Terpenoids and Steroids: Volume 10 (SPR Terpenoids and Steroids (RSC))

Terpenoids and Steroids Volume 10 A Specialist Periodical Report Terpenoids and Steroids Volume 10 A Review of the ...

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Terpenoids and Steroids Volume 10

A Specialist Periodical Report

Terpenoids and Steroids Volume 10

A Review of the Literature Published between September 1978 and August 1979

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 J. S. Roberts, University of Stirling

The Royal Society of Chemistry Burlington House, London W I V OBN

British Library Cataloguing in Publication Data Terpenoids and steroids. (The Royal Society of Chemistry. Specialist periodical reports). VOl. 10 1. Terpenes 2. Steroids I. Hanson, James Ralph 11. Series 547’.71 QD416 74-615720 ISBN 0-85186-336-1 ISSN 0300-5992

Copyright @ 1981 The Royal Society of Chemistry

All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means-graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems-without written permission from The Royal Society of Chemistry

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

In trod uc tion

The intention of this volume is to provide an annual survey of the terpenoid and steroid literature. In the past year a fascinating variety of terpenoid structures has been described, particularly from marine and insect sources. The value of high-field 'H n.m.r. and I3C n.m.r. data in structural elucidation is apparent although it has, inevitably, led to a decrease in the amount of new natural product chemistry which has been described. In some cases the spectroscopic elucidation of a structure has left the absolute stereochemistry undetermined or merely assigned by analogy. Since there are a number of examples where both enantiomers of a structure are known, this is a dangerous omission. There are now a number of areas amongst both the sesquiterpenoids and the diterpenoids where there is a clear need for an unambiguous correlation with known structures of proven absolute stereochemistry. The format of these Reports has remained relatively constant to fadilitate the location of subject matter. These chapters cover the period from September 1978 to August 1979. Unfortunately it has not been possible to include the customary chapter on the monoterpenoids. We hope to remedy this deficiency by including the chapter in the next volume. Whilst there has been some overlap with the companion volumes on the Alkaloids, on Aliphatic and Related Natural Product Chemistry, and on Biosynthesis, we have endeavoured to keep this to a minimum,. J. R. HANSON

V

Contents Part I Terpenoids

Chapter 1 Sesquiterpenoids By J. S. Roberts

3

1 Introduction

3

2 Farnesane

3

3 Bicyclofarnesane

5

4 Bisabolane, Sesquicarane

11

5 Sesquipinane, Sesquicamphane

17

6 Cuparane, Trichothecane

20

7 Chamigrane, Widdrane, Thujopsane,

21

8 Acorane, Cedrane, Carotane, Zizaane

25

9 Cadinane, Muurolane, Copaane, Cyclosesquifenchane, Sativane, Copacamphane, Picrotaxane

28

10 Himachalane, Longipinane, Longifolane

34

11 Caryophyllane, Humulane, Africane, Illudalane, Protoilludane, Hirsutane, Vellerane, Pentalane, Senoxydane

38

12 Germacrane

51

13 Elemane

65

14 Eudesmane

69

15 Vetispirane

75

16 Eremophilane, Nootkatane, Ishwarane

80

17 Guaiane, Pseudoguaiane, Seychellane, Patchoulane

87

18 Aromadendrane, Maaliane

99 101

19 Miscellaneous vii

'1erpenoids and Steroids

Vlll

Chapter 2 Diterpenoids By J. R. Hanson

106

1 Introduction

106

2 Acyclic and Related Diterpenoids

106

3 Bicyclic Diterpenoids

107 107 110

Labdanes Clerodanes

4 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids

5 Tetra- and Penta-cyclic Diterpenoids Kaurenoid Diterpenoids Beyerene Diterpenoids Atiserene Diterpenoids Trachylobane Diterpenoids Gibberellins Grayanotoxins Diterpenoid Alkaloids

114 114 116 117 117 119 120 120 121 123 123

6 Macrocyclic Diterpenoids and their Cyclization Products

124

7 Miscellaneous Diterpenoids

126

8 Diterpenoid Total Synthesis

131

Chapter 3 Triterpenoids By J. D. Connolly

135

1 Squalene group

135

2 Fusidane-Lanostane Group

137

3 Dammarane-Euphane Group

142 144 151 152

Tetranortriterpenoids Pentanortriterpenoids Quassinoids

4 Shionane-Baccharane Group

153

5 Lupane Group

154

6 Oleanane Group

155

7 Ursane Group

160

8 Hopane Group

162

9 Stictane Group

163

ix

Contents

Chapter 4 Carotenoids and Polyterpenoids By G.Brifton

164

1 Carotenoids Reviews New Structures and Stereochemistry New Carotenoid Structures Apocarotenoids New Stereochemical Assignments New Natural Products Related to Carotenoids Carotenoid-Protein Complexes Synthesis and Reactions Carotenoids Retinoids Degraded Carotenoids Physical Methods Separation and Assay N.M.R. Spectroscopy Mass Spectrometry Chiroptical Methods Electronic Absorption Spectroscopy Infrared and Resonance Raman Spectroscopy Other Spectroscopic Techniques Miscellaneous Physical Chemistry Photoreceptor Pigments Biosynthesis and Metabolism Stereochemistry Enzyme Systems Inhibition and Regulation

164 164 165 165 165 165 168 170 172 172 174 179 183 183 184 184 185 185 186 187 187 188 188 188 189 190

2 Polyterpenoids and Quinones Polyterpenoids Isoprenylated Quinones Chemistry Separation and Assay Biosynthesis

191 191 192 192 194 194

Part I! Steroids

Chapter 1 Physical Methods By D. N. Kirk

199

1 Structure and Conformation

199

2 N.M.R. Spectroscopy

201

3 Chiroptical Phenomena

205

4 Mass Spectrometry

207

Terpenoids and Steroids

X

5 Miscellaneous Physical Properties

210

6 Analytical Methods

21 1 21 1 212 213

Immunoassay of Steroids Chromatography Miscellaneous

Chapter 2 Steroid Reactions and Partial Syntheses By B. A. Marples

214

Section A : Steroid Reactions 1 Alcohols and Carboxylic Acids and their Derivatives, Halides, and Epoxides Substitution and Epimerization Oxidation and Reduction Epoxide Ring Opening Ethers, Esters, and Carboxylic Acids

214 214 215 216 217

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

218 218 220 221 222

3 Carbonyl Compounds

222 222 224 226

Reduction Other Reactions Reactions Involving Enols or Enolic Derivatives

4 Compounds of Nitrogen, Sulphur, Selenium, and Tellurium 228 5 Molecular Rearrangements Backbone Rearrangements and Double Bond Isomerizations Miscellaneous Rearrangements

232

6 Functionalization of Non-activated Positions

238

7 Photochemical Reactions

240

232 233

Section B : Partial Syntheses 8 Cholestane Derivatives and Analogues

242

9 Vitamin D and its Metabolites and Related Compounds

250

10 Pregnanes

254

11 Androstanes and Oestranes

256

12 Cardenolides

261

Contents

xi

13 Heterocyclic Steroids

263

14 Microbiological Oxidations

265

15 Miscellaneous Syntheses

266

Errata

268

Aurhor Index

269

Part I TERPENOIDS

Sesqu iterpenoids BY J. S . ROBERTS

1 Introduction This chapter follows the now established biogenetic grouping of sesquiterpenoids. The literature that has been reviewed encompasses a slightly longer period than normal in view of the delay of certain journals in reaching the previous Reporter. The approximate period September 1978-November 1979 has also witnessed a significant increase in the number of sesquiterpenoid syntheses and structural elucidation studies, and hence this Report is somewhat longer than in previous years. Professor F. Bohlmann and his group have contributed markedly to this increase by the publication of no less than 58 papers in sesquiterpenoid chemistry in the period under review.

2 Farnesane Several new farnesyl sesquiterpenoids have been reported; these include helepuberin acid (1)(Helenium puberulum),' caulerpenyne ( 2 ) (green alga, Caulerpa , ~ the two sweet praliferu),2 athanagrandione ( 3 ) (Athanasia g r ~ n d i c e p s )and potato stress metabolites (4)and ( 5 ) , which are related to the corresponding

0 (4) (5)

(3)

R1 = H,OH, R2 = 0 R' = 0,R2 = H,OH

' F. Bohlmann and J. Jakupovic, Phytochemistry, 1979,18,131. V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Tetrahedron Lett., 1978,3593. F.Bohlmann and C. Zdero, Phytochemistry, 1978,17,1595.

3

4

Terpenoids and Steroids

diketone m y ~ p o r o n e The . ~ epimeric sesquiterpenoids ( 6 ) and (7) have been isolated from Osmanthus essential oil and both have been synthesized from the known ketones (8) and (9).5The furanosesquiterpenoid longifolin (lo), which is of both marine and terrestrial origin, has been synthesized (Scheme 1)although the yield in the final coupling step was only 4% .6

boab Br

Reagents: i, (EtO),P(O)CHCO,Et; ii, LiAlH,; iii, PBr,; iv,

Scheme 1

A number of bicyclofarnesyl hydroquinones have already been isolated from the brown seaweed Dictyopteris unduluta. The parent acyclic compound (11)has now been found in the fresh alga.7 Two papers on the terminal functionalization of farnesyl derivatives have been published. These include the use of 2,4,4,6tetrabrornocyclohexadienone as an alternative to N-bromosuccinimide for the formation of the bromohydrin of the terminal double bond of methyl farnesoate

L. T. Burka and J. Iles, Phytochemistry, 1979, 18, 873.

’ R. Kaiser and D. Lamparsky, Helv. Chirn. Acta, 1979,62, 1887. N. Fukamiya and S. Yasuda, Chem. Ind. (London),1979,126. M. Ochi, H. Kotsuki, S . Inoue, M. Taniguchi, and T. Tokoroyama, Chem. Lett., 1979, 831.

Sesquite rpenoids

5

and farnesyl acetate.8 As is well known the bromohydrin can be converted into the corresponding epoxide with base. Masaki et al.9 have described the selective chlorosulphenylation of farnesol benzyl ether, which, by further elaboration (Scheme 2), has permitted the synthesis of the naturally occurring diacetate (12).

1

iii, iv

f OAc HO

J

Reagents: i, PhSCl; ii, Et,N; iii, [O]; iv, (MeO),P; v, Li-EtNH2; vi, Ac,O-py

Scheme 2

Still et a1.l' have reported a highly stereoselective synthesis of the alcohol (.4) which has been previously converted into the c18 Cecropia Juvenile Hormone (Scheme 3). The key step in this synthesis involves the recently described [2,3] sigmatropic rearrangement of the dilithio dianion derived from (13).Full details of the previously reported CI7 and Cecropia Juvenile Hormone syntheses have been published.'

3 Bicyclofarnesane Further biosynthetic studies by Cane et a1.12 have shown that the conversion of farnesyl pyrophosphate (15) into nerolidyl pyrophosphate (16) proceeds by a net syn (suprafacial) process and that the subsequent cyclization to cyclonerodiol(l7) occurs in a trans manner (Scheme 4).This careful piece of work was achieved by incorporation studies with doubly labelled nerolidol and mevalonate precursors and then by ascertaining the chirality of the acetate derived by Kuhn-Roth oxidation through enzymatic conversion (malate synthase/fumarase incubation) into labelled malate. In a subsequent series of experiments with labelled precursors, Cane et al.13 have confirmed that (i) only the C-7 hydroxy-group in cyclonerodiol is derived from water whereas the C-3 hydroxy-group is derived

lo

l1 l2 l3

I. Ichinose, T. Hosogai, and T. Kato, Synthesis, 1978, 605. Y. Masaki, K. Hashimoto, and K. Kaji, Tetrahedron Lett., 1978, 5123. W. C. Still, J. H. McDonald, D. B. Collum, and A. Mitra, Tetrahedron Lett., 1979, 593. A. Yasuda, S . Tanaka, H. Yamamoto, and H. Nozaki, Bull. Chem. SOC. Jpn., 1979,52, 1701. D. E. Cane, R. Iyengar, and M.-S. Shiao, J. A m . Chem. SOC., 1978,100,7122. D. E. Cane and R. Iyengar, J. A m . Chem. SOC.,1979,101,3385.

Terpenoids and Steroids

6

l i i , iii

1

vi

OH

OH

&i ; ii, Bu‘Li; iii, O H C A BuLi; vii, TsCI; viii, LiAlH,; ix, aq. H O A c

O

E

E ; iv, KH; v, Bu,SnCH,I; vi,

Scheme 3

Qlpp D

T

Scheme 4

T

=

\TOPP

Sesquiterpenoids

7

from the intermediate cyclonerodiol pyrophosphate by P-0 bond cleavage and (ii) the absolute configuration at C-3 in nerolidyl pyrophosphate is retained through the cyclization and pyrophosphate hydrolysis steps. Finally, by using [l-'80]farnesyl pyrophosphate as the labelled precursor, it was demonstrated that the most probable mechanism for the syn conversion of farnesyl pyrophosphate into nerolidyl pyrophosphate involves a tightly bound ion pair (Scheme 5). This follows from the observed retention of one third of the "0 label in the derived cyclonerodiol. Other possible mechanisms would have demanded zero, one-sixth, or complete retention of the "0 label in cyclonerodiol. Cyclonerodiol has in fact been synthesized in a biomimetic manner by a Hg"-induced cyclization of nerolidol. l4

Scheme 5

Nigaki alcohol (18)has been identified by spectroscopic and chemical means as a constituent of Picrasma ailanthoides P1anchon.l' Latia luciferin (19) has been synthesized in a stereoselective manner, A key step in this synthesis involves the addition of lithium dimethylcuprate to an enol phosphate derived from a P-ketoester to form an @-unsaturated ester.16 Dehydro-p-ionilideneacetic acid (20), an important intermediate in the synthesis of abscisic acid, has been prepared,I7 as have the two nor-abscisic acid derivatives (21).lg The metabolite (22) of abscisic acid has been identified in the seeds of Robinia pseudacacia L.19

wocH wco H

(18)'0

fCo2H (21) E o r Z 14 15

Y . Matsuki, M. Kodama, and S. It;, Tetrahedron Lett., 1979, 2901. Y . Sugimoto, T. Sakita, Y. Moriyama, T. Murae, T. Tsuyuki, and T . Takahashi, Tetrahedron Lett., 1978,4285.

F. W . Sum and L. Weiler, Tetrahedron Lett., 1979, 707. 19

G. Cainelli, G . Cardillo, and M. Orena, J. Chem. SOC.,Perkin Trans. 1, 1979, 1597. F. Kienzle, Helv. Chim. Acta, 1979,62, 155. N . Hirai, H. Fukui, and K. Koshimizu, Phytochemistry, 1978, 17, 1625.

Terpenoids and Steroids

8

A number of rearranged monocyclofarnesyl sesquiterpenoids have been isolated from the sea hare Aplysia dactylomela. These include dactyloxene-A (23), -B (24), and -C ( 2 5 ) and dactylenol (26) together with its acetate.20These compounds are related to other marine metabolites isolated from red algae. Aplysistatin (27), a metabolite of the sea hare Aplysia angasi, has been synthesized by a route which involves Hg"-mediated brominative cyclization and a novel oxidative debenzylation step (Scheme 6).21

vi, vii

Br

Br

1

viii

Br

H (27)

Reagents:

i, PhSCHC0,Me; ii, LDA-ZnCl,; iii, PhCH,OCH,CHO; iv, Hg(O,CCF,),; v, Br,KBr-LiBr; vi, [O]; vii, A; viii, Ph3C+BF,-

Scheme 6

The principal component of the defensive secretion of the termite soldiers Ancistrotermes cavithorax has been shown by spectroscopic methods and synthesis to be ancistrofuran (28).22 Further studies on the components of the defence secretion of the West African termite species Amitermes evuncifer have revealed the presence of the two bicyclic ethers (29) and (30) together with the

*' '*

F. J. Schmitz, F. J. McDonald, and D. J. Vanderah, J. Org. Chem., 1978,43, 4220. T. R. Hoye and M. J. Kurth, J. Am. Chem. SOC.,1979,101,5065. R. Baker, P. H. Briner, and D. A. Evans, J. Chem. Soc., Chem. Cornrnun., 1978,981.

9

Sesquiterpenoids

m, H

(31)

eudesmane hydrocarbon (3 l).23 The latter compound is obviously related to the major component (32) of the secretion. A detailed of the 13Cn.m.r. spectrum of ascochlorin (33) biosynthesized from [3-'3C,4-2H2]mevalonolactonehas supported an earlier proposal concerning the concerted nature of the 1,2-hydride and 1,2-methyl shifts (Scheme 7).

4

H--0

(33)

R= Ho*Me

OH CHO

Scheme 7

The potent biological activity (insect antifeedant, antitumour, antifungal) of warburganal (35) has stimulated considerable synthetic interest in this compound. Three total syntheses of this compound have been recorded in the period under re vie^.^'-^^ The synthesis by Tanis and Nakanishi2' has additional flexibility since the key intermediate diol (34) can be used in the syntheses of cinnamolide (36), drimenin (37), and polygodial (38). Both norisoambreinolide (39; R = 0)and isoambrox (39; R = H2) have been synthesized from (40),the product of the .~~ stannic chloride-catalysed cyclization of farnesyl phenyl ~ u l p h o n eYahazunol (41), a bicyclofarnesyl hydroquinone, has been identified in the brown seaweed 23 24 25

26

27

28 29

R. Baker, D. A. Evans, and P. G. McDowell, Tetrahedron Lett., 1978,4073. R. Hunter and G. Mellows, Tetrahedron Lett., 1978, 5051. S. P. Stanis and K. Nakanishi, J. A m . Chem. SOC.,1979,101,4398. T. Nakata, H. Akita, T. Naito, and T. Oishi, J. A m . Chem. SOC.,1979,101,4400. A. Ohsuka and A. Matsukawa, Chem. Lett., 1979,635. A. J. G. M. Peterse, J. H. Roskam, and Ae. de Groot, Rec. Trav. Chim. Pays Bas, 1978,97,277. S . Torii, K. Uneyama, and H. Ichimura, J. Org. Chern., 1978,43,4680.

10

Terpenoids and Steroids

Dictyopteris undulata O k a m ~ r a , ~while ' ~ ilimaquinone (42), which has a rearranged drimane skeleton, is a constituent of a Pacific Ocean marine Interestingly this latter compound is enantiomeric with respect to a related Mediterranean sponge metabolite. I3C N.m.r. spectral data and chemical evidence have led to a reassignment of the structure of spiniferin-l (43).This novel bridged sesquiterpenoid co-occurs with spiniferin-2 (44)(in the sponge Pleraply silla spinifera 3 1 ) . This structure has now been confirmed. Two new sponge

metabolites from Dysidea herbacea (Keller) are herbadysidolide (45)and the nor-seco-derivative herbasolide (46). The structures of both these compounds have been determined by X-ray analysis.32The same species of sponge, collected ( a ) M. Ochi, H. Kotsuki, K. Muraoka, and T. Tokoroyama, Bull. Chem. SOC. Jpn., 1979,52,629; (b)

31 32

R. T. Luibrand, T. R. Erdman, J. J. Vollmer, P. J. Scheuer, J. Finer, and J. Clardy, Tetrahedron, 1979, 35, 609. G. Cimino, S. De Stefano, L. Minale, and E. Trivellone, Experientia, 1978, 34, 1425. C. Charles, J. C. Braekman, D. Daloze, B. Tursch, J. P. Declercq, G. Germain, and M. Van Meerssche, Bull. SOC.Chim. Belg., 1978, 87, 481.

11

Sesquiterpen oids

H

H

a 'R m T

(45)

R

(47)

H

H

(48)

(49)

off the Queensland coast, has also yielded the closely related compound spirodysin (47).33In another study of Dysidea species Wells et aE.34have isolated and identified four more compounds, furodysin (48; R = H), furodysinin (49; R = H) and their corresponding thioacetates (48; R = SAC)and (49; R = SAC).It is interesting to note that BF,-catalysed rearrangement of spirodysin (47) gave a 1: 1 mixture of (48; R = H) and (49; R = H). The structure of karatavic acid (50) has been revised and as such is the first example of a seco-drimane se~quiterpenoid.~~

have indicated a mixed polyketide-terpenoid origin for Biosynthetic the unusual fungal metabolite andobenin (51) (Scheme 8). The two extra methyl groups (*) are derived from methionine. Andobenin co-occurs with andilesin (52) whose structure has been recently elucidated by X-ray and c.d. analy~is.~'

4 Bisabolane, Sesquicarane A large number of oxygenated bisabolane sesquiterpenoids (53)-(7 1)have been isolated and identified by Bohlmann's group3844 (see also ref. 342). A third 33 34

35

36 37

38 39

R. Kazlauskas, P. T. Murphy, and R. J. Wells, Tetrahedron Lett., 1978, 4949. R. Kazlauskas, P. T. Murphy, R. J. Wells, J. J. Daly, and P. Schonholzer, Tetrahedron Lett., 1978, 495 1. S. K. Paknikar and J. Veeravalli, Chem. Ind. (London), 1978, 431. J. S. E. Holker and T. J. Simpson, J. Chem. SOC.,Chem. Commun., 1978, 626. A. W. Dunn, R. A. W. Johnstone, B. Sklarz, L. Lessinger, and T. J. King, J. Chem. Soc., Chem. Commun., 1978,533. F. Bohlmann and A. Suwita, Phytochemistry, 1979,18, 677. F. Bohlmann and P. K. Mahanta, Phytochemistry, 1979, 18, 678.

12

Terpenoids and Steroids

11

Scheme 8

member of the marine-derived halogenated bisabolanes, deodactol(72), has been ~ ~structure and absolute isolated from the sea hare Aplysia d a c t y l ~ r n e l a .Its stereochemistry have been determined by X-ray analysis and are closely related to those of caespitol and iso-caespitol.

40 41 42 43 44 45

F. Bohlmann, C. Zdero, and A. A. Natu, Phytochemistry, 1978,17, 1757. F. Bohlmann and C. Zdero, Phytochemistry, 1978, 17, 1591. F. Bohlmann and C. Zdero, Phytochemistry, 1978,17, 1669. F. Bohlmann and M. Lonitz, Chem. Ber., 1978, 111, 843. F. Bohlmann, J. Jakupovic, and C. Zdero, Phytochemistry, 1978,17, 2034. K. H. Hollenbeak, F. J. Schmitz, M. B. Hossain, and D. van der Helm, Tetrahedron, 1979, 35,541.

13

Sesquiterpenoids

p (56) R (57) R

= =

R O

p0R3

OR2

COCHMe2 COCH(Me)CH2Me

(63) R1 = Ang, R2 = epoxy-Ang (64) R' = Me, R2 = Ang

(58) (59) (60) (61) (62)

R' = H, R2 = Ac, R3 = Me, R4 = Ang R' = R2 = Ac, R3 = Me, R4 = Ang R1 = R2 = H, R3 = Me, R4 = Ang R' = H, R2 = R3 = Me, R4 = Ang R' = R2 = H, R3 = R4 = Ang

(65)

(66) R = H (67) R = Ac

p@p w R

(68)

(69) R (70) R

C0,Me

=

=

Me H

Br*

Br

"c1

(71)

Stereospecific syntheses of both ( E ) - and (2)-a-bisabolenes, (73) and (74) respectively, have been carried out (Scheme 9) and the spectral data for each diastereoisomer have been The enantiomers of each have also been made starting from (+)- and (-)-limonene and as a result the P-bisabolene present in the essential oil of Opoponax has been shown to be the (+)-(S,Z)isomer, thus correcting a previous report. As might be expected the odour characteristics of the and (Z)-isomers are subtly different. Both diastereoisomeric racemic a-bisabolols (75) and (76) (only one enantiomer of each is shown) have been prepared from the two isoxazolidines (77) and (78) which, in turn, were derived from intramolecular cyclization of the nitrones of (6E)- and (62)-farnesal re~pectively.~~ From this work it is suggested that natural (-)-abisabolol must be (75) in contradiction to a recent report which held that (76) is the correct structure of the natural isomer. Further work will be needed to resolve this question.

(a-

46

47

F. Delay and G. Ohloff, Helv. Chirn. Acta, 1979,62,369. M.A. Schwartz and G. C. Swanson, J. Org. Chem., 1979,44,953.

14

Terpenoids and Steroids

1

v-viii

(+

Reagents: i, (MeO),P(O)CHCO,Me; ii, BuLi-TMEDA; iii, CO,; iv, MeOH-H’; v, Chrom.; vi, LiAlH,; vii, PBr,; viii,

CuLi

Scheme 9

/ n-N

0-N

/

New syntheses of (*)-ar-turmerone (79) and (&)-nuciferal (80) have been reported (Schemes lo4’ and 11“’) whereas Meyers and Smithso have used the (+)-oxazoline (81) to good effect in an asymmetrically induced synthesis of (+)-ar-turmerone (82) (Scheme 12). A neat one-pot synthesis of p-curcumene (83) has been developed which involves only two steps (Scheme 13).” In a synthesis of the aromatic analogue, (-)-a-curcumene (84), Kumada et aL5*have used an asymmetrically induced cross-coupling Grignard reaction in the presence of a nickel complex of (85) to produce (84) in 66% enantiomeric excess (Scheme 14). A Vilsmeier-Haack-Arnold formylation of (+)-limonene has been used as 48 49

51

52

Y. Masaki, K. Hashimoto, K. Sakuma, and K. Kaji, J. Chem. SOC., Chem. Commun., 1979,855. P. Gosselin, S. Masson, snd A. Thuillier, J. Org. Chem., 1979,44, 2807. A. I. Meyers and R. K. Smith, Tetrahedron Lett., 1979, 2749. J. S. R. Zilenovski and S. S. Hall, Synthesis, 1979, 698. K. Tamao, T. Hayashi, H. Matsumoto, H. Yamamoto, and M. Kumada, Tetrahedron Lett., 1979, 2155.

15

Sesquiterpenoids

op

i

(80)

vi, iii, vii

viii, ix, v

,

AcO (79) Reagents: i, PhSC1; ii, Et,N; iii, MeC0,H; iv, (MeO),P; v, MnO,; vi, NaOAc; vii, A; viii, PTSAAcOH; ix, OH-

Scheme 10

Reagents: i, Mg; ii, CS,; iii, MeI; iv, A M g B r ; v, AgN0,-CdC0,-H,O;

Scheme 11

H

+Lia

qOyPh \

'1 (81)

vi,

--*

OMe

Ph

,

p+i-0ii-iv

C0,Et \

0 (82) Reagents: i, H,O'-EtOH;

ii, (Pr'O),P(O)CH,Li; iii, B U T - ; iv, Me,CO

Scheme 12

16

Terpenoids and Steroids

-

ClMg

it(85)

\

ii +

\

\

SiC13

Reagents: i, CH,=CHBr; ii, HSiC1,-H,PtCl, -[Ni{Ph2P(CH,),PPh,}Clz]

- 6H20; iii, KF; iv, NBS; v, Mg; vi,

Scheme 14

+

Reagents: i, Me2N=CHCl Cl,PO2-; ii, OH-; iii, Y M g C l ; ivy PY2Cr03 Scheme 15

the key step in a synthesis of (+)-a-atlantone (86) (Scheme 15).53In another use of monoterpenoids for sesquiterpenoid synthesis, the ene products (87)-(89) from (+)-limonene and (-)-carvone with methyl vinyl ketone and methyl propiolate respectively have been used to prepare (+)-p-bisabolene (90), (-)cryptomerion (91), (+)-p-atlantone (92),and (+)-a-atlantone (86) r e ~ p e c t i v e l y . ~ ~ (-)-Limonene also features in a short synthesis of (-)-E-lanceol(96) in which the key step is conjugate addition of the lithio anion of (-)-limonene (93) to the keten dithioacetal(94) to give, after hydrolysis, the aldehyde ( 9 9 , which could then be reduced to (-)-(E)-lanceol (96).55 53 54

55

G. Dauphin, Synthesis, 1979, 799. G. Mehta and A. V. Reddy, Tetrahedron Lett., 1979, 2625. B. Cazes and S. Julia, Tetrahedron Lett., 1978, 4065.

17

Sesq ui terpenoids

Li+:k (93)

R, (95) R = CHO (96) R = CHZOH

Spectroscopic evidence has been used to deduce the structures of isosesquicarzne (97)56and the derivative of sesquisabinene (98)s7isolated from Haplopappus tenuisectus and Arctotis grarzdis respectively. Two isoprenylogues of a-phellandrene, namely the methyl esters of 3,4-dihydronidorellaurin acid (99) and nidorellaurin (loo), have been identified in Nidorella auriculatu DC.58

5 Sesquipinane, Sesquicamphane Following on from Money’s important work on the use of a monocyclic precursor ~ for the synthesis of bicyclic and tricyclic sesquiterpenoids, Noyori et ~ 1 . ’have now gone one step further and shown that the dibromo-ketone (101) (prepared 56

”

’’ 59

F. Bohlmann, U. Fritz, H. Robinson, and R. M. King, Phytochemistry, 1979,18, 1749. F. Bohlmann and N. L. Van, Phytochemistry, 1978,17, 1666. F. Bohlmann and U. Fritz, Phytochemistry, 1978,17, 1769. R. Noyori, M. Nishizawa, F. Shimizu, Y. Hayakawa, K. Maruoka, S. Hashimoto, H. Yamamoto, and H. Nozaki, J. A m . Chem. SOC.,1979,101,220.

18

Terpenoids and Steroids

0

Br

from E,E-farnesol) undergoes a [3 + 21 intramolecular cycloaddition in the presence of pentacarbonyliron to give a mixture of campherenone (102) and epi-campherenone (103) via the reactive 2-oxyallyl cation species. (-)-trans-P-Bergamotene (104) has been reported to be a constituent of the aerial parts of Clibadium cf. asperum.60This compound may not be new since a similcr hydrocarbon was recorded by Cane and Nozoe61 although no optical rotations were given.

Two new syntheses of P-santalene (106) have been reported. In the first one,62 the starting material (105) was obtained from the Diels-Alder reaction between cyclopentadiene and methyl buta-2,3-dienoate followed by hydrogenation (Scheme 16). The second synthesis63 (Scheme 17) starts from camphene .and

Reagents: i, LDA; ii, L

B

r ; iii, LiAIH,; iv, pyH'CrO,Cl-;

v, N,H,-OH-

Scheme 16

involves a rearrangement of the y-lactone by an exo-3,2-methyl shift with subsequent Wagner-Meerwein and hydride shifts to produce the S-lactone (107). This lactone could also be converted into p-santalol (109) by standard methodology. Another synthesis of P-santalol (109) involves the construction of (108) by a Diels-Alder reaction and subsequent side-group transformations (Scheme 18).64 In the synthesis of the naturally occurring tricyclo-eka-santalol -(1lo), the homoconjugate addition of phenylsulphenyl chloride was used to add the third ring (Scheme 19).65 H. Czerson, F. Bohlrnann, T. F. Stuessy, and N. H. Fischer, Phytochemistry, 1979, 18,257. D. E. Cane and G. G. S. King, Tetrahedron Lett., 1976, 4737; S. Nozoe, H. Kobayashi, and N. Morisaki, ibid., p. 4625. 6 2 M. Bertrand, H. Monti, and K. C. Huong, Tetrahedron Lett., 1979, 15. " P. A. Christenson and B. J. Willis, J. Org. Chem., 1979,44, 2012. 64 M. Baurnann and W. Hoffrnann, Justus Liebigs Ann. Chem., 1979,743. 6 5 D. Heissler and J.-J. Riehl, Tetrahedron Lett., 1979, 3957. 6o 61

19

Sesquiterpen oids

liii

Reagents: i, MeC0,H; ii, CH,CO,-; iii, H'; iv, Bu',AlH; v, Me,C=PPh,; vi, POCI,-py

Scheme 17

i, vi, ii

1

Reagents: i, H,-Pd; ii, MeOH-H'; iii, Bu'O-; iv, H,O'; v, EtCOMe-base; vi, HC0,Me-MeO-; vii, LiAlH4

Scheme 18

v-viil

'

(110)

Reagents: i, CrO, . py; ii, (EtO),P(O)CHCN; iii, Mg-MeOH; iv, PhSCl; v, Bu',AlH; vi, LiEt,BH; vii, Raney-Ni

Scheme 19

20

Terpenoids and Steroids

Full papers on the syntheses of (&)-isoalbene (111)and (-)-albene (112) have been Although there is no doubt that in this nice piece of work Kreiser et al. have synthesized naturally occurring albene from (+)camphenilone, there still must remain some doubt about the absolute configuration of this interesting tricyclic olefin. This follows from the fact that a rare endo-3,2 methyl shift is proposed in the synthetic conversion of (113) into (114) which is ultimately transformed into (-)-albene (112). A more circuitous but better precedented route" (Scheme 20) would produce the ketone (115) with the opposite absolute stereochemistry and hence it may be that the absolute stereochemistry of naturally occurring albene requires closer examination.

1

6 Cuparane, Trichothecane Another simple synthesis of a-cuparenone (116) based on a [3 + 21 cycloaddition has been published (Scheme 21).68

$3+Jy ZnC1z+

#+#

\

\

(116)

Scheme 21

* This mechanism was suggested by Prof. T. Money in correspondence with Prof. W. Kreiser (T Money, personal communication). 66 67

W. Kreiser, L. Janitschke, and W. Voss, Chem. Ber., 1979,112, 397. W. Kreiser and L. Janitschke, Chem. Ber., 1979,112,408. H. Sakurai, A. Shirahata, and A. Hosomi, Angew. Chem. Int. Ed. Engl., 1979, 18, 163.

ii-iv,

-0-

OQ0

qo+ 21

Sesquiterpen oids

o+-- 0 '

iii

Lo

+ epimer

Reagents: 1, A; ii, NaBH,; iii, H,O';

CH,OH

v, vi

(117)

iv, NaOH; v, Et,N-PhNCC,; vi, KHCO,

Scheme 22

The bicyclic lactone (117) has been considered as a useful synthon for the synthesis of verrucarol (118).69 A second synthesis of this lactone has been described (Scheme 22).70Starting from verrucarol (118), Tamm et aE.'l have appended the two requisite side-chains (119) which can be lactonized with di-(2-pyridyl) disulphide and triphenylphosphine to give tetrahydroverrucarin J (120). A recent investigation of the biosynthesis of trichodermin (121) using [l-13C]acetate is in accord with an earlier result although some reassignments of certain chemical shifts have been ~ u g g e s t e d . ~ ~

0

7 Chamigrane, Widdrane, Thujopsane A new synthesis of a-chamigrane (122) has been reported (Scheme 23).73 The halogenated chamigranes and related metabolites from the marine algae of the genus Laurencia continue to be actively investigated, with X-ray analysis 69

70

71 72

73

E. W. Colvin, S. Malchenko, R. A. Raphael, and J. S . Roberts, J. Chem. SOC., Perkin Trans. I, 1978, 658. B. B. Snider and S. G. Amin, Synth. Commun., 1978,8, 117. W. Breitenstein and C. Tamm, Helv. Chim. Acta, 1978, 61, 1975. T. Riisom, H. J. Jakobsen, N. Rastrup-Andersen, and H. Lorck, Acta Chem. Scand., Ser. B, 1978, 32,499. C. Iwata, M. Yamada, andY. Shinoo, Chem. Pharm. Bull., 1979, 27,274.

22

Terpenoids and Steroids

& ‘

0

0

OAc iv, v

1

(122) Reagents: i, MeCHN,; ii, Na,CO,-NaHC0,-aq. MeOH; iii, CuCI,; iv, NaBH,; v, H,-Pd/C; vi, MsC1-py ; vii, Me,SO; viii, MeMgI; ix, SiO,-FeCl,

Scheme 23

Br Ho%

HB:::lJ+

Br

(123)

(124)

Br

playing a crucial role in determining both relative and absolute stereochemistry. With the aid of this technique the absolute stereochemistries of iso-obtusol and obtusol have been reassigned as (123) and (124) re~pectively.’~ Gonzalez et al.75 have also examined a large number of these bromo-chloro-sesquiterpenoids and their derivatives by 13C n.m.r. spectroscopy and they have shown that subtle changes in chemical shifts can be used to assign the relative position and stereochemistry of the bromo- and chloro-groups (Scheme 24). The structures (125) and (126) have been assigned by this method to obtusane and isofurocaespitane respectively. A key biosynthetic intermediate in the sequence chamigrane + perforatane + perforane has now been isolated as a minor @*71.2-71.8

24.0-24.1

#~66.0-68.0

23.7-24.0

&

24.2-33.5

\

Br <62.3-63.6

\

L67S49.2

\65.2-46.6 c1

Scheme 24 74

75

A. G . Gonzalez, J. D. Martin, V. S. Martin, M. Martinez-Ripoll, and J. Fayos, Tetrahedron Lett., 1979,2717. A. G. Gonzalez, J. D. Martin, V. S. Martin, and M. Norte, Tetrahedron Lett., 1979, 2719.

23

Sesquiterpen oids

Br Br‘ (125)

I

Br

constituent of Laurencia perforata. The structure of this compound, perforenol (127), was deduced from chemical and X-ray crystallographic evidence.76 Two related compounds, guadalupol (128) and epiguadalupol (129), have been ~~ identified as metabolites of Laurencia snyderiae var. g u a d a l ~ p e n s i s .An examination of the red alga Laurencia majuscula Harvey has resulted in the isolation of the bromo-chamigrane derivatives (1 30) and (13 l),and once again

(128) R’ (129) R’

= =

H , R 2 = OH OH, R2 = H

X-ray analysis of a derivative of (130) has led to the determination of absolute stereochemi~try.~~ Suzuki et ~ 1 . ~ have ’ also established the absolute stereochemistries of the metabolites (132)-( 136) from Laurencia glandulifera Kutzing by an X-ray analysis of (132) and subsequent chemical interconversions with the other four compounds.

Last year the unusual structure of laureacetal-A (138) was reported. A further examination of Laurencia nipponica Yamada has revealed another closely related compound, laureacetal-B (137), and it is suggested that this compound is the 76

” 78

79

A. G. Gonzalez, J. M. Aguiar, J. Darias, E. Gonzalez, J. D. Martin, V. S. Martin, C. Ptrez, J. Fayos, and M. Martinez-Ripoll, Tetrahedron Lett., 1978, 3931. B. M. Howard and W. Fenical, Phytochemistry, 1979,18, 1224. M. Suzuki and E. Kurosawa, Tetrahedron Lett., 1978,4805; M. Suzuki, A. Kurusaki, N. Hashiba, and E. Kurosawa, ibid., 1979, 879. M. Suzuki, A. Furusaki, and E. Kurosawa, Tetrahedron, 1979, 35, 823.

24

Terpenoids and Steroids rOH --b

Br

Br

precursor of laureacetal-A.80 A low-yield biogenetic-type synthesis of (*)bromo-a-chamigrene (139) has been reported (Scheme 25).81 *

2

~

e

L

~

~

v

c

ii,iii 0

2

~

e

(139) Reagents: i, Br+Br

Br

; ii, AlH,; iii, I2

Br

Scheme 25

An X-ray structural analysis of one of the products obtained from thujopsene on treatment with peroxyacetic acid has been used to confirm the structure as (140).82For reasons which are not immediately obvious thujopsene has been oxidized with a variety of metal acetates in acetic acid (e.g. Pb'", TI'", Co"', and Mn"'). There is no apparent rationale for the different types of products formed and indeed there is some inconsistency of results between the two papers.833s4 Dihydromayurone (141), on treatment with boron trifluoride etherate in acetic acid-acetic anhydride at different temperatures, gives rise to the five rearranged acetates (142)-( 146).*'

.. OAc (140)

oAc(144) 8o 81

83 84

85

oAc

OAC (145)

(146)

T. Suzuki and E. Kurosawa, Chem. Lett., 1979, 301. I. Ichinose and T. Kato, Chem. Lett., 1979, 61. G . J. Olthof, A . R. Overbeek, N. van der Putten, and H. Schenk, Rec. Trav. Chim. Pays-Bas, 1979, 98, 5 2 . H. Sekizaki, M. Ito, and S. Inoue, Bull. Chem. SOC.Jpn., 1978, 51, 3663. H. Sekizaki, M. Ito, and S. Inoue, Bull. Chem. SOC.Jpn., 1978,51, 2439. H. Sekizaki, M. Ito, and S. Inoue, Chem. Lett., 1978, 1191; Bull. Chem. SOC.Jpn., 1979, 52, 2161.

Sesquiterpen oids

25

8 Acorane, Cedrane, Carotane, Zizaane Additional stereoselective syntheses of acorone (147) and isoacorone (148) have been recorded (Scheme 26).86

$./ 8

4

f--ix, x, ix

/

vi-viii

/

\

8;5.<

xi-xiii

0

+

(147)

(148)

Reagents: i, PTSA-

.; ii, ICH,CCl=CH,; iii, H,O; iv, Hg(OAc),-BF,-HOAc; v, KOH; vi, H LDA; vii, MeCHO; viii, PTSA; ix, Me,CuLi; x, HOAc; xi, B,H,; xii, Na,Cr,O,-H'; xiii, h.p.1.c.

Scheme 26

A number of model esters related to lac resin have been prepared. These esters have the basic cedrane skeleton (149) or the C-2 epimeric structure.87 In an approach to the synthesis of cedrene (152), the intramolecular photocycloaddition of the dienone (150) was carried out at low temperature. A major tricyclic compound (151) was obtained and its structure was verified by X-ray analysis of its anisylidene derivative.88Further work is required to bring about the rearrangement of a derivative of (151) to give cedrene. Further details on the hydroxylation (with 0,) and chlorination (with PhICl,) of cedrol, patchoulol, and their derivatives have been pre~ented.'~ The results of this study are in keeping with those obtained previously. 86 87

88

89

S. F. Martin and T. S. Chou, J. Org. Chem., 1978, 43, 1027. G. B. V. Subramanian, U. Majumdar, R. Nuzhat, V. K. Mahajan, and K. N. Ganesh, J. Chem. SOC., Perkin Trans. I, 1979, 2167. M. Fetizon, S. Lazare, C. Pascard, and T. Prange, J. Chem. SOC.,Perkin Trans. I, 1979, 1407. E. Trifilieff, L. Bang, A. S. Narula, and G. Ourisson, J. Chem. Res. ( S ) , 1978, 64.

26

Terpenoids and Steroids

From a careful study of vetiver oil (from the Moosanagar area of North India) Ganguly et aL9' have isolated and identified the two biogenetically important alcohols, (+)-allokhusiol (153) and (-)-khusiol (154). These two compounds co-occur with (+)-zizaene (155) and (+)-prezizaene (156), and furthermore it has been shown that (153) gives both (+)-zizaene (155) and (+)-prezizaene (156) on dehydration with phosphorus oxychloride, while treatment of khusiol tosylate with pyridine produces (+)-prezizaene as a minor product. It would also appear from these results that (-)-khusiol is enantiomeric with (+)-allocedrol isolated by Tomita and Hirose91but that (+)-allokhusiol is not the enantiomer of the alcohol identified by Carroll et al.92

A detailed study of the I3C n.m.r. spectra of anisatin (157) and neoanisatin The structure of anisatinic acid, (158) and their derivatives has been carried derived from anisatin by treatment with mild base, has been firmly established as (159).The synthesis of (-)-khusimone (161) has been accomplished starting from the methyl ester of (-)-a-campholenic acid (160) (Scheme 27).94

(157) R (158) R

=

=

OH H

(159)

'"R. N. Ganguly, G . K. Trivedi, and S . C. Bhattacharyya, Indian J. Chem., Sect. B, 1978, 16, 20, 23. 91

92

93 94

B. Tomita and Y. Hirose, Phytochemistry, 1973, 12, 1409. P. J. Carrol, E. L. Ghisalberti, and D. E. Ralph, Phytochemistry, 1976, 15,777. S. Manabe, K. Wakamatsu, Y. Hirata, and K. Yamada, Tetrahedron, 1979, 35, 1925. H. J. Liu and W. H. Chan, Can. J. Chem., 1979, 57,708.

27

Sesquiterpenoids

___)

0

Et0,C

Reagents: i, 0,;ii, PTSA; iii, (EtO),C=CH,,

0

__*

h v ; iv, H,O’; v, chrom.; vi, 0

U

NaOH; viii, NaH; ix, MeMgBr; x, CH,N,; xi, SOCl,-py; xii, LiAIH,; xiii, POCI,-py; xiv, N2CHCO2Et-BF,

Scheme 27

Further evidence has been presented for the structure of vaginatin (162) although the stereochemistry of the four chiral centres have still to be ascertained.”

For compounds belonging to the so-called isocedrane class, see p. 99.

95

K. Rajendran, S. K. Paknikar, G. K. Trivedi, andS. C. Bhattacharyya, IndianJ. Chem.,Sect. B, 1978, 16,4.

Terpenoids and Steroids

28

9 Cadinane, Muurolane, Copaane, Cyclosesquifenchane, Sativane, Copacamphane, Picrotoxane New cadinane sesquiterpenoids include (-)-cadala- 1,4,9-triene (163) (Acorus c ~ l u r n u s ) dihydroisochromolaenin ,~~ (164), 1,6-dihydrochromolaenin (165),

(168) R (169) R

= =

H Me

chromoarnottion (166) (Chrornoluertu ~ r n o t t i u n a ) 3,4,6,7,-bisdehydro-8a,~~ angeloyloxycadinane (167), 2-hydroxy-8a-angeloyloxycalamenene(168), and 2-methoxy-8a-angeloyloxycalamenene (169) (Heterotheca s u b a x i l l a r i ~ ) .A~ ~ further examination of the North Indian variety of vetiver oil, which is a rich source of sesquiterpenoids, has resulted in the isolation and identification of (+)-a-cadinol (170) and (+)-cadina-4a,lOP-diol (171).99 The structure of gmelofuran (172), an unusually oxygenated cadinane sesquiterpenoid isolated from the roots of Grnelina curborea, has been solved by a combination of n.m.r. spectroscopy and X-ray analysis.1ooThe two calamenenes (173) and (174) have been identified in a coral source."'

A (172)

(173) R (174) R

= =

H OH

M. Rohr and P. Naegeli, Phytochemistry, 1979,18, 328. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979,18, 1177. 98 F. Bohlmann and C. Zdero, Phytochemistry, 1979,18, 1185. 99 P. S. Kalsi, G. S. Arora, and R. S. Ghulati, Phytochemistry, 1979,18, 1223; R. C. Agrawal, T. D. Audichya, G. K. Trivedi, and S. C. Bhattacharyya, Indian J. Chem., Sect. B, 1978, 16, 267. loo K. C. Joshi, P. Singh, R. T. Pardasani, A. Pelter, R. S. Ward, and R. Reinhardt, Tetrahedron Lett., 1978,4719. lo' Y . Kashman, Tetrahedron, 1979,35, 263. 96

97

29

Sesqu iterpen oids

As reported last year, irradiation of piperitone with cyclobutenecarboxylic acid gives the synthetically useful tricyclic compound (175). This compound has now been prepared in optically active form starting with (-)-piperitone."* It undergoes a conrotatory ring opening followed by an intramolecular ene reaction to give the cadinane-type compound (176). In addition, borohydride reduction of (175) gives the lactone (177), which can be converted by thermolysis into the germacrane-type lactone (178), related to isoaristolactone (179) (Scheme 28). A similar strategy has been adopted to prepare the alcohol (180), which has been converted into the known compounds (181) and (182) (Scheme 29).lo3

i, ii

0

Me0,C /

H (175)

(177)

1

1

iv

(178) R (179) R

= =

Pr' C(Me)=CHZ

Reagents: i, hv; ii, CH,N,; iii, NaBH,; iv, A

Scheme 28

A new synthesis of torreyol (183) based on an intramolecular Diels-Alder reaction has been reported (Scheme 3O).lo4 A second synthesis of lacinilene C methyl ether (184), a constituent of cotton, has been p ~ b l i s h e d . ~ This ' ~ compound is thought to be responsible for byssinosis, a disease prevalent in the textile industry. lo3

lo4 lo5

G. L. Lange and F. C. McCarthy, Tetrahedron Lett., 1978,4749. J. R. Williams and J. F. Callahan, J. Chem. SOC.,Chem. Commun., 1979, 405. D. F. Taber and B. P. Gum, J. A m . Chem. Soc., 1979,101,3992. J. P. McCormick, J. P. Pachlatko, and T. R. Schafer, Tetrahedron Lett., 1978, 3993.

Terpenoids and Steroids

30

ii, iii

+ i

dH

,

HO i A

HO i A (180) l i i , iii

liv, v

Reagents: i, A; ii, Hg(OAc),; iii, NaBH,; iv, H,-Pt; v, POC1,-py

Scheme 29

Reagents: i, L , P P h ,

; ii, LiAlH,; iii, Me2SO-DDC-H';

iv, e M g B r ; v, H,Cr20,; vi, MeLi

Scheme 30

The structures of notonipetrone ( 185)'06 and the two abrotanifolone derivatives (186) and (187)39have been deduced on the basis of n.m.r. spectral evidence. A different type of ring-contracted cadinane sesquiterpenoid is seen in the structure of mutisianthol ( 188).lo7Another synthesis of oplopanone (189) has been reported (Scheme 31).'" lo6 lo'

F. Bohlmann and C. Zdero, Phytochernistry, 1979,18, 1063. F. Bohlmann, C. Zdero, and N. L. Van, Phytochernistry, 1979, 18,99. D. F. Taber and R. W. Korsmeyer, J. Org. Chern., 1978,43,4925.

Sesquiterpenoids

Acb

31

9 (186) R (187) R

x-xii, viii

= =

Ho% COBu' Ang

1

(189) Reagents: i, Li-NH,; ii, BrCH,OPh; iii, @Mg& -Cu'I; iv, CH,=PPh,; v, BBr,; vi, disiamylborane; vii, NaOH-H,O,; viii, pyH+CrO,Cl-; ix, KOBu'; x, MeLi; xi, Hg(OAc),-H,O; xii, NaBH,

Scheme 31

32

Terpenoids and Steroids

A careful analysis of the sesquiterpenoids from the soft coral Sinularia mayi has resulted in the isolation of (+)-a-muurolene (190), (+)-y-muurolene (191), (-)-6-cadinene (192)' (+)-P-copaene (193), (-)-aromadendrene (194), (-)bicyclogermacrene (195), (+)-germacrene D (196), a-copaene (197), P-bourbonene (198), calamenene (199), and (-)-sinularene (200), together with two aromadendranediols (see p. 100).'09In keeping with many other marine sesquiterpenoids, the first seven compounds are the enantiomers of those found in terrestrial sources. In connection with resports of enantiomeric sesquiterpenoids, it is'interesting to note that Naya eta/."' have found that a number of sesquiterpenoids (e.g. germacrene D, p-selinene, and 6-cadinene), which are secreted by the scale insect Ceroplastes ceriferus Anderson, are enantiomeric with respect to those from C. rubens Maskell which infests the same host tree. This unusual phenomenon suggests that the two different species of insect have almost identical enzyme systems but which are 'enantiomeric'. The chemistry of the most abundant hydrocarbon, (-)-sinularene (200), is discussed in further detaillogand at the moment it has a unique place in sesquiterpenoid classification since it belongs to the previously unknown cyclosesquifenchene group.

Interesting syntheses of racemic sativene (203), copacamphene (205), cissativenediol (206), and helminthosporal (207) have been reported (Scheme 32).11' The key step at the start of these syntheses is the acid-catalysed thermal rearrangement of (201), which is obtained by photolysis of piperitone in 1 , l dimethoxyethane, to give the two epimeric ketones (202). These two epimers are

'lo

C. M. Beechan, C. Djerassi, and H. Eggert, Tetrahedron, 1978,34, 2503. Y. Naya, F. Miyarnoto, and T. Takernoto, Experientia, 1978,34,984. M. Yanagiya, K . Kaneko, T. Kaji, and T. Matsurnoto, Tetrahedron Lett., 1979, 1761.

Sesquiterpenoids

33

essentially separated in the next stage when the Wittig reagent (Ph3P=CHOMe) only reacts at room temperature with the isomer having an equatorial isopropyl group. This permitted the ultimate synthesis of sativene (203). Copacamphene (205) could be obtained by a similar sequence starting from the axial isopropyl isomer (204), which undergoes the above-mentioned Wittig reaction at reflux temperature. cis-Sativenediol(206) and helminthosporal(207) were synthesized by suitable functional-group manipulation of an intermediate en route to sativene.

(201)

I

4

'

\

v-vii

@

ix, x, vii

(202)

viii, vi

/

A

A (204)

,OMe

(203)

(205)

+

CHO

fiH7

xiv, xv

xii, vi, xiii

>

/

(206)

(207)

Reagents: i, 200 "C; ii, Ph,P=CHOMe; iii, S O , ; iv, H,O'; v, NaBH,; vi, MsC1-py; vii, Bu'OK; viii, MeLi; ix, Ph3P=CH2; x, Br,; xi, OsO,; xii, Ac,O-py; xiii, LiAlH,; xiv, NaIO,; xv, NaOMe

Scheme 32

Terpenoids and Steroids

34

(210) R (211) R

=

=

H OH

Two new sesquiterpenoids of the picrotoxane group are amotin (208) and amoenin (2O9).ll2In the course of an investigation of the toxic substances of the honeydew honey excreted by a sap-sucking insect which feeds on Coriaria arborea Lindsey, the two dihydro-derivatives of tutin (210) and hyenanchin (211) have been identified.'13 Included in this paper are the 13Cn.m.r. spectral assignments of a number of compounds belonging to the picrotoxane series. Another milestone in sesquiterpenoid chemistry has been passed by the successful synthesis of (-)-picrotoxinin (212) starting from (-)-carvone (Scheme One of the crucial steps in this fairly long synthesis was the double lactonization towards the end of the route.

10 Himachalane, Longipinane, Longifolane New additions to the himachalane class include (213)-(215) (Cineraria geifolia)"' and podocephalol(216) (Lasianthaea p o d ~ c e p h a l a )Piers . ~ ~ et d 1 1 6 have now utilized the Cope rearrangement of ~-(2-vinylcyclopropyI)-a,~-unsaturated ketones for the construction of 0-himachalene (217) (Scheme 34). Two more longipinane derivatives (218) and (219) have been isolated from Stevia species.117A full paper on the chemistry of vulgarone A (220) and B (221) has been published.l18 In keeping with the general rule that enantiomeric sesquiterpenoids are often found in liverworts, Matsuo et ~ 1 . " have ~ identified the three ent-longipinanes (-)-marsupellone (222), (+)-marsupello1 (223), and (+)acetoxymarsupellone (224). Several papers on the chemistry of longifolene derivatives have been published. These include the conversion of the two half-esters (225) and (226) into the same olefinic ester (227) with P ~ ( O A C ) ~ - C U ( O A Cthe ) ~ , reaction ~*~ of longifolene (228) with mercuric acetate followed by iodine chloride to give (229) and (230),12' and the reaction of longicyclene (231) with bromine in pyridine and iodine chloride-pyridine complex in acetic acid to yield (232) and (233) respectively.122 'I3

'" 'I8 'I9

'" '*I 12'

J . Dahmen and K. Leander, Phytochemistry, 1978, 17, 1949. J. W. Blunt, M. H. G. Munro, and W. H. Swallow, Aust. J. Chem., 1979, 32,1339. E. J. Corey and H. L. Pearce, J. A m . Chem. SOC.,1979,101, 5841. F. Bohlmann and W. R. Abraham, Phytochemistry, 1978,17, 1629. E. Piers and E. H. Ruediger, J. Chem. SOC.,Chem. Commun., 1979, 166. F. Bohlmann, L. N. Dutta, W. Dorner, R. M. King, and H. Robinson, Phytochemistry, 1979,18,673. Y. Uchio, Tetrahedron, 1978,34, 2893. A. Matsuo, S. Uto, K. Sakuda, Y. Uchio, M. Nakayama, and S. Hayashi, Chem. Letl., 1979, 73. R. P. Deshpande, A. S. C. Prakasa Rao, and U. R. Nayak, Tetrahedron Lett., 1978,4423. S. N. Suryawanshi and U. R. Nayak, Tetrahedron Lett., 1978,4425. S. N. Suryawanshi and U. R. Nayak, Tetrahedron Lett., 1978, 4429.

&

Sesquiterpenoids

N,

35

+ i, ii

___* iii-vi

N,

NMe,

(Me0)2HC

“OCOPh

NMe,

1yii. viii

c--

*---

“OCOPh

“OCOPh

HO,C xv +

OCOPh

v, xvi ___,

Br

I xvii OCOPh

o@oH

a

~

xviii, xix

-4 Br

Reagents: i, LDA; ii, BrCH,CH,CH(OMe),; iii, aq. AcOH; iv, HCI; v, PhCOC1-py; vi, prep. h.p.1.c.; vii, HCECLi; viii, NBS; ix, (C6HI1),BH;x, H,O,-HCO,-; xi, HSCH,CH,SHBF,; xii, K2C03; xiii, (~yH+),Cr,0,~-; xiv, Me,S,-K0Bu‘-0,; xv, HgO-BF,; xvi, NaOCl; xvii, Pb(OAc),; xviii, Pr’,NEt; xix, CF,CO,H; xx, Zn-NH,CI

Scheme 33

(213) R’ = R2 = Ang (214) R1 = Epoxyang, R2 = Ang (215) R’ = Ang, R2 = Epoxyang

Terpenoids and Steroids

36

aa& ,ii, v, vi ,

f------* ii-iv

0

O H

(217) Reagents: i, A; ii, LDA; iii, Mel; iv, H,-[(Ph,P),RhCl];

v, (EtO),P(O)Br; vi, Li-EtNH,-Bu'OH

Scheme 34

a0a0

R20

(218) R1 = Epoxyang, R2 (219) dihydro-(2 18)

=

% (222)

Ang

(220)

&OH (223)

C0,Me (225) R' = H, R2 = Me (226) R1 = Me, R2 = H

(229) R = H (230) R = HgCl

(232) R1 = R2 = Br (233) R' = I, R2 = H

37

Sesquiterpenoids

It has also been reported that treatment of (233) with potassium acetate at 140 "C for 40 h gives the strained tricyclic diene (234) whereas treatment with potassium t-butoxide gives the isomeric diene (235).123

(234)'

(235)

The synthesis of the tricyclic enone (237) has been reported (Scheme 35).124 The carbonyl group has previously been removed from this ketone to produce isolongifolene. The key step in this synthesis is the facile intramolecular yalkylation of the keto-tosylate (236). C0,Me

C0,Me

OAc

lvi C0,Me

,vii, viii OAc

1

ix-xi

xii

0

@

(xv, xvi, xiv

0 (237) Reagents: i, K0Bu'-MeI; ii, CH,=PPh,; iii, disiamylborane; iv, OH-H,O,; v, Ac,O-py; vi, NBSCaCO,, hv ; vii, LiBr-HMPA; viii, HOCH,CH,OH-PTSA; ix, LiAlH,; x, TsCl; xi, H,O+; xii, KOBu'; xiii, DDQ; xiv, Me,CuLi; xv, pyH+Br-Br,; xvi, LiBr-Li,CO,-DMF

Scheme 35 123

lZ4

S. N. Suryawanshi and U. R. Nayak, Tetrahedron Lett., 1979,269. E. Piers and M. Zbozny, Can. J. Chem., 1979, 57, 2249.

Terpenoids and Steroids

38

11 Caryophyllane, Humulane, Africane, Illudalane, Protoilludane, Hirsutane, Vellerane, Pentalane, Senoxydane A full paper on the determination of the structure and absolute configuration of the two piscicidal sesquiterpenoids buddledins A (238) and B (239) has now appeared.125Buddledin A has also been isolated from another Buddleja species.lZ6In addition, the structures of buddledins C (240), D (241), and E (242) have been determined and toxicity tests have shown that the latter two are not pisci~idal.'~'Another interesting oxygenated caryophyllene derivative is lychnopholic acid (243) from Lychnophoru afinis Gardn. The structure of this compound has been elucidated by a combination of n.m.r. and X-ray spectral studies. l Z 8

(238) R (239) R (240) R

= = =

OAc OH H

(241)

(242)

The nor-ketone rudbeckianone (244) has been identified in Rudbeckia laciniata L.44 A very interesting new sesquiterpenoid ketone, (+)-bicyclohumulenone (245), has been isolated from the leafy liverwort Plugiochila acanthophylla subsp. j ~ p o n i c aThe . ~ ~structure ~ and absolute stereochemistry of this compound were ascertained by X-ray crystallographic analysis of the mono-p-bromobenzoate of the derived trio1 (246). This ketone co-occurs with the two enantiomeric sesquiterpenoids (-)-maalioxide (247) and (+)-cyclocolerenone (248). Complete details of the acid-catalysed rearrangement of humulene 1,2-epoxide (219) have now been presented.13* With 1.8M-sulphuric acid in acetone at 0 "C for 30 min the sole product is the previously known tricyclic diol (250). After an extended period this diol gives rise to five other identified products,

126

12'

"*

T. Yoshida, J. Nobuhara, M. Uchida, and T. Okuda, Chem. Pharm. Bull., 1978, 26, 2535. P. Susplugas, C. Susplugas, and J. C. Rossi, Plant. Med. Phytother., 1978, 12, 148. T. Yoshida. J. Nobuhara, N. Fujii, and T. Okuda, Chem. Pharm. Bull., 1978, 26, 2543. R. F. Raffauf, M. P. Pastore, C. J. Kelley, P. W. Le Quesne, I. Miura, K. Nakanishi, J. Finer, and J. Clardy, J. Am. Chem. SOC.,1978, 100, 7437. A. Matsuo, H. Nozaki, M. Nakayama, Y. Kushi, S. Hayashi, T. Komori, and N. Kamijo, J. Chem. SOC.,Chem. Commun., 1979, 174. M. Namikawa, T. Murae, and T. Takahashi, Bull. Chem. SOC.Jpn., 1978, 51, 3616.

Sesqu iterpen a ids

39

(246)

(247)

(248)

(252)-(256), whose mode of formation via the carbonium ion (25 1)is illustrated in Scheme 36. In recent years humulene has been viewed as a focal biogenetic precursor of an ever-increasing number of tricyclic sesquiterpenoids. To date, however, there has been little real success in the in vitro conversion of humulene or its derivatives into

+

+ (253)

(254) R' = OH, R2 = Me ( 2 5 5 ) R' = Me,R2 = OH Scheme 36

40

Terpenoids and Steroids

one of these naturally occurring tricyclic compounds. This situation has now been improved as a result of two independent studies. Matsumoto et al.”la have followed up their earlier work on the cyclization of humulene with mercuric acetate, the products of which, after borohydride reduction, are the two tricyclic ethers (257) and (260). They have now shown that with three equivalents of mercuric nitrate in aqueous acetic acid followed by borohydride reduction humulene gives the three tricyclic ethers (261)-(263) (for the mechanism of this reaction see below). Both (260) and (263) can be converted into the bicyclic alcohol (264) on hydrogenolysis with lithium in ethylamine. On the other hand treatment of the tricyclic ether (257) with boron trifluoride etherate in acetic anhydride gives the two rearrangement products (258) and (259) in 20% and 30% yield respectively. By using a suitably deuteriated derivative of (257) the mode of formation of (258) and (259) is considered to be as shown in Scheme 37.

1

(258)

1

Scheme 37

Formolysis of (264) produces the formate ester of (259) and (265) in 66% and 20% yield respectively; the latter hydrocarbon is related to the pentalane class of sesquiterpenoids (see below). A study of this rearrangement, again using a deuteriated substrate, provided evidence for the pathway outlined in Scheme 38. Matsumoto et ~ 1 . ’ ~have ~ ‘ also studied the mechanism of formation of the two tricyclic ethers (257) and (260) [with Hg(OAc),] and the three tricyclic ethers [with Hg(N03)J derived from humulene after NaBD4 work-up. Under these conditions the five deuteriated products are (266)-(270) respectively. The ( a ) S. Misumi, T. Ohtsuka, Y. Ohfune, K. Sugita, H. Shirahama, and T. Matsumoto, Tetrahedron Lett., 1979, 31; (b) S. Misumi, T. Ohtsuka, H. Hashimoto, Y. Ohfune, H . Shirahama, and T.

Matsumoto, ibid., p. 35.

Sesquiterpenoids

4'

q-j ,

H

41

R'

.

'

'

H

y--'

'

(261) R1 = Me, R2 = OH (262) R' = OH, R2 = Me (263) R',R2 = =CH2

mechanism shown in Scheme 39 has been suggested to account for the different deuterium labelling patterns. Compounds (266) and (267) are formed from the trimercurated species (271a) in which a transannular l$-hydride shift has taken place. Products (268)-(270) are formed by ring contraction from (271b) with subsequent demercuration or hydroxylation.

+ formate ester of (259) H' \

Scheme 38

Terpenoids and Steroids

42

OH

I"""'

i

(268)-(270)

(266) + (267) Scheme 39

In another attempt to mimic the in vivo cyclization of humulene, Mlotkiewicz et ul.'32 have shown that treatment of humulene 4,5-epoxide (272) with boron trifluoride etherate leads to the formation of the two tricyclic alcohols (273) and (274) in 70% yield. The carbon skeleton of these two compounds is exactly that found in africanol (276) and the more recently isolated keto-angelate (275).42 Further elaboration of the alcohol (273) has in fact resulted in a biomimetic synthesis of the keto-alcohol corresponding to (275).133 This work constitutes the first example of the direct conversion of a humulene derivative into a naturally occurring compound. Complete details of the extensive studies on the extraction, structural elucidation, and toxicity of the CI4and CISindanone sesquiterpenoids isolated from the young fronds of bracken fern have been In total the structures of 13*

133

135

J. A, Mlotkiewicz, J . Murray-Rust, P. Murray-Rust, W. Parker, F. G. Riddell, J. S. Roberts, and A. Sattar, TetrahedrofiLett., 1979, 3887. I. Bryson, J. A. Mlotkiewicz, and J. S. Roberts, Tetrahedron Lett., 1979, 3891. K. Yoshihira, M. Fukuoka, M. Kuroyanagi, S. Natori, M. Umeda, T. Morohoshi, M. Enomoto, and M. Saito, Chem. Pharm. Bull., 1978, 26, 2346. M. Fukuoka, M. Kuroyanagi, K. Yoshihira, and S. Natori, Chem. Pharm. Bull., 1978, 26, 2365.

Sesq u iterpe noids

43

0 R1o

0

(273) R' = H, R2 = H2 (275) R' = Ang, R2 = 0

(274)

twenty-four of these pterosins have been identified. All of them have the basic CI4 (277) or C15structure (278) and are hence classified as illudalane (secoprotoilludane or secoilludane) sesquiterpenoids. Although it has been known for many years that bracken fern contains carcinogenic constituents it would seem from these present studies that none of the pterosins or their glucosides, the pterosides, is responsible for the carcinogenicity.

(277) R (278) R

= =

H Me

A number of compounds with the protoilludane skeleton have been synthesized (Scheme 40).136The two keto-esters (279) and (280) have been converted by standard methods into a variety of tricyclic analogues. In addition, the bicyclic enone (281), obtained from 4,4-dimethylcyclopentene and acetylacetone by a similar procedure, has been converted into protoillud-7-ene (282) (Scheme 41). A long and rather low-yield synthesis of (283), a possible precursor of illudinine (284), has been rep~rted.'~' Undoubtedly one of the major sesquiterpenoid synthetic achievements of the year has been the synthesis of hirsutic acid C (288) (Scheme 42).138Intramolecular Michael reactions were used to generate the key tricyclic ketone (287)with the correct relative stereochemistry at four of the chiral centres. The ethylene bridge was then cleaved to create the two requisite methyl groups. Interestingly the first intramolecular Michael reaction [(285) + (286)] could be achieved with (-)quinine as the base and this produced the optically active ketone (286) with one enantiomer in excess (65%) of the other (35%). 136

137

13'

H. Takeshita, H. Iwabuchi, I. Kouno, M. Iino, and D. Nomura, Chem. Lett., 1979, 649. C. Misra and A. Ghosh, Synth. Commun., 1 9 7 8 , 8 , 4 0 3 . B. M. Trost, C. D. Shuey, and F. DiNinno, jun., J. Am. Chem. Soc., 1979,101,1284.

44

Terpenoids and Steroids

C0,Me

1

COzH

iii

C0,Me (279)

Reagents: i, hv; ii, PTSA; iii, hv, CH,=CH,

Scheme 40

H (281) Reagents: i, hu, CH,=C(OMe),;

ii-iv.

C0,Me (280)

qH

H Me0

OMe

ii, MeMgBr; iii, HSCH,CH,SH-BF,;

(282) iv, Raney-Ni

Scheme 41

Further work on the sesquiterpenoids of the mushroom species Lactarius has resulted in the isolation of 15-hydroxyblennin A (289)139and the four related compounds (290)-(293).'""" The two ethyl ethers (291) and (293) are almost certainly artefacts of the isolation procedure. Further details of the chemistry of isolactarorufin (294) have been p u b 1 i ~ h e d . lThe ~ ~ ~absolute stereochemistry of this unusual tetracyclic compound has not been ascertained as yet. The confusion concerning the precise structures of velleral (295), vellerolactone (296), and pyrovellerolactone (297) has now been firmly resolved by the synthesis of all three compounds as racemates (Scheme 43).14' K. G. Widtn and E. L. Seppa, Phytochemistry, 1979, 18, 1226. '41

( a ) M. de Bernardi, G. Fronza, G. Mellerio, G. Vidari, and P. Vita-Finzi, Phytochemistry, 1979,18,

293; ( b ) W. M. Daniewski, M. Kocor, and S. Thoren, Pol. J. Chem., 1978,52, 561. J . Froborg and G. Magnusson, J, A m . Chem. Soc., 1978, 100,6728.

Sesq uiterpe noids

n

45

r-l

0

5

-

NC

NC

-CO,Me

C0,Me

(285)

X I , XI1

(286)

1x Et0,C

OAc

0

JxIII-xv

xvi, xvii

xviii-xx ___3

Me02C

fi

0

0

OH

xxi-xxiii

0 -

H0,C H

1

1

xxiv xxv

H

xxvi,v,xvi

xxvii

H

0

0

H

11

Reagents: i, LDA; ii, BrCH,CGCSiMe,; iii, KOH-MeOH; iv, CO,; v, CH,N,; vi, aq. HCl; vii, Et,N; viii, H,-Pd/BaCO,; ix, BrZnCH,CO,Et; x, NaOMe; xi, B,H,; xii, Ac,O-py; xiii, NBS; xiv, LiBr-Li,CO,-DMF;

xv, K2CO3; xvi, pyH+CrO,Cl-; xvii,

2-

HO I--Et,N; xviii, K,CO,-MeOH-H,O; xix, NaBH,; xx, PPh,-Me0,CN=NC02Me; xxi, HCl-MPOH; xxii, 0,; xxiii, MeSH-BF,; xxiv, Raney Ni; xxv, aq. KOH; xxvi, MeLi; xxvii, Bu'OK

Scheme 42

Terpenoids and Steroids

46

(290) R' (291) R'

=

R2 = H

=

Et,R2 = H

R2

OH 0 (292) R1 = R2 = H (293) R' = Et, R2 = H

CH(OMe),

H

ii, iii/

/ iv-vi,

&c02Me

H

iii

H

CH(OMe),

'* -H

&CHO

,qJC02Me

CH,OAc/ vii, vi

CHO

H

CH .OAc

-&

/

i, iii

3

H

Reagents: i, A; ii, B,H,; iii, col. chrom.; iv, Bu',AlH; v, MnO,; vi, H,O'; vii, NaOH; viii, PTSA

Scheme 43

0

47

Sesquiterpenoids

The pentalane class of sesquiterpenoids has received substantial attention in the past year from the standpoints of structural elucidation, biosynthesis, and synthesis. Two new metabolites of this class are pentalenic acid (298) and pentalenolactone H (299).142Both these compounds have a secondary hydroxyl function adjacent to the gem-dimethyl group and are thus potential precursors of pentalenolactone (300) in which one of these methyl groups has undergone a 1,2-migration. Cane and R o s ~ i have l ~ ~ now identified a further metabolite of a Streptomyces strain which has been named pentalenolactone E (301) and is now OH

the fifth member of this important class. Pentalenolactone E appears to be an earlier product of the culture growth and as such lacks some of the oxygenated functions found in pentalenolactones G and H. In their biosynthetic studies of pentalenolactone (300), Cane et al.144were unable to effect incorporation of the usual isoprenoid precursors, uiz. [2-14C]acetate, [2-'4C]mevalonate, and [2''C,5-3H2]mevalonate, into pentalenolactone. The solution to this problem lay in the feeding of [UL-'3C6]glucose which acted as an in vivo precursor of [1,213 Clacetyl-CoA. This resulted in a 0.1% incorporation of glucose, and a subsequent study of the 13Cn.m.r. spectrum of enriched pentalenolactone methyl ester strongly suggested the biosynthetic pathway (Scheme 44) which involves humulene as the key monocyclic precursor. The only anomalous feature of the 13C n.m.r. spectrum was the coupling of C-1 to both C-8 and C-14 (there should have been no coupling to C-14). At present the only logical explanation of this is that two acetates from the same glucose have come together at some stage in mevalonate synthesis. An ingenious stereocontrolled synthesis of pentalenolactone (300) has been recorded by Danishefsky et al.145in which three of the five chiral centres are incorporated into a key tetracyclic intermediate (Scheme 45). Two other '41 143

144

'41

H. Seto, T. Sasaki, J. Uzawa, S. Takeuchi, and H. Yonehara, Tetrahedron Lett., 1978, 4411. D. E. Cane and T. Rossi, Tetrahedron Lett., 1979, 2973. D. E. Cane, T. Rossi, and J. P. Pachlatko, Tetrahedron Lett., 1979, 3639. S. Danishefsky, M. Hirama, K. Gombatz, T. Harayama, E. Berman, and P. Schuda, J. Am. Chem. SOC.,1978,100, 6536.

Terpenoids and Steroids

48

OH

Scheme 44

0

x

1

i, vii

Scheme 45

49

Sesquiterpenoids

C0,Me

0

1

xvii, xviii

viii, xxi, xxii

C0,Me

0

1

xxiii-xxv

xxvi, xxvii

xiv, iii

OH

0

(300) Reagents: i, OsO,; ii, Me,CO-H'; iii, OH-; iv, EtOCGCH; v, Ba(OH),; vi, NaHC0,-MeI; vii, Pb(OAc),; viii, NaBH,; ix, H'; x, SOCl,; xi, H,-BaS0,-Pd; xii, MeCH=PPh,; xiii, H,O'; xiv, Cr0,-H'; xv, MeOH-H'; xvi, A1Cl3; xvii, CH,=PPh,; xviii, HZ[(Ph,P),RhCl]; xix, Bu'OCH(NMe,),; xx, Si0,-H,O; xxi, MsC1-py; xxii, DBU; xxiii, LDA; xxiv, PhSeC1; xxv, NaIO,; xxvi, Bu',AlH; xxvii, Bu'OOH-[VO(acac),]

Scheme 45 (continued)

approaches to pentalenolactone have also been described. The involves the construction of the bicyclic diketone (302) (Scheme 46) while the second14' route hinges upon an intramolecular ene reaction to build up the bicyclic ester (303) (Scheme 47). A new tricyclic hydrocarbon, senoxydene, which has been isolated from Senecio oxyodontus, has been assigned the structure (304) on the basis of its n.m.r. l ~is~suggested that spectrum together with that of the corresponding e p 0 ~ i d e . It once again humulene could act as the precursor (Scheme 48);see, however, p. 104.

146

14' '41

M. L. Quesada, R. H. Schlessinger, and W. H. Parsons, 3. Org. Chem., 1978, 43, 3968. F. Plavac and C. H. Heathcock, Tetrahedron Lett., 1979, 2115. F. Bohlmann and C. Zdero, Phytochemistry, 1979, 18, 1747.

50

Terpenoids and Steroids OMe

OMe

0

0

C0,Me

+Q O Reagents: i, LDA; ii, @CO,Me

H 0 (302)

; iii, KOH; iv, MeLi; v, CH2N2; vi, NaOMe-C6H6

Scheme 46

,OMe C0,Me OMe 0

x, xi

.., OMe

vii-ix

-'-\OMe 0

..,,OMe C0,Me

1

xii

moMe .

Meo,C

'

'\OMe

Reagents: i, LiAlH,; ii, NaH-MeI; iii, 0,; iv, H z 0 2 ; v, CH,Nz; vi, NaH; vii, NaBH,; viii, TsC1-py; Br ; xii, 345 "C ix, NaOMe; x, LDA; xi,

Scheme 47

51

Sesquiterpenoids

12 Germacrane Molecular mechanics calculations have been carried out on germacrene B with the result that theoretical heats of formation have been ascribed to the four conformers (305)-(308) of 4.08,4.31,5.35,and 5.14 kcal mol-' re~pectively.'~~ Further calculations on the germacrene B supersurface indicates that the estimated barrier to inversion of the CT conformer (305) to its mirror image is

approximately 23 kcal mo1-l and hence it is predicted that resolution should be possible but that the racemization process should be quite facile. Similar but independent calculations have been carried out on the ground-state conformations of germacrene A (309), germacrene B, and hedycaryol (310).'50Additional calculations on the transition states of these three sesquiterpenoids leading to the corresponding elements indicate that it is not always the most stable ground-state conformer that produces the corresponding thermally derived elemene. Molecular mechanics calculations have also been used for an analysis of the conformation of agerol (31l).'" OH 1

Interesting results have been obtained from the acid-catalysed and thermal rearrangements of the four hedycaryol geometrical isomers (310) and (312)-(314) (Scheme 49).15*These results can be nicely accommodated by considering the four possible conformations of each hedycaryol isomer, and in the case of (310), (312), and (313) both the acid-catalysed and thermal reactions occur most favourably from a conformer(s) with the two double bonds in a crossed 149

lS1 lS2

H. Shirahama, E. bsawa, and T. Matsumoto, Tetrahedron Lett., 1979, 2245. Y. Terada and S. Yamamura, Tetrahedron Lett., 1979, 3303. F. Bellesia, U. M. Pagnoni, A. Pinetti, and R. Trave, Gazz. Chim. Ital., 1978, 108, 39. M. Kodama, S. Yokoo, Y. Matsuki, and S. It6, Tetrahedron Lett., 1979, 1687.

Terpenoids and Steroids

52

(314)

OH

Scheme 49

orientation. However, in the case of the (2,Z)-isomer (314), the reacting conformer appears to have the two double bonds parallel. In a separate communication, It6 et a~~~~have computed the heats of formation of the four principal conformers of the four hedycaryol isomers by empirical force-field calculations. As might be anticipated from the Curtin-Hammett principle the most stable conformer of each isomer is not the most reactive conformer with respect to the above-mentioned reactions [except possibly in the case of the (Z,Z)-isomer (3 14)]. In order to explain the stereospecificity of the thermally induced cyclization of preisocalamendiol (3 15) to give dehydroisocalamendiol (3 16), Terada and Y a m a m ~ r a have ~ ' ~ carried out molecular mechanics calculations on the groundstate conformers and probable transition states of (315). The computed values of the steric energies of the possible transition states are in good agreement with the observed experimental facts. Other studies related to the conformational aspects of germacrane sesquiterpenoids include an examination of the NOE effects in the isofuranodiene (317), which shows the 1,5-diene system to be in a crossed 15'

E. Osawa, K. Shimada, M. Kodama, and S. It6, Tetrahedron Lett., 1979, 2353. Y. Terada and S. Yamamura, Tetrahedron Lett., 1979, 1623.

53

Sesquiterpen oids

’ a refinement of the X-ray orientation with the two methyl groups ~ y t z , ~ ’ and structure of the costunolide-silver nitrate complex.156It has been noted in the latter investigation that the silver ion-co-ordinated double bonds are significantly longer than in the uncomplexed costunolide.

An interesting series of biogenetically significant reactions have been carried out on epoxygermacrene D (318) (Scheme 50).157,158 What is particularly intriguing about these rearrangements is that (320) and (321) embody the carbon OH

03y

+

f

OR

OR R

=

Hand Ac (319)

R

Q

=

H and Ac (320)

+

+

(322)

(323)

Scheme 50

skeleton of the marine sesquiterpenoids oppositol (325) and axisonitrile-1 (326) while (322) and (324) are related to periplanone A (327) and the recently isolated mintsulphide (328),159the latter of which co-occurs with (-)-germacrene D, the enantiomer of (196). As a further illustration of these interesting rearrangements it has been shown that (319) can be converted into juneol (329), and (323) has been transformed into (331) (Scheme 51), which is related to axisonitrile-3 (330). lS5

lS6 lS7

lS9

G. Rucker and M. Schikarski,Arch. Pharm. (Weinheim, Ger.), 1978,311, 125. A. Linek and C. Novik, Acta Crystallogr., 1978, B34, 3369. M. Niwa, M. Iguchi, and S. Yamamura, Tetrahedron Lett., 1978, 4043. M. Niwa, M. Iguchi, and S. Yamamura, Tetrahedron Lett., 1979,4291. T. Yoshida, S. Muraki, K. Takahashi,T. Kato, C. Kabuto, T. Suzuki, T. Uyehara, and T. Ohnuma, J. Chem. Soc., Chem. Commun., 1979,512.

Terpenoids and Steroids

54

OH

NC

Reagents: i, aq. H,SO,; ii, Cr0,-H'

Scheme 51

The most outstanding sesquiterpenoid synthesis of the year under review must surely be that of periplanone-B (333), one of the two extremely potent sex pheromones of the American cockroach.160 At the time this synthesis was initiated only the gross structure of periplanone-B had been determined and hence Still was faced with the problem of not knowing which of the four possible disastereoisomers was the active compound. In the event, not only did he synthesize the correct one but en route he also obtained two other diastereoisomers (334) and (335). The syntheses are brilliantly conceived and all three of them hinged upon the formation of the crucial cyclodecadienone (332) (Scheme 52). A detailed knowledge of conformational preferences in medium ring systems, together with the correct choice and order of reagents, permitted the syntheses of (333)-(335). In addition to the normal spectroscopic comparisons, the bioassay of racemic (333) clinched the structural assignment of periplanoneB. To complete this fascinating story the X-ray analysis of the synthetic alcohol (336) was performed as well as a c.d. study of the resolved C-9 (germacrane numbering) epimeric benzoate. 16' The combined evidence leaves no doubt that natural periplanone-B is represented as (333). 16'

W. C. Still, J. A m . Chem. SOC.,1979, 101, 2493. M. A . Adams, K. Nakanishi, W. C. Still, E. V. Arnold, J. Clardy, and C. J. Persoons, J. A m . Chem. Sac., 1979,101, 2495.

Sesquiterpenoids

55

&

Yo

__* i-iii

~

0

EEO

;

M

e

3

S

n

q

OAc OAc

'

E E O ~

1

v, vi

OH

./

/

EEO

EEO

EEO

/

1

ix, vi

1

xii-xiv

OSiMe,Bu' __+

(333) Reagents: i, LDA; ii, MeCH=CHCHO; iii, Ac,O; iv, Me,SnLi-Me,SiCl; v, Me,CuLi; vi, MCPBA; vii, f i L i

; viii, KH; ix, Me,SiCl; x, Bu'Me,SiCI; xi, aq. AcOH;

+-

xii, a-O,NC,H,SeCN-Bu,P; xiii, H,O,; xiv, Bu'OOH-KH; xv, Me,SCH,; xvi, Bu,N'F-; xvii, CrO,. py,

Scheme 52

A further examination of the essential oil of Asarum caulescens Maxim. has resulted in the isolation and identification of caulolactone A (338) and B (339).162 Interestingly both these compounds co-occur with germacrone 4,5-epoxide (337), and in fact treatment of this epoxide with anhydrous aluminium chloride gives both these lactones in 10% and 8% yields respectively. Mechanistically this has been rationalized in terms of two conformations of the epoxide as depicted in 162

J. Endo, M. Nagasawa, H. Itokawa, and Y . Iitaka, Chem. Pharm. Bull., 1979, 27, 275.

56

Terpenoids and Steroids

(337)

Scheme 53

(338)

0 H I

(339)

0

Scheme 53. Molecular models do not make this mechanism seem very likely and further work on the structures of caulolcatone A and B may be required. A further study of the photochemistry of germacrone (340) has shown that direct irradiation causes isomerization only of the A’”O-double bond whereas acetophenone-sensitized irradiation induces isomerization of both the and A4,5-do~ble

wo

(340)

(341)

A full paper on the cyclization of dihydrocostunolide (341) with aqueous NBS has appeared.’64 a-Cyclocostunolide (342), the product of acid-catalysed cyclization of costunolide, has been converted into santonin (343) by the process outlined in Scheme 54.’65

HOO” Reagents: i, hv, 0,; ii, MnO,; iii, DDQ

Scheme 54 164

P. J. M. Reijnders and H. M. Buck, Rec. Trav. Ckim.Pays Bas, 1978, 97, 263. T. C. Jain, C. M. Banks, and J. E. McCloskey, Tetrahedron,1979, 35, 885. S. A. Nadgouda, G. K. Trivedi, and S. C. Bhattacharyya, Indian J. Ckem., Sect. B, 1978,16, 16.

Sesquiterpenoids

HO

57

Q qg (345y7

(344)166

HO'

OH (346) R = Tig, Sen, or Ang16'

(347)167

(348) R

=

Ang or Sen167

AcO 1

During the period under review the germacrane sesquiterpenoids (344)-(350) have been identified.166-'68 New gerrnacranolides are listed in Table li69-i79

Table 1 Germacran-Gcu,l2-olides

Name Albicoilide* Salonitenolide* Costunolide* Costunolide* Costunolide* 166 167

168

:qo

R1 R2 R3 Other Ref. CH20H CHzOH a-OCOCH(Me)Et 169 CH20H Me a-OCOCH(Me)Et 169 Me CH20H H 60 Me Me H 3-OCOCH2CHMe2170 CH20H Me a-OCOC(Me)CH2 171 CH20H Me a-OCOCHMe2 171

F.Bohlmann and K. H. Knoll, Phytochemistry, 1979, 18, 995. F. Bohlmann and J. Ziesche, Phytochemistry, 1979,18, 1489.

E. Fattorusso, S. Magno, L. Mayol, V. Amico, G. Oriente, M. Piattelli, and C. Tringali, Tetrahedron Lett., 1978, 4149. F. Bohlmann and C . Zdero, Phytochemistry, 1979,18,95. 170 F. Bohlmann and C . Zdero, Phytochemistry, 1979,18, 336. 171 A. Rustaiyan, L. Nazarians, and F. Bohlmann, Phytochemistry, 1979,18, 883. 17* F. Bohlmann and L. N. Dutta, Phytochemistry, 1979,18, 847. 173 F. Bohlmann, L. N. Dutta, H. Robinson, and R. M. King, Phytochemistry, 1979,18, 1401. ' 7 1 F. Bohlmann and N. L. Van, Phytochemistry, 1978, 17, 1957. 17' W. Hertz, R.de Groote, R. Murari, N. Kumar, and J. F. Blount, J. Org. Chem., 1979,44,2784. ' 7 1 N. Ohno and T. J. Mabry, Phytochemistry, 1979, 18,1003. 177 L. Quijano, J. S. Calderon, F. Gomez G., and T. Rios C., Phytochemistry, 1979,18, 843. 17' M. E. Witt and S . F. Watkins, J. Chem. Soc., Perkin Trans. ZZ, 1978,204. 179 K. D. Onan and A. T. McPhail, J. Chem. Res. ( S ) , 1978, 12.

169

Terpenoids and Steroids

58 Table 1 Germacran- 6a,12-olides Liacylindrolide

Me

Liacylindrolide"

Me

Costunolide" Costunolide *

Me Me

Costunolide*

Me

Costunolide"

Me

I

Me Me

11

172

0

p-oco

Me Me

0-OTig a-OAc

W

Me

H

a-oco 0

30-OH

173

9p-OAc; 7a-OH

HH

Me Me

172

7a-OH

a-OCO 0 Me

3P-OH

9p-OAc

Me

,-OCoHH OH

Me

p-oco

174 174

175

YH

1751

AcO

Euserotin Mollisorin-A

C02H

Me

Me

Me

p-oco 0-OTig p-OCO 0

175

H

Montaf rusin

Me

Me

% a-OAng

Tamaulipin-A

Me

Me

H

Eupahyssopin

CH20H

Me

Mollisorin-B

Me

Me

* Derivative of.

f

2a-OH

176

2a-OH

176

2p-OH; 9P-OH

177

2a-OH

178

4,s-epoxide

179

Also 4,5-epoxide with 8p-OTig.

while others are shown in structures (351)-(363).180-189 Some of these lactones are new compounds, but in some cases certain structures have been confirmed by X-ray analysis etc. It should be noted that ursiniolides A, B, and C (361)-(363) belong to a rare group with the y-lactone cis-fused at C-6, C-7. Is"

18' Is*

'*'

ls6

'*' Is*

P. G. Jones and 0. Kennard, Acta Crystallogr., 1979, B35, 1273. S. E. Hull and 0. Kennard, Crystai. Struct. Commun., 1978, 7, 85. F. Bohlmann and M. Grenz, Phytochemistry, 1979, 18, 334. W. Herz, G. Ramakrishnan, and R. Murari, Phytochemistry, 1978, 17, 1953. W. Vichnewski, W. H e n , and N. Kumar, J. Org. Chem., 1979,44,2575. A. Rustaiyan, A. Niknejad, W. H. Watson, V. Zabel, T. J. Mabry, G. Yabuta, and S. B. Jones, jun., Rec. Latinoam. Quim., 1978, 9, 200. K. R. Ravindranath, R. Raghavan, S. K. Paknikar, G. V. Trivedi, and S. C. Bhattacharyya, Indian J. Chem., Sect. B, 1978, 16,27. A. G. Gonzalez, A. Galindo, H. Mansilla, and A. Alemany, Tetrahedron Lett., 1979, 3769. Z. Samek, M. Holub, U. Rychlewska, H. Grabarczyk, and B. Drozdi, Tetrahedron Lett., 1979,2691. W. Herz, R. de Groote, and R. Murari, J. Org. Chem., 1978, 43, 3559.

a,. a.0Wo 59

Sesquiterpenoids

0 Herbolide A (351)"'

Maroniolide (353)lg2

Herbolide B (352)"l

(355)lg4

'0 Dihydroelephantopin (356)lS5

Inunolide (357)

Neoalantalactone (35 9)'"

Dihydroinunolide (35

R'

co

R2

0

(361) %H

Ac Ursiniolide A

&o

I

/OAC

I

\

(362)CO-C-CH Gallicin (360)187

OH

Ac Ursiniolide B

H Ursiniolide C

'H

AcoQo:t RI-

AcO

0 Eurecurvin (364)lS9R = OH (365) R = H

0 (366)lg9

Terpenoids and Steroids

60

Woodhousin (367)I9O

Viguiepinin (368)19'

0

0 (370)'92 Schkuhrin-I1

0 (369) R = -C

II

S~hkuhrin-1'~~"~~ (= Hiyodorilactone A?)

HO HOH

Hiyodorilactone B

(372) R = H

Hiyodorilactone C

f OR3 R' OAng

OH

0

Provincialin derivatives (373)17* R' OAc H H 190

19*

193 lg4

R2 H OH OAc

'

R3

Centratherin (374)194

H H H

W. Herz and J. F. Blount, J. Org. Chem., 1978, 43, 4887. A. Romo de Vivar, G. Delgado, C. Guerrero, J. ResCndiz, and A. Ortega, Rev. Latinoam. Quim., 1978, 9, 171. M. J. Pettei, I. Miura, I. Kubo, and K. Nakanishi, Heterocycles, 1978, 11,471. T. Takahashi, H. Eto, T. Ichimura, and T. Murae, Chem. Lett., 1978, 1345. N. Ohno, S . McCormick, and T. J. Mabry, Phytochemisfry, 1979, 18, 681.

61

Sesqu iterpenoids 0

0

0

Leptocarpin (375)19'

Eremantholide A (376)196 R = Eremantholide B

R=

Eremantholide C

R=

-<

< <'

OR' Atripliciolide (37 7)1 9 7 ~ 1 9 8R1 derivatives H .OH OH H

R2 OH Oval' OSen H

(378) 199

R1 Ac

R2 CO-C-CH

I

CO-CH-CH

/

OH

\

OH

\

I

/

I

\

CO-C-CH

OH

+ diastereoisomer Tetraludins A, B, and C

Orientalide (379)200

0 Longipin (380)201

195

196

lg7

lg9

2oo

201

R. Martinez, J., I. S. Ayamante B., J. A. NCfiez-Alarch, and A . Romo de Vivar, Phytochemistry, 1979,18, 1527. P. W. Le Quesne, S. B. Levery, M. D. Menachery, T. F. Brennan, and R. F. Raffauf, J. Chem. SOC., Perkin Trans. I, 1978, 1572. F. Bohlmann and J. Jakupovic, Phytochemistry, 1979,18, 119. F. Bohlmann and L. N. Dutta, Phytochemistry, 1979, 18, 676. L. Quijano, D.Bloomenstiel, and N. H. Fischer, Phytochemistry, 1979,18, 1529. R. N. Baruah, R. P. Sharma, K. P. Madhusudanan, G. Thyagarajan, W. Herz, and R. Murari, Phytochemistry, 1979, 18, 991. F.C.Seaman and N. H. Fischer, Phytochemistry, 1979,18, 1065.

Tergenoids and Steroids

62 C0,Me

MR2

+JJ=

0

4

CO,Me

0

0 Polymatin A (381)202 R' Polymatin B H Ac Polymatin c

0

HO

0

Melnerin A (382)203 R =

<

Melnerin €3

OC&~

Ho--wo * 4S-epoxide

+YOR4

Various Acanthospermolide derivatives

0

'0

Baileyin ( 383)204

(384)205 e.g.R' = C H 0 , R 2 = CH20H, R3 = OAc,R4 = Mebu

9

Ha-

'

0

Tagitinin B (387)2"7 202 '03

204

2os 206 '07

4

0

Tirotundin (386)'07

Longipilin (385)206

0

0

&J

'71x 0

0 Tagitinin C (388)*07

N. L. Van and N. H. Fischer, Phytochemistry, 1979, 18, 851. S. F. Watkins, J. D. Korp, I. Bernal, D. L. Perry, N. S. Bhacca, and N. H. Fischer, J. Chem. Soc., Perkin Trans. 11, 1978, 599. W. Herz, R. Murari, and J. F. Blount, J. Org. Chem., 1979,44, 1873. F. Bohlmann, J. Jakupovic, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979,18,625. F. C. Seaman and N. H. Fischer, Phytochemistry, 1978,17,2131. N. C. Baruah, R. P. Sharma, K. P. Madhusudanan, G. Thyagarajan, W. Herz, and R. Murari, J. Org. Chem., 1979,44, 1831.

qR

63

Sesquiterpenoids

HO’.

0

0 Tifruticin (390)*07

Tagitinin F (389)’07 R=CO--<

Liatrin

HO

-&J -

0

HO‘.

0 Deoxytifruticin (391)’07

Tagitinin A (392)’07

Zexbrevin (393)’07

Tagitinin E (394)’07

Qoe

RO

-

0 Deacetylviguiestin (395)’07 R = H Viguiestin R=Ac

R’ Caleine A (396)’08 Ac Ang Caleine B

R2 Ang Ac

L. Quijano, A. Romo de Vivar, and T. Rios, Phytochemistry, 1979,18,1745; Rev. Latinoam. Quim., 1978, 9, 86.

Terpenoids and Steroids

64

Neurolenin A (397)2*9 R = H Neurolenin B R = OAc

Caleurticolide (398)19' R = Ac, OCA or Ang derivatives

F02Me

R'

R2

R2 0

(399)210R1 Melcanthin A H OH Melcanthin B Melcanthin C OH

0 R2 CH20H CH20H CH20H

R3 Ang Ang Bu'

(400)205R' CHO

R2 R3 / CHzOH OC-CH

L

etc.

Various 4,5-cis-Acanthospermolidederivativc

OAc

(401)211 R1

Ac

R2 Me

R3

OAc

(402)21' R'

Ac Ac

OAc

etc.

R2 Me H

Various Hirsutinolide derivatives212

HO

OAc

0 (403)213Fasciculide-B

A rather large collection of new heliangolides, melampolides, and related lactones are shown in structures (364)-(403).190-213 The continuing search for lactones with interesting biological activities has largely contributed to the isolation and identification of these compounds. Two very detailed papers by 209

*I0 211

212 *13

P. S. Manchand and J. F. Blount, J. Org. Chem., 1978, 43,4352. N. H. Fischer, F. C. Seaman, R. A. Wiley, and K. D. Haegele, J. Org. Chem., 1978,43,4984. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979,18, 987. F. Bohlmann, P. K. Mahanta, and L. N. Dutta, Phytochemistry, 1979, 18,289. N. K. Narain, Spectrosc. Lett., 1978, 11,267.

65

Sesquiterpenoids

samek214.215 indicate how allylic and vicinal coupling constants can be used to define the stereochemistry of the ring junction of a-exomethylene y-lactones. The mass spectra of five germacranolides are discussed in detail in a paper by Perry et aL216

13 Elemane An examination of Galbanum resin has revealed the presence of epishyobunone (404), shyobunol (405), epishyobunol (406) (with their corresponding acetates), and 10-epijunenyl acetate (407).217In an independent study the Firmenich group218 has isolated P-eudesmol (408),10-epielemol (409), guai-9-en- 11-01 (410), epiligulyl oxide (41l), and (2)-dihydrofarnesol (412) from the same

Q

H OH

H O

GO

0-y OAc

(407)

OH

(408)

(409)

Q &+ OH

(410)

(411)

OH

(412)

source. The isolation of the latter compound is significant since it helps to explain the occurrence of the 10-epi-compounds (these being derived from a cis-1,lOgermacrene precursor). In a recent paper219 it has been pointed out that the elemane sesquiterpenoids may play a more significant r61e in sesquiterpenoid biogenesis than has been appreciated in the past. This hypothesis derives from the fact that treatment of elemol acetate (413; R = Ac) with thallium(II1) nitrate, followed by acetate reduction, gives the guaiane derivative (416). On the other hand, hydroxymercuration of elemol (413; R = H) yields cryptomeridiol (415) after reductive demercuration. These results have been interpreted in terms of metal-induced cyclization to the common intermediate (4 14) followed by demercuration to give (415) and rearrangement to give (416). '14 'lS 216

'17 '18

'I9

Z. Samek and J. Harmatha, Collect. Czech. Chem. Commun., 1978, 43, 2779. Z. Samek, Collect. Czech. Chem. Commun., 1978, 43, 3210. D. L. Perry, D. M. Desiderio, and N. H. Fischer, Org. Muss Specfrom., 1978,13, 325. R. Kaiser and D . Lamparsky, Helv. Chim. Acta, 1978,61, 2671. A. F. Thomas and M. Ozainne, Helv. Chim. Actu, 1978,61, 2874. W. Renold, G . Ohloff, and T. Norin, Helv. Chim. Acta, 1979,62, 985.

66

Terpenoids and Steroids

+ A6’7-(E)-isomer (417)

CO,H

1”.

vi

l v i i , viii

0 (419)

(418)

(420)

Reagents: i, Base; ii, Me,SiCI; iii, room temp.; iv, H,O; v, SOCI,; vi, SnCI,; vii, DBN; viii, Ph,SnH

Scheme 55

Shybunone (4 19) and three of its diastereoisomers have been synthesized starting from geranyl and neryl senecionate (417) (Scheme 55).220This work shows that epishyobunone is (420) and not (418) as previously thought. An alternative synthesis of (-)-shyobunone (421) (the enantiomer of the naturally occurring compound) has been achieved (Scheme 56).221This route also results in the formation of (-)-2-epishyobunone (422) and (-)-3-epishyobunone (423).

”’ G. Frater, Helv. Chim. Acta, 1978, 61,2709. ”’

J. R. Williams and J. F. Callahan, J. Chem. SOC.,Chem. Commun., 1979, 404.

67

Sesquiterpenoids

+

+ 1

q...l0

Reagents: i, h v ; ii, NaBH,; iii, 250 "C; iv, Cr0,-H'

Scheme 56

/m0/m0:Goo New elemanolides include 8cr-H-secoeudesmanolide (424),222secoeudesmanolide (425),172 the two dihydromelitensin derivatives (426),223 various zinamultifloride esters (427) and the corresponding epoxy-compounds (428), and zinniadilactone (429).224 .O+OH

H

0

H

(424)

(425)

(426) R = CH20H or CHO

Although the synthetic challenge of vernolepin (430) and vernomenin (431) has been met by a number of groups, several interesting papers in this area have

0

0

r\

222

223 224

F. Bohlmann and L. Dutta, Phytochemistry, 1979, 18, 1228. A. Rustaiyan, L. Nazarians, and F. Bohlmann, Phytochemistry, 1979, 18, 879. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979,18, 1343.

68

Terpenoids and Steroids /OCH,Ph

,OCH,Ph

C0,Me

h,

vii

m** -

/OCH,Ph

m 0

*

-

O

,OCH,Ph

(OCHZPh

H+-x, xi

/

viii, ix

0

H

,

M e 0 2 C H SOPh

0 Me0,C

'y xiii ,OCH,Ph

,OCH,Ph ix, xiv, xv

OH

+xviii, xxi

0

H .:

H ' OAc

C0,Me

OAc

(432) Reagents: i, LDA; ii, CICH,OCH,Ph; iii, LiAlH,; iv, Bu'OK; v, CICOCH,CO,Me-py; vi, TsN,Et,N; vii, [Cu(acac),]; viii, NaSPh; ix, MCPBA; x, (MeO),P; xi, K,CO,; xii, Bu',AIH; xiii, MeOH-H'; xiv, LiCH,CO,Li; xv, CH,N,; xvi, Ac,O-py; xvii, H,-Pd/C; xviii, CrO, * py,; xix, CH,=PPh,; xx, H,O'; xxi, Ag,CO,-celite

Scheme 57

been presented recently. These include an alternative synthesis of Grieco's lactone (432) (Scheme 57),225 a full paper on the synthesis of the key intermediate (433),226 a route to the vernolepin isomer (434),227 and another synthesis of the bicyclic lactone (435).228 225

226 227

F. Zutterrnan, H. De Wilde, R. Mijngheer, P. De Clercq, and M. Vandewalle, Tetrahedron, 1979,35, 2389. H. Iio, M. Isobe, T. Kawai, and T. Goto, Tetrahedron, 1979, 35, 941. J. A. Marshall and G. A, Flynn, J. Org. Chem., 1979, 44, 1391. T. Wakarnatsu, H. Hara, and Y. Ban, Tetrahedron Lett., 1979, 1227.

69

Sesquiterpenoids

0 E t0,C H H

0

(433)

0 (435)

(434)

14 Eudesmane New eudesmane sesquiterpenoids include cnicothamnol (436), cnicothamnal (437),169(438),222the dehydro-oblodiol derivative (439),229(440),230gerin (441),231 ilicol (442),232(443), (444),233 heterophyllol (445),234kudtdiol (446),235 (447),236(448),237isointermedeol (449),238ocotealactol (450),239ent-5P-hydroxydiplophyllolide (45 l),ent-3-oxodiplophyllin (452), ent-dihydrodiplophyllin (453),240chloranthalactones A (454) and B (455),241(456), (457),242nehipetol (458), and nehipediol (459),243together with twelve new eudesmanes from Flourensia species.244

?H

Cnicothamnol(436) R = CH20H Cnicothamnal(437) R = CHO

(440) 229

230 23 I 232 233 234 235

236

237 238 239

240 241 242 243 244

(438)

C0,Me Gerin (441)

HO (439) Dehydro-oblodiol derivative

Q

HO'

OH

Ilicol (442)

F. Bohlmann, C. Zdero, D. Berger, A. Suwita, P. Mahanta, and C. Jeffrey, Phytochemistry, 1979,18, 79. K. Endo and H. Hikino, Bull. Chem. SOC. Jpn., 1979, 52, 2439. E. Rodriguez, B. Sanchez, P. A. Grieco, G. Majetichi, andT. Oguri, Phytochemistry, 1979,18,1741. E. Guerreiro, J. Kavka, 0. S . Giordano, and E. G. Gros, Phytochemistry, 1979,18, 1235. F. Bohlmann, A. Suwita, and C. Zdero, Phytochemistry, 1978,17, 1763. N. J. Eggers and A. J. Jones, Tetrahedron Lett., 1979, 3053. J. de Pascual Teresa, A. F. Barrero, A. San Feliciano, M. Grande, and M. Medarde, Tetrahedron Lett., 1978, 4141. F. Bohlrnann, W. Knauf, R. M. King, and H. Robinson, Phytochemistry, 1979,18, 1011. F. Bohlmann and J. Jakupovic, Phytochemistry, 1979,18, 1367. R. K. Thappa, K. L. Dhar, and C. K. Atal, Phyrochernistry, 1979,18,671. N. F. Roque, Z. S. Ferreira, 0. R. Gottlieb, R. L. Stephens, and E. Wenkert, Rev. Latinoam. Quim., 1978,9,25. Y. Asakawa, M. Toyota, T. Takernoto, and C. Suire, Phytochemistry, 1979, 18, 1007. M. Uchida, G. Kusano, Y. Kondo, S . Nozoe, and T. Takernoto, Heterocycles, 1978, 9, 139. W. Herz and N. Kurnar, Phytochemistry, 1979,18, 1743. J. St. Pyrek, M. Kocbr, E. Baranowska, C. K. Atal, and R. S. Sharma, Rocz. Chem., 1976,50, 1931. F. Bohlmann and J. Jakupovic, Phytochemistry, 1979, 18, 1189.

Terpenoids and Steroids

70

O H -

OH

O CHO *

"

Kudtdiol (446)

.

R

(447)

(448)

p

"'p

q

x

o

OH

HO' Isointermedeol (449)

P : ; ) o

p

Ocotealactol (450)

oJp::)o qJ:--Fo

OH (45 1)

enf-5 0-Hydroxydiplophyllolide

(452)

(453)

ent- 3 -0xodiplophyllin

Chloranthalactone-A (454)

Chloranthalactone-B (455)

I

/

RO

ent-Dihydrodiplophyllin

I

0 (456) R = H (457) R = A c

Nehipetol (458)

Nehipediol (459)

71

Sesq uiterpenoids

The structure of tetrahydroatractylon monoxide, the compound derived from aerial oxidation of the hydrogenation product of atractylon (460), has been assigned as (461).245A full paper on the structure of the biogenetically important sesquiterpenoid rosifoliol(462) has been Two bromo-eudesmanes,

@Q (460)

bT 9 J

q& (462)

@ (461)

brasudol (463) and isobrasudol (464), have been isolated from the mollusc Aplysia b r a ~ i l i a n aBoth . ~ ~ ~these compounds have also been found as constituents of a red alga which is the diet of the mollusc. Interestingly these two compounds are not antipodal with respect to most terrestrial eudesmanes unlike other marine-derived eudesmanes. A further penta-ester (465) has been isolated from

+ 2 Ac, 2 Val', 1 COPh (465)

Euonyrnus europaeus although the exact positions of the various esters are not yet known.248New eudesmanolides are listed in Table 2.249-253 A very neat intramolecular Diels-Alder route has been developed for the synthesis of the ketone (466) which can be converted into selina-3,7( 11)-diene (467) (Scheme 58).254Attempts to synthesize the cycloeudesmol obtained from the marine alga Chondria oppositiclada Dawson have so far not been successful. 245 246

247 248 249

250

252

253

254

H. Hikino, Chem. Ber., 1978, 111, 2726. I. A . Southwell, Aust. J. Chem., 1978, 31, 2527. R. K. Dieter, R. Kinnel, J. Meinwald, and T. Eisner, Tetrahedron Lett., 1979, 1645. L. Dubravkovi, L. DolejS, and Z. VotickL, Phytochemistry, 1979,18, 1740. F. S. El-Feraly, Y. M. Chan, and D. A. Benigni, Phytochemistry, 1979, 18, 881. J. D. Gomis, J. A. Marco, J. R. P. Llinares, J. S. Parareda, J. M. Sendra, and E. Seoane, Phytochemistry, 1979,18,1523. F. Bohlmann and C. Zdero, Phytochemistry, 1979,18,332. S. V. Serkerov and A . N. Aleskerova, Khim. Prir. Soedin., 1978,75. Z. Samek, M. Holub, V. Herout, E. Btoszyk, and B. Drozdz, Collect. Czech. Chem. Commun., 1979, 44, 1468. S . R. Wilson and D . T. Mao, J. A m . Chem. SOC.,1978, 100,6289.

72

Terpenoids and Steroids

Name Cyclocostunolide* Cyclocostunolide* Cyclocostunolide* Magnolialide Torrentin Gazaniolide Alkhanin (= Dehydroisoerivanin) Isoerivanin Montathanolide

Double bond position ( s ) 4,14; 11,13 4,14; 11,13 4,14; 11,13 4 3 ; 11,13 475 1,2; 3,4; 11,13 4.5

Substituents Ref. 1a-OH; 8a-OCOC(CHJCH20H 43 I~u-OCOC(CH~)CH~OH; 8a-OH 43 la-OH; 8a-OH 43 1P-OH 249 1P-OH; 8a-OAc;. lla-Me 250 8a-Oval' 25 1 3-keto; la-OH; lla-Me 252,253

4s 4 3 ; 11,13

la-OH; 3a-OH; lla-Me 1P-OH; 3P-OAc

253 166

* Derivative of.

/ (466) Reagents: 1, Me,SiCI-py; ii, A; iii, H,O';

(467)

iv, [ O ] ;v, CBr,-Ph3P; vi, Me,CuLi

Scheme 58

In two independent studies three [(468)-(470)] of the four possible diastereoisomers have been synthesized and none of these has proved to be identical to the naturally occurring ~ ~ m p ~ ~This n only d . leaves ~ ~ (471) ~ * as~the~ final ~ possibility with a cycloeudesmol structure. It may, however, be that this compound requires further investigation since the n.m.r. spectrum seems to have some anomalous features [e.g. the isopropylol methyl groups are reported at S 1.25 and 1.33 whereas the lowest-field methyl signal in (468)-(470) is at S 1.11; in addition, the cyclopropyl protons are reported as two doublets, J = 5 Hz, with no apparent coupling to the C-4 proton]. Complete details of the synthesis of the nor-sesquiterpenoid chamaecynone (472) have been A new route to 255

257

M. Ando, S. Sayama, and K. Takase, Chem. Lett., 1979, 191. R.A. Moss, E. Y. Chen, J. Banger, and M. Matsuo, Tetrahedron Lett., 1978, 4365. T. Harayama, H. Cho, and Y. Inubushi, Chem. Pharm. Bull., 1978,26, 1201.

73

Sesquiterpenoids

P-agarofuran (473) and dihydroagarofuran (474) has been reported by Biichi and Wiiest (Scheme 59),258 7,8-Epi-alantolactone (477) has been synthesized from the known lactone (475)259and in a subsequent study the intermediate bromo-lactone (476) has been converted into the rare 7a,8a-lactone, dihydrocallitrasin (478) (Scheme 60).260Another synthesis of frullanolide (479) has been recorded (Scheme 61).261

$lq* ,+q Me,Si

(473)

(474)

Reagents: i, H,-Pd/C; ii, I(CH,),C=CH-NaNH,-NH,; iii, PCI,; iv, EtMgBr; v, Me,SiCl; vi, Bu,SnH; vii, p-MeC,H,SO,H-MeCN-H,0; viii, NzH2

Scheme 59 G . Buchi and H. Wiiest, J. Org. Chem., 1979,44, 546.

”’ A. G. Schultz, J. D. Godfrey, E. V. Arnold, and J. Clardy, J. Am. Chem. SOC.,1979,101, 1276. 260

261

J. D. Godfrey and A. G. Schultz, Tetrahedron Lett., 1979, 3241. F. Kido, R. Murata, K. Tsutsumi, and A. Yoshikoshi, Chem. Lett., 1979, 311.

Terpenoids and Steroids

74

A

o +-J o-J- f+

m

C0,Me

Br

(475)

(476)

(476)

p Br

C0,Me

-

>

0

C0,Me

mo ii, ix-xii

,

/

xiii-xv

C02Me

(478) Reagents: i, NBS; ii, NaBH,CN-H'; iii, DBN; iv, Me,CuLi; v, NaOH; vi, CH,O-Et,NH; vii, NaOAc-AcOH; viii, Zn-AcOH; ix, B,H, SMe,; x, H,O,-NaOAc; xi, Cr0,-H'; NaOMe; xiii, CH,=PPh,; xiv, NaH-MeI; xv, NaCN-HMPA

xii,

-m Scheme 60

+

=bo

. ..

0

l i i i , iv

ix-xii

v-viii

c--

t--

OMe

(479) Reagents: i, NaBH,-NiCl,; ii, SOCI,-py; iii, Bd,AlH; iv, CH(OMe),-H'; v, LiAIH,; vi, CrO, . py,; vii, N,H,-OH-; viii, Cr0,-H'; ix, LDA; x, CH,O; xi, MsCl; xii, DBU

Scheme 61

75

Sesq u iterpe noids

n

The known derivative of a-santonin (480) has been transformed into the three lactones (481)-(483) which, in turn, have been converted into arglanine (484), vulgarin (485), and C-4-epivulgarin (486) respectively.262In a related study the ketone (487) has served as a synthetic precursor for douglanine (488) and ludovicins A (489) and B (490) (Scheme 62).263 The structure of chlorosantonin (491) obtained from santonin 4,5-epoxide with hydrogen chloride gas has been solved by X-ray Undoubtedly the most remarkable sesquiterpenoid rearrangement is that observed when the dried sodio salt of (492) is heated to reflux in excess phosphorus oxychloride. The rearrangement product in question was isolated by removal of the excess P0Cl3, followed by neutralization with concentrated aqueous ammonia. The resultant ether extract was treated with hot 15% sodium hydroxide and the product mixture was distilled and purified by column chromatography. One of the products (about 3% yield) has been identified by X-ray analysis as (493), but as yet no mechanism has been

15 Vetispirane Studies on the stress metabolites of Solanaceae species continue to produce interesting results as witnessed by a number of recent publications. In the case of 262 263 264 265

M. Ando, A. Akahane, and K. Takase, Bull. Chem. SOC.Jpn., 1978,61, 283. K. Yamakawa, K. Nishitani, and K. Azusawa, Heterocycles, 1978, 9, 499. H. Takayanagi, H. Ogura, and Y. Iitaka, Chem. Pharm. Bull., 1978,26,2729. S. Inayama, A. K. Singh, T. Kawamata, and Y. Iitaka, Tetrahedron Lett., 1979, 1125.

Terpenoids and Steroids

76

R-0 HO

0

'H0-Q

0.' 0 (489)

0 -

O (490)

O

Reagents: i, LiAl{OBu'),H; ii, chrom.; iii, LDA; iv, Ph,Se,; v, 2 eq. H,O,; vi, excess H,O,

Scheme 62

potatoes infected with Phytophthora infestans, Masamune et a1.266have identified oxyglutinosone (494) and epioxylubimin (495). The former compound has been synthesized from rishitin (496) by selective acetylation of the C-3 hydroxy-group, followed by epoxidation of the endocyclic double bond and subsequent oxidation of the C-2 hydroxy-group. Chromatography of the derived epoxy-ketone (497j and hydrolysis of the acetate group gave oxyglutinosone (494). Rishitin-M-1 (498), a metabolite of rishitin, has also been detected in low concentration in infected potato tubers and it has been synthesized from r i ~ h i t i n . ~In~ 'another 266 267

N. Katsui, F. Yagihashi, A . Murai, and T. Masamune, Chem. Lett., 1978, 1205. T. Masamune, A . Murai, Y. K. Takahashi, F. Yagihashi, N. Katsui, N. Doke, and K. Tomiyama, Chem. Lett., 1978, 1207.

77

Sesqu ite rpe noids

study Coxon et ~ 1 . ~have ~ ' identified cyclodehydroisolubimin (499) from potato tubers inoculated with P.infestans. Two independent reports2697270 necessitate a change in the structure of aubergenone, a phytoalexin derived from eggplants. Previously considered to be (500),it has now been shown to have the opposite aubergenone was stereochemistry at C-4, i.e. (501). In one of these

HO

'OH

(499)

unambiguously synthesized. The biogenetic pathway linking many of the Solanaceae metabolites has been somewhat modified to take into account recent results. Another structure requiring revision is that of a sesquiterpenoid isolated from tobacco some years ago. Instead of having structure (502) it has now been shown to have the structure (504) based on a synthesis starting from (+)-acyperone (503).271 OH

(+)-a-Cyperone (503) has also been used in a very elegant synthesis of phytuberin (505), another phytoalexin from diseased potato tubers (Scheme 63).272Phytuberin has also been detected in extracts of infected tobacco leaves.273 Conclusive evidence, based on radioactive labelling studies, has been presented 268

269 270 271

272 273

D. T. Coxon, K. R. Price, J. B. Stothers, and A . Stoessl, J. Chem. SOC.,Chem. Commun., 1979,348. A. Murai, A. Abiko, M. Ono, N. Katsui, and T. Masamune, Chem. Lett., 1978, 1209. R. B. Kelly, S. J. Alward, K. S. Murty, and J. B. Stothers, Can. J. Chem., 1978,56, 2508. A . Murai, M. Ono, and T. Masamune, Chem. Lett., 1978, 1005. A . Murai, M. Ono, A . Abiko, andT. Masamune, J. Am. Chem. SOC.,1978, 100,7751. R. Hammerschmidt and J. KuC, Phytochemistry, 1979, 18, 874.

78

Terpenoids and Steroids

HO viii, i, ii

Reagents: i, LDA; ii, MOO, . py . HMPA; iii, Bu‘Me,SiCl; iv, Li Bu”,BH; v, Bu‘00H-[VO(acac),]; vi, MsCI-py; vii, Li-NH,; viii, MnO,; ix, MCPBA; x, LiAlH,; xi, Pb(OAc),-py; xii, Bu’,AIH; xiii, Ac20-4-Me,Npy

Scheme 63

to demonstrate that oxylubimin (506) is a precursor of rishitin (496).274Previously it was considered that rishitin arose from degradation of a eudesmane-type compound. In another biosynthetic study it has been shown that 13-hydroxycapsidiol (507) it not derived from the corresponding exocyclic epoxide of capsidiol (508) in Nature.275 @-Vetivone(509) and its C-10 epimer (510) have been synthesized by a route involving Ar1-5 participation of the phenolic tosylate (Scheme 64).276 The same

..*Cx:j

HO H % o,

(506)

274

(507) R = O H (508) R = H

K. Sato, Y. Ishiguri, N. Doke, K. Tomiyama, F. Yagihashi, A. Murai, N. Katsui, and T. Masamune, Phytochernistry, 1978, 17,1901. 275 J. B. Stothers, A. Stoessl, and E. W. B. Ward, 2. Nuturforsch., 1978, 33c, 149. ”‘ S. Torii, K. Uneyama, and K. Okamoto, BuU. Chern. SOC.Jpn., 1978, 51,3590.

79

Sesquiterpenoids

oh +

\

-

o&

+vii, viii

\

O \

h

,

-

Reagents: i, LDA; ii, Me,CO; iii, SOCl,; iv, LiAlH,; v, TsC1-py; vi, Bu’OK; vii, Me,CuLi; viii, RhCl,

Scheme 64

paper reports the synthesis of a number of other vetispiranes by the same methodology. In a similar type of approach it has been shown that the successful intramolecular y-alkylation of the keto-tosylate ( 5 11) can be achieved to give 6-vetivone (509) and 10-epi-P-vetivone (5 10) with sodium hydroxide in aqueous (25%) dimethyl s ~ l p h o x i d e . ’If~ ~ dry dimethyl sulphoxide is used in this reaction the only product is the a-alkylated product ( 5 12). One of the key compounds in previous p-vetivone syntheses is Marshall’s spiro-ketone (5 13). This ketone has now been synthesized by an alternative route starting from the known diketone (514) which involves selective reduction of the six-membered ketone followed by

protection of the derived alcohol and 1,2-carbonyl transposition in the fivemembered ketone.278Another interesting method of constructing the vetispirane skeleton is the formation of the five-membered ring by an acyloin r e a ~ t i o n . ’ ’ ~ ~ ~ ~ ~ This key step has permitted the syntheses of (*)-hinesol (515), (*)-agarospirol (516), (*)-p-vetivone (509), and (*)-a-vetispirene (517) (Scheme 6 5 ) .

277 278 279

A. P. Johnson and V. Vajs, J. Chem. SOC., Chem. Commun., 1979,817. K. P. Subrahamanian ahd W. Reusch, Tetrahedron Lett., 1978,3789. T. Ibuka, K. Hayashi, H. Minakata, and Y. Inubushi, Tetrahedron Lett., 1979, 159. T. Ibuka, K. Hayashi, H. Minakata, Y. Ito, and Y. Inubushi, Can. J. Chem., 1979,57,1579.

80

Terpenoids and Steroids

/-4

i. ii

V C O , E t

j

v, vi

~

C0,Et

& 22 vii iv viii

OH

1..

vii, iv

\

CHO

Reagents: i, LDA; ii, Br(CH2),C02Et; iii, Na-toluene-Me3SiC1; iv, H,O'; v, MsC1-py; vi, ZnNH4Cl;.vii, Ph,P=CHOMe; viii, MeLi; ix, CrO,-H+; x, Ac,O-py; xi, H'

Scheme 65

16 Eremophilane, Nootkatane, Ishwarane The isolation and identification of new eremophilane sesquiterpenoids from various plant species continues to be an active area of research. For the sake of simplicity new furanoeremophilanes are shown in Table 3 .281-289 Other new eremophilane sesquiterpenoids include (518)-(532).290-295 A number of other eremophilanes have been isolated from various South African 281

282

283 284 285

286 287

288 289 29U

291 292

293 294

295

Y. Ishizaki, Y. Tanahashi, T. Tsuyuki, T. Takahashi, and K. Tori, Bull. Chem. SOC.Jpn., 1979,52, 1182. G. R. Woolard, J. A. Pretorius, P. C. Coleman, and D. E. A. Rivett, J. Chem. Soc., Perkin Trans. 11, 1979,930. F. Bohlmann and C. Zdero, Phytochemistry, 1979, 18, 125. F. Bohlmann and C. Zdero, Phytochemistry, 1979, 18, 339. F. Bohlmann and M. Grenz, Phytochemistry, 1979, 18, 491. F. Bohlmann and K. H. Knoll, Phytochemistry, 1979,18, 877. L. H. Zalkow, L. T. Gelbaum, and D. Van Derveer, J. Chem. SOC.,Perkin Trans. I, 1979,1542. H. Nagano and T. Takahashi, Bull. Chem. SOC.Jpn., 1978,51, 3335. C. Kuroda, T. Murae, M. Tada, H. Nagano, and T. Takahashi, Chem. Lett., 1978, 1313. J. Jizba, Z. Zamek, L. Novotny, E. Najdenova, and A. Boeva, Collect. Czech. Chem. Commun., 1978,43,1113. F. Bohlmann and K. H. Knoll, Justus Liebigs Ann. Chem., 1979, 470. K. Yamada, H. Tatematsu, Y. Kyotani, Y. Hirata, M. Haga, and I. Hirono, Phytochemistry, 1978,17, 1667. A. Ulubelen, N. Ates, and T. Nishida, Phytochemistry, 1979,18, 338. F. Bohlmann and C. Zdero, Justus Liebigs Ann. Chem., 1978, 3140. K. Omura, M. Nakanishi, K. Takai, and K. Naya, Chem. Left., 1978,1257.

81

Sesquiterpenoids

R4 Table 3 Furanoeremophilanes

R' R' p-OAc p-OAc &OAc @-OH p-OAc H

R3

R2 p-Me p-Me &Me p-Me &Me @-Me

R4

p-OAng 0-OTig 0-OSen P-OAng p-OTig p-OTig

L O 0

H a-OH H H H p-OAc H H

p-Me @-Me p-Me @-Me p-Me p-C02Me &Me

H a-OAng p-OAng p-OAng p-OAng P-OAng 0-OAng P-OAng

p-Me p-Me p-Me @-Me 0-CHO P-CHO (3-CO2H 0-CO2H

4

H H H H =O P-OH

Ref. 229 229 229 229 229 229

H

28 1

H =O 10a-H ~9.10. P-OCOEt H , 1-keto =O 10a-H; la-OH P-OAC =O 10a-H; la-OAc O-OAC =O P-OAng P-OAng H 2a-hydroxymethylH lP,lO@-epoxide acryloyl =O 10P-OH; la-OAng p-OAc H =O 10a-H H 0-OSen 100-OH H H .lOP-OH @-3-methylbutanoyl H p-OAng H p-3-me thylpentanoyl H 0-3-methylbutanoyl H

mo \

0 =

H, OH, OMe, or OEt ( 5 18)290

mo

282 283 283 283 284 285 286 167 287 288 288 289 289 289 289

%*,

OH

R

Other

\

\

mo(J& both epimers at C-1 ( 519)291

GlucO

(520)292

0

1

(521)'*'

Istanbulin C (522)293

(523)3

C02H

82

Terpenoids and Steroids

(%$&

J (A +

qA+g

/

/

0Ac

OR Cinalyratol derivatives (524)'15 R = Ang or Ac

(527)'

.

H

AcO

/

o

(5 26)'

(525)"'

Q

o

0 0 2-Hydroxyplatyphyllide (529)2g6

OAng

'

* O w

(528)229

OH Cacalohastin derivative (530)294

'

( 53 1)295

OH

(532)295

Senecio species233 and from Petasites h y b r i d ~ s . ~ ~New ~ , ~ cacalol ~' sesquiterpenoids are listed in Table 4. Other examples of cacalol sesquiterpenoids, (533)-(537), some of which have undergone further oxidation, have been isolated from Cineraria species.115

R'

R2

Table 4 Caculols*

R' R'

R2

R3

=O H H H H H =O

H OMe OMe OMe OMe OMe OH

H OAc OH H H H H

R4 H H H OAng H H H

R'

Other

OAng OH H

ring A aromatic ring A aromatic

Ref. 283 294 294 294 294 294 295

* In addition to these, eleven other cacalol derivatives have been isolated from South African Senecio species.229

''' M. Neuenschwander, A. Neuenschwander, E. Steinegger, and P. Engel, Helv. Chim. Acta, 1979,62, 609. 297

M. Neuenschwander, A. Neuenschwander, and E. Steinegger, Helv.Chim. Acta, 1979,62,627.

83

Sesquiterpenoids

I

I

Cinalbicol (533)

Isocinariolide (536)

(534)

Cinariolide (535)

(537)

Yamakawa et al.298have converted the triketone (538) (by standard procedures) into the racemates of furanoeremophilane (539), furanoligularane (540), 9,lO-dehydrofuranoeremophilane (541), ligularone (542), 3P-hydroxyfuranoeremophilane (543),and 3~-furanoligularanol(544). An alternative

(539) R1 = R2 = H (542) R ' = H , R 2 = 0 (543) R' = OH,R2 = H

Jpo\

R

(540) R = H (544) R = O H

'

(541)

synthesis of ligularone (542)and isoligularone (546)involves the reaction of the diketone (545)with l-nitro-l-phenylthiopropeneand subsequent oxidation followed by sulphoxide elimination (Scheme 66).299The key intermediate (547) has been used to synthesize isopetasol (548),3-epi-isopetasol (549),warburgiadione (550), and petasitol (551).300The same diketone (547)has also been converted into phomenone (553) via the dienone (552) (Scheme 67).301This route also permitted the synthesis of the 3-epi-isomer. In another synthesis of isopetasol (548),Torii et ~ 1 . ~have ' ~ used the tricyclic keto-lactone (554)as the 298 299 300

301 302

K. Yamakawa and T. Satoh, Chem. Pharm. Bull., 1978, 26,3704. M. Miyashita, T. Kumazawa, and A. Yoshikoshi, Chem. Lett., 1979, 163. K. Yamakawa, I. Izuta, H. Oka, R. Sakaguchi, M. Kobayashi, and T. Satoh, Chem. Pharm. Bull., 1979,27, 331. K. Yamakawa, M. Kobayashi, S. Hinata, and T. Satoh, Tetrahedron Letr., 1979, 3871. S. Torii, T. Inokuchi, and K. Kawai, Bull. Chem. SOC.Jpn., 1979, 52, 861.

Terpenoids a n d Steroids

84

Scheme 66

Po

0

R2.

(548) R1= H,R2 = OH (549)R’= OH,R2 = H

(547)

HO’

HO”

R,

,iii-vi

“0 \

OH

om,

OH

Reagents: i, MeO,CNSO,&Et,; ii, aq. AcOH; iii, NaBH,; iv, MCPBA; v, LiNEt,; vi, H,O,-HaHCO,

Scheme 67

85

Sesquiterpen o ids

n

n iii, iv

OH

0

OTs

(554)

1.

Po l x i i , xiii

xiv, xv,

HO'*

AcO-

(548) Reagents: i, HOCH,CH,OH-H'; ii, LiAlH,; iii, TsC1-py; iv, Me$-NCS; v, KOBu'; vi, Li-NH,MeI; vii, NaOMe; viii, LiA1(OBu')3H; ix, aq. HClO,; x, Ac,O-py; xi, NaBH,; xii, MsC1-py; xiii, Cr0,-py; xiv, LDA; xv, Me,CO; xvi, A; xvii, KOH

Scheme 68

starting material (Scheme 68). The synthesis of the two rearranged eremophilanes, cacalol (555)303and platyphyllide (556)304have been reported. OH

0 (555)

(556)

An extensive study of the autoxidation products of fukinone (557) has resulted in the isolation of (558)-(561).305 In the presence of base the products of oxidation are (562) and (563).306 ,03 ,04

305

J. W. Huffman and R. Pandian, J. Org. Chem., 1979,44, 1851. F. Bohlmann and E. Eickeler, Chem. Ber., 1979,112,2811. A. Horinaka and K. Naya, Bull. Chem. SOC.Jpn., 1979, 52, 1964. A. Horinaka, E. Yo, 0. Mori, and K. Naya, Bull. Chem. SOC.Jpn., 1979,52,2372.

86

Terpenoids and Steroids

Both (+)-nootkatone (566) and its (+)-4-isomer (565) have been synthesized from (+)-nopinone (564) (Scheme 69).307On the other hand, Hiyama et aL308 have used a completely different approach for the synthesis of nootkatone (566) (Scheme 70) which involves as a key step the acid-induced cyclopentenone annulation. In an alternative route to eremophilane and valencane sesquiterpenes, Naf et al.’09 have used a stereoselective intramolecular Diels-Alder

(565)

(566)

Reagents: i, Me,SiCl-Et,N; ii, (C,H,O),; iii, PTSA; iv, L S i M e , -TiCI,; v, NaNH,; vi, 0,; vii, Me$; viii, chrom.; ix, HCl-AcOH; x, A1203

Scheme 69 ,07 ’08

309

T. Yanami, M. Miyashita, and A. Yoshikoshi, J. Chem. SOC.,Chem. Commun., 1979, 525. T. Hiyama, M. SAinoda, and H. Nozaki, J. A m . Chem. SOC., 1979, 101, 1599; Tetrahedron Lett., 1979,3529. F. Naf, R. Decorzant, and W. Thommen, Helu. Chim. Actu, 1979, 6 2 , 114.

87

Sesqu iterpen oids M e SiO+ ,

OH -4-

'C0,Me

iiil

e

O

q

,

3o '

(566)

Reagents: i, H,O'; ii, HCECCH(0H)Me; iii, H,SO,-MeOH; iv, NaBH,-CeCI,; v, KOH; vi, MeLi; vii, Ph,P=CH,; viii, pyH+CrO,Cl-; ix, CHBr,Li; x, BuLi; xi, H 3 0 +

Scheme 70

reaction (Scheme 7 l),and suitable functional-group manipulation has resulted in the synthesis of the two known bicyclic compounds (567) and (568). An on-going investigation of the sesquiterpenoids of North Indian vetiver oil has revealed the presence of the three alcohols (569)-(571).3'0 A new and shorter synthesis of ishwarone (572) has been reported (Scheme 72).311

17 Guaiane, Pseudoguaiane, Seychellane, Patchoulane

A continuing investigation of sweet flag oil (Acorus calarnus) has resulted in the isolation and identification of calamusenone (573) and its isomer (574)together with the unusual trisnor-sesquiterpenoid (575).312Two other simple guaiane sesquiterpenoids are (576) and (577), isolated from Athanasia dregeana (DC.) Guaiazulene (578) has been synthesized by a route involving initial [6 + 41 cycloaddition of methylfulvene to the enamine of 2-isopropylcrotonaldehyde (Scheme 73).313In view of their significant biological activity, the guaianolides and pseudoguaianolides continue to be a challenging class of sesquiterpenoid for synthetic studies. Examples of such syntheses include damsinic acid (579), 31* 3'1

312 313

D. W. Karkhanis, G. K. Trivedi, and S. C. Bhattacharyya, Indian J. Chem., Sect. B, 1978,16,260. R. M. Cory, D. M. T. Chan, F. R. McLaren, M. H. Rasmussen, and R. M. Renneboog, Tetrahedron Lett., 1979, 4133. M. Rohr, P. Naegeli, and J. J. Daly, Phytochemistry, 1979, 18, 279. D. Mukherjee, L. C. Dunn, and K. N. Houk, J. A m . Chem. SOC., 1979,101,251.

Terpenoids and Steroids

88

li

tb tP

- 0 t $

'C0,Et

1

,

I

C0,Et

"C0,Et

\ "C0,Et '

(567)

'

Reagents: i, (MeO),CHNMe,; ii, 250 "C; iii, aq. PTSA; iv, NH,NHTs-H'; NaOEt; vii, MeLi; viii, SOC12-py

v,

(568)

U 4 * H

'

; vi,

0'

Scheme 71

0

0

(572) Reagents: i, MeLi; ii, pyH+CrO,Cl-; iii, Br2C:; viii, MeLi

CuLi ; iv, MCPBA; v, KOBu'; vi, H,O'; vii,

Scheme 72

89

Sesquiterpe noids

(573)

'

I

(574)

(575)

'

(577)

(576)

I

(578)

I

Reagents: i, A; ii, Pd/C, A; iii, POC1,-DMF; iv, N,H,-KOH

Scheme 73

confertin (580) (Scheme 74),314and bigelovin (582) (Scheme 75).31sThe same starting material (581) has also been used to prepare mexicanin I (583) and linifolin A (584) (Scheme 76).316The diol-lactone (586), which is closely related to the object of Grieco's work, has also been synthesized from the hydroxyketone (585).317 The Belgian group318has also synthesized neoambrosin (588), parthenin (589), and hymenin (590) starting from the known lactone (587) (Scheme 77). Estafiatin (592) has also been synthesized (Scheme 78) from the . ~ ~ ~ useful and lactone (591) which, in turn, can be derived from c u - ~ a n t o n i nOther 314

315

317

318 319

P. A. Wender, M. A. Eissenstat, and M. P. Filosa, J. Am. Chem. SOC.,1979, 101, 2196. P. A. Grieco, Y. Ohfune, and G. Majetich, J. Org. Chem., 1979, 44, 3092. P. A. Grieco, Y. Ohfune, and G . Majetich, Tetrahedron Lett., 1979, 3265. P. Kok, P. De Clercq, M. Vandewalle, J. P. Declercq, G . Germcin, and M. Van Meerssche, Tetrahedron Lett., 1979, 2063. P. Kok, P. De Clercq, and M. Vandewalle, Bull. SOC.Chim. Belg., 1978,87,615. M. T. Edgar, A. E. Greene, and P. Crabbt, J. Org. Chem., 1979,44, 159.

Terpenoids and Steroids

90

l v i , vii

1

viii

/

1

ix,

&Ao

Lo

0 (579)

CO2H

1

Reagents: i, A; ii, HOCH,CH,OH-H'; iii, pyH+CrO,Cl-; iv, LiMe,SiCHCO,Et; v, H2-Pd/Alz03; vi, H,O,-OH-; vii, Na(EtO),POCHCO,Et; viii, H,-PtO,; ix, H,O'; x, NaOH; xi, HzPd/C

Scheme 74

interesting approaches to the guaiane skeleton include the syntheses of (593),320 (594),321(595),322and (596)322and the neat method for the epimerization of the C-10 methyl group in (597).323 320 321

322 323

P. Geetha, K. Narasimhan, and S . Swaminathan, Tetrahedron Lett., 1979, 565. A. Alexakis, M. J. Chapdelaine, G. H. Posner, and A. W. Runquist, Tetrahedron Lett., 1978,4205. G. H. Posner and G. L. Loomis, Tetrahedron Lett., 1978, 4213. P. T. Lansbury and D. G. Hangauer, Tetrahedron Lett., 1979, 3623.

91

Sesq u i te rpen oids

vi, vii

--0

--0

c--

0

0

OAc (582) Reagents: i, LiAlH,; ii, MCPBA; iii, LiCH,CO,Li; iv, Li-NH,; v, H,O'; Me*NPY

vi, MnO,; vii, Ac,0-4-

Scheme 75

I i, ii

(583) R = H (584) R = O A c Reagents: i, Cr0,-H';

ii, NaBH,

Scheme 76

--0

HO

0

92

Terpenoids and Steroids

9

Q

iv-vii,

0 0

1 iii

0 0

0

4

viii

+ 0

0

0

(589)

(588)

(590)

Reagents: i, PhSeC1; ii, 0,; iii, py; iv, HOCH,CH,OH-H'; vii, TsC1-py; viii, H,O'; ix, MCPBA; x, SiOz

v, NaH-HC0,Et; vi, NaBH,;

q *q Scheme 77

iii-vi

___)

0--

0 0 I

A ;

-_-

0

0 (592)

(591) Reagents: i, NaBH,-py; ii, HMPA; iii, LDA; iv, (PhSe),; v, H,O,; vi, MCPBA

Scheme 78

93

Sesquiterpenoids

New guaian-6a,12-olides are listed in Table 5324--336 while others are illustrated in structures (598)-(610).337-342 The new pseudoguaianolides are represented by structures (611)-(619).343-349

Name Zaluzanin-C* Eupasessifolide-A Eupasessifolide-B Vernoflexin* Zaluzanin* Matricarin" Athamontanolide" Athamontanolide* Athanadregeolide

Ligustrin* Ligustrin* Euponin Elegin Santachin Preeupatundin* Preeupatundin* Lactucin Yomogiartemin

324

325

326 327 328 329

330

331 332

Double bond position ( s ) Substituents Ref. 9,lO; 11,13; 4,15 3-OAng; la,5a-H 224 10,14; 11,13; 4,15 9-OSen (and OAng); la,Sa-H 224 3,4; 11,13 2-keto; lOa,l4a-epoxy; SP-OTig 173 3,4; 11,13; 1 , l O 2-keto; 14-OH; 8P-OTig 173 4,15; 10,14; 11,13 30-Oval' 21 1 4,15; 10,14; 11,13 3-keto; 90-OH 212 3,4; 1,lO; 11,13 2-keto;, 8a-OAc 3 2,3; 4,15; 1,lO; 11,13 8a-OAc (O'Bu); 9a-OAc 166 2,3; 1,lO; 11,13 ~ c Y - O~ Hc;Y - O A~cx-OAC C; 166 2,3; 11,13 1&4P-peroxy; 10a- and lop- 166 OH; 9a-OAng CHzOH

I

3,4; 11,13; 10,14 8p-OCOC=CHCH,OH; ID-H 3,4; 10,14 8p-OH; 11a-Me; 1P-H 3,4; 1,lO 2-keto; 8a-OBz; llp-OAc 3,4; 5,6; 7 , l l ; 8,9; 1,lO 2-keto 11,13; 1 , l O 3,4-epoxy; 8-OAng; 14-OH 11,13; 10,14 3p-OH; 4a-OH; 15-Cl; 8tuOCOC(CH2)Me 394 2-keto; 1,lO-epoxy; lla-Me 11,13 2P-OAc; 3a,4a-epoxy; 5a-OH; 8P-OAng; lOP,14P-epoxy 3,4; 11,13 2P-OAc; 5a-OH; 80OAng; 10/3,14P-epoxy 3,4; 11,13; 1,lO 2-keto; 8a-OH; 15-OH 11,13 lP,2P-epoxy; 3P,4Pepoxy; 8a-OAc; 10a-OH 11,13 2a-OH; 3a,4a-epoxy; 80Oval'; 10a-OH; 2p,l4-oxido 11,13 2@-OH; 3cy,4a-epoxy; 8pOval'; 1Oa-OH 11,13 2p-OH; 3a,4a-epoxy; 8POval'; 1~ a14a-epoxy ,

117 117 324 325 326 327 328 329 329 330 331 332 332 332

V. Yu. Bagirov, V. I. Sheichenko, R. Yu. Gasanova, and M. G. Pimenov, Khim. Prir. Soedin., 1978, 810. V. Yu. Bagirov, V. I. Sheichenko, R. Yu. Gasanova, and M. G. Pimenov, Khim. Prir. Soedin., 1978,811. S. Nakajima and K. Kawazu, Heterocycles, 1978, 10, 117. I. D. Sham'yanov, A. Mallabaev, and G. P. Sidyakin, Khim. Prir. Soedin., 1978, 442. A. Mallabaev and G. P. Sidyakin, Khim. Prir. Soedin., 1978, 718. F. Bohlmann, P. Zitzkowski, A. Suwita, and L. Fiedler, Phytochemistry, 1978, 17, 2101. G. Ruban, V. Zabel, K. H. Gensch, and H. Smalla, Actu Crystullogr., 1978, B34, 1163; J. St. Pyrek, Rocz. Chem., 1977,51,2165. M. Koreeda, S. Matsueda, T. Satomi, K. Hirotsu, and J. Clardy, Chem. Lett., 1979,81. W. Herz, R. Murari, and S. Govindan, Phytochemistry, 1979,18, 1337; P. J. Cox,A. A. Freer, C. J. Gilmore, G. A. Sim, W. Herz, and R. Murari, Tetrahedron Lett., 1979, 3569.

94

Terpenoids and Steroids

Table 5-continued Zaluzanin-D* Zaluzanin-C* Achillicin Cynaratriol Centaurepensin

4,15; 11,13; 10,14 4,15; 11,13; 10,14 1,2; 4,5 10,14 10,14; 11,13

3p-OAc; 8a-OAc 333 3P-OH; 8a-OAc 333 8a-OAc; 10a-OH; l l a - M e 334 3P-OH; 4p-H; I l a - O H ; 13-0h 335 3P-OH; 4a-OH; 8a-OCOC(OH) 336 (Me)CH,CI; 1 5 4

* Derivative of.

H

0

oyJq+ 0

qR2

Ziniolide (598)224

Thieleanine (599)337

OR^ 0 Montanolide (600)338R' = H, R2= COCH=CMe2, R3= Ac Isomontanolide (601)338R' = H, R2 = Ang, R3= Ac Acetylisornontanolide (602)338R' = R3= Ac, R2= Ang Gradolide (603)339R1= H, R2 = R3= Ang Polhovolide (604)339R' = R3= Ac, R2 = COCHMe2

1

20 (606)

I

Helisplendiolide (605)340 333 334

335 336

337 338

339 340

Y. Asakawa and T. Takemoto, Phytochemistry, 1979,18, 285. C. Banh-Nhu, E. Gacs-Baitz, L. Radics, J. Tamas, K. Ujszaszy, and G. Verzar-Petri, Phytochemistry, 1979, 18, 331. H. 0 . Bernhard, K. Thiele, and E. Pretsch, Helv. Chim. Actu, 1979, 62, 1288. J. Lopez de Lerma, J. Fayos, S. Garcia-Blanco, and M . Martinez-Ripoll, Actu Crystallogr., 1978, B34, 2669; A. G. Gonzalez, J. Bermejo, J. L. Breton, G. M. Massanet, B. Dominguez, and J. M. Amaro, J. Chem. SOC.,Perkin Trans. I, 1976, 1663. S. Alvarado, J . F. Ciccio, J, Calzada, V. Zabel, and W. H. Watson, Phytochemistry, 1979, 18, 330. M. Holub, Z. Samek, S. VaSiEkova, and M. Masojidkovi, Collect. Czech. Chem. Commun., 1978,43, 2444. M . Holub, 0. Motl, and Z. Samek, Collect. Czech. Chem. Commun., 1978,43,2471. F. Bohlmann and A. Suwita, Phytochemistry, 1979, 18, 885.

95

Sesquite rpen oids

0

--0

--0

0 Mikanokryptin (607)341

Puberolide (608)’

H

HO’.

Chrysostomalide acetate (609)342

Pleniradin (610)204

qo qo

Qo

OH

Desacetyl-isobigelovin (611)’

( 6 1 5 ) ~R ~ ’= H or O H 2,3-Dihydro-aromatiCin derivatives

0r3

Multigilin (612)343R’= OH, R2 = H, R3= Ang Multistatin (613)343R’,R2 = 0, R3= Ang Helenalin methacrylate (6 14)344 R’= R2= H, R3= COC=CH2

0 %

9

Tigo

OH

0

(616)346Autumnolide derivative

“0

0 (617)347 Stramonin B 341

342 343 344 345

346

347

M. J. Bovill, M. H. P. Guy, G. A. Sim, D. N. J. White, and W. Herz, J. Chem. Soc., Perkin Trans. 11, 1979,53. F. Bohlmann and C. Zdero, Phytochemistry, 1978,17, 2032. G. R. Pettit, C. L. Herald, D. Gust, D. L. Herald, and L. D. Vanell, J. Org. Chem., 1978,43, 1092. H. D. Herrmann, G. Willuhn, and B. M. Hausen, Planta Med., 1978,34, 299. F. Bohlmann and P. K. Mahanta, Phytochemistry, 1 9 7 9 , 1 8 , 8 8 7 . H. Furukawa, M. Itoigawa, N. Kumagai,K. Ito, A. T. McPhail, and K. D. Onan, Chem. Pharm. Bull., 1978,26,1335. P. A. Grieco, T. Oguri, S. Burke, E. Rodriguez, G. T. DeTitta, and S . Fortier, J. Org. Chem., 1978, 43, 4552; S. Fortier, G. T. DeTitta, and P. A. Grieco, Acta Crystallogr., 1979, B35, 1742.

96

Terpenoids and Steroids

---L -0

Pulicariolide (619)349

Microlenin (618)348

In an attempt to induce a rearrangement to give the pseudoguaianolide (621) the epoxy-alcohol (620) was treated with boron trifluoride etherate. An X-ray analysis, however, has shown that one of the major products is the fluoro-alcohol (622).350A number of new xanthanolides, grafininacetate (623), desacetylxanthanol (624), and xanthanolacetate (625) have been isolated from Pulicaria These compounds co-occur with the unusual seco-eudesmane sesquiterpenoid, secocrispiolide (626).

0

0

In an examination of the mechanism of the solvolysis of the tricyclic alcohol (627) which led to the successful synthesis of seychellene (628), F r ~ i t e r has ~~l shown that the minor product is the tricyclic olefin (629) which is formed by the process depicted in Scheme 79. An alternative synthesis of seychellene (628) and patchouli alcohol (635) depends upon the construction of the key tricyclic ketol (631) by an intramolecular Michael reaction followed by an aldol cyclization of (630) (Scheme The minor ketol (632) can be converted into epi-sey348 349

350 351 352

Y. Imakura, K. H. Lee, D. Sims, and I. R. Hall, J. Pharm. Sci., 1978, 67, 1228. F. Bohlmann, K. H. Knoll, and N. A. El-Emary, Phytochemistry, 1979,18, 1231. F. R. Fronczek, J. Chem. SOC.,Perkin Trans. II, 1979, 195. G . FrPter, Helv. Chim. Acta, 1979,62, 1893. K. Yamada, Y. Kyotani, S. Manabe, and M. Suzuki, Tetrahedron, 1979, 35, 293.

97

Sesq u iterpe noids

(629)

Scheme 79

a aoMe /$joMx:xii+ GOH I ii, iii

G o M : v - v f-i

_ iv,vii I_,

viii,ix

__3

x

(635) Reagents: i, Bu'OK; ii, Zn-HCl; iii, Cr0,-py; iv, LDA; v, MOO,-py-HMPA; vi, NaH-MeI; vii, MeI; viii, MeLi; ix, SOCI,-py; x, CH,N,-Cu"; xi, H,-Pt0,-AcOH; xii, Cr0,-AcOH

Scheme 80

chellene (633).353Another synthesis of the important tricyclic ketone (634) has also been reported recently.354The main odoriferous constituent of patchouli oil, norpatchoulenol(636), has been synthesized by a route employing an intramolecular Diels-Alder reaction (Scheme 8 1).355 353 354

355

K. Yamada, Y. Kyotani, S. Manabe, and M. Suzuki, Bull. Chem. SOC.Jpn., 1978,51,3405. D. Spitzner, Tetrahedron Lett., 1978,3349. W.Oppolzer and R. L. Snowden, Tetrahedron Lett., 1978,3505.

98

Terpenoids and Steroids

- OGsiM y Reagents: i,

Et,SiO viii, MeLi

(636)

Li' ; ii, Me,SiCl; iii, KF; iv, 230°C; v, H,O';

vi, H,-PtO,; vii, TsNHNH,;

Scheme 81

Thomas and O ~ a i n n e ~have ' ~ published the full details of the reaction of patchouli alcohol (635)with lead tetra-acetate which produces the bicyclic ketone (637) as a major product. This ketone is the source of a number of interesting rearrangements as outlined in Scheme 82. What is particularly intriguing about

1

ii

ii

Reagents: i, Pb(OAc),; ii, PTSA; iii, LiAlH,

Scheme 82 356

A. F. Thomas and M. Ozainne, Helu. Chim.Acta, 1979, 62, 361.

Sesquiterperi o ids

99

this work is that Bohlmann and 2 d e r 0 ~ ~have ’ recently isolated (from Trixis species and from the tribe Mutisieae) a large number of sesquiterpenoids which have precisely the same carbon skeleton as (638). The simplest compounds are (639) and (640), but another twenty-two more heavily oxygenated compounds have also been identified, e.g. (641) and (642), the latter being named trixikingolides. It has been that this new carbon skeleton should be referred to as isocedrane but it seems to this author that this name is inappropriate because ( a ) this name has already been used in cedrane chemistry and ( b ) it is most unlikely that there is a common biogenetic link between the cedrane and OAc

(639) R = M e (640) R = C H O

‘isocedrane’ sesquiterpenoids. It is therefore suggested that a new name should be adopted for this new and interesting class of sesquiterpenoids. Another new tricyclic sesquiterpenoid is pardalianchol(644), which has been isolated from the ~ ~ been suggested that roots and aerial parts of Doronicurn p a r d a l i a n c h e ~It. ~has this novel carbon skeleton could be derived by rearrangement of a mexicanin D type compound (643).

A comprehensive review of the sesquiterpenoid lactones from various species of the genus Arternesia has been

18 Aromadendrane, Maaliane A reinvestigation of the structures of the two marine metabolites lemnalactone and 7-epilemnalactone has resulted in definitive evidence in favour of (645) and (646) re~pectively.~~’ The three aromadendrane sesquiterpenoids (647)-(649) 357

358 359

360

F. Bohlmann and C. Zdero, Chem. Ber., 1979,112,427,435; F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979,18, 855. F. Bohlmann and W. R. Abraham, Phytochemistry, 1979,18, 668. R. G. Kelsey and F. Shafizadeh, Phytochemistry, 1979, 18, 1591. A. Ahond, A. Chiaroni, J. C . Coll, J. D. Fourneron, C . Riche, J. C. Braekman, D. Daloze, B. Tursch, and P. J. Dunstan, Bull. SOC.Chim. Belg., 1979,88,313; A. Ahond, J. C. Coll, and J. D. Fourneron, Tetrahedron Lett., 1979, 1879.

Terpenoids and Steroids

100

have been identified in various Helichrysum species.361Two of the sesquiterpenoid components of the soft coral Sinularia mayi are the diols (650) and (65 l), which are almost enantiomeric.log

(648) R' = OAc, R2= H (649) R1 = H, R2= OAc

A continuing investigation of the sesquiterpenoids from liverworts (Plagiochila species) has revealed the presence of more seco-aromadendrane compounds, namely plagiochilines A (652), B (653), C (654), D (655), E (656), and F (657).362,363 Plagiochilide (658) has been found in the Swiss species of P. asplenioides but not in the French version.364The presumed precursor of these compounds, (-)-bicyclogermacrene (659), has also been identified in the extracts AcO

AcO

i ;

.OAc

\

R2 (652) R' = R2 = H (653) 'R'= OAc, R2 = H (655) R1 = R2= OAc

(656)

OAc

(657) 361

362 363 364

F. Bohlmann, C. Zdero, E. Hoffmann, P. K. Mahanta, and W. Dorner, Phytochemistry, 1978,17, 1917. Y. Asakawa, M. Toyota, and T. Takemoto, Phytochemistry, 1978,17, 1794. Y. Asakawa, M. Toyota, T. Takemoto, and C. Suire, Phytochemistry, 1979, 18, 1355. R. Mues, N. Ohno, H. D. Zinsmeister, and T. J. Mabry, Phytochernistry, 1979, 18, 1568.

Sesquiterpenoids

101

of these liverworts. Full details of the X-ray structural analysis of another interesting liverwort constituent, myliol (660), have been In a synthetic approach to the seco-aromadendrane taylorione (66l), Pattenden et ul.366have studied the photochemistry of the two geometrical isomers (662).Both undergo a di-.rr-methane rearrangement to produce (663),which could be further elaborated to (664) by a Wittig reaction.

19 Miscellaneous Further studies on the metabolites of the liverwort Porellu platyphylla have resulted in the isolation and structural determination of three more pinguisanetype sesquiterpenoids, namely pinguisanin (665), pinguisanolide (666), and p-pinguisenediol (667).367A very neat synthesis of the unusual sesquiterpenoid

isocomene (668) has been reported (Scheme 83).368The important step in this synthesis is the intramolecular thermal ene reaction to construct the basic tricyclic framework of the sesquiterpenoid. Two independent syntheses of 9-isocyanopupukeanane (670) have been accomplished. The first one (Scheme 84)369relies upon a key intramolecular alkylation step whereas the second one (Scheme 85)’” is based upon an intramolecular Diels-Alder reaction to form the tricyclic skeleton. The related marine metabolite 2-isocyanopupukeanane (67 1)has also been synthesized using 365 366

367 368 369

370

H. Nozaki, J. Chem. SOC.,Perkin Trans. II, 1979, 514. G . Pattenden and D. Whybrow, Tetrahedron Lett., 1979, 1885. Y . Asakawa, M. Toyota, and T. Takemoto, Phytochemistry, 1979,18,1349. W. Oppolzer, K.. Battig, and T. Hudlicky, Helu. Chim. Acta, 1979,62, 1493. E. J. Corey, M. Behforouz, andM. Ishiguro, J. A m . Chem. SOC.,1979,101,1608 H. Yamamoto and H. L. Sham, J. A m . Chem. SOC.,1979,101,1609.

Terpenoids and Steroids

102

iii, iv

,vi-viii

C0,Me e-

9 0

l x , xi

xii-xiv

SeAr

(668) Reagents: i, NaOMe; ii, Bu'OK; iii, Am'OK; iv, MeI; v, 280 "C; vi, H,-Pt; vii, Bu'OK-AmONO; viii, NaOCl-NH,; ix, hv, MeOH; x, LiAlH,; xi, ArSeCN-Bu,P-py; xii, NaIO,; xiii, 80°C; xiv, PT9A

Scheme 83

CO H

CO Me IV-v1

1-111

vii

,OTs

0

+o e---

t-

t

.

H

A H

(670) Reagents: i, TsMic-Bu'OK; ii, KOH-H,O,-H,O-EtOH; iii, CH,N,; iv, LDA; v, MeI; vi, BBr,; yii, Pt-Rh-H,-H+; viii, LiAlH,; ix, TsC1-py; x, pyH'CrO,CI-; xi, Bu'OK; xii, NH,OHCI-; xiii, Pt-Rh-H,; xiv, HC0,COMe; xv, MsC1-py

Scheme 84

Sesquiterpenoids

103

iii, iv ___,

V,

ii, vi, vii

I

A Reagents: i, 160 "C; ii, H,O+; iii, HOCH,CH,OH-H'; vii, H2-Ir

iv, Me,S-NCS; v, YLi ; vi, MsCl-Et,N;

Scheme 85

1

v, vi, iii

A

h (671)

Reagents: i, LiAlH,; ii, NBS-aq. DME; iii, pyH'CrO,Cl-; iv, K,CO,; v, HSCH,CH,SH-BF,; Raney Ni; vii, NH,OHCl-; viii, Pt-Rh-H,-H'; ix, HC0,COMe; x, MsC1-py

vi,

Scheme 86

the tricyclic lactone (669) (Scheme 86).371In this case the final ring closure was achieved by an intramolecular aldol condensation. Further additions to the ever-increasing number of marine sesquiterpenoids of unusual structure are brasilenol (672) and epibrasilenol (673).372These two compounds were isolated from the digestive glands of the sea hare Aplysia brasiliana. It has been established that they are also metabolites of the alga 371 372

E. J. Corey and M. Ishiguro, Tetrahedron Lett., 1979, 2745. h l . 0. Stallard, W. Fenical, and J. S. Kittredge, Tetrahedron, 1978, 34,2077.

Terpenoids and Steroids

104

Laurencia, the diet of the marine molluscs. Examples of capnellane sesquiterpenoids isolated from the soft coral Cupnella irnbricata continue to emerge. The latest additions are the tetrol (674)373and precapnelladiene (675).374The latter is considered to be the bicyclic precursor of the tricyclic capnellane group, the simplest of which is A9(12)-capnellene(676). Closely related to the diene (675) is dactylol (677), which has been isolated both from the sea hare Aplysia dactylomela and from its dietary source, the red seaweed Laurentia ~ o i t e i . ~ ~ ’ OH

A

A

How : H

HO

Although isocomene (668), mentioned above, is included in this section it is likely that this hydrocarbon, together with modhephene (679), is derived from a caryophyllene-type precursor. Indeed one can conceive of a biogenetic pathway (Scheme 87) which encompasses both these compounds as well as botrydial (681),376quadrone (682),377and the recently isolated senoxydene (304).148 To lend partial credence to this scheme is the fact that the hydrocarbon (680) is a product of acid-catalysed rearrangement of isocaryophyllene (678).378

373

374

375 376

377

378

M. Kaisin, B. Tursch, J. P. Declercq, G. Germain, and M. Van Meerssche, Bull. SOC.Chim. Belg., 1979,88, 253. E. Ayanoglu, T. Gebreyesus, C. M. Beechan, and C . Djerassi, Tetrahedron,1979, 35, 1035. F. J. Schmitz, K. H. Hollenbeak, and D . J. Vanderah, Tetrahedron, 1978, 34, 2719. H.-W. Fehlhaber, R. Geipel, H.-J. Mercker, R. Tschesche, and K. Welmar, Chem. Ber., 1974,107, 1720. R. L. Ranieri and G. J. Calton, Tetrahedron Lett., 1978,499. K. Gollnick, G. Schade, A. F. Cameron, C. Hannaway, J. S. Roberts, and J. M. Robertson, J. Chem. SOC.,Chem. Commun., 1970,248.

Sesq uite rpenoids

105 \

c

-Q

H

7

$p +$A

CHO CHO

\

'

(668)

Scheme 87

I

Diterpenoids BY J. R. HANSON

1 Introduction This chapter follows the pattern of previous Reports with sections based on the major skeletal types of diterpenoids. The literature that has been covered was that available to August, 1979. There have been a number of novel diterpenoid structures described during the year. The diterpenoids must now rival the sesquiterpenoids in their variety of skeleta. The absolute configuration of clerodin has now been revised with consequent ramifications in the configuration assigned to a number of other diterpenoids. Another notable advance during the year has been the total synthesis of gibberellic acid. Several useful reviews of diterpenoid chemistry have appeared.’ A collection of the 13Cn.m.r. data of diterpenoids has been made.* In recent years the extraction of Australian marine organisms has yielded some new diterpenoids. These have now formed the subject of a re vie^.^

2 Acyclic and Related Diterpenoids The olefin (E,E)-7,11,15-trimethyl-3-methylenehexadeca-l ,6,10714-tetraene (P-springene), which is the diterpenoid analogue of p-farnesene, has been isolated4 from the dorsal gland of the springbok. The alcohol (l),which shows anti-peptic ulcer activity, has been obtained’ from the ‘l‘hai medicinal plant Croton sublyratus (Euphorbiaceae) whilst the acid centipedic acid (2) is amongst the diterpenoid constituents of Centipeda orbicularis (Compositae).6 Peucelinendiol (3),a minor component of Peucedanum oreoselinum (Umbelliferae),7 may be an irregular diterpenoid formed by the head-to-head combination of two geranyl units. The Mexican plant zoapatle (Montanoa tomentosa) has been used in folk medicine as an abortifacient. Two unusual biologically active cyclic ethers, zoapatanol (4)and montanol ( 5 ) , have now been obtained8 from the plant.

‘

E. Fujita, K. Fuji, Y. Nagao, and M. Node, Bull. Inst. Chem. Res., Kyoto Univ., 1977,55,494; 1978, 56,11 1, 356. F. W. Wehrli and T. Nishida, Fortschr. Chem. org. Naturstoffe, 1978, 36, 1. R. J. Wells, Pure A p p l . Chem., 1979, 51, 1829. B. V. Burger, M. Le Roux, H. S. C . Spies, V. Truter, and R. C. Bigalke, Tetrahedron Letters, 1978, 5221. ’ A. Ogiso, E. Kitazawa, M. Kurabayashi, A. Sato, S. Takahashi, H. Noguchi, H. Kuwano, S. Kobayashi, and H. Mishima, Chem. and Pharm. Bull. (Japan),1978,26,3117. F. Bohlrnann and P. K. Mahanta, Phytochemistry, 1979,18, 1067. E. Lemmich, Phytochemrstry, 1979, 18, 1195.

’

106

Diterpenoids

107

C02H

R Me

(4)R = Me2C=CHCH2 Me I ( 5 ) R = Me2CH-C=CH

The a-cyclogeraniol skeleton has been assigned to magydardiendiol(6), which was isolated' together with the corresponding lO(20)-olefin and 17-acetate from Magydaris panacifolia (Umbelliferae). The geranyl-a-terpinene derivatives helicallen-16-01(7) and -16-a1 (8) are amongst" the constituents of Helichrysum calliconum (Compositae).

(7) R (8) R

= =

CH20H CHO

3 Bicyclic Diterpenoids Labdanes.-The cis- and trans-isomers of (-)-ozic acid (9) have been isolated'' from the wild sunflower, Helianthus occidentalis (Compositae). Their presence in this plant may be associated with resistance to insect attack. The diene S. D. Levine, R. E. Adams, R. Chen, M. L. Cotter, A. F. Hirsch, V. V. Kane, R. M. Kanojia, C. Shaw, M. P. Wachter, E. Chin, R. Huettemann, P. Ostrowski, J. L. Mateos, L. Noriega, A. Guzman, A. Mijarez, and L. Tovar, J. Amer. Chem. Soc., 1979, 101,3404. J. de Pascual Teresa, C. Grande, and M. Grande, Tetrahedron Letters, 1978,4563. l o F. Bohlmann and W. R. Abraham, Phytochernistry, 1979, 18, 889. l 1 R. D. Stipanovic, D. H. O'Brien, C. E. Rogers, and,T. E. Thompson, J. Agric. Food Chem., 1979,27, 458.

Terpenoids and Steroids

108

6-deoxyandalusol(lO) has been obtained'* from Sideritis arborescens (Labiatae) and its structure proven by spectral studies. The 9-hydroxylabdane (11)has been isolated13 from Bishovia boliviensis (Compositae) whilst the trio1 carterothaminotriol (12) and its 14-epimer, together with the unusual 8(12)-ether carterochaetasic acid (13) and the corresponding alcohol (14), were found14 in Carterothamnus anomalochaeta (Compositae).

(13) R (14) R

= =

COZH CH20H

The structure of the epoxy-dialdehyde ( 1 3 , from Afromomum daniellii (Zingiberaceae), was e~tablished'~ by correlation with cis-12-norambreinolide. The hydroxy-acid (16), salvic acid from Eupatoriurn salzlia,16 and the ring B seco-labdane jhanic acid ( 17)17 from Eupatorium jhanii are two further diterpenoids from these species of the Compositae. The structure of the latter rests on interpretation of the 'H and 13C n.m.r. data. Gutierrezia lucida (Compositae) contains" the 13-epimeric acids (18) related to agathic acid together with the butenolide (19). Some esters of 6-hydroxylabdane-17-carboxylicacids were detected in G. mandonii. The investigation of Cistus species has continued. The ent-labdane acetyl-laurifolic acid (20) is a component of Cistus laurifolius." The 13Cn.m.r. spectra of lagochilin (21) and some derivatives are consistent2' with the proposed structure. A butenolide, evillosin, which was isolated from Eupatorium uillosum (Compositae), was assignedz1 the structure (22) from an B. Rodriguez and C. von Carstenn-Lichterfelde, Anales de Quim., 1979, 75, 110. F. Bohlmann, C. Zdero, R. M. King, and H . Robinson, Phytochemistry, 1979,18, 1234. l4 F. Bohlrnann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979,18,621. l 5 S. F. Kimbu, T. K. Njirni, B. L. Sondengam, J. A. Akinniyi, and J. D. Connolly, J.C.S. Perkin I, 1979, 1303. l 6 M. Hoeneisen, P. G. Sammes, M. de Silva, and W. H. Watson, Rev. Latinoamer. Quim., 1979,10,37. l7 A . G . Gonzalez, J. M. Arteaga, B. M. Fraga, and M. G . Hernandez, Anales de Quim., 1979,75128. F. Bohlrnann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1979, 18,1533. l 9 J. de Pascual Teresa, J. G. Urones, and F. Bermejo Gonzalez, Anales de Quim., 1978,74, 1540. '' Z . I. Mavlyankulova, U. N. Zainutdinov, S. I. Mukhamedkhanova, V. B. Leont'ev, and Kh. A. Aslanev, Khim. prirod. Soedinenii, 1979, 41. 21 P. S. Manchand, J. F. Blount, T. McCabe, and J. Clardy, J. Org. Chem., 1979, 44, 1322.

l2

Diterpenoids

109

X-ray analysis and the c.d. curve of the 3-ketone. In the past few years, the examination of Ballota species (Labiatae) has afforded a number of new diterpenoids related to marrubiin. The furan hispanolone (23) has been obtainedz2 from B. hispanica whilst 18-hydroxyballonigrin (24) was isolated23 from B. acetobulosa and B. lanata affordedz4 13-hydroxyballonigrinolide (25). An examination of Marrubium species, including M. sericeum, M. supinum, and M. alysson aff ordedZ56-acetyl- and 19-acetyl-marrubenol, premarrubenol(26), and 6 -ace tylpremarrubenol. Calyone (27) and precalyone (28), the latter showing tumour inhibitory activity, have been isolatedz6from Roylea calycina (Labiatae), and coleosol(29) is a manoyl oxide derivative which has been isolated from another of the Labiatae used in folk medicine, Coleus f o r ~ k o h l i i . ~ ~ The investigation of potential perfumery compounds from manool has continued with the preparationz8of some 12-methylene derivatives [e.g. (30)]. A relatively stable ozonide (31) has been from manool. The crystal structure of the ruthenium tetroxide oxidation product (32) obtained from manool has been determined.30The sulphur derivatives of the perfumery acetals obtained from manool have been prepared.31 22 23 24 25

26

27 28

29 30

31

G. Savona, F. Piozzi, and B. Rodriguez, Heterocycles, 1978, 9, 257. G. Savona, F. Piozzi, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1978, 1271. G. Savona, F. Piozzi, and J. R. Hanson, Phytochemistry, 1978,17, 2132. G. Savona, F. Piozzi, L. M. Aranguez, and B. Rodriguez, Phytochemistry, 1979,18,859. 0 .Prakash, D. S. Bhakuni, R. S. Kapil, G. S. R. Subba Rao, and B. Ravindranath, J.C.S. Perkin I, 1979, 1305. P. K. Jauhari, S. B. Katti, J. S. Tandon, and M. M. Dhar, Indian J. Chem., 1978, 16B,1055. P. K. Grant and C. K. Lai, Austral. J. Chem., 1978, 31, 1785. P. K. Grant and H. T. L. Liau, Austral. J. Chem., 1978, 31, 1791. I. M. Godfrey, J. R Knox, C. L. Raston, and A. H. White, Austral. J. Chem., 1979,32, 205. P. K. Grant and H. T. L. Liau, Austral. J. Chem., 1978, 31, 1777.

do Terpenoids and Steroids

110

CH,CH,OH

HO' H

HOCH,

'0Ac

(22)

@cJ@Jo

&LJ R

H (23) R (27) R

OH

H OH C = =

H OAc

'*

co-0 (24)

6

co-0 (25)

( J x J $

AcO

HOCH2

OH

OH

Relhaniaic acid ( 3 3 ) from Relhania acerma (Compositae) represents a partial rearrangement to a clerodane derivative. However, the stereochemistry at C-9 is unusual bearing in mind the configuration at C-8 and the co-occurrence of the ent-labdane (34). A group of ent-l0,9-friedo-labdanes, including hydrohalimic acid (35) and the corresponding 2P-alcohol (36), have been ~ e p a r a t e das~ ~their methyl esters from extracts of Halimium viscosum (Cistaceae). C1erodanes.-Possibly because of near-octant effects, the c.d. curve of clerodane 6-ketones may not be a reliable guide to the absolute stereochemistry of this 32

33-

F. Bohlmann and J. Jakupovic, Phytochemistry, 1979, 18, 631. J . de Pascual Teresa, J. G . Urones, H. Carillo Sanchez, and M. A. Gonzalez Munoz, Andales de Quirn., 1979, 75, 140.

111

Diterpenoids

(35) R (36) R

= =

H OH

series. The absolute stereochemistry of 3-epicaryoptin and clerodin has been reassigned34y35 to (37) and (38). This has led to a revision of the stereochemistry assigned to a number of clerodanes. A new terminology has been proposed. Thus compounds formerly assigned the ent-clerodane stereochemistry are now known as neo-clerodanes. Teuflin, from Teucrium fravum (Labiatae) has been assigned36 the stereochemistry (39) epimeric at C-10 to teucvidin on the basis of an X-ray analysis. Isocrotocaudin (40) from Croton caudatus (Euphorbiaceae) is an 11(12)dehydro-derivative which is similar to crotocaudin and teucvidin. The c.d. curves of the @-unsaturated lactones have been used to assign the absolute stereochemistry in this series. Plaunol A (41) and plaunol B (42) are anti-ulcer diterpenoid lactones which have been isolated38from the Thai medicinal drug Croton subfyrutus (Euphorbiaceae). Baccharis genistefloides (Compositae) has afforded39 a clerodane dilactone (43) similar to that isolated previously from B. trim era. Montanin D is a new furanoid diterpenoid isolated from Teucrium montanum (Labiatae)40 to which the clerodane structure (44) has been assigned. The full paper has appeared41 on the teucrins HI-H4, (45)-(48), which were isolated4* from T. hyrcanicum. The mass spectral fragmentation pattern of these diter34

35

36

37 38

39 40 41

42

N. Harada and H. Uda, J. Amer. Chem. Soc., 1978, 100, 8022. D. Rogers, G. G. Unal, D. J. Williams, S. V. Ley, G. A. Sim, B. S. Joshi, and K. R. Ravindranath, J.C.S. Chem. Comm., 1979, 97. G. Savona, M. P. Paternostro, F. Piozzi, J. R. Hanson, P. B. Hitchcock, and S. A. Thomas, J.C.S. Perkin I, 1979, 1915. A. Chatterjee, A. Banerjee, and F. Bohlmann, Phytochemistry, 1978, 17, 1777. E. Kitazawa, A. Ogiso, S. Takahashi, A. Sato, M. Kurabayashi, H. Kuwano, T. Hata, and C. Tamura, Tetrahedron Letters, 1979, 1117. F. Bohlmann, W. Knauf, R. M. King, and H. Robinson, Phytochemistry, 1979, 18, 1011. P. Y. Malakov, G. Y. Papanov, and N. V. Mollov, Z . Naturforsch., 1978,33b, 1142. E. Gacs-Baitz, L. Radics, G. B. Oganessian, and V. A. Mnatsakanian, Phytochemistry, 1978, 17, 1967. G. B. Oganesyan and V. A. Mnatsakanyan, Armyan. Khim. Zhur., 1978,31,768 (Chem.Abs., 1979, 90, 168 775); ibid., p. 776 (Chem. Abs., 1979,91, 20 772).

Terpenoids and Steroids

112

A

H

o $ $ .

(37) R = OAc (38) R = H

0 (39)

"H

penoids has been a n a l y ~ e dGnaphalin .~~ (49) and its 19-acetate (= teucrin H3), together with the lactol-acetate gnaphalidin, were from T. gnaphalodes. The retro-aldol loss of C-19 from (49) and the formation of the 18-6 furan ring in the presence of base suggests a biogenetic relationship with montanin A and thence, by oxidation, to the teucvin series of lactones. Leonurus cardiac (Labiatae) contains some diterpenoids which have been provisionally assigned45 clerodane structures such as (50). Diasin (51) is a cis-labdane related to the clerodanes which has been isolated from Croton diasii (Euphorbiaceae). Its structure was determined46 by 'H and 13C n.m.r. spectroscopy. A series of furanoid nor-diterpenoids has been isolated from Dioscorea bulbifera (Dioscoreaceae). The structures of the diosbulbins D, E, F, G, and H, (52)-(56), were determined47 by a series of spectral and chemical studies and that of diosbulbin G (55) was confirmed4' by an X-ray analysis. Splendidin (57) is a new trans-clerodane, related to salviarin, which has been isolated49from Salvia splendens (Labiatae). Its structure and relative configuration rest on detailed spectral studies. A further series of trans-clerodane lactones 43 44

45 46

47

48 49

V. A. Mnatsakanyan and G . B. Oganesyan, Khim. prirod. Soedinenii, 1978,727. G . Savona, M. P. Paternostro, F. Piozzi, and B. Rodriguez, Tetrahedron Letters, 1979, 379. C. H. Brieskorn and R. Hofmann, Tetrahedron Letters, 1979, 2511. M. A. d e Alvarenga, H. E. Gottlieb, 0. R. Gottlieb, M. T. Magalhaes, and V. 0. da Silva, Phytochemistry, 1978, 17, 1773. Y. Ida, S . Kubo, M. Fujita, T. Komori, a n d T . Kawasaki, Annalen, 1978, 818. Y. Ida, T. Komori, and T. Kawasaki, Annalen, 1978,834. G . Savona, M. P. Paternostro, F. Piozzi, and J. R. Hanson, J.C.S. Perkin I, 1979, 533.

Diterpenoids

113

@

0

HO

HO

(44)

OR (47) R = Ac (49) R = H

FHH p P

(52) R = 0 (53) R = &-OH

p

p (54) R = Me ( 5 6 ) R = Bu

O

P

(55)

O

114

Terpenoids and Steroids

has been obtained“) from Nidorella species (Compositae). These include nidorellalactone (SS), isonidorellalactone (59), and methyl nidoresedate (60) from N. residifolia. The 5( 10)-seco-acid seconidoresedic acid (strictic acid) (61j has also been isolated” from Conya stricta (Cornpositae). The structure of the trans-clerodane dicarboxylic acid haplociliatic acid (62), obtained from Haplopappus ciliatus, was established by X-ray analysis. The presence of the known diterpenoid cis-kolavenic acid has been noted53in several members of the tribe Eupatorieae. Some cis-clerodanes [e.g. ( 6 3 ) ] have been from the Brazilian Compositae, including Symphiopappus itatiayerzsis.

0

4 Tricyclic Diterpenoids

Naturally Occurring Substances.-The hydrocarbons from the oil of Juniperus sabina berries contain55the homoannular abieta-8,9: 13,14-diene, palustradiene, which readily forms an endoperoxide. The structure of ibozol (64), which was obtained from Iboza riparia (Labiatae), was assigned” by examination of its I3C n.m.r. spectrum. A methylenetanshinquinone (65) has been describeds7 as a 511 51

52

53 54

52

56

57

F. Bohlrnann and U. Fritz, Phytochemistry, 1978, 17, 1769. S. Tandon and R. P. Rastogi, Phytochemistry, 1979, 18,494. M. L. Bittner, V. Zabel, W. B. Smith, and W. H. Watson, Phytochemistry, 1978, 17, 1797. F. Bohlrnann, P. Zitzkowski, A. Suwita, and L. Fiedler, Phytochemistry, 1979, 17, 2101. W . Vischnewski, R. Murari, and W. Herz, Phytochemistry, 1979, 18, 129. J. de Pascual Teresa, A. F. Barrero, M. C. Caballero, and A. San Feliciano, Anales de Quim., 1978, 74, 1093. R. Zelnik, E. Rabenhorst, A. K. Matida, H. E. Gottlieb, D. Lavie, and S. Panizza, Phytuchemsitry, 1978,17, 1795. M.-K. Chien, P.-T. Young, W.-H. Ku, Z . - X . Chen, H. T. Chen, and H. C. Yeh, Hua Hsueh Hsueh Pao, 1978, 36, 199 (Chem. Abs., 1979,90, 138 047).

115

Diterpenoids

constituent of the Chinese drug Tan-shen. Several diterpenoids related to ferruginol have been detected's359in Chamaecyparispisiferu. These include the C-20 carboxylic acid of ferruginol (pisiferic acid) and the corresponding alcohol. The C-15 configuration of the naturally occurring pimara-l5,16-diols kirenol (66) and darutigenol (67) have been assigned6' through a series of n.m.r. studies of the 8,15-furans. The changes in the 13C n.m.r. spectrum on glucosylation indicated6' the location at C-3 of the glucose moiety in darutoside. A number of known 8P, 110- and 12P-hydroxylated sandaracopimaranes have been isolated62 from Chrysanthemoides (Compositae) species, and Palafoxia rosea contains63 a series (68)-(72) of hydroxylated pimaranes.

(66) R1 (67) R'

$

= =

R3 = O H , R2 = H R3 = H , R 2 = OH

CH(OH)CH,OH

R1**

R2 (68) R' = OH,R2 = CH20H,R3 = H (69) R' = O H , R 2 = Me,R3 = H

R

l

*

~

~

c

~

R2 (70) R' (71) R' (72) R'

= = =

O H , R 2 = Me,R3 = OH O H , R 2 = Me,R3 = H H , R2 = Me,R3 = OH

'' H. Fukui, K. Koshimizu, and H. Egawa, Agric. and Biol. Chem. (Japan), 1978, 42, 1419. 59

6o 61 62 63

M. Yatagai and T. Takahashi, Phytochemistry, 1979, 18, 176. E. Wenkert, P. Ceccherelli, M. S. Raji, J. Polonsky, and M. Tingoli, J. Org. Chem., 1979, 44, 146. J. H. Kim, K. D. Han, K. Yamasaki, and 0. Tanaka, Phytochemistry, 1979, 18, 894. F. Bohlmann and M. Grenz, Phytochemistry, 1979,18, 683. F. Bohlmann and H. Czerson, Phytochemistry, 1979, 18, 115.

(

~

116

Terpenoids and Steroids

Two further cytotoxic nor-diterpenoid dilactones, (73) and (74), have been isolated64from Podocarpus nagi. Nagilactone F ( 7 5 ) has been synthesized6' from podocarpic acid. Two unusual diterpenoids, hispanonic acid (76) and hispaninic acid (77), both of which possess a seven-membered ring C , have been isolated66 from Ballota hispanica (Labiatae). Some naphthalenic nor-diterpenoids [e.g. (78)] with the cleistanthane skeleton have been isolated6' from Vellozia stipitata and V. declinans.

& d.. OH

0

111 oc -0

R

*<'

.*.-

(73)

oc-0 (74) R = OH (75) R = H

Chemistry of the Tricyclic Diterpenoids.-The 13Cn.m.r. spectra of abietic acid and its methyl este? and of a series of primarane epoxides have been Carbon-13 n.m.r. spectroscopy may play a role in the stereochemical assignment at C-13 in the pimaradiene~.~' The effect of borate ester formation on the 13C n.m.r. spectra of diols has been examined71 in the case of jesromotetrol. The X-ray analysis of the y-lactone (79) formed by acid treatment of dihydroisopimaric acid has that it possesses a trans A/B ring junction, in contrast to some previous structural assignments. The solvolysis of virescenol B 64 65

66

67 68 69

O' 71

72

Y. Hayashi, T. Matsumoto, and T. Sakan, Heterocycles, 1978,10, 123. Y. Hayashi, T. Matsumoto, T. Hyono, N. Nishikawa, M. Uemura, M. Nishizawa, M. Togami, and T. Sakan, TetrahedronLetters, 1979, 3311. B. Rodriguez, G . Savona, and F. Piozzi, J. Org. Chem., 1979, 44, 2219. A . da Cunho Pinto, R. Pinchin, D. H. T. Zocher, and C. C. Lopes, TetrahedronLetters, 1979,405. W. B. Smith, Org. Magn. Resonance, 1978, 11, 427. B. Delmond, B. Papillaud, J. Valade, M. Petraud, and B. Barbe, Org. Magn. Resonance, 1979, 12, 209. R. Beier, Org. Magn. Resonance, 1978, 11, 586. W. B. Smith, J. Org. Chem. 1979, 44, 1631. W. Herz and J. F. Blount, J. Org. Chem., 1979, 44, 1172 (cf. J. W. ApSimon, A . M. Holmes, H. Beierbeck, and J. K. Saunders, Canad. J. Chem., 1976,54,418).

Diterpenoids

117

19-toluene-p-sulphonate (80) the rearrangement products (81) and (82). The photochemistry of N-acylimidazole derivatives of dehydroabietic acid leads7* to the formation of some 6-substituted derivatives. The ozonolysis of phenolic dehydroabietic acid derivatives has been examined75 as a route to drimane sesquiterpenoids. A series of diterpenoid epoxides related to triptolide has been prepared76from the resin acid levopimaric acid. Attempts to induce the pimarane-cassane rearrangement using the apunsaturated ketone (83) obtained from virescenol B as a substrate were unsucc e s ~ f u lThe . ~ ~ rearrangement of 8,14-epoxypimaric acid with boron trifluoride gave a mixture of dienes and allylic alcohols but no tetracyclic diterpenoid~.~' Similar studies with methyl 8,14-epoxysandaracopimarategave79the 14-ketone and the products of backbone rearrangement, including (84).

5 Tetra- and Penta-cyclic Diterpenoids Kaurenoid Diterpenoids.-ent-1 la-Acetoxykaur-16-en-15-one and its dihydroderivative have been obtained" from the liverwort Jungermannia infusca. entKaur-16-en-19-oic acid has been detected in a number of Stevia (Compositae) species," and ent- 3P-acetoxy- and ent- 11a-acetoxy-kaur-16-en-19-oicacids have been isolated8*from Helichrysum cooperii (Compositae). ent-16P-Hydroxy73

74

75

76 77

78

79

82

P. Ceccherelli, M. Curini, R. Pellicciari, G. V. Baddeley, M. S. Raju, and E. Wenkert, J. Org. Chem., 1978,43,4244. S . Iwasaki, Helv. Chim. Acta, 1978,61, 2843. H. Akita and T. Oishi, Tetrahedron Letters, 1978, 3733. H. Koike and T. Tokoroyama, Tetrahedron Letters, 1978, 4531. P. Ceccherelli, M. Curini, M. Tingoli, and R. Pellicciari, Gaztetta, 1978, 108, 129. J. W. ApSimon and S . F. Hall, Canad. J. Chem., 1978, 56, 2156. B. Delmond, M. Taran, and J. Valade, Tetrahedron Letters, 1978, 4791. A. Matsuo, S. Uto, J. Kodama, M. Nakayama, and S . Hayashi, Nippon Kagaku Kaishi, 1978,1680 (Chem. Abs., 1979,90, 187 157). F. Bohlmann, L. N. Dutta, W. Dorner, R. M. King, and H. Robinson, Phytochemistry, 1979,18,673. F. Bohlmann, C. Zdero, E. Hofmann, P. K. Mahanta, and W. Dorner, Phytochemistry, 1978, 17, 1917.

Terpenoids and Steroids

118

kauran- 19-oic acid and the A9(I1’-o1efin were obtaineds3 from Ruilopezia margarita. ent- 15~-Tiglinoyloxykaur-16-en-19-oic acid may be the active molluscicidal principle of the plant Wedelia ~ c a b e r r i m a The . ~ ~ corresponding 15-cinnamate and its A”””-dehydro-derivative have been founds5 along with ent- 12a-hydroxykaur-9( 11),16-dien-l9-oic acid in Montanoa pteropoda (Compositae). The occurrenceg6 of the ent- 9a-hydroxy-15P-tigloyl- and, -angeloyl-kaurenoic acids in another species, Oyedaea boliviana, is of interest in view of the isolation of these A9“”-olefins. An X-ray analysis of xylopic acid has been published.” Some biogenetically interesting 19-10-lactones, eupatalbin (85) and its ent-6P-hydroxy relative (86), have been isolateds8 from Eupatorium album (Compositae). As in the rosane diterpenoid lactones, the C-20 methyl group which has migrated to C-9 lies on the same face of the molecule as the lactone ring. The occurrence of A’(’*)-kaurenesis also of interest in the generation of this rearrangement.

(85) R1 = H , R 2 = OH (86) R’ = OH,R2 = H

(87) R

=

Glucose

The chemistry of atractyloside has been reviewed.89A further relative (87) of cafestol has been isolated” from green coffee beans. Sideritis (Labiatae) species have continued to attract attention as a source of diterpenoids. The comparative phytochemistry of Canary Island species has been reviewed.” A number of 15-hydroxykaurenes (88)-(90) have been isolated92from S. crispata, S. ilicifolia, and S. tragoriganum together with the atisine (91) and beyerene (92) derivatives. ent- 18-Acetoxy-3~,7cu,l5~-trihydroxykaur-16-ene has also been from S. scardica. A number of polyhydroxylated kaurenes (93)-(98) have been isolated94from the fern Pteris plumbaea. Some further bitter diterpenoids have been 83

A. Usubillaga and T. Nakano, Planta Med., 1979, 35,331.

x4

T.C. B. Tomassini and M. E. 0. Matas, Phytochemistry, 1979, 18, 663.

’’ F. Bohlmann and N. Le Van, Phytochemistry, 1978, 17, 1957. 86 ”

” 89

9o 91

92 y3 94

”

F. Bohlmann and C. Zdero, Phytochemistry, 1978, 18,492. N. Fiagbe, B. Karlsson, A. M. Pilotti, and J. E. Berg, Actu Cryst., 1979, B35,236. W.Herz, S. Govindan, and J. F. Blount, J. Org. Chem., 1979, 44, 2999. F. Piozzi in ‘Atractyloside, Chemistry, Biochemistry and Toxicology’, ed. R. Santi and S. Luciani, Piccin Medical Books, Padova, Italy, 1978. H. Richter and G. Spiteller, Chern. Ber., 1979, 112, 1088. A. G . Gonzalez, B. M. Fraga, M. G. Hernandez, J. G. Luis, and F. Larruga, Biochem. Systematics Ecol., 1979, 7,115. M. I. Carrascal, R. M. Rabanal, C. Marquez, and S. Valverde, Anales de Quim., 1978,74, 1547. P. Venturella and A. Bellino, Phytochernistry, 1979, 18, 1571. N. Tanaka, K. Nakatani, T. Murakami, Y. Saiki, and C.-M:Chen, Chem. and Pharm. Bull. (Japan), 1978,26,3260. T. Fujita, Y . Takeda, and T. Shingu, Phytochemistry, 1979,18, 299.

Diterpenoids

119

'OH R20CH2 (88) R1 = H, R2

(91)

R3 = AC (89) R' = R3 = H , R 2 = A C (90) R' = A c , R 2 = R3 = H =

(92

from Isodon shikokianus (Labiatae), including shikodokaurin A (99) and the isomeric 7-hydroxy-14-acetate, shikodokaurin B. The inhibitory effect of these diterpenoids on insect growth and their antifeeding activity have been de~cribed.'~

(93) (94) (95) (96) (97)

$:rH

HO

'OH 'OH (98)

R' = H, R2 = Me, R3 = R4 = H R' = H , R 2 = Me,R3 = H,R4 = OH R1 = H, R2 = Me, R3 = OH, R4 = H R' = H, R2 = CHZOH, R3 = R4 = H R' = OGlu,R2 = Me,R3 = R4 = H

@ 'OH

AcO

OAc

(99)

The partial synthesis from epicandicandiol of some 14C- and 3H-labelled kaurene derivatives has been de~cribed.~' These have possible application in the study of the biosynthesis of the Isodon diterpenoids. The syntheses of [1714 C]kaur-16-en-20-01 from enmein and of 3-oxygenated derivatives of [1714C]kaur-16-ene from ent-3P,19-dihydroxy-kaur-16-ene have also been described.98 The synthesis of radioactive aphidicolin has also been reported.99 It has been shown'" that ent-kaur-15-ene is formed by the dwarf mutant (d,) of maize in place of ent-kaur-16-ene. Beyerene Diterpenoids.-The a-ketol ent-3/3-hydroxybeyer-1 S-ene-2,12-dione is amongst'" the constituents of the heartwood of Androstuchys johnsonii 96 97

98 99 loo

lo'

M. Taniguchi, M. Yamaguchi, I. Kubo, and T. Kubota, Agric. and Biol. Chem. (Japan),1979,43,71. T. Fujita, S. Takao, and E. Fujita, J.C.S. Perkin I, 1979, 910. T. Fujita, I. Masuda, S. Takao, and E. Fujita, J.C.S. Perkin I, 197.9, 915. S. Ikegami, K. Okano, and H . Muragaki, Agric. and Biol.Chem. (Japan), 1979,43, 889. P. Hedden and B. 0. Phinney, Phytochemistry, 1979,18, 1475. L. P. L. Piacenza, K. H. Pegel, L. Phillips, and E. S. Waight, J.C.S. Perkin I, 1979, 1004.

Terpenoids and Steroids

120

(Euphorbiaceae). Elimination of the corresponding C- 12 equatorial alcohol leads to a rearrangement of ring c. Two ring A seco-beyerenes, (100) and ( I O l ) , have been obtained102from Beyeria calycina. The stereospecificity of hydrogen transfer in the photochemical hydrolytic cleavage of ring A, (102) + (103),of these diterpenoids has been to involve the preferential transfer of the axial hydrogen atom from C-2 to C-4 and to involve the retention of configuration at c-4.

CH20Ac

CH,OAc

Atiserene Diterpenoids.-The assignment of the 13Cn.m.r. spectra of a series of ent-atisene derivatives has been made.lo4Margotianin, methyl ent-7a-angeloxy15a-acetoxyatis-16-en-oate, is a further atisene derivative which is related to gummiferolic acid, which has been isolated105 from Margotia gumrnifera (Umbellif erae). Trachylobane Diterpenoids.-The I3C n.m.r. spectra of the trachylobane series have also been assigned.lo6Helifulvanolic acid (104), which was iso1atedlo7from Helichrysum fulvum (Compositae), possesses an unusual isotrachylobane skeleton which was established by X-ray analysis.

(104) lo3 lo4 '05

'06

""

E. L. Ghisalberti, P. R. Jefferies, and M. A. Sefton, Phytochemistry, 1978, 17, 1961. E. L. Ghisalberti, P. R. Jefferies, and M. A. Sefton, Tetrahedron, 1978, 34, 3337. A. Lopez, C . Marquez, R. M. Rabanol, S. Valverde, and J . Garcia, Anales de Quim., 1978,74, 1100. B. Rodriguez and M. Pinar, Phytochemistry, 1979, 18,891. R. M. Cory and J. B. Stothers, Org. Magn. Resonance, 1978,11,252; A. Arnone, R. Mondelli, and J. St. Pyrek, ibid., 1979, 12, 429. F. Bohlmann, C . Zdero, R. Zeisberg, and W. S . Sheldrick, Phytochemistry, 1979,18, 1359.

121

Diterpenoids

Gibberellins.-An extensive review of the gibberellins has appeared.''* Gibberellin AS0 (105) and A52 (106) have been isolated1o9 from the seeds of Lagenaria leucantha. Gibberellin A51 (107) was obtained"' from Pisum sativum and gibberellin A53 (108) (13-hydroxygibberellin A12)has been identified"' in immature seeds of Vicia faba. The 3 -O-P-D-glucopyranoside of gibberellin Al has been detected112in Dolichos lablab (Leguminosae) seed and the changes in gibberellin content, particularly of gibberellin A19(109) during the development of the rice plant, have also been recorded.'13

HO

. . . "*

C02H

The differences of conformation of ring A between the c19 and CZ0gibberellins have been examined'14 by X-ray analysis. The mass spectrum of allogibberic acid has been analysed in detail.ll5 The studies on the photochemistry of the gibberellins have continued with reports116 on the cleavage of ring D of the 8,13-isogibberellins and on the X-ray analysis117 of the bromohydrin (110) formed by the hydrolysis of an oxetan which arose during the photolysis of gibberellin C (111).A full paper has appeared'" on the chemical removal of C-20 from compounds of the gibberellin A13 series. The preparation of 7-homogibberellic acid has been reported'" and the biological activity of some 1-iodinated gibberellins has been examined.12' The synthesis of gem-difluoro-derivatives of gibberellin ketones using diethylaminosulphurtrifluoride as a reagent has also lo' log 'lo

'I1

'15 '16

'I7

'19

J. E. Graebe and H. J. Ropers, in 'Phytohormones', Vol. 1, Elsevier, Amsterdam, 1978. H. Fukui, K. Koshimizu, and R. Nemori, Agric. and Biol. Chem. (Japan), 1978, 42, 1571. V. M. Sponsel and J. MacMillan, Planta, 1977, 135, 129. V. M. Sponsel, P. Gaskin, and J. MacMillan, Planta, 1979, 146, 101. T. Yokota, S. Kobayashi, H. Yamane, and N. Takahashi, Agric. and Biol. Chern. (Japan), 1978,42, 1811. S . Kurogochi, N. Murofushi, Y. Ota, and N. Takahashi, Planta, 1979, 146, 185. G. Ellames, J. R. Hanson, P. B. Hitchcock, and S. A. Thomas, J.C.S. Perkin I, 1979, 1922. D. Voigt, J Schmidt, and P. Frahke, Org. Mass Spectrom., 1978, 13, 599. G . Adam and T. Sung, Tetrahedron, 1979, 35, 557. G. Reck, L. Kutschabsky, G. Adam, and T. Sung, Tetrahedron, 1979,35, 839. J. R. Bearder, J. MacMillan, C. von Carstenn-Lichterfelde, and J. R. Hanson, J.C.S. Perkin I, 1979, 1918. E. P. Serebryakov, M. Lischewski, and G. Adam, Izuest. Akad. Nauks. S.S.R., Ser. khim., 1978, 2181. B. Keith, L. M. Srivastava, and N. Murofushi, Agric. and Biol. Chem. (Japan), 1979,43, 141.

122

Terpenoids and Steroids

been reported.121 The preparation of 3H-labelled gibberellin A3 3-0-p-Dglucopyranoside has been described.122

The metabolism of gibberellins in higher plants has been reviewed.123There have been several reports on the use of Gibberella fujikuroi in the microbiological transformation of diterpenoids. These include some ent-kaurene and a re-examination of the metabolism of stevi01.'~~ The formation of some fluorinated gibberellins [e.g. (112)] from ent-15~-fluorokaur-16-en-19-oicacid has been reported.126The lack of structure specificity extends to other skeleta. Thus trachylobanic acid is converted12' into the pentacyclic analogues (113)(116)of, inter alia, gibberellins A4,A9,A12,and A14 whereas ent-7a-hydroxyatis16-en-19-oic acid afforded128the atisagibberellins (117) and (118) related to gibberellins A12and A14.The metabolism of gibberellin A29 (1 19) in the seeds of Pisurn sativurn has been described.129 The compound (120) was found as a catabolite.

(113) R (114) R

= =

OH H

(115) R = H (116) R = OH

.-. .-.

R (117) R (118) R

12'

lZ2 123 124

lZ5 '26 127 12'

129

= =

H OH

K. Boulton and B. E. Cross, J.C.S. Perkin I, 1979, 1354. G. Schneider, 2. Chem., 1978, 18, 217. J. MacMillan, Pure A p p l . Chem., 1978, 50, 995. K. Wada, T . Imai, and K. Shibata, Agric. and Biol. Chem. (Japan), 1979, 43, 1157. N. Murofushi, S . Nagura, and N. Takahashi, Agric. and Biol. Chem. (Japan), 1979,43, 1159. B. E. Cross and A. Erasmuson, J.C.S. Chem. Comm., 1978, 1013. J. R. Bearder, J. MacMillan, A. Matsuo, and B. 0. Phinney, J.C.S. Chem. Comm., 1979, 649. J. R. Hanson, F. Y. Sarah, B. M. Fraga, and M. G . Hernindez, Phytochemistry, 1979,18, 1875. V. M. Sponsel and J. MacMillan, Planta, 1978, 144, 69.

123

Diterpenoids

Grayanotoxins.-Grayanotoxin XVIII (121) and its 3- 0-P-D-glucoside, grayfrom the methanolic extract of Leucothoe anoside B (122), have been ~btained'~' grayana. Grayathol A (123), also isolated from L. grayana, has been by an X-ray analysis to be the unusual C-1 epimer of the grayanotoxins. The X-ray analysis of the ring D norgrayanotoxin (124) has been described13*and the 13C n.m.r. spectra of some derivatives in this series have been assigned.133The conversion of grayanotoxin 111 into grayanotoxin V and the rhodojaponins I11 and IV the ozonolysis of ethylidene acetals for the selective formation of acetates. A simple oxidation of grayanotoxin I1 with palladium acetate brings the rarrangement to leucothol D (125). The base-catalysed acyloin rearrangement to form this series has also been d e ~ c r i b e d . ' ~ ~

(121) R (122) R

=

H

=

Glucose

Diterpenoid Alkaloids.-The diterpenoid alkaloids have been reviewed. 137 The acetate of garryfoline (ovatine) (126) and the corresponding imine lacking the oxazolidine ring (lindheimerine) have been isolated from Garrya o u ~ z f a . ~ ~ ~ Manganese dioxide is a suitable oxidant for reconstructing the oxazolidine ring from its dihydro-derivatives. 139 The oxazolidine and thiazolidine rings can also be con~tructed'~'by the condensation of ethylene oxide or ethylene sulphide with the relevant imines. The 7-20-ether of ajaconine (127) is cleaved141 in methanol 13* 13' 13*

133

134

13' 13'

13'

13' 13'

I4O 14'

J . Sakakibara, N. Shirai, T. Kaiya, and H. Nakata, Phytochemistry, 1979, 18, 135. A . Furusaki, S. Gasa, N, Hamanaka, R. Jkeda, and T. Matsumoto, Chem. Letrers, 1979,665. A. Furusaki, S. Gasa, and T. Matsumoto, Bull. Chem. SOC.Japan, 1979, 52,229. T. Masutani, K. Kawazu, K. Uneyama, S. Torii, and J. Iwasa, Agric. and Biol. Chem. (Japan),1979, 43, 631. T. Terai, M. Katai, N. Hamanaka, T. Matsumoto, and H. Meguri, Chem. and Pharm. Bull. (Japan), 1978,26, 1615. T . Kaiya, N. Shirai, and J. Sakakibara, J.C.S. Chem. Comm., 1979, 431. R. Iriye, A&. and Biol. Chem. (Japan), 1978, 42, 1495. S. W. Pelletier and N. V. Mody, in 'The Alkaloids', ed. R. H. F. Manske, Academic Press, New York, Vol. 17, 1978, p. 1. S. W. Pelletier, N. V. Mody, and D. S. Seigler, Heterocycles, 1978, 9, 1409. S. W. Pelletier, N. V. Mody, and J. Bhattacharyya, Tetrahedron Letters, 1978, 5187. S. W. Pelletier, J. Nowacki, and N . V. Mody, Synfh. Comm., 1 9 7 9 , 9 , 2 0 1 . S . W. Pelletier and N. V. Mody, J. Amer. Chem. SOC.,1979,101,492.

124

Terpenoids and Steroids

with the formation of 7a-hydroxyisoatisine. The cleavage of the C-14-(2-20 bond in the very rigid skeleton of kobusine has also been ~ e p 0 r t e d . I ~ ~

The structures of a number of new CI9alkaloids that have been obtained from various Aconitum and Delphinium species have been reported. These include ranaconitine from A . ran~nculaefolium,'~~ septentrioine and septentriodine from A. ~ e p t e n t r i o n a l e delbiterine ,~~~ from I>. bitern~tum,'~'and gadesine from D. pentagynurn. 146 These are reviewed in the Specialist Periodical Report on the Alkaloids.

6 Macrocyclic Diterpenoids and their Cyclization Products A number of cembranoid diterpenoids have been isolated from corals. These include (128) from a South Pacific soft trocheliophorol (129) from Sarcophyton t r o c h e l i ~ p h o r i u m ,flexibilide ~~~ (= sinularin) (130) from Sinularia f l e ~ i b i l i s , and ' ~ ~ isosarcophytoxide (131)and the corresponding diepoxide from a Sarcophyton species. A norcembrane (132) has been i ~ o l a t e d "from ~ Sinularia

(128)

c y o -

H

(130)

p & J (129)

(131)

T. Yatsunami, S. Furuya, and T. Okamoto, Chem. and Pharm. Bull. (Japan),1978,26,3199. 14' S . W. Pelletier, N. V. Mody, A. P. Venkor, and N. M. Mollov, Tetrahedron Letters, 1978, 5045. lU4 S. W. Pelletier, R. S . Sawhney, and A. J. Aasen, Heterocycles, 1979, 12, 377. 14' B. T. Salimov, M. S. Yunusov, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1978, 106. 146 A. G. Gonzalez, G. de la Fuente, R. Diaz, J. Fayos, M. Martinez-Ripoll, Tetrahedron Letters, 1979, 79. 147 B. N. Ravi and D. J. Faulkner, J. Org. Chem., 1978, 43, 2127. '41 A. Groweiss, Y. Kashman, D. J. Vanderah, B. Tursch, P. Cornet, J. C. Braekman, and D. Daloze, Bull. SOC.chim. belges, 1978, 87, 277. 149 R. Kazlauskas, P. T. Murphy, R. J. Wells, P. Schonholzer, and J. C. Coll, Austral. J. Chem., 1978,31, 1817. 150 B. F. Bowden, J. C. Coll, S . J. Mitchell, and G. J. Stokie, Austral, J. Chem., 1979, 32, 653. 15' B. F. Bowden, J. C. Coll, S. J. Mitchell, J. Mulder, andG. J. Stokie, Austral. J. Chem., 1978,31,2049. 14*

D iterpe noids

125

leptoclados. The 13C n.m.r. spectrum of crassin diacetate (133) has been assignedl’* using a novel irradiation technique (SESFORD) and that of asperdiol(l34) was assigned’53using Tl measurements.

@: (133)

An X-ray analysis of the diepoxide (135) derived from verticillol, which is obtained from the wood of Sciadopitys verticillata, has been to define the absolute configuration of this diterpenoid. The acid-catalysed cyclization of cembrene and isocembrenol, which leads to the formation of perhydrophenanthrene derivatives, has been s t ~ d i e d . ” ~ Ingol is a key derivative in the lathyrane series, plausible cyclizations of which may lead to the tigliane, daphnane, and ingenane series of tumour-promoting esters of the Euphorbiaceae. The X-ray analysis of ingol tetra-acetate (136) has been described.156Jatropholone A and its C-2 epimer, jatropholone B, have been obtained from the roots of Jutropha gossypiifolia (Euphorbiaceae). The structure of jatropholone B (137)was deduced’57from an X-ray analysis. The crotofolins A (138), B (139), C (140), and E (141) are also probably derived by cyclization of a lathyrane precursor [e.g. (142) + (143)l. The structure of crotofolin E (141), from Croton corylifolius (Euphorbiaceae), was also assigned from an X-ray analysis.

lS2

153

15’

15*

G. E. Martin, J. A. Matson, J. C. Turley, and A. J. Weinheimer, J. Amer. Chem. SOC., 1979, 101, 1888. G . E. Martin, J. A. Matson, and A. J. Weinheimer, Tetrahedron Letters, 1979, 2195. B. Karlsson, A. M. Pilotti, A. C. Soderholm, T. Norin, S. Sundin, and M. Sumimoto, Tetrahedron, 1978,34,2349. W. G. Dauben, J. P. Hubbell, P. Oberhansli, and W. E. Thiessen, J. Org. Chem., 1979, 44, 669. H. Lotter, H. J. Opferkuch, and E. Hecker, Tetrahedron Letters, 1979, 77. K. K. Purushothaman, S. Chandrasekharan, A. F. Cameron, J. D. Connolly, C. LabbC, A. Maltz, and D. S . Rycroft, Tetrahedron Letters, 1979, 979. B. A. Burke, W. R. Chan, K. 0.Pascoe, J. F. Blount, and P. S . Manchand, Tetrahedron Letters, 1979, 3345.

Terpenoids and Steroids

126

OH

:

OAc

OAc

\ o

R' H

RZ' (138) R1 (139) R'

= =

OH OH, R2 = Me Me,R2 = OH

(140)

(141)

OH (143)

7 Miscellaneous Diterpenoids Marine organisms have continued to provide unusual diterpenoid skeleta. 14Bromo-obtus-1-ene-13,ll -diol (144) has been from the sea hare Aplysia dactylomola. The irieols A-G (145)-(151) are a group of dibromoditerpenoids which have been obtained16' from the marine red alga Laurencia irieii. Their structures were established by 13C n,m.r. spectroscopy and by degradation to a bicyclic aldehyde. Xeniolides A (15 2) and B (15 3) are a pair of lactones, related to the prenylated 'caryophyllene' xeniaphyllenol and xenicin, which have been isolated16' from the soft coral Xenia macrospiculata. Hydroxydilophol (154) is a germacrene-like diterpenoid which has been obtained16* from the brown alga Dictyota masonii. The full paper, including an X-ray analysis, has appeared163on dictyodial and dictyolactone which were obtained from various Dictyota and Aplysia species. A 159

F. J . Schmitz, K. H. Hollenbeak, D. C. Carter, B. M. Hossain, and D. Van der Helm, J. Org. Chem.,

I60

B . M . Howard and W. Fenical, J. Org. Chem., 1978,43,4401. Y . Kashman and A . Groweiss, Tetrahedron Letters, 1978, 4833. H . H. Sun and W. Fenical, J. Org. Chem., 1979, 44, 1354. J . Finar, J. Clardy, W. Fenical, L. Minale, R. Riccio-Battaile, M. Kirkup, and R. E. Moore, J. Org. Chem., 1979,44, 2044.

1979,44,2445. 161 162

163

Diterpenoids

127

(146) (147) (148) (149) (150) (151)

R’ = OH, R2 = H R’ = R2 = H R1 = H, R2 = OH R’ = R2 = OH R’ = OH,R2 = OAc R’ = OAc,R2 = OH

’Br

stereoselective partial synthesis of (-)-dictyolene starting from 6-epi-a-santonin has been ~ e p 0 r t e d . l ~ ~ The occurrence of a group of novel bicyclic diterpenoid (155)-(158) in Dilophus prolificans (Dictyotaceae) has been rep~rted.’~’ The structure of the acetate (158) was established by X-ray analysis. Fuscol (159) is an ‘elemene’

1

H O* ‘

(152) R’ (153) R’

OH

= c), R2 = H2 = HZ, R2= 0

OH

(154)

diterpenoid which has been obtained from the Gorgonian Eunicea fusca.166The structure (160) of an alcohol from a soft coral has been e ~ t a b l i s h e dby ’ ~an ~ X-ray analysis. The sea hare Dolabella californica, which feeds on the brown seaweed Glossophora galapugensis, has been shown’68 to accumulate the dolabelladiene metabolites (161)-(163) as a protection against predators. 164

166 16’

A. E. Greene, Tetrahedron Letters, 1979, 6 3 . R. Kazlauskas, P. T. Murphy, R. J. Wells, and J. F. Blount, Tetrahedron Letters, 1978,4155. Y. Gopichand and F. J. Schmitz, Tetrahedron Letters, 1978, 3641. B. F. Bowden, J. C. Coll, S. J. Mitchell, G . J. Stokie, and J. F. Blount, Austral. J. Chem., 1978, 31, 2039. H. H. Sun and W. Fenical, Phytochemistry, 1979, 18, 340.

Terpenoids and Steroids

128

(156) R1 = R2 = H (157) R1 = O k c , R2 = H (158) R3 = H, R2 = OAc

(161) R = H (162) R = OAc (163) R = OH

The cyathins are a group of diterpenoid metabolites of the bird’s nest fungi Cyathus species. Their 13Cn.m.r. spectra have been assigned.169A further group of these compounds, cyafrins A, (164) and B4 (165), allocyafrin B4 (166), and ~ C. africanus and their structures cyafrin A, (167), have been i ~ o l a t e d ”from established by correlation with cyathin A3.The striatins A (168), B (169), and C (170) were obtained17’ from C.striatus. Their structures, which were established by X-ray analysis of striatin A (168), are derived from the cyathin skeleton. The 13C n.m.r. spectra of the cotylenins, which are fungal metabolites from Cladosporium species, have been assigned.172The results were in the determination of the structures of the minor metabolites, cotylenins H (171a) and I (171b). Carbon-13 n.m.r. methods have also played a role in deuterium migration in the biosynthesis of fusicoccin. Two pathways, ( a ) and ( b ) in (172), are possible in the cyclization of geranylgeranyl pyrophosphate to form the fusicoccin skeleton (173). [4-2H,3-13C]Mevalonate was fed to the fungus. 16’

‘70

173 174

W. A . Ayer, T. T. Nakashima, and D. E. Ward, Canad. J. Chem., 1978,56, 2197. W. A . Ayer, T. Yoshida, and D. M. J. van Schie, Canad. J. Chem., 1978,56, 2113. H. J. Hecht, G. Hoefle, W. Steglich, and T. Anke, J.C.S. Chem. Comm., 1978,665. T. Sassa and A . Takahama, Agric. and Biol. Chem. (Japan), 1979, 43, 385. A. Takahama, T. Sassa, M. Ikeda, and M. Nukina, Agric. and Biol.Chem. (Japan), 1979,43,647. A. Banerji, R. Hunter, G. Mellows, Kim-y-Sim, and D. H. R. Barton, J.C.S. Chem. Comm., 1978, 843.

Diterpenoids

129

(168) R1 = H,R2 = Ac (169) R' = OH, R2 = Ac (170) R' = OH, R2 = H

(171a) R =

H

O

e OCMe2CH=CH2 CH,OMe

I

(171b) R

=

HOWOH 0 ru\LCH,OH

Pathway ( a )involved the migration of a 4-2Hlabel within an isoprene unit to C-7 whereas this does not occur in pathway ( b ) .When the I3Cn.m.r. spectrum of the fusicoccin was examined the enhancement of the C-7 signal due to 13Cenrichment was suppressed because the 13Clabels also bore a 2H label, indicating that pathway ( a )was involved. from the marine A curious diterpenoid isocyanide (174) has been sponge Hymeniacidon amphilecta and its structure established by X-ray analysis. Divarol acetate (175), which is related to the dolatriols, has been from some marine Dolabella species. Two further trinervitene diterpenoids (176), the 2a,3a- and 2a,3P-diols, have been isolated17' from the frontal glands of the termite Nasutitermes costalis. The verrucosane skeleton has been assigned to some further diterpenoids from the liverwort Mylia verrucosa. Three more 175

'76

177

S. J. Wratten, D. J. Faulkner, K. Hirotsu, and J . Clardy, Tetrahedron Letters, 1978, 4345. W. Fenical, H. L. Sleeper, V. J. Paul, M. 0. Stallard, and H. H. Sun, Pure Appl. Chem., 1979, 51, 1865. J. VrkoC, M. BudgSinskL, and P. Sedrnera, Coll. Czech. Chem. Comm., 1978, 43, 2478..

Terpenoids and Steroids

130

p3

H+

C II

N

(175) (176) R

C

= a- or

OH @-OHrespectively

(174)

I.

&.-OR2

1.

'OAc (177)

(178) R' (179) R1

=

=

Ac, R2 = H H , R 2 = Ac

compounds (177)-( 179) with this skeleton have now been isolated17' from this species. Presphaerol (180), a minor constituent of the red alga Sphaerococcus coronopifolius, has been to possess a carbon skeleton related to that of spaero-

179

S. Hayashi, A. Matsuo, H. Nozaki, M. Nakayama, D. Takaoka, and M. Hiroi, Chem. Letters, 1978, 953. F. Cafieri, L. de Napoli, E. Fattorusso, M. Piattelli, and S. Sciuto, Tetrahedron Letters, 1979, 963.

Diterpenoids

131

coccenol A. Aplysillin (181), from the sponge Aplysilla rosea, has been assignedlgOa carbon skeleton reminiscent of the marine sesterterpenoids. Laurenene (182) is an unusual diterpenoid hydrocarbon which has been obtained'" from Dacrydium cupressinum. Its structure was established by an X-ray analysis. The full details of the X-ray structure bf colletotrichin have been published.ls2

ri)l

OAc

8 Diterpenoid Total Synthesis A synthesis of all-trans-geranylgeraniol and the assignment of its I3C n.m.r. spectrum has been recorded. lg3 A highly oxygenated derivative of geranylgeraniol, ligantrol (183), has also been synthesized.lg4 The trans-clerodane (k)-annonene (185) has been synthesizedlg5 uia the intermediate (184). In a similar approach to the clerodanes, the reactions of the decalone (186)have been examined.lg6The potential intermediate (187) has also been preparedlg7with the same objective and synthetic studies have been madelS8 on the preparation of diterpenoids with abnormal A/B ring junctions.

(185)

(186)

(187)

R. Kazlauskas, P. T. Murphy, R. J. Wells, and J. J. Daly, Tetrahedron Letters, 1979, 903. R. E. Corbett, D. R. Lauren, and R. T. Weavers, J.C.S. Perkin I, 1979, 1774; R. E. Corbett, C. M. Couldwell, D. R. Lauren, and R. T. Weavers, ibid., p. 1791. R. Goddard, I. K. Hatton, J. A. K. Howard, J. MacMillan, and T. J. Simpson, J.C.S. Perkin I, 1979, 1494. lU3

lU4 lS5 lS6 lS7

IS'

R. M. Coates, D. A. Ley, and P. L. Cavender, J. Org. Chem., 1978,43,4915. S . Takahashi, E. Kitazawa, and A. Ogiso, Chem. and Pharm. Bull. (Japan), 1978,26,3416. S. Takahashi, T. Kusumi, and H. Kakisawa, Chem. Letters, 1979, 515. A. Ardon-Jimenez and T. G. Halsall, J.C.S. Perkin I, 1978, 1461. J. W. ApSimon and K. Yamasaka, Polish J. Chem., 1979, 53, 107. F. Orsini, F. Pelissoni, and R. Destro, Gazzetta, 1978, 108,693.

132

Terpenoids and Steroids

A simple and novel route from phenanthrene to the intermediate (188) has been described.lS9Details have appeared’” of a total synthesis of ferruginol and hinokione. A synthetic strategy based on the Wittig reaction of a -cyclocitral (ring A) (189) and benzylphosphonium salts (ring c) [e.g. (190)] followed by partial reduction and cyclization, has been put to good effect in the synthesis of tricyclic diterpenoids including f e r r u g i n ~ l , ” ~sempervi1-01,~~~ disperrn01,~~~ maytenoquinone, 192 totar01,”~ p ~ d o t o t a r i n , ”t~a x ~ q u i n o n e , ’the ~ ~r ~ y l e a n o n e s , ~ ~ ~ and coleons U and V.19’ Triptolide has attracted attention, studies being reported on the partial synthesis of the ring A and the epoxides of ring C.lg7

The synthesis of the aromatic methyl ether (191) and the reduction of ring c has been studied. 198 The backbone rearrangement of the synthetic intermediate (192) has been examined199in the context of the synthesis of rearranged diterpenoids. The synthesis of the phenol (193), which is a degradation product of atisine, has been reported.20o

The construction of the tetracyclic diterpenoids has continued to attract attention. The intramolecular alkylation of an olefin by the acid-catalysed reaction of #-unsaturated diazo-ketones has been used2”’ to generate ring D in the step (194)+( 195) + (196). A benzocyclobutane route based on the thermal cyclization of (197) to (198) has been developed2’* for the synthesis of the beyerane skeleton. A stereoselective synthesis of stachenone, based on a series of A. L. Campbell and J. D. McChesney, Synth. Comm., 1979,471. D. L. Snitman, R. J. Himmelsbach, and D. S. Watt, J. Org. Chem., 1978, 43, 4758. 19‘ T. Matsumoto and S. Usui, Bull. Chem. SOC.Japan, 1979, 52,212. 1 9 2 T. Matsumoto and S. Usui, Chem. Letters, 1978, 897. 1 9 3 T. Matsumoto and A. Suetsugu, Bull. Chem. SOC.Japan, 1979,52, 1450. 194 T. Matsumoto and S. Harada, Bull. Chem. SOC.Japan, 1979,52, 1459. 195 T. Matsurnoto and S. Takeda, Chem. Letters, 1979, 409. Iy6 H. Koike and T. Tokoroyama, Chem. Letters, 1979, 333. ‘97 D. M. Frieze, G. A. Berchtold, and J . F. Blount, Tetrahedron Letters, 1978, 4607. 19’ A. J. Banerjee, C. D. Ceballo, M. N. Vallejo, and E. H. Bolivar, Bull. Chem. Soc. Japan, 1979,52,608. A. K. Banerjee, E. Bolivar, and M. Narvaez, Gazzetta, 1978,108, 505. 2oo U. R. Ghatak, S. K. Alain, and J. K. Ray, J. Org. Chem., 1978, 43, 4598. 2”1 P. Ceccherelli, M. Tingoli, M. Curini, and R. Pellicciari, Tetrahedron Letters, 1978,4959. 202 T. Kametani, K. Suzuki, H. Nemoto, and K . Fukurnoto, J. Org. Chem., 1979, 44, 1036. 19‘)

133

Diterpen oids

(19.5)

ring extension reactions, has been described.203A report has appeared2'I4of the synthesis of the A, B, and C rings of the grayanotoxins. The unusual structure of the anti-viral tetracyclic diterpenoid aphidicolin (199) has been the subject of two successful syntheses.205,206

(197)

MeO'

'

Undoubtedly one of the major synthetic achievements of the year has been the stereospecific total synthesis of gibberellic.acid (202).207The tricyclic compound (200)2n8formed a key intermediate and this was converted into the homoannular diene (201) and thence into gibberellic acid. Another strategy for gibberellin

(200) MeM 203 204

2n5 206

207

208

=

CH20CH2CH20Me

(201)

S. A. Monti and Y.-L. Yang, J. Org. Chem., 1979,44, 897. T. Karnetani, M. Tsubuki, H. Nemoto, andK. Fukurnoto, Chem. andPharm. Bull. (Japan),1979,27, 152. B. M. Trost, Y. Nishirnura, and K. Yarnarnoto, J. Amer. Chem. SOC., 1979, 101, 1328. J. E. McMurry, A. Andrus, G. M. Ksander, J. H. Musser, and M. A. Johnson, J. Amer. Chem. SOC., 1979,101,1330. E. J. Corey, R. L. Danheiser, S. Chandrasekaran, G. E. Keck, B. Gopalan, S. D. Larsen, P. Siret,and J. L. Gras, J. Amer. Chem. Suc., 1978, 100, 8034. E. J . Corey and J. Gorzynski Smith, J. Amer. Chem. SOC., 1979, 101, 1038.

e' Terpenoids and Steroids

134

HOa

O

'

H

OMe

CH(CO,Me),

C0,H

CH(CO,Me), (204)

synthesis makes use209of the cyclization of diazo-ketones [e.g. (203)-+(204)] for the formation of ring D and for the ring contraction [e.g. (205)] to form the five-membered ring B. This approach has also been used210for the synthesis of ring A nor-gibberellins as models for the 'effector part' of the skeleton. The acid-catalysed rearrangement of the tertiary alcohol (206) has been used211to generate the tetracyclic skeleton (207) of the gibberellins.

Q

0

C02H

C0,H

The cyclization of polyenes described in previous Reports has been extended212 to the synthesis of some cembrenols. A regio- and stereo-controlled synthesis of the stemodane nucleus, utilizing a surprising selectivity of reagents, has been claimed.213Readers are left to examine the paper and draw their own conclusions.

"N

'"' ''I '12

'I3

L. N. Mander and S. G. Pyne, J. Amer. Chem. SOC.,1979,101, 3373. A. L. Cossey and L. N. Mander, Tetrahedron Letters, 1979, 969. S. A. Monti and S.-C. Chen, J. Org. Chem., 1979, 44, 1170. M. Suzuki, A. Shimada, and T. Kato, Chem. Letters, 1978, 759. S. Chatterjee, J.C.S. Chem. Comm., 1979, 622.

3 Triterpenoids BY J. D. CONNOLLY

Reviews have appeared on the palaeochemistry and biochemistry of hopanoids,' the distribution of tetracyclic and pentacyclic triterpenoids,2 friedelin and associated triterpen~ids,~ triterpenoid alcohols of seed-bearing plants (Spermat ~ p h y t a )and , ~ the occurrence, biosynthesis, and metabolism of e p ~ x i d e s . ~

1 Squalene Group The racemic [21-'4C]oxidosqualene analogue (l),which has an 1 8 2 instead of the normal 1815 double bond, was converted by 2,3-oxidosqualene cyclase into the norlanosterol derivative (2) with the unnatural (20s) configuratiom6 This result is readily interpreted in terms of the Cornforth proposal of attachment, and subsequent elimination, of the enzyme or an exogenous nucleophile to C-20 during the initial cyclization. The syntheses of (1) and authentic samples of the (20s)- and (20R)-norlanosterol derivatives have been d e ~ c r i b e d . ~

Ulmoprenol (3) is an interesting new hexaprenoid from Eucornrnia ulrnoides.g A series of head-to-head linked isoprenoid hydrocarbons has been isolated from petroleum source^.^

' G. Ourisson, P. Albrecht, and M. Rohmer, Pure Appl. Chem., 1979,51,709. P. Pant and R. P. Rastogi, Phytochemistry, 1979, 18, 1095. R. F. Chandler and S. N. Hooper, Phytochemistry, 1979,18,711. T. Itoh and T. Matsumoto, Yukagaku, 1979,28, 231. S . Voigt and M. Luckner, Pharmazie, 1978,33,632. M. HCrin, P. Sandra, and A. Krief, Tetrahedron Lett., 1979,3103. Diagrams 4a and 4b in this paper should have R2 = Et and R1 = Et respectively. M. Herin, P. Delbar, J. Remion, P. Sandra, and A. Krief, Tetrahedron Lett., 1979, 3107. Z. Horii, Y. Ozaki, K. Nagao, and S.-W. Kim, Tetrahedron Lett., 1978, 5015. J. M. Moldowan and W. K. Seifert, Science, 1979,204, 169.

135

136

Terpenoids and Steroids

2,4,4,6-Tetrabromocyclohexadienonehas been shown to be an efficient alternative to N-bromosuccinimide for the preparation of terminal bromohydrins of polyenes like squalene. lo A stereoselective synthesis of mokupalide (4),an unusual head-to-tail linked hexaprenoid from a marine sponge, is summarized in the Scheme." PhS

A

\

\

A

OTHP

(5)

1

i-iii

I

vi, vii

Reagents: i , Bu"Li-DABCO; ii, v, Bu"Li-MsC1-LiBr; vi,

P

PhS

; iii, NiB-EtOH; iv, H,O'; ; vii, NaHg-MeOH

Scheme

The full details of the synthesis and resolution of presqualene and prephytoene alcohols1*and the stereochemistry of the non-oxidative cyclization of squalene to tetrahymanol by Tetruhymena pyriformisI3 have appeared (see Vol. 9, p. 187). lo

l3

I. Ichinose, T. Hosogai, and T. Kato, Synthesis, 1978, 605. F. W. Sum and L. Weiler, J. Am. Chem. SOC., 1979,101,4401. L. J. Altman, R. C. Kowerski, and D. R. Laungani, J. Am. Chem. SOC., 1978,100, 6174. D. J. Aberhart and E. Caspi, J. A m . Chem. SOC.,1979,101, 1013.

137

Triterpenoids

The biogenetic pathway for the formation of officinalic acid (8), a novel ~ immediately apparent. Its structure triterpenoid from Fomes o f i c i n ~ l i sis, ~not was determined by X-ray analysis of the dimethyl ester (9), derived from (8) by sodium borohydride reduction followed by methylation. The crystal structure of malabaricol (10) has been pub1i~hed.l~

-h

2 Fusidane-Lanostane Group An X-ray analysis of 3a -acetoxy-4a,8a, 14p-trimethyl-1 8 - n o r - h , 13p-androstan-17-one (ll),derived from fusidic acid, has confirmed the p-configuration of H-9.16 This result also substantiates the proposed stereochemistry of the protostene derivative (12) (see Vol. 2, p. 159).

l4

l6

W. W. Epstein, F. W. Sweat, G. Van Lear, F. M. Lovell, and E. J. Gabe, J. A m . Chem. SOC.,1979, 101,2748. W. F. Paton and I. C. Paul, Cryst. Struct. Commun., 1979,8,481. W. S. Murphy, D. Cocker, G. Ferguson, and M. Khan, J. Chem. SOC., Perkin Trans. I, 1979, 1447.

Terpenoids and Steroids

138

Fasciculol G (13) is a further member of the series of plant growth inhibitors from Neamatoloma fasciculare17 (see Vol. 9, p. 188). Structure (14) has been proposed for fasciculatol from Veronia fasciculata.l 8 Extraction of a fossil plant from the Ningyo-Toge uranium deposit afforded the nortriterpenoid ketones (15) and ( 16).19The structure (17) of a new tetracyclic triterpenoid from Pertya robusta was confirmed by partial synthesis of its dihydro-derivative from 24-methylenecycloartenoL2'

HO Me I

(13) R

=

COCH2CCH2CONHCH2C02Me I OH

(15) (16)

Whereas empirical force-field calculations predict a ring A boat conformation for lanost -8-en-3-one, combined empirical force-field-extended Huckel molecular orbital calculations favour a ring A chair conformation.21Europium-shift n.m.r. results indicate that the molecule adopts the latter conformation. Studies on the peracetic acid-boron trifluoride etherate Baeyer-Villiger oxidation of 4,4-dimethyl-3-keto-triterpenoids to 8-lactones (18) and their subsequent ring contraction to y-lactones have been Dehydrogenation of lanost-8en-3P -01 with 2,3-dichloro-5,6-dicyanobenzoquinoneafforded, in addition to the corresponding 7,9(11)-diene, the aromatic seco-lanostane derivatives (19) l7

19

2o 21

22 23

M. Ikeda, Y. Sato, T. Sassa, and Y. Miura, Chem. Abs., 1979,90, 204 294. N. K. Narain, Can. J. Pharm. Sci., 1979, 1 4 3 3 . T. Murae, M. Nakiwama, K. Hosokawa, H. Miyazaki, M. Ishibashi, T. Tsuyuki, and T. Takahashi, Chem. Abs., 1979,90,100 102. S. Nagumo, K. Izawa, and M. Nagai, Yakugaku Zasshi, 1978, 98, 1327. D. A, Dougherty, K . Mislow, J . W. Huffman, and J. Jacobus, J. Org. Chem., 1979,44, 1585. T. A. Hase and R. Huikko, Acta Chem. Scand., Ser. B, 1978, 32,467. R. Unsvuori, T. Hase, and E. Suokas, Acta Chem. Scand., Ser. B, 1978,32, 531.

139

Triterpen oids

a

0

and (20).243P-Acetoxylanost-8-en-7-onehas been transformed into (21) with aromatic rings A and B.25 Full accounts of the boron trifluoride etherate induced rearrangement of 3~-acetoxy-9~,11~-epoxylanostan-7-one have appeared26727 (see Vol. 9, p. 189). With the same reagent the corresponding 9 a , l la-epoxide (22) yielded 3P-acetoxy-9P-lanostane-7,ll-dione(23) in benzene solution and the 12methyl derivative (24) in acetic anhydride.26The 13Cchemical shifts of this group of rearranged lanostanes have been assigned.26In separate investigations, reaction of the ga,lla-epoxide (22) with boron trifluoride in acetic anhydride afforded the cucurbitane derivative (25)28while rearrangement of 3P -acetoxy9 a , l la-epoxylanostane (26) gave 3P,1l a -diacetoxyprotost-l3(17)-ene (27).29 The structures of holotoxins A and B, antifungal oligoglycosides from the sea cucumber Stichopus jupunicus, have been revised.30Their genuine sapogenol is holotoxigenol(28) and not stichopogenin A4as previously reported (see Vol. 6, p. 122 and Vol. 7, p. 136). The complete structure of holothurin A,a biologically active oligoglycoside from the sea cucumber Holothuriu Zeucospilotu, has been e ~ t a b l i s h e d It . ~ has ~ the same aglycone, holothurigenol (29), as holothurin B. Neither holotoxigenol nor holothurigenol has been isolated. A 13Cn.m.r. study of stichoposide A has been published.32

24

25 26

27

** 29 30

31 32

D. R. Crump, J. Chem. SOC.,Perkin Trans. I, 1979, 646. P. S. Cooper, C. M. Culshaw, R. E. Gall, and J. E. Nemorin, Aust. J. Chem.; 1979, 32,179. G. V. Baddeley, H. J. Samaan, J. J. H. Simes, and T. H. Ai, J. Chem. SOC.,Perkin Trans. f, 1979,7. Z . Paryzek, J. Chem. SOC.,Perkin Trans. I, 1979, 1222. Z. Paryzek. Bull. Acad. Pol. Sci. Ser. Sci. Chim., 1978, 26,583. Z. Paryzek and R. Wydra, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978,26, 591. I. Kitagawa, H. Yamanaka, M. Kobayashi, T. Nishino, I. Yosioka, and T. Sugawara, Chem. Pharm. Bull., 1978, 26, 3722. I. Kitagawa, T. Nishino, and Y. Kyogoku, Terrahedron Lett., 1979, 1419. V. A. Stonik, V. F. Sharypov, A . I. Kalmovskii, and G. B. Elyakov, Dokl. Akad. Nauk SSSR,1979, 245,1113.

Terpenoids and Steroids

140

AcO

(22) R (26) R

= =

0 H2

AcO

(25)

A short efficient synthesis of cycloartenol from 3~-acetoxylanost-24-en-l1~ yl nitrite has been achieved.33 Irradiation of the nitrite in carbon tetrachloride solution in the presence of oxygen afforded the nitrate ester (30) which was converted into cycloartenol uia the olefin (31) and the mesylate (32). The structure of abietospiran (33), the main component of the crystalline coating which is responsible for the silver-grey colour of the bark of Abies alba, has been 33

R. B. Boar and D. B. Copsey, J. Chem. SOC.,Perkin Trans. I, 1979, 563.

Triterpenoids

141

AcO

AcO

(32) R

=

Ms

established by X-ray analysis.34 Cymbidoside (34)is a new glucoside from Cymbidium gig~nteum.~'Further studies on acetylshengmanol xyloside from Cimifuga j ~ p o n i c a(see ~ ~ Vol. 8 , p. 185) and cycloswietenol from Swietenia mahoguni3' (see Vol. 9, p. 190) have been published.

MeO' (33)

4P,14a,24~-Trimethyl-9~,19-cyclo-5a -cholestan-3-one (35) has been prepared by treatment of the corresponding 4a -methyl epimer with lithium chloride in DMF. The cyclopropane ring of (35) and 24-methylenecycloartenol was resistant to cleavage by maize enzyme. These results indicate the importance of substitution and configuration at C-4 in the enzymatic cleavage rea~tion.~'

34

35 36

37 38

W. Steglich, M. Klaar, L. Zechlin, and H. J. Hecht, Angew. Chem. Inf. Ed. Engl., 1979,18,698. J. Dahmen and K. Leander, Phytochemistry, 1978,17,1975. N. Sakurai, T. Inoue, and M. Nagai, Chem. Pharm. Bull., 1979,27, 158. A. S. R. Anjaneyulu, Y. L. N. Murthy, and L. R. Row, Indian J. Chem. Sect. B, 1978, 16,650. L. Cattel, L. Delprino, P. Benveniste, and A . Rahier, J. Am. Oil Chem. SOC.,1979,56,6.

Terpenoids and Steroids

142

Arvenins I11 (36) and IV (37) are two further cucurbitacin glucosides from Anagallis a r v e n s i ~The . ~ ~former was reported last year from Ecballium elaterium (see Vol. 9, p. 193) while the latter has been isolated, together with the related glucosides (38) and (39) and iso-23,24-dihydrocwurbitacin D (40),from the roots of Bryonia alba.40 0

0

OH

(36) (37) (38) (39)

R' = P-D-glU, R2 = H 23,24-dihydro-(36) R' = H, R2 = p-D-glu; 23,24-dihydro R' = R2 = p-D-glu; 23,24-dihydro

(40)

3 Dammarane-Euphane Group Full details of the structure and partial synthesis of alnuseric acid (41)and alnuselide (42), secodammaranes from the male flowers of A h u s serrulatoides,

have been published.41 The related alnustic acid (43) has been isolated from A. ~ i e b o l d i a n aThe . ~ ~ unusual rearranged structure (44)has been proposed for a compound from Eumorphia ~ e r i c e a 20,24-Epoxydammarane-3P,6cr,25 .~~ - trio1 (45)and its 6-acetate occur in the leaves of Betula e r m a l ~ i i . ~ ~ Publications on the structure and analytical detection of saponins of Panax ginseng45and the effect of ginseng on cholesterol synthesis46and pyruvate kinase activity4' in rats have appeared. New saponins include ginsenosides Rhl (46)and 39 40

41 42 43

44

45 46 47

Y. Yamada, K. Hagiwara, K. Iguchi, S. Suzuki, andH.-Y. Hsu, Chem. Pharm. Bull., 1978,26,3107. A. G. Panosyan, M. N. Nikishchenko, V. A. Mnatsakanyan, and V. L. Sadovskaya, Bioorg. Khim., 1979,5, 721. T. Suga and T. Hirata, Bufl. Chem. SUC.Jpn., 1979, 52, 1153. T. Suga, S. Tanaka, H. Yamamoto, and H . Nozai, Bull. Chem. Suc. Jpn., 1979,52,1698. F. Bohlmann and C. Zdero, Phytochemistry, 1978, 1155. G. V. Malinovskaya, N. D. Pokhilo, V. V. Isakov, and N. I. Uvarova, Khim. Prir. Soedin., 1978,587. J. F. Pleinard, Plant. Med. Phytother., 1979, 13, 4. M. Ikehara, Y. Shibata, T. Higashi, S. Sanada, and J. Shoji, Chem. Pharm. Bull., 1978, 26, 2844. T. Yokozawa, N. Kitahara, S. Okuda, and H. Oura, Chem. Pharm. Bull., 1979,27,419.

143

Tritergenoids

(45)

M7cd(47) from P. ginseng48 and chikusetsusaponinsLT5, LT8, and LN4 from the leaves of P. j ~ p o n i c u sThe . ~ ~latter are 3,20-glycosides of (20S)-dammar-24-ene3&20-diol-12-one (48).The full structures of hovenosides D, G, and I, saponins based on jujubogenin (49) from the root bark of Hovenia dulcis, have been

HO

OH

48 49

50

S. Yahara, L. Kaji, and 0. Tanaka, Chem. Pharm. Bull., 1979, 27, 88. S. Yahara, 0. Tanaka, and I. Nishioka, Chem. Pharm. Bull., 1978,26, 3010. 0. Inoue, T. Takeda, and Y. Ogihara, J. Chem. SOC.,Perkin Trans. I, 1978, 1289.

Terpenoids and Steroids

144

3-Epi-isomasticadienolalic acid (50) is a further new compound from Schinus rn~lle.~' The galls of Pistacia palestrina contain several known compounds including 3P-hydroxytir~calla-7,24-diene~~ (see Vol. 8, p. 162). Structure (51) has been proposed for a triterpenoid from the fruits of Melia a ~ e d a r a c hThe .~~ lack of an oxygen substituent at C-3 is unusual. Four new apotirucallol derivatives (52)-(55) have been isolated from the wood of Chisochefon p a n i c ~ l a t u s . ~ ~ OHC?

.CO,H

Ho%

AcO- -

(52) R = 0 (53) R = H,a-OH

OH

Tetranortriterpen0ids.-The search for tetranortriterpenoids with cytotoxic activity continues. Two active compounds, amoorstatin (56)55and 12a-bydroxyT. Pozzo-Balbi, L. Nobile, G. Scapini, and M. Cini, Phytochemistry, 1978,17, 2107. R. Caputo, L. Mangoni, P. Monaco, and G. Palumbo, Phytochemistry, 1979, 18, 896. 53 K. E. Schulte, G. Ruecker, and H. U.Matern, Planta Med., 1979,35, 76. " J. D. Connoliy, C. Labbe, D. S. Rycroft, and D. A. H. Taylor, J. Chem. Soc., Perkin Trans. I, 1979, 2959. s5 J. Polonsky, Z. Varon, B. Arnoux, C. Pascard, G. R. Pettit, and J. M. Schmidt, J. A m . Chem. SOC., 1978,100,7731.

51

52

Triterpenoids

145

"OH

"OH

HO

HO

(58)

(56) R = H (57) R = OH

amoorstatin (57),56 have been obtained, together with amoorstatone (58),56 from Aphanamixis grandifolia (see Vol. 9, p. 196). Two separate investigations of the seeds of Chisocheton paniculatus have resulted in the isolation of the 6 a -oxygenated azadirone derivatives (59), (60), and (61)s7 and the y-lactone (62), hemiacetal (63), y-hydroxybutenolide (64), and 17p-hydroxy-&acetoxyazadiradione (65).54 Compounds (62) and (63) may be precursors of normal furanoid tetranortriterpenoids, e.g. (59). The wood of C. paniculatus yielded vilasinin 1,3-diacetate (66) in addition to several apotirucallol derivatives (see above).

R

0

R = C O

-,!3;;"2

0

OAc

OR1 'OR'

=do OH

'OAc

0

R

(59) R' = Ac, R2 = H,H (60) R' = Ac, R2 = 0 (61) R' = H, R2 = 0

OAc

'OAc

0

OAc (65) 56

57

'

'OH

0 (66)

J. Polonsky, Z. Varon, C. Marazano, B. Arnoux, G. R. Pettit, J. M. Schmidt, M. Ochi, and H. Kotsuki, Experientia, 1979,35, 987. B. Saikia, J. C. S. Kataky, R. K. Mathur, and J. N. Baruah, IndianJ. Chem., Sect. B, 1978,16, 1042.

146

Terpenoids and Steroids

Two interesting new variants in tetranortriterpenoids are represented by the rearranged spiro-lactone (67) from Carapa procera bark" and clausenolide (68) from Clausena h e ~ t a p h y l l aThe . ~ ~ latter.is formally a pentanortriterpenoid and presumably arises by decarboxylation of a ring A-cleaved intermediate. Although the mechanism of the formation of the spiro-lactone (67) remains obscure it is significant that several fungal metabolites of sesquiterpenoid-polyketide origin, e.g. andibenin (67a), have similar structural features in rings A and B. The structures of (67) and ( 6 8 )were confirmed by X-ray analysis.

0

&

0

0

0

I

--OH

\

!

0

"OH

The occurrence of tetranortriterpenoids in the Cneoracea, the source of the highly cleaved pentanortriterpenoids (see below), serves to illustrate the biogenetic relationship between the two groups. Tricoccins S2* (69) and S 3 2 , characterized as the triacetate (70), from Cneorum tricoccum, are the first On treatment with acid, tricoccin representatives with a 16a -hydro~y-group.~* S22(69) underwent a novel epoxide rearrangement to give the ketone (71). The structure of the novel 14P-hydroxy-derivative cneorin R (72), from Neochamaelea pulverulenta, was confirmed by its conversion into methyl ivorensate (73) on treatment with sodium hydride.60 Other ring A-cleaved tetranortriterpenoids include evodulone (74)61and gumulin (75)62from Carupu procera and surenone (76) and surenin (77) from Trichilia ~ u r e n iLast . ~ ~year it was reported 59

6o 61

62 63

A. F. Cameron, J. D. Connolly, A. Maltz, and D. A. H. Taylor, Tetrahedron Lett., 1979, 967. D. P. Chakraborty, P. Bhattacharyya, S . P. Bhattacharyya, J. Bordner, G. L. A. Hennessee, and B. Weinstein, J. Chem. SOC.,Chem. Commun., 1979, 246. B. Epe and A. Mondon, Tetrahedron Lett., 1979, 2015. B. L. Sondengarn, C. S . Karnga, and J. D. Connolly, Tetrahedron Lett., 1979, 1357. B. L. Sondengam, C. S . Kamga, and J. D. Connolly, unpublished results. W. Kraus and K. Kypke, Tetrahedron Lett., 1979, 2715.

147

Triterpenoids

- -0Ac

'OH 0

0 *

OAc

"OH

0 "OAc

(76) R1 = H, R2 = 0 (77) R' = Ac, R2 = H,a-OAc

'OAc

148

Terpenoids and Steroids

that the nomilin derivative (78) had been isolated from a member of the Rubiaceae, Uncaria gambia. The identification of the botanical source was erroneous. Subsequent work has shown that the true source is Xylocarpus mollucensis, a member of the Meliaceae family.64Febrifugin, from the heartwood of Soymida febrifuga, is 6-deoxyswietenine (79).65

Further publications have appeared on the group of Complex tetranortriterpenoids, related to rohitukin and dregeanin (see Vol. 8, p. 165), which exist in solution at room temperature as mixtures of sterically hindered conformational isomers. The structures of three new compounds, D-4 (80) and D-5(81) from the bark of Trichilia prieuriana, and B (82) from the root bark of Guarea thompsonii, have been assigned.66The reaction of these compounds to alkaline hydrolysis is exemplified by dregeanin (83) which gave the C-1 epimers (84) and (85) and in addition the hemiorthoester (86) or (87) and the bis-lactone (88).66 All the hydrolysis products have a 1,ll-ether function which prevents rotation about the C-9-C-10 bond and thus removes the source of the broadness observed in the room-temperature n.m.r. spectra of the parent compounds. The proposed intermediacy of a A'-compound in the alkaline hydrolysis reaction is supported by the fact that D-4 (80) afforded the same products as dregeanin. Compound C (89),

64

" 66

D. A. H. Taylor, personal communication. M. M. Rao, E. M. Krishna, P. S. Gupta, and P. P. Singh, Indian J. Chem., Sect. B, 1978,16, 823. J. D. Connolly, C. LabbC, D. S. Rycroft, D. A. Okorie, and D. A. H. Taylor, J. Chem. Res., 1979, (S) 256, ( M )2858.

Triterpenoids

M

e

149

0

2

C

G

HOH2CQ

M

e

0

C

p

HOH2C 0

0 (85)

(84)

+H

oco I

HO

2

,

0

Meo \,"

OH

150

Terpenoids and Steroids

from G. thompsonii, represents a natural 1 , l 1-ether.66The seeds of Aphanamixis polystacha provide a rich source of related complex tetranortriterpenoids. Eight new compounds (90)-(97) have been isolated and their structures elucidated by spectroscopic This group includes the first examples of compounds with a 15a-acetate function and, in addition, three further natural 1,ll-ethers (95)-( 97).

0R'

0

(90) R1 =

hco

, R 2 = H,R3 = H,a-OAc

OH

HCO, (91) R'

0

=

(92) R1 =

co

, R2 = H, R3 = H,a-OAc

hco , R 2 = Ac,R3 = 0

0

0

AcOH ,C (93)

(95)

67

(94)

(96) R (97) R

D. A. Brown and D. A. H. Taylor, Phytochemistry, 1978, 17, 1995.

= =

H,a-OAc 0

151

Triterpenoids

Pentanortriterpen0ids.-The latest results on this fascinating group of compounds from the Cneoracea serve to clarify some of the structural and stereochemical relationships.68 The structure of the hemiacetal cneorin K (98) was confirmed by X-ray analysis. The corresponding epoxide, tricoccin Rlo (99), on treatment with acid, afforded cneorin B1 (100) with the characteristic spiroacetal function. Cneorin K1 (101) and tricoccin R1(102)are the respective methyl acetals of cneorin K and tricoccin Rlo. Two further structural variants are represented by tricoccins SI4(103)and R, (104). The latter was transformed into cneorin BIII (105) by reactim with boron trifluoride etherate. A series of compounds containing a ring D hemiacetal in place of the usual y-lactone has been isolated.69Two of these, tricoccins S4 (106) and S,, (107), are stabilized by intramolecular acetal formation.

m3i \

0

=(y-q -

H

0

(98) R = H (101) R = Me

0

(99) R

=

R

=

(102)

H Me

A

0

68 69

A. Mondon, B. Epe, and D. Trautmann, Tetrahedron Lett., 1978, 4881. B. Epe, D. Trautmann, A. Mondon, and G. Remberg, Tetrahedron Lett., 1979, 1365.

152

Terpenoids and Steroids

F

0

Ch

0

(F \

HO

'.("

0

0

Quassinoids.-The structure of soulameolide (log), a new C25quassinoid from Soulamea tomentusa, has been established by X-ray analy~is.~' The search for biologically active compounds continues. Undulatone (109) from Hannoa ~ n d u l a t a 6a , ~ -tigloyloxychapparinone ~ ( 1 10) from Ailanthus i n t e g r i f ~ l i aand ,~~ 6a -senecioylchapparinone (1 1 1 ) from Simaba m~ltiflora'~ have antileukaemic

0 '0

' 70

71

72 73

(108)

J. Polonsky, M. V. Tri, T. PrangC, C. Pascard, and T. Sevenet, J. Chem. Soc., Chem. Commun., 1979, 641. M. C . Wani, H. L. Taylor, J. B. Thompson, M. E. Wall, A. T. McPhail, and K . D. Onan, Tetrahedron, 1979,35, 17. A. A. Seida, A. D. Kinghorn, G. A. Cordell, and N. R. Farnsworth, Lloydia, 1978, 41, 584. M. C. Wani, H. L. Taylor, J. B. Thompson, and M. E. Wall, Lloydia, 1978,41, 5783.

Triterpenoids

153

OR'

=wco ,R2 R' =wc0 ,R2 H

(109) R'

=

(110)

=

(111) R'

OAc

=hco ,R2 = H

activity which is due in part to the presence of the 6a-oxygen function. The structural requirements for antineoplastic activity in quassinoids have been discu~sed.'~The full details of the structure of bruceoside A (112), an antileukaemic glycoside from the seeds of Brucea javanica, have appeared." This paper includes another active glucoside, bruceoside B (113). Castelanone (1 14), from Castela tweedii, is glaucarubolone 1 5 - i s o ~ a l e r a t e . ~ ~

0

4 Shionane-Baccharane Group The full paper on the partial synthesis of methyl trisnorshionanoate (115) from friedelan-19a-01 has appeared77 (see Vol. 8, p. 168).

74

75

76 77

M. E. Wall and M. C. Wani, J. Med. Chem., 1978, 21, 1186. K.-H. Lee, Y. Imakura, Y. Sumida, R.-Y. Wu, I. H. Hall, and H.-C. Huang, J. Org. Chem., 1979,44, 2180. J. Polonsky, Z. Varon, and E. Soler, C. R. Hebd. Seances Acad. Sci., Ser. C, 1979, 288, 269. Y. Yokoyama, T. Tsuyuki, Y. Moriyama, T. Murae, H. Toyoshima, and T. Takahashi, Buff.Chem. SOC.Jpn., 1979,52, 1720.

Terpenoids and Steroids

154 5 Lupane Group

The details of the X-ray analysis of 3/3,28-diacetoxy-18/3,19/3-epoxylupane (116) have a p p e a ~ e d ' ~(see Vol. 8, p. 168). Four lupane derivatives, 20,29epoxylupan-3-one (117), 20,29-epoxy-22a -hydroxylupan-3-one (1IS), 30hydroxylup-20(29)-en-3-one (119), and 30-hydroxylupeol (120), have been .~~ was also obtained from isolated from Flourensia h e t e r ~ l e p i s30-Hydroxylupeol Gymnosporia wallichiana.80 The first reported occurrence was in Quercus championii (see Vol. 8 , p. 170). Other new compounds include rigidenol [6ahydroxylup-20(29)-en-3-one](12 1) from Maytenus rigida" and betulinic acid 3-~-/3-D-glucopyranosyl-( 1 + 6)-/3-~-glucopyranoside(122) from Eryngium bromeliifolium.82

& -!

H,OAC

Rl&.X2

AcO

(116)

CH,OH

(117) R' = 0 , R 2 = H (118) R1 = 0 , R 2 = OH

4.

4.

As (117)

:1-3

(119) R' = 0 (120) R' = H,P-OH

4HY CH,OH

HO

OH 78 79

M2

L. Hiltunen and L. Niinisto, Acta Cryst., Ser. B, 1979, 35, 1530. F. Bohlmann and J. Jakupovic, Phytochemistry, 1979, 18, 1189. D. K. Kulshreshtha, Phytochemistry, 1979, 18, 1239. M. Marta, F. Delle Monache, G. B. Marini-Bettolo, J. F. De Mello, and 0. Goncalves De Lima, Gazz. Chim. Ital., 1979,109,61. K. Hiller, K. Q. C. Nguyen, and P. Franke, 2. Chem., 1978,18, 260.

Triterpenoids

155

Dry ozonization of 3P,28-diacetoxylupane afforded 19p-hydroxy-3P,28diacetoxylupane (123).83During the course of this work the lactone (124) was prepared. The physical properties of this lactone differ from these reported for a compound from Dillenia indica which was assigned the structure (124). This

suggests that the structure of the natural compound requires revision. The preparation of a series of 12,20-disubstituted lupanes has been described.84 Cultured cells and leaves of Duboisia leichhardtii produce lupeol in contrast to the whole plant which yields oleanolic acid, ursolic acid, and related

6 Oleanane Group Acacigenin B (125), from the pods of Acacia concinna, has a novel monoterpenoid moiety attached to C-21.86 It occurs with the nortriterpenoid diene acacidiol (126) and acacic acid lactone monoacetate (127).87 Three other

HO

83 84

85 86 87

E. Suokas and T. Hase, Acta Chem. Scand., Ser. B, 1978,32,623. V. Pouzar and A. VystrEil, Collect. Czech. Chem. Commun., 1979,44, 194. K. Kagei, M. Ikeda, T. Sato, Y. Ogata, S. Toyoshima, and S. Matsuura, Yakugaku Zasshi, 1979,99, 583. A. S. R. Anjaneyulu, M. Bapuji, L. R. Row, and A. Sree, Phytochemistry, 1979,18,463. A. S. R. Anjaneyulu, f.. R. Row, and A. Sree, Phytochemistry, 1979,18, 1199.

Terpenoids and Steroids

154

HO

noroleanene derivatives, maragenins I (128), I1 (129), and I11 (130), have been isolated from Marah macrocarpus.88 The structure of (128) was confirmed by partial synthesis from echinocystic acid. Astrantiagenin G (13l ) , from Astrantia major, has the structure of one of the intermediates in the synthesis of primulagenin and echinocystic acid from oleanolic acid89(see Vol. 4, p. 210). Other new compounds include 3-0-cis-p-coumaroylmaslinic acid (132) from the fruits of Ziziphus jujuba," gymnorhizol (3-epi-8-amyrin) (133) from the leaves of Bruguera gymnorhi~a,~' 3-epierythrodiol (134) from Salvia l e ~ c a n t h a and ,~~ moronic acid (135) from Roylea e l e g a n ~ . ~ ~

0

HO

" 89

9" 9' 92 93

P. J. Hylands and A. M. Salama, Tetrahedron, 1979, 35, 417. H. D. Woitke, K. Hiller, and P. Franke, Pharmazie, 1978, 33, 541. A. Yagi, N. Okamura, Y. Haraguchi, K. Noda, and I. Nishioka, Chem. Pharm. Bull., 1978,26,3075. A. Sarkar and S. N. Ganguly, Zndian J. Chem., Sect. B, 1978, 16,742. K. S. Mukherjee and P. K. Ghosh, Current ScL, 1979,48, 107. P. L. Majumder, R. N. Maiti, S. K. Panda, D. Mal, and E. Wenkert, J. Org. Chem., 1979,44,2811.

Triterpenoids

157

Further work on the free and ester-bound triterpenoid alcohols in cellular subfractions of Calendula officinalis flowers has appeared.94An investigation of the mass spectral fragmentation of pentacyclic hydrocarbons in petroleum has been published.95 Attempted catalytic hydrogenation of the triterpenoid synthetic intermediate (136) resulted in methyl group migration with formation of ( 137).96

Papers have appeared on the effect of different reagents on the course of the dehydration of the 3P-hydroxy-group of acacic acid lactone and related pentacyclic triterpenoids,” the ring A conformation of 2-methyl-3-hydroxy- and 2-methyl-3-0x0-derivatives of 19/3,28-epoxy-l8a -01eananes,~’ the use of lead B. Wilkomirski and Z. Kasprzyk, Phytochemistry, 1979,18,253. B. G. Niyazov, S. R. Sergienko, A. A . Polyakova, and A. Aidogdyev, Izu. Akad. Nauk. Turkrn.SSR, Ser. Fiz.-Tekh., Khim. Geol. Nauk, 1979, 84. 96 J. W. ApSimon and I. Toth, J. Chem. Soc., Chem. Commun., 1979, 67. 97 A. S. R. Anjaneyulu, M. N. Rao, L. R. Row, and A. Sree, Tetrahedron, 1979,35, 519. ’’ 3. Klinot, J. Svctly, D. KulaEkova, M. Budtiinsky, and A. VystrEil, Collect. Czech. Chem. Commun., 1979, 44, 211. 94 95

Terpenoids and Steroids

158

tetra-acetate for cleavage of ring A in the conversion of a - and p-amyrin into roburic and nyctanthic acids,99and lithium-ethylenediamine reduction of some triterpenoid dienes. loo Further work on the saponins of Tetrapanax papyriferum has shown that papyriosides LIIc and LIId are glycoside esters of 11a -hydroxy-3,21-dioxoolean-12-en-28-oic acid (138) and 3 a , l l a -dihydroxy-21-oxo-olean-12-en-28oic acid (139) respectively."' Papyriosides LIIa and LIIb are the corresponding 11a -methoxy-derivatives and may be artefacts. The structure of phytolaccosides A (140), D (141), and E (142), from the roots of Phytolacca americana, have been elucidated. ' 0 2 Publications have appeared on saponins of Fatsia j a p ~ n i c a , ~ ~ ~ Bupleuri radix,lo4 Amaranthus s p i n o s u ~ chikusetsusaponin ,~~~ I1 from Panacis japonicus,106rivularinin from Anemone r i ~ ) ~ E a r and i s , ~lebbekanins ~~ D, E, F, G, and H from the flowers of Albizsia lebbek.'08*109

R2

0 QO

(138) R (139) R

=

0

=

H,a-OH

@02H' C H 2 0 H

R' OH (140) R1 = R2 = H (141) R' = @-D-glu,R2= H (142) R1 = P-D-glU, R2 = OH

The structure of salaspermic acid (143), a new friedelane hemiacetal from the stem and root wood of Salacia macrosperma, was confirmed by X-ray analysis of the rearrangement product (144).'lo Six new oxygenated friedelanes have been isolated from Kokoona zeylanica. Kokoonol (145), kokoonidiol (146), and kokoononol (147) provide rare examples of C-27 oxygenation'" and zeylanol (148), zeylanonol (149), and zeylandiol (150) are 6~-hydro~y-derivatives."~ 99 loo

A. K. Dev, G. K. Trivedi, and S. C. Bhartacharyya, Indian J. Chem., Sect. B, 1978, 16, 8. P. Sengupta, M. Sen, and N. S. Rao, Indian J. Chem., Sect. B,1 9 7 8 , 1 6 , 7 3 8 .

"' S. Amagaya, T. Takeda, Y. Ogihara, and Y. Yamisaki, J. Chem. SOC.,Perkin Trans. I, 1979,2044. W. S. Woo, S. S. Kang, H. Wagner, 0. Seligmann, and V. M. Chari, Planta Med., 1978,34, 87. T. Tomimori and H. Kizu, Yakugaku Zasshi, 1979, 9 9 , 9 2 . lo4 H. Kimata, C. Hiyama, S. Yahara, 0.Tanaka, 0.Ishikawa, and M. Aiura, Chem. Pharm. Bull., 1979, 27, 1836. Io5 N . Banerji, Indian J. Chem., Sect. B, 1979, 17, 180. '06 T.-D. Liu and J. Shoji, J. Chin. Chem. SOC.(Taipei), 1979,26, 29. lo7 K. P. Tiwari and R. B. Singh, Phytochemistry, 1978,17, 1991. lo* I. P. Varshney and D. C. Jain, Indian J. Chem., Sect. B, 1978, 16, 1131. '09 I. P. Varshney, P. Vyas, H. C. Srivastava, andP. P. Singh, Natl. Acad. Sci. Lett. (India), 1979,2,135. ' I o N . I. Viswanathan, J. Chem. SOC.,Perkin Trans. I, 1979, 349. "' A. A . L. Gunatilaka, N. P. D . Nanayakkara, and M. U. S. Sultanbawa, J. Chem. SOC.,Chem. Commun., 1979,434. A. A . L. Gunatilaka, N . P. D . Nanayakkara, and M. U. S. Sultanbawa, TetrahedronLett., 1979,1727. Io2

'03

159

Triterpenoids

R

R

0

OH (145) R = 0 (146) R = H,a-OH (147) R = H,H

(148) R = H,H (149) R = 0

(150) R

=

H,p-OH

3a-Hydroxyfriedelan-2-one (15 1) and 2P-acetoxyfriedelan-3-one (152) (epicerin) have been obtained from the bark of Quercus suber.l13 Homonuclear INDOR techniques, in conjunction with shift reagents, have been used for the In the course of assignment of methyl groups in friedelin-related this work the structures of pachysandienols A (153) and B (154), from Pachysandra terminalis, were determined.

'14

S. K. Talpatra, D. K. Pradhan, and B. Talpatra, Indian J. Chem., Sect. B,1978, 16, 361. T. Kikuchi, T. Shingu, T. Yokio, and M. Niwa, Chem. A h . , 1979, 90, 121 822.

Terpenoids and Steroids

160

Dry ozonization of friedelane afforded a range of products including the 3-, Chemical 15-, 16-, 19-, and 21-0x0-derivatives and lSp,l9p-epo~yfriedelane.~~~ evidence for the structures of putrone (155) and putrol(156), 25-norfriedelanes from the leaves of Putranjiva roxburghii, has been provided by the conversion of putrone (155) and 25-acetoxyfriedel-7-ene (157) into the same diene (158).l16 The full details of the preparation of glut-5(1O)-en-l-one have appeared117(see Vol. 9, p, 211). Boron tribromide is an efficient catalyst for the rearrangement of 3P-acetoxyglut-5-ene (159) and 3P-acetoxyglut-5(10)-ene(160) to P-amyrin acetate.' l8

(155) R (156) R

= =

0 H,(Y-OH

(159) As (160)

7 Ursane Group

The assignment of the I3C chemical shifts of a series of compounds related to 19a-hydroxyurs-12-en-28-oicacid has been reported."' Clethric acid (161), from the leaves of Clethra barbinervis, is a further member of this series.119A new ring A seco-derivative, calaminthadiol (162), hm been isolated from Satureia calamintha and S. graeca.lZoOther new compounds include rubitic acid (163) from Rubus fruticosus,121uncaric acid (164), diketouncaric acid (165) and diacetoxyuncaric acid (166) from Uncaria thwaitesii,'" and 23-hydroxytormentic

'"

E. Akiyama, M. Tada, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC. Jpn., 1979,52, 164. P. Sengupta, M. Sen, S. N. Rao, and K. G . Das, J. Chem. SOC.,Perkin Trans. I, 1979,60. E. Akiyama, Y. Moriyama,T. Murae,T.Tsuyuki, andT.Takahashi,Bull. Chem. SOC. Jpn., 1978,51, 2702. A . Chatterjee, S. K. Saha, and S. Mukhopadhyay, Indian J. Chem., Sect. B, 1978,16, 1038. 'I9 K . Takahashi and M. Takani, Chem. Pharm. Bull., 1978, 26,2689. l Z o P. Giannetto, G. Romeo, and M. C. Aversa, Phytochemistry, 1979, 18, 1203. '" A . Sarkar and S. N. Ganguly, Phytochemistry, 1978,17, 1983. lZz W. H. M. W. Herath, M. U. S. Sultanbawa, and G . P. Wannigama, Phytochemistry, 1978,17, 1979. 'I6

161

Triterpenoids

8

HO

(163) “OH

2H

R (164) R = HJ-OH (165) R = 0 (166) R = H,P-OAc

acid (167) from Epilobium h i r ~ u t u m . An ’ ~ ~X-ray analysis of methyl ursolate-3p-bromobenzoate has been p ~ b 1 i s h e d . l ~ ~ Irradiation of marsformoxide A (168) in acidic solution afforded the dienes (169) and (170).’25

123

lZ4 12’

T. J. De Pascual, B. Corrales, and M. Grande, An. Quim., 1979, 75, 135. W. F. Paton and I. C. Paul, Cryst. Struct. Commun., 1979,8, 207. K. Ito and J. Lai, Chem. Pharm. Bull., 1979, 21, 210.

Terpenoids and Steroids

162

Two new taraxastenes, heliantriols C (171) and F (172), have been isolated from the flowers of Helianthus annuus and their structures confirmed by correlation with faradiol ( 173).126Further studies of the mass spectral fragmentation of 16-oxotaraxastenes have been p ~ b 1 i s h e d . l ~ ~

(171) R' = H,a-OH,R2 = Me (172) R1 = H,H, R2 = CH20H (173) R1 = H,H, K2 = Me

8 Hopane Group 29-Ethoxyhopane (174) has been reported from the fern Oleandra neriifolia.12* The configuration at C-22 was confirmed by a partial synthesis of (174) from neriifoliol. The natural occurrence of an ethoxy-compound is unusual. The full paper on the structural elucidation of mollugogenol F (175), from Mollugo hirta, has appeared.129

-vH CH,OEt

2

OH

0

H

Fernenol palmitate (176) and 3p -acetoxyfern-9(1l)-ene (177) have been Trematol (178), from the isolated from the fern Polypodium ~ubpetiolaturn.'~~ stem bark of Trema orientalis, is the C-21 epimer of fernenol with which it CO-OCCU~S.~~~

n

@ (178) R

(177) R = Ac 126 12'

128 129 13" 13'

=

H

J. St. Pyrek, Pol. J. Chem., 1979,53, 1071. J. St. Pyrek, Pol. J. Chem., 1979, 53, 1795. A . Goswami, A . Dasgupta, A . Nath, T. K. Roy, and H. N. Khastgir, Tetrahedron Lett., 1979, 287. M. K. Choudhury and P. Chakrabarti, Phytochemistry, 1979,18, 1363. C. Anderson, F. Fuller, and W. W. Epstein, J. Nut. Prod., 1979, 42, 168. C. A . Obafemi, L. Ogunkoya, J. A . K. Quartey, and E. S. Waight, Phytochemistry, 1979, 18, 496.

163

Triterpenoids

9 Stictane Group

A new group of secostictanes has been isolated from the lichen Pseudocyphellaria degeZii.13’ It includes the acid (179), the aldehyde (180), and the acetate (181). G.c.-m.s. provides a powerful tool for the study of the stictane lichen triter~en0ids.I~~

(179) R = COzH (180) R = CHO (181) R = C H ~ O A C

13*

133

E. M.Goh, A. L. Wilkins, and P. T. Holland, J. Chem. SOC.,Perkin Trans. I, 1978, 1560. P. T. Holland and A. L. Wilkins, Org. Mass Spectrom., 1979, 14, 160.

4 Ca rote no ids a nd PoI yte r pe no ids BY G. B R I T O N

1 Carotenoids Reviews.-The main lectures of the 5th International Symposium on Carotenoids, held at Madison, Wisconsin, U.S.A. in 1978, have been published.' The chemistry section includes two general and historical surveysln'bas well as reviews on recent developments in the characterization, chemistry, and stereochemistry of carotenoids,lc and on physico-chemical and synthetic studies.ld Specialized chapters deal mainly with the synthesis of polyenes via phosphonium ylides,'" of optically active carotenoids,'f of carotenoid glycosyl esters," and of canthaxanthin.lh The biochemistry section also includes a general historical survey of carotenoid biosynthesis' and detailed reports on prenyl transferase," on enzymic,Ik general," and genetic'" aspects of carotenoid biosynthesis, on the violaxanthin cycle,'" and on photoprotection by carotenoids.'" The usefulness of carotenoids in chemosystematics and taxonomylPand the role of carotenoids and related substances in plant physiology14 are discussed, and some functions of vitamin A and related retinoids are considered.ir*SThe proceedings of two other relevant symposia have been published. One' deals with the biochemical functions of terpenoids, including carotenoids, abscisic acid, xanthoxin, trisporic acid, polyprenyl phosphates, and prenylquinones in plants, the other3 with molecular aspects of the visual processes. Reviews published include a historical discussion of carotene and provitamin A,4and surveys of marine carotenoids,' carotenoids in the Crustaceae,6 and the Pure Appl. Chem., 1979,51, pp. 435-4375, 857-886, also published as 'Carotenoids-5 (Madison, 1978)', ed. T. W. Goodwin, Pergamon Press, Oxford, 1979; ( a )B. C. L. Weedon, p. 435; (6) 0.Isler, p. 447; ( c )C. H. Eugster, p. 463; ( d ) G. P. Moss, p. 507; ( e )H. J. Bestmann, p. 515;(f) H. Mayer, p. 535; (g) H. Pfander, p. 565; ( h )M. Rosenberger, P. McDougal, G. Saucy, and J. Bahr, p. 871; ( i ) T. W. Goodwin, p. 593; ( j ) H. C. Rilling, p. 597; (k) J. W. Porter and S. L. Spurgeon, p. 609; (I) B. H. Davies, p. 623; ( m )E. Cerda-Olmedo and S. Torrez-Martinez, p. 631; ( n )H. Y. Yamamoto, p. 639; (0)N. I. Krinsky, p. 649; ( p )S. Liaaen-Jensen, p. 661; ( 4 )H. Thommen, p. 867; (r) L. M. De Luca, S. Adamo, P. V. Bhat, W. Sasak, C. S. Silverman-Jones, I. Akalovsky, J. P. Frot-Coutaz,T. R. Fletcher, and G. J. Chader, p. 581; (s) R. K. Boutwell and A. K. Verma, p. 857. 'The Biochemical Functions of Terpenoids in Plants', ed. T. W. Goodwin, Philos. Trans. R. SOC. London, Ser. B, 1978,284,439. Photochem. Photobiol., 1979, 29, 655. P. Karlson, Trends Biochem. Sci., 1978,3, 235. S . Liaaen-Jensen, in 'Marine Natural Products: Chemical and Biological Perspectives', ed. P. J. Scheuer, Academic Press, New York, 1978, Vol. 2, p. 1. R. Lenel, G. Negre-Sadargues, and R. Castillo, Arch. 2001. Exp. Gen., 1978, 119, 297.

164

Curoten oids and Po 1y terpenoids

165

chemistry’ and biosynthesis8 of carotenoids in photosynthetic bacteria. Carotenoid epoxides are included in a review’ on terpenoid epoxides. Other articles deal with retinoids” and abscisic acid.” New Structures and Stere0chemistry.-New Curotenoid Structures. A mutant strain of Rhizobium lupini contains a new nor-carotenoid, 2’,3’-truns-dihydroxy2-nor-P7P-carotene-3,4-dione (l).” The wild-type R. Eupini, when cultured in the presence of the cyclization inhibitors nicotine or CPTA, produced three new monocyclic carotenoids, 2,3-truns-dihydroxy-P, +-caroten-4-one (2), 3-hydroxyP,+-caroten-4-one (3), and P,+-carotene-2,3-tns-diol (4),13 which were characterized by m.s. and ‘H n.m.r. The light absorption and mass spectra of a carotenoid from Rhodopseudomonus cupsuluta allowed its identifi~ation’~ as demethylspheroidenone [1-hydroxy-3,4-didehydro- l,2,7’,8’-tetrahydro-t,b7t,bcar0ten-2-one (91. Unusual structures have been reported for several carotenoids of animal origin. The moth Cerulu vinulu contains small amounts of P7P-caroten-2-one(6).15The location of oxygen functions at C-2 was also suggested’‘ for four carotenoids from the red tilefish, which were provisionally identified as P,~-carotene-3,2’-diol(7), 3,2’-dihydroxy-P,~-caroten-4-one (8), 2,3‘-dihydroxy-P,P-carotene-4,4’-dione (9), and 3,3’-dihydroxy-~,~-carotene-4,2’-dione (10). Tedaniaxanthin, from the sponge Tedunia digitutu, has been assigned17718 the revised structure 7,8-didehydro-P7x-caroten-3-ol (11).rather than the remarkable 2,3-didehydro-P,~caroten-3-01 (12) structure previously suggested. l 9 Apocurotenoids. A new C,, diapocarotenoid has been isolated from the bacterium Pseudomonus rhodos and identified by m.s. and ‘H n.m.r. as 4,4’-diapocarotene4,4’-dioic acid (13). It occurs as mono- and di-glucosyl esters, and with the glucose residues esterified with fatty acids.” New Stereochemical Assignments. cis-Isomers. The structure of the poly-ciscarotenoid prolycopene from the Tangerine tomato mutant has been determinedz1-*’ by detailed ‘H and I3C n.m.r. studies as 7,9,7’,9’-tetra-cis-t,b7t,bcarotene (14). The phytoene 7,8,1 1,12,7’,8’,ll’,12’-octahydro-t,b7+-carotene

lo

12

l3

l4 l5

l6

” l8 l9 21

22

’’

S. Liaaen-Jensen, in ‘Photosynthetic Bacteria’, ed. R. K. Clayton and W. R. Sistrom, Plenum, New York, 1978, p. 233. K. Schmidt, ref. 7, p. 729. S. Voigt and M. Luckner, Pharmazie, 1978, 33, 632. H. Mayer, W. Bollag, R. Hanni, and R. Ruegg, Experientia, 1978,34, 1105. B. V. Milborrow, in ‘Phytohormones and Related Compounds, a Comprehensive Treatise’, ed. D. S. Letham, P. B. Goodwin, and T. J. V. Higgins, Elsevier, Amsterdam, 1978, Vol. 1, p. 295. P. Beyer, H. Kleinig, W. Meister, and G. Englert, Z. Namrforsch., 1979, 34c, 179. H. Kleinig, W. Meister, and G. Englert, Arch. Microbiol., 1978, 119,71. J. Manwaring, C. A. Pullin, E. H. Evans, and G. Britton, Biochem. SOC.Trans., 1978, 6 , 1041. H. Kayser, Z. Naturforsch., 1979, 34c, 483. M. Asahara, S. Matsuno, and S. Matsumori, Bull. Jpn. SOC.Sci. Fisheries, 1979, 45, 485. Y. Tanaka and T. Katayama, Bull. Jpn. SOC.Sci. Fisheries, 1979, 45, 633. Y. Tanaka, Kagoshima Daigaku Suisangakubu Kiyo, 1978, 27, 355. Y. Tanaka, Y. Fujita, and T. Katayama, Bull. Jpn. SOC.Sci. Fisheries, 1977, 43, 761. H. Kleinig, R. Schmitt, W. Meister, G. Englert, and H. Thommen, Z. Naturforsch., 1979, 34c, 181. G. Englert, B. 0.Brown, G. P. Moss, B. C. L. Weedon, G. Britton, T. W. Goodwin, K. L. Simpson, and R. J. H. Williams, J. Chem. Soc., Chem. Commun., 1979, 545. G. Englert, Helv. Chim. Acta, 1979, 62, 1497. J. M. Clough and G. Pattenden, J. Chem. SOC.,Chem. Commun., 1979,616.

166

Terpenoids and Steroids

0 d

e

h

f

1

j

k

(1) R’ = a, RZ = b (X = H,OH. Y = H,OH) (2) R’ = c (X = H,OH, Y = H,OH), R2 = d (3) R’ = c (X = H,H, Y = H,OH), R2 = d (4) R’ = b (X = H,OH, Y = H,OH), R2 = d (5) R ’ = e, R2 = f (6) R’ = b (X = 0, Y = H,H), R2 = b (X = H,H, Y = H,H) (7) R’ = b (X = H,H, Y = H,OH), R2 = g (X = H,OH, Y = H,H) (8) R’ = c (X = H,H, Y = H,OH), R2 = g (X = H,OH, Y = H,H) (9) R’ = c (X = H,OH, Y = H,H), R2 = c (X = H,H, Y = H,OH) (10) R’ = c (X = H,H, Y = H,OH), R2 = g (X = 0, Y = H,OH) (11) R’ = h , R 2 = i (12) R’ = j , R 2 = i (13) R’ = R2 = k

(15), phytofluene [7,8,11,12,7’,8’-hexahydro-$,$-carotene(16)], {-carotene [7,8,7’,8’-tetrahydro-+, +-carotene (17)],and neurosporene [7$-dihydro-$, $carotene (18)], isolated from the same tomato strain, have similarly been identified as the 15-cis-, 15,9’-di-cis-, 9,9’-di-cis-, and 9,7‘,9’-tri-cis-isomers r e ~ p e c t i v e l y The . ~ ~ antheraxanthin isomer isolated from the pollen of Lilium candidum has been to be the 9-cis-isomer [9-cis-5,6-epoxy-5,6-dihydro-P,P-carotene-3,3’-diol (19)]. 24

G. Toth, J. KajtAr, P. Molnar, and J . Szabolcs, Acta Chirn. Acud. Sci. Hung., 1978, 97, 359.

C aroten oids a n d Po 1y terpert o ids

L

167

(14)

2

a

(15) (16) (17) (18)

R’ = R2 = a (15-cis) R’ = a, R2 = b (15-cis) R’ = R2 = b R’ = b , R 2 = c b

Absolute configurations. The chirality of samples of tunaxanthin ( F , F -carotene3,3’-diol) obtained from several species of fish has been determined by ‘H n.m.r. and c.d. All were shown by c.d. correlation to have the (6S,6’S)configuration, i.e. opposite to that at C-6’ of lutein [(2R,3’R,6’R)-P,e-carotene-3,3’-diol(20)]. The sample from the tuna fish (Thunnus sp.) had two different end-groups, with 3,6-cis and 3’,6’- trans stereochemistry respectively, and hence it was the (3R,6S,3’S,6’S) isomer (21).25Three main isomers were obtained from the skin of Oxyjulis californica and identified as (3R,6S,3‘S,6’S), (3S,6S,3’S,6’S), and (3R,6S,3’R,6‘S) respectively, (21)-(23).26 Natural eschscholtzxanthin (4‘3didehydro-4,5’-retro-P,P-carotene-3,3’-diol) was shown by c.d. and ‘H n.m.r. to be identical to a semi-synthetic sample prepared from zeaxanthin [(3R,3‘R)-P,Pcarotene-3,3’-diol (24)] and therefore to have the (3S,3’S) configuration (26).27 The nor-carotenoid actinioerythrol [3,3’-dihydroxy-2,2’-dinor-&p-carotene4,4’-dione (25)] from the sea anemones Actinia equina and A. tenebrosa has been shown by two groups to have the (3S,3’S) configuration. One paper reports the c.d. correlation of natural actinioerythrol with synthetic (3S,3’S) and (3R,3’R) 25

26 27

H. R~nneberg,G. Borch, S. Liaaen-Jensen, H. Matsutaka, and T. Matsuno, Acta Chem. Scand., Ser. B, 1978,32,621. A . Bingham, jun., D. W. Wilkie, and H. S. Mosher, Comp. Biochem. Physiol., 1979, B62, 489. A. G. Andrewes, G. Englert, G. Borch, H. H. Strain, and S. Liaaen-Jensen, Phytochemistry, 1979, lS, 303.

Terpenoids and Steroids

168

isomers,28whereas in the second paper ozonolysis of natural actinioerythrol is reported to give a fragment (27),the chirality of which was determined by 0.r.d. comparison with synthetic

a

(20) R' (21) R' (22) R'

b

= = =

a,R2 = b c, R2 = d R2 = d

C

(23) R' = R2 = c (24) R' = R2 = a (25) R1 = R2 = e

New Natural Products Related to Carotenoids. Several new compounds have been identified which have carotenoid-like rings but short isoprenoid or modified isoprenoid side-chains. Some of these compounds may be derived from carotenoids either biosynthetically or by degradation occurring during processing of natural tissues. The latter is likely to be true of some compounds isolated from cured tobacco, e.g. (3S,5R,6S)-3-hydroxy-5,6-epoxy-5,6-dihydro-~-ionol (28),303-oxoactinidiol (29)31,and the 1-(2,3,6-trimethylphenyl)-but-2-en-l-one (30)32related to p-damascenone (31)and the aromatic carotenoids. Megastigmafrom passion 5,8(E)-dien-4-one (32)has been obtained from Virginia f r ~ i t , and, ~ ' along with megastigma-5,7(E),9-trien-4-one(33), from Osmanthus absolute.34The passion fruit, Passifloru edulis, has also afforded two other related 28

R. K. Muller, H. Mayer, K. Noack, and J. J. Daly, Helv. Chim. Actu, 1978,61, 2881.

30

Y. Takagi, T. Fujimori, H. Kaneko, T. Fukuzumi, and M. Noguchi, Agric. Biol. Chem., 1978,42, 1785. R. Uegaki, T. Fujimori, H. Kaneko, K. Kato, and M. Noguchi, Agric. Biol. Chem., 1979,43,1149. E. Demole and P. Enggist, Helv. Chim. Actu, 1978, 61, 2318. E. Demole, P. Enggist, M. Winter, A. Furrer, K. H. Schulte-Elte, B. Egger, and G. Ohloff, Helv. Chim. Acta, 1 9 7 9 , 6 2 , 6 7 . R. Kaiser and D. Lamparsky, Helv. Chim. Actu, 1978,61, 2328.

'' P. S. Foss, P. J. Green, and R. W. Rickards, Aust. J. Chem., 1978,31, 1981. 31 32 33

34

Caroten oids and Pol y te rpen oids

169

0

compounds (34) and (35)35 and two further edulan derivatives (36) and (37).'6 The structures of two carotenoid-like diterpenoids, trixagol (38) from Bellardia t r i ~ a g and o ~ ~jhanic acid (39) from Eupatorium jhanii,38have been determined.

(40)

(41)

The defensive secretions of two species of termites contain (40)39and (41).40 Various marine sources have yielded the bromo-compounds (42) and (43),41 (44),42(45),43 and (46).44 35 36

37

38 39 40 4'

42 43

44

F. B. Whitfield and G. Sugowdz, Aust. J. Chem., 1979, 32, 891. M. Winter, K. H. Schulte-Elte, A. Velluz, J. Limacher, W. Pickenhagen, and G. Ohloff, Helv. Chim. Ada, 1979,62, 131. T. J. De Pascual, E. Caballero, C. Caballero, M. Medarde, A. F. Barrero, and M. Grande, Tetrahedron Lett., 1978,3491. A. G. Gonzhlez, J. M. Arteaga, B. M. Fraga, and M. G. Hernandez, A n . Quim., 1979,75, 128. R. Baker, P. H. Briner, and D. A. Evans, J. Chem. SOC.,Chem. Commun., 1978,981. R. Baker, D. A. Evans, and P. G. McDowell, Tetrahedron Lett., 1978,4073. M. Susuki, A. Furusaki, N. Hashiba, and E. Kurosawa, Tetrahedron Lett., 1979, 879. B. M. Howard and W. Fenical, Tetrahedron Lett., 1978, 2453. F. J. Schmitz, K. H. Hollenbeak, D. C. Carter, M. B. Hossain, and D. Van der Helm, J. Org. Chem., 1979,442445. A. G. Gonzalez, J. D. Martin, V. S. Martin, M. Norte, J. Fayos, and M. Martinez-Ripoll, Tetrahedron Lett., 1978,2035.

Terpenoids and Steroids

170

(45)

(44)

Carotenoid-Protein Complexes. Three paper^^^-^' describe the general properties of a violet carotenoprotein (A,, 550-570 nm) from the starfish Asterias rubens. The carotenoid prosthetic group is a mixture of astaxanthin [(3S,3’S)3,3’-dihydroxy-P,P-carotene-4,4’-dione (47)] and its acetylenic derivatives (3S,3’S)-3,3’-dihydroxy-7,8-didehydro-P,P-carotene-4,4’-dione (48) and (3S,3’S)- 3,3’-dihydroxy-7,8,7’,8’-tetradehydro-P,P-carotene-4,4’-dione(49).

Ho+

X = Y = -CH=CH(48) X = -C=C-, Y --CH=CH(49) x = Y = -C=C(47)

0

The coral Allopora californica also contains a purple-blue complex between (3S,3’S)-astaxanthin and p r ~ t e i n . ~Both ’ these proteins are relatively simple structures, with molecular weight < 80 000 daltons. Photoacoustic spectroscopy has indicated the presence of a variety of carotenoprotein species in lobster shell, the distribution varying with the depth into the Resonance Raman spectroscopy has revealed that the lobster egg pigment ovoverdin contains two astaxanthin molecules at different sites in the p r ~ t e i n . ~ ’ 45 4h

47 Jn

49

so

A. Elgsaeter, J. D. Tauber, and S. Liaaen-Jensen, Biochim. Biophys. Acru, 1978, 530,402. B. Renstroem, J. D. Tauber, A. Elgsaeter, and S. Liaaen-Jensen, Biochem. Syst. Ecol., 1979,7, 147. C. C. Shone, G. Britton, and T. W. Goodwin, Comp. Biochem. Physiol., 1979,62B, 507. H. R~nneberg,G. Borch, D. L. Fox, and S. Liaaen-Jensen, Comp. Biochem. Physiol., 1979,62B, 309. M. L. Mackenthun, R. D. Tom, and T. A. Moore, Nature (London), 1979,278,861. V. R. Salares, N. M. Young, H. J. Bernstein, and P. R. Carey, Biochim. Biophys. Actu, 1979, 576, 176.

Carotenoids and Poly terperzoids

171

b

V

h

v, v

X --0

0 X w

467 u +u

v,

W

X

+ 0 X

m

,;I

5 iij 0, X u 0 X

u

+u

+

X

0 X

.-

3:

0

172

Terpenoids and Steroids

Synthesis and Reactions-Carotenoids. The synthesis of optically active (3S73’S)astaxanthin (47) has been described.’, In the end-group construction (Scheme 1) the Grignard reaction of the protected chiral hydroxy-ketone (50) with the protected acetylenic alcohol (51) gave a 4: 1 mixture of the epimeric triols (52) and (53). Acid-catalysed allylic rearrangement of this mixture afforded a mixture of the cis- and trans-isomers (54) and (55).Oxidation of the allylic hydroxygroups followed by catalytic hydrogenation gave the C,, keto-aldehyde (56).The 7,8-cis-double bond was very stable but underwent rearrangement to the trans configuration during standard formation of the Wittig salt (57). This, on reaction with the C,, dial (58), gave (3S,3’S)-astaxanthin. (3S73‘S)-15,15’-Didehydroastaxanthin (59)was prepared in a similar manner from (57)and the acetylenic Clodial (60). R’~

&

3

C

Y

R

2

(59) R’ = R’ = a (60) R’ = R2 = CHO

I*

HO

0

2,2’-Dinor-p7p-carotene has been synthesized.’* Nor-safranal (6 1) was prepared in four steps from 4-hydroxy-2,5,5-trimethylcyclopent-2-en1-one (62) and reduced to nor-p-cyclocitral (63). With the Grignard reagent (64) this gave the alcohol (65) and thence the Wittig salt (66) which was condensed with the C,, dial (67) to give the dinor-p-carotene (68).

(68) R’ = R2 = a 5’

52

b

F. Kienzle and H. Mayer, Heiv. Chim. Acta, 1978, 61, 2609. F. Kienzle and R. E. Minder, Helv. Chim. Actu, 1978,61, 2606.

173

Carotenoids and Polyterpenoids

The intermediate 4-(t-butylthio)-but-3-en-2-onehas been used in a new synthesis of isorenieratene [c$,c$-~arotene(69)].~~ Electroreduction of retinal (70) in the presence of diethyl malonate or diethyl ethylmalonate gave the pinacol 15,15’-dihydro-&@-carotene-15,lS-diol (7 l).54

Two methods of end-group construction were used in the synthesis of methyl azafrin [methyl 5,6-dihydroxy-5,6-dihydro10’-apo-@-caroten- 10’-oate (72)].55 The first route used the epoxy-intermediate (73) which on treatment with acid gave the 5,6-diol(74). In the second procedure the trimethylcyclohexanone (75) was converted into the hydroxy-ketone (76) which reacted with the C , fragment (77) to give the acetylenic compound (78). The Wittig salt (79) was made from either (74) or (78) and used in the condensation to form methyl azafrin.

v-’OH 53 54

55

(79)

S. Akiyama, S. Nakatsuji, S. Eda, h4. Kataoko, and M. Nakagawa, Tetrahedron Lett., 1979, 2813. L. A. Powell and R. M. Wightman, J. A m . Chem. SOC.,1979,101,4412. M. Akhtar, A. E. Faruk, C. J . Harris, G. P. Moss, S. W. Russell, and B. C. L. Weedon, J. Chem. SOC.,

Perkin Trans. I, 1978, 1511.

174

Terpenoids and Steroids

The preparation of carotene models by the Horner variation of the Wittig reaction has been Thus the intermediate (80) with an unsaturated aldehyde such as (81) gave, in the presence of butyl-lithium, the conjugated triene (82). The double bond formed was almost entirely (98%) in the 2-configuration.

(80) X (81) X

= =

CH,P(O)Ph, CHO

The model C,, and c26 @-carotene homologues (83) and (84) have been prepared5’ from p-cyclocitral ( 8 5 ) and p-ionone (86) respectively by the McMurry procedure5’ with LiAIH,-TiCI, reagent. Benzanthrone-sensitized irradiation of (83) gave 100% of the cis-isomer (87).

On treatment with perchloric acid, the 9,lO-, 11,12-, and 13,14-epoxides (88)-(90) of canthaxanthin (P,@-carotene-4,4’-dione)gave respectively the lo-, 12-, and 14-0x0-derivatives (91)-(93), which in turn were reduced to the corresponding alcohols.59 The steric stability of acetylenic carotenoids has been investigated.60 Stereoisomerization of all-trans- and 9,9’-di-cis-alloxanthin [7,8,7’,8’-tetradehydro-@,@-carotene-3,3’-diol (94)] and all-trans-7,8,7’,8’-tetradehydroastaxanthin (49) in the presence of I2 gave mainly the 9,9’-di-cis- and 9-mono-cisisomers, with none of the all-trans-form present in the pseudo-equilibrium mixture. All-trans-7,8-didehydroastaxanthin(48), however, gave a mixture of the 9-mono-cis- and all-trans-isomers. Retinoids. A new procedure has been described6’ for the synthesis of vitamin A [retinol (95)] and related compounds via r-ally1 Pd complexes. Thus prenyl acetate (96) with PdC1, gave the complex (97), the structure of which was 56 57 58 59

6o 61

J. M. Clough and G. Pattenden, Tetrahedron Lett., 1978,4159. G. Gapski, A. Kini, and R. S. H. Liu, Chem. Lett., 1978, 803. J. E. McMurry and M. P. Fleming, J. Am . Chem. SOC.,1974,96,4708. D. Osianu, E. Nicoara, and C. Bodea, Rev. Roum. Chim., 1978,23,573. A. Fiksdahl, J. D. Tauber, S. Liaaen-Jensen, G. Saucy, and G. F. Weber, Acra Chem. Scand., Ser. B., 1979, 33, 192. P. S. Manchand, H. S. Wong, and J. F. Blount, J. Org. Chem., 1978, 43, 4769.

Carotenoids and Polyterpenoids

175

OAc

c1 OAc

1 erpenoids and Steroids

176

established by X-ray crystallography. This complex reacted with the anion derived from the intermediate (98) to yield the sulphone (99) which with base gave retinol (mainly all-trans). A lithium complex (100) derived from 3-methylbut-3-en- 1-01 (101) and n-butyl-lithium reactedh2with p -ionylideneacetaldehyde (102) to give the diol (103). Selective hydrolysis of the'diacetate of (103) gave the primary alcohol (104) which was oxidized to the aldehyde (105). On

R2

(103) R' = OH,R2 = CH20H (104) R' = OAc, R2 = CH20H (105) R' = OAc,R2 = CHO

treatment with base, double bond migration and elimination of acetic acid occurred to give retinal (70). Efficient preparations have been described of two compounds, a pentenyne ( 106y3 and 4-acetoxy-2-methylbut-2-enal( 107),64 which are useful intermediates in the synthesis of vitamin A.

In a synthesis of all-trans-retinonitrile (108) the C,, aldehyde (109) was converted via the oxime into the nitrile (110). Oxidation of this gave the aldehyde (111) which with the P-cyclogeranyl Wittig salt (112) afforded retinonitrile in

R' (109) R1 = Me,R2 = CHO (110) R' = Me,R2 = CN (111) R' = CHO, R2 = CN 62 63

64

a

CH,$Ph, Br-

(112)

G. Cardillo, M. Contento, S. Sandri, and M . Panunzio, J. Chem. SOC.,Perkin Trans. I, 1979, 1729. M. S. Brouwer, A. Hulkenberg, J. G. J. Kok,R. Van Moorselaar, W. R. M. Overbeek, and P. G. J. Wesselman, Rec. Trav. Chim. Pays-Bas, 1979,98, 316. J. H. Babler, M. J . Coghlan, M. Feng, and P. Fries, J. Org. Chem., 1979, 44, 1716.

Caroten o ids and Po 1y terpenoids

177

25% overall yield.65The doubly hindered 7,ll-di-cis-isomer (113) of retinal has been synthesized (Scheme 2).66The preparation of [methyl- 14C)-labelledretinyl acetate has been de~cribed.~'A series of 4-methoxy-2,3,6-trimethylphenyl analogues (114) of retinoic acid, with fluorine substituents in the side-chain, has been prepared.68 Claisen condensation with MeCOCMe,OH followed by acidcatalysed cyclization was used to synthesize the retinoidal furanones (1 15)-(118) from the methyl esters (119) and (120).6'

1

I

Reagents: i, Ph,PCH,CI Br--Bu"Li; ii, Bu"Li-MeCHO; iii, MnO,; iv, H,-Lindlar catalyst; v, (EtO),P(O)CH,CN-NaH; vi, dibal

Scheme 2

65

M. V. Bhatt and H. N. V. Prasad, World Rev. Nutr. Diet., 1978,31,141.

66

A.Kini, H. Matsumoto, and R. S. H. Liu, J. Am. Chem. SOC.,1979,101,5078.

67 68

69

W. T. Colwell, C. Soohoo, and J. I. Degraw, J. Labelled Comp, Radiophann., 1979,16,551. B.A.Pawson, K.-K. Chan, J. De Noble, R.-J. L. Han, V. Piermattie, A. C. Specian, S. Srisethnil, P. W. Trown, 0.Bohoslawec, L. J. Machlin, and E. Gabriel, J. Med. Chem., 1979,22, 1059. M.Ito, M. Ohno, E. Takano, Y. Oda, and K. Tsukida, Heterocycles, 1979,12,505.

Terpenoids and Steroids

178

'0

With hydroxylamine, all-trans-, 11-cis-, and 13-cis-retinal gave a mixture of the syn- and anti-oximes, whereas 11,13-di-cis-retinal gave only the syno ~ i r n e .The ~ ~ )synthesis of the dansyl-lysyl-lysine-N-retinylideneSchiff base has been de~cribed.~' The products of a colour reaction of retinoic acid (121) in 74% H,SO, have been identified as (122) and ( 123).72The oxidation and isomerization of retinoic acid by I2 and light have been used to prepare the all-truns- and 13-cis-isomers of 4-oxoretinoic acid (124) which were separated by h . p . 1 . The ~~~ photoisomerization of the retinoid (125) has been studied. The many isomers produced were separated by h.p.1.c. and characterized by 'H and 13Cr~.m.r.~,

70 71

72

73 74

N. A. Sokolova, B. I. Mitsner, N. Y. Gorina, and R. P. Evstigneeva, Bioorg. Khim., 1978,4,956. B. I. Mitsner, E. N . Karnaukhova, E. N. Zvonkova, and R. P. Evstigneeva, Bioorg. Khim., 1978,4, 1684. K. Tsukida, M. Ito, F. Tomeoka, and A. Kodama, J. [email protected]. Vitaminol., 1978, 24, 335. R. M. McKenzie, D. M. Hellwege, M. L. McGregor, and E. C. Nelson, Lipids, 1979, 14, 714. G. Englert, S. Weber, and M. Klaus, Helv. Chim. Acta, 1978, 61, 2697.

Ca roten oids and Po1y terpen oids

179

The pyrolysis and photolysis of trans-retinoic acid in aqueous ethanol has been Mechanisms of thermal equilibration of retinylidene imines (Schiff bases) and their protonated immonium salts have been in~estigated.’~ Electrochemical studies on truns- and cis-retinal have been r e p ~ r t e d . ~ ’ Degraded Carotenoids. Syntheses have been reported for several compounds structurally related to carotenoids. Many of the procedures used may be relevant to the construction of carotenoid end-groups, The synthesis of optically active c a r ~ t e n o i d shas ~ ~ ,been ~ ~ extended to include the preparation of important possible carotenoid metabolites such as (+)abscisic acid (126), (-)-xanthoxin (127), (-)-loliolide (128), (-)-actinidiolide (130), and (-)-dihydroactinidiolide (129), all from one starting compound

(128) R (129) R

= =

OH H

(131).78 Racemic cis- and trans-nor-abscisic acid (132) and (133) have been prepared in five steps from the protected hydroxy-ketone (134) and the acetylene (135).79 Reaction between the dianion of 3-methylbut-2-enoic acid (136) and

(134)

‘

Me HCrC-C=CH20SiMe, (135)

safranal (137) introduces stereospecifically a 2-prenyl residue to give the hydroxy intermediate (138). This is readily dehydrated to (2)-dehydro-p-ionylideneacetic acid (139), which is a useful intermediate in abscisic acid synthesis.80 Pure safranal was prepared from a-cyclocitral (140). 75

76 77

78 79

Y . Takashima, T. Nakajima, M. Washitake, T. Anmo, M. Sugiura, and H. Matsumaru, #em. Phann. Bull., 1979,27, 12. P. C. Mowery and W. Stoeckenius, J. Am. Chem. SOC.,1979, 101,414. B. Czochralska, M. Szweykowska, N. A. Dencher, and D. Shugar, Bioelectrochem. Bioenerg., 1978, 5 , 713. F. Kienzle, H. Mayer, R. E. Minder, and H. Thommen, Helv. Chim. A c t 4 1978,61, 2616. F. Kienzle, Helv. Chim. Acta, 1979, 62, 155. G. Cainelli, G. Cardillo, and M. Orena, J. Chem. SOC.,Perkin Trans. I, 1979, 1597.

180

Terpenoids and Steroids

In a synthesis8' of p-damascenone (3 l),prenyl phenyl sulphone (141) reacted with the bromo-ester (142) to give methyl 5-phenylsulphonylgeranoate (143). Cyclization of (1 43) produced a mixture of the Q - and p -ring compounds (144) and (145). The former readily underwent an elimination to produce methyl safranate (146) which, with allyl-lithium, afforded p-damascenone. Another 50,ph

&CH,SO,Ph

*r&CO,Me

(141)

D PhS0,

&C02Me

(142)

O /

(144)

2

M

e

(143)

&02Me

&02Me \

PhSO, (145)

(146)

preparation of p-damascenone used dimedone (147) as the starting material.82 Acetylenic and allenic analogues of a-ionone (148) have been ~ r e p a r e d . ' ~ Reaction of Q -cyclocitral (140) with LiC(=N,)COMe gave the intermediate (149) which with BF3.Et20 afforded 7,8-didehydro-a-ionone (150). On treatment with NaOEt this underwent rearrangement to the allenic 6,7-didehydro-aionone (151). Syntheses have been described for (k)-eginetolide (152) and

'' 82 83

S. Torii, K . Okayama, and H. Ichimura, J. Org. Chem., 1979, 44, 2292. S. Torii, T. Inokuchi, and H. Ogawa, J, Org. Chem., 1979,44, 3412. R. Pellicciari, E. Castagnino, R. Fringuelli, and S. Corsano, Tetrahedron Left., 1979, 481.

Ca roten oids and Pol y terpenoids

181

(k)-dihydroactinidiolide (129) from 2.6,6-trimethylcyclohexanone( 153),84via an intermediate epoxide (154), and for dihydro- and tetrahydro-actinidiolide (155) from sulphones such as (156).85a-Ionone (148), truns-4-methyl-a-ionone

(152)

(153)

(154)

Me (155) R = H (156) R = SO;?Ph

(157), 2,6-trans-a-irone (158), 2,6-cis-a-irone (159), and p-irone (160) have been prepared from 6-methylgeranyl chloride ( 161),86 and 2,6-trans-yirone (162) from the dimethylcyclohexenone ( 163).87 Other carotenoid-like

'

(157)

(158) R1 = H, R2 = Me (159) R1 = M e , R 2 = H

(160)

compounds that have been synthesized include (*)-trisporol B (164) and (*)trisporic acid (165),88 vomifoliol (166) and its isomer (167),89 10-bromo-achamigrene ( 168),90the Latia luciferin ( 169),9ioptically active caulerpol ( 170),92 and (~)-[10-'4C]-3-hydroxy-~-ionylideneacetic acid ( 171).93The esters (172), (173), and (174) have been prepared from ethyl P-cyclofarnesoate (175).94 Carbonylation of the monoterpenoid hydrocarbon (176) gave the cyclic compound (177) as the main B. Goyau and F. Rouessac, Bull. SOC. Chim. Fr., Part II, 1978,590. K. Uneyama, M. Kuyama, and S. Torii, Bull. Chem. SOC.Jpn., 1978, 51,2108. x6 T. Saks, T. Pekh, H. Rang, and A. Ivanov, Eesti N.S.V. Tead. Akad. Toim. Keem., 1978,27,230. J. Garner0 and D. Joulain, Bull. SOC.Chim. Fr., Part 11, 1979, 15. " M. P. Prisbylla, K. Takabe, and J. D. White, J. A m . Chem. SOC.,1979, 101,762. " 0. S. Park and L. A. Maldonado, Synth. Commun., 1979,9, 81. 90 I. Ichinose and T. Kato, Chem. Len., 1979, 61. 91 F. W. Sum and L. Weiler. Tetrahedron Lett., 1979,707. 92 Y. Masaki, K. Hashimoto, H. Iwai, and K. Kaji, Chem. Lett, 1978, 1203. y3 T. Oritani and K. Yamashita, Agric. Biof. Chem., 1979, 43, 1613. 94 L. N. Polyachenko, L. P. Davydova, A. R. Bekker, and G. I. Samokhvalov, Zh. Org. Khim., 1978, 14,1821. 95 S. D. Pirozhkov, K. V. Puzitskii, T. N. Myshenkova, K. G. Ryabova, and S. S. Poddubnaya, Izu. Akad. Nauk. SSSR, Ser. Khim., 1979,841. n4

ns

''

q

182

0 0 ’

Terpenoids and Steroids

pO (166)

(167)

(164) R = CH20H (165) R = C02H

BrcP OFCH0

a -1onone (148) was efficiently reduced to a-ionol (1 78) with Amberlyst-26bound cyan~borohydride.~~ With VOSO,.H,O, a-ionone gave a 1: 1 vanadium(TV)c ~ m p l e x . The ~ ’ kinetics of liquid-phase hydrogenation of p-ionone (179) on a Ni-Cr”’ oxide catalyst have been

96 97 98

R. 0. Hutchins, N. R. Natale, and 1. M. Taffer, J. Chem. SOC.,Chem. Cornmun., 1978, 1088. M. Agrawal, R . Gupta, and R. K. Baslas, Cum. Sci., 1979, 48, 299. D. V. Sokol’skii, T. 0. Omarkulov, and U. Suyunbaev, Zh. Fir. Khim.,1979, 53, 1881.

Carotenoids and Polyterpenoids

183

The photochemistry of a number of ionone-like compounds, including the epoxy compounds ( 180)-(184),99-'03 the keto-acid (185),lo4and the ( E ) - and (2)-isomers of (&)- y-monocyclofarnesol ( 186)lo5 has been investigated intensively. In most cases a large number of products were produced.

x

X (180) X (181) X (182) X

=

= =

H2, R = H CH2, R = H H2, R = Me

(183) X (184) X

= 0 = CH2

Physical Methods.-Electronic absorption, mass, n.m.r., and increasingly c.d. spectra are used routinely in the elucidation of new carotenoid structures and the characterization of synthetic products. Spectroscopic data for individual carotenoids may be found in many of the papers already cited. The papers quoted in this section are those which are concerned largely or entirely with one or more of the physical methods used for the separation, assay, and spectroscopic analysis of carotenoids and related compounds. Separation and Assay. H.p.1.c. methods have been described for the determination of chloroplast pigments, lo6 phytoplankton pigments, lo' and provitamin A carotenoids in tomatoes. lo8 Other chromatographic procedures have been devised for the separation of Capsicum c a r o t e n o i d ~ and ' ~ ~ chloroplast pigments from tobacco mutants,"" and methods for the high-speed video-densitometric determination of carotenoids separated by t.l.c.,'l' and for the dual assay of carotenoids and vitamin A in human liver have been reported."* H.p.1.c. has been used for the separation of cis-trans-isomers of retinal, 1 3 , ' l 4 retinol and retinyl 99

lo"

lo4 lo5

lo' lo' lo9 111 112

'I4

A . P. Alder, H. R. Wolf, and 0. Jeger, Chimia, 1978, 32, 464. A . P. Alder, H. R. Wolf, and 0.Jeger, Helv. Chim. Acta, 1978,61, 2681. B. Frei, G. Deweck, K. Mullen, H. R. Wolf, and 0.Jeger, Helv. Chim. Acta, 1979, 62, 553. B. Frei, H. R. Wolf, and 0.Jeger, Helv. Chim. Acta, 1979,62, 1645. B. Frei, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1979,62, 1668. J. D. White and R. W. Skeean, J. A m . Chem. SOC.,1978,100,6296. K. H. Schulte-Elte, B. L. Muller, and G. Ohloff, Nouu. J. Chim., 1978, 2 , 4 2 7 . H. Stransky, 2.Naturforsch., 1978, 33c, 836. J. K. Abaychi and J. P. Riley, Anal. Chim. Acta, 1979, 107, 1. M. Zakaria, K. Simpson, P. R. Brown, and A. Krstulovic, J. Chromatogr., 1979, 176, 109. K. A . Buckle and F. M. M. Rahman, J. Chromatogr., 1979, 171, 385. D. W. DeJong and W. G. Woodlief, J. Agric. Food Chem., 1978, 26, 1281. I. Csorba, Z . Buzas, B. Polyak, and L. Boross, J. Chromatogr., 1979, 172, 287. J. A . Olson, Num'tion Rep. Internat., 1979, 19, 807. K. Tsukida, A . Kodama, and M. Ito, J. Nutr. Sci. Vitamino[.,1978, 24, 593. J. E. Paanakker and G. W. T. Groenendijk, J. Chromatogr., 1979,168, 125.

184

Terpenoids and Steroids

esters, l 4 methyl retinoate,' l 5 4-oxoretinoic acid ( 124),73and other r e t i n o i d ~ .l 6~ ~ ' ~ The h.1.p.c. purification of 14C-and 'H-labelled samples of retinoic acid has been described,' l7 and a method has been devised for the Ag'-reversed-phase h.p.1.c. separation of retinyl esters depending on the degree of unsaturation in the esterifying fatty acid. ''' Procedures for the simultaneous h.p.1.c. determination of retinol and retinyl esters in serum in the presence of other vitamins have been reported,' '9*'20 and an automated fluorimetric determination of vitamin A in milk has been described.12' Procedures for the microassay of abscisic acid by radioimmunoassay,122g.c.m.s. of the methyl or h.p.1.c. or t.1.c. of the p-nitrobenzyl ester'24 have been reported.

N.M.R. Spectroscopy. Details have been presented22 of the series of nuclear Overhauser difference spectra experiments which provided unambiguous proof of the stereochemistry of prolycopene (14). 13CN.m.r. data have been given for 11 4 s - and 13-cis-retinal and their butylamine Schiff bases.*2sN.m.r. studies have shown that 11-cis-13-demethylretinal (187) adopts a planar s-trans conformation.126

(187)

CHO

Muss Spectrometry. The chemical ionization m.s. of eight carotenoids have been determined.127Features such as losses of toluene and rn-xylene were retained but fragmentation patterns were generally much simpler than those obtained by electron-impact. Unusually, capsanthin [3,3'-dihydroxy-P,~-caroten-6'-one (188)lunderwent consecutive losses of xylene and toluene. The factors governing the loss of toluene and xylene in carotenoid electron-impact m.s. fragmentations have been studied.'28 The preferred loss of xylene, distance of the point of cleavage from cyclic end-groups, interference of methyl substituents, and the activating effect of aromatic groups were all important. High-resolution mass 11s

I16

117

1i n 119 120

121

122 123 124

12s 126 127

128

B. A . Halley and E. C. Nelson, J. Chromatogr., 1979, 175, 113. A. B. Roberts, M. D. Nichols, C . A . Frolik, D . L. Newton, and M. B. Sporn, Cancer Res., 1978,38, 3327. R. M. McKenzie, M. L. McGregor, and E. C. Nelson, J. Labelled Come. Radiopharm., 1978,15,265. M. G . M. D e Ruyter and A . P. D e Leenheer, Anal. Chem., 1 9 7 9 , 5 1 , 4 3 . M. G . M. D e Ruyter and A. P. D e Leenheer, Clin. Chem., 1978, 24, 1920. A. P. D e Leenheer, V. 0.R. C. D e Bevere, M. G. M. D e Ruyter, and A . E. Claeys, J. Chrornatogr., 1979,162,408. J. N. Thompson and R. Madere, J. Assoc. O f . Anal. Chem., 1978,61, 1370. D. Walton, W. Dashek, and E. Galston, Planta, 1979, 146, 139. B. Anderson, N. Haggstrom, and K. Anderson, J. Chromatogr., 1978, 157, 303. J. Velasco, G. R. Chandra, and N. Mandava, J. Agric. Food Chem., 1978,26, 1061. Y. Inoue, Y. Tokito, S. Tomonoh, and R. Chujo, Bull. Chem. SOC.Jpn., 1979,52,265. R. Rowan, J. A m . Chem. SOC.,1979,101,4755. J . Carnevale, E. R. Cole, D . Nelson, and J. S. Shannon, Biomed. Mass. Spectrom., 1978, 5, 641. B. Johannes, H. Brzezinka, and H. Budzikiewicz, Z. Naturforsch., 1979, 34b, 300.

Carotenoids and Polyterpenoids

185

spectra of ['80]-labelled carotenoids have been deterrnined.lz9 For the 5,6epoxide of p-carotene an '*O enrichment of less than 1% could be detected. Chiropticaf Methods. The c.d. spectra of some mono-cis-carotenoids have been studied. I3O All showed opposite Cotton effects relative to the all-trans-isomers. The intensity of c.d. bands in the 'cis-region' was enhanced in the cis-isomers, especially if the cis-double bond was near to the centre of the chromophore. It was confirmed that in &-ringcarotenoids, chiral centres at C-2 and C-3 do not contribute significantly to the c.d. spectra, but a 19-hydroxy-group does influence chiroptical properties. The c.d. properties of squid and octopus rhodopsin and metarhodopsin have been discussed in relation to the conformation of the retinal chromophore.l 3' 7 1 3 2 The 0.r.d. spectra of retinal and retinylidene phosphorylethanolamine in a micelle have been obtained.133

Y

a

b

(188) R' = a (X = OH, Y = H2), R2 = b (189) R' = R2 = a (X = H, Y = H2) (190) R1 = a (X = H, Y = H2), R2 = CHO

(191) R' = a (X = H , Y = H2), R2 = c (192) R1 = R2 = a (X = H, Y = 0)

Electronic Absorption Spectroscopy. Theoretical considerations of the light absorption spectra of p -carotene (189) and related polyenes have been presented. 34-' 36 A method has been devised for describing the shapes of the absorption spectra of polyenes such as p-carotene and retinyl acetate as lognormal distribution curves.137A new absorption band is seen in the spectrum of p-carotene acting as electron donor in charge-transfer complexes.13s The triplet-triplet 129

130

13' 132

133 134

135 13' 13'

H. Budzikiewicz, B. Johannes, H. Weigel, and M. Heimann, Fresenius' 2.Anal. Chem., 1978,290, 382. S. Hertzberg, G. Borch, and S. Liaaen-Jensen, Actu Chem. Scund., Ser. B, 1979, 33, 42. Y. Shichida, F. Tokunaga, and T. Yoshizawa, Biochim. Biophys. Actu, 1978,504, 413. M. Tsuda, Biochim. Biophys. Acta, 1979, 578, 372. B. Rabinovitch and M. Yamakawa, Photochem. Photobiol., 1979, 29, 575. T. Sugimoto, K. Nakano, H. Kitajima, and H. Suzuki, J. Phys. SOC.Jpn., 1979,46, 1307. M.-C. Chiang, Sci. Sinicu, 1978, 21, 207. R. R. Birge and B. M. Pierce, J. Chem. Phys., 1979,70, 165. D. E. Metzler and C. M. Harris, Vision Res., 1978, 18, 1417. B. Mallik, K. M. Jain, and T. N. Misra, Indian J. Biochem. Biophys., 1978, 15, 233.

186

Terpenoids and Steroids

absorption spectra of p-ionone (179), p -ionylideneacetaldehyde (102), 14'-apop-caroten- 14'-a1 (193), 8'-apo-~-caroten-8'-a1(190),and torularhodinaldehyde [3',4'-didehydr0-/3,~-caroten-l6'-al(191)] have been r e ~ 0 r t e d . l Several ~~ papers describe spectroscopic studies on retinal isomers and analogue^^^^'-'^^ and retinylidene Schiff bases. 145 Many spectroscopic studies have been made on the visual pigments and intermediates in the visual ~ y c l e ' ~ ~and - ' ~on ~ bacteriorhodopsin and intermediates in the bacteriorhodopsin photocycle.154-162 Infrared and Resonance Raman Spectroscopy. Reviews1639164 on the uses of resonance Raman spectroscopy in biochemistry and biology include sections on carotenoproteins, visual pigments, and bacteriorhodopsin. The resonance Raman l~~ spectrum of the lowest excited triplet state of p-carotene has been r e p 0 ~ t e d .A resonance Raman method has been used for the quantitative analysis of pcarotene and lutein (20) in tobacco.166The mechanism of carotenoid-protein interactions in the carotenoproteins ovoverdin and p -crustacyanin has been investigated by resonance Raman s p e c t r o ~ c o p yZeaxanthin .~~ (24) has been used as a resonance Raman probe of membrane The resonance Raman spectra have been reported of all-trans-anhydrovitamin A ( 194),168p-ionone, retinals, and Schiff The technique has been used extensively to study 13Y

14"

14' 142

14'

144 145 146 147 148 149

15"

''I 152

153

lS4 155

157

15' 159

I6l

IhZ lh3

164 165

167 16' 169

170

R. S. Becker, R. V. Bensasson, J. Lafferty, T. G. Truscott, and E. J. Land, J. Chem. SOC.,Faraday Trans. ZZ, 1978, 74, 2246. R. Bensasson, C. R. Goldschmidt, E. J. Land, and T. G. Truscott, Photochem. Photobiol., 1978,28, 277. R. Bensasson and E. J. Land, Nouv. J. Chim., 1978, 2,503. R. R. Birge, J. A. Bennett, H. L. B. Fang, and G. E. Leroi, Springer Ser. Chem. Phys., 1978,3,347. H. Suzuki, K. Ishikawa, H. Kitajima, and T. Komatsu, Waseda Daigaku Rikogaku Kenkyusho Hokoku, 1978,80,58. H. Suzuki, H. Kitajima, and K. Ishikawa, J. Phys. SOC.Jpn., 1979, 46, 937. P. K. Das, R. S. Becker, D. Hannak, and E. Bayer, J. Am. Chem. SOC.,1979, 101, 239. R. Uhl, K. P. Hofmann, and W. Kreutz, Biochemistry, 1978,17,5347. M. Tsuda, Biochim. Biophys. Acta, 1979, 545, 537. P. M. Rentzepis, Biophys. J., 1978, 24, 272. A. Lewis, Biophys. J., 1978, 24, 249. T. Kakitani and H . Kakitani, Biophys. Struct. Mech., 1979, 5, 55. R. R. Birge, C. T. Berge, L. L. Noble, and R. C. Neuman, jun., J. Am. Chem. SOC.,1979,101,5162. K. Chihara, T. Takemura, T. Yamaoka, N. Yamamoto, A. Schaffer, and R. S. Becker, Photochem. Photobiol., 1979, 29, 1001. I. B. Fedorovich and K. A. Avakyan, Biofizika, 1979,24,38. K. Tsuji and K. Rosenheck, FEBS Lett, 1979,98, 368. N. N. Vsevolodov and L. N. Chekulaeva, Biofizika, 1978, 23, 1019. A. N. Kriebel, T. Gillbro, and U. P. Wild, Biochim. Biophys. Acta, 1979, 546, 106. 0. Kalisky, U. Lachish, and M. Ottolenghi, Photochem. Photobiol., 1978, 28, 261. B. Hess and D. Kuschmitz, FEBS Lett., 1979, 100, 334. T. Iwasa, F. Tokunaga, and T. Yoshizawa, FEBSLett., 1979,101, 121. M. Applebury, K. S. Peters, and P. M. Rentzepis, Biophys. J., 1978, 23, 375. G. P. Borisevich, E. P. Lukashev, A. A. Kononenko, and A. B. Rubin, Dokl. Akad. Nauk SSSR, 1978,241,959. S. Druckmann, A. Samuni, and M. Ottolenghi, Biophys. J., 1979,26, 143. P. R. Carey, Quart. Rev. Biophys., 1978, 11, 309. R. Mathies, Chem. Biochem. Appl. Lasers, 1979, 4, 5 5 . R. F. Dallinger, J. J. Guanci, jun., W. H. Woodruff, and M. A. J. Rodgers, J. Am. Chem. SOC.,1979, 101, 1355. G. Forrest and G. Vilcins, J. Agric. Food Chem., 1979,27,609. R. Mendelsohn and R. W. Van Holten, Biophys. J., 1979, 27, 221. R. A. Auerbach, M. F. Granville, and B. E. Kohler, Biophys. J., 1979, 25, 443. R. E. Cookingham, A. Lewis, and A. T. Lemley, Biochemistry, 1978,17,4699. M. A. Marcus, A. T. Lemley, and A. Lewis, J. Raman Spectrosc., 1979,8,22.

Caroren oids and Pol y terpenoids

187

the chromophore conformation in visual pigment^'^'-'^^ and bacteriorhodopsin. 17i-- 18 I Retinal Schiff bases and visual pigments have also been studied by i.r.

spectroscopy. ''*J'

Other Spectroscopic Techniques. Photoacoustic spectroscopy has been used to investigate the carotenoproteins of lobster Visual pigments and bacteriorhodopsin have been studied by linear dichroism, 184 neutron diffraction, lS5 and emission spectroscopy. 186,187 Miscellaneous Physical Chemistry. A kinetic study has been made of the electrochemical reduction of p -carotene."' The photoelectron quantum yield spectrum and photoelectron microscopy of @ -carotene have been described.189 Second-order rate constants for electron-transfer reactions of radical cations and anions of six carotenoids have been determined.190 Electronic energy transfer from lo2to carotenoids, e.g. canthaxanthin [P,P-carotene-4,4'-dione (192)], has been demonstrated.19' Several aspects of the physical chemistry of retinal and related compounds have been reported, including studies of electrochemical r e d ~ c t i o n , 'the ~ ~ properties of symmetric and asymmetric retinal bilayers, 193 retinal as a source of 102,194 and the fluorescence lifetimes of ~ e t i n a 1 . I ~ ~ Calculations have been made of photoisomerization quantum yields for 11-cis-retinal and analogues196 and of the conversion of even-n-orbital into odd-7.r-orbital systems related to retinylidene Schiff bases.197

M. Sulkes, A. Lewis, and M. A. Marcus, Biochemistry, 1978,17,4712. B. Aton, R. H. Callender, and B. Honig, Nature (London),1978,273,784. 173 G. Eyring and R. Mathies, Proc. Nut. Acad. Sci. U.S.A., 1979, 76, 33. 174 B. Aton, A. G. Doukas, R. H. Callender, B. Becher, and T. G. Ebrey, Biochim. Biophys. Acta, 1979, 576, 424. ' 7 5 A. Lewis, M. A. Marcus, B. Ehrenberg, and H. Crespi, Proc. Natl. Acad. Sci. USA, 1978,75,4642. 176 M. A. Marcus and A. Lewis, Biochemistry, 1978,17,4722. 1 7 7 J. Terner and M. A. El-Sayed, Biophys. J., 1978,24, 262. I78 J. Terner, C.-L. Hsieh, A. R. Burns, and M. A. El-Sayed, Biochemistry, 1979,18, 3629. 179 J. Terner, C.-L. Hsieh, A. R. Burns, and M. A. El-Sayed, Proc. Narl. Acad. Sci. USA, 1979,76, 3046. J. Terner, C.-L. Hsieh, and M. A. El-Sayed, Biophys. J., 1979, 26, 527. M. A. El-Sayed and J. Terner, Photochem. Photobiol., 1979, 30, 125. 18' J. Favrot, J. M. Leclercq, R. Roberge, C. Sandorfy, and D. Vocelle, Photochem. Photobiol., 1979,29, 99. 18' J. Favrot, C. Sandorfy, and D. Vocelle, Photochem. Photobiol., 1978, 28, 271. lE4 J. I. Korenbrot and 0.Jones, J. Membr. Biol., 1979,46,239. 185 G. I. King, W. Stoeckenius, H. L. Crespi, and B. P. Schoenborn, J. Mol. Biol., 1979,130,395. 186 S . L. Shapiro, A. J. Campillo, A. Lewis, G. J. Perreault, J. P. Spoonhower, R. K. Clayton, and W. Stoeckenius, Biophys. J., 1978, 23, 383. 187 S. Hotchandani, P. Paquin, and R. M. Leblanc, J. Lumin., 1979, 20, 59. M. 0. Miralles, J. Vera, and A. Serna, An. Quim., 1977, 73, 478. 189 H. M. Brown, P. C. Kingzett, and 0. H. GriBths, Photochem. Photobiol., 1978, 27,445. 19* J. Lafferty, T. G. Truscott, and E. J. Land, J. Chem. Soc., Faraday Trans. I, 1978,74,2760. lY1 F. Wilkinson and W.-T. Ho, Spectrosc.Lett., 1978, 11, 455. 19' B. Czochralska, M. Szweykowska, N. A. Dencher, and D. Shugar, Bioelectrochem.Bioenerg., 1978, 5, 713. '93 M. Rich and S. S. Brody, 2.Natuiforsch., 1978,33c, 735. 194 M. Delmelle, Photochem. Photobiol., 1978, 27, 731. 195 R. D. Fugate and P.-S. Song, J. Am. Chem. SOC.,1979,101, 3408. 196 W. H. Waddell and J. L. West, Chem. Phys. Lett., 1979,62, 431. 197 H. V. Navangul and P. E. Blatz, J. Am. Chem. SOC.,1978,100,4340. 17'

17'

188

Terpenoids and Steroids

Photoreceptor Pigments. There have been several reviews on the structures, photochemistry, and functioning of the retinal-protein photoreceptor pigments involved in the processes of vision198-203and in the purple membrane of Halobacteria (bacteriorhodopsin).202-209 In addition to the papers quoted earlier 153- 162.171-1 8 3 on the spectroscopy of these pigments, many other reports have a p p e a ~ e d ~ " dealing - ~ ~ ~ with rhodopsin and intermediates in its photocycle, especially photochemistry, chromophore-protein conformation and binding, and reaction kinetics. Similar studies on bacteriorhodopsin have also been described. 219-228

Biosynthesis and Metabolism.-A general outline of the pathways and mechanisms of carotenoid biosynthesis has been and carotenoid biosynthesis in plants has been reviewed.230 Stereochemistry. I3C-Labelling has been used for the first time in the carotenoid When field to study the stereochemical course of the cyclization [2-13C]mevalonate was incubated with a Flavobacterium species, grown in the presence of the cyclization inhibitor nicotine, 13Cn.m.r. spectroscopy showed that T. Yoshizawa and F. Tokunaga, Photochem. Photobiol., 1979, 29, 197. T. Yoshizawa and Y. Shichida, Kagaku No Ryoiki, 1978, 32, 159. 2oo W. L. Hubbell and M. D. Bownds, Ann. Rev. Neurosci., 1979, 2, 17. '01 F. I. Harosi, J. Favrot, J. M. Leclercq, D. Vocelle, and C. Sandorfy, Rev. Can. Biol., 1978,37,257. 202 B. Honig, Ann. Rev. Phys. Chem., 1978, 29, 31. 2"3 M. Montal, A. Darszon, and R. Strasser, in 'Frontiers in Biological Energetics', ed. P. L. Dutton, J. S. Leigh, and A. Scarpa, Academic Press, New York, 1978, Vol. 2, p. 1109. 204 W. Stoeckenius, R. H. Lozier, and R. A. Bogomolni, Biochim. Biophys. Acta, 1979,505,215. *05 T. Schreckenbach, Top. Photosynth., 1979,3, 189. 206 D. Oesterhelt, R. Gottschlich, R. Hartmann, H. Michel, and G. Wagner, Symp. SOC.Gen. Microbiol., 1977, 27, 333. 207 J. K. Lanyi, Microbiol. Rev., 1978, 42, 682. 208 R. Henderson, Symp. SOC. Gen. Microbiol., 1978, 28, 225. 2oy Yu. A. Ovchinnikov, N. G. Abdulaev, M. Y. Feigina, A. V. Kiselev, and N. A. Lobanov, FEBS Lett., 1979,100,219. * l o B. Rabinovitch, Photochem. Photobiol., 1979, 29, 567. T. G. Monger, R. R. Alfano, and R. H. Callender, Biophys. J., 1979, 27, 105. 'I2 A. Maeda, Y. Shichida, and T. Yoshizawa, Biochemistry, 1979,18, 1449. 'I3 A. Maeda, T. Ogurusu, Y. Shichida, F. Tokunaga, and T. Yoshizawa, FEBS Lett., 1978,92, 77. '14 A. Gochev and S. Khristov, Dokl. Bolg. Akad. Nauk, 1979, 32, 493. 'I5 E. J. Braendas and L. J. Dunne, Chem. Phys. Lett., 1979, 64, 329. 'I6 A. Cooper, FEBS Letts., 1979, 100, 382. 2 1 7 F. J. M. Daemen, Nature (London),1978,276,847. 2 1 8 hl. Tsuda, Photochem. Photobiol., 1979, 29, 175. ''' B. Honig, T. Ebrey, R. H. Callender, U. Dinur, and M. Ottolenghi, Roc. Nutl. Acad. Sci. USA, 1979, 76, 2503. 220 W. Sperling, C. N. Rafferty, K. D. Kohl, and N. A. Dencher, FEBS Lett., 1979,97, 129. 221 T. Schreckenbach, B. Walckhoff, and D. Oesterhelt, Photochem. Photobiol., 1978,28, 205. 222 T. Schreckenbach, B. Walckhoff, and D. Oesterhelt, Biochemistry, 1978, 17, 5353. 2 2 3 A. V. Rodionov and A. M. Shkrob, Bioorg. Khim., 1979, 5, 376. 2 2 A G. Orlandi and K. Schulten, Chem. Phys. Lett., 1979,64, 370. 225 W. Hoffmann, M. Graca-Miguel, P. Barnard, and D. Chapman, FEBS Lett., 1978, 95, 31. 226 T. Gillbro, Biochim. Biophys. Acta, 1978, 504, 175. 227 R. Korenstein, B. Hess, and D. Kuschmitz, FEBS Lett., 1978,93, 266. 228 A. Lewis, M. A. Marcus, B. Ehrenberg, and H. Crespi, Proc. Natl. Acad. Sci. USA, 1978,75,4642. 229 G. Britton, in 'Comprehensive Organic Chemistry, Vol. 5', ed. E. Haslam, Pergamon, Oxford, 1979, p. 1025. 230 T. W. Goodwin, Ann. Rev. Plant. Physiol., 1979,30, 369. 231 G. Britton, T. W. Goodwin, W. J. S. Lockley, A. P. Mundy, N. J. Patel, and G. Englert, J. Chem. SOC., G e m . Commun., 1979,27. 19'

'''

Caro tenoids and Pol y terpenoids

189

the 13C-label was located, as expected, in the C-4, -8, -12 (and 4’,8’, and 12’) positions in the carbon chain, and in one of the C-1 (and C- 1’)methyl substituents, that trans to the main polyene chain (i.e. C-16 and C-16’). This provides direct proof that the two C - 1 methyl substituents retain their individuality during the biosynthetic sequence. In the absence of inhibitor, the Flavobacterium produces the cyclic carotenoid zeaxanthin (24), and a similar incorporation experiment with [2-’3C]mevalonate showed that, of the two C-1 methyl substituents, only the la (axial) methyl group (i.e. C-16) bore the I3Clabel. When taken in conjunction with previous workz3’ which demonstrated the incorporation of deuterium into the 2 p position during cyclization this allows the stereochemical course of the cyclization reaction to produce the p-ring of zeaxanthin to be defined (Scheme 3).

.

Scheme 3

of the 14Cand 3H incorporation Full details have been on the stereochemistry of formation of the C,, carotenoid decaprenoxanthin [(2R,6R,2’R,6’R)-2,2’- bis-(4-hydroxy-3-methylbut-2-enyl)-~,~-carotene (195)] (Scheme 4). Both the stereochemistry of the initial electrophilic attack at C-2 and that of the hydrogen loss from C-4 are opposite to those in the C,, series.232,235

J

El Scheme 4

Enzyme Systems. A crude enzyme system from Neurospora crassa has been which incorporates isopentenyl pyrophosphate into phytoene (15). The only absolute cofactor requirement is for Mg”. 232

233 234

23s 236

G. Britton, W. J. S. Lockley, N. J. Patel, T. W. Goodwin, and G. Englert, J. Chem. Soc., Chem. Commun., 1977,655. D. Fahey and B. V. Milborrow, Phytochemistry, 1978,17,2077. D. Fahey and B. V. Milborrow, Roc. Aust. Biochem. Soc., 1978,11,37. G. Britton, Pure Appl. Chem., 1976, 47, 223. S. L. Spurgeon, R. V. Turner, and R. W. Harding, Arch. Biochem. Biophys., 1979,195,23.

Terpenoids and Steroids

190

a

(195) R' (196) R' (197) R'

= = =

b

R2 = a R2 = b b, R2 = c (X = OH)

(198) R' = b, R2 = d (199) R1 = b, R2 = c (X = H)

An enzyme system from the yeast Saccharomyces cerevisiae is able to incorporate isoprenoid precursors into the C30phytoene analogue (200) only in the presence of Mn2+and absence of NADPH. If NADPH is present and Mn2' is The replaced by Mg2+, the sterol precursor squalene (201) is substrate specificity of the chloroplast enzyme violaxanthin deepoxidase has been examined.238 In addition to the normal substrate violaxanthin [(3S,5R,6S,3'S,SfR,6'S)- 5,6,5',6'- diepoxy- 5,6,5',6'- tetrahydro- &@-carotene3,3'-diol, (196)] several all-trans-monoepoxy-carotenoids,such as antheraxanthin [5,6-epoxy-5,6-dihydro-P,P-carotene-3,3'-diol (197)], diadinoxanthin [5,6-epoxy-7',8'-didehydro-5,6-dihydro-~,~-~arotene-3,3~-diol (198)], and pcryptoxanthin epoxide [5,6-epoxy-5,6-dihydro-p,p-caroten-3-01(199)], all with the (3S,5 R,6S) configuration, were utilized. Violeoxanthin (9-cis-violaxanthin) and other 9-cis-isomers were not affected.A carrot (Daucus carota) tissue culture has been shown to incorporate ['4C]acetate into carotenoid~.~~'

(200) X (201) X

= =

CH=CH CH2CH2

Inhibition and Regulation. There have been several reports on the effects of d e ~ a t u r a t i o n ~ ~and " - ~cyclization ~~ 13,245 inhibitors on carotenoid biosynthesis in various micro-organisms and plant tissues. 237

238 23q 250

24L 242

243 244

245

T. Nishino, H. Takatsuji, S. Hata, and H. Katsuki, Biochem. Biophys. Res. Commun., 1978,85,867. H. Y. Yamamoto and R. M. Higashi, Arch. Biochem. Biophys., 1978, 190, 514. K. Shimizu, T. Kikuchi, N. Sugano, and A. Nishi, Physiol. Plantarum, 1979,46, 127. L. R. G. Valadon and R. S. Mummery, Microbios Left., 1977, 6, 129. S. M. Ridley and J. Ridley, Dev. PlantBiol., 1978, 2 , 309. S. M. Ridley and J . Ridley, Plant Physiol., 1979,63, 392. S. Frosch, M. Jabben, R. Bergfeld, H. Kleinig, and H. Mohr, Planta, 1979, 145, 497. P. G. Bartels and C. W. Watson, Weed Sci., 1978, 26, 198. L. R. G. Valadon and R. S. Mummery, Z. Pflanzenphysiof.,1978, 90, 11.

Carotenoids and Polyterpenoids

191

The photoinduction of carotenoid biosynthesis in Phycomyces blakesleeanus has been shown to be under at least dual It has been suggested that phytochrome may mediate carotenogenesis in Verticillium a g a r i c i n ~ m . ~ ~ ’ 2 Polyterpenoids and Quinones

Po1yterpenoids.-The presence of dolichols (202)with up to 23 isoprene units, in various sources, has been reported. 248249 In addition to these dolichols, which have their terminal isoprene unit saturated, ‘fully unsaturated’ polyprenols have been found. Bovine pituitary contains a mixture of cis-trans-isomers of decaprenol (203),249a Clooprenol from bovine thyroid has been shown by n.m.r. to have eighteen cis- and two trans-isoprene residues,250and 2,3-dehydrodolichyl pyrophosphate (204) has been identified as a product of a chick enzyme system and isopentenyl pyroph~sphate.’~’The structure of ulmoprenol from Eucommia ulmoides has been elucidated (207).252

HO * ’ (202) n

=

11-22

(203) (204) (205) (206)

. L G L n R n = 10, R = OH

n = 12-23, R = OP206H-3 n = 9 , R = OH n = 11, R = OPO,H,

A method has been described for the functionalization of the isopropylidene terminus of i s o p r e n ~ i d s For . ~ ~example, ~ geranyl benzyl ether (208) was converted into the phenyl thioether (210)by treatment with PhSCl and elimination of HCl. Oxidation and reaction with trimethyl phosphite gave the primary alcohol (209) stereospecifically in 75% overall yield. Use has been made of this procedure in the synthesis of solanesol (C45)from three C15 The tosyl derivative of the hydroxylated farnesol (211) reacts with the bromide (212) prepared from (213) to give the C30 product (215), the bromide (216) of which, after further reaction with (214), affords the solanesol derivative (217) and thence solanesol (205). In a facile of allylic alcohols the o-terminal residue of an isoprenoici compound (218) is epoxidized with NBS or peracetic acid, and the 246 247

248 249

*” 251

2s2

253 254

2s5

M. Jayaram, D . Presti, and M. Delbruck, Exp. Mycol., 1979, 3,42. L. R. G. Valadon, M. Osman, and R. S. Mummery, Photochem. Photobiol., 1979,29,605. M. Katayama and S. Marumo, Agric. Biol. Chem., 1978, 42, 1967. A. Radominska-Pyrek, T. Chojnacki, and J. S. Pyrek, Biochem. Biophys. Res. Commun., 1979,86, 395. G. Van Dessel, A. Lagrou, H. J. Hilderson, R. Dommisse, E. Esmans, and W. Dierick, Biochim. Biophys. Acta, 1979, 573, 296. R . B. Wellner and J. J. Lucas, FEBS Lett., 1979, 104, 379. Z . Horii, Y. Ozaki, K. Nagao, and S.-W. Kim, TetrahedronLett., 1978,5015. Y. Masaki, K. Hashimoto, and K. Kaji, TetrahedronLett., 1978, 4539. Y. Masaki, K. Hashimoto, and K. Kaji, TetrahedronLett., 1978, 5123. S. Terao, M. Shiraishi, and K. Kato, Synthesis, 1979,467.

192

Terpenoids and Steroids

R U\ O

C

(208) R (209) R

H = =

z

P

h

SPh

Me CH20H

(211) (212) (213) (214)

R1 = R' = R1 = R' =

(210)

CH20H, R2 = S02C6H4Me CH2Br,R2 = OCH2Ph CH20H, R2 = OCH2Ph Me,R2 = S02C6H4Me S02C6H4Me

(215) R (216) R

= =

OH Br

resulting epoxide (2 19) treated with aluminium isopropoxide to yield the allylic alcohol (220). An improved synthesis of prenyl-disphosphate-galactose involves conversion of the prenylphosphate (206) into the imidazolide by reaction with sulphinyldiimidazole, and subsequent condensation with a-D-galactopyranose-1-phospha te .256

W

R

(218) n R

wR

0, 1, or 8 = OCH2Ph or S02C6H4Me

=

R *

(219)

OH

(220)

Isoprenylated Quinones.-Chemistry. An efficient method has been described257 for the preparation of ubiquinone-1 (221) and plastoquinone-1 (223) from the parent quinone and allyltributyltin. The synthesis of ubiquinone- 10 by isoprenoid chain-elongation of a ubiquinone- 1 derivative has been r e p ~ r t e d . ~The " sulphone derivative of the protected ubiquinol-1 (224) on reaction with solanesyl bromide (225) and Me,COK gave the sulphone (226) in 90% yield. Benseker reduction to remove the PhCH2- and PhS02-groups, followed by oxidation in air, afforded ubiquinone-10 (222). 256

257 258

V. B. Shibaev, L. L. Danilov, V. N. Chekunchikov, Y. Y. Kusov, and N. K. Kochetkov, Bioorg. Khim., 1979, 5 , 308. K. Maruyama and Y. Naruta, J. Org. Chem., 1978, 43, 3796. S. Terao, K. Kato, M. Shiraishi, and H. Morimoto, J. Org. Chem., 1979, 44, 868.

193

Caroten oids and Po 1y terpenoids

o

L

(221) n (222) n

= =

1 10

OCH2Ph

"M e 0

' OCH2Ph O

G

S0,Ph

(224) OCH,Ph

Me0

H

Benzoquinones such as (227) have been prepared by regiospecific oxidative prenylation of the corresponding methylhydroquinone with Me,C=CHCH,Br in the presence of p - c y c l o d e ~ t r i nDetailed . ~ ~ ~ descriptions are available of methods for the preparation of ubiquinone analogues,26oand the synthesis of some new ubiquinone analogues, e.g. (228), has been reported.z61 MMe& e0

Me0

e

O

0

3H

(228)

(227)

Further details have been presented of the one-step preparation of vitamin K analogues through the use of p -cyclodextrin extrusion catalysts.262A paper has appeared dealing with the photoreduction of vitamin K [phylloquinone (229)].263 0

(229) 259

260

"* 263

I. Tabushi, Y. Kuroda, K. Fujita, and H. Kawakubo, Tetrahedron Lett., 1978,2083. Y.-P. Wan and K. Folkers, Methods Enzymol., 1978,53, 591. T. H. Porter, T. Kishi, H. Kishi, and K. Folkers, Bioorg. Chem., 1978, 7 , 333. I. Tabushi, K. Yarnarnura, K. Fujita, and H. Kawakubo, J. Am. Chem. SOC.,1979,101, 1019. G. G. Lazarev, M. V. Serdobov, and N. G. Khrapova, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 1409.

Terpenoids and Steroids

194

Separation and Assay. Methods have been described for the h.p.1.c. and m.s. determination of ubiquinone homologues in animal h.p.1.c. analysis of ubiquinone and phylloquinone in blood,265 of menaquinone-4 (230), 2,3epoxymenaquinone-4 (23 1)’ and 4-demethylmenaquinone-4 (232)26hand of phylloquinone and m e n a q ~ i n o n e - 4 .The ~ ~ ~polarographic determination of phylloquinone and menaquinone-4 has been reported.268

0

Biosynthesis. Full details of the isolation and characterization of intermediates in the biosynthesis of ubiquinone-8 (233) in E. coli have been described.26yTwo review articles deal with the compartmentation of the biosynthesis of aromatic amino-acids and prenylquinones in higher plants2” and the regulation of prenylquinone biosynthesis by tyro~ine.~” Several papers report new findings on ubiquinone biosynthesis. A mitochondrial membrane-rich preparation from baker’s yeast can convert 4-hydroxybenzoate and isopentenyl pyrophosphate into the ubiquinone precursor 3-all-trans-hexaprenyl-4-hydroxybenzoate(234). Details of the cell-free system are p r e ~ e n t e d . ”With ~ preformed polyprenyl pyrophosphates, the system catalysed the polyprenylation of several aromatic compounds, e.g. methyl 4hydroxybenzoa te, 4- hydroxybenzalde hyde, 4- hydroxybenzyl alcohol, and 4hydroxycinnamate. No evidence was obtained for the involvement of 4-hydroxybenzoyl-CoA or 4-hydroxybenzoyl-S-proteinin the reaction. With shorterchain prenyl pyrophosphates a shorter prenyl side-chain was introduced, e.g. geranyl and farnesyl pyrophosphates gave products with a 3-diprenyl and 3triprenyl side-chain respectively. A crude enzyme preparation from E. coli 264

S. Imabayashi, T. Nakamura, Y. Sawa, J. Hasegawa, K. Sakaguchi, T. Fujita, Y. Mori, and K. Kawabe, Anal. Chern., 1979,51,534. S. Ikenoya, K. Abe, T. Tsuda, Y. Yamano, 0.Hiroshima, M. Ohmae, and K. Kawabe, Chern. Pharm. Bull., 1979, 27, 1237. 266 P. L. Donnahey, V. T. Burt, H. H. Rees, and J. F. Pennock, J. Chromatogr., 1979,170,272. 267 K. Abe, 0.Hiroshima, K. Ishibashi, M. Ohmae, K. Kawabe, and G. Katsui, YakugakuZasshi, 1979, 99, 192. ’” K. Takamura, M. Sakamoto, and V. Hayakawa, Anal. Chim. Acta, 1979,106, 261. ’“ F. Gibson and I. G . Young, Methods Enzymol., 1978, 53, 600. H . Bickel, B. Bucholtz, and G. Schultz, Deu. Plant Biol., 1978, 3, 369. ’” H. Bickel and G . Schultz, Deu. Plant. Biol., 1978, 3,377. 272 J. Casey and D. R. Threlfall, Biochirn. Biophys. Acta, 1978, 530, 487.

’‘’

’”

Ca ro tenoids and Pol y terpenoids

195

0

H

Me0 (233)

incorporated methyl-labelled S-adenosylmethionine and 2-octaprenylphenol (235) into ubiquinone-8.273 Although 2-octaprenylphenol can be formed in E coli. under anaerobic conditions, air is required for its subsequent conversion into ~ b i q u i n o n e - 8 It . ~has ~~ been demonstrated that in aerobic ubiquinone synthesis in E. coli three of the four oxygen atoms originate from molecular oxygen, whereas the fourth, one of the carbonyl oxygens, comes from the hydroxy-group of 4-hydroxyben~oate.~’~ E. coli mutants blocked in the aerobic pathway can still synthesize ubiquinone anaerobically by a route which involves an alternative source of oxygen for the methoxy and carbonyl groups.276

273 274

275 276

H. E. Knoell, FEBSLen., 1979, 97, 155. H. E. Knoell, R. Kraft, and J. Knappe, Eur. J. Biochem., 1978,90, 107. K. Alexander and I. G. Young, Biochemishy, 1978,17,4745. K. Alexander and I. G. Young, Biochemishy, 1978,17,4750.

Part 11 STEROlDS

1 Physical Methods BY D. N. KIRK

1 Structure and Conformation X-Ray crystallographic studies of steroids continue to reveal conformational subtleties, as well as helping in some instances with the determination of molecular structures. Ring A is more flattened in 17~-iodoacetoxy-4,4-dimethyl-5a-androst-7-en3-one than in the corresponding saturated compound, because A7-unsaturation forces ring B into a distorted half-chair, with accompanying increase in the non-bonded interactions which control the conformation of ring A.l 17P-Hydroxyandrosta-4, 14-dien-3-one2 and its 19-nor analogue3 differ in their conformations of ring A, which are described as ‘la-sofa’ and ‘la,2P-half-chair’, respectively, and illustrate the conformational influence of a 1OP-methyl group. hydrate has the ‘5aRing A in crystalline 17/3-hydroxy-5a-androst-l-en-3-one sofa’ c o n f ~ r m a t i o n . ~ The structures of the 9-methyl-Sa,9P,lOa-oestran-3-one (1) and its 2a- and 2P-bromo-derivatives have been studied by X-ray cry~tallography.~ Ring A in the 2~-bromo-compoundis forced into a twist-boat conformation by steric compression (2P-Br/9P-Me), but the other two compounds are only slightly deformed from the chair conformation. These findings are compatible with the properties (c.d. and n.m.r.) of the same compounds in solution. 3a-Acetoxy4a,8a, 14P-trimethyl-18-nor-5a,9P,13a-androstan- 17-one (2), another steroid of unusual configuration, derived from fusidic acid, has a twisted boat conformation of ring B . ~

(1)

(2)

1 G. Ferguson, R. J. Restivo, G. A. Lane, J. M. Midgley, and W. B. Whalley, J. Chem. SOC.,Perkin Trans. II, 1978, 1038. * D . C . Rohrer, P. D. Strong, W. L. Duax, and A. Segaloff, Acta Crystallogr., 1978, B34, 2913. D . C . Rohrer, W. L. Duax, and A. Segaloff, Acta Crystallogr., 1978, B34,2915. D . C. Rohrer, R. H. Blessing, and W. L. Duax, Acra Crysrallogr., 1979, B35, 1244. J. C. A. Boeyens, J. R. Bull, J. Floor, and A. Tuinmann, J. Chern. SOC., Perkin Trans. I, 1978,808. W. S. Murphy, D . Cocker, G. Ferguson, and M. Khan, J. Chem. SOC., Perkin Trans. I, 1979, 1447.

’

199

200

Terpenoids and Steroids

X-Ray analysis of the cholestane derivative (3) has established the structure DZ(4),which has and configuration of synthetic (24R)-24,25-dihydroxy-vitamin been identified for the first time as a kidney metabolite from rats fed with vitamin D2.7

HO”

U

(4)

A cyclization product (6) obtained from 3~-benzoyloxy-23,24-bisnorchol-7en-22-01 (5) was shown by X-ray analysis to have the 8p(H),14p-~onfiguration.~

2-Aza-~-homo-5a-cholestan-l-one ( 7 ) has a quasi-chair conformation of the lactam ring, but the geometric requirements for fusion to ring B force the ‘amide’ out of planarity to a mean torsion angle of moiety (C-10-CO-NH-C-3) -20 0.9 The sign of this torsion is the reverse of that adopted by caprolactam (8), where the amide torsion angle for the corresponding quasi-chair conformation has been reported” as +4.2 O.

Hm H

’ G. Jones, A. Rosenthal, D. Segev, Y. Mazur, F. Frolow, Y. Halfon, D . Rabinovich, and Z. Shakked, Tetrahedron Lett., 1979, 177. D . J. Aberhart, E. Caspi, C. M. Weeks, and W. L. Duax, J. Org. Chem., 1979, 4 4 , 7 5 . H. Suginome and A. Furusaki, J. Chem. SOC.,Chem. Commun., 1979,782. F. K. Winkler and J . D . Dunitz, Actu Crystallogr., 1975, B31, 268.

Physical Methods

201

The anaesthetic steroid 3a-hydroxy-5a-pregnane-l1,20-dione has normal conformational features, both in the crystal and in solution." X-Ray data show that deoxycholic acid can form an inclusion complex in which alternate molecules of dimethyl sulphoxide and water are held in canals formed by helically arranged host molecules.12 Six different crystalline forms of 170-ethynyloestradiol have been re~0gnized.l~X-Ray structural data are reported for 3-methoxy-2-azaoestra-l,3,5(10)-trien-17P-y1acetate,14 3P-hydroxypregn-5-en-2O-one (pregn e n ~ l o n e ) , ' 5a-cholest-2-ene,16 ~ 36-bromo- and 3~-ch1oro-cho1est-5-enes," and cholesteryl acetate (at 123 K)," b e n ~ o a t e , 'chloroformate,20 ~ laurate," methyl carbonate,22and 24-norcholesteryl a ~ e t a t e . ' ~ Empirical force-field (EFF) calculation^^^ failed to predict the A-ring chair conformation of lanost-8-en-3-one, which was indicated by n.m.r. studies. Combined EFF-extended Huckel MO calculations were successful, however, giving a preference of 1.14 kcal mol-' over the boat form, although quantitative accuracy is not claimed for the present method of calculation. A treatment of alcohol conformations by molecular mechanics25 may have applications in predicting the preferred conformations of hydroxy-steroids. 2 N.M.R. Spectroscopy

Only a few examples have been selected from the vast number of papers which report 'H n.m.r. spectra, now largely as a matter of routine, in structure determination. The downfield shift of the C H - 0 proton signal caused by the reaction of secondary alcohols with trichloroacetyl isocyanate has been examined in detail for steroidal hydroxy functions around the ring structure.26Shifts are of the order of 1p.p.m., but in general are some 0.1 p.p.m. larger for equatorial than for axial hydroxy-groups on a six-membered ring. The investigation has been extended to some compounds with modified steroidal frameworks, where neighbouring substituents were found to produce significant effects on C H - 0 shifts." Differences between lanthanide-induced shifts of methyl proton signals permit a clear distinction between pairs of sterols epimeric at C-5, or at the site of hydroxy J. M. Midgley, W. B. Whalley, G. Ferguson, and W. C. Marsh, J. Chem. SOC.,Perkin Trans. II, 1978, 1042. S. Candeloro-De Sanctis, E. Giglio, F. Petri, and C. Quagliata, Acta Crystallogr., 1979, B35, 226. l 3 A. R. Ebian, S. A. Khalil, M. A. Moustafa, and M. W. Gouda, Pharm. Acta Helv., 1979, 54, 111. l4 D.,C. Rohrer and W. L. Duax, Acta Crystallogr., 1978, B34, 3475. l5 J. Bordner, G. L. A. Hennessee, and R. J. Chandross, Cryst. Sfruct. Commun., 1978, 7, 513. l 6 W. S. Kemlo, J. C. Van Niekerk, and L. R. Nassimbeni, Cryst. Struct. Commun., 1979, 8, 107. l7 G. V. Vani and K. Vijayan, Mol. Cryst. Liq.Cryst., 1979, 51, 253. '* P. Sawzik and B. M. Craven, Acta Crystallogr., 1979, B35, 895. l9 N. C. Shivaprakash, P. Rajalakshrni, and J. S. Prasad, Curr. Sci., 1978, 47, 800. 2o R. J. Chandross and J. Bordner, Acta Crystallogr., 1978, B34, 2872. 21 P. Sawzik and B. M. Craven, Acta Crystallogr., 1979, B35, 789. 22 P. K. Rajalakshmi, N. C. Shivaprakash, and J. S. Prasad, 2.Kristallogr., Kristallgeom., Kristallphys., Kristallchem., 1979, 148, 163. 23 M. Van Meerssche, J. P. Declercq, G. Germain, M. Wilpart, and M. Piraux, Acta Crystallogr., 1979, B35, 983. 24 D. A. Dougherty, K. Mislow, J. W. Huffman, and J. Jacobus, J. Org. Chem., 1979, 44, 1585. '' U. Burkert, Tetrahedron, 1979, 35, 209. 26 B. Schonecker and D. Tresselt, Pharmazie, 1978,33, 275. 27 B. Schonecker, D. Tresselt, G. Schubert, L. Kohout, and J. Fajkoi, Collect. Czech. Chem. Commun., 1978,43,2609.

202

Tergenoids and Steroids

substitution.28 Similar studies, together with shifts induced by aromatic solvents, are reported for some 4-methyl and 4,4-dimethyl steroids and tetracyclic triterpenoid~.~’ The almost indistinguishable 19-norergosta-5,7,9-trien-3-01~ (9), epimeric at C-3, give different 19F n.m.r. spectra as their a-methoxy-atrifluoromethylphenylacetates, or distinguishable ‘H n.m.r. spectra in the presence of shift reagent^.^' Now that the two epimers have been separated (by crystallization of 3,5-dinitrobenzoates) and properly characterized it is possible to analyse mixtures by optical rotation measurements.

[ 19-2H]-19-Acetoxy-3~-methoxyandrost-5 -en- 17-one (1l), obtained via reduction of the [19-2H]-19-aldehyde (10) intermediate with horse liver alcohol dehydrogenase and NADH, had the (19s)-configuration illustrated, showing that reductim was stereo~pecific.~’ The ‘H n.m.r. spectrum showed only a signal for the 19-pro-R hydrogen at 64.45, in accordance with an earlier assignment which placed the 19-pro-S ‘H signal at 63.95.

‘H N.m.r. has been used for the rapid estimation of chenodeoxycholic and ursodeoxycholic acids (3a,7a- and 3a,7P-dihydroxy-SP-cholanicacids) in mixture~.~* Extensive use is now being made of 13Cn.m.r. for structural studies involving sterol side-chains. The separate assignments of C-26 and C-27 in the I3C n.m.r. spectrum of cholester01,~~ based upon 13C-enriched material of biosynthetic origin,34 have been confirmed by conversion of kryptogenin [(25R)-38,27dihydroxycholest-5-ene-16,22-dione(12)] into (25S)-27-deuteriocholesterol 28 29

3a

31 32

”

34

T. Iida, M. Kikuchi, T. Tamara, and T. Matsumoto, J. Lipid Res., 1979, 20,279. T. Iida, M. Kikuchi, T. Tamura, and T. Matsumoto, Chem. Phys. Lipids, 1977, 20, 157. G . Felsky, P. M. Fredericks, and G. D. Meakins, J. Chem. SOC.,Perkin Trans. I, 1978, 1529. E. Caspi, E. Santaniello, K. Patel, T. Arunachalam, and C . Eck, J. A m . Chem. SOC.,1978,100,5223. P. K. Bhattacharyya and Y. G. Barkawala, Anal. Chem., 1978, 50, 1462. ‘Terpenoids and Steroids’, ed. J . R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 8, p. 216. G . Popjak, J. Edmond, F. A . L. Anet, and N. R. Easton, J. Am. Chem. Soc., 1 9 7 7 , 9 9 , 9 3 1 .

Physical Methods

203

(13) by standard reaction^.^' Deuteriation removes the 27-I3C (pro-S) signal from the spectrum, showing this to be the carbon atom which contributes the lowerfield peak of the 26,27 pair. The terminal methyl signals of 24,25-didehydrocholesterol (desmosterol) have also been assigned. Diastereoisomers of 24-alkylated sterols can be distinguished by 13Cn.m.r.36 The preferred conformation about the C-24-C-25 bond depends on the configuration at C-24, with distinguishable shielding effects on the C-26 and C-27 of the parent cholestane side-chain. Other report 13Cn.m.r. data for (24S)-24-ethylcholesterol (p-sitosterol) and for (E)and (2)-24-ethylidenecholesterols (14) (fucosterol and isofucosterol) and their acetates.

A series comprising epimeric pairs of 24-hydroxy-, 24,25 -dihydroxy-, 1,24dihydroxy-, 24-methyl-, and 24-ethyl-cholesterols shows small differences ( ~p.p.m.) 1 for the C-20 and C-24 resonances according to the configuration at C-24.38 Both signals were at higher field for the (24R)- than for the (24s)isomers, possibly as the result of the presence of differing small populations of the high-energy gauche rotamers (15) about the C-22-C-23 bond, where C-20 and C-24 are in close proximity. R2 H,

Rl

/CZI

* > 4c 2 q0H

c25

" H (15) C-24 substituent at either R1or R2

The absolute configuration at C-24 in some ecdysteroids has been established by 13Cn.m.r.39 Assignments are reported also for some steroidal alkaloids,40p41 and for a series of twelve h - ~ a r d e n o l i d e s . ~ ~ Tautomerism involving hemiacetal bridges has been explored by I3C n.m.r. for aldosterone (16), 18-hydroxy-11-deoxycorticosterone(19), and 18-hydroxyprogesterone (18).43Aldosterone and its 21-acetate (17) each showed 32 lines in their broad-band proton-decoupled spectra, indicating the presence of both the 35 36

37

39 40 41

42 43

P. Joseph-Natham, G . Mejta, and D. Abramo-Bruno, J. Am. Chem. SOC.,1979,101,1289. J. L. C. Wright, A. G. Innes, S. Shimizu, D. G. Smith, J. A. Walter, D. Idler, and W. Khalil, Can. J. Chem., 1978,56,1898. G . S. Ricca and F. Nicotra, G a z z . Chim. Ital., 1978,108, 713. N. Koizumi, Y. Fujimoto, T. Takeshita, and N. Ikekawa, Chem. Pharm. Bull., 1979,27,38. J. W. Blunt, G . A . Lane, M. H. G. Munro, and G. B. Russell, Aust. J. Chem., 1979,32,779. M. L. Romanelli and D. D. Small, Ausr. J. Chem., 1979,32,783. G. J. Bird, D. J. Collins, F. W. Eastwood, and R. H. Exner, Ausr. J. Chem., 1979,32,797. T. Yamauchi, F. Abe, and M. Nishi, Chem. Pharm. Bull., 1978,26, 2894. P. Genard, Org. Magn. Reson., 1978, 11,478.

Terpenoids and Steroids

204

18,20-hemiacetal ( b ) and the 20-keto-forms ( a ) .The 18-hydroxy-compounds (18) and (19), in contrast, each showed only the 21 lines in CDC1, corresponding to the hemiacetal forms illustrated. In (CD,),SO or C D 3 0 D , however, extra lines appeared for 18-hydroxy-l l -deoxycorticosterone (19). The suggested that these may arise either from a dimer or from a second rotamer about the C-20-C-21 bond, stabilized by hydrogen-bonding to the solvent. The possibility of spectral differences between solvated isomers at C-20 is not discussed, although such isomerism is indicated by 'H n.rn.r. spectra of 1 8 , 2 0 - h e m i a ~ e t a l s . ~ ~ HO

CH,OR

I

ecfF

(16) R

=0 H

(17) R

=

ib)

AC

(18) R = H (19) R = OH

The difficulty of separating isomeric products from ring expansion of 3-0x0steroids and their derivatives (e.g. by diazomethane, or Tiffeneau-Demjanov, Baeyer-Villiger, or Schmidt reactions) has caused uncertainties as to product ratios. Integration of 13Cn.m.r spectral peaks for the two components of reaction products provides a reliable method for analysing such mixtures (to *3'/0).~' There seem to be no problems of unequal Overhauser effects. 13CN.m.r. data for A-homo, B-nor-, and A-homo-B-nor-cholestanes (and a few androstanes) of both the 5a- and SP-series will aid future assignments for such compounds; they provide evidence for conformational variations in the A-homo-ring according to s u b ~ t i t u t i o nThe . ~ ~ influences of substituents at C-3 (a-and @-OHor -OSiMe3) and at C-2 (N3, Br, OH, OAc, NH2) on I3C chemical shifts have been evaluated for 2,3-disubstituted compounds of the cholestane series47and should be applicable to other skeletal types. 13C Shifts induced by a wide variety of hetero44 45 46

47

D . N. Kirk and M. S. Rajagopalan, J. Chem. SOC.,Perkin Trans. I, 1975, 1860. V. Dave, J. B. Stothers, and E. W. Warnhoff, Can. J. Chem., 1979,57, 1557. V. Dave and J. B. Stothers, Can. J. Chem., 1979,57, 1550. G . Engelhardt, D. Zeigan, and B. Schonecker, J. Prakt. Chem., 1978, 320, 377.

Physical Methods

205

substituents in axial or equatorial positions on a cyclohexane ring4’ are likely to find applications in the study of steroids containing similar substituents (halogens, OH, OMe, OSiMe,, 0-acyl, SHYNR2, N3, NO2, Me, C G C H , CN, etc.). 13 C N.m.r. has been used for assignment of configuration to 5a-cholest-8(14)ene-3/3,7ay15a-triol and related compounds with allylic hydroxy-gr~ups.~’ 13C and ‘H n.m.r. studies have been applied to some C-19 substituted steroids and 6P-CH2X-substituted 19-nor-5(10)-enes, to evaluate a-,p-, y-, and &substituent effects and obtain information on the rotameric populations of substituted methyl groups.5o Other report 13C shift data for some 19-hydroxy-, 5,6-epoxy-, A5(10)-3-oxo-,and 24-ethyl steroids. The incorporation of *H and I3C from labelled ethanol into cholic acid in rats has been studied by high-resolution mass spectrometry and n.m.r.52 Cholesteryl acetate was used as a model to illustrate the application of ‘tailored detection’ to the assignment of 13Cspectra of complex m01ecules.~~ The noisedecoupled spectrum contains several regions where signals almost overlap, so that off -resonance decoupling, aimed at ascertaining the multiplicity of individual signals as a result of ‘H-I3C coupling, can cause much confusion. The ‘tailored detection’ method produces a spectrum in which the multiplicities of selected lines are displayed without interference from nearby signals. A review54of the use of 13C n.m.r. spectroscopy for natural products includes some steroid and terpenoid examples, and discusses the techniques available for the assignment of individual resonances. 3 Chiroptical Phenomena A new theoretical treatment of the optical activity of saturated ketones (‘Random Phase A p p r ~ x i m a t i o n ’provides )~~ further support for the concept that extended zig-zags of C-C bonds are primarily responsible for the observed n + T * (290 nm) c.d. of steroidal and related ketones. It is that the c.d. band at 190 nm may derive mainly from a u + T * transition, rather than from n + u * as previously proposed. C.d. curves provide evidence for non-chair rings in some 11-0x0-cholestanes with unnatural c o n f i g ~ r a t i o n s 5a,8P,9a,l4/3-Cholestan.~~ 11-one appears to have ring c in a twist conformation, to explain the strongly negative Cotton effect, Conversely, positive Cotton effects for 5a,8ay9/3,14Pcholestan-11-ones imply that ring c is twisted in the opposite sense. Abnormal conformations either in ring B or in ring C could account for the c.d. of 5ay8a,9a,14p-cholestan- 11-ones. The 0estra-4~9-dien-3-one(20) and 4,9,1l-trien-3-one (21) are shown by c.d. studies to exist in solution as equilibrium mixtures with the ‘normal’ (22) and 48 49

51 52

53 54

” 56

H.-J. Schneider and V. Hoppen, J. Org. Chem., 1978,43, 3866. M. Tsuda, E. J. Parish, and G. J. Schroepfer, jun., J. Org. Chem., 1979,44, 1282. K. N. Scott and J. H. Mareci, Can. J. Chem., 1979, 57, 27. H. L. Holland, P. R. P. Diakow, and G. J. Taylor, Can. J. Chem., 1978,56, 3121. D. M. Wilson, A. L. Burlingame, S. Evans, T. Cronholm, and J. Sjovall, Stable Isot., Proc. Int. Symp., 1977 (publ. 1978), 205 (Chem. Abs., 1979,90, 134 653). G. A. Morris and R. Freeman, J. A m . Chem. Soc., 1978,100,6763. F. W. Wehrli and T. Nishida, Fortschr. Chem. Org. Naturst., 1979, 36, 1. T. D. Bouman, B. Voigt, and A. E. Hansen, J. A m . Chem. Soc., 1979,101,550. D. G. Patterson and C. Djerassi, J. Org. Chem., 1979,44, 1866.

206

Terpenoids and Steroids

‘inverted’ (23) half-chair conformations of ring A both substantially p ~ p u l a t e d . ~ ’ Substitution by methyl at the 2a- or 2P-position displaces the equilibrium towards whichever conformer allows the 2-methyl group to be quasi-equatorial.

(20) 11,12-saturated (21)

C.d. curves (n -+T * ) for some steroidal 4-en-3-ones and l-en-3-ones, oriented by an electric field in a nematic phase comprising cholesteryl chloridecholesteryl laurate, show significant differences from the c.d. curves obtained in isotropic The orientation effect depends upon the nature of the 17P-substituent, in a way which suggests that the effectiveness of ordering of molecules increases with their overall length. This technique for studying oriented molecules should make a significant contribution to our understanding of chiroptical phenomena. Wide variations in c.d. of a series of 17-alkylidene-5a-androstanes are tentatively i n t e r ~ r e t e on d ~ the ~ ‘allylic bond polarization’ (ABP) model, rather than in terms of olefin torsion. Replacement of 5a-H by deuterium in 5a-cholesta-1,3diene causes a small but significant reduction in the (negative) c.d. at 262 nm,60in accordance with the view that allylic axial chirality is important in the chiroptical behaviour of dienes.61 A theoretical treatment62of the c.d. of chiral alcohols indicates that the c.d. band observed in the region 185-200 nm results from electron excitation from a non-bonding oxygen 2 p orbital to an upper state with mixed u* and Rydberg 3s character. The theoretical analysis provides support for an earlier postulate,63 based upon data for hydroxy-steroids, that the signs of c.d. curves can be predicted from a simple two-sector rule, provided that the hydroxy-group has a preferred conformation. A defect in bile acid synthesis leads to the ac(24) as well as the cumulation of 5~-cholestane-3a,7a,l2a,23(R),25-pentol 3a,7a,12a,24(R),25-pent01 mentioned in last year’s The configuration at C-23 in the former compound has now been determined6’ by a c.d. study in the presence of the ‘shift reagent’ [Eu(fod),], which forms a chiral complex with the 23- and 25-hydroxy-groups resulting in a bisignate Cotton effect near 300 nm. The signs follow the pattern expected for a diol of left-handed chirality (25). 57 58 59

“

‘’ 63 64 65

L. Nedelec, J. C. Gasc, V. Delarott, R. Bucourt, and G. Nomine, Tetrahedron, 1978, 34, 2729. H.-G. Kuball, M. Acimis, and J. Altschuh, J. A m . Chem. SOC.,1979, 101,20. J.-M. Bernassau, M. Fetizon, I. Hanna, J. Rens, and A. Viger, Tetrahedron, 1979, 35, 1657. A. W. Burgstahler and M. E. Sanders, Tetrahedron Lett., 1979, 2509. Ref. 33, 1977, Vol. 7, p. 231; ibid., 1978, Vol. 8 , p. 220. J . Texter and E. S. Stevens, J. Chem. Phys., 1979,70, 1440. D. N. Kirk, W. P. Mose, and P. M. Scopes, J. Chem. SOC.,Chem. Commun., 1972,81. Ref. 33, 1979, Vol. 9, p. 262. B. Dayal, G. S. Tint, S . Shefer, and G. Salen, Steroids, 1979, 33, 327.

Physical Methods

207

db(4-chloroC.d. data recorded for a series of 5cr-cho1estane-3~,6au-diol benzoates) with additional substituents at C-4 have indicated that the diterpenoids caryoptin, 3-epicaryoptin, and clerodin have the same absolute configuration.66 C.d. data are reported for four isomeric steroidal 3-spiroisoxazolidine[2,3-d]oxadiazolines,together with X-ray data confirming the structure (26) for one of them. These compounds result from 1,3-dipolar cycloadditions between benzonitrile oxide and the 3-methylene-steroid. An interpretation of the c.d. data at ca. 250 nm attributes the Cotton effect to coupled benzenoid transition^.^' A new sector rule is proposed68 for the c.d. of 2,2dialkyl-1,3-oxathiolans (ketone hemithioacetals), which are essentially of ‘thioether’ type with c.d. bands in the regions of 240 and 220 nm.

4 Mass Spectrometry Mass spectral fragmentation mechanisms of some saturated and unsaturated 14aand 14P-sterols and their derivatives have been re~iewed.~’ Sterols of the types represented by cholesta-5,24-dien-3P-o1(desmosterol) or fucosterol (14), with AZ4- or A24(28)-~n~at~ration, undergo competing mass spectra fragmentations in proportions which depend upon the structure of the side-chain and the configuration at C-20.’’ Deuterium labelling experiments show that one mode of fragmentation comprises loss of the entire side-chain together with two hydrogen atoms, one of them exclusively from C-17 and the other variously from ring 66

67

68

69 70

N. Harada and H. Uda, J. A m . Chem. Soc., 1978,100,8022. S . Colombi, G. Vecchio, G . Gottarelli, B. Samori, A. M. Manotti Lenfredi, and A. Tiripicchio, Tetrahedron, 1978, 34, 2967. P. Welzel, I. Muther, K. Hobert, F.-J. Witteler, T. Hartwig, and G. Snatzke, Jusrus Liebigs Ann. Chem., 1978, 1333. C. Djerassi, Pure Appl. Chem., 1978, 50, 171. I. J. Massey and C. Djerassi, J. Org. Chem., 1979,44, 2448.

208

Terpenoids and Steroids

positions such as C-16, C-14, and C-12. Alternative rupture of the C-22-C-23 bond, with transfer of a hydrogen atom from C-20, accounts for loss of only part of the side-chain as a neutral fragment. Mass spectra71 of an extensive series of mono-unsaturated derivatives of methyl 5p-cholan-24-oateYderived from the natural bile acids, show that it is 3ossible in conjunction with chromatographic b e h a v i o ~ rto~make ~ , ~ ~unequivocal identification of individual compounds within this group. These combined methods of analysis have been used in a study of the bile acids of a 3200-year old Egyptian mummy,74which closely matched those of modern man. The mass spectra of conjugated bile acids (linked to glycine or taurine), obtained by direct insertion of samples into the ion source, show fragmentation patterns similar to those of methyl esters of the free bile acids, with additional ions due to loss of NH2CH2C02Hor CH,=CHSO,H, r e ~ p e c t i v e l y . ~ ~ The 12a-acetoxy-group is preferentially eliminated from acetylated cholic acid derivatives under electron impact; 7a-acetoxy- and 3a-acetoxy-groups follow in that order (established by use of 2H-labelled acetate groups).76 for TMS ethers of SP-cholestane diols, G.c.-m.s. characteristics are triols, tetrols, and pentols, with O H variously at the 3a, 7a, 12a, 23, 24, 25, and 26 positions. These compounds may be biosynthetic precursors of bile acids. Diff er'ences in energy requirements for the mass spectral fragmentation of stereoisomers in the vitamin D3 series reflect the relative stabilities of these The 5,6(E)-isomer (27), for example, requires higher energy than the natural 5,6(Z)-isomer for fragmentation to give the ion (28), consistent with the greater stability of the (2)-isomer. The epimeric 1,3-diols derived from cholecalciferol can be distinguished by their mass spectral difference^.^^

Stereoelectronic control is implied in the preferential expulsion of a methyl radical from 3a-dimethylamino-3~-methyl-5a-cholestane (29) under electron 71

72 73 74

75 76 77 78

79

P. Child, A. Kuksis, and L. Marai, Can. J. Biochem., 1979, 57, 216. P. Child, A. Kuksis, and J. J. Myher, Can. J. Biochem., 1979, 57,639. P. Child and A. Kuksis, Natural Sci., 1979, 1, 51. A. Kuksis, P. Child, J. J. Myher, and L. Marai, Can. J. Biochem., 1978, 56, 1141. R. Shaw and W. H. Elliott, Biomed. Mass Spectrom., 1978, 5, 433. J. R. Dias and B. Nassim, Org. Mass. Spectrom., 1978, 13,402. G. S. Tint, J. Lipid Res., 1978, 19, 956. Z. V. I. Zaretskii, Nouv. J. Chim., 1978, 2, 531. Z. V. I. Zaretskii, Steroids, 1979, 33, 595.

Physical Methods

209

impact." Unlike its epimer ( 3l ) , the amine (29) has one highly populated rotamer (illustrated), as a consequence of 1,3-diaxial interactions. The antiparallel nitrogen n-orbital and C-methyl bond are ideally arranged for overlap in forming the exocyclic C=N bond of the product ion (30). The methylamino and amino analogues show smaller but qualitatively similar eff eck8'

t-Butyldimethylsilylimidazole in the presence of potassium acetate efficiently silylates steroidal secondary hydroxy-groups at the 17P- or 20a-positions, and converts 4-en-3-ones into their enol silyl ethers. The derivatives from androst-4ene-3,17-dione, testosterone, progesterone, and 20a-hydroxypregn-4-en-3-one give intense molecular-ion peaks under g.c.-m.s. conditions." Other authors82 refer to the use of t-butyldimethylchlorosilane for the similar derivatization of various androstane and oestrogen derivatives, and report that the silylated uerivatives exhibit characteristic ( M - 57)' ions as base-peaks in their mass spectra (loss of But). High-resolution mass spectrometry has been used to distinguish between equilenin and its 14P-is0mer.~'9a-Hydroxyandrost-4-en-3ones (32) fragment through an initial cleavage of the C-9-C-10 bond and hydrogen transfer, giving ions (33) of 9-0x0 type.84

Mass spectra of pregnane-3,6,20P-triols show distinctive differences according to the configurations at C-5 and of the hydroxy-group~.~~ Mass spectral analysis of a series of 5-methyl-19-nor-5P-cholest-9-ene('Westphalen') derivatives is reported.86 Chemical ionization (CI) mass spectra for 34 cholestane derivatives show correlations with structure. Methane, isobutane, and ammonia were used as 81 82

83

" 85

86

P. Longevialle and A. Astier, Isr. J. Chem., 1978,1?, 193. I. A. Blair and G. Phillipou, J. Chromatogr. Sci., 1978, 16, 201. L. Ballhorn, W. F. Mueller, and F. Korte, Steroids, 1979, 33, 379. Z . V. 1. Zaretskii, Org. Mass. Spectrom., 1978, 13, 59. G. Horvath and G. Ambrus, Biomed. Mass. Spectrom., 1977, 4, 376. A. Grupe and G. Spiteller, Org. Mass Spectrom., 1978, 1 3 , 4 4 8 . F. TureEek and P. KoEovsky, Collect. Czech. Chem. Commun., 1 9 7 9 , 4 4 , 4 2 9 .

Terpenoids and Steroids

210

reagent gases. Ammonia is particularly interesting in forming ( M + NH4)+ions, often in high abundance, as well as ( M + H)’ and ions resultingfrom eliminations involving hydroxy or ester functions from these two ions. [2H3]Ammoniawas used to assist in clarifying the origins of ions. Those ions which result from eliminations offer promise for the identification of functional groups.g7Exchange of active hydrogen between [2H3]ammonia and OH, C 0 2 H , SH, and other protic groups permits determination of the number of such groups from the CI mass spectrum.88 Mass spectra produced by the usual technique of negative chemical ionization (by OH-) are reported” for 35 steroids. The predominant reaction appears to be deprotonation from reactive sites to give ( M - 1)- ions. Proton loss is often followed by the loss of one or more H2 molecules, giving ( M - 3)- and sometimes ( M - 5 ) - ions, which are presumed to have conjugated or resonance-stabilized structures such as enolate or allylic anions. Loss of H 2 0 [ ( M - 19)-, and ( M - 37)- in the case of diols and triols] is another mode of cleavage observed to follow deprotonation. An alternative reaction, noticed especially with cholesteryl esters, involves nucleophilic attack by OH- on the ester, with cholesteryl-0 bond cleavage to give the acylate ion (RC02)-. Nucleophilic attack of the ( M - 1)- ion on N 2 0 (used with CH, under electron bombardment to generate OH-), may lead to ( M + 43)- ions, and in a few instances also gave ( M + 25)and ( M + 15)- ions.89

5 Miscellaneous Physical Properties Carbonyl and ethylenic stretching frequencies of a series of 3-0x0-steroids show solvent effects due to solute-solvent association, which appears to include C=C T-H bonding.” The association of 5aLcholestan-3a- and - 3p-01~in solution has also been studied by i.r. ~ p e c t r o s c o p y these ; ~ ~ compounds form both dimers and tetramers. Spectroscopic methods have been employed to distinguish between the synand anti-isomers of a series of 0-benzyloximes and 0-isopropyloximes of steroidal ketones.92U.V. absorption maxima for the derivatives of 4-en-3-ones 257 nm; anti ( E ) ,A,, 250-252 nm]. ‘H show small differences [syn ( Z ) ,A,, and ‘3C n.m.r. data show some quite large differences for both saturated and unsaturated ketoximes, which allow geometric assignments. Unhindered ketones generally give two isomeric oximes, but a 5-en-7-one and several 20-0x0-steroids apparently gave only single isomers. Fluorescence spectra of cholesta-4,6,8(14)triene and cholesta-5,7,9(1l)-triene-3P-ol have been Further spinlabelled nitroxide derivatives of corticosteroids are reported.94 Cholesteryl esters, as cholesteric liquid crystals, seem to offer no particular advantages as media for asymmetric synthesis. Several reactions conducted in 87

89

90 91

92 93 94

Y. Y. Lin and L. L. Smith, Biomed. Mass Spectrum., 1978, 5 , 604. Y. Y. Lin and L. L. Smith, Biomed. Mass Spectrum., 1979,6, 15. T. A. Roy, F. H . Field, Y. Y. Lin, and L. L. Smith, Anal. Chem., 1979, 51,272. K. C. James and M. Ramgoolam, Spectrochim. Actu, Part A , 1978, 34, 1145. M. Kunst, D. van Duijn, and P. Bordewijk, Recl. Trav. Chim. Pays-Bas, 1979, 98, 262 A. Bodor and A. Barabas, Tetrahedron, 1979, 35, 233. J. R. Andrews and B. S . Hudson, Chem. Phys. Lett., 1979,60, 380. G. Defaye, M. Basset, and E. M. Chambaz, Bull. SOC.Chim. Fr., Part II, 1978,471.

Physical Methods

21 1

such systems led to little if any enantiomeric excess.95 Some liquid-crystalline cholesteryl esters undergo a transition to a ‘blue phase’ which exists over only a very narrow temperature range between the white cholesteric and the isotropic phases. N.m.r. spectra of two such esters in the ‘blue phase’ resemble those of the isotropic phase.96 The structure of the ‘blue phase’ is not yet understood. Some thermodynamic properties of progesterone in its a- and &crystalline modifications have been c ~ m p a r e d . ~ ’ 6 Analytical Methods

A monograph9’ published in 1978 reviews the various chromatographic, spectroscopic, and other physically or chemically based methods which have been used for the analysis of steroid hormones and materials containing them. The book, which is in English and includes over 1300 references, should fulfil its primary purpose as a hand-book for analysts who are concerned with steroid problems. It will also be useful to chemists and biochemists whose work involves steroid analysis. Immunoassay of Steroids.-Oestrone 3-methylphosphonothiolate, electrostatically complexed with methylated bovine serum albumen (BSA), is an effective immunogen for the production of an antiserum for oestrone 3 - s ~ l p h a t e The .~~ phosphorus-containing ester apparently mimics the size of the sulphate, but is more stable. Reductive amination, involving the coupling of 5a-androstane-3,17by reduction of their Schiff bases dione and of 17P-hydroxy-Sa-androstan-3-one with NaBH3CN, resulted in coupling between the lysine residues of BSA and the C-3 position of the steroid, with up to 40 molecules of steroid per BSA molecule. These antigens led to effective antisera for the steroids.100 A sensitive enzyme-immunoassay for plasma or saliva testosterone uses ‘testosterone- 1la-hemisuccinate’ antiserum, bound to cellulose to provide a solid phase for convenient separation. Testosterone-horseradish peroxidase conjugate was employed as the label.”’ Another enzyme-immunoassay for testosterone employs a testosterone-3-( 0-carboxymethy1oxime)-pencillinase conjugate for competitive binding to the testosterone anfiserum.l0* 2 1-Amino11~,17a-dihydroxypregn-4-ene-3,20-dione (‘Cortisol 21-amine’) linked to alkaline phosphatase has been usedlo3in an effective enzyme-immunoassay for cortisol. A fluorescent-labelled conjugate has been prepared by reaction of fluorescein is0thiocyanate with the oestradiol6 -carboxyme thyloxime-BS A conjugate, lo4 for use in the fluorescence-immunoassay of oestradiol. 95 96

97 98 99 loo lo’

lo2 lo3

lo4

C. Eskenazi, J. F. Nicoud, and H. B. Kagan, J. Org. Chem., 1979,44, 995. P. J. Collings and J. R. McColl, J. Chem. Phys., 1978, 65, 3371. M. Muramatsu, M. Iwahashi, and U. Takeuchi, J. Pharm. Sci., 1979,68, 175. S. Gorog and Gy. Szasz, ‘Analysis of Steroid Hormone Drugs’, Acadkmiai Kiad6, Budapest, 1978. R. I. Cox, R. M. Hoskinson, and M. S. F. Wong, Steroids, 1979, 33, 549. R. Mueller, A. Scheuer, H. Gerdes, and K. 0. Mosebach, 2. Anal. Chem., 1978, 290, 164. A . Turkes, A. 0. Turkes, B. G. Joyce, G. F. Read, and D . Riad-Fahmy, Steroids, 1979,33,347. U. M. Joshi, H. P. Shah, and S. P. Sudhama, Steroids, 1979, 34, 35. Y. Kobayashi, T. Ogihara, K. Amitani, F. Watanabe, T. Kiguchi, I. Ninomiya, and Y. Kumahara, Steroids, 1978, 32, 137. J. R. Schaeffer, P. H. Frickey, andB. A . Burdick, Res. Disc/., 1979,181,231 (Chem.Abs., 1979,91, 104 790).

212

Terpenoids and Steroids

Chromatography.-Considerable attention is being paid to chromatographic methods for the separation and recognition of bile acids and their derivatives. The analysis (g.1.c.) of mixtures of bile acids and their conjugates is reported to be simplified by direct conversion into heptafluorobutyrate derivatives, which occurs with simultaneous deconjugation.l's The carboxyl function is apparently converted into its volatile mixed cholanyl-heptafluorobutyryl anhydride. Ethyldimethylsilyl ethers of bile acid ethyl esters are also reported to be suitable for g.1.c. H.p.1.c. of bile acids as their phenacyl esters is said to afford a good resolution.lo7Steroidal 17P-carboxylic acid and 20-hydroxypregnan-2 1-oic acid derivatives are also readily analysed 2s phenacyl esters.lo8An h.p.1.c. system has been described''' for the complete resolution of 3-sulphates of common bile acids and their glycine and taurine conjugates. Methods for the analysis of bile acid sulphates in serum have been examined critically;'1° among the problems still not fully overcome are the efficient extraction of the most polar compounds and the quantitative separation of the less polar ones. Reference has already been made (Section 4)to chromatographic separations of bile acids in conjunction with mass spectrometry. The C-25 isomers of 26-hydroxycholestero1 can be separated (as diacetates) by h.p.l.c., with up to seven recycles."' In this way it has been established that 26-hydroxycholestero1 from human aortic tissue is a 9 : 1 mixture of (25R)- and (25s)-isomers, whereas air-oxidized cholesterol contains these compounds in 1: 1 ratio. [According to the convention recommendedy1*for designation of C-26 and C-27, the (25R)-isomer is 27-hydroxycholesterol, and the (25s)-isomer is 26- hydroxycholesterol .] 'Methylene unit' values as an index of g.1.c. retention times are subject to variations with temperature. A procedure is r e ~ o m m e n d e d "for ~ corrections to a reference temperature of 275 "C. Chromatographic data for 61 polar pregnane derivatives on paper114and for 163 steroids of various types on silica gel plates1" compare the 'discriminating powers' of various solvent systems. A statistical analysis of the data offers the possibility of selecting a chromatographic system with high resolving power for the separation of a given group of compounds. A review"6 of the use of fluorescent labels in h.p.1.c. analysis of drugs includes examples of derivatives of oestrogens and some keto-steroids. Dansyl chloride has been used for fluorescence labelling of oestrogens.' l 7 B. C. Musial and C . N. Williams, J. Lipid Res., 1979, 20, 78. H. Miyazaki, M. Ishibashi, and K. Yamashita, Biomed. Mass Spectrom., 1978, 5 , 469. In' F. Stellaard, D. L. Hachey, and P. D. Klein, Anal. Biochem., 1978, 87, 359. 'OR R. L. Farhi and C. Monder, Anal. Biochem., 1978, 90, 58. J. Goto, K. Hiroaki, and T. Nambara, Lipids, 1978, 13, 908. ' ' O J. F. Pageaux, B. Duperray, D . Anker, and M. Dubois, Steroids, 1979, 34, 73. "' J. Redel, J. Chromatogr., 1979, 168, 273. ' I 2 G. Popjak, J. Edmond, F. A. L. Anet, and N. R . Easton, jun., J. A m . Chern. Soc., 1977,99,931; see also ref. 33 and formula (12). ' I 3 R. W. H. Edwards, J. Chromatogr., 1978,154, 183. 'I4 V. R. Mattox and R. D. Litwiller, Steroids, 1979, 34, 227. 'Is V. R. Mattox, R. D. Litwiller, and P. C. Carpenter, J. Chromatogr., 1979, 175, 243. ' I 6 J. F. Lawrence, J. Chromatogr. Sci., 1979, 17, 147. 'I7 G. J. Schmidt, F. I. Vandemark, and W. Slavin, Anal. Biochem., 1978,91, 636. ""

""

Physical Methods

213

Miscellaneous.-The sensitivity of the Zimmermann colour reaction for 17-oxosteroids (alkaline rn-dinitrobenzene) and the stability of the colour vary according to the base used.'" Assay methods for the active hydroxylated derivatives of vitamin D have been reviewed.'lg

'*' J. F. Sayegh and P. Vestergaard, Acta Endocrinol. (Copenhagen)Suppl., 1978,88, 121. J. G. Haddad, jun., 'Methods of Hormone Radioimmunoassay'(2nd Edn.), ed. B. M. Jaffe and H. R. Behrman, Academic Press, New York, 1979, p. 437.

2 Steroid Reactions and Partial Syntheses BY B. A. MARPLES

Section A: Steroid Reactions 1 Alcohols and Carboxylic Acids and their Derivatives, Halides, and Epoxides Substitutionand Epimerization.-Diethylaminosulphur trifluoride has been used for the conversion of alcohols into the fluorides.'*2The reactions proceeded with inversion of configuration, except for those with 3~-hydroxy-A5-compounds,and were particularly good for unhindered alcohols. Unhindered axial and equatorial alcohols were converted into the axial chlorides with [Pd(PhCN),CI2] although cholesteryl chloride was obtained from cholesterol. A carbocation mechanism was i m p l i ~ a t e d The . ~ syntheses of 13'I-labelled 6P-iodomethyl- 19-norstigmast5(10)-en-3P-ol (2) and 19-iodostigmast-5-en-3~-ol(Id) from 3P-acetoxy-19tosyloxystigmast-5-ene ( l a ) were r e p ~ r t e dReaction .~ of ( l a ) with NaI-propan2-01 gave exclusively the 19-iodo-compound (lc) whereas, in contrast to an earlier report, the similar reaction of its 3P-hydroxy-analogue gave a mixture of (Id) and (2). Hydrolysis of (lc) gave (Id), which was converted into (2) by heating in acetonitrile. Reaction of the tosylate ( l b ) with piperidine and dimethylacetamide gave the 5,19-cyclo-derivatives (3).5The rates of acetolyses of a series

(1) a; b; c; d;

'

R' = Ac, R2 = OTs, R3 = p-C10H21,H R'=Ac, R2 = OTs, R3 = 0 R' = Ac, R2 = I, R3 = P-CIOHZ1,H R' = H, R2 = I, R3 = P-ClOH21,H

(3) 6a and 6p

S. Rozen, Y. Faust, and H. Ben-Yakov, Tetrahedron Letters, 1979, 1823. T. G. C. Bird, P. M. Fredericks, E. R. H. Jones, and G. D. Meakins, J.C.S. Chem. Comm., 1979,65. E. Mincione, G. Ortaggi, and A. Sirna, Tetrahedron Letters, 1978, 4575. H. Komatsu, S. Yamauchi, H. Shimoirisa, T. Ito, M. Maeda, and M. Kojima, Steroids, 1979,33,339. P. Bite and I. Moravcsik, Acta Chim. Acad. Sci.Hung., 1977,95, 311.

214

Steroid Reactions and Partial Syntheses

215

of 3P-tosyloxy-steroids were shown to be affected by substituents separated by three bonds from the site of reaction.6The reaction of the 3a,5a-cyclo-6,7-secodiol(4) with toluene-p-sulphonyl chloride-pyridine gave the cyclized compound ( 5 ) and the rearrangement product (6).7

Allylic cholestenols gave rearranged ally1 methyl ethers on reaction with [(Ph3P)2PtC12]-SnC12.2H20in methanol.' Stereocontrolled synthesis of allylic azides, and hence amines, from allylic alcohols has been achieved using N3HBF,.Et,0.9 An ion-pair mechanism rather than one involving an allylic carbonium ion was implicated from a comparison of the results with those of the Ritter reaction with similar substrates." The stereoselectivity of these reactions was controlled by the quantity of HN3 employed. Thus 3P-hydroxypregn-4-ene gave largely the 3a-azido-A4-compound in the presence of a slight excess (1.15 molar equivalents) of HN3 whereas with a large excess (48 molar equivalents) the major product was the 3P-a~ido-A~-compound.~ Epimerization of 3P-hydroxy-A4compounds was achieved with sulphuric acid in aqueous acetone. l1 Epimerization at C-3 occurred during the Raney nickel-catalysed hydrogenation of methyl 3&7a-dihydroxy- 12-oxo-5~-cholanate.'2 Oxidation and Reduction.-Reviews on the use of supported reagents in organic synthesis have included oxidative methods with a number of steroidal examp l e ~ . ' Benzeneseleninic ~,~~ anhydride proved to be a useful oxidizing agent for simple alcohols and in certain cases the dehydrogenated ketones were obtained by further 0xidati0n.l~Tetra-n-butylammonium chromate was also a useful oxidizing agent.16 Iodine triacetate and iodine(1) acetate were reported as useful reagents for the cleavage of cis- and trans-vicinal di01s.l~ Reductive debromination of 9a-bromo-compounds proceeded smoothly with Bun3SnH,l' and tosyloxy-steroids were reductively and selectively cleaved with ti

* lo

l2 l3 l4 l5

l7 Is

R. Pozas, G. C. Perez, and J. L. Mateos, Rev. SOC.quim. Mexico, 1978, 22, 73. H. Velgova, D. Zeigan, G . Engelhardt, and A. Trka, Coll. Czech. Chem. Comm., 19?9,44, 128. Y. Ichinohe, H. Sakamaki, and N. Kameda, Chem. Letters, 1978,835. I. Z. KaborC, Q. Khuong-Huu, and A. Pancrazi, Tetrahedron, 1978,34, 2807. I. Z. KaborC, Q. Khuong-Huu, and A. Pancrazi, Tetrahedron, 1978, 34, 3815. M. Mori, S. Ikegami, and B. Tamaoki, Steroids, 1979, 33,467. F. C. Chang, Tetrahedron Letters, 1979, 2085. A. McKillop and D. W. Young, Synthesis, 1979, 401. A. McKillop and D. W. Young, Synthesis, 1979, 481. D. H. R. Barton, A. G . Brewster, R. A. H. F. Hui, D. J. Lester, S. V. Ley, and T. G . Back, J.C.S. Chem. Comm., 1978,952. S . Cacchi, F. LaTorre, and D. Misiti, Synthesis, 1979, 356. R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J.C.S.Perkin I, 1978, 1483. H. Parnes and J. Pease, J. Org. Chem., 1979,44, 151.

Terpenoids and Steroids

216

NaI-Zn dust. l 9 Attempted hydrogenolysis of the 5-mesyloxy-3,6-cyclo-A-nor3,5-secoandrostane (7) with LiAlH, gave the seco-alcohol (8), whereas with NaI-Zn dust, it gave the rearranged compound (9).*'

OAc

(7)

Epoxide Ring Opening.-A series of chlorohydrins has been prepared by reaction of epoxides with [Pd(PhCN),Cl,] in benzene.21The acid-catalysed cleavages of 19-meth0xy-~~ and 1 9 - a c e t o ~ y - ~2a, ~ ,3a~ ~ and -5a, 6a-epoxides were reported to involve participation of the 19-functional group in part. For example, the 19-methoxy-5a,6a-epoxycholestane(lo), with aqueous HBr, gave the ether (13) in addition to the normal bromohydrin22and, as expected from earlier work, the 19-acetoxy-compound (12) reacted similarly with aqueous HC10423*24 to give the 19-acetoxy-5P,6a-diol (15). In aqueous HBr (12) gave only the diaxial

AcO

AcO (10) R = Me (11) R = H (12) R = Ac

HO (13)

AH

(14) R = H (15) R = Ac

b r ~ m o h y d r i nowing ~ ~ to the effective competition from the nucleophilic bromide ion. The 19-hydroxy-epoxide (11)was anomalously opened with aqueous HClO, to the 50,6a-diol (14) though no adequate explanation was offered for this o b ~ e r v a t i o nReaction .~~ of la-hydroxy- and la-acetoxy-2a,3a-epoxy- and 3aacetoxy- 1a,2a-epoxy-androstanes gave products of both diequatorial and diaxial cleavage with HBr whereas 3@-hydroxy- and 3P-acetoxy- 1 @,2P-epoxides gave only diaxial The cleavage of the C-3-0 bond leading to the diequatorial products from the 2a,3a-epoxides was believed to be facilitated by hydrogen-bonding in the la-hydroxy-compound or by formation of an acetoxonium ion (bridged across l a , 3 a ) in the la-acetoxy-compound. The same 19

2o 21 22

23 24

25

P. KoEovskL and V. Cerny, Coll. Czech. Chem. Comm., 1979,44, 246. A. Kasal, Coll. Czech. Chem. Comm., 1979, 44, 1619. E. Mincione, G. Ortajgi, and A. Sirna, J. Org. Chem., 1979, 44, 1569. P. KoEovskjr and V. Tern$, Coll. Czech. Chem. Comm., 1979,44, 226. P. KoEovskjr and V. Cernjr, Coll. Czech. Chem. Comm., 1979,44, 1496. J. Joska and J. Fajkos, Coll. Czech. Chem. Comm., 1978,43, 3433. D. Baldwin, J. R. Hanson, and D. Raines, J.C.S. Perkin I, 1979, 344.

Steroid Reactions and Partial Syntheses

217

acetoxonium ion was implicated in the reaction of the 3a-acetoxy-la,2aepoxide. Hydrolysis of 3P-benzyloxy-l4a,15a-epoxy-5a-cholest-7-enewith aqueous KOH-EtOH gave the rearranged trio1 (16) which with HC1-EtOH gave the with lithium organoenone (17).26Treatment of 5a,lOa-epo~y-A~‘~~’-steroids cuprates gave 11P-substituted 5a-hydroxy-A9-compounds and is exemplified by

0

OBz I

the conversion of (18) into (19) with P h * c ~ L i . *The ~ Ritter reaction of 3methoxy-16,17-epoxyoestra-l,3,5( 10)-trienes has been reported.28Whereas the 16/3,17p-epoxide opened to give the vicinal acetamido-alcohols, the major product from the 16a,l7a-epoxide was the rearranged compound (20). Cholesteryl Sa,Ga-epoxide formed a strong complex with DNA and gave adducts with thiols (acid-catalysed) and heterocyclic amines.*’

Ethers, Esters, and Carboxylic Acids.-Monosulphates of partially formylated bile acids were prepared using SO,-Et,N complex in pyridine.30931Esters of testosterone and 19-norethisterone and hindered carboxylic acids were conveniently prepared by adding the alcohols in pyridine to a solution of the 26 27

28 29

30 31

M. Tsuda, E. J. Parish, and G. J. Schroepfer, jun., J. Org. Chem., 1979, 44, 1282. G. Teutsch and A. BClanger, Tetrahedron Letters, 1979, 205 1. G. Schneider and B. Schoenecker, Acta Chim. Acad. Sci. Hung., 1977, 95, 321. G. M. Blackburn, A. Rashid, and M. H. Thompson, J.C.S. Chem. Comm., 1979,420. K.-Y. Tserng and P. D. Klein, Steroids, 1979, 33, 167. K.-Y. Tserng and P. D. Klein, Lipids, 1978, 13,479.

Terpenoids and Steroids

218

carboxylic acid and benzenesulphonyl chloride in ~ y r i d i n e Me2NPOC12 .~~ and PhOPOClz were useful reagents for activation of carboxylic acids, thereby facilitating their reactions with alcohols to give Esters have been cleaved at the alkyl-oxygen bond with aluminium trihalide-thiol Methyl 3a,l2a-diacetoxy-5~-cholanate was selectively converted in high yield into 3a,12a-diacetoxy-5~-cholanicacid by this method. The degradation of the bile acids to the bromo-steroids (21) was achieved using the modified Hunsdiecker

(21)

reaction (HgO-Br2).35A series of steroidal alcohols were converted into their dimethylphosp hinates or dimethylthioph ~ s p h i n a t e s . ~4-Dimethylamino~ pyridine catalysed the reaction between cholesterol and trityl chloride3' or t-butyldimethylchlorosilane38to provide the trityl or silyl ethers. Alcohols, including cholesterol, were converted into the P,P,P-trichloroethoxymethyl ethers by reaction with NaH or Bu"Li followed by C13CCH20CH2C1.39 Deprotection was possible using Zn/Cu couple in methanol or Zn in methanol containing acetic acid and triethylamine. Cleavage of steroidal and other benzyl ethers was achieved with EtSH-BF3.Et20.40 2 Unsaturated Compounds

Electrophilic Addition.-The studies on the influence of 19-functional groups on the addition of HOBr to A2- and A5-steroids41have been to include the 19-acetoxycholestenes (22) and (24). In addition to the expected diaxial bromohydrins and, as expected from a comparison of the acid-catalysed reactions of the equivalent e p o x i d e ~ ,(22) ~ ~ gave , ~ ~ the ether (23) and (24) gave the 6a-bromo-SPhydroxy-compound (26). Similar participation of the 19-hydroxy-group was in the reaction of the 19-hydroxycholestene (25) with Hg(OCOCF3)2,which gave the ether (27). Reduction of (27) with NaBH4 gave the epimeric ethers (28). The reaction between 5a-androst-2-ene and NaN,-12 in chloroform was enhanced by addition of 18-cr0wn-6.~~ 32

33 34

35 36

37

39 4" 41

42

O3 44

A. A. L. Gunatilaka and S. Sotheeswaran, J.C.S. Chem. Comm., 1978,980. H.-J. Liu, W. H. Chan, and S. P. Lee, Tetrahedron Letters, 1978, 4461. M. Node, K. Nishide, M. Sai, and E. Fujita, Tetrahedron Letters, 1978, 5211. F. F. Knapp, jun., Steroids, 1977, 33, 245. K. Jacob, W. Vogt, and M. Knedel, Annalen, 1979,878. S. K. Chaudhary and 0. Hernandez, Tetrahedron Letters, 1979, 95. S. K. Chaudhary and 0. Hernandez, Tetrahedron Letters, 1979,99. R. M. Jacobson and J. W. Clader, Synth. Comm., 1979, 9, 57. K. Fuji, K. Ichikawa, M. Node, and E. Fujita, J. Org. Chem., 1979, 44, 1661. See 'Terpenoids and Steroids', ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1979, Vol. 9, p. 275. P. KoEovsky, V. tern$, and M. Synaekova, Coil. Czech. Chem. Comm., 1979,44,1483. P. Welzel, W. Holtmeier, and B. Wessling, Annalen, 1978, 1327. R. C. Cambie, R. C. Hayward, P. S. Rutledge, T. Smith-Palmer, B. E. Swedlund, and P. D. Woodgate, J.C.S. Perkin I, 1979, 180.

Steroid Reactions and Partial Syntheses

219

(25)

R

=

H

The full paper on the reactions of iodine(1) thiocyanate and 5a-androst-2-ene and other alkenes has a ~ p e a r e d . An ~ ’ i n ~ e s t i g a t i o ninto ~ ~ the stereochemistry of the addition of BrCl to cholesterol revealed that the ratio of a : p attack was 4.5 : 1, which was higher than that for other electrophilic additions. It was suggested that the reaction involved rapid reversible formation of the bromonium ions followed by attack by chloride ion and that the opening of the 5p,6/3bromonium ion was slow relative to that of the 5a,6a-bromonium ion owing to steric interactions with the l a - , 3a-, 7a-,and 9a-axial hydrogen atoms. 2-Methyl- and 3-rnethyl-5a-cholest-2-ene reacted with dichloroketen in the presence of POC& regiospecifically and stereospecifically to give the cyclobutanones (29) and (30) re~pectively,~’ whereas a number of enolate derivatives of 5a-cholestan-2-one and 5a-cholestan-3-one failed to react. Hydroxysulphenylation of olefins was achieved through reaction with P ~ ( O A C ) ~ Ph2S2-CF3C02H followed by a basic w o r k - ~ p . ~Thus * 5a-cholest-2-ene gave 2/3-hydroxy-3a-phenylsulphenyl-5a-cholestane (31) whereas cholesteryl benzoate gave a mixture (1 : 1)of the 6/3-hydroxy-5a-phenylsulphenylcholestane (32) and the 5a-hydroxy-6/3-phenylsulphenylcholestane(33) in which the benzoyloxy residue at C-3 was partially hydrolysed. 5a-Cholest-2-ene was converted into the 3a-phenylsulphe- yl-? p-tosylamino-compound (34) by sequential reaction with PhSSPh-TsNClNa and NaBH4.49 Simmons-Smith methylenation of the 19-hydroxycholest-5-ene (25), as expected, gave the 5p,6@methano-compound (35) as the major product owing to the 19-hydroxy-group directing the attack to the p-face.” In a study of the reactions of oso4and KMn04 with 20-cyano-A’7‘20’-pregnenesit was established that a catalytic oso4KC10, reaction worked satisfactorily in the presence of zinc nitrate which was required to sequester the released cyanide ion. The KMn04 oxidations were only successful in the presence of a 21-aceto~y-group.~’ 45 46 47

48 49

R. C. Cambie, H. H. Lee, P. S. Rutledge, and P. D . Woodgate, J.C.S. Perkin I, 1979, 757. A. Kasal, J.C.S. Perkin I, 1978, 1643. A. Hassner and L. R. Krepski, J. Org. Chem., 1979,44, 1376. B. M. Trost, M. Ochiai, and P. G. McDougal, J. Amer. Chem. SOC.,1978,100,7103. D . H. R. Barton, M. R. Britten-Kelly, and D . Ferreira, J.C.S. Perkin I, 1978, 1090, 1682. J. Fajkos and J. Joska, Coil. Czech. Chem. Comm., 1979,44,251. R. W. Freerksen, M. L. Raggio, C. A. Thomas, and D. S. Watt, J. Org. Chem., 1979, 44, 702.

220

Terpenoids and Steroids

RoL@

' &o H PhS'-

OH

(31)

(32) R

=

HorBz

Ro@

(33) R

SPh =

HorBz

AcO

The reactions of other a,p-unsaturated nitriles and esters have been discussed. Where as Hg O-H'-cat a1ysed hydra tion of the 17a -et hynyl-compounds (36) and (37) proceeded normally to give the corresponding 17a-acetyl-compounds (39) and (40),the corresponding 17P-nitro-oxy- 17a-ethynyl compounds (38)reacted in the presence of ethanol or methanol to give the 17a-alkoxy-17P-acetyl compounds (41) or (42).52 In the presence of H ~ ( O A Cand ) ~ acetic or formic acid the products were the 17a-acyloxy-17~-acetylcompounds (43)or (44)respectively and Ag(OAc)-HC02H-HMPA converted (38)into the l7a-formyloxy17P-ethynyl compound (45).It was proposed that attack of ROH or RC02- at C-17 of the complex (46)was responsible for the epimerization. Other Addition Reactions.-High yields of steroidal 5,6-dienes were obtained from their adducts with 4-phenyl-1,2,4-triazoline-3,5-dione by refluxing in tetramethylguanidine or ~ o l l i d i n eFurther .~~ support was reported for a cationradical mechanism for the Lewis acid-catalysed reaction of triplet oxygen with ergoesteryl Addition of the olefin (47)to a mixture of the epoxynitrone (48)and CF3S03SiMe3or CF3S03SiMe2Bu'followed by KCN treatment gave the 1,2-oxazine derivative (49),which was converted into the a-methylenelactone (50).56The similar reactions of some other olefins were also reported. Singlet oxygen reaction with 19-nor-As-steroids resulted in preferred a-face 52

53 54

55 56

H. Hofmeister, K . Annen, H. Laurent, and R. Wiechert, Chem. Ber., 1978, 111,3086. M. Anastasia and M. Derossi, J.C.S. Chem. Comm., 1979, 164. R. Tang, H. J . Yue, J. F. Wolf, and F. Mares, J. Amer. Chem. SOC.,1978, 100, 5248. See ref. 41, p. 279. M. Reidiker and W. Graf, Helv. Chim. A m , 1979, 6 2 , 1587.

Steroid Reactions and Partial Syntheses

(36) R = H (37) R = Ac (38) R = NO2

221

(39) R = H (40) R = Ac

(41) (42) (43) (44)

R = Et R = Me R = Ac R = HCO

(46) Nu = ROH or RC02M = Ag or HgOR

attack, leading to the A6-5a-hydroperoxide, although a greater proportion of &face attack, leading to the A4-6&hydroperoxide, was evident than in the case of chole~terol.~’It was suggested that these observations support the ene mechanism rather than that involving a peroxiran.

Other Reactions of Olefinic Steroid~.-[6P-~H]Cholest-4-ene reacts with [Pd(PhCN),CI,] to give the a-4-677 and p-4-677 PdCl derivatives with stereospecific syn elimination of the 6-H or 6-*H, confirming that in the case of the 3-0x0-A4-steroids the high proportion of anti e l i m i n a t i ~ nmust ~ ~ be attributed to

’’ J. A. M. Peters, N. P. Van Vliet, and F.‘J.Zeelan, Rec. Trau. chim., 1979, 98, 459. ’* See ref. 41, p. 279.

222

Terpenoids and Steroids

the influence of the 3-0xo-group.~~ The major products from the R u 0 4 oxidation of cholesta-2,4-diene and 3P-acetoxycholesta-5,7-dienewere respectively the lactone (51) and the highly oxygenated compound (52).60Oxidations of 3-0x0A4-derivatives of solasodine and diosgenin with KMn0,-NaIO, have been reported61 as have the full details of the oxidation of cholesterol with hydrogen with Jones reagent peroxide.62 Oxidation of 3P-acetoxy-5a-cholesta-8,14-diene (53) and not the isomeric 14agave63the 9a-hydroxy-1 5-oxo-A8~""'--compound hydroxy-7-0x0-A8-compound, as previously reported.

$847

0

AcO

OH (52)

(53)

Aromatic Compounds.-Electrolysis of the 3-methoxy-aromatic steroids (54) in liquid ammonia gave the enol ethers (56) whereas the equivalent hydroxycompounds (55) gave the further reduced alcohols (57), and reduction of the B-ring was possible only in liquid m e t h ~ l a r n i n e .It~was ~ established that iodination of ring A of oestradiol was non-specific, contrary to literature reports. The mixtures obtained contained mainly the 2- and 4-iodo-deri~atives.~~

(54) R = Me (55) R = H

(56)

(57) 3a and 3p

3 Carbonyl Compounds Reduction.-It has been established66s67 that K- and L-selectride reductions of 5a- and 5P-cholestan-3-one give high yields of axial alcohols, but cholest-4-en-3one was reduced with L-selectride mainly to the pseudo-equatorial 3P-hydroxyFrom a study of a number of 3-0xo-A~'~~)-decalin~ it was established that selectride reductions gave a high proportion of the 3a-alcohol in those compounds containing an &-ether or -acetal oxygen atom.67 Selective reduction of the 8-aza-12,17-dioxo-18-nor-A13-compound ( 5 8 ) to the compound (59) was 59

6o 61

62

63 64 65

66

67

I. J. Harvie and F. J. McQuillin, J.C.S. Chem. Comm., 1978, 747. W. J. Rodewald and Z. Boiicza-Tomaszewski, Tetrahedron Letters, 1979, 31 19. M. P. Irismetov, M. I. Goryaev, and V. V. Kuril'skaya, Izvest. Akad. Nauk kazakh. S.S.R., Ser. khim., 1978,28, 58. L. L. Smith, M. J. Kulig, D. Miller, and G . A. S. Ansari, J. Amer. Chem. SOC.,1978, 100, 6206. M. Anastasia, A . Fiecchi, and A . Scala, J.C.S. Perkin I, 1979, 1821. K. Junghaus, G.-A. Hoyer, and G . Cleve, Chem. Ber., 1979,112,2631. F. Sweet, T. B. Patrick, and J. M. Mudd, J. Org. Chem., 1979, 44, 2296. R. Contreras and L. Mendoza, Steroids, 1979, 34, 121. W. G . Dauben and J. W. Ashmore, Tetrahedron Letters, 1978, 4487.

Steroid Reactions and Partial Syntheses

223

(58) R = 0 ( 5 9 ) R = H2

reported68 using Et3SiH-CF3C02H in the presence of BF3.Et20-LiC104and a number of analogues were similarly reduced. Reduction of the 3P-hydroxy-11oxo-14~-cholest-8-ene(60) with Li-NH3 afforded a mixture of the 3P,1 1Pdihydroxy-8a,l4P-compound (61) and the 3P,11cr dhydroxy -14P-compound (62).69 Oxidation of the former product (61) to the 3,11-dioxo-Sa,l4Pcompound led through base-catalysed epimerization to the novel 3,l l-dioxo8a,9P,14P-compound (63). Treatment of testosterone with B2H6-Ac20 in

diglyme gave a high yield of 17~-acetoxy-5a-androst-3-ene provided that the diborane was generated in situ (NaBH4-BF3-Et20)and moisture and air were excluded.'' A study of the selective reduction of methyl dioxo-5P-cholanates has been r e p ~ r t e d . ~Finely ' divided titanium, produced by lithium or potassium reduction of TiC13, reductively couples ketones; this was exemplified7' by the coupling of acetone and 5a-cholestan-3-one to give a mixture of the olefins (64) (54%) and (65) (29%). A . A. Akhrem, F. A. Lakhvich, L. G. Lis, and 2. N. Parnes, Izvest. Akad. Nauk S.S.R., Ser. khim., 1978,1465. '' D . G . Patterson and C. Djerassi, J. Org. Chem., 1979,44, 1866. 70 R. C. Cambie, P. S. Rutledge, D. W. Scott, and P. D . Woodgate, Austral. J. Chem., 1979,32,695. 71 R. Caputo, L. Mangoni, P. Monaco, G. Palumbo, and L. Previtera, Gazzetta, 1978,108,69. 7 2 J. E. McMurry, M. P. Fleming, K. L. Kees, and L. R. Krepski, J. Org. Chem., 1978, 43, 3255. 68

Terpenoids and Steroids

224

Other Reactions.-Reaction of the 17-0x0-steroids (66) and (67) with LDAEtCN gave the 20-cyano-17~-hydroxy-compounds (68) and (69) which were dehydrated with SOC12-pyridine to the 2 0 - ~ y a n o - A ~ ~ ' ~ ~ ) - ~ 0 m(70) p o uand nd~ (7 1) Conversion of the 20-cyano-A'7'20'-compound(70) into the 22-aldehyde (72) demonstrated the potential utility of this approach to the

RO

RO (66) R = THP (67) R = Bu'Me3Si

(71) R

=

(68) R (69) R

=

=

THP Bu'Me3Si

Bu'Me3Si

synthesis of 1a,25 -dihydroxycholecalciferol since 1a,3P-dihydroxyandrost-5en-17-one is readily available. Reformatsky reaction7' of the 16-acetoxy-170x0-steroids (73) and (74) with Zn-BrCH2C02Me gave the hydroxy-esters (75) and (76) which were converted into the lactone (77). Oestrone methyl ether was transformed into the cyano-ester (78) which reacted with nitromethane and base to give a mixture of the cyclopropane derivatives (79) and Similar analogous cyclopropane syntheses were also reported. Acid-catalysed Michael additions of aryl thiols to the androst-1-en-3-one (81) gave the thioenolic 73 74

75

76

D. J. Aberhart and C. T. Hsu, J. Org. Chem., 1978, 43, 4374. See 'Terpenoids and Steroids', ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 8, p. 254. K . Oka and S. Hara, J. Org. Chem., 1978,43,4408. K. Annen, H. Hofmeister, H. Laurent, A . Seeger, and R. Wiechert, Chem. Ber., 1978, 111, 3094.

225

Steroid Reactions and Partial Syntheses

(73) 168 (74) 5a,6dihydro, 16a

NC

(75) 16P (76) 5a,6dihydro, 16a

C0,Me

(79)

.

(83) R = H o r I

(81)

(82) R = H , I , o r N 0 2

derivatives (82) whereas base-catalysed reactions gave the normal adducts (83).77 Similar additions, at la- and 7a-,were observed" in the reactions between RSH-Na and androsta-l,4-diene-3,17-dioneand its A4m6-isomer respectively. The structures (84) and (85) respectively were assigned to the products of the reactions between ethane dithiol and 17&acetoxyandrosta-4,6-dien-3-one and the A'D4*6-anal~g~e. The full experimental details of the previously reported 'I'

'I8

M. M. Campbell, V. B. Jigajinni, and R. H. Wightman, Terruhedron Lefters. 1979, 2455. R. W. Brueggemeier, E. E. Floyd, and R. E. Counsell, J, Medicin. Chem., 1978.21, 1007.

226

Terpenoids and Steroids

oxidative dethioacetalization procedure were also reported.79Isoamyl nitrite was used for dethioacetalization and was exemplified with 5a-cholestan-3-one diethylthioacetal." Reaction of diazomethane with 3,7,12-trioxo-5~-cholanic acid8' and with 17-benzyloxy-6-oxo-3a,5-cyclo-5a-androstane8* gave ringexpanded products.

Reactions Involving Enols or Enolic Derivatives.--Review~~~~~~ on the use of a-sulphenylated carbonyl compounds in organic synthesis contain some steroidal examples. Deuteriation of progesterone and testosterone propionate was achieved with [Pt(P.j%t3)3]-D20.85 Amberlyst-A26Br3- was used to brominate a number of ~ - o x o - s ~ & oThe ~ ~ soxidizing .~~ solution obtained from NaOCOCF3F2 was used for the conversion of enol acetates into the a - f l u o r ~ - k e t o n e s . ~ ~ * ~ ~ Sequential reaction of the enol silyl ether ( 8 6 ) with MeLi and C H 2 0 gave" the 17a-hydroxymethyl-20-0x0-compound (87), which was converted into the spirofuranone (88). The reaction of o-nitrophenyl disulphide with ketones in

NaH -THF providing a-0x0-dimethylthioacetals, which were readily converted into the a-0x0-dimethylacetals or the a-diketones, was exemplified with 17-0x0steroid~.~' 1,2-Transposition of 0x0-groups was exemplified by the conversion of Sa-cholestan-3-one into a mixture of the 2-0x0- and 4-0x0-compounds and employed" the dianion of the tosylhydrazone as indicated in Scheme 1. Methyl79

R3 84

86 87

9o

'*

P. R. Heaton, J. M. Midgley, and W. B. Whalley, J.C.S. Perkin I, 1978, 1011. K. Fuji, K. Ichikawa, and E. Fujita, Tetrahedron Letters, 1978, 3561. K. Gawronska, J. Gawronski, and M. Kielczewski, Polish J. Chem., 1978, 52, 873. H. Velgovi, M. Synatkovi, and V. t e r n $ , Coll. Czech. Chem. Comm., 1979,44260. B. M. Trost, Chem. Rev., 1978, 78, 363. B. M. Trost, Accounts Chem. Res., 1978,11,453. T. Yoshida, T. Matsude, T. Okano, T. Kitani, and S. Otsuka, J. Amer. Chem. SOC.,1979,101,2027 S . Cacchi, L. Caglioti, and E. Cernia, Synthesis, 1979, 64. S. Rozen and 0. Lerman, J. Amer. Chem. SOC., 1979,101, 278'2. S. Rozen and Y. Menachem, J.C.S. Chem. Comm., 1979,479. P. Wieland, Helv. Chim. Acta, 1978, 61, 3068. Y. Nago, K. Kaneko, K. Kawabata, and E. Fujita, Tetrahedron Letters, 1978, 5021. T . Nakai and T. Mimura, Tetrahedron Letters, 1979, 531.

Steroid Reactions and Partial Syntheses Li

NNHTs

227 Li

-A+

Li N-NTS

+

~~

Li+

+

hLi+ -

N-NTS

N-NTS

/ t S M e

i i i +

SMe

w

Reagents: i, BuLi-TMEDA-THF; ii, MeSSMe; iii, BuLi; iv, A, NH,CI; v, HgCI,

Scheme 1

ation of the dimethylhydrazone of androstenolone followed by deprotection (CuCI-THF) gave 16a-methylandrostenolone and led to a reassessment of the equilibrium between the 16a-methyl- and the 160-methyl-derivatives which favoured the latter by a factor of 4.92In addition, it was established that the previously reported 16a-methylspironolactone was the 16P-methyl d e r i ~ a t i v e . ~ ~ 0ximes.-Reduction of the Beckmann fragmentation product (89) with LiAlH4 gave,93after acidic (HCI) work-up, the hydrochloride (91) and the hemi-acetal (92) which may be derived from the imino-intermediate (90). Oxidation of the

(89)

D

OHH

c1(91)

oximes of a series of 6-0x0-5a-cholestanes (93) with Pb(OAc), in AcOHbenzene,gave9, the 6~-acetoxy-5a-nitroso-compounds (94) and the Sa-acetoxy60-nitro-compounds (95).A study of the geometrical isomerism of 0-substituted oximes established9’ that 3-0x0-A4-compounds formed mixtures of syn- and anti-isomers whereas the 7-0x0-As-compounds formed only the syn-isomers.

92

93 94 95

G. Neef, U. Eder, and R. Wiechert, J. Org. Chem., 1978,43,4679. D . MiljkoviC, J. PetroviE, and P. HadiiC, Tetrahedron, 1978, 34, 3575. D . Shafiullah and H. Ali, Synthesis, 1979, 124. A . Bodor and A. Barabas, Tetrahedron, 1979, 35, 233.

228

Terpenoids and Steroids

R

&

(93) R

NOH @ R \ @ R

=

Br,Cl,I,orOAc

AcO NO

AcO NO2 (95)

(94)

4 Compounds of Nitrogen, Sulphur, Selenium, and Tellurium Base-catalysed equilibration of 6a-nitrocholest-4-ene and the 6P-isomer led to a 1: 1 mixture in which the unusual stability of the 6P-isomer was tentatively attributed to h o m o c o n j ~ g a t i o n The . ~ ~ 20-azidopregnane (96) was into the imino-dimer (97) by reaction with BF,*Et,O according to the Scheme 2. In a studyggof the reactions of halogens with Sa-conanine (98) it was observed

(97)

Scheme 2 96 97 98

J. T. Pinhey and G. C. Smith, Austral. J. Chem., 1978, 31,2563. I. Z. Kabort, Q. Khuong-Huu, and A. Pancrazi, Tetrahedron Letters, 1979, 2613. A. Picot and X. Lusinchi, Tetrahedron,1978, 34, 2747.

n steroid Reactions and Partial Syntheses

229

I N.

(100)

(101)

Reagents: i, Br, (4 equivs.)-NaOH; ii, Br, (1 equiv.)-Na,CO,; iii, NaOH; iv, Br, (3 equivs.)NaOH

Scheme 3

that the reaction with four equivalents of bromine and NaOH gave the pyrollidinone (99). This latter product was also obtained via the immonium salt (100) and the enamine (101) as indicated in Scheme 3. The nitrone (102) reacted with trimethyl phosphite in MeOH to give the N-methoxyphosphonates (103)whereas in acetic acid it gave the imino-phosphonate (104) and in triethylamine the imine (105) was the major product.'' Similar reactions of triethyl phosphite were

reported and in ethanol the absence of any reaction was noted. The acid-catalysed isomerization of the hydroxy-nitrone (106) to (107) has been reported in full."' Reaction of 3a-and 3P-amino-Sa-cholestanes with Bu'OCl-12-C6H5N0 gavel" respectively the azoxy-compounds (108) and (109), which were successively alkylated (MeLi), reduced (Li-EtNH,), and acetylated to give the epimeric 3-acetamido-3-methyl compounds (110). Conversion of 3a-amino-steroids into the isocyanide, the isothiocyanates, and the isoselenocyanates and the reductive cleavage of these derivatives with Bun3SnH-AIBN was rep0rted.l" 99 loo lo'

P. Milliet and X. Lusinchi, Tetrahedron, 1979, 35, 43. H. Dadoun, J. P. Alazard, J. Parello, and X. Lusinchi, Tetrahedron, 1978,34, 2639. D. H. R. Barton, G. Lamotte, W. B. Motherwell, and S. C. Narang, J.C.S. Perkin I, 1979,2030. D. H. R. Barton, G. Bringmann, G. Lamotte, R. S. H. Motherwell, and W. B. Motherwell, Tetrahedron Letters, 1979, 2291.

230

Terpenoids and Steroids 0-

0-

Alkylation of the sulphone (111) with Bu"Li-Me,SiCH,I gave the p-silylsulphone (112) which with Bun4NFgavelo3 3-methylene-5a-cholestane(113). Alkenyl sulphoxides, such as (114), were reduced to the alkenyl sulphides, without double-bond isomerization, using EtMgBr-CuIlo4 and the terminal allene (115) was prepared by treatment of (114) with LTMP.loS Reaction of

AlS4-thiones(116) with Ph2CN2 gavelo6 the 3-diphenylmethylene-A1*4-dienes (117) and with 2-nitrobenzenesulphenyl chloride gavelo63-(2-nitrobenzenesulphonylthi~)-A'*~*~-trienes (118). Duplodithioketones (119), prepared by treatment of the 3-0x0-compounds with ammonium polysulphide, were reduced with LiAIH4 to give the 3p-thi0ls.'~~Oxidation of a-hydroxythioacetals with P ~ ( O A Cto) ~ketenethioacetals was exemplified by the conversion of (120) into lo3 lo4 lo'

lo6

lo'

P. J. Kocienski, Tetrahedron Letters, 1979, 2649. G. H. Posner and P.-W. Tang, J. Org. Chem., 1978,43,4131. G . H. Posner, P.-W. Tang, and J. P. Mallamo, Tetrahedron Letters, 1978, 3995. D. H. R. Barton, L. S. L. Choi, R. H. Hesse, M. M. Pechet, and C. Wilshire, J.C.S. Perkin I, 1979, 1166. P. A. Bobbio and F. 0. Bobbio, Anais Acad. brasil. Cienc., 1978, 50, 61.

23 1

Steroid Reactions and Partial Syntheses

'5 5

AcO

(121). Interestingly the allenic thioacetal (123) was obtained from the a-hydroxythioacetal (122).lo8 The diphenylseleninic anhydride oxidation of 3P-tbutyltellurocarbonyloxy-5a-cholestane(124) provided the ester (125) whereas reduction with NaHTe gave the ether (126) and the dimeric ether (127).'09 log lo9

W. Lottenbach and W. Graf, Helu. Chim.Actu, 1978,61, 3087. A. G. M. Barrett, D. H. R. Barton, and R. W. Read, J.C.S. Perkin I, 1979, 645.

Terpenoids and Steroids

232

(124) R (125) R (126) R

Te 0 = H2

= =

0

%t

5 Molecular Rearrangements Backbone Rearrangements and Double Bond 1somerizations.-Acid-catalysed (BF3.Et20or toluene-p-sulphonic acid) rearrangement of A7-, A8-, and A8(14)cholestenes gave'" the spiro-olefins (128). An earlier report that a A8(14)-01efin gave a partially backbone-rearranged Al3(l7'- compound was discounted and it was suggested that such an 8P,9a- A'3'17'-olefin would be strained. A similar study'" on 3P-benzoyloxy-A7-, -A8-, and -A8(14)-5a-cholestenesestablished the intermediacy of the analogous spiro-olefin in their conversion in HCl-Et20 into the 3~-benzoyloxy-1413-chloro-17a-cholestane (129). In HCl-CHCl, the product

(kinetic) was 3~-benzoyloxy-14a-chloro-5a-cholestane. Further support for the intervention of these spiro-olefin intermediates is available'l2 from a study of the isomerization of 17a-tritiated 3P-acetoxy-Sa-cholest-8( 14)-ene to the A14-17acompound with loss of the 17a-tritium. Backbone and partial backbone (to A8(I4)) rearrangement was reported"3 in the reaction of cholest-5-ene with HC104AcOH. The configuration was established as 8P for the ethers (131) obtained from the acid-catalysed isomerization-cyclization of the 22-hydroxy-A7compounds (13O).ll4

''I

'I2

M. Anastasia, A. M. Soave, and A. Scala, J.C.S. Perkin I, 1978, 1131. M. Anastasia, A. Fiecchi, and A. Scala, J. Org. Chem., 1978, 43, 3505. D. J. Aberhart, T.-Y. Chau, and E. Caspi, J.C.S. Perkin I, 1979, 220. R. U. Alrnoula, G. K. Trivedi, and S. C. Bhattacharyya, Indian J. Chem., 1978, 16B,257. D. i. Aberhart, E. Caspi, C. M. Weeks, and W. L. Duax, J. Org. Chem., 1979, 44, 75.

233

Steroid Reactions and Partial Syntheses

(130) R

=

R

=

P-OBZ, 5a 01 ~Y-OAC, 5p

Isomerization of the side-chain double bond of stigmasterol and its derivatives has been using N-lithioethylenediamine, and degradations to androstenolone, pregnenolone, and progesterone employed this reaction. Hexacarbonylchromium was used'" to isomerize 3@-acetoxy-Sa-ergosta7,14,22-triene to the A"14,22-trieneand ergosteryl acetate to the A6*'(14),22-triene. A study of the precholecalciferol-cholecalciferol equilibrium using [ 192H2]cholecalciferolshowed that there was limited transfer of deuterium to C-9 and that such transfer occurred preferentially to the 9a-position."' Thermal isomerization of cis-isotdchystero13 (132) gave"' the novel 9,lO-secocholesta5,7,14-trienols (133) and (134) by a similar intramolecular 1,7-hydrogen transfer,

(133) 10a (134) lop

Miscellaneous Rearrangements.-Westphalen rearrangement of the [ 5 - " 0 ] - 5 hydroxy-steroids (135) and (137) gave the oxygen-labelled Sa-acetoxy-derivatives (136) and (138) as by-products, suggesting that neighbouring group participation of the 6P-methoxy-group is unirnportantl2' and that the role of the 6P-substituent in these rearrangements should be reconsidered. Boron trifluoride-catalysed rearrangement of the 3a,Sa-epoxycholestane (139) gave the 2a,Sa-epoxide (140), the 3a,lOa-epoxide (141), and the 3a,SP-dihydroxy-GPP. Balakrishnan, R. Seshadri, K. K. Chakravarti, and S. C. Bhattacharyya, Indian J. Chem., 1978, 16B, 253. '16 A. Ayanoglu, A . Chan, and C. Djerassi, Tetrahedron, 1979, 35, 1591. D . H. R. Barton, S. G. Davies, and W. B. Motherwell, Synthesis, 1979, 265. '18 M. Sheaves, E. Berman, Y. Mazur, and Z. V. I. Zaretskii, J. Amer. Chem. Soc., 1979,101, 1882. *19 B. L. Onisko, H. K. Schnoes, and H. F. Deluca, J. Org. Chem., 1978,43,3441. l Z o P.KoEovskL, V. tern$, and F. TureEek, Coll. Czech. Chem. Comm., 1979, 44,234. '15

Terpenoids and Steroids

234

BzO

AcO

OMe (135) R (136) R

=

=

(137) R (138) R

H Ac

OAc

=

H

=

Ac

OAc

acetoxy-cholestane ( 142).121 Compound (142) arose from the reaction of the intermediate 5P,6P-acetoxonium ion (143) with water during work-up. This investigation and a further study122established that the solvolysis of 5-hydroxy3~-tosyloxy-5~-cholestan-6-one (144) gave the 3cu,5a-epoxy-A-homo-B-norketone (145) and not the 3P,SP-epoxy-6-ketone (146) as previously reported.

‘’I

R. W. G . Foster and B. A. Marples, Tetrahedron Letters, 1979, 2071.

”’V. Dave and E. W. Warnhoff, J. Org. Chem., 1978,43,4622.

Steroid Reactions and Partial Syntheses

235

AcO

Treatment of the 7cu,8a-epoxy-5-oxo-5,6-secocholestanealdehyde (147) with mineral acid or Lewis acid gave123the acetal (148)which with BF3.Et20 rearranged to the acetal (149). The olefin (154), which was formed in the BF3catalysed fragmentation of the exocyclic epoxides (150) and (151) and, as previously reported, in the similar fragmentation of the endocyclic epoxide (152), to arise from the oxetan (153) in all cases. was

@

H- -

Reaction of the pregnane-3&20P-diol(15 5) with [Pd(PhCN),C12] gavelz5the 17a-methylpregnane-3P,17 ap-diol (157) (uranediol) and similarly the 3&20pdimethoxypregn-5-ene (161) gavelz6the diacetate (158). Further studies on the solvolysis of the 17a-methyl-~-homo-tosylate(159) were reported1” and, as expected, it was established that the 20P-tosylate (156) gave the same distribution of products on acetolysis. Formolysis of (159) gave rather less rearrangement lZ3 lZ4 lZ5

126

’*’

W. J. Rodewald and Z . Boka-Tornaszewski, Tetrahedron Letters, 1979, 169. I. Morelli, S. Catalano, V. Scartoni, M. Feretti, and A. Marsili, J.C.S. Perkin I, 1979, 1665. E. Mincione, G . Ortaggi, and A. Sirna, J. Org. Chem., 1979,44, 2320. I. A. Blair, R. G. Frith, G. Phillipou, and C. J. Seaborn, Austral. J. Chem., 1978, 31, 2333. Y. Gopichand and H. Hirschmann, J. Org. Chem., 1979,44, 185.

Terpenoids and Steroids

236

(155) R' (156) R'

= =

R2 = H Ac, R2 = Ts

(157) (158) (159) (160)

R' = R2 = H; 17P-H R' = R2 = Ac; 17P-H; 5,6-dehydro R' = Ac, R2 = Ts; 17p-H R' = Ac, R2 = Ts; 17a-H

products than did acetolysis owing essentially to the better solvating properties of (160) proformic acid. The formolysis of the 17~-methyl-~-homo-tosylate ceeded12' 2.2 times faster than that of (159) and the major product (84%) was the D-homo-A'6-olefin (162). Acetolysis of (160) similarly gave a high proportion of olefins and these results contrasted with those for the solvolyses of (159) which gave very much less olefinic material. It was concluded that solvolysis of (159) involved the chair conformation in the transition state whereas that of (160) did not. The major product (50%) of the reaction between the 17a-hydroxy-20-0x0compound (163) and Zn-TiC1, was the 17-oxo-~-homo-compound( ~ 4 ) ' ~ and ' reaction of the 16,17-methano-20-hydroxy-compounds(165) with MeC02H at (166). A series 110 "C gavel3' the 16-acetoxy-17-ethylidene-~-homo-com~ound of 3 a,5a -cyclo-compounds gave 3' the 5a-chloro -4P-me thyl- A-nor-compounds (167) with HCI-CHCl, at -60 "C. Acid-catalysed rearrangement/hydrolysis of the 3a,20a-disulphate (168) (169). Rearrangement of the 17agavel3' the 17~-methyl-18-nor-compound hydroxy-3-0xo-A~~~*~"-triene (170) to the c-ring aromatic compound (17 1) occurred in formic as did the rearrangement of 17a-ethynyloestradiol to the chrysene derivative (172). The 9,1l-epoxy-17-hydroxy-steroids(173) and (174) were converted with BF3.Et20into the c-ring aromatic compounds (175) and (176) re~pective1y.l~~ Normal acetonide formation in the reaction of H. Hirschmann, F. B. Hirschmann, and Y. Gopichand, J. Org. Chem., 1979, 44, 180. J. E. McMurry, M. G . Silvestri, M. P. Fleming, T. Hoz, and M. W. Grayston, J. Org. Chem., 1978,43, 3249. I3O N. G . Steinberg, G. H. Rasmusson, and R. A. Reamer, J. Org. Chem., 1979,44, 2294. 13' E. J . Brunke, Chem. Ber., 1979, 112, 1607. 13' 1. Yoshizawa, R. Ofuchi, and N. Kawahara, Chem. and Pharm. Bull. (Japan), 1978,26, 2281. 133 A. B. Turner, J.C.S. Perkin I, 1979, 1333. 134 H. T. A. Cheung, R. G . McQueen, A. Vadasz, and T. R. Watson, J.C.S. Perkin I, 1979, 1048.

lZ9

237

Steroid Reactions and Partial Syntheses

+ 'OAc

&a"' /

/

0

/

(170)

\

HO (171)

(172)

hydrocortisone with acetone dimethylacetal and toluene-p-sulphonic acid was accompanied by formation of the acetonides (177) and (178), which were derived from products of the Mattox rearrangement.'35 A general study of ring-expansion reactions of 3 -oxo-steroids established that in the majority of cases the migratory aptitudes of C-2 and C-4 were e q ~ i v a 1 e n t . lBaeyer-Villiger ~~ oxidation of 4a-acetoxycholest-5-en-3-onewith perbenzoic acid (2.5 equivs.) gave the acetoxy-lactone (179) e x c l ~ s i v e l y . The '~~ Beckmann rearrangement of the tosylates of the syn- and anti-oximes of 3-OXOA4-steroids gave only the lactams from C-2 migration owing to the rapid preisomerization of the anti- to the s y n - c o m p o u n d ~ . ~ ~ ~ 13* 13' 13'

13'

K. B. Sloan, R. J. Little, and N. Bodor, J. Org. Chem., 1978,43, 3405. V. Dave, J. B. Stothers, and E. W. Warahoff, Canad. J. Chem., 1979,57, 1557. M. S. Ahmad, M. Asif, and M. Mushfig, Indian J. Chem., 1978,16B, 426. K. Oka and S. Hara, J. Org. Chem., 1978,43, 3790.

Terpenoids and Steroids

238

H0 O@

i174)

(173) H AcO+CH ,OAc

@

&I5

0

0 (175)

6 Functionalization of Non-activated Positions Reaction of cholestan-3a-yl xanthate with Fe(C104)2-HOAc-02 containing a trace of Fe3' gave'39 cholestan-la,3a-diyl diacetate (180) in reasonable yield (45%). Further studies on dry ozonization led to a series of 25-hyd r o x y c h o l e ~ t a n e Lead ~ . ~ ~ ~tetra-acetate oxidation of the bromohydrin (181) gave141a mixture of the 6&19-epoxide (182) and the hemiacetal acetates (183) and (184). OPiv

OH (181) 13'

'41 14'

(182) R1 = R2 = H (183) R' = OAc, R2 = H (184) R' = H, R2 = OAc

H. Patin and G. Mignani, J.C.S. Chem. Comm., 1979, 685. Z. Cohen and Y. Mazur, J. Org. Chem., 1979,442318. W. J. Rodewald, J. R. Jaszczynski, and R. R. Sicinski, Polish J. Chem., 1978, 52, 715.

Stfroid Reactions and Partial Syntheses

(185) R' (186) R'

= =

NO, R2 = H R2 = H

(187) R' = H , R 2 = (188) R'

=

239

€it N

H,R2 = N2+

An inve~tigation'~~ into the mechanism of by-product formation in the Barton reaction of the cholestanyl6P-nitrite (185) revealed that the 6-ketone (189) was formed by loss of hyponitrous acid and the 6P-alcohol(l86) arose independently from intermolecular hydrogen abstraction by the intermediate C- 19 alkyl radical. It was suggested that the 6,19-epoxide (28; 5 a ) was formed from the 19diazonium salt (188) which in turn arose from the photo-reaction of the nitrosodimer (187) with NO. P h o t ~ l y s i sof ' ~ the ~ 20-formyl-20-hydroxypregnen-1lp-yl nitrite (190) gave the 18-formyl-20-0x0-compound (191). The reaction mechanism (Scheme 4) is analogous to that for the similar transfer of a nitrile group in the P ~ ( O A C ) ~reaction -I~ of 20-cyano-20-hydroxy-compounds and to that (Scheme 5 ) in the photochemical interconversion in acetone of the 20-azido-20-cyanopregnane (192) to the 18-cyano-20-0~0compound (193). Photolysis of (192) in hexane led to the imino-nitriles (194) and (195) through the singlet nitrene.

(190)

OH

1

Scheme 4 143

'41

D. H. R. Barton, R. H. Hesse, M. M. Pechet, and L. C. Smith, J.C.S. Perkin I, 1979, 1159. J. Kalvoda and J. Grob, Helv. Chim. A m , 1978, 61, 1996. See ref. 74, p. 254. A. D. Barone and D. S. Watt, Tetrahedron Letters, 1978, 3673.

240

Terpenoids and Steroids

I

I

OMe

Scheme 5

7 Photochemical Reactions P h o t o l y ~ i sof ' ~ the ~ cyclobutyl nitrite (196) gave products of both possible modes of @scission ( a and b ) of the resultant alkoxy-radical(l98) and an unusually high proportion of the 16~-hydroxy-compound(197). Photoisomerization of D-ring

H (196) R (197) R

= =

NO H

substituted A5"-steroids provided an improved route to 9P,lOa-steroids of this type. 14' The photoi~omerization'~~ of l-oxo-androsta-2,4-diene(199) to the 10a-compound (201) proceeded through the keten (200), which was detected spectroscopically and by trapping with cyclohexylamine. Irradiation of the truxone (202) gave'49 the D-homo-c-nor-steroid (203) according to Scheme 6. A structure proposed earlier for the photoproduct was rejected.

'" '41

H. Suginome and T. Uchida, J.C.S. Chem. Comm., 1979, 701. S. J. Halkes, A. B. van Etten, T. L. Postmus, J. S. Bontekoe, and M. P. Rappoldt, Rec. Trav. chim., 1979,98, 78.

148

149

G . Quinkert, H. Englert, F. Cech, A. Stegk, E. Haupt, D. Leibfritz, and D. Rehm, Chem. Ber., 1979, 112,310. R. A. E. Ceustermans, H. J. Martens, and G. J. Hoornaert, J. Org. Chem., 1979,44, 1388.

Steroid Reactions and Partial Syntheses

24 1

-

Me0

-co

Me0

OFH Me0

Scheme 6

Photohydration of 3 -oxo-A4-compounds in water-methanol (4 : 1) gave the corresponding 5a-hydroxy-3-oxo-compounds.'50Photolysis of 3-0x0-4-tosyloxycholest-4-ene (204) gavel5' the hydroxy-compound (205) whereas the simple cyclohexenone derivatives (206) afforded the 3-aryl-2-hydroxycyclohexenones (207). It was established that photo-Beckmann rearrangement of A-nor-5acholestan-3-one oxime proceeded152with retention of configuration at C-5.

&

OS0,Ar

& OH o

0

Ar

OR

(206)

(207)

(204) R = Ts

(205) R = H

The full account has appeared153of the photocycloaddition reactions between the 3,s-dioxo-A4-compounds (208) and cyclopentene, dihydropyran, and various (209) and (210) were dienes. Although the 6,7-methano-3-oxo-A4-compounds 150

15' 153

D. G. Cornell, E. Avram, and N. Filipescu, Steroids, 1979, 33, 485. A. Feigenbaum, J.-P. Pete, and D. Scholler, Tetrahedron Letters, 1979, 537. H. Suginome, H. Takeda, and T. Masamune, Bull. Chem. SOC.Japan, 1979, 52, 269. G. R. Lenz, J. Org. Chem., 1979, 44, 1597.

Terpenoids and Steroids

242

photo-inert, in the presence of 2,3-dimethylbutadiene they both gave154the adduct (211). The behaviour of (209) and (210) was compared with that of the equivalent 3-oxo-A4~6-compound which had been reported earlier in brief. Photocycloaddition of the 3-0xo-A~*~-diene (212) with methyl acrylate gave155the trans-adducts (213) and (214) and the cis-adduct (215); this breakdown of stereospecificity relates to the electron-deficient nature of methyl acrylate and accords with theoretical predictions.

H

C0,Me

CO,Me

Section B: Partial Syntheses 8 Cholestane Derivatives and Analogues The major product of the reaction between the 3&acetoxy-la,2a-epoxy-6@-yl mesylate (2 16) and HC1-ether-MeOH was e ~ t a b l i s h e d 'as ~ ~la,2P-dihydroxycholesterol and not the epoxide (217) as had previously been reported. The epimeric 2-hydroxy-3-methylenecholestanes(219) were synthesized by reaction of the epoxy-sulphones (218) with Na/Hg in methan01.l~~The 14a-hydroxycholestanes (220),158(221),'58 and (222)'59 have been synthesized and the key step in each case was the SeOz oxidation of the 6-0x0-A7-compound. The key step in the synthesis of 3p,5 -dihydroxy-5~-cholestan-19-ol(223) was the HOBr addition to the 19-formyloxy-AS-compound(224) which gavel6' the 50-hydroxy154

156

'"

lS8

159

G. R. Lenz, J. Org. Chem., 1979, 44, 1382. G. R. Lenz and L. Swenton, J.C.S. Chem. Comm., 1979,444. B. Pelc, Tetrahedron, 1978, 34, 3079. P. J. Kocienski and J. Tideswell, Synth. Comm., 1979, 9,411. J. F. Kinnear, M.-D. Martin, Y. K. Chong, A. Faux, D. H. S. Horn, and J. S. Wilkie, Austral. J. Chem., 1978,31,2069. W. J. Rodewald, W. J. Szczepek, and J. Gumulka, Bull. Acad. polon. Sci., Sir. Sci. chim., 1978,26, 91. P. KoEovsk9, Coll. Czech, Chem. Comm., 1979,44, 2156.

Steroid Reactions and Partial Syntheses

& '

0

243

\ &oH

S0,Ph (218)

(219) 2a and 2 6

6a-bromocholestane (225) owing to participation of the formyloxy-group (see refs. 23 and 24). Hydroboration of tricarbonyliron ergosteryl benzoate led to syntheses of (22R )- and ( 2 2 s )- 3P-benzoyloxyergost a-5,7 -dien -22 -01 and (23R)- and (23S)-3~-benzoyloxyergosta-5,7-dien-23-ol.161 The previously reported products of the reaction between smilagenin and LiAlH4-BF3.Et20 A. A. L. Gunatilaka and A. F.Mateos, J.C.S. Perkin

I, 1979, 935.

Terpenoids and Steroids

244

R'

(226) R1 (227) R'

= =

OH, R2 = H H, R2 = OH

were identified as the (22R)- and (22S)-3&16&22,26-tetrols (226) and the (23R)- and (23S)-3&16&23,26-tetrols(227), and the reaction, which also gave dihydrosmilagenin, appears to be Treatment of 5P-cholestane3a,7a,12a,25 -tetrol with Ac20-MeC02H followed by hydrolysis with KOHMeOH gave a mixture of the 3~~,7~~,12a-trihydroxy-A~~and - A 2 5 - ~ ~ m p ~ ~ n d ~ , which on hydroboration and H202-NaOH oxidation gave163(24R)- and (24s)5P-cholestane-3a,7c,l2a,24-tetrols(228) and SP-cholestane-3a,7a,12a,26tetrols (229) epimeric at C-25. Syntheses of 3-epiecdysone and 3-epi-20-hydroxyecdysone (230) involved the NaBH4 reduction of the corresponding 3OH

(228)

dehydroecdysones which were prepared from the ecdysones by Pt-0, oxidat i ~ n Syntheses . ~ ~ ~ have been for 21-hydroxycholesterol (232) and 25-hydroxycholestero1(233)from the ethyl pregnan-21-oate (231) and involved 16'

163 164

'61

G. R. Pettit, J. J . Einck, and J. C. Knight, J. Amer. Chem. SOC., 1978, 100, 7781. B. Doyal, A. K. Batta, S . Shefer, G . S . Tint, and G . Salen, Steroids, 1978, 32,337. L.Dinan and H. H. Rees, Steroids, 1979, 32,629. J. Wicha and K. Bal, J.C.S. Perkin I, 1978, 1282.

Steroid Reactions and Partial Syntheses

245 HO

THPO

1

I

(231)

iii

iv

HO

r;E t

U HO

(232)

ii, v, ii, iii

(233)

n0

0 Reagents: i, LDA-Br(CH,),CHMe,; ii, LiAlH,; iii, H,O'; iv, LDA-Br(CH,), pyridine; vi, Ac,O-pyridine; vii, MeMgI

.x v, TsCI;

Scheme 7

the key alkylations of the lithium enolate of (231) which gave the (20R)configuration stereospecifically in each case (Scheme 7 ) . The conversion of diosgenin acetate into (25R)- 26-aminocholesterol and (25R)- 26-aminocholest5-ene-3P,16p-did has been reported.166 A synthesis of 23-deoxyantheridiol (235) from the 24-oxo-A22-compound (234) e m p l ~ y e d ' ~an ' intramolecular Wittig-Horner reaction for the construction of the lactone. The allylic oxidation at position 6 was achieved using singlet oxygen (Scheme 8). It was established that oogoniol (3P,11a,15P,29-tetrahydroxystigmast-5-en-7-one)has the (24R)configuration by comparison with 29-hydroxysitosterol and 29-hydroxyclionasterol, which were unambiguously synthesized.16* Syntheses have been reported'69 for 14a-methyl-5a-cholest-7-ene-3P,15Pdiol and its 15a-epimer. Syntheses of 24-epimers of 24-methyl- and 24-ethyl'66 16'

R. Tschesche and H. R. Brennecke, Chem. Ber., 1979,112,2680. G . R. Weihe and T. C. McMorris, J. Org. Chem., 1978,43,3942. M. W. Preus and T . T . McMorris, J. Amer. Chem. SOC.,1979, 101, 3066. T. E. Spike, J. A. Martin, S. Huntoon, A. H. J. Wang, F. F. Knapp, and G. J. Schroepfer, jun., Chem. and Phys. Lipids, 1978, 21, 31.

Terpenoids and Steroids

246 0

i,ii

AcO

1

(234)

iii

tl iv, v

Reagents: i, H,O,-OH-; ii, Ac,O-pyridine; iii, Al-Hg; iv, BrCH,COBr-pyridine; v, (EtO),P; vi, NaH-THF; vii, K,CO,-MeOH; viii, hv, haematoporphyrin-0,; ix, Cu(OAc),-pyridine

Scheme 8

cholesterols from the 24-alkylidene-cyclosteroids (236) and (237) employed17' hydroboration/oxidation and chromatographic separation of the resultant 29hydroxy-compounds followed by mesylation and NaBH4-HMPA reduction. The structures of the marine sterols stelliferasterol (238),171,172 isostelliferasterol (239),17' strongylosterol (240),17' verongulasterol (241),173 24-isopropenylcholesterol,'74 and 24-isopropylcholestero1174were established by partial syntheses. Two syntheses were r e p ~ r t e d ' ~ for ~ , 'demethylgorgosterol ~~ (243) and the more synthesis from the 3,5-cyclo-22-aldehyde (242) is outlined in Scheme 9. The 3,5-cyclo-22-aldehyde (242) served as the starting 17' 171

17*

173

175

176

Y. Fujimoto and N. Ikekawa, J. Org. Chem., 1979,44, 1011. N. Theobald, R. J. Wells, and C. Djerassi, J. Amer. Chem. Soc., 1978, 100, 7677. N. Theobald and C. Djerassi, Tetrahedron Letters, 1978, 4369. W. C. M. C. Kokke, W. H. Fenical, C. S. Pak, and C. Djerassi, Tetrahedron Letters, 1978, 4373. W. C. M. C. Kokke, C. S. Pak, W. Fenical, and C. Djerassi, Helu. Chim. Acta, 1979, 62, 1310. R. D. Walkup, G. D. Anderson, and C. Djerassi, Tetrahedron Letters, 1979, 767. M. Ishiguro, A. Akaiwa, Y. Fujimoto, S. Sato, and N. Ikekawa, Tetrahedron Letters, 1979,763.

Steroid Reactions and Partial Syntheses

247

OMe (236) R = H (237) R = Me

material in a synthesis of the 22,23-methano-24-norcholestene(244), which was shown to be different from the recently isolated cystoster01.~~~ This synthesis involved the intermediate 24-0xo-A~~-compound (245) which was also converted into 3P-hydroxy-26,27-bisnorcholest-5-en-24-one(246), a constituent of Psammaplysilla p ~ r p u r e a . The ' ~ ~ 3,5-cyclo-24-aldehyde (247) was transformed into the 24,25-methano-compounds (248) and (249).'79 Cholesta-8( 14),24-dien-3@-01 (25 l), which is implicated in cholesterol biosynthesis, has been synthesized'" from the A5-methylester (250) as in Scheme 10. Syntheses have been reportedlgl for a number of 7-ketocholesterol analogues in which one side-chain carbon atom (20, 22, 23, or 24) was replaced by oxygen [e.g. (252)]. The 5~,12-dirnethylcholesta-8,11,13-triene (253), which occurs in sediments and crude oils, has been synthesized182and improved syntheses for 5P-cholestan-26-oic acids from bile acids have been reported. lS3 An improved dehydration procedure for the alcohols (254) and (255)which involved treatment of their mesylates with NaOEt-EtOH led to the A3-compounds(256)and (257).lS4 The 2-bromocholestan-3-ones (258) and (259) were converted into the anhydrides (260) and (261) as indicated in Scheme 11 and the anhydrides (264) and (265) were prepared similarly from the 3-oxocholest-1-enes (262) and (263).lS5 17' '71 179

lS2

lS4

F. 0. Giilacar and C. Djerassi, Helv. Chim. Acta, 1979,62, 1640. E. Ayanoglu, C. Djerassi, T. R. Erdman, and P. J. Scheller, Steroids, 1978, 31, 815. C. Tarchini, M. Rohmer, and C. Djerassi, Helv. Chim. Acta, 1979,62, 1210. M. A . Apfel, J. Org. Chem., 1979, 44, 643. J. H. Dygos and B. N. Desai, J. Org. Chem., 1979, 44, 1590. J. Schaefle, B. Ludwig, P. Albrecht, and G. Ourisson, Tetrahedron Letters, 1978,4163. A. K. Batta, G. Salen, G. S. Tint, and S. Shefer, Steroids, 1979,33, 589. T . G. C. Bird, G. Felsky, and G. D. Meakins, J.C.S. Perkin I, 1978, 1533. G. Snatzke and B. Wessling, Annalen, 1979, 1028.

248

Terpenoids and Steroids

liv,v

1

ix, v

P

vi, x, xi

HO

Reagents: i, H,C=CHMgBr, ii, Cr0,-pyridine; iii, KCN-MeCN-H,O-18-crown-6; iv, NaBH,; v, chromatographic separation; vi, MsC1-pyridine; vii, Pr'Li-THF; viii, Ph,P=CH,; ix, B2H,-HzOZ-OH-; x, LiAIH,; xi, H,O+

Scheme 9

0

oMe (245)

249

Steroid Reactions and Partial Syntheses

I

OMe

(248) R (249) R

(247)

&

= =

H Me

C0,Me

AACO&

AcO

1

(250)

iii, iv

HO

HO l v i i , viii

&OHBzO

ix, x, viii

H

1

HO

H

(251)

Reagents: i, NBS; ii, (MeO),P; iii, SO,, A; iv, LiAlH,; v, Ni-H,; vi, Ac,O-pyridine; vii, BzClpyridine; viii, KOH; ix, (PhO),PBr,; x, LiCH,CH=CMe,

Scheme 10

Terpenoids and Steroids

250

(254) R (255) R

= =

(256) R (257) R

C9H17 C9H19

= =

C9H17 C9H19

Br-Jyy R\\

R\\

R \

A *Bo

O

H

(258) R (259) R

H

1

Me = C02Me =

iii

(260) R (261) R

= =

Me C02Me

Reagents: i, MCPBA; ii, DBU; iii, Ru0,-NaI04; iv, DCC

Scheme 11

(262) R (263) R

=

=

Me COzMe

(264) R (265) R

= =

Me C02Me

9 Vitamin D and its Metabolites and Related Compounds Lithocholic acid was transformedlg6 into the (24R)- and (24S)-24-hydroxycholesta-1,4,6-trien-3-one,which and 25-hydroxycholesta-l,4,6-trien-3one were converted into (24R)- and (24s)- la,24-dihydroxycholecalciferoland la,25-dihydroxycholecalciferolby the Kaneko deconjugation/oxidation procedure.lS7 In addition, the AlV4-dienone(266) was deconjugated t o give the A’.’-dienone (267), which was converted through the dihydr~xy-A~~’*~-triene

‘87

K. Ochi, I. Matsunaga, M. Shindo, and C. Kaneko, J.C.S. Perkin I, 1979, 161. K. Ochi, I. Matsunaga, H. Nagano, M. Fukushima, M. Shindo, C. Kaneko, M. Ishikawa, and H. F. DeLuca, J.C.S. Perkin I, 1979, 165.

Steroid R ea cti0n s and Pa rtia 1 Sy n theses

25 1

(268) into lcu,25-dihydroxycholecalciferol.'s7 A synthesis and X-ray analysis established that the natural 24,25-dihydroxyergocalciferol has the (24R)configuration. l g 8 A mixture of 25-fluoro-la-hydroxycholecalciferoland the l a - h y d r 0 ~ y - A ~ ~ and - A 2 5 - ~ ~ m p(270) ~ ~ nwas d ~obtained from the reaction of the diacetate (269)

Ac

OH

with diethylaminosulphur trifluoride and subsequent h y d r o l y ~ i s . A ' ~ synthesis ~ of 24,24-difluoro-25-hydroxycholecalciferol from the lithocholic acid derivative (271) has been reported;Ig0the side-chain construction is shown in Scheme 12. An alternative synthesis employing cholenic acid as starting material has been reported along with a synthesis of 24-fluoro-25-hydroxycholecalciferol.'gl A synthesis of 22,23-epoxyergocalciferol from the 4-phenyl-1,2,4-triazoline3,5-dione adducts (272) employed19*the K,CO,-DMSO reaction'93 for deprotection of the A577-diene(cf. ref. 53). The Reporter observes that the assignment of the 22&23P-~onfigurationis dubious in view of earlier work in this area.'94 25Syntheses have been reported for la,25-dihydroxy-24-nor-cholecalciferol, hydroxy -24 -nor- 5,6 - trans-cholecalciferol, and 2 5- hydroxy- 24a-homo- 5,6G. Jones, A. Rosenthal, D. Seger, Y . Mazur, F. Frolow, Y. Halfon, D. Rabinovich, and Z. Shakked, Tetrahedron Letters, 1979, 177. J. L. Napoli, M. A. Fivizzani, A. H. Hamstra, H. K. Schnoes, H. F. DeLuca, and P. H. Stern, Steroids, 1978, 32,453. 190 S. Yamada, M. Ohmori, and H. Takayama, Tetrahedron Letters, 1979, 1859. 19' Y. Kobayashi, T. Taguchi, T. Terada, J.-I. Oshida, M. Morisaki, and N. Ikekawa, Tetrahedron Letters, 1979, 2023. 192 M. Tada and A. Oikawa, J.C.S. Perkin I, 1979, 1858. 193 See ref. 41, p. 278. 194 J. Brynjolffsen, D.Hands, J. M. Midgley, and W. B. Whalley, J.C.S. Perkin I, 1976, 826.

lS9

qC

Terpenoids and Steroids

252

&co2Me

i,ii,

iii, iv

1

iii, iv

THPO'*

n

0 C02Et

v-vii

AcO'*

H

kii*

E

ix

H

0

Reagents: i, LiAIH,; ii, Cr0,-pyridine; iii, HS(CH,),SH-BF,-Et,O; iv, 0 /H+; v, Bu"LiClC0,Et; vi, H,O+; vii, Ac,O-pyridine; viii, DAST-CH,CI,; ix, MeMgBr

Scheme 12

Ph (272) R = AcorTHP

Steroid Reactions and Partial Syntheses

253

trans-cholecalciferol,195as have syntheses of 25-hydroxy-22-dehydrocholecalcifer01,'~~ 22-dehydrocholecalcifero1,197and 22,24-bisdehydrocholecalciferol.197 Direct C- 1 hydroxylation of cholecalciferol, ergocalciferol, and 25-hydroxycholecalciferol through the SeOz oxidation of the 7-methoxy-3,5-cycloderivatives (Scheme 13) has been r e ~ 0 r t e d . l ~ ~

1

----+

TsO"

... .

I l l , IV

HO'

HQ

Reagents: i, MeOH-NaOAc; ii, SeO,; iii, Ac,O-pyridine;

OH

iv, TsOH-H,O-dioxan

Scheme 13

A conformational study of vitamin D analogues involved the syntheses of 4,4-dimethylcholecalciferol, 4,4-dimethyl-la-hydroxycholecalciferol,and 4,4dimethyl- 1a-hydroxyepicholecalciferol.'99 A novel approach to the 1-hydroxyvitamins D involved*" sigmatropic rearrangement of vinyl allenes and is exemplified by the conversion of (273) into 1~-hydroxy-3-deoxycholecalciferol(274). Photochemically generated singlet oxygen is reportedzo1 to react with ergocalciferol or the benzoate to give the epidioxides (275) or (276) respectively. 195

196

'91 19*

199

A. Mouriiio, P. Blair, W. Wecksler, R. L. Johnson, A. W. Norman, and W. H. Okamura, J. Medicin. Chem., 1978,21, 1025. N. A. Bogoslovskii, G. E. Litvinova, A. R. Bekker, T. M. Filippova, and G. I. Samokhvalov, Zhur. obshchei Khim., 1978,48, 897. N. A. Bogoslovskii, G. E. Litvinova, and G. 1. Samokhvalov, Zhur. obshchei Khim., 1978,48,908. H . E. Paaren, D. E. Hamer, H. K. Schnoes, H. F. DeLuca, Proc. Nut. Acad. Sci, U.S.A., 1978,75, 2080. E. Berman, N. Friedman, Y. Mazur, and M. Sheves, J. Amer. Chem. Soc., 1978,100,5626. M. L. Hammond, A. Mouriiio, and W. H. Okamura, J. Amer. Chem. SOC.,1978,100,4907. S. Yamada, K . Nakayama, and H. Takayama, Tetrahedron Letters, 1978, 4895.

Terpenoids and Steroids

254

C

R 0' (275) R = H, 6cu and 6p (276) R = Bz, 6a and 6 p

(277)

Reduction of cholecalciferol and 5,6-trans-cholecalciferol using hydrozirconation [( s-C5H5)2Zr(C1)H]-protonation was reported202 to give the 10,19-dihydro-derivatives more efficiently than hydroboration-prot~nation~~~ though stereoselectivity was not improved. A convenient synthesis of tachysterol, involved the photolysis of ergosterol in the presence of [Fe(CO),]. The major products, the tachysterol, tricarbonylirons (277), were readily converted into tachystero12with FeC13.*04

10 Pregnanes A new synthesis of corticosteroids from 17-0x0-steroids employedzo5a sulphoxide-sulphenate rearrangement and the key steps in a synthesis of hydrocortisone acetate from the 9a-hydroxyandrostenedione (278), itself readily available from microbiological degradation of sitosterol, are shown in Scheme 14. The starfish saponin aglycone (279) was converted into the corticoid precursor (280) by successive treatment with Ag,CO,-celite and PPh,-CCl, in benzene.*06 An improved degradation has been reported207 for the degradation of NA. W. Messing, F. P. ROSS,A. W. Norman, and W. K. Okamura, Tetrahedron Letters, 1978, 3635. See ref. 41, p. 312. '04 A. G. M. Barrett, D. H. R. Barton, and G. Johnson, J.C.S. Perkin I, 1978, 1014. *"' V. VanRheenan and K. P. Shepherd, J. Org. Chem., 1979,44, 1582. *06 J. W. ApSimon, J. Burnell, and J. Eenkhoorn, Synth. Comm., 1979, 9, 215. '"'C. G. Bakker and P. Vrijhof, Tetrahedron Letters, 1978, 4699.

'02

'03

255

Steroid Reactions and Partial Syntheses 0

li

0

II

Ph t

Tl

Reagents: i, PhSCl-Et,N, -70 "C; ii, >-40 "C;iii, NaOMe; iv, MeOH-P(OMe),

Scheme 14

nitrososolasodine to the ~regna-5~16-dien-20-one (281). The previously reported method for the preparation of 16a717a-dimethylpregnan-20-ones,which involved conjugate addition of MeMgI to the 16-en-20-one system followed by in situ methylation of the resultant A17(20)-eno1atewith MeI, has been applied to c-ring substituted analogues.2o8 An improved synthesis of methyl 3a77a-diacetoxy-1l-oxo-5~-cholanoate from the 1la-bromo-3-oxo-compound (282) required the conversion of the latter into the epoxide (283) in reasonable yield. This was achieved by treatment with NaBH4 in pyridine-NaOAc*'' whereas complex mixtures were obtained in '08

209

J. Cairns, C. L. Hewett, R. T. Logan, G. McGarry, R. G. Roy, D. F. M. Stevenson, and G. F. Woods, J.C.S. Perkin I, 1978, 1594. G . Halperin, Steroids, 1979, 33, 295.

256

Terpenoids and Steroids &co2Me

AcO’.

&co2Me

‘OAc

AcO’.

H

‘OAc

H

EtOH or MeOH. Syntheses were reported for 30-hydroxy-SP-pregn-8(14)-en20-one and the 8,14-epoxides derived from this.210 The full account has appeared211 of the synthesis of the A2’-marine steroid (284). In addition the isolation and synthesis of the related 3P-hydroxy-A’compound (285)211and the 1la-hydroxy-3-0x0-A4-compound(286)212were reported. In the synthesis of (286) the 170-ethenyl group was constructed through exhaustive methylation of the 20-amino-compound followed by Hofmann elimination. Epimerization of pregnenolone at C-17 led to the synthesis of a number of 20-methyl-17a-pregna11es.~’~ Syntheses have been reported for the four isomeric 3 , l l-diarnino-Sa-pregnane~,~~~ and the 6,19-dimethoxy-3,5cyclopregnan-20-one (287) was synthesized in model experiments aimed at a strophanthidin synthesis.21s

0

HO

11 Androstanes and Oestranes A novel synthesis of 3a, 17a-dihydroxy-5a-androstane employed the stereospecific decomposition of the oxadiazoline (288) in KOH-MeOH and it is suggested that rapid protonation of the intermediate C-17 carbanion prevents *Io ’11

’I’ ’13

*I4 215

R. Tschesche and W. Fuhrer, Chem. Ber., 1979, 112,2692. J. F. Kingston, B. Gregory, and A. G. Fallis, J.C.S. Perkin I, 1979, 2064. G. C h i n o , B. Desiderio, S. De Stefano, and G. Sodano, Experientia, 1979,35, 298. E.-J. Brunke, Tetrahedron, 1979, 35, 781. A. C. Campbell, M. S. Maidment, J. H. Pick, and G . F. Woods, J.C.S. Perkin I, 1979, 1936. P. KoEovskjr and V. kern$, Coll. Czech. Chem. Comm., 1979,442275.

257

Steroid Reactions and Partial Syntheses

epimerization.216 The epimeric oxadiazoline (289) under similar conditions exclusively gave the 17P-alcohol. Reduction of the 15,16-epoxy-17-oxocompounds (290) and (291) with Cr(OAc), gave the 15P-hydroxy-derivatives (292) and (293) respecti~ely.~'~ An improved synthesis of 16a-hydroxyandrosten-17-ones involved the conversion of the l6a-bromo-17-0x0compounds with hydrazine in the cold into the 16u-hydro~y-hydrazones.~'~

(290) (291) k6-dihydro

(292) (293) 5q6-dihydro

A number of ethynyl steroids have been synthesized as potential suicide substrates in sterol biosynthesis or as potential antifertility compounds. In the former class were the 19-ethynyl-19-hydroxy-compounds (294) and (295)'19 and the 17-(l-hydroxy-2-propynyl)-compounds(296) and (297).220Among those in the latter class were the diethynyl-A-nor-compound (298),221its 19-nor-analogue,221,222 and the 18-homo-analogue (299).223A number of allenyl compounds

(294) R' (295) R' 'I6

= =

H, R2 = OH OH, R2 = H

(296) R' = H, R2 = OH (297) R' = OH, R2 = H

I. R. McDermott and C. H. Robinson, J.C.S. Chem. Comm., 1979,28.

'"G . Defaye and E. M. Chambaz, Tetrahedron Letters, 1978, 3849.

'18 '19 220

221 222

223

M. Numazawa and Y. Osawa, Steroids, 1978,32, 519. D. F. Covey, V. D . Parikh, and W. W. Chien, Tetrahedron Letters, 1979, 2105. D. F. Covey, Steroids, 1979,33, 199. P. CrabbC, H. Fillion, Y. Letourneaux, E. Diczfalusy, A.-R. Aedo, J. W. Goldzieher, A. A. Shaikh, and V. D . Castracane, Steroids, 1979, 33, 85. J. Canceill, J.-C. Gasc, L. Nedelac, F. Baert, M. Foulon, and J. Jacques, Bull. SOC.chim. France, 1979,157. P. CrabbC, D . Andrt, and H. Fillion, Tetrahedron Letters, 1979, 893.

Terpenoids and Steroids

258

(298) R (299) R

= =

H Me

were prepared from the ethynyl compounds (Scheme 15).223A synthesis of lumi-mestranol involved the reaction of lumi-oestrone methyl ether with MeMgBr-acetylene; the epimeric 17a-hydroxy-17P-ethynyl compound was a co-product .224 Pri2N,

OH

/

H

Me

I

p r i 2 ~ +I\

Reagents: i, CH,O-Pr’,NH-CuBr;

ii, MeI; iii, LiAIH,-pyridine

H -

Scheme 15

Syntheses of 16,17-disubstituted oestra-1,3,5(lo),14-tetraene 3-methyl ethers involved reaction of the corresponding 16,17 -epoxides with various nucleop h i l e ~ ~and ~ ’ similar reactions of the 17,20-epoxides (300) gave a range of androstanes (301).226A series of 16p-alkylated androstanes and oestranes has

224

M. P. Wachter, R. E. Adams, M. L: Cotter, and J. A. Settepani, Steroids, 1979, 33, 287.

226

K. Ponsold, M. Huebner, H. Wagner, and W. Schade, 2. Chem., 1978,18,259.

”’ K. Ponsold, G. Schubert, and D. Tresseit, Z. Chem., 1978, 18, 215.

Steroid Reactions and Partial Syntheses

259

been synthesized and evaluated as antiandrogenic Testosterone and 17a-methyltestosterone were synthesized from hyodeoxycholic acid.228 Syntheses have been for the 2,17a-dimethyl-17-hydroxyoestradienes (302) and (303) and the 2,17a-dimethyl-17-hydroxyoestratrienes(304) and (305). A mixture of (302) and (303) was obtained from the parent 3-0x0A4*9-compoundby sequential formylation and MeI-K2C03-DMF treatment. However, only the 2a-methyl epimer (304) was obtained from the similar treatment of the parent ~ - o x o - A ~-compound, ,~*~~ and its 2P-methyl epimer (305) was prepared by DDQ oxidation of the ~ - O X O - A ~ ~ ~ ( ~ ~ (306) ) - C which O ~ ~ was OU~~

::g:l

o

&o

OH

/ (302) 2a (303) 2P (304) 2a; 11,12-dehydro (305)2p; 11,12-dehydro

(306)

obtained from (303). A synthesis has been for 4,4,9-trimethyl9p,lOa-oestr-5-ene (307) and a comparison of its reactions with those of the earlier synthesized pregnane derivative (308) indicated that the l4a-methyl group of the latter played an important role.

Stereospecific syntheses have been for 4a-deuterio-3&17P-dihydroxyandrost-5-ene (310) and its 3a,4P-dideuterio-analogue (311).The former compound (310) was obtained from the LiAlH4 reduction of the 4-deuterio-6Pbromo-3-0x0-compound (309) and the latter compound (311)was obtained from the LiAlD4 reduction of the non-deuteriated analogue of (309). Androst-5-ene3,17-dione deuteriated at C-19232and 17a-ethynyloestradiol, tri- and pentadeuteriated in ring c~~~ have been prepared. 227

228 229

230

231 232

233

G. Goto, K. Yoshioka, K. Hiraga, M. Masuoka, R. Nakayama, and T. Miki, Chem. and Pharm. Bull. (Japan), 1978, 26, 1718. K. R. Bharucha, Steroids, 1978, 32, 589. L. Nedelec, J.-C. Gasc, V. Delaroff, R. Bucourt, and G. Nomine, Tetrahedron, 1978, 34, 2729. J. R. Bull, J. Floor, and A. Tuinman, J.C.S. Perkin I, 1978, 1537. A. Viger, S. Coustal, and A. Marquet, Tetrahedron, 1978, 34, 3285. R. L. Dyer and T. A. Harrow, Steroids, 1979, 33, 617. D . J. Collins and J. Sjovall, Tetrahedron Letters, 1979, 629.

260

Terpenoids and Steroids

The 9P-configuration has been e ~ t a b l i s h e dfor ~ ~the ~ , ~fusidic ~ ~ acid degradation product (312). Pimarene (313) was converted through the diazoketone (314) into the mixture of D-nor-compounds (315).236Reaction of the 7a-acetoxy-5,lOepoxy-6-ketone (3 16) with KOH-MeOH gave the ring-B aromatic compound (317) which was subsequently converted into 6,7-diacetoxyequilenin (318).237

234

235 236 237

W. S. Murphy, D. Cocker, G. Ferguson, and M. Khan, J.C.S. Perkin I, 1979, 1447. See ref. 41, p. 319. P. Ceccherelli, M. Tingoli, M. Curini, and R. Pellicciari, Tetrahedron Letters, 1979, 3869. M. Lj. MihailoviC, J . ForSek, and L. Lorenc, J.C.S. Chern. Cornrn., 1978, 916.

26 1

Steroid Reactions and Partial Syntheses

Syntheses have been for the chrysene derivatives (319) and (320) and it was reported that they exhibited little oestrogenic activity compared with 90-methyloestradiol. The syntheses of the anti-turnour nitrosourea steroids (321) and (322) the reaction of the respective corresponding 170-aminomethyl and 17~-amino-compoundswith N-alkyl-N-nitrosocarbamoyl azide. Syntheses have been reported for the amino-oestratrienes (323) and (324).241

HO (320) cis and trans

(319) nu

NO

NO

/ j-','CH,NHCON \

/

NHCON

\

R

(322) R (321) R

= Me or

=

R

Me or CH2CH2C1

CH2CH2CI

(323)

12 Cardenolides Advances in cardenolide syntheses have been reviewed.242Hydrogenation of digitoxigenin gave a mixture of (20R)- and (20S)-20,22-dihydrodigitoxigenin which was separated into its components by fractional c r y ~ t a l l i z a t i o n .A~ ~ ~ synthesis of 24-aza-24-desoxaxysmalogenin-3~-yl acetate (325) was reported.244 Syntheses of the cardenolide analogues (326) and (327) involved 31'' 239

240 241

242 243

244

D . J. Collins and W. A . Matthews, Austral. J. Chem., 1979,32, 1093. D. J. Collins, W. A. Matthews, and G . M. Stone, Austral. J. Chem., 1979, 32, 1107. H.-Y. P. Lam, A . Begleiter, G . J. Goldenberg, and C.-M. Wong, J. Medicin. Chem., 1979,22,200. A . Takadate and J. Fishman, J. Org. Chem., 1979, 44, 67. M. B. Gorovits and N. K. Abubakirov, Khim. prirod. Soedinenii, 1978, 283. D . S. Fullerton, K. Yoshioka, D . C. Rohrer, A . H. L. From, and K. Ahmed, J. Medicin. Chem., 1979, 22, 529. S. El-Dine, K. Faust, T. W. Guntert, E. Hauser, H. H. A . Linde, and S. Spengel, Helv. Chim. Acta, 1979,62, 1283.

Terpenoids and Steroids

262

(327) cis and trans

(326)

reactions of various 19-formyl compounds with (Me0)2P(0)CHC02Me and (MeO),P(O)CHCN respectively.245A of strophanthidin (330) from pregnenolone acetate invo!ved the intermediates (328) and (329). The latter stages of the synthesis (329) + (330) are shown in Scheme 16.

++ AcO

AcO

iii, iv t

i, v, vi

1

I0Y0 vii, i, viii ___*

OH

HO

OH

(330)

Reagents: i, KHC0,-MeOH; ii, 00,-H'; iii, AcNHBr; iv, Raney Ni; v, H,O,-OH-; pyridine; vii, Urushibara Ni-EtOH; viii, Cr0,-HMPA

Scheme 16 245 246

A. Gelbart, J. Boutagy, and R. Thomas, J. Medicin. Chem., 1979, 22, 287. E . Yoshii, T. Oribe, K. Tumura, and T. Koizumi, J. Org. Chem., 1978, 43, 3946.

vi, A@-

263

Steroid Reactions and Partial Syntheses

13 Heterocyclic Steroids The syntheses and biological activity of ring-A heterocyclic steroids have been from reviewed.247The N-cyano-2-aza-A-norandrostane(333) was the dibromo-seco-compound ( 3 31) via the N-phenyl-2-aza-A-norandrostane (332) (Scheme 17). The mixture of iodoisothiocyanates (334) and (335) (see ref.

+ B Br r* NC-N

H

H (331)

1L

Reagents: i, PhCH,NH,-DMSO;

(333)

ii, CNBr

Scheme 17

45) on heating in the dark with MeOH-C2C14 gave the thiazolidin-2-ones (336)

and (337), but on treatment with aniline-ether at 20°C the mixture gave the 2-aminothiazolines (338) and (339).249The acid-catalysed reactions between 2-amino-1,3,4-thiadiazoleand a-hydroxymethylene-0x0-steroidsled to 2-thiocyanatopyrimidines. These reactions were exemplified by the conversion of (340) into (342).250The similar reaction of 4-amino-l,2,4-triazole with (341) led to the triazolopyridazine (343) and analogous products were obtained from a series of 16-hydroxymethylene-17-oxo-steroids.251 However, the reaction of (340) and its cholestane analogue with 4-amino-l,2,4-triazole led to the acyclic bis-anil (344).251The saturated analogue (345) of chandonium iodide was synthesized along with some other analogues.252The oxazolidine (347), the thiazolidine

NH (334) R'

=

NCS, R2 = I

(336)

(337)

(335) R' = I, R2 = NCS

(338) 247 248 249

251 252

(339)

V. F. Shner, V. A. Rulin, and N. N. Suvorov, Khim. Farm. Zhur., 1978,12, 22. W. H. Chiu, T. H. Klein, and M. E. Wolff, J. Medicin. Chem., 1979, 22, 119. R. C. Cambie, H. H. Lee, P. S . Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1979, 765. J. S. Bajwa and P. J. Sykes, J.C.S. Perkin I, 1978, 1618. J. S. Bajwa and P. J. Sykes, J.C.S. Perkin I, 1979, 1816. H. Singh, T. R. Bhardwaj, N. K. Ahuja, and D. Paul, J.C.S. Perkin I, 1979, 305.

Terpenoids and Steroids

264

HO

(347)

(349)

(348), and the imidazolidine (349) were prepared from the 20-oxoaziridine (346) via the ethoxycarbonylhydrazone (350).253 The full account has appeared of the synthesis of the 17-phospha-steroid (351).254

253

2s4

A. V. Kamernitzky, A. M. Turuta, T. M. Fadeeva, and D. Calcines, Synthesis, 1979, 592. C. Symmes, jun. and L. D. Quin, J. Org. Chem., 1979,44, 1048.

Steroid Reactions and Partial Syntheses

265

14 Microbiological Oxidations Oxidation of the 3P-acetoxy - 5,6-epoxy-2 1-hydroxy- 2 0 -oxo-compound (352) with Flavobacterium dehydrogenans gavez5’the 6-hydroxy-A4-3-0x0-compound (353), which was readily dehydrated to the A4~6-3-oxo-compound(354). Oxidation of (354) with Aspergillus ochraceus and Curvurlaria lunata gave respectively the 1l a - and 11P-hydroxy-derivatives (355) and (356), which were dehydrogenated with Bacillus lentus to give the 1-dehydro-derivatives (357) and (358) respectively. Selective acetylation of (357) followed by oxidation and saponification gave the 11-oxo-derivative (359).255Oxidations of 9P,lOa-progesterone, 9P, lOa-androst-4-ene-3,17-dione,and 9P,lOa-testosterone with Rhizopus arrhizus Fischer CBS 12708 gave the 9P-hydroxy-derivatives, and the 6P-hydroxy-derivative was obtained from the second The studies of hydroxylations with Rhizopus arrhizus ATCC 11145 have continued and the substrates examined included androst-5-ene-3, 17-dione2” and 6-substituted androst-4-ene-3,17-dione~.*~~ Incubation of a series of D-homo-androstanes with Aspergillus ochraceus gave largely 11a-hydroxylated products but the conversions were lower than in the normal series.259The 6P-methoxy-3,5cycloandrostane (360) was hydroxylated predominantly in the 1P-position with Rhizopus nigricans, in contrast to the 2a- and 11a-hydroxylation previously noted for the 6 ~ - h y d r o ~ y - a n a l o g u e . ~ ~ ~

(352)

HoH2CYo (354)R (355) R (356) R (357) R (358) R (359) R 255

256

257

*”

259

260

0

=

= = P-OH,H = a-OH,H; 1,2-dehydro = P-OH,H; 1,2-dehydro = 0;1,2-dehydro

I

K. Kieslich, H. Wieglepp, and G.-A. Hoyer, Chem. Ber., 1979, 112,979. J. Favero, T. That, and F. Winternitz, Bull. SOC.chim. France, 1979, 56. H. L. Holland and P. R. P. Diakow, Canad. J. Chem., 1979, 57,436. H. L. Holland and P. R. P. Diakow, Canad. J. Chem., 1979, 57, 1585. D. de Marcano, J. F. del Giorgio, J. M. Evans, E. J. Hurtada, L. Kohout, E. Osorio, and M. J. Vitolo, J. Org. Chem., 1978, 43, 3961. H. K. Thoa, Z. Prochizka, M. BudGinsk9, and P. KoEovskjr, Coll. Czech. Chem. Comm., 1978,43, 2305.

Terpenoids and Steroids

266 '15 Miscellaneous Syntheses

The syntheses of c-nor-D-homo-steroids have been reviewed.261Syntheses of 4,6a-ethano-oestratrienes have been reported262and complement those of the 4,6P-analogues that were reported last year. The 13~,16~-propano-compound (362) and the related 11~,13~-propano-compound (363) were synthesized from the 18-phenoxyethyl compound (361).263The construction of the 13@,16@bridge involved the treatment of the tosylate (364) with ButOK-Bu'OH, and the key reaction in the synthesis of (363) was the Prins cyclization (Zn12-CH2C12)of the aldehyde (365), which gave the llp,l3P-bridged compound (366). A synthesis of the 16a, 17a-propano-steroid (367) has been Conversion of 5a-pregnan-20-one into the diol (370) involved the stereospecific

CHO

261

*" 263 264

E. Brown and M. Ragault, Tetrahedron, 1979, 35, 911. A. C. Ghosh, B. G. Hazra, H. C. Dalzell, and R. K. Razdan, J. Org. Chem., 1978,43,4795. C. G. Pitt, D. H. Rector, C. E. Cook, and M. C. Wani, J. Medicin. Chem., 1979, 22, 966. A. V. Karnernitskii, L. E. Kulikova, and I. S. Levina, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1978, 1395.

Steroid Reactions and Partial Syntheses

267 CN

fl

0

(368) Z a n d E

(369) 22R and 22s

(370)

reduction (NaBH,) of the alkylidene-cyanoacetate (368) to the saturated cyanoacetate (369).265Nuatagenin (371) and its 36-D-glucopyranoside have been synthesized from diosgenin.266Further spin-labelled corticosteroids (372)267and a number of 17a-aza-~-homo-nitroxides(373)268have been reported.

0.

I

0.

(373) R

=

Pr" or CH2CH=CH2

(372)

'" P. Tsita, G. Tsatsas, and C. Sandris, Steroids, 1979, 33, 23. R. Tschesche and W. Fuhrer, Chem. Ber., 1978,111, 3300. G. Defaye, M. Basset, and E. M. Chambaz, Bull. SOC. chim. France, 1978,471. '" 0.Martin-Borret, R. Ramasseul, and A. Rassat, Bull. SOC.chim. France, 1979,401.

266 267

Errata

VOl. 7, 1977

Page 145. Throughout formulae (114)-(1181, -(angelate).

for >-'(tiglate),

read

co

co Vol. 8, 1978 Page 173. Structures (168) and (169) should have a 3-keto-group instead of 3P-OH. Page 264, ref. 173, for F. J. Parish, read E. J. Parish. Page 295, Author Index, for Parish, F. J., read Parish, E. J. Vol. 9, 1979 Page 190, ref. 28, for 1677, read 1577.

Author Index Aasen, A. J., 124 Abaychi, J. K., 183 Abdulaev, N. G., 188 Abe, F., 203 Abe, K., 194 Aberhart, D. J., 136, 200, 224, 232 Abiko, A., 77 Abraham, W. R., 34, 99, 107 Abramo-Bruno, D., 203 Abubakirov, N. K., 261 Acimis, M., 206 Adam, G., 121 Adamo, S., 164 Adams, M. A., 54 Adams, R. E., 107, 258 Aedo, A.-R., 257 Agrawal, M., 182 Agrawal, R. C., 28 Aguiar, J. M., 23 Ahmad, M. S., 237 Ahmed, K., 261 Ahond, A., 99 Ahuja, N. K., 263 Ai, T. H., 139 Aidogdyev, A., 157 Aiura, M., 158 Akahane, A., 75 Akaiwa, A., 246 Akalovsky, I., 164 Akhrem, A. A., 223 Akhtar, M., 173 Akinniyi, J. A., 108 Akita, H., 9, 117 Akiyama, E., 160 Akiyama, S., 173 Alain, S. K., 132 Alazard, J. P., 229 Albrecht, P., 135, 247 Alder, A. P., 183 Alemany, A., 58 Aleskerova, A. N., 71 Alexakis, A., 90 Alexander, K., 195 Alfano, R. R., 188 Ali, H., 227 Almoula, R. U., 232 Altman, L. J., 136 Altschuh, J., 206 Alvarado, S., 94 Alward, S. J., 77 Amagaya, S., 158 Amaro, J. M., 94 Ambrus, G., 209 Amico, V., 3, 57

Amin, S. G., 21 Amitani, K., 211 Anastasia, M., 220, 222, 232 Anderson, C., 162 Anderson, G. D., 246 Anderson, K., 184 Ando, M., 72,75 Andrt, D., 257 Andrewes, A. G., 167 Andrews, J. R., 210 Andrus, A., 133 Anet, F. A. L., 202, 212 Anjaneyulu, A. S. R., 141, 155, 157 Anke, T., 1:18 Anker, D., 212 Anmo, T., 179 Annen, K., 220, 224 Ansari, G. A. S., 222 Apfel, M. A., 247 Applebury, M., 186 ApSimon, J. W., 117, 131, 157, 254 Aranguez, L. M., 109 Ardon-Jimenez, A,, 131 Arnold, E. V., 54, 73 Arnone, A., 120 Arnoux, B., 144, 145 Arora, G. S., 28 Arteaga, J. M., 108, 169 Arunachalam, T., 202 Asahara, M., 165 Asakawa, Y., 69, 94, 100, 101 Ashmore, J. W., 222 Asif, M., 237 Aslanev, Kh. A., 108 Astier, A., 209 Atal, C. K., 69 Ates, N., 80 Aton, B., 187 Audichya, T. D., 28 Auerbach, R. A., 186 Avakyan, K. A., 186 Aversa, M. C., 160 Avram, E., 241 Ayamante, B. I. S., 61 Ayanoglu, A., 233 Ayanoglu, E., 104, 247 Ayer, W. A., 128 Azusawa, K., 75 Babler, J. H., 176 Back, T. G., 215 Baddeley, G. V., 117, 139

269

Baert, F., 257 Battig, K., 101 Bagirov, V. Yu., 93 Bahr, J., 164 Bajwa, J. S., 263 Baker, R., 8, 9, 169 Bakker, C. G., 254 Bal, K., 244 Balakrishnan, P., 233 Baldwin, D., 216 Ballhorn, L., 209 Ban, Y., 68 Banerjee, A., 111 Banerjee, A. K., 132 Banerji, A., 128 Banerji, N., 158 Bang, L., 25 Banger, J., 72 Banh-Nhu, C., 94 Banks, C. M., 56 Bapuji, M., 155 Barabls, A., 210, 227 Baranowska, E., 69 Barbe, B., 116 Barkawala, Y. G., 202 Barnard, P., 188 Barone, A. D., 239 Barrero, A. F., 69, 114, 169 Barrett, A. G. M., 231, 254 Bartels, P. G., 190 Barton, D. H. R., 128, 215, 219, 229, 230, 231, 233, 239,254 Baruah, J. N., 145 Baruah, N. C., 62 Baruah, R. N., 61 Barucha, K. R., 259 Baslas, R. K., 182 Basset, M., 210, 267 Batta, A. K., 244, 247 Baumann, M., 18 Bayer, E., 186 Bearder, J. R., 121, 122 Becher, B., 187 Becker, R. S., 186 Beechan, C. M., 32, 104 Begleiter, A., 261 Behforouz, M., 101 Behrman, H. R., 213 Beier, R., 116 Beierbeck, H., 116 Bekker, A. R., 181 Btlanger, A., 217 Bellesia, F., 51 Bellino, A., 118

Author Index

270 Benigni, D. A., 71 Bennett, J. A., 186 Bensasson, R. V., 186 Benveniste, P., 141 Ben-Yakov, H., 214 Berchtold, G. A., 132 Berg, J. E., 118 Berge, C. T., 186 Berger, D., 69 Bergfeld, R., 190 Berman, E., 47, 233, 253 Bermejo, J., 94 Bermejo Gonzalez, F., 108 Bernal, I., 62 Bernassau, J.-M., 206 Bernhard, H. O., 94 Bernstein, H. J., 170 Bertrand, M., 18 Bestmann, H. J., 164 Beyer, P., 165 Bhacca, N. S., 62 Bhakuni, D. S., 109 Bhardwaj, T. R., 263 Bhat, P. V., 164 Bhatt, M. V., 177 Bhattacharyya, P., 146 Bhattacharyya, P. K., 202 Bhattacharyya, S. C., 26, 27, 28, 56, 58, 87, 123, 158, 232, 233 Bhattacharyya, S. P., 146 Bickel, H., 194 Bigalke, R. C., 106 Bingham, A., jun., 167 Bird, G. J., 203 Bird, T. G. C., 214, 247 Birge, R. R., 185, 186 Bite, P., 214 Bittner, M. L., 114 Blackburn, G. M., 217 Blair, I. A., 209, 235 Blair, P., 253 Blatz, P. E., 187 Blessing, R. H., 199 Bloomenstiel, D., 61 Bloszyk, E., 71 Blount, J. F., 125, 127, 132, 174 Blunt, J. W., 34, 57, 60, 62, 64, 108, 116, 118,203 Boar, R. B., 140 Bobbio, F. O., 230 Bobbio, P. A., 230 Sodea, C., 174 Bodor, A., 210, 227 Bodor, N., 237 Boeva, A,, 80 Boeyens, J. C. A., 199 Bogomolni, R. A., 188 Bogoslovskii, N. A,, 253 Bohlmann, F., 3, 11, 12, 17, 18, 28, 30, 34, 49, 57, 58, 61, 62, 64, 67, 69, 71, 80, 85, 93, 94, 95, 96, 99, 100,

106, 107, 108, 110, 111, 114, 115, 117, 118, 120, 142, 154 Bohoslawec, O., 177 Bolivar, E. H., 132 Bollag, W., 165 Boncza-Tomaszewski, Z., 222, 235 Bontekoe, J. S., 240 Borch, G., 167, 170, 185 Bordewijk, P., 210 Bordner, J., 146, 201 Borisevich, G. P., 186 Boross, L., 183 Boulton, K., 122 Bouman, T. D., 205 Boutagy, J., 262 Boutwell, R. K., 164 Bownds, M. D., 188 Bovill, M. J., 95 Bowden, B. F., 124, 127 Braekman, J. C., 10, 99, 124 Braendas, E. J., 188 Breitenstein, W., 21 Brennan, T. F., 61 Brennecke, H. R., 245 Breton, J. L., 9 3 Brewster, A. G., 215 Brieskorn, C. H., 112 Briner, P. H., 8, 169 Bringmann, G., 229 Britten-Kelly, M. R., 219 Britton, G., 165, 170, 188, 189 Brody, S. S., 187 Brouwer, M. S., 176 Brown, B. O., 165 Brown, D. A., 150 Brown, E., 266 Brown, H. M., 187 Brown, P. R., 183 Brueggemeier, R. W., 225 Brunke, E.-J., 236, 256 Brynjolffsen, J., 251 Bryson, I., 42 Brzezinka, H., 184 Bucholtz, B., 194 Buck, H. K.,56 Buckle, K. A., 183 Bucourt, R., 206, 259 Budcsinskq, M., 129, 157, 265 Budzikiewicz, H., 184, 185 Buchi, G., 73 Bull, J. R., 199, 259 Burdick, B. A., 211 Burger, B. V., 106 Burgstahler, A. W., 206 Burka, L. T., 4 Burke, €3. A., 125 Burke, S., 95 Burkert, U., 201 Burlingame, A. L., 205 Burnell, J., 254 Burns, A. R., 187

Burt, V. T., 194 BuzPs, Z., 183 Caballero, C., 169 Caballero, E., 169 Caballero, M. C., 114 Cacchi, S., 215, 226 Cafieri, F., 130 Caglioti, L., 226 Cainelli, G., 7, 179 Cairns, J., 255 Calcines, D., 264 Calderbn, J. S., 57 Callahan, J. F., 29, 66 Cailender, R. H., 187, 188 Calton, G. J., 104 Calzada, J., 94 Cambie, R. C., 215, 218, 219, 223, 263 Cameron, A. F., 104, 125, 146 Campbell, A. C., 256 Campbell, A. L., 132 Campbell, M. M., 225 Campillo, A. J., 187 Canceill, J., 257 Candeloro-De Sanctis, S., 201 Cane, D. E., 5, 18, 47 Caputo, R., 144, 223 Cardillo, G., 7, 176, 179 Carey, P. R., 170, 186 Carillo Sanchez, H., 110 Carnevale, J., 184 Carpenter, P. C., 212 Carrascal, M. I., 118 Carrol, P. J., 26 Carter, D. C., 126, 169 Casey, J., 194 Caspi, E., 136, 200, 202, 232 Castagnino, E., 180 Castillo, R., 164 Castracane, V. D., 257 Catllano, S., 235 Cattel, L., 141 Cavender, P. L., 131 Cazes, B., 16 Ceballo, C. D., 132 Cerda-Olmedo, E., 164 Cernia, E., 226 Ceccherelli, P., 115, 117, 132, 260 Fech, F., 240 Cernq, V., 216, 218, 226, 233, 256 Ceustermans, R. A. E., 240 Chader, G. J., 164 Chakrabarti, P., 162 Chakraborty, D. P., 146 Chakravarti, K. K., 233 Chambaz, E. M., 210, 257, 267 Chambers, D., 215 Chan, A., 233

27 1

Author Index Chan, D. M. T., 87 Chan, K.-K., 177 Chan, W. H., 26, 218 Chan, W. R., 125 Chan, Y. M., 71 Chandler, R. F., 135 Chandra, G. R., 184 Chandrasekharan, S., 125, 133 Chandross, R. J., 201 Chang, F. C., 215 Chapdelaine, M. J., 90 Chapman, D., 188 Chari, V. M., 158 Charles, C., 10 Chatterjee, A., 111, 160 Chatterjee, S., 134 Chau, T.-Y., 232 Chaudhary, S. K., 218 Chekulaeva, L. N., 186 Chekunchikov, V. N., 192 Chen, C.-M., 118 Chen, E. Y., 72 Chen, H. T., 114 Chen, R., 107 Chen, S.-C., 134 Cheung, H. T. A., 236 Chiang, M.-C., 185 Chiaroni, A., 99 Chien, M.-K., 114 Chien, W. W., 257 Chihara, K., 186 Child, P., 208 Chin, E., 107 Chiu, W. H., 263 Cho, H., 72 Choi, L. S. L., 230 Chojnacki, T., 191 Chong, Y. K., 242 Chou, T. S., 25 Choudhury, M. K., 162 Christenson, P. A., 18 Chujo, R., 184 Ciccio, J. F., 94 Cimino, G., 10, 256 Cini, M., 144 Clader, J. W., 218 Claeys, A. E., 184 Clardy, J., 10, 38, 54, 73, 93, 108, 126, 129 Clayton, R. K., 165, 187 Cleve, G., 222 Clough, J. M., 165, 174 Coates, R. M., 131 Cocker, D., 137, 199, 260 Coghlan, M. J., 176 Cohen, Z., 238 Cole, E. R., 184 Coleman, P. C., 80 CoII, J. C., 99, 124, 127 Collings, P. J., 211 Collins, D. J., 203, 259, 261 Collum, D. B., 5 Colombi, S., 207

Colvin, E. W., 21 Colwell, W. T., 177 Connolly, J. D., 108, 125, 144, 148 Contento, M., 176 Contreras, R., 222 Cook, C. E., 266 Cookingham, R. E., 186 Cooper, A., 188 Cooper, P. S., 139 Copsey, D. B., 140 Corbett, R. E., 131 Cordell, G. A., 152 Corey, E. J., 34, 101, 103, 133 Cornell, D. G., 241 Cornet, P., 124 Corrales, B., 161 Corsano, S., 180 Cory, R. M., 87, 120 Cossey, A. L., 134 Cotter, M. L., 107, 258 Couldwell, C. M., 131 Counsell, R. E., 225 Coustal, S., 259 Covey, D. F., 257 Cox, P. J., 93 Cox, R. I., 211 Coxon, D. T., 77 CrabbC, P., 89, 257 Craven, B. M., 201 Crespi, H., 187, 188 Crontolm, T., 205 Cross, B. E., 122 Crump, D. R., 139 Csorba, I., 183 Culshaw, C. M., 139 Curini, M., 117, 132, 260 Czerson, H., 18, 115 Czochralska, B., 179, 187 da Cunho Pinto, A., 116 Dadoun, H., 229 Daemen, F. J. M., 188 Dahmen, J., 34, 141 Dallinger, R. F., 186 Daloze, D., 10, 99, 124 Daly, J. J., 11, 87, 131, 168 Dalzell, H. C., 266 Danheiser, R. L., 133 Daniewski, W. M., 44 Danilov, L. L., 192 Danishefsky, S., 47 Darias, J., 23 Darszon, A., 188 Das, K. G., 160 Das, P. K., 186 Dasgupta, A., 162 Dashek, W., 184 da Silva, V. O., 112 Dauben, W. G., 125, 222 Dauphin, G., 16 Dave, V., 204,234,237 Davies, B. H., 164

Davies, S. G., 233 Davydova, L. P., 181 Dayal, B., 206 de Alvarenga, M. A., 112 de Bernardi, M., 44 De Bevere, V. 0. R. C., 184 Declercq, J. P., 10, 89, 104, 201 De Clercq, P., 68, 89 Decorzant, R., 86 Defaye, G., 210, 257, 267 Degraw, J. I., 177 de Groot. Ae., 9 de Groote, R., 57, 58 DeJong, D. W., 183 de la Fuente, G., 124 Delaroff, V., 206, 259 Delay, F., 13 Delbar, P., 135 Delbriick, M., 191 De Leenheer, A. P., 184 Delgado, G., 60 del Giorgio, J. F., 265 Delle Monache, F., 154 Delmelle, M., 187 Delmond, B., 116, 117 Delprino, L., 141 DeLuca, H. F., 233, 250, 251, 253 DeLuca, L. M., 164 de Marcano, D., 265 De Mello, J. F., 154 Demole, E., 168 de Napoli, L., 130 Dencher, N. A., 179,187, 188 De Noble, J., 177 de Pascual Teresa, J., 69, 107, 108, 110, 114, 161, 169 Derossi, M., 220 De Ruyter, M. G. M., 184 Desai, B. N., 247 Deshpande, R. P., 34 Desiderio, B., 256 Desiderio, D. M., 65 de Silva, M., 108 De Stefano, S., 10, 256 Destro, R., 131 DeTitta, G. T., 95 Dev, A. K., 158 Deweck, G., 183 De Wilde, H., 68 Dhar, K. L., 69 Dhar, M. M., 109 Diakow, P. R. P., 205,265 Dias, J. R., 208 Diaz, R., 124 Diczfalusy, E., 257 Dierick, W., 191 Dieter, R. K., 71 Dinan, L., 244 DiNinno, F., jun., 43 Dinur, U., 188 Djerassi, C., 32, 104, 205, 207, 223,233, 246, 247

272 Doke, N., 76, 78 DolejS, L., 71 Dominguez, B., 94 Dommisse, R., 191 Donnahey, P. L., 194 Dorner, W., 34, 100, 117 Dougherty, D. A., 138, 201 Doukas, A. G., 187 Doyal, B., 244 Droidz, B., 58, 71 Druckmann, S., 186 Duax, W. L., 199, 200, 201, 232 Dubois, M., 212 Dubravkovl, L., 71 Dunitz, J. D., 200 Dunn, A. W., 11 Dunn, L. C., 87 Dunne, L. J., 188 Dunstan, P. J., 99 Duperray, B., 212 Dutta, L. N., 34, 57, 61, 64, 67, 117 Dutton, P. L., 188 Dyer, R. L., 259 Dygos, J. H., 247 Easton, N. R., jun., 202, 212 Eastwood, F. W., 203 Ebian, A. R., 201 Ebrey, T. G., 187, 188 Eck, C., 202 Eda, S., 173 Eder, U., 227 Edgar, M. T., 89 Edmond, J., 202,212 Edwards, R. W. H., 212 Eenkhoorn, J., 254 Egawa, H., 115 Egger, B., 168 Eggers, N. J., 69 Eggert, H., 32 Ehrenberg, B., 187, 188 Eickeler, E., 85 Einck, J. J., 244 Eisner, T., 71 Eissenstat, M. A., 89 El-Dine, S., 261 El-Emary, N. A., 96 El-Feraly, F. S., 71 Elgsaeter, A., 170 Ellames, G., 121 Elliott, W. H., 208 El-Sayed, M. A., 187 Elyakov, G. B., 139 Endo, J., 55 Endo, K., 69 Engel, P., 82 Engelhardt, G., 204, 215 Enggist, P., 168 Englert, G., 165, 167, 178, 188, 189 Englert, H., 240 Enomoto, M., 42

Author Index Epe, B., 146, 151 Epstein, W. W., 137, 162 Erasmuson, A., 122 Erdman, T. R., 10, 247 Eskenazi, C., 211 Esmans, E., 191 Eto, H., 60 Eugster, C. H., 164 Evans, D. A., 8, 9, 169 Evans, E. H., 165 Evans, J. M., 265 Evans, S., 205 Evstigneeva, R. P., 178 Exner, R. H., 203 Eyring, G., 187 Fadeeva, T. M., 264 Fahey, D., 189 FajkoS, J., 201, 216, 219 Fallis, A. G., 256 Fang, H. L. B., 186 Farhi, R. L., 212 Farnsworth, N. R., 152 Faruk, A. E., 173 Fattorusso, E., 3, 57, 130 Faulkner, D. J., 124, 129 Faust, K., 261 Faust, Y., 214 Faux, A., 242 Favero, J., 265 Favrot, J., 187, 188 Fayos, J., 22, 23, 94, 124, 169 Fedorovich, I. B., 186 Fehlhaber, H.-W., 104 Feigenbaum, A., 241 Feigina, M. Y., 188 Felsky, G., 202, 247 Feng, M., 176 Fenical, W., 23, 103, 126, 127, 129, 169,246 Feretti, M., 235 Ferguson, G., 137, 199, 201, 260 Ferreira, D., 219 Ferreira, Z. S., 69 Fetizon, M., 25, 206 Fiagbe, N., 118 Fiecchi, A., 222 Fiedler, L., 93, 114 Field, F. H., 210 Fiksdahl, A., 174 Filipescu, N., 241 Fillion, H., 257 Filosa, M. P., 89 Finar, J., 126 Finer, J., 10, 38 Fischer, N. H., 18, 61, 62, 64, 65 Fishman, J., 261 Fivizzani, M. A., 251 Fleming, M. P., 174, 223, 236 Fletcher, T. R., 164 Floor, J., 199, 259 Floyd, E. E., 225

Flynn, G. A., 68 Folkers, K., 193 Forrest, G., 186 ForSek, J., 260 Fortier, S., 95 Foss, P. S., 168 Foster, R. W. G., 234 Foulon, M., 257 Fourneron, J. D., 99 Fox, D. L., 170 Fraga, B. M., 108, 118, 122, 169 Franke, P., 121, 154, 156 Frater, G., 66, 96 Fredericks, P. M., 202, 214 Freeman, R., 205 Freer, A. A., 93 Freerksen, R. W., 219 Frei, B., 183 Frickey, P. H., 211 Friedman, N., 253 Fries, P., 176 Frieze, D. M., 132 Fringuelli, R., 180 Frith, R. G., 235 Fritz, U., 17, 114 Froborg, J., 44 Frolik, C. A., 184 Frolow, F., 200, 251 From, A. H. L., 261 Fronczek, F. R., 96 Fronza, G., 44 Frosch, S., 190 Frot-Coutaz, J. P., 164 Fuhrer, W., 256, 267 Fugate, R. D., 187 Fuji, K., 106, 218, 226 Fujii, N., 38 Fujimori, T., 168 Fujimoto, Y., 203, 246 Fujita, E., 106, 119, 218, 226 Fujita, K., 193 Fujita, M., 112 Fujita, T., 118, 119, 194 Fujita, Y.,165 Fukarniya, N., 4 Fukui, H., 7, 115, 121 Fukumoto, K., 132, 133 Fukuoka, M., 42 Fukushima, M., 250 Fukuzumi, T., 168 Fuller, F., 162 Fullerton, D. S., 261 Furrer, A., 168 Furukawa, H., 95 Furusaki, A., 23, 123, 169, 200 Furuya, S., 124 Gabe, E. J., 137 Gabriel, E., 177 GBcs-Baitz, E., 94, 111 Galindo, A., 58 Gall, R. E., 139

273

Author Index Galston, E., 184 Ganesh, K. N., 25 Ganguly, R. N., 26 Ganguly, S. N., 156, 160 Gapski, G., 174 Garcia, J., 120 Garcia-Blanco, S., 94 Garnero, J., 181 Gasa, S., 123 Gasanova, R. Yu.,93 Gasc, J. C., 206, 257, 259 Gaskin, P., 121 Gawronska, K., 226 Gawronski, J., 226 Gebreyesus, T., 104 Geetha, P., 90 Geipel, R., 104 Gelbart, A., 262 Gelbaum, L. T., 80 Genard, P., 203 Gensch, K. H., 93 Gerdes, H., 211 Germain, G., 10, 89, 104, 201 Ghatak, U. R., 132 Ghisalberti, E. L., 26, 120 Ghosh, A., 43 Ghosh, A. C., 266 Ghosh, P. K., 156 Ghulati, R. S., 28 Giannetto, P., 160 Gibson, F., 194 Giglio, E., 201 Gillbro, T., 186, 188 Gilmore, C. J., 93 Giordano, 0. S., 69 Gochev, A., 188 Goddard, R., 131 Godfrey, I. M., 109 Godfrey, J. D., 73 Gorog, S., 211 Goh, E. M., 163 Goldenberg, G. J., 261 Goldschmidt, C. R., 186 Goldzieher, J. W., 257 Gollnick, K., 104 Gombatz, K., 47 Gomez, G. F., 57 Gomis, J. D., 71 GonGalves De Lima, O., 154 Gonzilez, A. G., 22, 23, 58, 94, 108, 118, 124, 169 Gonziilez, E., 23 Gonzalez Munoz, M. A., 110 Goodwin, P. B., 165 Goodwin, T. W., 164, 170, 188, 189 Gopalan, B., 133 Gopichand, Y., 127, 235, 236 Gorina, N. Y., 178 Gorovits, M. B., 261 Goryaev, M. I., 222 Gorzynski Smith, J., 133 Gosselin, P., 14 Goswami, A., 162

Goto, G., 259 Goto, J., 212 Goto, T., 68 Gottarelli, G., 207 Gottlieb, H. E., 112, 114 Gottlieb, 0. R., 69, 112 Gottschlich, R., 188 Gouda, M. W., 201 Govindan, S., 118 Goyau, B., 181 Grabarczyk, H., 58 Graca-Miguel, M., 188 Graebe, J. E., 121 Graf, W., 220, 231 Grande, C., 107 Grande, M., 69, 107, 161, 169 Grant, P. K., 109 Granville, M. F., 186 Gras, J. L., 133 Grayston, M. W., 236 Green, P. J., 168 Greene, A. E., 89, 127 Gregory, B., 256 Grenz, M., 58, 80, 115 Grieco, P. A., 69, 89, 95 Grifliths, 0. H., 187 Groenendijk, G. W. T., 183 Gros, E. G., 69 Groweiss, A., 124, 126 Grupe, A., 209 Guanci, J. J., jun., 186 Gulacar, F. O., 247 Guerreiro, E., 69 Guerrero, C., 60 Gumulka, J., 242 Gunatilaka, A. A. L., 158, 218, 243 Gum, B. P., 29 Guntert, T. W., 261 Gupta, P. S., 148 Gupta, R., 182 Gust, D., 95 Guy, M. H. P., 95 Guzman, A., 107 Hachey, D. L., 212 Haddad, J. G., jun., 213 Hadzit, P., 227 Haegele, K. D., 64 Haga, M., 80 Haggstrom, N., 184 Hagiwara, K., 142 Halfon, Y.,200, 251 Halkes, S. J., 240 Hall, I. H., 153 Hall, S. F., 117 Hall, S. S.,14 Halley, B. A., 184 Halperin, G., 255 Halsall, T. G., 131 Hamanaka, N., 123 Hamer, D. E., 253 Hammerschmidt, R., 77

Hammond, M. L., 253 Hamstra, A. H., 251 Han, K. D., 115 Han, R.-J. L., 177 Hands, D., 251 Hangauer, D. G., 90 Hanna, I., 206 Hannak, D., 186 Hannaway, C., 104 Hanni, R., 165 Hansen, A. E., 205 Hanson, J. R., 109, 111, 112, 121, 122, 202, 216, 218, 224 Hara, H., 68 Hara, S., 224, 237 Harada, N., 111, 207 Harada, S., 132 Haraguchi, Y., 156 Harayama, T., 47, 72 Harding, R. W., 189 Harmatha, J., 65 Harosi, F. I., 188 Harris, C. J., 173 Harris, C. M., 185 Harrow, T. A., 259 Hartmann, R., 188 Hartwig, T., 207 Harvie, I. J., 222 Hase, T. A., 138, 155 Hasegawa, J., 194 Hashiba, N., 23, 169 Hashimoto, H., 40 Hashimoto, K., 5, 14, 181, 191 Hashimoto, S., 17 Haslam, E., 188 Hassner, A., 219 Hata, S., 190 Hata, T., 111 Hatton, I. K., 131 Haupt, E., 240 Hausen, B. M., 95 Hauser, E., 261 Hayakawa, V., 194 Hayakawa, Y., 17 Hayashi, K., 79 Hayashi, S., 34, 38, 117, 130 Hayashi, T., 14 Hayashi, Y., 116 Hayward, R. C., 218 Hazra, B. G., 266 Heathcock, C. H., 49 Heaton, P. R., 226 Hecht, H. J., 128, 141 Hecker, E., 125 Hedden, P., 119 Heimann, M., 185 Heissler, D., 18 Hellwege, D. M., 178 Henderson, R., 188 Hennessee, G. L. A., 146, 201 Herald, C. L., 95

Author Index

274 Herald, D. L., 95 Herath, W. H. M. W., 160 Herin, M., 135 Hernandez, M. G., 108, 118, 122, 169 Hernandez, O., 218 Herout, V., 71 Herrmann, H. D., 95 Hertzberg, S., 185 Herz, W., 57, 58, 60, 61, 62, 69, 93, 95, 114, 116, 118 Hess, B., 186, 188 Hesse, R. H., 230, 239 Hewett, C. L., 255 Higashi, R. M., 190 Higashi, T., 142 Higgins, T. J. V., 165 Hikino, H., 69, 71 Hilderson, H. J., 191 Hiller, K., 154, 156 Hiltunen, L., 154 Himmelsbach, R. J., 132 Hinata, S., 83 Hiraga, K., 259 Hirai, N., 7 Hirama, M., 47 Hirata, T., 142 Hirata, Y., 26, 80 Hiroaki, K., 212 Hiroi, M., 130 Hirono, I., 80 Hirose, Y., 26 Hiroshima, O., 194 Hirotsu, K., 93, 129 Hirsch, A. F., 107 Hirschmann, F. B., 236 Hirschmann, H., 235, 236 Hitchcock, P. B., 111, 121 Hiyama, C., 158 Hiyama, T., 86 Ho, W.-T., 187 Hobert, K., 207 Hoefle, G., 128 Hoeneisen, M., 108 Hoffmann, E., 100, 117 Hoffmann, W., 18, 188 Hofrnann, K. P., 186 Hofmann, R., 112 Hofmeister, H., 220, 224 Holker, J. S. E., 11 Holland, H. L., 205, 265 Holland, P. T., 163 Hollenbeak, K. H., 12, 104, 126, 169 Holtmeier, W., 218 Holub, M., 58, 71, 94 Honig, B., 187, 188 Hooper, S. N., 135 Hoornaert, G. J., 240 Hoppen, V., 205 Horii, Z., 135, 191 Horinaka, A., 85 Horn, D. H. S., 242 Horvath, G., 209

Hoskinson, R. M., 211 Hosogai, T., 5, 136 Hosokawa, K., 138 Hosomi, A., 20 Hossain, B. M., 126, 169 Hossain, M. B., 12 Hotchandani, S., 187 Houk, K. N., 87 Howard, B. M., 23, 126, 169 Howard, J. A. K., 131 Hoye, T. R., 8 Hoyer, G.-A., 222,265 Hoz, T., 236 Hsieh, C.-L., 187 Hsu, C. T., 224 HSU,H.-Y., 142 Huang, H.-C., 153 Hubbell, J. P., 125 Hubbell, W. L., 188 Hudlicky, T., 101 Hudson, B. S., 210 Huebner, M., 258 Huettemann, R., 107 Huffman, J. W., 85, 138, 201 Huikko, R., 138 Hul, R. A. H. F., 215 Hulkenberg, A., 176 Hull, S. E., 58 Hunter, R., 9, 128 Huong, K. C., 18 Hurtada, E. J., 265 Hutchins, R. O., 182 Hylands, P. J., 156 Hyono, T., 116 Ibuka, T., 79 Ichikawa, K., 218, 226 Ichimura, H., 9, 180 Ichimura, T., 60 Ichinohe, Y., 215 Ichinose, I., 5, 24, 136, 181 Ida, Y., 112 Idler, D., 203 Iguchi, K., 142 Iguchi, M., 53 Iida, T., 202 Iino, M., 43 Iio, H., 68 Iitaka, Y., 55, 75 Ikeda, M., 128, 138, 155 Ikeda, R., 123 Ikegami, S., 119, 215 Ikehara, M., 142 Ikekawa, N., 203, 246, 251 Ikenoya, S., 194 Iles, J., 4 Imabayashi, S., 194 Imai, T., 122 Imakura, Y., 96, 153 Innes, A. G., 203 Inayama, S., 75 Inokuchi, T., 83, 180 Inoue, O., 143

Inoue, S., 4, 24 Inoue, T., 141 Inoue, Y., 184 Inubushi, Y., 72, 79 Irisrnetov, M. P., 222 Iriye, R., 123 Isakov, V. V., 142 Ishibashi, K., 194 Ishibashi, M., 138, 212 Ishiguri, Y., 78 Ishiguro, M., 101, 103, 246 Ishikawa, K., 186 Ishikawa, M., 250 Ishikawa, O., 158 Ishizaki, Y., 80 Isler, O., 164 Isobe, M., 68 Itiogawa, M., 95 Ito, K., 95, 161 Ito, M., 24, 177, 178, 183 It& S., 7, 51, 52 Ito, T., 214 Ito, Y., 79 Itoh, T., 135 Itokawa, H., 55 Ivanov, A., 181 Iwabuchi, H., 43 Iwahashi, M., 211 Iwai, H., 181 Iwasa, J., 123 Iwasa, T., 186 Iwasaki, S., 117 Iwata, C., 21 Iyengar, R., 5 Izawa, K., 138 Izuta, I., 83 Jabben, M., 190 Jacob, K., 218 Jacobson, R. M., 218 Jacobus, J., 138, 201 Jacques, J., 257 Jaffe, B. M., 213 Jain, D. C., 158 Jain, K. M., 185 Jain, T. C., 56 Jakobsen, H. J., 21 Jakupovic, J., 3, 12, 61, 62, 69, 110, 154 James, K. C., 210 Janitschke, L., 20 Jaszczynski, J. R., 238 Jauhari, P. K., 109 Jayaram, M., 191 Jefferies, P. R., 120 Jeffrey, C., 69 Jeger, O., 183 Jigajinni, V. B., 225 Jizba, J., 80 Johannes, B., 184, 185 Johnson, A. P., 79 Johnson, G., 254 Johnson, M. A., 133 Johnson, R. L., 253

275

Author Index Johnstone, R. A. W., 11 Jones, A. J., 69 Jones, E. R. H., 214 Jones, G., 200, 251 Jones, O., 187 Jones, P. G., 58 Jones, S. B., jun., 58 Joseph-Natham, P., 203 Joshi, B. S., 111 Joshi, K. C., 28 Joshi, U. M., 211 Joska, J., 216, 219 Joulain, D., 181 Joyce, B. G., 211 Julia, S., 16 KaborC, I. Z., 215, 228 Kabuto, C., 53 Kagan, H. B., 211 Kagei, K., 155 Kaiser, R., 4, 65, 168 Kaisin, M., 104 Kaiya, T., 123 Kaji, K., 5, 14, 181, 191 Kaji, L., 143 Kaji, T., 32 Kajtar, J., 166 Kakisawa, H., 131 Kakitani, H., 186 Kakitani, T., 186 Kalisky, O., 186 Kalmovskii, A. I., 139 Kalsi, P. S., 28 Kalvoda, J., 239 Kameda, N., 215 Kamernitzky, A. V., 264, 266 Kametani, T., 132, 133 Kamga, C. S., 146 Kamijo, N., 38 Kane, V. V., 107 Kaneko, C., 250 Kaneko, H., 168 Kaneko, K., 32, 226 Kang, S. S., 158 Kanojia, R. M., 107 Kapil, R. S., 109 Karkhanis, D. W., 87 Karlson, P., 164 Karlsson, B., 118, 125 Karnaukhova, E. N., 178 Kasal, A., 216, 219 Kashman, Y., 28, 124, 126 Kasprzyk, Z., 157 Katai, M., 123 Kataky, J. C. S., 145 Kataoko, M., 173 Katayama, M., 191 Katayama, T., 165 Kato, K., 168, 191, 192 Kato, T., 5, 24, 53, 134, 136, 181 Katsui, G., 194 Katsui, N., 76, 78 Katsuki, H., 190

Katti, S. B., 109 Kavka, J., 69 Kawabata, K., 226 Kawabe, K., 194 Kawahara, N., 236 Kawai, K., 83 Kawai, T., 68 Kawakubo, H., 193 Kawamata, T., 75 Kawasaki, T., 112 Kawazu, K., 93, 123 Kayser, H., 165 Kazlauskas, R., 11, 124, 127, 131 Keck, G. E., 133 Kees, K. L., 223 Keith, B., 121 Kelley, C. J., 38 Kelly, R. B., 77 Kelsey, R. G., 99 Kemlo, W. S., 201 Kennard, O., 58 Khalil, S. A., 201 Khalil, W., 203 Khan, M., 137, 199, 260 Khastgir, H. N., 162 Khrapova, N. G., 193 Khristov, S., 188 Khuong-Huu, Q., 215, 228 Kido, F., 73 Kielczewski, M., 226 Kienzle, F., 7, 172, 179 Kieslich, K., 265 Kiguchi, T., 21 1 Kikuchi, M., 202 Kikuchi, T., 159, 190 Kim, J. H., 115 Kim, S.-W., 135, 191 Kimata, H., 158 Kimbu, S. F., 108 Kim-y-Sim, 128 King, G. G. S., 18 King, G. I., 187 King, R. M., 17, 28, 34, 62, 64, 67, 69, 99, 108, 111, 117 King, T. J., 11 Kinghorn, A. D., 152 Kingston, J. F., 256 Kingzett, P. C., 187 Kini, A., 174, 177 Kinnear, J. F., 242 Kinnel, R., 71 Kirk, D. N., 204, 206 Kirkup, M., 126 Kiselev, A. V., 188 Kishi, H., 193 Kishi, T., 193 Kitagawa, I., 139 Kitahara, N., 142 Kitajima, H., 185, 186 Kitani, T., 226 Kitazawa, E., 106, 111, 131 Kittredge, J. S., 103

Kizu, H., 158 Klaar, M., 141 Klaus, M., 178 Klein, P. D., 212, 217 Klein, T. H., 263 Kleinig, H., 165, 190 Klinot, J., 157 Knapp, F. F., jun., 218, 245 Knappe, J., 195 Knauf, W., 69, 111 Knedel, M., 218 Knight, J. C., 244 Knoell, H. E., 195 Knoll, K. H., 57, 80, 96 Knox, J. R., 109 Kobayashi, H., 18 Kobayashi, M., 83, 139 Kobayashi, S., 106, 121 Kobayashi, Y., 211, 251 Kochetkov, N. K., 192 Kocienski, P. J., 230, 242 Kocbr, M., 44, 69 KoEovskjl, P., 209, 216, 218, 233,242, 256, 265 Kodama, A., 178, 183 Kodama, J., 117 Kodama, M., 7, 51, 52 Kohl, K. D., 188 Kohler, B. E., 186 Kohout, L., 201, 265 Koike, H., 117, 132 Koizumi, N., 203 Koizumi, T., 262 Kojima, M., 214 Kok, J. G. J., 176 Kok, P., 89 Kokke, W. C. M., 246 Komatsu, H., 214 Komatsu, T., 186 Komori, T., 38, 112 Kondo, Y., 69 Kononenko, A. A., 186 Koreeda, M., 93 Korenbrot, J. I., 187 Korenstein, R., 188 Korp, J. D., 62 Korsmeyer, R. W., 30 Korte, F., 209 Koshimizu, K., 7, 115, 121 Kotsuki, H., 4, 10, 145 Kouno, I., 43 Kowerski, R. C., 136 Kraft, R., 195 Kraus, W., 146 Kreiser, W., 20 Krepski, L. R., 219, 223 Kreutz, W., 186 Kriebel, A. N., 186 Krief, A., 135 Krinsky, N. I., 164 Krishna, E. M., 148 Krstulovic, A., 183 Ksander, G. M., 133 Ku, W.-H., 114

Author Index

276 Kuball, H.-G., 206 Kubo, I., 60, 119 Kubo, S., 112 Kubota, T., 119 KuC, J., 77 Kuksis, A,, 208 KulaEkova, D., 157 Kulig, M. J., 222 Kulikova, L. E., 266 Kulshreshtha, D. K., 154 Kumada, M., 14 Kumagai, N., 95 Kumahara, Y., 211 Kumar, N., 57, 58, 69 Kumazawa, T., 83 Kunst, M., 210 Kurabayashi, M., 106, 111 Kuril'skaya, V. V., 222 Kuroda, C., 80 Kuroda, Y., 193 Kurogochi, S., 121 Kurosawa, E., 23, 24, 169 Kuroyanagi, M., 32 Kurth, M. J., 8 Kurusaki, A., 23 Kusano, G., 69 Kuschmitz, D., 186, 188 Kushi, Y., 38 Kusov, Y. Y., 192 Kusumi, T., 131 Kutschabsky, L., 121 Kuwano, H., 106, 111 Kuyama, M., 181 Kyogoku, Y., 139 Kyotani, Y., 80, 96, 97 Kypke, K., 146 Labbt, C., 125, 144, 148 Lachish, U., 186 Lafferty, J., 186, 187 Lagrou, A., 191 Lai, C. K., 109 Lai, J., 161 Lakhvich, F. A., 223 Lam, H.-Y. P., 261 Lamotte, G., 229 Lamparsky, D., 4, 65, 168 Land, E. J., 186, 187 Lane, G. A., 199, 203 Lange, G. L., 29 Lansbury, P. T., 90 Lanyi, J. K., 188 Larruga, F., 118 Larsen, S. D., 133 LaTorre, F., 215 Laungani, D. R., 136 Lauren, D. R.,131 Laurent, H., 220, 224 Lavie, D., 114 Lawrence, J. F., 212 Lazare, S., 25 Lazarev, G. G., 193 Leander, K., 34, 141 Leblanc, R. M., 187

Leclercq, J. M., 187, 188 Lee, H. H., 219, 263 Lee, K. H., 96, 153 Lee, S. P., 218 Leibfritz, D., 240 Leigh, J. S., 188 Lemley, A. T., 186 Lemmich, E., 106 Lenel, R., 164 Lenz, G. R.,241, 242 Leont'ev, V. B., 108 Le Quesne, P. W., 38, 6 1 Lerman, O., 226 Leroi, G. E., 186 Le Roux, M., 106 Lessinger, L., 11 Lester, D. J., 215 Letham, D. S., 165 Letourneaux, Y., 257 Le Van, N., 118 Levery, S. B., 61 Levina, I. S., 266 Levine, S. D., 107 Lewis, A., 186, 187, 188 Ley, D. A., 131 Ley, S. V., 111, 215 Liaaen-Jensen, S., 164, 165, 167, 170, 174, 185 Liau, H. T. L., 109 Limacher, J., 169 Lin, Y. Y., 210 Linde, H. H. A., 261 Linek, A., 53 Lis, L. G., 223 Lischewski, M., 121 Little, R. J., 237 Litvinova, G. E., 253 Litwiller, R. D., 212 Liu, H. J., 26, 218 Liu, R. S . H., 174, 177 Liu, T.-D., 158 Llinares, J. R. P., 71 Lobanov, N. A., 188 Lockley, W. J. S., 188, 189 Logan, R. T., 255 Longevialle, P., 209 Lonitz, M., 12 Loomis, G. L., 90 Lopes, C. C., 116 Lbpez, A., 120 Lopez de Lerma, J., 94 Lorck, H., 21 Lorenc, L., 260 Lottenbach, W., 231 Lotter, H., 125 Lovell, F. M., 137 Lozier, R. H., 188 Lucas, J. J., 191 Luciani, S., 118 Luckner, M., 135, 165 Ludwig, B., 247 Luibrand, R. T., 10 Luis, J. G., 118 Lukashev, E. P., 186

Lusinchi, X.,228, 229 Mabry, T. J., 57, 58, 60, 100 McCabe, T., 108 McCarthy, F. C., 29 McChesney, J. D., 132 McClosky, J. E., 56 McColl, J. R.,211 McCormick, J. P., 29 McCormick, S., 60 McDermott, I. R., 257 McDonald, F. J., 8 McDonald, J. H., 5 McDougal, P. G., 164, 219 McDowell, P. G., 9, 169 McGarry, G., 255 McGregor, M. L., 178, 184 Machlin, L. J., 177 Mackenthun, M. L., 170 McKenzie, R.M., 178, 184 McKillop, A., 215 McLaren, F. R.,87 MacMillan, J., 121, 122, 131 McMorris, T. C., 245 McMurry, J. E., 133, 174, 223, 236 McPhail, A. T., 57, 95, 152 McQueen, R. G., 236 McQuillin, F. J., 222 Madkre, R.,184 Madhusudanan, K. P., 61,62 Maeda, A., 188 Maeda, M., 214 Magalhaes, M. T., 112 Magno, S., 3, 57 Magnusson, G., 44 Mahajan, V. K., 25 Mahanta, P. K., 11, 64, 69, 95, 100, 106, 117 Maidment, M. S., 256 Maiti, R. N., 156 Majetich, G., 69, 89 Majumdar, U., 25 Majumder, P. L., 156 Mal, D., 156 Malakov, P. Y., 111 Malchenko, S., 21 Maldonado, L. A., 181 Malinovskaya, G. V., 142 Mallabaev, A., 93 Mallamo, J. P., 230 Mallik, B., 185 Maltz, A., 125, 146 Manabe, S., 26, 96, 97 Manchand, P. S., 64, 108, 125, 174 Mandava, N., 184 Mander, L. N., 134 Mangoni, L., 144, 223 Manotti Lenfredi, A. M., 207 Mansilla, H., 58 Manwaring, J., 165 Mao, D. T., 71 Marai, L., 208

277

Author Index Marazano, C., 145 Marco, J. A., 71 . Marcus, M. A., 186, 187, 188 Mareci, J. H., 205 Mares, F., 220 Marguet, A., 259 Marini-Bettolo, G. B., 154 Marples, B. A., 234 Mirquez, C., 118, 120 Marsh, W. C., 201 Marshall, J. A., 68 Marsili, A., 235 Marta, M., 154 Martens, H. J., 240 Martin, G. E., 125 Martin, J. A., 245 Martin, J. D., 22, 23, 169 Martin, M.-D., 242 Martin, S. F., 25 Martin, V. S., 22, 23, 169 Martin-Borret, O., 267 Martinez, J. R., 61 Martinez-Ripoll, M., 22, 23, 94, 124, 169 Marumo, S., 191 Maruoka, K., 17 Maruyama, K., 192 Masaki, Y., 5, 14, 181, 191 Masamune, T., 76, 77, 78, 24 1 Masojidkovi, M., 94 Massanet, G. M., 94 Massey, I. J., 207 Masson, S., 14 Masuda, I., 119 Masuoka, M., 259 Masutani, T., 123 Matas, M. E. O., 118 Mateos, A. F., 243 Mateos, J. L., 107, 215 Matern, H. U., 144 Mathies, R., 186, 187 Mathur, R. K., 145 Matida, A. K., 114 Matson, J. A., 125 Matsude, T., 226 Matsueda, S., 93 Matsukawa, A., 9 Matsuki, Y., 7, 51 Matsumaru, H., 179 Matsumori, S., 165 Matsumoto, H., 14, 177 Matsumoto, T., 32, 40, 51, 116, 123, 132, 135, 202 Matsunaga, I., 250 Matsuno, S., 165 Matsuno, T., 167 Matsuo, A., 34, 38, 117, 122, 130 Matsuo, M., 72 Matsutaka, H., 167 Matsuura, S., 155 Matthews, W. A., 261 Mattox, V. R., 212

Mavlyankulova, Z. I., 108 Mayer, H . , 164, 165, 168, 172, 179 Mayol, L., 3, 57 Mazur, Y., 200, 233, 238, 251,253 Meakins, G. D., 202, 214, 247 Medarde, M., 69, 169 Meguri, H., 123 Mehta, G., 16 Meinwald, J., 71 Meister, W., 165 Mejta, G., 203 Mellerio, G., 44 Mellows, G., 9, 128 Menachem, Y., 226 Menachery, M. D., 61 Mendelsohn, R., 186 Mendoza, L., 222 Mercker, H.-J., 104 Messing, A. W., 254 Metzler, D. E., 185 Meyers, A. I., 14 Michel, H., 188 Midgley, J. M., 199, 201, 226, 25 1 Mignani, G., 238 MihailoviC, M. Lj., 260 Mijarez, A., 107 Mijngheer, R., 68 Miki, T., 259 Milborrow, B. V., 165, 189 MiljkoviC, D., 227 Miller, D., 222 Milliet, P., 229 Mimura, T., 226 Minakata, H., 79 Minale, L., 10, 126 Mincione, E., 214, 216, 235 Minder, R. E., 172, 179 Miralles, M. O., 187 Mishima, H., 106 Misiti, D., 215 Mislow, K., 138, 201 Misra, C., 43 Misra, T. N., 185 Misumi, S., 40 Mitchell, S. J., 124, 127 Mitra, A., 5 Mitsner, B. I., 178 Miura, I., 38, 60 Miura, Y., 138 Miyamoto, F., 32 Miyashita, M., 83, 86 Miyazaki, H., 138, 212 Mlotkiewicz, J. A., 42 Mnatsakanyan, V. A., 111, 112, 142 Mody, N. V., 123, 124 Mohr, H., 190 Moldowan, J. M., 135 Mollov, N. V., 111, 124 Molnir, P., 166

Monaco, P., 144 Mondelli, R., 120 Monder, C., 212 Mondon, A., 146, 151 Monger, T. G., 188 Montal, M., 188 Monti, H., 18 Monti, S. A., 133, 134 Moore, R. E., 126 Moore, T. A., 170 Moravcsik, I., 214 Morelli, I., 235 Mori, M., 215 Mori, O., 85 Mori, Y., 194 Morimoto, H., 192 Morisaki, M., 251 Morisaki, N., 18 Moriyama, Y., 7, 153, 160 Morohoshi, T., 42 Morris, G. A., 205 Mose, W. P., 206 Mosebach, K. O., 211 Mosher, H. S., 167 Moss, G. P., 164, 165, 173 Moss, R. A,, 72 Motherwell, R. S. H., 229 Motherwell, W. B., 229, 233 Motl, O., 94 Mouriiio, A., 253 Moustafa, M. A., 201 Mawery, P. C., 179 Mudd, J. M., 222 Mueller, R., 211 Muller, R. K., 168 Mueller, W. F., 209 Mues, R., 100 Muther, I., 207 Mukhamedkhanova, S. I., 108 Mukherjee, D., 87 Mukherjee, K. S., 156 Mukhopadhyay, S., 160 Mulder, J., 124 Mullen, K., 183 Muller, B. L., 183 Mummery, R. S., 190, 191 Mundy, A. P., 188 Munro, M. H. G., 34, 203 Murae, T., 7, 38, 60, 80, 138, 153, 160 Muragaki, H., 119 Murai, A., 76, 77, 78 Murakami, T., 118 Muraki, S., 53 Muramatsu, M., 211 Muraoka, K., 10 Murari, R., 57, 58, 61, 62, 93, 114 Murata, R., 73 Murofushi, N., 121, 122 Murphy, P. T., 11, 124, 127, 131 Murphy, W. S., 137, 199, 260 Murray-Rust, J., 42

278 Murray-Rust, P., 42 Murthy, Y. L. N., 141 Murty, K. S., 77 Mushfig, M., 237 Musial, B. C., 212 Musser, J. H., 133 Myher, J. J., 208 Myshenkova, T. N., 181 Nadgouda, S. A., 56 Naf, F., 86 Naegeli, P., 28, 8 7 Nagai, M., 138, 141 Nagano, H., 80, 250 Nagao, K., 135, 191 Nagao, Y., 106, 226 Nagasawa, M., 55 Nagumo, S., 138 Nagura, S., 122 Naito, T., 9 Najdenova, E., 80 Nakagawa, M., 173 Nakai, T., 226 Nakajima, S., 9 3 Nakajima, T., 179 Nakamura, T., 194 Nakanishi, K., 9, 38, 54, 6 0 Nakanishi, M., 80 Nakano, K., 185 Nakano, T., 118 Nakashima, T. T., 128 Nakata, H., 123 Nakata, T., 9 Nakatani, K., 118 Nakatsuji, S., 173 Nakayama, K., 253 Nakayama, M., 34, 38, 117, 130 Nakayama, R., 259 Nakiwama, M., 138 Nambara, T., 212 Namikawa, M., 38 Nanayakkara, N. P. D., 158 Napoli, J. L., 251 Narain, N. K., 64, 138 Narang, S. C., 229 Narasimhan, K., 9 0 Narula, A. S., 25 Naruta, Y., 192 Narvaez, M., 132 Nassim, B., 208 Nassimbeni, L. R., 201 Natale, N. R., 182 Nath, A,, 162 Natori, S., 42 Natu, A. A., 1 2 Navangul, H. V., 187 Naya, K., 80, 8 5 Naya, Y., 32 Nayak, U. R., 34, 37 Nazarians, L., 57, 67 Nedelec, L., 206, 257, 259 Neef, G., 227

Author Index Negre-Sadargues, G., 164 Nelson, D., 184 Nelson, E. C., 178, 184 Nemori, R., 121 Nemorin, J. E., 139 Nemoto, H., 132, 133 Neuenschwander, A., 8 2 Neuenschwander, M., 8 2 Neuman, R. C., jun., 186 Newton, D. L., 184 Nguyen, K. Q. C., 154 Nichols, M. D., 184 Nicoara, E., 174 Nicotra, F., 203 Nicoud, J. F., 211 Niinisto, L., 154 Nikishchenko, M. N., 142 Niknejad, A., 58 Ninomiya, I., 211 Nishi, A., 190 Nishi, M., 203 Nishida, T., 80, 106, 205 Nishide, K., 218 Nishikawa, N., 116 Nishimura, Y., 133 Nishino, T., 139, 190 Nishioka, I., 143, 156 Nishitani, K., 75 Nishizawa, M., 17, 116 Niwa, M., 53, 159 Niyazov, B. G., 157 Njimi, T. K., 108 Noack, K., 168 Nobile, L., 144 Noble, L. L., 186 Nobuhara, J., 38 Noda, K., 156 Node, M., 106, 218 Noguchi, H., 106 Noguchi, M., 168 Nomine, G., 206, 259 Nomura, D., 4 3 Noriega, L., 107 Norin, T., 65, 125 Norman, A. W., 253, 254 Norte, M., 22, 169 NovPk, C., 5 3 NovotnL, L., 80 Nowacki, J., 123 Noyori, R., 17 Nozai, H., 142 Nozaki, H., 5, 17, 38, 86, 101, 130 Nozoe, S., 18, 6 9 Nukina, M., 128 Numazawa, M., 257 Nuiiez-Alarc6n, J. A,, 6 1 Nuzhat, R., 25 Obafemi, C. A., 162 Oberhansli, P., 125 O’Brien, D. H., 107 Ochi, K., 250

Ochi, M., 4, 10, 145 Ochiai, M., 219 Oda, Y., 177 Oesterhelt, D., 188 Ofuchi, R., 236 Oganesyan, G. B., 111, 112 Ogata, Y., 155 Ogawa, H., 180 Ogihara, T., 211 Ogihara, Y., 143, 158 Ogiso, A., 106, 111, 1 3 1 Ogunkoya, L., 162 Ogura, H., 75 Oguri, T., 69, 95 Ogurusu, T., 188 Ohfune, Y., 40, 8 9 Ohloff, G., 13, 65, 168, 169, 183 Ohmae, M., 194 Ohmori, M., 251 Ohno, M., 177 Ohno, N., 5 7 , 6 0 , 100 Ohnuma, T., 5 3 Ohsuka, A., 9 Ohtsuka, T., 40 Oikawa, A., 251 Oishi, T., 9, 117 Oka, H., 83 Oka, K., 224, 237 Okamoto, K., 78 Okamoto, T., 124 Okamura, N., 156 Okamura, W. H., 253, 254 Okano, K., 119 Okano, T., 226 Okayama, K., 180 Okorie, D. A., 148 Okuda, S., 142 Okuda, T., 38 Olson, J. A., 183 Olthof, G. J., 24 Omarkulov, T. O., 182 Omura, K., 8 0 Onan, K. D., 5 7 , 9 5 , 152 Onisko, B. L., 233 Ono, M., 77 Opferkuch, H. J., 125 Oppolzer, W., 97, 101 Orena, M., 7, 179 Oribe, T., 262 Oriente, G., 3, 57 Oritani, T., 181 Orlandi, G., 188 Orsini, F., 131 Ortaggi, G., 214, 216, 235 Qrtega, A., 6 0 Osawa, E., 51, 52 Osawa, Y., 257 Oshida, J.-I., 251 Osianu, D., 174 Osman, M., 1 9 1 Osorio, E., 265 Ostrowski, P., 107 Ota, Y., 121

279

Author Index Otsuka, S., 226 Ottolenghi, M., 186, 188 Oura, H., 142 Ourisson, G., 25, 135, 247 Ovchinnikov, Yu. A., 188 Overbeek, A. R., 24 Overbeek, W. R. M., 176 Ozainne, M., 65, 98 Ozaki, Y., 135, 191 Paanakker, J. E., 183 Paaren, H. E., 253 Pachlatko, J. P., 29, 47 Pageaux, J. F., 212 Pagnoni, U. M., 51 Pak, C. S., 246 Paknikar, S. K., 11, 27, 58 Palumbo, G., 144, 223 Pancrazi, A., 215, 228 Panda, S. K., 156 Pandian, R., 85 Panizza, S., 114 Panosyan, A. G., 142 Pant, P., 135 Panunzio, M., 176 Papanov, G. Y., 111 Papillaud, B., 116 Paquin, P., 187 Parareda, J. S., 71 Pardasani, R. T., 28 Parello, J., 229 Parikh, V. D., 257 Parish, E. J., 205, 217 Park, 0. S., 181 Parker, W., 42 Parnes, H., 215 Parnes, Z. N., 223 Parsons, W. H., 49 Paryzek, Z., 139 Pascard, C., 25, 144, 152 Pascoe, K. O., 125 Pastore, M. P., 38 Patel, K., 202 Patel, N. J., 188, 189 Paternostro, M. P., 111, 112 Patin, H., 238 Paton, W. F., 137, 161 Patrick, T. B., 222 Pattenden, G., 101, 165, 174 Patterson, D. G., 205, 223 Paul, D., 263 Paul, I. C., 137, 161 Paul, V. J., 129 Pawson, B. A., 177 Pearce, H. L., 34 Pease, J., 215 Pechet, M. M., 230, 239 Pegel, K. H., 119 Pekh, T., 181 Pelc, B., 242 Pelissoni, F., 131 Pelletier, S. W., 123, 124 Pellicciari, R., 117, 132, 180, 260

Pelter, A., 28 Pennock, J. F., 194 PCrez, C., 23 Perez, G. C., 215 Perreault, G. J., 187 Perry, D. L., 62, 65 Persoons, C. J., 54 Pete, J.-P., 241 Peters, J. A. M., 221 Peters, K. S., 186 Peterse, A. J. G. M., 9 Petraud, M., 116 Petri, F., 201 PetroviC, J., 227 Pettei, M. J., 60 Pettit, G. R., 95, 144, 145, 244 Pfander, H., 164 Phillipou, G., 209, 235 Phillips, L., 119 Phinney, B. O., 119, 122 Piacenza, L. P. L., 119 Piatelli, M., 3, 57, 130 Pick, J. H., 256 Pickenhagen, W., 169 Picot, A., 228 Pierce, B. M., 185 Piermattie, V., 177 Piers, E., 34, 37 Pilotti, A. M., 118, 125 Pimenov, M. G., 93 Pinar, M., 120 Pinchin, R., 116 Pinetti, A,, 51 Pinhey, J. T., 228 Piozzi, F., 109, 111, 112, 116, 118 Piraux, M., 201 Pirozhkov, S. D., 181 Pitt, C. G., 266 Plavac, F., 49 Pleinard, J. F., 142 Poddubnaya, S. S., 181 Pokhilo, N. D., 142 Polonsky, J., 115, 144, 145, 152, 153 Polyachenko, L.-N., 181 Polylk, B., 183 Polyakova, A. A., 157 Ponsold, K., 258 Popjlk, G., 202, 212 Porter, J. W., 164 Porter, T. H., 193 Posner, G. H., 90, 230 Postmus, T. L., 240 Pouzar, V., 155 Powell, L. A., 173 Pozas, R., 215 Pozzo-Balbi, T., 144 Pradhan, D. K., 159 Prakasa Rao, A. S. C., 34 Prakash, O., 109 PrangC, T., 25, 152 Prasad, H. N. V., 177

Prasad, J. S., 201 Presti, D., 191 Pretorius, J. A., 80 Pretsch, E., 94 Preus, M. W., 245 Previtera, L., 223 Price, K. R., 77 Prisbylla, M. P., 181 Prochlzka, Z., 265 Pullin, C. A., 165 Purushothaman, K. K., 125 Puzitskii, K. V., 181 Pyne, S. G., 134 Pyrek, J. St., 69, 93, 120, 162, 191 Quagliata, C., 201 Quartey, J. A. K., 162 Quesada, M. L., 49 Quijano, L., 57, 61, 62 Quin, L. D., 264 Quinkert, G., 240 Rabanal, R. M., 118, 120 Rabenhorst, E., 114 Rabinovich, D., 200, 251 Rabinovitch, B., 185, 188 Radics, L., 94, 111 Radominska-Pyrek, A., 191 Raffauf, R. F., 38, 61 Rafferty, C. N., 188 Ragault, M., 266 Raggio, M. L., 219 Raghavan, R., 58 Rahier, A., 141 Rahman, F. M. M., 183 Raines, D., 216 Rajagopalan, M. S., 204 Rajalakshmi, P. K., 201 Rajendran, K., 27 Raji, M. S., 115, 117 Ralph, D. E., 26 Ramakrishnan, G., 58 Ramasseul, R., 267 Ramgoolam, M., 210 Rang, H., 181 Ranieri, R. L., 104 Rao, M. M., 148 Rao, M. N., 157 Rao, N. S., 158, 160 Raphael, R. A., 21 Rappoldt, M. P., 240 Rashid, A., 217 Rasmussen, M. H., 87 Rasmusson, G. H., 236 Rassat, A., 267 Rastogi, R. P., 114, 135 Raston, C. L., 109 Rastrup-Andersen, N., 21 Ravi, B. N., 124 Ravindranath, B., 109, 111 Ravindranath, K. R., 58 Ray, J. K., 132

280 Razdan, R. K., 266 Read, G. F., 211 Read, R. W., 231 Reamer, R. A., 236 Reck, G., 121 Rector, D. H., 266 Reddy, A. V., 16 Redel, J., 212 Rees, H. H., 194, 244 Rehm, D., 240 Reidiker, M., 220 Reijnders, P. J. M., 56 Reinhardt, R., 28 Remberg, G., 151 RCmion, J., 135 Renneboog, R. M., 87 Renold, W., 65 Rens, J., 206 Renstroem, B., 170 Rentzepis, P. M., 186 Restndiz, J., 60 Restivo, R. J., 199 Reusch, W., 79 Riad-Fahmy, D., 211 Ricca, G. S., 203 Riccio-Battaile, R., 126 Rich, M., 187 Riche, C., 99 Richter, H., 118 Rickards, R. W., 168 Riddell, F. G., 42 Ridley, J., 190 Ridley, S. M., 190 Riehl, J.-J., 18 Riisom, T., 21 Riley, J. P., 183 Rilling, H. C., 164 Rios, C. T., 57, 63 Rivett, D. E. A., 80 Roberge, R., 187 Roberts, A. B., 184 Roberts, J. S., 21, 42, 104 Robertson, J. M., 104 Robinson, C. H., 257 Robinson, H., 17, 28, 34, 62, 64, 67, 69, 99, 108, 111, 117 Rodewald, W. J., 222, 235, 238,242 Rodgers, M. A. J., 186 Rodionov, A. V., 188 Rodriguez, B., 108, 109, 112, 116, 120 Rodriguez, E., 69, 95 Rogers, C. E., 107 Rogers, D., 111 Rohmer, M., 135 Rohr, M., 28, 87 Rohrer, D. C., 199, 201, 261 Romanelli, M. L., 203 Romeo, G., 160 Romo de Vivar, A., 60, 61, 63 Rprnneberg, H., 167, 170

Author Index Ropers, H. J., 121 Roque, N. F., 69 Rosenberger, M., 164 Rosenheck, K., 186 Rosenthal, A., 200, 251 Roskam, J. H., 9 Ross, F. P., 254 Rossi, J. C., 38 Rossi, T., 47 Rouessac, F., 181 Row, L. R., 141, 155, 157 Rowan, R., 184 Roy, R. G., 255 Roy, T. A., 210 Roy, T. K., 162 Rozen, S., 214, 226 Ruban, G., 93 Rubin, A. B., 186 Riicker, G., 53, 144 Ruediger, E. H., 34 Riiegg, R., 165 Rulin, V. A., 263 Runquist, A. W., 90 Russell, G. B., 203 Russell, S. W., 173 Rustaiyan, A., 57, 58, 67 Rutledge, P. S., 215, 218, 219,223, 263 Ryabova, K. G., 181 Rychlewska, U., 58 Rycroft, D. S., 125, 144, 148 Sadovskaya, V. L., 142 Saha, S. K., 160 Sai, M., 218 Saiki, Y.,118 Saikia, B., 145 Saito, M., 42 Sakaguchi, K., 194 Sakaguchi, R., 83 Sakakibara, J., 123 Sakamaki, H., 215 Sakamoto, M., 194 Sakan, T., 116 Sakita, T., 7 Saks, T., 181 Sakuda, K., 34 Sakuma, K., 14 Sakurai, H., 20 Sakurai, N., 141 Salama, A. M., 156 Salares, V. R., 170 Salen, G., 206, 244, 247 Salimov, B. T., 124 Samaan, H. J., 139 Samek, Z., 58, 65, 71, 94 Sammes, P. G., 108 Samokhvalov, G. I., 181, 253 Samori, B., 207 Samuni, A., 186 Sanada, S., 142 Sanchez, B., 69 Sanders, M. E., 206 Sandorfy, C., 187, 188

Sandra, P., 135 Sandri, S., 176 Sandris, C., 267 San Feliciano, A., 69, 114 Santaniello, E., 202 Santi, R., 118 Sarah, F. Y., 122 Sarkar, A., 156, 160 Sasak, W., 164 Sasaki, T., 47 Sassa, T., 128, 138 Sato, A., 106, 111 Sato, K., 78 Sato, S., 246 Sato, T., 155 Sato, Y., 138 Satoh, T., 83 Satomi, T., 93 Sattar, A., 42 Saucy, G., 164, 174 Saunders, J. K., 116 Savona, G., 109, 111, 112, 116 Sawa, Y., 194 Sawhney, R. S., 124 Sawzik, P., 201 Sayama, S., 72 Sayegh,, J. F., 213 Scala, A., 222, 232 Scapini, G., 144 Scarpa, A., 188 Scartoni, V., 235 Schade, G., 104 Schade, W., 258 Schaeffer, J. R., 211 Schaefle, J., 247 Schafer, T. R., 29 Schaffer, A., 186 Scheller, P. J., 247 Schenk, H., 24 Scheuer, A., 211 Scheuer, P. J., 10, 164 Schikarski, M., 53 Schlessinger, R. H., 49 Schmidt, G. J., 212 Schmidt, K., 165 Schmidt, J., 121 Schmidt, J. M., 144, 145 Schmitt, R., 165 Schmitz, F. J., 8, 12, 104, 126, 127, 169 Schneider, G., 122, 217 Schneider, H.-J., 205 Schnoes, H. K., 233, 251, 253 Schoenborn, B. P., 187 Schonecker, B., 201, 204, 217 Schonholzer, P., 11, 124 Scholler, D., 241 Schreckenbach, T., 188 Schroepfer, G. J., jun., 205, 217,245 Schubert, G., 201, 258 Schuda, P., 47 Schulte, K. E., 144

28 1

Author Index Schulte-Elte, K. H., 168, 169, 183 Schulten, K., 188 Schultz, A. G., 73 Schultz, G., 194 Schwartz, M. A., 13 Sciuto, S., 130 Scopes, P. M., 206 Scott, D. W., 223 Scott, K. N., 205 Seaborn, C. J., 235 Seaman, F. C., 61, 62, 64 Sedmera, P., 129 Seeger, A., 224 Sefton, M. A., 120 Segaloff, A., 199 Seger, D., 200, 251 Seida, A. A., 152 Seifert, W. K., 135 Seigler, D. S.,123 Sekizaki, H., 24 Seligmann, O., 158 Sen, M., 158, 160 Sendra, J. M., 71 Sengupta, P., 158, 160 Seoane, E., 71 Seppa, E. L., 44 Serdobov, M. V., 193 Serebryakov, E. P., 121 Sergienko, S. R., 157 Serkerov, S. V., 71 Serna, A., 187 Seshadri, R., 233 Seto, H., 47 Settepani, J. A., 258 Sevenet, T., 152 Shafiullah, D., 227 Shafizadeh, F., 99 Shah, H. P., 211 Shaikh, A. A,, 257 Shakked, Z., 200, 251 Sham, H. L., 101 Sham'yanov, 1. D., 93 Shannon, J. S., 184 Shapiro, S. L., 187 Sharma, R. P., 61, 62, 69 Sharypov, V. F., 139 Shaw, C., 107 Shaw, R., 208 Sheaves, M., 233, 253 Shefer, S., 206, 244, 247 Sheichenko, V. I., 93 Sheldrick, W. S., 120 Shepherd, K. P., 254 Shiao, M.-S., 5 Shibaev, V. B., 192 Shibata, K., 122 Shibata, Y., 142 Shichida, Y., 185, 188 Shimada, A., 134 Shimada, K., 52 Shimizu, F., 17 Shimizu, K., 190 Shimizu, S., 203

Shimoirisa, H., 214 Shindo, M., 250 Shingu, T., 118, 159 Shinoda, M., 86 Shinoo, Y.,21 Shirahama, H., 40, 51 Shirahata, A., 20 Shirai, N., 123 Shiraishi, M., 191, 192 Shivaprakash, N. C., 201 Shkrob, A. M., 188 Shner, V. F., 263 Shoji, J., 142, 158 Shone, C. C., 170 Shuey, C. D., 43 Shugar, D., 179, 187 Sicinski, R. R., 238 Sidyakin, G. P., 93 Silverman-Jones, C. S., 164 Silvestri, M. G., 236 Sim, G. A., 93,95, 111 Simes, J. J. H., 139 Simpson, K., 183 Simpson, K. L., 165 Simpson, T. J., 11, 131 Sims, D., 96 Singh, A. K., 75 Singh, H., 263 Singh, P., 28 Singh, P. P., 148, 158 Singh, R. B., 158 Siret, P., 133 Sirna, A., 214, 216, 235 Sistrom, W. R., 165 Siverns, M., 109 Sjovall, J., 205, 259 Skeean, R. W., 183 Sklarz, B., 11 Slavin, W., 212 Sleeper, H. L., 129 Sloan, K. B., 237 Small, D. D., 203 Smalla, H., 93 Smith, D. G., 203 Smith, G. C., 228 Smith, L. C., 239 Smith, L. L., 210, 222 Smith, R. K., 14 Smith, W. B., 114, 116 Smith-Palmer, T., 218 Snatzke, G., 207, 247 Snider, B. B., 21 Snitman, D. L., 132 Snowden, R. L., 97 Soave, A. M., 232 Sodano, G., 256 Soderholm, A. C., 125 Sokolova, N. A., 178 Sokol'skii, D. V., 182 Soler, E., 153 Sondengam, B. L., 108, 146 Song, P.-S., 187 Soohoo, C., 177 Sotheeswaran, S., 218

Southwell, I. A., 71 Specian, A. C., 177 Spengel, S., 261 Sperling, W., 188 Spies, H. S. C., 106 Spike, T. E., 245 Spiteller, G., 118, 209 Spitzner, D., 97 Sponsel, V. M., 121, 122 Spoonhower, J. P., 187 Sporn, M. B., 184 Spurgeon, S. L., 164, 189 Sree, A., 155, 157 Srisethnil, S., 177 Srivastava, H. C., 158 Srivastava, L. M., 121 Stallard, M. O., 103, 129 Stanis, S. P., 9 Stegk, A., 240 Steglich, W., 128, 141 Steinberg, N. G., 236 Steinegger, E., 82 Stellaard, F., 212 Stephens, R. L., 69 Stern, P. H., 251 Stevens, E. S., 206 Stevenson, D. F. M., 255 Still, W. C., 5, 54 Stipanovic, R. D., 107 Stoeckenius, W., 179, 187, 188 Stoessl, A,, 77, 78 Stokie, G. J., 124, 127 Stonik, V. A., 139 Stothers, J. B., 77, 78, 120, 204,237 Strain, H. H., 167 Stransky, H., 183 Strasser, R., 188 Strong, P. D., 199 Stuessy, T. F., 18 Subba Rao, G. S. R., 109 Subrahamanian, K. P., 79 Subramanian, G. B. V., 25 Sudhama, S. P., 211 Suetsugu, A., 132 Suga, T., 142 Sugano, N., 190 Sugawara, T., 139 Sugimoto, T., 185 Sugimoto, Y., 7 Suginome, H., 200, 240, 241 Sugita, K., 40 Sugiura, M., 179 Sugowdz, G., 169 Suire, C., 69, 100 Sulkes, M., 187 Sultanbawa, M. U. S., 158, 160 Sum, F. W., 7, 136, 181 Sumida, Y., 153 Sumimoto, M., 125 Sun, H. H., 126, 127, 129 Sundin, S., 125

Author Index Sung, T., 121 Suokas, E., 138, 155 Suryawanshi, S. N., 34, 37 Susplugas, C., 38 Susplugas, P., 38 Suvorov, N. N., 263 Suwita, A,, 11, 69, 93, 94, 114 Suyunbaev, U., 182 Suzuki, H., 185, 186 Suzuki, K., 132 Suzuki, M., 23, 96, 97, 134, 169 Suzuki, S., 142 Suzuki, T., 24, 53 SvEtlL, J., 157 Swallow, W. H., 34 Swarninathan, S., 90 Swanson, G. C., 13 Sweat, F. W., 137 Swedlund, B. E., 218 Sweet, F., 222 Swenton, L., 242 Sykes, P. J., 263 Symmes, C., jun., 264 SynaEkova, M., 218, 226 Szablocs, J., 166 Szasz, Gy., 211 Szczepek, W. J., 242 Szweykowska, M., 179, 187 Taber, D. F., 29, 30 Tabushi, I., 193 Tada, M., 80, 160,251 Taffer, I. M., 182 Taguchi, T., 251 Takabe, K., 181 Takadate, A,, 261 Takagi, Y., 168 Takahama, A., 128 Takahashi, K., 53 Takahashi, N., 121, 122 Takahashi, S., 106, 111, 131 Takahashi, T., 7, 38, 60, 80, 115, 138, 153, 160 Takahashi, Y. K., 76 Takai, K., 80 Takamura, K., 194 Takani, M., 160 Takano, E., 177 Takao, S., 119 Takaoka, D., 130 Takase, K., 72, 75 Takashirna, Y., 179 Takatsuji, H., 190 Takayama, H., 251, 253 Takayanagi, H., 75 Takeda, H., 204 Takeda, S., 132 Takeda, T., 143, 158 Takeda, Y., 118 Takernoto, T., 32, 69, 94, 100,101

Takemura, T., 186 Takeshita, H., 43 Takeshita, T., 203 Takeuchi, S., 47 Takeuchi, U., 211 Talpatra, B., 159 Talpatra, S. K., 159 Tamao, K., 14 Tamaoki, B., 215 Tamb, J., 94 Tamm, C., 21 Tamura, C., 111 Tamura, T., 202 Tanahashi, Y., 80 Tanaka, N., 118 Tanaka, O., 115, 143, 158 Tanaka, S., 5, 142 Tanaka, Y., 165 Tandon, J. S., 109 Tandon, S., 114 Tang, P.-W., 230 Tang, R., 220 Taniguchi, M., 4, 119 Taran, M., 117 Tatematsu, H., 80 Tauber, J. D., 170, 174 Taylor, D. A. H., 144, 146, 148, 150 Taylor, G. J., 205 Taylor, H. L., 152 Terada, T., 251 Terada, Y., 51, 52 Terai, T., 123 Terao, S., 191, 192 Terner, J., 187 Teutsch, G., 217 Texter, J., 206 Thappa, R. K., 69 That, T., 265 Theobald, N., 246 Thiele, K., 94 Thiessen, W. E., 125 Thoa, H. K., 265 Thomas, A. F., 65, 98 Thomas, C . A., 219 Thomas, R., 97 Thomas, S. A., 111, 121 Thommen, H., 164, 165, 179 Thommen, W., 86 Thompson, J. B., 152 Thompson, J. N., 184 Thompson, M. H., 217 Thompson, T. E., 107 Thoren, S., 44 Threlfall, D. R., 194 Thuillier, A,, 14 Thyagarajan, G., 61, 62 Tideswell, J., 242 Tingoli, M., 115, 117, 132, 260 Tint, G. S., 206, 208, 244, 247 Tiripicchio, A., 207 Tiwari, K. P., 158

Togami, M., 116 Tokito, Y., 184 Tokoroyama, T., 4, 10, 117, 132 Tokunaga, F., 185, 186, 188 Tom, R. D., 170 Tomassini, T. C. B., 118 Tomeoka, F., 178 Tomimori, T., 158 Tomita, B., 26 Tomiyama, K., 76, 78 Tomonoh, S., 184 Tori, K.,80 Torii, S., 9, 78, 83, 123, 180, 181 Torrez-Martinez, S., 164 T6th, G., 166 Toth, I., 157 Tovar, L., 107 Toyoshima, H., 153 Toyoshima, S., 155 Toyota, M., 69, 100, 101 Trautmann, D., 151 Trave, R., 51 Tresselt, D., 201, 258 Tri, M. V., 152 Trifilieff, E., 25 Tringali, C., 3, 57 Trivedi, G. K., 26, 27, 28, 56, 58, 87, 158, 232 Trivellone, E., 10 Trka, A., 215 Trost, B. M., 43, 133, 219, 226 Trown, P. W., 177 Truscott, T. G., 186, 187 Truter, V., 106 Tsatsas, G., 267 Tschesche, R., 104, 245, 256, 267 Tserng, K.-Y., 217 Tsita, P., 267 Tsubuki, M., 133 Tsuda, M., 185, 186, 188, 205, 217 Tsuda, T., 194 Tsuji, K., 186 Tsukida, K., 177, 178, 183 Tsutsumi, K., 73 Tsuyuki, T., 7, 80, 138, 153, 160 Tuinmann, A., 199, 259 Tumura, K., 262 TureEek, F., 209, 233 Turkes, A., 211 Turkes, A. O., 211 Turley, J. C., 125 Turner, A. B., 236 Turner, R. V., 189 Tursch, B., 10, 99, 104, 124 Turuta, A. M., 264 Uchida, M., 38, 69 Uchio, Y., 34

283

Author Index Uda, H., 111, 207 Uegaki, R., 168 Uemura, M., 116 Uhl, R., 186 Ujszlszy, K., 94 Ulubelen, A., 80 Umeda, M., 42 Unal, G. G., 111 Uneyama, K., 9, 78, 123, 181 Unsvuori, R., 138 Urones, J. G., 108, 110 Usubillaga, A., 118 Usui, S., 132 Uto, S., 34, 117 Uvarova, N. I., 142 Uyehara, T., 53 Uzawa, J., 47 Vadasz, A., 236 Vajs, V., 79 Valade, J., 116, 117 Valadon, L. R. G., 190, 191 Vallejo, M. N., 132 Valverde, S., 118, 120 Van, N. L., 17, 30, 57, 62 Vandemark, F. I., 212 Vanderah, D. J., 8, 104, 124 van der Helm, D., 12, 126, 169 van der Putten, N., 24 Van Derveer, D., 80 Van Dessel, G., 191 Vandewalle, M., 68, 89 van Duijn, D., 210 Vanell, L. D., 95 van Etten, A. B., 240 Van Holten, R. W., 186 Vani, G. V., 201 Van Lear, G., 137 Van Meerssche, M., 10, 89, 104, 201 Van Moorselaar, R., 176 Van Niekerk, J. C., 201 Van Rheenan, V., 254 van Schie, D. M. J., 128 Van Vliet, N. P., 221 Varon, Z., 144, 145, 153 Varshney, I. P., 158 VaSiEkovl, S., 94 Vecchio, G., 207 Veeravalli, J., 11 Velasco, J., 184 VelgovL, H., 215, 226 Velluz, A., 169 Venkor, A. P., 124 Venturella, P., 118 Vera, J., 187 Verma, A. K., 164 Verzar-Petri, G., 94 Vestergaard, P., 213 Vichnewski, W., 58, 114 Vidari, G., 44 Viger, A,, 206, 259 Vijayan, K., 201

Vilcins, G., 186 Viswanathan, N. I., 158 Vita-Finzi, P., 44 Vitolo, M. J., 265 Vocelle, D., 187, 188 Vogt, W., 218 Voigt, B., 205 Voigt, D., 121 Voigt, S., 135. 165 Vollmer, J. J., 10 von Carstenn-Lichterfelde, C., 108, 121 Votickq, Z., 71 Vrijhof, P., 254 VrkoC, J., 129 Vsevolodov, N. N., 186 Vyas, P., 158 VystrEil, A., 155, 157 Wachter, M. P., 107, 258 Wada, K., 122 Waddell, W. H., 187 Wagner, G., 188 Wagner, H., 158, 258 Waight, E. S., 119, 162 Wakamatsu, K., 26 Wakamatsu, T., 68 Walckhoff, B., 188 Walkup, R. D., 246 Wall, M. E., 152, 153 Walter, J. A., 203 Walton, D., 184 Wan, Y.-P., 193 Wang, A. H. J., 245 Wani, M. C., 152, 153, 266 Wannigama, G. P., 160 Ward, D. E., 128 Ward, E. W. B., 78 Ward, R. S., 28 Warnhoff, E. W., 204, 234, 237 Washitake, M., 179 Watanabe, F., 211 Watkins, S. F., 57, 62 Watson, C. W., 190 Watson, T. R., 236 Watson, W. H., 58, 94, 108, 114 Watt, D. S., 132, 219, 239 Weavers, R. T., 131 Weber, G. F., 174 Weber, S., 178 Wecksler, W., 253 Weedon, B. C. L., 164, 165, 173 Weeks, C. M., 200, 232 Wehrli, F. W., 106, 205 Weigel, H., 185 Weihe, G. R., 245 Weiler, L., 7, 136, 181 Weinheimer, A. J., 125 Weinstein, B., 146 Wellner, R. B., 191

Wells, R. J., 11, 106, 124, 127, 131, 246 Welmar, K., 104 Welzel, P., 207, 218 Wender, P. A., 89 Wenkert, E., 69, 115, 117, 156 Wesselman, P. G. J., 176 Wessling, B., 218, 247 West, J. L., 187 Whalley, W. B., 199, 201, 226,251 White, A. H., 109 White, D. N. J., 95 White, J. D., 181, 183 Whitfield, F. B., 169 Whybrow, D., 101 Wicha, J., 244 WidCn, K. G., 44 Wiechert, R., 220, 224, 227 Wieglepp, H., 265 Wieland, P., 226 Wightman, R. H., 225 Wightman, R. M., 173 Wild, U. P., 186 Wiley, R. A., 64 Wilkie, D. W., 167 Wilkie, J. S., 242 Wilkins, A. L., 163 Wilkinson, F., 187 Wilkomirski, B., 157 Williams, C. N., 212 Williams, D. J., 111 Williams, J. R., 29, 66 Williams, R. J. H., 165 Willis, B. J., 18 Willuhn, G., 95 Wilpart, M., 201 Wilshire, C., 230 Wilson, D. M., 205 Wilson, S. R., 71 Winkler, F. K., 200 Winter, M., 168, 169 Winternitz, F., 265 Witt, M. E., 57 Witteler, F.-J., 207 Woitke, H. D., 156 Wolf, H. R., 183 Wolf, J. F., 220 Wolff, M. E., 263 Wong, C.-M., 261 Wong, H. S., 174 Wong, M. S. F., 211 Woo, W. S., 158 Woodgate, P. D., 215, 218, 219,223,263 Woodlief, W. G., 183 Woodruff, W. H., 186 Woods, G. F., 255, 256 Woolard, G. R., 80 Wratten, S. J., 129 Wright, J. L. C., 203 WU, R.-Y., 153 Wuest, H., 73

Author Index

284 Wydra, R., 139 Yabuta,, G., 58 Yagi, A., 156 Yagihashi, F., 76, 78 Yahara, S., 143, 158 Yamada, K., 26, 80, 96, 97 Yamada, M., 21 Yamada, S., 251, 253 Yamada, Y., 142 Yamaguchi, M., 119 Yamakawa, K., 75, 83 Yamakawa, M., 185 Yamamoto, H., 5, 14, 17, 101, 142 Yamamoto, H. Y., 164, 190 Yamamoto, K., 133 Yamamoto, N., 186 Yamamura, K., 193 Yamamura, S.,51, 52, 53 Yamanaka, H., 139 Yamane, H., 121 Yamano, Y., 194 Yamaoka, T., 186 Yamasaka, K., 131 Yamasaki, K., 115 Yamashita, K., 181, 212 Yamauchi, S., 214

Yamauchi, T., 203 Yamisaki, Y., 158 Yanagiya, M., 32 Yanami, T., 86 Yang, Y.-L., 133 Yasuda, A., 5 Yasuda, S., 4 Yatagai, M., 115 Yatsunami, T., 124 Yeh, H. C., 114 Yo, E., 85 Yokio, T., 159 Yokota, T., 121 Yokoyama, Y., 153 Yokozawa, T., 142 Yonehara, H., 47 Yoshida, T., 38, 53, 128, 226 Yoshihira, K., 42 Yoshii, E., 262 Yoshikoshi, A., 73, 83, 86 Yoshioka, K., 259, 261 Yoshizawa, I., 236 Yoshizawa, T., 185, 186, 188 Yosioka, I., 139 Young, D. W., 215 Young, I. G., 194, 195 Young, N. M., 170 Young, P.-T., 114

Yue, H. J., 220 Yunusov, M. S., 124 Yunusov, S. Yu., 124 Zabel, V., 58, 93, 94, 114 Zainutdinov, U. N., 108 Zakaria, M., 183 Zalkow, L. H., 80 Zamek, Z., 80 Zaretskii, Z. V. I., 208, 209, 233 Zbozny, M., 37 Zdero, C., 3, 12, 28, 30, 49, 57, 62, 64, 67, 69, 71, 80, 95, 99, 100, 108, 117, 118, 120, 142 Zechlin, L., 141 Zeelan, F. J., 221 Zeigan, D., 204, 215 Zeisberg, R., 120 Zelnik. R., 114 Ziesche, J., 57 Zilenovski, J. S. R., 14 Zinsmeister, H. D., 100 Zitzkowski, P., 93, 114 Zocher, D. H. T., 116 Zutterman, F., 68 Zvonkova, E. N., 178