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...

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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

...


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


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


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.


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


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.


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


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


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


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


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.


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.


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


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


-,>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.


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.


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,


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.


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

;:>


(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.


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.


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


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


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


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


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


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 ,
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.


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


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


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


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


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.


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


& 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.


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


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


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.


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

C,,) and degraded ( 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.


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.


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


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.


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


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


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


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


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.


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


(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


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.


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.


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.


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


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.


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

*

'

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