; xi, LiCI-HMPA-Et,O; xii, Bu'OK-THF; xiii, LiBHEt,-THF; xiv, CSH,NHCr03Cl-CH,Cl

Scheme 50

The absolute configuration of (+)-cacalol(5 19) has been deduced by oxidative and the corresponding degradation to (S)-(+)-2-methylhexanedioic aldehyde, cacalal (520), has been identified as a further constituent of Cacalia species168(cf.Vol. 8, p. 117). Cacalane derivatives (521) and (522), structurally OH

OMe

OMe

(519)R = M e (520) R = C H O

related to compounds (523)-(527) found in Senecio species'596 (cf.Vol. 8, p. 117), have been isolated from Roldana h e t e r o g ~ r n a . ' ~ ~

167

169

E. Piers and T.-W. Hall, J.C.S. Chem. Comm., 1977, 880. M. Terabe, M. Tada, andT. Takahashi, Bull. Chem. SOC.Japan, 1978, 51, 661. K. Naya, K. Takai, M. Nakanishi, and K. Omura, Chem. Letters, 1977, 1179. F. Bohlmann and C. Zdero, Phytochemistry, 1978, 17, 565.

Sesquiterpenoids

143 0

OMe

OMe

\OR

(523) R' = OH, R2= H (524) R' = H, R2 =OH

(525) R = COCH2CHMe2

* m OCOEt

OMe

CHO

\OAc (526)

(527)

14 Vetivane, Vetispirane A new general synthetic procedure for constructing cyclopentene derivatives [cf. (529)-(532)] has been illustrated by the completion of new synthetic routes to (*)-a-cuparenone (140)" (Scheme 5 1) and (rt)-p-vetivone (538) (Scheme 52).170*171Full details of the previously reported synthesis of (+)-hinesol (540)t from (-)-8-pinene (539) have been published'72 (cf. Vol. 7, p. 95). The key

Reagents: i, HC(OEt)3-MeOH-H+; ii, H+, 45 "C, 0.5 Torr; iii, MeCOCHNz-copper bronze; iv, HCl-Et,O; v, KOH-MeOH; vi, NaH-DMF-MeI; vii, H,-Pd/C

Scheme 51 170

17*

E. Wenkert, B. L. Buckwalter, A. A. Craveiro, E. L. Sanchez, and S.S. Sathe, J. Amer. Chem. SOC., 1978,100,1267. J. A. Marshall and P. C. Johnson, J. Amer. Chem. SOC.,1967,89,2750. D. A. Chass, D. Buddhasukh, and P. D. Magnus, J. Org. Chem., 1978,43,1750.

* An alternative synthetic route to a-cuparenone is described on p. 96 t (-)-Hinesol

is the natural enantiomer.

Terpenoids and Steroids

144

Ac

(534)

(533)

(535)

.1

oq)+-tqyq -

0

0

(538)

(537)

(536)

Reagents: i, HC(OEt)3-MeOH-H+; ii, H+, 45OC, 0.5 Torr; iii, KOBu'-DMF; iv, MeCOCHN2copper bronze; v, HCl-Et2O; vi, KOH-MeOH; vii, H2-Pd/C-NaOH-EtOH

Scheme 52

intermediates and rearrangement reactions in the synthetic routes are summarized in Scheme 53.

(539)

C0,Me

Lp Fco2 C0,Me

1 1 1

P

O

T

S

ttt

k

O

A

c

lii

C0,Me S02Ph

li"

Reagents: i, 12-HgO, h v ; ii, BF3,Et20-Ac20, 0 "C; ii, NaH-DMSO

Scheme 53

145

Sesquiterpenoids

A new spiroannulation procedure based on thermal rearrangement of a(cyclopropylmethy1ene)-cycloalkanones(Scheme 54)has been used to provide an alternative of the spiro-enone intermediate (543)previously used in

c2/s-.* OH

0

. ..

OSiMe,

(541)

1

(542a)

(542b)

iii

%+%

H'

0

H--

0

(544)

(543)

Reagents: i, MeMgI-CuI-EtzO, 0 'c;ii, M H O ; iii, TsOH-C&; iv, Pri2NLi-glyme, 0 "C;v, Me3SiCl-Et3N; vi, 380 "C, argon; vii, 'HC1-MeOH; viii, MeLi-Et20,O "C; ix, SiazBHTHF; x, H202-HO-; xi, C S H ~ N H C ~ O ~ C ~ - C H ~ C I ~ Scheme 54

q

q

the synthesis of (*)-vetispirene (545),(f)-vetivone (546),and ( f )-hinesol acetate (547) (cf.Vol. 7, p. 95; Vol. 8, p. 108). \

o

q

--H

\

OAc

(545)

(546)

(547)

Potato tubers which have been infected with fungi produce a variety of stress metabolites (phytoalexins) whose structure, synthesis, and biosynthesis have received considerable attention (cf.Vol. 8, pp. 65,106, 107). A recent provides a full account of recent studies on the biosynthesis of these compounds. 173

E. Piers and C. K. Lau, Synth. Comrn., 1 9 7 7 , 7 , 4 9 5 .

174

A.Stoessl, J. B. Stothers, and E. W. B. Ward, Canad. J. Chem., 1978, 56,645.

Terpenoids and Steroids

146

Thus it has been shown that addition of sodium [13C2]acetate to potato tuber slices, which have been inoculated with Moniliniu fructicolu or Glomerallu cingulutu, provides rishitin (549), lubimin (SO), hydroxylubimin (55 l), 15dihydrolubimin (552), solavetivone (553), isolubimin (554), 10-epilubimin (55 5), 13

13

CH3-c02H

-

m op2

1

H

(548) R = H or OH

1

1

1

(553)

(550) R = H (551) R = O H

Scheme 55

1

\

(549)

(555)

147

Sesquiterpenoids

15-dihydro-10-epilubimin(556),phytuberin (557), and phytuberol (558)with labelling patterns* consistent with their derivation by the routes outlined in Schemes 55 and 56.Solanascone, a new tetracyclic ketone produced by Nicotiana

--*

o&o~ \

CHO (557) R = A c (558) R = H

Scheme 56

tabacum, has been assigned the cyclovetispirane structure (560) on the basis of X-ray crystallographic analysis of its xim me.^" The novel structure of solanascone (560) is probably biosynthesized by [2 + 2lcyclization of an appropriate vetispirane intermediate [cf. (559)].A review of synthetic methods available for the synthesis of spiro-compounds has been ~ub1ished.l~~

17'

T. Fujimori, R. Kasuga, H. Kaneko, S. Sakamura, M. Noguchi, A. Furusaki, N. Hashiba, and T. Matsumoto, J.C.S. Chem. Comm., 1978, 563. A. P. Krapcho, Synthesis, 1978, 77.

* Since the stereochemistry of these compounds is shown in Schemes 5 5 and 56 the labelling patterns have been omitted.

Terpenoids and Steroids

148 15 Guaiane, Pseudoguaiane, Valerenane

During the past year a variety of new guaianolides have been isolated from various plant sources and their structures assigned on the basis of spectroscopic data. These compounds include linichlorin-A (561), -B (562), and -C (563) (Centaurea l i n i f ~ l i a ) ,aguerin-A '~~ (564) and -B (565) (Centuureu c u n a r i e l ~ s i s ) , ~ ~ ~

0

0

(561) R = COC(Me)=CH2

(562) R = COC(Me)CH2Cl I

0

(563) R = COC(Me)CH2Cl 1

OH

OH (564) R = COPr'

(565) R = COC(Me)=CH2

xerantholide (566) (Xerunthemum ~ylindraceum),"~arctolide (56-7) (Arctotis grundis Thunb.),18' eregoyazin (568) and eregoyazidin (569) (Eremanthus goy azensis),181 and the rupicolin derivatives (570) and (57 1) (Erlangea

(567)

AcOAcO- Q-R-

qR

AcO -

#

0

0 (570) R = COC=CH2

I

CH(0H)Me 177

17'

0

(571) R = COC=CH2

1

CH(0H)Me

A. G. Gonzhlez, J. Berrnejo, J. M. Amaro, G. M. Massanet, A. Galindo, and I. Cabrera, Cunad. J. Chem., 1978,56,491. A. G. Gonzalez, J. Bermejo, I. Cabrera, G. M. Massanet, H. Mansilla, and A. Galindo, Phytochemistry, 1978,17,955. Z . Sarnek, M. Holub, B. Droidi, H. Grabarczyk, and B. Hladon, Coll. Czech. Chem. Comm., 1977,

42,2441. "O

lS1

Z.Sarnek, M. Holub, B. Drozdz, and H. Grabarczyk, Coll. Czech. Chem. Comm., 1977,42,2217. W.Vichnewski, F. W. L. Machado, J. A. Rabi, R. Murari, and W. Herz, J. Org. Chem., 1977,42, 3910.

Sesquiterpenoids

149

inyangana).lg2In addition 5-guaien-11-01 (572) has been identified as a new constituent of gurjun-Bal~arn.'~~ The relative abundance of eremanthin (573) in

(573)

(572)

0

Eremanthus elaeagnus has led to an investigation of its use as a synthetic precursor of guaianolides which have potential as antitumour agents.lg4 Kessanol(579) and 8-epikessanol(578) have been synthesized for the first time by a reaction sequence in which the hydroazulene system is constructed by an ene reaction of the aldehyde (575) (cf,Scheme 57) and the cyclic ether functionality is

(574)

(576a) R = SiMe2Bu'

Q

(576b) R = SiMe2Bu'

/xiv,xv

SiMe,Bu,

xvi-xviii

,

OH

-OH

+ (578)

(577)

Reagents: i, CNCH2C02Et-P-alanine-95% EtOH; ii, NaBH4-MeOH, 0 "C;iii, LiAlH4-THF; iv, Ac,O-py; v, KOH-H,O-MeOH; vi, Cr0,-py-CH,Cl,; vii, SnCl,-CH,CI,; viii, Me2ButSiC1-imidazole-DMF; ix, Brz-CHzCl2-py; x, N204-CH2C12-NaOAc; xi, CC14, A; xii, Zn-HOAc-Et20; xiii, Na2C03-MeOH; xiv, C5H5NHCrO3Cl; xv, MeLi; xvi, Hg(OAc)2-THF; xvii, NaBH4; xviii, HOAc-H20-THF; xix, H30+-Cr03; xx, LiBHEt3

Scheme 57 F. Bohlmann and H. Czerson, Phytochemistry, 1978,17, 568. 183 G. Rucker and F. W. Hefendehl, Phytochemistry, 1978,17,809. lS4 L. A. Macaira, M. Garcia, and J. A. Rabi, J. Org. Chem., 1977, 42, 4207. lS2

Terpenoids and Steroids

150

formed by an intramolecular alkoxymercuration-demercuration r e a ~ t i o n ' ~ ' (577)+(578) (cf. Vol. 8, p. 102). An alternative route to the hydroazulene system present in the guaiane sesquiterpenoids has been accomplished by ring cleavage of the tricyclic diol (581) derived from the photoadduct (58O).lg6The ketonic product (582) of this reaction was subsequently converted into 5 epikessane (583) and dehydrokessane (584) (Scheme 58).

AcO

+

""n AcO

(583)

. ..

iii-vi

1,11

__+

w

@ O

x-xii c --

H OAc

viii,ix

+--

OH

Reagents: i, hv, C&; ii, TSOH-CbH6; iii, MeMgBr-CuI-Et20, 0 "C; iv, (CH2SH)2-BF3Et20; v, W-2 Raney Ni; vi, LiAIH4; vii, TsC1-py; viii, NaH-Me2C03; ix, MeI-NaH; x, Hg(OAc)Z-THF; xi, NaBH,-HO-; xii, LiAIH4; xiii, Me2NPOClz-Me2NH; xiv, LiEtNH2; XV,POC13-py, 0 "C

Scheme 58

Arborescin (586), a metabolite of Arfernisia arborescens, has been ~ynthesized'~'(Scheme 59) from the eudesmanolide derivative (421) previously used in the synthesis of v ~ l g a r i n (cf. ' ~ ~p. 128). Interest in the cytotoxic properties of extracts of Heleniurn amarum (bitterweed) has resulted in the isolation of a number of sesquiterpenoid lactones (e.g. tenulin, helenalin, etc.). The structure of heleniamarin (587), a recently discovered member of this group, has been determined by X-ray crystallographic analysis. N. H. Andersen and F. A. Golec, Tetrahedron Letters, 1977, 3783. H. J. Liu and S. P. Lee, Tetrahedron Letters, 1977, 3699. "'M. Ando, A. Akahane, and K. Takase, Chem. Letters, 1978,727. lX8 T. Ottersen, U. Sorensen, M. A. Elsohly, and C. E. Turner, Actu Chem. Scund., 1978, B32,79. lX5

186

Sesquiterpenoids

- _ - ,ix,vii,x

I

151

Bz0--q

B z o - - q - - -
_--

0 0

0

0

(586) Reagents: i, A1(OPr1)3-PhMe; ii, H2-Pt-EtOAc; iii, PhCOC1-py; iv, 50% HOAc; v, Zn(BH& DME; vi, MsC1-py; vii, KOAc-HOAc; viii, m-ClC6H4C03H-CH2Cl2; ix, K2CO3MeOH; x, LiBr-LizCO3-DMF

Scheme 59

0

H0'

Further studies on the development of synthetic routes to pseudoguaianolides have resulted in the stereospecific synthesis of (*)-ambrosin (593),lSgn(&)damsin (592),'"" (*)-helenalin (595),lgoand the seco-pseudoguaianolidepsilostachyin C (594)lS9O(cf.Schemes 61 and 62). An elegant feature of these synthetic routes is the use of a common cyclopentenol intermediate (591) ( R = H or CH2Ph) derived from norbornadiene (588)lg9' (Scheme 60) (cf.Vol. 6, p. 90). An alternative synthesis of damsin (592) (cf. Vol. 7, p. 104) has also been accomplished using the bicyclic hydroxy-diketone (596)191as starting material (cf. Scheme 63).lg2An unusual feature of this sequence is the cleavage of a (a) P. A. Grieco, Y. Ohfune, and G. Majetich, J. Amer. Chem. Soc., 1977,99,7393 (cf.P. A. Grieco,

190 191

192

Y. Yokohama, S. Gilman, and Y. Ohfune, J.C.S. Chem. Comm., 1977,870; ( b ) P. A. Grieco, C. S. Pogonowski,S. D. Burke, M. Nishizawa, M. Miyashita, Y. Masaki, C.-L. J. Wong, and G. Matejich, ibid., p. 4111 and references cited. Y. Ohfune, P, A. Grieco, C.-L. J. Wang, and G. Majetich, J. Amer. Chem. Soc., 1978, 100, 5946. D. Termont, P. de Clercq, D. De Keukeleire, and M. Vandewalle, Synthesis, 1977,46. P. de Clercq and M. Vandewalle, J, Ore. Chem., 1977,42,3447.

Terpenoids and Steroids

152 Me0,C

THPO

4

I

ref. 190,

i-vi

H I

, RO

0

(591; R = H ) Reagents: i, MeLi-Et20; ii, DBU-PhMe; iii, LiAlH,-THF; iv, 30% HOAc, 90 "C; v, DHPCH2CI2-TsOH; vi, Pr'2NLi-THF-MeI, 0 "C; vii, H202-HO--MeOH; viii, CHzN2

Scheme 60

(591; R = H ) lxi

Q

xii-xiv

xv-xviii

c---

lf'I>

PhCH,O

PhCH,O

0

0

0

\ oQ 00

0

0

0

0

(593)

(594)

Reagents: i, H2-PtO2-EtOAc; ii, LiAlH4-Et20; iii, TsC1-py; iv, NaCN-DMSO; v, NaH-THFPhCH2Br-HMPA; vi, DiBAL-PhMe, -78 "C; vii, NaBH4-EtOH, 0 "C; viii, MeOHTsOH; ix, CrO3-H30+-MezCO; x, NaI-Me2CO; xi, (Me3Si)zNLi-THF-HMPA; xii, Prf2NLi-MezC=CHCHzBr; xiii, 0 3 ; xiv, NaOAc-AczO, 140 "C; xv, H,-Pd/C; xvi, Pr'zNLi-HCHO; xvii, MSC1-py ; xviii, DBU-C&, 25 "C; xix, PhSeC1-EtOAc; xx, NaI04-Bu'OH; xxi, 30% H202-ButOH-PhSe02H

Scheme 61

153

Sesquiterpenoids

(591; R=CHzPh)

a

OH

. ,

PhCH,O

'0

ki-xix

-

i-iii

t xv,x

@

0

/

a

THPO

OTHP

PhCH,O

,

m

O

e x-xiv -

PhCH,O

PhCH,O

,

KCH

iv-vii

------*

xx,xi,xiv,xxi,xxii

0

T

I

0

, Qc

0

0

OH

(595) Reagents: i, MeOH-TsOH; ii, KOH-Et20-HzO; iii, DBU-TsC1-PhMe; iv, DiBAL-PhMe, 78 "C; v, Ph3(CH,0Me)P'Cl--Bu'CH,0Na-C6H6; vi, Cr03-C5H5N-CH2C12; vii, 1O0/o HCITHF; viii, KOH-MeOH; ix, DHP-TsOH, 0 "C; x, NaBH4-EtOH, 0 "C; xi, MsC1-py, 0 "C;xii, MeOH-TsOH; xiii, Cr03-H3Ot-MezCO; xiv, DBU-C~HG;xv, Bu'OOHTHF-Triton B; xvi, -CH,C02-2Li'-DME; xvii, Li-NH,; xviii, HCI-H,O; xix, DHPTsOH-CHzC12; xx, LDA-HCHO; xxi, 60% HOAc; xxii, Mno~-CH~cl~-C6H6

Scheme 62

VI

___* I-V

--*

THPO (597)

(596)

(592)

hi

6

:::$

xii-xiv

HO

0

0 Reagents: i, DHP-TsOH; ii, NaOH-MeOH; iii, Ph3P=CHz-THF; iv, LDA-BrCHZCOzEtHMPA; v, KOH-MeOH; vi, AczO-NaOAc; vii, Hz-Pt/C-EtOH; viii, H2Cr04MeZCO; ix, (CH20H)z-TsOH; x, NaH-HC02Et; xi, NaBH,-MeOH; xii, 3M-HC1MeOH; xiii, TsC1-py; xiv, py, A

Scheme 63

-

154

Terpenoids and Steroids

tetrahydropyranyl ether group during neutral catalytic hydrogenation of the unsaturated lactone (597).'93 Cyclization (7-endo-dig) of the enyne (598) to the enedione (599)followed by conversion into damsinic acid (600) represents a new synthetic route to the pseudoguaianolide framework'94(Scheme 64). It has also been proposedlg4that

& 0

0 (598)

___* several steps

0

@ -

0

(599)

Scheme 64

damsinic acid (600) may be a biosynthetic precursor of damsin (592). The novel tricyclic framework of pulchellon (603) may be produced in the plant (Gaillardia pulchellu)by cyclizationof a trisnorsesquiterpenoid derived from pulchellin (601) and this has led to the recent development of a similar transformation in the laboratory'95b(Scheme 65). AcO

OH 0

HO

AcO

AcO

OH

(601)

O t -

OH HO

J. vi-ix

AcO

Reagents: i, AqO-py; ii, 0 3 ; iii, KMn04-MgS04-H20-MezCO; iv, AczO-py; v, (CHzSHI2BF3Et20; vi, Raney-Ni-MeZCO; vii, BH3-THF; viii, H202-NaOH; ix, KOH-MeOH; x, Cr0,-H,SO,-Me,CO; xi, BF,Et,O-Ac,O-HOAc; xii, 2% KOH-MeOH, 0 "C

Scheme 65 193 194 195

Cf. G. P. Rozing, P. de Clercq, and M. Vanderwaile, Synthesis, 1978, 228. P. T. Lansbury and A. K. Serelis, Tetrahedron Letters, 1978, 1909. ( a )S. Inayama, T . Kawamata, and M. Yanagita, Phytochernistry, 1973,12, 1741; ( b )S. Inayama, T. Kawamata, and T. Ohkura, Tetrahedron Letters, 1978, 1557.

Sesquiterpenoids

155

Spectroscopic evidence has been cited in support of the structure assigned to altamisin (604), a new seco-pseudoguaianolide isolated from the aerial part of Ambrosia c ~ m u n e n s i sThe . ~ ~configuration ~ at C-5 in altamisin (604) was assigned on the basis of its co-occurrence with the psilostachyins [cf.psilostachyin C (594), p. 1511. A new structural variation of the seco-pseudoguaianolide skeleton is evident in the structure recently proposed for confertdiolide (606), a compound ~ ~addition the photolytic isolated from Purthenium conferturn var. l y r ~ t u m . 'In conversion of hymenin (605) (a known metabolite of Purthenium conferturn) into confertdiolide (606) provided further evidence for this structural assignment.197

QAo% EtOAc

0

0

In an elegant new synthetic route to (k)-seychellene (610) (cf.Vol. 4, p. 139; Vol. 5, p. 89), the bicyclo[2,2,2]octanone intermediate (608)is constructed by DielsAlder reaction between a 2-silyloxydiene (607) and methyl vinyl ketone. 19* Subsequent conversion of the product (608) into the seychellane framework involves intramolecular alkylation of the derived bromo-ketone (609) (Scheme 66).

vii,viiil

&;

, ix

,x-xii

(610)

A

Br

(609)

Reagents: i, LiNPr';?; ii, MesSiCl; iii, CH;?=CHCOMe, A; iv, CH2=CHMgBr; v, H O A C - H ~ S O ~ ; vi, Na2C03; vii, H;?-Rh-A1203-C&6; viii, NBS-Ph3P; ix, KH-Ph-,CH-DME-DMSO; x, silica chromatography; xi, MeLi; xii, SOCl;!

Scheme 66 196

Ig7 19'

J. Borges, M. T. Manresa, J. L. Martin, C. P. y P. Vazquez, Tetrahedron Letters, 1978, 1513. A. Romo de Vivar, A. L. PCrez, H. Flores, L. Rodriguez-Hahn, and M. JimCnez, Phytochemistry, 1978, 17, 279. M. E. Jung and C. A. McCombs, J. Amer. Chem. SOC.,1978,100,5207.

156

Terpenoids and Steroids

The valerenane sesquiterpenoids are produced by Valeriana officinalis L. and it has been suggested that their carbon skeleton [e.g. valerenal (612), valerenic acid (613)] is probably derived by ring contraction of a suitable g ~ a i a n o l i d e ' ~or~ " g ~ a i a n e derivative ' ~ ~ ~ [cf. (61l)].The stereochemistry of another member of this group, valerenolic acid (614), has recently been established by X-ray crystallographic analysis.2oo

R (612) R = C H O (613) R = C 0 2 H

CO, H (614)

16 Aromadendrane (-)-Alloaromadendrene (615), (-)-viridiflorol (616), and (+)-led01 (617) have been identified as minor co-metabolites of (+)-palustrol (618)201bin soft coral (Cespitularia aff. subviridis) collected in the Seychelles.20'" It has been noted201a that (+)-palustrol and (-)-viridiflorol of marine origin are enantiomeric to those found in terrestrial plants while only (+)-led01 (617) is found in both sources.

(615)

(616)

(617)

(618)

X- Ray crystallographic analysis has led to a revised cycloaromadendrane structure for (-)-myliol(619), a metabolite of the liverwort Mylia taylorii202(cf.Vol. 4 , p. 135; Vol. 6, p. 90). More recent investigations have resulted in the isolation of an isomeric compound, (-)-dihydromylione A (620) from the same source.2o3 Independent studies have also revealed the widespread occurrence of a closely related hydrocarbon, anastreptene (177), in the essential oils of various liverworts (Anastrepta oveadensis, Diplophyllum albicans, Barbilophozia (cf.p. 199

200 201

202

203 204

Cf. ( a )G. Buchi, T. L. Popper, and D . Stauffacher, J. Amer. Chem. SOC.,1960,82,2962; ( b ) R. B. Bates and S. K. Paknikar, Chem. and Znd., 1965, 1731. G . I. Birnbaum, J. A . Findlay, and J. J. Krepinsky, J. Org. Chem., 1978, 272. ( a ) J. C. Braekman, D. Daloze, R. Ottinger, and B. Tursch, Experientiu, 1977, 33, 993; ( 6 ) C. J. Cheer, D. H. Smith, C. Djerassi, B. Tursch, J. C. Braekman, and D . Daloze, Tetrahedron, 1976,32, 1807. A . Matsuo, H . Nozaki, M. Nakayama, Y. Kushi, S. Hayashi, N. Kamijo, V. BeneSova, and V. Herout, J.C.S. Chem. Comm., 1976, 1006. A . Matsuo, H. Nozaki, M. Shigemori, M. Nakayama, and S. Hayashi, Experientia, 1977, 33,991. N. H. Andersen, Y. Ohta, A . Moore, and C. L. W. Tseng, Tetrahedron, 1978, 34,41.

Sesq uite rpe noids

157

100). Chemical and spectroscopic evidence has been provided to support the seco-aromadendrane structures assigned to plagiochilide (621) and plagiochiline A (622).205 H

\

H \

17 Miscellaneous A variety of sesquiterpenoids having structures which are not easily rationalized in biosynthetic terms have been isolated from plants, fungi, and marine algae. In most cases the unusual structures of these compounds have required the use of X-ray crystallographic analysis for their elucidation. Members of this group whose structures have recently been determined by the X-ray method are poitediol (623), a co-metabolite of dactylol (624) in red seaweed (Laurencia poitei),206and the fungal products alliacolide (625) (Marasmius a l l i a c e ~ sand )~~~ quadrone (626) (Aspergillus terreus).208In addition the structure of modhephene

(629), a co-metabolite of isocomene (628) (Vol. 8, p. 121) in the toxic plant Iscoma wrightii (rayless goldenrod), has been determined by X-ray analysis of the corresponding ~ i s - d i o l . ~It' ~ has been suggested that isocomene (628) and modhephene (629) are formed in the plant from a common precursor [e.g. (627)].209

205

'06

'O' '08 '09

Y. Asakawa, M. Toyota, and T. Takemoto, Tetrahedron Letters, 1978, 1553. W. Fenical, G. R. Schulte, J. Finer, and J. Clardy, J. Org. Chem., 1978,43, 3628. R. J. King, I. W. Farrell, T. G. Halsall, and V. Thaller, J.C.S.Chem. Comm., 1977, 727. R. L. Ranieri and G. J. Calton, Tetrahedron Letters, 1978,499. L. H. Zalkow, R. N. Harris, and D. Van Derveer, J.C.S. Chem. Comm., 1978,420.

Terpenoids and Steroids

158

The structure of berkheyaradulene (630), isolated from the roots of Berkheya radula, has been deduced from spectroscopicevidence and transformation into a tricyclic alcohol (631) whose structure was established by X-ray analysis.21o

OH (631)

(630)

Pentalenolactone G (632), recently identified as a co-metabolite of pentalenolactone (634) in Streptornyces sp., has been assigned structure (632) on the basis of detailed n.m.r. spectroscopic analysis.211In particular the long-range selective proton-decougled (LSPD) 13C n.m.r. spectrum and selective 13C-('H) NOE experiments provided valuable evidence for the assigned structure. It has been proposed that pentalenolactone (634) is derived in the micro-organism by Nametkin rearrangemeni of dihydropentalenolactone G [cf. (633)].211

% H

C 0 2 H --+

b) 1

+ S

(633)

0 (632)

C

0

0 0

0

H2

H

(634)

Recent biosynthetic investigations have revealed that cantharidin (635), a well-known vesicant compound isolated from dried beetles (Lytta vesicatoria L.), can be regarded as a degraded sesquiterpenoid.212Thus the labelling pattern in cantharidin (635) after incorporation of [2-14C]mevalonic acid (35) and (E,E)-[11',12-3H2]farnesol(16) [but not the ( E , Z ) -or (2,Z)-isomers!] is consistent with the biosynthetic sequence outlined in Scheme 67.212 H O 2 K f i o H

t \

----+

*f

\

OH

F. Bohlmann, N. Le Van, and J. Pickardt, Chem. Ber., 1977,110, 3777. H. Seto, T. Sasaki, H. Yonehara, and J. Uzawa, Tetrahedron Letters, 1978, 923. "' W. D. Woggon, M. G. Peter, and H. Schmidt, ( a ) Helo. Chim. Actu, 1977, 60, 2288; ( b ) ibid., p. 2756.

'lo *I1

Sesquiterpenoids

159

The use of 13Cn.m.r. spectroscopy in sesquiterpenoid biosynthesis is now well established. Recent studies on the biosynthesis of dihydrobotrydial (636)*13have made use of the fact that under certain feeding conditions (i.e. when metabolite production is at a maximum) more than one labelled acetate unit can be incorporated into the natural product. The result is that additional couplings between labelled carbon atoms can be detected and used to reveal rearrangements occurring during the biosynthetic process. For example, addition of [l-13C]acetate to the plant pathogen Botrytis cinerea, at the time of maximum metabolite production, provided dihydrobotrydial (636) in which C-6-C-7 and C-7-C-8 couplings were detected, consistent with the derivation of dihydrobotrydial (636) from 2-trans-farnesyl pyrophosphate (16) and the 1,2-shift indicated in Scheme 68.*13

J

213

A. P. W. Bradshaw, J. R. Hanson, and M. Siverns, J.C.S. Chem. Comm., 1977,819.

3 Diterpenoids BY J. R. HANSON

1 Introduction This chapter follows the pattern of the previous Reports with sections based on the major skeletal types of diterpenoid. The literature that has been covered is that available to August, 1978. The number of known diterpenoids continues to increase although chemical studies and transformations of the various skeleta have diminished. During the year a number of novel skeletal types have been described, particularly in isolates from termites and marine organisms. The range of biological activities exhibited by the diterpenoids has attracted some attention. Several useful reviews of diterpenoid chemistry have appeared. 1*2 The analysis of the y-effect in the 13C n.m.r. spectra of some natural products, including diterpenoid examples, has been proposed3 as a basis for stereochemical assignments. A systematic study of the circular dichroism of strained, bridged-ring ketones includes4 many diterpenoid examples. The data were used to derive an empirical relationship between the strain energy in a bond and the contribution which the bond makes to the total value of A&. Eleganolone (1) is a 13-ketogeranylgeraniol derivative which has been isolated5 from the brown alga Cystoseira elegans, whilst the unusual 1,4-diacetoxybuta-1,3-diene (2), trifarin, came6 from a Caulerpa species. Trixagol ( 3 ) is a

'

E. Fujita, K. Fuji, Y. Nagao, M. Node, and M. Ochiai, Bull. Inst. Chem. Res., Kyoto Univ., 1975,53, 494; 1976,54, 197; 1977,55,323. * E. Fujita, Y. Nagao, and M. Node, Heterocycles, 1976, 5 , 793. P. Crews and E. Kho-Wiseman, Tetrahedron Letters, 1978, 2483. D. N. Kirk, J.C.S. PerkinI, 1977, 2122. ' C . Francisco, G . Combaut, J. Teste, and M. Prost, Phytochemistry, 1978, 17,1003. ' A. J . Blackman and R. J. Wells, Tetrahedron Letters, 1978, 3063.

160

161

Diterpenoids

y-cyclogeranylgeraniol derivative which has been obtained' from the parasitic plant Bellardia trixago. 2 Bicyclic Diterpenoids

Labdanes.-The I3Cn.m.r. spectra of some members of the eperuane series have been assigned.' The diterpenoids of the oleoresin of Picea (spruce) species have been surveyed.' Cistus species have been thoroughly examined. 15-Nor-8labdanol, labd-8( 17)-en-15-o17and 15-hydroxylabd-7-en-6-one(oxocativol) were obtained" from the resin of C. ladaniferus. An extensive study has also been reported" on the berries of Juniperus phoenicea. Myrceocommunic acid (4; R = H) and 12(R)-hydroxymyrceocommunicacid (4; R=OH) were amongst the many diterpenoid acids which were obtained. Both the neutral and the acidic fractions contained diterpenoids oxygenated on either C-18 or C-19. Juniperus comrnunis has also been thoroughly studied.'* Myrceocommunal and junicedral, labd-8( l7)-en-15,19-dial7 were amongst the aldehydes obtained. Hafimium umbellaturn (Cistaceae) afford^'^ labd-7-en-3& 15-diol and the corresponding 7,13-diene. Plant-growth inhibiting properties have been recorded14for sclareol. A la-acetoxy-derivative of ozic acid ( 5 ) and the 12,13-epoxide (6) were amongst the diterpenoids obtained" from Mikania (Compositae) species. The acid were isoangelate and tiglate esters of 19-hydroxylabd-7,13-dien-15-oic lated16 from Brickellia argyrolepsis (Compositae). The corresponding diol, villenol, the 7a-alcohol, villenatriol, the 7-ketone, villenolone, and the 7-keto-

. (4)

CO,H (5)

(6)

' J. de Pascual Teresa, E. Caballero, C. Caballero, M. Medarde, A. F. Barrero, and M. Grande, lo

l1

l2

l3

l4

*'

l6

Tetrahedron Letters, 1978, 3491. P. M. Imamura, A. J. Marsaiolo, L. E. S. Barata, and E. V. Ruveda, Phytochemistry, 1977,16,1842. E. N. Schmidt and V. A. Pentegova, Khim. prirod. Soedinenii, 1977, 653. J. de Pascual Teresa, J. G. Urones, and F. Gonzalez Mateos, Anales de Quim., 1977,73, 1024. J. de Pascual Teresa, A. San Feliciano, M. L. Tabernero, J. M. Miguel del Corral, A. F. Barrero, and M. Grande, Anales de Quim., 1978, 74,459,465. J. de Pascual Teresa, A. F. Barrero, A. San Feliciano, and 1. Sanchez Bellido, Anales de Quim., 1977, 73, 568. J. de Pascual Teresa, J. G. Urones, P. Basabe, and A. Llanos, Anales de Quim., 1977,73, 1029. H. G. Cutler, W. W. Reid, and J. Deletang, Plant and Cell Physiol., 1977, 18, 711. F. Bohlmann, A. A. Natu, and P. K. Mahanta, Phytochemistry, 1978, 17,483. F. Bohlmann, A. Suwita, and T. J. Mabry, Phytochemistry, 1978, 17, 763.

162

Terpenoids and Steroids

8p-alcohol together with their 19-acetates have been obtained” from Sideritis chamaedryfolia (Labiatae). The structure of andalusol (7) from S. arborescens was determined’’ by X-ray analysis and the absolute stereochemistry derived by an application of Horeau’s method to the C-18 benzoate ester. These are further examples of normal and ent-diterpenoids occurring in related species. Examination of the I3Cn.m.r. spectrum of borjatriol has led to a correction of its structure to (8).19 Further evidence for the structure of the manoyl oxide derivative coleonol has been presented.”

Neoconcinndiol hydroperoxide (9) is an unusual diterpenoid obtained21 from Laurencia species of red alga. The structure may arise through rearrangement and oxidation of a 3p-bromolabdane. Nivenolide (10) is a diterpenoid lactone,

,.I OOH

H CO, H

isomeric with pinusolide, which was isolated22 from Croton niveus (Euphorbiaceae). The structural evidence included a degradation to a derivative of polyalthic acid. Although rupestralic acid (1l),from Balluta rupestris (Labiatae), W

l7

C

H

O

B.Rodriguez. Phytochemistry, 1978,17,281.

’’ M.A. Lopez, C. von Carstenn-Lichterfelde,B. Rodriguez, J. Fayos, and ivl. Martinez-Ripoll,J. Org. l9

2o

*’

22

Chem., 1377,42,2517. S. Valverde and B. Rodriguez, Phytochemistry, 1977,16,1841. J. S.Tandon, M. M. Dhar, S. Ramakumar, and K. Venkatesan, Indian J. Chem., 1977,15B,880. B.M. Howard, W. Fenical, J. Finar, K. Hirotsu, and J. Clardy, J. Amer. Chern. SOC.,1977,99,6440. E.T. Rojas and L. Rodriguez-Hahn, Phytochemistry, 1978,17,574.

6 $FcH20H 163

Diterpenoids

Ii

,I

co-0

co-0 (12)

(13)

is in equilibrium with its lactol form, it undergoes addition of diazomethane to give the unstable epoxide (12) and thence the lactone (13).23 from Leonotis Leonitin (14) is a 9,13-epoxylabdane which was leonitis (Labiatae). It possesses a clear relationship to nepetaefolinol, which had previously been obtained from L. nepetaefolia.

p

gJjqR

o

0

co-0

Me0,C

The acid-catalysed cyclization of labdanes has continued to attract attention. The influence of a C-15 carbonyl group, as in (15), leads” to compounds of the pimarane series (16) and to the enol-ether (17) rather than isoagathic acid derivatives even in the presence of formic acid. The tetracyclic alcohol (20) has been obtained26 by dehydration of sclareol (18) with perchloric acid. It is presumably formed via the carbocation (19).

&\ { f j T H

OH

(18)

(19)

QAJ H

(20)

G . Savona, F. Piozzi, and M. Marino, Heterocycles, 1977, 7, 161. G. A. Eagle, E. R. Kaplan, K. Naidu, and D. E. A. Rivett, J.C.S. Perkin I, 1978, 994. ’’ M. Fetizon and N. Ragoussis, Tetrahedron,1978, 34, 287. 26 D. Joulain, F. Rouessac, and J. Garnero, Tetrahedron Letters, 1977, 3585. 23 24

--OH

164

Terpenoids and Steroids

The photosensitized oxygenation of 12(Z)-abienol has been studied2' in a biomimetic synthesis of tobacco labdanoids. In the reaction with singlet oxygen the major process is an ene-reaction involving attack at C-13 and yielding after reduction the 11(E),13(R and S)-labda-l1,14-diene-8,13-diols. Some minor products arose from attack at C-12 and include the 12(R)- and 12(S)-labda13(16)-14-diene-8,12-diols. Reaction of cis-abienol with m-chloroperbenzoic acid gave some 8,12- and 8,13-epoxides. The X-ray crystal structure of 12(S),13(S)-8,12 : 12,15-diepoxy-13-bromolabdanehas been determined.28The synthesis has been described29of some 13,8: 13,17-ethers of the enantio-14(15)dinorlabdane series from eperuic acid. C1erodanes.-Halimic acid (21), the corresponding 15-alcohol, its 13-oxo-14,15bisnor-derivative, and the 13(16)-ene-14,15-diolare3' components of Hulimium umbellatum (Cistaceae) which represent an unusual discharge of the C-10 carbonium ion intermediate in the labdane-clerodane rearrangement. Cistus populifolius contains some eat-clerodanes. The major component is3' 2acetoxypopulifolic acid (22) whilst 2-0x0-populifolic acid, the 1,3- and 2,4( 18)dienes, and the epimeric 2-hydroxy- and 2-methoxy-derivatives constitute3* minor components. Surprisingly both normal (labdane-8,15-diol) and entlabdanes (ent-13-epimanoyl oxide) together with ent-clerodanes (ent-15hydroxyclerod-3-en-2-one)were from the neutral fraction. The full paper on the structure of the cis-clerodane Iinarienone has appeared.34A number of kolavenic acid derivatives, (23) and (24), have been obtained3' from Bedfordia salicina (Compositae).

@

0,H

H,OAc \

,,'

H CO,H

(22)

(21)

R = CH20H R =CH~OAC R = CHO

*' 28

29 30

31 32

33 34

35

I. Wahlberg, K. Karlsson, M. Curvall, T. Nishida, and C. R. Enzell, Acta Chem. Scand., 1978, B32, 203; I. Wahlberg, M. Curvall, and C . R. Enzell, ibid., p.310. S . Martinez-Carrera, M. Martinez-Ripoll, and S. Garcia Blanco, Acra Cryst., 1978, B34, 1381. A. K. Dey and H. R. Wolf, Helu. Chim. Acta, 1978,61, 1004. J. de Pascual Teresa, J. G. Urones, and H. C. Carrillo Sanchez, Anales de Quim., 1978, 74,488. J. de Pascual Teresa, J. G. Urones, and J. A. Herrero, Anales de Quim., 1978, 74, 476. J. de Pascual Teresa, J. G. Urones, J. A. Herrero, M. S. Cinos de la Mano, and M. Grande, Anales de Quim., 1978,74, 166. J. de Pascual Teresa, J. Gonzalez, J. A. Herrero, and F. Bermejo, Anales de Quim., 1978,74, 531. I. Kitagawa, M. Yoshihara, and T. Kamigauchi, Chem. and Pharrn. Bull. (Japan), 1978, 26, 79. F. Bohlmann and N. L. Van, Phytochemistry, 1978, 17, 1173.

Diterpenoids

165

Harwickiic acid, the lactone (25), and the acid (26) have been isolated from Printzia laxa ( C ~ m p o s i t a e )Marrubiastrol(27), .~~ aldehydomarrubialactone (28), and the 20-nor-8-ketone desmethylmarrubiaketone are three new diterpenoid lactones which were obtained3' from Leonurus marrubiastrum (Labiatae). Their structures were determined by a combination of 'H and 13Cn.m.r. and X-ray methods. A full paper has appeared38describing the structures of floribundic acid,

Aoridiolic acid, and the butenolides floridiolides A and B from Evodia floribunda. Salviarin (29) is a clerodane bis-lactone from Salvia splendens (Labiatae) whose structure was also determined39by X-ray analysis. Its structure is of biogenetic interest in that the ring A double bond lies between C-2 and C-3 rather than C-3

0

14

1

'R

(29)

36

37 38 39

(30) R = H (31) R = O H (32) R = OH, A13"4'

(33) R' (34) R'

= a-OH,

R2 = =O

= =0, R2 = P-OH

F. Bohlmann and C. Zdero, Phytochemistry, 1978,17,487. R.Tschesche and B. Streuff, Chem. Ber., 1978,111,2130. D.Billet, M. Durgeat, S. Heitz, and J. P. Brouard, J. Chem. Research ( S ) , 1978,110. G.Savona, M. P. Paternostro, F. Piozzi, J. R. Hanson, P. B. Hitchcock, and S. A. Thomas, J.C.S. Perkin I, 1978,643.

166

Terpenoids and Steroids

and C-4. The isolation of three closely related trans-clerodane lactones (30)(32) from the medicinal plant Baccharis trimera (Compositae) has been de~cribed.~' Definitive evidence for their structure was provided by an X-ray analysis of (32). Teucrium (Labiatae)species have afferded a number of new diterpenoids2The structures of fruticolone (33) and isofruticolone (34), which together with 8 p hydroxyfruticolone were isoiated41 from T. fruticans, were assigned by a combination of 'H and 13C n.m.r. methods and an X-ray analysis of a common degradation product. The montanins A (35) and B (36) are furanoid norclerodane diterpenoids which were i ~ o l a t e d ~ along * ' ~ ~ with teucvin (37) and montanin C (38)from T. montanum. The loss of the primary acetoxymethyl group of montanin C by a retro-Prins reaction initiaied by the opening of the epoxide ring may serve to generate these nor-clerodanes. The structure of teuflidin (39), from T. fiauum, was established by X-ray analysis. It is possible that this conipound is identical with teucrin HI, obtained from T. h y r ~ u n i c u m . ~ ~ Crotocaudin (40) is another member of this series which has been isolated"6 from Croton caudatus (Euphorbiaceae) where it co-occurs with teucvidin.

p

&

o=c -0

OAc

(38) 40 41

42

43 44

45 46

(39)

"H

(40)

W. Herz, A. M. Pilotti, A. C. Soderholm, I. K. Shuhama, and W. Vichenewski, J, Org. Chem., 1977, 42, 3913. G. Savona, S . Passannanti, M. P. Paternostro, F. Piozzi, J. R. Hanson, P. B. Hitchcock, and M. Siverns, J.C.S. Perkin Z, 1978, 356; G. Savona, S . Passannanti, M. P. Paternostro, F. Piozzi, J. R. Hanson, and M. Siverns, Phytochemistry, 1978, 17, 320. P. Y. Malakov, G. Y. Papanov, and N. M. Mollov, Tetrahedron Letters, 1978, 2025. P. Y. Malakov, G. Y. Papanov, N. M. Mollov, and S . L. Spassov, Z. Naturforsch., 1978, 33b, 789. G. Savona, M. P. Paternostro, F. Piozzi, J. R. Hanson, P. B. Hitchcock, and S. A. Thomas, J.C.S. Perkin Z, 1978, 1080. G. B. Oganesyan and V. A. Mnatsakanyan, Khim. prirod. Soedinenii, 1977,215. A. Chatterjee, A. Banerjee, and F. Bohlrnann, Tetrahedron, 1977, 33, 2407.

Diterpenoids

167

3 Tricyclic Diterpenoids Naturally Occurring Substances.-Tall oil, obtained as a by-product of pulping conifer wood chips, contains a mixture of fatty and diterpenoid resin acids and neutral compounds. The latter include4’ pimara-8( 14),15-diene-3P,18-diol, abieta-8,11,13-triene- 15,18-diol, 19-hydroxy-15,16-bisnorlabda-8(17)-en-13(6a-hydroxy-13-epimanoyloxide), and the one, 8,13P-epoxylabd-14-en-6a-o1 9,lO-secoabietatriene (41).The latter was also isolated from the bark of the jack pine (Pinus banksiana) and western white pine (P. monticola). A range of 7-monohydroxy, 1,7- and 1 , l l -dihydroxy-, and 1,7,1l-trihydroxy-sandaracopimaradienes and their acetates (42) have been from Zexmenia (Compositae) species. The l,ll-diacetoxy-7-ketone and 6,7-epoxide were also isolated.

(-$y 8‘1,

’*R1

‘co (42)

(41)

R1

R2

OH H H OAc OAc OH OH OH OAc

H OAc OH OH OAc OAc OH OAc OH

R3 H OAc OH H OAc H H OAc OH

Darutigenol (43) has been obtained4’ from Palafoxia arida (Composibae). Veadeirol(44) and the corresponding acid are two unusual diterpenoids with the cleistanthene skeleton which were obtained” from Vellozia flavicans (Velloziaceae). The full paper has appeareds1describing the crystal structure of annonalide (45), which possesses an unusual 9P-hydrogen atom cis to the C-10 substituent. Caudicifolin (46),a relative of jolkinolide A, has been isolateds2fromthe root extract of the medicinal plant Euphorbia caudicifolia.

(43)

(44)

Examination of the minor diterpenoid components of the seed endosperms of Podocarpus nagi aff ordedS3the cytotoxic nor-diterpenoid dilactones (47) and 47

48

*’

’’ 53

A . H. Connor and J. W. Rowe, Phytochemistry, 1977, 16, 1777. F. Bohlmann and M. Lonitz, Chem. Ber., 1978, 111, 843. W. Herz, S. V. Bhat, and R. Murari, Phytochemistry, 1978, 17, 1060. R. Pinchin, L. M. U. Mayer, and A . da Cunha Pinto, Phytochemistry, 1978,17, 1671. K. D. Onan and A . T. McPhail, J. Chem. Research ( S ) , 1978, 15. S . Ahmad, 0. Seligmann, H. Wagner, and G. Hussain, Phytochemistry, 1977,16, 1844. Y. Hayashi, Y. Yuki, T. Matsumoto, and T. Sakan, Tetrahedron Letters, 1977,3637.

& G;Pi-‘

168

Terpenoids and Steroids

OH

O”*

CH,OH

J-O

0

(45)

(48). The modification of the epoxides on ring A of these dilactones has been r e - e ~ a r n i n e dwith ~ ~ results that are at variance with previous reports. The technique of droplet counter-current chromatography has led54to the separation of some further dilactones (49)-(51) from the rooti of Podocarpus nagi. 0

0

co-0

co -0 (49)

(50)

(51)

The quinones miltirhone, cryptotanshinone, and tanshinone-1 have been detected56 in the roots of Salvia drobovii, S. karabachensis, and S. trautvetteri (Labiatae). The leaf gland colouring matters of various Coleus and Plectrunthus (Labiatae) species contain a number of interesting highly oxygenated diterpenoids. Coleons U (52), V (52; 5a-6,7-diketone), and W (53), 14-0-formylfrom Plectranthus coleon V, and the royleanone (54) have been myrianthus whilst 3P-acetoxyfuerstion ( 5 5 ) and the dimeric diterpenoids nilgherron A (56; R = H ) and B (56; R=OAc), arising from addition of an

54

55

56 57

Y. Hayashi, T. Matsumoto, Y. Yuki, and T. Sakan, Tetrahedron Letters, 1977, 4215. Y. Hayashi, T. Matsumoto, T. Hyono, and T. Sakan, Chem. Letters, 1977, 1461. A. S. Romanova, A. V. Patudin, and A. I. Ban’kovski, Khim. prirod. Soedinenii, 1977,414. T. Miyase, P. Ruedi, and C . H . Eugster, Helv. Chim. Acta, 1977,60, 2770.

169

Diterpenoids

o-quinone across the 6,7-double bond of fuerstion and 3/3 -acetoxyfuerstion, are founds8 in P, nilgherricus. P. parviflorus also contains a series of esters of the highly conjugated quinomethene (57). The unusual structure of edulon A (58), obtained" from P.edulis, is possibly formed by cyclization of a 4,hecoabietane on to C-11 of a coleon.

R,o..&2

\

R30CH, (57)

FZO '

OH

HO \ 0 OH (58)

Solenostemon species (Labiatae) are the source6' of some unusual rearranged diterpenoids (cf. coleons G and J) in which one of the C-4 substituents has migrated to C-3. The compounds also contain a spiro-cyclopropane ring as found in barbatusin. S. sylvaticus afforded Syl A (59),Syl B (60),Syl C (61), and Syl D (62) whilst S. rnonostachys gave Mon A (63), Mon B (64), and Mon C (65).

'' T. Miyase, P. Ruedi, and C. H. Eugster, Helv. Chim. Actu, 1977, 60, 2789; P. Ruedi and C. H. 59 6o

Eugster, ibid., 1978,61, 709. G. Buchbauer, P. Ruedi, and C. H. Eugster, Helv. Chim. Acra, 1978,61, 1969. T. Miyase, P. Ruedi, and C. H. Eugster, J.C.S. Chem. Comm., 1977,859.

Terpenoids and Steroids

170

I,:is-" w: w: OH

o&cHzo*cH

HO

OAc

OAc

(59)

OH

,CH,RZ

&H

'OR-'

AcOCH,

*

OH

(61)

OH

(62) R1 = a-OH, R2 = H, R3 = Ac (63) R' = 0-OAc, R' = H, R3 = Ac (64) R' = P-OAc, R2 = H, R3= CHO (65) R' = 0-OAc o r P-CHO, R2= OAc, R3 = Ac

Chemistry of the Tricyclic Diterpenoids.-The conversion of virescenol A (66; R = OH) into virescenol B (66; R = H) was complicated by the ease of 2,19-ether formation. In the event the transformation was achieved61 through hydrogenolysis of the keto-furan (67). The chirality of nucleophilic reactions at the C-4 axial aldehydes and methyl ketones has been examined6' in the podocarpane series. The reaction of some ring B enol-acetates with thallium(1) acetate and iodine has been Iodination at the 6a-position is followed by elimination to form ap-unsaturated ketones.

The acid-catalysed dehydration of 13a-substituted- 13P-methylpodocarpan8p-ols has been examined.64The initial products are A'-, A8(14)-,and A8(9)-01efin~ 61 62

63 64

P. Ceccherelli, M. Curini, R. Pellicciari, M. S. Raja, and E. Wenkert, J. Org. Chem., 1977,42,3438. G . Aranda, J. M. Bernassau, and M. Fetizon, J. Org. Chem., 1977, 42, 4526. R. C. Cambie, R. C. Hayward, J. L. Jurlina, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1978,126. J. W.-Blunt, G. S. Boyd, M. P. Hartshorn, M. H. G . Munro, and 1. K. Pannell, Austral. J. Chem., 1977,30, 2015.

Diterpenoids

171

but after more prolonged reaction times 10 --+ 9 methyl migration occurs and the products are the %A5-, 8a-A5'10)-, arid 8P-A5('0)-r~~ane~. A partial elaboration of the rosane skeleton from podocarpic acid has been d e ~ c r i b e dThe . ~ ~ 13C n.m.r. spectra of some rosane diterpenoids have been assigned66 utilizing the biosynthetic incorporation of [13C2]acetate.The methyl migration in rosenonolactone biosynthesis has been studied.67 Photolysis of royleanone methyl ether affords an oxetanol(68), the structure of which was determined6* by X-ray analysis. 4 Tetracyclic Diterpenoids

Naturally Occurring Substances.-a-Dihydrophyllocladene occurs as a crust on Italian lignite obtained near Florence, which is known as bombacite. Its crystal structure has now been determined.69 Tetracyclic diterpenoids are widespread amongst the Compositae. Cinnamoylgrandifloric acid has been obtained7' from Mikania oblongifolia whilst a glycoside, doronicoside D, of its 15-epimer [desacetylxylopic acid (69)]occurs71 in the roots of Doronicum macrophylla. ent- 1la,l5a-Dihydroxykaur-16-en-19oic acid, its 11-ketone, and its a-dihydro-15-ketone have been in Adenostemma caffrum. The paniculosides I-V are diterpenoid C- 19 glucosides from another member of the Compositae, Stevia paniculata. The structures of the aglycones (69)-(72) were determined by hydrolysis and 13C n.m.r. spectroscopy. Some nor-kaurene derivatives (73) (R = CH,OH, CHO, or C02Me)have been from Arthrixia (Compositae) species. Examination

(69) R' = OH, R2= H (70) R' = R2= OH (71) R' = =o, R*= OH

(72)

(73)

"

C. G. de Grazia and W. B. Whalley, J.C.S. Perkin I, 1978, 84.

67

B. Dockerill and J. R. Hanson, Phytochehistry, 1978, 17, 1119. M. Przybylska and F. R. Ahmed, Acta Cryst., 1978, B34, 1384. E. F. Serantoni, A. Krajewski, R. Mongiorgi, L. Riva di Sanseverino, and G. M. Sheldrick, Actu Cryst., 1978, B34, 1311. W. Vichnewski, H. de Freitas Leitao Filho, R. Murari, and W. Herz, Phytochemistry, 1977,16,2028. Sh. A. Alieva, Zh. M. Putieva, E. S. Kondratenko, and N. K. Abubakirov, Khim. prirod. Soedinenii, 1977,658. F. Bohlmann and P. K. Mahanta, Phytochemistry, 1978,17,814. K. Yamasaki, H. Kohda, T. Kobayashi, N. Kaneda, R. Kasai, 0. Tanaka, and K. Nishi, Chem. and Pharm. Bull. (Japan), 1977,24, 2895. F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 1773.

'' B. Dockerill, J. R. Hanson, and M. Siverns, Phytochemistry, 1978, 17, 572. 68

69

70 71

72

73

74

172

Terpenoids and Steroids

of the fern Pteris ryukyuensis afforded75 pterokauran R (ent-2a,16&18-trihydroxykaurane). Over the past few years a number of Sideritis (Labiatae) species have been studied in various laboratories. Examination of S. incana afforded76the known diterpenoids sideridiol, foliol, and isofoliol whilst S. lurida gave 7-acetylepicandicandiol, siderol, epicandicandiol, and sideridiol. Eubotriol [ent- 7a, 15p, 18-trihydroxykaur-16-ene (74)] and its 7-acetate, eubol, were from S. euboea whilst S. sicula gave the known diterpenoids sideridiol and sideripol together with expoxysideritriol [ent- 15@,16P-epoxy-7a,17,18-trihydroxykaurane (75)]. Some glucosides of ent-3~416a,17-trihydroxykaurane have been from Operculina aurea (Convolvulaceae).

(74)

(75)

Two new anti-tumour diterpenoids have been isolated from Isodon (Labiatae) species. Kamebanin, which was obtained from I. kameba, was assigned79 the structure (76) on the basis of a thorough n.m.r. study and a correlation with mebadonin, whose structure had been determined by X-ray analysis. Shikodonin (77) is a unique spiro-secokaurene which was obtained" from I, shikokianus. Its structure was assigned by a combination of X-ray and spectroscopic methods.

(76)

(77)

The metabolism of ent-kaur-16-ene by Gibberella fujikuroi in the presence of the plant-growth retardant (78) follows the normal pattern.81However, kaur-16ene, phyllocladene (130-kaur-16-ene), with the steroid-like A/B fusion, and ent-kaur- 15-ene were not metabolized. The transformation by Gibberella fujikuroi of 2- and 3-hydroxylated kaurenoids to a range of hydroxylated 75

76 77

78

79

81

N. Tanaka, M. Kudo, T. Taniguchi, T. Murakarni, Y. Saiki, and C. M. Chen, Chem. and Pharm. Bull. (Japan), 1978,26, 1339. B. Rodriguez, Anales de Quim., 1978,74, 157; L. M. Aranguez and B. Rodriguez, ibid., p. 522. P. Venturella and A . Bellino, Experientia, 1977, 33, 1270; P. Venturella, A . Bellino, and M. L. Marino, Phyiuchemistry, 1978,17, 81 1. L. Canonica, F. Orsini, F. Pelizzoni, A . Zajotti, G. Ferrari, and V. Vecchietti, Gazzettu, 1977, 107,

501. I. Kubo, I. Miura, T. Kamikawa, T. Isobe, and T . Kubota, Chem. Letters, 1977, 1289. I. Kubo, M. J. Pettei, K. Hirotsu, H. Tsuji, and T. Kubota, J. Amer. Chem. Soc., 1978, 100,628. P. Hedeen, B. 0.Phinney, J. MacMillan, and V. M. Sponsel, Phytochemisiry, 1977, 16, 1913.

Diterpenoids

173

gibberellins has been examined8* by g.c.-m.s. An alternative pathway to gibberellic acid can be induced from ent-2P,19-dihydroxykaur-16-ene(79). The microbiological transformation of epicandicandiol [ent-7a,l8-dihydroxykaur16-ene (SO)] by Gibberella fujikuroi to 19-oxygenated derivatives has been The full paper has appeared84on the microbiological transformation by Rhizopus nigricans, Aspergillus ochraceus, and Calonectria decora of 19oxygenated ent-kaurenes. A 1,2-hydrogen shift from C-17 to C-16 has been shown to occur85 in the biosynthesis by Beyeria calycina of ent- 16aH-kauranes containing a 17-oxygen function.

Gummiferolic acid, which was isolated" from Margotia gummifera (Umbelliferae), is ent-7a-angeloxyatis-16-en-19-oic acid (81). Its structure followed from an analysis of its I3C n.m.r. spectrum8' and an inter-relationship with methyl atis-16-en-19-oate. The atisene derivatives (82)-(84) have been obtained8' from Garuleum sonchifolium (Compositae), which also contains some ent- Sphydroxysandaracopimarenes.

C0,H

CO, H

83 84

86

CO,H

M. W. Lunnon, J. MacMillan, and B. 0. Phinney, J.C.S. Perkin I, 1977,2308. B. M. Fraga, J. R. Hanson, and M. G. Hernandez, Phytochemistry, 1978,17, 812. E. L. Ghisalberti, P. R. Jefferies, M. A. Sefton, and P. N. Sheppard, Tetrahedron, 1977, 33, 2451. K. D. Croft, E. L. Ghisalberti, and P. R. Jefferies, Phytochemistry, 1978, 17, 695. M. Pinar, B. Rodriguez, and A. Alemany, Phytochemistry, 1978, 17, 1637. B. Rodriguez, A. Alemany, and M. Pinar, Tetrahedron Letters, 1978, 3069. F. Bohlmann and M. Grenz, Chem. Bcr., 1978, 111, 1509.

174

Terpenoids and Steroids

Chemistry of the Tetracyclic Diterpenoids.-The reductiong9 of 2,3-epoxides such as ent-2a,3a-epoxykaur-16-en-19-01by hydride affords the 2-equatorial alcohol involving participation of the 19-hydroxy-group. Hydrolysis of the ent-2a,3a-epoxides also proceeds with diequatorial opening, possibly influenced by steric hindrance to nucleophilic attack at C-3 from the adjacent C-4 substituent. The reaction of ent-kaur-16-ene and 13P-kaur-16-ene with thallium(Iz1) nitrate and the allylic rearrangement of the AI6-15-nitrate ester to the A15-17nitrate has been studied.” This work has been extended to afford a stereoselective synthesis of the 17-acids. Oxidative rearrangement of 17-nor-13P-kauranl6-0ne with thallium(II1) nitrate leads to 17-norkaur-9(1l)-en-12-one and to the migration of the angular methyl group from C-10 to C-9. Some products of the selective oxidation of atractyligenin methyl ester and its 15,16-epoxide have been described together with the crystal structure of its 16P-bromo-16a bromomethyl derivative. 91 of 4-epigibberellin AI2 (86) from epicandicandiol An interesting (80) involves a Favorski-type rearrangement of the chloro-lactone (85). The X-ray analysis has been publishedg3 of the 11-bromo-derivative of the norbeyerane lactone (87).

Gibberellins.-The metabolism of the gibberellins has been thoroughly reviewed and the application of h.p.1.c. and g.c.-m.s. methods to the separation of the gibberellins has been described.94Argentation h.p.1.c. of gibberellin p-nitrobenzyl esters has been ~ e c o r n m e n d e dfor ~ ~ the separation of difficult pairs of gibberellins, for example A, and A,. Further details of the mass spectra of gibberellin derivatives have been recorded.96 The p-methoxyphenacyl ester of gibberellic acid has been used9, as a photosensitive protecting group whilst

89

91

92 93 94

95

96 97

M. W. Lunnon and J. MacMillan, J.C.S. Perkin I, 1977, 2317. E. Fujita and M. Ochiai, J.C.S. Perkin I, 1977, 1948; Chem. and Pharm. Bull. (Japan), 1977, 25, 3013; Canad. J. Chem., 1 9 7 8 , 5 6 , 2 4 6 . G. Savona, F. Piozzi, and M. L. Marino, Gazzetta, 1977,107,5 11 ;S. Hauser, L. Riva di Sanseverino, P. Piozzi, and G. Savona, Cryst. Structure Comm., 1978, 7, 275. A. G . Gonzalez, B. M. Fraga, M. G. HernLndez, and J. G. Luis, Tetrahedron Letters, 1978,3499. P . Sommerville and M. Laing, Acta Cryst., 1978, B34,1736. P. Hedden, J. MacMillan, and B. 0.Phinney, Ann. Rev. Plant Physiol., 1978,29, 149; ‘Isolation of Plant Growth Substances’,ed. J. R. Hillman, Cambridge University Press, London, 1978, chs. 3 and 4. E. Heftmann, G . A . Saunders, and W. F. Haddon, J. Chromatog., 1978,156, 71. D. Voigt, G . Adam, J. Schmidt, and K. Schreiber, Org. Mass Spectrometry, 1977, 12, 169. E. P. Serebryakov, L. M. Suslova, and V. F. Kucherov, Tetrahedron, 1978, 34, 345. E. P. Serebryakov, V. F. Kucherov, and G . Adam, Izvest. A k a d . NaukS.S.S.R., Ser. khim., 1977,8,1831.

Diterpenoids

175

modifications of the C-3 and C-13 hydroxy-groups are made (e.g. by methylation). The full paper has appeared9*describing the Norrish Type I photochemical cleavage of ring A of dehydrogibberellin A1. The final fate of C-20, which is lost during the biosynthesis of the C19 gibberellin lactones, is as carbon di~xide.~' Gibberellin A,, aldehyde may be an intermediate in gibberellin biosynthesis prior to this step. The conversion of gibberellin A9 into gibberellin AZ0 in excised lettuce hypocotyls has been observed.100aGibberellins As, A16, and A24 and abscisic acid have been detectedloobby g.c.-m.s. in rye. Grayanotoxins.-The t.1.c. and spectroscopic characteristics of some of the grayanotoxins have been described.'" Grayanoside A, which was obtained'02 from Leucothoe grayana, is the 3-glucoside of grayanotoxin IV. Reduction of the lO(20)-methylene of grayanotoxin I1 (88) proceeds predominantly from the a-face of the molecule to afford the 20P-methyl d e r i v a t i ~ e . The ' ~ ~ C-3 hydroxygroup of grayanotoxin I1 is more reactive than C-6 towards acetylation but the C-6 acetate esters are hydrolysed more easily through neighbouring-group participation of the C-5 hydroxy-group.

Diterpenoid Alkaloids.-The application of 13Cn.m.r. to the structural elucidation of the C19 diterpenoid alkaloids of the Aconitum and Delphinium species has been reviewed.lo5 The structures of 14-acetylbrowniine (89; R = Ac) and delphatine (89; R = Me) were proposed on the basis of their 13Cn.m.r. spectra. Ajacusine and ajadine, two further alkaloids from D. ajacis, are anthranilic acid esters derived from (90; R1 = anthranilate). Sachaconitine (91)and isodelphinine (92)were isolatedlo6from Aconitum miyabei. 13CN.rn.r. spectroscopy also played a significant role in their structure determination. Pyrolysis of the diacetate salts, e.g. (93), affordslo7a method of degrading the oxazolidine ring of the CZ0diterpenoid alkaloids to the corresponding imine (94) G. Adam and T. V. Sung, Tetrahedron, 1978,34,717. B. Dockerill, R. Evans, and J. R. Hanson, J.C.S. Chem. Comm., 1977,919; Phytochemistry, 1978, 17,701. loo L. J. Nash, R. L. Jones, and J. L. Stoddart, Planta, 1978,140, 143; W. Dathe, G. Schneider, and G. Sembdner, Phytochemistry, 1978,17, 963. lo' A . D. Kinghorn, F. H. Jawad, andN. J. Doorenbos, J. Chromatog., 1978,147,299. J. Sakakibara, N. Shirai, T. Kaiya, and H. Nakata, Phytochemistry, 1978, 17, 1672. '03 T. Masutani and J. Iwasa, Agric. and Biol. Chem. (Japan), 1978, 42, 193. *04 R. Iriye and T. Hayashi, Agric. and Biol. Chem. (Japan), 1977,41, 1513. lo' S. W. Pelletier, N. V. Mody, R. S. Sawhney, and J. Bhattacharyya, Heterocycles, 1977,7,327;S. W. Pelletier and R. S. Sawhney, ibid., 1978,8,463. ' 0 6 S. W. Pelletier, N. V. Mody, and N. Katsu, Tetrahedron Letters, 1977, 4207. lo7 N. V. Mody and S. W. Pelletier, Tetrahedron Letters, 1978, 3313. 98

99

Terpenoids and Steroids

176

- -

foMe Et-

..-

_ _ /OMe ..

Y$k\

OH

R'O (89) R = COMe or Me

(90) R2 = COPh or COMe

,OMe

foMe --N $OH--

.

_....---

Me

Et ' s

OH

*OH

derivative. The controversy over the possible equilibration of atisine epimers has continued.

5 Macrocyclic Diterpenoids and their Cyclization Products Cubitene ( 9 3 , which was i~olated''~from an East African termite soldier, Cubitermes umbratus, possesses an unusual twelve-membered ring. Its structure was determined by X-ray analysis. The irregular isoprenoid structure may be derived via a cembrene derivative or by coupling farnesyl pyrophosphate with dimethylallyl pyrophosphate to give an irregular diterpenoid directly.

lox log

S. K. Pradhan, Tetrahedron Letters, 1978, 263. G. D. Prestwich, D. F. Wiemer, J. Meinwald, and J. Clardy, J. Amer. Chem. Soc., 1978,100,2560.

177

Diterpenoids

(98)

(99)

(100)

A 13C n.m.r. study of the 14-membered ring diterpenoids has been published."' The Coelenterata have been the source of a number of macrocyclic diterpenoids. The cembranolides of marine origin have been reviewed. ''I The structure (96) of a new sinulariolide, from Sinularia notanda, is also reported in this review. The soft coral Lobophytum crussum afforded (97),"* which is an isomer of lobophytolide, and crassolide (98). The keto-epoxide (99) and the 13-membered ring-contraction product (100) were obtained113 from another Lobophytum species. The structures of ovatodiolide (10 l ) , isolated from Anisomeles indica (Labiatae), and of its intramolecular cyclization product (102) have been described in full.' l4 Macrocyclic diterpenoids have also been obtained from some Eremophila species. The structure (103) was assigned on the basis of an X-ray analysis to an epoxycembradienol obtained from E. georgei.'",' l 6 A cembrenetriol(104), from E. clarkei, was also ~ u b j e c t e d " ~to*an ~ ~X-ray ~ analysis.

Q

oa ,

\

0

/

H

HOCH2---

'13

'I5

'Is

E. Gacs-Baitz, L. Radics, G. Fardella, and S. Corsano, J. Chem. Research ( S ) , 1978, 146. Y. Kashman, M. Bodner, Y. Loya, and Y. Benayahu, Israel J. Chem., 1977,16, 1. B. F. Bowden, J. A. Brittle, J. C. Coll, N. Liyanage, S. J. Mitchell, and G. J. Stokie, Tetrahedron Letters, 1977,3661; B. Tursch, J. C. Braekman, D. Daloze, and H. Dedeurwaerder, Bull. SOC.chim. belges, 1978,87,75. B. F. Bowden, J. C. Coll, S. J. Mitchell, and G. J. Stokie, Austral. J. Chem., 1978, 31, 1303. P. S. Manchand and J. F. Blount, J. Org. Chem., 1977, 42, 3824. E. L. Ghisalberti, P. R. Jefferies, J. R. Knox, and P. N. Sheppard, Tetrahedron, 1977, 33, 3301. E. N. Maslen, C. L. Raston, and A. H. White, Tetrahedron, 1977, 33, 3305. P. Coates, E. L. Ghisalberti, and P. R. Jefferies, Austral. J. Chem., 1977, 30, 2717. E. N. Maslen, C. L. Raston, and A. H. White, Austral. J. Chem., 1977, 30, 2723.

Terpenoids and Steroids

178

Tobacco has been the source of a number of macrocyclic diterpenoids. The 4-epimeric thunbergadiene-4,12-diols(105) are two further members of the series. The structure of one of the epimers was determined”’ by X-ray analysis. Further examples of nor-isoprenoids which are possible degradation products of the macrocyclic tobacco diterpenoids have been described. 120 Two further diterpenoids, cladiellin (106) and acetoxycladiellin (107), which are related to eunicellin, have been obtained121from a soft coral Cladiella species. The structure of the latter was derived by X-ray analysis.

(105)

(106)

(107)

The photochemistry of bertyadionol(108) has been The structures of the two major products, (109) and (110), were defined by X-ray ana1~sis.l~~

(108)

(109)

(110)

The biogenetic structural relationships and structure-activity relationships of the diterpenoid skin irritants and co-carcinogens of the Euphorbiaceae and Baliospermum Thymelaceae have been described in a number of montanum (Euphorbiaceae) contains1*’ the orthoester montanin (111) and baliospermin (112) together with some 12-deoxyphorbol-13-esters.A number of new highly irritant 1-alkyl-daphnane orthoester derivatives [(113) and the corresponding 3-ketone] have been obtained126from the Thymelaceae. The Chinese 119

120

121 122

123 124

125

126

D. Behr, I. Wahlberg, A. J. Aasen, T. Nishida, C. R. Enzell, J. E. Berg, and A. M. Pilotti, Acta Chem. Scand., 1978, B32, 221, Y. Takagi, T. Chumen, T. Fujimori, H. Kaneko, T. Fukuzumi, and M. Noguchi, Agric. and Biol. Chem. (Japan),1978,42.327. R. Kazlauskas, P. T. Murphy, R. J. Wells, and P. Schonholzer, Tetrahedron Letters, 1977,4643. E. L. Ghisalberti, P. R. Jefferies, and R. F. Toia, Tetrahedron, 1978, 34, 233. S. R. Hall, C. L. Raston, and A. H. White, Tetrahedron, 1978, 34, 753. F. J. Evans and C. J. Soper, Lloydia, 1978,41,193; W. Adolf and E. Hecker, Israel J. Chem., 1977, 16,75; E. Hecker, in ‘Carcinogenesis’,ed. T. J. Slaya, A. Sivak, and R. K. Boutwall, Raven Press, New York, 1978, Vol. 2. p. 11; E. Hecker, Pure A p p l . Chem., 1977, 49, 1423; J. Weber and E. Hecker, Experientia, 1978, 34,679. M. Ogura, K. Koike, G. A. Cordell, and N. R. Farnsworth, Planta Med., 1978,33,128. (The name ‘montanin’ has also been used for some diterpenoids from Teucrium montanum: cf. refs. 42 and 43.) S. Zayad, W. Adolf, A. Hafez, and E. Hecker, Tetrahedmn Letters, 1977, 3481.

179

Diterpenoids

medicinal plant Yuan-Hua (Daphne genkwa, Thymelaceae) also compounds of this type. A further ester (114) related to ingenol has been isolated128from Euphorbia poisonii.

HO CH,OH

Me I (113) R = -CH(CH2)7--, -(CH2),&H=CH-,

or

Me I -CH(CH2)&H(02CPh)-

6 Miscellaneous Diterpenoids Marine organisms have provided the source of a number of unusual diterpenoid skeleta. Obtusadiol (115) is a bromo-diterpenoid which has been ~btained’~’ from the red alga Laurencia obtusa. Its structure followed from chemical degradation including a facile ring contraction of the bromohydrin. A group of prenylated ‘caryophyllenes’, xeniaphyllenol (116), its 4,5-epoxide, and an enolether related to xenicin,130xeniculin (117), have been found’31 in Xenia macro-

Br

*: (115)

’”

”’ 13’

B. P. Ying, C. S.Wang, P. N. Chou, P. C. Pan, and J. S . Liu, Hua Hsueh, Hsueh Puo, 1977,35,103 (Chem. Abs., 1978, 89, 39 369). C. 0. Fakunle, J. I. Okogun, and D. E. U. Ekong, TetrahedronLetters, 1978, 2119. B. M. Howard and W. Fenical, TetrahedronLetters, 1978, 2483. D. J. Vanderah, P. A. Steudler, L. S.Ciereszka, F. J. Schmitz, J. D. Ekstrand, and D. van der Helm, J. Amer. Chem. SOC.,1977,99,5780. A. Groweiss and Y. Kashman, TetrahedronLetters, 1978, 2205.

Terpenoids and Steroids

180

%OAc

q-spiculutu. The comparison of their 13Cn.m.r. data with those of their sesquiterpenoid relatives provided useful structural evidence. The alcohol (118),related to dictyolene, has been from Lobophytum hedleyi. The guaiane diterpenoid pachydictyol A (119) has been synthesized from a - ~ a n t o n i n . ' ~ ~

An interesting base-catalysed c y c l i ~ a t i o n ' ~of~ the bromo-diterpenoid sphaerococcenol A (120) to generate the cyclobutane (121) involves an acyloin rearrangement prior to an intramolecular displacement.

(120)

(121)

A group of tricyclic diterpenoids related to dolatriol has been isolated135from the marine invertebrate Clavularia influta. The structure of the diol (122) was obtained by X-ray analysis and those of (123) and (124) by chemical correlation. 132

133 134

13'

B. F. Bowden, J. C. Coll, N. Liyanage, S. J. Mitchell, G . J. Stokie, and I. A . van Altena, Austral. J. Chem., 1978,31, 163. A . E. Greene, Terrahedron Letters, 1978, 85 1. F. Cafieri, L. de Napoli, E. Fattorusso, and M. Piatelli, Tetrahedron, 1978, 34, 1225. J. C. Braekman, D. Daloze, R. Schubert, M. Albericci, B. Tursch, and R. Karlsson, Tetrahedron, 1978,34, 1551.

Diterpenoids

181

(123) R = H (124) R = O H

The dialdehyde isosacculatal, previously isolated from the liverwort Trichocoleopsis sacculata, has also been in another member of the Hepaticae, Pellia endiviaefolia. Extensive chemical degradation based on opening of the cyclopropane ring and cleavage of rings A and B has led137to the unusual structure (125) for 2,9-dihydroxyverrucosane,which was found in another liverwort, Mylia verrucosa. A further group of trinervitene (126) diterpenoids have been isolated'38 from the frontal glands of a termite soldier, Nasutitermes rippertii. These include the 9~-mono-ol,the 2P,3a-diol and its acetates, the 2&3a,9a-triol and its triacetate, the 2P,3a, 13a-trio1 and its triacetate, and the 13-oxotrinervi-P,3a-diol and its diacetate. Isotrinervi-2@-01has been obtained from the defensive secretions of T. gratiosus. Kempene-1 (127) and kempene-2 (128) are tetracyclic diterpenoids of a related type which were from another Nasutitermes species. The structure (128) was established by X-ray analysis,

(127) R = H,OAc (128) R = O

Some further aspects of the chemistry and biological activity of the insecticidal substances cinnzeylanine and cinnzeylanol have been described. 140 The labelling pattern of colletotrichin (129), biosynthesized from [1-13C]- and [1,2-13C2]acetate, has been examined141and indicates that it is a nor-diterpenoid with an additional y-pyrone ring.

136 137 13'

139

140 14'

Y. Asakawa and T. Takemoto, Phytochemistry, 1978, 17, 153. A . Matuso, H. Nozaki, M. Nakayama, S. Hayashi, and D. Takaoka, J.C.S. Chem Comm., 1978,198. J.VrkoE, M. BudCSinskjr, and P. Sedmera, Coll. Czech. Chem. Comm., 1978, 43, 1125. G . D. Prestwich, B. A. Solheim, J. Clardy, F. G. Pilkiewicz, I. Miura, S. P. Tanis, and K. Nakanishi, J. Amer. Chem. Soc., 1977, 99, 8082. A. Isogai, S. Murakoshi, A . Suzuki, and S. Tamura, Agric. and Biol. Chem. (Japan), 1977,41, 1779. Y. Kimura, M. Gohbara, and A . Suzuki, Tetrahedron Letters, 1977, 4615.

182

Terpenoids and Steroids

C0,Me

7 Diterpenoid Total Synthesis"

A further route to the cembrane skeleton involves'42 the coupling of two geranyl units, (130) and (131), in the presence of tin(1v) chloride, to form the sulphone (132). This was dehydrochlorinated and the ester grouping converted into the corresponding ally1 bromide. The bromide was then displaced in an internal cyclization to form the sulphone (133; R = S02Ph). Reductive removal of the phenylsulphonyl group gave the termite trail pheromone (*)-neocembrene (133; R = H).Stepwise cyclization of the nitrile (134), which was prepared in a similar manner, afforded143(135) and thence a route to the secotaxane skeleton (136). Cyclization of farnesyl phenyl sulphone gave the drimane derivative (137), from which (*)-labda-7,14-dien-13-01was e1ab0rated.l~~

(133)

142 143

144

(134)

(135) R=C02Me and R=CH2Cl

H. Takayanagi, T . Uyehara, and T. Kato, J.C.S. Chem. Comm., 1978, 359. T. Kato, H. Takayanagi, T. Suzuki, and T. Uyehara, Tetrahedron Letters, 1978, 1201. S. Toru, K. Uneyama, I. Kawahara, and N. Kuyama, Chem. Letters, 1978, 455.

* The compounds described in this section are racemates.

183

Diterpenoids

An interesting synthesis of the marine diterpenoid dictyolene (139) proceeded14' via the lactone (138) in which the diene and cis ring junction were set up in a rational manner early ;,I the synthesis.

HO

\

An approach towards the synthesis of the clerodanes has afforded'46 the intermediate (140). The copper-catalysed 1,6-addition of a benzyl Grignard (142) to the dienone (141) affords14' an unsaturated ketone (143) which is readily cyclized to the ring C aromatic diterpenoid intermediate (144), providing an efficient route to this system.

(143)

(144)

In efforts to prepare the cyclopropane ring of erythroxydiol, the methanesulphonoxy-group in (145) was displaced148by a C-5 anion to give (146). However, facile hydrogenolysis of the cyclopropane ring occurs on reduction to afford the 146

I*'

'**

J. A. Marshall and P. G. M. Wuts, J. Arner. Chern. SOC., 1978, 100, 1627. J. W. ApSimon and K. Yamasaki, Chern. Letters, 1977, 1453. B. R. Davis and S. J. Johnson, J.C.S. Chem. Comm., 1978,614. T. Nakano and A. K. Banerjee, J.C.S. Perkin I, 1977,2581.

184

Terpenoids and Steroids

olefin (147). Full papers have appeared'49,'50 describing the synthesis of phyllocladene and hibaene utilizing the photochemical addition of olefins to the ap-unsaturated ketone (148).

pJjYo .

I

' 0

(1461

(147)

The total synthesis of (*)-kaur-16-ene-l la,lSa-diol, involving the Birch reduction of the tricyclic aromatic ether (149), has been described.lS1 A method has been developedlS2 for generating the bicyclo[2,2,2]octane moiety, e.g. (151), which is found in a number of diterpenoids. It is based on the intramolecular cyclization of compounds of the type (150).

The synthesis of gibberellins has continued to attract attention. The subject has been extensively reviewed. 153 The intramolecular Michael addition of anions derived from (152) has been explored154 as a route to angularly substituted cis-hydrindanes [e.g. (153)] in the context of gibberellic acid synthesis. A stereocontrolled bicyclo-annulation has been developedlS5 as an approach to the gibberellins involving the synthesis of the spiran system of rings B and D, ring C being constructed subsequently. An interesting and efficient synthetic route to the 149 150

lS2 153

lS4

Do Khac Manh, M. Fetizon, and S. Lazare, J. Chem. Research ( S ) , 1978, 22. Do Khac Manh, M. Fetizon, and S. Lazare, Tetrahedron, 1978,34, 1207. E. Fujita and M. Ochiai, Chem. and Pharm. Bull. (Japan), 1978,26,264. U. R. Ghatak, M. Sarkar, and S. K. Patra, Tetrahedron Letters, 1978, 2929. E. Fujita and M. Node, Heterocycles, 1977, 7, 709. G . Stork, D. F. Taber, and M. Marx, Tetrahedron Letters, 1978, 2445. B. M. Trost and L. H. Latimer, J. Org. Chem., 1978, 43, 1031.

185

Diterpenoids

lactone (156) based on the stepwise bromo-lactonization reaction of (154), via (155), has been described.156

p-Jp

BBr3-CH2C: -78°C

Me0 HO,C

NaHC03-KBr3

0

/

BrB \

/$

Br

0

An interesting review of the development of the synthesis of the Aconite alkaloids has appeared.lS7

*" H. 0. House and E. J. Zaiko, J. Org. Chem., 1977,42,3780. lS7

K. Wiesner, Chem. SOC.Rev., 1977, 6,413.

Triterpenoids BY J. D. CONNOLLY

1 Squalene Group The failure of 2,3-epoxysqualene cyclase to react with the modified substrates 4-norsqualene 2,3-oxide (1)and homosqualene 2,3-oxide (2) clearly indicates the specific substrate structural requirements in the region of the epoxide and neighbouring r-bond.’ On treatment with Lewis acids 4-norsqualene 2,3-oxide afforded (3), (4), and (5) while hornosqualene 2,3-oxide gave (6), (7), and (8). H

Palladium-catalysed reaction of trans-P-farnesene, formed by catalytic trimerization of isoprene, resulted in regioselective head-to-head coupling to a dimer which yielded squalene on hydrogenation.’ A detailed 13Cn.m.r. study of functionalized squalane derivatives and model compounds suggests the presence of ‘precoiled’ conformation^.^ Thyrsiferol, a novel squalene-derived metabolite of the red alga Laurencia thyrsifera, has been shown to have structure (9)by X-ray analy~is.~ The synthetic versatility of marine organisms is further demonstrated by the isolation of three E. E. van Tamelen, A . D. Pedlar, E. Li, and D. R. James, J. Amer. Chem. SOC., 1977,99,6778. S . Akutagawa, T.Taketomi, H. Kumobayashi, K. Takayama, T. Someya, and S. Otsuka, Bull. Chem. SOC.Japan, 1978,51,1158. M. E.Van Dommelen, L. J. M. Van de Ven, H. M. Buck, and J. W. D e Haan, Rec. Trav. chim., 1977, 96,295. J. W.Blunt, M. P. Hartshorn, T. J. McLennan, M. G. H. Munro, W. T. Robinson, and S. C. Yorke, Tetrahedron Letters, 1978,69.

186

Triterpenoids

187

regular hexaprenoids, mokupalide (lo), hydroxymokupalide (1l), and acetoxymokupalide (12), from a dark-green marine ~ p o n g eThe . ~ regular (non-squalene) nature of the isoprenoid chain was confirmed by the formation of 1,4-dibenzoyloxypentane from (10)on ozonolysis, reduction, and benzoylation. A series of regular C25-C40 acyclic isoprenoid hydrocarbons has been identified in Spanish crude

0

(10) R = H (11) R = O H (12) R=OAc

The resolution of synthetic presqualene and prephytoene alcohols via their etienic acid derivatives has been r e p ~ r t e d This . ~ work confirmed that the active (+)-enantiomers in both series have the same absolute configuration [(lR, 2R, 3R)]. It has been established, by use of *H n.m.r., that the proton (deuteron) introduced at C-3 during the cyclization of squalene to tetrahymanol by Tetruhymena pyriformis has the 3p configuration.' Both antipodes of the trimethyldecalol (13) have been shown to be effective inhibitors of cholesterol biosynthesis in rat 'liver enzyme preparations and cultured mammalian cells.' The accumulation of squalene 2,3-oxide and squalene 2,3 :22,23-dioxide in the treated systems indicates that inhibition occurs at the cyclization stage. The inhibitor is metabolized to the diol (14). The results of other sterol inhibition

(13) R = H (14) R = O H

' M. B. Yunker and P. J. Scheuer, J. Amer. Chem. SOC.,1978,100,307. J. Albaiges, J. Borbon, and P. Salagre, Tetrahedron Letters, 1978, 595. L. J. Altman, D. R. Laungani, H. C. Rilling, and J. Vasak, J.C.S. Chem. Comm., 1977,860. D. J. Aberhart, S. P. Jindal, and E. Caspi, J.C.S. Chem. Comrn., 1978, 333. J. A. Nelson, M. R. Czarny, T. A. Spenser, J. S. Limanek, K. R. McCrae, and T. Y. Chang, J. Amer. Chem. SOC.,1978,100,4900.

Terpenoids and Steroids

188

studies have appeared."-'* The cell-free extract of Rhizopus arrhizus is an efficient medium for the production of radiolabelled ~qua1ene.l~ In vivo experiments with rat liver have demonstrated that squalene undergoes degradation to metabolites which are utilized for the isoprene units of ubiq~inones.'~ The full paper on the alkaloids of Daphniphyllum macropodum and D. gracile has been p~b1ished.l~

2 Fusidane-Lanostane Group

An improved route to 3a -acetoxy-4a,8a, 14p-trimethyl-18-nor-androstan-17one from fusidic acid has been reported.16 The details of the synthesis of the tetracyclic triterpenoid synthon (15)" and the spectroscopic differentiation of the cis- and trans-isomers of (15)18have appeared.

(16) R = R2 = R3 = H, R' =Me (17) R2 = R3= H, R = OH, R' = Me (18) R2 = R3= H, R = OH, R' = CHzOH (19) R3= H, R = OH, R' =Me, R2 = X (20) R2= H, R = OH, R' = CHZOH, R3= X (21) R3 = H, R = OH, R1= CHZOH, R2 = X Me

1

X = MeO2CCH2NHC0CH2CCH2C0-

1

OH

Three new plant growth inhibitors, fasciculol A (16),19B (17),20and C (18),21 have been isolated from the fruit bodies of Neamatoloma fusciculure. The related depsipeptides ( 19),20 (20), and (21)21were also obtained. The distribution of 10 11

12 13 14

15

16 17

18

19 20

21

C. Frasinel, G. W. Patterson, and S. R. Dutky, Phytochemistry, 1978, 17, 1567. T. J. Douglas and L. G. Paleg, Phytochemistry, 1978, 17, 705. T. J. Douglas and L. G. Paleg, Phytochemistry, 1978, 17, 713. D. A. Campbell and J. D. Weete, Phytochemistry, 1978, 17, 431. 0.Wiss and V. Wiss, Helv. Chim. Acta, 1977, 60, 1961. S. Yamamura, J. A. Lamberton, H. Irikawa, Y. Okumura, M. Toda, and Y. Hirata, Bull. Chem. Soc., Japan, 1977,50, 1836. W. S. Murphy and D . S. Cocker, J.C.S.Perkin I, 1977, 2565. R. A. Packer and J. S. Whitehurst, J.C.S. Perkin I, 1978, 110. K. G. Orrell, R. A. Packer, V. Sik, and J. S. Whitehurst, J.C.S. Perkin I, 1978, 177. M. Ikeda, Y. Sato, M. Izawa,T. Sassa, andY. Miura, Agric. andBiol. Chem. (Japan),1977,41,1539. M. Ikeda, H. Watanabe, A. Hayakawa, K. Sato, T. Sassa, and Y. Miura, Agric. and Biol. Chem. (Japan), 1977,41, 1543. M. Ikeda, G. Niwa, K. Tohyama, T. Sassa, and Y. Miura, Agric. and Biol. Chem. (Japan),1977,41, 1803.

Triterpenoids

189

sterols in the seeds of the Solanaceae has been reviewed.22Two new sterols (22) and (23) have been found in the seeds of Brassica

Oxidation of 11-0xo1anostan-3p-yl acetate with selenium dioxide in acetic acid leads to the interesting rearranged product (24) with an aromatic ring D.24 Another investigation of the boron trifluoride etherate induced rearrangement of 3p -acetoxy-9/?,ll~-epoxylanostan-7-onein acetic anhydride has that the corresponding 7,ll-dione and the diacetate (25) are formed in addition to the

A

c

O

.1

m

reported cucurbitacin derivative (See Vol. 8, p. 160). In benzene the reaction was more complex and led inter alia to the novel B-homo-compound (26), which probably arises via a cyclopropane intermediate. Epoxidation of 30-acetoxylanost-9(1 l)-en-7-one affords a mixture of a- and P-epoxides.26In the absence of the C-7 carbonyl group only the a -epoxide is formed. A study of lanthanide- and aromatic solvent-induced shifts of a series of 4a -methyl-sterols and tetracyclic triterpenoids has been rep~rted.~’ 22

23 24 25

27

T. Itoh, T.Ishii, T. Tamura, and T. Matsumoto, Phytochernistry, 1978, 17, 971. T. Itoh, K. Uchikawa, T.Tamura, and T. Matsumoto, Phytochemistry, 1977, 16, 1448. W. Lawrie, W. Hamilton, J. McLean, and J. Meney, J.C.S. Perkin I, 1978, 471. G. V. Baddeley, H. J. Samaan, J. J. H. Simes, and T. Hoa Ai, J.C.S. Chem. Comm., 1978,411. Z . Paryzek, J.C.S. Perkin I, 1978, 329. T. Iida, M. Kikuchi, T. Tamura, and T. Matsumoto, Chem. and Phys. Lipids, 1977,20, 157.

Tergenoids and Steroids

190

The full details of the investigation of the stereochemistry of C-4 demethylation during the conversion of obtusifoliol into poriferasterol by Ochromonas ma1 hamensis have appeared.28 Labelling experiments demonstrated that the 4 p hydrogen of obtusifoliol undergoes inversion of configuration during the demethylatfon process. [2-3HJ-5a -Lanost-24-ene-3&9a -diol and [2-3H2]parkeol are transformed*’ into poriferasterol by 0. malhamensis. This is a notable finding since 5a -lanost-24-ene-3p,9a-diol is not accepted as a sterol precursor by higher plants, rat liver preparations, and other micro-organisms. The sea cucumber Stichopus californicus is capable of de novo synthesis of sterols from acetate in addition to the transformation of lanosterol into The fact that the sterols produced from [3-3H]lanosterol retain the tritium label at C-3 suggests that the normally accepted mechanism for loss of the C-4 methyl groups does not operate in this organism. The complete structure (27) of holothurin B, a saponin from the sea cucumber Holothuria leucospilota, has been establi~hed.~’ A new sapogenin from another sea cucumber, Bohadschia uitiensis, has been assigned structure (28).32Several papers dealing with the synthesis of sechellogenin (29) have a ~ p e a r e d . ~ ~ - ~ ~ Functionalization of C-18 was achieved by nitrite photolysis.

R0-7)

R = glycosyl

Cimifugoside (30), from the roots of Cimifuga simplex, is closely related to a ~ t e i nIt. ~is~converted into cimifugenin A (31) on treatment with acetic acid. Cycloswietenol (32), from the heartwood of Swietenia mahogani, has a novel methylation pattern in the ~ide-chain.~’The C34 triterpenoid methyl ether 29

30

31

32 33 34

35 36

37

F. F. Knapp, J. L. Goad, andT. W. Goodwin, Phytochemistry, 1977,16, 1677. M. A. Palmer, L. J. Goad, T. W. Goodwin, D. P. Copsey, and R. B. Boar, Phytochemistry, 1978,17, 1577. Y. M. Sheikh and C. Djerassi, Tetrahedron Letters, 1977, 3111. I. Kitagawa, T. Nishino, T. Matsuno, H. Akutsu, and Y. Kyogoku, Tetrahedron Letters, 1978, 985. A. Clastres, A . Ahond, C. Poupat, P. Potier, and A. Intes, Experientia, 1978, 34, 973. G . Habermehl, K. H. Seib, and K. P. Swidersky, Annalen, 1978, 419. G. Habermehl and K. H. Seib, Naturwiss., 1978,65, 155. G. Habermehl and J. Rubstein, Annalen, 1978, 411. G . Kusano, S. Hojo, Y. Kondo, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1977,25,3182. A. S. R. Anjaneyulu, Y. L. N. Murty, and L. R. Row, Current Sci., 1977,46, 141.

Triterpenoids

191

Me0

(33)

H

?--(--OH

(36) R' = R2 = R4=Me, R3 = H (37) R' = H, R2 =Me, R3, R4 = CH2

skimmiwallichin (33), from Skimmia wallichi, also has an unusual ~ i d e - c h a i n . ~ ~ The structure of passifloric acid methyl ester (34) has been confirmed by X-ray analysis.3924-Dehydropollinastanol (35) has been isolated from pollen.40Other new cycloartane derivatives obtained from the rhizomes of Polypodium juglandifoliurn include (36) and (37). 38 39 40

I. N. Kostova, N. Pardeshi, and S. Rangaswami, Indian J. Chem., 1977, 15B,811. G. D. Andreetti, G. Bocelli, and P. Sgarabotto, J.C.S. Perkin 11, 1978, 605. M. J. Thompson,S. R. Dutky, Y. Lehner, L. N. Standifier, and E. W. Herbert, Phytochemistry, 1978, 17, 1053.

Terpenoids and Steroids

192

More direct methods for the degradation of the side-chain of cyclolaudenol have been published.42 It has been shown, using the squalene 2,3-oxide (38) with a chiral methyl group, that the 1,3-proton loss in the formation of the cyclopropane ring of cycloartenol occurs with retention of configuration at the C-10 methyl group.43

The results of an investigation of the biosynthesis of cyclobuxine D from [2-14C, (4R)-4-3H1]mevalonicacid in Buxus sempervirens are consistent with the labelling pattern (39) and a biosynthetic pathway from cycloartenol via C-3 and C-20 ketonic intermediate^.^^ Buxozine C (40) is a new alkaloid from B. sempervirens.45*46

@;: 3.

MeHN

&Ni

MeHN

0

(39)

(40)

Isocucurbitacin D (41) and 3-epi-isocucurbitacin D (42) are new tumour' may be inhibitory compounds from the leaves of Phormium t e n a ~ . ~They artefacts of isolation since they are both formed by isomerization of cucurbitacin D (43) on silica gel. Dihydroisocucurbitacin B (44) has been isolated from Marah

0

0

R

(41) R = H , a-OH (42) R = H, p -OH (44) R = H, @-OH;23,24-dihydro

''

(43)

R. Sunder and S. Rangaswami, Indian J. Chem., 1977,15B, 541. C. Singh, J. Singh, and S. Dev, Tetrahedron, 1977, 33, 1759. 43 L. J. Altman, C. Y. Han, A . Bertolino, G. Handy, D. Laungani, W. Muller, S. Schwartz, D. Shanker, W. H. de Wolf, and F. Yang, J. Amer. Chem. SOC., 1978, 100, 3235. '' D. Abramson, F. F. Knapp, L. J. Goad, andT. W. Goodwin, Phytochemistry, 1977, 16, 1935. " Z. VotickL, 0.Bauerovh, V . Paulik, and L. Doleji, Phyfochemistry, 1977, 16, 1860. " Z . VotickL, L. Doleji, 0. Bauerovi, and V. Paulik, Coll. Czech. Chem. Comm., 1977,42, 2549. 47 S. M .Kupchan, H. Meshulam, and A . T. Sneden, Phytochemistry, 1978, 17,767.

42

193

Triterpenoids

(45)

(46) R = A c (47) R = H

o r e g a n ~ sThe . ~ ~stereochemistry of tetrahydrocucurbitacin I (45) (cucurbitacin R) has been e~tablished.~’ The corresponding iso-derivative was detected in the roots of Bryonia dioica after storage. Two cucurbitacin glycosides (46) and (47) have been obtained from Ecballium e l ~ t e r i u m The . ~ ~ former is identical to arvenin I (see Vol. 8, p. 160). A study of the I3C n.m.r. shifts of cucurbitacins has been p~blished.~’ A partially purified enzyme preparation which catalyses the hydroxylation of the C-19 methyl group of cucurbitacins has been isolated from the ripe fruit of Cucurbitu maxima.51Cucurbitacins E and I act as feeding inhibitors for the flea beetle in the green parts of Iberis a m ~ r a . ~ ~

3 Dammarane-Euphane Group (20S)-Dammar-24-ene-3&20,26- trio1 (48) and isofouquierol (49) have been ~ stereochemistry of the isolated from the resin of the buds of Elaegia ~ t i l i s . ’The latter was confirmed by hydrogenation to (20S)-darnmarane-3&2O-diol.The full paper on the X-ray analysis of alnuserol (50) has appeared.543-Epiocotillol I1 (51) has been obtained from the pollen grains of Betula p l ~ t y p h y l l a . ~ ~

The structure of panaxoside progenin I acetate (52), from Panax ginseng, has been determined by X-ray analy~is.’~ Chikusetsusaponins L9, (53) and Llo (54), 48

49 50

’’ ’*

53 s4

”

L. Cattel, 0. Caputo, L. Delprino, and G. Biglino, Gazzetca, 1978,108, 1. K. Seifert and M. H. R. Elgamal, Pharmazie, 1977, 32, 605. Y. Yamada, K. Hagiwara, K. Iguchi, Y. Takahashi, and S. Suzuki, Chem. Letters, 1978, 319. J. C. Schabort, Phytochemistry, 1978,17, 1062. J. K. Nielsen, L. M. Larsen, and H. Sorensen, Phytochemistry, 1977,16, 1519. T. Biftu and R. Stevenson, J.C.S. Perkin I, 1978,360. T. Hirata and T. Suga, J.C.S. Perkin II, 1978, 347. T. Ohmoto, T. Nikaido, and M. Ikuse, Chem. and Pharm. Bull. (Japan),1978,26, 1437. S. G. Iljin, A. K. Dzizenko, G. B. Elyakov, B. L. Tarnopolsky, and Z. S. Safina, TetrahedronLetters, 1978,593.

Terpenoids and Steroids

194

(51) R = H , a-OH (55) R = O

OAc

OH (53) R’ = P-D-GIu, R2= H (53a) R’= H, R2= glycosyl

(54)

R’= P-D-G~u,R2= H

the first 12-0-glucosides in this series, occur in the leaves of P. japonicus with chikusetsusaponin L5 (53a).57Photosensitized oxidation of (53), followed by sodium borohydride reduction, afforded (54). Two new saponins, pseudoginsenosides F8 and FI1,have been isolated from the leaves of P. p s e u d ~ g i n s e n g . ~ ~ The latter is the 6-0-glycoside of 3@,6c~, 12@,25-tetrahydroxy-(20S724R)epoxydammarane. This work” confirms the (24R) configuration of ocotillone (55) and invalidates the recently suggested revision (see Vol. 6, p. 124). The structures of jujubosides A and B, from the seeds of Ziziphus j ~ j u b a , ~and ’ ginsenoside Rb3 and 20-glucoginsenoside h60have been reported. Degradation of bacoside A, a saponin from Bacopa monniera, yielded pseudojujubogenin ( 56).61 ” ”

’’ 60 6’

S. Yahara, R. Kasai, and 0.Tanaka, Chem. and Pharm. Bull. (Japan), 1977,25,2041. 0 .Tanaka and S. Yahara, Phytockemistry, 1978,17, 1353. ( a )H. Otsuka, T. Akiyama, K. Kawai, S. Shibata, 0.Inoue, and Y. Ogihara, Phytochemistry, 1978, 17, 1349; ( b ) 0. Inoue, Y. Ogihara, and K. Yamasaki, J. Chem. Research (S), 1978, 144. S. Sanada and J. Shoji, Chem. and Pharm. Bull. (Japan), 1978,26,1694. K. Kawai and S. Shibata, Phytochemistry, 1978, 17, 287.

Triterpenoids

195

A detailed investigation of the reaction of dammarane C-20 carbonium ions, prepared in a variety of ways, failed to detect any products arising from enlargement of ring D . Useful ~ ~ structural information has been obtained from a study of the mass spectral fragmentation of ginseng saponins and related Entandrolide (57) and the trio1 (58) are new compounds from the seeds of Entundrophragmu species.64 Reaction of (58) with boron trifluoride afforded sapelin A (59). A new euphane derivative, sendanolactone (60) (6-oxokulactone), has been obtained from the bark of Melia azedarach and its structure

OH

1

-OH

(59)

confirmed by X-ray analysis.6520,21-Anhydromelianone (61)has been isolated from Simarouba amara and the 13C chemical shifts of a series of A7-tirucallols have been published.66New natural products from the oleoresin of the trunk of 62 63

64 65

66

M. Tori, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC.Japan, 1977, 50,3349. R. Kasai, K. Matsuura, 0.Tanaka, S. Sanada, and J. Shoji, Chem and Pharm. Bull. (Japan), 1977, 25,3277. D. A. Okorit: and D. A. H. Taylor, Phytochemistry, 1977, 16, 2029. ( a )M. Ochi, H. Kotsuki, T. Tokoroyama, and T. Kubota, Bull. Chem. SOC.Japan, 1977,50,2499; (6) H. Nakai and M.Shiro, Acta Cryst., 1978, B34, 2063. J. Polansky, Z. Varon, R. M. Rabanal, and H. Jacquemin, Israel J. Chem., 1977,16, 16.

196

Terpenoids and Steroids

Pistacia Vera include masticadienonic aldehyde (62) and the acetates (63) and (64) of 3-epimasticadienolic acid and 3-epi-isomasticadienolic A partial synthesis of corollatadiol (65) from tirucallol acetate has been reported.68 Evidence has been presented for the (20S,24R) configuration of (65).68

(62) R' (63) R' (64) R'

= 0;R2 = CHO

= H, a-OAc; = H,

R2 = C02H

a -0Ac; R2 = C02H, A'

Tetranortriterpen0ids.-The occurrence of limonoids in Citrus species has been reviewed.@ Several interesting new tetranortriterpenoid structural types, some with biological activity, have been reported this year. Aphnastatin (66), from Aphnarnixis

67

69

R. Caputo, L. Mangoni, P. Monaco, G . Palumbo, Y. Aynehchi, and M. Bagheri, Phytochemistry, 1978, 17, 815. K. A. Reimann and D. M. Piatak, Tetrahedron Letters, 1978, 2765. V. P. Maier, R. D. Bennet, and S . Hasegawa, Citrus Sci. Technol., 1977, 1,3 5 5 .

Triterpenoids

197

grandifolia, has cytotoxic a~tivity.~' Its structure was confirmed by X-ray analysis. Compound (67),71a close relative of sendanin, and sendanal (68),72a possible precursor of ring-c-cleaved tetranortriterpenoids, have been isolated from the bark of Melia azedarach. The closely related Azadirachta indica is the source of 17-epiazadiradione (69)73 and the epimeric 170- (70)73 and 17a-hydroxyazadiradione (71).74 These are the first 17-hydroxy-compoundsto be isolated. A

A

l

o

AcO'

(69) R = a - H (70) R = p - O H (71) R = a - O H

Two novel compounds, tricoccin S7 (72)75and tricoccin SI3(73),76have been isolated from Cneorum tricoccum, a source of the highly cleaved pentanortriterpenoids (see Vol. 8, p. 165). Tricoccin S7 has a cleaved ring B with an unusual

c:

0 o@

Il'o+o 0

0

' (72)

'OH

(73)

1,s-enol ether while tricoccin SI3 has a y-lactone in place of the usual psubstituted furan ring. The modified furan derivatives tricoccins Ss (74) and S19 (75) were also ~ b t a i n e dToonacilin .~~ (76) and 6-acetoxytoonacilin (77), from the bark of Toona ciliata, exhibit powerful antifeedant activity against the Mexican bean beetle.77Ochinal(78) is biogenetically interesting since it represents simple ring c cleavage of a 12-hydroxy precursor [e.g. (68)]. It occurs in the fruit of Melia azedarac h with ochinin acetate (79).78 70

71

72

73 74 75

76

77

78

J. Polonsky, Z . Varon, B. Arnoux, C. Pascard, G: R. Pettit, J. H. Schmidt, and L. M. Lange, J. Amer. Chem. SOC., 1978,100, 2575. M. Ochi, H. Kotsuki, H. Ishida, and T. Tokoroyama, Chem. Letters, 1978, 99. M. Ochi, H. Kotsuki, and T. Tokoroyama, Chem. Letters, 1978, 621. W. Kraus and R. Cramer, Tetrahedron Letters, 1978, 2395. S. Siddiqui, S.Fuchs, J. Liicke, and W. Voelter, Tetrahedron Letters, 1978, 611. A. Mondon, D. Trautmann, B. Epe, U. Oelbermann, and C. Wolf€, Tetrahedron Letters, 1978,3699. B. Epe and A. Mondon, Tetrahedron Letters, 1978, 3901. W. Kraus, W. Grimminger, and G. Sawitski, Angew. Chem. Internat. Edn. 1978, 17,476. M. Ochi, H. Kotsuki, T. Kataoka, T. Tada, and T. Tokoroyama, Chem. Letters, 1978, 331.

198

Terpenoids and Steroids

i

As ( 7 2 )

(78) R1= COPh, R2 = CHO (79) R’ = COCH=CHPh, R2 = C02Me

(76) R = H (77) R= OAc

The structure of the nomilin derivative (go), from the seeds of Uncaria gambia, has been established by X-ray analy~is.’~ This is the first reported occurrence of tetranortriterpenoids in the Rubiaceae. The modified furan derivatives (81) and (82) of deoxyandirobin and methyl ivorensate have been isolated from the bark of Soymida febrifuga.**

0 ‘OAc

0

0

0 C0,Me (81) 79

(82)

F. R. Ahmed, A. S. Ng, and A. G. Fallis, Canad. J. Chem., 1978, 56, 1020. K. K. Purushothaman, S. Chandrasekharan, J. D. Connolly, and D. S. Rycroft, J.C.S. Perkin I, 1977, 1873.

Triterpenoids

199

Three groups of workers have published the results of their investigations of the tetranortriterpenoids from Chukrusia tabuluris. The contained chukrasins A (83), B (84),C (85), D (86), and E (87), all close relatives of bussein, and tabularin (88),82which is of special interest since it lacks the oxygenation necessary for formation of the orthoacetate. The compounds from the seeds are

0

AcO

OH

'OAc

I

>-coo

AcO (83) R' = H; R2,R3= A c + >CO; R4 = OH (84) R ' = H ; R 2 = R 3 = ) - C O ; R 4 = H (85) R' = H; R2,R3= Ac + >CO; R4 = H (86) R ' = A c ; R 2 , R 3 = A c + >CO; R 4 = H (87) R' = Ac; R2 = R3 = >CO;

R" = H

I

OR (89) R = R'

= CO--(

(90) R = CO<, (91) R = R'

R' = COEt, R'

= CO-(,

(92) R = CO<,

,R~ = H

R'

=H

(93) R, R', R2as (89) (94) R, R1,R2 as (89)

R2 = OAc = COEt, R2= OAC

the simple esters (89), (90), (91), and (92) of phragmalin and 12a-acetoxyph~ a g m a l i nThe . ~ ~corresponding modified furan derivatives (93) and (94)were also obtained. The 13C chemical shifts of a series of entandrophragmin derivatives have been published.84 In the course of this work structures were assigned to 81

82

83

R4

T. Ragetti and C. Tamm, Helv. Chirn. Acta, 1978, 61, 1814. D. A. Brown and D. A. H. Taylor, J. Cham. Research ( S ) , 1978, 20. J. D. Connolly, C. L'abbC, and D. S. Rycroft, J.C.S. Perkin I, 1978, 285. T. G. Halsall, K. Wragg, J. D. Connolly, M. A. McLellan, L. D. Bredell, and D. A. H. Taylor, J. Chem. Research ( S ) , 1977, 154.

200

Terpenoids and Steroids

candollein (95) and compound E3 (96) from Entundrophragma cylindricum. The tentative structure (97) has been proposed for a minor constituent of Khaya i~orensis.~~

Me02

L

I

AcO

OR

(97)

(95) R=CO

Quassinoids.-2'-Acetylglaucarubine (98) and a new antineoplastic quassinoid, 13,18-dehydroglaucarubinone(99), have been isolated from Simurouba umuru.86 The related 13,18-dehydroglaucarubol-15-isovalerate(100)has been reported from Ailanthus e~celsa.~'The details of the crystal structural analyses of samaderin 7A (101),from Samaderu i n d i q g 8and 6-hydroxypicrasin B (102), from Suulamea species," have appeared. OH

I

?H

I

(98)

(99) R = 0,R'

HO =C

O

Y

(100) R = H , a - O H , R ' = C

O

Y

The continuing work on the modification of cholic acid in an approach to quassinoids has resulted in the formation of 6-lactones related to (103)and in several publication^.^^-^^

*'

D. A. H. Taylor, Phytochemistry, 1977, 16, 1847. J. Polonsky, Z. Varon, H. Jacquernin, and G. R. Pettit, Experientia, 1978, 34, 1122. 87 M. Ogura, G. A. Cordell, A. D. Kinghorn, and N. R. Farnsworth, Lloydia, 1977, 40, 579. K. D. Onan and A. T. McPhail, J. Chem. Resenrch ( S ) , 1978, 14. 89 C. Pascard, T. Prange, and J. Polonsky, J. Chem. Research (S), 1977, 324. '"J. R. Dias and R. Rarnachandra, J. Org. Chem., 1977,42, 3584. 9 1 J. R. Dias and R. Ramachandra, Synth. Comm., 1977,7,293. 92 J. R. Dias, R. Ramachandra, and B. Nassim, Org. Mass Spectrometry, 1978, 13, 307.

201

Triterpenoids .-0.

OMe

4 Lupane Group

Hydrogen bromide-catalysed rearrangement of lupenyl acetate affords the olefin (104) which is readily isomerized to (105).93Epoxidation of the latter gave the a-epoxide (106), whose structure was confirmed by X-ray analysis. Hydroboronation of 3P-acetoxy-30-norlup-19-ene (107) results in addition from the The corresponding ketone a-face with formation of the l9aH-alcohol (109), which undergoes facile epimerization at C- 19 in base, was converted into 19aH-lupeol (1lo), whose spectroscopic properties cast doubt on the recent

R

(108) R = H, OH (20R) (109) R = O 93 E. 94

Suokas and T. Hase, Actu Chem. Scand., 1977, B31,633. E. Klinotovi, S. Bosak, and A. VystrEil, Coll. Czech. Chem. Comm., 1978,43, 2204.

202

Terpenoids and Steroids

~ l a i m ~to' .have ~ ~ isolated this compound from a natural source. The preparation of the 29-acetoxy-30-norlup-12-ene-l1,20-dione derivatives (111) and (112) has been de~cribed.~' The assignment of the 13Cchemical shifts of a series of lupanes and hopanes has been reported.98 The crystal structure of lupenone has been published.99 COCH20AC

(111) R = H (112) R = O A c

Granulosic acid (113) and columbrinic acid (114),two new ring-A-contracted lupenes, have been isolated from Columbrina granulosa. loo Wallichianic acid

J..

8°2

H0,C.. HO

HO

R2

(113) R' = Me or CH20H, R2 = CH2OH or Me

(114)

(115) [(20S)-3p-hydroxylupan-29-oic acid], the corresponding alcohol wallichianol(l16), and gymnosporic acid (117)[(20R)-3@-hydroxylupan-29-oic acid] have been obtained from Gymnosporia wallichiana."' The trio1 (118), from Me$R

H H02C+Me

HO (115) R = C 0 2 H (116) R = CH20H J . E. Gearien and M. Klein, J. Pharm. Sci.,1975,64, 104. J. E. Gearien, L. Bauer, M. Klein, and B. Levine, J. Pharm. Sci., 1975,64, 152. 9' V. Pouzar and A. VystrEil, Coll. Czech. Chem. Comm., 1978,43,2190. '* E. Wenkert, G . V. Baddeley, I. R. Burfitt, and L. N. Moreno, Org. Magn. Resonance, 1978,11,337. p9 P. Dampawau, C. Huntrakul, V. Reutrakul, C. L. Raston, and A. H. White, J. Sci. SOC,Thailand, 1977,3, 14. loo J. N. Roitman and L. Jurd, Phytochemistry, 1978, 17, 491. lo' D. K. Kulshreshtha, Phytochemistry, 1977, 16, 1783. 95

96

Triterpenoids

203

Beyeria brevifolia, was omitted from last year's Report."* Three coumaroyl esters, (119)-(121), of alphitolic acid have been found in the fruits of Ziziphus jujuba.lo3Other new natural products include the diene (122) from the root bark of Crateva n ~ r v a l aepoxylupeol ,~~~ (123) from Eupatorium odoratum,105lupenyl

R'O

JdJ

(119) R' = trans-p-coumaroyl, R' = H (120) R1= H, R2 = trans-p-coumaroyl (121) R' = cis-p-coumaroyl, R*= H

cinnamate from Marsdenia formosana, '06 3-oxo- 1P,28 - dihydroxylup-20(29)ene (hexandrin) from Manilkara he~andru,'~'lup-20(29)-ene-1,3-dione,3a acetoxylup-20(29)-en-Ip-ol and l~-acetoxylup-20(29)-en-3a-olfrom the stems and leaves of Glochidion puberum,"' and lupeol3-0-P-D-maltcside from the roots of Cordia ~ b l i q u a . ' ~ ~

5 Oleanane Group The reported partial synthesis of oleanolic acid from P-amyrin (see Vol. 1,p. 193) has been re-examined. 'lo It has been established by deuterium labelling studies that epoxidation of P -amyrin acetate with m -chloroperbenzoic acid gives the 12a,l3a-epoxide and not the 12@,13p-epoxide as previously suggested. It follows, therefore, that the compound synthesized in the original work was the lactone (124), erroneously identified as oleanolic lactone acetate. Unexpectedly,

S. G. Errington, E. L. Ghisalberti, and P. R. Jefferies, Austral. J. Chem., 1976,29,1809. A.Yagi, N. Okamura, Y. Haraguchi, K. Noda, and I. Nishioka, Chem. and Pharm. Bull. (Japan), 1978,26,1798. lo* V. Lakshmi and J. S. Chauhan, Planta Med., 1977,32,214. lo' S . K.Talapatra, D. S. Bhar, and B. Talapatra, Indian J. Chem., 1977,15B,806. lo' K. Ito and J. Lai, Yakugaku Zasshi, 1978,98,249. lo' P. Pant and R. P. Rastogi, Indian J. Chem., 1977,15B,911. lo* W.-H. Hui and M.-M. Li, Phytochemistry, 1978,17,156. log J. S. Chauhan and S. K. Srivastava, Phytochemistry, 1978,17, 1005. 'lo R.B. Boar, L. Joukhadar, M. de Luque, J. F. McGhie, D. H. R. Barton, D. Arigoni, H. G. Brunner, and R. Giger, J.C.S. Perkin I, 1977,2104.

lo*

lo3

204

Terpenoids and Steroids

photolysis of the nitrite of authentic 13P-hydroxy-3P -acetoxyoleanane (125), prepared from oleanolic lactone, afforded the hydroxy-nitrone (126) and not the desired oxime, thus eliminating this particular approach to the interconversion of P -amyrin and oleanolic acid. The undoubted highlight of the year in triterpenoid synthesis is the paper by Kametani and his colleagues which describes"' the full details (see Vol. 8, p. 174) of a stereoselective synthesis of the pentacyclic intermediates (132) and (133), used by Ireland in his syntheses of alnusenone and friedelin. This paper also includes a short non-stereoselective synthesis .of (132) and (133) (see the Scheme). The key step is an intramolecular cycloaddition of the o-quinodimethane intermediate (130).

(127)

+

-3

w

(Et)MeO

, 'CN (Et)MeO

\

\

(132) R' =Me, R2 = Et (133) R' = Et, R2= M e Scheme 'I1

T. Kametani, Y. Hirai, Y. Shiratori, K. Fukumoto, and F. Satoh, J. Amer. Chem. Soc., 1978, 100, 554.

205

Triterpenoids

Compound (134) has been synthesized in an approach to pentacyclic triterpenoids and its structure confirmed by X-ray analysis.112The final stage involved cyclization of the diketone (135). The related diketone (136) undergoes an interesting rearrangement to (137) on treatment with toluene-p-sulphonic acid."3 The structure of the rearrangement product was established by X-ray analysis. Syntheses of the bicyclic intermediates (138),'14(139), and (14O)ll5have been reported.

Me0

Me0

( 135) (1 36) A7

M eO

(137)

(138)

(139)

(140)

The tetrahydrochrysene (141) and octahydrochrysene (142) have been isolated from geological sources and their structure confirmed by ~ y n t h e s i s . A ~ third ~~'~~~

112

113 114

116

J. W. ApSimon, S. Badripersaud, J. W. Hooper, R. Pike, G. I. Birnbaum, C. L. Huber, and M. L. Post, Canad. J. Chem., 1978, 56, 2139. J. W. ApSimon, S. Badripersaud, M. L. Post, and E. J. Gabe, Canad. J. Chem., 1978, 56,2150. J. W. ApSimon, S. Badripersaud, T. T. T. Nguyen, and R. Pike, Canad. J. Chem., 1978,56, 1646. 1. Sircar and P. C. Mukharji, J. Org. Chem., 1977,42,3744. C . Spyckerelle, A . C. Greiner, P. Albrecht, and G. Ourisson, J. Chem. Research ( S ) , 1977,330. C . Spyckerelle, A . C. Greiner, P. Albrecht, and G . Ourisson, 3. Chem. Research ( S ) , 1977, 332.

Terpenoids and Steroids

206

(143)

(144)

compound (143) has been tentatively identified.'" It is probable that these compounds are derived from 0 -amyrin. Further organic geochemical results are reported in the hopane section. Oleanolic acid and ursolic acid have been transformed into the ring E aromatic derivative (144).'18 The two most interesting compounds in this group to be published this year are baccatin (145), a novel nortriterpenoid peroxide from the bark of Sapium b a c c a t ~ m , " and ~ papyriogenin G (146), a 0-lactone from the leaves of Tetrapanax papyriferum.'*' The structure of the latter was solved by X-ray analysis.

The crystal structures of the triclinic and orthorhombic forms of 18cuH-oleanane (147), from Nigerian crude petroleum, have been reported.121 Other crystal structures include meristropic acid methyl ester ( 148),'22hederagenin (149) from

'*

C. H. Brieskorn and G. Unger, Chem. Ber., 1978, 111, 1160. B. Saha, D. B. Naskar, P.R. Misra, B. P. Pradhan, and H. N. Khastgir, Tetrahedron Letters, 1977, 3095. Y. Ogihara, M. Asada, and Y. Iitaka, J.C.S. Chem. Comm., 1978,364. D. T. Fowell, B . G. Melsom, and G. W. Smith, Acla Cryst., 1978, B34, 2264. A . N. Shnulin, G. G . Aleksandrov, Yu. T. Struchkov, K. S. Manedov, and G. S. Amirova, Kristallografiya, 1978, 23, 66.

Triterpenoids

207

& HO,C

x

A

HO

R'O &02H.R2

(149)R' = H, R2 = CH2OH (150)R' = Ac,R2= M e

the bark of Opiliu ~eltidifoliu,'~~ 3~-acetoxyolean-l2-en-28-oic acid (150) from Piptudeniustrum u f r i ~ u n u m , 'and ~ ~ glycyrrhetinic acid acetone hydrate (15 l).'25 Three new oleanenes, castanopsone (152),castanopsol(153), and castanopsin (154), have been isolated from the stem bark of Custunopsis i n d i ~ u . ' ~ ~The *'*~ related dienes, echinatic acid (155) and isoechinatic acid (156), have been reported.12' Cyclamiretin C, obtained by hydrolysis of the saponin of Cyclamen hederifolium and C. gruecum, exists as the internal hemiacetal (157).12' Other

HO (152) R = O (153) R = H,CZ -OH

(154)

OH

HO

123 124

125 126

12' 12*

129

R. Roques, D. Druet, and L. C. Comeau, Actu Cryst., 1978, B34, 1634. R. Roques, J. P. Declerq, and G. Germain, A m Cryst., 1978, B34, 2367. H. Campsteyn,L. Dupont, J. Lamolte, 0.Dideberg, and M. Vermeire, Actu Cryst., 1977, B33,3443. P. Pant and R. P. Rastogi. Phytochemistry, 1977, 16, 1787. P. Pant and R. P. Rastogi, Phytochemistry, 1978, 17, 575. N. P. Kir'yalov and V. F. Bogatkina, Khim. Prirod. Soedinenii, 1977, 120. C. Harvala and J. P. Hylands, Pluntu Med., 1978, 33, 180.

208

Terpenoids and Steroids

new compounds include epithelanthic acid (158) and its methyl ester from the 19a -hydroxyerythrodiol (159) from button cactus Epithelantha rni~rorneris,'~~ the stem bark of Gardenia g ~ m m i f e r a , 'paniculatadiol ~~ (160) from Celastrus -peltoboykinolic acid (161) from the rhizomes of Astilbe p a n i c ~ l a t u s , 'acetyl ~~ r i ~ u l a r i s , 'and ~ ~ the behenate, tetracosanoate, and other esters of germanicol from Euphorbia pulcherrirna.134*135

(159) R' = OH, R2 = CH20H, R3 = Me (1 60) R 1= H, R2 = Me, R3= CH20H

AcO

(161)

A compound from the seeds of Phytolacca americanu, previously believed to be acetyloleanolic acid, has been identified'36 as acetylaleuritolic acid (162), which has also been obtained from Jatropha rnacrorhiza.137 It has antitumour activity. The structure of marsformoxide B (163) from Marsdenia formosana has been

130 131 13*

133 134 135

136 I37

L. G. West and J. L. McLaughlin, Lloydia, 1977, 40, 499. G. C. S. Reddy, S. Rangaswami, and R. Sunder, Planta Med., 1977, 32, 206. D. D. Nanavati, J. Oil Technol. Assoc. India, 1977, 9, 1. B. S. Sastry and E. V. Rao, Indian J. Chem., 1977, 15B,494. S. B. Mahato, N. P. Sahu, B. C. Pal, and R. N. Chakravarti, J. Indian Chem. SOC., 1977,54, 388. W. J. Baas, Planta Med., 1977, 32, 1. W. S. Woo and M. Wagner, Phytochemistry, 1977, 16, 1845. S. J. Torrance, R.M. Wiedhopf, and J. R. Cole, J. Pharm. Sci.,1977, 66, 1348.

Triterpenoids

209

(164) R = H

(165) R = Ac, R’= CH20H (166) R = Ac, R1 = CHO

confirmed by partial synthesis from 0-arnyrin.I3*The structure of ‘ursadiol’ from the flowers of Calendula oficinalis has been revised (see Vol. 4,p. 218) to the 6-amyrin derivative ( 164).’39 The more appropriate name coflodiol has been suggested. 3-Acetylmoroladiol (165) and 3-acetylmoraldehyde (166) are new natural products from Agauria salicif~lia.~~~ The successful preparation of angeloyl chloride has been utilized in the partial synthesis of the hepatoxic triterpenoid lantadene A (167) from the diphenylmethyl ester (168) of 220 -hydroxyoleanolic acid.141 Several analogues of lantadene A have also been made.142Reaction of 220 -hydroxyoleanolic acid with dicyclohexylcarbodi-imideafforded142the p -1actone (169) [see (146) above]. Forced Wolff-Kishner reduction of the 19-0x0-olean-12-ene derivatives (170) and (17 1) yielded the corresponding 13aH-olean-18-ene products (172) and

0

(167) R1 = angeloyl, R2 = H (1 68) R1 = H, R2 = CHPh,

(1 70) R = CH2 OAC (171) R = M e ‘’13 139

I4O 14’ 14’

(169)

(172) R = C H ~ O A C (173) R = M e

K. Ito and J. Lai, Chem. and Pharm. Bull. (Japan), 1978, 26, 1908. J. St. Pyrek, Roczniki Chem., 1977, 51, 2493. J. Gregoire and L. Nyembo, Phytochemistry, 1977, 16, 1609. P. J. Beeby, Tetrahedron Letters, 1977, 3379. P. J. Beeby, Austral. J. Chem., 1978,31, 1313.

210

Terpenoids and Steroids

(173).143T h e ring A lactam of glycyrrhetic acid has been The results of studies into the biosynthesis of oleanene derivatives in the leaves of Calendula officinalis have been p~blished.'~' The methyl resonances of several oleanene derivatives have been assigned using lanthanide shifts and homonuclear INDOR techniques to measure the nuclear Overhauser effects between methyl signals. 146 The assignments of the 13C resonances of a series of 18PH- and 18cuH-oleanenes have been p ~ b l i s h e d . ~ ~ * ' ~ * The potential use of molecular rotation differences in the identification of triterpenoid structures has been d i s ~ u s s e d . ~ ~ ~ , ' ~ ~ The methods for the selective cleavage of glucuronides have been r e ~ i e w e d . ' ~ ~ A series of paper^'^*-^'' on the saponins and prosapogenins of the roots of Platycodon grandiflorurn illustrates the value of I3C n.m.r. spectroscopy in the structural elucidation of complex glycosides. During the course of these investigations an easy and reversible migration of an acetyl group between C-2 and C-3 of a rhamnose residue of the sugar chain was dete~ted.''~ A method for determining the absolute configuration of chiral secondary alcohols using I3Cglycosidation shifts has been described. l S 6 Preliminary s t u d i e ~ ' ~indicate ~ * ' ~ ~that field desorption mass spectroscopy will provide valuable information in structural work on saponins. Publications of varying degrees of sophistication have appeared on the following saponins: saponin F from Eryngiurn brorneliifoli~rn,'~~ dumetoronins A-F from the fruit pulp of Randia durnetorum,'60 vitalbosides A-J from Clematis uitalba,16' aegyptinins A and B from the seeds of Luffa aegyptica,'62 saponins I-IV from the roots of Pulsatilla c e r n ~ a hederagenin ,~~~ glycosides from the stems of Hederu ~ h o r n b ascheffleroside, ,~~~ a spermicidal saponin, from Scheflera

T. Honda,T. Murae,T. Tsyuyuki, andT. Takahashi, Chem. andPharm. Bull. (Japan), 1978,51,884. S. C. Puri, K. L. Dhar, and C . K. Atal, Indian J. Chem., 1977,15B, 917. 14' W. Janiszowska and Z. Kasprzyk, Pkytochemistry, 1977, 16, 1919. '41 T. Kikuchi, T. Yokio, M. Niwa, and T. Shingu, Chem. and Pharm. Bull. (Japan), 1977, 25, 2078. 147 H. Duddeck, M. H. A. Elgamal, G. S. Ricca, B. Danieli, and G . Palmisano, Org. Magn. Resonance, 1978, 11, 130. ' 4 1 G. S. Ricca, B. Danieli, G. Palmisano, H. Duddeck, and M. H. A. Elgamal, Org. Magn. Resonance, 1978, 11, 163. 149 L. Ogunkoya, Tetrahedron, 1977, 33, 3321. L. Ogunkoya, Phytochemistry, 1978,17. 1343. l S 1 I. Kitagawa and M. Yoshikawa, Heterocycles, 1977, 8, 783. T. Konishi, A. Tada, J. Shoji, R. Kasai, and 0.Tanaka, Chem. and Pharm. Bull. (Japan), 1978,26, 668. 153 H . Ishii, K. Tori, T. Tozyo, and Y. Yoshimura, Chem and Pharm. Bull. (Japan), 1978,26,671. H. Ishii, K. Tori, T. Tozyo, and Y. Yoshimura, Chem and Pharm. Bull. (Japan), 1978,26,674. 155 H. Ishii, K. Tori, T. Tozyo, and Y. Yoshimura, Chem. Letters, 1978,719. 156 S. Seo, Y. Tomita, K. Tori, and Y. Yoshimura, J. Amer. Chem. SOC.,1978, 100,3331. H.-R. Schulten, T. Komori, and T. Kawasaki, Tetrahedron, 1977, 33,2595. 15* H.-R. Schulten, T. Komori, T. Nohara, R. Higuchi, and T. Kawasaki, Tetrahedron, 1978,34, 1003. 159 K. Hiller, K. Q. C. Nguyen, and P. Franke, Pharmazie, 1978, 33,78. 160 I. P. Varshney, R. Pal, and H. C. Srivastava, J. Indian Chem. Soc., 1978,55397. 'I V. Y. Chirva, P. K. Kinlya,andV. N. Mel'nikov, Chem. Abs., 1978, 88, 148971. I. P. Varshney and M. F. A. Beg, Indian J. Chem., 1977, 15B, 394. M. Shimizu, K. Shingyouchi, N. Morita, H. Kizu, and T. Tomimori, Chern. and Pharm. Bull. (Japan), 1978,26,1666. M. Shimizu, M. Arisawa, N. Morita, H. Kizu, and T. Tomimori, Chem. and Pharm. Bull. (Japan), 1978, 26, 655. 143 144

21 1

Triterpenoids

cap it at^,'^^ fatsiasides A-G from Fatsia

the main saponin from the roots of Primula elatior,168phytolaccasaponins B, E, and G16' and phytolaccosides B and G170 from Phytolacca americana, papyrioside L-IIa from the leaves of Tetrapanax p~pyriferum,'~~ samanins A--C from Pithecillobium C from the seed kernel of Madhuca l o n g i f ~ l i a , ' ~ ~ s a m ~ n , ' ~ ~mi-saponin -'~~ saponins B-D from the stem bark of Anthocephalus ~ a d a m b a , ' ~and ~ . the ' ~ ~root saponins of Aralia m~ndshurica.'~~ Oxidation of D :~-friedo-olean-5( 10)-ene (174) affords17' the l-oxo-derivative (175)' whose physical constants and spectroscopic properties do not agree with those of 'alnus-5( 10)-en-1-one', previously reported from Euphorbia nerifolia. This indicates that the structure of the natural compound requires revision.

R

(174) R=H2 (175) R = O

(176) (1 77) (178) (179)

R = H,a-OAc R = H,P- OAC R = H,a-OAc;A7 R = H,P-OAc; A7

(180) R=H,cY-OAC (181) R=H,@-OAc G . K. Jain, J. P. S. Sarin, and N. M. Khanna, Indian J. Chem., 1977, 15B, 1139. T. V. Gabadadze, G. E. Dekanosidze, and E. P. Kemertelidze, Izuest. Akad. Nauk Gruz. S.S.R., Ser. khim., 1977,3,243. 167 T. Aoki and T. Suga, Phytochemistry, 1978,17,771. 168 T. Tschesche and W. Wiemann, Chem. Ber., 1977,110,2407. 169 Y. Suga, Y. Maruyama, S. Kawanishi, and J. Shoji, Chem. and Pharm. Bull. (Japan), 1978,26,520. 170 W. S. Woo and S. S. Kang, J. Pharm. SOC.Korea, 1977, 21, 159. 171 M. Takai, S. Amagaya, and Y. Ogihara, J.C.S. Perkin I, 1977, 1801. 172 I. P. Varshney, P. Vyas, H. C. Srivastava, and P. P. Singh, Indian J. Chem., 1978, 16B, 166. 173 I. P. Varshney and P. Vyas, J. Indian Chem. SOC., 1977, 54, 992. 174 I. P. Varshney and D . C. Jain, Indian J. Pharm., 1977,39, 80. 17' I. Kitagawa, K. Shirakawa, and M. Yoshikawa, Chem. and Pharm. Bull. (Japan), 1978,26, 1100. 176 N. Banerji, J. Indian Chem. SOC.,1978, 55, 275. 177 N. Banerji, Indian J. Chem., 1977, 15B,654. 17* J. Lutomski and T. N. Nguyen, Herba Pol., 1977, 23, 183. E. Akiyama, K. Ogawa, Y. Moriyama, T. Tsuyuki, and T. Takahashi, Chem. Letters, 1977, 1059. 16' 16'

Terpenoids and Steroids

212

COMe

(184) R = H z (185) R = O

Phosphorus oxychloride dehydration of 3a- (176) and 3/3-acetoxyfriedo-olean7p-01 (177) afforded the corresponding A7-products (178) and (179).'*' The previously reported formation of these compounds by acid-catalysed dehydration is erroneous and involved rearrangement to (180) and (181). Acid-catalysed rearrangement of (182) gave the diene ( 183).'*' The D-homoprogesterone analogues (184) and (185) have been prepared"' from friedelin and putranjivadione respectively. The full paper on the rearrangement of 3&4p-epoxyfriedelane to germanicol has been published. 18* The importance of solvent in determining the products of backbone rearrangement is discussed. Dry ozonization of friedelin yields the 18p,19P-epoxide (186) together with the ketones (187), (188), and (189).lS3

(187)

(188) R'=O, R 2 = H 2 (189) R' = H ~R~ , =O

Velutinic acid (190) is a new friedelin derivative from Xylosma ~ e l u t i n a .The '~~ crystal structure of epifriedelinol (191) has been p~blished."~

6 Ursane Group New ursene derivatives include acuminatic acid (192) (2a,3a,19a- trihydroxyurs-12-en-28-oic acid) from Pygeurn acuminatum,lS6 2a,3a,19a,23-tetra~ hydroxyursolic acid (193) from the leaves of Coleus a r n b i ~ n i c u s , ' ~and P. Sengupta, M. Sen, and U. Sarkar, J.C.S. Perkin I, 1978, 384. P. Sengupta and S. K. Saha, Indian J. Chem., 1977,15B, 1071. ln2 M. Tori, T. Tsuyuki, and T. Takahashi, Bull. Chem. Soc. Japan, 1977,50, 338. ln3 E. Akiyama, M. Tada, T. Tsuyuki, and T. Takahashi, Chem. Letters, 1978,305. lS4 P. T. 0.Chang, G. A. Cordell, H. H. S. Fong, and R. N. Farnsworth, Phytochemistry, 1977,16, 1443. Ins M. Laing, M. E. Burke-Laing, R. Bartho, and C. M. Weeks, Tetrahedron Letters, 1977, 3839. R. S. Chandel and R. P. Rastogi, Zndian J. Chem., 1977, 15B, 914. l X 7 C. H. Brieskorn and W. Riedel, Arch. Pharm., 1977, 310, 910.

la'

Triterpenoids

213

marsformol (194) and a-amyrin formate from Marsdenia formosana. lo6 Marsformoxide A (195) was also isolated from M. f o r m o ~ a n a .Its '~~ structure was confirmed by partial synthesis from a-amyrin. Isobaurenol (196) has been reported from the root bark of Evodia meliaefolia.'88

(192) R = M e (193) R=CH;?OH

(194)

The previously reported conversion of a-amyrin into ursolic acid has been retracted"' (cf. p. 203). A detailed study of the mass spectral fragmentation of 16-substituted taraxastane* derivatives has been published. 189 The full paper concerning the structural revision of faradiol and arnidiol from Compositae flowers has appeared'" (see Vol. 4, p. 218). 3 a -Acetoxy-l6a -hydroxytaraxast-20(30)-ene(197)" has

lS9

190

E. Lengyel and M. Gellert, Pharmazie, 1978, 33, 372. J. St. Pyrek and E. Baranowska, Polish J. Chem., 1978,52, 97 J. St. Pyrek, Roczniki Chem., 1977,51, 2331.

* This Reporter prefers to name these compounds as derivatives of taraxastane rather than taraxane since this is less confusing with respect to the taraxerane group.

Terpenoids and Steroids

2 14

been isolated from Centaurea solstitialis. 19' Studies on the oxidation of taraxasterol (198) have been r e ~ 0 r t e d . l ~ ~

7 Hopane Group The most notable work in this group concerns the organic geochemistry of shales, coals, lignites, sediments, and petroleum. Considerable progress has been made in the isolation, characterization, and synthesis of modified hopane derivatives from these sources. The novel 17aH-hopanes (199)-(206) and the corresponding moretanes (207)-(209) have been identified.'93 This work is of special

{eR

R.&

(199) R = H (200) R = E t /Me (201)-(206) R = CH \ (CHAMe n=0-5

(207) R = E t (208) R=Pr' (209) R = B u s

interest since 17aH-hopanes have not yet been detected in living organisms. The authors make the reasonable suggestion that these compounds are formed by degradation of a C35precursor. The C2* hopane (210) has been isolated from Monterey shale and its structure established by X-ray analysis. 194 Further examples (211)and (212) of partially aromatized hopanes have been (see Vol. 7, p. 151). The structures of (211) and (212) were confirmed by synthesis. The structure, stereochemistry, and mass spectral analysis of steranes and triterpanes have received a t t e n t i ~ n . l ' ~ - l ~ ~ 19' 19' 193 194

195 196

' 9 1

19'

J. M. Cassady and G. C. Hokanson, Phytochemistry, 1978, 17, 324. P. P. Pai and G. H. Kulkarni, Indiah J. Chem., 1977, 15B, 1134. A. Van Dorsselaer, P. Albrecht, and G. Ourisson, Bull. SOC. chim. France, 1977, 165. W. K. Siefert, J. M. Moldowan, G. W. Smith, and E. V. Whitehead, Nature, 1978, 271,436. A. C. Greiner, C. Spyckerelle, P. Albrecht, and G. Ourisson, J. Chem. Research ( S ) , 1977,334. A. Ensminger, G. Joly, and P. Albrecht, Tetrahedron Letters, 1978, 1575. A. A. Petrov, S. D. Pustil'nikova, N. A. Abryutina, and G . R. Kagramanova, Chem. A h . , 1978,88, 155 345. A. M. K. Wardroper, P. W. Brooks, M. J. Humberston, and J. R. Maxwell, Geochim. Cosmochim. Acta, 1977, 41, 499.

Triterpenoids

215

(212)

Two naturally occurring ozonides, gilvanol (213) from Quercus gilva 199 and adian-5-ene ozonide (214) from the leaves of Adiantum monochlamys,200have been isolated. Their structures were readily confirmed by the action of ozone on hop-17(21)-en-3P-o1 and adian-5-ene respectively. Amphistictinic acid (215), from the lichen Pseudocyphellaria amphisticta, is 15a -acetoxy-22-hydroxyhopan-24-oic acid.201The structure of the ‘6a,7a,22-triol’ previously reported from the lichen P. mougeotiana has been revised202 to 6a77p,22-trihydroxyhopane (216). The ‘llp,22-diol’ isolated from the same source has been shown202to be a mixture of 7@,22- (217) and 15a722-dihydroxyhopane(218).

&-*

199 200

201 202

OAc

H. Itokawa, Y. Tachi, Y. Kamono, and Y. Iitaka, Chem. and Pharm. Bull. (Japan), 1978,26,331. H. Ageta, K. Shiojima, R. Kamaya, and K. Masuda, Tetrahedron Letters, 1978, 899. K. J. Ronaldson and A. L.Wilkins, Austral. J. Chem., 1978,31, 215. R. E. Corbett and A. L.Wilkins, Austral. J. Chem., 1977, 30, 2329.

216

Terpenoids and Steroids

(217) R’ = OH, R2 = H (218) R’ = H, R2 = OH

The corresponding 7/3- and 15a-acetates were also obtained. The full details of the structural elucidation of spergulatriol(219), a genuine sapogenol from the root of Mollugo spergula, have appeared.203Acid-catalysed isomerization of 3-epimoretenyl acetate (220) affords (221) and (222).’04

Filican-3-one (223) and isomotiol (224) (fern-8-en-3/3-01) are new natural products from the stem bark of Strychnos dolic~thyrsa’~~ and the leaves of S. potatorum 206 respectively. The structure of the former was confirmed by X-ray

analysis.2o5New fern-g(ll)-ene derivatives from the rhizomes of Polypodium juglandifolium include the ketone (225)41and polypodinol A (226), B (227), and C (228).’07 The structures of the compounds from P. juglandifolium reported in Vol. 7, p. 153 have been revised.41

203

204 205 206

207

I. Kitagawa, H. Yamanaka, T. Nakanishi, and I. Yosioka, Chem. and Pharm. Bull. (Japan),1977,25, 2430. H. N. Khastgir and B. P. Pradhan, J. Indian Chem. Soc., 1977, 54, 922. R. Verpooste, Phytochemistry, 1978, 17, 817. H. Singh, V. K. Kapoor, F. Piozzi, S. Passannanti, and M. Paternostro, Phytochemistry, 1978, 17, 154. T. K. Ray, A. Dasgupta, A. Goswami, D . R. Misra, and H. N. Khastgir, J. Indian Chem. SOC.,1978, 55,415.

Triterpenoids

217

(225) (226) (227) (228)

R' = H, R2 = H2, R3= 0 R' = OH, Rz= R3= H2 R' = H, R2 = H,P-OH, R3 = H Z R' = H, Rz= H,a-OH, R3= H2

8 Stictane Group Durvilldiol (229) and durvillonol (230) from the lichen Pseudocyphellaria berberina (P. durvillei) have been identified as stictane-3&22a -diol and 22ahydroxystictan-3-one respectively.208 2a-Acetoxystictane-3P,22a-diol (231) was also obtained.

(229) R' = H, R2 = 0 (230) R' = H, R2 = H,p-OH (231) R1= OAc, R2 = H,P-OH

9 Miscellaneous Several new products have been characterizedzo9from the potassium permanganate oxidation of ambrein (232). These include compounds (233), (234), (235),

'08 209

A. L. Wilkins, Phytochemistry, 1977, 16,2031. G. Ohloff and C . Vial, Helv. Chim. Acta, 1977, 60, 2767.

5 Ca rotenoids and Polyterpenoids BY G. B R I T O N

1 Carotenoids Reviews.-Reviews published during the year include articles o n the chemistry and biochemistry of carotenoids of higher plants,1” algae,3 and citrus fruit^,^ a detailed discussion of bacterial C30 carotenoids,’ and a short account of carotenoids in the food industry.6 A review of the chemistry of polyene compounds7 includes carotenoids and retinoids; the chemistry of the latter group, especially of vitamin A itself, has also been r e ~ i e w e d .Two ~ . ~ articles10s11 on ionones, irones, and damascones include an evaluation of these compounds as ‘degraded carotenoids’. New Structures and Stere0chemistry.-Bicyclic Carotenoids. Of the few new carotenoid structures that have been described, the most interesting are pigments of animal origin. The marine sponge Agelas schmidtii provided three previously unknown carotenoids.12 Agelaxanthin A has the relatively simple structure (3R)-P,@-caroten-3-01(1)but agelaxanthin C [methoxy-19,3’,8’-trihydroxy-7,8didehydro-P,rc- caroten-6’-one (7)] combines a number of unusual structural features including a cyclopentane ring and an enolic P-diketone end-group as in mytiloxanthin [3,3’,8’-trihydroxy-7,8-didehydro-~,~-caroten-6’-one (S)], together with an acetylene, a hydroxylated methyl side-chain (C-19), and a methoxylated p -ring, which is a feature never previously encountered in any natural carotenoid. The position of the methoxy-group on the @-ringhas not yet been established. The limited data obtained for the third compound, agelaxanthin B, are compatible with its being the 19-0-methyl derivative of agelaxanthin C. Another sponge, Tethya amamensis, has yielded a new carotenoid hydrocarbon,

’ ’ lo

l2

B. H. Davies, Biochem. SOC.Trans., 1977, 5, 1256. B. H. Davies, in ‘Lipids and Lipid Polymers in Higher Plants’, ed. M. Tevini and H. K. Lichtenthaler, Springer, Berlin, 1977, p. 199. S. Liaaen-Jensen, N A T O Conf. Ser., Ser. 4, 1977, 1, 239. J. Gross, CitrusSci. Technol., 1977, 1, 302. B. H. Davies, Internat. Rev. Biochem., 1977,14, 51. A. Emodi, Food Technol. (Chicago), 1978,32, 38. K. Tsukida, Method. Chim., 1978, 11, 168. K. Kobayashi and H. Kasai, Method. Chim., 1978, 11, 122. C. Baumann, Method. Chim., 1978, 11; 200. W. Hoffmann, Seifen, Oele, Fette, Wachse, 1978, 104, 127. Y. R. Naves, Riv. Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1977, 59, 495. R. Buchecker, C. H. Eugster, and C. Litchfield, Hefv. Chim. Acta, 1977, 60, 2780.

218

Carotenoids and Polyterpenoids

219

RZ

d (1) R' = a, R2 = b (2) R' = c, R2 = d (3) R' = b, R2 = d

e (4) R ' = R 2 = b (5) R 1 = R 2 = d (6) R' = e(X = OH), R2 = e(X = H)

(7) X = 2-, 3-, or 4-OMe, Y = CHzOH (8) X = 3-OH, Y = Me

3,4-didehydro-P,~-carotene (2) (tethyatene). M.s., i.r., and visible absorption data support this structure.13 A series of three carotenoid derivatives with the 1,2,3- and 1,2,5-trimethylphenyl end-groups characteristic of the sponge carotenes renieratene [4,X-carotene (3)], isorenieratene [4,+carotene (4)],and renierapurpurin [X,X-carotene (5)], but with the linking polyene chain fully saturated, have been isolated from geological deposits of Toarcian schist.14 The synthesis of these compounds (9)-( 11) from perhydrocrocetindial (12) is reported.

a (9) R' = a, R2 = b (10) R 1 = R 2 = a l3

l4

b (11) R 1 = R 2 = b (12) R' = R2 = CHO

Y. Tanaka and T. Katayama, Bull. Japan. SOC.Sci. Fisheries, 1977, 43, 1229. J. Schaefle, B. Ludwig, P. Albrecht, and G. Ourisson, Tetrahedron Letters, 1977, 3673.

220

Terpenoids and Steroids

A carotenoid unfortunately named neothxanthin, from the fish Neothunnus albacoru, is considered to be &,e-caroten-3-01(6) but has not been characterized fullv.” Further details of the absorption and mass spectra of the series of y-ring carotenoids obtained from the ladybird beetle Coccinella septempunctuta l 6 have been p ~ b l i s h e d . ’It~is unfortunate that the small amounts of material available did not permit determination of the chirality at C-6 of the y-ring (13).

C.d. studies” have shown that the goldfish pigment a-doradexanthin [3,3’dihydroxy-P,s -caroten-4-one (14)] has the 3S,3’S,6’R chirality, i.e. is the C-3’ epimer of the newly described algal pigment fritschiellaxanthin. Similarly goldfish ‘lutein’ (P,E-carotene-3,3’-diol) is the 3’s-epimer [calthaxanthin (15)] of the common green plant pigment (16).

(14) X = O , Y = H , Z = O H (15) X = H , H , Y = H , Z = O H (16) X = H , H , Y = O H , Z = H

X

The absolute configurations of the algal pigments dinoxanthin [(3S,5R,6R,3’S,S’R,6’S)- 5’,6’- epoxy- 6,7 -didehydro - 5,6,5’6’- tetrahydro -&@carotene-3,5,3’-trio13-acetate (17)] and peridinin [(3S,SR,6R,3’S,5’R,6’S)-5‘,6’epoxy - 3,5,3’- trihydroxy-6,7 -didehydro - 5,6,5’,6’-tetrahydro- 10,11,20- trinor @,@-caroten-l9’,ll’-olide3-acetate (20)] have been determined” from their

b

a

(17) R’ = a , R2= b Is l6 17 l8

l9

(18) R’

= c,

C

R2 = a

(19) R1=R2=b

Y. Tanaka, F. Shirnamura,and T. Katayama, Kagoshima Daigaku Suisangakubu Kiyo, 1977,26,33. G . Britton, W. J. S. Lockley, G . A. Harriman, and T. W. Goodwin, Nature, 1977, 266, 49. G. Britton, T. W. Goodwin, G . A. Harriman, and W. J. S. Lockley, Insect Biochem., 1 9 7 7 , 7 , 337. R. Buchecker, C. H. Eugster, and A. Weber, Helv. Chim. Acta, 1978,61, 1962. J. E. Johansen, S. Liaaen-Jensen, and G. Borch, NATO Conf. Ser., Ser. 4, 1977, 1,225.

22 1

Carotenoids and Polyterpenoids

MeCO,

OH

‘H n.m.r. and c.d. spectra and by correlation with fucoxanthin [(3S,5R,6S,3’S,5‘R,6’R) - 5,6 - epoxy- 3,3’,5’- trihydroxy -6’,7’ -didehydro - 5,6,7, 8,5’,6’-hexahydro-&P -car0ten -8-one 3’acetate ( 18)] and violaxan thin [(3S,SR,6S,3’S,S’R,6’S)-5,6,5’,6’ - diepoxy - 5,6,5’,6’ - tetrahydro-P,P-carotene3,3’-diol(19)]. The two epimeric carotenoids flavoxanthin [(3S,5R,8R,3’R,6’R)5,8-epoxy-5,8-dihydro-P,~-carotene-3,3’-diol (21)] and chrysanthemaxanthin [(3S,5R,8S,3’R,6’R) - 5,8 - epoxy-5,8-dihydro-P,E -carotene-3,3‘-diol (22)] have been re-isolated from Taraxacum oficinale flowers and their absolute configurations determined by chemical degradation, ‘H and 13C n.m.r., and chiroptical methods.*’ Determination of the absolute configurations of 5-epiflavoxanthin (3S,5S,8R,3‘R,6’R)and 5-epichrysanthemaxanthin (3S,5S,8S,3’R,6’R) obtained by acid-catalysed rearrangement of semi-synthetic lutein epoxide [(3S,5S,6R,3’R,6’R)-5,6-epoxy-5,6-dihydro-~,~-carotene-3,3’-diol (23)] has

b

a

(21) R = a

(22) R = b

C

(23) R = c

revealed that, contrary to previous ideas, the relationship of the polyene chain to the C-18 methyl group on the dihydrofuran ring is cis for 5-epiflavoxanthin and for chrysanthemaxanthin.*’ The chirality of the semi-synthetic capsanthin epox(24)] A and B ides [5,6-epoxy-3,3‘-dihydroxy-5,6-dihydro-~,~-caroten-6’-one obtained by monoperphthalic acid oxidation of capsanthin [(3R,3’S,5’R)-3,3’dihydroxy-P,~-caroten-6’-one (25)] diacetate has been established as 3S,5S,6R and 3S,5R,6S respectively by n.m.r., o.r.d., and c.d. studies.22Physoxanthin, a

2* 21 22

H. Cadosch, U. Vogeli, P. Riiedi, and C. H. Eugster, Hefv. Chirn. Acta, 1978, 61, 783. H. Cadosch, U. Vogeli, P. Riiedi, and C. H . Eugster, Helv. Chirn. Acta, 1978, 61, 1511. M. Baranyai, J. Kajtar, G. Bujtas, and J. Szabolcs, Acta Chirn. Acad. Sci. Hung., 1977, 94, 67

Terpenoids and Steroids

222

minor pigment from Physalis alkekengi has been shownz3to be (3R,6’R)-p,~caroten-3-01 (26) ( = a-cryptoxanthin) and not, as previously P,Ecaroten-3’-01 (27). OH

a

(24) R = a

(26) X = O H , Y = H

b (25) R = b

(27) X = H , Y = O H

Monocyclic Carotenoids. The major pigments of the gliding bacterium Herpetosiphon gigunteus are monocyclic carotenoids based on the 1’-hydroxy3‘,4’-didehydro-1’,2’-dihydro-p,II.-caroten-4-one structure (28) with the C-1’ tertiary hydroxy-group substituted with fatty-acyl diglucosyl or fatty-acyl mannosyl residue^.'^

Acyclic Curotenoids. The etienate esters prepared by treatment of ( f)-prephytoene alcohol with 3p- acetoxy-17~-chloroformylandrost-5-ene have been resolved by h.p.l.c., and the prephytoene alcohol enantiomers obtained by

23 24

25

C . Bodea, A. G. And-ewes, G. Borch, and S. Liaaen-Jensen, Phytochemistry, 1978,17,2037. C. Bodea and E. Nicoara, Annalen, 1957,609, 181. H. Reichenbach, P. Beyar, and H. Kleinig, F.E.M.S. Microbiol. Letters, 1978, 3, 155.

223

Carotenoids and Polyterpenoids

reduction. Natural prephytoene alcohol has been identified as the (+)( 1R,2R,3R)- isomer (29).26v27

Apocarotenoids. A new apocarotenoid from the peel of ripe Golden Delicious apples has been identified as 5,6-epoxy-5,6-dihydro-10f-apo-~-caroten-10f-ol (30) by absorption spectroscopy and m.s.28

Degraded Carotenoids. Several new natural products have structures similar to carotenoid end-groups and thus may be considered as degraded carotenoids. A new abscisic acid (31) metabolite from seeds of Robinia pseudacacia has been ester of hydroxyabscisic acid (32). identified29as the 3-hydroxy-3-methylglutaryl

Me (31) R=Me

The isomeric vitispiranes (33) and (34) have been isolated as constituents of the aroma and flavour of grapes and wine3' and of vanilla.31Their constitution was proved31 by synthesis from the related theaspiranes (35) and (36). Osmanthus

(33) R1 =Me, R2= H (34) R' = H, R2= Me

(35) R' (36) R'

= Me, R2= H = H,

R2= Me

absolute has afforded a number of carotenoid-like structures including the 2,5-epoxymegastigma-6,8-dienes(37) and (38), 2,7-epoxymegastigma-4,8Ediene (39), and the oxodihydrotheaspiranes (40)-(43).32

26

27

28

29

30 31

32

L. J. Altman, D. R. Laungani, H. C. Rilling, and J. Vasak, J.C.S. Chem. Comm., 1977, 860. L. J. Altman, R. C. Kowerski, H. C. Rilling, a n d D . R. Laungani, J. Amer. Chem. Soc., 1978, 100, 6174. J. Gross and G . Eckhard, Phytochernistry, 1978,17, 1803. N. Hirai, H. Fukui, and K. Koshimizu, Phyrochemisrry, 1978, 17, 1625. R. F. Simpson, C. R. Strauss, and P. J. Williams, Chem. and Znd., 1977,663. K. H. Schulte-Elte, F. Gautschi, W. Renold, A . Hauser, P. Frankhauser, J. Lima-her, and G. Ohloff, Helv. Chim. Acra, 1978, 61, 1125. R. Kaiser and D . Lamparsky, Helu. Chim. Actu, 1978,61,373,383;R. Kaiser, A. Kappeler, and D. Lamparsky, ibid., p. 387.

Terpenoids and Steroids

224

(40) (41) (42) (43)

(39)

(38)

(37)

R’ = & M e , R2 = Me, R3= H R’ =&-Me, R2= Me, R3= H R’ = @Me, R2 = H, R3 = Me R’ = a-Me, R2 = H, R3 = Me

Further additions to the long list of tobacco constituents include 5(13),7Bmegastigmadiene-6,9-diol (44),33 (3S,6R,9R)-4,7E-megastigmadiene-3,9-diol (45) and its 9 S - e ~ i m e rand , ~ ~a ‘seco-nor-carotenoid’, 3,3-dimethyl-7-hydroxyoctan-2-one (46),35all from Greek tobacco. The structures (47), (48), and (49) of pallescensin-1, -2, and -A have been proved by synthesis from a-cyclocitral (50).36

woH HOP

(44)

O

H

(45)

Synthesis and Reactions.-Curotenoids. A method has been described for preparing unsymmetrical carotenoids from a symmetrical dialdehyde, with an insoluble polymer support used as a monoblocking group37(Scheme 1). Thus the Clo dial (52) treated with a 2% cross-linked divinylbenzene-styrene copolymer containing vicinal hydroxy-groups (51) gave the polymer-bound aldehyde (53). Reaction of this with Wittig reazents such as a-, p, or $-ionylideneethyltriphenylphosphonium bromides (54)-( 56) gave polymer-bound products which on acid treatment liberated 12’-apo-P-caroten- 12’-al (57), 12’-apo-~-caroten12’-a1( 5 8 ) , or 12’-apo-$-caroten-12’-a1(59). A second C15end-group could then be added to the apocarotenal by a further Wittig reaction.

33 34

35 36

37

D. Behr, I . Wahlberg, T. Nishida, and C. R. Enzell, Acta Chem. Scand., 1977, B31,609. D. Behr, I. Wahlberg, T. Nishida, and C . R. Enzell, Acta Chem. Scand., 1978, B32, 391. D. Behr, I. Wahlberg, and C. R. Enzell, Acta Chem. Scand., 1977, B31, 793. T. Matsumoto and S. Usui, Chem. Letters, 1978, 105. C. C. Leznoff and W. Sywanyk, J. O r g . Chem., 1977,42, 3203.

225

Carotenoids and Polyterpenoids

(54), (57) R =

Reagents: i, Bu"Li4ioxan; ii, H+

Scheme 1

A method for the preparation of symmetrical alkenes by oxidation of resonance-stabilized alkylidenephosphoranes with hydroperoxides has been extended to the preparation of symmetrical c a r o t e n o i d ~Thus . ~ ~ treatment of the triphenylphosphonium bromide (60) with hydrogen peroxide and sodium carbonate in aqueous propan-2-01 gave the C24 ester (61) in 33% yield. P-Carotene.

(60)

(61) 38

A. Niirrenbach, J. Paust, H. Pommer, J. Schneider, and B. Schulz, Annulen, 1977, 1146.

Terpenoids and Steroids

226

[P,P-carotene (62)] was similarly prepared from the Czo reagent (63). The preparation of a range of symmetrical carotenoids by this method is reported. In an interesting and novel synthesis of dimethylcrocetin (68) (Scheme 2) much of the carbon skeleton was derived from 2,6-dimethylphenol (64).39 Condensation of this with (E)-1,4-dibromobut-2-ene(65) gave as a main product the compound (66) which underwent photochemical ring cleavage in sunlight to give the acyclic product (67) and thence dimethylcrocetin (68). OH

39

OH

G. Quinkert, K. R. Schmieder, G. Durner, K. Hache, A. Stegk, and D. H. R. Barton, Chem. Ber., 1977,110,3582.

Carotenoids and Polyterpenoids

227

Full details have been described27 of the synthesis4’ of prephytoene alcohol (29). The synthetic route from geranylgeraniol (69) is outlined in Scheme 3.

Reagents: i, Mn0,-light petroleum; ii, Et,N-(NH,),;

iii, Mn0,-Na,CO,; iv, Zn1,-Et,O

Scheme 3

The synthesis of a number of 2,2’-dinor-carotenoids has been de~cribed.~’ Wittig reaction between the Clodial (52) and the appropriate CI4Wittig salt (70)

was used for the efficient preparation of actinioerythrol [3,3’-dihydroxy-2,2’dinor-P7P-carotene-4,4’-dione (72)], and oxidation of this with M n 0 2 gave violerythrin [2,2’-dinor-~,P-carotene-3,4,3’,4’-tetrone (73)]. Similarly the retrocarotenoid 2,2’-dinor-rhodoxanthin [4’,5’-didehydro-4,5’-retro-2,2’-dinor-~,~carotene-3,3’-dione (76)] was prepared from the Wittig salt (71). Reduction of (76) with Zn gave the 4,4’-dihydro-2,2‘-dinor-rhodoxanthin [2,2’-dinor-PYPcarotene-3,3’-dione (74)] and further reduction of this with (Me,CH),AlH afforded 2,2’-dinor-zeaxanthin [2,2’-dinor-P7P-carotene-3,3’-dio1 (75)].

40

41

L. J. Altman, R. C. Kowerski, and H. C . Rilling, J. Amer. Chem. SOC.,1971, 93, 1782. F. Kienzle and R. E. Minder, Helv. Chim. Acta, 1978,61, 242.

228

Terpenoids and Steroids

\

(76)

Wittig reaction between azafrinal [5,6-dihydroxy-5,6-dihydro-10f-apo-Pcaroten-10’-a1 (77)] and the Wittig compound (80) allowed the preparation of 5,6-dihydro-P,P-carotene-5,6-diol (78; 9’E and 9’2, 1:3).42The pure all-trans diol had a very much lower polarity than other carotenediols, a property attributed to reduction in the extent of hydrogen-bonding due to steric hindrance. Treatment of (78) with Ph2S[OC(CF3)2Ph]2yielded (5$,6R)-5,6-epoxy-5,6dihydro-P,P-carotene (79). This is the first time that a carotene epoxide of known chirality has been prepared, and ‘H and 13Cn.m.r. and c.d. data are presented.

OH a

(77) R1 = a, R2 = CHO

b

(78) R’= a, R2 = b

C

(79) R1= c, R2 = b

(80)

Electrochemical methods are being used increasingly in the carotenoid field. Electroreduction of P,P-carotene (62) at a mercury cathode gave 7,7’-dihydro8,7’-retro-P,P-calrotene (81). Similarly axerophtene (82) gave the 7,14-dihydroproduct (83).43Reductive electrochemical dehydrohalogenation of a 6-carotene-iodine complex prepared from p- carotene with iodine and trifluoroacetic

42 43

W. Eschenmoser and C. H. Eugster, Helv. Chim.Actu, 1978,61, 822. V. G. Mairanovskii, L. A. Vakulova, N. T. Ioffe, A. A. Engovatov, E. I. Korsunova, I. T. Maksakova, and G. I. Samokhvalov, Khim.-Farm. Zhur., 1977,11, 111.

229

Carotenoids and Polyterpenoids

acid in dichloroethane gave a retro-dehydro-P-~arotene.~~ In dry tetrahydrofuran with Bu4NC104 as supporting electrolyte, &carotene was reduced at a Pt electrode, mainly to 15,15’-dihydro-P,P-carotene(84). In the presence of water, oxidation to 12’-apo-P-caroten-l2’-al (57) occurred. In both wet and dry THF, retinal (85) and retinol (86) were reduced at various double

(84)

(85) R = CHO (86) R=CHZOH

The reduction of astacene [3,3’-dihydroxy-2,3,2’,3‘-tetradehydro-&p-carotene-4,4’-dione (87)J to astaxanthin [3,3‘-dihydroxy-P,@-carotene-4,4’-dione (SS)], difficult to achieve chemically, was accomplished electrochemically in the presence of acetic anhydride.46 Four-electron reduction gave astaxanthin (enol) tetra-acetate (89) which yielded astaxanthin on hydrolysis. A two-electron reduction produced the retro- tetra-acetate (91).

a

(87) R = a (88) R = b (X = OH)

b

C

(89) R = c (90) R = b (X = H) OAc

44 45

*6

A. A. Engovatov, V. G. Mairanovskii, and N. T. Ioffe, Zhur. obshchei Khim., 1977,47, 2616. S.-M. Park, J. Electrochem. SOC.,1978, 125, 216. E. A. H. Hall, G. P. Moss, J. H. P. Utley, and B. C. L. Weedon, J.C.S. Chem. Comm., 1978, 387.

Terpenoids and Steroids

230

Buffered epoxidation of canthaxanthin [P,P-carotene-4,4’-dione (90)] with perbenzoic acid is reported to give canthaxanthin 11,12-epoxide (92) and the 9,12-furanoid oxide (93) as the main The 11,12-epoxide and canthaxanthin 13,14-epoxide (94) undergo cleavage on magnesia to the apo-12’and apo-l4’-zarotenals (95) and (96), and these in turn readily undergo aldol condensation with acetone in the presence of magnesium oxide to give the methyl ketones (97) and (98).48

0

(92) (93) (94) (95)

R=a R=b R=c R=CHO

(96) R = CH=C(Me)CHO (97) R = CH=CHCOMe (98) R = CH=C(Me)CH=CHCOMe

The formation of blue complexes by treatment of violaxanthin (19) and neoxanthin [5’,6’-epoxy-6,7-didehydro-5,6,5’,6’-tetrahydro-P,~-carotene3,5,3’-trio1 (99)] with A1Cl3 or either lysine or histidine dichlorides has been described and possible mechanisms are

47

49

D. Osianu, E. Nicoara, and C. Bodea, Rev. Roumaine Chim., 1977, 22, 1085. M. J. Cyronak, D. Osianu, G. Britton, and K. L. Simpson, J. Agric. Food Chem., 1978, 26, 712. C, Costes and B. Monties, Physiol. Vkgktale, 1977, 15, 667.

23 1

Carotenoids and Polyterpenoids

Retinoids. Several routes have been described for ’the preparation of retinal and its derivatives. Two paper^^^.'^ on the use of trimethylsilyl and triphenylsilyl protecting groups describe the preparation of the C , intermediate E- 3 -methylpent-2-en-4-yn-1-01 triphenylsilyl ether (loo), and the four- or five-step synthesis of 112-retinal from this and the C14 aldehyde (101). A method for base-catalysed trans elimination of PhS02H from the sulphone (102) affords retinyl acetate (103) in 86% yield.’*

(102)

The synthesis of 10,14-dimethylretinal (104) isomers has been de~cribed.’~ Successive chain lengthening of p-ionone (108) by reaction with propylidenecyclohexylamine in the presence of lithium di-isopropylamide, followed by

(103) R = C H ~ O A CX, = Y = H (104) R = C H O , X = Y = M e (10.5) R=CHO, X = F , Y = H

(106) R=CHO, X = H , Y = F (107) R = C O M e , X = Y = H

treatment with iodine, gave the aldehyde (109) which then underwent aldol condensation with acetone to give the ketone (110). A second reaction with propylidenecyclohexylamine gave 10,14-dirnethylretinal. The pure all-trans- and 13-cis-isomers were obtained by h.p.1.c. The 9-cis-, 11-cis-, and all-trans-isomers of retro-y-retinal(ll1) have been prepared from the intermediate (112) obtained by irradiation of methyl p-ionylideneacetate (113).54The preparation of the 10-fluoro- (105) and 14-fluoro- (106) derivatives of retinal by standard CIS+ C s or Cls+C2 routes has been described.” In each case a range of cis- and trans-products was separated by h.p.1.c. Methods for the preparation of labelled

’* 53 54

55

B. I. Mitsner, I. A. Vasilenko, N. A. Sokolova, E. N. Zvonkova, G. A. Serebrennikova, and R. P. Evstigneeva, Biol. Akt. Soedin. Elem. ZVB Gruppy, 1977, 36. N . A. Sokolova, B. I. Mitsner, N. Yu. Gorina, R. P. Evstigneeva, S. S. Shchukolyukov, E. P. Chizhevich, and V. P. Korchagin, Bioorg. Khim., 1977, 3, 1234. P. Chabardes, J. P. Decor, and J. Varagnat, Tetrahedron, 1977, 33, 3799. S. P. Tanis, R. H. Brown, and K. Nakanishi, Tetrahedron Letters, 1978, 869. M. Ito, K. Hirata, A. Kodama, K. Tsukida, H. Matsumoto, K. Horiuchi, and T. Yoshizawa, Chem. and Pharm. Bull. (Japan), 1978, 26, 925. A. E. Asato, H. Matsumoto, M. Denny, and R. S. H. Liu, J. Amer. Chem. Soc., 1978, 100, 5957.

232 [6,7-’4C,]- and [21-3H]-species of reported.56

Terpenoids and Steroids 15-methylretinone (107) have been

(113)

Epoxidation of methyl 7&dihydroretinoate (114) with monoperphthalic acid gave three main products (115)-(117).57 In the presence of acid (115) gave the spiro-derivative (118). The autoxidation of solid all-trans- retinyl acetate and palmitate, trans-axerophtene (82), and 11-cis-retinol has been studied. From amorphous samples dialkyl peroxides and carbonyl and hydroxy-compounds were formed, but in the crystalline state carbonyl compounds were the only

A number of papers report the irradiation of all-trans-retinal and derivatives under various conditions and the preparation of several cis- isomers by these methods. Virtually all this work relies heavily on the use of h.p.1.c. to separate the 56

” 58

P. Tosukhowong and J. A. Olson, Biochim. Biophys. Acta, 1978, 529, 438. L. P. Davydova, L. N. Polyachenko, A. R. Bekker, and G. I. Samokhvalov, Zhur. org. Khim., 1978, 14, 721. E. I. Finkel’shtein, S. M. Dolotov, and E. I. Kozlov, Zhur. org. Khim., 1978, 14, 5 2 5 .

Carotenoids and Polyterpenoids

233

mixture of stereoisomers produced. Acetonitrile is a particularly useful solvent for preparation of the 11-cis- and hindered 7-cis-isomers of retinal;59in ethanol 7-cis-retinal is a main product, but the 9-cis-, 11-cis-, and 13-cis-isomers are also produced.60 An alternative procedure for the preparation of 1 1-cis-retinal has been reported.6' In polar solvents all-trans-3-dehydroretinal(119) and the C,, ketone (120) give a mixture of isomers with the 7-cis-compound as a major

(119) X=CHCHO (120) x = o

component.62A more detailed investigation of the trans-cis photoisomerization of all-trans-retinal as a function of excitation energy led to the conclusion that 1 3 4 s - and 9-cis-retinal are the primary photoproducts in non-polar solvents, whereas in polar solvents the 11-cis-isomer is a major product along with Under certain conditions all-trans- retinal is converted into the hexahydronaphthalene derivative (121). All-trans-p-ionylidenecrotonaldehyde(123) gives an analogous product ( 122).64,65 The photochemical synthesis of cis- isomers of 13-demethylretinal (124) has been described.66

R (121) R = C(Me)=CHCHO (122) R = CHO

(124) R = C H 2 0 H , X = H (125) R = C02H, X = Me

A simple procedure for the preparation of ethyl or isopropyl retinoates involves oxidation of retinol with Mn02-acetic acid-NaCN to yield retinoic acid ( 1 2 9 , 59

6o 62

64

65

66

M. Denny and R. S. H. Liu, J. Amer. Chem. SOC.,1977,99,4865. M. Maeda, Y. Shichida, and T. Yoshizawa, J. Biochem. (Japan), 1978,83, 661. A. Knowles and A. Priestly, Vision Res., 1978, 18, 115. R. S. H. Liu, A. E. Asato, and M. Denny, J. Amer. Chem. Soc., 1977,99, 8095. W. H. Waddell and D . L. Hopkins, J. Amer. Chem. SOC.,1977,99,6457. K. Tsukida, M. Ito, and A. Kodarna, J. Nutr. Sci. Vitaminol., 1977, 23, 375. K. Tsukida, M. Ito, and A. Kodama, J. Nutr. Sci. Vitaminol., 1978, 24, 143. W. H. Waddell, M. Uemura, and J. L. West, Tetrahedron Letters, 1978, 3223.

234

Terpenoids and Steroids

which is immediately esterified with the ethanol or propan-2-01 used as ~olvent.~’ Phosphorylation of retinol by phosphodimorpholine chloride or phosphorus oxychloride gives retinyl phosphate in low yield.68Treatment of all-trans-retinol with pyridinium tetra-acetylmannopyranosyl phosphate in dry pyridine containing dicyclohexylcarbodi-imide gave retinylmannosyl phosphate in 87% yield.69

Other Degraded Curotenoids. Several syntheses of ionones and related compounds have been described. Some of these may prove useful for end-group construction in carotenoid synthesis. Thus 4-keto-P-ionone (126) and 3,4dehydro-P-ionone (127) have been prepared by condensation of the sulphone (128) with propylene oxide, followed by elimination of phenylsulphinic acid and A novel method7’ utilizes a thermal acetylenic either oxidation or dehydrati~n.~’ oxy-Cope rearrangement process to prepare the ionone compounds (129-13 1; R = Me) and analogues (R = Et or Pr’) from cyclohex-2-enylprop-2rynols (132).

(132)

Full details of the synthesis7*of a-damascone (133)have been The ring system was constructed by a Diels-Alder reaction between 2-methylpropene and 4-methylhexa-3,5-dien-2-one to give (134) and the carbon chain extended by reaction with N-methylanilinomagnesium bromide, acetaldehyde, and sodium acetate-acetic anhydride to give a-damascone in low overall yield. Another synthesis of a-damascone utilized the mixed keto-esters (135) and (136).74 Thioacetalization yielded (137); (136) did not react. Conversion of the ester group via the alcohol into an aldehyde, followed by reaction with cis- and transpropenylmagnesium bromide, gave the alcohol (138)and thence cis- and trans-adamascone (133). In a new synthesis of y-damascone (139) from y-cyclocitral 67 68 69

70 71

72

73 74

A. B. Barua and K. Verma, Indian J. Chem., 1977,15B, 665. A. A. Drnitrovskii and S. P. Poznyakov, Priklad. Biokhim. Mikrobiol., 1978, 14, 5 5 8 .

A. Ya. Veinberg, A. M. Berdichevskaya, V. L. Khristoforov, I. N. Gracheva, and G. I. Samokhvalov, Zhur. obshchei Khim., 1977,47, 1205. S . Torii, K. Uneyama, and I. Kawahara, Bull. Chem. SOC.Japan, 1978, 51, 949. T. Onishi, Y. Fujita, and T. Nishida, J.C.S. Chem. Comm., 1978, 651. R. C. Cookson and R. M. Tuddenham, J.C.S. Chem. Comm., 1973,742. R. C. Cookson and R. M. Tuddenham, J.C.S.Perkin I, 1978, 678. H.-J. Liu, H.-K. Hung, G . L. Mhehe, and M. L. D. Weinberg, Canad. J. Chem., 1978,56, 1368.

235

Carotenoids and Polyterpenoids

(140), the lithium derivative of propyne provided the three additional side-chain carbon atoms7’

(133) R = CH=CHMe (134) R = M e

pmq

(1 39) R = COCH=CHMe (140) R = C H O

(137) R = COzEt (138) R = CH(OH)CH=CHMe

Two analogues (141) and (142) of trisporic acid (143) have been synthesized in high overall yield.76

\

0

0

(141)

0

(142)

0’

(143)

In the abscisic acid field, syntheses of 6’-monodemethylabscisic acid (144) and methyl 5-(1’,6’-epoxy-2’,2’-dimethylcyclohexyl--3-methyl-(22,4~)-penta-2,4dienoate (145) have been described,77and the synthesis of some compounds that may be considered to be aromatic analogues of abscisic acid has also been rep~rted.’~

(144)

(145)

Confirmation of the structures of several new ‘degraded carotenoids’ [(33), (34), (37)-(49)] has been obtained by their preparation from related compounds of known s t r u c t ~ r e . ~ l - ~ ~ Reaction of p-ionol (146) with singlet oxygen gave a number of oxygenated products, mainly (147)-( 15 1).33Similarly singlet oxygen oxidation of ambrein

’’ 0. Takazawa, K. Saigo, K. Narasaka, and T. Mukaiyama, Chem. Letters, 1977, 757. 76

77

’*

I. M. Yakovleva, L. A. Vakulova, A. R. Bekker, and G . I. Samokhvalov, Zhur. org. Khim., 1978,14, 714. M. Nanzyo, T. Oritani, and K. Yamashita, Agric. and Biol. Chem. (Japan), 1977, 41, 1711. T. Oritani, M. Nanjo, M. Fujita, and K. Yarnashita, Agric. and B i d . Chem. (Japan), 1978,42, 1437.

Terpenoids and Steroids

236

(152) followed by degradation of the resulting ally1 hydroperoxides gave various natural ambergris constituents including (153) and (154).79The chirality of (153) produced by permanganate oxidation of ambrein was established" by comparison with ( +)-dihydro-y-ionone (153) of known absolute configuration ( S ) .

(153) R' = M e , R2 = 0 (154) R' = CHO, R2 = CH2

The catalytic hydrogenation of p-ionone (108) over palladium on polysaccharide ion-exchange resins has been reported.81 Various hydroionones were produced, mainly (155) and (156). Hydrogenation of p-ionone in the presence of pentacyanocobaltate(I1) anion, K,[Co(CN),], gave a mixture of E- and Z (157)?* Details of the photolysis of the epoxyionone compounds (158)-(160)

(155)

(156)

(157)

have been investigated, and mechanisms suggested for the formation of some of the many Elsewhere it is reported that triplet photosensitization of Eand 2-retro-y-ionone (1 6 l ) and of E-retro-y- ionol (162) produces only E-2

'' G. Ohloff, K. H. Schulte-Elte, and B. L. Miiller, Helv. Chim. Actu, 1977,60, 2763. *' 83

G. Ohloff and C. Vial, Helv. Chim. Actu, 1977, 60, 2767. C. Allandrieu, G. Descotes, J. P. Pralp, and J. Sabadie, Bull. SOC.chim. France, 1977, 519. G . S. R. Subba Rao, J. Rajaram, S. Rathuamala, and R. Sivaramakrishnan, Proc. Indian Acud. Sci., 1977,86A, 435. B. Frei, H. Eichenberger, B. von Wartburg, H. R. Wolf, and 0.Jeger, Helv. Chim. Actu, 1977,60, 2968.

237

Carotenoids and Polyterpenoids

isomerization, whereas excitation via singlet states gives products such as (163) and (164).g4

(158) R' = H, R2 = Me (159) R' = R2 = M e (160) R1= H, R2= Ph

(161) X = O (162) X = H, OH

Carotenoid-Protein Complexes.-A blue carotenoprotein (A,= 5 50 nm) from the marine invertebrate Salpa cylindrica has as its carotenoid prosthetic group a pigment with properties somewhat reminiscent of fucoxanthin (18) and not astaxanthin (88) or a related compound, as in all other blue carotenoproteins so far examined. The Salpa carotenoid has not been characterized." In addition to the blue crustacyanin, the shell of the lobster contains a yellow carotenoidprotein complex, A,, 410 nm. This complex has approximately 20 astaxanthin molecules per protein molecule. Resonance Raman spectroscopy suggests that the spectral shift is due to chromophore-chromophore (exciton) interaction and considerable astaxanthin Carotenoid-protein complexes containing canthaxanthin (90) and lutein (16) have been isolatedg8 from the pigmented extrachloroplastic globules of the green alga Protosiphon botryoides. An artificial carotenoid-protein complex, mol. wt. 507 000, has been prepared from lutein and an aqueous solution of azuki Physical Methods.-Separation and Assay. Increasing use is being made of h.p.1.c. in the carotenoid field. This technique will clearly become the method of choice for carotenoid separation, purification, and analysis. The first papers on carotenoid h.p.1.c. have recently been p ~ b l i s h e d . ~ ' -These ~ ~ include a systematic study of the chromatography of model mixtures of carotenes, carotenediols, cis-trans isomers, and dia~tereoisomers.~~ Many papers report the use of h.p.1.c. 84 85

86 87

89 90

91 92

93

H. Cerfontain and J. A. J. Geenevasen, J.C.S. Perkin ZZ, 1978, 698. P. J. Herring, Comp. Biochem. Physiol., 1978, B61, 391. V.R.Salares, N. M. Young, H. J. Bernstein, and P. R. Carey, Biochemistry, 1977, 16, 4751. V.R.Salares, N. M. Young, P. R. Carey, and H. J. Bernstein, Proceedings of the 5th International Conference on Raman Spectroscopy, 1976, p. 210 (Chem. Abs., 1977, 87, 197 647). C. Berkaloff, Plant Sci. Letters, 1977, 10, 45. S. Takagi, Nippon Nogei Kagaku Kaishi, 1978,52, 25. A. Fiksdahl, J. T. Mortensen, and S. Liaaen-Jensen, J. Chromatog., 1978, 157, 11 1. J. E. Paanakker and G. M. Hallegraef, Comp. Biochem. Physiol., 1978, B60, 51. S. K. Hajibrahim, P. J. C. Tibbetts, C. D. Watts, J. R. Maxwell, G. Eglinton, H. Colin, and G. Guichon, Analyt. Chem., 1978, 50, 549. I. Stewart, J. Agric. Food. Chem., 1977, 25, 1132.

238

Terpenoids and Steroids

and for assay to separate cis-trans isomers of retinal derivatives,53.60,61.63*66*94-g7 of retinoids in natural tissues or fluid~.~~-l" Surveys of t.1.c. procedures for separating chloroplast pigments, including carotenoids,102carrot carotenoid~,~'~ and retinal and some derivative^,"^ have been presented. Methods for the assay of vitamin A and provitamin A carotenoids have been reviewed.1057106 Colorimetric procedures for the estimation of all-trans- and 13-cis- retinoic acidlo7and of retinyl acetate'" have been described.

N.M.R. Spectroscopy. The effects of lanthanoid shift reagents on the 'H and 13C n.m.r. spectra of canthaxanthin (90) have been studied in detail.lo9 Chemical shifts and signal broadening showed that the metal binds the carbonyl group at two sites. A computer programme was used to study the conformation of canthaxanthin. Similar studies"' have been performed with all-trans-, 9-cis-, 11-cis-, and 13-cis-retinal and 8'-apo-P-caroten-8'-al (165). A high-resolution

(165)

'H n.m.r. study of some retinyl and retinylidene derivatives has been reported, and differences in conformation at C-13, -14, and -15 have been analysed.'" N.m.r. studies of reconstituted bovine rhodopsin containing a chromophore enriched with 13Cat specific positions of the retinylidene chain strongly suggest an unprotonated retinylidene Schiff's base as the visual chromophore.112 Electronic Absorption Spectroscopy. A review has been published of the absorption spectra of a range of natural carotenoid~."~ A model has been presented which attributes the widths of carotenoid absorption bands to conformational 94

95

96

97 98

99 lo" lo'

lo2 lo3 lo4 lo'

'06

lo' lo' lo9

'lo

'12 '13

R. M. McKenzie, D. M. Hellwege, M. L. McGregor, N. L. Rockley, P. J. Riquetti, and E. C. Nelson, J. Chromatog., 1978, 155, 379. A. M. McCormick, J. L. Napoli, and H. F. Deluca, Analyt. Biochem., 1978,86, 25. K. Tsukida, A. Kodama, M. Ito, M. Kawamoto, and K. Takahashi, J. Nutr. Sci. Vitaminol., 1977,23, 263. C. A. Frolik, T. E. Tavela, and M. B. Sporn, J. Lipid Res., 1978, 19, 32. C. V. Puglisi and J. A. F. de Silva, J. Chromatog., 1978, 152, 421. K. Abe, K. Ishibashi, M. Ohmae, K. Kawabe, and G. Katsui, Vitumins, 1977, 51, 275. D. C. Egberg, J. C. Heroff, and R. H. Potter, J. Agric. Food Chem., 1977, 25, 1127. A. Maeda, T. Iwasa, and T. Yoshizawa, J. Biochem. (Japan), 1977,82, 1599. J. Sherma and M. Latta, J. Chromatog., 1978, 154, 73. A. K. Baloch, K. A. Buckle, and R. A. Edwards, J. Chromatog., 1977, 139, 149. Y. K. Fung, R. G. Rahwan, and R. A. Sams, J. Chromatog., 1978,147,528. D. B. Parrish, C.R.C. Crit. Rev. Food Sci. Nutr., 1977, 9, 375. H. R. Bolliger, R. Botinck, B. Borsje, H. S. Grainger, A. Mariani, J. Matet, F. J. Mulder, G. Nedelkovitch, G. Nicolaux, G. F. Phillips, P. J. Schorn, R. Strohecker, and P. Schwarze, Pharm. Acta Helv., 1977, 52, 161. C.-C. Wang, R. E. Hodges, and D. L. Hill, Analyt. Biochem., 1978, 89, 220. G. L. Soni, R. Singh, and I. S. Bhatia, Indian J. Biochem. Biophys., 1977, 14, 381. B. H. S. Lienard and A. J. Thomson, J.C.S. Perkin ZI, 1977, 1390. B. H. S. Lienard and A. J. Thomson, J.C.S. Perkin 11, 1977, 1400. L. A. Sibel'dina, L. P. Kayushin, E. N. Zvonkova, T. D. Skalaban, V. A. Khristoforov, and R. P. Evstigneeva, Stud. Biophys., 1978, 68, 187. J. Shriver, G. Mateescu, R. Fager, D. Torchia, and E. W. Abrahamson, Nature, 1977, 270, 271. A. M. P. Gallotti and S. T. Tolmasquirn, Znf. ZNT., 1977, 10, 20 (Chem. A h . , 1978,88,89 856).

239

Carotenoids and Polyterpenoids

disorder induced by the 0-ionylidene m ~ i e t y . ' 'A ~ detailed study of the absorption and emission spectra of a range of retinals, analogues, and homologues has been presented."' Resonance Raman Spectroscopy. This technique is finding increasing application in the carotenoid field. Details of the resonance Raman spectra of P-carotene,"6*"7 y-carotene [@,+carotene (166)], and torulene [3',4'-didehydro-P,$carotene (167)]"8 have been given. Details of the Raman excitation profiles of

(166)

R=

(167) R =

p- carotene have been a n a l y ~ e d . ' ~ Resonance ~~'*~ Raman spectra of aggregates of carotenoids, especially astaxanthin, have been correlated with the spectra of a natural yellow astaxanthin-protein complex from l o b ~ t e r . ~Resonance ~.~~.~~~ Raman spectroscopy has also been used to study the carotenoids in reaction centres of photosynthetic bacteria. Comparison with the behaviour of 15-cis-pcarotene suggests that the bacterial carotenoids have the cis configuration in vivo.122 Details of the resonance Raman spectra of retinal and retinal analogue^,'^^-'^^ and of visual pigments1265127 and bacteriorh~dopsin'~~-'~~ derived from them have been presented and analysed. X - R a y Structures. The X-ray structure of the 9-ethyl analogue (168) of retinoic acid has been dete~rnined.'~~ The polyene chain is slightly more curved than that of retinoic acid itself, and the cyclohexene ring is rotated 64" out of the s-cis conformation. 'I4

R. Hemley and B. E. Kohler, Biophys. J., 1977,20, 377.

11'

P. K. Das and R. S. Becker, J. Phys. Chem., 1978,82,2081,2093.

W. Nitsch and W. Kiefer, Ref. 87, p. 740. L.Horvath, Fiz. Szemle, 1977, 27, 287. Pham Van Huong, Compt. rend., 1978, 286, C, 25. 119 s. Sufra, G.Dellepiane, G. Masetti, and G. Zerbi, J. Raman Spectroscopy, 1977,6, 267. R. J. Thrash, H. L. B. Fang, and G. E. Leroi, J. Chem. Phys., 1977,67, 5930. 121 V. R. Salares, N. M. Young, P. R. Carey, and H. J. Bernstein, J. Raman Spectroscopy, 1977,6,282. M. Lutz, I. Agalidis, G. Hervo, and R. J. Cogdell, Biochim. Biophys. Acta, 1978, 503, 287. lZ3 R. Cookingham and A. Lewis, J. Mol. Biol., 1978, 119, 569. lZ4 A. G. Doukas, B. Aton, R. H. Callender, and B. Honig, Chem. Phys. Letters, 1978, 56, 248. A. Warshel, Ref. 87, p. 338. lZ6 B. Aton, R. H. Callender, and B. Honig, Nature, 1978, 273, 784. lZ7 A. G. Doukas, B. Aton, R. H. Callender, and T. G. Ebrey, Biochemistry, 1978, 17,2430. 12' J. Terner, A. Campion, and M. A. El-Sayed, Proc. Nut. Acad. Sci. U.S.A., 1977,74, 5212. lZ9 M. A. Marcus, A. Lewis, E. Racker, and H. Crespi, Biochem. Biophys. Res. Comm., 1977,78,669. A. Campion, M. A. El-Sayed, and J. Terner, Proc. SOC.Photo-Opt. Instr. Eng., 1977,113 (Adv. Laser Spectroscopy l), 128. 13' A. Campion, M. A. El-Sayed, and J. Terner, Biophys. J., 1977, 20, 369. 13' B. Ehrenberg and A. Lewis, Biochem. Biophys. Res. Comm., 1978,82, 1154. 133 H. Schenk, R.T. Kops, K. Van der Putten, and J. Bode, Acta Cryst., 1978, B34, 505.

'17

Terpenoids and Steroids

240

Linear Dichroism. A linear dichroism study of the orientation of p-carotene molecules in lamellar liquid-crystalline lipid systems has been reported. '34*'35 Linear dichroic spectra of the cross-conjugated carotenals renierapurpurin-20-a1 (169), 20-(2,3,4-trimethylbenzal)renierapurpurin(170), and 8,'8'-diapocarotene8,20,8'-trial (171) have been r e ~ 0 r d e d . The l ~ ~ results support the assignment of the 13-cis configuration to (169) and (170).

1 fyv

R'

\

-

a

-

R' (169) R1 = a, R2 = CHO

(170) R'

= R2= a

(171) R'

= R2 = CHO

Miscellaneous Spectroscopy and Physical Chemistry. The photochemistry of retinal and analogues and visual pigments has been reviewed. 13' Another review discusses flash photolysis and pulse radiolysis of some carotenoids and visual pigment^.'^' Theoretical and experimental studies of carotenoids by various spectroscopic methods have been r e p ~ r t e d . ' ~ ~ Similar - l ~ ~ studies on retinal and derivatives have also been p ~ b l i s h e d . ~ ~ ~ - ' ~ ' Dipole moments of retinal and its Schiff's base with b~tylamine"~and of all-trans- and 11-cis-retinal and of a-ionone (172) and p-ionone (108)152have been determined. 134

135

136 13' 13'

139 14"

14' 14* 143 144

145

'41 '41 '41 149

15' Is*

I. Jonas, K. Fontell, G. Lindblom, and B. Norden, Linear Dichroism Spectroscopy, Proceedings of the Nobel Workshop on Molecular Optical Dichroism and Chemical Applications of Polarization Spectroscopy 1976, ed. B. Norden, Lund University Press, Lund, Sweden, 1977, p. 217. I. Jonas, K. Fontell, G . Lindblom, and B. Norden, Spectroscopy Letters, 1977, 10, 501. Q. Chae, P.-S. Song, J. E. Johansen, and S. Liaaen-Jensen, J. Amer. Chem. SOC.,1977,99, 5609. K. Nakanishi, Pure Appl. Chem., 1977, 49, 333. E. J. Land, U. V.Spectrometry Group Bull., 1977, 5, 56. N. Wada and T. Sagawa, J. Phys. SOC.Japun, 1977,43, 2107. S. J. Chantrell, C. A. McAuliffe, R. W. Munn, A. C. Pratt, and E. J. Land, J.C.S. Faraday I, 1977,73, 858. R. Bensasson, E. A. Dawe, D. A. Long, and E. J. Land, J.C.S. Faraday I, 1977,73,1319. H. M. Brown, P. C. Kingzett, and 0. H. Griffith, Photochem. andPhotobiol., 1978, 27, 445. M. Wautelet, L. D. Laude, and A. H. Madjid, Chem. Phys. Letters, 1977, 51, 530. W. H. Waddell, A. M. Schaffer, and R. S. Becker, J. Amer. Chem. SOC.,1977,99,8456. R. R. Birge, J. A. Bennett, B. M. Pierce, a n d T . M. Thomas, J. Amer. Chem. SOC.,1978,100, 1533. R. M. Hochstrasser and D. L. Narva, Photochem. a n d Photobiol., 1977. 26. 595. E. J. Land, J. Lafferty, R. S. Sinclair, and T. G. Truscott, J.C.S. Furaduy I, 1978,74, 538. B. Veyret, S. G. Davis, M. Yoshida, and K. Weiss, J. Amer. Chem. SOC., 1978, 100,3283. W. H. Waddell and D. L. Hopkins, J. Amer. Chem. SOC.,1978,100, 1970. J. Simons, Proc. Nat. Acad. Sci. U.S.A., 1977, 74, 3375. J. P. Corsetti and.B. E. Kohler, J. Chem. Phys., 1977, 67, 5237. P. J. Bauer and P. Carl, J. Amer. Chem. SOC.,1977, 99,6850.

24 1

Car0te noids and Po 1y terpenoids

Dry all-trans- and 13-cis-retinals show no fluorescence in dry alkane solvents when at low concentration, but do so when hydrogen-bonded (wet) or in sufficiently high concentration to be present as dimeric aggregate^.^^^*^^^ Solid films of all-trans-, 9-cis-, and 13-cis-retinal are fluorescent at room temperat~re.l~~ Physical and spectroscopic properties have been described for liposomes containing &carotene, P-cryptoxanthin [ /3,/3-caroten-3-01(173)],or zeaxanthin [P,P-carotene-3,3'-diol ( 174)],'56 for molecular layers of fatty acids containing and for a photoresponsive membrane prepared from 11-&-retinal, phosphatidylcholine, and triacetylcellulose.'58

(173) X = O H , Y = H

(174) X = Y = O H

The electrical conductivity of surfaces of p- carotene and lycopene [$,$carotene (175)] in oxygen has been determined at different oxygen partial pressures. 159

The kinetics of the reaction of retinol or retinyl acetate with HC1 in acetone, to produce retru-anhydroretinol (176), have been studied.160

T. Takemura, P. K. Das, G. Hug, and R. S. Becker, J. Amer. Chem. Soc., 1978, 100,2626. T. Takemura, G. Hug, P. K. Das, and R. S. Becker, J. Amer. Chem. Soc., 1978,100,2631. 15' S. Hotchandani, P. Paquin,,and R. M. Leblanc, Canad. J. Chem., 1978, 56, 1985. l S 6 H. Y. Yamamoto and A. D . Bangham, Biochim. Biophys. Actu, 1978,507, 119. 15' T. Ohnishi, M. Hatakeyama, N. Yamamoto, and H. Tsubomura, Bull. Chem. Soc. Japun, 1978,51, 1714. 15' M. Aizawa, S. Tomono, and S. Suzuki, J. Membrane Sci., 1977, 2, 289. L. Brehmer and H. Hansel, 2. phys. Chem. (Leipzig), 1977, 258, 926. I6O L. Pekkarinen, Finn. Chem. Letters, 1977, 261. lS4

242

Terpenoids and Steroids

Photoreceptor Pigments. Several aspects of the spectroscopy and photochemistry Many of the retinal-containing visual pigments have been reviewed.137’138*161-169 papers report various aspects of the spectroscopy of retinal, retinal analogues, and Schiff’sbases derived from them, and of rhodopsin and other intermediates in the visual pigment cycle. 124,126,127,144.170-187 Similar studies on bacteriorhodopsin, the photoreceptor pigment of the purple membrane of halophilic bacteria, have also been reported. 128--132,187-203 Biosynthesis and Metabolism.-Several reviews include a consideration of the biosynthesis of carotenoids in plants’” or algae,3 and the biosynthesis of C30 A. Knowles and H. J. A. Dartnell, ‘The Eye, Vol. 2B. The Photobiology of Vision’, 2nd edn., Academic Press, New York, 1977. 162 W. Kiihne, Vision Res., 1977, 17, 1273. G. Beddard, Photochemistry, 1977, 8, 591. T. Rosenfeld and M. Ottolenghi, Proceedings of the 7th International Congress on Photobiological Research, ed. A. Castellani, Plenum, New York, 1977, p. 667. 165 H. Suzuki, T. Komatsu, and K. Nakachi, Kagaku No Ryoiki, 1978,32, 174. 166 C. N. Rafferty, Biophys. Struct. Mech., 1977, 3, 123. 167 T. Rosenfeld, B. Honig, and M. Ottolenghi, Pure Appl. Chem., 1977,49, 341. 168 A. Knowles, U. V. Spectrometry Group Bull., 1977, 5 , 46. 169 B. E. Kohler, Biophys. Struct. Mech., 1977, 3, 101. 170 A. Warshel, Proc. Nut. Acad. Sci. U.S.A., 1978, 75, 2.5.58. l 7 I A. Warshel and C. Deakyne, Chem. Phys. Letters, 1978,55,4.59. 172 J. Favrot, J. M. Leclercq, R. Roberge, C. Sandorfy, and D. Vocelle, Chem. Phys. Letters, 1978,53, 433. 173 L. J. Dunne, Jerusulem Symp. Quantum Chem. Biochem., 1977, 10 (Excited States Org. Chem. Biochem.), 187. 174 R. Hemley and B. E. Kohler, Biophys. J., 1977, 20, 377. 17’ T. V. Pushkareva, G. E. Shmelev, and A. G. Sverdlov, Radiobiologiya, 1977,17, 903. 176 M. A. Gawinowicz, V. Balogh-Nair, J. S. Sabol, and K. Nakanishi, J. Amer. Chem. SOC.,1977,99, 7720. 177 H. Matsumoto and T. Yoshizawa, Vision Res., 1978, 18, 607. M. Nanasawa and H. Kamogawa, Chem. Letters, 1977, 1183. 1 7 9 M. Muthukumar and L. J. Weimann, Chem. Phys. Letters, 1978, 53, 436. S. Kawamura, F. Tokunaga, and T. Yoshizawa, Vision Res., 1977, 17, 991. Y. Shichida, T. Kobayashi, H. Ohtani, T. Yoshizawa, and S. Nagakura, Photochem. and Photobiol., 1978, 27, 335. T. Kakitani and H. Kakitani, J. Phys. SOC.Japan, 1978, 44, 1403. R. Bensasson, E. J. Land, and T. G. Truscott, Photochem. and Photobiol., 1977, 26, 601. B. D. Gupta, I. C. Goyal, and A. K. Ghatak, Biophys. Struct. Mech., 1978,4, 129. B. H. Green, T. G. Monger, R. R. Alfano, B. Aton, and R. H. Callender, Nature, 1977,269, 179. J. B. Hurley, T. G. Ebrey, B. Honig, and M. Ottolenghi, Nature, 1977, 270, 540. Yu. A. Ovchinnikov, N. G. Abdullaev, M. Yu. Feigina, A. V. Kiselev, and N. A. Lobanov, F.E.B.S. Letters, 1977, 84, 1 . V. A. Sineshchekov and F. F. Litvin, Biochim. Biophys. Acta, 1977, 462,450. 189 W. Sperling, P. Carl, C. N. Rafferty, and N. A. Dencher, Biophys. Struct. Mech., 1977, 3, 79. 19’ B. Becher, F. Tokunaga, and T. G. Ebrey, Biochemistry, 1978,17, 2293. 191 M. P. Heyn, R. J. Cherry, and U. Miiller, J. Mol. Biol., 1977, 117, 607. 192 P. G. Kryukov, Yu. A. Lazarev, V. S.Letokhov, Yu. A. Matveets,E. L.Terpugov, L. N.Chekulaeva, and A. V. Sharkov, Biofizika, 1978, 23, 171. 193 F. F. Litvin and S. P. Balashov, Biofizika, 1977,22, 1111. 194 K. Ohno, Y. Takeuchi, and M. Yoshida, J. Biochem. (Japan), 1977,82,1177. A. Lewis, Proc. Nut. Acad. Sci. U.S.A., 1978,75, 549. 196 E. P. Ippen, C. V. Shank, A. Lewis, and M. A. Marcus, Science, 1978,200, 1279. 197 R. Korenstein and B. Hess, F.E.B.S. Letters, 1978, 89, 15. 19’ R. Korenstein and B. Hess, F.E.B.S. Letters, 1977, 82, 7. 199 R. Govindjee, B. Becher, andT. G. Ebrey, Biophys. J., 1978, 21, 67. 2oo R. A. Bogomolni, L. Stubbs, and J. K. Lanyi, Biochemistry, 1978, 17, 1037. 201 R. Korenstein and B. Hess, Nature, 1977, 270, 184. 202 J. B. Hurley, B. Becher, and T. G. Ebrey, Nature, 1978, 272, 87. 203 A. M. Shkrob, A. V. Rodionov, and Yu. A. Ovchinnikov, Bioorg. Khim., 1978, 4, 354.

”’

Carotenoids and Po1y terpenoids

243

carotenoids in some bacteria.' Other reviews deal with the formation of some C30, C45,and C50c a r o t e n ~ i d sand , ~ ~with ~ stereochemical aspects of carotene biosyn-

Stereochemistry. It is well known that formation of the first C40 hydrocarbon in carotenoid biosynthesis proceeds uia an intermediate, prephytoene pyrophosphate. It has now been shown that only the pyrophosphate of the (+)(lR,2R,3R)-isomer of prephytoene alcohol is utilized for carotene production by Phycomyces blakesleeanus. Detailed mechanisms for the formation of (lR,2R,3R)-prephytoene pyrophosphate (178) from geranylgeranyl pyrophosphate (177) have been proposed (Scheme 4).26,27 OPP I ,Hs

Hs

H

\

~

R'.

c

R

j'

c-OPP

f

C-$---H / I

C

II

(177)

f

+..

/ c , Me

3 9 M e

c +.

'R

'Me

( a )Inversion at C-1, bond formed t o C-2'; ( b ) Inversion at C-1, bond formed to C-3' Scheme 4

Some details of the stereochemistry of carotenoid cyclization have been elucidated. In the C40series labelling with stable isotopes (deuterium) has been used for the first time in studies of carotenoid biosynthesis.206A Flavobacterium species in the presence of nicotine accumulated the acyclic precursor lycopene (175). When the cells were washed free from the inhibitor and suspended in 2H20 cyclization of the lycopene proceeded, initiated by *H+.High-resolution 'H n.m.r. spectroscopy showed that in the product, (3R,3'R)-zeaxanthin (174), the deuterium had been introduced into the 2p position, thus proving that the first step in *04

'05 206

K. Harashima, Kagaku No Ryoiki, 1977,31, 163. M. Sugumaran and C. S. Vaidyanathan, J. Sci. Ind. Res., India, 1977, 36, 32. G. Britton, W. J. S. Lockley, N. J. Patel, T. W. Goodwin, and G . Englert, J.C.S. Chem. Comm., 1977, 655.

244

Terpenoids and Steroids

Scheme 5

the cyclization process occurs with the stereochemistry outlined in Scheme 5 . Conventional radioisotope studies involving the use of stereospecifically tritiated mevalonates established the stereochemistry of the loss of hydrogen from C-4 in the biosynthesis of the C5"carotenoid decaprenoxanthin [(2R,6R,2'R,6'R)- 2,2'bis-(4-hydroxy-3-rnethylbut-2-enyl)-~,e-carotene(179)] in Flavobacteriurn

dehydr~genans.~"' In this case the cyclization appears to follow the stereochemical course outlined in Scheme 6. In both cases the behaviour of the C-1 methyl substituents remains to be elucidated.

Scheme 6

Pathways. Studies of carotenoid transformations that take place when a mutant strain, PG1, of the green alga Scenedesmus obliquus is transferred from dark to light conditions have indicated that the transformations 15-cis-phytoene (180) -+ 15-cis-phytofluene (181)-+ 15-cis-5-carotene (182) -+ trans-5-carotene (183) (Scheme 7) take place in the biosynthesis of the normal cyclic carotenoids. The results were also in agreement with the formation of the xanthophylls lutein (16) and zeaxanthin (174) from the corresponding carotenes.'08 Inhibitor studies with the photosynthetic bacterium Rhodornicrobiurn vannielii showed that both nicotine and CPTA [2-(4-chlorophenylthio)triethylammonium chloride] block the formation of both P-carotene and the major acyclic carotenoids such as rhodopin [ l ,2-dihydro-$,$-caroten- 1-01 (184)] and spirilloxanthin [l,l'-di~ethoxy-3,4,3',4'-tetradehydro-1,2,1',2'-tetrahydro-$,~-caro'07 '08

D. Fahey and B. V. Milborrow, Proc. Austral. Biochem. Soc., 1978, 11, 37. R. Powls and G . Britton, Arch. Microbiol., 1977, 115, 175.

245

Carotenoids and Polyterpenoids

I

R

R

(183)

R= Scheme 7

246

Terpenoids and Steroids

(184) R' = a , R2= b

(185) R'

= R2= c

tene ( 185)].209,210 At low nicotine concentrations some y-carotene was detected.210On removal of the inhibitor p-carotene and rhodopin were synthesized at the expense of the accumulated lycopene only when synthesis de novo was prevented, e.g . by di~henylamine.~'~ The results are in agreement with proposals that the two reactions, cyclization and hydration of the C-1=C-2 double bond, involve similar mechanisms. The possible involvement of enzyme aggregates in carotenoid biosynthesis in Rm. vannielii is

Inhibition and Regulation. In addition to the work quoted above,209CPTA has been used on Turkish lemons and oranges, and found to promote the accumulation of large amounts of lycopene, and to inhibit cyclic carotenoid formation.211 No specific inhibition was observed when a soluble tomato plastid enzyme system was incubated in the presence of CPTA, diphenylamine, 9-fluorenone, or 2hydroxybiphenyl.212 Two albino mutants of Neurospora crassa have been isolated in which carotenoid biosynthesis is blocked between prephytoene pyrophosphate and phyt~ene.~'~ The photoinduction and photoregulation of carotenogenesis in some fungal species have been studied in relation to light quality214and illumination Metabolism in Animals. The conversion of [14C]-P-carotene into its 2-hydroxyand 3-hydroxy-metabolites by two species of moths has been demonstrated.216 The sea anemone Metridium senile can utilize dietary canthaxanthin but not @-carotene, echinenone ( p,@-caroten-4-one), or zeaxanthin to produce astaof the 3-hydroxy-&-ringcarotenoids xanthin in its The chirality (3's) a-doradexanthin (14) and 'lutein' (15) of goldfish suggests that these carotenoids

'09 'lo

"*

*" '13 214

'15 '16

'17

G. Britton, R. K. Singh, and T. W. Goodwin, Biochim. Biophys. Acta, 1977, 488, 475. L. S. Leutwiler and D. J. Chapman, F.E.B.S. Letters, 1978, 89, 248. L. R. G. Valadon and R. S. Mummery, Phytochemistry, 1978, 17, 818. M. L. Bucholtz, B. Maudinas, and J. W. Porter, Chem.-Biol. Interactions, 1977, 17, 359. S. C. Kushawaha, M. Kates, R. L. Renaud, and R. E. Subden, Ltpids, 1978,13, 352. M. Osman and L. R. G . Valadon, Microbios, 1978, 18, 229. W. Rau and A. Rau-Hund, Planta, 1977, 136,49. H. Kayser, Comp. Biochem. Physiol., 1977, B58,177. D. L. Fox, D. W. Wilkie, and F. T. Haxo, Comp. Biochem. Physiol., 1978, 59B, 289.

Carotenoids and Polyterpenoids

247

are not of dietary origin but their production involves an epimerization process.18 In other freshwater fish the metabolism of lutein to 3-hydroxyretinol (186) has been shown.218

Retinoids. Biosynthesis is included in a general review on vitamin A.8 The cis-trans isomerization of retinals by crude tissue extracts has been achieved.219 After oral administration of the synthetic retinoid (187) to human subjects some eighteen metabolites were isolated from the urine and faeces, almost all having a shortened polyene chain.220

Ionones. The biogenesis of ionones, irones, and related compounds has been reviewed, with particular consideration to the possibility of their formation as carotenoid metabolites." The microbial transformation of p-ionone (108) into its (2s)-hydroxy- and 45- hydroxy-derivatives (188) and (189) by a strain of Aspergillus niger has been demonstrated.221

2 Polyterpenoids and Quinones Polyterpen~ids.--'~C N.m.r. has been used to investigate the structure of the CSS polyprenol moraprenol-1 1(190) from leaves of Morus alba. The main component has the o-trans-trans-trans-cis-cis-cis-cis-cis-cis-cisOH configuration.222The monophosphate of this compound was prepared in 34% yield by treatment with o-phenylenephosphorochloridate.Biosynthetic studies have provided evidence for the formation of 2,3-dehydrodolichyl phosphate (191) as an intermediate in dolichyl phosphate (192) bio~ynthesis.~~' Most of the members of a series of C25-C40 acyclic hydrocarbons obtained from crude oil have isoprenoid or degraded isoprenoid The mokupalides from a marine sponge have been shown to be hexaprenoids with structures (193)-(195).225 'I8 219 220

"*

222

223 224

A. B. Barua, R. C. Das, and K. Verma, Biochem. J., 1977,168, 557. R. A. Sack and S. Seltzer, Vision Res., 1978,18,423. R. Hanni, F. Bigler, W. Vetter, G. Englert, and P. Laliger, Helu. Chim. Acta, 1977,60, 2309. Y. Mikami, E. Watanabe, Y. Fukunaga, and T. Kisaki, Agric. and Biol. Chem. (Japan), 1978,42, 1075. G. I. Vergunova, I. S . Glukhoded, L. L. Danilov, G. I. Eliseeva, N. K. Kochetkov, M. F. Troitskii, A. I. Usov,A. S. Shashkov, and V. N. Shibaev, Bioorg. Khim., 1977, 3, 1484. D. K. Grange and W. L. Adair, Biochem. Biophys. Res. Comm., 1977,79,734. J. Albaigb, J. Borbon, and P. Salagre, Tetrahedron Letters, 1978, 595. M. B. Yunker and P. J. Scheuer, J. Amer. Chem. SOC.,1978,100, 307.

'"

Terpenoids and Steroids

248

0

(193) X = H

(194) X = O H

(195) X = O A c

The most interesting new polyterpenoids are a series of C40diols that form part of macrocyclic diglycerol tetraethers which constitute the major membrane lipids of the extremely thermo- and acido-philic bacterium Caldariella. These compounds, (196)-(200), which may be acyclic or may have from one to four isolated cyclopentane rings are formally dimers of Cz0 isoprenoid structures linked ‘head-to-head’ rather than the conventional ‘tail-to-tail’ linkage in, for example, carotenoids.226The isoprenoid nature of these compounds has been shown by 13Clabelling.227

HOH ,c

...

a

(196) R’ = R2 = a (197) R’ = a , R2 = b (198) R’ = R2 = b

226

H

o

H

z

‘

~

.

(199) R’= b, R2 = c (200) R1= R2 = c

M. De Rosa, S. De Rosa, A. Gambacorta, and J. D. Bu’Lock, J.C.S. Chem. Comm., 1977,514.

’” M. De Rosa, S. De Rosa, and A. Gambacorta, Phytochemistry, 1977,16,

1909.

.

.

Carotenoids and Polyterpenoids

249

A new approach to the synthesis of bifunctional cis-1,5-polyprenols (201) involves the ozonolysis of long-chain cis-polyisoprenes (202; n = 8-9 x 103).228

Isoprenylated Quinones.-A book has been published dealing with biomedical and clinical aspects of coenzyme Q [ubiquinone (203)].229Other reviews have appeared on the chemistry and biochemistry of u b i q ~ i n o n e , ~vitamin '~ K [phylloquinone (204) and menaquinone (205)],231and plastoquinone (206)232and on the chemical methods for prenylation of q ~ i n o n e s . ~ ~ ~

Meoh + Me0

H

(203)

0

(204)

0

Chemistry. Several new methods for the synthesis of isoprenylated quinones have been published. A method for elongation of the isoprenoid side-chain of ubiquinone involves preparation of the chloride (207) by the reaction sequence outlined in Scheme 8 and the condensation of (207) with an aryl sulphone prepared from a prenyl (C5,Cl0,or C15)halide, followed by reductive elimination of the sulphone group.234Syntheses have been of some ubiquinone analogues (208)-(2 10) and of urinary metabolites of these and of ubiquinone itself. The metabolites were compounds having an abbreviated isoprenoid sidechain (c8)and containing one or two carboxy-groups, e.g. (211).The preparation 228

23" 231 232 233 234

23s

G. A. Tolstikov, V. N. Odinokov, V. K. Ignatyuk, A. V. Semenovskii, and A. M. Moiseenkov, Doklady Akad. Nauk S.S.S.R., 1977, 236,901. 'Biomedical and Clinical Aspects of Coenzyme Q', ed. K. Folkers and Y. Yamamura, Elsevier, Amsterdam, 1977. H. Morimoto and I. Imada, Method. Chim.,1977, 11, 117. G. Katsui and M. Ohmae, Method. Chim., 1977, 11, 135. H. Morimoto and I. Imada, Method. Chim.,1977,11, 120. K. Maruyama and Y. Naruta, Kagaku (Kyoto),1977,32, 668. S. Terao, K. Kato, M. Shiraishi, and H. Morimoto, J.C.S. Perkin I, 1978, 1101. M. Watanabe, K. Okamoto, I. Imada, and H. Morimoto, Chem. and Pharm. Bull. (Japan), 1978,26, 774.

250

Terpenoids and Steroids

““‘h

R= Me0

)i

, iii

iv

OAc

R+

OH

Reagents: i, NBS-aq. 1,2-dimethoxyethane; ii, K,CO,-MeOH; iii, HC104, aq.-1,2-dimethoxyethane; iv, Ac,O-py; v, SOC1,-py; vi, NaOH; vii, SOC1,-n-hexane; vii, Na arylsulphinate; ix, BuLi-THF-HMPA; x, Li-EtNH, ~

Scheme 8

of a series of piericidin A analogues (212; n = 1 , 2 , 3 , or 9) and (213) has been The ring system was constructed by cyclization of 3-methoxyacetylamino-2-methylacrylonitrile to 4-amino-2-pyridone (214), and prenylation was achieved by reaction of the 6-lithio-compound (215) with the appropriateprenyl bromide.

RhH 0

R

0

R& H z

(208) R=MeCO (209) R = M e (210) R-R= -CH=CH-CH=CH236

F. P. Schmidtchen and H. Rapoport, J. Amer. Chem. SOC.,1977, 99, 7014.

Carotenoids and Polyterpenoids

25 1

OH

OH

O

MeofIMe Me0

N H

N

Li

I

Acyl (214)

(215)

An easy synthesis of prenyl naphthoquinones, e.g. menaquinone-2 (205; n = 2), was achieved by coupling the appropriate prenyl halide with an organocopper derivative of the electrochemically derived quinone bisacetal (216).237 Menaquinone-2 and phylloquinone (204) were also obtained in good yields by reaction of 2-methyl-1,4-naphthoquinone(205; n = 0) with geranyl and phytyl halides in the presence of metal A one-step method for the preparation of vitamin K analogues uses cyclodextrin inclusion catalysts.239Thus reaction of the diol(217) with ally1 bromide in the presence of oxygen and P-cyclodextrin at pH 9 afforded the menaquinone analogue (218).

(216)

(217)

(218)

A new method has been devised for the spectrophotometric determination of vitamin K compounds as their Ti'" complexes.24oH.p.1.c. procedures for determination of vitamin K241and ubiquinone homologues and isomers242have been reported. Biosynthesis. Two reviews have been published on the biosynthesis of ~ b i q u i n o n and e ~ ~one ~ ~on~ the ~ ~ regulation of prenylquinone b i o s y n t h e s i ~ . ~ ~ ~ A new intermediate in ubiquinone biosynthesis by Saccharomyces cereuisiae, 237 238

239 240 241 242

243 244 245

P. W. Raynolds, M. J. Manning, and J. S. Swenton, J.C.S. Chem. Comm., 1977, 499. Y. Tachibana, Chem. Letters, 1977, 901. I. Tabushi, K. Fujita, and H. Kawakubo, J. Amer. Chem. SOC., 1977,99,6456. J. C. Vire, G. J. Patriarche, R. J. Nowak, and H. B. Mark, Analyt. Chem., 1977, 49, 1343. T. D. Bjornsson, S. E. Swezey, P. J. Meffin, andT. F. Blaschke, Thromb.Huemostasis, 1978,39,466. Y. Yamano, S. Ikenoya, T. Tsuda, M. Ohmae, and K. Kawabe, Yakugaku Zasshi, 1977, 97,486. G. C. Donchenko and L. A. Chernukhina, Vitaminy, 1976,9, 20. H. Rudney, in Ref. 229, p. 29. H. K. Lichtenthaler, in 'Lipids and Lipid Polymers in Higher Plants', ed. M. Tevini and H. K. Lichtenthaler, Springer, Berlin, 1977, p. 231.

Terpenoids and Steroids

252

3-methoxy-4-hydroxy-5-hexaprenylbenzoic acid (219), has been identified in a mutant The enzymic conversion of either 4-hydroxybenzoate and isopentenyl pyrophosphate or 3-hexaprenyl-4-hydroxybenzoate (220) into 6-methoxy-2-hexaprenylphenol (221), 5-demethoxyubiquinone-6 (222), and ubiquinone-6 (203; n = 6) by mitochondria of Saccharomyces carlsbergensis has been and some properties of the enzyme polyprenyl pyrophosphate:4-hydroxybenzoate polyprenyl transferase have been The role of molecular oxygen in ubiquinone biosynthesis by E. coli has been evaluated.249

(219) R' = OMe, R2 = H, R3= C02H (220) R1 = R2 = H, R3= C02H (221) R' = OMe, R2 = R3= H

The incorporation of [1,6-14C2]shikimate, [a-''C]homogentisate, and [p- 14C]DL-tyrosine into plastoquinone (206) by isolated chloroplasts has been

246 247 248

24q 250

R. R. Goewert, C. J. Sippel, M. F. Grimm, and R. E. Olson, F.E.B.S. Letters, 1978, 87, 219. J. Casey and D. R. Threlfall, F.E.B.S. Letters, 1978, 85, 249. J. Casey and D. R. Threlfall, Biochim. Biophys. Actu, 1977, 489, 343. K. Alexander, Proc. Austral. Biochem. Soc., 1978, 11, 39. H. Bickel, L. Palme, and G. Schultz, Phytochemistry, 1978, 17, 119.

Part II STEROl DS

1 Physical Methods BY D. N. KIRK

This section follows the same pattern as in last year’s Report, giving a survey of the year’s literature on spectroscopic and other analytical methods as applied to steroids.

1 Structure and Conformation A new review’ of crystal structures of steroids presents a discussion of the main features which affect the conformations of an extensive range of compounds of the oestrane, androstane, and pregnane series. Structural data for groups of compounds which share a common structural component (e.g. different 4-en-3ones) are analysed to determine the ‘normal’ conformations of such systems, and to assess the effects of those structural features which cause departures from normality. This analysis is a useful supplement to the ‘Atlas of Steroid Structure’,* which was published from the same laboratory in 1975, but was inadvertently and inexcusably omitted from the reviewer’s Report of that year’s steroid literature. The ‘Atlas’ provides a superb collection of structural data for reference. Steroids were generally allotted four pages each, with listing of atomic co-ordinates, bond angles, torsion angles, and other details calculated from X-ray data, illustrated by clear diagrams showing the general molecular shape and packing of each steroid. The variability of ring A conformation even in 5a-saturated steroids is well illustrated by X-ray crystallographic data for two 3-0x0-derivatives: 17pbromoacetoxy-19-nor-5a-androstan-3-one has an abnormally flattened ring A, whereas the ring is more puckered than expected in the corresponding compound with a 1OP-methyl group. Both effects appear to result from intramolecular forces in the c r y ~ t a lAnalysis ,~ of the ‘H n.m.r. spectrum of a 4,4-dimethyl-3-oxo-5a steroid by computer simulation4 gave coupling constants between protons at C- 1 and those at C-2 compatible with the slightly flattened chair conformation found in the crystal. Last year’s Report’ that the dipole moment of 4,4-dirnethyl-handrostane-3,17-dione is too small to be compatible with any accessible conformation of ring A has been explained4 as due to incomplete hydrogenation of As-unsaturation in the preparation of this compound. Calculated and observed

*

W. L. Duax, C. M. Weeks, and D. C. Rohrer, in ‘Topics in Stereochemistry’, ed. N. L. Allinger and E. L. Eliel, Wiley-Interscience, New York, Vol. 9, 1976. W. L. Duax and D. A. Norton, ‘Atlas of Steroid Structure’, Plenum, New York, Vol. 1, 1975. G. Ferguson, D. F. Rendle, J. M. Midgley, and W. B. Whalley, J.C.S. Perkin I, 1978, 267. U. Burkert and N. L. Allinger, Tetrahedron, 1978,34, 807. N. L. Allinger, U. Burkert, and W. H. De Camp, Tetrahedron, 1977, 33, 1381.

255

Terpenoids and Steroids

256

dipole moments for 4,4-dimethylandrost-5-ene-3,17-dione agree well, and are close to the value erroneously reported for the saturated dione. 17pIodoacetoxy-4,4-dimethylandrost-5-en-3-one is reported to have a ‘skewed boat’ ring A and a half-chair ring B.6 Abnormal ‘twist-boat’ conformations are indicated by c.d. and n.m.r. data for ring A in 2a-acetoxy-5-hydroxy-5a-cholestan-3-one(1) and 3a-acetoxy-5hydroxy-5a -cholestan-2-one (2)’ although their 5-deoxy analogues have normal chair conformations. Hydrogen-bonding between the O H and OAc groups explains the behaviour of the first compound, but the isomer (2) seems to be responding to the unfavourable 3a -0Ac-5a-OH diaxial compression, with no compensating stabilization from hydrogen-b~nding.~

”*

’ +O

AcO

0

OH

X-Ray study of 3,3-dimethoxy-19-norandrosta-5(10),6-dien- 17-one (3), which exhibits a negative c.d. curve, confirms that the cisoid diene system has right-handed helicity;’ the c.d. behaviour is therefore contrary to the simple diene helicity rule, in accordance with a recent report.’

(3)

17a-Acetoxyprogesterone has an atypical ‘sofa’ conformation of ring A, apparently imposed by transmission of strains in ring D associated with the acetoxy-group. A further effect of the acetoxy-group is to restrict the conformational mobility of the pregnane side-chain and of the molecule as a whole, an effect which may, it is suggested, favour its interaction with binding sites in u ~ u o .X-Ray ~ ~ ) analyses of androst-5-ene-3,17-dione(4),the 5,10-seco-oestr-5yne derivative (6), and the corresponding allenic compound (7) indicate conformational features which may help to explain the isomerization of the acetylenic compound to the allene by the A5-3-ketoisomerase of Pseudomonas testosteroni ;

lo

G. Ferguson, W. C. Marsh, J. M. Midgley, and W. B. Whalley, J.C.S. Perkin I, 1978, 272. A. Schwartz and E. Glotter, J.C.S. Perkin I, 1978, 224. R. Ahmad, R. Carrington, J. M. Midgley, W. B. Whalley, U. Weiss, G . Ferguson, and P. J. Roberts, J.C.S. Perkin 11, 1978, 263. ‘Terpenoids and Steroids’, ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1977, Vol. 7, p. 232. W. L. Duax, V. Cody, and J. Hazel, Steroids, 1977, 30, 471.

Physical Methods

257

both of the 5,10-seco-compounds cause rapid and irreversible inhibition by binding to the enzyme." The conclusions are compatible with the accepted mechanism for conversion of the 5-en-3-one (4) into the 4-en-3-one ( 5 )by P-face transfer of a proton from C-4 to C-6, uia a basic site in the enzyme (represented by B in the diagrams). B

B

.'

B.

The stereochemistry of the 6&7&adduct (8) from the corresponding 6-chloro4,6-dien-3-one and nitromethane has been established by X-ray analysis.'* The l a , 2 a -adduct (9) formed from a 2-bromo-1,4,6-trien-3-one has been similarly characterized.l 3

X-Ray crystal structures are reported for the first 9a-fluoro-A"-steroid (lo),'" and for 17a -ethynyl-17~-hydroxy-l3~-(3-hydroxypropyl)gon-4-en-3-one (11).15

l2

l3

l4

H. L. Carreil, J. P. Glusker, D. F. Covey, F. H. Batzold, and C. H. Robinson, J. Amer. Chem. Soc., 1978,100,4282. E. L. Shapiro, G . Page, L. Weber, M. J. Gentles, A. T. McPhail, and K. D. Onan, Tetrahedron Letters, 1977,3553. E. L. Shapiro, M. J. Gentles, L. Weber, G. Page, A. T. McPhail, and K. D. Onan, Tetrahedron Letters, 1977,3557. M. J. Green, H.-J. Shue, M. Tanabe, D. M. Yasuda, A. T. McPhail, and K. D. Onan, J.C.S. Chem. Comm., 1977,611. C. G . Pitt, D. H. Rector, M. C. Wani, A. T. McPhail, and K. D. Onan, J. Chem. Research ( S ) , 1977, 295.

Terpenoids and Steroids

258

The absolute configurations at C-25 of the epimeric 25,26-dihydroxycholesterols, and thence of the derived 25,26-dihydroxy-cholecalciferols,are now known as the result of an X-ray study of the less polar epimer.16 Chiroptical methods would not permit an assignment of configuration. The crystal structure of anhydrous cholester01~~ differs from that reported earlier for the monohydrate, although both have a unit cell comprising eight molecules. In the anhydrous crystal, O H groups form two independent chains of hydrogen bonds. Although all eight steroid skeletons are identical, the side-chains pack in different conformations. Chenodeoxycholic acid exhibits polymorphism, giving three crystalline forms and an amorphous form with different characteristics (X-ray)." 1P-Hydroxy-vitamin D3 has been shown by n.m.r. to exist mainly as the 1,3-diaxial hydrogen-bonded conformer in a non-polar solvent (CCI,), but in the diequatorial form when dissolved in a polar medium ([2Hs]acetone). These findings are in contrast to the behaviour of the la-isomer, which exists as an equilibrium mixture of its two axial-equatorial conformers. l9 Studies using both 13 C and 'H n.m.r. have provided data on the conformational flexibility of ring A in vitamin D3 and its 3a-epimer, and in a number of related compounds. In both vitamin D3 and the 3a-epimer the 10-methylene group has a marked stabilizing effect on the conformer with an axial 3-hydro~y-group.~'

2 N.M.R. Spectroscopy An attempt has been made to correlate deviations from 'predicted' 13Cshifts in hydroxyandrostanes with geometric distortion.21Allinger's molecular force field was used to calculate geometries of the molecules. Although some correlation of 13 C shifts with non-bonded interactions can be achieved, it seems unwise to postulate geometric distortion alone as the cause of observed n.m.r. deviations. A computer-based method for prediction of 13Cchemical shifts in saturated monoand poly-cyclic frameworks gives, inter alia, a close fit with data for the individual carbon atoms in 5 a - a n d r o ~ t a n e . ~ ~

l6

l7

*' 2o 21 22

M. Cesario, J. Guilhem, C. Pascard, and J. Redel, Tetrahedron Letters, 1978, 1097. H. S. Shiek, L. G. Hoard, and C. E. Nordman, Nature, 1977,267, 287. G. Giuseppetti and M. Paciotti, Farmaco, Ed. xi.,1978, 33, 64. M. Sheves, N. Friedman, and Y. Mazur, J. Org. Chem., 1977,42, 3597. E. Berman, Z. Luz, Y. Mazur, and M. Sheves, J. Org. Chem., 1977,42,3325. G. M. Schwenzer, J. Org. Chem., 1978, 43, 1079. D. H. Smith and P. C. Jurs, J. Amer. Chem. Soc., 1978, 100, 3316.

Physical Methods

259

The effects of a-,@-, y-, and 6-azido-substituents on 13C shifts have been evaluated from a series of azido-substituted ~teroids,’~ and 13C n.m.r. spectra have beeR assigned for some 5-methyl-l9-nor~5~-cholest-9( 10)-enes (‘Westphalen’ s e r i e ~ ) ’for ~ the steroid alkaloids solasodine, solasonine, tomatine, and t~matidine,’~and for the oogoniols,26 which are shown to be 29-hydroxystigmastane derivatives (12) and not 26-hydroxystigmastanes as proposed originally.

The shifts in 13C n.m.r. spectra of glucopyranosides of chiral secondary alcohols, compared with those for the methyl glucosides and the parent alcohols, can be used to assign absolute configurations to the alcohol^.'^ The method is illustrated by data for a series of alcohols of steroid and triterpenoid type. It offers the advantage that examination of both enantiomers is unnecessary, but the practical difficulties in preparing reasonably pure glucopyranosides seem likely to limit its application to cases where simpler procedures fail to give decisive results. Spin-lattice relaxation times (”C) have been determined for k-strophanthoside (13).**The values of TI, averaged over ring carbons for each sugar unit, increase

CH,OH 0-CH, H O( $

OH

A. Pancrazi, I. KaborC, B. Delpech, A. Astier, Q. Khuong Huu, and G. Lukacs, Canad. J. Chem., 1977,55,2829. 24 J. M. Coxon, P. R. Hoskins, andT. K. Ridley, Austral. J. Chem., 1977, 30, 1735. 25 R. J. Weston, H. E. Gottlieb, E. W. Hagaman, and E. Wenkert, Austral. J. Chem., 1977, 30, 917. 26 T. C. McMorris, S. R. Schow, and G. R. Weihe, Tetrahedron Letters, 1978, 335. ” S. Seo, Y. Tomita, K. Tori, and Y. Yoshimura, J. Amer. Chem. SOC.,1978, 100,3331. 28 A. Neszmelyi, K. Tori, and G. Lukacs, J.C.S. Chem. Comm., 1977,613. 23

Tergenoids and Steroids

260

progressively the further the sugar is from the steroid nucleus (ca. 0.17,0.24, and 0.35 s, respectively, for the three monosaccharide units), offering a potentially useful sequencing procedure. The 21-methyl 'H signal appears at somewhat lower field for cholesterol (6 0.91 p.p.m.) than for 20-isocholesterol(S 0.81 ~ . p . m . ) .A ' ~previously suggested analogy with data for E- and 2-isomers of pregn-l7(20)-ene has been criticized on the basis that 20-methylcholesterol shows two signals in similar regions of the spectrum, implying different magnetic environments due to chirality about C-17. The earlier assumption of highly restricted rotation about the 17-20-bond in cholesterol derivatives is not supported by data for a 17P-tbutylandrostane, which gave a singlet resonance for the t-butyl protons. It seems probable that both the cholestane (20R) and isocholestane (20s) side-chains have a modest preference for the conformation (Figure) in which the bulky isohexyl group lies between C16and the 17a -hydrogen when viewed in projection along the 17-20 bond.29 H

Figure Preferred conformation of cholestane and 20-isocholestane side-chains

The selective formation of t-butyldimethylsilyl ethers, which is often possible with bifunctional steroids, facilitates n.m.r. study with the use of lanthanide shift reagents by blocking co-ordination at the derivatized po~ition.~' The assignment of configurations to substituents at both C-16 and C-17 by 'H n.m.r. can be unreliable unless all four isomers are available for c o m p a r i ~ o n .Data ~ ~ are presented for J , 6, 17 in 16,17-disubsti tu ted 3 -methoxyoes tra- 1,3,5( 10)-trienes, for chemical shifts of the 13P-methyl protons, and for C-17 protons in 17hydroxy-derivatives, including acylation shifts. Through-space coupling is significant between @-fluorine and 13Cat C-19 in two 6P-fluoroandrostane derivatives ( J = 9.2 Hz), where the C. * -F internuclear distance is only ca. 2.5 A.32

3 Chiroptical Phenomena of the c.d. ( n + T * ) of ketones shows that any strained carbon-carbon bonds of the molecular framework which are either a$-related to the carbonyl group or coupled to it through an extended periplanar zig-zag of bonds appear to make contributions to A& which are larger, in the consignate

A new empirical

29 30

31

32 33

E. N. Trachtenberg, C. Byon, and M. Gut, J. Amer. Chem. SOC.,1977,99,6145. H. Hosoda, K. Yamashita, S. Ikegawa, and T. Nambara, Chem. and Pharm. Bull. (Japan), 1977,25, 2545. B. Schoenecker, J. prakt. Chem., 1977, 319,419. H. L. Holland, Tetrahedron Letters, 1978, 881. D. N. Kirk, J.C.S. Perkin I, 1977, 2122.

Physical Methods

26 1

sense, than those of unstrained bonds in similar locations. Torsion angle ( w ) effects in the O=C-C,-R systems are expressed empirically as being proportional to sin2o.The new treatment rationalizes the enhanced Cotton effects of normal 6-0x0-steroids compared with their D-homo-analogues, and offers an interpretation of the c.d. characteristics of A-homo- and B-homo-0x0-steroids (cycloheptanone type) and pregnan-20-ones. Analysis of data for terpenoid ketones includes compounds of bicyclo[2,2,l]heptan-2-onetype (camphor etc.) and bicyclo[3,2,l]octan-6-ones (ketones of the kaurane, gibberellane, and related series); numerous other bridged bicyclo- and tricylo-alkanones are included in this first attempt to bring such diverse ketones within the scope of a single empirical but quantitative treatment.33 a-Axial deuterio-ketones (14) and (15) are among compounds in which a small but significant dissignate effect of deuterium relative to hydrogen has been d e m ~ n s t r a t e dCalculations .~~ (CND0/2) suggest that deuterium substitution o n a zig-zag coupling path should have a dissignate effect if deuterium is more electronegative than hydrogen, although C-H bond-shortening may also make some contribution. C.d. data reported for other a-, p-,35 and y-deuterioketones34are consistent with these findings for steroids.

The contribution of a 2a-bromo-substituent to the Cotton effect of a 4,4,6trimethyl-5-en-3-one (16)is only weakly negative, despite evidence from U.V. and n.m.r. data that ring A exists in a ‘twist’ conformation with bromine This system therefore constitutes an apparent exception to the ‘axial halogeno-ketone’ rule as originally stated, although the chiroptical behaviour is evidently complicated by the presence of py-unsaturation, the effect of which may well vary according to its precise orientation with respect to the carbonyl group. The orientation would be a function of the degree of ‘twist’ imposed upon ring A by the high degree of substitution. The c.d. of testosterone propionate aligned in a liquid-crystal matrix depends upon the direction of propagation of the light beam in relation to the molecular f r a m e w ~ r kThe . ~ ~data, including vibrational fine structure, are analysed in terms of two progressions with opposite-signed c.d. bands, either of which can be dominant depending upon the conditions of measurement.

W. L. Meyer, A . P. Lobo, E. E. Ernstbrunner, M. R. Giddings, and J. Hudec, Tetrahedron Letters, 1978,1771. C. Djerassi, C. L. Van Antwerp, and P. Sundararaman, Tetrahedron Letters, 1978, 535; P. Sundararaman and C. Djerassi, ibid., p. 2457; H. Numan and H. Wynberg, J. Org. Chem., 1978,43, 2232. J. S. E. Holker, W. R. Jones, M. G . R. Leeming, G. M. Holder, J. M. Midgley, J. E. Parkin, and W. B. Whalley, J.C.S. Perkin I, 1978, 253. H. G . Kuball, J. Altschuh, R. Kulbach, and A. Schonhofer, Helv. Chim. Acta, 1978,61, 571.

Terpenoids and Steroids

262

A new approach to the interpretation of chiroptical data for substituted benzene derivatives is based upon a simple polarization model. The pronounced effects of achiral substituents on c.d. data for steroids with an aromatic ring A are seen as the consequence of changes in directions of electric and magnetic moments, according to the substitution pattern on the aromatic ring.38Molecular rotation differences, and more significantly the circular dichroism induced in the spectrum of the 'lanthanide shift reagent' [Eu(fod),], have been used to assign configurations to a series of (24R)- and (24s)-compounds of 5P-cholestane24,25-diol type which accumulate abnormally in some patients with impaired bile acid A review of optical resolutions includes applications of 3P-acetoxyeti-5-enic acid as a resolving agent.39 4 Mass Spectrometry

G.1.c. and m.s. data are reported for some hydroxy-steroids protected as their t-butyldimethylsiyl, cyclotetramethyleneisopropylsilyl, or cyclotetramethylene t-butysilyl derivatives. These sterically crowded groups give derivatives which are more stable to t.1.c. and give better separations on g.1.c. than the corresponding trimethylsilyl derivative^.^' The ions [ M -But]+ or [ M - Pri]+are abundant in the mass spectra, and give useful indications of molecular The ease of elimination of a silyloxy-group is dependent on conformational and stereochemical features, and can be used to distinguish between epimers. An application is reported in the study of hydroxylated metabolites of 2a,3a-cyclopropano-5a androstan-17P-01, obtained from rabbits.42 On the other hand a comparison of g.1.c.-m.s. behaviour of fourteen differently substituted silyl derivatives (R'R2R3Si-) of hydroxy-steroids has shown t5at dimethylsilyl derivatives generally produce the most extensive fragmentation, with minimal appearance of [ M - R]' ions by loss of an alkyl group from the silyl function.43 The main fragmentation paths of cholesteryl acetate have been clairfied by the use of deuterium-labelled material^.^^ The mass spectrum differs in several respects from that of free cholesterol; the acetate fails to show a molecular ion peak, since acetic acid is lost very readily to give the largest fragment in the spectrum ( m / e 368, M' - 60) corresponding to a cholestadiene. Further fragmentations mainly involve loss of an angular methyl group (predominantly C-19), rupture of the unsaturated ring B, or, independently, scission of the 13-17-bond which is a point of weakness in most steroids. Mass spectra of deuterium-labelled A'- and A8('4)-~n~aturated 5a-steroids show loss of a fragment comprising the side-chains with C-15, -16, and -17 and a hydrogen atom which is drawn mainly from C-7. This with other evidence implies that the A'-steroid rearranges to a J. Sagiv, Tetrahedron, 1977, 33, 2315. B. Dayal, G. Salen, G. S . Tint, V. Toome, S . Shefer, and E. H. Mosbach, J. Lipid Res., 1978,19,187; B. Dayal, A. K. Batta, S. Shefer, G. S . Tint, G. Salen, a n d E . H. Mosbach, ibid.,p. 191;A. K. Batta,B. Dayal, G. S . Tint, S . Shefer, V. Toome, G. Salen, and E. H. Mosbach, Steroids, 1978, 31,99. 39 S . H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 1977, 33, 2725. 40 M. A. Quilliam and J. B. Westmore, Analyt. Chem., 1978,50, 59. " M. A. Quilliam and J. B. Westmore, Steroids, 1977,29, 579. 42 M. A. Quilliam, J. F. Templeton, and J. B. Westmore, Steroids, 1977, 29, 613. I 3 D. J. Harvey, J. Chromatog., 1978,147, 291. 44 L. G. Partridge and C. Djerassi, J. Org. Chem., 1977, 42, 2799.

Physical Methods

263

A8(’4)-01efini~structure, with 14a-H being transferred to C-7 before being abstracted by the C-17 radical (Scheme). Other details of this analysis account for a competing fragmentation which results in loss of the side-chain with only C-16 and C-17 attached, and distinguishes between fragmentations involving the C-18 and C-19 methyl groups.45

1 R

Scheme

G.1.c.-m.s. data are for a series of C1903(androstane) derivatives with oxygen substituents at either C-2, -6, -7, -11, or -16 in addition to those at C-3 and C-17. Field desorption mass spectra are reported for some saponins (kryptogenin 3- 0-P-D-glucopyranoside, dioscin, e t ~ . ) . ~Progress ’ is reported towards the computer-aided recognition of structural features of steroids from low-resolution mass s p e ~ t r a . ~ ~ ’ ~ ~

5 Miscellaneous Physical Properties The ‘Woodward-Fieser rules’ for predicting the wavelength of the lowest-energy T -+T * absorption band of an @unsaturated ketone have been subjected to a critical re-evaluation, with particular attention to the torsion angle between the C=O and C=C The remarkable reliability of the original ‘rules’, whether applied to s-cis- or s-trans-enones, seems to be due to a fortuitous cancellation of effects associated with conformation, provided that the system is not excessively twisted from planarity. Modified ‘rules’ are now presented in two forms. The simpler scheme, applicable (in ethanol) to planar or moderately twisted systems whether cyclic or acyclic, uses ‘parent’ values of 209nm for s-trans and 215 nm for s-cis, with alkyl shifts of +10 nm for a-substitution or 45 46

47

48 49

50

L. G. Partridge, I. Midgley, and C. Djerassi, J. Amer. Chem. Soc., 1977,99, 7686. A . Kerebel, R. F. Morfin, F. L. Berthou, D. Picart, L. G. Bardou, and H. H. Floch, J. Chromatog., 1977,140,229. H. R. Schulten, T. Komori, and T. Kawasaki, Tetrahedron, 1977, 33, 2595. H. Rotter and K. Varmuza, Analyt. Chim. Acta, 1977,9525. H. Rotter and K. Varmuza, Analyt. Chim. Acta, 1978, 103,61. T. Liljefors and N. L. Allinger, J. Amer. Chem. Soc., 1978, 100, 1068.

Terpenoids and Steroids

264

+12 nm for @-substitutionas previously, and a ‘ring closure’ correction of +7 nm if the double bond is endocyclic in a six-membered ring. A more complex scheme takes account of the enone torsion angle, and requires reference to figures in the original paper: it permits prediction of absorption maxima for both the lowestenergy (ca. 225-250 nm in steroids) and the higher-energy T + T* band (ca. 200-220 nm), which is forbidden for planar enones but becomes pronounced in twisted U.V. spectra in sulphuric acid have been used to determine substituent effects on the basicities of some 1,4-dien-3-ones,51 and fluorescence measurements in the same solvent have been used to estimate 4,6-dien-3-one metabolites of ‘spironolactone’ in serum.52 A review53 of the synthesis and chemistry of nitroxide spin labels includes a number of steroid derivatives. Novel spin-labelled steroids have been prepared by esterification with the nitroxyl carboxylic acid derivative ( 1 7 y 4for use in ‘spin immunoassays’ (SIA) as an alternative to radioactive labelling. The prednisolone ester (18),for example, exhibits an e.s.r. spectrum with narrow lines when it is in a free state in solution, but when bound to antibody the rate of tumbling is reduced, and linewidths are broad. Signals from bound and unbound derivatives are easily distinguished and measured, so SIA of antibody-bound prednisolone provides a potentially useful serum assay method.55

N

I

0-

Novel dinitroxide derivatives of ketones, of type (19),have been obtained from the corresponding imidazolidines (20) and offer prospects as spin labels.55

(19) R = 0 * (20) R = H 51

52

53 54

55

H. Kokocinska and R. I. Zalewski, Bull. Acad. polon. Sci., Ski. Sci. chim., 1977, 25, 915. P. Neubert and K. Koch, J. Pharm. Sci., 1977,66, 1131. J. F. W. Keana, Chem. Rev., 1978,78,37. W. R. Benson, M. Maienthal, G. C. Yang, E. B. Sheinin, and C . W. Chung, J. Medicin. Chem., 1977, 20, 1308. J. F. W. Keana, R. S. Norton, M. Morella, D. Van Engen, and J. Clardy, J. Amer. Chem. SOC., 1978, 100, 934.

265

Physical Methods

P-Sitosteryl esters of some dicarboxylic acidss6 and perfluoroalkanecarboxylates of c h o l e ~ t e r o 1are ~ ~ added to the range of steroids which form liquidcrystalline phases. Measurements of surface tension, viscosity, and electrode potential have been used to study the interactions and micelle formation between dodecyltrimethylammonium bromide and sodium deo~ycholate.~'Steroid aggregation and solubility in water have been examined by light-scattering measurements on the turbid mixtures obtained by diluting methanolic solutions with water.s9

6 Analytical Methods Immunoassay of Steroids.60-Radioimmunoassays (RIA) for steroid hormones and their major metabolites are proliferating very rapidly. The present selection refers mainly to those which have novel chemical features, generally in the type of linking groups used to bind the steroid covalently to protein. Antibodies for RIA of 3a-hydroxy-5a-androstan-17-one and of 5a-androstane-3a,l7P- and -3P,17P-diols were obtained by use of antigens [e.g. (21)] in which the steroid is linked at C-16 through sulphur to albumins.61The linking process comprises the introduction of thiol groups into the protein by reaction of S-acetylmercaptosuccinic anhydride with amino-groups of lysine, followed by deacetylation and nucleophilic reaction with the 16a-bromo-derivative of the steroid.

S-CH

I

co

* I

NH

HO-'

H

An effective antiserum for dehydroepiandrosterone 3-sulphate has been obtained by use of the 17-hydrazone as hapten, coupled to BSA.62 3a,5P'Tetrahydroaldosterone' (22), the main urinary metabolite of aldosterone, is efficiently bound by an antiserum induced by the conjugate of BSA with the 3-carboxymethyloxime of aldosterone 1 8 , 2 1 - d i a ~ e t a t eHaptens .~~ for RIA of cortisone and cortisol have been prepared by the introduction of 7a- and 7P-carboxymethyl substituents (23) through a malonic ester condensation with the 7-bromo-derivative (24).64 56

57

59

6o 61

62 63

64

M. V. Mukhina, P. S. Komarov, and A. S. Sopova, Zhur. obshchei Khim., 1977, 47, 1429. M. M. Murza, K. N. Bildinov, andM. S. Shcherbakova, Zhur. org. Khim., 1978, 14,544. I. Kellaway and C. Marriott, Canad. J. Pharm. Sci.,1977, 12, 70. C. H. Blomquist, C. E. Kotts, and E. Y. Hakanson, Analyr. Biochem., 1978,87,631. Ref. 9, 1977, Vol. 7, p. 309; 1978, Vol. 8, p. 224. J. Zamecnik, G. Barbe, W. H. Moger, and D. T. Armstrong, Steroids, 1977, 30, 679. M. Numazawa, Y. Sawade, and T. Nambara, Rinsho Kagaku, 1978,6, 131. A. Delassalle, F. Cesselin, A. Carayon, S. Legrand, J. Antreassian, A. Lagoguey, J. C. Legrand, and P. Desgrez, Steroids, 1977, 29, 725. D. Duval, R. Condom, and R. Emiliozzi, Compt. rend., 1977, 285, C, 281.

Terpenoids and Steroids

266

0 0

HO”

H

(22)

(23) R = CH2C02H (24) R = B r

Other new but conventional radioimmunoassays have involved oestra1 ’ 3 3(10)-triene-3,15a, 16a,170- tetrol (‘oestetrol’), as its 6-(O-carboxymet hyloximino)-derivative,6s the 16-carboxymethy loximino-derivative of androst-5-ene-30, 170-di01,~~ the 15-hemisuccinate of 15a-hydroxyt e s t o s t e r ~ n e ,some ~ ~ oestriol monoglucoside derivatives,68 the 6-carboxymethyloximino- and 3-hemisuccinate derivatives of the synthetic oestrogen 17a-ethynyIoestradi01,~~the 3-carboxymethyloximes of the contraceptive steroids ‘norethindrone’ and ‘ n o r g e ~ t r e l ’ ,and ~ ~ the pituitary gonadotropin inhibitor, the isoxazole derivative ‘Danazol’ (25), which was effectively bound by an antiserum for the corresponding 17-carboxymethyloxime (26).70

The convenience of using 1251 (a gamma-emitter) for RIA purposes, rather than 3H, is exploited in a new radioimmunoassay of progesterone, with progesterone 3-( 0-carboxymethyl)oximino[ ‘251]iodohistamine (27) as the radio-ligand.’l ’2sI-Iodinatedcholylhistamine is a useful radioactive conjugate for RIA of cholic acid, by competitive binding to antisera developed against the cholic acid-bovine serum albumin c ~ n j u g a t e . ~ ~ Enzyme immunoassay (EIA) is emerging as possibly an effective alternative to RIA, avoiding the use of radioactive isotopes. A steroid-enzyme complex (e.g. testosterone-gluc~amylase~~) competes with the free steroid for binding sites on K. D e n , H . Matsumoto, K. T. Fujii, K. Furuya,T. Yoshida, S. Takagi,A. Kanbegawa,andT. Kokubu, Steroids, 1977, 30, 521. 66 K. M. Pirke, Steroids, 1977, 30, 53. 67 T. Nambara, H. Hosoda, K. Tadano, K. Yamashita, and N. Chino, Chem. and Pharm. Bull (Japan), 1977, 25,2969. 68 T. Nambara, J. Goto, H. Furuyama, and H. Kato, Chem. and Pharm. Bull. (Japan), 1978,26,591. 69 N . Kundu, S. Kennan, and W. R. Slaunwhite, jun., Steroids, 1977, 30, 85. 70 T. A. Williams, J. Edelson, and R. W. Ross, jun., Steroids, 1978, 31, 205. 71 J. Z. Scott, F. Z . Stanczyk, U. Goebelsmann, and D. R. Mishell, jun., Steroids, 1978,31, 393. 7 2 P. B. Weinberg, J. M. Kinkade, jun., and D. C . Collins, Steroids, 1977, 30, 637. 73 K. Tateishi, H. Yamamoto, T. Ogihara, C . Hayashi, and M. Kitagawa, J. Biochem., 1976,80, 191. 65

Physical Methods

267

an antiserum for the steroid, and the bound enzyme is estimated by its chemical effect. In the example the glucose liberated from amylose by the enzyme is estimated fluorimetrically. The sensitivity claimed for EIA is comparable with that of RIA. An alternative EIA of testosterone uses a complex of testosterone with horseradish p e r ~ x i d a s e For . ~ ~ convenience in separating the bound testosterone-antibody from unbound steroid the antibody was first immobilized by linking it to microcrystalline cellulose. In this case the assay depends upon absorbance measurements at 490 nm, after allowing the bound peroxidasetestosterone to react with hydrogen peroxide-5-aminosalicylicacid. Fluorescein-labelled oestradiol has been used as a probe for anti-oestradiol antibody. The probe material was prepared by condensing the 6-carboxymethyloximino-derivative of oestradiol with ‘fluorescein amine’. It had a fluorescence emission spectrum similar to that of fluorescein, and permitted a sensitive immunoassay of o e ~ t r a d i o l .A ~ ~system suitable for spin-immunoassay of steroids, using nitroxides for spin-labelling, is described on p. 264. Chromatography.-Amberlite XAD-2 has found wide use in recent years for the absorption and concentration of polar steroids and steroid conjugates from aqueous media, with subsequent elution by an alcohol. Recoveries of steroid conjugates from some batches of resin are now reported to be very greatly improved by conversion on the column into their triethylammonium salts prior to Accurate g.1.c. analysis of mixtures of substances with a flame ionization detector (f.i.d.) depends upon a knowledge of the relative detector response of each compound. Variations in the f.i.d. responses of steroids in molar terms have now been put on a quantitative basis. There is a good linear relationship between molar f.i.d. response and the ‘effective carbon number’, which is the number of carbon atoms per molecule less half the number of oxygen atoms (over the ranges C18-C31, and O,--O,).’* This behaviour parallels earlier conclusions for paraffin hydrocarbons, alcohols, and esters. G.1.c. data are reported for the trimethylsilyl ethers of 49 plant sterols on eight different Correlations between t.1.c. and h.p.1.c. characteristics have been used to optimize conditions in preparative h.p.1.c. for the purification of reaction 74 75

”

77

’’ 79

K. Tateishi, H. Yamamoto, T. Ogihara, and C. Hayashi, Steroids, 1977, 30, 25. K. M. Rajkowski, N. Cittanova, P. Urios, and M. F. Jayle, Steroids, 1977, 30, 129. W. B. Dandliker, A. N. Hicks, S. A. Levison, and R. J. Brawn, Res. Comm. Chem. Pathol. and Pharmacol., 1977, 18, 147. H. L. Bradlow, Steroids, 1977, 30, 581. R. W. H. Edwards, J. Chromatog., 1978, 153, 1 . E. Homberg, J. Chromatog., 1977,139,77.

268

Terpenoids and Steroids

products.80 Free and conjugated bile acids are efficiently separated by reversedphase h.p.1.c. on a 'Zorbax ODs' column, with methanol-potassium phosphateacetic acid as the mobile phase." A procedure is described for the separation and estimation of androgen-oestrogen mixtures by h.p.l.c., with linked differential U.V. and refractometer detectors.82 Analytical methods for vitamin D assay have been compared between laboratories, and found to be in need of irnpro~ement.'~

82

83

S. Hara, J. Chromatog., 1977, 137, 41. D. Baylocq, A. Guffroy, F. Pellerin, and J. P. Ferrier, Compt. rend., 1978, 286, C, 71. P. G. Satyaswaroop, E. Lopez de la Osa, and E. Gurpide, Steroids, 1977, 30, 139. F. J. Mulder and E. J. de Vries, J. Assoc. Ofic. Analyt. Chemists, 1978,61, 122.

Steroid Reactions and Partial Syntheses BY B. A. MARPLES

Section A: Steroid Reactions

1 Alcohols and their Derivatives, Halides, and Epoxides Substitution, Solvolysis, and Elimination.-An improved synthesis of 2 1-fluoroprogesterone (also "F-labelled) employed the treatment of the 2 1-mesyloxycompound with KF in acetonitrile containing 18-crown-6.' The influence of neighbouring groups at C-20 on the reactivity of 18-iodopregnanes has been studied.2Simple nucleophilic substitution may be achieved (e.g. NaN3-HMPA) in (20R)-3P-acetoxy- 18-iodo-5a -pregnan-20-01 provided the 20-hydroxy-group is acetylated, thereby preventing the formation of the 18,20-epoxide. The Baeyer-Villiger oxidation (with CF3C03H)of 3P-acetoxy- 18-iodo-5a-pregnan20-one gave the lactone (2) and isomeric acetates (3) and (4)owing to the intermediacy of (1) which resulted from the intramolecular displacement of iodide ion in the initially formed peracid-ketone adduct. Unimolecular solvolyses of 30- and 3a-trifluoroacetoxycholest-4-enesgave different mixtures of 3substituted-A4- and 5-substituted-A3-products, implying the intervention of the two conformationally distinct allylic carbocations (5) and (6) re~pectively.~

H

(3) R' = H , R * = A C (4) R' = AC,R~ = H

6:::::; -

- -,+

H

L. A. Spitznagle and C. A. Marino, Steroids, 1977, 30, 435. P. Choay, C. Monneret, and Q . Khuong-Huu, Tetrahedron, 1978,34, 1529. G. Ortar, M. P. Paradisi, E. Morera, and A. Romeo, J.C.S. Perkin I, 1978, 5.

269

Terpenoids and Steroids

270

These observations contrast with those of Shoppee and co-workers in a study of the epimeric 3-chloro-A4-compounds which were believed to solvolyse via a single allylic carbocation. A re-examination of the solvolysis of the chlorocompounds appeared to confirm the intermediacy of two carbocations since the product ratios were very similar to those from the trifluoroacetates. Treatment of the trifluoroacetates with NaN3-HMPA resulted in substitution at C-3 with inversion of configuration. Reaction of the 17~-trifluoroacetoxy-l7a-vinyl compounds (7) and (8) under similar conditions gave the E-17(20)-dehydro-21azido-compounds (9).4 These reactions are not regarded as pure SN2’processes since the compounds (7) and (8) may rearrange to compounds (10) in HMPA. Solvolysis of compounds (7) and (8)in MeOH-NaOAc gave product distributions OCOCF,

OCOCF,

Me0

AcO

H-CH,R

(9) R = N 3 (10) R = OCOCF3

expected for competing SN1and BAc2 mechanism^.^ Treatment of 3-hydroxysteroids, including cholesterol, with Bu;P-N-arylthio-succinimides cleanly gave the 3-arylthio-ethers with inversion at C-3.5 Selective removal of bromine from 3P,5,6P-tribromo-5a-cholestane to give 3P-bromocholest-5-ene was achieved by reaction with [~-CsHsCr(N02)2],.6 The reactions of 11P-hydroxy-steroids with dialkylaminosulphur trifluorides depend on the substitution at C-9’ and involve the formation of intermediate (11) (Scheme 1) (see ref. 232). Selective dehydration with FeCl, adsorbed on silica gel allowed the conversion of 5a-cholestane-3P75-diol into cholesterol (80%) and 3~-acetoxy-5a-cholestane-5,25-diol into 3~-acetoxycholest-5-en-25-ol (72y0).~Other examples and additionally the hydrolysis of 5,6a-epoxy-5acholestan-3/3-01 to the 3P,5a76P-triol (90’/0) were reported. Chromatographic alumina is reported to effect smooth elimination of sulphonic acids from the esters with less than normal rearrangement.’ Thus lanosteryl tosylate and cycloartenyl tosylate gave the respective A2-compounds in yields of 90% and 45% respecG. Ortar, E. Morera, and A. Romeo, J. Org. Chem., 1978,43, 2927. K. A. M. Walker, Tetrahedron Letters, 1977, 4475. B. W. S. Kolthammer, P. Legzdins, and D. T. Martin, Tetrahedron Letters, 1978, 323. M. Biollaz and J. Kalvoda, Helv. Chim. Acta, 1977, 60, 2703. E. Keinan and Y. Mazur, J. Org. Chem., 1978,43, 1020. G . H. Posner, G. M. Gurria, and K. A. Babiak, J. Org. Chem., 1977,42, 3173.

Steroid Reactions and Partial Syntheses

27 1

F

Scheme 1

tively. The latter was accompanied by a similar quantity of an A-nor-compound. Similar treatment of methyl 3a,7a-diacetoxy-12a-mesyloxy-5~-cholanoate gave the corresponding A"-compound (78%). A review on the general use of chromatographic alumina includes similar results in addition to its use in the dehydration of alcohols.10 Oxidation and Reduction.-Silver carbonate on celite is reported to be a selective oxidizing agent for the bile acids, allowing the oxidation of the 3-hydroxygroup.'' Chromic acid on silica gel is reported to be an efficient oxidizing agent for primary and secondary hydroxy-groups, the major advantage being in the ease of work-up.'* The use of this reagent, with only one steroidal example however (5a-cholestan-3&01), is reported. Treatment of steroidal alcohols sequentially with t-butoxymagnesium bromide and 1,l'-(azodicarbony1)dipiperidinegave the ketones in good yield.I3 The 3,5-dimethylpyrazole-Cr03complex is reported to oxidize 5a -hydroxy-A6-cholestenes to the 7-0x0-As-compounds very rapidly and ~1eanly.l~ In contrast the equivalent 5~-hydroxy-compoundwas oxidized much more slowly and the intermediates (12) and (13) are implicated (Scheme 2). The latter intermediate is thought to be formed via an equivalent Cr'" species in the direct allylic oxidation of the As-compounds. Prolonged treatment of androsta4,6-dien-3-one with LiAiH4 in refluxing tetrahydrofuran gave androst-5-en-3P01 and 5a-androst-6-en-3P-01." Use of LiAlD4 established that intramolecular hydride transfer to C-4 occurs in the aluminium alkoxide (14) followed by lo

G. H. Posner, Angew. Chem. Internat. Edn., 1978, 17,487.

K.-Y.Tserng, J. Lipid Res., 1978,19, 501. l2

l3

l4 l5

E. Santaniello, F. Ponti, and A. Manzocchi, Synthesis, 1978, 534. K. Narasaka, A. Morikawa, K. Saigo, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1977,50,2773. W . G. Salmond, M. A. Barta, and J. L. Havens, J. Org. Chem., 1978,43,2057. M. Fetizon, H. T. Huy, and P. Mourgues, Tetrahedron, 1978,34,209.

Terpenoids and Steroids

272

\ Scheme 2

protonation of the allyl-lithium (15) at C-5 or C-7. Protonation at C-7 is non-stereospecific and the a-protonation at C-5 occurs owing to the product being thermodynamically favoured. Deoxygenation of epoxides, particularly a$-epoxy-ketones, using [Fe(C0)5]16has been reported and is exemplified by the conversion of the epoxy-ketone (16) into the enone (17).

Epoxide Formation and Ring Opening.-Treatment of 2a,3a-epoxy-5a-cholestane with PhSeH in the presence of chromatographic alumina gave the 2pphenylselenyl-3 a-hydroxy-derivative. l7 This reaction was the only steroidal example in a series of alumina-catalysed epoxide openings with a variety of reagents. Treatment of the 4~,5~-epoxy-3-oxo-compounds (18)-(20) with HF-pyridine at -55 "C gave the corresponding 4-hydroxy-A4-3-0x0compounds (22).'* At -75 "C the major products were the 3-oxo-Sa-fluoro-4ahydroxy-compounds (21) which are thought to be formed by epimerization of the l6

l7 l8

H. Alper and D. Des Roches, Tetrahedron Letters, 1977, 4155. G. H. Posner and D. Z. Rogers, J. Amer. Chem. SOC.,1977,99, 8208. B. H. Jennings and J. M. Bengtson, Steroids, 1978, 31, 49.

Steroid Reactions and Partial Syntheses

273

normal diaxial fluorohydrins. It is suggested that the dehydrofluorination proceeds by a transfer of hydride ion from C-4 to C-5 as indicated (Scheme 3).

QJp+O&‘-O&

0

0

(18) R = O (19) R = P-OH,H (20) R = P-OAc,H

6 ,.9

0 ,H

H

(21)

J

@

0

OH

(22) Scheme 3

Conversion of the 3~-acetoxy-5~,6~-epoxy-7~-hydroxyandrostane (23)into the 3P-mesyloxyandrost-5-en-7-one (24)in high, yield occurred on treatment with MeS02C1-S02(5O/O )-collidine in DMF.I9 The proposed mechanism of this transformation is shown in Scheme 4.The studies on the influence of neighbouring hydroxy- and acetoxy-groups on the reactions of epoxides with HBr have been extended.20*21 In addition, NaBH,-MeOH reactions of the epoxycholestanes (25)-(3 1) have been investigated.*’ In general, trans-a,& and -&y-epoxyalcohols were cleaved to give methoxyhydrins whereas the corresponding cis-derivatives were unreactive. For example, the trans-hydroxy-epoxide (26) reacted via the boron complex (32)to give la,3P-dihydroxy-2&methoxy-5acholestane (33)whereas the cis-hydroxy-epoxide (27)was unreactive. The trans-hydroxy-epoxide (29)was exceptional in that it did not react owing to its inability to achieve a similar conformation to (32)in which the attacking OMe and the breaking C - 0 bond of the epoxide are quasidiaxial.

Ethers, Esters, and Related Derivatives of Alcohols.-5a-Cholestanyl methyl ether has been cleaved (inter alia) and converted into 50-cholestanol by successive treatment with trimethylsilyl iodide and ~ a t e r . ’Pyridinium ~ toluene-psulphonate has been reported as an efficient and mild catalyst for the conversion of alcohols into their tetrahydropyranyl Bile acids were efficiently performylated by treatment with 90% HCO’H-HClO,. Selective base-catalysed l9 2o

21 22

23 24

J. R. Hanson, A. W. Johnson, and M. A. C. Kaplan, J.C.S. Perkin I, 1978, 263. See ‘Terpenoids and Steroids’, ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1977, Vol. 7, p. 239. E. Glotter and P. Krinsky, J.C.S. Perkin I, 1978, 413. M. Weissenberg, P. Krinsky, and E. Glotter, J.C.S. Perkin I, 1978, 565. M. E. JungandM. A. Lyster, J. Org. Chem., 1977, 42, 3761. M. Miyashita, A. Yoshikoshi, and P. A. Grieco, J. Org. Chem., 1977, 42, 3773.

Terpenoids and Steroids

274

0

I

OH

Me

4$

(23)

0

1

not concerted

Scheme 4

H

O

Y

(25) (26) l a , 2a, 3/3, 5a (27) l a , 2a, 3 a , 5a

LfY

0

H

OH

0

Steroid Reactions and Partial Syntheses

275

hydrolysis of the 3-formyloxy-group was possible with a number of reagent^.^' Esters of 17a-ethynyl-19-nortestosteronewere prepared by reaction with thallous ethoxide followed by reaction with acid chloride.26The pivalate of 17aethynyl-19-nortestosterone was available via successive reaction of the acetal (34) with Bu”Li, pivaloyl chloride in THF, and aqueous acid.27Syntheses of 0-cholesteryl and 0-5a-cholestanyl selenoformates and selenoacetates have been reported.28 OH

2 Unsaturated Compounds

Electrophilic Addition.-The use of electrophilic fluorinating agents has been re~iewed.~’ A review on organoselenium chemistry includes data on the addition of PhSeBr to steroidal 01efins.~’ An improved procedure for chlorosulphenylation was exemplified by treatment of 5a-cholest-2-ene with thiophenol a:id N-chlorosuccinimide. The resultant adduct (35) was readily converted into the unsaturated aryl sulphone (36).31 Bromine fluoride is conveniently

(35)

(36)

generated from NBA-FClCHCF2NEt2 and its reactions with A’”’- and Assteroids have been reported.32 The reactions of 19-hydroxy-, lO-carboxy-19nor-, and 19-methoxy-5a-cholest-2-enesand 19-hydroxy- and 19-methoxycholest-5-enes with HOBr (from NBA) and 12-AgOAc (Woodward conditions) have been The common feature in all of these reactions was participation by the 19-oxygen. Thus, for example, with HOBr compounds (37) and (38) gave the 3a-bromo-2&19-epoxide (40) and the carboxylic acid (39) gave the 3a-bromo-lactone (41). Participation of the 19-OMe at C-6 in the reactions of the As-compounds with HOBr was slightly less efficient than that at ”

’’ ** 29

30

32 33 34

K.-Y. Tserng and P. D. Klein, Steroids, 1977, 29, 635. J. E. Herz, S. Cruz M., J. V. Torres, and A. Murillo, Synth. Comm., 1977, 7 , 383. J. E. Herz, S. Cruz M., and A. Murillo, Steroids, 1977, 30, 111. D. H. R. Barton, P.-E. Hansen, and K. Picker, J.C.S. Perkin I, 1977, 1723. D. H. R. Barton, PureAppl. Chem., 1977,49, 1241. D. L. J. Clive, Tetrahedron, 1978, 34, 1049. P. B. Hopkins and P. L. Fuchs, J. Org. Chem., 1978,43, 1208. R. MiEkovP, J. Moural, and V. Schwarz, Tetrahedron Letters, 1977, 1315. P. KoEovskL and V. eernq, Coll. Czech. Chem. Comm., 1978,43,327. P. KoEovskjr and V. CernL, Coll. Czech. Chem. Comm., 1978,43,1924.

276

Terpenoids and Steroids

Rr'

I .

H

(37) R' (38) R' (39) R'

H

= H,

R2 = H2 = Me, R2= H2 = H, R* = o

(40) R = H 2 (41) R = O

C-2 in the equivalent A2-compounds. Under Woodward cis-hydroxylation conditions the compounds (37) and (38) gave the 3a-acetoxy-2@,19-epoxide(44) via the 3a-iodo-2P,19-epoxide (42). The retention of configuration at C-3 implies participation of the epoxide oxygen as indicated in (43) (Scheme 5 ) . The

I

AcO

(44)

(43)

(42)

Scheme 5

studies of the neighbouring-group effects on HBr opening of hydroxy- and acetoxy-epoxycholestanes20.21were complemented by a of HOBr additions to the 1-hydroxy- or l-acetoxy-5a-cholest-2-enes(45) and the isomeric A'-compounds (46). The former mainly gave 2a,3a-bromonium ions from which

(45)

(46)

the products were derived by attack at C-3 (diequatorial opening-slightly favoured electronically) while the latter gave 1a,2a-bromonium ions from which the products were derived by attack at C-2 (diaxial opening-favoured sterically). Iodine triacetate, generated from IC13-AgOAc, reacted with 5a-androst-2-ene to give the 2~-acetoxy-3a-iodo-compound in moderate yield ( 5 1O/O).,~ Reaction of 5 a -androst-2-ene with ICl,-AcOH gave a mixture of chloroacetoxy-, chloroReaction between IC1-NaN, and 3iodo-, and dichlor0-5a-androstanes.~~ methyl-5a-androst-2-ene (47) in CH2C12gave the cis-iodoazide (49) as a major product accompanied by the minor trans-product (50) and trans-diaxial p r o d u ~ t s . ~The ' cis-iodoazide (49) and the trans-isomer (50) are thought to be 35 36 37

E. Glotter and P. Krinsky, J.C.S.Perkin I, 1978,408. R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1977,2231. R. C. Cambie, P. S. Rutledge, T. Smith-Palmer, and P. D. Woodgate, J.C.S. Perkin I, 1977, 2250.

Steroid Reactions and Partial Syntheses

277

derived from attack of the azide ion on the carbocation (48)while the transdiaxial products are formed by the normal diaxial opening of a - or P-iodonium ions. In acetonitrile the major product was the A-nor-iodoazide (52) formed via the 2a,3a-iodonium ion (5 1)(Scheme 6). The reaction of 3-methyl-5a-androst2-ene (47)with thallium(1) azide and iodine, with and without the use of 18crown-6, was also reported as was the reaction of 3-methylene-5a-androstane

n

Scheme 6

with iodine(1) a ~ i d eFurther . ~ ~ studies on the mechanisms of electrophilic attack3* confirmed that cholest-5-en-3-one was more readily halogenated on the p-face than 3-substituted cholest-5-enes when intermediate halogenium ions were involved.394' Stabilization of the p -halogenonium ion in the boat conformation (53) is believed to be largely responsible for this difference since such a con-

(53)

formation is not readily available in the 3-substituted cornpo~nds.~' In those cases where an A d E 3mechanism operated (BrCl-C1-) no significant difference in the stereochemical course was observed for cholest-5-en-3-one uersus the 3-substituted-As-compounds owing to a more sterically demanding transition state, and accordingly the much preferred a-attack was observed. Peracid oxidation of both cholest-5-en-3-one and 3-substituted-As-compounds resulted in similar proportions of a to p attack (ca.2 : 1).A relatively less sterically hindered unsymmetrical 38

39 40 41

See 'Terpenoids and Steroids', ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 8, p. 235. P. B. D. de la Mare and R. D. Wilson, J.C.S. Perkin 11, 1977, 2048. P. B. D. de la Mare and R. D. Wilson, J.C.S. Perkin 11, 1977, 2055. P. B. D. de la Mare and R. D. Wilson, J.C.S. Perkin II, 1977, 2062.

Terpenoids and Steroids

278

transition state (54) may be involved in which interaction with the 100-methyl becomes less important. Other work has shown that a 0-carbonyl group may

(54)

profoundly affect the stereochemistry of epoxidation of certain steroidal and triterpenoid 01efins,~*resulting in greater than normal attack from the more hindered face. Interaction of the carbonyl dipole with the transition state of epoxidation is believed to be an important factor. A study of the stereochemistry of epoxidation of A’-compounds with p-methoxycarbonylperbenzoic acid has been reported.43Further on the stereochemistry of the addition of HN3 to A 1 4 - ~ ~ m p indicated ~ ~ n d ~a dependence on the configuration at C-17 in the case of 20-acetoxypregn-14-enes (see ref. 247). Hydration of 17-ethynylcompounds with Hg(OA~)~-cation-exchange resin (DOWEX 50) in aqueous methanol gave the corresponding pregnan-20-0nes.~~ Hydration of the diacety.~~ lene adducts (55) and (56) gave the ketones (57) and (58) r e ~ p e c t i v e l yReduction of (57) gave the spiro-compound (59).

Other Addition Reactions.-A review on the applications of retro-Diels-Alder reactions has appea~ed.~’Reformation of the steroidal 5,7-dienes from the 4-phenyl- 1,2,4-triazoline-3,5-dioneadducts was achieved by heating with K2CO3 in DMSO or DMF.48 This provides a very useful alternative to the previously reported LiAlH4 cleavage. A cation-radical mechanism was proposed 42 43

44 45 46

47 48

Z. Paryzek, J.C.S. Perkin I, 1978, 329, G. S. Bylina, U. M. Dzhemilev, N. S. Vostrikov, G . A. Tolstikov, A. M. Moiseenkov, A. V. Ser. khim., 1978,447. Semenovskii, and S. S. Shavanov, Izvest. Akad. Nauk S.S.S.R., A. Astier, Q. Khuong-Huu, and A. Pancrazi, Tetrahedron, 1978, 34, 1481. 0. I. Federova and G. S. Grinenko, Khim. Farm. Zhur., 1978,12, 112. T. N. Romashina, I. A. Savost’yana, V. A. Rudenko, M. S. Burmistrova, G. M. Segal, and I. V. Torgov, Tezisy Dok1.-Vses. Konf. khim. Atsetilena, 5th 1975, 84 (Chem. Abs., 89, 43 919m). J. L. Ripoll, A. Rouessac, and F. Rouessac, Tetrahedron, 1978, 34, 19. M. Tada and A. Oikawa, J.C.S. Chem. Comm., 1978,727.

Steroid Reactions and Partial Syntheses

279

for the Lewis acid-catalysed reaction of triplet oxygen with ergosteryl and singlet oxygen was shown not to be involved. A study of nitrile oxide addition to methylene steroids was rep~rted,~’ and is exemplified by the conversion of the 3-methyleneandrostane (60) into the spiroisoxazolines (61) and (62). Similarly, the 17-methyleneandrostane (63) was converted into the spiroisoxazoline (64).

Other Reactions of Unsaturated Steroids.-A review on organopalladium intermediates includes several steroidal example^.'^ A mechanistic study of the formation of the w-ally1 palladium complex (65) from the corresponding 3oxocholest-4-ene led to the conclusion that initial 7.r-complexing was rate limitir~g.~’ Reactions of a series of similar 7.r-ally1palladium complexes (66)-(68) with dialkyl malonate ion gave the 3-oxo-A4-6p-ylmalonates (69)-(71) respecR

‘h

PdC1/2 (66) R = P-CgH17, H (67) R = &OH, H (68) R = P-COMe, H

(69) R = P-CgH17, H (70) R = &OH, H (71) R = P-COMe, H

ti~ely.~’ Ergocalciferol was converted into the 7.r-ally1palladium complex (72) with bis(benzonitri1e)palladiumdichloride while ergosterol and epiergosterol gave the 7.r-ally1 palladium complex (73).54 7-Dehydrocholesterol gave the analogue of (73). 49 50

” 52

53 54

R. K. Haynes, Austral. J. Chem., 1978,31, 121. C. Parini, S. Colombi, A. Ius, R. h u g h i , and G. Vecchio, Guzretta, 1977, 107, 559. B. M. Trost, Tetrahedron, 1977,33,2615. K. Henderson and F. J. McQuillin, J.C.S. Chem. Comm., 1978, 15. D. J. Collins, W. R. Jackson, and R. N. Timms, Austral. J. Chem., 1977,30, 2167. D. H. R. Barton and H. Patin, J.C.S. Chem. Comm., 1977, 799.

Terpenoids and Steroids

280

(72)

(73)

Selenium dioxide oxidation of cholecalciferol afforded a mixture from which the l a - and ID-hydroxycholecalciferols were is~lated.’~ Autoxidation of pseudodiosgenin diacetate (74) gave the alcohol (75) from which the lactone (76)

(75)

(76)

Thermal degradation of mestranol and could be obtained by further ethynyloestradiol in the presence of air led to the 6-hydroxy-, 6-0xo-, and A 6 - ~ ~ m p ~ ~ nThe d ~ mechanism .57 of the colour reaction of cholesterol with trichloroacetic acid and SbCl, was shown to involve cation radical^.^' Aromatic Compounds.-A study of the mechanism of the chromic oxidation of the methoxyoestratriene (77) to the ketol (78), using the 9a -deuterio-analogue,

M eO

Me0

(77)

(78)

B. Pelc, Steroids, 1977, 30, 193. G.G. Malanina, L. I. Klimova, L. M. Morozovskaya, 0. S. Anisimova, A . G. Arsent’ev, and G. S. Grinenko, Khim. Farm. Zhur., 1978, 12, 101. ’’ M. L. Potter, S. D. Levine, R. Mallory, and C. Shaw, Tetrahedron Letters, 1978, 1939. 58 Y. Kurasawa, A. Takada, and T. Ueda, Steroids, 1978, 31, 163. 55 56

Steroid Reactions and Partial Syntheses

28 1

suggested that the 9p,1lp-epoxide and the 12-0x0-9a-compound are the likely intermediate^.^' Direct oxidation at C-9 leading to the 9i$-hydroxy-compound, the A 9 ( 1 1 ) - ~ ~ m pand ~ ~ the n d ,9a,1la-epoxide had previously been suggested as a possible sequence. Reaction of the pregnatetraene (79) with NBS-CC1,-azobisisobutyronitrile gave a mixture of the five compounds (80)-(84) which were

Me O

M eO

Br

Br

(81) R=HZ (82) R = OMe, Br

Me0

Br

Br

(83)

(84)

separated by chromatography and crystallization from The DDQ ) for oxidation of neoergosteryl acetate (85)was shown to be quicker (CQ. 2 0 ~than the oestratriene (86).61It was concluded from a study of de-A-oestratrienes that relief of C/D ring junction strain was unimportant even though earlier work had suggested that this may be a contributory factor in the ease of oxidation of B-ring aromatic compounds. The long-known but ambiguously characterized second Diels Hydrocarbon from cholesterol has been identified as compound (87).62 59

6o

62

P. Aclinou, B. Gastambide, D Deruaz, Y. Desage, and R. Guilluy, Tetrahedron, 1978,34, 393. J. Zjawiony and H. Zajac, Tetrahedron Letters, 1978, 639. D. R. Brown and A. B. Turner, J.C.S. Perkin II, 1978, 165. D . Nasipuri, P. K. Bhattacharya, and D . N. Roy, J.C.S. Perkin I, 1977, 1814.

Terpenoids and Steroids

282

OH

3 Carbonyl Compounds Reduction.-A detailed study of the reductions of 12-0x0-steroidswith Li-NH3MeOH and with NaBH4has been The reductions of compounds (88), (89), and (90) were compared with those reported earlier for the compounds (91) and (92). Under kinetic conditions of Li-NH3-MeOH reduction, the compounds (88), (89), and (91) all gave 71-75% of the 12a-hydroxy-compounds whereas compounds (90) and (92) gave the 12P-hydroxy-compounds in 89% and 84% yield respectively. These differences were attributed to the shielding of the 6-face by the 20-methyl group in compounds (88), (89), and (91) thereby leading to rapid equatorial protonation of the slowly formed carbanion. Such shielding is absent in the compounds (90) and (92). The sodium borohydride reactions were similar in that the cholanones (88), (89), and (91) gave the 12a-hydroxycompounds in 72-77% yield whereas the pregnanones (90) and (92) gave the

(88) R ' = H , R 2 = E t (89) R' = H, R2 = Me (90) R ' = R ~ = H (91) R' = H, R2 = Pr" (92) R' = OH, R2 = H

12P-hydroxy-compounds in 84% and 54% yield respectively. Normal conformational arguments do not satisfactorily explain the NaBH4 results but they may be rationalized by assuming that the transition state is as suggested by Wigfield and co-workers. Clemmensen reduction of the y-hydroxy-ketones (93) 63

J. W. Huffman and D. J. Copley, J. Org. Chem., 1977,42,3811.

283

Steroid Reactions and Partial Syntheses

and (94; 7 1O h 5 R ) gave the saturated alcohols with no inversion at the hydroxylbearing carbon atoms.64The latter gave a number of additional products. It is suggested that the y-hydroxy-group participates in the reaction giving rise to the intermediate hemiacetals (95) rather than the previously proposed intermediates (96) which require transfer of the carbonyl oxygen to the y-position. The Reporter suggests that the intermediate corresponding to (95) in the steroid case would be rather strained owing to the requirement of the A-ring to adopt a skew-boat conformation. Accordingly the reduction of the steroid (93) may proceed via a different mechanism from that proposed for the compound (94). A

(93)

(94)

(95)

(96)

re-examination of the steric course of NaBH, reduction of o,P-epoxy-ketones has been rep~rted.~’ The direction of attack was rationalized in terms of the reactions of the unsubstituted ketones and the steric hindrance exerted by the epoxide ring. Huang-Minlon reduction of the 3a,5a-cycloergost-7-en-6-one (97) gave the 14@-A8-compound(98).66A study6’ of the stereochemistry of the reductions of the 3,6-cyclo-~-nor-3,5-seco-6~-cholestanes (99) and (100) has appeared (see ref. 253).

0

(97)

Other Reactions.-Addition of lithium P-lithiopropionate to androstenolone leads to the synthesis of the spirolactone (101).68Reaction of the lactone (102) 64

” 66 67

68

B. R. Davis, G. W. Rewcastle, R. J. Stevenson, and P. D. Woodgate, J.C.S. Perkin I, 1977,2148. M. Weissenberg and E. Glotter, J.C.S. Perkin I, 1978, 568. E.-J. Brunke, Chem. Ber., 1978,111, 3015. A. Kasal, Coll. Czech. Chem. Comm., 1978, 43,498. D. Caine and A. S. Frobese, Tetrahedron Letters, 1978, 883.

284

Terpenoids and Steroids

with PhMgBr gave mainly the dihydropyran (103) whereas the major product with p-MeOC6H4MgBr was the tetrahydropyran (105).69The latter was accompanied by the dihydropyran (104) and the hydroxy-olefin (106). It is suggested that the electron-releasing properties of the methoxy-group are important in promoting breakdown of the intermediate (107) to the carbonyl compound which could react further in the expected manner.

R

Me0 (103) R = H

Me0

OMe

p

(104)

R = OMe

(105)

-0-

Me0

\

&\ ‘

OMgBr

OMe

(107)

(106)

Further studies on the stereochemistry of Grignard addition to 20-0x0-steroids have been Rotational isomerism around the C- 17-C-20 bond highly favours the above D-ring conformation (108) for pregnenolone with the

(108) 69

70 71

S. S. Dehal, B. A. Marples, and. R. J. Stretton, Tetrahedron Letters, 1978, 2183. See ref. 38, p. 270. T. Makino, K. Shibata, D . C. Rohrer, and Y. Osawa, J. Org. Chem., 1978, 43, 276.

Steroid Reactions and Partial Syntheses

285

result that the favoured product is 20s. This result contradicts the earlier o b s e r ~ a t i o nthat ~ ~ pregnenolone exists as cis- and trans-conformers in equilibrium (6 :4). A one-step conversion73 of the aldehyde (109) into the methyl ester (110) using MeOH-KOH-03 at -78 "C and selective ethylenethioa~etalization~~

(109)

(1 10)

of the 3-0x0-group of progesterone and androst-4-ene-3,17-dioneusing Me3SiSCH2CH2SSiMe3-Zn12have been reported. Wet silica gel was a useful selective reagent for the cleavage of acetals of ( ~ , p - e n o n e sRegeneration .~~ of 5a -cholestan-3-one from the ethylenethioacetal with benzeneseleninic anhydride has been and thiocarbonyl compounds (xanthates, thioesters, thiocarbonates, and thioamides) were convefted into the carbonyl compounds using this versatile reagent.77 Reactions involving Enols or Enolic Derivatives.-A review of the structure and reactivity of alkali-metal en01ates~~ includes some steroidal reactions. A study of the mechanism of isomerization of androst-5-en-17P-ol-3-one to testosterone indicated that the acid-catalysed process proceeds through rate-determining enolization whereas the base-catalysed reaction proceeds through rate-determining protonation of an enolate Bromination of the 4,4,6-trimethyl-As-30x0-compounds (111)-( 113) gave the 2a-bromo-derivatives, each of which showed anomalous 0.r.d. curves.8o Bromination at C-2 was favoured for the

(111) R ' = H , R * = O H (112) R ' = M ~ ,R ~ = O H (113) R1=Me, R2=C8Hl7 72

73 74

75

76 77 78 79

W. R. Nes and T. E. Varkey, J. Org. Chem., 1976 41,1652. P. Sundararaman, E. C. Walker, and C. Djerassi, Tetrahedron Letters, 1978, 1627. D. A. Evans, L. K. Truesdale, K. G. Grimm, and S. L. Nesbitt, J. Amer. Chem. SOC.,1977,99,5009. F. Huet, A. Lechevallier, M. Pellet, and J. M. Conia, Synthesis, 1978, 63. D. H. R. Barton, N. J. Cussans, and S. V. Ley, J.C.S. Chem. Comm., 1977,751. D. H. R. Barton, N. J. Cussans, and S. V. Ley, J.C.S. Chem. Comm., 1978, 393. L. M. Jackman and B. C. Lange, Tetrahedron, 1977,33,2737. T. Okuyama, A. Kitada, andT. Fueno, Bull. Chem. SOC. Japan, 1977,50, 2358. J. S.E. Holker, W. R. Jones, M. G. R. Leeming, G. M. Holder, J. M. Midgley, J. E. Parkin, and W. B. Whalley, J.C.S. Perkin I, 1978, 253.

Terpenoids and Steroids

286

9~-methyl-lOa-compounds(1 14) and was discussed in terms of long-range conformational transmission.81 The 3a-alkyl-5/3-cholestar1-2-ones (1 15) were brominated at the 3P-position in contrast to the parent ketone.82 OAc

(114)

(115) R = M e , Et,orPr"

3-Trimethylsilyloxycholesta-2,4-diene(116) was converted by successive treatment with MCPBA and Et3NHF-Ac,O into the 2-acetoxy-A'-3-oxocompounds (117). Similar treatment with MCPBA and Et3NHF-CH2C12 gave the hydroxy-compounds (118).83 The chromous chloride-promoted addition of EtOCONHCl to the enol ether (119)gave the 17a-chloro-compound (120) by a free-radical me~hanism.~' Hydrolysis of the adduct (120) gave the 17-chloro-17formyl compound (121). A full account of the cyclopropanation of the enol

(117) R = A c (118) R = H

derivatives (122) has been reported.85 Treatment of cholest-4-en-3-one with Et2A1CN followed by Mc,SiCl-pyridine gave the 5~-cyano-trimethylsilylerris1 ether (123) which could be hydrolysed (H'-MeOH) to the cyano-ketone (124).86 The yields were improved by avoiding the elimination of HCN in the mild hydrolysis conditions. The syntheses of a-hydroxy-ketones by treatment of lithium enolates with Moo,-pyridine-HMPA have been reported in full." The reaction of enol acetates with T1'OAc-I2 provided a route to a-iodo-ketones 82 83 84

85 86 87

J. C. A. Boeyens, J. R. Bull, J. Floor, and A. Tuinman, J.C.S. Perkin I, 1978, 808. J. Y. Satoh, C. A. Hornicki, and A. Hagitani, Bull. Chem. Soc. Japan, 1978, 51, 192. G . M. Rubottom and J. M. Gruber, J. Org. Chem., 1978,43,1599. H. Driguez, J.-P. Vermes, and J. Lessard, Canad. J. Chem., 1978, 56, 119. J. F. Templeton, V. G. Paslat, and C. W. Wie, Canad. J. Chem., 1978, 56, 2058. M. Samson and M. Vandewalle, Synth. Comm., 1978,8,231. E. Vedejs, D . A. Engler, and J. E. Telschow, J. Org. Chem., 1978,43, 188.

Steroid Reactions and Partial Syntheses

287

(122) R = Me, ClCH2CH2,Ac, or SiMe3

which appeared to be better than the use of AgOAc-I2 in certain cases. Thus the A16-eno1acetate (125) gave the 16-iodo-17-0x0-compound although 5a-cholest2-en-3-yl acetate failed to react." Reduction of enol phosphates with titanium OAc

(125)

metal in aprotic conditions gave improved yields of alkenes;" thus, for example, A4-3-ones were converted into A2*4-or A3*5-dienes. An efficient synthesis of enol carbonates, including methyl 5a-cholest-2-en-3yl carbonate (126) was reported by treatment of the 3-ketone with lithium

(1 26)

2,2,6,6-tetramethylpiperidide in THF followed by dilution with HMPA and addition of methyl c h l o r ~ f o r m a t eChromatography .~~ on silica of the (20R)-20hydroxy- 18-methyl- 18-0x0-compound (128) gave a high yield of the enol ether (130).91Reaction of compound (130) with Pb(OAc)4gave the acetoxy-enol ether (131).The corresponding acetoxy-enol ethers were similarly obtained by reaction of compounds (127) and (129) with Pb(OAc)4.The relatively unhindered nature R. C. Cambie, R. C. Hayward, J. L. Jurlina, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1978,126. " S . C. Welch and M. E. Walters, J. Org. Chem., 1978, 43, 2715. 'O R. A. Olofson, J. Cuomo, and B. A. Bauman, J. Org. Chem., 1978,43, 2073. " G. R. Lenz, J.C.S. Chem. Comm., 1978,241.

288

Terpenoids and Steroids

(127) R = H (128) R = A c

of the enol ether structure compared with that of the possible hemiacetals of the hydroxy-ketones is believed to be an important factor in these reactions. with pyrrolidine in the Prolonged treatment of androsta-1,4-diene-3,17-dione absence of solvent gave the dienamine (132) which was further transformed, by heating at 150 "C, to the trienamine (133).92 Base-catalysed hydrolysis of (132) and (133) gave the parent ketone.

Regioselective a,@-dehydrogenation of 2-0x0- and 3-0x0-steroids was achieved93with PdC1,-HCl-Bu'OH at 80 "C. For example, 5a-cholestan-3-one gave the A1-3-oxo-compound (80%) while 5P-cholestan-3-one gave the A4-3om-compound (80%). Dehydrogenation of 3,20-dioxo-compounds occurred only in the A-ring. The dehydrogenations of hecogenin acetate to the A9(")derivative and of 5n-cholestan-3-one and cholest-4-en-3-one to the A1."-dien-3one were considerably improved using benzeneseleninic anhydride.94One major advantage of these Leactions over the use of, for example, SeO, is that the by-product (PhSeSePh) may be readily separated and oxidized. Oximes and Related Derivatives.-Beckmann fragmentation of a-hydroxyketoximes occurred with dichlorocarbene. For example, a chloroform-ethyl acetate solution of the 5a-hydroxy-6-oximinocholestane(134) gave the ketonitrile (135) with acqueous NaOH in the presence of benzyltriethylammonium Improved reduction of nitrimines to nitramines with NaBH4 and acetic acid has been reported and is exemplified by the conversion of the nitriminocholestane (136) into the 6~-nitramino-compound(137).96 92 93 94 95

96

R. Bucourt and J. Dube, Bull. Joc. chim. France, 1978,33. E. Mincione, G. Ortaggi, and A. Sirna, Synthesis, 1978, 773. D. H. R. Barton, D . J. Lester, and S. V. Ley, J.C.S. Chem. Comm., 1978, 130. J. N. Shah, Y. P. Mehta, and G. M. Shah, J. Org. Chem., 1978, 43, 2078. M. J. Haire, J. O r g . Chem., 1977,42, 3446.

Steroid Reactions and Partial Syntheses

289

AcO

d @

AcO

AcO

\

4 Compounds of Nitrogen

Treatment of a series of a-azido-ketones with bromine in acetic acid led through a novel carbon-carbon cleavage to the o-cyano-carboxylic acids.97 Thus, 2a-azido-5a-cholestan-3-onegave the cyano-carboxylic acid (138) and 3pacetoxy-7a-azido-5c-cholestan-6-onegave the cyano-carboxylic (139). The

(138)

(139)

lactamo-ester (140) was cleanly reductively cyclized to the A-nor-B-homo-azasteroid (141) with LiAlH4 in boiling THF.98 Under less forcing conditions

0 (140)

(141)

partially reduced and/or cyclized materials were obtained. Dehydrogenation of the 4-azacholestan-3-one (142) with benzeneseleninic anhydride gave the A*-3one (143) in high yield.99 A full account of the oxidation of N-alkyl-N'-tosylhydrazines with H202-Na202 included some steroidal examples. loo The 97

98 99 loo

T. T. Takahashi and J. Y. Satoh, J.C.S. Chem. Comm., 1978,409. W. J. Rodewald and J. W. Morzycki, Tetrahedron Letters, 1978, 1077. T. G. Back, J.C.S. Chem. Comm., 1978,278. L. Gaglioti, F. Gasparrini, D. Misiti, and G. Palmieri, Tetrahedron, 1978, 34, 135.

290

Terpenoids and Steroids

(142)

(143)

cholestanyl derivative (144) was converted into the epimeric mixture of 3-hydroperoxides (145). The 1,3-dipoiar cycloaddition of nitronic esters to a series of

(144)

(145)

16-dehydro-20-0x0-steroidshas been reported in full."' A series of 6@,7@nitromethylene steroids (147) were synthesized by reaction of -CH2N02 with 6-~hloro-A~~~-3-0nes (146).'02 Similarly the 2-brom0-A~*~*~-3-0ne (148) gave the la,2a-nitromethylene compound (149) and the 5P-2-bromo-A1-3-one (150) gave the 1@,2@-nitromethylenecompound (15 1).103*104 It is noteworthy that in the reaction of compounds (146) no 6a,7a-nitromethylene compound was

AcOH~C O

HH

0

e

/

\

Br&"

'

0

02:a:;l:.

0

H

(149)

(150)

H (151)

formed, in contrast to the reactions of dimethyloxosulphonium methylide with similar compounds.

Io2 Io4

A. V. Kamernitzky, I. S. Levina, E. I. Mortikova, V. M. Shitkin, and B. S. El'yanov, Tetrahedron, 1977,33,2135. E. L. Shapiro, G. Page, L. Weber, and M. J. Gentles, Tetrahedron Letters, 1977, 3 5 5 3 . E. L. Shapiro, M. J. Gentles, L. Weber, and G. Page, Tetrahedron Letters, 1977, 3557. See ref. 38, p. 246.

Steroid Reactions and Partial Syntheses

291

NN-Dimethylation of the amino-compound (152) was smoothly effected by conversion with CH20-MeOH into the bisalkoxymethylamine and reduction with NaCNBH3.105Protection of the amino-group of 3 a - and 3P-amino-Saandrostane was effected by heating with 1,2-diphenylmaleic anhydride. The resultant maleimides (153) were converted back into the amines by treatment

(152)

with ethanolic hydrazine.lo6 Selective protection of the 3-dimethylamino-group of dihydroconessine was achieved by its conversion with one equivalent of NaBH,-BF,,Et,O into the 3-amin0borane.~~' 5 Molecular Rearrangements

Backbone Rearrangements.-Reductive rearrangement of androst-4-ene-3,17dione in HF-SbF5 and in the presence of a hydrogen donor was dependent on the acidity. At high acidity the major products were the 6a-methyl-14P-oestranediones (154) and (155) whereas at low acidity the major product was the

6P-methyl-14P-oestranedione (156).'08 The isolation of these 6-methyl compounds clarifies the mechanism whereby the previously reported 7P-methyl compound (157)was formed.'" The trication (158)is a key intermediate in these rearrangements and appears to rearrange by successive shifts of the SP-methyl group to C-6 and then C-7. Treatment of androsta-1,4-diene-3,17-dionewith HF-SbF5 gave the expected 1-methyloestrone (159) and the l-hydroxy-4methyloestratrienone (160) (9 : l).l10 The former rearranged further to the more stable l-methyl-8a,14@-oestrone(161) via diprotonation of the aromatic ring at C-4 and C-10 as evidenced by the isolation of the l-methyl-5~-A1-compound H. Kapnang, G. Charles, B. L. Sondengam, and J. Hentchoya Hemo, Tetrahedron Letters, 1977, 3469. lo6 U. Zehavi, J. Org. Chem., 1977,42,2819. lo' A. Picot and X. Lusinchi, Bull. SOC.chim. France, 1977, 1227. R. Jacquesy and C. Narbonne, Bull. SOC.chim. France, 1978, 163. See ref. 20, p. 274. 'lo R. Jacquesy and H. L. Ung, Tetrahedron, 1977,33,2543. lo'

Terpenoids and Steroids

292

&& H a

0

+

'

0

(161)

0

(162)

(162) when the reaction was carried out in the presence of a hydrogen donor. Acid-catalysed rearrangements of a series of unsaturated l'l-hydroxyandrostanes gave backbone-rearranged products when the C - 18 and the 17-OH were cis but gave c-nor-spiroketones when the C-18 and the 17-OH were trans."' These reactions are exemplified by the conversion of the cis-compound (163) into the backbone-rearranged product (164) and of the trans-compound (165) into the c-nor-spiroketones (166). Both reaction pathways are believed to

&& H

H

\

l1

C. Chavis, J. Marchand, J. Bascoul, and A. Crastes de Paulet, Tetrahedron, 1977, 33, 265 1.

Steroid Reactions and Partial Syntheses

293

involve concerted rearrangements of the C- 14 carbocations as indicated in Scheme 7.

U

Scheme 7

Treatment of the isomeric 20-methyl-~-norpregnadienes (167) and (168)and the 20-methyl-3a,5a-cyclopregnene(169) with HBr gave the 17a-A3s'4-diene (170).112*1l 3 Dissolution of the 3-0x0-A4-compounds (171) in concentrated

(169)

(170)

sulphuric acid and dilution with ethanol gave the rearranged 3 - 0 x o - A ~ * ~ * ~ " ~ ) compounds (172) in which the 13P-substituent had migrated to the site of the

(171) R' = R2 = Me, R3 = 0 R ' = H , R2=Me, R 3 = 0 R ' = H , R2=Et, R 3 = 0 R' = R2 = Me, R3 = P-COMe, H

(172) R ' = R 2 = M e R'=H, R ~ = M ~ R'=H, R2=Et R' = Me, R2 = Pr'

original carbonyl group at C-17 or C-20.'14 The effect of D-ring substitution on the acid-catalysed equilibrium between A*- and A9'"'-oestrenes was studied' l 6 " J

'I2

''' 'I6

E.-J. Brunke, R. Bohm, L. Grotjahn, and H. Wolf, Chem. Ber., 1978,111, 1404. E.-J. Brunke and H. Wolf, Tetrahedron, 1978, 34, 707. G. Tbth, A. Szabo, D. Muller, and G . Snatzke, Coll. Czech. Chem. Comm., 1978, 43, 165. D. Hainaut and R. Bucourt, Bull. SOC.chim. France, 1978,119. D. Hainaut and R. Bucourt, Bull. SOC.chim. France, 1978,126.

Terpenoids and Steroids

294

along with similar isomerizations in model ~ystems.~'""~ For the oestrenes, increased flattening of the D-ring increased the proportion of the A9(")-*isomer. One of the concentrated hydrochloric acid-catalysed dehydration products of chenodeoxycholic acid was identified as the 14@-A8-compound ( 173).119The (175). 13-epiandrostene (174) rearranged in HC1-CHCl3 to the A'3('7'-deri~ati~e

(173)

(174)

(175)

It is suggested that the bulk of substituents at C-7 is critical in determining the outcome of rearrangements of 13-epi-ster0ids.'~'

Miscellaneous Rearrangements.-An improved non-photochemical route to 13-epi-androstanes and -0estranes involved conversion of the appropriate 17oximino-compounds with boiling acetic anhydride-pyridine into the enamide (176) and the enimide (177) which were readily hydrolysed to the 17-0x0-

(176) R = H (177) R = Ac

compounds."' A free-radical mechanism is proposed. The rearrangement of 2,2-dibromo-5a -cholestan-3-one to the 2a,4a -dibromo-compound was shown to proceed only via the loss of Br' (reductive rearrangement) despite evidence that the alternative loss of Br- (a'-enol-allylic rearrangement) occurred in other systems."' Baeyer-Villiger oxidation of 2-acetylcholest-2-ene, available from Sa-cholestan-2-one, led to 5a-cholestan-2-one owing to selective alkenyl uersus alkyl rnig~ation.~'~ Reinvestigation of the Baeyer-Villiger oxidations of 6-0x0-5acholestanes confirmed that C-7 competed effectively with C-5 in its migratory aptitude and a dependence in these reactions on the substitution at C-3 was Oxidation of 3~-acetoxycholest-4-en-6-onewith excess perbenzoic 'I7

G. Amiard and R. Bucourt, Bull. SOC. chim. France, 1978, 343.

''* G. Amiard and R. Bucourt, Bull. SOC.chim. France, 1978, 350. ".* ''I

12' lZ3

T. Harano, C . Fujita, K. Harano, and K. Yamasaki, Steroids, 1977, 30, 393. R. C. Sheppard and S. Turner, J.C.S. Perkin I, 1977, 2551. R. B. Boar, F. K. Jetuah, J. F. McGhie, M. S. Robinson, and D. H. R. Barton, J.C.S. Perkin I, 1977, 2163. E. Warnhoff, M. Rampersad, P. S. Raman, and F. W. Yerhoff, Tetrahedron Letters, 1978, 1659. M. Montury and J. GorC, Tetrahedron, 1977, 33, 2819. M. S. Ahmad, G. Moinuddin, and I. A. Khan, J. Org. Chem., 1978,43, 163.

Steroid Reactions and Partial Syntheses

295

acid-toluene-p-sulphonic acid gave the seco-steroids (178), (179), and ( 180),’25 suggesting that some alkyl as well as alkenyl migration occurs. A number of

(178) R = H (179) R = O H

unexceptional Baeyer-Villiger oxidations of 5-oxo-5,6-seco- and 6-0x0-43seco-cholestanes have been reported. lZ6 Similarly the Schmidt reactions were reported for 5-0~0-5,6-secocholestanes, lZ7 7-0x0-pregn-5 -enes128’129and chole~t-4-ene-3,6-dione,~~~ and 3~-chloro-5a-cholestan-7-androst-5-ene~,~’~ In certain cases the Beckmann rearrangements of the corresponding oximes were reported. The Schmidt reactions of the enones gave tetrazoles derived from the lactams which were formed by migration of the alkyl rather than the alkenyl bond. Treatment of the tosylhydrazones of 17a-hydroxy-20-oxopregnaneswith Na-ethylene glycol provided an alternative route to 17ap-methyl-~-hornoandrostanes (181).13’ Further on the mechanism of the Lewis acid (BF,) catalysed D-homoannulation of 17a-hydroxypregnan-20-ones e ~ t a b l i s h e d ’ ~ ~ that a relatively rigid transition state is involved in which the oxygens are co-ordinated to BF3 and are held in a syn arrangement by a bridging proton. As a result, migration of C-16 through the transition state (182) is preferred to the

alternative C-13 migration. A similar hydrogen-bridged transition state is thought to be involved in kinetically controlled thermal D-homoannulations. Magnesium ethoxide-catalysed D-homoannulation gave a mixture of products y derived from C-16 and C-13 migration whereas lithium t-butoxide gave o ~ l the normal base-catalysed products (C-13 migration), indicating that the former may function, in part, as a weak Lewis acid. M. S. Ahrnad and I. A . Khan, Austral. J. Chem., 1978,31, 171. M. S. Ahrnad and F. Waris, Indian J. Chem., 1977, 15B, 919. 12’ M. S. Ahmad and F. Waris, Indian J. Chem., 1977, 15B, 1142. lZ8 H.Singh, T. R. Bhardwaj, and D. Paul, J.C.S. Perkin I, 1977, 1987. lZ9 H. Singh, K. K. Bhutani, R. K. Malhotra, and D. Paul, Experientia, 1978, 34, 557. H. Singh and K. K. Bhutani, Indian J. Chem., 1978, 16B, 95. 13’ A. H. Siddiqui, M. H. Baig, and C. Lakshmi, Austral. J. Chem., 1977, 30, 2271. 13* M. Fetizon and P. Jaudon, Tetrahedron, 1977, 33,2079. 133 See ref. 38, p. 251. 134 D. N. Kirk and C. R. McHugh, J.C.S. Perkin I, 1978, 173. lZ5

lZ6

Terpenoids and Steroids

296

Reaction of epicholesterol with thallium triacetate gave the 3a, lOa-epoxy-5pmethyl compound (183) through a Westphalen-type rearrangement.I3’ The

OAc

3a-hydroxy-group of epicholesterol appears to be essential for this rearrangement. Further studies on the rearrangements of 2- and 6-substituted Sa-hydroxycompounds supported the view that Westphalen rearrangement requires an electron-withdrawing substituent at C-6 (configuration unimportant) and steric compression of the lop-methyl group. 136 The conformational preferences of 5-methyl-19-nor-5/?-cholest-9-enes have been further i n ~ e s t i g a t e d . ’Rear~~ rangement of 10~-ethenyl-5a-hydroxy-compounds (184), (185), and (186) with Ac20-AcOH-H2S04 gave the corresponding 50-ethenyl compounds (187). R2

(184) R’ = Ac, R2 = P-CSH17, H (185) R1 = Ac, R2 = 0 (186) R’ = M e , R2 = 0

Treatment of the 10~-ethenyl-5a,6a-epoxycholestanes (188), (189), and (190) with BF3,Et*O-C6H6 gave the corresponding fluorohydrins (191) in yields of

RO

0-’ (188) R = A c (189) R = H (190) R = M e

47%, 33%, and 16% respectively in addition to varying amounts of 5pethen~1-A~and -A”“7’-compounds.’38 The relatively slow rearrangements of 5a-hydroxy-compounds and the significant yields of fluorohydrins imply that 13’

13’

13’

A. Schwartz and E. Glotter, J.C.S. Perkin I, 1977, 2470. P. KoEovsky and V. tern$, Coll. Czech. Chem. Comm., 1977,42,2415. P. KoEovskL, V. Cerny, S. VaSifkovi, and M. SynaEkova, Coll. Czech. Chem. Comm., 1977, 42, 3339. B. W. Cubberley, I. G. Guest, J. G. L1. Jones, and B. A. Marples, J.C.S. Perkin I, 1977, 1916.

Steroid Reactions and Partial Syntheses

297

homoallylic participation of the 1 00-ethenyl group is not significant, a conclusion which is supported by conformational arguments. In contradiction to the preliminary report, deuterium substituted in the ethenyl group was not scrambled during the rearrangement of the 5a-hydroxy-compounds, indicating the absence of cationic intermediates other than the C-10 carbocation. Reaction of 5,6P-epoxy-SP-androstane-4,17-dionewith Bu'O- gave the A-nor-carboxylic acid (192)by a Favorskii-type reaction (Scheme 8). The iso-

+

Scheme 8

meric 5 a,6a-epoxide was unreactive towards Bu'O- owing to the unfavourable conformational requirements of the intermediates. 139 Treatment of 2p, 19epoxy-5a-cholestane with Ac20-BF3 followed by hydrolysis gave inter aka the rearranged 1 a,19-diol (193)which was shown by deuterium labelling studies to arise via a non-concerted C-1 to C-2 hydride shift.'40 The toluene-p-sulphonic acid catalysed rearrangement of the hydroxy-olefin (106)to the ketone (194)

(193)

(194)

involved the transfer of hydride ion from C-5 to C-3.69Rearrangements of oxaspiropentanes to cyclobutanones [e.g. (195) to (196)]were achieved via the P-hydroxyselenides which were prepared by reaction with NaSePh. Subsequent oxidation with MCPBA and rearrangement in pyridine at -30°C gave the cyclobutanone, in some cases having the opposite configuration to that obtained by the acid-catalysed rearrangements of the oxaspiropentanes.14' The mechanism 139 140

'*'

J. R. Hanson, D. Raines, and H. Wadsworth, J.C.S. Perkin I, 1978, 743. R. E. Gall and J. Taylor, Austral. J. Chem., 1977, 30, 2249. B. M. Trost and P. H. Scudder, J. Amer. Chem. SOC.,1977,99,7601.

Terpenoids and steroids

298

of the rearrangement of 2a-hydroxycholest-4-en-3-one to 2-methoxy-4-methyl19-norcholesta-l,3,5(10)-triene (197) in MeOH-toluene-p-sulphonic acid was

& @ Meor-$y -.o

0

(195)

(196)

(197)

investigated by using the 4-l3C-labelled substrate.14*The original C-4 becomes C-10 in the aromatic product and supports a previously proposed mechanism involving the 2-methoxy-l,4-dien-3-01 and not the 1,4-dien-3-one. Treatment of 17a-hydroperoxyprogesterone with NOC1-pyridine gave 17a-nitratoprogesterone via rearrangement of the unstable p e r o ~ y n i t r i t e . ' ~ ~

6 Photochemical Reactions Reviews on photochemical rearrangements and fragmentations of alkenes and p01yenesl~~ and on the industrial applications of photochemical ~yntheses'~' include steroid examples; the sections on vitamin D are of particular interest. includes some early work A review on the photochemistry of aromatic (198) and other enol benzoates. A study of on 3-benzoyloxy-5a-cholest-2-ene the photochemical rearrangements of the epoxy-ketones (199)-(202) includes

(199) R' = Ph, R2= H (200) R' = H, R2= Ph

(201) R' = Ph, R2= H (202) R1= H, R2= Ph

some further work on the enol benzoate (198).14' The epoxy-ketones (199) and (200) gave mixtures of the 5a- and 5P-diketones (203) and (204) which were isolated in several tautomeric forms. However, the epoxy-ketones (201) and (202) gave no well-defined products. The SP-compound (204) was produced also in the photolysis of the enol benzoate (198)in cyclohexane. It is suggested that the epimerization at C-5 (which was not reported in the earlier work) occurs in all of these photolyses according to Scheme 9. 142

143 144

145 146

'41

B. R. Davis, G. W. Rewcastle, and P. D. Woodgate, J.C.S. Perkin Z, 1978, 735. D. H. R. Barton, R. H. Hesse, M. M. Pechet, and L. C. Smith, J.C.S. Chem. Comm., 1977, 754. G. Kaupp, Angew. Chem. Internat. Edn., 1977, 17,150. M. Fischer, Angew. Chem. Internat. Edn., 1978, 17, 16. M. Pfau and M. Julliard, Bull. SOC.chim. France, 1977,785. J. Muzart and J.-P. Pete, Tetrahedron, 1978, 34, 1179.

Steroid Reactions and Partial Syntheses

299

Scheme 9

Irradiation of 5a-cholest-1-en-3-one in the presence of acetaldehyde and benzophenone gave the la-acetylcholestanone (205).14’ The unsaturated lactone (206) underwent a di-?r-methane rearrangement to afford the spirolactones (207) and (208). The oxa-anthrasteroid (209) was a co-product which was derived from the intermediate biradical (210) by ~ e a r r a n g e m e n t . ’Similar ~~ di-7r-methane rearrangement of the aza-analogue (211) was, however, not o b ~ e r v e d . ” ~ OAc

0

*p$To* 0 0

(208)

(209)

0

(2 10)

(211)

The formation of the hydroxamic acids (213) by cyclization of the nitrosoaldehydes (212), which are intermediates in the photolysis of 17p-yl nitrites, was shown not to involve electronically excited species. 15’ Further studies relevant to the photochemistry of veratr-13(17)-enin-l1~-ylnitrites (214)15’ have been reported: photolysis of the etiojerva-5,13(17)-dien-llP-y1nitrite (215) gave the parent alcohol, the nitrone (216), and the N-oxide (217).’53 Although this reaction is more complex than that reported for the 12a-analogue (214), the

B. Fraser-Reid, R. C. Anderson, D. R. Hicks, and D. L. Walker, Canad.J. Chem., 1977,55,3986. J. A. Vallet, J. Boix, J.-J. Bonet, M. C. Brianso, C. Miravitlles, and J. L. Briansb, Helv. Chim. Acta, 1978, 61, 1158. 150 J. A. Vallet, A. CBnovas, J. Boix, and J. J. Bonet, Helv. Chim. Acta, 1978, 61, 1165. 151 H. Suginome, N. Yonekura, T. Mizuguchi, and T. Masamune, Bull. Chem. SOC.Japan, 1977, 50, 3010. 152 See ref. 38, p. 259. 153 H. Suginome, S. Sugiura, N. Yonekura, T. Masamune, and E. Osawa, J.C.S. Perkin I, 1978,612. 148

149

Terpenoids and Steroids

300 OH

iGH0 Ac

111

AcO AcO

H

AcO-

& O

C0,Et Ac

H

AcO-

\

\

AcO

(216)

(217)

isolation of the nitrone (216) supports the previously proposed mechanism involving the nitroso-aldehydes, and the differences are attributed to the polar effects of the C-17 substituents rather than differences in the configuration of the C/D-ring junction. A full account of the photochemistry of 3P-acetoxy-6-nitrocholest-5-ene and 6-nitrocholest-5-ene has been r e p ~ r t e dand ~ ~degradative ~ , ~ ~ ~ evidence presented in support of the structures of the heterocyclic products (218) and (219).lS6

(218) R = Ac or H

(219)

R = A c or H

The photochemically induced oxidation of the isoxazolidines (220), (221), and (222) has been in~estigated.”~ Typically, the major product from the photolysis of (220) in acetone was the nitro-compound (223),whereas in benzene it was the dimer (224).In an attempt to establish the general mechanism, photo-Beckmann rearrangements were studied for a series of o ~ i m e s . ’ ~In* each case a pair of

”’

See ref. 38, p. 259. J. T. Pinhey, E. Rizzardo, and G. C. Smith, Austral. J. Chem., 1978,31, 97. J. T. Pinhey, E. Rizzardo, and G. C. Smith, Austral. J. Chem., 1978,31, 113. L. Lorenc, I. Juranit, and M. Lj. MihailoviC, J.C.S. Chem. Comm., 1977, 749. H. Suginome and F. Yagihashi, J.C.S. Perkin I, 1977, 2488.

Steroid Reactions and Partial Syntheses

301

,OAc

R (220) R = H (221) R = M e (222) R = A c

isomeric lactams was obtained in which the chirality of the migrating group was retained. It was concluded that singlet oxime is converted into an intermediate oxaziridine which rearranges concertedly to the lactams and that equilibration of the oximes (2+ E ) proceeds faster than oxaziridine formation. in MeOH gave a Photolysis of 3~-acetoxy-5-methoxy-5a-cholestan-6-one high yield of methyl 3~-acetoxy-5-methoxy-5,6-seco-5cu-cholestan-6-oate whereas in benzene the corresponding carboxylic acid was 0btair1ed.l~~ The studies on the photochemistry of 4-methoxycholest-4-en-3-one160 have been extended16' to include the compounds (225). The oxetanones (226) and oxetanols (227) were generally formed except in the case where R' = H, R2= Ph, when the corresponding oxetanone (226) was not formed. 3-Methoxycholest-2-en-4-one

gave 5a-cholest-2-en-4-one and the oxetanone (228) whereas 4-methoxycholeSta-l,4-dien-3-one gave the cyclopropane (229). Photochemical addition of the 3,6-dioxo-A'-compound (230) to cyclopentene gave the adducts (231) and (232). With dihydropyran and 2,3-dimethylbutadiene the adducts were (233) and (234) respectively.'62 Irradiation of thioacetals in an oxygen atmosphere with a high-pressure mercury lamp gave the corresponding ketones in good ~ i e 1 d s .Irradiation l~~ of the ls9 160 16' 16'

163

P. Morand and S. A. Samad, Bangladesh. J. Sci. Znd. Res., 1977, 12, 219. See ref. 38, p. 256. A. Enger, A. Feigenbaum, J.-P. Pete, and J. L. Wolfhugel, Tetrahedron, 1978, 34, 1509. G. R. Lenz, J.C.S. Chem. Comm., 1977,700. T. T. Takahashi, C . Y. Nakamura, and J. Y. Satoh, J.C.S. Chew. Comm., 1977,680.

302

Terpenoids and Steroids

phenylglyoxalylamide (235) [prepared from (153)lo6]in ethanol-benzene-H2S04 gave 5a -cholestan-3-one. 164 Selective chlorination at C-9 was achieved by irradiation of the steroid in the presence of NN-dichlorourethane. Thus the pregnane (236) may, by this process and subsequent dehydrochlorination with AgC104, be converted into the A9(11)-analogue.165 OAc

16' 16'

U. Zehavi, J. Org. Chem., 1977,42, 2821. Y. Mazur and Z . Cohen, Angew. Chem. Internat. Edn., 1978, 17, 281.

Steroid Reactions and Partial Syntheses

3 03

Section B: Partial Syntheses 7 Cholestane Derivatives and Analogues

Approaches to the construction of steroidal side-chains have been reviewed.'66 The full account of the stereocontrolled syntheses of steroidal side-chains using organopalladium compounds has appeared.'67*168Reaction of the enol acetates (237) in catalytic palladium reactions employing Ph3P-(Ph3P)4PdNaCH(C02Me)2gave the ester (238) with the natural C-20 configuration. The stoicheiometric palladium reaction between NaCH(C02Me)2 and the T-ally1 complex (239) afforded the epimeric ester (240). The synthesis of 5a-eholestan%one from testosterone demonstrates the utility of these methods.

(237)

(238)

(239)

(240)

20-Isocholesterol was synthesized from 3-tetrahydropyranyloxypregn-5-en20-one (241) by the route shown in Scheme and this is an improvement

Reagents: i, dimethybulphoxonium methylide; ii, isoamylmagnesium bromide; iii, pyridinium chlorochromate; iv, MeOH-HCl; v, H S C H ~ C H Z S H - B F ~ , E ~vi, ~ ORaney ; nickel

Scheme 10

over the previously reported route employing hydrogenation of E-20(22)dehydro- derivative^."^ There is some disagreement over the conformational '66 167

169

170

D. M. Piatak and J. Wicha, Chem. Rev., 1978,78, 199. See ref. 38, p. 264. B. M. Trost and T. R. Verhoeven, J. Amer. Chem. SOC.,1978,100,3435. M. Koreeda and N. Koizumi, Tetrahedron Letters, 1978, 1641. W. R. Nes, T. E. Varkey, and K. Krevitz, J. Amer. Chem. SOC.,1977,99,260.

Terpenoids and Steroids

304

implications of this hydrogenation route. 1719172 The synthesis of epicholesterol involved conversion of 3@,6@-dihydroxy-Sa-cholestane into 3a -benzoyloxy-5acholestan-6P-01 by reaction with triphenylphosphine, diethyl azodicarboxylate and benzoic Elimination of the 6P-hydroxy-group was achieved by conversion into the mesylate and treatment with Li2C03-DMF. An improved synthesis of desmosterol (243)involved the coupling of the bromo-derivative (242)with dimethylallyl-lithium.'74 Desmosterol (243)was also synthesized together with epidesmosterol, from hyodeoxycholic The construction of the side-chain was achieved by reaction of the acid chloride (244)with P r i e d to give the ketone (245).A synthesis of the (24S)-24-methyl-27-nor-h -cholest-

0

Ac0-O OAc

(244)

22-enol(246;patinosterol), a new marine sterol, was reported from 3P-acetoxy5a-cholanic Oxidative decarboxylation gave the A22-compound (247) which on ozonolysis gave the aldehyde (248).Wittig reaction of the latter with the ylide generated from (2s)-2-methylbutyltriphenylphosphonium bromide gave

(247) R=CH2 (248) R = O 171

173

17' 176

E. N. Trachtenberg, C.-Y. Byon, and M. Gut, J. Amer. Chem. SOC.,1977,99, 6145. W. R. Nes, J. Amer. Chem. SOC.,1978, 100, 999. L. P. L. Piacenza, J. Org. Chem., 1977,42, 3778. M. A . Apfel, J. Org. Chem., 1978, 43, 2284. K. Ochi, I. Matsunaga, M. Shindo, and C. Kaneko, Steroids, 1977, 30, 795. M. Kobayashi, T. Minamizawa, and H. Mitsuhashi, Steroids, 1977, 29, 823.

Steroid Reactions and Partial Syntheses

305

patinosteryl acetate. Similar syntheses were reported for the marine sterols (249)-(252) which have the unnatural 20P-H c ~ n f i g u r a t i o n Base-catalysed .~~~ epimerization at C-20 of the aldehyde (253), which was derived from stigmasterol, was followed by elaboration of the side-chain. Improved syntheses of a series of 24-nor-5P -chol-22-enes by oxidative decarboxylation of the formyloxycholanic acid derivatives have been r e p 0 ~ t e d . l ~ ~

il-::4"

rco*Me

AcO

OMe

(253)

(249) (250)22,23-dihydro(251) 5a-5,6-dihydro(252)5&-5,6,22,23-tetrahydro-

Syntheses of 56-cholest- 1-ene and 56-cholest-2-ene have been reported from 2~-bromo-5~-cholestan-3-one,179 which was prepared from the 2&4P-dibromo-ketone by reaction with chromous acetate. A series of 5psubstituted-5a-hydroxy-5a-cholest-2-enes was prepared from 5a,6a-epoxycholestanes.lgO Acid-catalysed dehydrobromination of the 7,11,22,23-tetrabromide (254) gave the aromatic dibromide (255).lg1

'Br

(254)

AcO

(255)

Hydroboration of 5a-ergost-8-en-30-01 followed by oxidation with OH-H 2 0 2 gave the unnatural 5a,9P-ergostane-3P,7P-diol(256) owing to rearrangement of the intermediate borane.lg2 A synthesis of [1,2-3H2]-7a-hydroxycholesterol from cholesta- 1,4,6-trien-3-0ne involved Zn reduction of the bromohydrin (257) to the intermediate 3-oxo-dienol(258) which was reduced in situ with NaBH, to give cholesta-1,5-diene-3P,7a-diol(259). Catalytic addition '71 179 ''O

'" '*

D . J. Vanderah and C. Djerassi, J. Org. Chem., 1978, 43, 1442. G. L. Carlson, D. T. E. Belobaba, A . F. Hofmann, and Y. Wedmid, Steroids, 1977, 30, 787. K. Abe and J. Y. Satoh, Bull. Chem. SOC.Japan, 1978,51,941. P. KoEovskL and V. CernL, Coll. Czech. Chem. Comm., 1978,43,1933. R. Edmunds, J. M. Midgley, L. G. Tagg, B. J. Wilkins, and W. B. Whalley, J.C.S. Perkin I, 1978,76. E. Mincione, Ann. Chim. (Italy), 1977,67, 119.

Terpenoids and Steroids

306

\

\ 0@OH

HO

O&OH Br

(257)

mo~ \

(258)

(259)

of tritium to this gave the required [ 1,2-3H2]-7a-hydroxycholesterol.183 Improvements were claimed in the experimental conditions for synthesis of 1a,3@-dihydroxycholesta-5,7-diene originally reported by Barton and coworker~A .~~ ~ synthesis of la,3P-dihydroxyergosta-5,7-dienewas reported which was analogous to that previously described for the cholestane analogue185 and used Sa-ergost-7-en-3-one as starting materia1.1g6 A synthesis of la,3Pdihydroxy-4,4-dimethylergosta-5,7-diene and 4,4-dimethylergosta-5,7-dien3p-01 was included. A new synthesis of (20R)-cholest-5-ene-3@,21-diol (260) and the (20s)-epimer (261) from the tetrahydropyranyloxypregnenone (241) involved hydroboration of the A20-compound(262) and suggestedlg7that earlier

(260)

(261)

(262)

syntheses may have given mixtures. The preparation of 14a-ethyl-5a-cholest-7ene-3@,15a-diol(265), a potent inhibitor of sterol biosynthesis, involved alkylation of the enone (263) and LiAIH4reduction of the resultant ketone (264).lg8 The synthesis of cholest-5-ene-3p,l la,lSP-triol-7-one (267), a model for the Achlya sex hormone oogoniol, was achieved (Scheme 11) from 3-benzyloxycholesta-7,14-diene (266), itself available from acid-catalysed isomerization of 7-dehydrocholesteryl ben~0ate.l'~Syntheses of (24R)- and (24S)-SP-choleslS3

lS4 lS5 186

'" 189

C.-Y.Byon, H. L. Kimball, and M. Gut, Steroids, 1977, 30, 419. A. Mourino, Synth. Comm., 1978, 8, 127. See ref. 38, p. 266. R. Ahmad, D. Hands, S. L. Leung, J. M. Midgley, H. Safwat, and W. B. Whalley, J.C.S. Perkin I, 1978,74. C.-Y. Byon, G. Biiyiiktiir, P. Choay, and M. Gut, J. Org. Chem., 1977.42, 3619. G. J. Schroepfer, jun.,E. J. Parish, and A. A. Kandutsch, J. Amer. Chem. SOC.,1977, 99, 5494. E. J. Taylor and C. Djerassi, J. Org. Chem., 1977,42,3571.

Steroid Reactions and Partial Syntheses

307

(265)

tane-3&,7a,24,25-tetrols and (24R)- and (24S)-5/3-cholestane-3a,24,25-triols involved OSO, hydroxylation of the corresponding A 2 4 - ~ ~ m p 190 ~ ~Hydrond~. boration of 3a,7a-dihydroxy-5P-cholest-24-ene led to the (24R)- and (24S)-5/3cholestane-3a,7a,24-triols, and the corresponding A25-compoundsimilarly gave the (25R)- and (25S)-3a,7a,26-triol~.”~ A selective reducing agent for double bonds (potassium azodicarboxylateacetic acid) allowed the preparation of the epidioxide (268) from the A6v22A synthesis was reported for the 18,20-lactone (269) through the hypoiodite reaction of (20S)-20-hydroxy-5a-cholestan-3~-yl acetate.193 A second synthesis of the 18,20-lactone (269) from the known lactone (270) involved the stereoselective reaction of the acetoxy-ketone (27 1) with isohexylmagnesium bromide to give the (20s)-20-hydroxy-compound (272).19, These syntheses served as models for the synthesis of seychellogenin (273)195and the 7,8,9,11-tetrahydro-derivative.196 A number of 3-ethynyl-5a-cholestan-3-ols have been synthesi~ed.’~~ The synthesis of 4-spiro[cyclopropanecholestan-3/3-ol](274) required the reaction of 4-methylene-5a-cholestan-3-one(275) with CH2N2-Pb(OAc), to give the spirocyclopropyl ketone (276).198 An improved synthesis of 19-iodocholester3P-yl acetate involved a single-step replacement of the 19-hydroxy-group by iodine using carbodi-imidonium methiodide or Ph3P-N-iodosuccinimide. 199The preparations of monosulphates of chenodeoxycholip and deoxycholic acids and of 190

19’

19’ 19’ ‘91

19’ 19‘ 19’ 19’ 199

A. K. Batta, B. Dayal, G . S. Tint, S. Shefer, V. Toome, G . Salen, and E. H. Mosbach, Steroids, 1978, 31, 99. B. Dayal, A. K. Batta, S. Shefer, G. S. Tint, G . Salen, and E. H. Mosbach, J. Lipid Res., 1978,19, 191. W . Adam and H. J. Eggelte, Angew. Chem. Internat. Edn., 1977, 16, 713. G. Habermehl and K.-P. Swidersky, Annalen, 1978,405. G. Habermehl and K. Miyahara, Annalen, 1977, 1285. G. Habermehl and K.-H. Seib, Nuturwiss. 1978,65, 155. G . Habermehl, K.-H. Seib, and K.-P. Swidersky, Annalen, 1978, 419. H. Berbalk, K. Eichinger, and R. Schuster, Helv. Chim. Acta, 1977, 60, 2499. M. R. Czarny, J. A. Nelson, and T. A. Spencer, J. Org. Chem., 1977, 42,2941. H. E. Hadd, Steroids, 1978,31,453.

Terpenoids and Steroids

3 08

&

1

7

BzO

&;

%

&;;-

4;;

v, vi, iv

AcO

viii-x

,:1:5”:7

H j i i . iv

H

AcO

AcO

HO

H

A

H

c

o

~

o

H

’

7

H

Reagents: i, OH-; ii, B ~ H ~ - H ~ O Z - O Hiii, - ; Hg(OAc)2; iv, Ac2O-pyridine; v, HC03H; vi, KOH-

MeOH; vii, H,-Pd/C; viii, pyridinium hydrobromide perbromide; ix, CaC03-MeZNCOMe; x, Cr03; xi, Li(BuCO)3AlH;xii, M n 0 2

Scheme 11

9 -l

(269)

309

Steroid Reactions and Partial Syntheses

(274)

(275)

(276)

their taurine or glycine conjugates were reported.20019-Norcholesta-3,5-dien-7one and 19-norcholesta-4,6-dien-3-onehave been synthesized.201 Reaction of 1,2-dimethylethenylenephosphochloridate (277), in the presence of Et,N, with cholesterol and then HOCH2CH2fiMe3 C1- followed by hydrolysis gave cholesterylphosphorylcholine (278).202The phosphatidylcholesterol (279) was synthesized in a similar fashion.*03

/(f? [ A-

0 (277)

0 - PO -I I0

(278) '01

202 ' 0 3

Cl SH31CO2

&

{"';-" 0- r j H E t ,

O,CC,SH,*

AMe,

'O0

O I1

(279)

G. Parmentier and H. Eyssen, Steroids, 1977, 30, 583. J. FajkoS and J. Joska, Coll. Czech. Chem. Comm., 1978,43, 1142. F. Ramirez, H. Okazaki, and J. F. Marecek, I. Org. Chem., 1978,43, 2331. F. Ramirez, P. V. Ioannou, and J. F. Marecek, Synthesis, 1977,673.

3 10

Terpenoids and Steroids

8 Vitamin D and its Metabolites From a study of thermal transformations of cholecalciferol, it was concluded that, contrary to previous reports, conversion into pyro- and isopyro-cholecalciferol was measurable at temperatures as low as 110 "C. It was further established that between 100 and 160°C the rate of formation of pyro- and isopyro-cholecalciferol is lower than that of the precalciferol to calciferol conversions.2o4Reaction of the 22-0x0-compound (253) with the ylide (2801, derived from reaction of methylenetriphenylphosphorane in THF with isobutylene oxide at 0 "C, gave the AZ2-compound(281) (2: E ; 15 : 85).,05 The complete retention of configura-

Ph,P

o.,/P (280)

I

OMe (281)

tion at C-20 makes this reaction particularly useful for the synthesis of 25-hydroxycholecalciferol. Catalytic tritium reduction of the 3a,5a-cyclocholest-23-yne (282) followed by the usual reaction sequence led to [23-3Hz,24-3Hz]-25-hydroxycholecalciferol with high specific Full experimental details were available for the preparation of 1a-hydroxyergocalciferol including the reductive deconjugation of the epoxydienone (283) to the enediol (284).208

Oxidation of la-hydroxycholecalciferol and la,25-dihydroxycholecalciferol with MnO, gave the corresponding 1-oxo-previtamins which could be reduced with LiAlH, at -25°C in each case to give a mixture of la-hydroxy- and lp-hydroxy-previtamins in which the 1P-epimers (285) and (286) predominated.*09 Thermal equilibration allowed the isolation of the 1P-hydroxychoiecalciferol and 1~,25-dihydroxycholecalciferol.A similar independent synthesis of 1P-hydroxycholecalciferol employed NaBH, for the reduction 20* '05

'06 '07

'08 '04

B. Pelc and D. H. Marshall, Steroids, 1978, 31,23. W. G. Salmond, M. A. Basta, and J. L. Havens, J. Org. Chem., 1978, 43, 790. R. R. Muccino, G. G. Vernice, J. Cupano, E. Oliveto, and A. A. Liebman, Steroids, 1978,31,645. S. Yamada, H.K. Schnoes, and W.F. DeLuca, Analyt. Eiochem., 1978, 85, 34. H.-Y. Lam, H.K. Schnoes, and H. F. DeLuca, Steroids, 1977, 30,671. H. E. Paaren, H. K.Schnoes, and H. F. DeLuca, J.C.S. Chem. Comm., 1977,890.

Steroid Reactions and Partial Syntheses

311

(285) R = H (286) R = O H

of the l-oxo-previtamin and this gave only the 10-hydroxy-compound (285). Interestingly, ID-hydroxycholecalciferol showed n o vitamin D activity and the hydroxy-groups were found to be in the diaxial conformation owing to hydrogen-bonding.210 Syntheses of (25R ) - and (25S)-25,26-dihydroxycholecalciferol from cholenic acid via the corresponding 38,25,26 -trihydroxycholest-5enes were described (Scheme 12).211The configurations of the intermediate 3,26-dibenzoyloxy-24,25-epoxy-compounds (287) and (288) were determined by correlation with the known 3,24-dibenzoyloxycholest-5-en-25-yl trimethyl silyl ethers. The absolute configuration of the natural 25,26-dihydroxycholecalciferol is expected to be determined by biological evaluation of the synthetic products. X-Ray work has allowed the assignment of the configurations (25s) to 25(1,26-dihydroxycholecalciferol and (25R) to 25(2,26-dihydroxycholecalciferol which were synthesized from the less polar and more polar 25,26dihydroxycholesterols respectively.212 3,5-Cyclocholecalciferol (289; R = H)213was into the 3D-halogenocholecalciferols by reaction with H X (X = F, C1, or Br). 3~-Iodocholecalciferol was prepared, along with 5,6-trans-3~-iodocholecalciferol, using the similar reaction with NaI-ZnC12, and 3 p -fluoro- 1a -hydroxycholecalciferol was R = OH). Reaction of prepared from la-hydroxy-3,5-cyclocholecalcifero1(289; the cholecalciferol and ergocalciferol with Ph,P-diethyl azocarboxylate-HN, gave the corresponding 3a-azido-3-deoxy-compounds which were reduced with LiAlH4 to the 3a-amino-3-deoxy-compounds(290; R = CsHI7) and (290; R = C,H,,) r e ~ p e c t i v e l y . Epicholecalciferol ~~ was similarly converted into 3 -amino3-deoxycholecalciferol. Cholecalciferol reacted with 4-phenyl-1,2,4-triazoline3,5-dione to give the adducts (291) and (292).216The adducts may be converted into 5,6-trans-cholecalciferolwith KOH-butanol. Accordingly, modification of the 3-hydroxy-group, by Ph,P-diethyl azodicarboxylate-mediated reactions, followed by base-catalysed hydrolysis, afforded 5,6-trans-cholecalciferol derivatives and the 3-epimers. Syntheses were reported for 3-deoxy-lahydroxy-3a -methylcholecalciferol and 3 -deoxy - 1a,25 -dihydroxy -3a -methylcholecalciferol,217 and their conformational preferences were compared with M. Sheves, N. Friedman, and Y. Mazur, J. Org. Chem., 1977,42, 3597. N. Koizumi, M. Morisaki, and N. Ikekawa, Tetrahedron Letters, 1978, 2899. '12 M. Cesario, J. Guilhem, C . Pascard, and J. Redel, Tetrahedron Letters, 1978, 1097. '13 See ref. 38, p. 268. 214 M. Sheves, B. Sialom, and Y . Mazur, J.C.S. Chem. Comm., 1978, 554. '15 H. Loibner and'E. Zbiral, Tetrahedron, 1978, 34, 713. '16 W. Reischl and E. Zbiral, Annalen, 1978, 745. '" W. H. Okamura, M. N. Mitra, M. R. Pirio, A. Mouritio, S. S. Carey, and A. W. Norman, J. Org. Chem., 1978,43,574. 2'o

211

312

Terpenoids and Steroids

mBz

\OBZ

\

RzO

BzO

\

L

HO

Reagents: i,

0 I

-H+; ii, LiAlH,; iii, pyridinium chlorochromate; iv, Ph,P=CHCO,Et; v, HCl-

MeOH; vi, PhCOC1-pyridine; vii, Os04-N-methylmorpholine oxide; viii, TsC1-pyridine, ix, K2C03

Scheme 12

those of 1 a-hydroxy-3-epicholecalciferol. A study of the 10,19-dihydro-derivatives of ergocalciferol established that the structures of compounds reported in the earlier literature as DHV211, DHV2111, DHV21V, and DHT, were (293), (294), (295), and (296) respectively.21 8721 218

*19

See ref. 38, p. 269. A . Mouriiio and W. H. Okamura, J. Org. Chem., 1978,43,1653.

313

Steroid Reactions and Partial Syntheses

C8H17

C8H17

0

HO

Q

NPh 0

R

(291) 6a-H (292) 6/3-H 17

17

9 Pregnanes Irradiation of the aldehyde (253) in the presence of KOH-02-Rose Bengal gave the ketone (297) which was readily converted into progesterone.220A series of 18-substituted progesterones has been synthesized from the 18-nitrile (298) which could only be satisfactorilyhydrolysed, to give the lactone (300), by partial reduction to the alcohol (299) followed by treatment with KOH-BU'OH.~~~ Two of 17a-hydroxymethylprogesterone (302) have been reported. The first involved the intermediacy of the previously described lactone

OMe (297) 221

'*'

223

(298)

P. Sundararaman and C. Djerassi, J. Org. Chem., 1977,42, 3633. R. A. M. Auel, R. W. Freerkson, and D. S. Watt, Steroids, 1978, 31, 367. Ch. R. Engel and D. Mukherjee, Steroids, 1977, 29, 827. D. Mukherjee and Ch. R. Engel, Canad. J. Chem., 1978,56,410.

Terpenoids and Steroids

3 14

(299)

(300)

(301) as shown in Scheme 13,222and a key step in the second was the preparation of the ester (303) by reaction of the lithium enolate (304) with dimethyl carbonate or with CO, followed by esterification with d i a ~ o r n e t h a n e . ~ ~ ~

l i i i , iv

. &ZHzOAc

P\

v,

v, vi, iv, v, vii

0 H

m-

0

(302)

Reagents: i, SOCI;?; ii, Me2Cd; iii, HOCH2CH20H-H+; iv, LiAIH4; v, AczO-pyridine; vi, TsC1-pyridine; vii, H+-Me2CO; viii, Br2; ix, NWzNHCONHz; x, MeCOCO2H; xi, K2C03MeOH

Scheme 13

Steroid Reactions and Partial Syntheses

315

Syntheses have been reported for the A2'-marine steroids (305) and (306).224,225 The introduction of the 17P-ethenyl group, which is an unusual

feature, was achieved by reaction of the tosylhydrazone of a 20-0x0-derivative of the ethylenethioacetal of a 20-0x0-derivative with with B u " L or ~ by ~ ~reaction ~ deactivated Raney A number of ring-A-reduced 6-hydroxylated corticoids were synthesized from hydrocortisone or cortisone,226and an improved synthesis of 6P-hydroxy-5Ppregnane-3,20-dione involved autoxidation of the dienol ether (307) to the 6P-hydroxypregn-4-en-3-one(308) and subsequent h y d r ~ g e n a t i o n .The ~~~

&

O

H

Jd?

M eO

OH

(305)

(306) 4,5 -dehydro

(308)

(307)

pregnenoic acid derivative (309), which possesses certain structural elements of prostaglandins, was synthesized from 3P-acetoxyandrost-5-en- 17-one (Scheme 14).228The alkyl 20-oxopregnen-21-oates (310)-(313) were synthesized from

,x -0

'OH

..o -0

(309) Reagents: i, Zn-BrCH,CO,Et; ii, Ac,O-pyridine; iii, distil; iv, H,-Pt ; v, KOH-MeOH; vi, CH,N,; vii, DDQ; viii, H,O,-OH-; ix, MCPBA; x, AI-Hg

Scheme 14 224

225 226

227 228

S. R. Schow and T. C. McMorris, Steroids, 1977, 30, 389. J. F. Kingston, B. Gregory, and A. G. Fallis, Tetrahedron Letters, 1977,4261. H. J. G. M. Derks and N. M. Drayer, Steroids, 1978,31, 9. R. Chaudhri, G . Cooley, and W. F. Coulson, Steroids, 1978, 31, 495. J. Wicha and K. Bal, Steroids, 1977, 30, 363.

316

Terpenoids and Steroids

the corresponding 17-0x0-compounds (Scheme 15).229Oxidative decarboxylation of the keto-acid (314) with P ~ ( O A C ) , - C U ( O A Cin) ~benzene gave largely

c- 0 , E t

CO Et C C N

\rwCN

Reagents: i, CNCH2CO2Et-@-alanine-H+ or KF-CNCH2C02Et; ii, Pd/C-H2 or NaBH,; iii, LiHCUI-DMF-02

Scheme 15

C,O,Et

&

AcO

CO Me $0

the 18-norpregn-13-en-20-one(3 15) whereas in HMPA the isomeric A13(17’compound (316) was formed.230Reaction of the 9 a , l la-epoxy-17P-hydroxycompound (317) in benzene with BF,,Et,O gave the 8,11,13-triene (318), and 229

230

G. Haffer, U. Eder, G. Neef, G. Sauer, and R. Wiechert, Chem. Ber., 1978, 111, 1533. R. G. Frith, G. Phillipou, and C . J. Seaborn, Tetrahedron Letters, 1977, 3403.

Steroid Reactions and Partial Syntheses

317

(315)

(317)

similarly the 8,11,13-triene (320) was synthesized from the A'3-~ompound(319) by bromination followed by treatment with N a I - a ~ e t o n e . ~Syntheses ~' of 9afluoro-A"-corticoids (321) by reaction of 9a-fluoro-1 lp-hydroxy-compounds with NN-diethylaminosulphur trichloride have been (see ref. 7). 0Bz

0Bz

AcO..~

ki3 0

'

(321) R' = R2 = COEt, R3 =@-Me R ' = C O M e , R 2 , R 3 =. .'.'bXzz

A synthesis of the 21-amino-bisethylene-acetal (322) was confirmed by The two glucocorticoid its conversion into 2 1-acetylaminopr~gesterone.~~~ alkylating agents (323) and (324) have been synthesized by reaction of the 231

232

233

A. C . Campbell, M. S. Maidment, J. H. Pick, D. F. M. Stevenson, and G. F. Woods, J.C.S. Perkin I, 1978, 163. M. J. Green, H. -J. Shue, M. Tanabe, D. M. Yasuda, A. T. McPhail, and K. D. Onan, J.C.S. Chem. Comm., 1977,611. F. Sweet, Steroids, 1977, 30, 719.

Terpenoids and Steroids

3 18

corresponding 2 1-hydroxy-compounds successively with phosgene and di-2chl~roethylamine.~~~

10 Androstanes and Oestranes An improved degradation of methyl fusidate (325) to the 14p-methyl-18norandrostane (328) has been described (Scheme 16). Evidence was presented that the conversion of the 1la-acetoxy-compound (326) into the A'*-compound

Reagents: i, Ac,O-NaOAc; ii,

0 3 ;

iii, Me2S; iv, pyridine; v, AcOH; vi, Pd/C-H2

Scheme 16 234

A. H. El Masry, V. C. Braun, C. J. Nielsen, and W. B. Pratt, J. Medicin. Chem., 1977, 20, 1134.

Steroid Reactions and Partial Syntheses

319

(327) involved the intermediacy of a A9(1’)-species. Accordingly, the 9pconfiguration in (328) may not be assumed.235Improved syntheses of derivatives of androst-5-ene-3@,17@,19 -trio1 have been claimed.236 Certain O-aryloximinoandrostanes were synthesized and evaluated as contragestational and 3-fluoroanagents.237 Syntheses of 2a-chlor0-5a-androstan-3-0ls~~~ d r o ~ t a n e have s ~ ~ been ~ reported. The anionic oxy-Cope rearrangement of the naphthylbicycloheptene (329) with Na-THF gave the all-cis-oestrapentaene (330).240 A synthesis of

&

Me0

OMe

/

\

\

/

&Me

+

/ \

(329)

/

(330)

18-hydroxyoestrone from 3-hydroxy- 19-norpregn-1,3,5(1O)-trien-20-one involved the conversion of the 16,17-epoxy-20-hydroxy-compound(331) into the 18,20-epoxy-compound (332) by the hypoiodite reaction.241The 1lp-substi-

(331)

(332)

tuted 17a-ethynyloestr-4-en-17p-ols (333) were synthesized along with the 11,18-epoxy-compound (334) and evaluated biologically.242A simple, though

(333) R = F, C1, OH, OMe, alkyl, CH20H,CH20Me, or CH2CI 235 236

”*

239

’*’ 241

242

(334)

W. S. Murphy and D. Cocker, J.C.S. Perkin I, 1977, 2565. W. J. Rodewald, J. R. Jaszczynski, and R. R. Sicinski, Polish J. Chem., 1978,52, 501. F. Wong, R. A. Mallory, M. L. Cotter, and A. F. Hirsch, Steroids, 1978, 31,605. A. Castonguay, R. E. Counsell, R. W. S. Skinner, and R. V. Pozderac, J. Medicin. Chem., 1978,21, 391. M. E. Jung and J. P. Hudspeth, J. Amer. Chem. SOC., 1978, 100,4309. H. Breuer and K. Engel, Annulen, 1978,580. A. J. van den Broek, A. I. A. Broess,M.J. van den Heuvel, H. P. de Jongh, J. Leemhuis, K. H. Schonemann, J. Smits, J. de Visser, N. P. van Vliet, and F. J. Zeelen, Steroids, 1977, 30, 481.

320

Terpenoids and Steroids

low-yielding, one-step process for the synthesis of 2- and 4-hydroxymestranol involved the oxidation of 17a-ethynyloestradiol-3-yl methyl ether with MCPBA in methylene Improved procedures have been reported for the ]~~~ preparations of pyrogalloloestrogens [e.g. (335) from 2 - m e t h o x y o e ~ t r o n e and the compounds (336) were evaluated as a n t i o e s t r o g e n ~ . ~ ~ ~

Meo@ HO

'

HO

OH

@ ' /

Ph

(336) R = H or Me

(335)

11 Cardenolides and Bufadienolides Emmons-Horner condensation of (EtO),P(O)CH,CN with 21-acetoxy-21-oxocompounds gave the 2-cyano-olefins (337) which on treatment with H'-EtOH gave the cardenolides (338).246Similar earlier work had reported the Econfiguration for one of the cyano-olefins (337). Acetyldigitoxigenin (339) was

CN

Aco16H (337)

(338)

(339)

converted into the A14- and A 8 ' 1 4 ' - ~ ~ m p (340) ~ ~ n dand ~ (341) respectively on treatment with 0.25M-HN3-BF3,Et20 in benzene whereas the 17a-epimer of

(340) 243

(341)

245

R. M. Kanojia, Steroids, 1977, 30, 343. G. Stubenrauch, 0. Haupt, and R. Knuppen, Steroids, 1977, 29, 849. E. R. Clark, A. M. E. Omar, and G. Prestwich, J. Medicin. Chem., 1977, 20, 1096.

246

G. R. Lenz and J. A. Schulz, J. Org. Chem., 1978,452334.

244

Steroid Reactions and Pa rtia 1 S y ntheses

321

(339) readily gave the 14~-azido-compound(342).247Higher concentrations of HN3 allowed the conversion of acetyldigitoxigenin (339) or the A 1 4 - ~ ~ m p ~ ~ n d (340) into the 14~-azido-compound(343) (see ref. 44). Modification of k-

(342) 17a (343) 17p

strophanthidin by reaction with (Et0),P(0)CH2CNand (EtO),P(0)CH,C02Et gave the cardenolides (344) and (345) respectively. The cardiac activity of

(344)

(345)

glycosides of these was evaluated and other modifications of k-strophanthidin were reported.248 Preparations were reported for the glucosides and the rhamnosides of the 3-methyl- and 3-ethynyl-cardenolides (346).24' An improved chemical degradation of neriifolin provided an alternative source of

HO (346) R = Me or C r C H 247 248 249

A. Astier, A. Pancrazi, and Q. Khuong-Huu, Tetrahedron, 1978, 34, 1487. U. Stache, W. Fritsch, W. Haede, and K. Radscheit, Annalen, 1977, 1461. H. P. Albrecht, Annalen, 1977, 1429.

322

Terpenoids and Steroids

digit~xigenin.~~' Reaction of the 17P-formylandrostanes (347) with aminoguanidine bicarbonate gave the cardenolide analogues (348).251An improved synthesis of the bufadienolide (352) was reported along with a synthesis of the 23-ethoxycarbonyl derivative (353).2'2 Reaction of the methoxymethylenealdehyde (349) with acetyl lithioacetate gave the ester (35 1) which upon hydrolysis (HCl-EtOH) and reacetylation gave (352). Reaction of the chloromethylene-aldehyde (350) with NaCH(C02Et), in HMPA directly gave (353).

NH

II

CH=NNHCNH,

HO

H (347) 3&5a 30950 3%5P 30,4,5 -dehydro

(349) R =Z-OMe (350) R=C1

(348)

(351)

(352) R = H (353) R = COZEt

12 Cyclo-steroids and Seco-steroids The 3,6-cyclo-~-nor-3,5-secoandrostanes (354) were ~ y n t h e s i z e d ~through '~ reduction of the enol lactones (355) (see ref. 67). The syntheses of 5,7p-cyclo-Bhomo-5P- and 6~,7a~-cyclo-~-homo-Sa-cholest-2-enes and derivatives of these were r e p ~ r t e d . ~ Notably, ' ~ * ~ ~ ~reaction of the 6&7a P-cyclo-~-homocompound (356) with HOBr and with peracid gave, in each case, a single product resulting from exclusive a-face attack.25' Methylenation of cholesta-4,6-dien-3one with dimethyloxosulphoniummethylide gave 6&7a P-cyclo-B-homocholest4-en-3-one and the 6 ~ ~ , 7 a - e p i m e r . ~ ' ~ 250

251

252 253 254 255

256

A. Cruz, I. Garcia, J. Iriarte, J. M. Muchowski, and I. Regla, J. Org. Chem., 1977, 42, 3580. A. Gelbart and R. Thomas, J. Medicin. Chem., 1978, 21, 284. Ch. R. Engel and G. Dionne, Cunud. J. Chem., 1978,56,424. A. Kasal, Coll. Czech. Chem. Comm., 1978, 43, 1778. L. Kohout and J. FajkoS, Coll. Czech. Chem. Comm., 1978,43, 638. L. Kohout, Coll. Czech. Chem. Comm., 1978,43, 889. L. Kohout and J. FajkoE, Coll. Czech. Chem. Comm., 1978,43, 1134.

Steroid Reactions and Partial Syntheses

323

(354) R' = a-OH,H, R2 = R3 = 0 R' = R3 = 0,R2 = a-OH,H R' = R2= R3 = 0 R' = 0, R2 = R3 = P-OH,H R' = 0,R2= a-OH,H, R3 = P-OH,H

Following the earlier study on the synthesis of 16,17-seco-dicarboxylicacids from cholic a ~ i d a, number ~ ~ ~ of*6-lactones, ~ ~ ~ 5, 14-epi-28,30-bisnorquassinoids, have been ~ynthesized.~'~ Oxidation of the 4-methyloestratetraene (357) and the 4-methyl-19-norpregnatetraene(358) with Os0,-NaIO, gave the bis-aldehydes (359) which were decarbonylated with [(Ph,P),PdCl] to the compounds (360).260

Me0

Me0

CHO

Me0

(357) R = O (358) R = P-Ac,H

13 Heterocyclic Steroids A synthesis of the 17~-[3-pyrrolin-2-on-4-yl]androstane(361) from acetyldigitoxigenin (339) has been reported.261 The conversion of the N-acetyl compound (362) into dihydrosolacongestidine (363) was improved by use of B u ~ A ~ and H thereby improved the synthesis of solacongestidine (364).262 Addition of diarylnitrilimines to a series of 17-substituted androst-16-enes gave the [16a,17cu-d]-2'-pyrazolines (365) or, when R = OAc, the [16,17-d]pyrazoles (366).263 The pyrazolines (367) were synthesized from 3~-acetoxy-21-benzylidenepregn-5-en-20-one by reaction with phenyl- or p-methoxyphenyl-hydra~ine.~~~ Reaction of cholest-4-en-6-one with hydrazines and o-phenylenediamine led to the heterocyclic structures (368) and (369) 257 258

25q 260 261 262 264

See ref. 38, p. 274. J. R. Dias and R. Ramachandra, Org. Preps. Procedures, Internat., 1977, 9, 109. J. R. Dias and R. Ramachandra, J. Org. Chem., 1977,42, 3584. F. M. Hauser and K.-H. Park, J. Org. Chem., 1978, 43, 113. T. W. Guntert, H. H. A. Linde, M. S. Ragab, and S. Spengel, Helv. Chim. Acta, 1978, 61, 977. R. Tschesche and M. Spindler, Chem. Ber., 1978,111, 801. B. Green, B. L. Jensen, and P. L. Lalan, Tetrahedron, 1978,34, 1633. P. Catsoulacos and C. I. Stassinopolou, J. Heterocyclic Chem., 1978, 15, 313.

Terpenoids and Steroids

324

respectively,265and similar compounds were obtained from cholest-5-en-4-one. It was established that mono- and di-acetylation of 17~-(2-amino-oxazol-4-yl)H M O

H

(362) R = Ac (363) R = H

R

1

(367) R = H or OMe

(368) R = H, Me, or Ph

(369)

androstanes (370) occurred only at the exocyclic nitrogen, in contrast to some earlier reports.266A synthesis of the steroidal dioxan (372) has been reported from the 16,17-cycloborate (371) (Scheme 17).267Heterocyclizations of 23substituted 16a, 17a-epoxy-compounds have been and are exemplified by the conversion of the ester (373) into the lactone (374).268 265

266

267

268

269

J. Daunis, G. Del Vecchio, R. Jacquier, H. Lopez, and G. Maury, J. Heterocyclic Chem., 1 9 7 8 , 1 5 2 3 . G. Rapi, M. Grinanneschi, M. Chelli, and A. Andrea, J.C.S. Perkin I, 1978, 249. C. M. Cimarusti, P. Gragowich, R. K. Varma, S. T. Chao, S. D. Levine, and F. L. Weisenborn, J. Org. Chem., 1977, 42, 3035. A. V. Kamernitskii, V. A. Krivoruchko, and I. G. Reshetova, Izvest. A k a d . Nauk S.S.S.R., Ser. khim., 1978, 188. A. V. Kamernitskii, I. G. Reshetova, and K. Y. Chernyuk, Izvest. A k a d . Nauk S.S.S.R., Ser. khim., 1978. 184.

325

Steroid Reactions and Pa rtia 1 Syntheses

OAc

OAc

Reagents: i, THPOCH2CHN2; ii, AczO-pyridine; iii, AcOH-H20; iv, MsC1-pyridine; v, NaHC03DMSO

Scheme 17

,$

CH2C02Et

4

AcO

(373)

(374)

14 Microbiological Transformations Microbial cleavage of sterol side-chains has been reviewed.270Nocardia sp. M29-40 is reported to degrade /3-sitosterol to the hydroxyhexahydroindanone (375).271 0

HO'

-P /

CO, H

(375)

A significant yield (37%) of the 14a-hydroxylated compound (376) was obtained from Withaferin A with Cunninghamella elegans (NRRL 1393).272 270 271

272

C. K. A. Christoph, Adu. Appl. Microbiol., 1977,22,29. U. Schomer, W. S. Sheldrick, and F. Wagner, J.C.S. Perkin I, 1978,337. J. P. Rosazza, A. W. Nicholas, and M. E. Gustafson, Steroids, 1978,31, 671.

326

Terpenoids and Steroids

The mushroom Pleurotus ostreatus (Jacq. ex Fr.) Kumm transformed 3ph ydroxyandrost - 5 -en- 17-one into the 16 -h ydroxylated compound (37 7).273 3p-Hydroxy-Sa-androstan-17-one was 15a-hydroxylated with Fusarium graminearurn whereas the A5-equivalent was mostly 7 a - h ~ d r o x y l a t e d . ~ ~ ~ The B-nor-analogue of Reichstein’s substance S (378) gave four products of mono-hydroxylation (7a-, 1l a - , 11P-, and 15a-) with Beuuveria bassiana. The 3P-hydroxy-A5-analoguewas similarly monohydroxylated at position 11 (a and p ) and position 15 (a).275

The mechanism of 6P-hydroxylation of andro~t-4-ene-3~17-dione and related compounds by Rhizopus arrhizus ATCC 11145 was studied using deuteriumlabelled The reaction appears to involve the formation of the A3*5-dienolsubsequent to the rate-determining step, which may be the binding of the enone to the enzyme. Hydroxylation of 3a-acetoxy-5~-pregnane-20-carboxylicacid with Calonectria decora and Syncephalastrum racernosum has been The highest yield recorded was for 11P-hydroxylation (18%) with S. rucemosum. 6P-Hydroxylation was the major process in the incubation of 3a-acetoxy-17aaza-D-hdmo-5a-androstan-17-one with Cunninghamella elegans whereas 3 a acetoxy-5a -androstan- 17-one was 6p,1l p - d i h y d r ~ x y l a t e d . ~ ~ ~ 273

274

27s

276 277

H. K. Thoa, V. SaSek, M. BudESinskq, I. Jablonsky, L. Eignerova, N . G. Chan, and Z. Prochhka, Coil. Czech. Chem. Comm., 1978,43,336. G. Defaye, M. J . Luche, and E. M. Chambaz, J. Steroid Biochem., 1978,9, 331. V. Sanda, J. FajkoS, and J. Protiva, Coll. Czech. Chem. Comm., 1977, 42, 3646. H. L. Holland and P. R. P. Diakow, Canad. J. Chem., 1978,56, 694. H.-J. Vidic, D. Rosenberg, and K. Kieslich, Chem. Ber., 1978, 111, 2143. T. A. Crabb, J. A. Saul, and R. 0. Williams, J.C.S. Perkin I, 1977, 2599

327

Steroid Reactions and Partial Syntheses

15 Miscellaneous Syntheses The syntheses of carbocyclic spiro-compounds via cycloaddition have been reviewed and sQme steroid examples are included.279 The synthesis of the antimineralocorticoid (379)was reported along with the syntheses of the 60-

(379)

deuterio-, the 6@-bromo-, and the 6a- and 6 @ - m e t h y l - a n a l o g ~ e s The .~~~ 4,6P-ethano-oestratrienes (380) were synthesized through the Friedel-Crafts cyclization of the acid chloride (381).281The 6-substituted cyclohexanopregna-

COCl

(380) R = 0,&OH,H, or &OH, C r C H

(381)

4,6-dien-3-ones (382) have been synthesized.282 Several 11-substituted 17a-acetyl-12,13-epoxyetiojervanes, (384)have been synthesizedzg3from 17ethyl-3@-hydroxyetiojerva-5,12,17(20)-trien-11-one (383)which was shown to

R

(382) R = Me or C1 279

’*’

”’ 282

283

A. P. Krapcho, Synthesis, 1978,77. R. M. Weier, and L. M. Hofmann, J. Medicin. Chem., 1977, 20, 1304. A. C. Ghosh, B. G. Hazra, and W. L. Duax, J. Org. Chem., 1977,42, 3091. A. A. Akhrern, A. V. Kamernitskii, L. E. Kulikova, and I. S. Levina, Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1978,444. A. Murai, H. Sasarnori, and T. Masarnune, Bull. Chem. SOC.Japan, 1978, 51, 234.

Terpenoids and Steroids

328

(384) R = H or Ac

(383)

have the E-configuration for the 17,20-double bond.284Spin-labelled nitroxyl esters (385) were prepared from prednisolone, prednisone, cortisone, and deoxycorticosterone by reaction with the anhydride (386).285 The cholesteryl analogue was also synthesized. The bis-steroids (387), which were synthesized

d

J

0

E

t

I

I

0.

0.

(385) R = H or OH

(386)

\NA

I

(387) n = 4 , 5 , or 10

from conessine, together with similar derivatives synthesized from cholic acid, have been investigated as potential enzyme models.286

284

A. Murai, H. Sasamori, and T. Masarnune, Bull. Chem. SOC.Japan, 1978,51,243.

286

J. McKenna, J. M. McKenna, and D. W. Thornthwaite, J.C.S. Chem. Comm., 1977,809.

**’ W.R. Benson, M. Maienthal, G. C. Yang, E. B. Sheinin, and C. W. Chung, J.Medicin. Chem., 1977, 20, 1308.

Errata

Vol. 8,1978 p. 10, line 23. For ‘salt’ read ‘salts’.

p. 20, last line. For ‘[Pd(PEt),-COJ’ read ‘[Pd(PEt3)3-C02]’. p. 22, line 5. For ‘R = COHMe2’ read ‘R = COCHMe2’. p. 41, ref. 365. Delete ‘as’. p. 49, line 21. For ‘Vulgarole (202; R = Ac)’ read ‘Vulgarole (208; R = Ac)’. p. 58, ref. 522. For ‘Chem Abs., 1977,85, 143 311’ read ‘Chem. Abs., 1976’85, 143 3 11’. p. 160, formulae (75) and (76). Add hydroxy-groups at C-16 and C-20.

329

Author Index

Aasen, A., 10 Aasen, A. J., 4, 178 Abdel-Salam, M., 51 Abdel-Salam, N., 51 Abdullaev, N. G., 242 Abe, F., 47 Abe, K., 238,305 Aberhart, D. J., 187 Abraham, W.-R., 59 Abrahamson, D., 192 Abrahamson, E. W., 238 Abryutina, N. A., 214 Abubakirov, N. K., 171 Abushanab, E., 24 Achini, R. S., 103 Acker, R.-D., 20 Ackerman, M. E., 29 Aclinou, P., 281 Adair, W. L., 247 Adam, G., 174,175 Adam, W., 19,307 Adams, D. R., 16 Adolf, W., 178 Adret, T., 48 Agalidis, I., 239 Agarysheva, 2. I., 39 Ageishi, S., 19 Ageta, H., 215 Aggarwal, R. C., 42 Agosta, W. C., 37 Agurell, S., 79 Ahmad, M. S., 294,295 Ahmad, R., 256,306 Ahmad, S., 167 Ahmed, F. R., 171,198 Ahond, A., 190 Aizawa, M., 241 Akahane, A., 128,150 Akashi, K., 17 Aketa, K.-I., 29 Akhrem, A. A., 327 Akiyama, E., 211, 212 Akiyama, T., 194 Akutagawa, S., 35, 56, 81, 186 Akutsu, H., 190 Albaiges, J., 187, 247 Alberdi Albistegui, M. R.., 60, 72 Albericci, M., 180

Albizati, K. F., 22 Albrecht, H. P., 321 Albrecht, P., 205, 214,219 Alden, R. A., 9 Alderweireldt, F. C., 13 Aleksandrov, G. G., 206 Alemany, A., 173 Aleshina, V. A., 73 Alexander, K., 252 Alexandre, C., 129 Alfano, R. R., 242 Alieva, Sh. A., 171 Allandrieu, C., 236 Allegra, G., 11 Allen, F. H., 8 Allen, M. S., 66 Allinger, N. L., 255, 263 Allison, K., 100 Alper, H., 272 Alper, J. B., 11 Altman, L. J., 187, 192, 223, 227 Altschuh, J., 261 Alvarez Gonzalez, J. R., 64 Amagaya, S., 21 1 Amaro, J. M., 123, 148 Amiard, G., 294 Amirova, G. S.,206 Ananthasubramanian, L., 5 1 Anderson, N. H., 99, 100, 150, 156 Anderson, P. L., 102 Anderson, R. C., 299 Anderson, R. J., 16, 103 Ando, M., 128,129, 150 Andrea, A., 324 Andreetti, G. D., 120, 191 Andrewes, A. G., 222 Andrieu, C. G., 69 Anisimova, 0. S., 280 Anjaneyulu, A. S. R., 190 Antreassian, J., 265 Aoki, T., 21 1 Apfel, M. A., 304 ApSimon, J. W., 183, 205 Aranda, G., 170 Aranguez, L. M., 172 Arata, K., 56, 74 Arbuzov, B. A., 73

331

Archer, R. A., 79 Arends, P., 6 Arigoni, D., 203 Arisawa, M., 210 Armstrong, D. T., 265 Arndt, V., 50 Arnoux, B., 197 Arsent’ev, A. G., 280 Arteaga, J. M., 5 Asada, M., 206 Asai, M., 29 Asakawa, Y., 121, 157,181 Asato, A. E., 231, 233 Ashby, E. C., 19 Ashmore, J. W., 122 Assante, G., 86 Astier, A., 259, 278, 321 Atal, C. K., 27, 76, 210 Aton, B., 239,242 Auel, R. A. M., 313 Aviv, D., 25 Axelrod, M., 7 Ayanoglu, E., 119 Ayer, W. A., 86 Aynehchi, Y., 196 Baas, W. J., 208 Babiak, K. A., 72, 270 Bachmann, J.-P., 46, 103 Bachmann, K., 59 Back, T. G., 289 Baddeley, G. V., 189,202 Badripersaud, S., 205 Baerheim Svendsen, A., 16 Baert, F., 7, 8 Bagheri, M., 196 Baig, M. H., 295 Bailey, T. R., 17 Baker, F. C., 24 Baker, R., 38,85 Bakhtinov, A. A., 39 Bal, B. S., 24 Bal, K., 315 Balashov, S. P., 242 Baldwin, J. E., 79 Baldwin, S. W., 69 Baloch, A. K., 238 Balogh-Nair, V.. 242

332 Balsevich, J., 63 Baltes, H., 31 Balyeat, J. R., 69 Bambagiotti, M., 55, 58 Bandaranayake, W. M., 10 Banerjee, A., 166 Banerjee, A. K., 183 Banerjee, S., 66 Banerji, N., 211 Bang, L., 107 Bangham, A. D., 241 Ban’ Kovski, A. I., 168 Banno, K., 116 Banthorpe, D. V., 25 Baptista, A., 8 Baranowska, E., 213 Barany, F., 37 Baranyai, M., 221 Barata, L. E. S., 161 Barbe, G., 265 Barbot, F., 31 Bardouille, V., 116 Bardou, L. G., 263 Bardyshev, I. I., 54, 59,72,73 Barillier, D., 69 Barkhash, V. A., 54 Barrans, Y.,10 Barrero, A. F., 161 Barta, M. A., 271 Barthtlkmy, M., 70 Bartho, R., 212 Barton, D. H. R., 18, 23, 203, 226,275,279,285,288,294, 298 Barton, D. L., 37 Barton, H., 24 Barua, A. B., 234,247 Basa, S. C., 77 Basabe, P., 161 Bascoul, J., 292 Baslas, R. K., 55 Basta, M. A., 310 Bates, R. B., 156 Bathia, M. S., 16 Batta, A. K., 262, 307 Battig, K., 103 Batzold, F. H., 257 Baudry, D., 17 Bauer, L., 110,202 Bauer, P. J., 240 Bauerova, O., 192 Bauman, B. A., 287 Baumann, C., 218 Baxter, R. L., 38 Baylocq, D., 268 Bazbouz, A., 69 Bazyl’chik, V. V., 57, 58, 59 Beard, C. C., 36 Beaupin, C., 46 Becher, B., 242 Becker, C., 51 Becker, R. S., 239, 240,241 Beckwith, A. L. J., 38 Beddard, G., 242

Author Index Beeby, P. J., 209 Beechan, C. M., 119 Beg, M. F. A., 210 Begley, M. J., 6, 10 BiguC, J.-P., 68 Behari, M., 27 Behr, D., 32,60, 178, 224 Bekker, A. R., 232,235 Bell, A. A., 108, 109 Bellesia, F., 120 Bellino, A., 172 Belobaba, D. T. E., 305 Belzecki, C., 14 Benayache, S., 63 Benayahu, Y.,177 Benecke, R., 16 BeneSovi, V., 156 Bengtson, J. M., 272 Benn, R., 31 Bennet, R. D., 196 Bennett, G. B., 16 Bennett, J. A., 240 Benschop, H. P., 7 Benson, W. R., 264, 328 Bensosson, R., 240, 242 Ben-Zvi, Z., 79 Berbalk, H., 307 Berdichevskaya, A. M., 234 Berg, J. E., 178 Berges, D. A., 45, 137 Bergmann, F., 28 Bergot, B. J., 16 Berkaloff, C., 237 Berman, E., 258 Bermejo, F., 164 Bermejo, J., 123, 148 Bernassau, J. M., 170 Bernstein, H. J., 237, 239 Berthou, F. L., 263 Berthou, J., 8 Bertolino, A., 192 Bertrand, M., 34 Bessikre, Y.,56, 70, 71 Beukes, M. S., 42 Beyer, P., 222 Bhar, D. S.,203 Bhardwaj, T. R., 295 Bhat, S. V., 167 Bhatia, I. S., 238 Bhatnagar, S. P., 16 Bhattacharvyam, J., 175 Bhattacharya, P. K., 281 Bhattacharyya, P. K., 36 Bhattacharyya, S. C., 51, 76 Bhutani, K. K., 295 Bianco, A., 47,48 Bickel, H., 252 Bierenbaum, R., 21 Biftu, T., 193 Bigler, F., 247 Biglino, G., 193 Bignardi, G., 69 Bikbulatova, G. Sh., 74 Bildinov, K. N., 265

Biller, S. A., 17 Billet, D., 165 Billings, R. F., 26 Birch, M. C., 26 Birge, R. R., 240 Birnbaum, G. I., 156,205 Bissonette, P., 100 Biollaz, M., 270 Bjornsson, T. D., 251 Blackman, A. J., 160 Blanchard, W. B., 79 Blaschke, T. F., 251 Blaszczak, L. C., 102 Bledsoe, J. O., jun., 74 Bloch, R., 24 Blomquist, C. H., 265 Blount, J. F., 7, 122, 177 Blum, M. S., 46 Blunt, J. W., 170, 186 Boar, R. B., 190,203,294 Bocelli, G., 120, 191 Bochwic, B., 51 Bock, K., 1 7 , 9 1 Bode, J., 239 Bodea, C., 222,230 Boden, R. M., 94 Bodenhausen, G., 11 Bodkin, C. L., 38 Bodner, M., 177 Bohm, R., 293 Boeren, E. G., 10,78,79 Boeyens, J. C. A., 286 Bogacheva, K. I., 39 Bogatkina, V. F., 207 Bogomolni, R. A., 242 Bogucka-Ledochowska, M., 116 Bohlmann, F., 50, 58, 59, 82, 91, 108, 110, 122, 123, 124, 139,142,149,158,161,164, 165, 166,167, 171,173 Boisseau, J., 29 Boix, J., 299 Bokadia, K. P., 50 Bokadia, M. M., 50 Bolliger, H. R., 238 Bond, F. T., 21,69 Bondavalli, F., 57 Bonini, C. C., 47,48 Bonnet, J. J., 8, 299 Bontinck, R., 238 Borbon, J., 187, 247 Borch, G., 220, 222 Borden, J. H., 45 Bordner, J., 10 Borges, J., 155 Borowiecki, L., 65 Borowski, E., 116 Borsje, B., 238 Bosik, S., 201 Bosch, T., 50 Bose, A. K., 7 Bouquant, J., 11 Bourcier, S.. 4

Author Index Boussac, G., 70, 71 Bowden, B. F., 177, 180 Boyd, G. S., 170 Boyer, J., 58 Bradlow, H. L., 267 Bradshaw, A. P. W., 116, 159 Braekman, J. C., 119,156, 177, 180 Braga de Oliveira, A., 110 Branca, S. J., 102 Brand, J. M., 46 Bratus, I. N., 39 Brauman, J. I., 19 Braun, V. C., 318 Brawn, R. J., 267 BrazFilho, R., 110 Brecknell, D. G., 136 Bredell, L. D., 199 Brehmer, L., 241 Breitholle, E. G., 106 Breitmaier, E., 32 Brems, D. N., 24 Breuer, H., 319 Brianso, J. L., 299 Brianso, M. C., 299 Brice, M. J., 10 Brieskorn, C. H., 206, 212 Brine, D. R., 78 Briner, P. H., 85 Brion, F., 62 Brittain, H. G., 64 Brittle, J. A., 177 Britton, G., 220,230,243,244, 246 Broess, A. I. A., 319 Brooks, P. W., 214 Brossi, A., 78 Brouard, J. P., 165 Brown, B. O., 10 Brown, C. A., 22, 70 Brown, D. A., 199 Brown, D. R., 281 Brown, F. C., 63, 66 Brown, H. C., 14 Brown, H. M., 240 Brown, K. L., 8 Brown, R. H., 231 Brown, R. T., 48 Brubaker, G. R., 9 Brueckner, D. A., 8 Bruhn, W., 94 Brunel, Y., 8 Brunetti, P., 73 Brunie, S., 8 Bruning, R., 126 Brunke, E.-J., 283, 293 Brunner, H. G., 15, 203 Bryan, R. F., 9 Bryant, P. J., 78 Bualek, S., 13 Bubnov, Yu. N., 21 Buchan, G. M., 39 Buchanan, G. L., 58 Buchbauer, G., 9, 64, 65, 169

333 Buchecker, R., 318,220 Bucholtz, M. L., 246 Buck, H. M., 32,186 Buckle, K. A., 238 Buckwalter, B. L., 143 Bucourt, R., 288, 293, 294 Buddhasukh, D., 143 Buddrus, J., 107 Budeiinsky, M., 181, 326 Buchi, G., 156 Buhrer, H., 51 Burkle, W., 15 Buyuktur, G., 306 Burgstahler, A. W., 9 Buil, P., 27 Buinova, E. F., 54 Bujtas, G., 221 Bu’Lock, J. D., 248 Bull, J. R., 286 Bundy, G. L., 23 Burfitt, I. R., 202 Burka, L. T., 83 Burke, S. D., 94, 129, 151 Burkert, U., 255 Burke-Laing, M. E., 212 Burmistrova, M. S., 278 Bursey, J. T., 78 Bylina, G. S., 278 Byon, C.-Y., 260, 304, 306 Caballero, E., 161 Cabrera, I., 148 Cadosch, H., 221 Cafieri, F., 180 Caine, D., 283 Cais, M., 78 Calas, R., 16 Callender, R. H., 239, 242 Calton, G. J., 157 Cambie, R. C., 170, 276, 287 Camerman, A., 7 Cameron, G. G., 39 Campbell, A. C., 317 Campbell, C. B., 17 Campbell, D. A., 188 Campbell, D. E., 19 Campion, A., 239 Camps, F., 18, 36 Campsteyn, H., 207 Camus, A., 19 Cane, D. E., 87, 116 Canela, R., 36 Canonica, L., 89, 172 Cinovas, A., 299 Capka, M., 15 Caputo, O., 193 Caputo, R., 196 Carayon, A., 265 Carazza, F., 110 Cardillo, G., 30 Carey, F. A., 9 Carey, P. R., 237,239 Carey, S. S., 31 1 Carl, P., 240, 242

Carlson, G. L., 305 Carlson, R. M., 120 Carman, R. M., 136 Carrell, H. L., 257 Carrillo Sanchez, H. C., 164 Carrington, R., 256 Carruthers, R., 63 Casadevall, E., 66 Casella, L., 9 Casey, J., 252 Cashyap, M. M., 25 Casida, J. E., 9, 29 Casinovi, C. G., 50 Caspi, E., 187 Cassady, J. M., 214 Castonguay, A., 31? Catalan, C. A. N., 72 Catsoulacos, P., 323 Cattel, L., 193 Cazes, B., 40 Ceccherelli, P., 170 Cecchi, A., 58 Cerfontain, H., 237 Cernigliaro, G. J., 36 Cernjr, V., 275, 296, 305 Cesario, M., 258, 311 Cesselin, F., 265 Chabardes, P., 35, 231 Chabudzinski, Z., 51, 67 Chae, Q., 240 Chafin, T. C., 59 Chaineaux, J., 37 Chakraborty, D. P., 4, 10 Chakravarti, R. N., 208 Chambaz, E. M., 326 Chamberlin, A. R., 21, 69 Chambers, D., 276 Chan, N. G., 326 Chan, W. H., 20 Chandel, R. S., 212 Chandrasekharan, S., 198 Chang, P. T. O., 212 Chang, T. Y., 187 Chang, Y.-H., 19 Chantrell, S. J., 240 Chao, S. T., 324 Chapman, D. J., 246 Charles, G., 291 Charpentier-Morize, M., 68 Chass, D. A., 143 Chatterjee, A., 166 Chatzopoulos-Ouar, F., 70 Chauhan, J. S., 203 Chaudhri, R., 315 Chavis, C., 292 Chawla, H. P. S., 111 Cheer, C. J., 156 Chekulaeva, L. N., 242 Chelli, M., 324 Chelovskaya, L. N., 28 Chen, C. M., 172 Chen, G. C., 12 Chen, L.-.C., 61 Cherbuliez, E., 5

334 Chernousova, N. I., 39 Cherry, R. J., 242 Chernukhina, L. A., 251 Chernyuk, K. Y., 324 Chhabra, B. R., 112 Childs, R. F., 62 Chidgey, R., 62 Chino, N., 266 Chirva, V. Y., 210 Chizhevich, E. P., 231 Cho, H., 54, 138 Choay, P., 269, 306 Chobanu, V. I., 28 Chou, P. N., 179 Choudhary, D. K., 27 Chowdhury, B. K., 10 Christensen, N. J., 29 Christie, R. M., 79 Christol, H., 69 Christoph, C. K. A., 325 Chuche, J., 11 Chuiko, V. A., 72 Chuit, C., 35 Chuman, T., 46, 178 Chung, C. W., 264,328 Ciani, G., 9 Ciereszka, L. S., 179 Cimarusti, C. M., 324 Cinos de la Mano, M. S., 164 Ciper, F., 32 Cittanova, N., 267 Clardy, J., 5, 6, 85, 116, 157, 162,176,181,264 Clark, B. C. jun., 59 Clark, E. R., 320 Clarke, D. G., 10 Clastres, A,, 190 Clinet, J.-C., 30, 34 Clive, D. L. J., 16, 18, 275 Close, R. E., 31 Coates, P., 177 Cochran, T. G., 7 Cocker, D. S., 188, 319 Cocker, W., 60, 73,74 Coddington, J. M., 64 Cody, V., 256 Cogdell, R. J., 239 Coben, Z., 302 Cole, J. R., 124, 208 Cole, S. M., 20 Colin, H., 237 Coll, J., 18, 36 Coll, J. C., 177, 180 Collet, A., 13, 262 Collins, D. C., 266 Collins, D. J., 279 Collman, J. P., 19 Colombo, A., 3 1 Colombo, L., 89 Colombi, S., 279 Colvin, E. W., 97 Combaut, G., 160 Comeau, L. C., 207 Condom, R., 265

Author Index Conia, J. M., 65, 285 Connolly, J. D., 198, 199 Connor, A. H., 167 Contento, M., 30 Cooke, F., 23 Cookingham, R., 239 Cookson, R. C., 234 Cooley, G., 315 Copley, D. J., 282 Copsey, D. P., 190 Coran, S. A., 55,58 Corbett, R. E., 215 Cordell, G. A., 4, 122, 178, 200,212 Corey, E. J., 16, 52 Corke, N. T., 64 Corrales, B., 72 Corriu, R. J. P., 58 Corsano, S . , 177 Corsetti, J. P., 240 Cortese, N. A., 19 Cory, R. M., 141 Coste, J., 69 Costes, C., 230 Cotter, M. L., 280, 319 Couffignal, R., 34 Couldwell, C., 9 Coulson, W. F., 315 Counsell, R. E., 319 Coutrot, P., 22 Covey, D. F., 257 Coxon, J. M., 10, 64, 259 Crabb, T. A., 326 CrabbC, P., 18, 56 Craig, D. P., 13 Cramer, R., 197 Crastes de Paulet, A., 292 Craveiro, A. A., 143 Crespi, H., 239 Crews, P., 5, 12,43, 160 Critch, S. C., 67 Croft, K. D., 110, 173 Crombie, L.,6, 10, 35 Cros, E., 56 Croteau, R., 25 Crowley, K. J., 60, 71 Cruickshank, D. W. J., 5 Cruz, A., 322 Cruz, M. S., 275 Cubberley, B. W., 296 Cunlifie, A. V., 32 Cuomo, J., 287 Cupano, J., 310 Cupas, C. A., 24 Curini, M., 170 Curvall, M., 164 Cussans, N. J., 18, 23, 285 Cutler, H. G., 161 Cyronak, M. J., 230 Czarny, M. R., 187, 307 Czerson, H., 110, 123, 149 da Cunha Pinto, A., 167 D’Auria, M., 28

Dahlgren, R., 47 Dailey, 0. D. jun., 9 Dailey, R. G., 99 Daloze, D., 119, 156, 177, 180 Daly, J. J., 125 Dalzell, H. C . , 78, 79 Dampawaa, P., 202 Dandliker, W. B., 267 Dani, S., 78 Danieli, B., 210 Daniil, D., 66 Danilov, L. L., 36, 247 Dansted, E., 10 Danter, Z., 116 Darby, N., 66 Darias, J., 101 Dartnell, H. J. A., 242 Das, D. P., 77 Das, K. C., 10 Das, P. K., 239, 241 Das, R. C., 247 Dasgupta, A,, 216 Dathe, W., 175 Dauben, W. G., 7 Daunis, J., 324 David, G., 28 Davies, B. H., 218 Davis, B. R., 183, 283, 298 Davis, R. E., 3 Davis, S. G., 240 Davydova, L. P., 232 Dawe, E. A., 240 Day, W. A., 79 Dayal, B., 262, 307 de A. B. Silva, G. A., 110 de Alleluia, I. B., 78 De Camp, W. H., 255 de Clercq, P., 151, 154 de Freitas Leitao Filho, H., 171 de Haan, J. W., 32, 186 de Grazia, C. G., 171 De Jong, A. J., 33 de Jongh, H. P., 319 De Keukeleire, D., 151 de la Mare, P. B. D., 277 De Luca, H. F., 310 de Luque, M., 203 de Mayo, P., 66 de Napoli, L., 180 de Oliveira, G. G., 110 de Pascual Teresa, J., 60, 72, 161, 164 De Rosa, S., 248 de Silva, J. A. F., 238 De Simone, R. S., 39 de Souza, J. P., 61 De Titta, G. T., 128 de Waard, E. R., 30 De Wilde, H., 20 de Wolf, W. H., 192 de Visser, J., 319 de Vries, E. J., 268 Deakyne, C., 242 Declerq, J. P., 207

Author Index Decor, J. P., 231 Dedeunvaerder, H., 177 Defaye, G., 326 Dehal, S. S., 284 Dekanosidze, G. E., 21 1 Delassalle, A., 265 Deleris, G., 16 Deletang, J., 161 Dellepiane, G., 239 Delpech, B., 259 Delprino, L., 193 Deluca, H. F., 238 Del Vecchio, G., 324 Demole, E., 138 Den, K., 266 Dencher, N. A., 242 Denis, J. N., 41 Denisenko, V. A., 75 Denny, M., 231,233 Derdzinski, K., 33 Derfer, J. M., 31 Derguini-BoumCchal, F., 56 Derks, H. J. G. M., 315 Derry, J. E., 3 Deruaz, D., 281 Desage, Y., 281 Descotes, G., 236 Desgrez, P., 265 Deshayes, H., 19 Deshchits, G. V., 59, 73 Des Roches, D., 272 Dessy, G., 9 Dev, S., 18, 50, 90, 111, 192 Devaprabhakara, D., 114 Devos, M. J., 41 Dey, A. K., 164 Dhar, D. N., 58 Dhar, K. L., 76,210 Dhar, M. M., 162 Dhekne, V. V., 55 Diakow, P. R. P., 326 Dias, J. R., 200, 323 Di Corcia, A., 15 Dideberg, O., 207 Dietsche, T. J., 21 Dighe, S. S., 75 Dike, S. Y., 79 Dimmel, D. R., 73 Dionne, G., 322 Divakar, K. J., 53 Dizdar, A. V., 28 Djerassi, C., 51, 119, 156, 190, 261,262,263,285,305,306, 313 Dmitrovskii, A. A., 234 Dockerill, B., 98, 171, 175 Dobler, C., 14 DoKhac Manh, 184 DolejS, L., 192 Dolotov, S. M., 232 Donchenko, G. C., 251 Donohue, J., 7 Doorenbos, N. J., 175 Doppelberger, J., 15

335 Dorn, F., 26 Dorner, W., 50, 122 Doskotch, R. W., 122 Douglas, T. J., 188 Doukas, A. G., 239 Doyle, M. P., 22 Drawert, F., 24 Drayer, N. M., 315 Dren, A. T., 79 Driguez, H., 286 Droidi, B., 148 Druet, D., 207 Duax, W. L., 255,256,327 Dube, J., 288 Dubovenko, Z. V., 54 Duddeck, H., 210 Durner, G., 226 Duffield, A. M., 10 Duffield, R. M., 46 Dunogues, J., 16 Dunne, L. J., 242 Duong, T., 38 Dupont, L., 207 Durgeat, M., 165 Duschek, Ch., 77 Dutky, S. R., 188, 191 Duval, D., 265 Dwivedi, G. L., 9 Dzhemilev, U. M., 39,278 Dzizenko, A. K., 193 Eagle, G. A., 163 Ebel, J., 136 Ebrey, T. G., 239, 242 Eckhard, G., 223 Edelson, J., 266 Eden, Y., 78 Eder, U., 316 Edmunds, R., 305 Edwards, J. H., 36, 37 Edwards, R. A., 238 Edwards, R. W. H., 267 Egberg, D. C., 238 Eggelte, H. J., 19, 307 Eglinton, G., 237 Eguchi, S., 12, 70 Ehlers, C., 42 Ehlers, D., 50, 59, 122, 139 Ehmann, W. J., 57 Ehrenberg, B., 239 Eibach, F., 20 Eichenberger, H., 236 Eichinger, K., 307 Eiermann, B., 48 Eignerova, L., 326 Eissenstat, M. A., 20 Ekong, D. E. U., 179 Ekstrand, J. D., 179 Ekundayo, O., 25 El-Feraly, F. S., 10, 122 Elgamal, M. H. R., 193,210 Eliseeva, G. I., 247 Elliott, M. 29 El Masry, A. H., 318

Eloranta, J., 64 Elphimoff-Felkin, I., 56 El-Sayed, M. A., 239 Elsohly, M. A., 10, 78, 79, 150 Elyakov, G. B., 193 El’yanov, B. S., 290 Emiliozzi, R., 265 Emodi, A., 218 Endo, M., 21 Engel, Ch. R., 313, 322 Engel, J. L., 29 Engel, K., 319 Engen, D. V., 85 Enger, A., 301 Enggist, P., 138 Engler, D. A., 18, 286 Englert, G., 243, 247 Engovatov, A. A., 228,229 Enomoto, S., 44 Enqvist, J., 67 Ensley, H. E., 52 Ensminger, A., 214 Enzell, C. R., 4, 32, 60, 164, 178,224 Epe, B., 197 Ephritikhine, M., 17 Epstein, W. W., 40,75 Erdman, A. A., 65 Erickson, K. L., 126 Erman, W. F., 93 Ernst, L., 66 Ernst, R. R., 63 Ernstbrunner, E. E., 64,261 Errington, S. G., 203 Eschenmoser, W., 228 Esteban, I., 28 Eugster, C. H., 5, 168, 169, 218,220,221,228 Evans, D. A., 26,62,85,285 Evans, F. J., 178 Evags, R., 87, 175 Evstigneeva, R. P., 36,231,238 Eyssen, H., 309 FQbregas,J. L., 5 1 Fackler, J. P., jun., 8 Fager, R., 238 Fahey, D., 244 Fairchild, E. H., 122 FajkoS, J., 309, 322, 326 Fakhretdinov, R. N., 39 Fakunle, C. O., 179 Fales, H. M., 46 Falgueirettes, J., 7 Fallis, A. G., 67, 106, 198,315 Falvello, L., 10 Fang, H. L. B., 239 Fardella, G., 177 Fares, V., 9 Farias, G. M., 51 Farnham, A. W., 29 Farnham, W. B., 7 Farnsworth, N. R., 122, 178, 200,212

336 Farrell, I. W., 157 Fattorusso, E., 180 Faulkner, D. J., 5, 43, 44, 85, 137 Favrot, J., 242 Fayos, J., 5, 162 Federlin, P., 12 Federova, 0. I., 278 Fedoreev, S. A., 75 Fedorov, P. I., 57, 58 Feigenbaum, A,, 301 Feigina, M. Yu,242 Felkin, H., 17 Fenical, W., 43, 90, 157, 162, 179 Ferguson, G., 6, 8 , 9 , 255, 256 Ferrari, G., 172 Ferrier, J. P., 268 Fetizon,M., 163,170,184,271, 295 Fiedler, L., 82, 122 Fiksdahl, A., 237 Filatova, T. I., 39 Fiorini, M., 14 Finar, J., 162 Findlay, J. A., 156 Finer, J., 116, 157 Finke, R. G., 19 Finkel’shtein, E. I., 232 Firl, J., 50 Firouzabadi, H., 17 Fischer, M., 298 Fleischer, E. B., 7 Floch, H. H., 263 Floor, J., 286 Flores, H., 155 Fo, R. B., 78 Focella, A., 78 Fong, H. H. S., 212 Fontell, K., 240 Forne, E., 56 Forni, A., 14 Forrest, G. I., 27 Forys, W., 58 Foulon, M., 7, 8 Fouret, R., 7 , 8 Fournier, J., 69 Fowell, D. T., 206 Fox, D. L., 246 Fracheboud, M. G., 120 Fraefel, A., 51 Fraga, B. M., 173,174 Francisco, C., 160 Francke, W., 27 Franck-Neumann, M., 41,62 Franco, J. M., 8 Franke, P., 210 Frankhauser, P., 223 Fraser, R. K., 63 Fraser-Reid, B., 54, 299 Frasinel, C., 188 Frater, G., 71, 129 Freeman, P. K., 69 Freeman, R., 11

Author Index Freerkson, R. W., 313 Frei, B., 236 Frejaville, C., 63 Friedman, N., 258, 311 Fringuelli, F., 73 Fristad, W. E., 17 Fritchie, C. J., 8 Frith, R. G., 316 Fritsch, W., 321 Frobese, A. S., 283 Froborg, J., 114 Frolik, C. A., 238 Fryxell, P. A., 109 Fuchs, P. L., 275 Fuchs, S., 197 Fueno, T., 285 Fuji, K., 6, 160 Fujihara, Y., 52 Fujii, K. T., 266 Fujimori, T., 147, 178 Fujita, A., 67 Fujita, C., 294 Fujita, E., 160, 174, 184 Fujita, K., 251 Fujita, M., 235 Fujita, S.-I., 26, 27 Fujita, Y., 4, 26, 27, 35, 234 Fujitsu, H., 31 Fukazawa, Y., 8 Fukui, H., 223 Fukumoto, K., 37, 204 Fukunaga, Y., 247 Fukuyo, M., 6 Fukuzumi, T., 178 Fullerton, T. J., 21 Fullmer, D. G., 29 Fung, S., 86 Fung, Y. K., 238 Furlani, A., 11 Furusaki, A., 101, 147 Furuya, K., 266 Furuyama, H., 266 Gabadadze, T. V., 211 Gabe, E. J., 7, 205 Gacs-Baitz, E., 177 Gaglioti, L., 289 Gailyunas, I. A., 18 Gal’chenko, G. L., 73 GalignC, J.-L., 7 Galindo, A., 123, 148 Gall, R. E., 297 Gallino, M., 28 Gallotti, A. M. P., 238 Galun, E., 25 Gambacorta, A,, 248 Can, 0. H. M., 78 Gandolfi, O., 78 Ganguli, S. N., 10 Gansel, C. R., 27 Gantchev, G. P. 75 Garbers, C. F., 42 Garcia, D., 54 Garcia, I., 322

Gardia, M., 121, 149 Garcia-Blanco, S., 8, 164 Garcia Martinez, A., 64 Gardner, J. O., 36 Garnero, J., 27, 163 Garrett, E. R., 80 Gasparrini, F., 289 Gassman, P. G., 20 Gastambide, B., 281 Gaughan, L. C., 29 Gautschi, F., 223 Gawinowicz, M. A., 242 Gayot, G., 29 Gearien, J. E., 202 Gebreyesus, T., 119 Gedge, D. R., 76 Geenevasen, J. A. J., 237 Gelbart, A., 322 Gellert, M., 213 Gennari, C., 89 Genov, W. S., 75 Gentles, M. J., 257, 290 Georgiev, E. V., 75 Geraghty, N. W. A., 73 Germain, G., 207 Gershenzon, J., 27 Ghaderi, E., 17 Ghatak, A. K., 242 Ghatak, U. R., 184 Ghisalberti, E. L., 110, 173, 177,178,203 Ghosh, A., 79 Ghosh, A. C., 327 Gibson, T. W., 93 Giddings, M. R., 64, 261 Giger, R., 203 Gilbert, D. P., 20 Gill, G. B., 10 Gilman, S., 128, 151 Gilmore, A. R., 27 Ginebreda, A., 23 Ginzburg, M. A., 39 Giongo, G. M., 14 Giuseppetti, G., 258 Gladysz, J. A., 71 Glotter, E., 256,273,276,283, 296 Glusker, J. P., 257 Glukhoded, 1. S., 247 Go, K. T., 7 Goad, L. J., 190, 192 Godel, T., 110 Goebelsmann, U., 266 Goel, A. B., 19 Goewert, R. R., 252 Gogte, V. N., 12 Gohbara, M., 181 Golec, F. A., 150 Golob, N. F., 45, 137 Gomel, M., 12 Gomez Marin, M., 64 Goncalves, A. M. R., 61 Gonzalez, A. G., 5, 101, 123, 148, 174

Author Index Gonzllez, J., 164 Gonzllez Mateos, F., 161 Goodhead, K., 51 Goodwin, T. W., 190,192,220, 243,246 Gordon, D. C., 50 GorC, J., 294 Gorina, N. Yu, 231 Gors, C., 8 Gosselin, P., 40 Goswami, A., 216 Goto, J., 266 Goto, S., 18 Goto, T., 129 Gottlieb, H. E., 259 Gottlieb, 0. R.,78 Gouyette, A. J., 80 Govindjee, R.,242 Goyal, I. C., 242 Grabarczyk, H., 148 Grabowich, P., 324 Gracheva, I. N., 234 Gradeff, P. S., 39 Grainger, H. S., 238 Grande, M., 161, 164 Grande Benito, M., 60, 72 Grandi, R.,28 Grandolini, G., 50 Grange, D. K., 247 Granger, R., 46 Grant, D. F., 7 Gras, J.-L., 70 Gray, R. T., 6 Grayson, D. H., 73,74 Greaves, J. H., 51 Green, B., 323 Green, B. H., 242 Green, M., 7 Green, M. J., 257,317 Greene, A. E., 180 Gregoire, J., 209 Gregorius, H. R.,28 Gregory, B., 315 Greiner, A. C., 205,214 Grenz, M., 50,59, 122, 173 Grevels, F.-W., 7 Grieco, P. A., 17, 23, 94, 128, 129,151,273 Grieder, A., 126 Griffith, 0. H., 240 Grigoryan, M. Sh., 21 Grimm, K. G., 285 Grimm, M. F., 252 Grimminger, W., 197 Grinanneschi, M., 324 Grinenko, G. S., 278, 280 Grisebach, H., 136 Grison, C., 71 Gros, C., 4 Gross, J., 218, 223 Grotjahn, L., 293 Gross, K. P., 51 Grote, H., 78 Groweiss, A., 179

337 Gruber, J. M., 286 Grundon, M. F., 4 Grushka, E., 29 GryiT-Keller, A., 61 Guastini, C., 11 Giintert, T. W., 323 GuCrin, M., 12 Guest, I. G., 296 Guffroy, A., 268 Guichon, G., 237 Guilhem, J., 258, 311 Guilluy, R.,281 Guiso, M., 47, 48 Guittet, E., 34 Gullotti, M., 9 Gupta, B. D., 242 Gupta, G. S., 27 Gurpide, E., 268 Gurria, G. M., 72, 270 Gustafson, M. E., 325 Gut, M., 260,304, 306 Gutman-Naveh, N., 108 Gutshall, P. L., 78

Harano, K., 294 Harashima, K., 243 Harayama, T., 54, 138 Harington, J. S., 97 Harlow, R. L., 9 Harrirnan, G. A., 220 Harris, R.K., 32 Harris, R. N., 157 Hart, D. J., 62 Hartshorn, M. P., 10, 170, 186 Harvala, C., 207 Harvey, D. J., 78,79, 262 Harvey, T. M., 78 Hase, 201 Hasegawa, K., 24 Hasegawa, S., 196 Hashiba, N., 101, 147 Hashimoto, H., 24, 31, 33 Haslouin, J., 33 Hatakeyama, M., 241 Hatanaka, Y., 67 Hatsui, T., 101 Haupt, O., 320 Hauser, A., 223 Habermehl, G., 190, 307 Hauser, F. M., 323 Hauser, S., 174 Hache, K., 226 Havens, J. L., 271, 310 Hackler, R. E., 36 Haxo, F. T., 246 Hadd, H. E., 307 Hayakawa, A., 188 Haddon, W. F., 174 Hayakawa, K., 39 Haede, W., 321 Hayakawa, Y., 24,61,96 Hanni, R., 247 Hansel, H., 241 Hayano, K., 114 Hafez, A., 178 Hayashi, C., 266, 267 Haffer, G., 316 Hayashi, S., 4, 12, 70, 96, 99, Hagaman, E. W., 259 156,181 Hayashi, T., 32, 53, 175 Hagitani, A., 286 Hagiwara, K., 193 Hayashi, Y., ' 16, 167, 168 Hainaut, D., 293 Haynes, R. k.,55,279 Haire, M. J., 288 Hayward, R. C., 170,287 Hajibrahirn, S. K., 237 Hazel, J., 256 Hakanson, E. Y., 265 Hazra, B. G., 327 Heck, R. F., 19 Hall, D., 8 Hall, E. A. H., 229 Hecker, E., 178 Hall, M. S., 24, 85 Hedden, P., 172, 174 Heemann, V., 27 Hall, S. R., 178 Hefendehl, F. W., 149 Hall, T.-W., 142 Heftmann, E., 174 Hallegraef, G. M., 237 Heggemeier, H., 13 Halsall, T. G., 157, 199 Hegnauer, R.,45 Hamilton, W., 189 Heist, R. H., 51 Hamor, T. A., 3, 8 Heitz, S., 165 Han, C. Y., 192 Helbling, A. M., 49 Hana, G. W., 9 , 6 5 Hellwege, D. M., 238 Hanafusa, T., 41 Hemley, R., 239,242 Handa, V. K., 78 Hempel, A., 116 Handjieva, N., 48 Henderson, K., 279 Handrick, G. R., 78, 79 Hands, D., 306 Hendry, L. B., 26 Henneberg, D., 31 Handy, G., 192 Hennion, J., 31 Hansen, P.-E., 275 Hanson, J. R., 87,98,116,159, Henrick, C. A., 16 165,166,171,173,175,273, Hentchoya Vemo, J., 291 Hebert, E. W., 191 297 Herbstein, F. H., 8 Hara, S., 268 Hernindez, M. G., 173,174 Haraguchi, Y., 203

338 Heroff, J. C., 238 Herout, V., 156 Herpin, P., 8 Herranz, E., 17 Herrero, J. A., 164 Herring, P. J., 237 Hervo, G., 239 H e n , J. E., 275 Herz, W., 122, 148, 166, 167, 171 Hess, B., 242 Hesse, R. H., 298 Heyn, M. P., 242 Hicks, A. N., 267 Hicks, D. R., 54,299 Higgs, M. D., 5, 26,43 Higuchi, R., 210 Hikino, H., 4 Hill, D. L., 238 Hill, R. K., 120 Hiller, K., 210 Hiltunen, R., 28 Hirabayashi, M., 6 Hirai, N., 223 Hirai, Y., 204 Hiramatsu, T., 39 Hirano, H., 78 Hirata, K., 231 Hirata, T., 53, 193 Hirata, Y., 18, 126, 188 Hirose, Y., 44,67 Hirotsu, K., 116, 162, 172 Hirsch, A. F., 319 Hisayama, M., 77 Hitchcock, P. B., 87, 165, 66 Hiyama, T., 31 Htadon, B., 148 Hoa Ai, T., 189 Hoard, L. G., 258 Hocart, C. H., 110 Hochstrasser, R. M., 240 Hodge, P., 16 Hodges, R. E., 238 Hofle, G., 16 Hoft, E., 14 Hoffman, E. G., 31 Hoffman, J. J., 124 Hoffman, W., 218 Hoffmann, H. M. R., 62 Hofmann, A. F., 305 Hofmann, L. M., 327 Hojo, S., 190 Hokanson, G. C., 214 Holan, G., 29 Holder, G. M., 261, 285 Holder, N. L., 54 Holker, J. S. E., 261, 285 Holland, H. L., 260, 326 Hollister, L. E., 78 Holmstead, R. L., 28, 29 Holub, M., 148 Hornberg, E., 267 Honda, T., 210 Honig, B., 239, 242

Author Index Hooper, J. W., 205 Hopkins, D. L., 233, 240 Hopkins, P. B., 275 Hoppmann, A., 12,21 Hor, Y.-C., 62 Horeau, A., 7, 13 Hori, T., 18.20 Horiba, M., 28 Horino, J., 29 Horiuchi, K., 231 Horn, M., 78 Hornicki, C. A., 286 Horrocks, W. De W. jun., 9 Horvath, L., 239 Hosangadi, B. D., 51 Hoshi, N., 22 Hoskins, P. R., 259 Hosoda, H., 260,266 Hosogai, T., 16 Hosogi, F., 74 Hosokawa, T., 15 Hosomi, A., 21 Hotchandani, S., 241 Hotta, Y., 19 Houkal, D. J., 27 House, H. O., 185 Houtan, M., 12 Howard, B. M., 162, 179 Hoye, T. R., 77, 114 Huang, C.-T., 122 Huang, S. L., 17 Huber, C. L., 205 Hudec, J., 64,261 Hudson, A., 64 Hudspeth, J. P., 319 Huet, F., 285 Huff, S. R., 79 Huffman, J. W., 282 Hug, G., 241 Huhtinen, O., 28 Hui, W.-H., 203 Huisman, H. O., 30 Huitric, A. C., 7 Humphrey, A. M., 51 Humberston, M. J., 214 Huneck, S., 100 Hung, H.-K., 234 Hunt, R. S., 27 Hunter, G. L. K., 59 Huntrakul, C., 202 Hurley, J. B., 242 Huser, H., 12 Hussain, G., 167 Hutchins, R. O., 20 Hutchinson, C. R., 6, 48 Huy, H. T., 271 Huynh, C., 34 Hylands, J. P., 207 Hyono, T., 168 Iavarone, C., 47, 48 Ibaraki, S., 50 Ichikawa, N., 44 Ichikawa, Y., 39

Ichinose, I., 16 Iglesias, I., 48 Ignatyuk, V. K., 249 Iguchi, K., 193 Iguchi, M., 129 Iida, T., 50, 189 Iio, H., 129 Iitaka, Y., 7, 8, 107, 206, 215 Ikeda, H., 31 Ikeda, M., 188 Ikegawa, S., 260 Ikekawa, N., 311 Ikenoya, S., 251 Ikuse, M., 193 11, M., 139 Iljin, S. G., 193 Imada, I., 249 Imagawa, T., 76 Imaizumi, S., 59 Imamura, P. M., 161 Imamura, T., 24 Imperato, F., 42 Inayama, S., 154 Inoue, O., 194 Inouye, H., 6 , 2 5 , 4 8 Inouye, Y., 14, 31 Intes, A., 190 Inubushi, Y., 54, 138 Ioannou, P. V., 309 Ioffe, N. T., 228,229 Ionin, B. I., 56 Ionova, E. A., 59 Ippen, E. P., 242 Iriarte, J., 322 Irikawa, H., 188 Iriye, R., 53, 175 Isaacs, E. E., 78 Isaeva, Z. G., 73,74 Isako, T., 41 Ishibashi, H., 61 Ishibashi, K., 238 Ishida, H., 197 Ishiguri, Y., 136 Ishii, H., 210 Ishii, T., 189 Ishikawa, H., 54 Ishobe, M., 129 Isobe, T., 172 Isogai, A., 181 Isogai, K., 19 Itai, A., 7 Itaya, N., 29 Ito, I., 67 Ito, K., 39, 77, 203,209 Ito, M., 67, 231, 233,238 Ito, O., 24 It6, s., 8, 120 Itoh, A., 113 Itoh, M., 68 Itoh, T., 189 Itoi, K., 4 Itokawa, H., 36, 215 Ius, A., 279 Iwamura, J.-I., 17

Author Index Iwamuro, H., 55 Iwasa, J., 175 Iwasaki, S., 5 3 Iwase, T., 238 Iyengar, R., 87 Izawa, M., 188 Jablonsky, I., 326 Jackrnan, L. M., 285 Jackson, R. A., 64 Jackson, W. R., 279 Jacques, J., 4, 1 3 , 2 6 2 Jacquernin, H., 195, 200 Jacquesy, R., 5 4 , 2 9 1 Jacquier, R., 324 Jacobsen, N., 66 Jain, D. C., 21 1 Jain, G. K., 211 Jakovac, I. J., 14 Jakupovic, J., 50, 123 James, D. R., 186 Janes, N. F., 29 Janitschke, L., 66, 94 Janiszowska, W., 210 Jarvis, B. B., 9 9 Jaszczynski, J. R., 319 Jaudon, P., 295 Jawad, F. H., 175 Jayle, M. F. 267 Jeannin, Y.,8 Jefferies, P. R., 10, 110, 173, 177,178,203 Jeffrey, G. A., 5, 11 Jeffs, P. W., 109 Jeger, O., 236 Jemison, R. W., 6 3 Jennings, B. H., 272 Jensen, B., 6 Jensen, B. L., 323 Jensen, H. P., 6 4 Jensen, L. H., 7 Jensen, S. R., 47 Jetuah, F. K., 294 JimCnez, M., 155 Jindal, S. P., 187 Jizba, J., 139 Johansen, J. E., 220,240 Johnson, A. W., 273 Johnson, D. W., 7 9 Johnson, P. C., 143 Johnson, S. J., 183 Johnson, T. J., 32 Johnson, W. C. jun., 64 Johnston, D. L., 9 Johnston, J., 21 Joly, G., 214 Jonas, I., 240 Jones, A. J., 6 4 Jones, G., 6 Jones, J. B., 14 Jones, J. G. LI., 296 Jones, P. G., 1 0 Jones, R. A., 32 Jones, R. L., 175

339 Jones, T. H., 46 Jones, W. R., 261, 285 Joniaux, D., 10 Jonkers, F. L., 2 3 Jordan, E. G., 29 Jose, C. I., 12 Josephy, Y., 78 Joshi, S. K., 50 Joshi, V. S., 18 Joska, J., 309 Joulain, D., 27, 163 Joukhadar, L., 203 Judy, K. J., 24, 8 5 Julia, S., 23, 30, 34, 4 0 Julia, M., 3 0 Julliard, M., 298 Jullien, R.,6 3 Jung, M. E., 1 5 5 , 2 7 3 , 3 1 9 Juranic, I., 300 Jurd, L., 202 Jurlina, J. L., 170, 287 Jurs, P. C., 258 KaborC, I., 259 Kabuto, K., 13 Kagan, H. B., 7 Kagotani, M., 38 Kagramanova, G. R., 214 Kai, Y., 7 Kaiser, R., 61, 223 Kaisin, M., 119 Kaito, M., 22 Kaiya, T., 175 Kajtar, J., 221 Kakitani, H., 242 Kakitani, T., 242 Kalsi, P. S., 112 Kalvoda, J., 270 Kamaeva, 2. V., 56 Karnaya, R., 215 Karnernitskii, A. V., 290, 324.327 Karnetani, T., 37, 204 Kamigauchi, T., 164 Karnijo, N., 99, 156 Kamikawa, T., 172 Kamiyama, S.-I., 5 9 Karno, Y., 7 Kamogawa, H., 242 Kamono, Y., 215 Kan, K., 7 Kanaoka, Y., 67 Kanbegawa, A., 266 Kandutsch, A. A., 306 Kaneda, M., 107 Kaneda, N., 171 Keneko, C., 304 Kaneko, H., 4 6 , 1 4 7 , 1 7 8 Kang, S. S., 211 Kanojia, R. M., 320 Kanter, S. L., 7 8 Kanters, J. A., 7 Kaplan, E. R., 163 Kaplan, M. A. C., 273

Kapnang, H., 291 Kapoor, V. K., 216 Kappeler, A., 223 Karanjgoakar, C. G., 10 Karasawa, D., 2 7 , 6 3 Karaseva, A. N., 7 3 Karlsson, B., 8 Karlsson, K., 164 Karlsson, R., 119, 180 Karp, F., 25 Karrer, W., 5 Kartashov, V. R., 67 Kartha, G., 7 Kartonozhkina, 0. I., 39 Kasai, H., 218 Kasai, N., 7 Kasai, R., 171, 194, 195, 210 Kasal, A., 283, 322 Kasano, M., 7 2 , 7 4 Kashirnura, S., 1 9 Kashrnan, Y., 108, 177, 179 Kasprzyk, Z., 210 Kasuga, R., 147 Katagiri, T., 33, 39, 67, 81 Kataoka, T., 197 Katayarna, T., 219, 220 Kates, M., 246 Kato, H., 266 Kato, K., 39, 249 Kato, T., 16, 182 Katsui, G., 238, 249 Katsui, N., 135, 136, 175 Kaufman, D. D., 29 Kaul, B. L., 27 Kaupp, G., 298 Kawabe, K., 238,251 Kawaguchi, T., 39 Kawahara, I., 61, 77, 182, 234 Kawai, K., 194 Kawai, N., 15 Kawai, T., 129 Kawakarni, Y., 76 Kawakita, M., 67 Kawakubo, H., 251 Kawamata, T., 154 Kawarnoto, M., 238 Kawamura, S., 242 Kawanishi, S., 21 1 Kawanisi, M., 76 Kawasaki, T., 210, 263 Kawashirna, K., 5 1 Kayser, A. J., 29 Kayser, H., 246 Kayser, M. M., 6 8 Kayushin, L. P., 238 Kazlauskas, R., 125, 178 Keana, J. F. W., 264 Keehn, P. M., 54 Keinan, E., 270 Kellaway, I., 265 Kelly, D. P., 7 1 Kemertelidze, E. P., 21 1 Kennan, S., 266 Kennard, O., 10

Author Index

340 Kerebel, A., 263 Kergomard, A., 91 Kern, J. M., 12 Khalifa, S., 9 Khan, I. A., 294, 295 Khanna, N. M., 22 1 Khastgir, H. N., 206, 216 Kheifits, L. A., 56 Kho-Wiseman, E., 5, 12, 43, 160 Khristoforov, V. A., 238 Khristoforov, V. L., 234 Khuong Huu, Q., 259, 269, 278,321 Kieczykowski, G. R.,129 Kiefer, W., 239 Kienzle, F., 227 Kieslich, K., 326 Kikta, E. J., jun., 29 Kikuchi, M., 32, 50, 189 Kikuchi, T., 210 Killinger, T. A., 36 Kim, S. G., 14 Kimball, H. L., 306 Kimura, T., 14 Kimura, Y., 181 King, A. O., 22 King, L. J., 78 King, R. J., 157 King, R. M., 123 King, R.W., 10 Kinghorn, A. D., 175, 200 Kingston, J. F., 315 Kingzett, P. C., 240 Kinishi, R., 14 Kinkade, J. M., jun., 266 Kinoshita, M., 15 Kinoshita, Y., 54 Kintya, P. K., 210 Kirillov, S. T., 64 Kirk, D. N., 64, 160, 260, 295 Kirtany, J. K., 6 0 Kir’yalov, N. P., 207 Kisaki, T., 247 Kiselev, A. V., 242 Kiseleva, E. N., 39 Kisiel, W., 123 Kitada, A., 285 Kitagawa, I., 164, 190, 210, 211,216 Kitagawa, K., 31 Kitagawa, M., 266 Kitahara, H., 28 Kitamura, T., 76 Kiyokawa, H., 61 Kizu, H., 210 Klaiber, E. M., 6 4 Klein, E., 4, 32, 50, 94 Klein, M., 202 Klein, P. D., 275 Kleinig, H., 222 Kleinpeter, E., 77 Klemmensen, P D., 42 Klimova, L. I., 280

KlinotovB, E., 201 Knapp, F. F., 190, 192 Knoll, F. M., 17 Knoll, K.-H., 59, 139 Knowles, A., 233,242 Knox, J. R., 9, 177 Knuppen, R.,320 Kobayshi, A., 29, 102 Kobayashi, K., 218 Kobayashi, M., 304 Kobayashi, R., 24 Kobayashi, S., 9 0 Kobayashi, T., 171, 242 Koch, H., 9, 64, 65 Koch, K., 264 Kochetkov, N. K., 247 Kocienski, P. J., 36 KoEovskjl, P., 275, 296, 305 Kodama, A., 231,233,238 Kodama, M., 120 Koedam, A., 16 Koelsch, P. M., 62 Koerner von Gustorf, E., 7 Klitter, H., 31 Koh, S.-W., 79 Kohda, H., 171 Kohler, B. E., 239, 240, 242 Kohout, L., 322 Koike, K., 178 Koizumi, N., 303, 311 Kojo, A., 73 Kokocinska, H., 264 Kokubu, T., 266 Kolb, V. M., 69 Kolind-Anderson, H., 42 Kologrivova, N. E., 56 Kolthammer, B. W. S., 22, 270 Komalenkova, N. G., 1 8 Komarov, P. S., 265 Komatsu, A., 53 Komatsu, T., 242 Komori, T., 210, 263 Komoto, R. G., 19 Kondo, Y., 190 Kondratenko, E. S., 171 Konishi, A., 15 Konishi, T., 210 Konitz, A., 116 Konno, A., 31 Konowal, A., 47 Konuspaev, S. R., 39 Kooiman, P., 45 Kooskora, K. E., 7 3 Koppenhofer, B., 7 Kops, R. T., 239 Korany, M. A., 51 Korchagin, V. P., 231 Koreeda, M., 303 Korenstein, R., 242 Korsunova, E. I., 228 Korte, E.-H., 13 Korte, F., 64, 79 Koshimizu. K.. 223 Kostova, I.”.,. 191

Kosugi, H., 22 Kotsuki, H., 195, 197 Kolts, C. E., 265 Kotynski, A., 15 KovaEeviC, D., 51 Kowalski, J., 16 Kowerski, R. C., 223,227 Koyama, T., 8 2 Kozhin, S. A., 56 Kozina, M. P., 7 3 Kozlov, E. I., 232 Kraatz, U., 79 Krabbe, H.-J., 13 Krajewski, A., 171 Kramer, C. M., 100 Krapcho, A. P., 147, 327 Kratsmar-Smogrovic, J., 58 Kraus, W., 197 Kraut, J., 9 Kreiser, W., 66, 9 4 Krepinsky, J. J., 156 Kresze, G., 50 Krevitz, K., 303 Krief, A., 41, 42 Krieger, H., 73 Krieger, P. E., 15 Kriek, R. P. J., 97 Krinsky, P., 273, 276 Krishnamurthy, S., 22 Krishnappa, S., 50, 90 Krishnasamy, V., 74 Krivoruchko, V. A., 324 Krivoshchekova, 0. E., 75 Krom, C. J., 8 Kroon, J., 7 Kropf, H., 18 Kruger, C., 7 Kruse, C. G., 23 Kryukov, P. G., 242 Kuball, H.-G., 261 Kubo, I., 86, 172 Kubota, S., 54 Kubota, T., 172, 195 Kucherov, V. F., 174 Kudo, M., 15,172 Kudo, Y., 67 Kudryavtseva, M. I., 56 Kueh, J. S. H., 25 Kuhne, W., 242 Kuhnert, L., 8 3 Kulbach, R., 261 Kulesza, J., 46, 74 Kulikova, L. E., 327 Kulkarni, A. B., 75 Kulkarni, B. D., 46, 53 Kulkarni, G. H., 214 Kulshreshtha, D. K., 202 Kumada, M., 31 Kumobayashi, H., 35, 81, 186 Kundu, N., 266 Kunieda, N., 15 . . Kuntz, E., 35 KuDchan. S. M., 99,122, 192 Kuiasawa, Y., 280

Author Index Kurata, T., 56 Kurihara, T., 32 Kuroiwa, M., 67 Kurokawa, T., 17 Kurosawa, E., 97, 101 Kurth, M. J., 77 Kusano, G., 190 Kushi, Y., 99, 156 Kushwaha, S. C., 246 Kutney, J. P., 63 Kutschabsky, L., 9, 10 Kuyama, G., 77 Kuyama, M., 77 Kuyama, N., 182 Kyogoku, Y., 190 Kyotani, Y., 18 Kyutoku, H., 19 Labadie, R. P., 45 L'abbC, C., 199 Lafferty, J., 240 Lagoguey, A., 265 Lai, J., 203, 209 Laing, M., 174, 212 Lajis, N. H., 17, 23, 24 Lakshmi, C., 295 Lakshmi, V., 203 Lalan, P. L., 323 Lam, H.-Y., 310 Lam, S., 29 Lamazoukre, A.-M., 69 Lamberton, J. A., 188 Lamolte, J., 207 Lamparsky, D., 61, 223 Land, E. J., 240,242 Landgrebe, J. A., 15 Landmesser, N. G., 69 Lange, B. C., 285 Lange, G. L., 46, 65, 103 Lange, L. M., 197 Langenheim, J. H., 27 Lansbury, P. T., 94, 154 Lanteri, S., 57 Lanyi, J. K., 242 Larsen, L. M., 193 Larsen, S. D., 65,70,93,94 Latimer, L. H., 184 Latta, M., 238 Lau, C. K., 145 Laude, L. D., 240 Laufer, J. L., 48 Laungani, D. R., 187,192,223 Laurent, A., 8 Laurie, W. A., 38 Lavagnino, E. R., 79 Lavrinenko, B. I., 39 Lawesson, S.-O., 24 Lawrence, B. M., 26 Lawrie, W., 189 Lawton, D., 8 Lazare, S., 184 Lazarev, Yu. A., 242 Lazarova, R. D., 75 Lazurin, E. A., 63

34 1 Leblanc, R. M., 241 Lechevallier, A., 285 Lechleiter, J. C., 126 Leclercq, J. M., 242 Lee, B., 9 Lee, C.-M., 79 Lee, E., 24,85 Lee, P. L., 59 Lee, S. P., 20, 150 Lee, Y.-W., 86 Leemhuis, J., 319 Leeming, M. G. R., 261,285 Legrand, J. C., 265 Legrand, S., 265 Legzdins, P., 22, 270 Lehmkuhl, H., 31 Lehner, Y., 191 Leimgruber, W., 35 Lemikre, G. L., 13 Lengyel, E., 213 Lenhert, P. G., 6 Lentsch, S. E., 67 Lentz, C., 97 Lentz, P. J., jun., 6 Lenz, G. R., 287,301,320 Leonard, J., 48 Lepoivre, J. A., 13 Leroi, G. E., 239 Le Roy, E., 31 Lesiak, T., 58 Lessard, J., 286 Lester, D. J., 288 Letokhov, V. S., 242 Leung, S. L., 306 Leutwiler, L. S., 246 Le Van, N., 123,139, 158 Levina, I. S., 290, 327 Levine, B., 202 Levine, S. D., 280, 324 Levison, S. A., 267 Levy, J., 29 Levy, S., 79 Lewis, A., 239, 242 Ley, S. V., 18,23, 285, 288 Leznoff, C. C., 16,224 Li, E., 186 Li, M.-M., 203 Liaaen-Jensen, S., 218, 220, 222,237,240 Liberti, A., 15 Lichtenthaler, H. K., 251 Liebman, A. A., 310 Liknard, B. H. S., 63, 238 Light, D. M., 26 Liljefors, T., 263 Limacher, J., 223 Limanek, J. S., 187 Lin, J. J., 19 Lincoln, D. E., 27 Lindblom, G., 240 Linde, H. H. A., 323 Linder, M., 63 Lindgren, J.-E., 79 Linstrumelle, G., 34

Liotta, D., 21 Lippmaa, E. T., 73 Lipscbmb, W. N., 7 Lisenkov, V. I., 73 Litchfield, C., 218 Litvin, F. F., 242 Liu, C.-B., 100 Liu, H.-J., 20, 150, 234 Liu, J. S., 179 Liu, R. S. H., 231, 233 Liyanage, N., 177, 180 Llanos, A., 161 Lobanov, N. A., 242 Lobo, A. P., 64,261 Lock, R. L., 102 Lockhart, N. C., 64 Lockley, W. J. S., 220, 243 Loeffler, K. O., 78 Loliger, P., 247 Lohmann, J. J., 41 Lohmar, R., 40 Loibner, H., 3 11 Lombardo, L., 22 Long, A. K., 16 Long, D. A., 240 Lonitz, M., 108, 124, 167 Lopez, H., 324 Lopez, M. A., 162 Lopez de la Osa, E., 268 Lorenc, L., 300 Lotter, H., 126 Lotz, F., 79 Loughi, R., 279 Lovegreen, P. D., 78 Loya, Y., 177 Lubega, R., 26 Luche, J.-L., 18, 56 Luche, M. J., 326 Ludwig, B., 219 Ludvik, G. F., 16 Lucke, J., 197 Luis, J. G., 174 Lukacs, G., 259 Lukefahr, M. J., 108 Lundin, R. E., 9 Lunn, G., 58 Lunnon, M. W., 173,174 Lusinchi, X.,291 Luteyn, J. M., 80 Lutomski, J., 21 1 Lutz, M., 239 Luz, Z., 258 Lynn, D. G., 109 Lysenkov, V. I., 54 Lyster, M. A., 273 Mabry, T. J., 161 Macaira, L. A., 149 MacAlpine, G. A., 56 McAuliffe, C. A., 240 McCombs, C. A., 155 McConnell, J. F., 6 MacConnel, J. G., 45 McConnell, 0.J., 43

Author Index

342 McCormick, A. M., 238 McCormick, J. P., 37 McCrae, K. R., 187 Macdonald, T. L., 62 McEnroe, F. J., 90 McGhie, J. F., 203, 294 McGrath, M. J., 63 McGregor, M. L., 238 Machado, F. W. L., 148 McHale, D., 38 Machida, H., 53 McHugh, C. R., 295 MacInnes, D., 9 McKenna, J., 328 McKenna, J. M., 328 Mackenzie, I. A., 25 McKenzie, M. J., 42 McKenzie, R. M., 238 McLaren, F. R., 141 McLaughlin, J. L., 208 McLean, J., 189 McLean, S., 48 McLellan, M. A., 199 McLennan, T. J., 186 MdcMillan, J., 172, 173, 174 McMorris, T. C., 259,315 McMurry. J. E., 97, 102 McOsker, C. C., 22 McPhail, A. T., 6, 112, 167, 200,257,317 McQuillin, F. J., 36, 37, 279 Maddocks, P. J., 35 Madjid, A. H., 240 Madonik, A. M., 50 Maeda, A., 238 Maeda, M., 233 Malkonen, P., 64 Mandli, H., 51 Magalhaes, E. G., 78 Magnus, P. D., 23, 143 Magnusson, G., 114 Mahalanabis, K. K., 103 Mahanta, P. K., 50, 59, 122, 123,124,139, 161, 171 Mahanty, P., 77 Mahato, S. B., 208 Maher, R. J., 9 Maidment, M. S., 317 Maienthal, M., 264, 328 Mgier, N. A., 65 Maier, V. P., 196 Mairanovskii, V. G., 228, 229 Majetich, G., 94, 151 Makaiyama, T., 116 Makino, H., 78 Makino, S . , 61 Makino, T., 284 Makiyama, Y., 139 Maksakova, I. T., 228 Maksimov, 0. B., 75 Malakov, P. Y., 166 Malanina, G. G., 280 Malchenko, S., 97 Malhotra, R.K., 79, 295

Mallory, R. A., 280, 3 19 Manassero, M., 9 Manchand, P. S., 177 Mancuso, A. J., 17 Mandai, T., 22 Mandal, A. K., 14 Mandel, N., 7 Manedov, K. S., 206 Manerikar, S. V., 75 Manfredotti, A. G., 11 Mangoni, L., 196 Manning, M. J., 251 Manning, T. D. R., 4 Manresa, M. T., 155 Mansilla, H., 123, 148 Manukov, E. N., 72 Manville, J. F., 91 Manzocchi, A., 271 Maradufu, A., 26 Marcati, F., 14 Marchand, J., 292 Marcus, M. A., 239, 242 Marecek, J. F., 309 Marekov, N., 48 Mariani, A., 238 Mariani, E., 69 Marino, C. A., 269 Marino, M. L., 163, 172, 174 Marinovic, N., 17 Mark, F., 7 Mark, H. B., 251 Markowicz, S. W., 51 Markus, A., 63 Marrnor, R. S., 42, 111 Maroski, J. G., 111 Marples, B. A., 284,296 Marques, R., 78 Marriott, C., 265 Marsaiolo, A. J., 161 Marsh, W. C., 6,256 Marshall, D. H., 310 Marshall, J. A., 21, 127, 143, 183 Martin, B. R., 79 Martin, D. T., 22, 270 Martin, J. D., 5, 101 Martin, J. L., 155 Martin, V. S., 101 Martina, D., 62 Martinelli, F., 19 Martinez-Carrera, S., 8, 164 Martinez-Ripolls, M., 5, 162, 164 Maruyama, K., 249 Maruyarna, Y., 211 Marx, M., 184 Marx, P., 48 Masaki, N., 6,94, 151 Masamune, T., 135, 136, 299, 327,328 Masetti, G., 239 Masilamani, D., 54 Maslen, E. N., 10, 177 Massanet, G. M., 123, 148

Masson, S., 34,40 Mastropaolo, D., 11 Masuda, K., 215 Masure, D., 35 Masutani, T., 175 Mateescu, G., 238 Matet, J., 238 Mathew, C. P., 58, 75 Mathieson, A. McL., 6 Mathur, H. H., 76 Matlock, P. L., 19 Matsubara, Y., 52, 55, 72,74 Matsui, M., 29, 76, 102, 138 Matsumoto, H., 231, 242, 266 Matsumoto, K., 74 Matsumoto, T., 33, 86, 112, 114,147, 167,168,189,224 Matsumura, Y., 19 Matsunaga, I., 304 Matsuno, T., 190 Matsuo, A., 70, 96, 99, 156, 181 Matsuura, K., 195 Matsuura, T., 139 Mattay, J., 42 Mattes, K. C., 48 Matthews, R. S., 46, 49 Matthews, W. S., 51 Maudinas, B., 246 Mauer, B., 126 Maury, G., 324 Matveets, Yu,A., 242 Maxwell, J. R., 214, 237 Mayer, L. M. U., 167 Mazur, Y., 258, 270,302,311 Mechoulam, R., 10,79 Medarde, M., 161 Meffin, P. J., 25 1 Mehler, K., 31 Mehta, G., 58 Mehta, Y. P., 23, 288 Meier, B., 47 Meier, H., 66 Meinwald, J., 46, 176 Melian, M. A., 101 Mellor, D. P., 13 Mel’nikov, V. N., 210 Melsom, B. G., 206 Menchen, S. M., 18 Meney, J., 189 Merchant, J. R., 79 Merckx, E. M., 13 Merep, D. J., 72 Merlini, L., 86 Meshulam, H., 192 Messeguer, A., 36 Messerotti, W., 28, 120 Mestroni, G., 19 Metz, W., 129 Metzger, J., 58 Metzger, P., 66 Meyer, B., 64 Meyer, W. L., 64,261 Meyers, C. Y., 69

Author Index Mhehe, G. L., 234 Michaels, R. J., 79 Micha-Screttas, M., 21 Michna, A., 64 MiEkovi, R., 275 Midgley, I., 263 Midgley, J. M., 9, 255, 256, 261,285,305,306 Midland, M. M., 18, 75 Miginiac, Ph., 3 1 Miguel del Corral, J. M., 161 Mihailovi6,M. Lj, 300 Mihashi, S., 36 Mikami, Y., 247 Mikhailov, B. M., 21 Miki, K., 7 Milborrow, B. V., 244 Millard, A., 72 Miller, R. W., 6, 9 Millis, N. F., 71 Milne, G. M., 103 Milz, S., 47 Mimura, T., 17,51 Minale, L., 42 Minamizawa, T., 304 Mincione, E., 288, 305 Minder, R. E., 227 Miravitlles, C., 299 Misaka, M., 54 Mishell, D. R., jun., 266 Misiti, D., 289 Mislow, K., 7 Misra, D. R., 206, 216 Mitchell, S. J., 177, 180 Mitra, M. N., 311 Mitsner, B. I., 231 Mitsuhashi, H., 304 Mitsuta, Y., 29 Miura, I., 86, 172, 181 Miura, Y., 188 Miyagi, S., 15 Miyahara, K., 307 Miyahara, M., 24 Miyakoshi, T., 31 Miyano, S., 24 Miyase, T., 168, 169 Miyashita, M., 23,94, 151,273 Mizuguchi, T., 299 Mnastakanyan, V. A., 166 Mochida, I., 31 Modawi, B. M., 25 Mody, N. V., 175 Moews, P. C., 9 Moffat, A. C., 78 Moger, W. H., 265 Moinuddin, G., 294 Moiseenkov, A. M., 249, 278 Moldowan, J. M., 214 Mollov, N. M., 166 Monaco, P., 196 Mondon, A., 197 Money, T., 66 Monger, T. G., 242 Mongiorgi, R., 171

343 Monneret, C., 269 Montana, P., 43 Monteath Robertson, J., 8 Monteau, J., 12 Monti, S. A., 65,70,93,94 Monties, B., 230 Montury, M., 294 Moolenaar, M. J., 30 Moore, A., 99, 100, 156 Moore, R. E., 5 Mootoo, B. S., 116 Morand, P., 68, 301 Moreau, J.-L., 34 Moreira Bacha, C. T., 110 Morella, M., 264 Moreno, L. N., 202 Morera, E., 269,270 Moretti, I., 14 Morfin, R. F., 263 Mori, K., 26,45, 102 Moriguchi, K., 29 Morikawa, A., 17,271 Morimoto, H., 249 Morin, L., 69 Morisaki, M., 31 1 Morita, N., 210 Moriyama, Y., 211 Mornon, J.-P., 8 Morozovskaya, L. M., 280 Morris, D. G., 63, 66 Morris, G. A., 11 Mortensen, J. T., 237 Mortikova, E. I., 290 Morzycki, J. W., 289 Mosbach, E. H., 262,307 Moss, G. P., 229 Mossman, A., 14 Mostowicz, D., 14 Motoki, H., 15 Moural, J., 275 Mourgues, P., 271 Mouriiio, A., 306, 311, 312 Mourot, D., 29 Moyler, D. A., 51 Mrozinska, D.,58 Muccino, R. R., 310 Muchowski, J. M., 322 Muhlstadt, M., 77 Muller, B. L., 236 Muller, D., 293 Miiller, P., 68 Miiller, U., 242 Mukaiyama,T., 16,17,90,235, 27 1 Mukhamedova, L. A., 56 Mukharji, P. C., 205 Mukherjee, D., 313 Mukhina, M. V., 265 Mulder, F. J., 238, 268 Muller, W., 192 Mummery, R. S., 246 Munn, R. W., 240 Munro, M. H. G., 170,186 Murae, T., 210

Murahashi, S.-I., 15, 22 Murai, A., 135, 136, 327, 328 Murai, S., 20, 24 Murakami, T., 172 Murakoshi, S., 181Muramatsu, S., 29 Murano, A., 28 Murari, R., 148, 167, 171 Murata, A., 31 Murayama, E., 54 Murillo, A., 275 Murphy, P. T., 125, 178 Murphy, R., 38,57 Murphy, W. S., 188,319 Murray, A. M., 63 Murray, R. D. H., 4 Murray, R. K., jun., 7 Murty, Y. L. N., 190 Murza, M. M., 265; Muthukumar, M., 242 Muzart, J., 298 Mynderse, J. S., 44 Nachbar, R. B., 116 Naegeli, P., 106 Nagai, K., 12 Nagai, S. I., 67 Nagai, U., 7 Nagai, Y., 42 Nagakura, S., 242 Nagano, H., 139 Nagao, Y., 160 Nagasawa, T., 27 Nagase, H., 18 Nagase, T., 42 Naidu, K., 163 Nakachi, K., 242 Nakada, Y., 29 Nakahara, F., 39 Nakahara, Y., 138 Nakai, H., 195 Nakai, T., 17, 51 Nakajima, O., 53 Nakajima, Y., 14 Nakamoto, T., 39 Nakamura, A., 15 Nakamura, C. Y., 23,301 Nakamura, M., 77 Nakamura, S., 42 Nakane, M., 6,48,142 Nakanishi, K., 86, 181, 231, 240,242 Nakanishi, T., 216 Nakano, T., 26,27, 183 Nakano, Y., 31 Nakata, H., 175 Nakatani, N., 29 Nakatani, Y., 29, 51 Nakatsuka, I., 29 Nakayama, I., 29 Nakayama, M., 12, 53, 70, 96, 99,156,181 Nambara, T., 260,265, 266 Namjoshi, A. G., 12

Author Index

344 Nanasawa, M., 242 Nanavati, D. D., 208 Nanjo, M., 235 Nanzyo, M., 235 Napoli, J. L., 238 Narang, R. S., 6 4 Narang, S. C., 24 Narasaka, K., 17,116,235,271 Narbonne, C., 291 Narula, A. S., 107 Naruta, Y., 249 Narva, D. L., 240 Nash, L. J., 175 Nasini, G., 8 6 Nasipuri, D., 281 Naskar, D. B., 206 Nassim, B., 200 Nasybullina, F. G., 56 Natale, N. R., 20 Natsukawa, K., 3 1 Natu, A. A., 50, 59, 110, 122, 123, 161 Navaza, A., 8 Naves, Y. R., 7 5 , 2 1 8 Naya, K., 139, 142 Naya, Y., 44 Nayak, U. R., 67,69, 111 Nedelkovitch, G., 238 Nederlof, P. J. R., 3 0 Neef, G., 316 Negishi, E.-I., 22 Nehl, H., 31 Neidert, E. E., 46, 103 Nelson, E. C., 238 Nelson, J. A., 187, 307 Nemoto, H., 37 Nes, W. R., 285, 303, 304 Nesbitt, S. L., 285 Neszmelyi, A., 259 Neubert, P., 264 Ng, A. S., 198 Nguyen, K. Q. C., 210 Nguyen, Q. Z., 28 Nguyen, T. N., 211 Nguyen, T. T. T., 205 Nicoara, E., 222, 230 Nicholas, A. W., 325 Nicolaux, G., 238 Nicole, J., 31 Niela, Nieto, J. J., 6 4 Nielsen, B. J., 47 Nielson, C. J., 318 Nielsen, J. K., 193 Niemeyer, U., 48 Nihama, K., 7 6 Nikaido, T., 193 Nikolaev, A. G., 28 Nilsson, N H., 24 Ninagawa, Y., 39 Nishi, K., 171 Nishida,T.,4,32,35, 164, 178, 224,234 Nishino, T., 190 Nishioka, I., 78, 203

Nichiyama, T., 6 9 Nishizakura, K., 135 Nishizawa, M., 94, 116, 129, 151 Nitsch, W., 239 Nitta, K., 107 Nitz, S., 6 4 Niu, H. C., 78 Niwa, G., 188 Niwa, I., 2 0 Niwa, M., 1 2 9 , 2 1 0 Noble, T. A., 4 0 , 7 5 Noda, K., 203 Node, M., 160, 184 Noguchi, M., 46, 147, 178 Nohara, T., 210 Noma, Y., 52 Nomura, M., 52 Norden, B., 240 Nordman, C. E., 258 Norman, A. W., 31 1 Normant, J. F., 35 Norn, V., 47 Norte, M., 101 Northolt, M. G., 8 Norton, D. A,, 255 Norton, R. S., 4 4 , 2 6 4 Novikova, L. K., 7 4 NovotnL, L., 139 Nowak, R. J., 251 Noyori, R., 24,61, 9 6 Nozaki, H., 1 6 , 1 9 , 3 1 , 9 9 , 113, 156,181 Nozaki, M., 29 Nuerrenbach, A., 4 , 2 2 5 Numan, H., 261 Numazawa, M., 265 Nyembo, L., 209 Nyfeler, R., 87 Oakleaf, J. A., 22 Oberhansli, W. E., 125 O’Brien, D. H., 108, 109 Ochi, 304 Ochi, M., 195, 197 Ochiai, M., 160, 174, 184 Ochsner, P. A., 31 Oda, J., 1 4 Oda, N., 67 Odinokov, V. N., 249 Oelbermann, U., 197 Oganesyan, G. B., 166 Ogawa, K., 211 Ogawa, S., 6 8 Ogawa, T., 76 Ogihara, T., 266, 267 Ogihara, Y., 194, 206, 211 Ogino, Y., 3 9 Ognyanov, I., 136 Ogunkoya, L., 210 Ogura, K., 52, 8 2 Ogura, M., 122, 178, 200 Oguri, T., 15, 128 Ohfune, Y., 114, 151

Ohkata, K., 4 1 Ohki, M., 102 Ohkura, T., 154 Ohloff, G., 4, 26, 36, 217, 223, 236 Ohmae, M., 2 3 8 , 2 4 9 , 2 5 1 Ohmoto, T., 193 Ohmura, Y., 39 Ohnishi, T., 241 Ohnishi, Y., 1 4 Ohno, A., 1 4 Ohno, K., 242 Ohno, N., 29 Ohno, S., 29 Ohrt, J., 7 Ohsawa, K., 29 Ohshio, T., 55 Ohta, H., 22 Ohta, Y., 99, 100, 156 Ohtani, H., 242 Oikarinen, A., 7 3 Oikawa, A., 278 Oishi, T., 3 2 Ojima, H., 19 Oka, S., 14 Okabe, H., 4 7 Okada, K., 29 Okajima, H., 67 Okamoto, K., 249 Okamura, N., 203 Okamura, W. H., 311,312 Okazaki, H., 309 Okazaki, S., 31 O’Keefe, D. F., 29 Okigawa, M., 48 Okogun, J. I., 179 Okorie, D. A., 195 Okude, Y., 31 Okukado, N., 22 Okumura, Y., 188 Okuyama, T., 285 Olah, G. A., 24 Olbrich, G., 7 Ol’dekop, Yu. A., 6 5 Oldenziel, 0. H., 22 Olejniczak, B., 72 Oliveto, E., 310 Olofson, R. A., 287 Olson, J. A., 232 Olsen, R. E., 252 Omar, A. M. E., 320 Omichi, H., 31 Omura, H., 39 Omura, K., 17, 142 Onan,K.D., 167,200,257,317 Onishi, T., 35, 234 Ono, F., 8 1 Oonk, H. A. J., 7 , 8 Oppolzer, W., 16, 103, 110 Oritani, T., 235 Orrell, K. G., 188 Orrom, W. J., 4 6 , 1 0 3 Orsini, F., 172 Orszanska, H., 5 1

Author Index Ortaggi, G., 288 Ortar, G., 269, 270 Osaki, K., 6 Osawa, E., 112, 299 Osawa, Y.,284 Oshima, K., 19 Osianu, D., 230 Osman, M., 246 Osokin, Yu. G., 63 Osowska, K., 72 Otsuka, H., 194 Otsuka, S., 15,35, 81, 186 Ottersen, T., 10, 150 Ottinger, R., 156 Ottolenghi, M., 242 Ourisson, G., 107, 205, 214, 219 Ovchinnikov, Yu. A., 242 Overman, L. E., 17 Owen, J. D., 6 Paanakker, J. E., 237 Paaren, H. E., 310 Paciotti, M., 258 Packer, R. A., 188 Page, G., 257 Page, G., 290 Pagnoni, U. M., 28, 120 Pai, P. P., 214 Paiaro, G., 14 Pak, A. M., 39 Paknikar, S. K., 60, 156 Pal, B. C., 208 Pal, R., 210 Paleg, L. G., 188 Palermo, R. E., 17 Palm, J. H., 8 Palme, L., 252 Palmer, K. J., 9, 10 Palmer, M. A., 190 Palmieri, G., 289 Palmisano, G., 210 Palumbo, G., 196 Pan, P. C., 179 Pancrazi, A,, 259, 278,321 Panda, C. S., 68 Pandolfo, L., 14 Pannell, L. K., 170 Panova, G. V., 58 Pant, P., 203, 207 Panunzio, M., 30 Papanov, G . Y., 166 Paquer, D., 69 Paquette, L. A., 17 Paquin, P., 241 Paradisi, M. P., 269 Pardeshi, N., 191 Pardo, C., 68 Parente, A., 18 Parini, C., 279 Parish, E. J.. 306 Park, K.-H., 323 Park, S.-M., 229 Parkin, J. E., 261, 285

345 Parlar, H., 64 Parmentier, G., 309 Parnell, C. A., 52 Parrish, D. B., 238 Parthasarathy, R., 7 Partridge, J. J., 48 Partridge, L. G., 262, 263 Paryzek, Z., 189, 278 Pascard, C., 197,200,258,311 Pascard-Billy, C., 10 Pascual, J., 56 Pasini, A,, 9 Paslat, V. G., 286 Passacantilli, P., 48 Passannanti, S., 166, 216 Passet, J, 46 Patel, J. S., 76 Patel, N. J., 243 Paternostro, M. P., 165, 166, 216 Patin, H., 279 Patoiseau, J.-F., 54 Paton, W. D. M., 79 Patra, S. K., 184 Patriarche, G. J., 25 1 Patrick, D. W., 17 Pattenden, G., 25, 35,76 Patterson, G. W., 188 Patudin, A . V., 168 Paty, P. B., 21 Paul, D., 295 Paulik, V., 192 Paust, J., 15, 225 Pawson, B. A., 7 Pearson, R. L., 24 Pechet, M. M., 298 Pederson, B. S., 24 Pedlar, A . D., 186 Pekhk, T. I., 73 Pekkarinen, L., 241 Pelc, B., 280, 310 Pelizzoni, F., 172 Pellerin, F., 268 Pellet, M., 285 Pelletier, S. W., 175 Pellicciari, R., 170 Pelyakh, E. M., 28 Pentegova, V. A., 161 Perales, A., 8 Perez, A. L., 155 Perez, C., 30 Peries, R., 22 Perlberger, J.-C., 68 Perry, R. G., 51 Perz, R., 58 Pesaro, M., 46, 103 Pete, J.-P., 19,298, 301 Peter, M. G., 158 Petit, F., 31 Petrov, A . A., 214 Pettei, M. J:, 86, 172 Pettit, G. R., 197, 200 Peyron, L., 46 Pfau, M., 298

Pfohl, S., 15 Pham Van Huong, 239 Phillipou, G., 316 Phillips, G. F., 238 Phinney, B. O., 172, 173, 174 Piacenza, L. P. L., 304 Piancatelli, G., 28 Piatak, D. M., 196, 303 Piatelli, M., 180 Piatkowski, K., 58 Picart, D., 263 Pick, J. H., 317 Pickardt, J., 158 Pickenhagen, W., 36,70 Picker, K., 275 Picot, A., 291 Pierce, B. M., 240 Piers, E., 142, 145 Pigon, K., 64 Pike, R., 205 Pilati, T., 9 Pilkiewicz, F. G., 86, 181 Pillay, P. P., 74 Pilotti, A.-M., 8, 166, 178 Pinar, M., 173 Pinetti, A., 120 Pinchin, R., 167 Pinhey, J. T., 300 Pinnick, H. W., 17, 19,23,24 Piozzi, F., 163, 165, 166, 174, 216 Piozzi, P., 174 Pirio, M. R., 31 1 Pirke, K. M., 266 Pirkle, W. H., 14 Pitt, C. G., 79, 257 Pltnat, F., 69 Plettenberg, H., 107 Plotnikoff, N. P., 79 Podlejski, J., 74 Poels, E. K., 23 Pogonowski, C. S., 94, 15 1 Polonsky, J., 195, 197, 200 Polyachenko, L: N., 232 Pommer, H., 225 Ponti, F., 271 Poots, I., 25 Popov, S., 48 Popov, S. S., 46 Popov, Yu. S., 28 Popova, L. A., 54 Popova, N. I., 72 Popova, T. K., 72 Popper, T. L., 156 Popplestone, R. J., 38 Porter, J. W., 246 Posner, G., 97 Posner, G. H., 16,72,270,271, 272 Post, M. L., 205 Potapov, V. M., 58 Potier, P., 190 Potter, R. H., 238 Potter, S. D., 280

346 Poulose, A. J., 25 Poulter, C. D., 24, 82 Poupat, C., 190 Pouzar, V., 202 Povelikina, L. N., 67 Powls, R., 244 Pozderac, R. V., 319 Poznyakov, S. P., 234 Pradhan, B. P., 206, 216 Pradhan, S. K., 176 Prager, R. H., 38, 57 Praly, J. P., 236 Prangi, T., 200 Prasad, R., 63 Pratt, A. C., 240 Pratt, W. B., 318 Prestwich, G., 320 Prestwich, G. D., 176, 181 Priestly, A.,J33 Prochazka, Z., 326 Prost, M., 160 Proth, N., 68 Protiva, J., 326 Prout, K., 9 Przybylska, M., 171 Puchalski, A. E., 5 5 Puglisi, C. V., 238 Pulman, D. A,, 29 Purdy, J., 48 Puri, S. C., 210 Purushothaman, K. K., 198 Pushkareva, T. V., 242 Pustil’nikova, S. D., 214 Putieva, Zh., M., 171 Qui, N. T., 91 Quilliam, M. A., 262 Quinkert, G., 226 Rabanal, R. M., 195 Rabi, J. A,, 121, 148, 149 Rabie, C. J., 97 Racker, E., 239 Radics, L., 50, 177 Radscheit, K., 321 Rae, A. I. M . , 10 Rae, I. D., 64 Rafferty, C. N., 242 Ragab, M. S., 323 Ragetti, T., 199 Ragoussis, N., 163 Rahwan, R. G., 238 Raines, D., 297 Raja, M. S., 170 Rajaram, J., 19, 236 Rajkowski, K. M., 267 Ramachandra, R., 200, 323 Rama Devi, J., 36 Ramakumar, S., 162 Raman, H., 68 Raman, P. S., 294 Rama Rao, A. V., 10 Ramirez, F., 309 Rampersad, M., 294

Author Index Ramsay, I. W., 7 Ranganathan, S., 68 Rangaswami, S., 191, 192,208 Ranieri, R. L., 157 Ranise, A., 57 Ranzi, B. M., 89 Rao, A. S., 46, 53, 5 5 Rao,A. S. C.P., 86, 111 Rao, E. V., 208 Rao, V. V. R., 114 Raphael, R. A,, 97 Rapi, G., 324 Rapoport, H., 250 Rassat, A., 8, 68 Rastogi, R. C., 50 Rastogi, R. P., 203, 207, 212 Raston, C. L., 110, 177, 178, 202 Rathke, M. W., 72 Rathnamala, S., 19, 236 Ratovelomanana, V., 30 Rau, W., 246 Rau-Hund, A., 246 Rautenstrauch, V., 45 Ray, T. K., 216 Raynolds, P. W., 25 1 Razdan, R. K., 7 8 , 7 9 Rebek, J., 14 Reca, E., 70 Reck, G., 9, 10 Rector, D. H., 257 Reddy, G. C. S., 208 Redel, J., 258, 311 Reed, D., 24 Reetz, M. T., 20 Regla, I., 322 Reichenbach, H., 222 Reid, J. J., 42 Reid, W. W., 161 Reif, W., 15 Reimann, K. A., 196 Reinehr, D., 31 Reischl, W., 31 1 Reisner, M. G., 8 Reiss, H., 5 1 Reitsema, R. H., 26 Renaud, R. L., 246 Rendle, D. F., 255 Renold, W., 223 Rerat, C., 8 Reshetova, I. G., 324 Retamar, J . A., 72 Reuter, J . M., 59 Reutrakul, V., 202 Rewcastle, G. W., 283, 298 Reye, C., 58 Ricca, G. S., 210 Riccio, R., 42 Richards, G. F., 7 Richardson, F. S., 64 Rickards, R. W., 79 Ridley, T. K., 259 Ridlington, J., 51 Riedel, W., 212

Rigby, J. H., 97 Rilling, H. C., 24, 82, 187, 223, 227 Rimpler, H., 47 Rinaldi, P. L., 14 Rioult, P., 69 Ripoll, J. L., 16, 278 Ripperger, H., 49 Riquetti, P. J., 238 Riva di Sanseverino, L., 171, 174 Rivers, G. T., 7 Rivett, D. E. A,, 163 Rizzardo, E., 300 Robacker, D. C., 26 Robbiani, R., 51 Roberge, R., 242 Roberts, J. S., 97 Roberts, P.J., 9, 256 Roberts, T. R., 29 Robertson, L. W., 79 Robey, D., 9 Robinson, C. H., 257 Robinson, H., 123 Robinson, M. S., 294 Robinson, W. T., 10, 186 Roca, A., 36 Rockley, N. L., 238 Rodewald, W. J., 289, 319 Rodionov, A. V., 242 Rodrigues, A. A. S., 121 Rodriguez, B., 162, 172, 173 Rodriguez, M. L., 5 Rodriguez-Hahn, L., 18, 56, 155, 162 Rogers, D., 7, 8 Rogers, D. Z., 272 Rogic, M. M., 54 Rohrer, D. C., 255, 284 Roitman, J. N., 202 Rojahn, W., 4, 32, 50, 94 Rojas, E. T., 162 Romanikhin, A. M., 72 Romanova, A. S., 168 Romashina, T. N., 278 Romeo, A., 269,270 Romo de Vivar, A., 155 Ronaldson, K. J., 215 Roques, R., 207 Rosazza, J. P., 325 Rose, A. F., 125 Roseboom, H., 80 Rosenberg, D., 326 Rosenfeld, J., 78 Rosenfeld, T., 242 Rosenqvist, E., 10 Rosenthal, D., 78 Rossi, C., 50 Rossi, J. C., 46 Rossi, R., 16 Rogs, R. W., jun., 266 Rossmann, M. G., 6 , 7 Rossotti, F. J. C., 9 Rostogi, R. C . , 123

Author Index Roth, W. D., 36 Rothbacher, H., 56 Rotter, H., 263 Rouessac, A., 16, 278 Rouessac, F., 16, 33, 129, 163, 278 Row, L. R., 190 Rowan, M. G., 25 Rowe, J. W., 167 Roy, D. N., 281 Rozing, G. P., 154 Rozmanova, L. D., 39 Rubakha, T. A., 65 Rubottom, G. M., 286 Rubstein, J., 190 Rucker, G., 149 Rudenko, V. A., 278 Rudi, A., 108 Rudler-Chauvin, M. C., 103 Rudney, H., 251 Ruedi, P., 168, 169, 221 Russel, R. K., 36 Russo, M. V., 11 Rutledge, P. S., 170, 276, 287 Ruveda, E. V., 161 Ruzo, L. O., 29 Ryabushikina, N. M., 58 Ryan, C. W., 79 Rycroft, D. S., 198, 199 Rykowski, Z., 51 Ryu, I., 20 Saar, Y., 78 Sabadie. J., 236 Sabol, J. S., 242 Sacco, T., 28 Sack, R. A., 247 Sadowska, H., 74 Safina, Z. S., 193 Safwat, H., 306 Sagawa, T., 240 Sagiv, J., 262 Saha, B., 206 Saha, S. K., 212 Sahu, N. P., 208 Saigo, K., 17, 235, 271 Saiki, Y., 172 St. Pyrek, J., 209, 213 Saito, S., 31 Saito, T., 61 Saito, Y., 39 Sakai, T., 45 Sakai, Y., 72 Sakakibara, J., 175 Sakamura, S., 147 Sakan, T., 45, 116, 167, 168 Sakurai, A., 32 Sakurai, H., 21 Salagre, P., 187, 247 Salares, V. R., 237,239 Saleh, M. A., 29 Salemink, C. A., 80 Salen, G., 262, 307 Salisbury, P., 66

347 Salmond, W. G., 271,310 Salo, E., 64 Salomon, R. G., 59 Samaan, H. J., 189 Samad, S. A., 301 Sambucini, C., 15 Samek, Z., 139,148 Samokhvalov, G. I., 228, 232, 234,235 Samperi, R., 15 Sams, R. A., 238 Samson, M., 20,286 Sanada, O., 195 Sanada, S., 194 Sanchez, E. L., 143 Sanchez Bellido, I., 60, 72, 161 Sanda, V., 326 Sandorfy, C., 242 San Feliciano, A., 60, 72, 161 San Martin, R., 48 Sansoulet, J., 68 Santaniello, E., 271 Saquet, M., 34 Saraswathi, G. N., 51, 58, 59 Sarda, P., 56 Sarin, J. P. S., 21 1 Sarkar, M., 184 Sarkar, U., 212 Sasaki, T., 158 Sasaki, Y., 31 !asamori, H., 327, 328 SaSek, V., 326 Sassa, T., 188 Sastry, B. S., 208 Sathe, S. S., 143 Sato, H., 22 Sato, K., -188 Sato, T., 24, 54 Sato, Y., 188 Satoh, F., 204 Satoh, J. Y., 23, 286, 289, 301, 305 Satterwhite, D. M., 82 Satyaswaroop, P. G., 268 Saucy, G., 7 Sauer, G., 316 Saul, J. A., 326 Saunders, G. A., 174 Saussine, L., 30 Sauvetre, R., 35 Savignac, P., 22 Savona, G., 163,165, 166, 174 Savost’yana, I. A., 278 Sawada, S., 120 Sawade, Y., 265 Sawhney, R. S., 175 Sawaki, T., 39 Sawasaki, T., 27 Sawitski, G., 197 Sayed, Y., 79 Scettri, A., 28 Schabort, J. C., 193 Schafer, H. J., 31 Schaefle, J., 219

Schaer, B., 30 Schaffer, A. M., 240 Scharf, H.-D., 42 Schatz, P. F., 41 Scheffer, J. J. C., 16 Scheibye, S., 24 Schenk, H., 239 Schenone, P., 57,69 Scheuer, P. J., 187,247 Schevitz, R. W., 7 Schlessinger, R. H., 129 Schlosser, M., 16 Schomer, U., 325 Schoenborn, B. P., 6 Schoenecker, B., 260 Schonemann, K. H., 319 Schonhofer, A., 261 Scholl, P. S., 67 Schomburg, G., 31 Schonholzer, P., 178 Schoofs, A., 13 Schooley, D. A., 16, 24, 85 Schorn, P. J., 238 Schow, S. R., 259,315 Schmid, H., 39 Schmidmayer, I., 65 Schmidt, E. N., 161 Schmidt, H., 158 Schmidt, J. H., 174, 197 Schmidt, W., 15 Schmidtchen, F. P., 250 Schmieder, K. R., 226 Schmitz, F. J., 179 Schneider, G., 175 Schneider, J., 225 Schnepp, O., 51 Schnoes, H. K., 310 Schrader, B., 13 Schreiber, K., 174 Schroepfer, G. J., jun., 306 Schroth, G., 31 Schubert, R., 180 Schusler, M. Th. I. W., 16 Schulte, G. R., 157 Schulte-Elte, K. H., 223, 236 Schulten, H.-R., 210, 263 Schultz, G., 252 Schulz, B., 225 Schulz, D., 7 Schulz, J. A., 320 Schurig, V., 7, 15 Schuster, R., 307 Schwartz, A., 256, 296 Schwartz, S., 192 Schwarz, V., 275 Schwarze, P., 238 Schwenzer, G. M., 258 Schwier, J. R., 14 Scolastico, C., 89 Scott, J. W., 13 Scott, J. Z., 266 Scott, W. E., 7 Screttas, C. G., 21 Scudder, P. H., 297

348 Seaborn, C. J., 316 Seckel, B., 48 Sedmera, P., 181 Sefton, M. A., 173 Segal, G. M., 278 Segal, R., 121 Segiet-Kujawa, E., 71, 72 Seib, K. H., 190, 307 Seibl, J., 51 Seifert, K., 193 Sekiya, S., 31 Seligmann, O., 167 Seltzer, S., 247 Seltzman, H. H., 79 Sembdner, G., 175 Semenovskii, A. V., 249, 278 Sen, M., 212 Senda, Y., 59 Sengupta, P., 212 Seo, S., 13, 210, 259 Serantoni, E. F., 171 Serebrennikova, G. A., 231 Serebryakov, E. P., 174 Serelis, A. K., 154 Seressova, V., 58 Sethi, A. S., 41 Seto, H., 158 Seto, S., 82 Seube, S., 69 Seym, P. T. A., 48 Seymour, J. P., 9 Sgarabotto, P., 120, 191 Shaffner, T. J., 6 Shah, G. M . , 23,288 Shah, J. N., 23,288 Shank, C. V., 242 Shanker, D., 192 Shapiro, E. L., 257,290 Sharkov, A. V., 242 Sharma, M. L., 41 Sharma, S. D., 41, 42, 78 Sharpless, K. B., 17, 18,20 Shashkov, A. S., 247 Shavanov, S. S., 278 Shaw, C., 280 Shcherbakova, M. S., 265 Shchukolyukov, S. S., 231 Shefer, S., 262, 307 Sheikh, Y. M., 119, 190 Sheinin, E. B., 264, 328 Sheldrick, G. M., 10, 171 Sheldrick, W. S., 66, 94, 325 Sheppard, P. N., 173, 177 Sheppard, R. C., 294 Sherma, J., 238 Sherwood, J. N., 64 Sheves, M., 258,311 Shiao, M.-S., 87 Shibaev, V. N., 247 Shibata, K., 284 Shibata, M., 67 Shibata, S., 194 Shichida, Y., 233, 242 Shiek, H. S., 258

Author Index Shierling, J. P., 29 Shigemori, M., 156 Shilina, R. F., 39 Shimada, A., 6 Shimamura, F., 220 Shimizu, F., 96 Shimizu, M., 210 Shimizu, S., 27 Shimokowa, N., 48 Shimooda, I., 101 Shindo, M., 304 Shingel, I. A., 59, 65 Shingu, T., 210 Shingyouchi, K., 210 Shinoda, A., 53 Shioiri, T., 15 Shiojima, K., 215 Shirahama, H., 33, 112, 114 Shirahata, A., 21 Shirai, N., 175 Shiraishi, M., 249 Shirakawa, K., 211 Shiratori, Y., 204 Shiro, M., 195 Shitkin, V. M., 290 Shizuri, Y., 126 Shkrob, A. M., 242 Shmelev, G. E., 242 Shnulin, A. N., 206 Shoji, J., 194, 195, 210, 211 Shono, F., 29 Shono, T., 19 Shoyama, Y., 78 Shriver, J., 238 Shue, H.-J., 257, 317 Shuhama, I. K., 166 Shunk, B., 100 Sialom, B., 31 1 Sibel’dina, L. A., 238 Sicinski, R. R., 319 Siddiqui, A. H., 295 Siddiqui, S., 197 Siefert, W. K., 214 Siemieniuk, A., 58 Sih, C. J., 24 Sik, V., 188 Sikora, M., 46 Silverstein, R. M., 45 Sim, G. A., 8,112 Sims, J. J., 125 Simes, J. J. H., 189 Simmonds, D. J., 6 Simmons, N. P. C., 64 Simonetta, M., 9 Simons, J., 240 Simonsen, J. L., 74 Sirnonsen, S. H., 9 Simpson, K. L., 230 Simpson, R. F., 223 Sinclair, R. S., 240 Sineshchekov, V. A., 242 Singaram, B., 14,50,51,54,58, 59 Singer, S. P., 20

Singh, B. B., 68 Singh, C., 192 Singh, H., 216, 295 Singh, J., 192 Singh, 0. S., 112 Singh, P. P., 211 Singh, R. K., 238,246 Sippel, C. J., 252 Siqueira, N. C. S., 110 Sircar, I., 205 Sirna, A., 288 Sironi, A,, 9 Siv, C., 58 Sivarmakrishnan, R., 19,236 Siverns, M., 98, 116, 159, 166, 171 Skalaban, T. D., 238 Skinner, R. W. S., 319 Skorobogatova, E. V., 67 Skripnik, 0. B., 74 Slack, D. A., 10 Slaunwhite, W. R. jun., 266 Slovin, E., 78 Smirnova, N. A., 39 Smith, A. B., 102 Smith, D. H., 156,258 Smith, G. C., 300 Smith, G. W., 206,214 Smith, H. E., 6 Smith, L. C., 298 Smith, R. H., 27 Smith, S. G., 68 Smith-Palmer, T., 276 Smits, J., 319 Snarsky, L., 78 Snatzke, G., 47, 293 Sneden, A. T., 99,122,192 Snider, B. B., 36 Snieckus, V., 16,22 Snoussi, M., 22 Snyder, P. A., 64 Sobata, P., 74 Soderholm, A. C., 166 Soderlund, D. M., 28,29 Sokoloff, S., 121 Sokoloski, E. A., 46 Sokolova, L. A., 39 Sokolova, N. A., 231 Sokol’skii, D. V., 39 Solheim, B. A., 181 Solodar, J., 57 Solov’eva, N. I., 18 Sommerville, P., 174 Someya, T., 81, 186 Sondengam, B. L., 291 Song, P.-S!, 240 Soni, G. L., 238 Sonoda, A., 15,22 Sonoda, N., 20,24 Soper, C. J., 178 Sopova, A. S., 265 Sorensen, H., 193 Sorensen, U., 150 Sorm, F., 120

Author Index Sotiropoulos, J., 69 Spassov, S. L., 166 Spengel, S., 323 Spenser, T. A., 187, 307 Sperling, W., 242 Spiegel, B. I., 22 Spindler, M., 323 Spiteller, G., 78 Spitznagle, L. A., 269 Spongliarich, R., 19 Sponsel, V. M., 172 Sporn, M. B., 238 Spronck, H. J. W., 80 Spyckerelle, C., 205, 214 Squillace, A. E., 27 Srinivasan, C. V., 68 Srinivasan, K., 60 Srivastava, H. C., 210, 211 Srivastava, R. C., 9 Srivastava, S. K., 203 Staal, G. B., 16 Stache, U., 321 Stanczyk, F. Z., 266 Standen, M. E., 29 Standifier, L. N., 191 Starkemann, C., 70 Stassinopolou, C. I., 323 Stauffacher, D., 156 Stec, W. J., 15 Steckel, T. P., 67 Steckhan, E., 31 Steel, P. J., 64 Stegk, A., 226 Steglich, W., 16, 40 Stemke, J. E., 21 Stephen, J. D., 63 Steudler, P. A., 179 Stevens, E. S., 64 Stevenson, D. F. M., 317 Stevenson, R., 193, 283 Stewart, I., 237 Steyn, P. S., 97 Sticher, O., 47 Still, W. C., 81 Stipanovic, R. D., 108, 109 Stocks, R. A., 51 Stoddart, J. L., 175 Stoessl, A., 139, 145 Stokie, G. J., 177, 180 Stokkink, E., 45 Stork, G., 184 Stothers, J. B., 64, 139, 145 Strauss, C. R., 223 Streelman, D. R., 99 Strege, P. E., 21 Stretton, R. J., 284 Streuff, B., 165 Strohecker, R., 238 Struchkov, Y. T., 206 Stryukov, V. B., 64 Stubbs, L., 242 Stubenrauch, G., 320 Subba Rao, G. S. R., 19,236 Subden, R. E., 246

349 Suffness, M. I., 103 Sufra, S., 239 Suga, T., 53, 193, 211 Suga, Y., 211 Sugawara, F., 29 Suginome, H., 299, 300 Sugiura, S., 299 Sugiyama, T., 29 Sugumaran, M., 243 Suhr, I. H., 6 Sun, H. H., 126 Sundararaman, P., 51, 261, 285,313 Sunder, R., 192,208 Sung, T. V., 175 Suokas, E., 201 Suri, S. C., 58 Suryawanshi, S. N., 67,69 Suslova, L. M., 174 Susuki, M., 97 Suteu, F., 56 Suwita, A., 50, 58, 59, 82, 110, 122,124, 161 Suzuki, A., 181 Suzuki, F., 24 Suzuki, H., 242 Suzuki, S., 193,241 Suzuki, T., 68, 101, 182 Sverdlov, A. G., 242 Sweet, F., 317 Swenton, J. S., 251 Swern, D., 17 Swezey, S. E., 251 Swiatkiewicz,J., 64 Swidersky, K. P., 190, 307 SynlEkovd, M., 296 Sywanyk, W., 224 Syndes, L. K., 23 Szabo, A., 293 Szabolcs, J., 221 Szajewski, R. P., 20 Tabacchi, R., 27 Taber, D. F., 184 Tabernero, M. L., 161 Tabushi, I., 251 Taccetti, N., 58 Tachi, Y., 215 Tachibana, Y., 251 Tada, A., 107,210 Tada, M., 142,212,278 Tada, T., 197 Tadano, K., 266 Tadasa, K., 53 Tagg, L. G., 305 Taillefer, R., 65, 66 Tajima, K., 129 Takabe, K., 33,39,67 Takada, A., 280 Takagi, G., 39 Takagi, I., 139 Takagi, S., 237, 266 Takagi, Y., 138,178 Takahashi, K., 238

Takahashi, T., 139, 142, 195, 210;211,212 Takahashi, T. T., 23, 289, 301 Takahashi, Y., 193 Takai, K., 19, 142 Takai, M., 21 1 Takaoka, D., 181 Takasaka, N., 76 Takase, K., 128, 129, 150 Takashima, Y.: 29 Takaya, H., 24,61 Takayama, K., 81, 186 Takayanagi, H., 182 Takazawa, O., 235 Takeda, A., 76 Takegami, Y., 68 Takemoto, T., 121, 157, 181, 190 Takemura, T., 241 Takeshita, K., 31 Takeshita, T., 101 Taketomi, T., 81, 186 Takeuchi, Y., 242 Takeya, K., 36 Talapatra, B., 203 Talapatra, S. K., 203 Tamao, K., 31 Tamaru, Y., 38, 76 Tamm, C., 199 Tamura, S., 181 Tamura, T., 189 Tamura, Y., 61 Tanabe, K., 56,74 Tanabe, M., 257,317 Tanaka, H., 42 Tanaka, J., 33, 39, 60, 67, 81 Tanaka, N., 172 Tanaka, O., 171,194,195,210 Tanaka, Y., 219,220 Tandon, J. S., 162 Taneja, S. C., 76 Tang, G. H., 39 Tani, H., 31 Tanielian, C., 37 Tanigawa, Y., 22 Taniguchi, T., 172 Tanis, S. P., 181, 231 Tarnopolsky, B. L., 193 .Tasca, A., 69 Taskinen, J., 54 Tateishi, K., 266, 267 Taticchi, A., 73 Tatovelomanana, V., 34 Tatsumi, C., 53 Tatsuno, Y., 15 Tavela, T. E., 238 Taylor, D. A. H., 195,199,200 Taylor, E. J., 306 Taylor, J., 297 Taylor, R., 9 Taylor, R. J. K., 22 Tazuke, Y., 139 Teitel,. S., 78 Telschow, J. E., 18, 286

350 Templeton, J. F., 262, 286 Teo, K. C., 64 Terabe, M., 142 Terada, I., 96 Terada, Y., 129 Terao, S., 249 Teratani, S., 39 Termont, D., 151 Terner, J., 239 Terpinski, J., 61 Terpugov, E. L., 242 Teste, J., 160 Texter, J., 64 Thaller, V., 157 Theimer, E. T., 64 Thiem, J., 64 Thieme, H., 16 Thies, P. W., 47 Thoa, H. K., 326 Thomas, A. F., 70 Thomas, M. T., 22 Thomas, R., 322 Thomas, S. A., 165, 166 Thomas, T. M., 240 Thompson, E. D., 78 Thompson, M. J., 191 Thomson, A. J., 63, 238 Thomthwaite, D. W., 328 Thorstenson, J. H., 57 Thrash, R. J., 239 Threlfall, D. R., 252 Thuillier, A., 34, 40 Tibbetts, M. S., 7 Tibbetts, P. J. C., 237 Tietze, L.-F., 48 Tilak, B. D., 12 Timms, R. N., 279 Tint, G. S., 262, 307 Tittel, G., 47 Toda, M., 188 Tohyama, K., 188 Toia, R. F., 178 Tokoroyama, T., 195, 197 Tokunaga, F., 242 Tolmasquim, S. T., 238 Tolstikov, G. A,, 39, 249,278 Tomimori, T., 210 Tomita, Y., 13, 210, 259 Tomiyama, K., 136 Tomono, S., 241 Toome, V., 262, 307 Torchia, D., 238 Torgov, I. V., 278 Tori, K., 13, 210, 259 Tori, M., 195, 212 Torii, S., 42, 61, 77, 234 Torrance, S. J., 208 Torre, G., 14 Torrent, M., 48 Torres, J. V., 275 Toru, S., 182 Tosukhowong, P., 232 T6th, G., 293 Toyota, M., 121, 157

Author Index Tozyo, T., 210 Trachtenberg, E. N., 260, 304 Trammell, G. L., 86 Tramontano, A., 18, 75 Trautmann, D., 197 Trave, R., 120 Traylor, T. G., 9 Traynor, S. G., 71 Trifilieff, E., 107 Trogolo, C., 47, 48 Troitskii, M. F., 247 Trost, B. M., 21, 58, 97, 184, 279,297,303 Truesdale, L. K., 17,285 Truscott, T. G., 240, 242 Tsankova, E., 136 Tschesche, R., 32, 165, 323 Tschesche, T., 21 1 Tseng, C.-L. W.. 99. 101). 156 Tserng, K.-Y., 271, 275 Tsoucaris, G., 8 Tsubomura, H., 24 1 Tsuchihashi, G.-I., 5 1 Tsuchiya, S., 31 Tsuda, T., 25 1 Tsuda, Y., 107 Tsuji, H., 172 Tsuji, J., 22, 38, 91 Tsujitani, R., 15 Tsukida, K., 218,231,233,238 Tsuruta, H., 39 Tsutsui, M., 90 Tsuyuki, T., 195,210,211,212 Tsuzuki, K., 33 Tsyban, A. V., 21 Tsyrlina, E. M., 18 Tuddenham, R. M., 234 Tudroszen, N. J., 71 Tuinman, A., 286 Tulinsky, A., 3 Turner, A. B., 281 Turner, C. E., 10,78,79, 150 Turner, S., 294 Turner, W. V., 29 Tursch, B., 119, 156, 177, 180 Twine, C. E., jun., 79 Twitchett, P. J., 78 Uchikawa, K., 189 Uchio, Y., 63, 70 Uda, H., 22 Udarov, B. G., 54 Ueda, S., 25 Ueda, T., 280 Uemura, M., 233 Uesato, S., 25 Uliss, D. B., 78, 79 Umani-Ronchi, A., 30 Umekita, N., 78 Umemoto, K., 27, 28 Unai, T., 29 Uneyama, K., 61,77,182,234 Ung, H. L., 291 Unger, G., 206

Urios, P., 267 Urones, J. G., 161, 164 Ushiyama, H., 24 Uskokovic, M. R., 48 Usov, A. I., 247 Usui, S., 86, 224 Utko, J., 74 Utley, J. H. P., 229 Uyehara, T., 182 Uzarewicz, A., 71,72,73 Uzarewicz, I., 72, 73 Uzawa, J., 158 Vaidyanathan, C. S., 243 Vakulova, L. A., 228,235 Valadon, L. R. G., 246 Valentine, D. H., jun., 13, 35 Valentine, J. L., 78 Vallet, J. A., 299 Valverde, S., 162 Van, N. L., 50, 59, 164 van Altena, I. A., 180 Van Antwerp, C. L., 261 Van De Mark, M. R., 67 van den Broek, A. J., 319 van den Heuvel, M. J., 319 Vanderah, D. J., 43, 179, 305 van der Gen, A., 23 van der Helm, D., 179 Van der Putten, K., 239 van der Sluis, W. G., 45 Van Derveer, D., 157 van de Ven, L. J. M., 32,186 Van de Wal, A. J., 13 Vandewalle, M., 20, 151, 154, 286 van Dommelen, M. E., 32, 186 Van Dorselaer, A., 214 Van Engen, D., 5,6,264 van Gurp, P. R. E., 7 Van Horn, D. E., 22 Vankar, Y. D., 12 van Leusen, A. M., 22 van Leusen, D., 22 Van Osselaer, T. A., 13 van Tamelen, E. E., 103, 186 van Veen, A. M., 7 van Vliet, N. P., 319 Varagnat, J., 231 Varkey, T. E., 285,303 Varma, R. K., 324 Varmuza, K., 263 Varon, Z., 195, 197, 200 Varshney, I. P., 210, 211 Vasak, J., 187, 223 VaSiEkova, S., 296 Vasilenko, I. A., 231 Vaughan, W. R., 9 Vazquez, C. P. y P., 155 Vazeux, M., 69 Vecchietti, V., 172 Vecchio, G., 279 Vedejs, E., 18, 286 Veeravalli, J., 60

351

Author Index Veinberg, A. Ya., 234 Venkataraman, K., 10 Venkatesan, K., 162 Venturella, P., 172 Vereshchagin, A. N., 74 Verghese, J., 50,51,54,58, 59, 75 Vergunova, G. I., 247 Verhoeven, T. R., 303 Verma, K., 234, 247 Verma, N. K., 78 Verma, S. M., 63 Vermeire, M., 207 Vermes, J.-P., 286 Vernice, G. G., 310 Vernin, G., 58 Verpooste, R., 216 Veschambre, H., 91 Vetter, W., 247 Veyret, B., 240 Vial, C., 217, 236 Viala, J., 34 Vichnewski, W., 148, 166, 171 Vidal, J.-P., 7 Vidic, H.-J., 326 Vig, 0. P., 41, 78 Vigne-ron, J. P., 7 Vikulova, N. K., 58 Vilkas, E., 10 Vilkas, M., 10 Villa, A. C., 11 Vincieri, F., 55, 58 Vire, J. C., 251 Virgona, C., 29 VitC, J. P., 26 Vleggaar, R., 97 Vocelle, D., 242 Vogeli, U., 221 Voelter, W., 197 Vogel, M. K., 57 Voigt, D., 174 Voitekhovskaya, G. I., 59 Volkova, L. V., 36 von Beroldingen, L. A., 97 von Carstenn-Lichterfelde, C., 162 von Rudloff, E. M., 27,91 von Wartburg, B., 236 Vorbruggen, H., 16 Voronenkov, V. V., 63 Voss, W., 66 Vostrikov, N. S., 278 Votickjl, Z., 192 Vree, T. B., 78 Vrkot, J., 181 Vul’fson, S. G., 74 Vyas, P., 21 1 VystrEil, A., 201, 202 Wada, N., 240 Waddell, W. H., 233,240 Wadsworth, H., 297 Wagner, F., 325 Wagner, H., 47, 126, 167

Wagner, M., 208 Wagner, P. J., 55 Wagner, R., 7 Wahlberg, I., 4, 32, 60, 164, 178,224 Wahren, R., 19 Warkentin, J., 56 Walker, B. J., 72 Walker, D. L., 54, 299 Walker, E. C., 285 Walker, G. T., 32 Walker, K. A. M., 270 Wall, M. E., 78 Wallace, B., 10 Wallace, D. J., 46, 103 Wallace, J. B., 46 Walser, R., 29 Walters, M. E., 20, 287 Wanat, M., 63 Wang, C.-C., 238 Wang,C.-L. J.,94, 128, 151 Wang, C. S., 179 Wang, P. K. S., 49 Wani, M. C., 257 Ward, E. W. B., 139, 145 Wardroper, A. M. K., 214 Waris, F., 295 Warnhoff, E., 294 Warren, R. G., 44 Warshel, A., 239, 242 Watanabe, E., 247 Watanabe, H., 24, 188 Watanabe, M., 134,249 Watson, G., 51 Watson, W. P., 79 Watt, D. S., 313 Watts, C. D., 237 Wautelet, M., 240 Wawrzenczyk, C., 72,74 Webb, L. E., 9 Weber, A., 7,220 Weber, J., 178 Weber, L., 21,257,290 Wedmid, Y., 305 Weedon, A. C., 66 Weedon, B. C. L., 229 Weeks, C. M., 212,255 Weete, J. D., 188 Wehrli, P. A., 30 Weier, R. M., 327 Weihe, G. R., 259 Weimann, L. J., 242 Weinberg, M. L. D., 234 Weinberg, P. B., 266 Weinstein, B., 10 Weisenborn, F. L., 324 Weiss, K., 240 Weiss, U., 256 Weissenberg, M., 273, 283 Welch, S. C., 20, 86, 287 Wells, R. J., 44, 125, 160, 178 Welniak, M., 65 Welti, D. H., 63 Wender, P. A., 20, 126

Wenkert, E., 45,137, 143,170, 202,259 Werstiuk, N. H., 65, 66 West, J. L., 233 West, L. G., 208 Westmore, J. B., 262 Weston, R. J., 259 Weyerstahl, P., 12, 21 Whalley, W. B., 9, 171, 255, 256,261,285,305,306 White, A. H., 110, 177, 178, 202 Whitehead, E. V., 214 Whitehurst, J. S., 188 Whitesell, J. K., 46, 49 Whiting, D. A., 6, 10 Wicha, J., 303, 315 Widman, M., 79 Wie, C. W., 286 Wiebenga, E. H., 8 Wiechert, R., 316 Wiedhopf, R. M., 208 Wiegers, K. E., 68 Wiehager, A.-C., 8 Wiemann, W., 21 1 Wiemer, D. F., 176 Wiesner, K., 185 Wiger, G. M., 125 Wiled, S. H., 13, 262 Wilkie, D. W., 246 Wilkins, A. L., 215, 217 Wilkins, B. J., 305 Williams, D. J., 8 Williams, D. L., 79 Williams, E., 128 Williams, P. J., 223 Williams, P. L., 78 Williams, P. P., 3, 8 Williams, R. O., 326 Williams, S. B., 22 Williams, T. A., 266 Wilson, R. D., 277 Wing, R. M., 125 Winter, W., 7 Wiss, O., 188 Wiss, V., 188 Witkiewcz, K., 67 Woggon, W.-D., 158 Wolf, H., 293 Wolf, H. R., 164, 236 Wolf, S., 14 Wolff, C., 197 Wolff, s.,37 Wolfhugel, J. L., 301 Wolinsky, J., 57 Wollenberg, R. H., 22 Wong, F., 319 Wong, R. Y., 9 Woo, W. S., 208,211 Wood, M., 37 Woodgate, P. D., 170, 276, 283,287,298 Woods, G. F., 317 Woodward, R. B., 114

352 Woolard, F. X., 5 Worth, B. R., 63 Wragg, K., 199 Wratten, S. J., 85, 137 Wu, A., 22 Wuest, J. D., 50 Wunderlich, J. A., 7, 9 Wuts, P. G. M., 127, 183 Wynberg, H., 261 Yadav, Y. S., 111 Yagen, B., 79 Yagi, A., 203 Yagihashi, F., 136, 300 Yahara, S., 194 Yakovleva, I. M., 235 Yamada, H., 120 Yamada, K., 18, 126 Yamada, S.-I., 15, 81, 310 Yamada, Y., 2 4 , 7 6 , 1 9 3 Yamagiwa, S., 22 Yamaguchi, S., 13 Yamaguchi, Y., 53 Yamaji, T., 39 Yamakawa, T., 22 Yamamoto, H., 14, 16, 113, 266, 267 Yamamoto, H. Y., 241 Yamamoto, K., 9 1 Yamamoto, M., 39 Yamamoto, N., 241 Yamamoto, Y., 107 Yamamura, S., 24, 129, 188 Yamanaka, H., 216 Yamano, Y., 251 Yamasaki, K., 171, 183, 194, 294 Yamashita, K., 29, 235, 260, 266 Yamashita, M., 51 Yamato, T., 77

Author Index Yamauchi, T., 47 Yan, S.-J., 120 Yanagi, K., 69 Yanagita, M., 154 Yang, F., 192 Yang, G. C., 264,328 Yang, J. T., 12 Yasuda, D. M., 257, 317 Yasuda, H., 31 Yasuhara, F., 13 Yasuoka, N., 7 Yazdanbakhch, M. R., 18 Yerhoff, F. W., 294 Yemul, S. S., 10 Ying, B. P., 179 Yisak, W., 79 Yokio, T., 210 Yokohama, Y., 151 Yokoi, K., 72 Yokoo, S., 120 Yonehara, H., 158 Yonekura, N., 299 Yooeyoshi, Y., 42 Yoon, N. M., 14 Yorke, S. C., 186 Yoshida, M., 240, 242 Yoshida, T., 27,64, 266 Yoshida, Z.-I., 38, 76 Yoshihara, K., 44, 45 Yoshihara, M., 164 Yoshiie, S., 24 Yoshikawa, M., 210, 211 Yoshikoshi, A., 23, 134, 273 Yoshimoto, M., 29 Yoshimura, C., 7 2 , 7 4 Yoshimura, Y., 13,210, 259 Yoshioka, H., 29 Yoshisato, E., 39 Yoshitake, A., 29 Yoshitake, J., 9 1 Yoshizawa, T., 231, 233, 238, 242

Yosioka, I., 216 Young, N. M., 237,239 Young, P. R., 79 Young, R. N., 6 3 Yu, Y. s., 71 Yuki, Y., 167, 168 Yunker, M. B., 187, 247 Yura, Y., 29 Yur’ev, V. P., 18

Zabza, A., 3 3 , 7 2 Zaiko, E. J., 185 Zaitsev, V. V., 56 Zajac, H., 281 Zajotti, A., 172 Zalewski, R. I., 264 Zalkow, L. H., 157 Zamecnik, J., 265 Zanasi, R., 120 Zassinovich, G., 19 Zaugg, H. E., 79 Zayad, S., 178 Zbiral, E., 311 Zderic, S. A,, 75 Zdero, C., 50, 59, 82, 91, 122, 139, 142,165,171 Zeelen, F. J., 319 Zehavi, U., 291,302 Zen’ko, I. V., 59 Zerbi, G., 239 Zientek, E., 73 Zima, G., 21 Zimina, N. G., 59 Zimmerman, W. T., 7 Zjawiony, J., 281 Zummack, W., 12 Zvonkova, E. N., 231,238 Zwierzak, A., 72 Zwving, J., 48