Terpenoids and Steroids: Volume 11 (SPR Terpenoids and Steroids (RSC))

Terpenoids and Steroids

Volume 11

A Specialist Periodical Report

Terpenoids and Steroids Volume 11

A Review of the Literature Published between September 1979 and August 1980

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

R. B. Boar Chelsea College, London G. Britton University of Liverpool 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 WIV OBN

British Library Cataloguing in Publication Data Terpenoids and steroids.-Vol. 11.(Specialist periodical report/Royal Society of Chemistry) 1. Terpenes-Periodicals 2. Steroids-Periodicals I. Royal Society of Chemistry 11. Series 547.7’1’05 QD416.Al ISBN 0-85186-346-9 ISSN 0300-5992

Copyright @ 1982 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 uction

This volume follows the pattern of the previous volumes in the series. The last volume suffered from the omission of a chapter on the monoterpenoids and an effort was made to remedy this. However, despite written assurances (September, 1980) of a contribution on the monoterpenoids, this has not been forthcoming and rather than delay publication any further, I decided reluctantly that production of this volume should go ahead without a chapter on the monoterpenoids. The rapid increase in the number of new structures is clearly apparent from reading the various chapters in this volume. However, some of these structures are proposed on the basis of very tenuous spectroscopic evidence and in some instances without complete purification. In situations where several related carbon skeleta are known, the assumption of an underlying skeleton for a natural product, followed by a spectroscopic argument for the relative disposition of the functional groups, is a procedure that is fraught with pitfalls. There is a very pressing need, particularly amongst the sesqui- and di-terpenoids, for a series of partial syntheses to establish inter-relationships which substantiate structural assignments.

J. R. HANSON

V

Contents

Part I Terpenoids 3

Chapter 1 Sesq u iterpenoids By J. S. Roberts 1 Farnesane

3

2 Mono- and Bi-cyclofarnesane

6

3 Bisabolane

10

4 Sesquipinane, Sesquicamphane

12

5 Cuparane, Laurane, Trichothecane

14

6 Chamigrane, Widdrane, Thujopsane

24

7 Acorane, Cedrane, Carotane, Zizaane

26

8 Cadinane, Cyclosesquifenchane, Cyclosativane, Picrotoxane

29

9 Himachalane, Longifolane

35

10 CarophyUane, Humulane, Hirsutane, Pentalenane, etc.

37

11 Germacrane

52

12 Elemane

66

13 Eudesmane

69

14 Vetispirane

75

15 Eremophilane, Nootkatane, Ishwarane

77

16 Guaiane, Pseudoguaiane, Patchoulane, Seychellane

79

17 Bicyclogermacrane, Maaliane, Aromadendrane

87

18 Miscellaneous

89 vii

...

Terpenoids and Steroids

Vlll

Chapter 2 Diterpenoids

91

By J. R. Hanson 1 Introduction

91

2 Alicyclic and Related Diterpenoids

91

3 Bicyclic Diterpenoids Labdanes Clerodanes

92 92 95

4 Tricyclic Diterpenoids

96

5 Tetracyclic Diterpenoids Kaurenoid Diterpenoids Beyerenes Atiserenes Gibberellins Grayanotoxins Diterpenoid Alkaloids

99 99 101 101 102 103 104

6 Macrocyclic Diterpenoids and their Cyclization Products

104

7 Miscellaneous Diterpenoids

105

8 Diterpenoid Total Synthesis

108

Chapter 3 Triterpenoids

110

By R. B. Boar 1 Introduction

110

2 Squalene Group and Triterpenoid Biosynthesis

110

3 Fusidane-Lanostane Group

113

4 Dammarane-Euphane Group Tetranortriterpenoids Pentanortriterpenoids Quassinoids

115 117 119 120

5 Lupane Group

122

6 Oleanane Group

125

7 Ursane Group

129

8 Hopane Group

131

9 Miscellaneous

132

Contents

ix

Chapter 4 Carotenoids and Polyterpenoids

133

By G. Britton 1 Carotenoids Reviews New Structures and Stereochemistry Carotenoids New Natural Products Related to Carotenoids Carotenoid-Protein Complexes Synthesis and Reactions Carotenoids Retinoids Other Carotenoid-like compounds Physical Methods Separation and Assay Chiroptical Methods N.M.R. Spectroscopy X-Ray Crystallography Electronic Absorption Spectroscopy Infrared and Raman Spectroscopy Other Spectroscopic Techniques Miscellaneous Physical Chemistry Photoreceptor Pigments Biosynthesis and Metabolism Reviews Reactions, Pathways, and Cell-free Systems Inhibition and Regulation Metabolism

133 133 133 133 136 137 137 137 142 146 151 151 152 153 153 153 154 154 155 155 156 156 156 157 158

2 Polyterpenoids and Quinones Polyterpenoids Isoprenylated Quinones Chemistry Biosyn thesis

158 158 160 160 162

Part I/ Steroids Chapter 1 Physical Methods

165

By D.N. Kirk 1 Structure and Conformation

165

2 N.M.R. Spectroscopy 'H and 2H Spectra 13 C Spectra 19 F Spectra

171 171 174 176

Terpenoids and Steroids

X

3 Chiroptical Phenomena and U.V. Spectra

176

4 Mass Spectrometry

180

5 Gas Chromatography and Gas Chromatography-Mass

Spectrometry

182

6 High-pressure Liquid Chromatography

183

7 Immunoassay of Steroids

184

8 Miscellaneous

185

Chapter 2 Steroid Reactions and Partial Syntheses

187

By B. A. Marples Section A: Steroid Reactions

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

187 187 189 189 190

2 Unsaturated compounds Electrophilic Addition Other Addition Reactions Other Reactions of Unsaturated Steroids

190 190 191 192

3 Carbonyl Compounds Reduction Other Reactions Reactions Inolving Enols or Enolic Derivatives Oximes, Semicarbazones, Hydrazones, and Related Derivatives

193 193 194 195

4 Compounds of Nitrogen and Sulphur

197

5 Molecular Rearrangements

199

Backbone Rearrangements and Double Bond Isomerizations Miscellaneous Rearrangements

197

199 20 1

6 Functionalization of Non-activated Positions

207

7 Photochemical Reactions

208

Section B: Partial Syntheses 8 Cholestane Derivatives and Analogues

210

9 Vitamin D, Its Metabolites, and Related Compounds

216

xi

Contents

10 Pregnanes

217

11 Androgens and Oestrogens

219

12 Cardenolides and Bufadienolides

222

13 Cyclo-steroids and Seco-steroids

223

14 Heterocyclic Steroids

225

15 Microbiological Transformations

227

16 Miscellaneous Syntheses

228

Author Index

229

Part I TERPENOIDS

Sesquiterpenoids BY J. S . ROBERTS

1 Farnesane The continuing search for new marine natural products has led to the discovery of the farnesic acid glycerides (1)-(3) in the nudibranch Archidoris odhneri' and the two hydrocarbons (4)and ( 5 ) from the gorgonian Plexaurella grisea Kunze.2 Other new farnesyl/nerolidyl sesquiterpenoids include (6)-(1 1)3-5 and the interesting acetal eremoacetal (12) from Eremophila rotundifolia.6

(1) R' (2) R' (3) R'

= = =

R2 = H H,R' = AC Ac,R2 = H

A

R'

'

R2

(9) R' = Me,R2 = CH,OAng (10) R' = Me, R2 = CH2OH (11) R' = CH20H, R2 = Me R. J. Andersen and F. W. Sum, Tetrahedron Lett., 1980, 21, 797. Y. Gopichand, F. J. Schmitz, and P. G. Schmidt, J. Org. Chem., 1980,45, 2523. F. Bohlmann and C. Zdero, Phytochemistry, 1980,19, 149. F. Bohlmann, U. Fritz, and L. Dutta, Phytochemistry, 1980,19,841.

' F. Bohlmann and C. Zdero, Phytochemistry, 1980, 19, 587. ' E. Dimitriadis and R. A. Massy-Westropp, Aust. J. Chem., 1979, 32, 2003. 3

Terpenoids and Steroids

4

Epi-7-hydroxymyoporone (13) has been synthesized by a route which makes use of the dianion (14) as a crucial intermediate.' Dendrolasin (15) has been prepared by reaction of homogeranyl iodide with lithium di-(3-furyl)~uprate.~

, Li

phseYG

P-Sinensal (18) and p-farnesene (19) have both been synthesized from the thioncarbamate (16), which undergoes a [3,3] sigmatropic rearrangement to produce the allylic thiolcarbamate (17) (Scheme lh9 The Grignard reagent

R (16)

(17)

(18) R = CHO (19) R = Me

Reagents: i, A; ii, LDA-Me,S,; iii, HgCI,; iv, LiAIH,-CuCI, Scheme 1

from homogeranyl bromide has been added to 3-methyl-P-propiolactone in the presence of copper(1) iodide to produce dihydrofarnesic acid (20) which could be elaborated in two steps to farnesol."

(20)

One mechanism which has been advanced for the 1 ' 4 condensation between isopentenyl pyrophosphate and an allylic pyrophosphate is that shown in Scheme 2. This mechanism involves an enzyme-assisted coupling with nucleophilic attack at C-3 followed by a subsequent elimination reaction. By

lo

H. J. Reich, P. M. Gold, and F. Chow, Tetrahedron Lett., 1979,4433. Y. Kojima, S. Wakita, and N. Kato, Tetrahedron Lett., 1979, 4577. T. Mimura, Y. Kimura, andT. Nakai, Chern. Lett., 1979,1361. T. Fujisawa, T. Sato, T. Kawara, A. Noda, and T. Obinata, Tetrahedron Lett., 1980, 21, 2553.

Sesquiterpenoids

5

R

OPP

Scheme 2

using 2-fluoroisopentenyl and 2,2-difluoroisopentenyl pyrophosphate as substrates Poulter and Rilling" sought to intercept an X-containing intermediate (either bound or unbound to avian liver farnesyl pyrophosphate synthetase). In neither case was this detected and hence it is suggested that the X-group mechanism is an unlikely process (see Ref. 12 for a comprehensive review of allylic pyrophosphate metabolism). In a continuing investigation of the substrate specificity of farnesyl pyrophosphate synthetase, Ogura et al.l 3 have studied the enzyme-catalysed condensation of homologues of isopentenyl pyrophosphate (21) with dimethylallyl and geranyl pyrophosphate. As a result of varying the

R 2 +(, 2[H20pp , R3 (21) R'

=

Me,R2

=

R3 = H , n

=

1

parameters R'-R3 and n, it has been shown that for pig liver farnesyl pyrophosphate synthetase R' can be Me or Et, R2 and R3 can be H, Me, or Et, R' and R2can be part of a five- or six-membered ring system, and n should be 1 or 2. A method for the asymmetric synthesis of R-(-)-[1 -*H]farnesol has been described, based on the reduction of [l-2H]farnesal with the optically active hydride reagent (22).14 The cyclic analogue (23) of juvenile hormone-I1 has been synthesized starting from R- ( + ) - I i m ~ n e n e . 'This ~ compound is less active than the natural hormone.

Li[g:;A

*-,@ OzMe

\

/

(22) l2 l3

l4 Is

0

(23)

C. D. Poulter, E. A . Mash, J . C. Argyle, 0. J . Muscio, and H. C. Rilling, J. Am. Chem. Soc., 1979,101,6761. D. E. Cane, Tetrahedron, 1980, 36, 1109. T. Koyama, A. Saito, K. Ogura, and S. Seto, J. A m . Chem. SOC.,1980,102, 3614. M. Nishizawa and R. Noyori, Tetrahedron Lett., 1980, 21,2821. C. Wawrzenczyk and A. Zabza, Tetrahedron, 1980, 36, 3091.

Terpenoids and Steroids

6

2 Mono- and Bi-cyclofarnesane Full details of the structural determination of nigakialcohol (24) have been published.16 Co-occurring with aplysistatin (25) in Laurencia cf. palisada Yamada are the marine sesquiterpenoids palisadin A (26) and B (27), 5 acetoxypalisadin B (28), 12-hydroxypalisadin B (29), and palisol (30).17 3pBromo-8-epi-caparrapi oxide (32) has been synthesized by a procedure which

0

QdOH / *;, Br

0

OH (24)

Br

H (25) R = 0 (26) R = H2

RZ (27) R' (28) R' (29) R'

=

= =

R2 = H H , R 2 = OAc O H , R2 = H

involves brominative cyclization of the hydroxy-ester (31) as a key step.18 The marine sesquiterpenoid (33), in which a methyl migration has taken place, has All eight racemic diastereoisomers of the marine been synthesized in four metabolite dactyloxene-B have been synthesized and this work shows that natural dactyloxene-B has the relative configuration (34) whereas dactyloxene-C is considered to be (35).20Interestingly all eight compounds have individually

different odours. In a related area of olefaction eight stereoisomeric sesquirose oxides, which have yet to be discovered in nature, have been synthesized.21 These compounds correspond to the eight possible stereoisomers (36) according to the chiralities at C-2 and C-4 and to the E / Z configuration of the A7p8-do~ble l6

l7

l9 2o

21

Y. Sugimoto, T. Sakita, T. Ikeda, Y. Moriyama, T. Murae, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC.Jpn., 1979,52,3027. V. J. Paul and W. Fenical, Tetrahedron Lett., 1980, 21, 2787. T. R. Hoye and M. J. Kurth, J. Org. Chem., 1979,44, 3461. W. Oppolzer, P. H. Briner, and R. L. Snowden, Helu. Chim. Actu, 1980,63,967. B. Maurer, A. Hauser, W. Thommen, K. H. Schulte-Elte, and G. Ohloff, Helu. Chim. Actu, 1980, 63,293. G. Ohloff, W. Giersch, R. Decorzant, and G . Buchi, Helu. Chim. Actu, 1980, 63, 1589; G. Ohloff and W. Giersch, ibid., p. 1598.

7

Sesquiterpenoids

bond. The same authors have also methodically synthesized eighteen sesquiterpenoid theaspirane derivatives, of which (37)-(39) are representative examples.22

New drimane sesquiterpenoids include polyonal (40), isodrimeninol (41) (from the seeds of Polygonurn h y d r ~ p i p e r ) uvidin , ~ ~ A (42), uvidin B (43) (from Lactarius uuidus and 7a,8P,11- trihydroxydrimane (44) (from Fornes a n n o s ~ s )Three . ~ ~ new indolosesquiterpenoids, polyavolensin (43,polyavolensinol (46), and polyavolensinone (47), have been identified in the stem extract of Polyathia suaveo1ens.26

(42) R (43) R

(44)

22

= =

H OH

R (45) R

=

Ac

(46) R (47) R

= =

H

=O

K. H. Schulte-Eke, T. Umiker, and G . Ohloff, Hefu. Chim. Actu, 1980,63, 284.

24

Y.Asakawa and T. Takemoto, Experientia, 1979,35, 1420. M.De Bernardi, G . Mellerio, G . Vidari, P. Vita-Finzi, and G . Fronza, J. Chem. Soc., Perkin Truns.

25

I , 1980,221. D. M. X. Donnelly, J. O’Reilly, A. Chiaroni, and J. Polonsky, J. Chem. Soc., Perkin Truns. 1,

26

D. A. Okorie, Tetrahedron, 1980,36, 2005.

23

1980,2196.

8

Terpenoids and Steroids

A second synthesis of the marine sesquiterpenoid pallescensin A (49) has been achieved by acid-catalysed cyclization of the furanodiene (48).27Continued

(49)

(48)

interest in the synthesis of warburganal (52) has resulted in two very similar syntheses (Scheme 3). In both cases the troublesome step was the homologation of the bicyclic keto-aldehyde (50). In Kende's synthesis28 this was solved by using the Magnus reagent, lithium methoxy(trimethylsilyl)methylide,which ultimately led to both warburganal (52) and isotadeonal ( 5 1).In the other synthesis by Goldsmith29 the extra carbon was introduced by methyl-lithium followed by dehydration with the Burgess reagent. .Additional routes to confertifolin (53),

@'"" 0

0 . ..

iii-v

vi-Y

bi-xiii

lx CHO

(51) Reagents: i, HC0,Et-NaH; ii, DDQ; iii, HO(CH,),OH-PTSA; iv, MeLi; v, Me02CNS0,NEt,Et,N; vi, HO(CH,),OH-PTSA; vii, MeOCHLiSiMe,; viii, KH; ix MCPBA; x, H,O+; xi, OsO,-py; xii, Me,SO-py-CF,CO,H-DCC; xiii, PTSA-acetone

Scheme 3 27

'*

29

D. Nasipuri and G. Das, J. Chem. SOC.,Perkin Trans. 1, 1979,2776. A. S. Kende and T. J. Blacklock, Tetrahedron Lett., 1980, 21, 31 19. D. J. Goldsmith and H. S. Kezar, 111, Tetrahedron Left., 1980,21, 3543.

9

Sesquiterpenoids

isodrimenin (54),30 cinnamodial ( 5 5 ) , and cinnamosmolide (56)" have also been reported.

The dihydro-derivative (58) of the unique sesquiterpenoid spiniferin-1 (57), which incorporates the novel 1,6-methano[ lolannulene skeleton, has been synthesized (Scheme 4) and this confirms beyond doubt its precise 0

I

(58) Reagents: i, MeLi; ii, Na-NH,-EtOH; iii, H,O'; iv, Me,CuLi; v, NaBH,; vi, Zn/Cu-CHJ,; vii, Cr0,-H'; viii, HC0,Et-NaOMe; ix, DDQ; x, H'; xi, MeI-K,CO,; xii, MeOCH=PPh,

Scheme 4

30 31

32

H. Akita, T. Naito, and T. Oishi, Chem. Lett., 1979,1365.

T.Naito, T. Nakata, H. Akita, and T. Oishi, Chem. Lett., 1980,445. J. A. Marshall and R. E. Conrow, J. A m . Chem. SOC.,1980,102,4274.

Terpenoids and Steroids

10

3 Bisabolane New bisabolane sesquiterpenoids include (59),33(60),34and the perezone derivatives (61)-(63).35 Based on mass spectral evidence structures (64) and (65) have been assigned to two minor constituents of Chinese cinnamon oil; both ketones have been synthesized from a-c ~ r c u m e n eDihydroxydeodactol(66), .~~ a derivative of deodactol, has been isolated from the mollusc Aplysia d a ~ t y l o m e l aA .~~

(62) R' (63) R'

= =

H , R 2 = Ang Ang,R2 = H

related metabolite, 8-desoxy-isocaespitol (67), is a minor constituent of the marine alga, Laurencia ~ a e s p i t o s aThis . ~ ~ compound has been synthesized from farnesol acetate in low yield (Scheme 5 ) .

ii. iii

Br

OAc

HO

OAc

(67)

c1

Reagents: i, NBS; ii, LiC10,-Ac,O-AcOH; iii, BrCl

Scheme 5

A careful study of the mechanism of the oxy-Cope rearrangement of 1,5-diene alkoxides has provided a neat synthesis of erythro-juvabione (68) (Scheme 6). This has shown that the [3,3] sigmatropic process proceeds in a concerted fashion predominantly via a chair transition state. F. Bohlmann, K.-H. Knoll, R. M. King, and H. Robinson, Phyrochemistry, 1979, 18, 1997. F. Bohlmann, L. Dutta, H. Robinson, and R. M. King, Phyrochemistry, 1979,18, 1889. 35 F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phyrochemistry, 1979, 18, 1894. 36 A. F. Thomas, Helu. Chim. Actu, 1980, 63, 1615. '' F. J. Schmitz, D. P. Michaud, and K. H. Hollenbeak, J. Org. Chem., 1980, 45, 1525. 38 A . G. Gonzalez: J. D. Martin, C. Ptrez, M. A . Ramirez, and F. Ravelo, Tetrahedron Lett., 1980, 21, 187. 39 D. A . Evans and J. V. Nelson, J. A m . Chem. Soc., 1980,102,774. 33

34

11

Sesquiterpenoids

Q

C0,Me

vii, viii

H C0,Me ,

iv-vi

e--

H

t

C0,H

H

H

Ht

OMe

C0,Me

H

/ OMe

1

% ix, x

H

(68) Reagents: i, KH, 110°C; ii, CO(OMe),-NaH; iii, H , N - N L P h ; vii, H,O'; viii, Cr0,-H'; ix, (COCI),; x, Bu',Cd

iv, LDA; v, H'; vi, NaOMe;

Scheme 6

A number of relatively short and straightforward syntheses of bisabolane sesquiterpenoids have been reported; these include E- and 2 - a - bisabolene, (69) and (70) (together with the isopropenyl analogue^),^' a-curcumene (71),41*42 P-curcumene (72),41ar- turmerone (73),41*43 iso-a-curcumene (74),42*44

(70) *O

41

42 43 44

M. Becker and P. Weyerstahl, Helv. Chim. Acta, 1979,62, 2724. H. H. Bokel, A. Hoppmann, and P. Weyerstahl, Tetrahedron, 1980, 36, 651. P. N. Chaudhari, Bull. SOC.Chim. Fr., Phrt2, 1979,429. T. Sato, T. Kawara, A. Nishizawa, and T. Fujisawa, Tetrahedron Lett., 1980, 21, 3377. T. Kametani, M. Tsubuki, and H. Nemoto, J. Chem. SOC.,Perkin Trans. 1, 1980, 759.

12

Terplnoids and Steroids

(73)

(72)

(74)

(75)

and delobanone (75).45Last year a synthesis of (-)-a- bisabolol(76) was reported in which intramolecular 1,3-dipolar addition of a nitrone of 62-farnesal was used as a key step (Vol. 10, p. 13).This route has been achieved i n d e ~ e n d e n t l y , ~ ~ thus confirming the structure of a- bisabolol. Compound (77) and its oxidation ; ~ ~former is the product (78) have been prepared from R- ( + ) - ~ i t r o n e l l a lthe enantiomer of a naturally occurring enone and the latter is identical to a metabolite from the plant Lasianthaea podocephala and the coral Pseudopterogorgia rigida.

4 Sesquipinane, Sesquicamphane The two a-santalene derivatives (79) and (80) are constituents of the aerial parts o f Ayapana ~ r n y g d a l i n a(+)-Epi-cis-P-santalol .~~ ( 8 1 ) has been identified as a new minor component of East Indian sandalwood oil. Treatment of (+)a-santalyl acetate (82) with hydrogen chloride followed by dehydrochlorination with basic alumina produces a mixture of 0-santalyl acetate (83) and the acetate of (81).48Last year Christenson and Willis reported the acid-catalysed rearrange-

(79) R' (80) R' " 46 47

48

= =

C 0 2 H , R 2 = R3 = Me R3 = C02H, R3 = Me

I (81)

L. M. Harwood and M. Julia, Tetrahedron Lett., 1980, 21, 1743. T. Iwashita, T. Kusurni, and H. Kakisawa, Chem. Lett., 1979, 947. E. L. Ghisalberti, P. R. Jefferies, and A. D. Stuart, Aust. J. Chem., 1979, 32, 1627. E. J. Brunke, F.-J. Hammerschrnidt, and H. Struwe, Tetrahedron Lett., 1980, 21, 2405.

13

Sesq uiterpen oids

ment of (84) to give (85) (Vol. 10, p. 18). In an attempt to intercept the rearranged cationic intermediates in this process, the rearrangement has now . ~ ~ bicyclic ester-amides been carried out in the presence of a ~ e t o n i t r i l eThree (86)-(88) were isolated after esterification. The major isomer (86) undergoes a retro-Ritter reaction with toluene-p-sulphonyl chloride in pyridine to produce the esters (89) and (90) in a ratio of 2 3 : 2 . The ester (89) serves as a useful precursor to epi-P-santalene (91), epi-cis-P-santalol (81), epi-trans-P-santalol (92), and dihydroepi-P-santalo1(93),and (90) can be converted into a-santalene (94).

FtC

,

49

(91) R = H (92) R = OH

P. A. Christenson and B. J. Willis, J. o r g . Chem., 1980,45, 3068.

14

Terpenoids and Steroids

5 Cuparane, Laurane, Trichothecane A short synthesis of the ketone (95) has been and this constitutes a formal synthesis of cuparene (96), since (95) has been converted into (96) previously. As an alternative strategy to the cuparane skeleton a three-carbo‘n

annulation process has been applied to the synthesis of cuparenone (99) (Scheme 7).” A more direct approach involving an initial Diels-Alder reaction between (97) and the olefin (100) failed because of steric hindrance. Another synthesis of the cuparenone precursor (98) involves Friedel-Crafts acylation Me0

CI

OMe

Me0

OMe

0

OAc

(97)

lv

0

,fi hOH

t

t

CiH Me - p

Ck H Me - p

(99)

(98)

Reagents: i, A; ii, K,CO,-MeOH; viii, Ref. 51

MeoVoMe

0

iii, Li-NH,-EtOH;

C,H4 Me - p

iv, PCC; v, p-tolyl-Li; vi, KMnO,; vii, H,O’;

Scheme 7

of E- 1- trimethylsilyl-2-(4-methylphenyl)ethene with p,p- dimethylacryloyl chloride in the presence of aluminium chloride to afford (101). Acid-catalysed cyclization of (101) with boron trifluoride etherate produces the enone (98) in rather low yield.’* Reduction of the tosylhydrazone of the aldehyde (102) with

M. E. Jung and C. D. Radcliffe, Tetrahedron Lett., 1980,21,4397. ”

A.Casares and L. A. Maldonado, Synth. Commun., 1976,6,11. L. A. Paquette, W. E. Fristad, D. S. Dime, and T. R. Bailey, J. Org. Chern., 1980,45,3017.

15

Sesquiterpenoids

catecholborane followed by treatment with sodium acetate yields both laurene (103) and itsepimer (104) in the ratio of 65 : 35.53

The red algal genus Laurencia is a rich source of halogenated sesquiterpenoids. Further work in this area has resulted in the identification of the first examples of iodinated sesquiterpenoids, namely the laurene derivatives (105) and (106) which co-occur with (107).54The Japanese varieties of Laurencia are Br

also well endowed with related compounds as revealed by the isolation of (108)-(112), the first three being metabolites of L. glandulifera Kutzing” and the last two being extracted from L. okamurui Yamada.56

HO (108) R’ = R2 = Br (109) R’ = Br, R2 = H (110) R’ = H , R 2 = Br

R’

0‘

(111) R = H (112) R = Br

Both (-)-aplysin (117) and (-)-debromoaplysin (116) have been synthesized (Scheme 8).57The initial step involves the coupling of the chlorocyclopentenone (114) with the optically active metalated bromo-ether (113), which was derived from (+)-a-pinene. This reaction produces (115) together with the diastereoisomeric chlorohydrin. In another synthesis of aplysin (117) (Scheme 9) the key step is the acid-catalysed rearrangement of the trichothecane-type ” 54

55

56 57

D. F. Taber and J. M. Anthony, Tetrahedron Lett., 1980, 21, 2779. R. R. Izac and J. J. Sims, J. A m . Chem. SOC.,1979,101,6136. M. Suzuki and E. Kurosawa, Bull. Chem. SOC.Jpn., 1979, 52, 3349. M. Suzuki and E. Kurosawa, Bull. Chem. SOC.Jpn., 1979, 52,3352. R. C. Ronald, M. B. Gewali, and B. P. Ronald, J. Org. Chem., 1980, 45, 2224.

16

Terpenoids and Steroids

Li

b O - O @

'

(113) (115)

'

li

(117)

(114)

Reagents: i, KOH-MeOH; ii, PCl,; iii, MeMgBr; iv, (PPh,),RhCI; v, Pt-H,-EtOH; vi, Br,-Na,CO,

Scheme 8

ii

Br

\

Br

\

c1

Q \

Br

1

iii

Br

\

Br

Reagents: i, SO,CI,; ii, DBN; iii, CH,=PPh,; iv, MCPBA; v, PTSA; vi, [HI; vii, Pt-H,-EtOH Scheme 9

17

Sesquiterpenoids

precursor (118).58Interestingly the corresponding epoxide (119) undergoes an acid-catalysed aryl migrat.ion to yield (120). Hydrogenation of (118) affords filiformin (121). New trichothecane sesquiterpenoids include trichodermadiene (12 2 y 9 satratoxin F (123), and satratoxin G (124).60An X-ray analysis has established the absolute configuration of verrucarin B (125).61This result means that the

\

==J

OfJ 0.-

0 0

0 H

(123) R (124) R

=

=

0 H,OH

process of conversion of mevalonic acid (126) into verrucarinic acid (128) via 2S,3R-2,3-epoxyanhydromevalonicacid (127) is placed on a firm footing (Scheme 10).

HO

HO

Scheme 10

58 s9

6o

D. J. Goldsmith, T. K. John, C. D. Kwong, and G . R. Painter,-111,J. Org. Chem., 1980.45, 3989. B. B. Jarvis, J. 0. Midiwo, and E. P. Mauola, Tetrahedron Left., 1980, 21, 787. R. M. Eppley, E. P. Mazzola, M. E. Stack, and P. A. Dreifuss, J. Org. Chem., 1980,45, 2522. W. Breitenstein, C. Tamm, E. V. Arnold, and J. Clardy, Helv. Chim. Acra, 1979, 62, 2699.

18

Terpenoids and Steroids

The wide range of important biological properties of a number of trichothecane sesquiterpenoids has stimulated a considerable flurry of synthetic interest in this area. An important paper in this context describes the facile conversion of anguidine (129), a readily available fermentation product, into verrucarol (130) and trichodermol (131) (Scheme 11).62"In a new approach to the synthesis of H

H -

Reagents: i, PhCONMe,-COCl,; ii, H,S-py; iii, Bu,SnH; iv, NaOMe; v, ClSiMe,Bu'-Et,N; Ac,O-py; vii, Bu,NF; viii, MsCl

vi,

Scheme 11

trichodermol (13l ) , Still and T ~ a have i ~ ~constructed a bicyclic intermediate (132) with the correct relative stereochemistry by a Diels-Alder reaction followed by a subsequent P-oxido fragmentation (Scheme 12). Acid-promoted diol formation of (133) followed by an intramolecular Michael addition was used to form the tricyclic precursor (134) of trichodermol. A different strategy has been used by Roush and D'Ambra64 in the synthesis of 13,14-dinor-15hydroxytrichothec-9-ene (135) (Scheme 13). Aromatic analogues of trichothecenes have also been synthesized and these include (136)-( 138).65*66 Compound (137) shows significant cytotoxicity in the 9KB assay and antileukaemic activity in the P388 assay. Model studies in trichothecane synthesis have also been reported in which the tricyclic ether (141) was elaborated from the tricarbonyliron complex (140), which, in turn, was obtained from the reaction of the salt (139) with the potassium enolate of methyl 2-oxocyclopentane~arboxylate.~'Treatment of the secondary alcohol derived from (140) with dehydrated ferric chloride on silica gel results in an oxidative cyclization to give (142).68 ( a ) D. B. Tulshian and B. Fraser-Reid, Tetrahedron Lett., 1980, 21, 4549; ( b ) D. H. R. Barton and S. W. McCombie, J. Chem. SOC.Perkin, Trans. 1, 1975, 1574. 63 W. C. Still and M.-Y. Tsai, J. A m . CFem. Soc., 1980, 102, 3654. 64 W. R. Roush and T. E. D'Ambra, J. Org. Chem., 1980,45,3927. 65 W. K. Anderson and G. E. Lee, J. Org. Chem., 1980,45,501. 66 W. K. Anderson and G. E. Lee, J. Med. Chem., 1980,23,96. 67 A . J. Pearson and P. R. Raithby, J. Chem. SOC.,Perkin Trans. 1, 1980, 395. " C. W. Ong and A . J. Pearson, Tetrahedron Lett., 1980, 21, 2349. 62

19

Sesq u ite rpen oids

1

.. ...

11, I l l

iv, v t

o %

A viii, xi

-

o %

xii

&

0SiMe B u'

oQoH OH

0,CPh ( 1 32)

OH (133)

(134)

1

xiii, vi, xiv

e xv-xvii --

OH

Q 02CPh

Reagents: i, Bu'OOH-Triton B; ii, NaOH-EtOH; iii, Li-NH,-EtOH; iv, Ac,O-py; v, hv, HMPA; vi, PhCOCI-py; vii, Bu,NF; viii, K,CO,-MeOH; ix, MsCl-Et,N; x, NaH; xi, Bu'OOHVO(acac),; xii, H,O'; xiii, MeLi; xiv, CrO,.py,; xv, POC1,-py; xvi, CH,=PPh,; xvii, MCPBA

Scheme 12

20

Terpenoids and Steroids

1

iii, iv

C:*

THPO'

ix

.OH

-

HO'H

THPO'

(135) Reagents: i, MCPBA-NaHCO,; HS(CH,),SHBF,; vi,

0

ii,

HC0,Bu'-KOBu';

iii,

MVK-KOBu';

iv, NaBH,;

- H+;vii, Bu',AlH; viii, NBS-collidine; ix, KOH-MeOH; x Scheme 13

Me0

Me0

(136) R (138) R

= =

'R OAc H

(137)

v,

MeLi; xi, H,O'

Sesquiterpen oids

21

Within the space of two months, no fewer than five independent syntheses of the liverwort sesquiterpenoid gymnomitrol (144)have been r e p ~ r t e d . ~ ~ - ~ ~ This must constitute some kind of record. In three of the s y n t h e ~ e s ~the ~ -key ~~ building block was the known bicyclic ketone (143)and from that point the three syntheses converged to gymnomitrol (144)(Schemes 14-16). In the 0

0

@$

xii, xiii,

OH

(144) +

Reagents: i, HO(CH,),OH-H'; ii, N,H,-KOH; iii, H,O'; iv, trioxan-PhNH,Me.CF,CO;; v, SiMe,CuBr.Me,S; vi, MeI-HMPA; vii, MCPBA; viii, H,O+-MeOH; ix, BrMg .% aq. KOH; x, 00,-H'; xi, MeLi; xii, POCI,-py; xiii, LiAlH,

-mo do Scheme 1469

(143)

i-iii

&Et

__* iv,v

xii, xiii VIII-XI

0

xiv

&To

5

e px,xvi,xvii

e--

(144)

---_

0 Reagents: i, (Me,Si),NLi; ii, (EtO),POCI; iii, H,-Pt/C; iv, HC0,Et-NaH; v, NH,OH-NaOMe; vi, CH,=CHCH(OEt),, A; vii, HO(CH,),OH-H'; viii, Li-NH,; ix, Me,SiCl; x, MeLi; xi, MeI; xii, H,O'; xiii, Cr0,-H'; xiv, Ac,O-HCIO,; xv, Bu',AIH; xvi, POC1,-py; xvii, LiAIH, Scheme lS70 69 Y.-K. Han and L. A. Paquette, J. Org. Chem., 1979,44, 3781. 'O R. M. Coates, S. K.Shah, and R. W. Mason, J. Am. Chem. SOC.,1979,101,6765.

Terpenoids and Steroids

22

(143) +

1

ii, iii

Reagents: i, MeI-NaH; ii, (i-C5H,,),BH; iii, H,O,-OH-; iv, Cr0,-H'; vii, Bu'Me,SiCl; viii, NaBH,; ix, H,C=CMe(OMe)-POCl,; xii, H 3 0 + Scheme 16'l

v, CH,N,; vi, (Me,Si),NLi; x, Bu,NF; xi, CH,=PPh,;

0""' OoMe OMe

OMe

Me0

Me

+ . I1..

OMe

~

I,

\

CHO

OH

0 ,

(145) liv, v

Reagents: i, MCPBA; ii, KOH; iii, DDQ-MeOH; iv, vii.

a

(147)

SnCI,; v, NaBH,; vi, H,-Pd/C;

*amphorsulphonic acid; viii, Ca-NH,; ix, CH,=PPh,; X,H,O+

Scheme 1772 "

S.C. Welch and S . Chayabunjonglerd, J. A m . Chem. SOC.,1979,101,6768.

"

G. Buchi and P.-S. Chu, J. A m . Chem. SOC.,1979,101,6767.

23

Sesquiterpenoids

fourth ~ynthesis’~ (Scheme 17) the crucial step was the acid-catalysed addition of the p-quinone acetal (145) to 1,2-dimethylcyclopentene to produce, after borohydride reduction, the diastereoisomeric tricyclic compounds (146) and (147). Finally, the fifth ~ynthesis’~ (Scheme 18) hinged upon the rearrangement

1

iv-vi

1

1

xii

ix

I

xiv,xv

Reagents: i, A; ii, BBr,; iii, LiAIH,; iv, MsCI-py; v, Na,S; vi, Li-EtNH,; vii, HI; viii, SiO,; ix, MeMgI; x, SOCI,-py; xi, POC1,-py; xii, MCPBA; xiii, Al,O,; xiv, Cr0,-H’; xv, Ref. 70

Scheme 73

M. Kodama, T. Kurihara, J. Sasaki, and S. It6. Can. J. Chem., 1979,57, 3,343.

Terpenoids and Steroids

24

of the tricycl0[5.2.2.O~*~]undecyl compounds (149) and (150) to produce the tricyclo[5.3.1.02~6]undecylprecursors, (151) and (152), of gymnomitrol (144) as well as a-(153) and f3-barbatene (154). In a more recent paper74the trio1 (148) has been converted into bazzanene (155),which is considered to be the biogenetic precursor of the gyrnnornitrane class of sesquiterpenoids (Scheme 19).

1

111, LV

...

\

OH

'

\

0,CPh

Reagents: i, PhCOCI-py; ii, NaOH-MeOH; iii, MsCI-py; iv, KOBu'; v, CH,=PPh,; vii, CrO,; viii, N,H,-KOH

vi, Na-BuOH;

Scheme 19

6 Chamigrane, Widdrane, Thujopsane As mentioned earlier the Laurencia algae provide a rich source of halogenated sesquiterpenoids whose various carbon skeletons are related by biogenetically plausible rearrangement^.^^ Since the inter-relationships cannot be directly studied by proper biosynthetic methods the next best criterion for the validity of the postulated schemes is to study in vitro rearrangements which might simulate the in vivo pathways. To this end a number of biogenetically motivated transformations have been examined recently (Scheme 20).76These include the rearrangement of obtusane (156) into (+)-isobromocuparane (157) and subsequently into (+)-isolaurene (158); the conversion of obtusol (159) and perforene (160) into the perforane-type compound (161), the obtention of perforene (160) from (162) and perforenol (163), and the isomerization of (164) into the naturally occurring alcohol (165). The absolute stereochemistry of obtusol(l59) has been verified by X-ray crystallographic analysis.77 Two additional chamigrane-type metabolites from Laurencia nipponica Yamada are (166) and (167)," which co-occur with pacifenol (168). A full report on the structure of 74 75

76

77

M. Kodama, T. Takahashi, T. Kurihara, and S. Itb, Tetrahedron Lett., 1980,21,2811. T. Suzuki, A. Furusaki, N. Hashiba, and E. Kurosawa, Tetrahedron Lett., 1977,37. A. G.Gonzalez, J. Darias, J. D. Martin, V. S. Martin, M. Norte, C. PCrez, A. Perales, and J. Fayos, Tetrahedron Lett., 1980,21, 1151. A. Perales, M. Martinez-Ripoll, and J. Fayos, Acta Crystallogr., 1979,B35,2771. T.Suzuki, Chem. Lett., 1980,541.

25

Sesquiterpenoids

Br

Br

H0'

(1 64)

(165)

Reagents: i, H'; ii, SO,;iii, Zn-AcOH; iv, AcOH-LiCIO,

Scheme 20

(167) R (168) R

= OH = C1

spirolaurenone (169) and the biogenetically significant rearrangement of the naturally occurring glanduliferol (170) to spirolaurenone with silver oxide has appea~ed.'~ The marine sesquiterpenoid kylinone (17 l), with a new carbon skeleton, has been identified as a constituent of the red seaweed Laurencia pacifica." It co-occurs with aplysin (1 17), debromoaplysin (1 16), pacifenol(168), 79

M. Suzuki, N. Kowata, and E. Kurosawa, Tetrahedron, 1980,36, 1551. S. J. Selover and P. Crews, J. Org. Chem., 1980,45, 69.

26

Terpenoids and Steroids

and pacifidiene (172). Kylinone (171) can be obtained by treatment of deoxyprepacifenol (173) with boron trifluoride etherate, thus suggesting a biogenetic link between the two compounds. Photolysis of widdrol hypoiodite (generated in situ with the alcohol, iodine, and mercuric oxide) yields the bicyclic ether (174) in high yield."

7 Acorane, Cedrane, Carotane, Zizaane A new strategy for the synthesis of spiro[4,5]decane sesquiterpenoids has been developed which relies upon the activating and rnetu-directing effects of the tricarbonylchromium group in T-anisoletricarbonylchromium complexes with cyano-stabilized nucleophiles.** This new methodology is nicely illustrated in the synthesis of acorenone (175) and acorenone B (176), which combine both inter- and intra-molecular variants of the process (Scheme 21). The absolute stereochemistries of a- and p- pipitzol have been unambiguously established as (177) and (178) respectively by the chemical transformation of a-pipitzol into (-)-a-cedrene (179) and by X-ray analysis of a-pipitzol ben~oate.'~ An examination of the minor constituents of Cupressus duprezianu has resulted in the isolation of the three alaskane-type sesquiterpenoids (180)-(182) together with the two 1,7-diepi-cedrane derivatives (183) and (184).84In view of the importance of absolute stereochemistry in these and related compounds it is regrettable that the [aIDvalue of only one of them (183)is quoted. Indeed this is all the more surprising when the comparison of [a],,values has played an important role in the proposals of the same authors to account for the distribution and biogenesis of acorane, alaskane, cedrane, 1,7-diepi-cedrane,

82 83

H. Takahashi, M. Ito, H.Suginome, and T. Masamune, Chem. Lett., 1979, 901. M. F. Semmelhack and A. Yamashita, J. A m . Chem. SOC.,1980, 102, 5924. P. Joseph-Nathan, L. U. Roman, J. D. Hernandez, Z. Taira, and W. H. Watson, Tetrahedron, 1980,36, 731. L. Piovetti, G. Combaut, and A. Diara, Phytochemistry, 1980, 19,2117.

27

Sesquiterpenoids

CN

J

xi-xiii,

CN

\

xi-xiii,

iii

; ii, I,; iii, H,O';

Reagents: i,

iii

iv, OH-; v, CH,=CHCH,MgBr; vi, CF,CO,H-

O Y 0 1 Et,SiH; vii, HBr; viii, KCN; ix, Cr(CO1,; x, CO; xi, LDA; xii, CF,SO,H; xiii, NH,OH

Scheme 21

OH

OH

@?yo"

28

Terpenoids and Steroids

-,>OH

H

H (183)

( 1 84)

and 2,5-diepi-cedrane sesquiterpenoids in Cupressaceae, Taxodiaceae, and Gramineae species.85 The thermal rearrangement of the P-cyclopropyl-a$-unsaturated ketone (185) to afford (186) has been used as the starting point for a synthesis of the tricyclic ketones (187) and (188) (Scheme 22).86 Previously these two compounds have been converted into (+)-zizaene (189). Another method of constructing this tricyclo[6.2.1.0'*5]undecyl skeleton involves the intramolecular

1

iii-v,

-

-

0

vi, vii

viii-x

PhS*

i

PhS'

OTs 1 x i . xii

xiii-xv

+

Ph 0,S'o m *

(187)

(188)

(189)

Reagents: i, A; ii, (H,C=CH),CuLi; iii, LDA; iv, Ph,S,; v, NaIO,; vi, PhSH, Bu4NF; vii, Me,C(CH,OH),-PTSA; viii, H,B.SMe,; ix, H,O,-OH-; x, TsCI-py ; xi, MCPBA; xii, KOBu'; xiii, Na-Hg-Na2HP04; xiv, (CO,H),-H,O; xv, NaOMe Scheme 22

" 86

L. Piovetti and A . Diara, Phytochemistry, 1977, 16, 103; L. Piovetti and A . Diara, Tetrahedron Lett., 1980, 21, 1453. E. Piers and J. Banville, J. Chem. Soc., Chem. Commun., 1979, 1138.

Sesquiterpenoids

29

photocycloaddition of (190) to give (191) followed by a subsequent Grob fragmentation (Scheme 23).87aA very similar and independent result has been obtained by Oppolzer and B ~ r f o r d . ~ ’ ~

AcO

p

P l+ &o*c

lii,

iii

OMS

Reagents: i, hv; ii, NaBH,; iii, MsC1-py; iv, KOH-EtOH

Scheme 23

8 Cadinane, Cyclosesquifenchane, Cyclosativane, Picrotoxane New cadinane sesquiterpenoids include isokhusinoloxide (192)88and raimondal (193).89A number of timbers undergo a colour change on exposure to daylight,

H9

u

,I

an example of which is the wood of Blue Mahoe (Hibiscus elutus), the national tree of Jamaica. In an investigation of this interesting phenomenon the heartwood of this tree was extracted which led to the identification of the colourless hibiscones A-D (194)-( 197) and the coloured hibiscoquinones A-D (198)(201) r e s p e c t i ~ e l y .It~ ~turns out that hibiscone C (196) is identical to the

’’ ( a ) A. J. Barker

and G. Pattenden, Tetrahedron Lett., 1980, 21, 3513; ( b ) W. Oppolzer and

S . C. Burford, Helu. Chim.Acta. 1980, 63, 788. 88

P. S. Kalsi, B. C. Gupta, S. Chahal, Y.K. Mehta, and M. S. Wadia, Bull. Soc. Chim. Fr., Part 2. 1979,599.

89 90

R. D. Stipanovic, A. A. Bell, and D. H. O’Brien, Phyrochemistry, 1980,19, 1735. M. A. Ferreira, T. J. King, S. Ali, and R. H. Thomson, J. Chem. Soc., Perkin Trans. 1, 1980, 249.

Terpenoids and Steroids

30

O m o H

H i

A (194) R’ = R2 = H (195) R’ = H , R 2 = OH (196) R’,R2 = 0

A ,

(197)

previously known compound gmelofuran. These eight compounds have also been identified as constituents of the heartwood of the related species H. tiliaceus (from Fiji and Sri Lanka). I n vitro experiments suggest that the hibiscoquinones are derived in vivo from the hibiscones.” Gmelofuran (196) as well as the new compound agarol (202) has been isolated from the evergreen tree Aquilaria agallo~ha.’~ The data for this compound correspond closely to those given for hibiscone B (195) and hence they may be identical, in which case a structural revision is required.

Compounds with rearranged cadinane skeletons include the fungal antibiotic heptelidic acid (203),93the most unusual endo-peroxide qinghaosu (204),94which is an active principle from the Chinese medicinal herb Artemisia annua L., and koidzumiol (205).3The biogenesis of the latter compound is considered to be as shown in Scheme 24. Some further derivatives of abrotanifolone (206) have also been i~olated.’~ 91

92

93 94

95

S. Ali, P. Singh, and R. H. Thomson, J. Chem. SOC.,Perkin Trans. I , 1980, 257. P. Pant and R. P. Rastogi, Phytochemistry, 1980, 19, 1869. Y. Itoh, S. Takahashi. T. Haneishi, and M. Arai, J. Antibiorics, 1980,’33, 525. Qinghaosu Research Group, Sci. Sinica, 1980, 23, 380. F. Bohlmann and H. Suding, Phytochemistry, 1980, 19, 687.

31

Sesquiterpenoids

H \

+H-'

A (205)

Scheme 24

A short synthesis of calamenene (208) has been achieved by cyclodehydration of the tertiary alcohol (207) with phosphorus p e n t ~ x i d e The . ~ ~ mechanism of this reaction probably involves a carbonium ion re-organization followed by an intramolecular Friedel-Crafts alkylation. In an independent study Wender and

0 ;

OCOCH=C(Me)Et

qH \

Hubbs have confirmed the result obtained last year (Vol. 10, p. 29) that the piperitone photo-adduct (209) undergoes a thermal rearrangement to produce (210). These authors have now shown that (210) can be converted into calameon (see also Ref. 228). (211) in four

A synthesis of the unique marine sesquiterpenoid sinularene (212) has been achieved by a route which closely parallels the methodology used by Money et uL9* to synthesize copacamphor and ylangocamphor (Scheme 25).99Full details of the very interesting synthesis of cyclosativene (215) have been published.loO As shown in Scheme 26, the critical synthetic step involves the solvolysis of the bicyclic tosylate (213) which proceeds by intramolecular capture of the cyclopropylcarbinyl cation by the pendant acetylene group to afford (214). 96

97 98

99

loo

F. E. Condon and D. L. West, J. Org. Chem., 1980,45,2006. P. A. Wender and J. C. Hubbs, J. Org. Chem., 1980,45,365. C. R. Eck,G. L. Hodgson, D. F. MacSweeney, R. W. Mills, and T. Money, J. Chem. SOC.,Perkin Trans. 1, 1974, 1938. P. A. Collins and D. Wege, Ausr. J. Chem., 1979,32, 1819. S. W. Baldwin and J. C. Tomesch, J. Org. Chem., 1980.45, 1455.

Terpenoids and Steroids

32

G~ L_, i-iii

6

0

~

iv-vi, s

0

0 3 1

vii, viii

/

Reagents: i, LiAIH,; ii, TsCI-py; iii, CrO,.py,; iv, NaI; v, HO(CH,),OH-H+; vi, Br,

Ni' , ,Br; Ni

Scheme 25 .

The very fine single-handed synthesis of dendrobine (220) has been reported in full (Scheme 27).lo1 Unfortunately the preliminary details of this synthesis were inadvertently omitted from Volume 9. As can be seen from the flow diagram a key step in the synthesis is the intramolecular Diels-Alder reaction of (216) which produces the two trans-perhydroindanes (217) and (218) as the lo'

W. R. Roush, J. Am. Chem. Soc., 1980, 102, 1390; ibid., 1978, 100, 3599; J. Org. Chem., 1979, 44,4008.

33

Sesquiterpenoids

1..

vi

OCH,CF, (214)

ii, xii-xiv

0

0

Reagents: i, &OH-K,CO,; ii, LiAlH,; iii, Br,-Ph,P-py; iv, L E E C H ; v, Na-NH,; vi, TsC1-py; vii, CF,CH,OH; viii, H,O'; ix, HC0,Et-NaOMe; x, Ac,O-py; xi, Me,CuLi; xii, MsC1-py; xiii, KOBu'; xiv, Pd/C-H,

Scheme 26

major products, both of which are converted into the desired cis-fused ketone (219) in subsequent steps. Following on from the successful synthesis of picrotoxinin (221) reported last year (Vol. 10, p. 34) Corey and Pearce''* have now converted it into picrotin (223) by the indirect process of first of all protecting the tertiary hydroxy-group as a trifluoroacetate followed by oxymercuration of the isopropenyl group to give (222). The only satisfactory method for demercuration of (222) involved reduction with Bu3SnH followed by hydrolysis of the two trifluoroacetate groups.

E. J. Corey and H. L. Pearce, Tetrahedron Len., 1980, 21, 1823,

Terpenoids and Steroids

34 HO

C0,Me ‘C0,Me

\

A 1

1

iii

iii

H?

A

A liv. v

,

C0,Me

C02Me

,

A 1

A

O

H

A (219)

ix

NHMe

H- Br‘

,

A

,

A

C0,Me

HO”

,

A 1

xvii, xviii

I;r

(220) Reagents: i, A, BSA; ii, H,O’; iii, NaOMe; iv, (CF,CO),O-Me,SO; v, S O , ; vi, MeI-KOBu’; vii, TosMIC-KOBu‘; viii, H,O,-OH-; ix, aq. NBS; x, Zn-HOAc; xi, (COCI),; xii, LiAI(OBu‘)3H; xiii, MsC1-py; xiv, MeNH,; xv, CICOCH,CCI,-py ; xvi, MCPBA; xvii, Cr0,-H’; xviii, NaBH,

Scheme 27

35

Sesquiterpenoids

9 Himachalane, Longifolane An X-ray crystallographic analysis of the p- bromobenzoate of (+)allohimachalol, a constituent of the essential oil of Cedrus deoduru Loud., has resulted in a slight revision of its stereochemistry to (224).'03

(224)

A long standing mechanistic problem has been the route by (+)-longifolene (225) undergoes the acid-catalysed rearrangement to (-)-isolongifolene (232). Initially a mechanism was proposed in 1964 by O u r i s ~ o nwhich ' ~ ~ was attractive especially in the economy of the number of steps (225)-(232). However, in 1967 Berson and ~ o - w o r k e r spointed ~ ~ ~ out that one of the steps, (227) + (228), involved an endo- 2,3-methyl migration which lacked precedent in simpler methylnorbornyl systems. This led Berson to put forward an alternative mechanism (234)-(240) which, albeit more circuitous, circumvented the off ending endo migration, and indeed one of the proposed steps, (236) + (237), en route to isolongifolene involved an exo- methyl migration, a process which was considered to be much more favourable. A careful inspection of the two mechanisms suggested appropriate 13C-or ''C-labelling studies which should settle the issue, but this challenge was not taken up. Recently, however, Sukh Dev and coworkerslo6 recognized that a solution to this problem could be achieved by deuterium labelling studies, uit. by the original mechanism the tetradeuteriolongifolene (226) should proceed to labelled isolongifolene (232) whereas the Berson mechanism should lead to (240). The requisite labelled longifolene (226) was duly prepared by a ten-step route from 3-isolongifolol and treatment of lo3

lo4 lo'

A. G. Bajaj, Sukh Dev, B. Tagle, J. Telser, and J. Clardy, Tetrahedron Lett., 1980, 21, 325. G. Ourisson, Proc. Chem. Soc., 1964, 274. J. A. Berson, J. H. Hammons, A. W. McRowe, R. G. Bergman, A. Remanick, and D. Houston,

J. A m . Chem. Soc., 1967,89, 2590. J. S. Yadav, U. R. Nayak, and Sukh Dev, Tetrahedron, 1980, 36, 309.

Terpenoids and Steroids

36

R’ $ R

$jS@+&

(225) R (226) R

= =

H D

(227)

(228)

1

this with boron trifluoride etherate afforded (240). The precise location of the four deuterium atoms was unequivocally established by careful degradation and mass spectral studies. Thus the Berson mechanism finds support from experimental evidence. In a subsequent paper the same sought evidence lo’

J. S. Yadav, R. Soman, R. R. Sobti, U. R. Nayak, and Sukh Dev, Tetrahedron, 1980,36,2105.

Sesquiterpenoids

37

for the intermediacy of longicyclene (241) in the longifolene-isolongifolene rearrangement since this was suggested by McMurry"' in a third alternative mechanism [in essence this mechanism provided a shorter route to the cation (242) equivalent to (236) in Berson's mechanism]. Once again deuterium labelling studies were carried out using BF,.Et,O-AcOD as the acid catalyst for the rearrangement. If longicyclene (241)had been an intermediate, deuterium should become attached to certain carbon atoms in the resultant isolongifolene, e.g. (243). As a result of degradation/mass spectral studies this was shown not to be the case and hence the implication of longicyclene seemed to be untenable. D

However, in a nice example of carrying out one too many experiments (in an effort to intercept possible intermediates in the rearrangement), longifolene was treated with D,PO,-dioxan. Under these conditions isolongifolene incorporated almost double the number of deuterium atoms as under the previous conditions and degradation/mass spectral studies clearly indicated the involvement of longicyclene (indeed longicyclene is formed in up to 20% in this process after a certain time interval). Thus it is concluded that longicyclene is not an obligatory intermediate under certain conditions but can be so under others.

10 Caryophyllane, Humulane, Hirsutane, Pentalenane, etc. It is interesting to observe how, over the past ten years or so, this group of sesquiterpenoids has grown in stature largely because of the rich diversity of structural types which can be formally derived from caryophyllene- or humulenetype precursors. Some very challenging problems in synthesis and biosynthesis have emerged from this group and it is a credit to those research chemists who have met these challenges with alacrity and ingenious solutions. Motivated by an investigation into the aroma/flavour of beer, two groups have identified sulphur-containing compounds in hop oil. These include the two episulphides of humulene, (244) and (245), as well as caryophyllene-4,5-episulphide (246).'09 Whereas the detection of these compounds is understandable since they emanate from hops which have been treated with sulphur in the growth cycle, the isolation of the methyl sulphide (247) of tentatively assigned structure from hops that have received no sulphur treatment is more puzzling.'" The recently reported compound lychnopholic acid (248) and its acetate have been isolated from Lychnophora rnartiana."' The humulene alcohol (249) has 'On

'lo

'11

J. E. McMurry, J. Org. Chem., 1971, 36, 2826. T. L. Peppard, F. R. Sharpe, and J. A. Elvidge, J. Chem. SOC., Perkin Trans. 1, 1980, 311 M. Moir, I. M. Gallacher, J. C. Seaton, and A. Suggett, Chern.-Ind. (London), 1980, 624. W. Vichnewski, A. P. Lins, W. Herz, and R. Murari, Phytochemistry, 1980, 19,685.

38

;:>

Terpenoids and Steroids

(245)

(247)

been isolated from Helichrysurn chionosphaerurn.l12 An interesting study of the intra- uersus inter-molecular hydride transfer in the caryophyllene-derived ketol (250) has been carried In this case the rate of the intermolecular transfer is increased by changing the nature of the cation, i.e. A13+> Li' > Na' > K ' , whereas the rate of intramolecular transfer is in the reverse order. Also the rate of the intramolecular hydride shift increased with increasing basicity of the medium. These results have been interpreted in terms of the cyclic transition state (25 1)for intramolecular transfer and (252) for the intermolecular process.

A neat synthesis of a- and P-panasinsene (255) has been described which incorporates an intramolecular variant of the cuprous triflate-catalysed photocycloaddition of the allylic alcohol (253) to afford (254).l14Oxidation of (254), followed by treatment with methyl-lithium and dehydration yielded a mixture

'" 'I4

F. Bohlmann, W.-R. Abraham, and W. S. Sheldrick, Phytochemistry, 1980, 19,869. E. W. Warnhoff, P. Reynolds-Warnhoff, and M. Y. H. Wong, J. A m . Chem. SOC., 1980,102,5956. J. E. McMurry and W. Choy, Tetrahedron Lett., 1980, 21, 2477.

Sesquiterpenoids

39

of the two panasinsenes. X-Ray analysis has been used to determine the structure of the unique alcohol (256) named koraiol, which is isolated from Pinus k o r i c e n ~ i s . ~It' ~is suggested that this compound may be derived from humulene rather than caryophyllene since the gem-dimethylcyclobutane ring is cis-fused. Rearrangement of humulene-8,9-epoxide (257) with tin(1v) chloride gives rise to the bicyclic alcohol (258) dhose carbon skeleton is the same as that of the recently identified mintsulphide (259).' l 6

A full and important paper on the conformational properties of humulene as studied by empirical force-field calculations has been published.' l7 In addition to defining the four minimal strain conformers of humulene (260)-(263), the calculations also give an estimate of 14.17 kcal mol-' for the enthalpy of activation for humulene ring inversion, which is in reasonable agreement with a AG' value of 10.6 kcal mol-' obtained by an earlier n.m.r. study. The authors also emphasize the implications of relating the various conformers of humulene (particularly the CC and CT conformers) to the biosyntheses of the protoilludane, illudane, and hirsutane sesquiterpenoids as illustrated. They also note that the biogenesis of the recently isolated bicyclohumulenone (264) can be considered in terms of the RRR-CC conformer (261) and back up this suggestion with as yet unpublished results.

(260) RSR- CT

(263) RRS-TC

'15

197

(262) RSS- TT

(261) RRR-CC

I

(264)

V. A. Khan, Yu. V. Gatilov, Zh. V. Dubovenko, and V. A. Pentegova, Khirn. yrir. Soedin. (Engl. Transl.), 1979, 572. I. Bryson, J. S. Roberts, and A. Sattar, Tetrahedron Lett., 1980, 21, 201. H. Shirahama, E. Osawa, and T. Matsumoto, J. Am. Chem. SOC.,1980, 102,3208.

Terpenoids and Steroids

40

(260)

-

'&@ H,,

-

Protoilludanes, Illudanes

H H

SSS-(261) +

1

Hirsutanes

Three additional metabolites of the fungal plant pathogen Botrytis cinerea include botryaloic acid (265), its corresponding acetate (266), and botryoloic acid (267)."* Further studies on the biosynthesis of dihydrobotrydial(268)have revealed that the hemiacetal ring of (268) is formed with retention of the pro-2R This and pro-5R mevalonoid hydrogen atoms at C-15 and C-10 respe~tively."~ information can be extrapolated to the retention of configuration at the relevant centres of farnesyl pyrophosphate (269).

(265) R' = CHO, R2 = COzH, R3 = H (266) R' = C H 0 , R 2 = C02H,R3 = AC (267) R' = COZH,R2 = CHZOH, R3 = Ac

(268)

(269)

A further investigation of fern species has resulted in the identification of additional pterosin and ptersoide derivatives, viz. setulosopteroside (270), pterosin Y (271), histiopterosin A (272), isopterosin B (273), isopterosin C (274), isohistiopterosin A (275), pterosin R (276), and the two onitin derivatives (277) and (278).'" A new class of seco-illudalanes, named cybodins, have been identified from the bird's nest fungus Cyathus bulleri Brodie. These include cybrodol (279), isocybrodol (280), cybrodic acid (281), cybrodal (282), and trisnorcybrodolide (283).12' The latter compound has been synthesized from mesitylene.'*' A. P. W. Bradshaw and J. R. Hanson, J. Chem. SOC.,Perkin Trans. 1, 1980, 741. A. P. W. Bradshaw and J. R. Hanson, J. Chem. SOC.,Chem. Commun., 1979,924. 120 T . Murakami, T. Satake, K. Ninomiya, H. Iida, K. Yamauchi, N. Tanaka, Y. Saiki, and C.-M. Chen, Phytochemistry, 1980, 19, 1743. 12' W. A. Ayer and R. H. McCaskill, Tetrahedron Lett., 1980, 21, 1917. 122 W. A. Ayer and R. H. McCaskill, Tetrahedron Lett., 1980, 21, 1921.

Sesquiterpenoids

41 CH20H

GlucO

HO OH

OH

(271)

(270)

H02C* OH (272)

* R

(273) R (2741 R

= =

H OH

\

OH

OH (276) R (277) R (278) R

= = =

C1 OGluc OAllosyl

(279) R' (280) R' (281) R'

= = =

CH20H, R2 = Me Me,R2 = CH20H C02H, R2 = Me

A full report on the synthesis of dihydrofomannosin acetate (284) has been p ~ b l i s h e d . ' In ~ ~a follow-up paper on the biosynthesis of fomannosin (287), Cane and N a ~ h b e r have l ~ ~ used a number of incorporation experiments (particularly with [5,5-2H2]mevalonate)to show that fomannosin cannot be formed by the sequence (285) + (287) as shown in Scheme 28, since no deuterium incorporation could be detected at C-12. Since deuterium atoms were located at C-10 and C-15 the obvious route from (285) must involve loss of deuterium to give humulene (288) followed by re-protonation. They have commented further that the proposed biosynthesis of illudin M (289) involving two hydride shifts in the cation (290) seems unlikely since such a mechanism would place a deuterium atom at C-12 in fomannosin (287). Nonetheless the fact remains that Hanson's clearly indicate that the hydrogen at C-3' in illudin M is 123 124

H. Kosugi and H. Uda, Bull. Chem. SOC. Jpn., 1980, 53, 160. D. E. Cane and R. B. Nachber, Tetrahedron Len., 1980, 21,437. J. R. Hanson, T. Marten, and R. Nyfeler, J. Chem. SOC.,Perkin Trans. I , 1976, 876.

Terpenoids and Steroids

42

--* --*

I H

fi +-?H

H (288) Scheme 28

derived from the pro-5R hydrogen of mevalonate, but it is not absolutely clear whether this hydrogen originates from C-1 or C-9 of farnesyl pyrophosphate.

4

(289)

The marasmane and iso-marasmane derivatives (291) and (292) have been synthesized by an intramolecular carbene route from the diazo-keto-ester (293).'26 &r2Et &I02Et N2

C02Et

H

H

H

O

An investigation of the metabolites of Russula sardoniu has resulted in the identification of three new vellerane sesquiterpenoids, furanether A (294), furosardosin A (295), and sardonialactone A (296).'27These compounds cooccur with a number of other known vellerane sesquiterpenoids which have been isolated previously from Lacturius species. Two related compounds, blennin A (297) and blennin D (298), have been isolated from Lucturius blennius. 128*129 126

N. Morisaki, J. Furukawa, S. Nozoe, A . Itai, and Y. Iitaka, Chem. Pharm. Bull., 1980,28, 500.

lZ8

Phytochemistry, 1980.19,93. M. D e Bernardi, G . Fronza, G. Mellerio, G. Vidari, and P. Vita-Finzi, Phytochemistry, 1980,19,99. A. Talvitie, K. G . Widen, and E. L. Seppa, Finn. Chem. Lett., 1980,62.

'*' D . Andina, M. D e Bernardi, A. Del Vecchio, G. Fronza, G. Mellerio, G . Vidari, and P. Vita-Finzi, 129

43

Sesquiterpenoids

(295)

(296) R' = H , R 2 = OH (297) R' = R2 = H (298) R' = O H , R 2 = H

Prompted in part by the significant antibiotic and antitumour properties of several members of the hirsutane class of sesquiterpenoids, there has been a dramatic surge in synthetic endeavour towards these compounds. In this context three independent syntheses of hirsutene (302) have been announced in the 'year under review. The first of these'30 (Scheme 29) involves two key steps,

g

n +

x5

n

OAc

I

AcO

OAc

H OAc

AcO

(300) \-iv

n

n

OCH,OMe

OCH,OMe

v, vi

c--

J

vii, viii

0 (30 1)

HO

H OH

OCH,OMe

OCH,OMe

0

ix, x

H

A

H

H

H (302)

Reagents: i, h v ; ii, NaBH,; iii, MeOCH,Cl-EtNPr',; iv, NaOMe; v, TsC1-py; vi, K,CO,; vii, NaI-Zn; viii, H,O'; ix, H,-Pd; x, LiAIH,; xi, NaH-CS,-MeI; xii, Bu,SnH; xiii, PCC; xiv, Ref. 1306 Scheme 29 (a) K. Tatsuta, K. Akimoto, and M. Kinoshita, J. A m . Chem. SOC.,1979,101,6116; ( 6 ) S . Nozoe, J. Furukawa, U. Sankawa, and S. Shibata, Tetrahedron Lett., 1976, 195.

44

Terpenoids and Steroids

namely the initial photocycloaddition which yields both (299) and (300) and the Grob-type rearrangement to give (301). The second synthesis13' (Scheme 30) is ingenious in its simplicity and relies upon an application of the recently described process for the three-carbon annulation of olefins. The third

0

iii, iv .+

&

H

v, ii

H

vi, vii t--

\

iii, iv

0

(302) C1 Reagents: i,

'C=C=O; /

ii, CH,N,; iii, NaBH,; iv, Cr(CIO,),; v,

Me HC0,H; vii, CH,=PPh,

C1 'C=C=O; / CI

vi, HCI0,-

Scheme 30

(Scheme 31), which can be achieved in 37% overall yield from the aldehyde (303), makes use of an intramolecular cyclopropanation followed by a vinylcyclopropane + cyclopentene rearrangement to construct the required cis,anti,cistricycl0[6.3.O.O~*~]undecane carbon skeleton of hirsutene (302).

I

OH

do (302)

H

H

Reagents: i, H,C=CHMgBr; ii, MeC(COEt),-Hg(OAc),-EtC0,H;iii, KOH; iv, (COCI),; v, MeCHN,; vi, Cu(acac),, A; vii, 580 "C, PbCO, glass; viii, H,-PtO,; ix, CH,=PPh,

Scheme 31 A. E. Greene, Tetrahedron Lett., 1980,21,3059.

T.Hudlicky, T.M. Kutchan, S. R. Wilson, and D. T. Mao, J. Am. Chem. SOC.,1980,102,6351.

45

Sesquiterpen oids

The more heavily oxygenated hirsutane sesquiterpenoid, coriolin (307), poses an even more demanding synthetic challenge and here again this daunting task has been accomplished in three beautifully conceived syntheses. The first of these is illustrated in Scheme 32.'33Only the final step, in the creation of the OMe

0

0

OMe

1 H

g & diM LI "3,Me

C0,Me

0

0

t--. vi

H

liii

0

iv, v e -

H

H

1

vii-x

xi, ii, xiii, xiv _____, &OH

xi, xii

H H

lxv

Wo

xvi-xviii

xv, iii

xxi +

(305)

)Q#H

OH

OH

-OH

O

OH OH (306)

OH (307)

Reagents: i, NaOMe; ii, H'; iii, A; iv, PhSeC1; v, [ O ] ;vi, MeLi; vii, 0,; viii, Cr0,-H'; ix. aq. Ba(OH),; x, Pb(OAc),; xi, KQBu'; xii, PTSA; xiii, Bu',AlH; xiv, Li-NH,-MeOH; xv, MCPBA; xvi, PCC; xvii, LDA; xviii, PhSS0,Ph; xix. H,O,-NaHCO,; xx, NaBH,; xxi, Bu'0,H-VO(acac),

Scheme 32 S. Danishefsky, R. Zamboni, M. Kahn. and S. J. Etheredge, J. Am. Chem. Soc., 1980,102, 2097.

46

Terpenoids and Steroids

spiroepoxide, was non-stereospecific, but in a subsequent publication Danishefsky and Z a m b ~ n ihave * ~ ~provided a solution to this problem. This was achieved by monoepoxidation of (304) with alkaline peroxide followed by sodium borohydride reduction to give (305). The allylic hydroxy-group then directed

epoxidation of the exocyclic double bond in the desired sense with Bu'OOHVO(acac)2. Subsequent oxidation of (306) with Sarret's reagent afforded coriolin (307). Double esterification of (306) with octanoyl chloride followed by selective hydrolysis gave coriolin B (308). The second synthesis (Scheme 33) makes use

n \

I

OCH,OMe

OH

0 iii

/

H

iii. iv

L

O

H

1..

(301)

vi

OMe

vii-ix

e--

OMe 0

0-A

o-%

1

x-xii

q&-

AcO

xiii, xiv

OH

OAc

(307) Reagents: i, NaI-Zn; ii, H,O'; iii, OS0,-

(3

; iv, Me,C(OMe),-H';

v, PCC; vi, NaH-

N

/ \

0-

o-NO,PhS,Me; vii, TI(NO,),; viii, MeLi; ix, Li-NH,; x, CF,CO,H; xi, Ac,O-py; xii, MsCl-DMAP; xiii, LiOH; xiv, H,O,-NaHCO, Scheme 33 13*

S. Danishefsky and R. Zamboni, Tetrahedron Lett., 1980, 21, 3439.

47

Sesquiterpenoids

of the intermediate (301) previously used in the hirsutene synthesis (see Scheme 29).135It should be noted that Danishefsky claims that the final double epoxidation step is not nearly as stereospecific as implied from Tatsuta's results. The third synthesis (Scheme 34) is a formal one in the sense that (309) has been

i,ii

,~

o s i M e 2 B u liii-vi,

coo H

H

bii,viii

THPO

THPO 0 -

02-

00

1

H

H

H

1

xiii

0%

0

OH (309) Reagents: i, Me,CuLi; ii, K0Bu'-Mel;

iii, Li-NH,;

iv,

-H+; v, F-; vi, PCC; vii, NaH-

CH,=CHCH,Br; viii, PdC1,-CuCI-0,; ix, KOBu'; x, LDA-MeI; xi, LDA-PhSeBr; xii, H,O,; xiii, H,O+; xiv, MCPBA; xv, DBU

Scheme 34

converted into coriolin (307).'36Other papers relevant to coriolins include the synthesis of the coriolin model compounds (310) and (311)137and the conversion of coriolin B (308) into coriolin (307) and related ana10gues.l~~ In terms of the

(310) R = OH (311) R = =O K. Tatsuta, K. Akimoto, and M. Kinoshita, J. Antibiotics, 1980,33,100.

M.Shibasaki, K. Iseki, and S. Ikegami, Tetrahedron Lett., 1980,21,3587. 13'

H. Hashirnoto, T. Ito, H. Shirahama, and T. Matsumoto, Heterocycles, 1979,13,151. Y.Nishimura, Y.Koyama, S. Umezawa, T. Takeuchi, M. Ishizuka, and H. Umezawa, J. Antibiotics, 1980,33,404.

48

Terpenoids and Steroids

general strategy of constructing the linearly fused tricyclopentanoid skeleton of the hirsutane class, a number of other papers are worthy of note. These include a cleverly conceived synthesis of (313) (Scheme 35) which proceeds by generation of and subsequent intramolecular trapping of the 1,3-diyl (312).'39 The

J: C0,Me (313) Reagents: i, NaBH,;

ii, Bu',AIH;

iii,

Ph,P=CHCO,Me;

iv, PCC; v , 0 - E t 2 N H ;

vi,

I

CI3CCH~0,CN=NCO2CH,CCl3; vii, K,Fe(CN),; x, A

H,-Pd/C;

viii,

electrochemical

redn.; ix,

Scheme 35

others involve the synthesis of (314),14"the conversion of (315) into (316) with tris(phenylthi~)methyl-lithium,'~~ and the annulation of 2-phenylthiocyclopentenone with 2-chloromethyl-3-trimethylsilylpropene to give (317), which was ultimately converted into (318).'42 Complete details of the very elegant first OAc

0 (314)

(315)

(316) 0

(317) 139

14'

H (318)

R. D. Little and G. W. Muller, J. A m . Chem. SOC.,1979,101,7129. B. M. Trost and D. P. Curran, J. Am. Chem. SOC.,1980,102, 5699. S. Knapp, A. F. Trope, and R. M. Ornaf, Tetrahedron Lett., 1980, 21,4301. S . Knapp. U. O'Connor, and D. Mobilio, Tetrahedron Lett., 1980, 21, 4557.

Sesquiterpenoids

49

synthesis of the antibiotic pentalenolactone (319) have been p ~ b 1 i s h e d . lA~ ~ second interesting synthesis from Schlessinger and his group uses a different approach (Scheme 36).144 OMe

OMe

d'

0'

(

k 0 , E t

b lv-viii

&CHO

I

OMe

o p eH

.

xii, vii, xiii I

l

C0,Me c--

.

'-OH 4

2Me

.

C02Me

lxiv-xvi

\\

H

Lo/

L O ) OMe

0

0

0 ,CO,Et

Reagents: i, LDA; ii, CH,=CHCH,Br; iii,

==))

(319)

[

; iv, NaH-OC(OMe),; v, KN(SiMeJ,; vi, CO,; C0,Et vii, H,O'; viii, CH,N,; ix, NaBH,; x, MsCl-Et3N; xi, collidine, A; xii. Bu',AlH; xiii, MnO,; xiv, 0,-py-Me,S; xv, CH(OMe),-H'; xvi, CH,=PPh,; xvii, (Ph,P),RhCI-H,; xviii, Cr0,-H'; xix, MMC; xx, HCHO-Et,NH

Scheme 36

A detailed investigation of several Berkheya species has resulted in the identification of p-isocomene (320).14' In certain of the species this compound co-occurs with the previously known isomer isocomene (32 1) and modhephene (322). These three hydrocarbons also co-occur in the roots of some Silphium

(320)

(321)

R (322) R = H (323) R = OAc

143

S. Danishefsky, M. Hirama, K. Gombatz, T. Harayama, E. Berman, and P. F. Schuda, J. A m .

144

W.H. Parsons, R. H. Schlessinger, and M. L. Quesada, J. A m . Chem. Suc., 1980,102,889. F.Bohlmann, N. L. Van, T. V. C. Pham, J. Jacupovic, A. Schuster, V. Zabel, and W. H. Watson,

Chem. Suc., 1979,101,7020. 145

Phytochemistry, 1979,18,1831.

50

Terpenoids and Steroids

species, which also produce the four new sesquiterpenoids silphinene (325), silphiperfol-6-ene (326),7a H-silphiperfol-5-ene (327),and 7PH-silphiperfol-Sene (328).'46 It is suggested that these novel compounds could be derived from the cation generated from caryophyllene (324) as shown in Scheme37. Two

(327) R' = M e , R 2 = H (328) R' = H , R 2 = Me Scheme 37

oxygenated derivatives, 13-acetoxymodhephene (323) and 5-0x0-5,6Hsilphiperfolene (329), have been isolated from the roots of Liabum ~pecies,'~' and arnicenone (330), an isocomene derivative, occurs in the rhizomes and roots

-T

(Q'

(329) 146 147

0

a 4-o

(330)

F. Bohlmann and J. Jakupovic, Phytochernistry, 1980,19, 259. F. Bohlmann, C. Zdero, R. Bohlmann, R. M. King, and H. Robinson, Phytochernistry, 1980, 19, 579.

Sesqu iterpenoids

51

of various Arnica species.148Two memorable syntheses of isocomene (321) have been reported. The first one (Scheme 38) by Paquette and Han149relies upon a successful cyclopentane annulation of the bicyclic enone (331). This paper also draws attention to some inconsistencies in an earlier claimed synthesis of isocomene which leaves some doubt as to the authenticity of the claim.1soThe second synthesis (Scheme 39) by PirrunglS1is ingenious in its economy of steps hinging upon a high-yield intramolecular photochemical addition.

c"

* i

&*

.. ...

%

1

(3311

iv, v

(321) Reagents: i, [ z p M g B r - C u B r - S M e 2 ; Cr0,-H';

ii, MeLi; iii, SOC1,-py; iv, H,O';

v, SnCl,; vi,

vii, LDA; viii, PhSeCl; ix, MCPBA; x, A; xi, Me,CuLi; xii, N2H,-K2C0,, A

Scheme 38

@ ** L @ % & O

(321) Reagents: i, LDA; ii, MeI; iii, L

M

g

B

r ; iv, H 3 0 + ;V, h v ; vi, CH,=PPh,; vii, PTSA

Scheme 39 14' 149

151

R. Schmitz, A. W. Frahm, and H. Kating, Phytochernistry, 1980, 19, 1477. L. A. Paquette and Y.K. Han, J. Org. Chem., 1979,44, '4014. S . Chatterjee, J. Chem. Soc., Chem. Commun., 1979,620. M . C. Pirrung, J. A m . Chem. SOC.,1979,101,7130.

52

Terpenoids and Steroids

The unique [3,3,3]propellane sesquiterpenoid modhephene (322) has also been synthesized (Scheme 40).15*The crucial construction of the propellane system was achieved by a thermally induced intramolecular carbene insertion of the intermediate alkylidene carbene derived from (332). n

H

:

CO,H

\

ix, x

c--

pJ 0

Reagents: i, KCN; ii, CH,=PPh,; iii, H,-Pt/C; iv, KOH; v, SOCI,; vi, Me,SiC=CSiMe,-AlCl,; vii, Na,B,O,; viii, 620 "C; ix, MeLi; x, 0 0 , - H ' ; xi, MeCu-BF,; xii, RhCI, Scheme 40

Yet another superb synthetic achievement from Danishefsky's laboratory is that of quadrone (334).'53As outlined in Scheme 41 this synthesis was completed in 19 steps starting from the cyclopentenone (333).

11 Germacrane A photochemical study of E,E-germacrene (335) has been carried Direct irradiation leads to the formation of the photoproducts (336)-(340), whereas sensitized irradiation produces mainly the isomerized 2,Z-derivative (341) together with small amounts of (336), (337), and (339). Direct irradiation of (341) yields (337) and' (339). Acid-catalysed cyclization of germacrene D (342)155with acetic acid gives primarily the cadinane-type hydrocarbons (343)(346).lS6Cyclization of germacrone (347) takes place on oxymercurationdemercuration to give (348)-(350).'57 A similar process is observed when germacrone is treated with thionyl chloride to produce (351).'58Recently it was lS2 153

lSs 156

Is' Is*

M. Karpf and A. S. Dreiding, Tetrahedron Lett., 1980, 21,4569. S. Danishefsky, K. Vaughan, R. C. Gadwood, and K. Tsuzuki, J. A m . Chem. SOC.,1980, 102, 4262; S. Danishefsky, K. Vaughan, R. C. Gadwood, K. Tsuzuki, and J. P. Springer, Tetrahedron Lett., 1980, 21, 2625. P. J. M. Reijnders, R. G. van Putten, J. W. de Haan, H. N. Koning, and H. M. Buck, J. R. Netherlands Chem. SOC.,1980,99, 67. M. Niwa, M. Iguchi, and S . Yamamura, Chem. Pharm. Bull., 1980,28,997. H. Nishimura, H. Hasegawa, A. Seo, H. Nakano, and J. Mizutani, Agric. Biol. Chem., 1979, 43, 2397. E. Tsankova, I. Ognyanov, and T. Norin, Tetrahedron. 1980,36, 669. E. T. Tsankova, I. V. Ognyanov, and A. S. Orahovats, Chem. Ind. (London), 1980,87.

53

Sesq uiterpen oids

Br

Me0,C

(333)

v

Br

Br

x, viii, xi

0

Me0,C

0.

1

xvi, xvii

xxi

xviii-x.x

*--

CH~OH (334) Reagents: i, H,C=CHMgBr-Bu,P.CuI;

OMe ii, Br&CO,Me

; iii,

HO(CH,),OH-H';

iv, BH,;

OBu' v, -0OH; vi, MsCl-Et3N vii, LiBr; viii, H,O';

ix, NaOMe; x , <

-Tic&; OSiMe,Bu'

xi, CH,N,; xii, NaI; xiii, LiN(SiMe,),; xiv, Me,CO-H'; xv, KOH; xvi, PhSeC1; xvii, H,O,; xviii, LDA; xix, CH,O; xx, H,-Pd/C; xxi, 190 "C

Scheme 4 1

54

Terpenoids and Steroids

(343)

(344)

shown that gallicin (352) could be cyclized with HCl to produce eudesmanolides. 159 In the presence of mesyl chloride in pyridine gallicin undergoes a different cyclization with displacement of the C-1 mesylate to yield a number of guaianolides, e.g. (353).'59 Both costunolide (354) and dehydrosaussurea lactone (355) give the bicyclic lactones (356)-(358) on treatment with aqueous

m q m acl R o HO'

(347)

H

(348)

(349) A3,4 (350) A4*I4

(351)

(352)

N- bromosuccinimide.'60 In a study of the microbial transformation of costunolide (354),it has' been shown that Aspergillus niger brings about the conversion into dihydrocostunolide (359) and the four eudesmanolides (360)-(363).16' 159

A. G . Gonzalez, A. Galindo, and H. Mansilla, Tetrahedron, 1980, 36, 2015. T. C. Jain and C. M. Banks, Can. J. Chem., 1980,58,447. A. M. Clark and C. D. Hufford, J. Chem. SOC., Perkin Trans. 1, 1979, 3022.

55

Sesquiterpenoids

(353)

0

(355)

(354)

@ (xf

HO'

0

(356)

(357) A3*4 (358) A4*14

These results indicate that this organism is capable of three different types of biotransformation, including reduction of the a,P-unsaturated- y-lactone, epoxidation, and cyclization. In another biogenetically motivated experiment it has been demonstrated that selenium dioxide oxidation of costunolide (354) proceeds with isomerization of the A','' double bond to produce the melampolidetype compounds (364) and (365).'62

HO' 0

0 (359)

(360) R (361) R

= =

H OH

(362) A3*4 (363) A4*

New germacrane sesquiterpenoids include the furan (366),'63 (367),'64 bacchascandone (368),16' cyclachaenin (369),'66 and P-germacrene C (370).34 The three furanogermacrenes (371)-(373) have been identified in the essential oil of myrrh.16' A very comprehensive review of all sesquiterpenoid lactones reported in the literature up until the early part of 1979 has been published.'68 Recent additions S. Krishnan, S. K. Paknikar, S. C. Bhattacharyya, A. L. Hall, and W. Herz, J. Indian Chem. SOC., 163 164

lbS

'''

1978,55, 1142. B. F. Bowden, J. C. Braekman, J. C. Coll, and S. J. Mitchell, Aust. J. Chem., 1980,33, 927. F. Bohlmann and J. Ziesche, Phytochemistry, 1980, 19, 1851. F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1979,18, 1993. F. Bohlmann and C. Zdero, Phytochemistry, 1979,18, 1892. C. H. Brieskorn and P. Noble, Tetrahedron Lett., 1980, 21, 1511. N. H. Fischer, E. J. Olivier, and H. D. Fischer, Prog. Chem. Org. Nut. Prod., 1979, 38,47.

Terpenoids and Steroids

56

Qo (364) R = CHO (365) R = CH20H

(373)

(371) R = H (372) R = OAc

to the germacranolides are illustrated in structures (374)-(399),’69-’82 and the

G

h

c

~

o

0

(374)’69 Dihydrotulipinolide

(375)”O Taraxinic Acid Derivative (+11,13-dihydro-derivative)

Y. Asakawa, R. Matsuda, and T. Takemoto, Phytochemistry, 1980,19,567. R. Hansel, M.Kartarahardia, J.-T. Huang, and F. Bohlmann, Phytochemistry, 1980, 19, 857. 171 F. Bohlmann, C.Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980,19, 1141. 172 A. Ortega, R. Lara, R. Martinez, and E. Diaz, Phytochemistry, 1980, 19, 1545. 173 T. Takahashi, T.Ichimura, and T. Murae, Chem. Pharm. Bull., 1979, 27, 2539. 174 L. Quijano, J. S. Calderon, F. G6mez G., J. T. Garduiio, and T. Rios C., Phytochemistry, 1980, 170

19, 1975.

A. Rustaiyan, L. Nazarians, and F. Bohlmann, Phytochemistry, 1980, 19, 1230. 176 K. Ito, Y. Sakakibara, and M. Haruna, Chem. Lett., 1979, 1503. 177 F. S. El-Feraly, Y.-M. Chan, G. A. Capiton, R. W. Doskotch, and E. H. Fairchild, J. Org. Chem., 17’

1979,44,3952. 17*

lSo

lS2

F. C.Seaman and N. H. Fischer, Phytochemistry, 1980.19.849. W. Herz, N. Kumar, and J. F. Blount, J. Org. Chem., 1980,45, 489. W. Herz, S. V. Govindan, and J. F. Blount, J. Org. Chem., 1980,45, 1113. N. A. El-Emary and F. Bohlmann, Phytochemistry, 1980,19,845. F. Bohlmann, C . Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980,19, 115.

Sesquiterpenoids

RoR"

57

/

Bu'CO

II

O

O

e-

0 (376)171 Costunolide Derivatives

(377)'72 Sphaerocephalin

R'O

R'

(378)'73 Hiyodorilactone D

=

H, R2

H

OC

AcouoH AcouoH

(379) HiyodorilactoneE

R'

=

(380) Hiyodorilactone F

R'

= Ac, R2 =

(384)'76 Peroxysachalinin

R' = OH, R2

H,R2

=

=

H

OC

OC

HouoH

= OC

II

0

(386)'76 Sachalin R' = H, R2 = OH (387)'77 Peroxycostunolide R' = OH,R2 = H

H

58

Terpenoids and Steroids

Go

HOO

(388)'77 Peroxyparthenolide

co-occurs with

AcO (389)17' Linearilobin A-G, R' = COP?, R~ = H erc.

0 (390)17' Linearilobin H and I

HO..

Me

H

R = Ho$sH etc. CO CH20H

'

OH

(392)4 Laurenobiolide (39 1) '79

(393)' 3-Desacetoxy-Ursinolide

(394)lgo R' = OAc, R2 = OEpoxang, R3 = H (395) R' = OEpoxang,R2 = O H , R 3 = H (396) R' = OAc, R2 = OEpoxang, R3 = OH

0 /

AcO OH

OH (397)18' Argentiolide A

(398)'" Argentiolide B

(399)'82 Polymniolide

Sesquiterpenoids

59

new heliangolides and melampolides are depicted in structures (400)(414) 82-190 and (415)-(436)191-199 respectively. In addition to the woodhousin analogue (4 14), Picradeniopsis woodhousei from New Mexico also elaborates

m o A n g

Po

~ ~ 0' '

R

(400)'47 Liabinolide R = CHO (4O1)ls3 Scorpioidine R = C02Me

q

O

C

Me I E t

H

HO" a

R'

0

R'

R2 OH H OH

OH OH H

(4O2)ls4 Niveusin A (403) Niveusin B (404) Niveusin C

"

O

x

R3 H H H

o H H

mocd

0-&

0 0

(4O5)lg5 Viguilenin

' 1 3 '

186

190

l9' '91

193 194

19'

'91 197

'91 199

(4O6)ls6 Eucannabinolide (=20-Hydroxychromolaenide, Hiyodorilactone A, and Schkuhrin I)

M. G. B. Drew, S. P. Hitch'man, J. Mann, and J. L. C. Lopes, J. Chem. Soc., Chem. Commun., 1980,802. N. Ohno and T. J. Mabry, Phytochemistry, 1980,19, 609. A. Romo de Vivar, E. Bratoeff, E. Ontiveros, D. C. Lankin, and N. S. Bhacca, Phytochemistry, 1980,19, 1795. W. Herz and S. V. Govindan, Phytochemistry, 1980, 19, 1234. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 1547. K. Ito. Y. Sakakibara, M. Haruna, and K.-H. Lee, Chem. Lett., 1979, 1469. P. K. Chowdury, N. C. Barua, R. P. Sharma, G. Thyagarajan, and W. Herz, J. Org. Chem., 1980, 45, 535. W. Herz, S. V. Govindan, and J. F. Blount, J. Org. Chem., 1980,45, 3163. E. J. Olivier, D. L. Perry, and N. H. Fischer, J. Org. Chem., 1980, 45, 4028. F. C. Seaman, G. P. Juneau, D. R. DiFeo, S. Jungk, and N. H. Fischer, J. Org. Chem., 1979, 44, 3400. Z. Samek, M. Holub, E. Bloszyk, and B. Drozdz, Z. Chem., 1979,19,449. L. Quijano, E. J. Olivier, and N. H. Fischer, Phytochemistry, 1980, 19, 1485. F. Bohlmann, J. Ziesche, R. M.King, and H. Robinson, Phytochemistry, 1980, 19,973. F. C. Seaman and N. H. Fischer, Phytochemistry, 1980,19, 583. R. N. Barua, R. P. Sharma, G. Thyagarajan, W. Herz, and S. V. Govindan, Phytochemistry, 1980, 19, 323. A. A. Saleh, G. A. Cordell, and N. R. Farnsworth, J. Chem. SOC.,Perkin Trans. 1, 1980, 1090. F. Bohlmann, K.-H. Knoll, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 107.

60

Terpenoids and Steroids

acC

0 I1

0

(407)18' Conoprasiolide-3'-O-Acetate, R' (408) Conoprasiolide, R' = R2 = H

=

OAc, R2 R'

=

4 R3

R2

co

OAc H

(409)'" Eupalinin A

H

H 0

H

(410) Eupalinin C

OAc

co H

c o y

OAc H (41 1 ) Eupalinin B

OH

a

H

(412) Eupalinin D

OAc

CO \

O H'

'OPr'

oc+ O II

AcOw

HO

-

HO'

0 0

(413)lg9 Deacetylviguiestenin (Tagitinin E)

(414)

C0,Me

Pi

HO

0

(415)19' 9-Acetoxymelnerin A R = COBu' (416) 9-Acetoxymelnerin B R = COCHEt I Me

H

61

Sesquiterpenoids C0,Me

R'

R2

(417)'92 Repandin A

co Me

I

(418) Repandin B

(419) Repandin C

c o q H

COPri

coqI-I Me CO).HEt

(420) Repandin D

Q C0,Me

Qng CHO

0

0

OH (421)'93 Schkuhriolide

(422)194Tetraludins D-N (Various R' and R2 groups)

(423)'95 Acanthospermolide Derivative

(-&

Q n gC 0 , M e

C0,Me

'00 0

(424)'95 Longipilin Acetate

(425)'96 Tetrahelins A-F (Various R', R2, and R3 groups)

CHO

(426)19'R1 = A c , R 2 = Me (427) R' = M e , R 2 = CHzOH

Terpenoids and Steroids

62 CHO

Q 0

(428)'98 Acanthospermolide (429) Glabratolide (430) 9a-Hydroxyglabratolide (431) Acanthoglabrolide (432) Dihydroacanthospermal A (CH20H in place of CHO)

OCOPr' OCOPr' OCOPr' OCOPr' OCOPr'

OH NHCOPr'

OH

I

(433) Acanthamolide C0,Me

C0,Me

'

0 4 0 (434)'99 Isouvedalin

R2

R' OMe H OH OCOPr' OCOCMe2

HO

.J

0 4 0

Melnerin A Derivatives (435)199R1 = H, R2 = Ang (436) R' = O H , R 2 = Ang

the secoeudesmanolide (437), the guaianolide (438), and the secoheliangolide (439). Interestingly the Arizona collection of the same plant contains the two disecoeudesmanolides (440) and (441). In the same paper the X-ray structure of bahia I (442) is also reported.'" Eupachifolin-A (443) is a new example of

qoz OH

R -0 HO CH,OAc I

H :

0

OH

(437)

HOF)0"

63

Sesquiterpenoids

L '

0

-

a0 0

R

0

(440)

0

(439)

R

a.

q

H

0s. *'

0o

H

(441)

H 0

(442)

the rarer group of cis- A4*5,cisA1v10-germacrano1ides.200 This compound cooccurs with four related guaianolides, eupachifolins-B to -E (444)-(447). f i 2 C - C H E t

Me I

0 (443) Eupachifolin A

Aq (444) Eupachifolin B

(445) Eupachifolin C

02c

H ; 0

O H ' 0

(446) Eupachifolin D 2oo

(447) Eupachifolin E

K. Ito, Y. Sakakibara, and M. Haruna, Chon. Lett., 1979, 1473.

64

Terpenoids a n d Steroids

Melampodin B (448) has been shown by X-ray analysis to be a c i ~ - A ~ ' ~ , t r u n s A9*10-germacranolide.20' Tulirinol (449), on the other hand, has been identified as a trans- A4*',cis-A9v'0-germacranolide.202Arucanolide, isolated from the aerial AcO

(448) Melampodin B

(449)

parts of Calea pinnatifida, has been assigned the structure (450).203 This paper, together with a detailed analysis of other lactones from the genus C a l e ~ , ~calls O~ attention to the fact that the stereochemical assignments of several lactones from this genus require revision in keeping with the unambiguously defined structure of neurolenin B (45 1). 0

OR'

'0 (450) Arucanolide, R'

= CO<,

(451) Neurolenin B,R'

=

R2

=

Ac

Ac, R2 = COBu'

Two notable germacrane syntheses have been completed. The first one (Scheme 42) involves the synthesis of isolinderalactone (452) and epi-isolinderalactone (453), each of which undergoes a thermal Cope rearrangement to yield finderalactone (454) and neolinderalactone (455) r e s p e c t i ~ e l y . ~The '~ second synthetic achievement in this area is that of isabelin (457) in which the key step is the thermally induced opening of photoisabelin (456) to produce isabelin and its cis-A'.'o-isomef (Scheme 43).206

201

*02

' 0 3

'04 205

206

F. R. Fronczek, S. F. Watkins, N. H. Fischer, and J. W. Klimash, J. Chem. Soc., Perkin Truns. 2, 1980,1425. R. W. Doskotch, E. H. Fairchild, C.-T. Huang, J. H. Wilton, M. A. Beno, and G . G. Christoph, J. Org. Chem., 1980,45,1441. Z. S. Ferreira, N. F. Roque, 0.R. Gottlieb, F. Oliveira, and H. E. Gottlieb, Phytochemistry, 1980,19, 1481. W. Herz and N. Kumar, Phytochemistry, 1980,19, 593. A. Gopalan and P. Magnus, J. A m . Chem. Soc., 1980,102,1756. P. A. Wender and J. C. Lechleiter, J. A m . Chem. SOC., 1980,102,6341.

65

Sesq uiterpenoids H O ~ c ~ o Md i-iii e H

OMe

C0,Et

O

T

o

M

OMe

e

iv, v

~

M

e

O

T

0

k,

xii, xv, ii, xvi

(454)

Reagents: i, Li-NH,; ii, MeI; iii, LiAlH,; iv, NaH-MeI; v, aq. HCl; vi, MeCOCH(Cl)CO,Et-KOH; vii, KOH; viii, Cu-py; ix, BBr,; x, pyH+CrO,Cl-; xi, CH,=PPh,; xii, LDA; xiii, BrCH,CO,Et; xiv, NaBH,; xv, Me,N+CH,I-; xvi, Na,CO,

Scheme 42

a

66

I!

H

H

a

i

a.;

Terpenoids and Steroids

iii-viii

:

o

C0,Me

C0,Me

,

o

C0,Me

1

ix, x

-

xiii, xiv

xi, xii

0-

: H !

04-o

o.--o

:

C0,Me

o

1

xv-xviii

Reagents: i, LDA-Me,SiCI; ii, Pd(OAc),; iii, NaBH,-CeCI,; iv, PTSA; v, NBS; vi, K,CO,-NaOH; vii, RuO,; viii, CH,N,; ix, Me,CuLi; x, CH,=CHCH,I; xi, NaBH,; xii, H,O'; xiii, 0,; xiv, Ag,CO,-celite; xv, LDA; xvi, Me,N+CH21y; xvii, MeI; xviii, Na,CO,; xix, 200 "C Scheme 43

12 Elemane A full report on the identification of the six related lactones callitrin (458), callitrisin (459),dihydrocallitrisin (460), columellarin (46 l),dihydrocolumellarin (462), and the germacranolide (463) has been These compounds are the first examples of sesquiterpenoid lactones isolated from Cupressaceae. At 220 "C callitrin (458) undergoes partial isomerization to epicallitrin (464), with (458) favoured to the extent of 2 : 1.*08 Since none of the germacranolide (463) was produced in the equilibrium mixture and since epicallitrin (464) was not detected in the original extract of Allitris columellaris it is concluded that callitrin (458) cannot be derived from (463) during the extraction/isolation procedures. 207 208

D. J . Brecknell and R. M. Carman, Aust. J. Chem., 1979, 32, 2455. D. J. Brecknell and R. M. Carman, Aust. J. Chem., 1979,32, 2097.

67

Sesquiterpenoids

(46 1)

(462)

Geijerone (465) and y-elemene (466) have both been synthesized by reductive fragmentation of the keto-mesylate (468) which is readily available from the Wieland-Miescher ketone (467).209Another synthesis of the key vernolepin

(465) R (466) R

= =

0 CMe2

M SO

precursor, bisnorvernolepin (469), has been accomplished (Scheme 44).210 Tetrahydrosantonin (470) has been converted into the biologically important compound, (+)-deoxyvernolepin (47 1).211Full details of the conversion of (472) into vernolepin (473)212and the synthesis of eriolanin (474) and eriolangin (475) have been p ~ b l i s h e d . ~ ' ~ 209 210

*I1 212

213

M. Kato, M. Kurihara, and A. Yoshikoshi, J. Chem. SOC.,Perkin Trans. 1 , 1979, 2740. G . R. Kieczykowski, M. L. Quesada, and R. H. Schlessinger, J. Am. Chem. SOC.,1980, 102,782. Y. Fujimoto, H. Miura, T. Shimizu, and T. Tatsuna, Tetrahedron Lett., 1980, 21,3409; H.Miura, Y. Fujimoto, and T. Tatsuno, Synthesis, 1979, 898. H. Iio, M. Isobe, T. Kawai, and T. Goto, J. Am. Chem. SOC.,1979, 101,6076. P. A. Grieco, T. Oguri, and S. Gilman, J. Am. Chem. SOC.,1980,102, 5886.

Terpenoids and Steroids

68

1

viii, ix

o%OMeL Me0

\

I

&Me

d vii, xi

Me0

Me0

H

0

0

1

xii, xiii

.O-OMe

xiv, xv

Me0

/v,

~

Me0

H

'-0

xvi, xvii

/V

O xviii-5

o+o

M

~

Me0 O

O (469)

Reagents: i, LDA; ii, HCECCH,Br; iii, BrCH,CO,Et; iv, HgS0,-H,SO,; v, -0Bu'; vi, HC(OMe),H'; vii, LiAIH,; viii, MeOCH(Br)CH,Br-DMAP; ix, NaI; x, (Me,Si),NLi; xi, I,; xii, Bu',AIH; xiii, MCPBA; xiv, NaH-CICH,OMe; xv, LiCH,COCH(Li)CO,Bu'; xvi, i-amylnitrite; xvii, Ac,O-AcOH; xviii, PhSH-BF,; xix, Ce(NH,),(N02)6; xx, Cr0,-H'

Scheme 44

Sesqu iterpe noids

69

(471) R (473) R

(475) R

=

= =

CO

H OH

5

13 Eudesmane New eudesmane sesquiterpenoids include iso-P-costal (476),171 ivanuol (477) (and its a-epoxykudtdiol (478), 5-epi-kudtriol (479), kudtriol (480),215balanitol (481),216plucheinol (482),217the 3-epi-cuauhtemone and 3-epi-plucheinol derivatives (483) and (484),218 3a,4a-oxidoagarofuran (485),219manicol (486),220and the two selinene derivatives (487) and (488).221

OCOPh

'I5

F. Bohlmann and C. Zdero, Phytochemistry, 1979, 18, 2034. J. de Pascual Teresa, A. F. Barrero, A. San Feliciano, and M. Medarde, Phytochemistry, 1980,

'I6

G . Cordano, M. A. Merrien, J. Polonsky, R. M. Rabanal, and P. Varenne, J. Indian Chem. Soc.,

217

M. T. Chiang, M. Bittner, M. Silva, W. H. Watson, and P. G. Sammes, Phytochemistry, 1979, 18,

4I'

19, 2155.

1978,55, 1148. 2033. 218

'I9 220

221

F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochernistry, 1980, 19, 969. H. Itokawa, K. Watanabe, S. Mihashi, and Y. Iitaka, Chem. Pharm Bull., 1980, 28, 681. J. Polonsky, Z. Varon, H. Jacquemin, D. M. X. Donnelly, and M. J. Meegan, J. Chem. Soc., Perkin Trans. 1 , 1980, 2065. F. Bohlmann, C. Zdero, J. Cuatrecasas, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 1145.

Terpenoids and Steroids

70

Q H. OH (479) R (480) R

= =

H HO 0. .

*

q

o

H

0-OH (Y-OH

qlyq3y CHO

CHO

CHO

CHO

Various eudesmane diols and triols (489)-(498) have been isolated from the plant species Chenopodiurn botrys.222These co-occur with the guaiane sesquiterpenoid (499) and its acetate.

OH (489) (490) (491) (492)

R' R' R' R'

=

= = =

(497) R' (498) R' 222

R2 = H, R3 = OAC OH, R2 = R3 = H H, R2 = R3 = OH R3 = OH,R2 = H

=

=

OH OH H, R2 = OH OH,R2 = H

OAc

OAc

(493)

(499)

OH

J. de Pascual-Teresa, I. S. Bellido, and M . S. Gonzalez, Tetrahedron, 1980, 36, 371.

Sesquiterpenoids

71

Collaboration between Crombie's group at Nottingham and the U.N. Narcotics Laboratory, Geneva has led to the isolation and identification of eleven polyoxygenated sesquiterpenoids from the tree Catha edulis which is used to prepare a drug known as khat.223These complex structures (500)-(510) are all known as cathedulins with the following letter, E or K, denoting the country of origin (Et.hiopia or Kenya). 0 R' AcO / o C O P h

~co., @OR2

(500) E2 R'

=

(501)E8 R'

=

R2

=

CO

0

co

H

(502)K2 (503) K1 (504)K6 (505)K15

H , R 2 = R3 = AC R2 = R3 = Ac R' = R2 = H , R 3 = AC R' = R2 = R3 = H R'

=

R'

=

OMe

(508)E5 R' = H , R 2 = COPh (509)E6 R' = Ac, R2 = COPh = H (510)K12 R' = R2 = AC Full reports on the syntheses of hydroxyisochamaecynone ( 5 11),224 chamaecynone (5 12), isochamaecynone ( 5 13), and dihydroisochamaecynone ( 5 14)225have been published. New syntheses of juneol(5 1 3 , acolamone (516),226 and occidentalol ( 5 17)227have also been recorded. Using the olefin metathesis(506)E3 R (507)E4 R

=

Ac

"' R. L. Baxter, L. Crombie, D. J. Simmonds, D. A. Whiting, 0. J. Braenden, and K. Szendrei, J.

224 225

226

Chem. SOC., Perkin Truns. I, 1979, 2965; R. L. Baxter, L. Crombie, D. J. Simmonds, and D. A. Whiting, ibid., p. 2972; L. Crombie, W. M. L. Crombie, D. A. Whiting, and K. Szendrei, ibid., p. 2976; R. L. Baxter, W. M. L. Crombie, L. Crombie, D. J. Simmonds, D. A. Whiting, and J. Szendrei, ibid., p. 2982. M. Ando, T. Asao, and K. Takase, Bull. Chem. SOC.Jpn., 1980, 53, 1039. M. Ando, T. Asao, N. Hiratsuka, K. Takase, and T. Nozoe, Bull. Chem. SOC., Jpn., 1980,53,1425. A. K. Banerjee, H. H. Hurtado, and M. C. Carrasco, Synth. Commun., 1980, 261. Y.Mizuno, M. Tomita, and H. Irie, Chem. Lett., 1980, 107.

"'

72

Terpenoids and Steroids

( 5 14)

(511) R' = OH, R2 = Me (512) R' = Me,R2 = H (513) R' = H , R 2 = Me

/

(515) R =,

(516) R

=

H 0

transannular ene sequence (cf. Ref. 97) Wender and Letendre228have converted the tricyclic ester (5 18) into (519) by thermolysis. Elaboration of (519) gives the ketone (520) which has been used previously in the synthesis of eudesmane

F

sesquiterpenoids. Condensation of vinylacetyl chloride with the chloride (521) derived from (+)-limonene in the presence of aluminium chloride produces the two bicyclic ketones (522) and (523), the former of which has been converted into (+)-p-selinene (524) and neointermedeol (525) while occidol (526) can be derived from (523).229Another synthesis of the tricyclic alcohol (527) has been

H' Qcl (521)

qQ c1

(522)

CI

(523)

oymcpy HO

(524) 22a 229

(525)

(526)

P. A . Wender and L. J. Letendre, J. Org. Chem., 1980, 45, 367. B. D. MacKenzie, M. M. Angelo, and J. Wolinsky, J. Org. Chem., 1979, 44, 4042.

Sesquiterpenoids

73

Obtained in optically active form, this compound is not identical to the marine-derived cycloeudesmol, whose structure must be in doubt (Vol. 10, p. 7 2 ) . A further product from the strange rearrangement of 3-deoxyhexahydrosantonin (528) (Vol. 10, p.75) has been identified as the tricyclic ketone (529).231The crystal structure of 2 a - bromo-a- tetrahydrosantonin (530) has been determined,232 and the two isomers of santonin (531) have been prepared.233

q q-@--OH

H

0

(527)

(529)

(528)

Recent additions to the eudesmanolide family are illustrated in structures (532)-( 549). 5*170*234--238 The three eudesmanolides (550)-(552) co-occur with the five valerenane sesquiterpenoids (553)-(557), the major one of which has been s y n t h e s i ~ e d . ' ~ ~

HO

HO (532) Ur~ialpinolide~

GlucO

(533) Ridentin B Deri~ative'~'

Q-.qKp

0

0

(534) Taraxacolide Glucopyranoside''O 230

231 232

233

H

(535) At~thernidin*~~

D. Caine, P.-C. Chen, A. S. Frobese, and J. T. Gupton, 111, J. Org. Chem., 1979,44,4981. S . Inayama, A. K. Singh, T. Kawamata, T. Hirose, and Y. Iitaka, Chem. Len., 1979, 1219. S. V. L. Narayana and H. N. Shrivastava, J. Chem. SOC.,Perkin Trans. 2, 1980, 1116. S. Inayama, N. Shimizu, T. Shibata, H. Hori, and Y. Iitaka, J. Chem. SOC.,Chem. Commun., 1980, 495.

234

23s 236 237

238 239

W. W. Epstein and E. E. U. Jenkins, J. Nut. Prod., 1979,42, 279. F. Bohlmann, K.-H. Knoll, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 971. F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 689. M. Uchida, Y. Koike, G. Kusano, Y. Kondo, S. Nozoe, C. Kabuto, and T. Takernoto, Chem. Pharm. Bull., 1980, 28,92. F. Bohlmann, L. N. Dutta, W. Knauf, H. Robinson, and R. M. King, Phytochemistry, 1980,19,433. F. Bohlmann and M. Lonitz, Chem. Ber., 1980, 113, 2410.

74

Terpenoids and Steroids

wo (J-Jq0 mo m0 (536) Ivangustin Derivative235

(537) O n ~ s e r i o l i d e ~ ~ ~

1

1

m

o

H

H

(538) Chloranthalactone A237

AcO

(539) B237

/

(540) C237

1

H

(542) E237

(541) D237

(543) F237 (= Atractylenolide 111)

(544) 8-Epia~terolide~~'

(547) R (548) R

=

=

(545) R (546) R

a-Me Isoasterolide &Me Isoasterolide B238

= =

H A~terolide~~~ OH 8P-Hydroxya~terolide~~~

(549) 8,9-Dehydroa~terolide~~~

c;c?. q. ?R

OCOCHMe,

0

(550)

0

(551) R = COC(Me)=CH2 (552) R = COC(CH20H)=CH2

75

Sesquiterpenoids

(553) R' (554) R' (555) R'

= = =

Me,R2 = CH20H Me,R2 = CHO CH20H,R2 = Me

(556) R (557) R

=

=

CHO CH20H

Full reports of the syntheses of frullanolide (558),24" 3-oxodiplophyllin (559),241yomogin (560),241 dihydrocallitrisin (561), epialantolactone (562), epiisoalantolactone (563), and atractylon (564)242have been presented. Another synthesis of vulgarin (565) has been

qq+

; 0

(558)

(559) (560)

l

o double bond

14 Vetispirane

In a continuing investigation of sesquiterpenoid stress compounds from Nicotiana species it has been shown that phytuberin (566) and phytuberol (567) are produced on treatment of N . tabacurn with the ethylene-releasing substance Phytuberol is also generated on inocuethrel (2-chloroethylphosphonic lation of N . rustica with tobacco mosaic virus (TMV),245and solavetivone (568) 240 241

242 243 244 245

F. Kido, K. Tsutsumi, R. Maruta, and A. Yoshikoshi, J. Am. Chem. SOC.,1979, 101, 6420. D. Caine and G. Hasenhuettl, J. Org. Chem., 1980, 45, 3278. A. G . Schultz and J. D. Godfrey, J. A m . Chem. SOC.,1980, 102, 2414. M. Ando, K. Tajima, and K. Takase, Bull. Chem. SOC.Jpn., 1979, 52, 2737. R. Uegaki, T. Fujirnori, H. Kaneko, S. Kubo, and K. Kato, Phytochemistry, 1980, 19, 1543. R. Uegaki, T. Fujimori, H. Kaneko, S. Kubo, and K. Kato, Phytochemistry, 1980, 19, 1229.

76

Terpenoids and Steroids

production is markedly increased on infection of N. tabacum with TMV.24hThe same research group has also noted the occurrence of phytuberol in the healthy leaves of N . tabacum cv. S u i f ~ . ~In~ a' related study the glycoside (569) and the corresponding aglycone (570) have been isolated from potato tubers infected .~~~ the glycoside was previously detected in a with Phoma e ~ i g u aInterestingly flue-cured Virginia tobacco extract.

(566) R (567) R

= =

AC H

(568)

(569) R (570) R

=

Gluc

=

H

A full paper describing the photochemical interconversion of various crossconjugated dienones and spiro-dienones of sesquiterpenoid interest has been As an example of the results published with a thorough mechanistic from this study, reaction conditions have been developed for the photochemical rearrangement of 3,4-dehydronootkatone (571) to anhydro-P-rotunol (572). In have examined the acid-catalysed rearrangea subsequent paper Caine et ments of some dihydro-lumiproducts; e.g. boron trifluoride treatment of (573) gives mainly 11,12-dihydronootkatone (574) whereas (575) produces 11,12dihydrosolavetivone ( 576).

(576)

'

An excellent example of the use of *H n.m.r. spectroscopy for biosynthetic studies is seen in the work of Stothers et a1.,251who have provided very good evidence for the involvement of a hydride shift in the biosynthesis of capsidiol (577). Thus incorporation experiments with [4,4-2H,]mevalonolactone revealed the presence of deuterium atoms at C-1, C-4, and C-7 and this has been interpreted in terms of Scheme 45. 246

247 248 249

250 25'

T. Fujimori, R. Uegaki, Y. Takagi, S. Kubo, and K. Kato, Phytochemistry, 1979, 18,2032. Y. Takagi, T. Fujimori, H. Kaneko, and K. Kato, Agric. Biol. Chem., 1979,43, 2395. A. G. Malmberg and 0.Theander, Phytochemistry, 1980, 19, 1739. D. Caine, C.-Y. Chu, and S. L. Graham, J. Org. Chem., 1980, 45, 3790. D. Caine, S. L. Graham, and T. T. Vora, J. Org. Chem., 1980, 45, 3798. Y. Hoyano, A. Stoessl, and J. B. Stothers, Can. J. Chem., 1980, 58, 1894.

77

Sesquiterpenoids

1 HO“ Scheme 45

(577)

Full details of the structural determination of the phytoalexins (+)glutinosone (578) and (+)-oxyglutinosone (579),252 together with the synthesis of (578), have been

HO (578) R (579) R

= =

H OH

15 Eremophilane, Nootkatane, Ishwarane New eremophilane sesquiterpenoids include (580),254the two petasol derivatives (581) and (582),”’ and the closely related metabolites eremofortins A-E (583)-(587), which are obtained from Penicilliurn r o q h e f ~ r t i . ~ ~ ~

un

- OTig (582) RL = OSen /en*\

q

(3bl) H

OH

252

253 254

”’ 256

(583)R (585) R (587) R

=

= =

Me CHZOH CONHz

A. Murai, H. Taketsuru, F. Yagihashi, N. Katsui, and T. Masamune, Bull. Chem. SOC.Jpn., 1980, 53, 1045. A. Murai, H. Taketsuru, and T. Masamune, Bull. Chem. SOC.Jpn., 1980, 53, 1049. F. Bohlmann and C. Zdero, Phytochemistry, 1980,19,1550. C. Zdero, F. Bohlmann, H. Robinson, and R. M. King, Phytochemistry, 1980,19,975. S . Moreau, J. Biguet, A. Lablache-Combier, F. Baert, M. Foulon, and C. Delfosse, Tetrahedron, 1980,36,2989.

Terpenoids and Steroids

78

R

=

(589) R

=

(588)

C02H CH20H

q o x g-qo\

R

OH

(591) R (592) R

= =

OH H

(593)

g--& (594)

Quite a large number of relatively straightforward syntheses of several eremophilane sesquiterpenoids have been reported in the year under review. These include isovalencenic acid (588),257 isovalencenol (589),257 dehydrofukinone (590),258furanofukinol (591),259petasalbin (592),259ligularone (593),260*261 isoligularone (594),260eremophilenolide (595),262and the conversion of fukinone (596) into furanoeremophilane (597) has been recorded.263 The known dimethyloctalone (598) has been shown to be a versatile synthetic intermediate. Thus it has been transformed into (599) which, on reaction with LDA followed by methyl a-bromoacrylate, gave the tetracyclic keto-ester (600) in 20% yield. This compound was readily converted into ishwarane (601).

The enone has also been used as the starting material for the synthesis of dehydrof ukinone (590), hydroxyeremophilone (602), 9 , l O-dehydrof uranoeremophilane (603), 10a-furanoeremophilone (604), and 9,lO-dehydrofuranoeremophil-l-one (605).264

’” A. R. Pinder, J. Chem. SOC.,Perkin Trans. 1, 1980, 1752. 258 259 260

261 262

263 264

S. Torii, T. Inokuchi, and T. Yamafuji, Bull. Chem. SOC.Jpn., 1979,52, 2640. K. Yamakawa and T. Satoh, Chem. Pharm Bull., 1979,27,1747. M. Miyashita, T. Kumazawa, and A. Yoshikoshi, J. Org. Chem., 1980,45,2945. M. Tada, Y. Sugimoto, and T. Takahashi, Chem. Lett., 1979, 1441. S. Pennanen, Acta Chem. Scand., Ser. B , 1980,34, 261. T. Sato, M. Tada, and T. Takahashi, Bull. Chem. SOC.Jpn., 1979,52, 3129. H. Hagiwara, H. Uda, and T. Kodama, J. Chem. SOC.,Perkin Trans. 1, 1980, 963.

79

Sesq uiterpenoids

Full details of the synthesis of (+)-nootkatone (606) from (+)-nopinone (607) have been described.265The rearranged eremophilane phenol cinalbicol (608) has also been synthesized.266

16 Guaiane, Pseudoguaiane, Patchoulane, Seychellane New additions to the guaiane family include sclerosporin (609),267sclerosporal (610),267sclerosporene (611),267the guaienes (612) and (613)-[which co-occurs with precatabrone (614)],268 and the guaioxide (615).269 The unusual pseudoguaiane caespitenone (616) has been isolated from the liverwort Porella c a e s p i t ~ n s . *This ~ ~ compound co-occurs with (+)-arktolone (617) and (-)a-eudesmol (618), which are enantiomeric to those found in higher plants.

I

(609) R (610) R

26s 266

*" "*

269 270

= =

COzH CHO

(612) R (613) R

= =

H OH

T. Yanami, M. Miyashita, and A. Yoshikoshi, J. Org. Chem., 1980,45,607. F. Bohlmann and E. Eickeler, Chem. Ber., 1980,113,1189. M. Katayama and S. Marumo, Tetrahedron Lett., 1979,1773. F.Bohlmann and J. Jakupovic, Phytochemistry, 1979,18,1987. H.Hirota, Y.Tanahashi, and T. Takahashi, Bull. Chem. SOC.Jpn., 1980,53,785. Y. Asakawa, A. Yarnamura, T. Waki, and T. Takemoto, Phytochemistry, 1980,19,603.

80

Terpenoids and Steroids

(617)

(618)

The new guaian-6cu,l2-olides are listed in the Table'71*27'-280and the others are represented by structures (619)-(622).28'-283 The new pseudoguaianolides are depicted by structures (623)-(631).283-289

\

' I

--_

0

0

0

(619) Absinthin281

(622) H y r n e n o ~ i g n i n ~ ~ ~

27'

272 273 274

275 276 277 278

279 280

282

283 284 285

'*' 287 288

289

0

R (620) Xantholide A R (621) Xantholide B R

= =

=CH2282 a-Me,H

(623) A~etylhymenograndin~'~

P. Barbetti, C. G. Casinovi, B. Santurbano, and R. Longo, COIL.Czech. Chem. Commun., 1979, 44,3123. S. B. Christensen, U. Rasmussen, and C. Christophersen, Tetrahedron Lett., 1980, 21, 3829. F. Bohlmann and J. Ziesche, Phytochemistry, 1980, 19, 692. F. Bohlmann, K.-H. Knoll, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 599. F. Bohlmann and R. Bohlmann, Phytochemistry, 1980, 19, 2045. F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1980,19, 1873. F. Bohlmann, A. Suwita, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 1233. W. Herz, N. Kumar, W. Vichnewski, and J. F. Blount, J. Org. Chem., 1980,45, 2503. G. Y. Papano, P. Y. Malakov, and F. Bohlmann, Phytochemistry, 1980,19, 152. N. Ohno, J. Gershenzon, C. Roane, and T. J. Mabry, Phytochemistry, 1980,19, 103. J. Beauhaire, J. L. Fourrey, M. Vuilhorgne, and J. Y. Lallemand, Tetrahedron Lett., 1980,21,3191. T. Tahara, Y. Sakuda, M. Kodama, Y. Fukazawa, S. Itb, K. Kawazu, and S. Nakajima, Tetrahedron Lett., 1980, 21, 1861. W. Herz, S. V. Govindan, M. W. Bierner, and J. F. Blount, J. Org. Chem., 1980, 45, 493. X. A. Dominguez, R. Frnaco, F. Bohlmann, and R. Bohlmann, Phytochemistry, 1980, 19, 2204. F. Bohlmann, E. Rosenberg, H. Robinson, and R. M. King, Phytochemistry, 1980,19,2047. S . Gill, W. Dembinska-Migas, E. Sliwinska, W. M. Daniewski, and F. Bohlmann, Phytochemistry, 1980,19,2049. F. Bohlmann, J. Jakupovic, L. Dutta, and M. Goodman, Phytochemistry, 1980,19, 1491. D. Sims, K.-H. Lee, R.-Y.Wu. H. Furukawa, M. Itoigawa, and K. Yonaha, J. Nut. Prod., 1979, 42, 282. W. Herz, N. Kumar, and J. F. Blount, J. Org. Chem., 1979, 44, 4437.

81

Sesquiterpenoids .14

Table (la,SaH Guaian-6a,l2-olides stereochemistry unless otherwise stated)

Q 3 15

Double bond position (s)

Name

Substiluen Is

11,13; 9,lO 9,lO 4,15; 9,lO 3,4; 11,13; 1,lO

2-keto; &-OH

4,15; 10,14; 11,13 10,14; 11,13 495

Subluteolide* (also l l a - M e ) Rupicolin-A* Rupicolin-B* Desacetyl-zuurbergein Hyporadiolide*

10,14; 11,13 3,4; 10,14; 11,13 3,4; 9,lO; 11,13 3,4; 1,lO; 11,13 3,4; 11,13 3,4; 11,13 3,4; 11,13; 1,lO 3,4; 11,13; 10,4

Eregoyazin Dihydroeregoyazidin 8P- Hydroxydihydroeremanthin 11,13-Dehydrodesacetylmatricarin

* Derivative of.

H

L

Ref.

3&(2-Methylbutyrate) 171 4a-Me; 3-keto; @-OH 271 2 -OCO(CH&,Me; 272 3-OAng; 7,ll-diOH; 8-OCO(CH2)2Me; 10-OAc 3P-OH; 4a,l5a-epoxy; 273 8a- OCO(Me)=CHZ l a - 0 0 H ; 8a-OH(OAc) 274 la-OOH; 8a.-OH(OAc) 274 8a-OH 274 2-keto; 15-OH; 10a-Me; 275 8a- OCinn(Meacr) 2P-OH; 8P-OTig; 276 lOa,l4a-epoxy; 9a-OH 2-keto; 5a-OH; 14-OH; 277 8P- OTig 2p-OH; 5a-OH; 277 8P- OAng 3-keto; 4a-Me 278 3-keto; 4a-Me; l l a - M e 278 8P-OH; 11P-Me 279

Zaluzanin-C* 8-epi-Grosheimin Thapsigargin

Agriant holide (also 3a,4a-epoxy) Sa-HydroxyEupasessifolide-B Preeupatundin*

13

O

(624) Linearifolin Derivative284

(625) Wedelifloride Derivatives (Various R' and R2

280

Terpenoids and Steroids

82

oq$ OH

0

Spathulin Derivatives R

RZO

=

O'H

Ang or i-Va12s6

0

(627) 4-Hydroxynorpsilotr~pin~~'

..

T I

OR'

\OR

Hymenoxone Derivative R'

=

H, R2

=

Hymenolide Derivative R'

=

Et, R2

=

Ac

(630) Isoheleno1288

Ac287

(631)289

A neat synthesis of bulnesene (632) has been achieved in which the key steps are an intramolecular photochemical addition and a subsequent fragmentation (Scheme 46).290Another transformation of eremanthin (633) into estafiatin (634) has been a c ~ o m p l i s h e d .Considerable ~~' activity in the field of pseudoguaianolide synthesis has resulted in the conversion of the previously reported bicyclic ketones (635) and (636) (Vol. 10, p. 90) into aromaticin (637),292aromatin (638),292and damsinic acid (639).293Vandewalle and co-workers have also capitalized on earlier syntheses of key intermediates (Vol. 9, p. 151; Vol. 10, p. 89) to convert (640) into carpesiolin (641)294and (642) into hysterin (643), which required structural revision as a result of this This revision has been confirmed by X-ray analysis.296Roberts and Schlessinger have 290 291

292 293

294

295 296

W. Oppolzer and R. D . Wylie, Helu. Chim. Acta, 1980, 63, 1198. L. A. Macaira, F. W. L. Machado, M. Garcia, and J. A. Rabi, Tetrahedron Lett., 1980, 21, 773. P. T. Lansbury, D. G. Hangauer, jun. and J. P. Vacca, J. A m . Chem. Soc., 1980,102, 3964. P. T. Lansbury, A. K. Serelis, J. E. Hengeveld, and D . G . Hangauer, jun., Tetrahedron, 1980,36, 2701. P. Kok, P. J. D e Clercq, and M. E. Vandewalle, J. Org. Chem., 1979,444553. M. Demuynck, P. J. D e Clercq, and M. E. Vandewalle, J. Org. Chem., 1979,44, 4863. J. P. Declercq, G. Germain, M. Van Meerssche, M. Demuynck, P. D e Clercq, and M. E. Vandewalle, Acta Crystallogr., 1980, B36, 213.

83

Sesquiterpenoids

Reagents: i, h v ; ii, MeMgI; iii, KOH; iv, MsCI-Et,N; v, Me,C=PPh,

Scheme 46

Bu'O

'0

Bu'O (636)

-_

0

0

qo

(Q

0

0

/

(639)

- -0 THPO (640) R (642) R

OH = =

CH2 0

(641)

CO,H

Q

AcO

(643)

84

Terpenoids and Steroids

used the bicyclic enone (644) as the common starting material for the syntheses of helenalin (645),297confertin (646),298and damsin (647)298(Scheme 47). In Grieco's synthesis of various pseudoguaianolides (Vol. 9, p. 151; Vol. 10, p. 89) the key bicyclic enone (649) has featured as a valuable intermediate. This compound has now been synthesized by a shorter, more efficient route starting from (648).299 Two diastereoisomers (650) and (651) of furopelargones A (652) and B (653) have been synthesized by conjugate addition of the Grignard reagent derived from 2-bromo-3-isopropylfuran to (654).300In an attempt to improve an earlier synthesis of seychellene (657) (Vol. 9, p. 155) Jung and Pan301 have

Bu'O

Bu'O

Bu ' 0

lv lxiii-xv

xix-xxi,

XVI-XVIII

0 -

0

xiv, xvii'

I

'HPO

THPO

OSiMe,

1

xxii-xxiv

Scheme 47 297

298 299

300

301

M. R. Roberts and R. H. Schlessinger, J. A m . Chem. SOC.,1979, 101, 7626. G. J. Quallich and R. H. Schlessinger, J. Am. Chem. SOC.,1979,101,7627. P. A. Grieco and Y. Ohfune, J. Org. Chem., 1980,45, 2251. A. Takeda, K. Shinhama, and S. Tsuboi, J. Org. Chem., 1980,45, 3125. M. E. Jung and Y.-G. Pan, Tetrahedron Lett., 1980, 21, 3127.

85

Sesquiterpenoids

xxx

xxvi, xxix,

c-

xxiii

0

HO

AcO

(646) Txxviii

xxv, xvii,

Bud

1

C0,Bu'

xvi-xviii

-

xix,

xxvi, xxx

xxxiBu'O

Bu'O

bH C0,Bu'

1

9Q

xxviii, xxxii, xxvi

xxix, xvii, xxx

0

AcO

(647)

0

0

Reagents: i, MeNHOH.HC1-py; ii, TsC1-py; iii, LiCH,PO(OMe),; iv, NaOAc-AcOH; v, -0Bu'; vi, MeMgBr-CuI-Me$; vii, HCI; viii, HO(CH,),OH-H'; ix, PCC; x, Ph,S,-NaH; xi, MCPBA; xii, A; xiii, Bu',AlH; xiv, H,O';

xv,

(2 I

H'; xvi, LiN(SiMe,),; xvii, Me,SiCl;

xviii, Pd(OAc),; xix, NaOH-H,O,; xx, Bu',Al; xxi, LiCH,CO,Li; xxii, MMC; xxiii, CH,O-Et,NH; xxiv, MnO,; xxv, Me,CuLi; xxvi, H,-Rh.A1203; xxvii, ICH,CO,Bu'; xxviii, Ac,O-HClO,; xxix, KOH; xxx, 00,-H'; xxxi, N,H,-AcOH; xxxii, Ac,O-NaOAc

Scheme 47 (conf.)

Terpenoids and Steroids

86

-f

(654)

succeeded in a seven-step synthesis (Scheme 48) in which the only drawback is the low-yield cyclization ( 5 % ) of (655) to give (656). Treatment of (655) with TiC14 promotes a retro-Michael reaction rather than the desired intramolecular cyclization. An interesting synthesis of norpatchoulenol(659) has been recorded in which the final ring closure appears to proceed by a ScN,mechanism involving anionic attack on the allylic methoxymethyl ether (658) (Scheme 49).302A

(656):

(655)

1

ii-iv

(657)

(major isomer) ,

Reagents: i, TiCl,; ii, MeLi; iii, POCI,-py; iv, H,-Pd/C; v, SOCI,

Scheme 40

CHO

OAc-; iv, H,C=CHMgBr; v, Et$CH,OMeCI-;

Reagents: i, A; ii, H,-Pd/C, iii,

H2 302

liv

Scheme49

M. Bertrand, P. Teisseire, and G. Pelerin, Tetrahedron Lett., 1980, 21, 2051

vi, Na

Sesquiterpenoids

87

similar methodology has been used to convert the methyl analogue (660) of (658) into patchoulol (661).303

17 Bicyclogermacrane, Maaliane, Aromadendrane The continuing search for novel sesquiterpenoids from liverworts and marine organisms has added significantly to this section and of particular interest are the wide variety of secoaromadendrane sesquiterpenoids now known. Thus (-)-isobicyclogermacrenal (662) has been isolated from the liverwort Lepidozia u i t ~ e a . ~This O ~ compound, which inhibits the growth of rice, is the first naturally occurring isobicyclogermacrane sesquiterpenoid. Two new metabolites from the soft coral Pararythropodium fulvurn have been identified as the bicyclogermacrene derivatives (663) and (664), which co-occur with two lemnalane derivatives, lemnacarnol (665) and 2-oxolemnacarnol (666).305The biogenetically R'

(663) R (664) R

(662)

= =

(665) R' (666) R'

OAc

OH

= =

H,R2 = OH R2 = 0

related compounds (667) and (668) have been isolated from another soft coral, Paralemnalia thyr~oides.~'~ Yet another soft coral, Lemnalia humesi, elaborates the two aristolane compounds (669) and (670).307

Po A $J3J p

:

4)

(667)

303 304

305

306 307

OAc

H

OH

(668)

(669) R' (670) R'

=

=

R2 = 0 H,R2 = OH

M. Bertrand, P. Teisseire, and G. Pelerin, Tetrahedron Lett., 1980, 21, 2055, A. Matsuo, N. Kubota, S. Uto, M. Nakayama, S. Hayashi, and K. Yamasaki, Chem. Lett., 1979, 1383. B. F. Bowden, J. C. Coll, S. J. Mitchell, J. L. E. Nemorin, and S . Sternhell, Tetrahedron Lett., 1980,21,3105. B. F. Bowden, J. C. Coll, and S. J. Mitchell, Aust. J. Chem., 1980, 33, 885. B. F. Bowden, J. C. Coll, and S. J. Mitchell, Aust. J. Chem., 1980, 33, 681.

Terpenoids and Steroids

88

An examination of the sesquiterpenoid constituents of the liverwort Plagiochila semidecurrens has resulted in the isolation of ovalifoliene (=plagiochiline C) (67 1),308 hanegokidial (672),308 and ovalifolienalone (673).309A related and wide ranging investigation of other Plagiochila species

has led to the identification of (-)-maalian-5-01 (674),310furanoplagiochilal (675), plagiochilin G (676), plagiochiline H (678), plagiochiline I (677), and ? the methoxyplagiochilines A1 (679), A, (680), and C (681), these latter three compounds being artefacts of the isolation p r ~ c e d u r e . ~ " *Most ~ ' ~ interesting is the isolation of the C-3 epimer of the acetoxybicyclogermacrene (663) from P. yokogurensis, which was mentioned earlier as a soft coral metabolite. Plagio-

(676) R' (677) R'

(679) R' (680) R'

'08

309 'lo 311

'12

= =

=

=

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

OMe,R2 = H H,R2 = OMe

A. Matsuo, K. Atsumi, M. Nakayama, S. Hayashi, and K. Kuriyama, J. Chem. SOC., Chem. Commun., 1979,1010. A . Matsuo, H. Nozaki, K.Atsumi, H. Kataoka, M. Nakayama, Y. Kushi, and S. Hayashi, J. Chem. SOC.,Chem. Commun., 1979,1012. A. Matsuo, H. Nozaki, H. Kataoka, M. Nakayama, and S. Hayashi, Experientiu, 1979, 35, 1279. Y. Asakawa, M. Toyota, and T. Takemoto, Phytochemistry, 1980,19,2141. Y. Asakawa, M. Toyota, T. Takemoto, I. Kubo, and K.Nakanishi, Phytochemistry, 1980,19,2147.

89

Sesquiterpenoids

chiline A (682) is also shown to be a very potent anti-feedant of the African army worm. Taylorione (683), an unusual ent- 1,lO- secoaromadendrane sesquiterpenoid ' ~ been synthesized from (+)from the leafy liverwort Mylia t a y l ~ r i i , ~has A3-carene.314

18 Miscellaneous The non-isoprenoid aromatic ester methyl nidorellaurinate (684) has been synthesized.315Another non-isoprenoid compound is upial (685), which has ~~ the rare been isolated from the marine sponge Dysidea f r ~ g i l i sIt. ~possesses bicyclo[3.3.l]octyl system and possibly it is related to microcionin-4 (686),

(685)

another sponge metabolite (Vol. 7, p. 57). Following closely behind the two syntheses of 9-isocyanopupukeanane (688) reported last year (Vol. 10, p. 101) is a third synthesis of the tricyclic ketone (687), which has already been converted into (688).317Like one of the previous routes this synthesis uses a very facile intramolecular Diels-Alder reaction for the construction of the tricyclic framework (Scheme 50). 313 314

315

316 317

A. Matsuo, S. Sato, M. Nakayama, and S. Hayashi, J. Chem. SOC.,Perkin Trans. 1, 1979,2652. M. Nakayama, S. Ohira, S. Shinke, Y. Matsuchita, A. Matsuo, and S. Hayashi, Chem. Lett., 1979, 1245. R. Sangaiah, and G. S. Krishna Rao, Tetrahedron Lett., 1980,21, 2767. G. Schulte, P. J. Scheuer, and 0.J. McConnell, J. Org. Chem., 1980,45, 552. G. A. Schiehser and J. D. White, J. Org. Chem., 1980, 45, 1864.

Terpenoids and Steroids

90 OMe

OMe

OMe

C0,Me Et0,C

ko -Q OMe

OMe

viii, vii

6 liv, v

c vi,vii-

CHO

C0,Me

Reagents: i, Zn/Ag-CH,I,; ii, N,CHCO,Et-Cu; iii, H+-MeOH; iv, HC(OMe),-H+; v, A; vi, LiAIH,; vii, py.SO,-Me,SO-Et,N; viii, H,C=CHMgBr; ix, H,C=CMeLi; x, Me,SO, A; xi, H2PtO,

Scheme 50

Diterpenoids BY J. R . HANSON

1 Introduction This chapter follows the sequence of the previous Reports with sections based on the major skeletal types of diterpenoids. The literature that has been covered was that available to August 1980. There have been a number of novel diterpenoid skeleta described during the year based on alternative modes of discharge of the carbocation derived from the initial cyclizations of geranylgeranyl pyrophosphate. Diterpenoids of different skeletal types appear to be characteristic taxonomic markers in a current survey of the Compositae. The useful Kyoto series of reviews of diterpenoid chemistry has been continued.'

2 Alicyclic and Related Diterpenoids A further pair of alcohols, (1)and (2),derived from geranylgeraniol and showing inhibitory action against ulcers, has been obtained from Croton species.* Similar compounds [e.g. (3) and (4)] and some 'prenylated monoterpenoid skeleta' such

CH,OH (1) R = CH20H

(2) R = CHO

' E. Fujita, K.Fuji, Y.Nagao, and M. Node, Bull. Inst. Chem. Res., Kyoto Univ., 1979,57,260,385. ' A. Sato, A. Ogiso and H. Kuwano, Phytochemistry, 1980,19,2207. 91

92

Terpenoids and Steroids

as geranyl-a-terpinene, have been found in an extensive survey of Helichrysum and they may be more common than has hitherto been realized. Epoxyeleganolone (5) and 13-alcohol eleganediol were obtained' from Bifurcuria bifurcata (Cystoseiraceae).

3 Bicyclic Diterpenoids Labdanes.-The E-configuration of dehydropinifolic acid (6) has been confirmed6 by the use of n.m.r. shift reagents. The viscidic acids A and B, which were obtained from Chrysothamnus viscidiflorus (Compositae), are' ent- 15-hydroxylabda-8,13-dien-18-oic acid and the corresponding acetate. 19-Noranticopalic acid has been isolated' from Agathis lanceolata. A number of 3-oxygenated labda-7,13-dien-15-oic acids have been isolated' from Chrysotharnnus nuuseusus (Compositae) whilst a group of 3-, 7-, 8-, and 17-oxygenated labdanes was found in Ayapana arnygdalina.'o Stevinsol (=austroinulin) (7) was obtained from Stevia salicifolia '' and S. rebaudiana.'* The X-ray analysis of acetyl-laurifolic acid (6a-acetoxy-8cu-hydroxylabd-13-en-15-oic acid) has been acid described. l 3 (14 s ) - 14,15-Dihydroxylabda-8( 17),13(16)-dien-l9-0ic acid were amongst the acids together with 7-oxo-13-epipimara-8,15-dien-18-oic ~ b t a i n e d from ' ~ Juniperus comrnunis. The abienol derivatives (8) were isolated" from Aristeguietia buddleaefolia (Compositae).

g3 CO,H (6)

w:

'0 H

OAc

(7)

(8)

F. Bohlmann and W. R. Abraham, Phytochemistry, 1979,18,1754. F. Bohlmann, C. Zdero, W. R. Abraham, A. Suwita, and M. Grenz, Phytochemistry, 1980,19,873. J. F. Biard, J. F. Verbist, R. Floch, and Y . Letourneux, Tetrahedron Lett., 1980, 1849. T. Norin, S. Sudin, and 0. Theander, Acta Chem. Scand., Ser. B, 1980,34,30. ' N. Le Van and T. Van Wong Pham, Phytochemistry, 1980,19, 1971. * Duc D o Khac, J. Bastard, and M. Fetizon, Phytochemistry, 1979,18, 1839. F. Bohlmann, L. Dutta, H. Robinson, and R. M. King, Phytochemistry, 1979,18, 1889. l o F. Bohlmann, K. H. Knoll, R. M. King, and H. Robinson, Phytochemistry, 1979,18, 1997. A. Ortega, R. Martinez, and G. L. Garcia, Rev. Latinoam. Quim., 1980, 11, 45 (Chem. Abstr., 1980,93,22 603). M. Sholichin, K. Yamasaki, R. Miyama, S. Yahara, and 0.Tanaka, Phytochemistry, 1980,19,326. l3 P. Smith-Verdier, F. Florencio, and S . Garcia-Blanco, Crystal Structure Commun., 1979, 8, 537. l4 J. d e Pascual Teresa, A. F. Barrero, L. Muriel, A. San Feliciano, and M. Grande, Phytochemistry, 1980,19, 1153. F. Bohlmann, E. Rosenberg, R. M. King, and H . Robinson, Phytochemistry, 1980,19,977.

93

Diterpenoids

A series of furanoid 7P-acetoxylabdanes [e.g. (9)] was found16 in Austroeupatorium chaparense (Compositae) whilst galeopsin (10) (8P -acetoxyhispanolone) and the corresponding pre-furan were obtained," along with hispanolone, from Galeopsis angustifolia (Labiatae). The furan daniellol and the corresponding lactone (11) have been isolated'' from Xanthocephalum linearifolium (Compositae).

CHO .&CH,OH

m q o

1.'

CH,OH

Sensitized photo-oxygenation of (12E)-abienol affordslg products oxygenated at C-12 that are reminiscent of the tobacco labdanoids. Amongst new labdane derivatives with 8,12-ether bridges are (12), which was isolated2' from a group of Silphiurn species. The cyclization reactions of manool derivatives have continued to attract attention.21 A synthesis of the strobane skeleton based on oxymercuration reactions of 13-epimanool has been described.22*The oxidation of sclareol by chromium salts has been re-examined in a series of papers.23 The circular dichroism curves of manoyl oxide and its 13-epimers have been examined.24 Some further 11-oxomanoyl oxide derivatives, coleonol E and F, (13) and (14), l6

l9 20

21 22

23

24

F. Bohlmann, A. Suwita, R. M. King, and H. Robinson, Phytochemistry, 1980,19, 11 1. B. Rodriguez and G. Savona, Phytochemistry, 1980,19,1805;J. Lopez de Lerma, S. Garcia-Blanco, and J. G . Rodriguez, Tetrahedron Lett., 1980, 1273. F. Bohlmann, W. Knauf, M. Grenz, and M. A. Lane, Phytochemistry, 1979, 18, 2040. K. Nordfors, I. Wahlberg, M. Curvall, T. Nishida, and C . R. Enzell, Acta Chem. Scand. Ser. B, 1979, 33,437. F. Bohlmann and J. Jakupovic, Phytochernistry, 1979, 18, 1987. P. F. Wad, N. D. Ungur, and M. N. Kiltsa, Khim. Prir. Soedin., 1979, 581. Y. Matsuki, M. Kodama, and S. Ito, Tetrahedron Lett., 1979, 4081. P. F. Wad, M. N. Koltsa, V. E. Sibirtseva, and S. D. Kustova, Zh. Obshchei Khim., 1980, 50, 195 et seq. J. M. Bernassau, M. Fetizon, and I. Hanna, Tetrahedron, 1979, 35, 1649.

Terpenoids and Steroids

94

mo 0R’ “OR2

(13) R’ (14) R’

= =

R3 = H,R2 = AC OH, R2 = H, R3 = AC

were from Coleus furskohlii. The oxidized derivatives (15) and (16) were obtained26from Schkuhria (Compositae) species. 2-Ketomanoyl oxide (17), which is readily obtained from Podocarpus species, has been converted2’ into the 3-hydroxy-norlabdene acid (18), which is a useful triterpenoid synthon. A lactone (19), related to lagochilin, has been detected28 in Lagochilus hirsutissirnus. The order of acetylation of the hydroxy-groups of lagochilin is C-15 > C-16 > C-18 > C-3.29

,CO,H

o&--y

(17)

QJJ

HO

(18)

(19)

The configuration at C-13 in the prefuran 9:13-ethers has continued to attract attention. N.m.r. studies have been recorded3’ on some premarrubiin derivatives. The X-ray crystal structures of leonitin (20), methoxynepetaefolin (21), and nepetaefolinol (22) have been The C-13 configuration of the bromine-containing diterpenoid isoaplysin-20 was determined33 by a partial ” 26

27 28

29

30

31

32 33

P. Painuly, S. B. Katti, and J. S. Tandon, Indian J. Chem., Sect. B,1979, 18, 214. F. Bohlmann, J. Jakupovic, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 881. R. C. Cambie, S. H. Leong, B. D. Palmer, and A. F. Preston, Aust. J. Chem., 1980, 30, 155. M. P. Nurmatova, U. N. Zainutdinov, F. G. Kamaev, and Kh. A. Aslanov, Khim. Prir. Soedin., 1979,788. Z. I. Mavlyankulova, U. N. Zainutdinov, S. I. Mukhamedkhanova, V. B. Leont’ev, and Kh. A. Aslanov, Khim. Prir. Soedin., 1980,46. G. Laonigro, R. Lanzetta, M. Parrilli, M. Adinolfi, and L. Mangoni, G a z z . Chim. Ital., 1979, 109, 145. G. J. Kruger and D. E. A. Rivett, S. Afr. J. Chem., 1979,32, 59. J. F. Blount and P. S. Manchand, J. Chem. SOC.,Perkin Trans. 1, 1980, 264. P. M. Imamura and E. A. Ruveda, J. Org. Chem., 1980,45,510.

Diterpenoids

Afl

95

,OMe

co-0

OAC

OH

synthesis from methyl isocopalate. The full paper on the structure of hardwickiic acid has been published.34 The unusual cyclopropane structure (23) has been for a labdane isolated from Gnaphalium indulatum. C1erodanes.-The reversal of the absolute configuration assigned to clerodin has led to some controversy over that assigned to the ajugarins. They now appear to Teucrium (Labiatae) have the neo-clerodane absolute stere~chemistry.~~*~’ species have continued to be a source of new clerodanes. Eriocephalin, isolated from T.eriocephalum, was assigned38the structure (24) on the basis of an X-ray analysis and the structure (25) has been assigned39to a clerodane from T. polium.

(24) 34

35

36

37 38

’’

(25)

R. Misra, R. C. Pandey, and S. Dev, Tetrahedron, 1979,35. 2301. F. Bohlrnann and J. Ziesche, Phytochemistry, 1980, 19, 71. G. Trivedi, H. Komura, I. Kubo, K. Nakanishi, and B. S. Joshi, J. Chtim. Soc., Chem. Commun., 1979,885. I. Kubo, M. Kido, and Y. Fukuyama, J. Chem. SOC.,Chem. Commun., 1980,897. J. Fayos, M. Martinez-Ripoll, M. P. Paternostro, F. Piozzi, B. Rodriguez, and G . Savona, J. Org. Chem., 1979,44,4992. C. Marquez and S. Valverde, J. Chem. Soc.,Perkin Trans. 1, 1979, 2526.

Terpenoids and Steroids

96

(27) (28) A3*4,A7’8

A number of these compounds have insect antifeedant activity. The total synthesis of the substituted cis-decalin (26) as an antifeedant has been r e p ~ r t e d . ~ ’ Clerodanes have previously been detected in Salvia (Labiatae) species. The gesnerofilins A and B, obtained from S. gesneraefolia, have been assigned4’ the structures (27) and (28) although their absolute stereochemistry was not determined. A further series of clerodanes of uncertain stereochemistry has been isolated from Baccharis species, including bacrispine (29) from B. crispa4* and the rnalonate ester (30) from B. t r i ~ u n e a t a . ~ ~ 4 Tricyclic Diterpenoids The circular dichroism curves associated with olefins of various pimarenes have been a n a l y ~ e dand ~ ~ the curve and crystal structure of 8P-(hydroxymethyl)podocarpane-13~-carboxylic acid lactone have been r e p ~ r t e d . ~Several ’ collections of I3C n.m.r. data of tricyclic diterpenoids have been presented including those of some isopimaric acid derivatives and diterpenoids from Prernna l ~ t i f o l i aThe . ~ ~influence of the configuration of the epoxide ring on the chemical shifts of neighbouring atoms has been examined in a series of pimarane e p o x i d e ~The . ~ ~isomerization of the epimeric 7,g-epoxides of methyl isopimarate by boron trifluoride has been The a-epoxide gives products arising from the extrusion of a formyl group and of a backbone rearrangement whereas the P-epoxide gives the products of elimination and a ketone arising by a hydride shift. 19-Norisopimara-7,15-dien-3-onehas been detected as a metabolite of Acrernoniurn l ~ z u l a eThe . ~ ~ketol compactone (31)was obtained” from Vellozia W. P. Jackson and S. V. Ley, J. Chem. SOC.,Chem. Commun., 1979,732. M. Jimenez, E. D. Moreno, and E. Diaz, Rev. Latinoam. Quim., 1979,10, 166. 42 C. E. T o m , J. C. Gianello, and 0. S. Giordano, An. Assoc. Quim. Argent., 1979, 67, 1 (Chem. Abstr., 1980, 93, 128 732). 43 F. Bohlmann, C. Zdero, H. Robinson, and R. M. King, Phytochemistry, 1979,18, 1993. 44 J. M. Bernassau, M. Fetizon, and I. Hanna, Tetrahedron, 1979,35, 1653. 45 A. F. Beecham, R. C. Cambie, R. C. Hayward, and B. J. Poppleton, Aust. J. Chem., 1979,32,2617. 46 A. I. Rezvukhin, I. V. Solomennikova, S. F. Bychkova, and E. N. Schmidt, Zzu. Akad. Nauk SSR, Ser. Khim., 1980,317; C. B. Rao and E. K. S. Vijayakumar, Org. Magn. Reson., 1980,14,322. “ B. Delmond, B. Papillaud, J. Valade, M. Petraud, and B. Barbe, Org. Magn. Reson., 1979,13,209. 48 B. Delmond, M. Taran, and J. Valade, Tetrahedron Lett., 1980, 21, 1339. 49 N. Cagnoli, P. Ceccherelli, M. Curini, N. Spagnoli, and M. Ribaldi, J. Chem. Res. ( S ) , 1980, 276. 50 A. C. Pinto, A. J. R. Silva, L. M. U. Mayer, and R. Braz Filho, Phyrochemisrry, 1979,18,2036. 40

41

97

Diterpenoids

compacta. The structure of cleonionic acid (32) from Cleonia lusitunica (Labiatae) was established5’ by a combination of spectral methods and chemical correlation with isopirnara-7,15-dien-18-01.Extraction of the root-bark of Acacia leucophloea (Mimisaceae) has afforded5’ a group of pimaranes including leucophleol (33) and leucophleoxol (34). 7a-Methoxy- and 7P-hydroxy-deoxycryptojaponol (35) have been from Juniperus formosana.

CO’H

(33)

8

;5c7:

(32)

‘OMe

The leaf pigments of Coleus (Labiatae) species continue to be the source of highly oxidized diterpenoids. A group of eleven coleons and royleanones includfrom C. carnosus and coleon X (37) and ing carnosolone (36) were the unusual cis-butadiene coleon Z (38) were from Solenostemon

&

&iH

‘OAc

H

: OH (36)

51

’*

0

OH (37)

(38)

M. C. Garcia-Alvarez, M. P. Paternostro, F. Piozzi, B . Rodriguez, and G. Savona, Phytochemistry,

1979,18,1835.

53

R. K. Bansal, M. C. Garcia-Alvarez, K. C. Joshi, B. Rodriguez, and R. Patri, Phytochemistry, 1980,19,1979;A . Perales, M. Martinez-Ripoll, J. Fayos, R. K. Bansal, K. C. Joshi, R. Patri, and B. Rodriguez, Tetrahedron Lett., 1980,21,2843. Y.-H. Kuo, N.-H. Lin, and Y.-T. Lin, J. Cfin. Chem. SOC.(Taipei), 1980,27, 19 (Chem. Abstr.,

54

F. Yoshizaki, P. Ruedi, and C. H. Eugster, Helu. Chim. Acta, 1979,62,2754.

1980,93,41506). 55

T. Miyase, F. Yoshizaki, N. T. Kabengele, P. Ruedi, and C. H. Eugster, Hefu. Chim. Acta, 1979,

62,2374.

98

Terpenoids and Steroids

syltraticus and Coleus garckeanus. Some aspects of the chemistry of the diterpenoid barbatusin have been revised.56 A ring-expansion product, pisiferin (39), related to ferruginol, has been isolated5’ from Chamaecyparis pisifera together with some C-20 oxygenated products. A cleistanthene, spruceanol (40), was from Cunuria spruceana (Euphorbiaceae).

(39)

There are now many biologically active norditerpenoid lactones known. A detailed investigation of the 13Cn.m.r. spectra of this series has been reported.59 The structure of the plant-growth regulator wentilactone A (41), which is a metabolite of the fungus Aspergillus wentii, was established6’ by X-ray analysis. The 1,2-epoxide is required for biological activity since a co-metabolite, wentilactone B, lacking the epoxide, is relatively inactive. Two cytotoxic dilactones, milanjilactones A (42) and its 7,8-dehydro-derivative B, were obtained61 from Podocarpus milanjianus. Nagilactone G was also obtained6*from P. sellowii. 0

The alkaloids icacine (43) and icaceine (44) are novel lactones from Icacina guesfeldtii (Icacinaceae),which is a plant that is used in African folk medicine as an anti-convulsant. An interesting feature of the structure of icacine 56

”

’’ 59

6o

R. Zelnik, H. E. Gottlieb, and D.Lavie, Tetrahedron, 1979,35, 2693. M. Yatagai and T. Takahashi, Phytuchernistry, 1980,19,1149. S. P. Gunasekera, G. A. Cordell, and N. R. Farnsworth, J. Nat. Products, 1979,42,658. Y.Hayashi, T. Matsumoto, M. Uemure, and M. Koreeda, Org. Magn. Reson., 1980,14,86. J. W. Dorner, R. J. Cole, J. P. Springer, R. H. Cox, H. Cutler, and D. T. Wicklow, Phytochemistry,

1980,19,1157. 61

62

63

J. A. Hembree, C. J. Chang, J. L. McLaughlin, and J. M. Cassady, Experientia, 1980,36,28. J. A.Hembree, C. J. Chang, J. L. McLaughlin, 3. M. Cassady, D. J. Watts, E. Wenkert, S. F. Fonseca, and J. D e Paiva Campello, Phytuchernistry, 1979,18,1691. P. On’okoko and M. Vanhaelen, Phytochernistry, 1980,19,303.

Diterpenoids

99

is the syn-relationship between the 9P-H and C-20 (cf. annonalide). Hypolide (45) and tripterolide (46) have been from Tripterygium hypoglucum and 7'.regelii respectively whilst a tissue culture of 7'. wildfordii has been established6' for the production of the tumour inhibitor triptdiolide. The structures assigned to a group of diterpenoids obtained from Palafoxia rosea have been corrected66to structures based on rimuene. A group of tricyclic diterpenoids from Spongia oficianilis. [e.g. (47)]has been

HO"

0

0

0 CO,H

5 Tetracyclic Diterpenoids

Kaurenoid Diterpenoids.-Some further collections of 13C n.m.r. data have a ~ p e a r e d , ~including * * ~ ~ some I3C n.m.r. evidence for the biosynthesis of ring D of ent-kaurene by Gibberella fujikuroi. ent-Kaur-16-en-19-oic acid is a very common diterpenoid which has been reported7' in Wedelia glauca (Compositae). The related grandifloric acid and 7a-hydroxytrachylobanic acid (ciliaric acid) were obtained71 from Helianthus niveus (Compositae). ent- 3/3,19-Dihydroxykaur-16-ene and the corresponding 19-acid were isolated72from Stachys lanata (Labiatae). ent- 3P-Hydroxykaur-9( 11),15-dien-l9-oic acid, some 3-esters, and 64

6s 66 67

68 69

'O

71 72

D. G. Wu, X.-C. Sun, F. Li Yun-nan, Chih Wu Yen Chiu, 1979,29 (Chem. Abstr., 1980,93,72 010). J. P. Kutney, M. H. Beale, P. J. Salisbury, R. D. Sindelar, K. L. Stuart, B. R. Worth, P. M. Townsley, W. T. Chalmers, D. J. Donnelly, K. Nisson, and G. G. Jacoli, Heterocycles, 1980, 14, 1465. F. Bohlmann and C. Zdero, Phytochemistry, 1979,18,2038. N. Capelle, J. C. Braekman, D. Daloze, and B. Tursch, Bull. SOC.Chim. Belg., 1980,89, 399. M. A. Lopez-Gomez, C. Marquez, R. M. Rabaud, and S. Valverde, A n . Quim., 1979,75911. A. Patra, A. K. Mitra, S. R. Mitra, C. L. Kirtaniya, and N. Adityachaudhury, Org. Magn. Reson., 1980,14, 58; K . Honda, T. Shishibori, and T. Suga, J. Chem. Res. (S), 1980, 218. J. C. Oberti, A. B. Pomilio, and E. G. Gros, Phytochemistry, 1980,19, 2051. N. Ohno and T. J. Mabry, Phytochemistry, 1980,19,609. F. Piozzi, G. Savona, and J. R. Hanson, Phytochemistry, 1980,19, 1237.

100

Terpenoids and Steroids

the corresponding 9P-alcohols were from Polymnia canadensis (Compositae). This phytochemical survey of the Compositae has revealed74 the presence of a series of esters of 15-hydroxykaurenoic acid and their 19-nor relatives in Libanothamnus species. Smallanthus f r u t i ~ o s u sand ~ ~ S. ~ v e d a l i a ' ~ contain 18-hydroxy kaur- 16 -en - 19-oic acid. 12 -Ox0 - (48) and 12- hydroxygrandiflorenic acids have been together with some 19-nor alcohols as constituents of Espeletia (Compositae) species. The partial synthesis of ent-1 1p-, acid from the A9(l"-acid, ent-l2a-, and ent-l2~-hydroxykaur-l6-en-19-oic grandiflorenic acid, has been described.78

9

CO,H

CH,OH

Sideritis (Labiatae) species have continued to attract attention as a source of diterpenoids. ent-1 !p, 18-Dihydroxykaur-15-ene (49) was from S. chamaedryfolia and the known diterpenoids folio1 (ent- 3&7a,l8-trihydroxykaur-16-ene) and its 3- and 18-monoacetates (sidol and linearol) were detected in S. arborescens8' and along with their A15-isomers and 18-hydroxykaur-16-ene (candol B) in S. @auouirens.81A similar group of hydroxykaurenes was foundg2 in S. funkiana whilst ent- 18-acetoxy-3P,6a,7a-trihydroxykaur-15-ene (funkiol) and the isomeric 3-acetate (sidofunkiol) were amongst the minor ~ ~ n ~ t i t u e n t ~ . ~ The selective allylic oxidation of the kaur-16-enes at C-15by hydrogen peroxide and selenium dioxide is facilitatedg4by the presence of a 7-hydroxy-group. Amongst new glycosides that have been describedg5 is lindokaurenoside C from Lindsaea chienii which is ent-2a,l3-dihydroxykaur16-ene 2-o-P-D-glucoside. Some analogues of stevioside have been examined86 for their sweetness. 73 74

F. Bohlmann, C. Zdero, R. M. King, and H. Robinson, Phytochemistry, 1980,19, 115. F. Bohlmann, C. Zdero, J. Cuatrecasas, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 1145.

75

76 77

F. Bohlmann, J. Ziesche, R. M. King, and H. Robinson, Phytochemistry, 1980,19,973. F. Bohlmann, K. H. Knoll, H. Robinson, and R. M. King, Phytochemistry, 1980, 19, 107. F. Bohlmann, H. Suding, J. Cuatrecasas, R. M. King, and H. Robinson, Phytochemistry, 1980,19, 267.

78 79

84 85

N. J. Lewis and J. MacMillan, J. Chem. SOC.,Perkin Trans. 1, 1980, 1270. M. C. Garcia-Alvarez, F. M. Panizo, and B. Rodriguez, A n . Quim., 1979,75, 752. A. Garcia-Granados, A. Parra Sanchez, and A. Pena Carrillo, A n . Quim., C, 1980,76,98. E. Escamilla and B. Rodriguez, A n . Quim., C, 1980,76, 189. A. Garcia-Granados, J. A. Garrido, A. Parra, and A. Pena, A n . Quim., 1979, 75, 780. A. Garcia-Granados, A. Parra, A. Pena, and S . Valverde, An. Quim., C, 1980,76, 178. A. Garcia-Granados, A. Parra, and A. Pena, A n . Quim., C, 1980, 76, 85. T. Satake, T. Murakami, Y. Saiki, and C.-M. Chen, Chem. Pharm. Bull., 1980, 28, 1859. S. Kamiya, F. Konishi, and S . Esaki, Agric. B i d . Chem., 1979, 43, 1863.

Diterpenoids

101

Turbicoritin and corimbositin are8’ the glycosides of ent-6a, 16,17- and

16,17,19-trihydroxykaurane. The preparation has been described88 of some kaurenolides based on the differing reactivities of the 7- and 18-hydroxy-groups of 7,18-dihydroxykaurenolide. In continuation of studies on the biologically active enmein group of diterpenoids, two further cytotoxic compounds, longikaurin A (50) and longikaurin B (51) have been isolated89 from Rabdosia longituba. The biosyntheses of enmein and oridonin from 7- and 15-mono-oxygenated and dioxygenated kaurenoids have been studied.” The structure of tetrachyrin (52), a kaurenoid analogue of the rosane diterpenoids that was obtained from Tetrachyron orizabaensis, has been determined9* by X-ray analysis.

CH,R (50) (51)

R R

=

=

H OAC

Beyerenes.-ent- 18- and -19-Hydroxybeyer-15-ene and the 15,16-epoxide have been from Baccharis tola (Compositae), and 1,12- and 1,17diacetoxyjativatriol have been detected93 as constituents of Sideritis serrata (Labiatae). Atiserenes.-A series of 12-oxygenated kaurenes together with 11- and 13oxygenated atiseren-19-oic acids have been recorded as constituents of Helianthus (Compositae) species.94 Atiserenic acid and the unusual helifulvanic acid (53) have been isolated from Helichrysum chionosphaerum. The structure of the isotrachylobane was established9’ by X-ray analysis.

89

90

91 92

93 94

95

J. F. Garcia, 0. Collera, G. Larios, J. Taboada, and M. C . Perezarnador, Rev. Latinoam. Quim., 1979,10, 181 (Chem. Abstr., 1980,93, 26 719). J. R. Hanson and F. Y. Sarah, J. Chem. SOC.,Perkin Trans. 1, 1979,2488. T. Fujita, Y. Takeda, andT. Shingu, J. Chem. SOC.,Chem. Commun., 1980,205. E. Fujita, N. Ito, I. Uchida, K. Fuji, T. Taga, and K. Osaki, J. Chem. Soc., Chem. Commun., 1979,806. T. Fujita, S. Takao, and E. Fujita, J. Chem. SOC.,Perkin Trans. 1 , 1979, 2468. N. Ohno, T. J. Mabry, V. Zabel, and W. H. Watson, Phytochemistry, 1979, 18, 1687. A. San Martin, J. Ronrosa, R. Becker, and M. Castilo, Phytochemistry, 1980, 19, 1985. E. M. Escamilla and B. Rodriguez, Phytochemistry, 1980, 19,463. F. Bohlmann, J. Jakupovic, R. M. King, and H. Robinson, Phytochemistry, 1980, 19, 863. F. Bohlrnann, W. R. Abraham, and W. S. Sheldrick, Phytochemistry, 1980, 19, 869.

102

Terpenoids and Steroids

Gibberellins.-A number of reviews concerning gibberellin c h e r n i ~ t r ybiosyn,~~ thesis,97 and biological activity98 have appeared. Gibberellin A, (54) has been positively as a metabolite of the cassava pathogen, Sphaceloma manihoticola. Some 1-hydroxygibberellins have been isolated101*102from G. fujikuroi. Gibberellins A5,-AS7 have structures (55)-(58) and gibberellin A58, obtainedlo3from Curcurbita maxima, has structure (59).The gibberellins of developing wheat, Tricitum aestivium, have been examined", by g.c.-m.s., and gibberellins A', and were identified. Gibberellin A, has been found"' in Pyrus serotina (pear).

R' O

H

(54) R' = R2 = H ( 5 5 ) R' = OH,R2 = H (56) R' = R2 = OH

The construction of ring A of gibberellic acid has presented a major synthetic problem. Procedures based on an aldol condensation between a C-3 aldehyde and C-4 have been explored. *06 The conjugate addition of sulphur nucleophiles in the position at C-1 to ring A unsaturated ketones has been described."' The replacement of the C-13 bridgehead hydroxy-group by halogen in the presence of fluoraminelo8 or with triphenylphosphine-carbon tetrachloride has been 96 97

98

99 loo

lo' lo*

Io4

'06

lo7

P. Hedden, A m . Chem. SOC.Symp. Ser., 1979, No. 111, p. 19. B. 0. Phinney, Amer. Chem. SOC.Symp. Ser., 1979, No. 111, p. 57. See reviews in 'Gibberellins, Chemistry, Physiology and Use', ed. J. R. Lenton, British Plant Growth Regulator Group Monograph, No. 5, Oxford, 1980. W. Rademacher and J. Graebe, Biochem. Biophys. Res. Commun., 1980,91, 3 5 . R. S. Zeigler, L. E. Powell, and H. D. Thurston, Phytopathology, 1980, 70, 589. N. Murofushi, M. Sugimoto, K. Itoh, and N. Takahashi, Agric. Biol. Chem., 1979, 43, 2179. N. Murofushi, M. Sugimoto, K. Itoh, and N. Takahashi, Agric. Biol. Chem., 1980, 44, 1583. J. Graebe, in ref. 98, p. 41. P. Gaskin, P. S. Kirkwood, J. R. Lenton, J. MacMillan, and M. Radley, Agric. Biol. Chem., 1980, 4, 1589. S. Nakagawa, H. Matsui, E. Yuda, N. Murofushi, N. Takahashi, N. Akimori, and S . Hishida, Phytochemistry, 1979,18, 1695. G. Stork and J. Singh, J. A m . Chem. SOC.,1979,101,7109. B. Voigt and G. Adam, Pharmazie, 1979, 34, 362. I. C. Simpson and B. E. Cross, Tetrahedron Lett., 1980, 21, 215.

Diterpenoids

103

reported. lo9 Dimeric 13-phosphite esters have been isolated from the reaction with phosphorus tribromide.' l o Routes have been described 1097111*1'2for the preparation of less readily available gibberellins from gibberellic acid and gibberellin A13 and another preparation of 14C-labelled gibberellin A, has been reported.'13 The photochemistry of the gibberellins has continued to attract attention. The photocyclization of some A"-gibberellin 7-aldehydes to afford compounds such as (60) has been described."* The details of the crystal structure of the photochemical cleavage product (61) obtained from gibberellin C (an 8,13-isogibberellin) have appeared.'"

The microbiological transformation of hydroxylated kaurenes has continued to be examined as a method of preparing novel gibberellins and of defining the substrate specificity of the gibberellin pathway. A series of 12a-hydroxy-Czo gibberellins was obtained'16 when ent-12P-hydroxykaurene was incubated with G. fujikuroi. The effect of 7-, 1 5 , and 18-hydroxy-groups on the microbiological transformation of some ent-kaur-16-enes by G. fujikuroi has been examined."' An 18-substituent appears to exert an inhibitory effect on transformations involving the 6P-position. Some biosynthetic relationships between the kaurenolides and other metabolites of G. fujikuroi have been reported."* Grayanotoxins.-Several assignments of I3C n.m.r. data of the grayanotoxins have been r e p ~ r t e d . ~Recently ~ ~ ' ~ * a~ number of the grayanotoxins have been isolated as glycosides. Grayanoside C, from Leucothoe grayana, has been shownlZ1 to be 3 - 0 - (~-D-glucopyranosy~)-(~~H)-grayanotoxin XVII and is epimeric at C-1 to the normal grayanotoxins. Grayanoside D has lO(20)-dehydrograyanotoxin XV as the aglycone with the sugar attached at C-3.'22 Oxidation of grayanotoxin I1 (62) with thallium(II1)nitrate Eads to cleavage of the A/B ring J. R. Hanson, in ref. 98, p. 5. T. V. Romanchenko, A . 6. Druganov, and V. A. Raldugin, Khim. Prir. Soedin., 1980,269. M. H. Beale and J. MacMillan, J. Chem. SOC.,Perkin Trans. I, 1980, 877. '12 M. H. Beale, P. Gaskin, P. S. Kirkwood, and J. MacMillan, J. Chem. SOC.,Perkin Trans. 1 , 1980, 885. E. Heftmann and J.-T. Lin, J. Labelled Compounds, 1979,16,537. M. Lischewski, G . Adam, and E. P. Serebryakov, Tetrahedron Lett., 1980, 21,45. L. Kutschabsky, G. Reck, G . Adam, and V. T. Sung, Tetrahedron, 1980,36,741. '16 K. Wada and H. Yamashita, Agric. Biol. Chem., 1980,44, 2249. ''' B. M. Fraga, J. R. Hanson, M. G. Hernandez, and F. Y. Sarah, Phytochemistry, 1980,19, 1087. '18 J. R. Hanson and F. Y. Sarah, J. Chem. SOC.,Perkin Trans. 1, 1979, 3151. 'I9 T. Ohta and H. Hikino, Org. Magn. Reson., 1979,12,445. 120 N. Shirai, H. Nakata, T. Kaiya, and J. Sakakibara, Chem. Pharm. Bull., 1980, 28, 365. 12' J. Sakakibara, N. Shirai, T. Kaiya, and Y. Iitaka, Phytochemistry, 1980, 19, 1495. 122 J. Sakakibara and N. Shirai, Phytochemistry, 1980, 19, 2159. '09

'lo

Terpenoids and Steroids

104

junction and the formation of the unusual ketol (63) the structure of which was proven by X-ray ana1y~is.I~~ Diterpenoid Alkaloids.-The Delphinium alkaloids have been reviewed in detail in the companion Specialist Periodical Report on Alkaloids. The structure of cuauchichicine, and in particular the stereochemistry at C- 16, has been revised as a result of a correlation with (-)-P-dihydr~kaurane.'~~ The mechanism of the garryfoline-cuauchicine rearrangement has been examined by deuteriation studies. 12'

6 Macrocyclic Diterpenoids and their Cyclization Products A full paper on the isolation of cembrene-A (64) and (32)-cembrene A from a termite soldier, Cubitermes umbrutus, has appeared.126 An 11,12-epoxycembrene (65), which has been from Greek tobacco, may act as a biogenetic precursor of some of the 8 , l l - and 8,12-epoxycembranoids which are also found in tobacco. HO

HO

Many cembranoid diterpenoids have been isolated from corals. Sarcophytol-A (66), its acetate, sarcophytol-B (67), and sarcophytonin A (68) have been isolated12*from the soft coral Surcophyton gluucum and some epoxycembranes (69) and (70) (sarcophine) were obtainedlZ9from S. crussocuule. Extraction of Lobophyturn crussospiculutum yielded13' a further group of cembranolides. A lZ3 124

125

lZ6 '21 12* lZ9

T. Kaiya, N. Shirai, J. Sakakibara, and Y. Iitaka, Tetrahedron Lerr., 1979, 4297. S. W. Pelletier, H. K. Desai, J. Finer-Moore, and N. V. Mody, J. A m . Chem. Soc., 1979,101,6741. S . W. Pelletier, H. K. Desai, and N. V. Mody, Heterocycles, 1979, 12, 277. D . F. Wiemer, J. Meinwald, G. D. Prestwich, and I. Miura, J. Org. Chem., 1979, 44, 3950. D. Behr, I. Wahlberg, T. Nishida, C. R. Enzell, J. E. Berg, and A. M. Pilotti, Actu Chem. Scand., Ser. B. 1980.34. 195. M. Kobayashi, T. Nakagawa, and H. Mitsuhashi, Chem. Pharm. Bull., 1979, 27, 2382. B. F. Bowden, J. C. Coll, and S. J. Mitchell, Ausr. J. Chem., 1980, 33, 879. A. Ahond, B. F. Bowden, J. C. Coll, J. D . Fourneron, and S. J. Mitchell, Ausr. J. Chem., 1979,32, 1273.

Diterpenoids

105

(66) R (67) R

= =

H OH

cembranolide with a 13-membered ring (71) has been from the soft coral Lobophytum pauciflorum. A group of phorbol esters, such as the 13-acetate of 12-O-palmitoyl-16hydroxyphorbol, have been to be piscicidal constituents of Aleurites fordii (Euphorbiaceae). Further details of some mevalonate incorporation studies into fusicoccin have appeared.'33

7 Miscellaneous Diterpenoids Marine organisms have again continued to provide some' very unusual diterpenoids. The sea-pen, Stylatula sp., was the source of the compounds (72) and (73).134X-Ray analysis has that cleomeolide, from Cleorne icosandra, has the structure (74). A further diterpenoid related to eunicellin, ophirin ( 7 9 , has been from a Muricella sp. A full paper on the ether dictyoxide (76) has appeared.137 A prenylated cadinene, biflora-4,10(19),15-triene (77), has been isolated138 from a termite soldier. Prenylated sesquiterpenoid structures have also been assigned'39 to perrottetianal A (78) and B (79), which were isolated from Porella perrottetiana, and a further series of sacculatane diterpenoids including 18- and 131

13' 133

134 135

13'

139

Y. Yamada, S. Suzuki, K. Igushi, K. Hosaka, H. Kikuchi, Y.Tsukitani, H. Horiai, and F. Shibayama, Chem. Pharm. Bull., 1979,27,2394. M. Hirota, H. Ohigashi, and F. Koshimizu, Agric. Biol. Chem., 1979,43,2523. G . Randazzo, A. Evidente, R. Capasso, F. Colantuoni, L. Tuttobello, and A. Ballio, Gazz. Chim. Ztal., 1979, 109, 101. S . J . Wratten and D. J. Faulkner, Tetrahedron, 1979, 35, 1907. S. B. Mahato, B. C. Pal, T. Kawasaki, K. Miyahara, 0.Tanaka, and K. Yamasaki, I. A m . Chem. SOC.,1979, 101,4720. Y. Kashman, Tetrahedron Lett., 1980,21,879. V. Amico, G. Qriente, M. Piattelli, and C. Tringali, Phytachemistry, 1979, 18, 1895. D. F. Wiemer, J. Meinwald, G. D. Prestwich, B. A. Solheim, and J. Clardy, I. Org. Chem., 1980, 45, 191. Y. Asakawa, M. Toyota, and T. Takernoto, Phytochemistry, 1979, 18, 1681.

Terpenoids and Steroids

106

OAc

OAc

(XJ HO-'

o

HO' q

c

0

1

0

AcO" -,--Me

bH

+$-J /t\ OAc

(74)

(75)

19-hydroxysaccu1ata1,(80)and (81), and 3-hydroxy-9-isosacculatal(82)has been obtained14' from the liverwort Trichocoleopsis sacculata. A full paper has appeared141 on the structure of the verrucosanes from the liverwort Mylia verrucosa. The cyathins are a group of metabolites from the Bird's Nest fungi. Cyathatriol (83),which is related to cyathin A3, together with its mono- and di-acetates, has been isolated14*from CyathuS earlei. The labelling and coupling patterns produced in 11-0-acetylcyathatriol (85),when it is biosynthesized from ["C],-

w-. H (77)

(78) R (79) R

= =

Y.Asakawa, M.Toyota, and T. Takemoto, Phytochemistry, 1980, 19, 1799. D.Takaoka, J. Chem. SOC.,Perkin Trans. 1, 1979, 2711. 142 W.A . Ayer and S. P. Lee, Can. J. Chem., 1979,57, 3332. 140

14'

H OH

Diterpenoids

107

a;o CHO

HO

I

R (80) R

=

CH2CH=C

/

CH20H

'Me (81) R

=

/Me CH=CHC-OH 'Me

that geranylgeranyl pyrophosphate is folded as in (84) to acetate, generate this skeleton.

(83) R (85) R

= =

H Ac

(84)

Extraction of the gorgonian Briareum asbestinurn has afforded144the asbestinins (86)-(90). Their structures were elucidated by spectral and chemical correlations and by an X-ray analysis of asbestinin-1. Another group of diterpene isocyanides [e.g. (91)] have been isolated145from Adocia species of sponges. The

M

e

w R

H

.-

Me OR'

(86) R' = Ac,R2 = COPr' (87) R' = A c , R 2 = COPr',A-isomer (88) R' = H , R 2 = COPr' 143 144

14'

OAc (89) R = 0 (90) R = a-OH,P-H

W. A . Ayer, S. P. Lee, andT. T. Nakashima, Can. J. Chem., 1979,57,3338. D. B. Stierle, B. Carte, D. J. Faulkner, B. Tagle, and J. Clardy, J. A m . Chem. SOC.,1980,102,5088. R. Kazlauskas, P. T. Murphy, R. J. Wells, and J. F. Blount, Tepuhedron Lett., 1980, 21,315.

108

a NC

Terpenoids and Steroids

& o HO OAc

diterpenoid defensive secretions of the termite Nasutitermes octophifis contain ' ~ ~X-ray analysis the compound (92), the structure of which was e l u ~ i d a t e d by of the p-bromobenzoate. Some aspects of the oxidative chemistry of the hydrocarbon lauren-1 -ene have been examined.147

8 Diterpenoid Total Synthesis

*

A number of major synthetic achievements in the diterpenoid area have been

reported during the year. One of these has been the completion of the total synthesis of the insecticidal diterpenoid ryanodol (95) from the two units (93) and (94).148The more highly oxidized diterpenoid phenols have attracted attention. Syntheses of the tricyclic phenol c r y p t o j a p ~ n o l , t' ~a~~ o d i o n eand , ~ ~coleon ~ U150 and approaches to coleon A'51and coleon C'52have been reported.

(P 0

HO

The antileukaemic diterpenoids triptolide and stemolide have been important synthetic targets. The preparations of the lactone isodehydroabietenolide (96),153 stemolide (97),'54and triptolide (98)15s.156 uia dehydroabietic acid have been 146

14' 14'

149

lS0

15'

Is' lS4 lSs

lS6

G. D. Prestwich, J. W. Lauher, and M. S. Collins, Tetrahedron Left., 1979, 3827. P. J. Eaton, J. M. Fawcett, M. K. Jogia, and R. T. Weavers, Aust. J. Chem., 1980, 33, 371. A. Belanger, D. J. F. Berney, H.-J. Borschberg, R. Brousseau, A. Doutheau, R. Durand, H. Katayama, R. Lapalme, D. M. Leturc, C.-C. Liao, F. N. MacLachlan, J.-P. Maffrand, F. Marazza, R. Martino, C. Moreau, L. Saint-Laurent, R. Saintonge, P. Soucy, L. Ruest, and P. Deslongchamps, Can. J. Chem., 1979,57,3348. D. L. Snitman, R. J. Himmelsbach, R. C. Haltiwanger, and D. S. Watt, Tetrahedron Left., 1979, 2477. T. Matsumoto and S. Takeda, Bull. Chem. SOC. Jpn., 1979, 52,2611. T. Matsumoto, S. Imai, K. Ondo, N. Takeyama, and K. Fukui, Chem. Left., 1980,425. A. Andersen, M. Nero-Desbiens, S. Savard, and R. H. Burnell, Synth. Commun., 1980, 10, 183. E. E. van Tamelen, E. G. Taylor, and A. F. Kreft, J. A m . Chem. Soc., 1979, 101,7423. E. E. van Tamelen and E. G. Taylor, J. A m . Chem. Soc., 1980,102, 1202. E. E. van Tamelen, J. P. Demers, E. G. Taylor, and K. Koller, J. A m . Chem. SOC., 1980, 102, 5424. R. S. Buckanin, S. J. Chen, D. M. Frieze, F. T. Sher, and G. A. Berchtold, J. A m . Chem. SOC., 1980, 102,1200.

Diterpenoids

109

(96)

(97)

described. The total synthesis of the norditerpenoid nagilactone F (99) via podocarpic acid has been rep~rted.’~’ The synthesis of the biologically active diterpenoid aphidicolin (100) has been described,158 and other reports have appea~ed’~’ of different approaches to this system. A novel Wittig reaction of cyclohexenones using vinylphosphonium ylides leads to the construction of the cyclopropane ring and this has found application in the stereoselective synthesis of trachyloban-19-oic acid.160s161 A further synthesis of gibberone has been reported. 16* The sesquiterpenoid santonin formed the starting material for syntheses of pachydictyol and dictyolene. 163

Y.Hayashi, T. Matsumoto, T. Hyono, N. Nishikawa, M. Togami, M. Uemura, M. Hishizawa, and T. Sakan, Tetrahedron Lett., 1979,3311. E.J. Corey, M. A. Tius, and J. Das, J. A m . Chem. SOC.,1980,102,1742. lS9 R. E.Ireland and P. A. Aristoff, J. Org. Chem., 1979,44,4323. 160 R. M.Cory, D. M. Chan, Y.M. A. Naguib, M. H. Rastall, and R. M. Renneboog, J. Org. Chem., 1980,45,1852. 16‘ R. M. Cory, Y.M. A. Naguib, and M. H. Rasmussen, J. Chem. Soc., Chem. Commun., 1979,504. 16* U.R.Ghatak and P. C. Chakraborti, J. Org. Chern., 1979,44,4562. 163 A. E.Greene, J. A m . Chem. SOC.,1980,102,5337. 15’

3 Trite rpenoi ds BY R. B. BOAR

1 Introduction This chapter largely follows the pattern of previous Reports with sections based on the major skeletal types of triterpenoid. All work on biosynthesis is gathered together in Section 2. The literature that has been covered is that available to August 1980. Quassinoids, certain of which show exciting cytotoxic activity, are the subject of increasing attention, particularly from the synthetic organic chemist. Otherwise, triterpenoid chemistry continues much as in recent years with a bias towards isolation and structure determination. Regretfully, the recommendations of the IUPAC Commission on the nomenclature of natural products' have so far had little effect on the coining of new and generally unhelpful trivial names. Two publications arising from recent symposia contain triterpenoid componen ts. 2*3

2 Squalene Group and Triterpenoid Biosynthesis The crystal structure of squalene at -1 10 "C has been determined.4 The molecule adopts a stretched conformation which differs significantly from the conformation of squalene when included within the host molecule hexakis( p- tb~tylphenylthiomethy1)benzene.~ (3s)-Squalene 2,3-epoxide has been isolated from the green alga Caulerpa proZifera.6 Oxidation of squalene with t-butyl hydroperoxide in the presence of M ~ O ~ ( a c aand c ) ~di-isopropyl (+)-tartrate gave the 2,3-epoxide (31%) with an induced asymmetry of about 14% in favour of the (3S)-isomer.' The ability of oxidosqualene cyclases to accept unnatural precursors has been further extended by the observation that lanosterol cyclase from rabbit liver converts the synthetic epoxide (1)into the p-onocerin derivative (2). An authentic sample of (2) was prepared by sodium cyanoborohydride reduction of P-onoceradione

'

IUPAC Commission on the Nomenclature of Organic Chemistry, Eur. J. Biochern., 1978, 86, 1. Symposia Papers, IUPAC 11th International Symposium on the Chemistry of Natural Products, ed. N. Marekov, I. Ognyanov, and A. Orahovats, Izd. BAN, Sofia, Bulgaria, 1978. Abstracts of Posters, International Research Congress on Natural Products as Medicinal Agents, Strasbourg, France, 1980,Planta Med., 1980,39, 194-292. J. Ernst and J.-H. Fuhrhop, Liebigs Ann. Chern., 1979,1635. A. Freer, C. J. Gilmore, D. D. MacNicol, and D. R. Wilson, TetrahedronLett., 1980,21,1159. L.de Napoli, E. Fattorusso, S. Magno, and L. Mayol, TetrahedronLett., 1980,21,2917. K. Tani, M. Hanafusa, and S . Otsuka, TetrahedronLett., 1979,3017.

110

111

Triterpenoids

H-

nNNHT monotoluene-p-sulphonylhydrazone (3).8A microsomal preparation from Pisum sativum (Leguminosae) cyclizes 22-methylene-22,23-dihydrosqualene2,3(5).9 The epoxide (4)to afford 29,29-dimethyl-30-nor-18~-olean-12-en-3/3-01 structure of the product was established by an independent synthesis of (5) and the C-20 epimer from glycyrrhetic acid."

An efficient synthesis of squalane (7) from the readily available geranylacetone (6) has been described (Scheme l)." A review on the stereochemistry of allylic pyrophosphate metabolism includes much information of relevance to the biosynthesis of triterpenoids.'* Lanosterol and various of its oxidized derivatives are efficiently utilized by Trichoderma viride for the production of the interesting antibiotic viridin (8).13Sterol biosynthesis in the fungus Uromyces phaseoli proceeds by way of lanosterol, not c y ~ l o a r t e n o lWhen . ~ ~ bramble [Rubusfruticosus (Rosaceae)] suspension cultures E. E. van Tamelen and R. E. Hopla, J. A m . Chem. Soc., 1979,101,6112.

' A. Dietsch, L. Delprino, P. Benveniste, and L. Cattel, J. Chem. Res. ( S ) , 1980, 60. lo

" l2 l3 l4

L. Cattel, L. Delprino, and G. Biglino, J. Chem. Res. (S), 1980, 58. J. W. Scott and D . Valentine, Org. Prep. Proced. Inst., 1980, 12, 7. D . E. Cane, Tetrahedron, 1980,36, 1109. W. S. Golder and T. R. Watson, J. Chem. SOC.,Perkin Trans. 1, 1980,422. S. K. Bansal and H. W. Knoche, Phytochemistry, 1980.19,1240.

Terpenoids and Steroids

112

(7) Reagents: i, H,-Pd/C; ii, NaCrCH; iii, 0,-CuCI-TMEDA

Scheme 1

were grown in the presence of fenarimol [a-(2-chlorophenyl)-a-(4-chlorophenyl)-5-pyrimidinemethanol], two new 14a-methyl stigmasterol derivatives (9) and (10) were obtained." Fenarimol is structurally very similar to triarimol, a known inhibitor of the l4a-demethylase involved in sterol biosynthesis. The effect of side-chain analogues of lanosterol on the biosynthesis of cholesterol has been discussed.16Only very low incorporations of radioactivity into squalene and p- amyrin were observed when germinating pea seedlings (Pisurn satiuurn) were supplied with the [ U-'4C]-labelled amino-acids leucine and ~ a 1 i n e . lGer~ minating soybeans [Glycine max (Leguminosae)] provide a convenient medium for the incorporation of [2-'4C]mevalonic acid into soyasapogenols A, B, C, and E.'* The biosynthesis of tetrahymanol (11) has been r e ~ i e w e d . ' ~ 0

HO'

W , R

l5 l6 i7

l9

(9)R = H (10) R = M e

P. Schmitt and P. Benveniste, Phytochemistry, 1979, 18, 1659. Y. Sat0 and Y. Sonoda, Chem. Abstr., 1980, 93,67 095. T. Suga, K. Tange, K. Iccho, and T. Hirata, Phytochemistry, 1980,19,67. I. Peri, U. Mor, E. Heftmann, A. Bondi, and Y. Tencer, Phytochemistry, 1979, 18, 1671 ; E. Heftmann, R. E. Lundin, W. F. Haddon, I. Peri, U. Mor, and A. Bondi, J. Nut. Prod., 1979, 42, 410. E. Caspi, Acc. Chem. Res., 1980,13,97.

113

Triterpenoids

3 Fusidane-Lanostane Group An alternative, but rather expensive, method of isolating pure 3p-acetoxy-Salanosta-8,24-dien-3P-yl acetate from commercial lanosterol has been described.20Oxidation of the lanost-8-enes (12) with ruthenium dioxide-sodium periodate gives the 8,9-seco-8,9-diketones (13) together with lesser amounts of the corresponding 8-ene-7,11-diketones2' Under either acidic or basic conditions the former cyclize to afford the C(14a)-homo-~-norlanost-8-en-14a-ones

(12) R = CH2CHMe2or C02Me

(14), which are amenable to further synthetic transformations.21'22Fasciculol-A (17) has been synthesized from the known diosphenol (15) (Scheme 2).23The intermediate C-24 diastereoisomers were separated by h.p.1.c. of the 3 3 dinitrobenzoates (16). The deuteriated pentanorlanost-8-enes (18)and (19) have been synthesized. Deuterium n.m.r. studies indicated that, within experimental error, each had the same relaxation time ( The interesting 27-nortriterpenoid eucosterol (20) is the major aglycone of Muscari cornosurn (Lilia~eae).'~ The corresponding 3-ketone is a minor component.26 Following methanolysis of the saponin, the methoxy-derivative (21) was The 13C n.m.r. spectra of some holothurinogenins have been reported.28 A synthesis of cycloeucalanone (24) from cyclolaudanone (22) has been achieved. In the key step, functionalization of the 4a-methyl group was accomplished via photolysis of the 3p- hydroxymethyl compound (23) with lead

'*

W. J. Rodewald and J. J. Jagodzinski, Pol. J. Chem., 1978,52, 2473.

W.J. Rodewald and J. J. Jagodzinski, Pol. J. Chem., 1979, 53, 1203.

''T.W.Kikuchi, J. Rodewald and J. J. Jagodzinski, Pol. J. Chem., 1979, 53, 2525. M. Kanaoka, S. Hanagaki, and S. Kadota, Chem. Lett., 1979, 1495.

23

Y. Sato, Y. Sonoda, and H. Saito, Chem. Pharm. Bull., 1980, 28, 1150. M. Parrilli, M. Adinolfi, V. Dovinola, and L. Mangoni, Gazz. Chim. Ital., 1979, 109, 391. " M. Parrilli, M. Adinolfi, and L. Mangoni, G a z z . Chim. Ital., 1979, 109, 611. 27 M. Parrilli, M. Adinolfi, V. Dovinola, and L. Mangoni, Chem. Abstr., 1979,91, 193 464. 28 A. I. Kalinovskii, V. F. Sharypov, V. A. Stonik, A. K. Dzizenko, and G. B. Elyakov, Bioorg. Khim., 1980,6, 86. 24

2s

Terpenoids and Steroids

114 H

i, ii

AcO

1

iii, iv, ii

v, vi t

AcO

OH

Reagents: i, NaBH,; ii, Ac,O-pyridine; iii, Collins reagent; iv, Na-n-C,H, ,OH; v, Os0,-pyridinediethyl ether; vi, 3,s-dinitrobenzoyl chloride-pyridine; vii, OH-

Scheme 2

pH

HO

(18) R' = Me, R2 = CH2D (19)R'=CH2D,R2=Me

tetra-a~etate-iodine.~'Polysthicol (25) from the fern Polysthicum a c u l e u t ~ m ~ ~ and cycloeuphornol (26) from Euphorbia tiruculli3' are new cycloartane triterpenoids. 29 30

''

M. C. Desai, C. Singh, H. P. S. Chawla, and S. Dev, Tetrahedron Lett., 1979,5047. G.Laonigro, F. Siervo, R. Lanzetta, M. Adinolfi, and L. Mangoni, Tetrahedron Lett., 1980,21,3109, N.Afza, A, Malik, and S . Siddiqui, Pak. J. Sci. Ind. Res., 1979,22, 173.

Triterpenoids

115

0

HO

HO'

Nine minor cometabolites (27)-(35) of the important antibiotic fusidic acid from the fungus Fusidium coccineum have been identified.32Structure-activity relationships among fusidic acid type antibiotics have been reviewed.33 10aCucurbita-5,24-dien-3@-01 (36) have been isolated from Lagenaria feucantha (Cu~urbitaceae).~~ The I3C n.m.r. spectra of various cucurbitacins have been

4 Dammarane-Euphane Group Dammaranes oxygenated at C-11 are a rarity. Two new examples are (20S,24R)epoxydammarane-3@,1la,25-triol(37) and the corresponding acetate (38) from the leaves of Betufa ermanii.36A molecular ion is not normally seen in the mass spectra of compounds such as (20s)-protopanaxatriol (39). Chemical ionization mass spectra using ammonia or isobutane as the carrier have ( M + H)' ions as 32

33 34

35 36

W. 0. Godtfredsen, N. Rastrup-Andersen, S. Vangedal, and W. D. Ollis, Tetrahedron, 1979, 35, 2419. W. von Daehne, W. 0. Godtfredsen, and P. R. Rasmussen, A d v . Appl. Microbiol., 1979, 25, 95. T. Itoh, T. Tamura, T. M. Jeong, T. Tamura, and T. Matsumoto, Lipids, 1980, 15, 122. J. R. Bull, A. A. Chalmers, and P. C. Coleman, S. Afr. J. Chem., 1979, 32, 27. V. L. Novikov, G. V. Malinovskaya, N. D. Pokhilo, and N. I. Uvarova, Khim. Prir. Soedin., 1980, 50.

116

Terpenoids and Steroids

R'&OAc (27)R'=0,R2=H,a=OH (28) R' = H , a = OH, R2 = 0 (29) R' = H,P-OH,R~= H, a (30) R' = H , ~ - o H , R=~H, P-OH

(31)R=H (32)R=OH ~

~

i HO'

H

HO"

HO

I H (35)

the base peaks3' Readers of Korean may find further useful information on the mass spectra of dammarane derivative^.^^ Hispidone (40) and the known bourjotinolone A (41) have been isolated from the leaves of Trichilia hispida ( M e l i a ~ e a e )The . ~ ~ structure and stereochemistry of hispidone were established by showing that the derived acetonide was identical with the product obtained by oxidizing the acetonide of sapelin B (see Vol. 1, 37 38 39

M. Desage, M. Becchi, M. Trouilloud, and J. Raynaud, Planta Med., 1980,39, 189. B. H. Han and J. H. Kim, Chem. Abstr., 1980,92,164 112. S. D. Jolad, J. J. Hoffmann, J. R. Cole, M. S. Tempesta, and R. B. Bates, J. Org. Chem., 1980, 45, 3132.

117

Triterpenoids

OH

OH (38) R = Ac

(39)

OH

\c/

+%" 1

p. 172).39(24S)-3By24,25-Trihydroxytirucall-7-ene (42) is a new natural product from the root bark of Ailanthus excelsa (Simar~ubaceae).~' Euphorbinol from Euphorbiu tiruculli has been assigned the tentative structure (43).41 Tetranortriterpen0ids.-Two further new limonoids from Melia atedarach are ohchinolides A (44) and B (45).42X-Ray analysis confirmed the structure of ohchinolide A.43Other new limonoids reported this year are pseudrelone B (46) from Pseudocedrelu kotschyii ( M e l i a ~ e a e )febrinins ,~~ A (47) and B (48) 40

M. M. Sherman, R. P. Borris, M. Ogura, G. A. Cordell, and N. R. Farnsworth, Phytochemistry,

1980,19,1499. 41

42

43 44

N. Afza, A. Malik, andS. Siddiqui, Pak. J. Sci. Ind. Res., 1979,22, 124. M.Ochi, H. Kotsuki, M. Ido, H. Nakai, M. Shiro, and T. Tokoroyama, Chem. Lett., 1979,1137. H.Nakai, M. Shiro, and M. Ochi, Actu Crystallogr., 1980,B36, 1698. D.A. H. Taylor, Phytochemistry, 1979,18, 1574.

Terpenoids und Steroids

118

’-0 (44) R = PhCO (45) R = tiglate

(46)

OAc

OTig

(47) R = COEt (48) R = COMe

co

0 0

’OAc

(50)

from Soymida febrifugu (Melia~eae),~’ and polystachin (49) from Aphanamixis polystacha ( M e l i a ~ e a e )The . ~ ~identification of the seeds from which the nomilin derivative (50) was isolated as Uncaria gambia (Rubiaceae) was erroneous (see Vol. 9, p. 198). They were, in fact, Xylucarpus granatum (Melia~eae).~’ Swietenine ( 5 1)has been converted into swietenolide diacetate (52), thus achieving the previously elusive interrelation of the two major constituents of the seeds of Swietenia macrophylla (Meliaceae) (Scheme 3).48A radioimmunoassay method has been developed which allows the accurate determination of limonin in Citrus.49The metabolism of limonoids in Citrus has been investigated.” 45 46 47 48

49

M. M. Rao, P. S. Gupta, P. P. Singh, and E. M. Krishna, Ind. J. Chem., Sect. B, 1979, 17, 158. D. A. Mulholland and D. A. H. Taylor, J. Chem. Res. ( S ) , 1979, 294. A. S. Ng and A. G. Fallis, Can. J. Chem., 1979, 57, 3088. J. D. Connolly and C. LabbC, J. Chem. SOC.,Perkin Trans. 1, 1980, 529. R. L. Mansell and E. W. Weiler, Phytochemistry, 1980,19, 1403. S. Hasegawa, R. D. Bennett, and C. P. Verdon, Phytochemistry, 1980,19, 1445.

119

Triterpen oids

HO

i, ii +

.

j\f OTig

(5l)

V

t-

I

OAc

1

OAc

(52)

Reagents: i, SeO,; ii, Os0,-NaI0,-HCO;;

iii, Ac,O-pyridine; iv, SOC1,-pyridine;

v,

HI-Pd/C

Scheme 3

Pentanortriterpen0ids.-The intriguing range of compounds isolated from the family Cneoraceae continues to be extended. The availability of tricoccin S42, the C-7 epimer of tricoccin S4 (see Vol. 10, p. 151), has led to a revision of the stereochemistry of the latter. Tricoccins S4 and S42 are now represented by structures (53) and (54) respectively.” Tricoccins SI6 and S2, are the bishemiacetal (55) and the corresponding peroxide (56). Both are extremely acid sensitive, readily losing water to form the spiro-acetals (57) and (58) re~pectively.~~ The structures of cneorins Q (59) and NPZ9 (60) have been established. They differ only in the stereochemistry at C-7 and C-9.”

52

B. Epe and A, Mondon, Tetrahedron Lett., 1979, 4045. B. Epe, U. Oelbermann, A . Mondon, and G. Remberg, Tetrahedron Lett., 1979, 3839.

Terpenoids and Steroids

120

0 (57) n = 1 ( 5 8 )n = 2

0 ( 5 5 )n = 1 (56) n = 2

Quassinoids.-An X-ray crystal analysis of the tetra-acetate of bruceine C (61) has confirmed the previously established structure and established the E configuration of the double bond in the ester side-chain. Bruceantinol, a potent antileukaemic compound, has been shown to be 4'-0-acetylbruceine C (62).53 Simaba cuspidata and Ailanthus grandis (Simaroubaceae) both yielded the same two quassinoids, 6a-tigloyloxychaparrinone (63)and the new 6a-tigloyloxychaparrin (64).54A. excelsa contains excelsin (65), an ester of the known

(61) R = H (62) R = Ac 53 54

J. Polonsky, J. Varenne, T. Prange, and C. Pascard, Tetrahedron Lett., 1980,21,1853. J. Polonsky, Z. Varon, C. Moretti, G. R. Pettit, C. L. Herald, J. A. Rideout, S. B. Saha, and H. N. Khastgir, J. Nat. Prod., 1980,43,503.

121

Triterpenoids OH

OTig (63) R = 0 (64) R = H,a-OH

(65)R = C

" (66) R = H

OMe

<

and co-occurring glaucarubol (66).55In addition to the continued screening of plants for new, and hopefully medicinally useful, substances, increasing attention is being given to the synthesis of quassinoid-like compounds. The array of functional groups and asymmetric centres present in, for example, quassin (67) offers a considerable challenge. Of the various approaches reported this year, s ~particularly ~ noteworthy. The known acetal that of Grieco and his c o - w ~ r k e r is (68) was converted into the enone (69) in 51% overall yield (Scheme 4).

3-

0

5

i

& M

j H

C0,Et

C0,Et

: H

: H a

tMb0

(71)

(69)

lviii

(72) R = Me (73) R = H Reagents: i, NaH-MeI-Bu,NI; ii, 70% HClO,; iii, methylation, conditions not specified; iv, Li-NH,; v, PhWMe,Br;; vi, LiBr-Li,CO,-DMF; vii, (70); viii, NaBH,

Scheme 4 " "

S. A. Khan, S. S. Zuberi, and K. M. Shamsuddin, Ind. J. Chem., Sect. B, 1980,19,183. P. A. Grieco, G. Vidari, S. Ferrino, and R. C. Haltiwanger, Tetrahedron Lett., 1980,21,1619.

122

Terpenoids and Steroids

Treatment of the enone (69) with an excess of the diene (70) in the presence of aluminium trichloride and 4,4-thiobis-(6-t-butyl-3-methylphenol) gave the tricyclic ketone (71) (40%) as the sole Diels-Alder product. Reduction then afforded the lactone (72) whose constitution and stereochemistry were established by X-ray analysis. Finally, demethylation gave the racemic alcohol (73) which differs from the quassin skeleton only in the stereochemistry at C-9.56 The Diels-Alder reaction also plays a key role in two other de nduo syntheses. The ring A seco-derivative (75) has been prepared from the adduct (74),57and the ring A nor-compound (77), a possible intermediate for the synthesis of quassimarin (78), has been obtained from the Diels-Alder product (76).58

Me0,C Me0,C

I

V"

(74)

0-C-F-

AcO

OAC I

H

Et

An alternative approach is to make use of a steroidal starting material. The products are then optically active. A major achievement here is the synthesis of the highly functionalized derivative (80) from testosterone (79). The overall yield was low, as expected for a sequence involving some 28 Chenodeoxycholic acid (81) has been converted into the lactone (82).60 5 Lupane Group

The structures of cymbopogone (see Vol. 6, p. 139) and cymbopogonol (see Vol. 7, p. 149)have been revised to (83) and (84) respectively.61The realization

(79) " 59

6o 61

(80)

N. Stojanac, Z . Stojanac, P. S. White, and Z. Valenta, Can. J. Chem., 1979, 57, 3346. G. A. Kraus and M. J. Taschner, J. Org. Chem., 1980,45, 1175. J. Pfenninger and W. Graf, Helv. Chim. Acta, 1980, 63, 1562. J. R. Dias and B. Nassim, Steroids, 1980,35, 405. Y. Yokoyama, T. Tsuyuki, N. Nakamura, T. Takahashi, S. W. Hanson, and K. Matsushita, Tetrahedron Lett., 1980,21,3701.

Triterpenoids

123

&CO,Me

that these compounds are friedolupane derivatives rather than friedoursanes followed from an independent synthesis of the ketone (83) by oxidation of the alcohol (86) (Scheme 5).62 Alternatively, dehydration and epoxidation of (86) afforded the epoxides (87) and (88). X-Ray crystal analysis established the structure and stereochemistry of the 3a,4a-epoxide (87) and hence of the other compounds in this series.62The boron trifluoride induced backbone rearrangement of the epoxides (87) and (88) was studied as a function of Further reactions of the ketone (85) have been described.64 The ketone (83) has been converted into an inseparable mixture of the rearranged ketones (89) and (90) which on reduction gave the expected four alcohols.62The least abundant (91) was shown to be different from guimarenol (92).6sThe stereochemistry of the latter triterpenoid therefore remains unknown. New lupanes include heliantriol B2(93) from the flowers of Helianthus annuus and also Calendula officinalis (Compositae)66and the trio1 (94) from the bark . ~ ~ (known) triterof an unidentified Glochidion species ( E ~ p h o r b i a c e a e ) The penoids from several other species from Euphorbiaceae have been identified.67 The preparation and reactions of some substituted 3,4-secolupane-3,28-dioic acids have been described.68The 13Cn.m.r. spectra of some lupanes have been assigned.69

62

63

'' 67

69

Y. Yokoyarna, Y. Moriyarna, T. Tsuyuki, T. Takahashi, A. Itai, and Y. Iitaka, Chem. Lett., 1979, 1463. Y. Yokoyama, Y. Moriyama, T. Tsuyuki, and T. Takahashi, Chem. Lett., 1980,67. Y. Yokoyama, Y. Moriyama, T. Tsuyuki, and T. Takahashi, Chem. Abstr., 1980,93,26 585. A. G. Gonzblez, F. Gutierrez Jerez, and M. Luque Escalona, A n . Quim., 1973, 69, 921. J. St. Pyrek, Pol. J. Chem., 1979, 53, 2465. R. C. Carpenter, S . Sotheeswaran, M. U. S. Sultanbawa, and S. Balasubrarnaniarn, Phytochemistry, 1980,19,1171. I. Valterova, J. Klinot, and A. Vystrcil, Coll. Czech. Chem. Commun., 1980, 45, 1964. M. Sholichin, K. Yarnasaki, R. Kasai, and 0.Tanaka, Chem. Pharm. Bull., 1980,28, 1006.

Terpenoids and Steroids

124

i-iv

HO

1

vi, vii

/

I

viii-x

/i..",

9

0

(87) 3a,4a-epoxide (88) 3p,4p- epoxide

0

Reagents: i, NaBH,; ii, Ac,O-pyridine; iii, H,-Pt; iv, LiAlH,; v, CrO,; vi, POC1,-pyridine; vii, m-chloroperbenzoic acid; viii, PhCOCl; ix, Br,-pyridine; x, AgOAc

Scheme 5

HO

Triterpenoids

125

(94)

6 Oleanane Group Olean-12-enes occur in a variety of plant families and new representatives of this series continue to be found. Amongst those reported this year are pokeberry2a- hydroxy-3-0~0genin (95) from Phytolacca americana (Phytolac~aceae),~~ olean-12-en-28-oic acid from Salvia officinalis (Labiatae),71 pridentigenins B (96)* and E (97) from Primula denticulata ( P r i r n u l a ~ e a e )3-epikatonic ,~~~~~ 28,23 - dihyacid (98) from Cyamopsis tetragonoloba (Legumino~ae),~~ droxyacacic acid (99) (a presumed artefact from the corresponding hydroxyacid) from Gymnocladus dioica ( L eg~ m i nos ae) ,and ~ ~ 3P,16a,23- trihydroxy.~~ olean-12-en-28-oic acid (100) from Chrysanthellum p r o c ~ m b e n sOleananes

/Co','

OMe

(97)

* The structural formula given for pridentigenin B in the original paper is clearly incorrect. 70 71 72

73 74

7s 76

S. S. Kang and W. S . Woo, J. Nar. Prod., 1980,43,510. C. H. Brieskorn and Z. Kapadia, Planru Med., 1980,38,86. V. U. Ahmad, Q. Najmus-Saqib, K. Usmanghani, W. Fuchs, and W. Voelter, 2. Narurforsch., Teil B, 1980, 35, 511. V. U. Ahmad, Q. Najmus-Saqib, and K. Usmanghani, Phyrochemistry, 1980,19,1875. D. T. Coxon and J. W. Wells, Phytochemistry, 1980, 19, 1247. R. M. Parkhurst, D. W. Thomas, L. W. Cary, and E. J. Reist, Phytochemistry, 1980,19,273. M. Becchi, M. Brueneteau, M. Trouilloud, H. Combier, H. Pontanier, and G. Michel, Eur. J. Biochem., 1980,108,271.

Terpenoids and Steroids

126

oxygenated at either C-6 or C-27 are still rare. Manevalic acid (101) and azizic acid (102) from Cornulaca monacantha (Chenopodiaceae) are functionalized at both C-6a and C-27. Oxidation of manevalic acid gave 3,6-dioxo-olean-12-en27-oic acid, identical with material obtained by the oxidation of astilbic acid (3P,6P-dihydroxyolean-12-en-27-oicacid).77 The hexa-acetate (103) of napoleogenin from Napoleonaea imperialis (Lecythidaceae) has been the subject of an X-ray crystal analysis.78Napoleogenol (104) is new aglycone from the same source.79Publications have appeared on saponins of Anchusa oficinalis (Boraginaceae)," Polemonium reptans,81 Terminalia arjuna,82and Verbascum ph lomoides.83

HO OH (101)R=Me (102) R = COZH

77 78 79

82

83

A.-A. Dawidar, J. Reisch, and M. Amer. Chem. Pharm. Bull., 1979,21, 2938. M. R. Spirlet, L. Dupont, 0. Dideberg, and M. Kapundu, Acta Crystallogr., 1980, B36, 1593. M. Kapundu, R. Warin, C. Delaude, and R. Huls, Phytochernistry, 1980,19, 615. G . Romussi, G. Ciarallo, G. Falsone, and C. Schneider, Liebigs Ann. Chem., 1979, 2028. J. Jurenitsch, E. Haslinger, and W. Kubelka, Pharmazie, 1979, 34, 445. T. Tsuyuki, Y. Hamada, T. Honda, T. Takahashi, and K. Matsushita, Bull. Chem. SOC. Jpn, 1979, 52, 3127. R. Tschesche, S. Sepulveda, and T. M. Braun, Chem. Ber., 1980,113, 1754.

Triterpenoids

127

Treatment of triterpenoid 3-ketones [as (105)] with ammonium acetate and sodium cyanoborohydride in methanol and subsequent acidification with hydrochloric acid gives a 90% yield of the 3p- (106) and 3a- (107) ammonium chlorides in a ratio of ca. 2 : l.84 A range of 3-amino/28-amido-derivativesof oleanolic and ursolic acids has been prepared.R5The use of n.m.r. and U.V. spectra to establish the configuration at C-18 of olean-12-en-11-ones has been further exemplified.86

GI-: & K l + H ; - l H P

0

(105)

c1-

(106)

CI- (107)

Moronic acid (108) has been isolated from Ozoroa mucronata (Anacardia~eae).'~ It is also a major component of the acidic fraction from gum mastic [Pistacia lentiscus (Anacardiaceae)]." Rather surprisingly, it shows antimicrobial activity against gram-positive bacteria. This activity is lost if any one of the three functional groups is rn~dified.'~ Heliantriol A1 is olean-13(18)-ene-3P,l6p,28trio1 ( 109).66 The isolation from Tetrapanax papyriferum (Araliaceae) of papyriogenins D (110), E ( l l l ) , F (112), and G (113) has been detailed.89 The structure and stereochemistry of prionostemmadione (114), a new friedelane derivative from Prionostemma aspera (Celastraceae), has been established by X-ray crystal analy~is.~' The same plant also yielded a new triterpenoid

, .

HO"

(110) R = O (111) R = H,a-OH

C. H. Brieskorn and H. Eschelbach, Arch. Phann. (Weinheim. Ger.), 1979,312, 752. H. Linde, Arch. Pharm. (Weinheim. Ger.), 1979, 312, 832. 86 A. S. R. Anjaneyulu, L. Ramachandra Row,and A . Sree, Ind. J. Chem., Sect. B, 1979,18, 112. '' M. Hostettmann-Kaldas and K. Nakanishi, Planta Med., 1979, 37, 358. R. B. Boar, L. A . Couchman, and M. J. Perkins, unpublished observation. M. Asada, S. Amagaya, M. Takai, and Y. Ogihara, J. Chem. SOC.,Perkin Trans. 1, 1980, 325. 90 F. Delle Monache, G. B. Marini-Bettblo, M. Pomponi, J. F. de MCllo, T. J. King, and R. H. Thomson, J. Chem. SOC.,Perkin Trans. 1, 1979,2649. 84

Terpenoids and Steroids

128

quinone methide, pristimerinene (115). The related compound, 21phydroxypristimerin (116), was isolated from an unidentified Salacia species (Hippocrateaceae), as was an incompletely identified hydroxypristimerinene in which the additional hydroxy-group was evidently (by mass spectrometry) in ring D or E.91Elaeodendrol (117) and elaeodendradiol (118) are two new and unusual 28-norfriedelanes from the bark of Elaeodendron glaucum (Celastraceae). The structures were assigned largely on the basis of n.m.r. data.92 Another product (see Vol. 6, pp. 136-7) of the reaction of the 7P-hydroxyfriedelane (119) with lead tetra-acetate-iodine is the rearranged ether (120). Presumably elimination of acetic acid affords the friedel-4-ene which then rearranges with methyl migrati~n.’~ 3a-Hydroxymultiflora-7,9( 1l)-dien-29-oic acid (121) from the roots of Bryonia dioica (Cucurbitaceae) is a new natural A smfill percentage of the A-nor-compound (123) is formed when

(117) R = H (118)R=OH 91

92

93 94

F. Delle Monache, G. B. Marini-Bettolo, M. Pornponi, J. F. de Mkllo, 0. GonGalves de Lima, and R. H. Thornson, J. Chem. SOC.,Perkin Trans. I , 1979, 3127. A. S. R. Anjaneyulu and M. Narayana Rao, Phytuchemistry, 1980, 19, 1163; Curr. Sci., 1980, 49, 226. P. Sengupta, M. Sen, and S. N. Maiti, Ind. J. Chem., Sect. B, 1979, 18, 504. P. J. Hylands and M. T. Oskoui, Phytuchemistry, 1979,18,1843.

Triterpenoids

129

As (122)

AcO

(122)

taraxeryl acetate (122) is subjected to prolonged treatment with mercuric acetate in acetic acid.95 The mass spectra of some ring A substituted allobetulane derivatives have been reported.96

7 Ursane Group The reaction of ursolic acid acetate (124) with hydrogen peroxide in hot acetic acid has been reinvestigated. Structures (125)-(127) have been assigned to the p r o d ~ c t s . ~Treatment ’ of the keto-lactone (128) with oxygen in t-butyl alcoholpotassium t-butoxide gave the a-hydroxy-acid (129) (80%), presumably the result of a benzilic acid type rearrangement of an intermediate 2 1,22-diket0ne.~~ A minor product was the keto-lactone ( 130).99 Isocalaminthadiol from Satureia calamintha and S. graeca (Labiatae) has been assigned the most unusual

H

AcO

”

96

’’ 98

99

AcO

A. Dasgupta, A. Goswami, T. K. Ray, A. Nath, and H. N. Khastgir, Ind. J. Chem., Sect. B, 1980,

19, 165. J. Schmidt and S. Huneck, Org. Mass Spectrom., 1979, 14, 646. P. L. Majurnder and M. Chakraborty, Tetrahedron, 1979, 35, 2397. E. Klinotova, H. Skorkovska, J. Protiva, and A. Vystrcil, Coll. Czech. Chem. Commun., 1980, 45, 1366. E. Klinotova, H. Skorkovska, J. Protiva, J. Urban, and A. Vystrcil, Coll. Czech. Chem. Commun., 1980,45,2351.

Terpenoids and Steroids

130

{fiPH CO,H

As (128)

:

{&

As (128)

j

(129)

AcO

0

(130)

(128)

structure (13 1). loo Marsformosanone (132) from Mursdenia formusam (Asclepiadaceae)"' and 2a- hydroxyursolic acid from Corchorus capsularis and C. olitorius'02 have been reported. The crystal and molecular structures of u- amyrin acetate and benzoate have been determined.lo3 Heliantriol Bo (133) and heliantriol B, (134) are two further new taraxastenes. The occurrence in the same plant of 3p,16p,28- trihydroxy-derivatives of three different triterpenoid skeletons is noteworthy.66

(1 33) 20-ene (134) 20(30)-ene loo

lo2

'03

G. Romeo, P. Giannetto, and M. C. Aversa, Phytochernistry, 1980, 19, 437. J. Lai and K. Ito, Chem. Pharm. Bull., 1979, 27, 2248. M. Manzoor-i-Khuda and G. Habermehl, 2.Naturforsch., Teil B, 1979, 34, 1320. M. Grynpas and P. F. Lindley, J. Cryst. Mol. Struct., 1980, 9, 199.

Triterpenoids

131

8 Hopane Group Triterpenoids of, or related to, the hopane skeleton (135) are ubiquitous components of sediments. They occur as three stereochemical series (17P-H,21P-H; 17a-H,21P-H; 17P-H,21a-H). A variety of functional classes is found as a range of extended (>C,,) and degraded (
-w

\

As (135)

.&C02H

(138)

Ho2c2 $-

}" I

1

HO,C

(139)

(140)

(141)

3-ketone has be,en described. Whether their origin is indeed photochemical, or rather photomimetic, remains to be e~tab1ished.l~'The crystal and molecular structure of 28,30-dinor-l7a(H),18a (H),2lp(H)-hopane (142) from a Monterey (California) shale oil has been determined by X-ray crystal analysis.1o8 Spergulagenol from Mollugo spergulu (Ficoidaceae) is considered to have structure (143).."' Some reactions of the co-occurring spergulagenin A (144) have

.i:l-"--H

&...-

OH

HO (142) lo4 lo5

lo' lo' lo9 110

(143)

M. Dastillung, P. Albrecht, and G. Ourisson, J. Chem. Res. ( S ) , 1980, 166. M. Dastillung, P. Albrecht, and G. Ourisson, J. Chem. Res. ( S ) , 1980, 168. J. Taylor, A. M. K. Wardroper, and J. R. Maxwell, Tetrahedron Lett., 1980, 21,655. B. Corbet, P. Albrecht, and G. Ourisson, J. A m . Chem. SOC.,1980, 102, 1171. G. W. Smith, Acta Crystallogr., 1979, B35, 2173. D. Scholefield and J. S. Whitehurst, J. Chem. SOC.,Chem. Commun., 1980, 135. A . K. Barua, S. K. Banerjee, C. Das Gupta, K. Basu, L. Bose, and P. Chakrabarti, Phytochernistry, 1980,19, 1551.

132

Terpenoids and Steroids

been described."' Papers have appeared on the mass spectra1'* and lowfrequency (900450cm-') i.r. s p e ~ t r a ' 'of ~ hopanoids.

'C0,Me

(144) OH (145)

9 Miscellaneous X-Ray crystal analysis has established the novel structure (145) for terretonin, a toxic compound from the fungus Aspergillus terre~4s.l'~The carbon skeleton bears no obvious relationship to that of other known triterpenoids. Further work relating to the genesis of this compound is eagerly awaited. The structure of malabaricol has been published again (see Vol. 10, p. 137)."'

'12

'I3 'I4

'"

A. K. Barua, A. Basak, S. K. Banerjee, T. K. Chatterjee, K. Basu, and P. Chakrabarti, Trans. Bose Res. Inst. (Calcutta),1978, 41, 95. J. Schmidt and S. Huneck, Org. Mass Spectrom., 1979,14,656. K. J. Ronaldson and A. L. Wilkins, J. Chem. Res. ( S ) , 1979, 295. J. P. Springer, J. W. Dorner, R. J. Cole, and R. H. Cox, 1.Org. Chem., 1979, 44,4852. W. F. Paton, I. C. Paul, A. G. Bajaj, and S. Dev, Tetrahedron Lett., 1979,4153.

4 Carotenoids and Polyterpenoids By

G. BRITTON

1 Carotenoids Reviews.-Of the several reviews published during the year on the chemistry and biochemistry of carotenoids and related compounds the most useful is an extensive article by Liaaen-Jensen' dealing with all aspects of the stereochemistry of naturally occurring carotenoids. Some useful methods for the synthesis of natural carotenoids are surveyed by Muller et a1.' The application of some of these carotenoids as food colorants has been discussed by Kienzle and I ~ l e r . ~ Szabolcs4 has also reviewed recent advances in carotenoid chemistry and research, and general accounts of carotenoids have been presented by Farges' and Goodwin.6 More specialized articles deal with carotenoids and their biosynthesis in bacteria' and microbial production of carotenoids.' Carotenoids in marine organisms are discussed by Katayama' and in an article on pigments in general by Fox." A new volume in the Methods in Enzymology series" includes experimental procedures in the carotenoid and vitamin A fields. The proceedings of a symposium on vitamin A and retinoids have been published,'2 and the -'~ chemistry of retinoids is also reviewed elsewhere. l 3 Three a r t i c l e ~ l ~describe various aspects of the chemistry, biochemistry, and functioning of abscisic acid. New Structures and Stere0chemistry.-Carotenoids. A major pigment in aerobic cultures of Rhodopseudomonas capsulata has been identified" by spectroscopic S. Liaaen-Jensen, Fortschr. Chem. Org. Naturst., 1980,39, 123. R. K. Muller, K. Bernhard, F. Kienzle, H. Mayer, and A . Ruttimann, Food Chem., 1980, 5 , 15. F. Kienzle and 0.Isler, Chem. Synth. Dyes, 1978, 8, 389. ' J. Szabolcs, Magy. Kem. Lapja, 1979, 34, 336. M. Farges, Riv. Ital. Essenze, Profumi, Piante Off., Aromat., Syndets, Saponi, Cosmet., Aerosols, 1980, 62, 25. T. W. Goodwin, Encyl. Plant Physiol., New Ser., 1980, 8, 257. R. Czerpak and B. Czeczuga, Wiad. Bot., 1979,23,73. L . Ninet and J. Renaut, Microb. Technol., 1979, 1, 529. T. Katayama, Kagaku Sosetsu, 1979,25, 139. l o D. L. Fox,Biol. Rev. Cambridge Phil. SOC.,1979, 54, 237. l 1 D. B. McCormick and L. D. Wright, eds., Methods Enzymol., Vol. 67, 1980, Academic Press, New York, London, Toronto, Sydney, and San Francisco. l 2 D. S. Goodman, Fed. Proc., 1979, 38, 2501. l3 K. Tsukida, Bitamin, 1979, 53, 337. D. C. Walton, Ann. Rev. PlantPhysiol., 1980, 31, 453. Is J. A. D. Zeevaart, ACSSymp. Ser., 1979, 111,99. l 6 D. P. Popa, Izv. Akad. Nauk Mold. SSR, Ser. Biol. Khim. Nauk., 1979, 27. l7 J. Manwaring, E. H. Evans, G. Britton, and D. R. Schneider, FEBS Lett., 1980, 110,47.

*

133

Terpenoids and Steroids

134

methods (including ‘H n.m.r.) as demethylspheroidenone [ 1-hydroxy-3,4didehydro-1,2,7’,8’-tetrahydro-I,b,t,b-caroten-2-one (l)]. Demethylspheroidene [3,4-didehydro-1,2,7‘,8’-t,b,I,b-caroten-l-01 (2)] was also present. A mutant HO (1) x = 0 (2) X = Hz

strain of Rhizobium lupini has yielded several carotenoids including the novel (2R,3S)-2,3-dihydroxy-P,p-caroten-4-one (3), (2R,3S)-2,3-dihydroxy-&Pcarotene-4,4’-dione (4), and (2R,3S, 2’R, 3’S)-2,3,2’,3’-tetrahydrox~-P,P carotene-4,4‘-dione (5). Light absorption, m.s., ‘H n.m.r., and c.d. properties of all these compounds are given.18 3’-O-Didehydrolutein [3-hydroxy-P,~-caroten3’-one (6)] has been detected in egg yolk and in flowers of Caltha palustri~.‘~ Compound (6) was very labile to alkali; e.g. with 1% KOH many products were obtained including the unusual (3R)-3-hydroxy-4’,12‘-retro-p,p-carotene3’,12’-dione (16). 3’-Epilutein [(3R, 3’R)-& ~-carotene-3,3’-diol(7)] was also isolated from C. palustris, but was not found in egg yolk. The presence of (7) and of three isomers of tunaxanthin [s,~-carotene-3,3‘-diol(8),chirality not determined] has been reported.20-22 The structure of salmoxanthin [5,6-epoxy5,6-dihydro-P,~-carotene-3,3’,6’trio1 (9)], which constitutes 30% of the total and the sea sponge carotenoid of the salmon 0. keta, has been dete~mined,’~ Tedania digitata has yielded isotedaniaxanthin [7,8-didehydro-P,~$-caroten-3-01

(1011.~~

H.p.1.c. separation of the (-)-camphanic diesters of astaxanthin [3,3’-dihydroxy-P,P -carotene-4,4’-dione (1l)] from lobster eggs (Homarus gammarus) showed that all three isomers, (3R,3’R), (3S,3’S), and (3R,3’S), were present. Details This is the first identification of a meso-carotenoid in a natural of the previously reported26 determination of the chirality of peridinin [(3S,SR,SR,3’S,S’R,6’S)5’,6’-epoxy-3,5,3’-trihydroxy-6,7-didehydro-5,6,5’,6’tetrahydro-l0,11,20-trinor-~,~-caroten-19,1l’-olide 3-acetate (17)] and [(3S,5R,6R,3’S,5’R,6’S)-5’,6‘-epoxy-6,7-didehydro-5,6,5’,6’ dinoxanthin tetrahydro-P,P-carotene-3,5,3’-triol 3-acetate (12)] have been given.*’ ‘Sulcatoxanthin’ from Anemonia sulcata has been shown to be identical to peridinin. 28 l9

21

’* 23 24 25

26 27

’’

P. Beyer, H. Kleinig, G. Englert, W. Meister, and K. Noack, Helu. Chim. Acru, 1979, 62, 2551. R. Buchecker and C. H. Eugster, Helu. Chim. Acta, 1979,62, 2817. T. Matsuno, H. Matsutaka, M. Katsuyama, and S. Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1980, 46, 113. T. Matsuno, H. Matsutaka, M. Katsuyama, and S. Nagata, Bull. Jpn. SOC.Sci. Fisheries, 1980, 46, 337. T. Matsuno, H. Matsutaka, M. Katsuyama, and S. Nagata, Bull Jpn. SOC.Sci. Fisheries, 1980, 46, 333. T. Matsuno, S . Nagata, and M. Katsuyama, Bull. Jpn. SOC.Sci. Fisheries, 1980, 46, 91 1. Y. Tanaka and T. Katayama, Bull. Jpn. Soc. Sci. Fisheries, 1980, 46, 381. H. Renneberg, B. Renstrprm, K. Aareskjold, S. Liaaen-Jensen, M. Vecchi, F. J. Leuenberger, R. K. Muller, and H. Mayer, Helu. Chim. Actu, 1980,63, 711. J. E. Johansen, S. Liaaen-Jensen, and G. Borch, N A T O Conf. Ser., Ser. 4, 1977, 1, 225. J. E. Johansen, G . Borch, and S. Liaaen-Jensen, Phytochemistry, 1980, 19, 441. A . Fiksdahl, M. Hallenstvet, L. Beress, and S. Liaaen-Jensen, Biochem. Syst. Ecol., 1979, 7, 173.

135

Carotenoids and Polyterpenoids R2

a / ’

HO

HO d

f

e

(3) R’ = a(X = Y = OH),R2 = b(X = H) (4) R’ = a(X = Y = OHj,R2 = a(X = Y = H) ( 5 ) R’ = R~ = a(X = Y = OH) (6) R’ = b(X = OH), R2 = c(Y,Z = 0) (7) R’ = b(X = OH), R2 = c(Y = OH, Z = H) (8) R’ = R2 = c(Y,Z = H,OH) (9) R’ = d, R2 = e

(10) (11) (12) (13) (14) (15)

R’ R’ R’ R’ R’ R’

f,R2 = g R2 = a(X = H,Y = OH) = h,R2 = d = R2 = d = d, R2 = &O = b(X = H ) , R 2 = CHO

=

=

The natural occurrence of the 15-cis-isomer of violaxanthin [5,6,5’,6’-diepoxy5,6,5’,6’-tetrahydro-P,P-carotene-3,3’-diol (13)] as a minor (0.6% of total carotenoid) constituent of Viola tricolor has been Isomerization to trans-violaxanthin and c.d. correlation established the (3S,SR,SS,3’S,S’R,6’S)chirality. Reinvestigation of the carotenoids of Elodea canadensis failed to reveal any ‘eloxanthin’. It is proposed that the name be a b a n d ~ n e d . ~A’ minor carotenoid from Valencia orange peel has been identified31 as P -citraurin epoxide [3 -hydroxy-5,6 -epoxy-5,6 -dihydro- 8 ‘-apo-P -car0ten-8’-al ( 14)]. N.m.r. correlation (270 MHz) with synthetic products has confirmed3* that the citrus C,, pigments such as 8’-apo-P- caroten-8’-al have the proposed unsymmetrical Czo-ClOapocarotenoid structures (15) and not the alternative symmetrical c15-cl5 diapocarotenoid structure (18). 29

31

P. Molnar and J. Szabolcs, Phytochernistry, 1980, 19, 623. G. Toth and J. Szabolcs, Phytochernistry, 1980, 19, 629. P. Molnir and J. Szabolcs, Phytochemistry, 1980, 19, 633.

32

H. Pfander, M. Hadorn, and A. Lachenmeier, Helv. Chim. Actu, 1980, 63, 716.

30

Terpenoids and Steroids

136

New Natural Products Related to Carotenoids. Tobacco continues to yield volatile constituents with carotenoid-like rings, described by some authors as ‘norcarotenoids’. New structures reported are 5-hydroxy-5,6-dihydro-3,6-epoxy-/3 ionol [carotene numbering ( 19)]33-35and the related 5,8-epoxide (20).35An The epoxymegastigmadiene (21) has been identified in Osmanthus

a3” OH

(19)

@c-

HO (20)

(21)

latter source has also yielded a range of other epoxy- and spiro-compounds such as (22)-(24).37 Other carotenoid-like compounds to have been isolated and characterized include m a n ~ a l i d e(25) ~ ~ and m ~ q u b i l i n(26) ~ ~ from marine sponges and n i g a k i a l c ~ h o l(27), ~ ~ fekro141 (28), and aeginetoside (29) and the related hydroxy-P -ionone glucoside (30)42from plant sources. 33 34

35 36 3’

38 39 40

41

42

T. Kato, H. Kondo, Y. Kitano, G. Hata, and Y. Takagi, Chem. Lett., 1980, 757. Y. Takagi, T. Fujirnori, T. Hata, H. Kaneko, and K. Kato, Agric. Biol. Chem., 1980,44,705. D. Behr, I. Wahlberg, T. Nishida, and C. R. Enzell, Acta Chem. Scand., Ser. B, 1979, 33, 701. R. Kaiser and D. Lamparsky, Helu. Chim. Acfa, 1979,62, 1878. R. Kaiser and D. Lamparsky, Int. Congr. Essent. Oils, 7th 1977, 1979, 7, 395. E. D. DeSilva and P. J. Scheuer, Tetrahedron Lett., 1980, 21, 1611. Y. Kashman and M. Rotem, Tetrahedron Lett., 1979, 1707. Y. Sugimoto, T. Sakita, T. Ikeda, Y. Moriyarna, T. Murae, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC.Jpn., 1979,52, 3027. N. V. Veselovskaya, Yu. E. Skylar, D. A. Fesenko, and M. G. Pimenov, Khim. Prir. Soedin., 1979, 851. T. Endo, H. Taguchi, H. Sasaki, and I. Yosioka, Chem. Pharm. Bull., 1979, 27, 2807.

Carotenoids and Polyterpenoids

137

O-glucose 22131 22132

(29) X (30) x

= =

CHCHZOH 0

Carotenoid-Protein Complexes. The partial characterization of an astaxanthin- or zeaxanthin-containing carotenoprotein (mol. wt. >30 000) from hydrocorals has been Other papers present a spectroscopic characterization of the lobster pigment a - c r u ~ t a c y a n i nand ~ ~ report effects of changes in pH and ionic strength on its spectroscopic proper tie^.^' Synthesis and Reactions.-Curotenoids. Two papers report the synthesis of model polyenes related to naturally occurring carotenoids. Condensation of the two Clo reagents (31) and (32) gave the /3-oxosulphone (33) which was converted

(31) R (32) R

" 44

''

=

=

C02Me CH2S02Ph

(331

H. Ranneberg, D. L. Fox, and S. Liaaen-Jensen, Comp. Biochem. Physiol., 1979,64B, 407. T. Y. Lee, J. Jung, and P . 4 . Song, J. Biochem. (Tokyo),1980,88,663. L. Wahlgren-Brannstrom and M. Baltscheffsky, Acta Chem. Scand., Ser. B, 1979, 33, 613.

Terpenoids and Steroids

138

into the enolphosphate (34) and thence into the ( E ,E)-tetraenyne (35). Hydrogenation of (35) gave the (E,Z,E)-pentaene (36),a model of the natural (E,Z,E)or 15-cis-phytoene (37).46The stereocontrolled synthesis of a model polyene O=P(OEt), I

(36) R'

=

R2 = Me

(38) by Horner reactions with appropriate phosphine oxides has been described.47This model (38) had spectroscopic properties very similar to those of the 15,9'-di-cis-phytofluene (39) of tangerine tomatoes.

46 47

(38) R'

=

R2

=

(39) R'

=

R2

=

Me

L..'

B. Lythgoe and I. Waterhouse, J. Chem. SOC., Perkin Trans. 1, 1979, 2429. J. M. Clough and G. Pattenden, Tetrahedron Lett., 1979, 5043.

139

Carotenoids and Polyterpenoids

Tedanin [3-hydroxy-P, X-caroten-4-one (40)] and its isomer 3-hydroxy-P,4caroten-4-one (41) have been synthesized from the appropriate C 2 , aromatic aldehydes (48) and (49) and the substituted Wittig salt (50).48 Full details of the of tetra-anhydrobacterioruberin (42) from (-)-(R)-lavandulol ( 5 1) have been p~blished,~' together with the c.d. correlations which led to the establishment of the chirality of (42) and the related bacterioruberin [(2S,2'S)2,2' - bis - (3 - hydroxy - 3 - methylbutyl) - 3,4,3', 4' - tetradehydro - 1,2, l', 2' tetrahydro-$,$-carotene-1 ,l'-diol (43)].

OH

/ \

OH

e

d

h

g

(40) (41) (42) (43)

R' R' R' R'

= = = =

a, R2 = b a,R2 = c R2 = d R~ = e

f

1

(44) R' = f , R 2 = g (45) R' = f , R 2 = h (46) R' = i , R 2 = g (47) R' = i , R 2 = h

Wittig condensation of azafrinal (52) with the phosphoranes derived from (aIl-E)-+ionol (53) and (+)-(R)-a-ionol (54) led, respectively, to the optically active (SR,6R)-5,6-dihydro-P,$-carotene-5,6-diol (44) and (5R,6R,6'R)-5,6dihydro-P,e -carotene-5,6-diol (45). Treatment of these diols with the sulphurane reagent Ph2S-[OC(CF3)2Ph]2gave the epoxides (5S,6R)-5,6-epoxy5,6-dihydro-P,$-carotene (46) and (5S,6R,6'R)-5,6-epoxy-5,6-dihydro-P,~ 48 49

5"

M. Yasuhara, K . Inanaga, T. Kumae, H. R. Brahmana, N. Okukado, and M. Yamaguchi, Bull. Chem. Sac. Jpn., 1980, 53, 1629. J. E. Johansen and S. Liaaen-Jensen, Tetrahedron Lett., 1976, 955. J. E. Johansen and S. Liaaen-Jensen, Acra Chem. Scand., Ser. B, 1979, 33, 551.

140

Terpenoids and Steroids

carotene (47).5’ Methyl (R)-[rnethyl-2H3]-homo-@-geran~ate (55) has been prepared from dehydroabietic acid (56) and converted into ( l R , l ’ R ) [16,16,16,16’,16’,16’-’H6]-p,p-carotene (57).’*The deuterium substitution renders the carotene weakly optically active.

(48) X (49) X

= =

Me, Y = H H , Y = Me

)I

.I”’”” ..%

r

1

An efficient procedure has been reported for the preparation of carotenoid glycosyl esters in high yield, via the irnidazol-1-yl or 1,2,4-triazol-l-y1 derivatives of the carotenoic Thus the p-D-glucosyl, ~-D-galaCtOSyl,and p-Dmannosyl esters (58) of 8’-apo-p- caroten-8’- oic acid (59) were prepared by 51

W. Eschenmoser, P. Ubelhart, and C. H. Eugster, Helu. Chim. Acta, 1 9 7 9 , 6 2 , 2 5 3 4 .

’* H.P. Marki and C. H. Eugster, J. Chem. Soc., Chem. Commun., 1980, 527. H. Pfander, M. Laederach, and F. Wittwer, Helv. Chim. Acta, 1 9 8 0 , 6 3 , 277. ’‘ H.Pfander, R. Dumont, and M. Laederach, Chimia, 1980, 34, 20. 53

141

Carotenoids and Poly terpenoids

condensation of the derivatives (60) or (61) with the free sugar in the presence of NaH. Sugar esters of retinoic acid ( 6 3 ) and the crocetindioic acid (64) were prepared similarly. The synthesis of C,, apocarotenoids with a methyl group at C-14 instead of C-13, e.g. (18), has been described.32 These products differ slightly in properties (especially 270 MHz 'H n.m.r.) from the normal c30 apocarotenals such as (62).

R

(58) R (59) R

= =

C02-sugar C02H

(61) R

=

A

(60) R

=

CO-N

N ' u

(62) R =

CO-yAy N-' CHO

Controlled alkaline permanganate oxidation of 5,6-epoxy-5,6-dihydro-p,@ carotene (70), 5,6,5',6'-diepoxy-5,6,5',6'-tetrahydro-P,p-carotene(71), antheraxanthin (5,6-epoxy-5,6-dihydro-p,@ -carotene - 3,3'-diol) diacetate (72), and violaxanthin diacetate (73) gave a range of epoxy C25, C2,, and C30

R2 (64) R' = R2 = C 0 2 H , R 3 = Me (65) R' = R2 = CHzOH,R3 = Me (66) R' = R2 = CH26Ph3Br-,R3 = Me

(67) R' = R3 = Me, R2 = CHO (68) R' = R2 = C H 2 0 H , R 3 = CHzOAc (69) R' = M e , R 2 = C H 0 , R 3 = CH20Ac

apocarotenals, e.g. (74-76; X = H or O A C ) .Treatment ~~ of crocetindiol (65) with phenylphosphonium bromide did not give the expected product (66) but a cis-trans mixture of the monoaldehyde (67).56Similarly the acetoxy-derivative

X

Go a

(70) R' = a(X = H),R2 = b(Y = H) (71) R' = R2 = a(X = H) 55 56

b (72) R' = a(X = OAc), R2 = b(Y (73) R' = R~ = a(X = OAC)

P. Molnir and J. Szabolcs, Acta Chim. Acad. Sci. Hung., 1979, 99, 155. J. E. Johansen and S. Liaaen-Jensen, Acta Chem. Scand., Ser. B, 1 9 7 9 , 3 3 , 5 8 3 .

=

OAc)

142

Terpenoids and Steroids

(68) of crocetindiol gave the related monoaldehyde (69). This procedure thus provides a route for the conversion of w,w -polyenedials into monoaldehydes.

(74) R (75) R (76) R

=

= =

CHO CH=CHCHO CH=CHCH=C(Me)CHO

Retinoids. In a new synthesis of vitamin A [retinol (77)] the ring is constructed by acid-catalysed direct cyclocondensation and cycloaddition of acrolein and ethyl isopropyl ketone to give 2,6,6-trimethylcyclohex-2-enone(78) in 62% yield. Base-catalysed addition of the enyne HC=C-CMe=CH, gives the intermediate (79) and thence, after further chain-lengthening steps, vitamin A.57

A general procedure has been published for the synthesis of retinoids, including vitamin A, by direct condensation of the side-chain, as ethyl 3,7-dimethylnona2,4,6-trien-8-ynoate (80) to the appropriate cyclic ketone, e.g. 2,2,6-trimethylcyclohexanone (8 l)? The acetylenic intermediate (82) is readily converted into vitamin A and derivatives. The side-chain reagent (80) is prepared in high yield by Emmons reaction between the acetylenic aldehyde (83) and the phosphosenecioate (84). In another synthesis of trans-vitamin A,59P-ionylideneacetal-

’’ M. Baumann, W. Hoffmann, and A. Niirrenbach, Liebigs Ann. Chem., 1979, 1945. 58 59

F. Derguini, V. Balogh-Nair, and K. Nakanishi, Tetrahedron Lett., 1979, 4899. G . Cardillo, M. Contento, S. Sandri, and M. Panunzio, J. Chem. SOC., Perkin Trans. 1, 1979, 1729.

Carotenoids and Polyterpenoids

143

dehyde (85) reacts with the lithium salt of the dianion of isopentenol (86).

In a novel preparation of cis- isomers of retinoids,60 thermal rearrangement of the vinylallene (87) gave an equimolar mixture of (112)-,(112,132)-, and (92,112,132)-retinol. Synthesis of the vinylallene (87) is described. Another synthesis of (1 1 2 ) - ,(132)-,and (112,13Z)-retinal used organosilane protecting groups;61syn- and anti-oximes of these retinol isomers were prepared.

Several papers have described the synthesis of epoxyretinoids. The 5,6epoxides of trans-retinal (88) and its (92)-, (112)-,and (132)-isomers were prepared by direct epoxidation of retinal with m-chloroperbenzoic acid.62The 7,s-epoxides (89) of retinal, retinol, and retinoic acid and its methyl esters were synthesized from the p -ionone epoxide (90).63The exceedingly labile methyl 13,14-epoxy-13,14-dihydroretinoate(91) was made by addition of the epoxyaldehyde (92) to the phosphorane (93).64'Chromogen 574', a product of the epoxidation of retinol first described in 1945, has now been identified65as the

(89) R

6" 61

62

63 64

65

=

CHO, CHzOH, C02H,or C02Me

C. G . Knudsen, S. C. Carey, and W. H. Okamura, J. A m . Chem. SOC.,1980,102,6355. B. I. Mitsner, N . A. Sokolova, Yu. N. Gorina, and R. P. Evstigneeva, Tezisy Dok1.-Sou.-lndiiskii Simp. Khim. Prir. Soedin., 5th, 1978, 59 (Chem. Abstr., 1980,93, 186 599). M. Ito, A. Kodama, M. Murata, M. Kobayashi, K. Tsukida, Y. Shichida, and T. Yoshizawa, J. Nutr. Sci. Vitaminol., 1979, 25, 343. D. Davalian and C. H. Heathcock. J. Org. Chem., 1979,44,4458. D. Davalian and C. H. Heathcock, J. Org. Chem., 1979,44,4988. S . C. Welch, J. M. Gruber, and A. S. C. P. Rao, Tetrahedron, 1980, 36, 1179.

144

Terpenoids and Steroids

11,15-epoxy-compound (9'4). Simple procedures have been described for preparing 4-oxoretinal(95) and 4-hydroxyretinal(96) from retinal,66and 3-hydroxyanA number of procedures have been published hydroretinol (102) from retin01.~~ for the preparation of retinol derivatives labelled with radioactive isotopes, e.g. [l-methyl- 14C]retinyl acetate,68 [6,7-'4C2]-(13Z)-retinoic acid69 and [ l 1-3H1](132)-retinoic acid.70

0

OH b

a

Q... f

F

OMe

g

(95) R (96) R (97) R

= = =

a b c

(98) R (99) R

= =

d e

(100) R (101) R

=

f

= g

Many retinal and retinoic acid analogues have been synthesized. Many of the seven aromatic analogues of retinal (97)-(lOl), (103), and (104) and their geometrical isomers form stable complexes with cattle ~ p s i n ,as ~ *does the allenic adamantyl retinal analogue (105) synthesized from adamantan-2-0ne.~~ 5,6Dihydro-, 7,8-dihydro, 9,10-dihydro-, 11,12-dihydro, and 9,10,11,12-tetrahydro-retinals (106)-(110) have been synthesized from carbonyl intermediates, e.g. (111) prepared by selective reduction of the a$-unsaturation with

66

67 68 69 70 71

72

N. A. Sokolova, B. I. Mitsner, and V. I. Zakis, Bioorg. Khim., 1979, 5 , 1053. A. B. Barua and S. R. Das, Indian J. Chem., Sect. B, 1979, 18, 554. W. T. Colwell, C. SooHoo, and J. I. DeGraw, J. Labelled Comp. Radiopharm., 1979,16,5516. R. R. Muccino and C . A . Wasiowich, J. Labelled Comp. Radiopharm., 1980,17,463. P.-L. Chien, M . 4 . Sung, and D. B. Bailey, J. Labelled Comp. Radiopharm., 1979, 16, 791. H. Matsumoto, A. E. Asato, M. Denny, B. Baretz, Y.-P. Yen, D . Tong, and R. S. H . Liu, Biochemistry, 1980, 19, 4589. R. A . Blatchly, J. D. Carriker, V. Balogh-Nair, and K. Nakanishi, J. A m . Chem. SOC.,1980, 102, 2495.

Carotenoids and Pol y terpenoids

145

HO

Na,Fe(CO),-l.5-dio~an.~~ Model rhodopsins were again made. Syntheses of the norbornenyl analogue of retinoic acid (112) and of other analogues containing, for example, a C-5 ethyl substituent (113) have been described.74

Derivatives such as the cyclohexane-1,3-dione (114) have been made by reaction between retinal and acyclic or cyclic diketones in the presence of piperidine (or its acetate) as catalyst.75 p- Cyclodextrin inclusion products of

'' M. Arnaboldi, M. G. Motto, K. Tsujimoto, V. Balogh-Nair, and K. Nakanishi, J. A m . Chem. Soc., 1979,101,7082. M. I. Dawson, P. D. Hobbs, K. Kuhlmann, V. A. Fung, C. T. Helmes, and W.-R. Chao, J. Med. Chem., 1980,23, 1013. '' N. Acton, A. Brossi, D. L. Newton, and M. B. Sporn, J. Med. Chem., 1980,23, 8 0 5 . 74

146

Terpenoids and Steroids

retinal derivatives have been prepared and used for spectral The preparation and properties of the syn- and anti-oximes of retinal have been de~cribed.’~

Photoisomerization of trans-13-demethylretinal (115) gave a mixture of C-7, C-9, C-11, and C-13 stereoisomers which were separated by h.p.1.c. and identified by 400MHz ‘H n.m.r.78 The photochemistry of (115) and of 14methylretinal (116) in polar and non-polar solvents has been e ~ a m i n e d . ’Condi~ tions for the photoisomerization of methyl retinoate (117) to various cis-isomers have been studied.” Photoisomerization studies of the all-trans- isomers of 3,4-dehydroretinal(l18), lO-fluororetinal(119), and 14-fluororetina1(120) suggest Zwitterion intermediates, e.g. (121), the stability of which is influenced by the fluorine substituent or the extra double bond.81 Conditions have been optimized for reduction of the retinal-hydroquinone complex to retinol by aluminium isopropylate.82The electrodimerization of retinal in the presence of electron donors has been

p p A .-- -.,

,

#CHO

B

(120)

1

.*

*--.

.

,.**..

.,I

..-..-... .-.’

+

(121)

Other Curotenoid-like Compounds. Stereoselective epoxidation of (-)-(S)-aionone (122) gave the 4,5-epoxide (123). Treatment of this with NaOMe gave I. Tabushi and K. Shimokawa, J. A m . Chem. SOC.,1980,102, 5400. G . W. T. Groenendijk, W. J. D e Grip, and F. J. M. Daemen, Analyt. Biochem., 1979,99, 304. 78 W. Gartner, H . Hopf, W. E. Hull, D. Oesterhelt, D . Schutzow, and P. Towner, Tetrahedron Left., 1980, 21, 347. ’’ W. H. Waddell and J. L. West, J. Phys. Chem., 1980, 84, 134. B. A. Halley and E. C. Nelson, Znt. J. Vitamin Nutr. Res., 1979, 49, 347. R. S. H. Liu, M. Denny, M. Grodowski, and A. E. Asato, Nouu. J. Chim., 1979, 3, 503. A. N. Shchavlinskii, L. I. Sirotkina, L. I. Shemaeva, Z. Ya. Fedoseeva, and S. V. Pugacheva, Khim.-Farm. Zh., 1979, 13, 79. 8 3 L. A. Powell and R. M. Wightman, J. Elecfroanal. Chem. Interfacial Electrochem., 1980,106, 377. 76

77

147

Carotenoids and Po 1y terpenoids

(-)-(4R)-4-hydroxy-P-ionone (124), whereas with dibal the product was (-)-(5R,6S)-5-hydroxy-4,5-dihydro-a-ionol (125) which was readily oxidized to the 5-hydroxy-4,5-dihydro-a-ionone ( 126).84These optically active ionones should prove very useful in syntheses of carotenoids with appropriate chiral end-groups. (*)-p-Irone (127) and (*)-(6-rac)-au-irone (129) have been prepared uia the respective cyclocitryl phenyl sulphones (128) and (130).*’ These intermediates were prepared by a reaction sequence involving electrochemical epoxidation of the acyclic sulphone (13 l ) , conversion into the alcohol (132),

--0

wx

OH

(123)

(124)

HO

(125) X (126) X

=

H,OH 0

(127) R (128) R

=

CH=CHCOMe CHZS02Ph

(129) R = CH=CHCOMe (130) R = CH2S02Ph

flH2sozph aH2

=

=

HO

and elimination-cyclization. A synthesis of (*)-trans-2,6-y-irone (133) from the substituted cyclohexanone (134) has also been reported.86In a novel synthesis of safranal (135), the key intermediate (136) was obtained by cyclization of a selenium derivative (137) of geranyl acetate (138).” A method for the conversion

84 85

86

A. Haag, W. Eschenmoser, and C. H. Eugster, Helv. Chim. Acra, 1980, 63, 10.

S. Torii, K. Uneyama, and S. Matsunami, J. Org. Chem. 1980, 45, 16. J. Garner0 and D. Joulain, Bull. Soc. Chim. Fr., 1979, 15. T. Kametani, K. Suzuki, H. Kurobe, and H. Nemoto, J. Chem. Soc., Chem. Commun., 1979,1128.

Terpenoids and Steroids

148

of methyl ketones into terminal acetylenes has been used to prepare the CIS alcohol (139) from dihydro-P-ionone (140).88

The synthetic chemistry of damascones and damascenones has been reviewed.89 New syntheses have been reported of 0 -damaxenone (141) from dimedone,” of 3-hydroxy-P -damascone (142) and 3-hydroxydihydro-P-damascone ( 143),91 and of various damascones and their demethyl analogues.92

Methods for the synthesis of damascones by cross-aldol reactions93 and from a-cyclocitral (144) by treatment with ethyl diazo(1ithio)acetate or l-diazol i t h i ~ a c e t o n ehave ~ ~ been described. Eighteen new sesquiterpenoid theaspirane derivatives, e.g, (145) and (146), have been prepared from the dehydro-Pcyclonerolidol epoxide (147).95Racemic theaspirane (148) and dihydroedulan (149) have been synthesized by photosensitized oxidation of dihydra-a- ionol (152) uia (150) and (151).96Other carotenoid-like compounds for which syntheses have been reported include 30-bromo-8-epicaparrapi oxide ( 153),97

WMe a Me

(147)

*’ 90 9’ y2

93

94

95

96 97

(148)

(149)

E. Negishi, A. 0. King, W. L. Klima, W. Patterson, and A. Silveira, jun., J. Org. Chem., 1980, 45, 2526. S. Torii, K. Uneyama, and T. Inokuchi, Koryo, 1979.125.47. S . Torii, T. Inokuchi, and H. Ogawa, J. Org. Chem., 1979,44, 3412. T. Kitahara, Y. Takagi, and M. Matsui, Agric. Biol. Chem., 1979, 43, 2359. T. Kitahara, Y. Takagi, and M. Matsui, Znt. Congr. Essent. Oils, (Pap.) 7th 1977, 1979,7, 278. Y. Arai, T. Miyakoshi, H. Ohmichi, and S. Saito, Koen Yoshishu-Koryo, Terupen oyobi Seiyu Kagaku ni kansuru Toronkai, 23rd, 1979, 153. R. Pellicciari, E. Castagnino, and S. Corsano, J. Chem. Res. ( S ) , 1979, 76. K. H. Schulte-Elte, T. Umiker, and G. Ohloff, Helu. Chim. Acta, 1980, 63, 284. H. Okawara, S. Kobayashi, and M. Ohno, Heterocycles, 1979, 191. T. R. Hoye and M. J. Kurth, J. Org. Chem., 1979.44, 3461.

Carotenoids and Polyterpenoids

149

OH (150)

mokupalide (1 54),98 the P-snyderol analogue ( 155),99 and tetrahydroactinidiolide (156) derivatives."' The synthesis of immobilized abscisic acid (1 57) linked to carboxymethylcellulose hydrazide has been described. lo' The optical resolution of a -ionylideneacetic acid (158) has been reported.lo2

Conditions for the catalytic hydrogenation of p-ionone (159) to dihydro and tetrahydro products have been i n ~ e s t i g a t e d . ~ ' ~The * ~ ' ~autoxidation of a-,p-, and y-ionones and their dehydro-derivatives in aprotic solvents has been studied. lo5Products included epoxy-, 0x0-, and hydroxy-derivatives. Mechanistic studies of p- ionone oxidation have been reported. lo6 In the presence of Cr'", /3 -ionone, p- ionylideneacetaldehyde (160), and retinal undergo electroreduction to pinacols (161)-( 163). A mechanism involving reduction of a complex between Cr"' and the carbonyl compound is propo~ed.~"

99 loo

lo'

lo5

107

F. W. Sum and L. Weiler, J. A m . Chem. SOC.,1979, 101,4401. F. Rouessac and H. Zamarlik, C.R. Hebd. Siances Acad. Sci.,Ser. C, 1979,289, 377. F. Rouessac and H. Zamarlik, Tetrahedron Lett., 1979, 3417, 3421. H. Lehmann and H. R. Schutte, Z. Chem., 1979,19,345. K. Yamashita, E. Nagano, and T. Oritani, Agric. Biol. Chem., 1980, 44, 1441. D. V. Sokol'skii, T. 0. Omarkulov, V. Zapletal, U. Suyunbaev, Ya. Prkhlik, G. I. Samokhvalov, and M. A. Miropol'skaya, Dokl. Akad. Nauk SSSR, 1980,252,152. U . Suyunbaev, T. K. Dzharikbaev, and T. 0. Omarkulov, Vesfn.Akad. Nauk Kaz. SSSR, 1980, 64 (Chem. Abstr., 1980,93, 150 402). H. Iwamuro, K. Okazaki, and Y. Matsubara, Koen Yoshishu-Koryo, Terupen oyobi Seiyu Kagaku ni Kansuru Toronkai, 23rd, 1979, 86 (Chem. Abstr., 1980, 93,72 025). I. F. Rusina, N. M. Evteeva, A. B. Gagarina, and N. M. Emanuel, Dokl. Akad. Nauk SSSR, 1979,249,414. D. W. Sopher and J. H. P. Utley, J. Chem. SOC.,Chem. Commun., 1979, 1087.

150

Terpenoids and Steroids

w x

Abscisic acid (157) methyl ester undergoes cathodic cyclization to ( 164).108

(159) X (160) X

= =

0 CHCHO

The photochemistry of 7,8-dihydro-/3-ionone (165) has been studied"' under different conditions of solvent, temperature, etc. Products included (166)-( 170). Photo-oxygenation of /3 -ionone gave products including dihydroactinidiolide (171) and various epoxides.ll' The photosensitized isomerization of /3 -ionone to the corresponding a-pyran (172)"' and the cyclization of hydroxy-a-ionones by photoirradiationlt2have also been studied.

(171)

(172)

'I1

B. Terem and J. H. P. Utley, Electrochim. Acta, 1979, 24, 1081. J. Berger, M. Yoshioka, M. P. Zink, H. R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1980, 63, 154. H. Etoh and K. h a , Agric. Biol. Chem., 1979,43, 2593. H. Cerfontain, J. A. J. Geenevasen, and P. C. M. Van Noort, J. Chem. SOC., Perkin Trans. 2,

'I2

1980. 1057. H. Etoh, K. Ina, and M. Iguchi, J. Agric. Chem. SOC.Jpn., 1980, 54, 279.

'lo

Carotenoids and Polyterpenoids

151

Physical Methods.-Most papers on new natural or synthetic products include details of purification procedures and extensive spectroscopic data. This section will concentrate on those papers which include systematic studies of, or are primarily devoted to physico-chemical methods.

Separation and Assay. Procedures for the separation, purification, and assay of carotenoids and retinoids by h.p.l.c., g.c., and g.c.-m.s. are given in an extensive article.'13 Another, general, review includes information on the h.p.1.c. separation of retinoids.' l4 A particularly useful method has been developed for resolution and analysis of some carotenoid optical isomers. 'I5 For example, (3R,3'R)-, (3S,3'S)-, and (3R,3'S)-astaxanthin were converted into the diastereomeric (-)-camphank acid diesters, which were separated by h.p.1.c. This procedure has been used to analyse the isomeric composition of a natural astaxanthin sample.25 An h.p.1.c. procedure for separation of a-,0-, and y carotenes (173)-(175) and lycopene (176) has been described.'l6 Several papers describe methods for the h.p.1.c. separation and purification of various retinal and retinol isomers and derivatives.' 17-122 A procedure for the preparative t.1.c. of oxidation products of retinyl acetate has been described,123and a competitive protein-binding radioassay for retinoic has been r e p 0 ~ t e d . l ~ ~

R2

a (173) R' = a , R 2 = b (174) R' = R2 = a

b

C

(175) R' (176) R'

= =

a, R2 = c R2 = c

In addition to a rapid method for extraction and analysis of abscisic acid from plant tissue^,''^ radioimrnunoassaylz6 and h.p.1.c. analysis12' of this compound have been described.. Combined g.c.-m.s. has been used for the identification

'I8

'I9

"' 122

123

lZ4 125

lZ6 12'

R. F. Taylor and M. Ikawa, Methods Enzymol., 1980, 67, 233. M. A . Adams and K. Nakanishi, J. Liq. Chromatogr., 1979, 2, 1097. M. Vecchi and R. K. Muller, J. High Resolut. Chromatogr., Chromatogr. Commun., 1979, 2, 195. H. Pfander, H. Schurtenberger, and V. R. Meyer, Chimia, 1980,34, 179. W. H. Waddell, P. M. Dawson, D. L. Hopkins, K. L. Rach, M. Uemura, and J. L. West, J. Liq. Chromatogr., 1979, 2, 1205. K . Abe, M. Ohmae, K. Kawabe, and G . Katsui, Bitamin, 1979, 53, 385. G. W. T. Groenendijk, W. J. D e Grip, and F. J. M. Daernen, Biochim. Biophys. Acta, 1980, 617, 430. C. D. B . Bridges, S. L. Fong, and R. A . Alvarez, Vision Res., 1980, 20, 355. K. Tsukida, R. Masahara, and M. Ito, J. Chromatogr., 1980, 192, 395. P. V. Bhat, L. M. DeLuca, and M. L. Wind, Anal. Biochem., 1980,102, 243. H. Parizkova and J. Blattna, J. Chromatogr., 1980, 191, 301. Y. Shidoji and N. Hosoya, Anal. Biochem., 1980,104,457. K. T . Hubick and D . M. Reid, Plant Physiol., 1980, 65, 523. E. W. Weiler, Planta, 1980, 148, 262. N. L. Cargile, R. Borchert, and J. D . McChesney, Anal. Biochem., 1979,97, 331.

152

Terpenoids and Steroids

and characterization of abscisic acid metabolites including phaseic acid (177) and dihydrophaseic acid (178).'*' 1 I

(177) X (178) X

= =

0 H,OH

Chiroptical Methods. Correlation of 0.r.d. and c.d. properties has been used for several years as a means of determining the absolute configuration of natural carotenoids. Two papers have now been published which discuss new ideas about the origin of chirality and optical activity in carotenoids. Noack and T h o m ~ o consider n ~ ~ ~ the total chromophore of the carotenoid to be intrinsically chiral. The chirality arises because the ring end-groups adopt a preferred conformation. This conformation, locked by the presence of ring substituents, e.g. OH, together with steric hindrance around the C-6-C-7 single bond, imposes 'handedness' on the twist about the C-6-C-7 bond, and thus upon the T electron chromophore. The introduction of cis-double bonds may alter the symmetry group of the chromophore and thus greatly affect the c.d. spectrum; e.g. a trans- and a di-cis-isomer may have similar spectra, whereas the mono-cisisomer may give Cotton effects of opposite sign. A similar idea is used by Sturzenegger et al.,13' who have introduced a scheme for classification of carotenoid c.d. spectra into three categories, conservative, non-conservative, and intermediate. Published data for about fifty carotenoids are tabulated and classified according to this scheme. Another effect is described by Lematre et ~ 1 . ' Several ~' carotenoids such as lutein [3R,3'R-~,~-carotene-3,3'-diol (179)],

in aqueous ethanol, exhibit strong c.d. in the main absorption band region. This c.d., which is dependent on the water content and is affected by temperature and detergent, is considered to indicate the ability of carotenoid molecules for spontaneous stereospecific multimolecular organization in a hydrophilic environment. The induced c.d. of @-carotenehas been used as a probe of lipid domains in lipoprotein^.'^^ Similarly, induced 0.r.d. of all-trans-retinal has been detected and studied in m i ~ e 1 l e s . l ~ ~ D. Tietz, K. Dorffling, D. Wohrle, I. Erxleben, and F. Liemann, Pluntu, 1979, 147, 168. K. Noack and A. J. Thomson, Helv. Chim. Acta, 1979,62, 1902. 130 V. Sturzenegger, R. Buchecker, and G. Wagniere, Helv. Chim. Acta, 1980, 63, 1074. 1 3 ' J. Lematre, B. Maudinas, and C. Ernst, Photochem. Photobiol., 1980, 31, 201. 132 G. C. Chen, M. Krieger, J. P. Kane, C.-S. C. Wu, M. S. Brown, and J. L. Goldstein, Biochemistry, 1980,19,4706. 133 B. Rabinovitch and M. Yamakawa, Photochem. Photobiol., 1979, 29, 575. '29

Carotenoids and Polyterpenoids

153

N.M.R. Spectroscopy. The ‘H and 13Cn.m.r. spectra of several molecules, e.g. @-ionol (1SO), have been determined as models of hindered isomers of ~ e t i n a 1 . I ~ ~ The conformation of the chromophore of retinylidene Schiff bases, as visual pigment models, has been investigated by ‘H and 13Cn.m.r.’3””36Rhodopsinphospholipid interactions have also been studied by n.m.r.13’

(180)

X-Ray Crystallography. The crystal structures of all-trans-, 11-cis-, and 13-cisretinal, methyl 7,9-di-cis-retinoate, and the corresponding C17acid have been determined. 1 3 8 Electronic Absorption Spectroscopy. Doping with iodine and SO3 had a significant effect on the absorption spectrum of @-carotene.13’ Triplet-triplet absorption spectra have been obtained for six carotenoids, e.g. canthaxanthin [&@-carotene4,4’-dione (18l)l in benzene,14’ and bimolecular rate constants for energy transfer from singlet oxygen to carotenoids evaluated. U.V. spectra of retinal, retinyl acetate, and axerophtene (182) in solid films have been determined.141 Several papers discuss the light absorption spectra of retinal derivatives as rhodopsin models. 142-147*

13* 135 136

13’ 13* 139

140 14’ 142 143 144

14’

146

14’

V. Ramamurthy and R. S. H. Liu, Proc. Indian Acad. Sci., Sect. A , 1979,88, 239. Y. Hanafusa, M. Toda, Y. Inoue, and R. Chujo, Bull. Chem. SOC.Jpn., 1980, 53, 239. J. W. Shriver, G. D. Mateescu, and E. W. Abrahamson, Biochemistry, 1979, 18, 4785, N. Zumbulyadis and D. F. O’Brien, Biochemistry, 1979, 18, 5427. H. M%tsumoto, R. S. H. Liu, C. J. Simmons, and K. Seff, J. A m . Chem. SOC.,1980,102,4259. I. Harada, Y. Furukawa, M. Tasumi, H. Shirakawa, and S. Ikeda, Chem. Lett., 1980, 267. M. A. J. Rodgers and A. L. Bates, Photochem. Photobiol., 1980, 31, 533. E. I. Finkel’shtein and E. I. Kozlov, Photochem. Photobiol., 1979, 30, 279. I. Tabushi, K. Shimokawa, and Y. Kuroda, Kokagaku Toronkai Koen Yoshishu, 1979,62. H. Kitajima, K. Ishikawa, and H. Suzuki, J. Phys. SOC.Jpn., 1980, 48, 2055. B. Honig, U. Dinur, R. R. Birge, and T. G. Ebrey, J. A m . Chem. SOC.,1980,102,488. T. Takemura, K. Chihara, R. S. Becker, P. K. Das, and G. L. Hug, J. A m . Chem. SOC.,1980, 102,2604. K. Chihara, and W. H. Waddell, J. A m . Chem. SOC.,1980,102, 2963. P. K. Das, G. Kogan, and R. S. Becker, Photochem. Photobiol., 1979, 30, 689.

154

Terpenoids and Steroids

Other papers deal with the spectroscopic properties of visual pigments and visual cycle intermediate^^^'-^^" or of bacteriorhodopsin.1s1”52 Infrared a n d Raman Spectroscopy. Resonance Raman spectra of all-truns- and 15-cis-p -carotene have been c ~ m p a r e d . ’ ’ ~ - ~The ~ ’ ps resonance Raman spectrum of p-carotene has been described,156and solvent effects on the excitation profile of the v 2 line of p-carotene have been s t ~ d i e d . ”Model ~ calculations have been used to interpret observed p-carotene Raman spectra and excitation profiles. 15’ Raman scattering spectra of p -carotene-I, complexes have been determined. l S 9 Resonance Raman spectra of carotenoids have been used as an intrinsic probe for membrane potential, e.g. neurosporene [7,8-dihydro-$,$carotene (1 83)] in chromatophores of Rhodopseudomonas sphueroides. 16” Resonance Raman spectroscopy and i.r. spectroscopy have been used in studies of the chromophore of visual pigments and visual cycle intermediates161-16’ and of bacteriorhodopsin and its photocycle i n t e r m e d i a t e ~ . l ~ ~ - l ~ ~

(183)

Other Spectroscopic Techniques. Carotenoid triplet states have been detected and studied by e.p.r.17’ Helium-I photoelectron spectra of @-carotene, retinal, B. Mao, T. G. Ebrey, and R. Crouch, Biophys. J., 1980,29, 247. P. J. G. M. Van Breugel, P. H. M. Bovee-Geurts, S. L. Bonting, and F. J. M. Daemen, Biochim. Biophys. Acta, 1979,557, 188. 150 I. Tabushi and K. Shimokawa, J. A m . Chem. Sac., 1980,102, 5400. Is’ M. Tsuda and T. G. Ebrey, Biophys. J., 1980, 30, 149. U. Fischer and D. Oesterhelt, Biophys. J., 1979, 28, 211. 153 S. Saito, K.Harada, and M. Tasumi, Koen Yoshishu, Shunki Koenkai, Sekigai Raman Kenkyubukai Shinpojumu, Nippon Bunko Gakkai, 1979, 20. I J 4 S . Saito, I. Harada, M. Tasumi, and C. H. Eugster, Chem. Lett., 1980, 1045. IJ5 M. Lutz and I. Agalidis, Proc. Znt. Conf. Raman Spectrosc., 6th, 1978, 2 , 162. l J 6 R. F.Dallinger, W. H. Woodruff, and M. A. J. Rodgers, Appl. Spectrosc., 1979, 33,522. 157 L. C. Hoskins, J. Chem. Phys., 1980,72,4487. Is’ W. Siebrand and M. Z . Zgierski, J. Chem. Phys., 1979, 71, 3561. lS9 Y. Furukawa, K. Harada, M. Tasumi, M. Shirokawa, and S. Ikeda, Koen Yoshishu-Bunshi Kozo Sogo Toronkai, 1979, 554 (Chem. Abstr., 1980,93, 57 201). Y. Koyama, R. A. Long, W. G. Martin, and P. R. Carey. Biochim. Biophys. Acta, 1979, 548, 1 5 3 . l 6 I G. Eyring, B. Curry, R. Mathies, R. Fransen, I. Palings, and J. Lugtenburg, Biochemistry, 1980, 19,2410. B. Aton, A. G. Doukas, D. Narva, R. H. Callender, U. Dinur, and B. Honig, Biophys. J., 1980, 29, 79. 16’ M. A. Marcus and A. Lewis, Photochem. Photobiol., 1979, 29, 699. 164 Z. Iqbal, E.Weidekamm, and 0. Romero, Helv. Phys. Acta, 1980, 52, 386. 16’ F. Siebert and W. Mantele, Biophys. Struct. Mech., 1980,6, 147. M. A. El-Sayed and J. Terner, Photochem. Photobiol., 1979, 30, 125. 167 M. Stockburger, W. Klusmann, H. Gattermann, G. Massig, and R. Peters, Biochemistry, 1979, 18, 4886. A. Lewis, Philos. Trans. R. SOC.London, Set. A , 1979,293, 315. 169 J. Tretzel and F. W. Schneider, Chem. Phys. Lett., 1979,66,475. 170 H. A. Frank, J. D. Bolt, S . M. de B. Costa, and K. Sauer, J. A m . Chem. SOC.,1980,102,4893. 14’ 149

“’

C aro tenoids and Pol y terpenoids

155

retinyl acetate, and retinoic acid have been determined and i n t e r ~ r e t e d . ' Linear ~' dichroism has been used to study chromophore orientations in the metarhodopsins' 7 2 and bacteriorhodopsin. 1 7 3 Miscellaneous Physical Chemistry. A review has been published on charge- and energy-transfer mechanisms of carotenoids. 174 Two papers report studies of electron-transfer mechanisms involving p -carotene radical ions,175and between carotenes and porphyrins. 176 The quenching of singlet oxygen by p -carotene'77 has been studied. The kinetics of or by all-trans-, 11-cis-, and 13-~is-retinal'~* the inhibitory effect of @-caroteneon the photochemical reactivity of anthracene have been i n ~ e s t i g a t e d . Kinetic '~~ studies of the autoxidation of P-carotene180 and of the liquid-phase oxidation of retinyl acetate1*' have been reported. The ~~ interfaces has behaviour of carotenoids182and a p o ~ a r o t e n o i d sat~ air-water been studied. High-pressure fluorescence studies have been performed of radiative and non-radiative processes in polyenes including retinyl acetate. l g 4 Several papers report studies of various p h o t o p h y s i ~ a l ' ~ ~ -and '~~c o n d ~ c t i v i t y ~ ~ * * ' ~ ~ properties of retinal and related compounds. Photoreceptor Pigments. There have been several reviews which deal with structural and photochemical aspects of rhodopsins and model visual pigment^.^^^-^^' In addition to the papers reported above on spectroscopic studies of visual pigments, other publications report work on molecular aspects of rhodopsin

'"

Z. Jericevic, L. Klasinc, B. Kovac, and I. Novak, Kem. Ind., 1980, 29, 117. M. Chabre and J. Breton, Vision Res., 1979, 19, 1005. 173 A. U. Acuna and J. Gonzalez-Rodriguez, A n . Quim., 1979,75, 630. 174 V. Gheorghe and E. Vasile, Exp. Trends Phys., 1979, 197. 175 M. Almgren and J . K. Thomas, Photochem. Photobiol., 1980,31, 329. J. McVie, R. S. Sinclair, D. Tait, and T. G. Truscott, J. Chem. SOC.,Faraday Trans. 1, 1979, 7 5 , 2869. I" L. V. Stopolyanskaya and I. M. Byteva, Biofizika, 1979, 24, 945. 17' A. A. Krasnovskii and V. E. Kagan, FEBS Lett., 1979, 108, 152. 179 M. Nowakowska, Makromol. Chem., 1980,181,1013. 0.T. Kasaikina and Le-Ben-Un, Dokl. Akad. Nauk SSSR, 1979, 249, 394. IS' E. I. Finkel'shtein, N. A. Mednikova, and E. I. Kozlov, Zh. Org. Khim., 1980,16, 593. J. Zsako, E. Chifu, and M. Tomoaia-Cotisel, G a z z . Chim. Ital., 1979, 109, 663. M. Tomoaia-Cotisel, E. Chifu, V. Tamas, and V. Marculetiu, Rev. Roum. Chim., 1980, 25, 175. L. A. Brey, G. B. Schuster, and H. G . Drickamer, J. Chem. Phys., 1979,71, 2765. P. K. Das and R. S . Becker, J. A m . Chem. SOC.,1979, 101,6348. V. A. Kuzmin, D. S. Kliger, and G. S . Hammond, Photochem. Photobiol., 1980, 31,607. Is' M. Grodowski, R. S. H. Liu, and W. G. Herkstroeter, Chem. Phys. Lett., 1979,65, 42. "' B. Mallik, A. Ghosh, a n d T . N. Misra, Bull. Chem. SOC.Jpn., 1979,52, 2091. B. Mallik, A. Ghosh, and T. N. Misra, Proc. Indian Acad. Sci., Sect. A , 1979, 88, 25. '91 H. Shichi and C. N. Rafferty, Photochem. Photobiol., 1980, 31, 631. 19' D. S. Kliger, Int. J. Quantum Chem., 1979, 16, 809. '91 R. V. Bensasson, N A T O A d v . Study Inst. Ser., Ser. A . , 1980, 33, 211. 193 J. Brown, H. M. Brown, B. Hess, P. Muller, D. Oesterhelt, W. Parson, H. Ruppel, W. Sperling, and H. Stieve, Life Sci. Res. Rep. 1978, (Publ. 1979), 12, 525. 194 P.-S. Song, N A T O A d v . Study Inst. Ser., Ser. A . , 1980,33, 189. M. Montal, Biochim. Biophys. Acta, 1979, 559, 231.

'"

156

Terpenoids and Steroids

structure and p h o t o c y ~ l e s ~and ~ ~ on - ~ the ~ ~ Halobacterium photoreceptor pigment bacteriorhodopsin.211-221 Biosynthesis and Metabolism.-Reviews. A review has been published which discusses carotenoid biosynthesis as a possible target for herbicide activity.222 Another article reviews the photocontrol of carotenoid b i o ~ y n t h e s i s ,and ~ ~ ~a yearly literature survey on light-mediated biosynthesis in plants224 includes carotenoids. Reactions, Pathways, and Cell-free Systems. The stereochemistry of introduction of deuterium at C-2 and C-2’ of (3R,3’R)-lutein (179) formed by cyclization, in D 2 0 ,of [-carotene [7,8,7’,8’-tetrahydro-rL,rl-carotene (184)]accumulated by

& A

\

\

\

\

\

\

\

\

\

a Scenedesrnus obliquus mutant has been determined.225 The stereochemistry of the hydrogen attack which initiates formation of the &-ring is the same as ‘91 197

R. R. Birge and L. M. Hubbard, J. A m . Chem. Soc., 1980, 102, 2195. S. Kawamura, S. Miyatani, H. Matsumoto, T. Yoshizawa, and R. S. H. Liu, Biochemistry, 1980,

S. Kawamura, T. Yoshizawa, K. Horiuchi, M. Ito, A. Kodama, and K. Tsukida, Biochim. Biophys. Acta, 1979, 548, 147. T. Kobayashi, FEBS Lett., 1979,106, 313. B. Mao, T. G. Ebrey, and R. Crouch, Biophys. J., 1980,29, 247. H. Matsumoto, R. S. H. Liu, C. J. Simmons, and K. Seff, J. A m . Chem. Soc., 1980,102,4259. 202 M. Chabre and J. Breton, Vision Res., 1979, 19, 1005. ’03 P. J. G. M. van Breugel, P. H. M. Bovee-Geurts, S . L. Bonting, and F. J. M. Daemen, Biochim. Biophys. Acta, 1979,557, 188. 204 M. Sheves, K. Nakanishi, and B. Honig, J. A m . Chem. SOC.,1979,101, 7086. ”” T. Kakitani, Chem. Phys. Lett., 1980, 70, 189. 206 B. Honig, U. Dinur, K. Nakanishi, V. Balogh-Nair, M. A. Gawinowicz, M. Arnaboldi, and M. G . Motto, J. A m . Chem. SOC.,1979,101,7084. ’07 B. D. Gupta, A. Sharma, and I. C. Goyal, Biophys. Struct. Mech., 1979, 5 , 321. , ’08 T. Kakitani, Biophys. Struct. Mech., 1979, 5, 293. ’OY H. Akita, S. P. Tanis, M. Adams, V. Balogh-Nair, and K. Nakanishi, J. A m . Chem. SOC.,1980, 102,6370. ’lo F. T. Hong, Biophys. J., 1980, 29, 343. E. N. Karnaukhova, B. I. Mitsner, E. N. Zvonkova, and R. P. Evstigneeva, Zh. Org. Khim., 1979, 15,718. ’I2 W. Sperling, C. N. Rafferty, K. D. Kohl, and N. A. Dencher, Deu. Halophilic Microorg., 1978, 1,. 323. 2 1 3 K. Schulten, Deu. Halophilic Microorg., 1978, 1, 331. R. H. Lozier, W. Niederberger, M. Ottolenghi, G. Sivorinovsky, and W. Stoeckenius, Deu. Halophilic Microorg., 1978, 1, 123. T. Gillbro, Deu. Halophilic Microorg., 1978, 1,277. Y. Takeuchi and H. Ohno, Koseibutsugaku, 1979,1, 181. 217 A. Warshel and M. Ottolenghi, Photochem. Photobiol., 1979, 30, 291. 218 T. Iwasa, F. Tokunaga, T. Yoshizawa, and T. G . Ebrey, Photochem. Photobiol., 1980,31, 83. U. Fischer and D. Oesterhelt, Biophys. J., 1979, 28, 211. M. Tsuda, M. Glaccum, B. Nelson, and T. G. Ebrey, Nature, 1980, 287, 351. W. Sperling and A. Schimz, Biophys. Struct. Mech., 1980,6, 165. 222 G. Britton, Z. Naturforsch., Teil C, 1979, 34, 979. 223 R. W. Harding and W. Shropshire, jun., Ann. Rev. Plant Physiol., 1980, 31, 217. 224 W. Rau and E. L. Schrott, Photochem. Photobiol., 1979,30,727. G . Britton and A. P. Mundy, Deu. Plant Biol., 1980,6, 345. 199

’”

157

Carote noids and Po 1y te rpenoids

that established for the P-ring (Scheme). Studies of the incorporation of [2I4C,(4R)-4-3Hl]mevalonate into c40 and c50 carotenoids by Halobacterium

Scheme

halobium have shown that the 4-pro-R hydrogen atom of mevalonate is retained at C-2 and C-2’ of bacterioruberin (43).226Genetic studies with Rhodopseudomonas capsulata mutants have provided evidence in support of the proposed pathway of biosynthesis of spheroidene [1-methoxy-3,4-didehydro1,2,7’,8’-tetrahydro-$,$-carotene (185)l and related carotenoids from neuros p o ~ e n e The . ~ ~ incorporation ~ of stereospecifically labelled mevalonates has given results in agreement with the formation of capsorubin [3,3’-dihydroxy-~,~carotene-6,6’-dione (186)] from an epoxy intermediate.228The conversion of labelled violaxanthin into capsorubin by a cell-free system from Capiscum Details have been presented of a Flavoannuum fruits has been bacterium enzyme system capable of phytoene and zeaxanthin b i o s y n t h e ~ i s , ~ ~ ~ and a Micrococcus luteus membrane preparation which can convert mevalonate into carotenoids and menaquinone has been described.231 Me0

Inhibition and Regulation. Evidence has been obtained for the existence of two P -carotene pools and two biosynthetic sites in the Light-induced carotene synthesis has been studied in mutants of Phycornyces blakesleeanus with abnormal The use of substances which affect carotenoid biosynthesis continues. Nicotine has been used in studies of Cso carotenoid formation in Halobacteria 234.235 and of arylcarotene synthesis in C h l o r o b i ~ r n . ~ ~ ~ 226

227 228 229

230 231

232 233 234

235

236

I. E. Swift and B. V. Milborrow, Biochem. J., 1980, 187, 261. P. A. Scolnik, M. A. Walker, and B. L. Marrs, J. Biol. Chem., 1980,255, 2427. B. Camara, FEBSLett., 1980, 118, 315. B. Camara, Biochem. Biophys., Res. Commun., 1980,93, 113. G. Britton, T. W. Goodwin, D. J. Brown, and N. J. Patel, Methods Enzymol., 1980, 67, 264. J. A. Evans and J. N. Prebble, Biochem. Sac. Trans., 1980,8, 125. K. H. Grumbach 2. Nururforsch., Ted C, 1979.34, 1205. M. Jayaram, L. Leutwiler, and M. Delbruck, Photochern. Photobiol., 1980,32, 241. S. C. Kushwaha and M.Kates, Can. J. Microbiol. 1979, 25, 1292. S. C. Kushwaha and M. Kates, Phytochemistry, 1979,18,2061. L. S. Leutwiler and D. J. Chapman, Arch. Microbiol., 1979, 123, 267.

158

Terpenoids and Steroids

The effect of glycerol on Halobacterium carotenogenesis has also been investigated,237and the effect of the cyclization inhibitor CPTA on carotene synthesis by Phycomyces carA mutants Carotenogenesis in Blakeslea trispora is stimulated by abscisic acid, p-ionone, a-ionone, and retinol, though not as strongly as by trisporic The possible role of cyclic AMP in this sytem has been considered.240A range of aromatic amines has been found to affect normal carotenoid biosynthesis in citrus fruits, and to cause the accumulation of poly-cis-carotenoids including prolycopene (7,9,7’,9’-tetra-~i~-lycopene).~~* Metabolism. A survey of the metabolic transformation of carotenoids by animals is included in the review by Fox.’” 4-Hydroxyretinoic acid (187) and 4oxoretinoic acid (188) have been identified as metabolites of retinoic acid (all-trans and 13-cis) by hamsters, and hamster liver micro some^.^^^^^^^

X (187) X = H,OH (188) x = 0

2 Polyterpenoids and Quinones

Po1yterpenoids.-A general review has been published of the structures, occurrence, biosynthesis, and metabolism of polyprenols and isoprenylated quinones.244A diol from insect wax has been identified by spectroscopic methods as the C25isoprenoid w - hydroxygeranylfarnesol (189).24513CN.m.r. has shown

(189) R = CH20H (190) R = Me

that ficaprenol-11 from Ficus elusticus has seven cis- and three truns-isoprene units (191).246c19-c28 isoprenoid alkanes, e.g. (192), were among the products obtained from some Georgia-S. Carolina clays.247The absolute configuration of dolichol has been established as 3 s (193)248by correlation with (R)-citronellol. Further detailed studies of the 16,16’-biphytanyl ether lipids of Archaebacteria 237 238 239 240 241

242

243 244 245 246 247

248

S. C. Kushwaha and M. Kates, Can. J. Microbiol., 1979,25, 1288. F. J. Murillo, PlantSci. Lett., 1980, 17, 201. S. Dandekar, V. V. Modi, and U. K. Jani, Phytochemistry, 1980, 19, 795. S. Dandekar and V. V. Modi, Biochim. Biophys. Acta, 1980,628, 398. S. M. Poling, W.-J. Hsu, and H . Yokoyama, Phytochemistry, 1980, 19, 1677. A. B. Roberts, L. C. Lamb, and M. B. Sporn, Arch. Biochem. Biophys., 1980,199,374. C. A. Frolick, P. P. Roller, A. B. Roberts, and M. B. Sporn, J. Biol. Chem., 1980, 255, 8057. D . R. Threlfall, Encycl. Plant Physiol., New Ser., 1980, 8, 288. L. Quijano, J. S. Calderon, andT. Rios, Chem. Lett., 1979, 1387. Y. Tanaka and M. Takagi, Biochem. J., 1979,183,163. D . Scholefield and J. Whitehurst, J. Chem. SOC., Chem. Commun., 1980, 135. W. L. Adair, jun., and S. Robertson, Biochem. J., 1980, 189, 441.

159

Carotenoids and Pol y terpenoids

such as Caldariella, including characterization of new structures containing the branched-chain nonitol calditol (194), and elucidation of the partial

CHOH

I

CHOH

H

I

HOH,C-C-(CHOH),CH,OH I

OH (194)

stereochemistry (195) have been r e p ~ r f e d , ~ ~Biosynthetic ~-~’~ work with [1,213C2]acetatehas demonstrated that these unusual compounds are biosynthesized by the normal isoprenoid pathway.253 Other biosynthetic studies have demonstrated the biotransformation of polyprenols by larvae of the butterfly Pieris ~ a p a e , * and ’ ~ a heptaprenyl pyrophosphate synthetase from Bacillus subtilis has been d e s ~ r i b e d . ~ ~ ’ YH,OH H-

(195)

CH,OH

Methods have been described for the h.p.1.c. separation and analysis of p r e n y l - l i p i d ~and ~ ~ ~of dolichol in human and a chromatographic procedure has been devised for the separation of retinylmannosyl phosphate from dolich ylmannos yl phosphate. 258 249

M. De Rosa, S. De Rosa, A. Gambacorta, and J. D. Bu’Lock, Phytochemistry, 1980,19,249.

251

M.De Rosa, A. Gambacorta, B. Nicolaus, and J. D. Bu’Lock, Phytochemistry, 1980,19,821. M.De Rosa, E. Esposito, A. Gambacorta, B. Nicolaus, and J. D. Bu’Lock, Phytochemistry, 1980, 19,827.

252

M.D e Rosa, A. Gambacorta, B. Nicolaus, S. Sodano, and J. D. Bu’Lock, Phytochemistry, 1980, 19,833.

253 254 255 256 257

M.De Rosa, A. Gambacorta, and B. Nicolaus, Phytochemistry, 1980,19,791. T.Suga and T. Shishibori, Experientia, 1979,35, 1423. I. Takahashi, K. Ogura, and S. Seto, J. Biol. Chem., 1980,255,4539. U.Prenzel and H. K. Lichtenthaler, Dev. Plant Eiol., 1979,3,319. D.J. Freeman, C. A. Rupar, and K. K. Carroll, Lipids, 1980,15,191. W. Sasak, C. S. Silverman-Jones, and L. M. DeLuca, Anal. Biochem., 1979,97,298.

Terpenoids and Steroids

160

A procedure for the preparation of geranylfarnesol(l90) from geranylacetone (196) has been reported.259In a stereoselective synthesis of solanesol (197) and its analogues, tosyl intermediates such as (198) are used in condensations to give the tosyl derivative (199) and thence solaneso1.26"Regioselective o -epoxidation of polyisoprenoids has been achieved by NaBr-promoted electrochemical oxidation.261Spin-labelled prenol derivatives, e.g. phosphodiesters o f tempo1 with dolichol, ficaprenol, and solanesol, have been prepared in high yield with tripropylbenzenesulphonyl chloride as condensing agent.262

Isoprenylated Quinones.-A review has been published on the chemistry, distribution, and functioning of vitamins K.263 A new volume in the Methods in Enzymology series' contains experimental procedures used in the ubiquinone and vitamin K fields.

Chemistry. A new method has been described for the regio- and stereo-controlled polyprenylation of quinones by means of trimethyltin derivatives. The polyprenyl trimethylstannanes (200) were prepared from the polyprenyl halides (201) and trimethylstannyl-lithium, and were then coupled with the required benzoquinone (202) or naphthoquinone (203) in the presence of BF3-ether to give a quinol which was reduced with A g 2 0 to the ubiquinone (204) or vitamin K

(200) R (201) R

= =

SnMe3 ClorBr

0 (202)

H (203) 259

260

261

262

263

(204)

0. P. Vig, S. D. Sharma, S. S. Bari, and S. S. Rana, Indian J. Chem., Sect. B, 1979, 17, 31. K. Sato, S. Inoue, A. Onishi, and N. Uchida, Int. Congr. Essent. Oils (Pap.), 7th, 1977, 1979, 7 ,

297. S. Torii, K. Uneyama, M. Ono, H. Tazawa, and S. Matsunami, Tetrahedron Lett., 1979, 4661. M. A. McCloskey and F. A. Troy, Biochemistry, 1980, 19, 2056. R. E. Olson, Human Nutrition, 1980, 3B, 267.

161

Carotenoids and Po1y terpenoids

[phylloquinone (205) or menaquinone (206)].264--266Another method for synthesis of phylloquinone and menaquinone uses organocuprates of 1,4-naphthoquinone bisacetals (207) formed from the corresponding lithium reagent. 0

0

(205)

( 206 )

Reaction with the polyprenyl halide, e.g. phytyl bromide (208), occurs efficiently to yield the isoprenylated q ~ i n o n e Oxidative .~~~ demethylation of alkenylhydroquinone ethers with argentic oxide or ceric ammonium nitrate in the presence of pyridine-2,4,6-tricarboxylicacid has been found useful in syntheses of ubiquinone and menaquinone analogues.268Vitamin K epoxide (209) has been prepared from vitamin K and potassium oxide in the presence of crown The reaction involves superoxide ion 0,. The wavelength-dependent oxidative photodegradation of vitamin K analogues has been Photoisomerization of menaquinone-4 (206; n = 4) and phylloquinone (205) gives a cis-trans mixture, and the isomers have been separated by h . p . l . ~ . * ~Other l h.p.1.c. procedures have been described for analysing cis-trans isomers of menaquinones-2, -4, and -9 and their epoxides in serum,272for determination of phylloquinone and menaquinone-4 and their 2 , 3 - e p o ~ i d e s for , ~ ~separation ~ of menaquinone homologues on a silver-ion modified and for simultaneous determination of ubiquinone-10 (204; n = 10) and ubiquinol-10 (210) in tissues and

264 265

266 267 268 269

270

271 272 273 274

Y. Naruta and K. Maruyama, Chem. Lett., 1979, 881. Y. Naruta and K. Maruyama, Chem. Lett., 1979, 885. Y. Naruta, J. Org. Chem., 1980, 45,4097. B. L. Chenard, M. J. Manning, P. W. Raynolds, and J. S. Swenton, J. Org. Chem., 1980, 45, 378. L. Syper, K. Kloc, and J. Mlochowski, Tetrahedron, 1980, 36, 123. I. Saito, T. Otsuki, and T. Matsuura, Tetrahedron Lett., 1979, 1693. R. M. Wilson, T. F. Walsh, and S. K. Gee, Tetrahedron Lett., 1980, 21, 3459. Y. Yamano, S. Ikenoya, M. Ohmae, and K. Kawabe, Yakugaku Zasshi, 1979,99, 1102. M. F. Lefevre, A. P. DeLeenheer, and A. E. Claeys, J. Chromatogr., 1979, 186, 749.’ 0. Hiroshima, K. Abe, S. Ikenoya, M. Ohmae, and K. Kawabe, J. Pharm. SOC.Jpn., 1979,99,1007. D. 0. Mack, J. Liq. Chromatogr., 1980, 3, 1005.

Terpenoids and Steroids

162

m i t ~ c h o n d r i a . ~G.1.c. ~ ’ methods for analysis of vitamin K in leaves276and in plasma277have also been published.

Biosynthesis. The asymmetric incorporation of 4-(2’-carboxyphenyl-4-oxobutyrate [o-succinylbenzoate (2 11)] into phylloquinone by Zea mays has been The incorporation of (211), via its coenzyme A thioester, into 1,4-dihydroxy-2-naphthoicacid (212) and menaquinone has been studied in cell-free extracts o f Mycobacterium and Micrococcus luteus.280The biosynthesis and metabolism of menaquinone-4 in the crab has been described.281 A soluble enzyme complex capable of converting 2-octaprenylphenol (213) into OH

ubiquinone-8 (204; n = 8) has been isolated from E. culi.282The role of polyprenyl p -hydroxybenzoate carboxylase and the ubiquinone biosynthetic ~~~,~~~ pathway in flagellation of Salmonella typhimuriurn has been d i s c ~ s s e d .The biosynthesis of ubiquinone in isolated rat heart cells has been investigated.285

27s

276 277 278

279

282

283 284

285

K. Katayarna, M. Takada, T. Yuzuriha, K. Abe, and S. Ikenoya, Biochem. Biophys. Res. Commun., 1980, 95, 971. R. M. Seifert, J. Agric. Food Chem., 1979, 27, 1301. H. Bechtold and E. Jahnchen, J. Chromatogr., 1979,164,85. K. G . Hutson and D. R. Threlfall, Phytochemistry, 1980, 19, 535. R. Meganathan and R. Bentley, J. Bacteriol., 1979, 140, 92. R. Meganathan, T. Folger, and R. Bentley, Vitamin K Metab. Vitamin K-Dependent Proteins (Proc. Steenbock Symp.) 8th, 1979, 1980, 188. J. F. Pennock and V. T. Burt, Vitamin K Metab. Vitamin K-Dependent Proteins, (Proc. Steenbock Symp.) 8th, 1979, 1980, 208. H. E. Knoll, Biochem. Biophys. Res. Commun., 1979,91, 919. J. Bar-Tana, B. J. Howlett, and R. Hertz, J. Bacteriol., 1980, 143, 637. B. J. Howlett and J. Bar-Tana, J. Bacteriol., 1980, 143, 644. S. Ranganathan, A. M. D. Nambudiri, and H. Rudney, Arch. Biochem. Biophys., 1979,198, 506.

Part 11 STEROIDS

1 Physical Methods BY D. N. KIRK

Two developments this year invite special comment. There has been a notable increase in the rate of publication of X-ray crystallographic analyses of steroids, accompanied by critical comment on the chemical and biological significance of the vast accumulation of structural parameters now available for steroids in the crystalline state. At the same time an exciting new phase in the study of structures and conformations in solution has been opened by the first complete analyses of chemical shifts and coupling constants in the 'H n.m.r. spectra of steroids. This has been achieved by the use of high-field spectrometers under computer control, to obtain two-dimensional (2D) J spectra, with n.0.e. and decoupling 'difference' spectra to aid the assignment of signals.

1 Structure and Conformation The Table beginning on p. 169 lists steroids which have been the subject of X-ray crystallographic studies during the year. In a critical survey of crystallographic data for over 400 steroids,' attention is drawn in particular to the conformational preferences of the 17P-side-chain in pregnan-20-ones (see below), where force-field calculations are not yet very reliable. The cholestane side-chain is also discussed; despite being energetically preferred, the extended conformation (Figure 1) of the side-chain is not always J M + J e

Me

H Figure 1 The extended conformation of the cholestane side-chain, found in 69 out of 96 derivatives studied'

observed in crystalline cholestane derivatives. Other conformations about various bonds of the side-chain are also frequently found. The unsaturated ring B of cholesterol is another region of flexibility, allowing the existence of conformationally distinct forms when the crystallographic asymmetric unit contains more than one molecule. Apart from such special cases of flexibility, however, it is concluded that conformations of steroids are generally controlled intramolecularly, rather than by crystal packing forces.' W. L. Duax, J. F. Griffin, D. C. Rohrer, and C. M. Weeks, J. A m . Oil Chem. Soc., 1980,57,267.

165

166

Terpenoids and Steroids

X-Ray crystallographic analyses of oestrone methyl ether, 14-dehydrooestradiol hemihydrate and 3-methyl ether, and 14-dehydro-oestrone methyl ether provided structural information which has been analysed along with data for 21 other oestra-l,3,5(10)-trienesto show that non-bonded interactions; particularly between C-1 and C-11 and between C-7 and C-15, are largely responsible for the overall conformational features and differences in such molecules.’ An attempt has been made to correlate oestrogenic and antioestrogenic activities of active steroidal and non-steroidal compounds with their structures as determined by X-ray analysisn3The phenolic ring A appears to provide the receptor-binding site, but it is suggested that structural variations of the other end of the molecules may decide whether the compound is oestrogenic or an antagonist. Hydrogen-bonded water molecules may have a critical role in the binding mechanism. Similar studies on progestins4 also suggest that binding of ring A at the receptor site is critical for activity, and that those progesterone analogues which prefer the ‘inverted’ conformation of ring A may best suit the characteristics of the binding site. Consistent with this view, various compounds which have the inverted conformation of ring A (Figure 2) even in

Figure 2 Normal ( a ) and inverted ( b ) conformations of ring A, as found respectively in progesterone, for example, and in 17a-acetoxy-6a-methylprogesterone

the crystal, and those where ring A appears flexible enough to adopt that conformation without undue strain, are among the steroids most strongly bound (e.g. 17a-acetoxy-6a- methylprogesterone, 9p, 1Oa-progesterone, and 17a,2 1dimethyl-19-norpregna-4,9-diene-3,20-dione).The observation5 that 17aacetoxy-6a-methylprogesterone exists in the crystal with the inverted half-chair conformation of ring A has prompted similar study of related compounds.6 Neither the 17a-acetoxy nor the 6a-methyl substituent alone is sufficient to cause the A-ring inversion. Even 17a-hydroxy-6a-methylprogesterone is now shown to crystallize with ring A in a normal la,2&half-chair conformation (Figure 2). These findings seem to substantiate the view that the high affinity of 17a-acetoxy-6a-methylprogesterone for the progesterone receptor is due more to its unusual conformation than to the substituent groups themselves. X - Ray data for 17P-iodoacetoxy-4,4-dimethyl-5aandrostan-3-one and its 19-nor-analogue show some flattening of ring A even in the 19-nor-compound, W. L. Duax, D. C . Rohrer, R. H. Blessing, P. D. Strong, and A. Segaloff, Acta Crystullogr., 1979, B35,2656. W. L. Duax and C. M. Weeks, ‘Molecular Basis of Estrogenicity; X-ray crystallographic studies’, in ‘Estrogens in the Environment’, ed. McLachlan, Elsevier North Holland, Amsterdam, 1980, p. 11. W. L. Duax, V. Cody, J. F. Griffin, D. C. Rohrer, and C. M. Weeks, J. Toxicol. Environ. Health, 1978,4, 205. W. L. Duax, V. Cody, J. F. Griffin, J. Hazel, and C. M. Weeks, J. Steroid Biochem., 1978, 9, 901. W. L. Duax and P. D . Strong, Steroids, 1979, 34, 501.

Physical Methods

167

although less so than in the androstane.' To minimize strains in 6a-hydroxy-4,4dimethyl-5a-androstan-3-oneY however, ring A adopts a fully staggered twistboat conformation.8 Only slight flattening of ring A is produced by a 2P-bromo or 2p-methoxy substituent in 3a-hydroxy-5a-pregnane-11,20-dione.' Crystals of the 2a-methyl derivative are isomorphous with those of the 2p-bromocompound.' Ring A in 9a-fluoro- 1lP, 17P-dihydroxy-17a-methylandrost-4-en3-one has a near perfect laY2P-half-chairconformation.l o 19-Norpregn-4-ene3,20-dione also has a laY2P-half-chairring A," differing appreciably from progesterone itself, where ring A has a distorted la-sofa conformation. The androgenically active 1,2-seco-A-bisnor-5a-androstan-l7~-yl acetate (1) has virtually the same conformations of rings B, C, and D as Sa-dihydrotestosterone. l 2 19-Hydroxyandrost-4-ene-3,17-dione exists with the 19-OH group lying over ring A, trans to the 9,lO-bond. Potential strains are relieved by ring A bowing 'downwards' to a greater extent than in andro~t-4-ene-3~17-dione.'~ 17pHydroxy-9a- methyloe~tra-4~14-dien-3-one crystallizes with two molecules with different A- and D-ring conformations forming an asymmetric unit. l4 The authors speculate as to whether the existence of two distinct forms represents minor deformations of one or both molecules from a single minimum-energy conformation, as a result of crystal-packing forces, or a co-crystallization of two conformers which are separated by an appreciable energy barrier. A resolution of' this problem, which may require highly refined force-field calculations, seems desirable in view of the recent tendency of authors to assume that conformations in solution are generally close to those adopted in the crystal. X-Ray crystal structures and the results of force-field calculations agree well for three isomers of 17p-acetoxy-5-methyloestran-3-one,placing them in the strain order 5p,lOp > 5a,lOa > 5~y,lOp.'~ The 5pYlOa-isomer was too strained to be formed. X-Ray and force-field methods also agree on the preferred conformations of three 6,ll-diols in the 4,4,14a-trimethyl-l9(10 + 9P)abeo-5/?,lOapregnane series. l6 N.m.r. and c.d. data for 3a- and 3p- hydroxyanthrasteroids (2) show that ring A adopts whichever half-chair conformation permits the C-3 substituent to be equatorial, whereas ring c is in a half-chair conformation with negative helicity, as shown by X-ray analy~is.'~ 'The 90-isomer of 11-keto-oestrone, despite having a structure confirmed by X-ray analysis as being essentially L-shaped,18 is a much more active oestrogen

' G. Ferguson, E. W. Macaulay, J. M. Robertson, J. M. Midgley, W. B. Whalley, and B. A. Lodge, J. Chem. SOC., Perkin Trans. 2, 1980, 1170. W. B. Whalley, G. Ferguson, and M. A. Khan, J. Chem. SOC.,Perkin Trans. 2, 1980, 1183. J. M. Midgley, W. B. Whalley, B. E. Ayres, G. H. Phillipps, G. Ferguson, and M. Parvez, J. Chem. SOC., Perkins Trans. 2, 1980, 1176. l o W. L. Duax, P. D. Strong, and M. E. Wolff, Cryst. Struct. Commun., 1979,8,985. l 1 W. L. Duax, D. C. Rohrer, and P. D. Strong, Acra Crystallogr., 1979, B35, 2741. l 2 D. C. Rohrer, W. L. Duax, and M. E. Wolff, Steroids, 1979, 34,589. l3 W. L.Duax and Y.Osawa, J. Steroid Biochem., 1980, 13, 383. l4 W. L.Duax, P. D. Strong, D. C. Rohrer, and A. Segaloff, Acra Crystallogr., 1980, B36, 824. J. C. A. Boeyens, J. R. Bull, and P. H. van Rooyen, S. Afr. J. Chem., 1980,33,4S. l6 J. C. A. Boeyens, J. R. Bull, A. Tuinrnan, and P. H. van Rooyen, J. Chem. SOC., Perkin Trans. 2, 1979, 1279. '' A, Ernke, J. M. Midgley, and W. B. Whalley, J. Chem. SOC., Perkin Trans. 1, 1980, 1779. l 8 A. Segaloff, R. B. Gabbard, A. Flores, R. F. Borne, J. K. Baker, W. L. Duax, P. D. Strong, and D. C. Rohrer, Steroids, 1980, 35, 335.

168

Terpenoidsand and Steroids Steroids Terpenoids R

than 11-keto-oestrone with the natural 9a-configuration, from which the 9pisomer was readily formed under conditions favourable to enolization. The endoperoxides formed from vitamins D by dye-sensitized photo-oxidation have been shown by X-ray study to have the structures (3).19 The two molecules forming the unit cell of 3p- hydroxy- 16-methylpregna5,16-dien-20-one have nearly identical conformations of the side-chain, with the 20-carbonyl group anti-periplanar to the 16,17-double bond.20The same side-chain orientation was found in 6a-methylpregna-4,16-diene-3,2O-di0ne,*~ and helps to explain the formation of an unusually large proportion of the 20a-alcohol when a 16-en-20-one is reduced with hydride donors; the 6 a methyl substituent is insufficient on its own to bring about the inversion of the conformation of ring A which has been reported for 17a- acetoxy-6a-methylproge~terone.~ The two molecules that form the unit cell in 3P-acetoxy16p-methylpregn-5-en-20-one, however, have their C-17 side-chains in quite different conformations.22 The side-chain in 20-methylpregn-5-ene-3P,20-diol takes up the expected conformation in the crystal, with the 20-OH projecting over ring D.23 The two diastereoisomers of 3a,7a,12a- trihydroxy-5/3-cholestan-26-oic acid (4),isomeric at C-25, have been distinguished by X-ray crystallographic analys ~ sIt. should ~ ~ now be possible to establish the configurations of samples obtained from natural sources. The earlier literature contains apparently conflicting evidence, which may result from the possibility of equilibration at C-25 during hydrolytic steps in the isolation of the natural material, thought to be a key biosynthetic intermediate between cholesterol and cholic acid. l9 2o 22

23 24

S. Yamada, K. Nakayama, H. Takayama, A. Itai, and Y. Iitaka, Chem. Pharm. Bull., 1979,27,1949. W. L. Duax, D. Langs, P. Strong, and Y. Osawa, Cryst. Struct. Commun., 1979, 8, 565. W. L. Duax, C. M. Weeks, and P. D. Strong, Cryst. Struct. Commun., 1979,8,659. H. Campsteyn, 0. Dideberg, L. Dupont, and J. Lamotte, Actu Crystullogr., 1979, B35, 2971. W. L. Duax and Y. Osawa, Cryst. Struct. Commun., 1980,9, 267. A. K. Batta, G . Salen, J. F. Blount, and S. Shefer, J. Lipid Res., 1979, 20, 935.

Physical Methods

169

9 a - Fluoro - 1l & 2 1 - dihydroxy - 16a,17a - isopropylidenedioxypregna - 1,4 diene-3,20 - dione forms a crystalline inclusion complex with methanol, comprising infinite channels in which the guest molecules fit.25 Prednisolone (11&17a,21- trihydroxypregna-l,4-diene-3,20-dione)can crystallize with the molecules forming either a single- or a double-stranded helix.26 The 2 : 3 complex of deoxycholic acid and water comprises hydrogen-bonded layers of the acid, forming channels which contain chains of hydrogen-bonded water m01ecules.~’ The ‘choleic acid’ comprising palmitic acid in deoxycholic acid comprises an assembly of bilayers, forming canals which differ slightly from those when acetic acid is the ‘guest’. A host :guest ratio of 8 : 1, with a molecule of ethanol also occluded, has been proposed.28 A discontinuity in the thermodynamic properties and phase behaviour of the cholesteryl n-alkanoates between C8 and Cg is matched by a distinct difference . ~ ~nonanoate between the crystal structures of the octanoate and n ~ n a n o a t eThe chains pack with cholesteryl ring systems rather than with each other, the molecules lying anti~arallel.~’ The d e ~ a n o a t e , ~~’n d e c a n o a t e , ~and ’ laurate (dodecanoate) show very similar crystal structures to the nonanoate. X - Ray data are also reported for a series of polymerizable liquid-crystalline cholesteryl and for petrosterol p-bromobenzoate, which is shown to have the structure (5),34 and not the side-chain (6) as reported in 1978.

Table Steroids studied by X-ray crystallography (Compounds with references 2-34

are mentioned also in the text.)

Compound Oestranes Oestrone methyl ether 14-Dehydro-oestrone methyl ether 14-Dehydro-oestradiol hemihydrate 14-Dehydro-oestradiol methyl ether 11-Keto-9p-oestrone 16a-Bromo-3-meth6xyoestra-1,3,5( lO)-trien-17a-o1 25 26 27

28

29 30

31

32 33 34

35

Ref.

2 2 2 2 18

35

E. Surcouf, Acta Crystallogr., 1979,B35, 2638. V. N. Agafonov, N. B. Leonidov, and V. P. Kobzareva, Zh. Obshch. Khim., 1980,50, 166. C. P. Tang, R. Popovitz-Biro, M. Lahav, and L. Leiserowitz, Isr. J. Chem., 1979,18,385. V.M. Coiro, A. D’Andrea, and E. Giglio, Acta Crystallogr., 1980,B36,848. B.M. Craven and N. G. Guerina, Chem. Phys. Lipids, 1979,24,157. N. G.Guerina and B. M. Craven, J. Chem. SOC.,Perkin Trans. 2, 1979,1414. V. Pattabhi and B. M. Craven, J. Lipid Res., 1979,20, 753. P. Sawzik and B. M. Craven, Acta Crystallogr., 1980,B36,215. K. Nyitrai, F. Cser, and G. Hardy, Acta Chim. Acad. Sci. Hung., 1979,102,361. C. A . Mattia, L. Mazzarella, R. Puliti, D. Sica, and F. Zollo, Tetrahedron Lett., 1978,3953. K. Szulzewsky, Krist. Tech., 1979,14,1445.

170

Terpenoids and Steroids

Table Steroids studied by X-ray crystallography (Compounds with references 2-34 are mentioned also in the text.) Compound Oestranes 16a- Bromo-3-methoxyoestra-1,3,5( 10)-trien-17p-01 170-Iodoacetoxy-4,4-dimethyl-5a-oestran-3-one 17~-Acetoxy-5-methyloestran-3-one isomers

17~-Hydroxy-7~-methyloestra-4,14-dien-3-one 17p-Hydroxy-9a- methyloestra-4,14-dien-3-one 17p- Hydroxyoestra-4,9,11 -trien-3-one A ndrostanes 6a-Hydroxy-4,4-dimethyl-5a-androstan-3-one 4-Hydroxyandrost-4-ene-3,17-dione 19-Hydroxyandrost-4-ene-3,17-dione 9 a - Fluoro- 11p, 17p- dihydroxy- 17a- methylandrost-4-en-3-one 3~-Hydroxy-16~-morpholinoandrost-5-en-17-one 17(S)- and 17(R)-spiro[(androst-4-ene)-17:5’-(1’,2’-oxathiolane)]3-one-2’-oxides Methyl-3p- acetoxy- 17a-methyl- 18-nor-5a- androstane- 17p-carboxylate 1,2-Seco-2,3 -dinor-5a- androstan- 17p-01 acetate Pregnanes 20-Methylpregn-5-ene-3@,20-diol

19-Norpregn-4-ene-3,20-dione 17a- Hydroxy-6a- methylpregn-4-ene-3,20-dione 6a- Hydroxypregn-4-ene-3,20-dione 3p-Acetoxy- 16P-methylpregn-5-en-20-one 3P-Hydroxy- 16-methylpregna-5,16-dien-20-one 6a-Methylpregna-4,16-diene-3,20-dione 2P-Bromo,2p-methoxy, and 2a-methyl derivatives of 3a- hydroxy5a-pregnane- 11,2O-dione 1l p , 17a,21-Trihydroxypregna- 1,4-diene-3,20-dione 17a,2 1- Dihydroxypregna- 1,4-diene-3,11,2O-trione 17a.21 -Dihydroxypregn-4-ene-3,2O-dione 21-acetate monohydrate 2 1-Hydroxypregna-4,9( 1l ) ,16-triene-3,2O-dione 18-Ethyl-17p- hydroxy-19-norpregn-4-en-20-yn-3-one 17p-Hydroxy- 19-norpregna- 1,4-dien-20-yn-3 -one 17p-Hydroxy- 18-methyl- 19-norpregna-4,9-dien-2O-yn-3-one 36

37 38

39

40 41 42 43 44

”

46

47 48

49 50

Ref.

36 7 15 37 14 38 8 39 13 10 40 41,42 43 12 23 11 6 44 22 20 21 9 26 45 46 47 48 49 50

K. Szulzewsky and I. Seidei, Krist. Tech., 1979, 14, 1127. W. L. Duax, D. C. Rohrer, and P. N. Rao, Acta Crystallogr., 1979, B35, 3074. G. Precigoux, Y. Barrans, and M. Hospital, Cryst. Struct. Commun., 1979,8, 883. J. F. Griffin, P. D. Strong, W. L. Duax, A. M. H. Brodie, and H. J. Brodie, Acta Crystallogr., 1980, B36,201. D. C. Swenson, W. L. Duax, M. Numazawa, and Y. Osawa, Acta Crystallogr., 1980, B36, 1981. E.Surcouf, Acta Crystallogr., 1979, B35, 1922. E.Surcouf, Acta Crystallogr., 1979, B35, 1925. S. Fortier and F. R. Ahmed, Acta Crystallogr., 1980, B36, 994. W.L. Duax and P. D. Strong, Cryst. Struct. Commun., 1979,8, 655. V. M. Tseikinskii, V. I. Simonov, V. B. Rybakov, and N. N. Petropavlov, Bioorg. Khim.,1979, 5, 1677. V. M. Tseikinskii, V. B. Rybakov, V. I. Simonov, and N. N. Petropavlov, Bioorg. Khim., 1979, 5, 1537. E. Surcouf, Acta Crystallogr., 1979, B35, 2744. J. Delettre, J. P. Mornon, and G. Lepicard, Acta Crystallogr., 1980, B36, 1430. G.Lepicard, J. Delettre, and J. P. Mornon, Acta Crystallogr., 1980, B36, 1503. J. Delettre, G. Lepicard, and J. P. Mornon, Acta Crystallogr., 1980, B36, 1505.

171

Physical Methods Table Steroids studied by X-ray crystallography (Compounds with references 2-34 are mentioned also in the text.) Compound

16a717a-Cyclopentanopregn-4-ene-3,20-dione 16a,17a- Cyclohexanopregn-4-ene-3,20-dione 9a-Fluoro-1 l&21 -dihydroxy-l6a, 17a-isopropylidenedioxypregna1,4-diene-3,2O-dione, methanol complex 4,4,14a- Trimethyl-1 9(10 + 9P)abeo- 5p,l0a-pregnane-6,ll-diol isomers a- (4-6q)-Progesterone complex of pentane-2,4-dionatopalladium

Ref. 51 52 25 16 53

Bile acids Deoxychoiic acid-water (2 : 3 ) Deoxycholic acid-ethanol-water (2 : 1: 1) Deoxycholic acid-palmitic acid-ethanol (8 : 1: 1) Rubidium deoxycholate Sodium cholate monohydrate 3 a,7 a,12a- Trihydroxy-5 p- cholestan -26-oic acid

27 54 28 55 56 24

Sterols etc. Cholesteryl octanoate Cholesteryl nonanoate Cholesteryl decanoate Cholesteryl undecanoate Cholesteryl dihydrocinnamate 14a-Ethyl-5a-cholest-7-ene-3P,15a-diol di-p- bromobenzoate 5 ( 10 -+ 10H)abeo-cholest-10( 19)ene-3P75a-diol3-p- bromobenzoate Some 173-cyclo-5,10-secocholestane derivatives Petrosterol p-bromobenzoate 3a- and 30-hydroxyanthrasteroids 6,19-Epidioxy-9,10-seco-5( 10),7,22-ergostatrien-3&01 benzoate

29 30 31 32 57 58 59 60 34 17 19

2 N.M.R. Spectroscopy

‘H and ’H Spectra.-Ten years ago the first Report in this series mentioned the newly introduced lanthanide shift reagents,61which for the first time offered the prospect of separating proton resonances in complex molecules so that at least a part of the spectrum could be seen in ‘first-order’ simplicity. Now one of the pioneers of that earlier work has contributed to the first application of techniques 51

V. M. Tseikinskii, V. B. Rybakov, V. I. Simonov, A. V. Kamernitskii, L. E. Kulikova, and I. S. Levina, Bioorg. Khim., 1980, 6,99. V. M. Tseikinskii, V. B. Rybakov, V. I. Simonov, A. V. Kamernitskii, L. E. Kulikova, and I. S. Levina, Bioorg. Khim., 1980, 6,259. 53 D. J. Collins, B. M. K. Gatehouse, W. R. Jackson, G. A. Kakos, and R. N. Timms, J. Chem. SOC., Chem. Commun.,1980,138. 54 V. M. Coiro, A. D’Andrea, and E. Giglio, Actu Crystullogr., 1979, B35,2941. 5’ V. M. Coiro, E. Giglio, S. Morosetti, and A. Palleschi, Actu Crystullogr., 1980, B36, 1478. ’6 R. E. Cobbledick and F. W. B. Einstein, Acta Crystullogr., 1980, B36, 287. ” A. P. Polishchuk, M. Y. Antipin, R. G. Gerr, V. I. Kulishov, Yu. T. Struchkov, and L. G. Derkach, Cryst. Struct. Commun., 1980, 9, 263. ” D. J. Monger, E. J. Parish, G. J. Schroepfer, and F. A. Quiocho, Actu Crystullogr., 1980, B36,1460. ’9 1. Krstanovic, L. Karanovic, M. Lj. Mihailovik, Z. Maksimovic, and L. Lorenc, Cryst. Struct. Commun., 1979,8, 517. 6 o M. Lj. MihailoviC, L. Lorenc, M. DaboviC, and I. Juranik, Tetrahedron Lett., 1979, 4917. 61 ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1971, Vol. 1, p. 270. 52

Terpenoids and Steroids

172 Ilp +8

20

15a

16p

1 5 ~ 12a

9

7a

08

Figure 3

‘Tilted’partial 2 0 J spectra (400MHz) of 1-dehydrotestosterone, showing splittings of signals for individual ring protons in the fi dimension (Reproduced by permission from J. A m . Chem. SOC.,1980, 102, 5703)

which, at 400 MHz, allow virtually complete analysis of steroid n.m.r. Proton two-dimensional (2D) J spectroscopy provides a spectrum (Figure 3) in which ideally each individual proton resonance is displayed, with all its spin couplings in a dimension inclined to the chemical shift co-ordinate.62 The acquisition of data required to produce such a spectrum from a small sample in quite a short time has been made possible by use of a 400 MHz spectrometer which is completely under computer control. The assignment of signals to individual protons is achieved by a combination of techniques. Partially relaxed spectra obtained with a 18Oo-t-9O0 sequence separate overlapping methine and methylene protons on the basis of more rapid methylene ela ax at ion.^^ N.0.e. ‘difference’ and ‘H-’H spin-decoupling ‘difference’ spectra, obtained by subtraction of the normal ~ p e c t r u m , will ~ ~ .often ~ ~ reveal hidden proton signals when two or more overlap, because they eliminate all those parts of the normal spectrum which are unaffected by the double-irradiation experiment. Particularly impressive n.0.e. results are obtained by irradiating the protons of either of the angular methyl groups. N.0.e.s are normally found between 19-methyl and the adjacent lP,2P,4P,6P, and 8P-protons, while irradiation of the 18-methyl protons will give an n.0.e. difference spectrum showing SP, 110, 12P, and probably also the 16P-protons. In difficult cases it is possible to use the 13Cspectrum as an aid to proton assignments, and we are a further publication in which the scope of the 2D J method is improved even further by the use of a lanthanide shift reagent. 62

64

L. D. Hall, J. K. M. Sanders, and S. Sukumar, J. Chem. SOC., Chem. Commun., 1980,366. L. D. Hall and J. K. M. Sanders, J. Chem. SOC.,Chem. Commun., 1980,368. L.D. Hall and J. K. M. Sanders, J. A m . Chem. SOC., 1980,102,5703.

Physical Methods

173

In the steroid example so far described in greatest all the proton chemical shifts and geminal and vicinal coupling constants were determined for 1-dehydrotestosterone (Figure 3). A preliminary report describes the resolution which and assignment of every proton resonance of 1 1p- hydroxypr~gesterone,~~ proved to be a more difficult case. A few other reports of 'H spectra invite comment. A partial assignment of proton signals in the 360MHz spectrum of cholesterol was aided by study of the [2,2,4,4,6-2H5]derivative, permitting the identification of proton resonances from rings A and B. The 15 MHz deuterium spectrum is also reported for the 400 MHz proton spectra have been recorded for vitamins D2 [2H,] (7) and D, (8), and for la,25-dihydroxy-D3 (9). Previous 21- and 28-methyl assignments for vitamin Dz have been reversed on the basis of relaxation studies. Dipolar correlation times of the order of lO-'Os have been obtained for different protons by comparison of relaxation times at 200 and 400MHz, and the 19Z/ 1 9 E inter-proton distance has been calculated from Tl values, agreeing well with results obtained by electron diffraction.66N.0.e. difference spectroscopy has allowed an unambiguous assignment of the higher-field proton signal at C-19 to H, despite the conformational mobility of ring A.67

HO'. (7) A'', R' = Me, R2 = R3 = H (8) 22,23-saturated, R' = R2 = R3 = H (9) 22,23-saturated, R' = H, R2 = R ' = OH

The lanthanide shift reagent Yb(fod)3 has been used in a 'H n.m.r. study of a wide variety of phytosterols.68 The oogoniol (10) side-chain has been shown to have the 24R-configuration by stereospecific syntheses of the 24R- and 24S-isomers, which are distinguishable by their 'H n.m.r. ~pectra.~' The appreciable contributions to solvent shifts of 18- and 19-methyl proton resonances which are associated with hydroxy or keto substituents have been evaluated for CDC1, and C6D6 as solvents (values of 8cDC13 - Sc6D6are positive)." Shifts are generally approximately additive for combinations of substituents.

'' S. P. Sawan, T. L. James, L. D . Gruenke, and J. C. Craig, J. Mugn. Reson., 1979,35,409. " 67

68 69 70

G. Kotowycz, T. T. Nakashima, M. K. Green, and G. H. M. Aarts, Can. J. Chem., 1980, 58, 45. G. Kotowycz. G . H. M. Aarts, and K. Bock, Can. J. Chem., 1980,58, 1206. T. Iida, T. Tamura, and T. Matsumota, J. Lipid Res., 1980, 21,326. J. R. Wiersig, N. Waespe-Sarcevic, and C. Djerassi, J. Org. Chem., 1980, 44, 3374. P. Genard, Org. Mugn. Reson., 1979, 12,396.

Terpenoids and Steroids

174

’H N.m.r. has been used to establish that the hydrogen atom introduced at C-28 in the biosynthesis of poriferasterol (11) from a 24-ethylidene precursor assumes the 28-pro-R position.71 28/

H

O

\ W

(1 1)

’H N.m.r. analysis of products from the hydrogenolysis of 3P- tolyl-psulphonyloxyandrost-5-en-17-one(by LiAl’HJ and 3P-iodoandrost-5-en-17one (by Zn-[2H]acetic acid) showed the reactions to be non-stereospecific, with ca. 3 : 2 ratios of ’H-epimers at C-3,72 contrary to earlier reports. The 23,24,25,26,27-pentanor analogues of cholesterol and dihydrolanosterol have been synthesized with deuterium-labelled 21- or 22-methyl groups.732H Relaxation times are interpreted as evidence that there is a significant barrier to rotation of the side-chain, which appears to be slow compared with tumbling of the whole molecule about its long axis. 13

C Spectra.-A review74of 13Cn.m.r. spectroscopy of steroids (102 references) discusses applications of shift reagents and relaxation measurements, and gives ‘rules’ for the prediction of chemical shifts according to the number of a- and P-carbon atoms and other local structural features. The ‘rules’ allowed the calculation of chemical shifts for the carbon atoms of 5a-cholestane with an average deviation of f 1.4 p.p.m. Collected data75for a series of mono-, di-, and tri-unsaturated sterols have been used in an analysis of 13C olefinic carbon shielding parameters. The double bonds fall into three classes according to their substitution classes. The shielding effects of unsaturation on allylic and homoallylic carbon atoms are also considered. 13 C N.m.r. spectra have been assigned for the hydroxylated metabolites of cholecalciferol [la-OH, 25-OH, 1a,25-(OH)2, 24R725-(OH)2, la,24R,25(OH),, and 25S,26-(OH),] by comparisons of spectra with that of cholecalcifer01.’~Substituent effects due to the hydroxy-groups are also given for the ‘H ~pectra.’~ The 25R- and 25s-isomers of 5~-cholestane-3a77a,26-triolare distinguishable by 13C n . m . ~ - 13C . ~ ~N.m.r. assignments are also for some double-bond isomers (12)-(14) of vitamin D,, and for the ‘backbonerearranged’ cholestene (15), required for comparison with (13). F. Nicotra, B. M. Ranzi, F. Ronchetti, G . Russo, and L. Toma, J. Chem. Soc., Chem. Commun., 1980,752. 7 2 J. R. Hanson, H. J. Wadsworth, and W. E. Hull, J. Chem. Soc., Perkin Trans. I, 1980, 1381. 73 Y. Sato, Y. Sonoda, and H. Saito, Chem. Pharm. Bull., 1980, 28, 1150. 74 W. B. Smith, Annu. Rev. NMR Spectrosc., 1978, 8, 199. ” M. Tsuda and G . J. Schroepfer, Jr., Chem. Phys. Lipids, 1979, 25, 49. 76 T. H. Williams, .D. N. Greeley, E. G . Baggiolini, J. J. Partridge, S.-J. Shiuey, and M. R. UskokoviC, Helv. Chim. Acta, 1980, 63, 1609. 77. A. K. Batta, T. H. Williams, G . Salen, D. N. Greeley, and S. Shefer, J. Lipid Res., 1980, 21, 130. ’’ W. Reischl and E. Zbiral, Helu. Chim. Actu, 1980, 63, 860. 71

Physical Methods

175

HO13

C N.m.r. data for some 3-methoxyoestra-l,3,5(10)-trienes, substituted in ring D (C-16 and/or C-17), showed appreciable deviation from additivity of substituent effects when both C-16 and C-17 were s u b s t i t ~ t e d . ~ ~ 13 C Data for some 21-halogeno-progesterones, steroidal Scw,6P-dihalides and halohydrins, and 5a-hydroxy-6-ketones include evidence of long-range l3C-I9F coupling between C-19 and 6p-F.80 Spectra of some 10-0x0-5,10-seco-steroids (16)-(18) include evidence of intramolecular hydrogen bonding in the 3phydroxy-compound (17).*l 13 C Spectral assignments are reported for ‘spironolactone’ and some related 7-thiol derivatives,82for 19 compounds of the withanolide class,83for CZ7sterol precursors of cholester01,~~ and for cucurbitacins A, B, C, and E and related

(16) R (17) R 79

82

83 84

=

O=

=

0-OH

H (18)

G . Engelhardt, D. Zeigan, and B. Schoenecker, Org. Magn. Reson., 1979,12, 628. H. L. Holland and E. M. Thomas, Can. J. Chem., 1979, 57, 3069. R. J. Highet, D. F. Covey, and C. H. Robinson, J. Org. Chem., 1980,45, 3286. R. J. Highet, T. R. Burke, W. F. Trager, L. R. Pohl, R. H. Menard, A. M. Taburet, and J. R. Gillette, Steroids, 1980, 35, 119. S. W. Pelletier, N. V. Mody, J. Nowack, and J. Bhattacharyya, J. Natural Products, 1979,42, 515. M. Tsuda and G . J. Schroepfer, Jr., J. A m . Chem. SOC.,1979,44, 1290.

176

Terpenoids and Steroids

13C Spin-lattice relaxation measurements have been usedg6 to investigate the properties of cholesteryl ester-phosphatidylcholine systems, in relation to cholesteryl ester transport in vivo and the onset of atherosclerosis. The techniques of ‘magic-angle’ spinning and cross polarization, which dramatically improve solid-state n.m.r. spectra, allowed a I3C study of gallstones, and a non-destructive classification according to cholesterol and bilirubin ~ o n t e n t . ~ ’ 19

F Spectra.--”F Spectra of isomeric fluorohydrins, their acetates, and fluoroketones at positions 2 and 3 of the steroid nucleus show distinctions between axial and equatorial fluorine.88A curve of Karplus type for fluoro-ketones gives evidence of deviations from ideal conformations.

3 Chiroptical Phenomena and U.V. Spectra The first detailed empirical analysis of c.d. data in the 190 nm region for a wide variety of chiral ketones, now reported in finds dominant consignate effects of a-axial and p-axial methyl (or other alkyl) substitution. Signs of group contributions (in hexane as solvent) are for the most part octant-consignate, but any parts of the structure which extend into geometric front-octant regions exhibit c.d. contributions which for the most part imply a quadrant rule. An apparent anomaly was observed for polycyclic structures of ‘extended decalone’ type which include rings in the far rear region, where a sign reversal of ring contributions was observed. A study of some of the same ketones in 2,2,2trifluoroethanol as solventgo revealed a very different pattern of c.d. behaviour below 200 nm, in some cases amounting to a reversal of the sign of the Cotton effect compared with that in hexane. The results are tentatively interpreted as evidence that the observed c.d. in hexane is a composite of two bands. One of these is thought to be red-shifted and the other blue-shifted in trifluoroethanol, to produce the observed changes in profile or even in the sign of the c.d. curve. Most of the compounds studied were steroids. The results of this investigation offer possibilities for structural studies by c.d. which complement the information available from the familiar n -+?r* transition (ca. 290 nm). Filling a gap in our empirical appreciation of substituent effects in the n -+r * region, the small contributions of a-equatorial methyl and methoxy-groups in ketones have been shown to be both temperature and solvent dependent, and sometimes di~signate.~’ An a-axial methoxy substituent has an appreciable dissignate effect in a polar solvent (EPA), but little if any in heptane. Methoxy effects, like those of hydroxy- or acetoxy-groups, are expected to vary with conformer populations. C.d. data for 8-methyl-trans- 1-decalones (19) and (20), bicyclic analogues of 4-methyl-6-0x0- and 6-methyl-4-oxo-Sa-steroids, show that the methyl group makes a front-octant-consignate contribution in each

86

87

J. R. Bull, A. A. Chalmers, and P. C. Coleman, S. Afr. J. Chem., 1979,32, 27. R. J. Cushley and B. J. Forrest, Can. J. Chem., 1979,57,2364. K.,W. Zilm, D. M. Grant, E. Englert, and R. C. Straight, Biochem. Biophys. Res. Commun., 1980,

93,857.

J. Levisalles, M.Rudler Chauvin, and J. Martin, Bull. Soc. Chim. Fr. (ZZ),1980,167. 89 90

91

D. N. Kirk, J. Chem. SOC.,Perkin Trans. I , 1980,787. D.N. Kirk, J. Chem. Soc., Perkin Trans. 1, 1980,1810. D.A. Lightner and F. P. C. Eng., Steroids, 1980,35,189.

Physical Methods

177

case, but that the increment is larger when the methyl group is equatorial than for the axial epimer (ca. -0.9 us. +0.4, respectively, in mefhan01).~*An earlier analysis of group increments for made no distinction between conformations of the front-octant methyl group, which appear from Dreiding models to make equal and opposite angles with the C=O bond direction. The larger effect of the equatorial methyl group is consistent with the ‘coupling path’ hypothesis [cf.heavy lines in formula (19)].94

(20)

(19)

C.d. curves have been as a means for distinguishing between keto-bile acids with the keto-group at C-3, C-7, or C-12. The c.d. curves of a series of oestr-4-en-3-ones (2l ) , -4,9-dien-3-ones (22), and -4,9,11 -trien-3-ones (23), including compounds substituted in ring A and elsewhere, show temperature sensitivity indicative of conformational equilibria between normal and ‘inverted’ Some apparent anomalies in earlier c.d. data for compounds with 2 0 or 10-methyl substituents are explained in terms of equilibria involving predominant inverted conformations, rather than single twist or boat conformers in ring A.

:yJ&

R& O

H

4

(24)

k (21) (22) (23)

A4 A4*9 A4*9*11

(25)

The chiroptical behaviour of cisoid conjugated dienes, already known to be controlled by a combination of diene helicity and axial chirality effects, is further influenced by methyl substituents on the unsaturated carbon atoms.97 The observed methyl group contributions are not susceptible to a simple interpretation, for in some cases [e.g. at C-2 or C-3 in a 2,4-diene (24), or at C-3 in a 19-nor-1,3-diene (25)] the signs of methyl group contributions to AE and to the rotatory strength ( R ) are opposite. Computer resolution showed that the c.d. and U.V. absorption curves are of composite form, with up to five vibronic components. Moreover the wavelength shifts accompanying methyl substitution do not accurately follow the Fieser-Woodward rules. It is concluded9’ that

’* ” 94

95

96

”

S. Hagishita and K. Kuriyama, J. Chem. SOC., Perkin Trans. 1, 1980, 950. D. N. Kirk and W. Klyne, J. Chem. SOC.,Perkin Trans. 1 , 1974, 1076. ‘Terpenoids and Steroids’, ed. J. R. Hanson, (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 8, p. 218. B. Dayal, V. Toome, and G. Salen, Steroids, 1980, 35, 81. V. Delaroff, N. Dupuy, L. Nedelec, and M. Legrand, Tetrahedron, 1979,35, 2681. M. Kielczewski, J. Koput, and A. Galat, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978, 26, 835.

178

Terpenoids and Steroids

methyl substitution may produce a change in the direction of the transition moment, and possibly also a conformational change, neither of which has yet been evaluated. It is clearly unwise to take A& values as being directly proportional to the more fundamental rotatory strength (R), except in those cases where the c.d. band is of simple Gaussian form. Polar substituents (OH, NHAc, etc.) at the axial 6p-position make oppositely signed contributions to the lowest-energy n- + 7 ~ *Cotton effects of the s-cisand s-trans-dienes (26) and (27). These observations support the recent view

I

1

X (26) X

=

X

H, OH, NHEt, or NHAc

(27) X

=

H,OH,OAc,orNHAc

that axial chirality contributions can dominate the chiroptical behaviour even of skewed dienes. The sign difference in the present case is attributed to the difference in location of the 6p-substituent with respect to the directions of the transition moments in the two dienes (Figure 4).98

( a1

(6) Figure 4 Directions of transition moments in (a) diene ( 2 6 )and (b) diene (27)

Further studies9' of conjugated dienes and a,& unsaturated ketones in rings and B of steroids confirm the suspected existence of a second electronic in addition to the transition of T + T * type, in the region 200-210nm, strongly allowed transition near 240 nm. Conclusions reached from theoretical studies (VESCF-CI method), including all singly and double excited configurations, are supported by c.d. studies in solution, and by linear dichroism measurements in stretched polyethylene films. The transition near 200 nm is not normally observed in the U.V. absorption spectrum, but possesses a high rotational strength. Although the helicities of dienes and enones undoubtedly contribute to their c.d. behaviour, large rotational strengths derived even for planar conformations of the conjugated chromophores confirm that axial substituents on adjacent carbon atoms have major perturbing effects, which may dominate the c.d. behaviour. The presence of A 8 ( ' 4 ) - ~ n ~ a t ~ r a tin i o na steroidal 4-en-3-one of natural configuration causes a blue shift of the '240nm' U.V.absorption band by some 4-10 nm.'" No such effect was observed in a 9P-analogue, where the A4- and A8(14)-do~ble bonds are not favourably aligned for interaction. A

" q9 100

J. Gawronski and K. Gawronska, J. Chem. SOC.,Chem. Commun., 1980,346. J. Gawronski, T. Liljefors, and B. Norden, J. A m . Chem. SOC.,1979, 101, 5515. E. C. Hermann and G.-A. Hoyer, Chem. Ber., 1979,112, 3748.

Physical Methods

179

The n + T * c.d. (ca. 300 nm) of 0-benzyloximes or 0-isopropyloximes of steroidal 4-en-3-ones depends upon the oxime configuration (positive for Zoxime, negative for E-oxime)."' The T 3 T* c.d. (ca. 255 nm) is positive for either configuration, but of larger value for the E-isomer. A simple sector rule is proposed for these and other a,P-unsaturated ketoximes, but the saturated analogues give less clear-cut distinctions. A semiquantitative 'prediction' of the Cotton effects of epimeric 17-vinylandrostan- 17-01s is based upon application of the allylic bond polarization model to the conformer distribution, calculated by the force-field method.'"* C.d. data for steroid and terpenoid structures which include a seven-membered (€)-lactam ring have afforded correlation^^"^ between the Cotton effect (at 210-230 nm) and structure which reveal limitations to the scope of Ogura's chirality rule (Figure 5).lo4Fusion to additional rings uia the 4 3 - or 5,6-positions gives E-lactams which generally obey the earlier 'rule', but 3,4- or 6,7-ring

214

HN-0

c.d. (+)

Figure 5 Signs o n -+ 10d et al.

IT* Cotton

QNH c.d. (-)

effects for the chiral e-lactam ring, according to Ogura

fusion can profoundly alter the c.d. behaviour in a manner which appears to depend upon changes in the torsion angle of the C-CO-NH-C moiety, enforced by the geometry of the ring junction. Although some direct contribution to the c.d. no doubt comes from any substituents on the lactam ring, the sign of the c.d. band appears generally to correspond to the sign of the C-CO-NH-C torsion angle.'02*'05More limited c.d. data for steroidal E-lactones suggest a similar dependence on torsion angles, but with reversed signs. Polarized (linear dichroic) spectroscopy of vitamin D3 (28) and its p-N,Ndimethylaminobenzoate, the 10,19-dihydro-derivative(29), and simple model compounds of analogous structure [e.g. (30)], lead to smaller dichroic ratios than would be expected for rod-like molecules in a fully extended s-trans conformation. lo6 These observations are interpreted as evidence of considerable oscillation about the 6,7-single bond, which in the extreme case of elevated temperature is necessary for the thermal vitamin provitamin interconversion. Configurations assigned in 1975 to the 24,28-epoxides (31) of fucosterol and the derived 24,28-diols (32) and (33), by c.d. study of their Pr(dpm)3 complexes, have now been revised on the basis of chemical transformations which included conversion into the known 24-ethyl isomers clionasterol and sitosterol. lo' The earlier error is attributed to mistaken judgement of the most stable conformations of the glycol-Pr(dpm)3 complexes. lo'

lo2 lo3 Io4

lo'

lo'

A. Bodor, D . Breazu, J. Miklbs, B. Demian, and F. Kerek, Tetrahedron, 1980, 36, 1785. J.-M. Bernassau, M. Fetizon, and I. Hanna, Tetrahedron, 1979, 35, 1649. W. Klyne, D . N. Kirk, J. Tilley and H. Suginome, Tetrahedron, 1980, 36, 543. H. Ogura, H. Takayanagi, K. Kubo, and K. Furuhata, J. Am. Chem. SOC.,1973, 95, 8056; H. Ogura, H. Takayanagi, and K. Furuhata, J. Chem. SOC.,Perkin Trans. 1, 1976, 665. I. FriE, P. Maloii, M. Tich?, and K. Bliiha, Collect. Czech. Chem. Commun., 1977, 42, 678. M. Sheves, N. Friedman, D. Levendis, L. Margulies, and Y. Mazur, Zsr. J. Chem., 1979, 18, 359. Y. Fujimoto, K. Murakami, and N. Ikekawa, J. Org. Chem., 1980,45, 566.

Terpenoids and Steroids

180

:I

HO' (28) (29)

A10(19) 10,19-saturated

+ (31)

(32)

(33)

The c.d. spectrum of 5a-cholest-2-eno[3,2-b]pyridine(34) has been interpreted on a MO basis."* Cholesterol and ergosterol form complexes in solution with the polyene antibiotic 'Amphotericin B', revealed by the development of characteristic U.V. absorption spectra and c.d. curves in the range 3 0 0 - 4 2 0 nm.'09

(34)

4 Mass Spectrometry

Some aspects of m.s. research in steroids have been briefly reviewed,'" with particular emphasis on the use of trimethylsilyl ethers of sterols, their hydroxy derivatives, and alkoximes of pregnan-20-ones. The trimethylsilyl ethers of 6-hydroxy-steroids influence fragmentation patterns, giving characteristic ions particularly when a 3-hydroxy- (TMS) or 3-0x0-group is also present.'" Experiments with deuterium-labelled materials"* have confirmed the major lo'

'lo

'11

'12

S. Gladiali, G. Gottarelli, B. Samori, and P. Palmieri, J. Chem. SOC., Perkin Trans. 2, 1980,598. C.Ernst, J. Lematre, H. Rinnert, G. Dupont, and J. Grange, C. R. Hebd. Seances Acad. Sci., Ser. 0, 1979,289,1145. C. J. W. Brooks, Philos. Trans. R. SOC.Lond. Ser. A , 1979,293,53. D . J. Harvey and P. Vouros, Biomed. Mass Spectrom., 1979,6,135. F.J. Brown and C. Djerassi, J. Am. Chem. SOC.,1980,102,807.

Physical Methods

181

fragmentations of steroidal 4-en-3-ones and 1,4-dien-3-ones as those in Figure 6. Hydrogen migrations that occur during scission of ring B mainly involve 8p-H, which shifts to C-10 following initial rupture of the 9-10 bond, although hydrogen migrations from C-11, C-14, and C-15 also contribute. [M

@

0

[M

-

42]+

0&135]+

-

145]+

[ M - 1211'

[ M - 123]+

(a) (b) Figure 6 Principal fragmentations of (a) steroidal 4-en-3-ones and (b) 1,4-dien-3 -ones. Some fragmentations proceed with hydrogen migration

Nitrate esters of 5a-cholestan-3/3-01 and of methyl cholate fragment mainly by loss of HN03, NO2*, or HN02, the latter apparently leaving behind an o ~ o - g r o u p The . ~ ~ order ~ of loss of carboxylic acid or water from 3a,7a,12atrihydroxy-5p-cholan-24-oatesand their acyl derivatives is 12a > 7 a > 3a. Study of the pregnan-20-one analogue has contributed to a mechanistic understanding of these fragmentation^.^^^ An intriguing explanation for the apparent long-range intramolecular transfer of a hydrogen atom between the amino-groups in a 3,20-diaminopregnane (35) involves a 180" rotation of the steroid nucleus following fragmentation of the side-chain."' If the velocity of separation of the fragments is sufficiently low, an ion-molecule interaction (36) will allow hydrogen transfer in a small proportion of the material, giving the observed [M - 431' ion (37). An approximate calculation of energies and times involved in this process shows it to be quite plausible for those parent ions that have only a small excess of energy in the direction of the reaction co-ordinate.lls The fragmentation of steroids with a lactonic side-chain in the 17p-position is insensitive to the nature of the lactone ring.'16 Mass spectra are r e p ~ r t e d " ~ for some steroids bridged by oxygen between C-19 and the 2p-, 4p-, or 60positions, B-homo-steroids with 7p,19- and 7ap,l9-oxygen bridges, and for some cholestanes vicinally substituted by halogens, or bromo- and hydroxygroups, in rings A and B."* Further ~tudies'" of chemical ionization mass spectrometry (CIMS) applied to steroids show that the method has considerable potential for molecular weight determinations, and for the recognition of functional groups with active hydro'13

'I8

J. R. Dias, J. Org. Chem., 1979, 44,4572. J. R. Dias and B. Nassim, J. Org. Chem., 1980, 45, 337. P. Longevialle and R. Botter, J. Chem. Sac., Chem. Commun., 1980, 823. A. M. Seldes and E. G . Gros, J. Steroid Biochem., 1979, 11, 1573. F. Turecek and P. Kocovsky, Collect. Czech. Chem. Commun., 1980, 45, 274. A. Trka and A. Kasal, Collect. Czech. Chem. Commun., 1980, 45, 1720. Y. Y. Lin, J. A m . Oil Chem. Sac., 1980,57, 265.

Terpenoids and Steroids

182

gens (OH, C 0 2 H , NH2, SH). The direct application of CIMS to plant extracts can provide a method for identifying constituent stero1s.12" With ammonia as reagent gas, intense [M + 181' ions are observed. Unsaturation in sterol sidechains has been located by micro-scale oxidation with ruthenium tetroxide and CIMS study of the fragment acids and their methyl esters. Differences in methane CI mass spectra and g.c. data for bile-acid methyl esters permitted the identification of 3 1 different compounds of this class.121 Field-desorption m.s. has been used to study some natural sapogenins including tomatine, gracillin, and ginsenosides. 122

5 Gas Chromatography and Gas ChromatographyMass Spectrometry The cyclic 20,21-boronates (38) provide an excellent means for qualitative g.c.-m.s. analysis of aldosterone, giving single g.c. peaks and abundant molecular ions.123 G.c.-m.s. study of 24R,25-dihydroxycholecalciferol is conveniently carried out by forming the methylboronate or n-butylboronate of the side-chain diol system before silylating the 3p- OH group.124

(38) R lZo

lZ1

lZ2 lZ3

=

MeorBu"

A. K. Bose, H. Fujiwara, and B. N. Pramanik, J. Indian Chem. Soc., 1978, 55, 1246. G. M. Muschik, L. H. Wright, and J. A. Schroer, Biomed. Mass Spectrom., 1979,6, 266. H. R. Schulten, Z. Naturforsch. Teil C, 1979, 34, 1094. S. J. Gaskell and C. J. W. Brooks, J. Chromatogr., 1978, 158, 331.

J. M. Halket, I. Ganschow, and B. P. Lisboa, J. Chromatogr., 1980, 192, 434.

Physical Methods

183

Dimethoxymethylsilyl ethers of steroid alcohols combine stability to hydrolysis, found also in t-butyldimethylsilyl ethers, with the typical fragmentation patterns of trimethylsilyl Because of steric hindrance, equatorial alcohols can be dimethoxymethylsilylated selectively at room temperature in the presence of axial alcohols. The derivatives have excellent g.c.-m.s. characteristics. Although fairly stable in aqueous methanol, the dimethoxymethylsilyl group is removable by either acidic or alkaline hydrolysis. Dimethylisopropylsilyl ethers of hydroxy-steroids are also reported to have value for g.c.-m.s.; spectra are simple, usually giving [MI', [ M - 15]+, and especially [ M - 431' ions, the latter corresponding to loss of the MezCH group.126 G.c.-m.s. with selected ion monitoring provides a very sensitive determination of oestrogens on a scale of pi cog ram^.^^' Standards with high specific deuterium labelling (e.g. [2H8]oestradiol)were prepared for this purpose. Various dimethylalkylsilyl ethers (alkyl = Et, Pr", or Pr') have proved superior to trimethylsilyl ethers for the g.c. separation of bile-acid methyl esters.128G.c.-m.s. has been applied to the separation and identification of unsaturated bile acids found in natural extracts,lZ9 and, with computerized recognition, to a series of sterols and bile-acid G.c. separation of various steroids and bile acids has been affected on the nematic liquid crystal N,N'-bis( p-phenylbenzy1idene)-a,a'bi-p- toluidine as stationary phase.13' A series of non-polar cation exchangers based upon Sephadex LH-20 or Lipidex-1000 is claimed to have useful characteristics for the isolation of steroids from biological fluids prior to g.c.-m.s. a n a 1 y ~ i s . lA ~ ~rapid and inexpensive enzymic method for analysis of bile-acid mixtures from natural sources is claimed to give results similar to those obtained by chromatographic ~ r 0 c e d u r e s . l ~ ~ G.c. conditions have been established for the separation of 24R- and 24Sisomers of 24-methyl-steranes and -stanol acetates, and are applied to the analysis of steranes in a sedimentary rock and in petroleum. 134 Isomeric 24-ethylsteranes were sufficiently separated under the same conditions to allow a rough analysis of 24R-24s mixtures. Liquid crystalline cholesteryl cinnamate has proved effective as a stationary phase for the capillary-g.c. separation of insect pheromones (e.g. tetradecen-1 -yl acetates differing in the position of unsaturati~n).'~~ 6 High-pressure Liquid Chromatography A of high-pressure liquid chromatography (h.p.1.c.) of steroids surveys the literature to 1978 (135 references). It includes discussions of sterols, ecdylZ5 126 127

I3O 13'

13' 133 134 13'

136

D.J. Harvey, J. Chromatogr., 1980,196, 156. H. Miyazaki, M. Ishibashi, and K. Yamashita, Biomed. Mass Spectrom., 1979, 6, 57. R. Knuppen, 0. Haupt, W. Schrarnm, and H.-0. Hoppen, 1 Steroid Biochem., 1979,11, 153. A. Fukunaga, Y. Hatta, M. Ishibashi, and H. Miyazaki, J. Chromatogr., 1980, 190, 339. A. Kuksis and P. Child, J. Am. Oil Chem. SOC., 1980,57, 149. W. H. Elliott, J. Am. Oil Chem. Soc., 1980, 57, 271. G.M. Janini, W. B. Manning, W. L. Zielinski, jun., and G. M. Muschik, J. Chromatogr., 1980, 193,444. M. Axelson and J. Sjovall, J. Chromatogr., 1979, 186, 725. I. A. Macdonald, C. N. Williams, and B. C. Musial, J. Lipid Res., 1980, 21, 381. J. R. Maxwell, A. S. Mackenzie, and J. K. Volkman, Nature, 1980, 286, 694. R. R. Heath, J. R. Jordan, P. E. Sonnet, and J. H. Tumlinson, J. High Resolut. Chromatogr. Chromatogr. Commun., 1979, 2, 712. E.Heftmann and I. R. Hunter, J. Chromatogr., 1979,165, 283.

Terpenoids and Steroids

184

steroids, vitamins D, steroidal sapogenins and alkaloids, withanolides, pregnanes, androstanes, oestrogens, bile acids, cardiac genins, and glycosides. A wider review of h.p.1.c. of natural products (409 includes sections on terpenoids and steroids, including examples of separations which have been achieved among the common natural and synthetic steroids, vitamin D and related compounds, and plant glycosides. Reports on the applications of h.p.1.c. to specific problems include an efficient separation of the reduction products of of the conjugates of natural bile acids,139and of 2-hydroxy- and 2-methoxy-oestrogens (‘catechol’ o e ~ t r o g e n s )Fluorescence .~~~ detection is reported to be some 500 times more sensitive than U.V. absorption for h.p.1.c. of 0estrio1.l~~ The h.p.1.c. behaviour of compounds in the vitamin D series appears to be correlated with the degree of molecular planarity. 142 A first report on the use of cholesteric liquid crystals as stationary phases for h.p.1.c. shows Various cholesteryl esters coated on or bonded to Corasil I1 showed increased capacity factors ( k ’ )when steroids were chromatographed, and permitted some useful separations. 7 Immunoassay of Steroids

A welcome second edition144of a book on immunoassay of steroid hormones shows the rapid pace of development in this area since 1975.145 Radioimmunoassays have been developed for 2 - h y d r o x y o e ~ t r o n eand ~~~*~~~ 2-methoxyoe~trone,~~’”~~ despite the sensitivity of the catechol system to oxidation, by preparing the immunogen (2-hydroxyoestrone 17-0-carboxymethyl oxime-BSA conjugate) under the protection of ascorbic acid. An alternative immunogen has been obtained by linking 2-methoxyoestradiol 17-hydrogen succinate to BSA, followed by demethylation by periodate oxidation and subsequent reduction with ascorbic acid.149As a labelled indicator, a conjugate of 2-methoxyoestrone was prepared, with ‘251-iodinatedhistamine linked via the 17-carboxymethyloxime.1so The conjugate was demethylated (periodate; ascorbic acid) immediately before use in the radioimmunoassay. A radioimmunoassay with high specificity for 3p- hydroxypregn-5-en-20-one uses the 16acarboxyethyl thioether-BSA conjugate to raise antibodies,151 and 3-carboxymethyloximes have been employed as haptens for 18-hydroxycorticosterone and its 11-deoxy analogue. 15* 137 13’ 13’

140 14’ 142

143 144 145 146

14’ 14* 149

15’ lS2

D. G. I. Kingston, J. Nut. Prod., 1979, 42, 237. J.-T. Lin, E. Heftmann, and I. R. Hunter, J. Chromatogr., 1980, 190, 169. T. Nambara, J. Goto, M. Hasegawa, and H. Kato, Chromatogr. Sci., 1979, 12, 359. K. Shimada, T. Tanaka, and T. Nambara, J. Chrornatogr., 1979,178, 350. J. T. Taylor, J. G. Knotts, and G. J. Schmidt, Chromatogr. Newsl., 1979, 7 , 39. D. T. Burns, C. MacKay, and J. Tillman, J. Chromatogr., 1980,190, 141. P. J. Taylor and P. L. Sherman, J. Liq. Chromatogr., 1980, 3, 21. D. Gupta, ‘Radioimmunoassay of Steroid Hormones’, 2nd Edn., Verlag Chemie, Weinheim, 1980. Ref. 94, 1977, Vol. 7, p. 309. P. Ball, G . Emons, 0. Haupt, H.-0. Hoppen, and R. Knuppen, Steroids, 1978,31, 249. P. Ball, G. Reu, J. Schwab, and R. Knuppen, Steroids, 1979, 33, 563. G. Emons, P. Ball, G. D. Postel, and R. Knuppen, Acta Endocrinoi., 1979, 91, 158. D. Berg and E. Kuss, Hoppe-Seyfer’sZ. Physiol. Chem., 1979, 360, 1683. D. Berg, W. Huber, and E. Kuss, Hoppe-Seyler’sZ. Physiol. Chem., 1979, 360, 1685. T. Inaba, W. G. Wiest, and G. D. Niswender, Steroids, 1979, 34, 663. L. Belkien, M. Schoneshofer, and W. Oelkers, Steroids, 1980, 35, 427.

Physical Methods

185

Immunoassays based upon fluorescence-labelled steroid derivatives as tracers continue to be an attractive alternative to RIA, but the efficient linking of a molecule with high fluorescence quantum yield to the steroid presents a challenge to organic chemists. Yields have been generally very low up to the present. Immunoreactivities of such complexes are often appreciably below those of their parent steroids. Nevertheless, encouraging results have been obtained by linking the 3-0-carboxymethyloxime of testosterone via a 1,o-disubstituted hydrocarbon chain (C,-C,) to either fluorescein isothiocyanate or 5-(iodoacetylaminoethy1)aminonaphthalenesulphonic acid, to form conjugates of the types (39) or (40). Yields are described as ‘suffi~ient’.’~~ OH

/ m

S (39) R

It

=

NH-C-NH

0

II (40) R = SCH,CNH(CH,),-YH

I

0

I

CH ,CONH(CH,),R

SO3H

The condensation product of oestradiol 17-hydrogen succinate and ethylenediamine has been linked to fluorescein isothiocyanate to provide a fluorescencelabelled oestradiol for study of oestradiol uptake by cell n ~ c 1 e i .Fluorescence l~~ polarization immunoassay of serum cortisol provides a sensitive method which does not depend upon separation of bound and free material^.'^^ An enzyme-immunoassay for testosterone in female plasma and saliva uses 11a-hydroxytestosterone 11-hydrogen succinate-horseradish peroxidase conjugate as enzyme label, and p - hydroxyphenylacetic acid to provide a fluorimetric ‘end-point’. 15‘ A solid-phase enzyme-immunoassay has been described for 19norethisterone, based upon the 1la-hydrogen succinoyloxy derivative. 157

8 Miscellaneous The strange ‘blue phase’ liquid-crystalline condition of certain cholesteryl esters (nonanoate and myristate) exists over a very narrow temperature range between the cholesteric and isotropic phase~.’~’ Its structure has now been probed by study of deuterium-labelled materials. The 2H n.m.r. spectra have been interlS3 lS4

”’ ’” ’”

Ch. Evrain, K. M. Rajkowski, N. Cittanova, and M. F. Jayle, Steroids, 1980, 35, 611. G. H. Barrow, S. B . Stroupe, and J. D. Riehm, Am. J. Clin. Pufhol., 1980, 73, 330. Y. Kobayashi, K. Miyai, N. Tsubota, and F. Watanabe, Steroids, 1979, 34, 829. A. 0. Turkes, A. Turkes, B. G . Joyce, and D . Riad-Fahmy, Steroids, 1980, 35, 89. A. Turkes, J. Dyas, G. F. Read, and D . Riad-Fahmy, Steroids, 1980,35, 445. E. T. Samulski and Z. Luz, J. Chem. Phys., 1980, 73, 142.

186

Terpenoids a n d Steroids

preted in terms of a structure comprising chiral cholesteric segments made up of units in a cubic arrangement. Studies under high pressure have further complicated the situation, however, by showing the existence of two forms of the 'blue phase' of cholesteryl n ~ n a n o a t e . ' ~ ~ Transition temperatures between coexisting phases, including liquid-crystalline states, have been measured for cholesteryl myristate and palmitate: liquid crystals disappeared on adding alkanes. 160 Long-chain alkanoates of cholesterol with a-, p-, or y-halogen substituents in the acid residue form liquid crystals, although the short-chain a-halogeno-esters (up to C,) do not. 1 6 ' Other cholestane derivatives reported to form liquid crystals include some 3-aryl-cholest-2-enes ortho-, meta-, and para-substituted fluorobenzoates and -~holesta-3,5-dienes,~~' of and para-substituted benzoates of p-sitostero1.164 Light-scattering studies are reported for cholesteryl pelargonate liquid Optically active trans- cyclo-octene has been obtained, albeit with low enantiomeric excess (ca. 1-7'/0), by Hofmann elimination of trimethylcyclooctylammonium hydroxide in cholesteric liquid crystals comprising various

3-arylchole~ta-3,5-dienes.~~~ The phase transitions and latent heats of cholesterol crystallized from various solvents over a range of conditions suggest the possibility of several transitions between ststes characterized by differences in the conformation of the sidechain. 167 The solubilities of cholesterol and p-sitosterol have been measured for a wide range of organic Attention is drawn to the possibility of misleading results from the crystallization of radio-labelled steroids to constant specific activity. Confirmatory evidence of chemical purity is also necessary.169 Water analyses in West Berlin have shown that oestrogens are below the level which would produce any biological effects.170

lS9 160

16'

163 164

16' 166 167

169

170

P. Pollrnann and G. Scherer, High Temp.-High Pressures, 1980, 12,103. I. Miyata and H. Kishimoto, Chem. Pharm. Bull., 1979, 27, 1412. A . V. Bogatskii, A . I. Galatina, and N. S . Novikova, Zh. Org. Khim., 1979, 15, 2582. L. Verbit, A . R. Pinhas, and J. Hudec, Mol. Cryst. Liq. Cryst., 1980, 59, 159. P. M. Agocs, G. Motika, J. A. Szabo, and A . I. Zoltai, Acta Phys. Chem., 1979,25, 173. C. Motoc, 0. Savin, and I. Baciu, Mol. Cryst. Liq. Cryst., 1979, 53, 69. S.-R. Hu and M. Xu, Tzu Jan Tsa Chih, 1980, 3, 7. P. Seuron and G. Solladie, J. Org. Chem., 1980, 45, 715. N. Garti, L. Karpuj, and S. Sarig, Thermochim. Acta, 1980, 35, 343. G . L. Flynn, Y. Shah, S. Prakongpan, K. H. Kwan, W. I. Higuchi, and A . F. Hofmann, J. Pharm. Sci., 1979,68, 1090. B. D . Albertson, R. J. Schiebinger, G. B. Cutler, jun., S. E. Davis, and D. L. Loriaux, Steroids, 1980, 35, 351. M. Rathner and M. Sonneborn, Forum Staedte-Hyg., 1979,30,45.

Steroid Reactions a n d Partial Syntheses BY 6. A. MARPLES

Section A: Steroid Reactions

1 Alcohols and their Derivatives, Halides, and Epoxides Solvolysis, Substitution, Epimerization, and Elimination.-The use of the angle of torsion notation has been discussed in the interpretation of the SN2reactions of certain steroids (inter alia). The acetolysis rate of 3~-p-tolylsulphonyloxyandrost-5-enes was retarded by a 4P-acetoxy- or hydroxy-group, indicating that inductive electron withdrawal by the substituents is most important.* Acetolysis of the 19-p-tolylsulphonyloxy- 5P,6P-methylenecholestane (1) gave3 the rearranged compounds (2) and (3).Alcoholysis of cholesteryl toluene-p-sulphonate

was satisfactory for the preparation of cholesteryl alkyl ethers including radiolabelled long-chain unsaturated ethers of high specific a ~ t i v i t yStudies .~ on the solvolyses of 5,10-secocholest-1 (lO)-en-5-yl p-nitrobenzoates have been extended;' the most and least reactive compounds studied are the E- and 2-isomers (4) and (5) respectively. Transannular participation of the 1(10)-double bond is markedly dependent on its configuration and that of the C-5 substituent. The 2-isomer ( 5 ) reacts less readily than its saturated Sa-analogue. Acetolysis of 3~-chloro-5,7~-dibromo-5a-cholestan-6-one gave the SP-acetoxy-7P-brorno3~-chloro-compound.6 Full details have been reported7 o n the use of Et,NSF, for the conversion of hydroxy-ketones into fluoro-ketones. Protection of the hydroxy-ketone by acetyE. Toromanoff, Tetrahedron, 1980,36, 1971. J. R. Hanson and H. J. Wadsworth, J. Chem. SOC.,Perkin Trans. 1 , 1980,933. J . FajkoS, J. Joska, and F. TureEek, Collect. Czech. Chem. Commun., 1980, 45, 584. G. Halperin and S. Gatt, Steroids, 1980, 35, 39. Lj. Lorenc, M. J. GaSiC, M. DaboviC, N. VuletiC, and M. Lj. MihailoviC, Tetrahedron, 1979, 35, 2445. Shafiullah, Islamuddin, and H. Ali, Curr. Sci.,1979, 48, 154. T. G. C. Bird, G . Felsky, P. M. Fredericks, E. R. H. Jones, and G. D. Meakins, J. Chem. Res. ( S ) , 1979,388.

187

Terpenoids and Steroids

188

\ AcO

OPNB

PNBO

OPNB

lation followed by the use of more vigorous reaction conditions converted the ketone into the gem-difluoride. Sa-Cholestan-3-01s were converted uia the cholestanyl phenyl selenides into the cholestanyl bromides with overall retention of configuration.8 Efficient SN2 displacements have been reported for 3-mesylates by fluoride ion carried on Amberlite I R A 900 and Amberlyst A26 anion-exchange resins.' The latter resin was also used as a carrier for thiocyanate ion in its reaction with a 3-iodide." The iodohydrin (6) reacted with Bu'OH-H20 to give the 2P,3a-diol and the 2P,3P-epoxide.11 The methanesulphinates of mestranol" and e p i m e ~ t r a n o l ' ~ were converted respectively into the S-allene (7) and the R-allene (8) by silver(1)and copper(1)-induced 1,3-~ubstitution.The observed syn -reaction course is identical to that reported earlier for similar reactions in the steroid series.

(6)

(7)

(8) R = Me,But, or Ph

Reaction of steroidal tosylates with K N 0 2 in DMSO or DMF gave reasonable yields of alcohols with inverted configuration. l4 The previously reported epimerization at c - 3 during Raney nickel-catalysed hydrogenation of methyl 3P,7adihydroxy- 12-0x0-SP-cholanate was incorporated in a report of the synthesis of 3P,7a,l2P-trihydroxy-5P-cholanicacid and the 3a,7cu, 12P-trihydroxyana10gue.l' Conversion of mestranol into epimestranol was achieved by treatment of the 17-mesylate with silver nitrate in aqueous THF.16 It was established" that acetic acid was eliminated from 17a-acetoxy-20oxopregnanes in KOAc-DMF to give the A16-compounds only when 21-acetoxy-

lo l1

l2 l3 l4

Is l6

l7

M. Sevrin and A. Krief, J. Chem. SOC.,Chem. Commun., 1980,656. S . Colonna, A. Re, G. Gelbard, and E. Cesarotti, J. Chem. SOC., Perkin Trans. 1, 1979, 2248. C. R. Harrison and P. Hodge, Synthesis, 1980, 299. R. C. Cambie, D. Chambers, B. G. Lindsay, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC., Perkin Trans. I, 1980, 822. H. Westmijze and P. Vermeer, Tetrahedron Lett., 1980, 21, 1789. H. Westmijze and P. Vermeer, Tetrahedron Lett., 1979, 4101. B. Raduchel, Synrhesis, 1980, 293. F. C. Chang, J. Org. Chem., 1979,44,4567. H. Westmijze, H. Kleijn, P. Vermeer, and L. A. van Dijck, Tetrahedron Lett., 1980, 21, 2665. A. J. Solo and M. Suto, J. Org. Chem., 1980,45, 2012.

Steroid Reactions and Partial Syntheses

189

or 21 -tetrahydropyranyloxy-groupswere present. A study of the sodium iodideinduced elimination of the four diastereomeric 5a-cholestane-2,3-diyl bismethanesulphonates showed'' that rates of reaction decreased in the order 2p,3p. Earlier work had suggested that the slowest 2a,3a > 2 a , 3 0 >> 2&3a reacting isomers would not react at all. The rate-determining step is the initial displacement of one mesyloxy-group by iodide ion, and the observed relative rates were rationalized by consideration of the steric effects of the 100-methyl group and the 2-mesyloxy-group.

-

Oxidation and Reduction.-Pyridinium chlorochromate adsorbed on alumina has been reported as a selective oxidant: cholesterol was converted in high yield into cholest-5-en-3-one. l 9 Similar oxidations have been reported with CrO, in Et20-CH2C12 in the presence of celite2' and with NaOCl-AcOH.2' When chromic acid in an acidic medium was used to oxidize steroidal allylic acetates to the corresponding a$-unsaturated ketones22 the quasi-axial acetates were more reactive than their quasi-equatorial epimers. Cholesterol and cholest-4-en30-01 were converted, with Raney nickel and cyclohexanone in toluene, into 5P-cholestanone in modest yield.23 Contrary to earlier reports, hydrogenolyses of 3~-p-tolylsulphonyloxyandrost5-en-17-one with LiA12H4and of 30-iodoandrost-5-en-17-one with Zn-Ac02H have been shown not to be s t e r e o ~ p e c i f i c .Deoxygenation ~~ of alcohols was achieved25 by treatment of the derived dithiocarbonates and thiocarbamates with potassium in t-butylamine containing 18-crown-6. The mechanism was similar to that involved in the deoxygenation of carboxylic esters, which was shown26to proceed by alkyl oxygen cleavage of the initially formed radical anion in the absence of nucleophiles. Epoxide Ring Opening.-Treatment of 5,6a-epoxy- 5a-cholestane sequentially with Bu'Me2SiI-MeCN and DBN-THF gave" the allylic silyl ethers (9) and (10). The anion formed from the reaction of phenylthiomethyltrimethylsilane with BuLi reacted with epoxides (and alkyl iodides) to give aphenylthioalkyltrimethylsilanes, which may be readily converted into

OSiMe2Bu' (9) l9 'O

22

23 24 25

26

27

S. J. Angyal, R. G . Nicholls, and J. T. Pinhey, Aust. J. Chem., 1979, 32, 2433 Y.-S. Cheng, W.-L. Liu, and S. Chen, Synthesis, 1980, 223. S. J. Flatt, G . W. J. Fleet, and B. J. Taylor, Synthesis, 1979, 815. R. V. Stevens, K. T. Chapman, and H. N. Weller, J. Org. Chem., 1980,45,2030. E. Glotter, P. Krinsky-Feibush, and Y. Rabinsohn, J. Chem. Soc., Perkin Trans. 1 , 1980, 1769. J. ForSek, Tetrahedron Lett., 1980, 21, 1071. J. R. Hanson, H. J. Wadsworth, and W. E. Hull, J. Chem. SOC.,Perkin Trans. I , 1980, 1381. A . G. M. Barrett, P. A . Prokopiou, and D. H. R. Barton, J. Chem. SOC.,Chem. Commun., 1979, 1175. A. G. M. Barrett, P. A. Prokopiou, D. H. R. Barton, R. B. Boar, and J. F. McGhie, J. Chem. SOC.,Chem. Commun., 1979, 1173. M . R. Detty, J. Org. Chem., 1980, 45, 924.

Terpenoids and Steroids

190

aldehydes.’* Thallium nitrate in hexane converted epoxides into the diaxial a-hydroxy-nitrate esters and, in acetic anhydride, was used to cleave methyl ethers.29 Studies o n the BF,-catalysed cleavage of 11-oxygenated3(’ and 17showed that, in the main, oxygenated” 12,13-epoxy-~-nor-~-homo-steroids the former gave products of C-13-0 bond cleavage and the latter gave products of C-12-0 bond cleavage. Treatment of a number of 17a-acetyl-12,13-epoxyc-nor-D-homo-steroids with KOH-MeOH-H20 gave the 12-hyd~-oxy-A’~“~’compounds which, in some cases, were further transformed.30 Ethers and Esters.-Deprotection of.steroidal (inter alia) t-butyldimethylsilyl ethers has been reported32 with NBS-DMSO-H20. Trityl and lithium tetrafluoroborate were also useful deprotecting agents33 and the former did not give oxidation products as reported earlier for trimethylsilyl ethers. Thiotrimethylsilanes (e.g. PhSSiMeJ were reported to be useful in the cleavage of methyl and benzyl The reaction of 20-hydroxy-17-yl methylthiomethyl ethers (11)with HgCl,-CaCO,-MeCN-H,O gave the dioxolans (12)

as the major products in contrast to similar reactions in the acyclic series.35The use of 2-dibromomethylbenzoyl as an easily removable acyl protecting group was demonstrated in steroids and other compound^.^^ 2 Unsaturated Compounds Electrophilic Addition.-The hydroxylation of alkenes, including several steroids, with osmium tetroxide has been reviewed.37 Addition of HOBr to the 19-functionalized-5a-cholest-6-enes (13) gave mixtures of the corresponding bromohydrins (14) and the 6,19-epoxides (15) whereas the analogous B-homocompounds (16) gave only the 6,19-epoxides (17).38*39 Similar effects were noted for the related HBr- and HClO,-catalysed opening of the 6a,7a-epoxides and it was observed that the predominant attack by the 1 9 - 0 atom [ 5 ( 0 ) ” attack] in the B-homo-series lay in the possibility of its linear approach with the C-6-Br or C-6-0 bond. The reactions of chromyl chloride and chromyl fluoride with steroidal alkenes and dienes have been reported4’ and it was observed that the 28 29

30

31 32

33 34

3s 36

37 38 39

40

P. J. Kocienski, Tetrahedron Lett., 1980, 21, 1559. E. Mincione and F. Lanciano, Tetrahedron Lett., 1980, 21, 1149. A. Murai, H. Sasamori, and T. Masamune, Bull. Chem. SOC.Jpn., 1980, 53, 254. A. Murai, N. Iwasa, M. Takeda, a n d T . Masamune, Bull. Chem. Soc. Jpn., 1980, 53, 243. R. J. Batten, A. J. Dixon, R. J. K. Taylor, and R. F. Newton, Synthesis, 1980, 234. B. W. Metcalf, J. P. Burkhart, and K. Jund, Tetrahedron Lett., 1980, 21, 35. S. Hanessian and Y. Guindon, Tetrahedron Lett., 1980, 21, 2305. M. P. Wachter and R. E. Adams, Synth. Commun., 1980,10, 111. J. B. Chattopadhyaya, C. B. Reese, and A. H. Todd, J. Chem. SOC.,Chem. Commun., 1979, 987. M. Schroder, Chem. Rev., 1980,80, 187. P. KoEovski, L. Kohout, and V. Cernp, Collect. Czech. Chem. Commun., 1980, 45, 559. See ‘Terpenoids and Steroids’, ed. J. R. Hanson (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1981, Vol. 10, pp. 216, 218. A. G. M. Barrett, D. H. R. Barton, and T. Tsushima, J. Chem. SOC.,P e h Trans. 1, 1980, 639.

Roa

Steroid Reactions and Partial Syntheses

191

JfyJ\\

R20

H

H OH

(13) R' = H , R 2 = AC R' = R2 = Me R' = R2 = Ac

(15) R

=

Acor Me

(14) R = Ac or Me

(16) R' R' R'

= = =

H , R 2 = Ac R2 = Me R2 = Ac

(17) R

= Ac

or Me

absence of cis-halogenohydrins in the products from simple alkenes was inconsistent with an earlier proposed reaction mechanism. The stereochemistry of bromine addition to cholest-5-en-7-ones was observed41 to be dependent on substituents at C-3 which possibly influence the ease of rearrangement of the initially formed 5cu,6P-dibromo-compound. Thus, 3/3-acetoxycholest-5-en-7one gave the 5a,6P-dibromo-compound whereas cholest-5-en-7-one gave the 5P,6a-dibromo-analogue. The major product of neutral or alkaline potassium permanganate oxidation of ergosterol was to be the 5aY6a-dihydroxy7a,8a-epoxide and the products in earlier work by Fieser were shown to be derived from cleavage of this epoxide during w o r k - ~ p .Ozonolysis ~~ of 7dehydrocholesteryl acetate epidioxide gave44the diketone (18) and the hemiacetal (19). Treatment45 of 18-acetoxypregna-1,4,20-trien-3-one, a constituent with the 18-hydroxy-analogue of Telestu cuser, with (Ph3P)3RhCl-02in benzene gave the known ketone (20) obtained from progesterone. 0

>*

AcO

AcO

(18)

&*

fyJp

0

'

OH

(19)

(20)

Other Addition Reactions.-The influence of conformation on the steric course of the photosensitized oxidation of steroidal and other endocyclic alkenes has been The major products of singlet oxygen reactions of 19-nor-A4steroids were the A3-5a-hydroperoxides resulting from preferred a-face 41

42 43 44

45

46

Shafiullah, E. A . Khan, H. Ogura, and H. Takayanagi, J. Chem. SOC., Perkin Trans. 1, 1979, 2727. M. Anastasia, A . Fiecchi, and A. Scala, Tetrahedron Lett., 1979, 3323. M. Anastasia, A . Fiecchi, and A . Scala, J. Org. Chem., 1979, 44, 3657. J. Gumulka, W. J. Szczepek, and Z. Wielog6vski, Tetrahedron Lett., 1979, 4847. R. A. Ross and P. J. Scheuer, Tetrahedron Lett., 1979,4701. E. Toromanoff, Tetrahedron, 1980,36, 207.

192

Terpenoids and Steroids

which was also observed for similar 19-nor-A’-~teroids.~~ The reaction of 52-cholecalciferol with SO, the mixed adducts (21) and (23). A similar mixture was obtained” from the SE-isomer and the analogous adducts (22) and (24) were obtained in the ergocalciferol series.” Thermally induced elimination of SO2 from the adducts (21) and (23) was reported” to give a mixture of isotachysterol, and isovitamin D3 whereas the adducts (22) and (24)

(21) R (22) R

= =

CgH17 C9H17

(23) R (24) R

= =

C8H17 C9H17

were reported to give mainly S E - e r g o ~ a l c i f e r o l Extrusion .~~ of SO, from the adducts (21) and (23) by treatment with KOH-MeOH gave SE-cholecalciferol and by using MeOD-Bu‘OK-D20 it was possible to obtain 5E-6,19,19trideuteriocholecalciferol.so~sl Similarly trideuteriated derivatives were prepared from SO2 adducts with 25-hydroxycholecalciferol,epicholecalciferol, and other analogues.’1 Selective catalytic hydrogenation of the 6,7-double bond of 17P-acetoxy-7methylandrosta-4,6-dien-3-onewas achieved with Pd-C-PhCH20H and gave the 7P-methyl d i h y d r o - c o r n p o ~ n d Added .~~ FeCI, has been reported to improve the selectivity of reduction of a,P-enones in metal-ammonia reactions, thereby improving the yield of the saturated ketone^.'^ Similar improvements were observed in the lithium-ethylamine reductions at -78 “C when a substantial excess of lithium was used and t-butyl alcohol was the proton source.” The influence of solvent and added nitrogenous bases on the stereoselectivity of hydrogenation of A4- and A’74-3-oxo-steroids with Pd catalysts has been s t ~ d i e d , ’and ~ the stereoselectivity of Pd-catalysed hydrogenation of various A5-7-0x0-steroids has been reported5’ to be unaffected by substituents at C-3 or C-17. Other Reactions of Unsaturated Steroids.-Asymmetric synthesis of optically active tricarbonyliron complexes of 1,3-dienes was achieveds8 using the tricarbonyliron complex (25) as a transfer agent for Fe(CO),. Further i n ~ e s t i g a t i o n ~ ~ of the stereochemistry of formation of a-(4-6q)-PdCl complexes from A4-3-oxo47 48

49

’2

53 ” ” 56

’’ 58

J. A. M. Peters, K. H. Schonemann, N. P. van Vliet, and F. J. Zeelan, J. Chem. Res. ( S ) , 1979,402. K. H. Schonemann, N. P. van Vliet, and F. J. Zeelan, R e d . Trau. Chim. Pays Bas, 1980, 99, 91. See ref. 39, p. 221. W. Reischl and E. Zbiral, Helu. Chim. Acta, 1979, 62, 1763. W. Reischl and E. Zbiral, Monatsh. Chem., 1979, 110, 1463. S. Yamada and H. Takayama, Chem. Lett., 1979, 583. W.-H. Chiu and M. E. Wolff, Steroids, 1979, 34, 361. G. S. R. Subba Rao and N. S. Sundar, J. Chem. Res. ( S ) , 1979,282. A. W. Burgstahler and M. E. Sanders, Synthesis, 1980, 400. N. Tsuji, J. Suzuki, M. Shiota, I. Takahashi, and S. Nishimura, J. Org. Chem., 1980, 45, 2728. T. Kolek, I. Malunowicz, and A. Mironowicz, Pol. J. Chem., 1979, 53, 453. A. J . Birch, W. D. Raverty, and G . R. Stephenson, Tetrahedron Lett., 1980, 21, 197.

193

Steroid Reactions and Partial Syntheses

confirmed that highly stereoselective loss of the 6p-H occurred and it was suggested that the greater reactivity of the pseudo-axial 6p-H over that of the pseudo-equatorial 6 a - H could be of importance. The syntheses of a number of .rr-allylpalladium chloride complexes from A'-, A2-, A3-, A4-, and A'-cholestenes have been reported," and 3P-acetoxypregna-5,17-diene reacted" selectively with palladium trifluoracetate to give the r-ally1 complex (26).

(25)

(26)

The oxidation of A5-steroids to the As-7-0x0-compound with Cr03-pyridine 1 : 1 and 1 : 2 complexes revealed that the 1 : 1 complex gave faster reactions. The reaction conditions were optimized by using an excess of the oxidant in the presence of P 2 0 5 in refluxing CH2C12.62Direct oxidation of 3P-acetoxy- 5 0 cholest-8( 14)-ene to the 15-0x0-derivative was achieved in useful preparative yield with Cr0,-3,5-dirnethylpyrazole complex.63 Cholesteryl acetate reacted64 with Bu'OOH-Fe"'(acac), to give a mixture of the 7-oxo-compound, the 5,6epoxides, and the peroxides (27) and (28).

Further reductions of 17-hydroxy-17-alkynyl-steroidswith LiAlH,-AlCl, to give the 17(20),2O-dienes (allenes) that the reactions proceeded by a stereospecific cis-SN2' mechanism. Aromatic fluorides were prepared in high yield by treatment of aryl-triazenes with 70% H F in pyridine and 4-fluorooestrone methyl ether was prepared by this method.66

3 Carbonyl Compounds Reduction.-Electrochemical reduction of a series of 7-0x0-steroids to the deoxygenated species has been r e p ~ r t e d ; ~with ' deuterated sulphuric acid59

6" 6' 62 63 64 65

66

67

D . J . Collins, B. M. K. Gatehouse, W. R. Jackson, G. A. Kakos, and R. N . Timms, J. Chem. Suc., Chem. Commun., 1980, 138. J . Y . Satoh and C. A. Horiuchi, Bull. Chem. SUC.Jpn., 1979,52,2653. B. M. Trost and P. J. Metzner, J. A m . Chem. SOC.,1980,102, 3572. E. Mappus and C.-Y. Cuilleron, J. Chem. Res. ( S ) , 1979,42. R. J. Chorvat and B. N. Desai, J. Org. Chem., 1979,44,3974. M. Kimura and T. Muto, Chem. Pharm. Bull., 1979, 27, 109. L. A. van Dijck, B. J. Lankwerden, and J. C. G . M. Vermeer, R e d . Trav. Chim. Pays Bas, 1979, 98, 553. M. H . Rosenfeld and D . A. Widdowson, J. Chem. SOC.,Chem. Commun., 1979,914. G. Phillipou, C. J. Seaborn, and I. A. Blair, Aust. J. Chem., 1979, 32, 2767.

194

Terpenoids and Steroids

D20-dioxane the products were the 7,7-dideuterio-compounds. Axial alcohols were reported68to be the preferred products of hydrogenation of 5cu-cholestan-3one with Urushibara nickel A catalyst and of 5P-cholestan-3-one with Urushibara cobalt A catalyst. Some dependence of the stereoselectivity with solvent was noted. A study of the heterogeneous hydrogenation of steroidal ketones and enones with N ~ H - R O N ~ - N ~ ( O A C ) ~ [included N ~ C ] the selective reduction of androstane-3,17-dione to the 3 - hydroxy- 1 7 - k e t 0 n e . ~Other ~ selective reductions of 3- and 17-0x0-groups were also reported." A radical decarboxylation reaction of steroidal carboxylic acids (inter alia) leading to the hydrocarbons involved the Bu3SnH reduction of their esters with truns-9hydroxy-l0-phenylthio(-or-l0-chloro)-9,1O-dihydr0phenanthrene.~~ A reductive 1,2 transposition of ketones, involving hydroboration (9-BBN) of the enol silyl ether followed by hydroboration and oxidation of the resultant alkene, was applied72to pregnenolone and gave the 17-hydroxyethylandrost-5-ene(29). OH

Other Reactions.-Reaction of 17-0x0-steroids with ally1 or methallyl phosphorodiamidates and two equivalents of butyl-lithium gave the spirolactones (30a) or (30b) r e ~ p e c t i v e l y .Trimethylsilylallylzinc ~~ chloride reacted with the 17-0x0-steroids to give the hydroxyvinylsilanes (31), which were converted into the spirolactone (30a).74Oestrone methyl ether and 5a-cholestan-3-one reacted with the sodium salt of dimethyl-N(to1uene-p-sulphony1)sulphoximine (32) to give the oxetans (33)and (34) r e ~ p e c t i v e l yReaction .~~ of Scu-androstan- 17p-013-one with 2,4,6-tri-isopropylbenzenesulphonylhydrazinefollowed by treatment SiMe,

(30) a; R = H b; R = M e 68 69 70 71

72 73 74

75

M. Ishige and M. Shiota, Can. J. Chem., 1980, 58, 1061. P. Gallois, J.-J. Brunet, and P. Caubere, J. Org. Chem., 1980, 45, 1946. J. FajkoS and J. Joska, Collect. Czech. Chem. Commun., 1980,45, 1845. D. H. R. Barton, H. A. Dowlatshahi, W. B. Motherwell, and D. Villemin, J. Chem. SOC.,Chem. Commun., 1980,732. G. L. Larson and L. M. Fuentes, Synth. Commun., 1979, 9, 841. G. Sturtz, J.-J. Yaouanc, F. Krausz, and B. Labeeuw, Synthesis, 1980, 289. E. Ehlinger and P. Magnus, Tetrahedron Lett., 1980, 21, 11. S. C. Welch and A. S. C. P. Rao, J. A m . Chem. SOC., 1979,101,6135.

Steroid Reactions and Partial Syntheses

195 0 1

0

II

Me-S -CH2Na

II

NTs (32)

(33) 17a and 17p

(34)

with KCN-MeOH gave the 3-cyano-compounds (35).76Nucleophilic addition to the trioxoallene (36) gave two types of products, (37) and (38), dependent The addition of HCN to a,P-enones, upon the particular nucleophile and the reverse reaction (Elcb), was shown to be subject to stereoelectronic control since the kinetic product of addition was the axial cyanide. Equilibration to the thermodynamic equatorial-axial mixture was not possible in h1-3-OXOsteroids owing to these stereoelectronic factors and steric interaction between the C-1 and C-11 s u b ~ t i t u e n t s . ~ ~

(35) 3a and 30

rn

0

R (37) R = imidazol-1-yl, PhS, PhO, or AcO

(38) R

=

R

pyrrolidin-1-yl, MeO, or OH

The use of benzeneseleninic anhydride in the conversion of thiocarbonyl compounds into the corresponding 0x0-derivatives has been reported in similar reactions were achieved using diary1 telluroxides.80*81 Steroidal ketones reacteds2 with tris(phenylse1eno)borane or tris(methylse1eno)borane to give phenyl or methyl selenoacetals. of the dienolate Reactions Involving Enols or Enolic Derivatives.-Protonation to be the rate-determining step in amino-catalysed isomerizions was ations of androst-5-ene-3,17-dioneand 17a-ethynyl- 17P-hydroxyoestr-5 (10)en-3-one to the corresponding A4-3-oxo-derivatives.84 The 6-methylenepregnenone (41)was available from the dimethylaminopregnenone (40), which was 76

J. Jiricny, D. M. Orere, and C. B. Reese, J. Chem. Soc., Perkin Trans 1, 1980, 1487. D. F. Covey, K. A. Albert, and C. H. Robinson, J. Chem. Sac., Chem. Commun., 1979, 795. 78 C. Agami, M. Fadlallah, and J. Levissalles, Tetrahedron Lett., 1980, 21, 59. 79 N. J. Cussans, S. V. Ley, and D. H. R. Barton, J. Chem. Soc., Perkin Trans. 1, 1980, 1650. " D. H. R. Barton, S. V. Ley, and C. A. Meerholz, J. Chem. Soc., Chem. Commun., 1979, 755. S. V. Ley, C . A. Meerholz, and D. H. R. Barton, Tetrahedron Lett., 1980, 21, 1785. D. L. J. Clive and S . M. Menchen, J. Org. Chem., 1979,44,4279. 83 S. K. Perera, W. A. Dunn, and L. R. Fedor, J. Org. Chem., 1980,45, 2816. 84 See 'Terpenoids and Steroids', ed. j. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1979, Vol. 9, p. 285. 77

196

Terpenoids and Steroids

(39)

the product of the reaction of the trimethylsilyl dienol ether (39) with Eschenmoser’s Cholest- 1-en-3-one was cleanly prepared from the A2-trimethylsilyl enol ether by oxidation with D D Q in the presence of collidine.86 The reaction of 3-0x0-steroids with diethyl phosphorocyanidate [(C,H,O),POCN] in the presence of amines gave the 3-amino-3-cyano-compounds and is exemplified by the preparation of the 3~-pyrollidino-3a-cyanocholestane(42) from 5a-cholestan-3-0ne.~~ Treatment of the pyrrolidine enamine (43) with diethyl phosphorocyanidate also gave the compound (42).” Sequential treatment of 5a-cholestan-3-one and 4,4-dimethylcholest-5-en-3-onewith KH and triphenylbismuth carbonate gave respectively 2,2-diphenyl-5a-cholestan-3-one and the highly hindered 4,4-dimethy1-2,2-diphenylcholest-5-en-3-0ne,~~

(44) 16a and 16p

(45) 16a and 16p

The epimeric mixture of 16-ethoxycarbonylmethyl-17-0x0-compounds(45) was prepared from the P-keto-thiolesters (44) by successive alkylation with bromoacetic ester and treatment with Raney nickel.” The epimeric 16-phenylselenylandrostenones (46) were prepared via LDA-PhSeCl reaction of the 17-0x0-compound appropriately protected at C-3. Similar reaction of a 20oxopregnane gave the 21-phenylselenyl derivative (47), and the preparation of the 17a-phenylselenyl analogue involved the reaction of the A”‘**’-enol acetate

89

S. Danishefsky, M. Prisbylla, and B. Lipisko, Tetrahedron Lett., 1980, 21, 805. I. Fleming and I. Patterson, Synthesis, 1979, 736. S. Harusawa, Y. Hamada, and T. Shiori, Tetrahedron Left., 1979,4663. S. Harusawa, Y. Hamada, and T. Shiori, Synthesis, 1979,716. D. H. R. Barton, D. J. Lester, W. B. Motherwell, and T. Barros Papoula, J. Chem. SOC.,Chem.

90

Commun., 1980,246. H.-J. Liu, H. K. Lai, and S. K. Attah-Poku, Tetrahedron Left., 1979, 4121.

85

86

”

197

Steroid Reactions and Partial Syntheses SePh

As (46)

1

with MeLi-PhSeCl.” Conversion of 17-0x0-steroids into 17/3-acetoxy-16-oxocompounds has been reported.92 The major products of MCPBA oxidation 01 ethyl cholesta-3,5,7-trienyl ether were reported to be the epimeric 6-hydroxydienones (48).93Fluorination of 2-ethoxycarbonyl-5a-cholestan-3-onewith C,9XeF, gave94the 2-fluoro-derivative (49).

Oximes, Semicarbazones, Hydrazones, and Related Derivatives.-Lead tetraacetate was used to regenerate ketones from the semicarbazones and allowed a novel synthetic approach to 18-hydroxycorticosterone from 18-hydroxy-11o x o p r o g e s t e r ~ n e .The ~ ~ use of benzeneseleninic anhydride as a deprotecting agent for phenylhydrazones, semicarbazones, oximes, and related derivatives has been described in 4 Compounds of Nitrogen and Sulphur

Treatment of the azirine (50)with HF-pyridine in CH2C12containing Et,N gave The N-acetylaziridines a reasonable yield (30% ) of 17a-fl~oropregnenolon&~~ (51) and (52) were synthesized by base treatment of the 5a-hydroxy-6P-

(50)

(51) 5P,6P (52) 5a,6cu

92

J . P. Konopelski, C. Djerassi, and J. P. Raynaud, J. Med. Chem., 1980, 23, 722. I. V. Micovic, M. M. Mojasevic, K. M. Popovic, and J. J. Trbojevic, Glas. Hem. Drus. Beograd,

93

J. F. Kinnear, M. D. Martin, A. F. Faux, D. H. S. Horn, and J. J. Wilkie, Aust. J. Chem., 1979,

91

1979,44, 249.

94

9s 96

9’

32,2017. S. S. Yemul, H. B. Kagan, and R. Setton, Tetrahedron Lett., 1980, 21, 277. D. N. Kirk and C. J. Slade, Tetrahedron Lett., 1980, 21,651. D. H. R. Barton, D. J . Lester, and S. V. Ley, J. Chem. SOC., Perkin Trans 1, 1980, 1212. G. Alvernhe, S. Lacombe, and A. Laurent, Tetrahedron Lett., 1980, 21, 1437.

198

Terpenoids and Steroids

acetamido- and the 5a-acetamido-6~-hydroxy-cholestane respectively.98Oxidation of the enol lactam ( 5 3 )with benzeneseleninic anhydride gave the 5-hydroxy6-oxo-lactam ( 5 5 ) and the 7-hydroxy-6-phenylselenylenol lactams ( 5 6 ) and (57) as major products99 arising from the intermediate selenoxide (54) as outlined in Scheme 1.

f

(53)

HO

(56) 7a (57) 7 p

(55)

Scheme 1

Steroidal and other primary amines were converted into perhydrodioxazepines, for example (58), by treatment with paraformaldehyde and a vic-diol."' Deamination of N,N-dimethylamines with CC13CH20COCI was exemplified by the conversion of the 3a-dimethylaminopregnane (59) into the A2-compound.101The deamination appears to be controlled by stereoelectronic factors as conessine underwent demethylation to give (60). Cleavages of 16a,17au-epimino-20-oxo-steroidsand their 20-hydrazones with thioacetic acid were reported,lo2 as were the reactions of 16a,l7a-episulphides with HSCN

I

\

0

uo "

" lo"

I"'

Shafiullah and M. A. Ghaffari, Synth. Commun., 1979, 9, 677. T. G. Back and N. Ibrahim, Tetrahedron Lett., 1979, 4931. H. Kapnang and G. Charles, Tetrahedron Lett., 1980, 21, 2949. H. Kapnang and G. Charles, Tetrahedron Lett., 1980, 21, 2951. A. V. Kamernitskii, A. M. Turuta, T . M. Fadeeva, and V. A. Pavlov, Izv. Akad. Nauk SSSR, Ser. Khim.,1979, 881.

Steroid Reactions and Partial Syntheses

199

YSoPh

and PhCH2SH.'03 The 2a,3a-episulphide (61) was converted into the A2analogue by reaction with the N-methyloxaziridine (62)via the ylide (63).'04 The reaction of MeLi with the allene sulphoxides (64)gave the allenes (65). A 3-methoxyoestra-l,3,5(10)-trieneallene of this type was shown to have been previously assigned an incorrect stereochemi~try.'~~ Similar reactions were reported leading to allenes at C-3, and the sulphoxide (66) gave the diene (67) on reaction with MeLi (Scheme 2). &SOPh

iL[$,

+

(67) Scheme 2

5 Molecular Rearrangements Backbone Rearrangements and Double Bond 1somerizations.-Backbone rear rangements in steroids and related molecules have been reviewed. lo6 Treatment of the mixed adducts (68)of cholecalciferol and 4-phenyl-1,2,4-triazoline-3,5lo3

'04

lo5 lo6

A. V. Karnernitskii, A. M. Turuta, T. K. Ustynyuk, and Ngo Thi Mai Anh, Izu. Akud. Nuuk SSSR, Ser. Khim., 1979, 180. Y. Hata and M. Watanabe, J. Org. Chem., 1980, 45, 1691. G. Neef, U. Eder, and A. Seeger, Terrahedron Lett., 1980, 21, 903. P. KoEovskL, Chem. Listy, 1979, 73, 583.

Terpenoids and Steroids

200

CEH17

17

'8

17

HO.

HO" (69)

(70)

dione with BF3.Et20followed by deprotection with KOH-BuOH gave the and A13'17'-derivatives (69) and (70) respectively. lo7 The isomerization-hydrogenation reactions of A5*7-,A7-, As-, and A 8 ' 1 4 ' - ~ t e r ~have i d ~ been shown'o8 to depend on the configuration at C-13. This was demonstrated by the confirmation of the observation that A 5 v 7 - ~ ~ m in p ~the ~ n13P-series d~ gave the A7-compound with H,-Raney nickel and the A 8 7 1 4 - ~ ~ m with p ~ ~ H2-Pd-C nd whereas in the 13a-series the former reaction gave a mixture of A7- and A8-compounds and the latter gave the As-compound quantitatively. Isomerization of 3P-acetoxy5a,l4P-cholest-7-ene to the A8-compound was almost quantitative with H2-PdC whereas HC1-catalysed isomerization of the A7-or A*- 14P-compounds initially gavelo9 the A 8 ' 1 4 ' - ~ ~ m pwhich ~ ~ n dwas subsequently converted into the 14Pchloro- 17a-cholestane (7l)."' Treatment of testosterone with concentrated H 2 S 0 4led to the trienone (74) via the dications (72) and (73).111q112 The reductive isomerization of the unsaturated ketone (75) to the saturated ketone (76) in SbF5-HF-methylcyclopentane was shown to occur via a 1,3-shift of hydride ion

&

H'7

AcO

Hd) H (71)

' (72)

(73) '07

'09

'lo

'" 'I2

W. Reischl and E. Zbiral, Helv. Chim. Acta, 1980, 63, 860. G. Acklin and W. Graf, Helv. Chim. Acfa, 1979, 62, 2733. M. Anastasia, A . Fiecchi, P. Gariboldi, and G. Galli, J. Org. Chem., 1980, 45, 2528. See ref. 39, p. 232. T. Miura, H. Takagi, and M. Kirnura, Chem. Pharm. Bull,, 1979, 27, 783. T. Miura, H . Takagi, K. Harita, and M. Kirnura, Chem. Pharm. Bull., 1979, 27,452.

Steroid Reactions and Partial Syntheses

20 1

H

(75)

(76)

(C-7 to C-5).I1' The similar reductive isomerization of androsta-4,6-diene-3,17dione gave a mixture of the 14P-6,7-dihydro-diketone(77), the spiro-diketone (78), and the 6-methyltetrahydro-diketone (79), the composition of which was dependent on temperature and acidity.'14

0 (77)

(78)

(79) 6 a and 6 p

The thermal isomerization of 19-substituted precholecalciferols has been shown115.116 to be dependent on the nature of the substituent at C-19. 19,19Difluoroprecalciferol gavelts 19,19-difluorotachy~terol~rather than the cholecalciferol and the previously described rearrangement of 19acetoxyprecholecalciferol to the E- 19-acetoxycholecalciferol was shown to proceed by transfer of the pro-R 19-H to the 9p-po~ition."~The latter result contrasts with previous observations made on cholecalciferol.'17 Miscellaneous Rearrangements.-BF3.Et20-catalysed rearrangement of 3pacetoxy-la,2a-epoxy-l~-methylandrostane(80) gave a mixture of the A-noraldehyde (82) and the allylic alcohol (84). The 3a-epimer (81) similarly gave the A-nor-aldehyde (83) and the allylic alcohol (85), indicating that the configuration of the 3-acetoxy-group was unimportant."* Treatment of (80) with toluene-p-sulphonic acid-Ac20 or with H C 0 2 H did not cause rearrangement but gave products of simple epoxide cleavage. Acid-catalysed rearrangement of the 1,2-epoxy-3,5-oxidocholestane (86) gave the A-nor-B-homo-compound (87). BF3.Et20-Ac20 reaction of the 16a,17aepoxypregna-5,7-dien-20-one(88) or its A63sc14)-isomer gave the rearranged triene (89), which was converted into the c-ring aromatic compound (90) and CF3C02H reaction of the 17a-hydroxy-20-acetoxypregna-5,7-diene(9 1) gave the aromatic D-homo-compound (92).l2' The major product of the treatment R. Jacquesy and C. Narbonne, J. Chem. SOC.,Chem. Commun., 1979,765. R. Jacquesy, C. Narbonne, and H.-L. Ung, J. Chem. Res. ( S ) , 1979, 288, 'I5 B. Sialorn and Y. Mazur, J. Org. Chem., 1980, 45, 2201. ' I 6 R. M. Moriarty and H. E. Paaren, Tetrahedron Lett., 1980, 2389. 'I7 See ref. 39, p. 233. 'I8 I. Torrini, A. M. Maione, and A. Calcagni, J. Chem. SOC.,Perkin Trans. 1, 1980, 440. ' I 9 R. Iriye, M. Sasakura, and T. Ikeda, Agric. Biof. Chem., 1979, 43, 251. '*" A. J. Bridgewater, H. T. A. Cheung, A. Vadasz, and T. R. Watson, J. Chem. SOC.,Perkin Trans. I, 1980, 556. 'I3

'I4

202

gC

Terpenoids and Steroids

AcO

H (80) 3P ( 8 1 ) 3ff

(82) 2P ( 8 3 ) 2a

(84) 3P

(85) 3 a

(88)

&?oo*c AcO

H ( 9 0 ) 5 a and

SP

of 5-bromo- 3~-chloro-5a-cholestan-6-one with pyridine was the aromatic compound (93) and 3P-chloro- 5,7P-dibromo-5cy-cholestan-6-one under similar conditions gave the aromatic compound (94).12' Dienone-phenol rearrangement of androsta-2,5-diene-4,17-dioneled to the 4-hydroxy-1 -methyloestratriene (95).lZ2 The major products of HBr-AcOH-catalysed rearrangement of the 3,5-cyclo-steroids (96) and (97) were the 4-methyloestratrienes (98) and (99) Reaction of the quinols (100) with HBr or HCl followed by acetylation gave the 3-bromo- or 3-chloro-4-methyloestratrienes (101) and (102) whereas similar treatment using HI gave the 4-methyloestratriene ( 1O3).lz4Interestingly, reac12'

122 123 124

Shafiullah and Islamuddin, Bull. Suc. Chem. Jpn., 1980, 53, 523. J. R. Hanson, D. Raines, and S. G. Knights, J. Chem. Soc., Perkin Trans. 1 , 1980, 1311. J. R. Hacson and S. G. Knights, J. Chem. Soc., Perkin Trans. I, 1980, 1306. T. M. Zydowsky, C. E. Totten, D. M. Piatak, M. J. GaSi6, and J. Stankovic, J. Chem. Soc., Perkin Trans. 1 , 1980, 1679.

Steroid Reactions and Partial Syntheses

203 0

I

0 (93) R = H (94) R = Me

1

HO

HO

(95)

(96)

R

OH

(98) R (99) R

(97)

HO (100)

(101) R' (102) R' (103) R' (104) R' (105) R'

= = = =

=

Br, R2 = Me C1, R2 = Me H, R2 = Me Me, R2 = OAc OAc, R2 Me

H

= =

O

0 P-OAc,H

*

'<

.

W N

/'

'k'po 0h

h

(106)

tion of the quinols (100) with BF,.Et20 followed by acetylation gave the 3-methyloestratriene (104) and the reaction with ZnC12-Ac20 gave the 4rnethyloestratriene (105). The BF,.Et,O-catalysed anthrasteroid rearrangement of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct (106) of 3a-hydroxycholesta5,7-diene proceeded quite slowly relative to its 3P-analogue and the 3a-benzoyloxy-derivative, in accord with the earlier suggestion that the preferential site for co-ordination of the BF, is at the NCO group attached to C-5. In (106) intramolecular hydrogen-bonding between the C-5 nitrogen and the 3a-OH reduces the availability of its lone pair.125 The reactions of bromohydrins in the cholestane series with A g 2 0 have been shown to depend markedly on the conformation of the bromine. Thus, for example, the 6a-bromo-7~-hydroxy-compounds(107) and (1OS), which have the equatorial bromine, gave the B-nor-aldehyde (110) whereas the 60-bromo7P-hydroxy-compound (109) gave the 7-0x0-compound (111) uia a hydride shift. 126 Hydrolysis of the dipotassium 5P-pregnane-3au,20a-diylsulphate in 3N-HCl gave the D-homo-steroids (112) and (113) in addition to the expected 12'

A. Ernke, J. M. Midgley, and W. B. Whalley, J. Chem. SOC., Perkin Trans. 1, 1980, 1779. H. R. Nace and G. A. Crosby, J. Org. Chem., 1979,44, 3105.

204

Terpenoids a n d Steroids

(1 11)

(1 10)

(107) 6a,7a (108) 6a,70 (109) 6P,7P

As (112)

HO'. &-*-

(112) H R (113) R

= =

OH CI

unrearranged diol and the 17-methyl-17-ethylandrost-13-ene(114).12' The Dhomo-17-oxoandrostadienones (116) and (1 17) were obtained from the sequential base-catalysed rearrangement and acetylation of the 17a-hydroxy-20oxopregnadienone (115), and BF3.Et20-AcOH-Ac20 treatment of (115) gave the ~-homo-17a-oxoandrostadienone(118).12'

I (1 15)

(1 16) R = 0-OAC (1 17) R = a-OAc

Thermal rearrangement of the 3-oxo-5-vinyl steroids (119) and (120) gave the bicyclo[2.2.l]heptanes (121) and (122) respectively via the ene reaction of the corresponding A2-eno1s.129An additional minor product from (120), the A-nor-5-propenyl-ketone (123) was believed to arise from thermolysis of the cyclopropane (124) which was formed from the ene reaction of the A3-en01 of (120). The reaction of the 16P-~-nor-acidchloride (125) with MCPBA gave the bicyclo[5.1 .O]octane derivative (131)directly whereas the 16a-epimer (126) gave the stable intermediate acyl aroyl peroxide (127) which on heating gave the carboxy inversion product (130) and the Wagner-Meerwein rearrangement product (129) (Scheme 3).130 The rapid rearrangement of the acyl aroyl peroxide (128) prevented any competitive carboxy inversion reaction. Solvolysis of the cholesteryl triflate (132) in buffered aqueous acetone gave the A-norderivatives (133) and (134). In contrast, the triflate (135) was very unreactive

'*' I. Yoshizawa, K. Nagata, R. Oh'uchi, S. Itoh, Y. Kanaiwa, and T. Amiya, Steroids, 1980,36,2629. '21 129

J. C. Knight, Steroids, 1980, 35, 511. F. M. Walliser and P. Yates, J. Chem. SOC., Chem. Commun., 1979, 1025. H . Suginome and T. Uchida, J. Chem. SOC.,Perkin Trans. 1, 1980, 943.

Steroid Reactions and Partial Syntheses

Scheme 3

205

Terpenoids and Steroids

206 CF,SO,O

tfi?

HO*

w

H

(132)

H

O

D

(133) 10a and l o p

Aco&2cF3

(134) 2a and 2p

H

(135)

and steric repulsion between C-1 and the triflate group in (132) was thought to be of importance.13' Acetolysis of the 6a,7a-methylene-4/3-mesyloxycholestane(136) gave the 7a-acetoxymethyl compound (137) as the sole The ring expansion of steroidal halogenocyclopropyl acetates derived from enol acetates and halogenated carbenes has been studied in further The base-catalysed reactions

involved cleavage of the cyclopropane ring to give the anion (138) and either elimination of a halogen atom to give the enone (139) or protonation to give the saturated ketone (140) (Scheme 4). The competition between these path-

R1qR3 X

xx2

oY q

0 (139)

R3

R'+.R' H

Me

X b 0R 3 (140) Scheme 4 13'

132

133

G. Ortar and E. Morera, Tetrahedron Lett., 1979, 4881. L. Kohout and J. FajkoS, Collect. Czech. Chem. Commun., 1979, 44, 3308. P. Crabbt. J.-L. Luche, J.-C. Damiano, M.-J. Luche, and A. Cruz, J. O r g . Chem., 1979,44, 2929.

Steroid Reactions and Partial Syntheses

207

ways was determined by the nature and stereochemistry of the substituents (halogen and others), the stability of the anion, and the steric hindrance to protonation. For example the fluorocyclopropyl acetate (141) gave exclusively the saturated fluoro-ketone (143) whereas its isomer (142) gave the enone (144) owing to the ready loss of the endo-fluorine. The addition of ethoxycarbonylnitrene to the pregn-16-en-20-one (145) was complicated by a rearrangement, in part, to the A 1 3 - ~ ~ m p( ~ 146).'34 ~nd

OAc

F (141) R' (142)R'

= =

F,R2 = H H,R2 = F

& (143) 3a and 3p

--NHC0,Et 0 As (145)

(144)

AcO

(146)

6 Functionalization of Non-activated Positions Remote functionalization has been re~iewed.'~'The yields in functionalization of C-18 by decomposition of 20a-pera~etoxynitriles~~~ were improved by thermolysis in pyridine in the presence of Cur' ch10ride.I~'A synthesis of digitoxigenin employed the photolysis of the butenolide (147) with PhIC12in benzene (Breslow r e a ~ t i o n ) .Similar ' ~ ~ photolyses of the cholestanes (148), (149), and (150) with

\

h>..-@ -

AcO

H (147)

134

135 136

137

'''

(148)X = -CONH(149)X = -CH20(150)X = -SO3-

A. V. Kamernitskii, Z. I. Istomina, E. P. Serebryakov, and A. M. Turuta, Izv. Akad. Nauk SSSR, Ser. Khim., 1979, 186. R. Breslow, Acc. Chem. Res., 1979, 13,170. See 'Terpenoids and Steroids', ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 8, p. 254. G. Neef, U. Eder, G. Haffer, G. Sauer, and R. Wiechert, Chem. Ber., 1980,113, 1106. S. F. Donovan, M. A. Avery, and J. E. McMurry, Tetrahedron Leu., 1979, 3287.

208

Terpenoids and Steroids

PhIClz in each case gave the 9-chloro-derivatives and in (149) the benzylic methylene was also halogenated. 139 Hypoiodite reaction of the C-nor-D-homoalcohol (151), which was obtained from 1l - d e o x o j e r ~ i n e ~or~ from " jervine,141 gave an 18-functionalized compound (152).

7 Photochemical Reactions Photolysis of 1l-oxo- and 11-hydro~y-A'*~-3-oxo-steroids has been s h o ~ n ' ~ ~ , ' ~ ~ to give products typical of the simpler A1~4-3-oxo-compoundsand, contrary to earlier reports and in accord with the general trend, lumiprednisone acetate has been to have the structure (153). Further irradiation of lumiprednisone acetate (153) in dioxan gave the aromatic compound (154) whereas in aqueous AcOH the hemiacetal (155) was formed.I4* The further irradiation products of the lumi-l1P-hydroxy-compoundswere the 1,ll-epoxides (156) in dioxan and in aqueous AcOH whereas an 1la-hydroxy-analogue gave other rearrangement products owing to the inability of the hydroxy-group to trap the photo-intermedi-

ate^.^^^

(155)

(153)

R

(156) R

= OH =

H

Photolysis of the epoxy-lactone (157) gave144the ketone-lactone (159). The analogous photo-rearrangement of the epoxy-lactam (158) to the keto-lactam (160) has also been r e ~ 0 r t e d . lPhoto-rearrangement ~~ of the epoxyetiojervenedione (161) to the diketone (162) was a key step in the conversion of (161) into t e ~ f o s t e r o n e . ' ~Photo-Beckmann ~ rearrangement of the oximes of 4,4dimethyl-5cu-cholestan-3-one and the 2a,4,4-trimethyl analogue gave the normal rearrangement products only and no nitriles, in contrast to the acid-catalysed rearrangement^.'^' Photo-Beckmann rearrangement of the a-hydroxycholes139 140 141

14' 143 144 145

146

14'

D. Wolner, Tetrahedron Lett., 1979, 4613. H. Suginome, N. Sato, a n d T . Masamune, Bull. Chem. Sac. Jpn., 1979, 52, 3043, 3770. H. Suginome, N. Yonekura, and T. Masamune, Bull. Chem. SOC.Jpn., 1980, 53, 210. J. R. Williams, R. H. Moore, R. Li, and J. F. Blount, J. A m . Chem. SOC.,1979, 101, 5019. J. R. Williams, R. H. Moore, R. Li, and C. M. Weeks, J. Org. Chem., 1980, 45, 2324. M. J. Caus, A. Canovas, and J.-J. Bonet, Helv. Chim. Acta, 1980, 63, 473. A. Cinovas and J.-J. Bonet, Helv. Chim. Acta, 1980,63, 486. A. Murai, N. Iwasa, and T. Masamune, Bull. Chem. SOC. Jpn., 1980, 53,259. H. Suginome and Y. Takahashi, J. Chem. SOC., Perkin Trans. 1, 1979, 2920.

209

Steroid Reactions and Partial Syntheses

As (161)

(162)

tanone oximes (163) similarly gave no fragmentation products and gave the expected a-hydroxy-lactams.148 Photolyses of steroidal acetylhydrazones in the presence of oxygen gave the lactams and are exemplified by the conversion of the acetylhydrazone (164) into (165) and (166); it is noteworthy that some inversion at C- 13 occurred.149 The studies on photoaddition of A4’6-3-oxocompounds with 1,3-dienes have been continued and the products appear to be determined by the diene ionization potential. 15’ Similar photoadditions of the A4-3-0x0-compound (1 67) and the A4*6-3-oxo-analogue(168) with norbornene and norbornadiene were reported in detail.151The major products from (167) and (168) and norbornene were respectively the cis-adduct (169) and the /

NHAc

H

AcO \

(165) 13p (166) 13a

OH

(163) 5a and 5 p

4

1

0 (167) (168) 6,7-dehydro 148 149

151

(169)

H. Suginome and C.-M. Shea, Synthesis, 1980, 229. H. Suginome and T. Uchida, J. Chem. Suc., Perkin Trans 1 , 1980, 1356. G. R. Lenz, J. Org. Chem., 1979, 44, 4299. G. R. Lenz, Tetrahedron, 1979, 35, 2613.

210

Terpenoids and Steroids

trans-adduct (170) whereas with norbornadiene they were (171) and (172) respectively. A review has appeared which compares photochemical and thermal rearrangements with particular reference to Vitamin D.”* Section B: Partial Syntheses

8 Cholestane Derivatives and Analogues Stereocontrol in the synthesis of acyclic systems in natural products has been reviewed and some steroidal examples are i n ~ l u d e d . ”Desmosterol ~ (176) was synthesized stereospecifically from the epoxy-ketone (173) and the key step was the oxy-Cope rearrangement of the unsaturated alcohol (174) to the unsaturated ketone (175) (Scheme 5 ) . l S 4 Similar stereocontrol was achieved in the Claisen rearrangement of the ester (177) to the ketone (178).”’ Starting from pregnenolone, side chains with the 20R-configuration were constructed by sequential Wittig reaction and stereoselective catalytic hydrogenation.Is6 The previously reported configurational assignments of fucosterol 24,28-epoxides were corrected by correlation with sitosterol and c l i o n a ~ t e r o l . ’ ~ ~ The marine sterol field has been reviewed’58 and a number of new marine sterols have been synthesized. Ficisterol (180), which has the unusual feature of a 23-ethyl group, was synthesized from the aldehyde (179). It was suggested that the configuration at C-24 was S, but that at C-23 has yet to be established (Scheme 6 y 9 Other new marine sterols that have been synthesized include xestosterol (181),160 23-methyl-22-dehydrocholesterol(182),16’ (24R)-24,26dimethylcholesta-5,26-dien-3~-ol(183),’62 and 23-demethylacanthasterol (18 4 p 3 Is* 15’ 154

lSs lS6 Is’

lS9 16”

16*

163

E. Havinga, Chem. Weekbl., 1979,427. P. A. Bartlett, Tetrahedron, 1980, 36, 3. M. Koreeda, Y. Tanaka, and A. Schwartz, J. Org. Chem., 1980, 45, 1173. M. Tanabe and K. Hayashi, J. A m . Chem. SOC., 1980,102,862. S. R. Schow and T. C. McMorris, J. Org. Chem., 1979, 44, 3760. Y. Fujimoto, K. Murakami, and N. Ikekawa, J. Org. Chem., 1980, 45, 566. C. Djerassi, N. Theobald, W. C. M. C. Kokke, C. S. Pak, and R. M. K. Carlson, Pure Appl. Chem , 1979, 51, 1815. M. Karpf and C. Djerassi, Tetrahedron Lett., 1980, 21, 1603. W. C. M. C. Kokke, C. Tarchini, D. B. Stierle, and C. Djerassi, J. Org. Chem., 1979,44, 3385. W. C. M. C. Kokke, N. W. Withers, I. J. Massey, W. Fenical, and C. Djerassi, Tetrahedron Lett., 1979,3601. M. W. Khalid and C. Djerassi, Steroids, 1980, 35, 707. S. Sato, N. Ikekawa, A. Kanazawa, and T. Ando, Steroids, 1980, 36, 6 5 .

21 1

Steroid Reactions and Partial Syntheses

THPO-

1

\

(173)

iii

v-vii t--

1 viii, i x

Reagents: i, N,H,-KOH-DEG; ii, pyridiniurn dichrornate-pyridiniurn trifluoroacetate; iii, CH,=CHCH,MgBr; iv, KHciioxan; v, LiAlH,; vi, (Me,N),POCI-TMEDA-THF; vii, x, pyridiniurn dichrornate; xi, Li-NH,-THF; viii, IjH,.SMe,; ix, H,O,-OH; Ph,P=CHMe,; xii, H,O

Scheme 5

--OCOCH,COCH,CHMe, ---*

OMe (177)

The oogoniol analogue (187) was synthesized from Sa-cholest-7-en-3/3-01 via the epoxy-hydroxy-enone (186),which was obtained by oxidation of the dienone (185) with two equivalents of MCPBA.'64 The compounds (190) and (191), which contain the oogoniol side-chain, were synthesized from the A'-aldehyde (188)'65 and the 3,5-cyclosteroid aldehyde (189)'66 respectively. The syntheses each involved the Claisen rearrangement brought about by treatment of the A23-22-hydroxy-compounds (192) with trialkyl orthoacetate, which gave the carboxylic esters (193). '64

'65

M. Anastasia, A. Fiecchi, P. Gariboldi, and A. Scala, J. Org. Chem., 1979, 44, 4447. M. Anastasia, A. Fiecchi, and A. Scala, J. Chem. SOC.,Chem. Commun., 1979, 858. J. R. Wiersig, N. Waespe-Sarcevic, and C. Djerassi, J. Org. Chem., 1979, 44, 3374.

Terpenoids and Steroids

212 V C H O

i . ii

P

C0,Et

iv, v t-

,@OH

CHO

vii, viii

HO (180) Reagents: i, Ph,P=CHCO,Me; ii, NaAIHz(OCzH,OMe),;+iii, EtC(OEt),; iv, H,-Pd-BaCO,; LiAlH,; vi, Cr0,-pyridine; vii, NaH-DMSO-PH,PMef; viii, H,O'

Scheme 6

v,

213

Steroid Reactions and Partial Syntheses

H O&cHo H

J" (190) (191)

A, B

A, B

A/

rings as (188) rings as (189)

(189)

Terpenoids and Steroids

214

The syntheses of (22S )-22 -hydroxycampes terol and 7p- hydroxycampes terol from the 3,5-cyclo-aldehyde (189) have been r e p 0 ~ t e d . The l ~ ~ two brassinosteroids (194) and (195) were synthesized from ergosteryl tosylate.’6R The 24-nor-5P-cholestane tetrols (196) and (197) were synthesized by hydroboration-oxidation of the corresponding A23- and A 2 5 - ~ ~ m p ~ ~ nand d ~the , 1 6tetrol 9 (198) was synthesized from cholic Lithocholic acid was converted in HO

,

HO.. As(194)

HO” (195)

0

(196) 23R and 23s

(197) 25R and 25s

(198)

5p-cholestan-3a,25-diol into 25-hydro~ycholesterol.~~~ A synthesis of chol-5ene-3P,24-diol from cholesterol employed a preparatively useful oxidative degradation of the protected derivative (199) to the 24-hydroxy-compound (200) with CF3C03H-H2S04-H20.”* (24R and 24S)-27-Nor-24-methyl-3a,7~-dihydroxy-5~-cho~estan-26-oic acid was a product of the electrolytic coupling of chenodeoxycholic acid and methyl hemisuccinate. 173 The adduct (201) was converted into the 25-oxo-27167 168

169

170

I7l 17’ 173

K.-P. Cheng, L. Bang, G. Ourisson, and J.-P. Beck, J. Chem. Res. ( S ) , 1979, 84. M. J. Thompson, N. Mandava, J. L. Flippen-Anderson, J. F. Worley, S. R. Dutky, W. E. Robbins, and W. Lusby, J. Org. Chem., 1979,44,5002. B. Dayal, G . S. Tint, and G. Salen, Steroids, 1979, 34, 581. B. Dayal, E. Bagan, J. Speck, and G. Salen, Steroids, 1980, 35, 439. K. Ochi, I. Matsunaga, M. Shindo, and C. Kaneko, Chem. Pharm. Bull., 1979, 27, 252. N. C. Den0 and M. D. Meyer, J. Org. Chem., 1979,44,3383. K. Kihira, K. A. Batta, E. H. Mosbach, and G. Salen, J. Lipid Res., 1979, 20, 421.

Steroid Reactions and Partial Syntheses

215

OH AcO

NHAc

AcO NHAc

(200)

1

AcO

norcholestadiene (202).'74The 4-diazo-3-0x0-derivative (203), a potential 5areductase inhibitor, has been synthesized,.17' A series of steroidal a-methylene-lactones, potential anti-tumour agents, has been synthesized and is exemplified by the cholestane derivative (204).'76 14P,17a-Cholest-5-en-3P-o1 (206) was synthesized from the A 1 4 - ~ ~ m p ~ ~ n d and fatty cholesteryl (205),'77 and syntheses of radiolabelled bile have been reported.

a ' &;0/y.p17

0

H (204)

HO OAc

(206)

(205) 174

17' 176

17' 17*

'79

N. Bogoslovskii, G . E. Litvinova, and G . I. Samokhvalov, Zh. Obshch. Khim., 1979, 49, 227. B. W. Metcalf, K. Jund, and J. P. Burkhart, Tetrahedron Lett., 1980, 21, 15. S. S. Dehal, B . A . Marples, R. J. Stretton, and J. R. Traynor, J. Med. Chem., 1980, 23, 90. M. Anastasia, G. C. Galli, and P. Allevi, I. Org. Chem., 1979, 44, 4983. B. Dayal, E. Bagan, G. S. Tint, S. Shefer, and G. Salen, Steroids, 1979,34, 2455. A . K. Grover and R. Cushley, J. Labelled Comp. Radiopharm, 1979,16,307.

Terpenoids and Steroids

216

9 Vitamin D, Its Metabolites, and Related Compounds Recent advances in the chemistry and biology of vitamin D have been reviewed. 180*181The C,D-fragment (208) became readily available from the degradation of cholesterol through the A9-compound (207).'81 Syntheses (formally total) of la-hydroxycholecalcifero1183~184 and 1cu-hydroxyprecholecalcifer01'~~ employed the key intermediate (208). A key step in the degradation

of 3cu-hydroxycholest-9( 11)-ene to the c,D-fragment (212) was the LiA1H4 reduction of the epoxide (209) to the 8-arylethyl-9-hydroxy-des-AB-cholestane (211) and involved the dienol-benzene rearrangement of the intermediate (210).186Dry ozonization or reaction with MeC03H-hv converted the 8-acetoxydes-AB-cholestane (2 13) directly into the 25-hydroxy-analogue in modest yield.'87 Alternatively the trifluoroacetate (214) was converted into the 25chloro-analogue with EtOCONCI,-hv and then into the 25-hydroxy-analogue.

C8H 1 7

f CH,OH (212) (211)

0 1

OR (213) R = Ac (214) R = CF3CO

R. I. Yakhimovich, Russ. Chem. Rev., 1980, 49, 371. H. Jones and G. H. Rasmusson, Fortschr. Chem. Org. Naturst., 1980, 39, 6 3 . P. J. Kocienski, B. Lythgoe, and D. A. Roberts, J. Chem. SOC.,Perkin Trans. I , 1980, 897. 183 P. J. Kocienski, B. Lythgoe, and I. Waterhouse, Tetrahedron Lett., 1979,4419. P. J. Kocienski and B. Lythgoe, J. Chem. SOC.,Perkin Trans. I , 1980, 1400. '" B. Lythgoe and I. Waterhouse, J. Chem. SOC.,Perkin Trans. I , 1980, 1405. B. Lythgoe and D. A. Roberts, J. Chem. SOC.,Perkin Trans. 1, 1980, 892. "' Z. Cohen, E. Berman. and Y. Mazur, J. Org. Chem., 1979,44, 3077. I8O

''I

Steroid Reactions and Partial Syntheses

217

A synthesis of 26,26,26,27,27,27-hexafluoro-25-hydroxycholecalciferol has been reported, and the two side-chain constructions used are shown in Scheme 7.1882P-Fluoro- la-hydroxycholecalciferol was synthesized by standard procedures from the dihydroxyfluorocholest-5-ene (216) which was obtained from the epoxide (215) by treatment with KHF,-ethylene Syntheses of

1

iii

1

F

s

S02Ph

o

2

p

h

1@;

+ iv,ii

Reagents: i, Mg; ii, (CF,),CO; iii, PhS0,Na; iv, LDA; v, Na/Hg-Na,HPO, Scheme 7

25,26,27-trisnorcholecalciferol-24-oicacid (217) and its la-hydroxy-analogue

*\

(218) have been reported. Degradation of the side-chain was achieved by Baeyer-Villiger reaction of appropriate 24-0xo-derivatives.~~~ A synthesis of 24-dehydrocholecalciferol from 3~-acetoxy-25-hydroxycholesta-5,7-diene has been r e p ~ r t e d . ” ~ COzH

\ &F

HO

HO

(215)

(216)

HO‘* (217) R = H (218) R = OH

10 Pregnanes The reaction of the lithium enolate (219) with formaldehyde-ZnC12 provided the 17a-hydroxymethyl-20-oxopregnane(220) d i r e ~ t l y . ’Reaction ~~ of the

’’’ 190

19’

Y. Kobayashi, T. Taguchi, N. Kanuma, N. Ikekawa, and J.-I. Oshida, J. Chem. SOC., Chem. Commun., 1980,459. J.-I. Oshida, M. Morisaki, and N. Ikekawa, Tetrahedron Lett., 1980,21, 1755. N. Koizumi, M. Morisaki, N. Ikekawa, Y. Tanaka, and H. F. DeLuca, J. Steroid Biochem., 1979, 10,26 1. S. S. Yang, C. P. Dorn, and H. Jones, Steroids, 1980,35,329. D.Mukherjee and Ch. R. Engel, Steroids, 1979,34,597.

218

Terpenoids and Steroids

(22 1)

androstan-17-one (221) with methyl lithiomethoxyacetate gave the adduct (222) which on dehydration with SOC1,-pyridine afforded the A'7'20'-methoxy-ester (223).19' This may be converted by reduction with BulAlH into the alcohol (224) which on acetylation gave (225). The syntheses from these of the 17a,21-dihydroxy-20-oxo- or the A16-21-acetoxy-20-oxo-pregnanesand others are shown in Scheme 8.

Reagents: i, H,O'; ii, MCPBA; iii, '0,; iv, PPh,; v, CuC1,-pyridine

Scheme 8

A number of 7a-halogenocorticoids have been synthesized and evaluated as anti-inflammatory agents.'94 A synthesis of 17a-acetoxy-6-methylpregna-4,6dien-3P-ol-20-one involved the isomerization of the 6-methylene-A4-3-0x0derivative (226) to the 6-methyl-A4~6-3-oxo-compound (227) with a Pd-C cataly~t."~An improved synthesis of aldactone has been reported'96 and the G. Neef, U. Eder, A. Seeger, and R. Wiechert, Chem. Ber., 1980,113,1184. H. J. Shue, M. J. Green, J. Berkenkoph, M. Monahan, X. Fernandez, and B. N. Lutsky, J. Med. 'Chem., 1980,23,430. 19' G. M. Kadatskii, G. S. Grimenko, A. I. Terekhina, L. Litisa, I. V. Ganina, and E. I. Gorenburgova, Khim. Farm. Zh., 1979,13,63. 196 M. Stefanovic, S. Mladenovic, and B. Rihter, Glas. Hem. Drus. Beograd., 1979, 44, 159. 193

194

Steroid Reactions and Partial Syntheses

219

(228)

potential anti-progestins (228) and (229) have been synthesized from the corresponding A’*,- and A4*6-3-oxo-compounds with Na-RSH.I9’ Epi-ethynyloestradiol was synthesized by demethylation of epimestranol and by LiAIH4 reduction of the 16,17-epoxide (231), which was obtained from the A16-17-ethynyl compound (230).19* CH

Ill

C

CH

Ill

(230)

11 Androgens and Oestrogens The syntheses of 3a,7a-dihydroxy -5P-androstan- 17-one (23 2) and the 3ahydroxy-7,17-dioxo-compound(233) from 3a,7a-diacetoxycholanic acid have been reported (Scheme 9).199A synthesis of lSP, 17P-dihydroxyandrost-4-en-3one (236) employed the non-reductive cleavage of the androsten-15-yl ally1 ether (234) by successive treatment with (Ph3P)3RhC1-EtOH-C6H6-H20 and H2S0,-Me2CO-H20 to give the 15~-hydroxy-compound(235).200Syntheses of the 3-methoxy-14-methyl-14P-oestratrienone (238) involved methylation of the 14~-15-oxo-compound (237) with K0Bu‘-Me1 or of the 140-17-ethylenedioxy- 15-oxo-compound (239) with NaNH2-Me1 followed by LiAlH, reduction of the resultant enol derivative (240).201Contrary to an earlier report, treatment of the 14a- 17~-acetoxy-15-oxo-compound (241) with K0Bu‘-Me1

”’ B. Beyer, L. Terenius, and R. E. Counsell, Steroids, 1980, 35, 481.

*’*

lg9

R. M. Kanojia, G. 0. Allen, J. M. Killiniger, and J. L. McGuire, J. Med. Chem., 1979, 22, 1538. J. C. Beloeil, C. Esnault, M. Fitizon, and R. Henry, Steroids, 1980, 35, 281. J. E. T. Corrie, J. Chem. Res. (S), 1979, 9. J. R. Bull, J. Floor, and G. J. Kruger, J. Chem. Res. ( S ) , 1979, 224.

220

Terpenoids and Steroids

~ c o 2

AcO**

H

'OAc

HO'

H

1

viii

0

@ H

HO"

'OH

HO-

H (233)

(232) Reagents: i, Pb(OAc),; ii, N-lithioethylenediarnine;iii, Bu'Me,SiCl-irnidazole-DMF; iv, AqOpyridine; v, 0,;vi, K0Bu'-0,-Et,P; vii, NaBH,; viii, NaBiO,; ix, NaOMe; x, NBS

Scheme 9

(234)

(236) R

=

H

gave the 14P-methylated product (242), which was also converted into (238). Interestingly, methylation of the 8-dehydro-compound (243) under similar conditions gave mainly the 14a-methyl derivative (244).202Steroidal ethers (245) were prepared203from the 17-ethylenedioxy-steroidsby the sequence shown in Scheme 10. 202

J. R. Bull and J. Floor, J. Chem. SOC., Chem. Comm., 1980, 270. '(u H. J. J. Loozen and M. S. de Winter, Red. Trau. Chim. Pays Bas., 1979,98,484.

Steroid Reactions and Partial Syntheses

22 1

&

As (237)

Me0

(237) R (238) R

1,fiTM 0

H = Me =

(240)

Me0

1

iii

C0,Me

1fiAco2"' +- 16'"" iv

(245)

Reagents: i, LiAIH,-AICI,;

ii, CrO,; iii, MeOH-H'; iv, LDA-CIC0,Me

Scheme 10

Syntheses of 2-hydroxy-3-amino-5a-androstan-17-ones204and their r e g i o i ~ o r n e r sand ~ ~ ~their A5-analogues205have been reported. The 19-nor-A41,2-epoxide (246) and isomeric A1-4,5-epoxides (247) and (248) were synthesized in an essentially similar manner by epoxidation of the appropriate enone 10)followed by dehydrogenation with Se02.*06 3-Hydroxy-9/3-oestra-1,3,5( ,04

205

206

M. M. Campbell, R. C. Craig, A. C. Boyd, I. M. Gilbert, R. T. Logan, J. Redpath, R. G. Roy, D. S. Savage, and T. Sleigh, J. Chem. SOC.,Perkin Trans. 1, 1979, 2235. M. M. Campbell, R. C. Craig, J. Redpath, D. S. Savage, and T. Sleigh, J. Chem. Soc., Perkin Trans. 1, 1979, 3042. P. W. LeQuesne, A. V. Durga, V. Subramanyan, A. H. Soloway, R. W. Hart, and R. H. Purdy, J. Med. Chem., 1980, 23, 239.

Terpenoids and Steroids

222

(246)

(248) 4a,5a

triene-l1,17-dione, which was obtained from the 9a-11 -oxo-compound by acidor base-catalysed epimerization, was reported to have remarkable oestrogenicit^.^'' The dimethoxy-ester (249) was converted into the [18-2H]aldehyde (250), which on electrochemical reduction in 'H2S04-*H20 gave208 the [ 18,18,18'H3]compound (251) which, in turn, was converted into the [18,18,18-*H3]D-homo-androstane (252) using the previously reported acid-catalysed rearrangement .209 MeO,' MeO,$

I'

12 Cardenolides and Bufadienolides The key step in the syntheses of 14-deoxy-14a-strophanthido1210 and 14-deoxy14a-~trophanthidin,*"which is the introduction of the 5/3-hydroxy-group, was achieved through the now well known212 participation of a 19-acetoxy- or 19-formyloxy-group in the HOBr addition to the 5,6-double bond (see also refs. 38 and 39). The reaction of triphenylphosphoranylideneketen [Ph,P=C=C=O] with the 21-hydroxy-20-0x0-steroids (253) gave the cardenolides (254) directly.*13 As expected addition of methylene to the 4,5-bond of the 3-hydroxybufadienolides (255) and (256) was directed in a cis-manner 207

208 209 210 211 212 213

A. Segaloff, R. B. Gabbard, A. Flores, R. F. Borne, J. K. Baker, W. L. Duax, P. D. Strong, and D. C. Rohrer, Steroids, 1980, 35, 335. I. A. Blair, R. G. Frith, G. Phillipou, and C. J. Seaborn, A u s f . J. Chem., 1979, 32,2327. See ref. 39, p. 235. P. KoEovsky and V. eerny, Collect. Czech. Chem. Commun., 1980, 45, 921. P. KoEovsky, Tetrahedron Lett., 1980, 21, 555. See ref. 39, p. 242. K. Nickisch, W. Klose, and F. Bohlmann, Chem. Ber., 1980, 113, 2038.

go I

Steroid Reactions and Partial Syntheses

,&'

R2

R2

(253) R'

=

R'

=

223

H, R2 = OH OH, R2 = H

(254) R'

R'

= =

H, R2 = OH OH, R2 = H

0

0

1

OH ( 2 5 5 ) 3P (256) 3 a

by the 3-hydroxy-group and gave respectively (257)and (258).'14 The syntheses of the trans-adducts (259) and (260) were achieved by oxidation of (257) and (258) and reduction of the resultant 3-0x0-compounds with Li(Bu'O),AlH. The synthesis of 4P,SP-methyleneproscillaridin has also been r e p ~ r t e d . ~ ' ~

13 Cyclo-steroids and Seco-steroids Simmons-Smith cis-methylenation of the 4,5-double bond in 19-acetoxy-3hydroxycholestanes gave the 4,5-methylene-compounds.21s A series of 6a17amethyleneandrostanes has been reported216as have the 5,6-methylenepregnanes (261) and (262).'17 A stereospecific synthesis of the 6P,7P-methylenespirolac-

'I4 *15 '16 217

H. P. Albrecht, Liebigs. Ann. Chem., 1980,886. J. Joska and J. FajkoB, Collect. Czech. Chem. Commun., 1980, 45, 1850. L. Kohout and J. Fajkoi, Collect. Czech. Chem. Commun., 1980, 45, 1974. V. Sanda. L. Kohout, and J. FajkoS, Collect. Czech. Chem. Commun., 1980,45, 269.

Terpenoids and Steroids

224

4cO HO

xv&AcO

(263)

ii,v/

Reagents: i, NBS; ii, NaOH; iii, NaBH,-PhSeSePh; iv, NaOAc-H,O,; Zn-Cu; vii, Cr0,-pyridine

v, pyridine-DBN; vi, CH,12-

Scheme 11

tone (264) (prorenone) involved methylenation218 of the 5P-hydroxy-A6compound (263) as indicated in Scheme 11. Reaction of the 18-iodopregnan-20one (265) with Bu'OK gave the 17,18-cyclo-steroids (266) and (267).*19The 5,lO-seco-cholest-l(lO)-en-5-ones (269) and (270) were prepared2*' via the photochemical lead tetra-acetate fragmentation of the 5-hydroxy-compound (268) (see also ref. 5). \

(266) R (267) R

(269) R (270) R 218

*I9

**'

= =

=

Ac

=

H

(Y-OH,H 0

P. Wieland, Helv. Chim. Acta, 1979, 62, 2276. P. Bogan and R. E. Gall, Aust. J. Chem., 1979,32, 2323. H. Fuhrer, L. Lorenc, V. PavloviC, G. Rihs, G . Rist, J. Kalvoda, and M. Lj. Mihailovii, Helv. Chim. Acta, 1979,62, 1770.

Steroid Reactions and Partial Syntheses

225

14 Heterocyclic Steroids Reaction of the acetoxyvinyloxocholestanes(27 1) and (272) with benzylamine(Ph,P),Pd gave the pyrroles (273) and (274) respectively.221The reaction of 2-hydroxymethylene-5a-steroids with 3-aminopyrazole gave products of the general type (275) and (277).222Analogous products were obtained with 3amino-4-cyanopyrazole but with 3-amino-4-cyano-5-cyanomethylpyrazole only the angularly fused product (276) was produced. The reactions of all the 3aminopyrazoles with 2-hydroxymethylene-3-0x0-A4-steroids and 16-hydroxymethylene- 17-0x0-steroids gave only angularly fused products.222An analogous study with 5-aminotetrazole led to a series of tetraz~lopyrimidines,~~~ and the reaction of 3P-acetoxy-A5-oxo-steroids with HN,-BF3-Et20 gave the tetrazolosteroids (278), which were converted into the A4-3-0x0-derivatives (279).224

a ' OAc

H

(273)

(277) R2

(275) R' = R2 = H (276) R 1 = CN, R2 = CH2CN

222

223 224

B. M. Trost and E. Keinan, J. Org. Chem., 1980,45, 2741. J. S. Bajwa and P. J. Sykes, J. Chem. SOC.,Perkin Trans. 1, 1980, 481. J. S. Bajwa and P. J. Sykes, J. Chem. SOC.,Perkin Trans. I , 1980, 1019. H. Singh, K. K. Bhutani, R. K. Malhotra, and D. Paul, J. Chem. SOC.,Perkin Trans. I , 1979. 3166.

Terpenoids and Steroids

226

A number of interesting A-ring-fused heterocycles have been synthesized from steroidal-2,3-aziridines including thiazolines and imidazo[2,1-b]thiazolines, and a typical synthesis of the latter type from (280) is outlined in Scheme 12.22s The spontaneous elimination of HCI from the intermediate (281) is noteworthy since the equivalent regioisomeric intermediate obtained from the 2a,3a-epimers of (280) is quite stable. A number of 17-spiro-oxazolidinones

n H

1

H

ii

l

C1' Reagents: i,

rnF.1;

ii, Et,N.HCl

Scheme 12

(282) have been reported,226 as have the 15-oxaoestratrienes (283).227Activated M n 0 2 was used for the biomimetic conversion of 16P-hydroxy-22,26epiminocholestanes (284) into the spirosolane alkaloids (285); the reaction is thought to involve ring closure of the originally formed azomethine.228Syntheses of the chandonium iodide analogue (286) and its acetate have been

R' = C r C H , R 2 = OH,R3 = Me R', R2 = 0, R3 = cyclopentyl

225 226 227 228 229

M. M. Campbell and R. C. Craig, J. Chem. SOC.,Perkin Trans. I , 1980, 7 6 6 . S. Sblyom, K. Szilagyi, and L. Toldy, Steroids, 1980,35, 361. P. Rosen, A . Boris, and G. Oliva, J. Med. Chem., 1980, 23, 329. G. Adam and H. Th. Huong, Tetrahedron Lett., 1980, 21, 1931. H. Singh, T. R. Bhardwaj, and D. Paul, J. Chem. SOC., Perkin Trans. 1, 1979, 2451.

Steroid Reactions and Partial Syntheses

227

15 Microbiological Transformations The importance of bioconversions in the industrial production of steroids has been reviewed230and other reviews on the applications of microbial transformations have Biotransformations by plant tissue and the application of mathematical models to optimization of fermentation235have been reviewed. Lithocholic acid was 12P-hydroxylated by the fungus Helicostylum piriforme in reasonable yield (40°/0).236A study of the oxidations of fluoro-5a-androstanones by Calonectria decora, Rhizopus nigricans, and Aspergillus ochraceus indicated that hydroxylation is inhibited at, or adjacent to, the fluorine-bearing carbons even though these sites may be favoured in the parent ketone.237 16P, 18-Dihydroxylation of 5a-androstanes with one oxygen function in ring A and one in ring B or ring C was observed with Leptoporus f i s ~ i l i s A . ~study ~ ~ of the microbial transformations of D-homoprogesterone has been reported and hydroxylation of the 11-0x0-derivative (287) with Curvularia lunata gave a mixture of the 14a-hydroxy- and the 7a, 14a-dihydro~y-derivatives.~~~

(287)

Studies on the use of immobilized cells in microbial transformations have ~~~ continued and the 1,2-dehydrogenation activity of Nocardia r h o d o c r ~ u sand 230 231

232 233 234 235

236

237

238

239 240

G. Nornine, Bull. SOC.Chim. Fr., 1980, 18. A. Sato, Kagaku Kojo, 1979, 23,31. 0. K. Sebek and D. Perlrnan, Microbiol. Technol., 1979, 1,483. K. Kieslich, Bull. SOC.Chim. Fr., 1980, 9. A. W. Alfermann and E. Reinhard, Bull. SOC. Chim. Fr., 1980, 35. C. M. P. Deshayes, Bull. SOC.Chim. Fr., 1980, 24. S. Hayakawa, K. Yao, M. Iijima, and K. Sesaki, J. Chem. SOC.,Chem. Commun., 1980, 84. T. G. C. Bird, P. M. Fredericks, E. R. H. Jones, and G . D. Meakins, J. Chem. SOC.,Perkin Trans. 1, 1980, 750. W. A. Denny, P. M. Fredericks, I. Ghilezan, E. R. H. Jones, G. D. Meakins, and J. 0. Miners, J. Chem. Res. (S)., 1980, 20. K. Kieslich, G.-A. Hoyer, A. Seeger, R. Wiechert, and U. Kerb, Chem. Ber., 1980,113, 203. T. Yamane, H. Nakatani, E. Sada, T. Ornata, A. Tanaka, and S. Fukui, Biotechnol. Bioeng., 1979, 21, 2133.

228

Terpenoids and Steroids

Arthobacter simplex 2 4 ' * 2 4 2 and the ketone reducing activity of Rhodoturula r n u c i l ~ g i n o s awere ~ ~ ~reported in this context.

16 Miscellaneous Syntheses A number of ferrocenemonocarboxylic acid steroid esters have been typically the oestradiol derivatives (288). The cholestano-cobaloximes (289) and ..H, 0"'

0. .. (288) R' R' R'

=

= =

R2 = Fc-CO H, R2 = Fc-CO Fc-C0,R2 = H

(290)

"

0

H

,o

(291)

the analogous rhodoximes were prepared.245 A series of 17P-carboxamide derivatives (291) was prepared from the glucocorticoid degradation product (290) by sequential reaction with N-hydroxybenzotriazole-DCC and R3NH2.246 The syntheses and biological activity of 1-(P-D-arabinofuranosy1)cytosine conjugates of prednisolone and prednisone have been The reaction of 2,2,6,6-tetrameth ylpiperidine -N-oxyl-4 -carboxylic anhydride (29 2) with alcohols including androstenolone gave spin-labelled esters (293).248

s0a I

I

0.

0.

RO-CO

(J-o*

(293)

(292)

24'

242

243

244

"'

246

247 248

S. Ohlson, P. 0. Larsson, and K. Mosbach, Eur. J. Appl. Microbiol. Biotechnol., 1979, 7 , 103. K. Sonomoto, A . Tanaka, T. Omata, T. Yamane, and S. Fukui, Eur. J. Appl. Microbiol. Biotechnol., 1979, 6, 325. W. Peczynska-Czoch, A . Siewinski, and A . Szewczuk, Arch. Immunol. Ther. Exp., 1979, 27, 441. K. Hoffmann, B. Riesselmann, and M. Wenzel, Liebigs. A n n . Chem., 1980, 1181. M. Fountoulakis and J . Retey, Chem. Ber., 1980, 113,650. P. Formstecher, P. Lustenberger, and M. Dautrevaux, Steroids, 1980, 35, 265. C. I. Hong, A. Nechaev, and C. R. West, J. Med. Chem., 1979,22, 1428. H. W. Whitlock and S. P. Adams, J. Org. Chem., 1979, 44, 3433.

Author Index Aareskjold, K., 134 Aarts, G. H. M., 173 Abe, K., 151, 161, 162 Abraham, W.-R., 38, 92, 101 Abrahamson, E. W., 153 Acklin, G., 200 Acton, N., 145 Acuna, A. U.. 155 Adair, W. L., jun., 158 Adam, G., 102, 103,226 Adarns, M. A., 151, 156 Adams, R. E., 190 Adams, S. P., 228 Adinolfi, M., 94, 113, 114 Adityachaudhury, N., 99, Afza, N., 114, 117 Agafonov, V. N., 169 Agalidis, I., 154 Agarni, C., 195 Agocs, P. M., 186 Ahmad, V. U., 125 Ahmed, F. R., 170 Ahond, A., 104 Akimori, N., 102 Akimoto, K., 43, 47 Akita, H., 9, 30, 156 Albert, K. A., 195 Albertson, B. D., 186 Albrecht, H. P., 223 Albrecht, P., 131 Alferrnann, A. W., 227 Ali, H., 187 Ali, S., 29, 30 Allen, G. O., 219 Alleri, P., 215 Alrngren, M., 155 Alvarez, R. A., 151 Alvernhe, G., 197 Amagaya, S., 127 Amer, M., 126 Arnico, V., 105 Amiya, T., 204 Anastasia, M., 191, 200, 211, 215 Andersen, A., 108 Andersen, R. J., 3 Anderson, W. K., 18 Andina, D., 42 Ando, M., 71,75 Ando, T., 210 Angelo, M. M., 72 Angyal, S. J., 189 Anjaneyulu, A, S. R., 127, 128 Anthony, J. M., 15 Antipin, M. Y., 171

Arai, M., 30 Arai, Y., 148 Argyle, J. C., 5 Aristoff, P. A., 109 Arnaboldi, M., 145, 156 Arnold, E. V., 17 Asada, M., 127 Asakawa, Y., 7,56,79,88,105, 106 Asao, T., 71 Asato, A. E., 144, 146 Aslanov, Kh. A., 94 Aton, B., 154 Atsurni, K., 88 Attah-Poku, S. K., 196 Aversa, M. C., 130 Avery, M. A., 207 Axelson, M., 183 Ayer, W. A., 40, 106, 107 Ayres, B. E., 167

Baciu, I., 186 Back, T. G., 198 Baert, F., 77 Bagan, E., 214, 215 Baggiolini, E. G., 174 Bailey, D. B., 144 Bailey, T. R., 14 Bajaj, A. G., 35, 132 Bajwa, J. S., 225 Baker, J. K., 167,222 Balasubramaniarn, S., 123 Baldwin, S. W., 31 Ball, P., 184 Ballio, A., 105 Balogh-Nair, V., 142, 144, 156 Baltscheffsky, M., 137 Banerjee, A. K., 71 Banerjee, S. K., 131, 132 Bang, L., 214 Banks, C. M., 54 Bansal, R. K., 97, 111 Banville, J., 28 Barbe, B., 96 Barbetti, P., 80 Baretz, B., 144 Bari, S. S., 160 Barker, A. J., 29 Barrans, Y., 170 Barrero, A. F., 69,92 Barrett, A. G. M., 189 Barros Papoula, T., 196 Barrow, G. H., 185

Bar-Tana, J., 162 Bartlett, P. A., 210 Barton, D. H. R., 18, 189, 190, 194, 195, 196, 197 Barua, A. B., 132, 144 Barua, N. C., 59 Barua, R. N., 59 Basak, A., 132 Bastard, J., 92 Basu, K., 131, 132 Bates, A. L., 153 Bates, R. B., 116 Batta, A. K., 168, 174, 214 Batten, R. J., 190 Baumann, M., 142 Baxter, R. L., 71 Beale, M. H., 99, 103 Beauhaire, J., 80 Becchi, M., 116, 125 Bechtold, H., 162 Beck, J.-P., 214 Becker, M., 11 Becker, R., 101 Becker, R. S., 153, 155 Beecham, A. F., 96 Behr, D., 104, 136 Belanger, A., 108 Belkien, L., 184 Bell, A. A., 29 Bellido, I. S., 70 Beloeil, J. C., 219 Bennett, R. D., 118 Beno, M. A,, 64 Bensasson, R. V., 155 Bentley, R., 162 Benveniste, P., 111, 112 Berchtold, G. A,, 108 Beress, L., 134 Berg, D., 184 Berg, J. E., 104 Berger, J., 150 Bergman, R. G., 35 Berkenkoph, J., 218 Berman, E., 49,219 Bernassau, J. M., 93, 96, 179 Bernhard, K., 133 Berney, D. J. F., 108 Berson, J. A., 35 Bertrand, M., 86, 87 Beyer, B., 219 Beyer, P., 134 Bhacca, N. S., 59 Bhardwaj, T. R., 226 Bhat, P. V., 151 Bhattacharyya, J., 175

230 Bhattacharyya, S. C., 55 Bhutani, K. K., 225 Biard, J. F., 92 Bierner, M. W., 80 Biglino, G., 111 Biguet, J., 77 Birch, A. J., 192 Bird, T. G. C., 187, 227 Birge, R. R., 153, 156 Bittner, M., 69 Blacklock, T. J., 8 Blaha, K., 179 Blair, I. A,, 193, 222 Blatchly, R. A., 144 Blattna, J., 151 Blessing, R. H., 166 Bloszyk, E., 59 Blount, J. F., 56, 59, 80, 94, 107, 168,208 Boar, R. B., 127, 189 Bock, K., 173 Bodor, A., 179 Boeyens, J. C. A., 167 Bogan, P., 224 Bogatskii, A. V., 186 Bogoslovskii, N., 215 Bohlmann, F., 3, 10,30,38,49, 50, 56, 59,69, 73,77,79,80, 92, 93, 94, 95, 96, 99, 100, 101,222 Bohlmann, R., 8 0 Bokel, H. H., 11 Bolt, J. D., 154 Bondi, A., 112 Bonet, J.-J., 208 Bonting, S. L., 154, 156 Borch, G., 134 Borchert, R., 151 Boris, A., 226 Borne, R. F., 167, 222 Borris, R. P., 117 Borschberg, H.-J., 108 Bose, A. K., 182 Bose, L., 131 Botter, R., 181 Bovee-Geurts, P. H. M., 154, 156 Bowden, B. F., 55,87, 104 Boyd, A. C., 221 Bradshaw, A. P. W., 40 Braekman, J. C., 55, 99 Braenden, 0. J., 71 Brahmana, H. R., 139 Bratoeff, E., 59 Braun, T. M., 126 Braz Filho, R., 96 Breazu, D., 179 Brecknell, D. J., 66 Breitenstein, W., 17 Breslow, R., 207 Breton, J., 155, 156 Brey, L. A., 155 Bridges, C. D. B., 151 Bridgewater, A. J., 201

Author Index Brieskorn, C. H., 55, 125, 127 Briner, P. H., 6 Britton, G., 133, 156, 157 Brodie, A. H. H., 170 Brooks, C. J. W., 180, 182 Brossi, A., 145 Brousseau, R., 108 Brown, D. J., 157 Brown, F. J., 180 Brown, H. M., 155 Brown, M. S., 152 Brueneteau, M., 125 Brunet, J.-J., 194 Brunke, E. J., 12 Bryson, I . , 39 Buchecker, R., 134, 152 Buck, H. M., 52 Buckanin, R. S., 108 Buchi, G., 6, 22 Bull, J. R., 115, 167, 176, 219, 220 Bu’Lock, J. D., 159 Burford, S. C., 29 Burgstahler, A. W., 192 Burke, T. R., 175 Burkhart, J. P., 190, 215 Burnell, R. H., 108 Burns, D. T., 184 Burt, V. T., 162 Bychkova, S. F., 96 Bytera, I. M., 155 Cagnoli, N., 96 Caine, D., 73, 75, 76 Calcagni, A., 201 C a l d e r h , J. S., 56, 158 Callender, R. H., 154 Camara, B., 157 Cambie, R. C., 94, 96, 188 Campbell, M. M., 221, 226 Campsteyn, H., 168 Cane, D. E., 5 , 4 1 , 111 C h o v a s , A., 208 Capasso, R., 105 Capelle, N., 99 Capiton, G . A., 56 Cardillo, G., 142 Carey, P. R., 154 Carey, S . C., 143 Cargile, N. L., 151 Carlson, R. M. K., 216 Carman, R. M., 206 Carpenter, R. C., 123 Carrasco, M. C., 71 Carriker, J. D., 144 Carroll, K. K., 159 Carte, B., 107 Cary, L. W., 125 Casares, A., 14 Casinovi, C. G., 80 Caspi, E., 112 Cassady, J. M., 9 8 Castagnino, E., 148 Castilo, M., 101

Cattel, L., 111 Caubere, P., 194 Caus, M. J., 208 Ceccherelli, P., 96 Cerfontain, H., 1 SO Cernq, V., 190, 222 Cesarotti, E., 188 Chabre, M., 155, 156 Chahal, S., 29 Chakrabarti, P., 131, 132 Chakraborti, P. C., 109 Chakraborty, M., 129 Chalmers, A. A,, 115, 176 Chalmers, W. T., 99 Chambers, D., 188 Chan, D. M., 109 Chan, Y.-M., 56 Chang, C. J., 98 Chang, F. C., 188 Chao, W.-R., 145 Chapman, D. J., 157 Chapman, K. T., 189 Charles, G., 198 Chatterjee, S., 51 Chattopadhyaya, J. B., 190 Chaudhari, P. N., 11 Chawla, H. P. S., 114 Chayabunjonglerd, S., 22 Chen, C.-M., 40, 100 Chen, G. C., 152 Chen, P.-C., 73 Chen, S., 189 Chen, S. J., 108 Chenard, B. L., 161 Cheng, K.-P., 214 Cheng, Y.-S., 189 Cheung, H. T. A., 201 Chiang, M. T., 69 Chiaroni, A., 7 Chien, P.-L., 144 Chifu, E., 155 Chihara, K., 153 Child, P., 183 Chiu, W.-H., 192 Chorrat, R. J., 193 Chow, F., 4 Chowdury, P. K., 59 Choy, W., 38 Christensen, S. B., 80 Christenson, P. A., 13 Christoph, G. G., 64 Christophersen, C., 80 Chu, C.-Y., 76 Chu, P.-S., 22 Chujo, R., 153 Ciarallo, G., 126 Cittanova, N., 185 Claeys, A. E., 161 Clardy, J., 17, 35, 105, 107 Clark, A. M., 54 Clive, D. L. J., 195 Clough, J. M., 138 Coates, R. M., 21 Cobbledick, R. E.,.171

Author Index Cody, V., 166 Cohen, Z . , 216 Coiro, V. M., 169, 171 Colantuoni, F., 104 Cole, J. R., 116 Cole, R. J., 98, 132 Coleman, P. C., 115, 176 Coll, J. C., 55, 87, 104 Collera, O., 101 Collins, D. J., 171, 193 Collins, M. S., 108 Collins, P. A., 31 Colonna, S., 188 Colwell, W. T., 144 Combaut, G., 26 Combier, H., 125 Condon, F. E., 31 Connolly, J. D., 118 Conrow, R. E., 9 Contento, M., 142 Corbet, B., 131 Cordano, G., 69 Cordell, G. A., 59,98, 117 Corey, E. J., 33, 109 Corrie, J. E. T., 219 Corsano, S., 148 Cory, R. M., 109 Costa, S. M. de B., 154 Couchman, L. A., 127 Counsell, R. E., 219 Covey, D. F., 175, 195 Cox, R. H., 98,132 Coxon, D. T., 125 CrabbC, P., 206 Craig, J. C., 173, 221, 226 Craven, B. M., 169 Crews, P., 25 Crombie, L., 71 Crombie, W. M. L., 71 Crosby, G. A., 203 Cross, B. E., 102 Crouch, R., 154, 156 Cruz, A., 206 Cser, F., 169 Cuatrecasas, J., 69, 100 Cuilleron, C.-Y., 193 Curini, M., 96 Curran, D. P., 48 Curry, B., 154 Curvall, M., 93 Cushley, R., 215 Cushley, R. J., 176 Cussans, N. J., 195 Cutler, G. B., jun., 186 Cutler, H., 98 Czeczuga, B., 133 Czerpak, R., 133 DaboviC, M., 171, 187 Daemen, F. J. M., 146, 151, 154,156 Dallinger, R. F., 154 Daloze, D., 99 D’Ambra, T. E., 18

23 1 Damiano, J.-C., 206 Dandekar, S., 158 D’Andrea, A., 169, 171 Daniewski, W. M., 80 Danishefsky, S., 45, 46, 49, 52, 196 Darias, J., 24 Das, G., 8 Das, J., 109 Das, P. K., 153, 155 Das, S. R., 144 Dasgupta, A., 129 Das Gupta, C., 131 Dastillung, M., 131 Dautrevaux, M., 228 Davalian, D., 143 Davis, S. E., 186 Dawidar, A.-A., 126 Dawson, M. I., 145 Dawson, P. M., 151 Dayal, B., 177, 214, 215 De Bernardi, M., 7,42 Declercq, J. P., 82 Decorzant, R., 6 DeGraw, J. I., 144 De Grip, W. J., 146, 151 de Haan, J. W., 52 Dehal, S. S., 215 Delaroff, V., 177 Delaude, C . , 126 Delbruck, M., 157 DeLeenheer, A. P., 161 Delettre, J., 170 Delfosse, C., 77 Delle Monache, F., 127, 128 Delmond, B., 96 Delprino, L., 111 DeLuca, H. F., 217 DeLuca, L. M., 151, 159 Del Vechio, A., 42 Dembinska-Migas, W., 80 de Mtllo, J. F., 127, 128 Demers, J. P., 108 Demian, B., 179 Demuynck, M., 82 de Napoli, L., 110 Dencher, N. A., 156 Denny, M., 144, 146 Denny, W. A., 227 Deno, N. C., 214 De Paira Campello, J., 98 de Pascual-Teresa, J., 69,70,92 Derguini, F., 142 Derkach, L. G., 171 De Rosa, M., 159 De Rosa, S., 159 Desage, M., 116 Desai, B. N., 193 Desai, H. K., 104 Desai, M. C., 114 Deshayes, C. M. P., 227 DeSilva, E. D., 136 Deslongchamps, P., 108 Detty, M. R., 189

Dev, S., 95, 114, 132 de Winter, M . S., 220 Diara, A,, 26, 28 Dias, J. R., 122, 187 Diaz, E., 56, 96 Dideberg, O., 126, 168 Dietsch, A., 111 DiFeo, D. R., 59 Dime, D. S., 14 Dimitriadis, E., 3 Dinur, U., 153, 154, 156 Dixon, A. J., 190 Djerassi, C., 173, 197,210,211 Dominguez, X. A., 80 Donnelly, D. J., 99 Donnelly, D. M. X., 7, 69 Donovan, S. F., 207 Dorffling, K., 152 Dorn, C. P., 217 Dorner, J. W., 98, 132 Doskotch, R. W., 56, 64 Donkas, A. G . , 154 Doutheau, A., 108 Dovinola, V., 113 Dowlatshahi, H. A., 194 Dreiding, A. S., 152 Dreifuss, P. A,, 17 Drew, M. G . B., 59 Drickamer, H. G., 155 Drozdz, B., 59 Druganov, A. G., 103 Duax, W. L., 165, 166, 167, 168, 170,222 Dubovenko, Zh. V., 39 Duc Do Khac, 92 Dumont, R., 140 Dunn, W. A., 195 Dupont, G., 180 Dupont, L., 126, 168 Dupuy, N., 177 Durand, R., 108 Durga, A. V., 221 Dutky, S. R., 214 Dutta, L., 3, 10, 73, 80, 92 Dyas, J., 185 Dzharikbaev, T. K., 149 Dzizenko, A. K., 113 Eaton, P. J., 108 Ebrey, T. G., 153, 154, 156 Eck, C. R., 31 Eder, U., 199, 207, 218 Ehlinger, E., 194 Eickeler, E., 79 Einstein, F. W. B., 171 El-Emany, N. A., 56 El-Feraly, F. S., 56 Elliott, W. H., 183 El-Sayed, M. A., 154 Elvidge, J. A,, 37 Elyakov, G. B., 113 Emanuel, N. M., 149 Emke, A., 167,203

232 Emons, G., 184 Endo, T., 136 Eng, F. P. C., 176 Engel, Ch. L., 217 Engelhardt, G . , 175 Englert, E., 176 Englert, G., 134 Enzell, C. R., 93, 104, 136 Epe, B., 119 Eppley, R. M., 17 Epstein, W. W., 73 Ernst, C., 152, 180 Ernst, J., 110 Erxleben, I., 152 Esaki, S., 100 Escamilla, E., 100, 101 Eschelbach, H., 127 Eschenmoser, W., 140, 147 Esnault, C., 218 Esposito, E., 159 Etheredge, S. J., 45 Etoh, H., 150 Eugster, C. H., 97, 134, 140, 147, 154 Evans, D. A., 10 Evans, E. H., 133 Evans, J. A., 157 Evidente, A., 105 Evrain, Ch., 185 Evstigneeva, R. P., 143, 156 Evteeva, N. M., 149 Eyring, G., 154 Fadeeva, T. M., 198 Fadlallah, M., 195 Fairchild, E. H., 56, 64 FajkoS, J., 187, 194, 206, 223 Fallis, A. G., 118 Falsone, G., 126 Farges, M., 133 Farnsworth, N. R., 59, 98, 117 Fattorusso, E., 110 Faulkner, D. J., 105, 107 Faux, A. F., 197 Fawcett, J. M., 108 Fayos, J., 24, 9 5 9 7 Fedor, L. R., 195 Fedoseeva, Z . Ya., 146 Feliciano, A., 92 Felsky, G., 187 Fenical, W., 6, 210 Ferguson, G., 167 Fernandez, X., 218 Ferreira, M. A., 29 Ferreira, Z. S., 64 Ferrino, S., 121 Fesenko, D. A., 136 Fetizon, M., 92, 93, 96, 179, 219 Fiecchi, A., 191,200,211 Fiksdahl, A., 134 Finer-Moore, J., 104 Finkel’shstein, E. I., 153, 155 Fischer, H. D., 55

Author Index Fischer, N. H., 55, 56, 59, 64 Fischer, U., 154, 156 Flatt, S. J., 189 Fleet, G. W. J., 189 Fleming, I., 196 Flippen-Anderson, J. L., 214 Floch, R., 92 Floor, J., 219, 220 Florencio, F., 92 Flores, A., 167, 222 Flynn, G. L., 186 Folger, T., 162 Fong, S. L., 151 Fonseca, S. F., 98 ForSek, J., 189 Formstechev, P., 228 Forrest, B. J., 176 Fortier, S., 170 Foulon, M., 77 Fountoulakis, M., 228 Fourneron, J. D., 104 Fourrey, J. L., 80 Fox, D. L., 133, 137 Fraga, B. M., 103 Frahm, A. W., 51 Frank, H. A., 154 Fransen, R., 154 Fraser-Reid, B., 18 Fredericks, P. M., 187, 227 Freeman, D. J., 159 Freer, A., 110 FriE, I., 179 Friedman, N., 179 Frieze, D. M., 108 Fristad, W. E., 14 Frith, R. G., 222 Fritz, U., 3 Frnaco, R., 80 Frobese, A. S., 73 Frolick, C. A., 158 Fronczek, F. R., 64 Fronza, G., 7,42 Fuchs, W., 125 Fuentes, L. M., 194 Fuhrer, H., 224 Fuhrhop, J.-H., 110 Fuji, K., 91, 101 Fujimori, T., 75, 76, 136 Fujimoto, Y., 67, 179, 210 Fujisawa, T., 4, 11 Fujita, E., 91, 101 Fujita, T., 101 Fujiwara, H., 182 Fukazawa, Y . ,80 Fukui, K., 108 Fukui, S., 227, 228 Fukunaga, A., 183 Fukuyama, Y., 95 Fung, V. A., 145 Furuhata, K., 179 Furukawa, J., 42,43 Furukawa, Wu. H., 80 Furukawa, Y., 153, 154 Furusaki, A., 24

Gabbard, R. B., 167, 222 Gadwood, R. C . , 52 Gartner, W., 146 Gagarina, A. B., 149 Galat, A,, 177 Galatina, A. I., 186 Galindo, A,, 54 Gall, R. E., 224 Gallacher, I. M., 37 Galli, G., 200, 215 Gallois, P., 194 Gambacorta, A., 159 Ganina, I. V., 218 Ganschow, I., 182 Garcia, G. L., 92 Garcia, J. F., 101 Garcia, M., 82 Garcia-Alvarez, M. C., 97, 100 Garcia-Blanco, S., 92, 93 Garcia-Granados, A., 100 Garduiio, J. T., 56 Gariboldi, P., 200, 211 Garnero, J., 147 Garrido, J. A., 100 Ciarti, N., 186 GaSiC, M. J., 187, 202 Gaskell, S. J., 182 Gaskin, P., 102, 103 Gatehouse, B. M. K., 171, 193 Gatilov, Yu. V., 39 Gatt, S., 187 Gattermann, H., 154 Gawinowicz, M. A., 156 Gawronska, K., 178 Gawronski, J., 178 Gee, S. K., 161 Geenerasen, J. A. J., 150 Gelbard, G., 188 Genard, P., 173 Germain, G., 82 Gerr, R. G., 171 Gershenzon, J., 80 Ghaffari, M. A., 198 Ghatak, U. R., 109 Gheorghe, V., 155 Ghilezan, I., 227 Ghisalberti, E. L., 12 Ghosh, A., 155 Gianello, J. C., 96 Giannetto, P., 130 Giersch, W., 6 Giglio, E., 169, 171 Gilbert, I. M., 221 Gill, S., 80 Gillbro, T., 156 Gillette, J. R., 175 Gilman, S., 67 Gilmore, C . J., 110 Giordano, 0. S., 96 Glaccurn, M., 156 Gladiali, S., 108 Glotter, E., 189 Godtfredsen, W. O., 115 Godfrey, J. O., 75

Author Index Gold, P. M., 4 Golder, W. S., 111 Goldsmith, D. J., 8, 17 Goldstein, J. L., 152 Gombatz, K., 49 Gomez, G. F., 56 Gonqalves, de Lima, O., 128 Gonzalez, A, G., 10, 24, 54, 123 Gonzalez, M. S., 70 Gonzalez-Rodriguez, J., 155 Goodman, D. S., 133 Goodman, M., 80 Goodwin, T. W., 133, 157 Gopalan, A., 64 Gopichand, Y., 3 Gorenburgova, E. I., 218 Gorina, Yu. N., 143 Goswami, A., 129 Goto, J., 184 Goto, T., 67 Gottarelli, G., 180 Gottlieb, H. E., 64, 98 Gottlieb, 0. R., 64 Govindan, S. V., 56, 59, 80 Goyal, I. C., 156 Graebe, J., 102 Graf, W., 122, 200 Graham, S. L., 76 Grande, M., 92 Grange, J., 180 Grant, D. M., 176 Greeley, D. N., 174 Green, M. J., 218 Green, M. K., 173 Greene, A. E., 44, 109 Grenz, M., 92,93 Grewali, M. B., 15 Grieco, P. A., 67, 84, 121 Griffin, J. F., 165, 170 Grimenko, G. S., 218 Grodowski, M., 146, 155 Groenendijk, G. W. T., 146, 151 Gros, E. G., 99, 181 Grover, A. K., 215 Gruber, J. M., 143 Gruenke, L. D., 173 Grumbach, K. H., 157 Grynpas, M., 130 Guerina, N. G., 169 Guindon, Y., 190 Gumulka, J., 191 Gunasekera, S. P., 98 Gupta, B. C., 29 Gupta, B. D., 156 Gupta, D., 184 Gupta, P. S., 118 Gupton, J. T., 73 Gutierrez Jerez, F., 123 Haag, A., 147 Habermehl, G., 130

233 Haddon, W. F., 112 Hadorn, M., 135 Haffer, G., 207 Hagishita, S., 177 Hagiwara, H., 78 Halket, J. M., 182 Hall, A. L., 55 Hall, L. D., 172 Hallenstvet, M., 134 Halley, B. A., 146 Halperin, G., 187 Haltiwanger, R. C., 108, 121 Hamada, Y., 126, 196 Hammerschmidt, F.-J., 12 Hammond, G. S., 155 Hamrnons, J. H., 35 Han, B. H., 116 Han, Y.-K., 21, 51 Hanafusa, M., 110 Hanafusa, Y., 153 Hanagaki, S., 113 Haneishi, T., 30 Hanessian, S., 190 Hangauer, D. G., jun., 82 Hangeveld, J. E., 82 Hanna, I., 93, 96, 179 Hansel, R., 56 Hanson, J. R., 40, 41, 99, 101, 103,174, 187, 189,202 Hanson, S. W., 122 Harada, I., 153, 154 Harada, K., 154 Harayama, T., 49 Harding, R. W., 156 Hardy, G., 169 Harita, K., 200 Harrison, C. R., 188 Hart, R. W., 221 Haruna, M., 56, 59,63 Harusawa, S., 196 Harvey, C. J. W., 180 Harvey, D. J., 183 Harwood, L. M., 12 Hasegawa, H., 52 Hasegawa, M., 184 Hasegawa, S., 118 Hasenhuettl, G., 75 Hashiba, N., 24 Hashimoto, H., 47 Haslinger, E., 126 Hata, G., 136 Hata, T., 136 Hata, Y., 199 Hatta, Y., 183 Haupt, O., 183, 184 Hauser, A., 6 Havinga, E., 210 Hayakawa, S., 227 Hayashi, K., 210 Hayashi, S., 87, 88, 89 Hayashi, Y., 98, 109 Hayward, R. C., 96 Hazel, J., 166 Heathcock, C. H., 143

Hedden, P., 102 Heftmann, E., 103, 112, 183, 184 Helmes, C. T., 145 Hembree, J. A., 98 Henry, R., 219 Herald, C. L., 120 Herkstroeter, W. G., 155 Hermann, E. C., 178 Hernandez, J. D., 26 Hernandez, M. G., 103 Hertz, R., 162 Herz, W., 37, 55,56, 59, 64,80 Hess, B., 155 Higlet, R. J., 175 Higuchi, W. I., 186 Hikino, H., 103 Himmelsbach, R. J., 108 Hirama, M., 49 Hirata, T., 112 Hiratsuka, N., 71 Hirose, T., 73 Hiroshima, O., 161 Hirota, M., 105 Hishida, S., 102 Hishizawa, M., 109 Hitchman, S. P., 59 Hobbs, P. D., 145 Hodge, P., 188 Hodgson, G. L., 31 Hoffmann, J. J., 116 Hoffrnann, K., 228 Hoffmann, W., 142 Hofmann, A. F., 186 Holland, H. L., 175 Hollenbeak, K. H., 10 Holub, M., 59 Honda, K., 99 Honda, T., 126 Hong, C. I., 228 Hong, F. T., 156 Honig, B., 153, 154, 156 Hopf, H., 146 Hopkins, D. L., 151 Hopla, R. E., 111 Hoppen, H.-O., 183,184 Hopprnann, A., 11 Hori, H., 73 Horiai, H., 105 Horiuchi, C. A., 193 Horiuchi, K., 156 Horn, D. H. S., 197 Hosaka, K., 105 Hoskins, L. C., 154 Hosoya, N., 151 Hospital, M., 170 Hostettmann-Kaldas, M., 127 Houston, D., 35 Howlett, B. J., 162 Hoyano, Y., 76 Hoye, T. R., 6,148 Hoyer, G.-A., 178, 227 HSU,W.-J., 158 Hu, S.-R., 186

234 Huang, C.-T., 64 Huang, J.-T., 56 Hubbard, L. M., 156 Hubbs, J. C., Huber, W., 184 Hubick, K. T., 151 Hudec, J., 186 Hudlicky, T., 44 Hufford, C. D., 54 Hug, G. L., 153 Hull, W. E., 146, 174, 189 Huls, R., 126 Huneck, S., 129, 132 Hunter, I. R., 183, 184 Huong, H. Th., 226 Hurtado, H. H., 7 1 Hutson, K. G., 162 Hylands, P. J., 128 Hyono, T., 109 Ibrahim, N., 198 Iccho, K., 112 Ichimura, T., 56 Ido, M., 117 Iguchi, M., 52, 150 Igushi, K., 105 Iida, H., 40 Iida, T., 173 Iijima, M., 227 Iio, H., 6 7 Iitaka, Y., 42, 69,73, 103, 104, 123,168 Ikawa, M., 151 Ikeda, S., 153, 154 Ikeda, T., 6, 136, 201 Ikegami, S., 47 Ikekawa, N., 179,210,217 Ikenoya, S., 161, 162 Imai, S., 108 Imamura, P. M., 94 h a , K., 150 Inaba, T., 184 Inanaga, K., 139 Inayama, S., 7 3 Inokuchi, T., 78, 148 Inoue, S., 160 Inoue, Y., 153 Iqbal, Z., 154 Ireland, R. E., 109 Irie, H., 71 Iriye, R., 201 Iseki, K., 47 Ishibashi, M., 183 Ishiga, M., 194 Ishikawa, K., 153 Ishizuka, M., 47 Islamuddin, 187, 202 Isler, O., 133 Isobe, M., 6 7 Istomina, Z. I., 207 Itai, A., 42, 123, 168 Ito, K., 56, 59,63, 130 Ito, M., 26, 143, 151, 156

Author Index Ito, N., 101 rt6, S., 23, 24, 80, 93 Ito, T., 47 Itoh, K., 102 Itoh, S., 204 Itoh, T., 119 Itoh, Y., 30 Itoigawa, M., 80 Itokawa, H., 69 Iwamuro, H., 149 Iwasa, N., 190, 208 Iwasa, T., 156 Iwashita, T., 12 Izac, R. R., 15 Jackson, W. P., 96 Jackson, W. R., 171, 193 Jacoli, G. G., 99 Jacyuemin, H., 69 Jacquesy, R., 201 Jahnchen, E., 162 Jagodzinski, J. J., 113 Jain, T. C., 54 Jakupovic, J., 49, 50, 79, 80, 9 3 , 9 4 , 101 James, T. L., 173 Jani, U. K., 158 Janini, G. M., 183 Jarvis, B. B., 17 Jayaram, M., 157 Jayle, M. F., 185 Jefferies, P. R., 12 Jeger, O., 150 Jenkins, E. E. U., 73 Jericevic, Z., 155 Jeong, T. M., 115 Jimenez, M., 96 Jiricny, J., 195 Jogia, M. K., 108 Johansen, E., 139 Johansen, J. E., 134, 141 John, T. K., 17 Jolad, S. D., 116 Jones, E. R. H., 187, 227 Jones, H., 216, 217 Jordan, 183 Joseph-Nathan, P., 26 Joshi, B: S., 95 Joshi, K. C., 97 Joska, J., 187, 194, 223 Joulain, D., 147 Joyce, B. G., 185 Julia, M., 12 Jund, K., 190,215 Juneau, G. P., 59 Jung, J., 137 Jung, M. E., 1 4 , 8 4 Jungk, S., 5 9 Juranii, I., 171 Jurenitsch, J., 126 Kabengele, N. T., 97 Kabuto, C., 7 3

Kacovsky, P., 181 Kadatskii, G. M., 218 Kadota, S., 113 Kagan, H. B., 197 Kagan, V. E., 155 Kahn, M., 45 Kaiser, R., 136 Kaiya, T., 103, 104 Kakisawa, H., 12 Kakitani, T., 156 Kakos, G. A., 171, 193 Kalinovskii, A. I., 113 Kalsi, P. S., 29 Kalvoda, J., 224 Kamaev, F. G., 94 Kamernitskii, A. V., 171, 1 199,207 Kametani, T., 11, 147 Kamiya, S., 100 Kanaiwa, Y., 204 Kanaoka, M., 113 Kane, J. P., 152 Kaneko, C., 214 Kaneko, H., 75, 136 Kang, S. S., 125 Kanojia, R. M., 219 Kanuma, N., 217 Kapadia, Z., 125 Kapnang, H., 198 Kapundu, M., 126 Karanovic, L., 171 Karnaukhova, E. N., 156 Karpf, M., 52,210 Karpuj, L., 186 Kartarahardia, M., 56 Kasai, R., 123 Kasaikina, 0. T., 155 Kasal, A,, 181 Kashman, Y., 105, 136 Kataoka, H., 8 8 Katayama, H., 108 Katayarna, K., 162 Katayarna, M., 79 Katayama, T., 133, 134 Kates, M., 157, 158 Kating, H., 51 Kato, H., 184 Kato, K., 75, 76 Kato, M., 67 Kato, N., 4 Kato, T., 136 Katsui, G., 151 Katsui, N., 77 Katsuyama, M., 134 Katti, S. B., 9 4 Kawabe, K., 151, 161 Kawai, T., 67 Kawamata, T., 7 3 Kawamura, S., 156 Kawara, T., 4, 11 Kawasaki, T., 105 Kawazu, K., 8 0 Kazlauskas, R., 107 Keinan, E., 225

Author Index Kende, A. S., 8 Kerb, U., 227 Kerek, F., 179 Kezar, H. S., tert., 8 Khalid, M. W., 210 Khan, E. A., 191 Khan, M. A., 167 Khan, S. A., 121 Khan, V. A., 39 Khastgir, H. N., 120, 129 Kido, F., 75 Kido, M., 95 Kieczykowski, G. R., 67 Kielczewski, M., 177 Kienzle, F., 133 Kieslich, K., 227 Kihira, K., 214 Kikuchi, H., 105 Kikuchi, T., 113 Killiniger, J. M., 219 Kiltsa, M. N., 93 Kim, J. H., 116 Kimura, M., 193, 200 King, A. O., 148 King, R. M., 10, 50, 55, 56, 59, 69, 73, 77, 80, 92, 93, 94, 100,101 King, T. J., 29, 127 Kingston, D. G. I., 184 Kinnear, J. F., 197 Kinoshita, M., 43, 47 Kirk, D. N., 176, 177,179,197 Kirkwood, P. S., 102, 103 Kirtaniya, C. L., 99 Kishimoto, H., 186 Kitahara, T., 148 Kitajima, H., 153 Kitano, Y., 136 Klasinc, L., 155 Kleijn, H., 188 Kleinig, H., 134 Kliger, D. S., 155 Klima, W. L., 148 Klimash, J. W., 64 Klinot, J., 123 Klinotova, E., 129 Kloc, K., 161 Klose, W., 222 Klusmann, W., 154 Klyne, W., 177, 179 Knapp, S., 48 Knauf, W., 73, 93 Knight, J. C., 204 Knights, S. G., 202 Knoche, H. W., 111 Knoll, H. E., 162 Knoll, K.-H., 10,59,73,80,92, 100 Knotts, J. G . , 184 Knudsen, C. G., 143 Knuppen, R., 183,184 Kobayashi, M., 104, 143 Kobayashi, S., 148 Kobayashi, T., 156

235 Kobayashi, Y., 185, 217 Kobzareva, V. P., 169 Kocienski, P. J., 190, 216 Kofovsky, P., 190, 199, 222 Kodama, A., 143, 156 Kodama, M., 23, 2 4 , 8 0 , 9 3 Kodama, T., 78 Kogan, G., 153 Kohl, K. D., 156 Kohout, L., 190, 206, 223 Koike, Y., 73 Koizumi, N., 217 Kojima, Y., 4 Kok, P., 82 Kokke, W. C. M. C., 210 Kolek, T., 192 Koller, K., 108 Koltsa, M. N., 9 3 Komura, H., 95 Kondo, H., 136 Kondo, Y., 7 3 Koning, H. N., 52 Konishi, F., 100 Konopelski, J. P., 197 Koput, J., 177 Koreeda, M., 9 8 , 2 1 0 Koshimizu, F., 105 Kosugi, H., 41 Kotowycz, G., 173 Kotsuki, H., 117 Kovac, B., 155 Kowata, N., 25 Koyama, T., 5 Koyama, Y., 47, 154 Kozlov, E. I., 153, 155 Krasnovkii, A. A., 155 Kraus, G. A., 122 Krausz, F., 194 Kreft, A. F., 108 Krief, A., 188 Krieger, M., 152 Krinsky-Feibush, P., 189 Krishna, E. M., 118 Krishnan, S., 55 Krishna Rao, G. S., 89 Krstanovic, I., 171 Kruger, G. J., 94, 219 Kubelka, W., 126 Kubo, I., 88, 95 Kubo, K., 179 Kubo, S., 75, 76 Kubota, N., 87 Kuhlmann, K., 145 Kuksis, A,, 183 Kulikova, L. E., 171 Kulishov, V. I., 171 Kumae, T., 139 Kumar, N., 56,64, 80 Kumazawa, T., 7 8 KUO, Y.-H., 97 Kurihara, H., 6 7 Kurihara, T., 23, 24 Kuriyama, K., 88, 177 Kurobe, H., 147

Kuroda, Y., 153 Kurosawa, E., 15, 24, 25 Kurth, M. J., 6, 148 Kusano, G., 73 Kushi, Y., 88 Kushwaha, S. C . , 157, 158 Kuss, E., 184 Kustova, S. D., 93 Kusumi, T., 12 Kutchan, T. M., 44 Kutney, J. P., 99 Kutschabsky, L., 103 Kuwano, H., 91 Kuzmin, V. A., 155 Kwan, K. H., 186 Kwong, C. D., 17 Labbe, C . , 118 Labeeuw, B., 194 Lablache-Cornbier, A., 77 Lachenmeier, A., 135 Lacombe, S., 197 Laederach, M., 140 Lahav, M., 169 Lai, H. K., 196 Lai, J., 130 Lallemand, J. Y., 80 Lamb, L. C., 158 Lamotte, J., 168 Lamparsky, D., 136 Lanciano, F., 190 Lane, M. A., 93 Langs, D., 168 Lankin, D. C., 59 Lankwerden, B. J., 193 Lansbury, P. T., 82 Lanzetta, R., 94, 114 Laonigro, G., 94, 114 Lapalme, R., 1 0 8 Lara, R., 56 Larios, G . , 101 Larson, G. L., 194 Larsson, P. O., 228 Lauher, J. W., 108 Laurent, A., 197 Lavie, D., 98 Le-Ben-Un, 155 Lechleiter, J. C . , 64 Lee, G. E., 18 Lee, K.-H., 59, 8 0 Lee, S. P., 106, 107 Lee, T. Y., 137 Lefevre, M. F., 161 Legrand, M., 177 Lehmann, H., 149 Leiserowitz, L., 169 Lematre, J., 152, 180 Lenton, J. R., 102 Lenz, G. R., 209 Leong, S. H., 94 Leonidov, N. B., 169 Leont’ev, V. B., 94 Lepicard, G., 170 LeQuesne, P. W., 221

Author Index

236 Lester, D. J., 196, 197 Letendre, L. J., 72 Letourneux, Y., 92 Leturc, D. M., 108 Leuenberger, F. J., 134 Leutwiler, L. S., 157 LeVan, N., 92 Levendis, D., 179 Levina, I. S., 171 Levisalles, J., 176, 195 Lewis, A., 154 Lewis, N. J., 100 Ley, S. V., 96, 195, 197 Li, R., 208 Liaaen-Jensen, S., 133, 134, 137, 139, 141 Liao, C.-C., 108 Lichtenthaler, H. K., 159 Liemann, F., 152 Lightner, D. A., 176 Liljefors, T., 178 Lin, J.-T., 103, 184 Lin, N.-H., 97 Lin, Y.-T., 97 Lin, Y. Y., 181 Linde, H., 127 Lindley, P. F., 130 Lindsay, B. G., 188 Lins, A. P., 37 Lipisko, B., 196 Lisboa, B. P., 182 Lischewski, M., 103 Litisa, L., 218 Little, R. D., 48 Litvinova, G. E., 215 Liu, H.-J., 196 Liu, R. S . H., 144, 146, 153, 155, 156 Liu, W.-L., 189 Li Yun-nan, F., 99 Lodge, B. A,, 167 Logan, R. T., 221 Long, R. A., 154 Longevialle, P., 181 Longo, R., 8 0 Lonitz, M., 7 3 Loozen, H. J. J., 220 Lopes, J. L. C., 59 Lopez de Lerma, J., 93 Lopez-Gomez, M. A., 99 Lorenc, L., 171, 187, 224 Loriaux, D. L., 186 Lozier, R. H., 156 Luche, J.-L., 206 Luche, M.-J., 206 Lugtenburg, J., 154 Lundin, R. E., 112 Luque Escalona, M., 123 Lusby, W., 214 Lustenberger, P., 228 Lutsky, B. N., 218 Lutz, M., 154 Luz, Z., 185 Lythgoe, B., 138, 216

Mabry, T. J., 59, 80, 99, 101 Macaira, L. A, , 82 Macaulay, E. W., 167 McCaskill, R. H., 40 McChesney, J. D., 151 McCloskey, M. A., 160 McCombie, S. W., 18 McConell, 0. J., 89 McCormick, D. B., 133 Macdonald, I. A., 183 McGhie, J . F., 189 McGuire, J. L., 219 Machado, F. W. L., 82 Mack, D. O., 161 MacKay, C., 184 MacKenzie, B. D., 72 MacLachlan, F. N., 108 McLaughlin, J. L., 98 MacMillan, J., 100, 102, 103 McMorris, T. C., 210 McMurry, J . E., 37, 38, 207 MacNicol, D. D., 110 McRowe, A. W., 35 MacSweeney, D. F., 31 McVie, J., 155 Mantele, W., 154 Maffrand, J.-P., 108 Magno, S . , 110 Magnus, P., 64, 194 Mahato, S. B., 105 Maione, A. M., 201 Maiti, S. N., 128 Majumder, P. L., 129 Maksimovic, Z., 171 Malakov, P. Y., 80 Maldonado, L. A., 14 Malhotra, R. K., 225 Malik, A., 114, 117 Malinovskaya, G . V., 115 Mallik, B., 155 Malmberg, A. G., 76 Maloii, P., 179 Malunowicz, I., 192 Manchand, P. S., 94 Mandava, N., 214 Mangoni, L., 94, 113, 114 Mann, J., 59 Manning, M. J., 161 Mannhg, W. B., 183 Mansell, R. L., 118 Mansilla, H., 54 Manwaring, J., 133 Manzoor-i-Khuda, M., 130 Mao, B., 154,156 Mao, D. T., 44 Mappus, E., 193 Marazza, F., 108 Marculetiu, V., 155 Marcus, M. A., 154 Margulies, L., 179 Marini-Bettblo, G. B., 127, 128 Marki, H. P., 140 Marples, B. A., 215 Marquez, C., 9 5 , 9 9

Marrs, B. L., 157 Marshall, J . A., 9 Martin, J., 176 Martin, J. D., 10, 24 Martin, M. D., 197 Martin, T., 41 Martin, V. S., 24 Martin, W. G., 154 Martinez, R., 56, 92 Martinez-Ripoll, M., 24, 95, 97 Martino, R., 108 Marumo, S., 79 Maruta, P., 75 Maruyama, K., 161 Masahara, R., 15 1 Masarnune, T., 26,77, 190,208 Mash, E. A., 5 Mason, R. W., 21 Massey, I. J., 210 Massig, G., 154 Massy-Westropp, R. A., 3 Mateescu, G. D., 153 Mathies, R., 154 Matsubara, Y., 149 Matsuchita, Y., 89 Matsudo, R., 56 Matsui, H., 102 Matsui, M., 148 Matsuki, Y., 9 3 Matsumoto, H., 144, 153, 156 Matsumoto, T., 39,47,98, 108, 109,115, 173 Matsunaga, I., 214 Matsunami, S., 147, 160 Matsuno, T., 134 Matsuo, A., 87, 88, 89 Matsushita, K., 122, 126 Matsutaka, H., 134 Matsuura, T., 161 Mattia, C. A., 169 Maudinas, B., 152 Maurer, B., 6 Mavlyankulova, Z. I., 94 Maxwell, J. R., 131, 183 Mayer, H., 133, 134 Mayer, L. M. U., 96 Mayol, L., 110 Mazur, Y., 179,201,216 Mazzarella, L., 169 Mazzola, E. P., 17 Meakins, G. D., 187, 227 Medarde, M., 6 9 Mednikova, N. A., 155 Meegan, M. J., 69 Meerholz, C. A., 195 Meganathan, R., 162 Mehta, Y. K., 29 Meinwald, J., 104, 105 Meister, W., 134 Mellerio, G., 7, 42 Menard, R. H., 175 Menchen, S. M., 195 Merrien, M. A., 6 9 Metcalf, B. W., 190, 215

237

Author Index Metzner, P. J., 193 Meyer, M. D., 214 Meyer, V. R., 15 1 Michaud, D. P., 10 Michel, G., 125 Micovic, I. V., 197 Midgley, J. M., 167, 203 Midiwo, J. O., 17 MihailoviC, M. Lj., 171, 187, 224 Mihashi, S., 69 Miklhs, J., 179 Milborrow, B. V., 157 Mills, R. W., 31 Mimura, T., 4 Mincione, E., 190 Miners, J. O., 227 Mironowicz, A., 192 Miropol’skaya, M. A., 149 Misra, R., 95 Misra, T. N., 155 Mitchell, S. J., 55, 87, 104 Mitra, A. K., 99 Mitra, S. R., 99 Mitsner, B. I., 143, 144, 156 Mitsuhashi, H., 104 Miura, H., 67 Miura, I., 104 Miura, T., 200 Miyahara, K., 105 Miyai, K., 185 Miyakoshi, T., 148 Miyama, R., 92 Miyase, T., 97 Miyashita, M., 78, 79 Miyata, I., 186 Miyatani, S., 156 Miyazaki, H., 183 Mizuno, Y., 71 Mizutani, J., 52 Mladenovic, S., 218 Mlochowski, J., 161 Mobilio, D., 48 M o d , V. V., 158 Mody, N. V., 104,175 Moir, M., 37 Mojasevic, M. M., 197 Molnhr, P., 135, 141 Monahan, M., 218 Mondon, A., 119 Money, T., 31 Monger, D. J., 171 Montal, M., 155 Moore, R. H., 208 Mor, U., 112 Moreau, C., 108 Moreau, S., 77 Moreno, E. D., 96 Morera, E., 206 Moretti, C., 120 Moriarty, R. M., 201 Morisaki, M., 217 Morisaki, N., 42 Moriyama, Y., 6, 123, 136

Nath, A., 129 Nayak, U. R., 35, 36 Nazarians, L., 56 Nechaev, A., 228 Nedelec, L., 177 Neef, G., 199, 207, 218 Negishi, E., 148 Nelson, B., 156 Nelson, E. C., 146 Nelson, J. V., 10 Nemorin, J. L. E., 87 Nemoto, H., 11, 147 Nero-Desbiens, M., 108 Newton, D. L., 145 Newton, R. F., 190 Ng, A. S., 118 Ngo Thi Mai Anh, 199 Nicholls, R. G., 189 Nickisch, K., 213 Nicolaus, B., 159 Nicotra, F., 174 Niederberger, W., 156 Ninet, L., 133 Ninomiya, K., 40 Nishida, T., 93, 104, 136 Nishikawa, N., 109 Nishimura, H., 52 Nishimura, S., 192 Nishimura, Y., 47 Nishizawa, A., 11 Nishizawa, M., 5 Nisson, K., 99 Nace, H. R., 203 Niswender, G. D., 184 Nachber, R. B., 41 Niwa, M., 52 Nagano, E., 149 Noack, K., 134, 152 Nagao, Y., 91 Noble, P., 55 Nagata, K., 204 Noda, A., 4 Nagata, S., 134 Node, M., 91 Naguib, Y.M. A., 109 Nomine, G., 227 Naito, T., 9 NordCn, B., 178 Najmus-Saqib, Q., 125 Nordfors, K., 9 3 Nakagawa, S., 102 Norin, T., 52, 92 Nakagawa, T., 104 Norte, M., 24 Nakajima, S., 8 0 Novak, I., 155 Nakai, H., 117 Novikov, V. L., 115 Nakai, T., 4 Novikova, N. S., 186 Nakamura, N., 122 Nakanishi, K., 88,95,127, 142, . Nowack, J., 175 Nowakowska, M., 155 144,151,156 Noyori, R., 5 Nakano, H., 52 Nozaki, H., 88 Nakashima, T. T., 107, 173 Nozoe, S., 42, 43, 7 3 Nakata, H., 103 Niirrenbach, A,, 142 Nakata, T., 9 Numazawa, M., 170 Nakatani, H., 227 Nurmatova, M. P., 94 Nakayama, K., 168 Nyfeler, R., 41 Nakayama, M., 87, 88,89 Nyitrai, K., 169 Nambara, T., 184 Nambudiri, A. M. D., 162 Oberti, J. C., 99 Narayana, S. V. L., 7 3 Obinata, T., 4 Narayana Rao, M., 128 O’Brien, D. F., 153 Narbonne, C., 201 O’Brien, D. H., 29 Naruta, Y., 161 Ochi, K., 214 Narva, D., 154 Ochi, M., 117 Nasipuri, D., 8 O’Connor, U., 48 Nassim, B., 122, 181 Mornon, J. P., 170 Morosetti, S., 171 Mosbach, E. H., 214 Mosbach, K., 228 Motherwell, W. B., 194, 196 Motika, G., 186 Motoc, C., 186 Motto, M. G., 145, 156 Muccino, R. R., 144 Miiller, P., 155 Miiller, R. K., 133, 134, 151 Mukhamedkhanova, S. I., 94 Mukherjee, D., 217 Mulholland, D. A., 118 Muller, G. W., 48 Mundy, A. P., 156 Murae, T., 6, 56, 136 Murai, A., 77, 190, 208 Murakami, K., 179, 210 Murakami, T., 40, 100 Murari, R., 37 Murata, M., 143 Muriel, L., 92 Murillo, F. J., 158 Murofushi, N., 102 Murphy, P. T., 107 Muschik, G. M., 182, 183 Muscio, 0. J., 5 Musial, B. C., 183 Muto, T., 193

238 Oelbermann, U., 119 Oelkers, W., 134 Oesterhelt, D., 146, 154, 155, 156 Ogawa, H., 148 Ogihara, Y., 127 Ogiso, A., 91 Ognyanov, I. V., 52 Ogura, H., 179, 191 Ogura, M., 117 Ogura, K. S., 159 Oguri, T., 67 Ohigashi, H., 105 Ohira, S.. 89 Ohloff, G., 6, 7, 148 Ohlson, S., 228 Ohmae, M., 151, 161 Ohmichi, H., 148 Ohno, H., 156 Ohno, M., 148 Ohno, N., 59, 80, 99, 101 Ohta, T., 103 Oh’uchi, R., 204 Oishi, T., 9 Okamura, W. H., 143 Okawara, H., 148 Okazaki, K., 149 Okorie, D. A., 7 Okukado, N., 139 Oliva, G., 226 Olivier, E. J., 55, 59 Oliviera, F., 64 Ollis, W. D., 115 Olson, R. E., 160 Omarkulov, T. O., 149 Omata, T., 227, 228 Ondo, K., 108 Ong, C. W., 18 Onishi, A., 160 Ono, M., 160 On’okoko, P., 98 Ontiveros, E., 59 Oppolzer, W., 6, 29, 82 Orahorats, A. S., 52 Orere, D. M., 195 O’Reilly, J., 7 Oriente, G., 105 Oritani, T., 149 Ornaf, R. M., 48 Ortar, G., 206 Ortega, A., 56, 92 Osaki, K., 101 Osawa, E., 39 Osawa, Y., 167, 168, 170 Oshida, J.-I., 217 Oskoui, M. T., 128 Otsuka, S.,110 Otsuki, T., 161 Ottolenghi, M., 156 Ourisson, G., 35, 131, 214 Paaren, H. E., 201 Painter, G. R., 17 Painuly, P., 94

Author Index Pak, C. S., 210 Paknikar, S. K., 55 Pal, B. C., 105 Palings, I., 154 Palleschi, A., 171 Palmer, B. D., 94 Palmieri, P., 180 Pan, Y . - G . ,84 Pandey, R. C., 95 Panizo, F. M., 100 Pant, P., 30 Panunzio, M., 142 Papano, G. Y., 80 Papillaud, B., 96 Paquette, L. A., 14, 21, 51 Parish, E. J., 171 Parizkova, H., 151 Parkhurst, R. M., 125 Parra, A., 100 Parra Sanchez, A., 100 Parrilli, M., 94, 113 Parson, W., 155 Parsons, W. H., 49 Partridge, J. J., 174 Parvez, M., 167 Pascard, C., 120 Patel, N. J., 157 Paternostro, M. P., 95, 97 Paton, W. F., 132 Patra, A., 99 Patri, R., 97 Pattabhi, V., 169 Pattenden, G., 29, 138 Patterson, I., 146 Patterson, W., 148 Paul, D., 225, 226 Paul, I. C., 132 Paul, V. J., 6 Pavlov, V. A,, 198 PavloviC, V., 224 Pearce, H. L., 33 Pearson, A. J., 18 Peczynska-Czoch, W., 228 Pelerin, G., 86, 87 Pelletier, S. W., 104, 175 Pellicciari, R., 148 Pena, A., 100 Pena Carrillo, A., 100 Pennanen, S., 78 Pennock, J. F., 162 Pentegora, V. A., 39 Peppard, T. L., 37 Perales, A., 24, 97 Perera, S. K., 195 PCrez, C., 10, 24 Perezamador, M. C., 101 Peri, I., 112 Perkins, M. J., 127 Perlman, D., 227 Perry, D. L., 59 Peters, J. A. M., 192 Peters, R., 154 Petraud, M., 96 Petropavlov, N. N., 170

Pettit, G. R., 120 Pfander, H., 135, 140, 151 Pfenninger, J., 122 Pham, T. V. C., 49 Phillipou, G., 193, 222 Phillipps, G. H., 167 Phinney, B. O., 102 Piatak, D. M., 202 Piattelli, M., 105 Piers, E., 28 Pilotti, A. M., 104 Pimenov, M. G., 136 Pinder, A. R., 78 Pinhas, A. R., 186 Pinhey, J. T., 189 Pinto, A. C., 96 Piovetti, L., 26, 28 Piozzi, F., 95, 97, 99 Pirrung, M. C., 51 Pohl, L. R., 175 Pokhilo, N. O., 119 Poling, S. M., 158 Polishchuk, A. P., 171 Pollmann, P., 186 Polonsky, J., 7, 69, 120 Pomilio, A. B., 99 Pomponi, M., 127, 128 Pontanier, H., 125 Popa, D. P., 133 Popovic, K. M., 197 Popovitz-Biro, R., 169 Poppleton, B. J., 96 Postel, G. D., 184 Poulter, C. D., 5 Powell, L. A., 146 Powell, L. E., 102 Prakongpan, S., 186 Pramanik, B. N., 182 Prange, T., 120 Prebble, J. N., 157 Precigoux, G., 170 Prenzel, U., 159 Preston, A. F., 94 Prestwich, G. D., 104,105, 108 Prisbylla, M., 196 Prkhlik, Ya., 149 Prokopiou, P. A., 189 Protiva, J., 129 Pugacheva, S. V., 146 Puliti, R., 169 Purdy, R. H., 221 Quallich, G. J., 84 Quesada, M. L., 49, 67 Quijano, L., 56, 59, 158 Quiocho, F. A., 171 Rabanal, R. M., 69 Rabaud, R. M., 99 Rabi, J. A., 82 Rabinovitch, B., 152 Rabinsohn, Y., 189 Rach, K. L., 151 Radcliffe, C. D., 14

Author Index Radernacher, W., 102 Radley, M., 102 Raduchel, B., 188 Rafferty, C. N., 155, 156 Raines, D., 202 Raithby, P. R., 18 Rajkowski, K. M., 185 Raldugin, V. A., 103 Ramachandra Row, L., 127 Ramamurthy, V., 153 Ramirez, M. A., 10 Rana, S. S., 160 Randazzo, G., 105 Ranganathan, S., 162 Ranzi, B. M., 174 Rao, A . S. C. P., 143, 194 Rao, C. B., 96 Rao, M. M., 118 Rao, P. N., 170 Rasmussen, G. H., 216 Rasmussen, M. H., 109 Rasmussen, P. R., 115 Rasmussen, U., 8 0 Rastall, M. H., 109 Rastogi, R. P., 30 Rastrup-Andersen, N., 115 Rathner, M., 186 Rau, W., 156 Ravelo, F., 10 Raverty, W. D., 192 Ray, T. K., 129 Raynaud, J., 116 Raynaud, J. P., 197 Raynolds, P. W., 161 Re, A., 188 Read, G. F., 185 Reck, G., 103 Redpath, J., 22 1 Reese, C. B., 190, 195 Reich, H. J., 4 Reid, D. M., 151 Reijnders, P. J. M., 52 Reinhard, E., 227 Reisch, J., 126 Reischl, W., 174, 192, 200 Reist, E. J., 125 Remanick, A., 35 Remberg, G., 119 Renaut, J., 133 Renneboog, R. M., 109 R e n s t r ~ m B., , 134 Retey, J., 228 Reu, G., 184 Reynolds-Warnhoff, P., 38 Rezvukhin, A. I., 96 Riad-Fahmy, D., 185 Ribaldi, M., 96 Rideout, J. A., 120 Riehm, J. O., 185 Riesselmann, B., 228 Rihs, G., 224 Rihter, B., 218 Rilling, H. C., 5 Rinnert, H., 180

239 Rios C., T., 56 Rios, T., 158 Rist, G., 224 Rivett, D. E. A., 94 Roane, C., 80 Robbins, W. E., 214 Roberts, A. B., 158 Roberts, D. A., 216 Roberts, J. S., 39 Roberts, M. R., 84 Robertson, J. M., 167 Robertson, S., 158 Robinson, C. H., 175, 195 Robinson, H., 10, 50, 55, 56, 59,69,73, 7 7 , 8 0 , 9 2 , 9 3 , 9 4 , 96,100, 101 Rodewald, W. J., 113 Rodgers, M. A. J., 153, 154 Rodriguez, B., 93, 95, 97, 100, 101 Rodriguez, J. G., 9 3 Rohrer, D. C., 165, 166, 167, 170,222 Roller, P. P., 158 Roman, L. U., 26 Romanchenko, T. V., 103 Romeo, G., 130 Romero, O., 154 Romo de Vivar, A., 59 Romussi, G., 126 Ronald, B. P., 15 Ronald, R. C., 15 Ronaldson, K. J., 132 Ronchetti, F., 174 R ~ n n e b e r g H., , 134, 137 Ronrosa, J., 101 Roque, N. F., 64 Rosen, P., 226 Rosenberg, E., 8 0 , 9 2 Rosenfeld, M. H., 193 Ross, R. A., 191 Rotem, M., 136 Rouessac, F., 149 Roush, W. R., 1 8 , 3 2 Roy, R. G., 221 Rudler Chauvin, M., 176 Rudney, H., 162 Rueedi, P., 97 Ruppel, H., 155 Ruest, L., 108 Ruttimann, A., 133 Rupar, C. A., 159 Rusina, I. F., 149 Russo, G., 174 Rustaiyan, A., 56 Rutledge, P. S., 188 Ruveda, E. A., 94 Rybakov, V. B., 170, 171 Sada, E., 227 Saha, S. B., 120 Saiki, Y., 40, 100 Saint-Laurent, L., 108 Saintonge, R., 108

St. Pyrek, J., 123 Saito, A., 5 Saito, H., 113, 174 Saito, I., 161 Saito, S., 148, 154 Sakakibara, J., 103, 104 Sakakibara, Y., 56, 59, 6 3 Sakan, T., 109 Sakita, T., 6, 136 Sakuda, Y., 8 0 Saleh, A. A., 59 Salen, G., 168, 174, 177, 214, 215 Salisbury, P. J., 99 Samek, Z., 59 Sammes, P. G., 69 Samokhvalov, G. I., 149, 215 Samori, B., 180 $amulski, E. T., 185 Sanda, V., 223 Sanders, J. K. M., 172 Sanders, M. E., 192 Sandri, S., 142 San Feliciano, A., 69 Sangaiah, R., 89 Sankawa, U., 43 Sari Martin, A,, 101 Santurbano, B., 80 Sarah, F. Y., 101, 103 Sarig, S., 186 Sasak, W., 159 Sasaki, H., 136 Sasaki, J., 23 Sasakura, M., 201 Sasamori, H., 190 Satake, T., 40, 100 Sato, A., 91, 227 Sato, K., 160 Sato, M. W., 210 Sato, N., 208 Sato, S., 89 Sato, T., 4, 1 1 , 7 8 Sato, Y., 112, 113, 174 Satoh, J. Y., 193 Satoh, T., 7 8 Sattar, A., 39 Sauer, G., 207 Sauer, K., 154 Savage, D. S., 221 Savard, S., 108 Savin, O., 186 Savona, G., 9 3 , 9 5 , 9 7 , 99 Sawan, S. P., 173 Sawzik, P., 169 Scala, A., 191, 211 Scherer, G., 186 Scheuer, P. J., 19, 89, 136 Schiebinger, R. J., 186 Schiehser, G. A., 89 Schlessinger, R. H., 49, 67, 84 Schimz, A., 156 Schmidt, E. N., 96 Schmidt, G. J., 184 Schmidt, J., 129, 132

Author Index

240 Schmitt, P., 112 Schmitz, F. J., 3, 10 Schmitz, R., 51 Schneider, C., 126 Schneider, D. R., 133 Schneider, F. W., 154 Schoenecker, B., 175 Schonemann, K. H., 192 Schoneshofer, M., 184 Scholefield, D., 131, 158 Schow, S. R., 210 Schramm, W., 183 Schroder, M., 190 Schropfer, G. J., 171, 174, 175 Schroer, J. A., 182 Schrott, E. L., 156 Schuda, P. F., 49 Schutzow, D., 146 Schulte, G., 89 Schulte-Elte, K. H., 6, 7, 148 Schulten, K., 156 Schultz, A. G., 75 Schurtenberger, H., 151 Schuster, A., 49 Schuster, G. B., 155 Schutte, H. R., 149, 182 Schwab, J., 184 Schwartz, A., 210 Scolnik, P. A., 157 Scott, J. W., 111 Seaborn, C. J., 193,222 Seaman, F. C., 5 6 , 5 9 Seaton, J. C., 37 Sebek, 0. K., 227 Seeger, A., 199,218,227 Seff, K.. 153,156 Segalot?, .4., 166, 167, 222 Seidel, -., 170 Seifert, R. M., 162 Seldes, A. M., 181 Selover, S. J., 25 Semmelhack, M. F., 26 Sen, M., 128 Sengupta, P., 128 Seo, A,, 52 Seppa, E. L., 42 Sepiilveda, S., 126 Seralis, A. K., 82 Serebryakov, E. P., 103, 207 Sesaki, K., 227 Seto, S., 5, 159 Setton, R., 197 Seuron, P., 186 Sevrin, M., 188 Shafiullah, 187, 191, 198, 232 Shah, S. K., 71 Shah, Y., 186 Shamsuddin, K. M., 121 Sharma, A., 156 Sharma, R. P., 59 Sharma, S. D., 160 Sharpe, F. R., 37 Sharypov, V. F., 113 Shchavlinskii, A. N., 146

Shea, C.-M., 209 Shefer, S., 168, 174, 215 Sheldrick, W. S., 38, 101 Shemaeva, L. I., 146 Sher, F. T., 108 Sherman, M. M., 117 Sherman, P. L., 184 Sheves, M., 156, 179 Shibasaki, M., 47 Shibata, S., 43 Shibata, T., 73 Shibayama, F., 105 Shichi, H., 155 Shichida, Y., 143 Shidoji, Y., 151 Shimada, K., 184 Shimizu, N., 73 Shimizu, T., 67 Shimokawa, K., 146, 153, 154 Shindo, M., 214 Shingu, T., 101 Shinhama, K., 84 Shinke, S., 89 Shiori, T., 196 Shiota, M., 192, 194 Shirahama, H., 39, 47 Shirai, N., 103, 104 Shirakawa, H., 153 Shiro, M., 117 Shirokawa, M., 154 Shishibori, T., 99, 159 Shiuey, S.-J., 174 Sholichin, M., 92, 123 Shrivastava, H. N., 73 Shriver, J. W., 153 Shropshire, W., jun., 156 Shue, H. J., 218 Sialom, B., 201 Sibirtseva, V. E., 9 3 Sica, D., 169 Siddiqui, S., 114, 117 Siebert, F., 154 Siebrand, W., 154 Siervo, F., 114 Siewinski, A., 228 Silva, A. J. R., 96 Silva, M., 6 9 Silveira, A., jun., 148 Silverman-Jones, C. S., 159 Simmonds, D. J., 71 Simmons, C. J., 153, 156 Simonov, V. I., 170, 171 Simpson, I. C., 102 Sims, D., 80 Sims, J. J., 15 Sinclair, R. S., 155 Sindelar, R. D., 99 Singh, A. K., 73 Singh, C., 114 Singh, H., 225, 226 Singh, J., 102 Singh, P., 30 Singh, P. P., 118 Sirotkina, L. I., 146

Sivorinovsky, G., 156 Sjovall, J., 183 Sklyar, Yu. E., 136 Skorkovska, H., 129 Slade, C. J., 197 Sleigh, T., 221 Sliwinska, E., 80 Smith, G. W., 131 Smith, W. j3., 174 Smith-Verdier, P., 92 Snitman, D. L., 108 Snowden, R. L., 6 Sodano, S., 159 Sokolova, N. A., 143, 144 Sokol’skii, D. V.. 149 Solheim, B. A., 105 Solladie, G., 186 Solo, A. J., 188 Solomennikova, I. V., 96 Soloway, A. H., 221 Solyom, S., 226 Soman, R., 36 Song, P.-S., 137, 155 Sonneborn, M., 186 Sonnet, P. E., 183 Sonoda, Y., 112,113,174 Sonomoto, K., 228 SooHoo, C., 144 Sopher, D. W., 149 Sotheeswaran, S., 123 Soucy, P., 108 Spagnoli, N., 96 Speck, J., 214 Sperling, W., 155, 156 Spirlet, M. R., 126 Sporn, M. B., 145,158 Springer, J. P., 98, 132 Sree, A., 127 Stack, M. E., 17 Stankovic, J., 202 Stefanovic, M., 218 Stephenson, G. R., 192 Sternhell, S., 87 Stevens, R. V., 189 Stierle, D. B., 107, 210 Stieve, H., 155 Still, W. C., 18 Stipanovic, R. D., 29 Stockburger, M., 154 Stoeckenius, W., 156 Stoessl, A., 76 Stojanac, N., 122 Stojanac, Z., 122 Stonik, V. A., 113 Stopolyanskaya, L. V., 155 Stork, G., 102 Stothers, J. B., 76 Straight, R. C., 176 Stretton, R. J., 215 Strong, P. D., 166, 167, 168, 170,222 Stroupe, S. B., 185 Struchkov, Yu. T., 171 Struwe, H., 12

24 1

Author Index Stuart, A. D., 12 Stuart, K. L., 99 Sturtz, G., 194 Sturzenegger, V., 152 Subba Rao, G. S. R., 192 Subramanyan, V., 221 Suding, H., 30, 100 Suga, T., 99, 112, 159 Suggett, A., 37 Sugimoto, M., 102 Sugimoto, Y., 6, 78, 136 Suginome, H., 26, 179, 204, 208,209 Sukh Dev, 35,36 Sukumar, S., 172 Sultanbawa, M. U. S., 123 Sum, F. W., 3,149 Sun, X.-C., 99 Sundar, N. S., 192 Sung, M.-S., 144 Sung, V. T., 103 Surcouf, E., 169, 170 Suto, M., 188 Suwita, A., 80, 92, 93 Suxdin, S., 92 Suyunbaev, U., 149 Suzuki, H., 153 Suzuki, J., 192 Suzuki, K., 147 Suzuki, M., 15, 25 Suzuki, S., 105 Suzuki, T., 24 Swenson, D. C., 170 Swenton, J. S., 161 Swift, I. E., 157 Sykes, P. J., 225 Syper, L., 161 Szabo, J. A., 186 Szabolcs, J., 133, 135, 141 Szczepek, W. J., 191 Szendrei, K., 71 Szewczuk, A., 228 Szilagyi, K., 226 Szulzewsky, K., 169, 170 Taber, D. F., 15 Taboada, J., 101 Taburet, A. M., 175 Tabushi, I., 146, 153, 154 Tada, M., 78 Taga, T., 101 Tagle, B., 35, 107 Taguchi, H., 136 Taguchi, T., 217 Tahara, T., 80 Taira, Z., 26 Tait, D., 155 Tajima, K., 75 Takada, M., 162 Takagi, M., 158,200 Takagi, Y., 76, 136, 148 Takahashi, H., 26 Takahashi, I., 159, 192 Takahashi, N., 102

.

Takahashi, S., 30 Takahashi, T., 6,24,56,78,98, 122,123,126, 136 Takahashi, Y., 208 Takai, M., 127 Takao, S., 101 Takaoka, D., 106 Takase, K., 71, 75 Takayama, H., 168,192 Takayanagi, H., 179,191 Takeda, A., 84 Takeda, M., 190 Takeda, S., 108 Takeda, Y., 101 Takemoto, T., 7,56,73,79,88, 105, 106 Takemura, T., 153 Taketsuru, H., 77 Takeuchi, T., 47 Takeuchi, Y., 156 Takeyama, N., 108 Talvitie, A., 42 Tamas, V., 155 Tamm, C., 17 Tamura, T., 115, 119, 173 Tanabe, M., 210 Tanaka, A., 227,228 Tanaka, N., 40 Tanaka, O., 92, 105, 123 Tanaka, T., 184 Tanaka, Y., 134,158,210,217 Tandon, J. S., 94 Tang, C. P., 169 Tange, K., 112 Tani, K., 110 Tanis, S. P., 156 Taran, M., 96 Tarchini, C., 210 Taschner, M. J., 122 Tasumi, M., 153, 154 Tatsuno, T., 67 Tatsuta, K., 43, 47 Taylor, B. J., 189 Taylor, D. A. H., 117, 118 Taylor, E. G., 108 Taylor, J., 131 Taylor, J. T., 184 Taylor, P. J., 184 Taylor, R. F., 151 Taylor, R. J. K., 190 Tazawa, H., 160 Teisseire, P., 86, 87 Telser J., 35 Tempesta, M. S., 116 Tencer, Y., 112 Terekhina, A. I., 218 Terem, B., 150 Terenius, L., 219 Terner, J., 154 Theander, O., 76,92 Theobald, N., 210 Thomas, A. T., 10 Thomas, D. W., 125 Thomas, E. M., 175

Thomas, J. K., 155 Thommen, W., 6 Thompson, M. J., 214 Thornson, A. J., 152 Thornson, R. H., 29, 30, 127, 128 Threlfall, D. R., 158, 162 Thurston, H. D., 102 Thyagarajan, G., 59 TichL, M., 179 Tietz, D., 152 Tilley, J., 179 Tillman, J., 184 Timms, R. N., 171, 193 Tint, G. S., 214, 215 Tius, M. A., 109 Toda, M., 153 Todd, A. H., 190 Togami, M., 109 Tokunaga, F., 156 Toldy, L., 226 I’oma, L., 174 Tomesch, J. C., 31 Tomita, M., 71 Tomoaia-Cotisel, M., 155 Tong, D., 144 Tom, C. E., 96 Toome, V., 177 Torii, S., 78, 147, 148, 160 Toromanoff, E., 187, 191 Torrini, I., 201 Toth, G., 135 Totten, C. E., 202 Towner, P., 146 Townsley, P. M., 99 Toyota, M., 88, 105, 106 Trager, W. F., 175 Traynor, J. R., 215 Trbojevic, J. J., 197 Tretzel, J., 154 Tringali, C., 105 Trivedi, G., 95 Trka, A., 181 Trope, A. F., 48 Trost, B. M., 48, 193, 225 Trouilloud, M., 116, 125 Troy, F. A., 160 Truscott, T. G., 155 Tsai, M.-Y., 18 Tsankova, E. T., 52 Tschesche, R., 126 Tseikinskii, V. M., 170, 171 Tsuboi, S., 84 Tsubota, N., 185 Tsubuki, M., 11 Tsuda, M., 154, 156, 174, 175 Tsuji, N., 192 Tsujimoto, K., 145 Tsukida, K., 133, 143,151,156 Tsukitani Y., 105 Tsushima, T., 190 Tsutsumi, K., 75 Tsuyuki, T., 6, 122, 123, 126, 136

242 Tsuzuki, K., 52 Tuinrnan, A., 167 Tulshian, D. B., 18 Turnlinson, J. H., 183 Turecek, F., 181, 187 Turkes, A., 185 Turkes, A. O., 185 Tursch, B., 99 Turuta, A. M., 198, 199, 207 Tuttobello, L., 105 Uchida, I., 101 Uchida, M., 7 3 Uchida, N., 160 Uchida, T., 204, 209 Uda, H., 41, 78 Ubelhart, P., 140 Uegaki, R., 75, 76 Uemura, M., 98, 109, 15 1 Umezawa, H., 47 Urnezawa, S., 47 Umiker, T., 7, 148 Uneyarna, K., 147,148, 160 Ungur, N. D., 93 Urban, J., 129 UskokoviC, M. R., 174 Usrnanghani, K . , 125 Ustynyuk, T. K., 199 Utley, J. H. P., 149 Uto, S., 87 Uvarova, N. I., 115 Vacca, J. P., 82 Vadasz, A., 201 Valade, J., 96 Valenta, Z., 122 Valentine, D., 11 1 Valterova, I., 123 Valverde, S., 95, 99, 100 Van, N. L., 49 Van Bruegel, P. J. G. M., 154, 156 Vandewalle, M. E., 82 Van Dijck, L. A., 188, 193 Vangedal, S . , 115 Vanhallen, M., 98 van Kliet, N. P., 192 Van Meerssche, M., 82 Van Noort, P. C. M., 150 van Putten, R. G., 52 van Rooyen, P. H., 167 van Tamelen, E. E., 108, 111 Van Wong, Pham, T., 92 Varenne, J., 120 Varenne, P., 69 Varon, Z., 69, 120 Vasile, E., 155 Vaughan, K., 52 Vecchi, M., 134, 151 Verbist, J. F., 92 Verbit, L., 186 Verdon, C. P., 118 Verrneer, J. C. G. M., 193 Verrneer, P., 188

Author Index Veselovskaya, N. V., 136 Vichnewski, W., 37, 80 Vidari, G., 7, 42, 121 Vig, 0. P., 160 Vijayakumar, E. K. S., 96 Villernin, D., 194 Vita-Finzi, P., 7, 127 Vlad, P. F., 9 3 Voelter, W., 125 Voigt, B., 102 von Daehne, W., 115 Vora, T. T., 76 Vouros, P., 180 Vuilhorgne, M., 80 VuletiC, N., 187 Vystrcil, A., 123, 129 Wachter, M. P., 190 Wada, K., 103 Waddell, W. H., 146, 151, 153 Wadia, M. S., 29 Wadsworth, H. J., 174, 187, 189 Waespe-Sarcevic, N., 173, 21 1 Wagniere, G., 152 Wahlberg, I., 93, 104, 136 Wahlgren-Brannstrorn, L., 137 Waki, T., 79 Wakita, S., 4 Walker, M. A., 157 Walliser, F. M., 204 Walsh, T. F., 161 Walton, D. C., 133 Wardroper, A. M. K., 131 Warin, R., 126 Warnhoff, E. W., 38 Warshel, A., 156 Wasiowich, C. A,, 144 Watanabe, F., 185 Watanabe, K., 6 9 Watanabe, M., 199 Waterhouse, I., 138, 216 Watkins, S. F., 64 Watson, T. R., 111, 201 .Watson, W. H., 2 6 , 4 9 , 6 9 , 101 Watt, D. S . , 108 Watts, D. J., 98 Wawrzenzyk, C., 5 Weavers, R. T., 108 Weeks, C. M., 165, 166, 168, 208 Wege, D., 31 Weidekamm, E., 154 Weiler, E. W., 118, 151 Weiler, L., 149 Welch, S. C., 22, 143, 194 Weller, H. N., 189 Wells, J. W., 125 Wells, R. J., 107 Wender, P. A., 31, 64, 72 Wenkert, E., 98 Wenzel, M., 228 West, C. R., 228 West, D. L., 31

West, J. L., 146, 151 Westrnijze, H., 188 Weyerstahl, P., 11 Whalley, W. B., 167, 203 White, J. D., 89 White, P. S., 122 Whitehurst, J. S., 131, 158 Whiting, D. A., 71 Whitlock, H . W., 228 Wicklow, D. T., 98 Widdowson, D. A., 193 Widen, K. G., 42 Wiechert, R., 207, 218, 227 Wieland, P., 224 Wielogorski, Z., 191 Wiemer, D. F., 104, 105 Wiersig, J. R., 173, 211 Wiest, W. G., 184 Wightrnan, R. M., 146 Wilkie, J. J., 197 Wilkins, A. L., 132 Williams, C. N., 183 Williams, J. R., 208 Williams, T. H., 174 Willis, B. J., 13 Wilson, D. R., 110 Wilson, R. M., 161 Wilson, S. R., 44 Wilton, J. H., 64 Wind, M. L., 151 Withers, N. W., 210 Wittwer, F., 140 Wohrle, D., 152 Wolf, H . R., 150 Wolff, M. E., 167, 192 Wolinsky, J., 72 Wolner, D., 208 Wong, M. Y. H., 38 Woo, W. S., 125 Woodgate, P. D., 188 Woodruff, W. H., 154 Worley, J. F., 214 Worth, B. R., 99 Wratten, S. J., 105 Wright, L. D., 133 Wright, L. H., 182 WU, C.-S. C., 152 Wu, D. G.,99 WU, R.-Y., 80 Wylie, R. D., 82

Xu, M., 186 Yadar, J. S . , 35, 36 Yagihashi, F., 77 Yahara, S., 92 Yakhimovich, R. I., 216 Yarnada, S., 168, 192 Yarnada, Y., 105 Yamafuji, T., 78 Yamaguchi, M., 139 Yarnakawa, K., 78 Yamakawa, M., 152

Author Index Yamamura, A., 79 Yamamura, S., 52 Yamane, T., 227, 228 Yamano, Y., 161 Yamasaki, K., 87, 92, 105, 123 Yarnashita, A,, 26 Yamashita, H., 103 Yamashita, K., 149, 183 Yamauchi, K., 40 Yanami, T., 79 Yang, S. S., 217 Yao, K., 227 Yaouanc, J.-J., 194 Yasuhara, M., 139 Yatagai, M., 98 Yates, P., 204 Yemul, S. S., 197 Yen, Y.-P., 144 Yokoyama, H., 158 Yokoyama, Y., 122, 123

243 Yonaha, K., 80 Yonekura, N., 208 Yoshihshi, A., 67, 75, 78 Yoshioka, M., 150 Yoshizaki, F., 97 Yoshizawa, I., 204 Yoshizawa, T., 143, 156 Yosioka, I., 136 Yuda, E., 102 Yuzuriha, T., 162 Zabel, V., 49, 101 Zabza, A,, 5 Zainutdinov, U. N., 94 Zakis, V. I., 144 Zarnarlik, H., 149 Zamboni, R., 45,46 Zapletal, V., 149 Zbiral, E., 174, 192, 200

Zdero, C., 3, 10, 50, 5 5 , 56, 59, 69,73,77,80,92,96,99,100 Zeelan, F. J., 192 Zeevaart, J. A. D., 133 Zeigan, D., 175 Zeigler, R. S., 102 Zelnik, R., 98 Zgierski, M. Z., 154 Zielinski, W. L., jun., 183 Ziesche, J., 5 5 , 59, 69, 80, 95, 100 Zilm, K. W., 176 Zink, M. P., 150 Zollo, F., 169 Zoltai, A. I., 186 Zsako, J., 155 Zuberi, S . S., 121 Zumbulyadis, N., 153 Zvonkova, E. N., 156 Zydowsky, T. M., 202