Terpenoids and Steroids: Volume 5 (SPR Terpenoids and Steroids (RSC))

A Specialist Periodical Report

Terpenoids and Steroids Volume 5

A Review of the Literature Published between Sep+ember1973 and August 1974

Senior Reporter

K. H. Overton, Department of Chemistry, University of Glasgow Reporters

D. V. Banthorpe. University College, London G . Britton, University of Liverpool B. V. Charlwood, King's College, London J. D. Connolly, University of Glasgow J. R. Hanson, University of Sussex

D. N. Kirk, Westfield College, London T. Money, University of British Columbia, Vancouver, Canada

P. J. Sykes, University of Edinburgh A. F. Thomas, Firmenich SA, Geneva, Switzerland J. S. Whitehurst, University of Exeter

0 Copyright 1975

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

ISBN: 0 85186 296 9

ISSN: 0300-5992 Library of Congress Catalog Card No. 74-615720

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

Introduction

This Report covers the literature published between September 1973 and August 1974, except for the chapter on Steroid Synthesis, a topic omitted from Volume 4, which consequently reviews a two-year period from September 1972 to August 1974. The tight-rope economics of producing these Reports have unfortunately forced us to abandon our plan to include occasional reviews, which we had hopefully begun in Volume 4. We do include a list of selected Reviews on Steroid Chemistry 1969-1974, to complement the Reviews on Terpenoid Chemistry that appeared in Volume 4, and also a classified list, which just eluded the economic axe, of Terpenoid Structures determined by X-Ray Analysis. As always, comments, criticisms, and suggestions for future volumes will be heartily welcomed.

K. H. OVERTON

Contents Part I

Terpenoids

Chapter 1 Monoterpenoids

3

B y A. F. Thomas 1 Physical Measurements: Spectra etc. ;Chirality

3

2 General Chemistry

5

3 Occurrence, Biogenesis, and Biological Activity

7

4 Acyclic hlonoterpenoids Terpene Synthesis from Isoprene 2,6-Dimethyloctanes Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives

8 8 9

14

5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, Iridoids p-Menthanes o-Menthanes m-Menthanes Tetramethy lcyclohexanes 1,4-Dimethyl-1-ethylcyclohexane Cycloheptanes

16 16 16 20 27 27 27 29 29

6 Bicyclic Monoperpenoids Bicyclo[3,1,O]hexanes Bicyclo[2,2,1]heptanes Bicyclo[3,1, ljheptanes Bicyclo[4,1,O]heptanes 7 Furanoid and Pyranoid Monoterpenoids

30 30 30 36 41 42

8 Cannabinoidsand other Phenolic Monoterpenoids

43

Chapter 2 Sesquiterpenoids By T. Money

46

1 Introduction

46 V

Terpenoids and Steroids

vi

2 Farnesanes

46

3 Bisabolanes

48

4 Cuparane, Laurane, Trichothecane, utc.

51

5 Acorane, Cedrane, etc.

53

6 Chamigrane, Widdrane, and Thujopsane

55

7 Sesquicamphane, PSantalane, Epi-Psantalane, etc.

57

8 Amorphane, Cadinane, Copaane, Copacamphane, Ylangocamphane, Sativane, etc.

59

9 Himachalane, Longipinane, Longica.-,phane, Longifolane, etc.

63

10 Humulane, Caryophyllane, Illudane, Hirsutane, etc.

65

11 Germacrane, Eudesmane, Eremophilane, Vetispirane, etc.

71

12 Guaiane, Pseudoguaiane, Seychellane, Aromadendrane, etc.

86

13 Mono- and Bi-cyclofarnesanes

90

Chapter 3 Diterpenoids By J. R. Hanson

93

1 Introduction

93

2 Bicyclic Diterpenoids Labdanes Clerodanes

93 93 98

3 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids

102 102 105

4 Tetracyclic Diterpenoids The Kaurene--Phyllocladene Series Beyeranes Gibberel lin s Other Tetracyclic Diterpenoids

108 108 111 112

5 Macrocyclic Diterpenoids and their Cyclization Products

116

6 Diterpenoid Synthesis

117

Chapter 4 Triterpenoids By J. 0. Connolly

122

115

1 SqualeneGroup

122

2 Fusidane-Lanostane Group

126

vii

Contents 3 Dammarane-Euphane Group Tetranor-tri terpenoids Quassinoids

130 133 135

4 Shionane Group

135

5 Lupane Group

136

6 Oleanane Group

137

7 UrsaneGroup

143

8 Hopane Group

144

Chapter 5 Carotenoids and Polyterpenoids By G. Britton

146

1 Introduction

146

2 Carotenoids New Natural Carotenoids Hydrocarbons Oxygenated Carotenoids Acyclic Monocyclic xanthophylls Bicyclic xanthophylls Isoprenylated Carotenoids Triterpenoid Carotenoids Degraded Carotenoids Stereochemistry ; Absolute Configuration C-6 c-3 c-2 Carotenoid Epoxides Isomytiloxanthin Degraded Carotenoids Conformation Car0tenoids Retinal and Derivatives Irone Synthesis Carotenoids Degraded Carotenoids Chemistry Carotenoids Degraded Carotenoids Physical Methods Separation Methods Electronic Spectroscopy Resonance Raman Spectroscopy

146 146 146 146 146 148 149 151 151 152 153 153 153 154 155 155 155 155 155 156 156 157 157 159 161 161 162 166 166 166 166

...

Terpenoids and Steroids

Vlll

Low-resolution Microwave Spectroscopy Infrared Spectroscopy N .M.R. Spectroscopy Mass Spectrometry Circular Dichroism X-Ray Crystallography 3 Polyterpenoids and Quinones Polyterpenoids Quinones

Chapter 6 Biosynthesis of Terpenoids and Steroids By D. V. Banthorpe and B. V. Charlwood

168 168 168 170

1 Introduction

170

2 Acyclic Precursors

170

3 Monoterpenoids

176

4 Sesquiterpenoids

178

5 Diterpenoids

183

6 Steroidal Triterpenoids

186

7 Further Metabolism of Steroids

190

8 Non-steroidal Triterpenoids

195

9 Carotenoids

195

10 Meroterpenoids

199

11 Polyterpenoids

203

12 Methods

203

Naturally Occurring Terpenoids whose Structures have been Determined by X - Ray Analysis

Part I/

166 166 166 167 167 168

206

Steroids

Chapter 1 Steroid Properties and Reactions By 0.N. Kirk 1 Structure, Stereochemistry, and Conformational Analysis

Spectroscopic Methods N. M.R. Spectroscopy Circular Dichroism Mass Spectrometry Miscellaneous

223 223 224 224 227 229 23 1

ix

Contents

2 Alcohols and their Derivatives, Halides, and Epoxides Substitution and Elimination Ring-opening of Epoxides Esters, Ethers, and Related Derivatives of Alcohols Oxidation Reduction Miscellaneous

231 23 1 235 235 237 238 239

3 Unsaturated Compounds Electrophilic Addition Epoxidation Miscellaneous Additions Reduction Oxidation Miscellaneous

239 239 24 1 242 243 244 245

4 Carbonyl Compounds Reduction of Ketones Other Reactions at the Carbonyl Carbon Atom Reactions of Enols and Enolate Ions Reactions of Enamines and Enol Derivatives Dehydrogenation and Oxidation Reactions of Oximes and Related Compounds Carboxylic Acids, Nitriles, and Aldehydes

246 246 248 25 1 254 256 258 259

5 Compounds of Nitrogen and Sulphur

26 1

6 Molecular Rearrangements Contraction and Expansion of Rings ‘Backbone’ and Related Rearrangements Aromatization of Rings Chromogenic Reactions Miscellaneous Rearrangements

264 264 266 268 27 1 272

7 Functionalization at Non-activated Positions

275

8 Photochemical Reactions Olefinic Compounds Carbonyl Compounds Miscellaneous

278 278 279 28 1

9 Miscellaneous

283

Chapter 2 Steroid Synthesis By P. J. Sykes and S. J. Whitehurst

285

1 Total Synthesis

285

2 Halogeno-steroids

296

Terpenoids and Steroids

X

3 Oestranes

300

4 Androstanes

304

5 Pregnanes and Corticoids

318

6 Seco-steroids

325

7 Cholestane and Analogues

330

8 Steroidal Insect and Plant Hormones

347

9 Steroidal Alkaloids

349

10 Sapogenins

352

11 Cardenolides

354

12 Bufadienolides

357

Reviews on Steroid Chemistry

36 1

Errata

367

Author Index

369

Part I TERPENOIDS

1 Monoterpenoids BY A.

F. THOMAS

There has been little increase in the volume of work published this year, but the space available for this Report is slightly reduced, so economy has been achieved in two ways. Papers not requiring any discussion, either because they are repetitive or because the minor point they make is evident from little more than the title, are placed at the end of each section. The number of formulae has been reduced, and more extensive use is made of names in the text. With these limitations, every effort has been made to quote all papers relevant to monoterpenoids.

1 Physical Measurements: Spectra etc. ;Chirality

'

Titanium tetrachloride is recommended as a useful shift reagent in assigning 3C n.m.r. frequencies, particularly in ag-unsaturated ketones such as carvone (1). which has a shift of - 5.83 Hz for the P-carbon frequency,compared with - 1.51 Hz using [Eu(fod),].' The 13Csignals of the bridge methyl groups of camphor (2) (C-9 and C-10) have been assigned using another new shift reagent, tris-[4,4,4-trifluoro-1-(2-thienyl)-1,3-butadiThe ene]europium(~~r),* and 3Cchemical shifts of substituted tricyclenes are discu~sed.~ importance of non-axial symmetry in interpreting lanthanide-induced shifts in ketones has special relevance for monoterpenoids, and Newman discusses the case of camphor (2).4 Shifts induced by [Eu(dpm),] in saturated 0- and p-menthone~,~ and its effect on the rotation of the isopropyl group in menthone and menthol have been measured.6 Some well known mass spectra of monoterpenoid alcohols have been published again7

'

-x

0

A

'

(1) (2) A. K. Bose, P. R. Srinivasan, and G. L. Trainor, J. Amer. Chem. SOC.,1974, 96, 3670; 9th International Symposium on the Chemistry of Natural Products, Ottawa, 1974, Abstracts 20B; A. K. Bose, personal communication. K. Beyer, Org. Magn. Resonance, 1974,5,471. E. Lippmaa, T. Pehk, and J. Paasivirta, Org. Magn. Resonance, 1973, 5 , 277. R. H. Newman, Tetrahedron, 1974, 30, 969. R. Enriquez, J. Taboada, I. Salazar, and E. Diaz, Org. Magn. Resonance. 1973,5, 291. K. Yamada, S. Ishihara, and H. Iida, Chem. Letters, 1973, 549. G . R. Rik and L. V. Kravchenko, Vestnik Sef'skokhoz. Nauki (Moscow),1973, 104 (Chern. A h . , 1973, 79, 70083).

Terpenoids and Steroids

4

The adsorption on a mercury electrode of borneol and adamantan-1-01 has been compared with that of camphor because of similar polarographic behaviour.' The chirality of alcohols, notably ( -)-linalool, ( - )-menthol, and cis-menth-2-enol(3) (the name in the text is different), is rapidly established by measuring the c.d. of the complex with copper hexafluoroacetylacetonate.9 Photodecomposition of racemic camphor with circularly polarized light occurs enantiomerically, the optical purity of recovered camphor theoretically rising to lOO:, at the end of the reaction. After 99% destruction of the (+)-camphor, the remainder has 20% optical activity."

( 5 ; R cis) (6; R [runs)

Notable examples of the induction of asymmetry by complexing with monoterpenoids are the resolutions of the iron complex (4)' and a titanium', complex. The menthyl( 5 ; R = PPh,) and neomenthyl- (6 ; R = PPh,) diphenylphosphines are epimeric, chiral ligands, suitable for asymmetric syntheses.' Another account has appeared of an attempt to induce asymmetry by cyclization of homogeranic ( -)-menthy1 ester. l 4 Various micro-organisms (Tridioderrnu, Absidia, etc.) hydrolyse some racemic acetates chirally ; thus a mixture of (+)-isopulegyl acetate [( +)-(7 ; R = COMe)] and (k)-neoisopulegyl acetate [( -k)-(8; R = COMe)] is converted into a separable mixture of (-)-isopulegol [( -)-[7 ; R = H)], (+)-isopulegyl acetate [( +)-(7; R = COMe)], and ( +)-neoisopulegyl acetate. Since interconversion with citronella1 (9) is easy, this represents a practical resolution of ( +)-citronellal.15 The acetates of menthol and carvomenthol undergo this reaction, but not those of the stable axial alcohols, neomenthyl

lo

"

'*

1

l4

'

'

S. L. Dyatkina and B. B. Damaskin, Elektrukhimiya, 1974, 10, 318. J . Dillon and K. Nakanishi, J. Amer. Chem. Soc., 1974, 96, 4056. G . Balavoine, A. Moradpour, and H . B. Kagan, J. Amer. Chem. Soc., 1974,96, 5152. C. T. Flood and D. L. Mills, J . Amer. Chem. Soc., 1973,95, 6460. H . Brunner and H . D . Schindier, J. Organometallic Chem., 1973, 55, C71. J. D . Morrison and W . F. Masler, J. Org. Chem., 1974, 39, 270. S. Kumazawa, T. Kato, and Y. Kitahara, Chern. Lc'tters, 1973, 633. T. Oritani and K. Yamashita, Agric. and Bid. Chern. (Japan), 1973, 37, 1687.

5

Monoterpenoids

acetate ( 5 ; R = OCOMe) and neocarvomenthyl acetate (10).l6 The further the acetate group is from the asymmetric centre, the lower is the optical yield.” New separation techniques for monoterpenoids are liquid chromatography on porous polymer (Hitachi gel 3010)’ and gas chromatography on graphitized carbon black for the notoriously delicate separation of the menthol isomers (although neomenthol and menthol are not cleanly separated).” 2 General Chemistry

Acid-catalysed isomerization of terpenoid hydrocarbons occupies much space in the literature, usually without the emergence of great novelty (see, however, pinenes). The use of mentha-2,8-diene as substrate2’ and other hydrocarbons on Ti0,-H2S0, catalysts is described.21 Liquid-phase rearrangements of pinene and limonene give results varying with acid strength,22and similar variations occur with basic strength in the base-catalysed rearrangement^.^^ By judicious choice of base, it is possible to prepare a particular menthene from one more a c ~ e s s i b l eRearrangement .~~ of limonene (1 1) in phosphoric acid was known to yield a bicyclic hydrocarbon ; 2 5 the latter is shown to be a mixture of three isomers (Scheme 1).26 Isomerization of a-pinene over ferric phosphate

A

+ menthadienes

(11)

Scheme 1

at 180-560 “C leads to rearrangements and ring-opening to men thane^,^' and heating terpenes with diethyl hydrogen phosphite yields phosphonates, also with rearranged skeletons ; pinenes give menthenes, camphene gives isocamphenyl ethylphosphonate, and limonene (1 1)gives a mixture containing a small amount of a bornyl phosphonate.28 Another paper on the hydration of monoterpenoids in the presence of an ion-exchange resin has appeared ( c j . Vol. 4, p. 13).29Treatment of linalool(l2) with chloranil results l6

‘’ Is l9

” ” 22

23 24 25 26

’’

29

T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973,37, 1691, 1695.

T.Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973,37, 1923. M. Nakayama, M. Hiraoka, A. Matsuo, and S. Hayashi, Nippon Kagaku Kaishi. 1973,2314.

V. B. Yakubovich and G. M. Petrov, Khim. Izmenchivost. Rust., 1972,95. 1. I. Bardyshev, Zh. F. Loiko, L. A. Popova, and L. V. Sionskaya, Doklady Akad. Nauk Beloruss. S . S . R . , 1973, 17,534. M. Dul and M. Bukala, Chem. Stosowana, 1973, 17, 19. R.Ohnishi, K. Tanabe, S. Morikawa, and T. Nishizaki, Bull. Chem. SOC.Japan, 1974,47,571. A. Ferro and Y.-R. Naves, Helv. Chim. Acta, 1974,57, 1152. A. Ferro and Y.-R. Naves, Helv. Chim. Acta, 1974,57, 1 141. V. N . Ipatieff, J. E. Germain, W. W. Thompson, and H. Pines, J. Org. Chem., 1952, 17,272. G. Accrombessy, M. Blanchard, F. Petit, and J.-E. Germain, Bull. SOC.chim. France, 1974, 705. V. V. Pechkovskii, Yu. P. Klyuev, L. S. Eschchenko, L. N. Shchegrov, V. M. Sycheva, and I. V. Petrashen, Izvest. Vyssh. Ucheb. Zaced., Les. Zhur., 1973, 16, 107 (Chem. Abs., 1974, 80, 48 172). R. L.Kennedy and G. S. Fisher, J. Org. Chem., 1974,39,682;Some related work is discussed in the bicyclo[3,1, Ilheptane section. Y. Matsubara, T. Fujiwara, and K. Tanaka, Yuki Gosei Kagaku Kyokai Shi, 1973, 31, 924.

Terpenoids and Steroids

6

(12)

(13)

(14)

(15) E

(17)

(16)

h a series of dehydrations and hydrations; myrcene (13), ocimene (14),and their hydration products are formed, but cyclization to menthadienes and subsequent hydration also occur. Geraniol (15), nerol (16), and linalool (12) are interconverted, and give similar products, nerol favouring the cyclized alcohol (17).30The claim that j3-pinene is among the dehydration products of linalool(l2)could not be confirmed using boron trifluoride or iodine as catalyst.31 Of particular relevance to monoterpenoids is the comparison of reaction parameters for triphenyl phospite ozonide (TPPO) formation and those of photosensitized oxygenation, where it has been shown that singlet oxygen cannot be a common active species for both types; limonene ( l l ) , for example, shows a very different product distribution in the two cases. TPPO oxidation occurs at lower temperatures than ozonide decomposition, and is in some cases, e.g. a-terpinene (18), more selective.32A general study of epoxidation of methylenecyclohexanes, closely related to monoterpenoids, includes a discussion of the epoxide conformation^.^^ Epoxidation of ally1 alcohols with t-nutyl hydroperoxide catalysed by vanadium or molybdenum complexes has enabled the new epoxides of geraniol(l9) and linalool(20) to be prepared.34 Oxidation of alcohols to ketones (menthol to menthone, borneol to camphor, etc.)generally occurs with N-chlorosaccharin, but limonene (11) gives a 4-chloro insertion product.35

(18)

(19)

(20)

Details of the highly stereoselective reductions of ketones, (mostly bicyclic monoterpenoids) with alkylboranes are published.36 A new method for alkylating methyl groups via 7r-ally1complexes3’ uses geranylacetone as a typical example ; this method tackles the general difficulty of making valuable higher terpenoids from cheap monoterpenoids. 3o 31

32 33

34 3s

” ”

S. Fujita, Y. Kimura, T. Iguchi, R. Suemitsu, and Y. Fujita, Nippon Kuguku Kuishi, 1972,2140. Y . Fujita, S. Fujita, and H. Okura, Nippon Kugaku Kaishi, 1974, 132. E. Koch, Anulyt. Chem., 1973,45, 2120. A. Sevin and J.-M. Cense, Bull. SOC.chim. France, 1974, 963, 969. K. B. Sharpless and R. C. Michaelson, J. Amer. Chem. Soc., 1973, 95, 6136. J. M. Bachhawat, A. K. Koul, B. Prashad, N. S. Ramegowda, C. K. Narang, and N. K. Mathur, Indian J . Chem., 1973, 1 1 , 609. H. C. Brown and V. Varma, J. Org. Chem., 1974, 39, 1631. B. M. Trost, T. J. Dietsche, and T. J. Fullerton, J. Org. Chem., 1974, 39, 737.

7

Monoterpenoids

3 Occurrence, Biogenesis, and Biological Activity A review has appeared on the distribution of terpenoids among different plant species, with sections on biosynthesis and m e t a b o l i ~ m . ~ ~ Some traditional monoterpenoid plant sources are becoming rarer, adding interest to the flourishing analytical work ;examples are the following species : Artemisia (several and Origanum (containing sabinene h~drate),~’ of which contain i s ~ t h u j o n e )Majurana ,~~ Citrus iyo peel oil (containing several rare oxygenated menthanes):’ and saffron.42The C,, substance (21) from Greek tobacco is possibly not monoterpenoid but derived from a d i t e r ~ e n e The . ~ ~ monoterpenoid hydrocarbon content of Cymbopogen oils varies widely with geographical source (large amounts from Ceylon, small from Java).44 A similar study has been made on the monoterpenoids of balsam fir.45

OMe (22)

A structure-activity correlation study of the substituted monoterpenoid type (22) of juvenile hormone attempts to show certain structural similarities with e c d y ~ o n eA. ~ ~ juvenile hormone antibody has been developed which binds specifically with the naturally occurring hormone, thereby distinguishing it from mimics such as the monot e r p e n o i d ~A. ~large ~ number of variants of the geranyl part of the monoterpenoid ether juvenoids, including cyclogeranyl, linalool oxide (tetrahydrofuryl), and reduced and oxidized types, have been tested for insecticidal Pharmacological activities are reported for but-2-ynamine derivatives of borneol and and of pinol and camphene.” The full paper on the repellant action of diethylthujamide against the yellow fever mosquito (Aedes aegypti) and other insects has appeared (Vol. 3, p. 38

39 40 41

42

43

44

45 46 47 48 49 50 51

H. J. Nicholas, in ‘Phytochemistry’, ed. L. P. Miller, Van Nostrand, New York, 1973, Vol. 2, p. 254. A. Matsuo, H . Hara, M. Nakayama, and S. Hayashi, Flavour Znd., 1973,4, 343. G . Marczal and M. V. Vincze, Gyogyszereszet, 1973, 17, 214 (Chern. Abs., 1973, 79, 149 277). M. Hiroi and D. Takaoka, Nippon Kagaku Kaishi, 1973, 1339. A. I. Akhmedov, Sh. K. Chogovadze, M. I. Goryaev, and A. D. Dembitskii, Masfob-Zhir. Prom., 1973, 26 (Chern. Abs., 1973,79,83 384). A. J. Aasen, J. R. Hlubucek, S.-0. Almquist, B. Kimland, and C. R. Enzell, Acra Chern. Scand., 1973, 27, 2405. R. 0. B. Wijesekera, A. L. Jayewardene, and B. D. Fonseka, Phytochemistry, 1973, 12, 2597. D. T. Lester, Canad. J. Forest Res., 1974, 4, 55. J. F. Grove, R. C. Jennings, A. W. Johnson, and A. F. White, Chern. and Ind., 1974, 346. R. C. Lauer, P. H. Solomon, K. Nakanishi, and B. F. Erlanger, Experientia, 1974, 30, 5 5 8 . B. D. Hammock, S. S. Gill, and J. E. Casida, J. Agric. Food Chern., 1974, 22, 379, 386. E. Mariani, M. Longobardi, P. Schenone, F. Bondavalli, and C. Bianchi, Chirn. thPr., 1973,8, 281. E. Mariani and P. Schenone, Educ. Sci., 1974, 29, 113. V. Hach and E. C. McDonald, Canad. J . Chern., 1973,51, 3230.

Terpenoids and Steroids

8 4 Acyclic Monoterpenoids

Terpenoid Synthesis from Isoprene.-Isoprene could be one substance affected by current raw material shortages, and its synthesis is vital for entry into the terpenoid field. Reactien of isobutylene with formaldehyde yields isoprene and 20% of a dioxan (23) which can be converted into a mixture of alcohols (Scheme 2) with oxalic acid, one of which (24) is produced i n d ~ s t r i a l l y . ~ ~

+

’ CH,O

--+

0

+

I\/cH20H

(COZWZ,

’

OH

0

+

(23)

&cH20H

L C H , O H

+

& OH (24)

Scheme 2

The thermodynamics of the Diels-Alder dimerization of isoprene are consistent with a one-step concerted m e ~ h a n i s m Dimerization .~~ of isoprene over certain palladium complexes yields only tail-to-tail-linked hydrocarbons (cf. Vol. 4, p. 1 1),54 and more has been published on the stannic chloride telomerization, giving a 61 % mixture of E- and 2-geranyl chlorides (25; R = H,) (besides tail-to-tail isomers),55the 2-isomer cyclizing to 8-chloromenthene under the telomerizing condition^.^^ Further work has appeared on the alkali-metal-catalysed dimerizations of isoprene using sodium naphthalene5’ or lithium and t-butylamine, the latter yielding head-to-tail and tail-to-tail products in equal amounts.58The dimer obtained in low yield using sodium in benzene is 92 myrcene (1 3).59 The chloride (25;R = 0)is available from the reaction between isoprene and senecioyl chloride (26) in the presence of stannic chloride. It has been converted into the ocimenones (27) and filifolone (28), and a similar route using isovaleroyl chloride instead of (26) leads to the tagetones (29).60 ,’;.”,

Isoprene

+ I , , , -) (26) 52

53 54

55

5b

” 58 59

6o

(25)

(27)

S. K. Ogorodnikov and Yu. M. Blazhin, Khim. Prom., 1974, 2 , 87; J. 0 . Turner and H. F. Peterson, Amer. Chem. Soc., Div. Petroleum Chem., Preprints, 1974, 19, 88. J . Rimmelin and G . Jenner, Tetrahedron, 1974, 30, 3081. A. D. Josey, J . Org. Chem., 1974, 39, 139. K. V. Laats, T. A. Kaal, I. A. Kal’ya, I. B. Kudryavtsev, E. A. Muks, M. A. Tali, S. E. Teng, and A. Yu. Erm, Zhur. org. Khim., 1974, 10, 159; K. V. Laats and E. A. Muks, ibid., p. 162. K. V. Laats, S. Teng, and T. 0. Savich, Zhur. org. Khim., 1974, 10, 164. T. Fujita, K. Suga, and S. Watanabe, Nippon Kagaku Kaishi, 1973, 2182. Y . Suga, S. Watanabe, and S. Tanaka, Jap. P., 28 403/1973(Chem. Abs., 1973,79, 145 948). J. Tanaka, T. Katagiri, and K. Takabe, Jap. P., 26 70611973 (Chem. Abs., 1973, 79, 66 610). D. R. Adams, S. P. Bhatnagar, R. C. Cookson, and R. M. Tuddenham, Tetrahedron Letters, 1974, 3197.

9

Mono terpenoids

(30)

(29)

Further syntheses with isoprene units are discussed in the next section.

2,6-Dimethyloctanes-Dehydroneryl isovalerate (30) [the formula (4 1) in Volume 4, p. 12, has wrong stereochemistry] has been synthesized from nerol(1Q6'One of the two coumarin monoterpenoids (3 1) in Capnophyllum peregrinum has been synthesized directly (Scheme 3) from the tetrahydropyranyl ether of linalool (12);62 the other is described in the furanoid section.

THP = tetrahydropyranyl

Reagents: i, SeO,; ii, PBr,; iii, 0

Scheme 3

The novel structure (32) reported from Psiada salvifolia is insufficiently supported (only mass and i.r. spectra).63 The two allo-ocimene isomers (33) from cz-pinene can be separated by allowing the Eisomer (more reactive) to form an adduct with methyl acrylate, leaving the pure Zisomer.64The reduced ocimene (34), formed by pyrolysis of pinane, can be converted into optically active citronellol (35) on hydroboration and oxidation [( +)-(35) from ( - p inane].^' Various cyclizations of the hydrocarbon (34) have been described (Scheme 4), formation of the palladium complex apparently occurring by sequential isomerization of the initially co-ordinated vinyl group, giving the strongly co-ordinated diene (36), which is reduced by available palladium hydride.66 61

62

63

" 65

66

F. Bohlmann and H.-J. Bax, Chem. Ber., 1974, 107, 1773. F. Bohlmann and D. Kornig, Chem. Ber., 1974, 107, 1780. R. Dennis, Phytochernistry, 1973, 12, 2705. Y . Fujihara, C. Hata, T. Noguchi, and Y. Matsubara, Nippun Kagaku Kaishi, 1973, 1802. K. Suga, S. Watanabe, and T. Fujita, Yukugaku, 1973, 22, 738. F. J. McQuillin and D. G. Parker, J.C.S. Perkin I, 1974, 809.

Terpeiioids and Steroids

10

6

CH,OH

(33)

(34)

(35)

I

(36) Reagents: i, PdC1,-CuC1,-DMF; ii, Hg(OAc),; iii, PdC1,-aq. acetone; iv, HC0,H-H,SO,.

Scheme 4

Reduction by diborane of the tricarbonyliron complexes of myrcene (13) and 2-ocimene (37) adds hydrogen across the isopropylidene double bond ; the a-phellandrene complex (see menthanes) was also e ~ a m i n e d . ~ Multistage ' syntheses of a-myrcene (38), myrcene (13), and a related alcohol have been published.68

Metal-catalysed addition of acetic acid to myrcene (13) yields mainly addition products to the conjugated diene system (cf. Vol. 4, p. 14).69Sensitized photo-oxygenation of the diene (34)70or linal0ol(l2)'~ results in the introduction of oxygen on the more 67

68 69 'O

-'

D . V. Banthorpe, H. Fitton, and J . Lewis, J.C.S. Perkin I, 1973, 2051. 0. P. Vig, B. Ram, U. Rani, and J . Kaur, J . Indian Chem. Soc., 1973,50, 329. K . Suga, S. Watanabe, T. Fujita, and K . Takeda, Yukugaku, 1973, 22, 321. D. V. Banthorpe, M. R. Young, and W. D. Fordham, Chem. and Ind., 1973, 901. H . Kjosen and S. Liaaen-Jensen, Acta Chem. Scand., 1973, 27, 2495.

Mon ot erpeno ids

11

substituted double bond, but autoxidation of myrcene is less specific. Upwards of 42 substances are formed by oxygegation, cyclization, disproportionation, and polymerization, including pinenes, linalool oxides, camphor, and carvone, besides expected corn pound^.^^ The pyrolysis of allo-ocimene peroxide (Vol. 1, p. 12) has been reinvestigated.73 Direct introduction of an amino-group into myrcene (13) occurs with diethylamine and sodium naphthalene, sodium acetate in acetic anhydride converting the products into geranyl acetate.74

Access to oxygenated 2,6-dimethyloctanes can also be achieved by ring-opening of oxygenated menthanes ; for example, Bayer-Villiger oxidation of ( - )-menthone (39), followed by metal hydride reduction to the glycol (40) and pyrolysis over potassium bisulphite, yields 60% of (+)-citronello1 [( + )-(35)], (+)-menthone similarly giving (-)citronellol of high optical The total synthesis of tagetonol (41) in five stages from isobutyl methyl ketone has been reported,76 and 2-methyl-6-methyleneocta-2,7dien-4-01 (42) was prepared following Scheme 5. Allylic rearrangement of (42) to the

Q

dcH2Br ___, Zn

HO

--bA

Scheme 5

alcohol (43),together with polymerization, occurs above 100 0C.77These total syntheses yield racemates, but Lefebvre et a!. have made (+)-dihydrotagetone (44)by photolysis of ( + )-3-methylcyclopentanone (49, followed by Grignard addition and oxidation. Natural tagetone was thus shown to be highly racemized [although some racemization occurred during irradiation of (45)].’

’’ R. H. Dieckmann and S. R. Palamand, J . Agric. Food Chem., 1974, 22,498. l 3

75 7b ”

78

I. P. Mash’yanov and G . L. Dranishnikov, Trudy Arkhangel’sk. fesotekh. Inst., 1972, 32, 60 (Chem. Abs., 1974,80,60 044). T. Fujita, K. Suga, and S. Watanabe, Austral. J . Chem., 1974, 27, 531. T. Shono, Y. Matsumura, K. Hibino, and S. Miyawaki, Tetrahedron Letters, 1974, 1295. 0. P. Vig, B. Ram, and B. Vig, J . Indian Chem. SOC.,1973, 50, 408. R. G. Riley, R. M. Silverstein, J. A. Katzenellenbogen, and R. S. Lenox, J . Org. Chem., 1974, 39, 1957. B. Lefebvre, J.-P. Le Roux, J. Kossanyi, and J.-J. Basselier, Compt. rend., 1973, 277, C,1049.

Terpenoids and Steroids

12

A

(45)

(44)

Treatment of the dilithium salt (46) with an alkyl halide is equivalent to adding isoprene. The double-bond isomer (47) of geraniol was thus made, converted into the corresponding aldehyde and acid, and isomerized to the geraniol series.79The dianion (48) of methyl acetoacetate can replace (46), the additional methyl group being added to the en01 acetate (49)80to obtain a 1 : 10 mixture of 2 : E methyl geranates (50). Use of the enol benzoate, however, results (loo"//,!) in a 2 : E ratio of 5.8 : 1." The principle of activating a methylene group with a sulphone unit (Vol. 4,pp. 15,16) has been applied to couple a second geranyl group to geranyl sulphone.82 1

.+

0

.I

(50)

0

0

(49)

Conversion of linalool(l2) into geranyl, neryl, and a-terpinyl acetates with toluene-psulphonic acid in acetic anhydride83 is less interesting than the reverse rearrangement, which occurs on heating geranyldimethylamine oxide (51). Very pure linalool (12) is obtained from the substance (52) thus obtained after reduction with zinc in acetic acid, while heating (52) results in isomerization to the corresponding nerol and geraniol

isomer^.'^

'' "

'' 83

84

G. Cardillo, M . Contento, and S. Sandri, Tetrahedron Letters, 1974, 2215. C. P. Casey and D. F . Marten, Synth. Comm., 1973, 3, 321; c:f: S. N. Huckin and L. Weiler, Canad. J . Chem., 1974,52; 2157. C. P. Casey and D. F. Marten, Tetrahedron Letters, 1974, 925. P. A. Grieco and Y. Masaki, J . Org. Chem., 1974, 39, 2135. J. H. Babler and D. 0. Olsen, Terrahedron Letters, 1974, 351. V. Rautenstrauch, Helv. Chim. Acta, 1973, 56, 2492.

Mono t erpenoids

13

Base treatment of the sea hare monoterpenoid (Vol. 4, p. 12), a bromohydrin, yields the epoxide (53)” The fact that selenium dioxide introduces oxygen on the isopropylidene terminal carbon atom of geranyl compounds in exclusively the E geometry has been used to prepare E-1-chloro-2,6-dimethyloctanesfor further specific reactions.86

Cyclizations of carbonium ions derived from geranyl compounds are used as ‘biogenetic’ type models for polycyclic terpenoids. Using acetyl, crotonyl, and 2,6-dimethyl3-methoxybenzoyl chlorides and Lewis acids (Scheme 6), geranyl acetate (54)cyclizes to (55) or (56),but methyl geranate (50) does not cy~lize.~’ Citronellol, lacking the extra

Reagents: i, AICI,; ii, SnCl,; iii, LiCl-DMF. Scbeme 6

”

86 13’

M. R. Willcott, R. E. Davis, D. J. Faulkner, and M. 0. Stallard, Tetrahedron Letters, 1973, 3967. L. J. Altman, L. Ash, and S. Marson, Synthesis, 1974, 129. S. Kumazawa, Y. Nakano, T. Kato, and Y. Kitahara, Tetrahedron Letters, 1973, 3967.

14

Terpenoids and Steroids

double bond, gives the dimeric ether (57) with boron trifluoride etherate.’* A novel cyclization is discussed in the section on iridoids. Further relevant papers in this section (besides Cookson’s syntheses noted in the previous section) concern measurement of the triplet lifetime of a l l o - ~ c i m e n evarious ,~~ Diels-Alder reactions of allo-ocimene and homologues,90 the formation of hydrooxycitronellal and its ethers by hydration of citronella1 imines,” specific reduction of certain positions in gerani01~~ and ~ i t r awith l ~ ~different catalysts, epoxidation of geranyl chloride (25; R = H2),94and the preparation of (R)-6methylhexane from (-)-citronellol [( -)-(35)J9’

Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-A review of rearrangements in this series has appeared.96 Julia et al. have made artemisia ketone (58) from the sulphide (59) and lithium 3methylbut-1-yn-3-yl chloride [Li-(60)], the allene (61) resulting from the sigmatropic rearrangement being readily converted into the ketone (58). Alternatively, reaction of the sulphide (59) with (60) in aqueous sodium hydroxide gives the acetylene (62; R = C-CH)-not, apparently, by simple alkylation of the sulphide (59), which does not react with alkyl halides under these conditions. Sigmatropic rearrangement of the ylide

L

’

SMe

\*\* SMe

Reagents : i, Protonating solvent: ii, hydrolysis, HgCI,; iii, prolonged heat.

Scheme 7 89

92 93 94

’’ 96

K. Nagai, M. Nakayama, and S . Hayashi, Chem. Letters, 1973, 665. R. S. H . Liu, Y . Butt, and W . G. Herkstroeter, J.C.S. Chem. Comm., 1973, 799. Y . Matsubara, T. Kishimoto, M. Kasano, and W. Minematsu, Nippon Kagaku Kaishi, 1973, 972; Y . Matsubara, T. Kishimoto, Y. Imoto, and W. Minematsu, ibid., p. 1064; Y . Matsubara, T. Kishimoto, and W. Minematsu, ibid., p. 968. R . Ishino and J. Kumanotani, J . Org. Chem., 1974,39,108; P. Chabardes, Ger. Offen 2 262 740; Ogawa and Co., Ltd., Fr. P. 2 146 563 (Chem. Abs., 1973, 79, 78 997); CJ also Vol. 2, p. 11. Sou Phouti, Hua Hsueh, 1973, 72 (Chem. Abs., 1974, 80, 37 307). E. Mourier, Ger. Offen 2 322 584. J. H. H. Chan, U.S. P. (appl.) 219 866/1973. C. Carlini, D. Pini, 0. Bonsignori, and P. Neuenschwander, Gazzettu, 1973, 103, 1297. C. D. Poultier, J . Agric. Food Chem., 1974, 22, 167.

15

Monoterpenoids

anion (63) is proposed.97 The maximum enantiomeric purity of the artemisyl product (62; R = CH=CH,) from the sigmatropic rearrangement of the salt (64) using chiral bases was only 12%.98 Lavandulol(65; R = CH,OH) is produced (6 % yield) from the isoprene-magnesium . ~ ~nitrile (65 ; R = CN) complex (Vol. 2, p. 8) and prenyl chloride with air ~ x i d a t i o nThe smells of anise !loo Details have appeared of the preparation of chrysanthemic acids from carene ozonolysis (Vol. 3, p. 23)"' and of the pyrethrin crystal structure."' Photolysis of pyrethrin affects only the non-terpenoid portion. l o 3

.

R

= CH=NNHTs or CMe=NNHTs

*\

(64)

(65)

(66)

Thermal or photochemical decomposition of lithium salts of the tosylates (66) gives hydrocarbons of the artemisia and santolina series [690/,of santolinatriene (67)thermally], together with ring-expanded substances (cyclobutenes), the reaction proceeding via

II, 111 __*

NOH

(70) R = CH,CN (68) R = CH,OH Reagents: i, h v ; ii, Pd/C-H,; iii, C,H,ONO-t-amyl-K-dry C,H,; iv, N,H,-KOH; v, TiCl,; vi, PC1,-lutidine-ether; vii, KOH-triglyme-HOCH,CH ,OH ; viii, LiAIH,.

Scheme 8 97

98 99

loo lo'

lo'

Io3

D. Michelot, G. Linstrumelle, and S. Julia, J.C.S. Chem. Comm., 1974, 10; Cornpt. rend., 1974, 278, C , 1523. B. M. Trost and W. G. Biddlecom, J. Org. Chem., 1973, 38, 3483. H. E. Ramsden, Ger. Offen 2 311 068. H. Kappeler and J. Wild, Ger. Offen 1 817 925. W. Cocker, H. St. J. Lauder, and P. V. R. Shannon, J.C.S. Perkin Z, 1974, 194; see also the excellent modification by R. Sobti and Sukh Dev, Tetrahedron, 1974,30,2927, of the old Matsui synthesis, Agric. and Biol. Chem. (Japan), 1965, 29, 784; 1967, 31, 33. M. J. Begley, L. Crombie, D. J. Simmonds, and D. A. Whiting, J.C.S. Perkin Z, 1974, 1230. M. J. Bullivant and G. Pattenden, Tetrahedron Letters, 1973, 3679.

Terpenoids and Steroids

16

chrysanthemyl carbenes. 'O 4 Homologues of methyl chrysanthemate have been made by ozonolysis of chrysanthemate and Wittig rea~tion,'~' and other related materials, some of which are both more persistent and more photostable than the natural substances, have been described.lo6 5 Monocyclic Monoterpenoids

Cyc1obutane.--The synthesis of grandisol(68) from the eucarvone photoisomer (69) is shown in Scheme 8.'" The acid chloride (71) [from methylbutanolide (72)] reacts with isoprene and triethylamine in an autoclave to form the carbon skeleton of grandisol, but the synthesis failed when the halide (73) could not be converted into the alcohol.lo8 CH ,CH,Cl FfCI-SOCI,

I

Isoprene

CHCOCl

I

Me

(73)

A successful synthesis made use of the fact that if either four- or five-membered rings can be formed by cyclization of an epoxy-nitrile the cyclobutane is always preferred, the epoxide (74) giving the cyanocyclobutane (75) with lithium hexamethyldisilazane. Subsequently, the cyano-group was converted into methyl via the aldehyde, and the hydroxyl was removed by oxidation and a Wittig reaction.'"

OH (75)

Cyclopentanes, 1ridoids.-A new, antileukaemic iridoid lactone, allamandin (76) (dihydroplumericin), occurs with plumericin in Allarnandia cathartica.' l o Arornia mosdmfa, a Cerambycid of the Coleoptera, contains two iridodials (77).'11 From two Cornus spp. (dogwood), the new dihydrocornin (78 ; R' = Me, R 2 = R3 = H) has been isolated. The corresponding ketone, cornin, has long been known and is identical with 'verbanalin'; the latter name should be abandoned.' l 2 Other new iridoid glucosides are T. Sasaki, S. Eguchi, M. Ohno, and T. Umemura, J. Org. Chem., 1973, 38. 4095. K . Okada, K. Fujimoto, and M . Matsui, Agric. and B i d . Chem. (Japan), 1974, 38, 827. M . Elliott, A. W . Farnham, N. F. James, P. H . Needham. D . A. Pulman, and J . H . Stevenson, Nature, 1973,246, 169: 1974,248, 710; J. M. Barnes and R. D . Verschoyle, ibid., 1974,248,711 : K . Fujimoto, N . Itaya, Y . Okuno, T. Kadota, and T. Yamaguchi, Agric. and Biol. Chem. (Japan), 1973, 37, 2681. W. A. Ayer and L. M. Browne, Canad. J. Chem., 1974,52, 1352. J.-C. Grandguillot and F. Rouessac, Compt. rend., 1973, 277, C, 1273. G. Stork and J. F. Cohen, J. Amer. Chem. Soc., 1974, 96, 5270. S. M. Kupchan, A. L. Dessertine, B. T. Blaycock, and R. F. Bryan, J. Org. Chem., 1974, 39, 2477. G. Vidari, M. De Bernardi, M. Pavan, and L. Ragozzino, Tetrahedron Letters, 1973, 4065. S. R . Jensen, A . Kjaer, and B. J . Nielsen, Acra Chem. Scand., 1973, 27. 2581.

Io4

Io5

Io6

lo'

Io8 lo'

'lo

I I ' I 2

17

Mono terpeno ids

W H O

T C H O

lamiridoside (78; R' = R3 = OH, R 2 = Me) from the white dead-nettle (Larnium alburn),'13 durantoside (79; R = H) and two of its esters (79; R = methoxy- or dimethoxy-cinammoyl) from Duranta repens,' deutzioside (mentzeloside? cf. Vol. 4,p. 24) from Deutzia s ~ a b r a , 'and ~ ~ ajugol(80; R = H) and its acetate ajugoside (80; R = Ac) from Ajugu reptuns and other Labiatae. l 6 Ajugoside is very similar to leonuride, from Leonurus cardiaca.' l 7 Two new sweroside derivatives (81 ; R = /I-glucose esters)

' '

qo Ri:40

CH,OCOCH,CHMe,

C0,Me

H

O

G

o

MeFjo FI

I'

O-P-Glu

OR (81)

(82) R'

=

H or OH, RZ = HOC,H,CH,CH,

(83) R'

=

H, R 2 = (HO),C6H3CH,CH2

O-P-Glu (84)

have been isolated from Gentiana spp.,' and new secoiridoids (82 ;R = H or OH) from Ligustrum obtusifolium.l 1 Oleuropin (83), kingoside, and morronoside have been

I l3

'I4 'I6 'I7

'"

'I9

P. Eigtved, S. R. Jensen, and B. J. Nielsen, Acra Chem. Scand., 1974, B28, 8 5 . H. Rimpler and H. Timm, 2. Naturforsch., 1974, 29c, 1 1 1 . F. Bonadies, P. Esposito, and M. Guiso, Gazzetta, 1974, 104, 17. M. Guiso, T. Martini-Bettolo, and A. Agostini, Gazzetta, 1974, 104, 25. K. Weinges, P. Kloss, and W. D. Henkels, Annalen, 1973, 566. H. Inouye, S. Ueda, Y . Nakanmra, K. Inoue, T. Hayano, and H. Matsumura, Tetrahedron, 1974, 30, 571; H. Wagner and K. Vasirian, Phytochemistry, 1974, 13, 615. Y . Asaka, T. Kamikawa, T. Kubota, and H. Sakamoto, Chem. Letters, 1972, 615.

Terpenoids and Steroids

18

correlated with asperuloside ; I '' similar correlation of didrovaltrate and valerosidate (84)led to amendment of the structure of the latter.12' The structure of the hydrolysis product, elenolic acid (85), from oleuropin (83) has been established by converting it into ajmalicine (86).This showed that in the hydrolysis step the acyclic hydroxy-aldehyde system (87) undergoes conjugate addition of the ahydroxymethylene ester to the &unsaturated aldehyde.' 2 2

r2;q0 -

HO,C Y C CO,Me H O

C0,Me

(83)

+

OH

I

H0,C

--+ CHO (87)

OHC (85)

Me

1

Tryptamine (five steps)

A supposed difference between ( +)-boschniakin (88) and (+)-indicainz arose because the aldehyde group was converted into the acetal during recrystallization of the picrates ! The new cis,cis-nepetalinic acid (89) was prepared during full elucidation of the stereochemistries of all four acids.'24 The total synthesis of elenolic acid is shown in Scheme 9.12' Although only low yields of iridanes were obtained from cyclopentenaldehyde and ethyl 3-ethoxyacrylate,' 26 Tietze has made hydroxyloganin and hydroxyloganic acid from an intermediate (90) of the Buchi synthesis (Vol. 1, p. 20). Epimerization at C-6 in (91) gave a diacetate (92) which was glucosylated as in the Buchi synthesis.127The cis stereochemistry at C-1 and C-6 prevents cleavage of the ring by the dimethyl sulphoxide anion, but the trans-glycol monotosylate from (91) was cleaved to a mixture of the

'

12'

'''

124

127

H . Inouye, T. Yoshida, S . Tobita, K. Tanaka, and T. Nishioka, Tetrahedron, 1974, 30, 201 ; a preliminary note (Tetrahedron Letters, 1970, 2459) was omitted from these Reports, but full structures have been given with other papers from this group (Vol. 3, p. 28). H. Inouye, S. Ueda, S. Uesato, T. Shingu, and P. W. Thies, Tetrahedron, 1974, 30,2317. F. A. MacKellar, R. C. Kelly, E. E. van Tamelen, and C. Dorschel, J . Amer. Chem. Soc., 1973, 9 5 , 7 1 5 5 ; CJ recent conversion of secologanin into corynanthe-type alkaloids, R. T. Brown and C. L. Chapple, J.C.S. Chem. Comm., 1973, 886, and the total synthesis of elenolic acid ( 8 5 ) , below. D. Gross, W. Berg, and H . R. Schutte, Z . Chem., 1973, 13, 296. H . G. Grant and M. D. Sutherland, Austral. J . Chem., 1973, 26, 2183. R . C. Kelly and 1. Schetter, J . Amer. Chem. SOC.,1973, 95, 7156. L.-F. Tietze, Chem. Ber., 1974, 107, 2491. L.-F. Tietze, Angew. Chem. Internat. Edn., 1973, 12, 757; Chem. Ber., 1974, 107, 2499.

Mono terpeno ids

19 MeO,CCH,,

0

+ BrCH2C0,Me

Na

C H ,CO, Me

0

i."

x

/C02Me M

s

O

W

o

,

z

M

e

*I

I

'OH

HO

xO C O * M e CO,Me

-%

MsO

( 8 5 ) dimethylester

OH

Reagents: i, Citraconic anhydride; ii, H,O; iii, KClO,-OsO,; iv, acetone; v, electrolytic decarboxylation; vi, KMn0,-KIO,; vii, CH,N,; viii, NaBH,; ix, MsC1-py; x, 60 % H C 0 , H ; xi, HIO,; xii, py-H,O.

eo ,H

Scheme 9 C0,Me

C02Me

0

A c O - - e 0

H I

OMe

OMe

Ho2C

1

(90)

(91) IV, \.I, V I I

HOC

C0,Me

+ H

OMe

C0,Me

5 OMe

(92)

Hoq (81 ; R = Me)

i i - H tOYM0 e

Reagents: i, MeMgCO,; ii, NaBH,; iii, Ac,O-py; iv, B,H,; v, hydrolyse, then treat dimesylate with AcONEt,; vi, TsC1-py; vii, NaCH,SOMe.

Scbeme 10

Terpenoidsand Steroids

20

secologanin aglucone methyl ether (93), and the lactol of secologanic acid ether (94), from which sweroside methyl ether (81 ; R = Me) was obtained (Scheme 10). A postulated biogenetic path from the cis-loganin series, e.g. (92),is thus not realizable in vitro.' 2 8 A new type of geraniol cyclization occurs when either the E- or Z-isomer (15) or (16), cyclogeraniol (95; R = CH,OH), or irid-1-en-9-01 (96) is treated with fluorosulphonic acid in sulphur dioxide and carbon disulphide at - 78 "C.The presence of the oxonium ion (97)of the new iridoid (98)was demonstrated by n.m.r. spectrometry (Scheme 1l).'29

Scheme 11

p-Menthanes.-An excellent review of methods for synthesizing optically active menthol' 30 and one on pterpineol' have appeared. Addition of acetone to the dilithium salt of 4-methylcyclohex-3-enecarboxylicacid leads to a hydroxy-acid (99) which lactonizes with benzenesulphonyl chloride, the lactone (100)giving terpinolene (101)on heating.' 3 2 4-Methyl-2-hydroxycyclohexanone isomerizesduring reaction with 1-methyl-2-ethoxyethenyltriphenylphosphonium iodide, SO that two menthofurans (102) and (103) are oblained. Efforts to trap the single anion needed to form only (102)were not successful.' 3 3 Methyl 4-methylcyclohexa-l,4-dienecarboxylate is readily converted into mentha-l,4-dien-8-01 (104; R = OH), which is

'IR ""

13'

'"'"

L.-F. Tietze, J . Arne?. Chem. Soc., 1974, 96, 946. D. V. Banthorpe, P. A. Boullier, and W. D. Fordham, J.C.S. Perkin I , 1974, 1637. J . C. Leffingwell and R. E. Shackelford, Cosmetics and Perfumery, 1974, 89, 69. J . Verghese, Indian Perfumer, 1972, 16. 3 5 . A. P. Krapcho and E. G . E. Jahngen, jun., J . Org. Chem.. 1974, 39, 1322. M. E. Garst and T. Spencer, f . Org. Chem., 1974, 39, 584.

Monoterpenoids

21

readily oxidized by air to the aromatic alcohol. Claisen rearrangement of the vinyl ether (104; R = OCH=CH,) introduces a C2 unit at C-3.'34 The tricarbonyliron complexes (105) of ~+phellandrene~'.'~~ are isomerized by acid, subsequent removal of the iron (with Cu2+)giving mentha-2,4-diene.l 3 5 U.V. irradiation of a-phellandrene gives two isomers [(106); exo : endo = 5 : 13 arising from cyclization of triene (107).'36

Heptafluorinated menthanes and menthols (fluorine in the isopropyl group) have been made. 37 4-Chloromentha- 1,8-dienehas been noted above,3s trans-8-chloromenth2-ene is made by addition of hydrogen chloride to mentha-2,8-die11e,'~*and chlorination of menthone (39) and carvomenthone leads to substitution of the more substituted carbon atom adjacent to the carbonyl group.' 39 Carman and Venzke have prepared the 1,2,4,8-, 1,2,8,9-, and 1,4,7,8-tetrahaIogenomenthanesand have extended their work (Vol. 4,p. 31) by making optically active terpinolene tetrabromide (108)from (+)-or-terpineol (17).' 40 Bromination of ( - )-a-phellandrene and (- )-P-phellandrene [mentha-1(7),2diene] was examined ; the 1,2,3,7-tetrabromide from the latter showed greater stability than the limonene or terpinolene tetrabromides (108).14' Action of base on 1,4,8tribromomenthane, followed by bromination, gives the two tetrabromides (108)and (109) derived from terpinolene and mentha-l(7),4(8)-diene respectively. The tetrabromide of mentha-1(7),3-diene (p-terpinene) is also described. 42 In a discussion of halogenated

'

'

134 135

136 13'

13' 139

I4O 14' 14'

A. Hoppmann and P. Weyerstahl, Chem. Ber., 1974, 107, 1102. A. J. Birch, J . Agric. Food Chem., 1974, 22, 162. K. J. Crowley, K. L. Erickson, A. Eckell, and J. Meinwald, J . C . S . Perkin Z, 1973,2671. A. N. Blakitnyi, V. N. Boiko, E. V. Konovalov, Yu. A. Fialkov, and L. M. Yagupol'skii, Zhur. org Khim., 1974,10, 503; A. N. Blakitnyi, E. V. Konovalov, A. P. Sevast'yan, Yu. A. Fialkov, and L. M. Yagupol'skii, ibid., p. 509; cf: Vol. 2, p. 21. A. B. Booth, U S . P. 3 755 472. F. Yasuhara, Nippon Kagaku Kaishi, 1973, 1938. R. M. Carman and B. N. Venzke, Austral. J. Chem., 1973, 26, 2235; 1974, 21, 383. R. M. Carman and B. N. Venzke, Austral. J. Chem., 1974, 27, 441. R. M. Carman and B. N. Venzke, Austral. J. Chem., 1974, 27, 449.

Terpenoids and Steroids

22 CH,Br

Qr

---Br

menthones. it is suggested that some a,a'-dibromocyclohexanones can exist in boat form ( f 10) if there is an additional halogen-carbonyl i n t e r a ~ t i 0 n . l ~ ~ Photoinitiated auto-oxidation of l i m ~ n e n e ' ~ has ~''~ been ~ shown to involve 41 % unsensitized photo-oxidation by singlet oxygen, occurring concurrently with radical oxidation. 1 4 5 Limonene cis- and trans-monoepoxides can be separated by spinning-band distillation instead of the long route previously used (Vol. 1, p. 26); catalytic hydrogenation of the pure isomers has been studied.'46 The monoepoxide (1 11) of y-terpinene occurs in Origanum heracleoticum and was reported to be the sole product from epoxidation of the hydrocarbon with monoperphthalic acid,147which is surprising since peracetic acid148 and peroxybenzimidic acids' 49 yield both monoepoxides. a-Terpinene (18) also yields both monoepoxides,'50 and metal hydride reduction of all these substances has been investigated.'49*'5 o Ring-opening by ethanol in basic or acid media of limonene (11) 1,2epoxides and diepoxides has been studied ; the latter undergo 1,2-ring-opening with boron trifluoride etherate but 8,9-opening with base catalysis.' 5 1 The complete stereochemistry of (lS, 2S, 3R, 4S)-piperityl acetate epoxide (1 12) isolated from several Mentha spp. is established.'52

14' '44

145

146

14'

14'

' '

5o I

15*

R. M. Carman and B. N. Venzke, Austral. J. Chem., 1973,26, 1977. I . I . Bardyshev, V . S. Shavyrin, and V. V. Budylina, Sbornik, Trudov, (sent. nauchn.-issled. Proekt. Inst. lesokhim. Prom., 1971, NO.21, p. 25 (Chem. Abs., 1974, 80, 70 973). T. Sato and E. Murayama, Bull. Chem. SOC.Japan, 1974, 47, 715. A. Kergomard and H. Veschambre, Compt. rend., 1974, 279, C , 155. B. M. Lawrence, S. J. Terhune, and J. W. Hogg, Phytochemistry, 1974, 13, 1012. A. F. Thomas, unpublished work. S. A. Kozhin and E. I. Sorochinskaya, Zhur. obshchei Khim., 1974, 48, 944; cf- Vol. 4, p. 30. M. Zaidlewicz and A. Uzarewicz, Roczniki Chem., 1974,48,467. L. A. Mukhamedova, M. I. Kudryavtseva, R. R. Shagidullin, and Yu. Yu. Samitov. Izvesr. Akad. Nauk S . S . S . R . , Ser. khim., 1973, 1061; L. A. Mukhamedova, M. I. Kudryavtseva, and A. A. Martynov, ibid., 1974, p. 404. H . Shibata and S. Shimizu, Agric. and Biol. Chem. (Japan), 1973, 37, 2675.

Monoterpenoids

23

Hydroperoxides and other p-menthanes oxygenated at C-4 and C-8 are formed from menthan-4-01and hydrogen peroxide in acid.lS3A product of ene addition to isopulegol (8; R = H) dwing selenium oxide oxidation can be trapped as the selenino-lactone (1 13), thus supporting a step in the postulated mechanism of allyl alcohol oxidation (Vol. 4, p. 17). s4 Mercuric acetate and limonene (11) yield (after borohydride reduction) aterpineol (17) and menth-8-en-1-01. With less mercuric acetate, the 1,8-di0l (114) and 1,8-cineol (115) were found, together with (17),1 5 5 but possible dehydration of diols [e.g. (114)], known to occur on gas ~ h r o m a t o g r a p h y , was ' ~ ~ not taken into account. Dehydrocineol(ll6) has been isolated from Laurus nobilis, in which cineol (115) is the major constituent.' 5 7 Surprisingly, silver carbonate<elite oxidation of isopulegol (8 ; R = H) is slow and gives an unidentifiable mixture.15* Better stereoselectivity in the allyl oxidation by benzoyloxy-radicals of menth-2-ene is achieved by using copper octanoate as the catalyst (the radical attacking anti to the isopropyl group).'59

'

Nitration of p-cymene (117; R' = R 2 = H) has been known for well over a century to yield p-nitrotoluene by ips0 electrophilic attack (nitrodeisopropylation); now a novel mechanism, based on the idea of the C-1 position as that most active towards attack by nitronium ion, is supported by the isolation of up to 41 % of the ipso-adducts (1 18 ; cis and trans) and 41% of 2-nitrocymene (117; R' = H, R2 = NO,). Migration of the nitrogroup to C-2 masks the existence of the ipsu-products unless conditions allow their isolation, and their thermolysis leads to thymol acetate (117; R 1 = OAc, R2 = H).16' Esterification of 8-hydroxycuminic acid (119 ; R' = R 2 = H) with dry methanol and sulphuric acid gives the esters (119; R' = Me, R2 = H) and (119; R' = R2 = Me), but the presence ofmoisture results only in dehydration of the alcohol. Treatment with hydrochloric acid followed by methanol leads to the dimer (120).16' The protecting group (p-methylbenzyl ether) of perilla alcohol (121) was removed with perchloric acid in acetic acid after hydroboration of the 8,9-double bond.'62 This reaction might have been less successful if the double bond had still been present, owing to rearrangement in the acid conditions ( c j . Vol. 1, p. 23). 153

154 155

156

15'

Is8

I6O 161 16*

Yu. A. Ol'dekop, L. B. Beresnevich, and L. Ya. Shveidel, Vestsi Akud. Nauuk Belurusk. S . S . R . , Ser. khim. Nauuk, 1974, 50. D. Arigoni, A. Vasella, K. B. Sharpless, and H. P. Jensen, J . Amer. Chem. Soc., 1973,95, 7917. M. Bambagiotti A., F. F. Vincieri, and S. A. Coran, J . Org. Chem., 1974, 39, 680. L. Peyron, L. Benezet, D. de Dortan, and J. Garnero, Buii. Soc. chim. France, 1969, 339. J. W. Hogg, S. J. Terhune, and B. M. Lawrence, Phytochemistry, 1974, 13, 868. F. J. Kakis, M. Fetizon, N. Douchkin, M. Golfier, P. Mourges, andT. Prange, J . Org. Chem., 1974, 39, 523. A. L. J. Beckwith and G. Phillipou, Tetrahedron Letters, 1974, 69. R. C. Hahn and D . L. Strack, J. Amer. Chem. Soc., 1974,96,4335. J . Alexander and G. S. K. Rao, Indian J . Chem., 1973, 11, 619. G. Frages and H. Veschambre, Buli. SOC.chim. France, 1973, 3172.

24

Terpenoids and Steroids I

a-Terpinene (18) gives a nitro-oxime (122) with nitrous acid (the 'nitrosite' of W a l l a ~ h ) ; ' "oximes ~ (123) can also be obtained from y-terpinene (104; R = H) by addition of nitrosyl chloride, followed by treatment with amines. 164

Microbiological reduction of carvone (1) with Pseudomanas ovalis or Aspergillus niger occurs with inversion at C-4; the configuration at C-1 varies: (+)-carvone yields (-)isodihydrocarvone (124) and ( - )-isodihydrocarveols (125); ( - )-carvone gives ( + )dihydrocarvone (126)and ( -)-dihydrocarveols, the alcohols corresponding to (126)?

A

A

A

(124)

(125)

(126)

Rate measurements on the borohydride reduction of menthone (39) do not support epimerization before reduction, and the authors do not agree with Hach et al. (Vol. 2, p. 30) that 'extensive epimerization' occurs in dry propan-2-01.' 66 ( f)-Menthone is reduced to menthol with 29.2 % optical purity using chiral bis(cyclohexylmethy1-oanisy1phosphine)cyclo-octa-1,5-dienerhodium tetrafluoroborate and hydr~gen.'~'A thermoanalytical study of the menthol enantiomers has been carried out,'68 and con-

163

'64

16'

166

16*

R. M. Carman, B. Singaram, and J. Verghese, Austral. J. Chem., 1974, 27, 453; 0. Wallach, Annalen, 1887, 239, 33. R. M. Carman, B. Singaram, and J. Verghese, Austral. J. Chem., 1974, 27, 909. Y . Noma and C. Tatsumi, Nippon Nijgeikagaku Kaishi, 1973,47,705; Y . Noma, S. Nonomura, H. Ueda, and C. Tatsumi, Agric. and Biol. Chem. (Japan), 1974, 38, 735; Y. Noma and S. Nonomura, ibid., p. 741. D. C. Wigfield and D. J. Phelps, J. Amer. Chem. Sac., 1974, 96, 543. A. J . Solodar, Ger. Offen 2 312 924. M. Kuhnert-Brandstatter, R. Ulmer, and L. Langhammer, Arch. Pharm., 1974, 307,497.

Monoterpenoids

25

1

iii

Reagents: i, Anodic oxidation; ii, H,O,-OH-; iii, N,H,; iv, MnO,; v, Pd-H,. Scheme 12

version of (-)-menthone (39) into (+)-menthone (Scheme 12) was needed in a preparation of optically pure citronellols (above).75 Hydroxymethylation of menthone (39) gives a 5 : 1 mixture of cis : trans isomers (127) ;169based on the chemical shift of the enol proton, the formulation (127) is preferred to the alternative ( 128).170Reaction of these products with butenone reportedly gives (129) and (130), but the stereochemistry may be more complex than that described.17' Reformatsky reaction of (-)-menthone (39) leads to 80-90% equatorial entry of reagent, the presence of dimethyl sulphoxide increasing the amount of the other isomer.1 7 2 Preparation of the C-2 isomer by Reformatsky reaction of carvomenthone is also d e ~ c r i b e d . 'Variations ~~ in the proportion of axial : equatorial attack on menthone (39), depending on the metal atom, are noted with (131).17, Pulegone (132) and isopropylmagnesium chloride give a chloromagnesium enolate that reacts with p-substituted benzaldehydes (but not saturated ketones), yielding two of the four possible stereoisomers ( 1 33). s Reaction of carbon tetrachloride with limonene (1 1) is catalysed by benzoyl peroxide ; the product (134)can be hydrolysed to the corresponding acid, which was used to add a C, unit in synthesizing the sesquiterpenoid atlantone. 17' Hydroformylation of limonene in the presence of [CO(CO)~PR,],(R = Bu or Ph) or rhodium carbonyl complexes also results in addition to the isopropenyl group.177

'

16'

'-O

IT6

V . M. Potapov, G. V. Kiryushkina, 1. K. Talebarovskaya, N . N . Shapet'ko, and I. L. Radushnova, Zhur. org. Khim., 1973, 10, 21 34. C . Metge, P. Cuillier, and C. Bertand, Compt. rend., 1974, 278, C, 1141. G. D. Joshi, P. H. Ladwa, and S. N . Kulkarni, Indian J . Chem., 1973, 11, 824. J. Pansard and M. Gaudemar, Bull. Soc. chim. France, 1973, 3472. J . F. Ruppert and J. D. White, J . Org. Chem., 1974, 39, 269. N. Idriss, M. Perry, and Y . Maroni-Barnaud, Tetrahedron Letters, 1973, 4447. F. Ghozland,Y. Maroni-Barnaud, and P. Maroni, Bull. Soc. chim. France, 1974, 147, 155. J. Alexander and G. S. K. Rao, Indian J . Chem., 1973, 11, 859. K. Kogami, 0.Takahashi, T. Yanai, and J. Kumanotani, Yakagaku, 1973,22,316 (Chem. A b s . , 1973, 79, 92 400).

Terpenoids and Steroids

26

BU‘OC-.Q

1.:’

-

CHR M = metal (Mg, Zn, etc.)

’

A

(131)

CCI,

Ring contraction of the epoxide of (132) leads to cyclopentanes ; particularly interesting are the preparation of (1R,2R)-dimethylcyclopentane’ ” and the spirolactone (135). 7 9 C-Silylation (at C-6) occurs when carvone (1) is treated with trimethylchlorosilane in the presence of lithium in tetrahydrofuran.

I

+ ‘

0

(135)

The two diols (136) and (137) from hydroboration of (-)-piperitone (138), whose absolute stereochemistries have been confirmed, were used to check Nakanishi’s dibenzoate chirality rule.’ The conformation and reactions of cineolic acid (139), a product of the permanganate oxidation of cineol(ll5), have been studied.’ *

’’

(136)

(137)

(138)

( 139)

W. C. M. C. Kokke and F. A. Varkevisser, J . Org. Chem., 1974, 39, 1535. K. Hayashi, H. Nakamura, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1973, 21,

‘‘I

2806. R. Calas, J. Dunogues, A. Ekouya, G . Merault, and N. Duffant, J. Organometallic Chem., 1974, 65, C4. J. I. Seeman and H. Ziffer, J. Org. Chem., 1974, 39, 2444. I. D. Rae and A. M. Redwood, Austral. J. Chem., 1974, 27, 1143.

27

Monoterpenoids

Other publications related to p-menthanes concern confirmation of two of the ‘carvelone’ structure^,'^^ selenium oxide-hydrogen peroxide oxidation of l i m ~ n e n e , ’ ~ ~ reaction of ( + )-pulegone (132) and benzoyl chloride, l 8 addition of carbene to carvone (l), piperitone (138), and pulegone (132),186addition of dibromocarbene to pulegone (132) and isopulegols (7; R = H) and (8; R = H) and conversion of the products into allene~,’~’and coupling of diazonium salts with menthadienes and of diazotized 3amino-p-cymene (117; R’ = NH,, R2 = H) with o-Menthane.-Spectra

of some o-menthenes have been studied.’ 89

rn-Menthanes.-Ficini has extended her stereospecific addition of an ynamine and an unsaturated ketone (Vol. 3, p. 39) to the rn-menthanes by using 5-methylcyclohex-2enone as substrate. The acids thus obtained were required in the juvabione synthesis.

Tetramethylcyclohexanes.4ne of the two new lactones from Avtemisia filifolia (Vol. 4, p. 38), (-)-filifolide-A (141), can be made from (-)-chrysanthenone epoxide ( l a ) , a rearrangement that is symmetry-forbidden if concerted. The stereochemistry at the aserisk

OR (142) (144)

R R

=

H

=

isopentyl

OAc

( 1 43)

Reagents: i, Pb(OAc),; ii, v. dil. NaOH in MeCN.

Scheme 13 J . Grimshaw and J. Trocha-Grimshaw, J.C.S. Perkin I , 1973, 2584; cJ Vol, 4, p. 33. I E 4 M. Sumimoto, T. Suzuki, and T. Kondo, Agric. and Biol. Chem. (Japan), 1974, 38, 1061. I M 5P. Crabbe, Recent Adc. Phytochem., 1973, 6, 1. I M 6F. Rocquet and A. Sevin, B u f f .Soc. chim. France, 1974, 888; cJ notes by these authors: Tetrahedron Letters, 1971. 1049; Compt. rend., 1971, 272, C , 417; and the (unquoted) work of M. Narayanaswamy, V. M. Sathe, and A. S. Rao, Chem. and Ind., 1969,921. l E 7M. Santelli and M. Bertrand, Bull. SOC.chim. France, 1973, 2326; B. Ragonnet, M. Santelli, and M. Bertrand, ibid., p. 3119. C. H. Brieskorn and H. H. Frohlich, Arch. Pharm., 1973, 306, 641.

19’

V. V. Bazyl’chik, I. I. Bardyshev, N. M. Ryabushkina, N . P. Polyakova, and P. I. Fedorov, Vestsi Akad. Navuk Belarusk. S . S . R . , Ser. khim. Navuk, 1973, 104. J. Ficini and A. M. Touzin, Tetrahedron Letters, 1974, 1447.

28

Terpenoids and Steroids

is consistent with that of lavandulol analogues from other Arternisia spp.19' Naturally occurring hydroxy-aldehydes (142) and (143) and the ester (144) have been synthesized (Scheme 13).192 Conversion of a-cyclogeraniol (95 ; R = CH,OH) into a-cyclocitral (95 ; R = CHO) without loss of optical activity requires careful modification of Oppenauer condit i o n ~ one ; ~ of ~ ~the corresponding saturated acids (145) (having a higher m.p.) is

identical with a naturally occurring acid from Californian crude oil.' 94 Some transformations of P-pyronene (146), available from pyrolysis of a-pinene, are described (Scheme 14),in the course of which dehydro-1,4-cineol(l48) is quoted [the analogous oxide (149)

HO

R

=

(147) R

=

(146)

Reagents: i, hv, O,-sensitizer; ii, LiAlH,; iii, HCrO, (two-phase); iv, NaBH,; vi, monoperphthalic acid.

Me CHO

V,

perbenzoic acid;

Scheme 14

was not encountered] however, the reference given196expresses doubt about its existence. a-Cyclogeranyl chloride (95 ; R = CH,CI) is conveniently made by cyclizing geranyl chloride (25; R = H,) with boron trifluoride etherate.197The action of lead tetra-acetate on P-cyclogeraniol(l50; R = C H 2 0 H )is less clean than that on a-cyclogeranisl(95; R = CH,OH), which yields a 50 : 30 mixture of the acetates (95; R = OAc) and (150; R = OAc).19*The vinyl ether (150; R = CH,OCH=CH,) gives a mixture containing 30"/; of the ketone (150; R = CH,COMe) and j?-cyclogeraniol (150; 19'

'92

S. J . Torrance and C. Steelink, J . Org. Chem., 1974, 39, 1068. F. Bohlmann and G. Weickgenannt, Chem. Bet-., 1974, 107, 1769;

CJ

Vol. 1, p. 36; Vol. 2, p.

35. 193

195 196

19' 19*

R. Buchecker, R. Egli, H. Regel-Wild, C. Tscharner, C. H. Eugster, G. Uhde, and G . Ohloff, Helv. Chim. Acta. 1973, 56, 2548. R. Buchecker and C. H. Eugster, Helv. Chim. Acra, 1973, 56, 2563. W . Cocker, K. J. Crowley, and K. Srinivasan, J.C.S. Perkin I, 1973, 2485. G. 0. Pierssn and 0. A. Rundquist, J. Org. Chem., 1969, 34, 3654. Y . Butsugan, K. Sahaki, T. Bito, and M. Muto, Nippon Kagaku Kaishi, 1973, 1804. J . Ehrenfreund, M. P. Zink, and H. R. Wolf, Helc. Chim. Acta, 1974, 57, 1098.

29

Monoterpenoids

R = CH,OH) with buty1-lithi~m.l~~ Safranal (147) is made by allylic bromination ( N bromosuccinimide of j3-cyclocitral(l50; R = CHO) followed by dehydrobromination, a-cyclocitral(95 ; R = CHO) decarbonylating under these conditions.200 Allyiic bromination of isophorone (151 ; R = H) yields the bromide (151 ; R = Br), reacting with sodium aryl sulphonates or sulphides to give the substitution products (152). Debromination of (151 ; R = Br) with zinc and chromium trichloride gives flisophorone (153)and isophorone (151; R = H) in the ratio 5 : 1.201 The ene reaction of isophorone (151; R = H) with tetracyanoethylene yields (154).’02

1,4Dimethyl- 1-ethylcyc1ohexane.-The methyl ketone has been improved.203

preparation of 1,4-dimethylcyclohex-3-enyl

Cycloheptanes-The eucarvone (155) ring-inversion energy barrier is 8.3 kcal mol- 1.204 The complexity of the products from photoisomerisation of eucarvone (155) is well known; a study in strong acids and methanolic solvents revealed the new product (156),probably formed from the protonated ketone ( 157).205

”’ V. Rautenstrauch, G. Biichi, and H. Wuest, J . Amer. Chem. SOC.,1974, 96, 2576. 2oo 20’ 202

203

W. M. B. Konst, L. M. van der Linde, and H. Boelens, Tetrahedron Letters, 1974, 3175. J. N . Marx, Org. Prep. Proc. Internat., 1973, 5, 45. A. Cornelis, P. Laszlo, and C. Pasquet, Tetrahedron Letters, 1973, 4335. W. Kreiser, W. Haumesser, and A. F. Thomas, Helv. Chim. Acta, 1974, 57, 164; cf. Vol. 4, p. 40.

204 205

E. Cuthbertson and D. D. MacNicol, Tetrahedron Letters, 1974, 2689. K . E. Hine and R. F. Childs, J . Amer. Chem. Soc., 1973, 95, 6116; cf. V O ~2,. p. 36; Vol. 3, p. 54.

30

Terpenoids and Steroids 6 Bicyclic Monoterpenoids

Bicycl~3,1,O]hexane~-The conformation of several thujanoi (1 58 ; unspecified stereochemistry) isomers is shown to be boat-like by both ‘H n.m.r.206and I3Cn.m.r. spectroscopy.207Nomenclature is not yet uniform : Norin (and this Report) uses ‘iso’ as with menthanes, to mean cis methyl and isopropyl groups,2o6 but Whittaker et a1.2 07.2 0 8 use the opposite convention. These authors have shown how transformations of the ion (159), derived from neothujanol (158) (which they call ‘neoisothujanol’) depend on the presence or absence of antimony pentafluoride.208

Bicyclo(2,2,l]heptanes.-A new synthesis of epicamphor (160; R‘ = Me, R2 = H2) not involving camphor has been effected (Scheme 15).*09 The fenchane (161) is obtained

4 n

CHCl

/ + I 1

f-3

-&

0

0

1

iv

/-I

r7 O@OH

O

k

O

Ht vi,ii,vii CHO

\

(+ isomer)

( 160) Reagents: i, hv; ii, acetalize; iii, Na; iv, B,H,-oxidation; v, deacetalize vii, LiAlH,; viii, NaH on tosylate.

+ retroaldol; vi, oxidize;

Scheme 15 206

207 208 209

T. Norin, S. Stromberg, and M. Weber, Acta Chem. Scand., 1973, 27, 1579. R. J. Abraham, C. M. Holden, P. Loftus, and D. Whittaker, Org. Magn. Resonance, 1974,6, 184. C . M . Holden and D. Whittaker, J.C.S. Chem. Comm., 1974, 3 5 3 . C. Boust and P. Leriverend, Bull. SOC.chim. France, 1974, 1201.

31

Monoterpenoids

by the action of stannic chloride on the cyclopropane (162).'" Full details of Money's camphor synthesis (Vol. 1, p. 39) have appeared.2' Mass spectrometric fragmentation of bornyl acetates and alcohols involves principally l 2 The molecular geometry of the fluorescent state of camphorci~-1,2-elirnination.~ quinone (160; R' = Me, R2 = 0)has been studied in the light of circularly polarized luminescence and c.d. meas~rements.~'C.d. measurments have also been carried out on the followingcompounds; (160; R' = 2H, R 2 = 0),214 (163; R = CF,, M = Co, n = 2),2'5 and (163; R = Me, M = Ru, n = 3).216 The chelate-forming ability of hydroxymethylene derivatives of camphor (2) has been examined2l 7 and the rotatory dispersion and c.d. of the copper chelates have been measured.218

&, GlM/n

M..O\X~\-J

Mec&

( 142)

(141)

(143)

Use of an algebraic model and a computer programme have enabled Johnson and Collins to solve problems such as the rearrangement of the lacton'e (164) in sulphuric acid ; they have confirmed Sorensen's idea that fenchyl ions in ultra-strong acid do not form sequentially, but seek out those structures which are thermodynamically most stable at a given temperature.*lg Olah and Liang were unable to detect non-classical ions of the dimethylnorbornyl type by n.m.r. spectroscopy, although they are not excluded as higher-energy species on solvolytic pathways.220 Camphene (165), tricyclene, and bornene all yield the same acetate mixture with acetic acid-sulphuric acid ; the kinetics of the reaction have been measured.221Re-calculation of data purporting to involve a small amount of endo-3,2-methyl shift during racemization of [8-' 3C]camphene (165) (Vol. 4,44) shows that this is not necessary.222The interconversion of

1641

210

2L1 212 213 214 215 216

218

220 221

222

P. A. Grieco and R. S. Finkelhor, Tetrahedron Letters, 1974, 527. J. C. Fairley, G. L. Hodgson, and T. Money, J.C.S. Perkin I, 1973, 2109. R. Robbiani and J. Seibl, Org. Mass Spectrometry, 1973, 7 , 1 1 5 3 . C. K . Luk and F. S. Richardson, J . Amrr. Chem. SOC.,1974,96, 2006. W. C. M. C. Kokke and L. J. Oosterhoff, J . Amer. Chern. SOC.,1973, 95, 7159. E. C. Hsu and G. Holzwarth, J. Amer. Chem. SOC.,1973, 95, 6902. G. W. Everett, jun., and R. R. Horn, J. Amer. Chem. SOC.,1974, 96, 2087. V. M. Potapov, G. V. Panova, N. K. Vikulova, and N. B. Kupletskaya, Zhur. obshchei Khim., 1973,43, 926, 930. V. M. Potapov, G. V. Panova, and N. K. Vikulova, Zhur. obshchei Khim., 1973,43,939. C. K. Johnson and C. J . Collins, J . Amer. Chem. SOC.,1974, 96, 2514; C. J. Collins, C. K. Johnson, and V. F. Raaen, ibid., p. 2524. G . A. Olah and G. Liang, J. Amer. Chem. SOC.,1974, 96, 189. Y . Castanet, F. Petit, and M. Evrard, Bull. SOC.chim. France, 1974, 1097. C. J. Collins and M. H. Lietzke, J. Amer. Chem. SOC.,1973, 95, 6842.

32

Terpenuids and Steroids

8-, 9-, and 10-homocamphene (165; +Me at positions indicated) under the same conditions as this racemization has been studied and a homotricyclene isolated.223 Re-examination of the thermal decomposition of borneol and isoborneol p-nitrobenzoates and urethanes has led to the detection of a small amount of pinene besides the known tricyclene, camphene, etc. 24 Rearrangement of bromonitrocamphane (166; R’ = Br, R 2 = NO2)to anhydronitrocamphane (167; R = Br) involves (i) loss of NO,, (ii) rearrangement of the cation, and (iii) recombination of NO,, the latter being postulated to occur by addition of H 2 N 0 2 +to 4-bromocarnpheney a precedent for this step being the addition of nitrous acid to camphene (165), which leads to anhydronitrocamphane (167; R = H).225

Rearrangements of the Wagner-Meerwein type occur if the amino-acid (166; R’ = NH,, R 2 = C 0 2 H )(made from camphor) is deaminated with nitrous acid,226and also on treatment of camphor (2) with isocyanides in the presence of acetic acid (Passerini reaction).227 Hydrogenolysis of bornylurea [166; R’ = H, R2 = Oc(NHC6Hl1)= NC6H is not easy because of steric hindrance, but the exu-isomer is hydrogenolysed in 20 h to the rearranged endu-isocamphene (168).228Similar rearrangements occur if exo-2,10-dibromobornane (169) is treated with bases (leading to o-bromocamphene), but not with silver nitrate, when substitution takes place.229Eliminations of bromoborneols with base take a different route from those of the tosylates (which form epoxides ; cf. Vol. 3, p. 68). syn-Elimination from 3-endu-bromoisoborneol(l70),yielding camphor, occurred with most bases except potassium t-butoxide in dimethylformamide, this course being followed exclusively with bromo-epi-borneol (1 71).230 Bromination of

camphor (Scheme 16) to endo-3,9-dibromocamphor (172) involves an exo-methyl migration, which Money et al. reasoned could be hindered by placing a bulky group (e.g. 223 224

22s 226

”’ 228

’”

230

W . R. Vaughan and D. M. Teegarden, J. Amer. Chem. SOC.,1974,96, 4902. P. Malkdnen and J. Korvola, Finn. Chem. Letters, 1974, 1, 19, 23. S. Ranganathan and A. H. Raman, Tetrahedron, 1974, 39, 63. Y. Maki, T. Masugi, and K. Ozeki, Chem. and Pharm. Bull. (Japan), 1973, 21, 2466. G. Minardi, E. Bottini, and A. Gallazzi, Farmaco, Ed. sci., 1973, 28, 1030. E. Vowinkel and I . Biithe, Chem. Ber., 1974, 107, 1353. G. Mehta, Indian J . Chem., 1973, 11, 843. K. Marks and M. Szkoda, Roczniki Chem., 1973,47, 2295.

Monoterpenoids

33

bromine) in the 3-exo-position (173; X = Br). Whether the actual mechanism is really a 2-endo-methyl migration is not clear, but the result is the formation of the desired 3,3,8-tribromocamphor (174)from the bromination of dibromocamphor (173;X = Y = Br). Zinc-acid reduction removes the secondary bromines, making either 8- or 9bromocamphor available.’ Dimmel has demonstrated that optical activity is lost in the bornyl sultone rearrangement (Vol. 4, p. 47), but there is almost no endo-3,2-methyl shift.23’ An exo-’H-labelled camphor was made by reduction of endo-bromocamphor (1 73 ; X = H, Y = Br) with sodium borohydride and rhodium t r i ~ h l o r i d e Arylidene.~~~ camphors are reduced in the presence of [RUC~,(PP~,),].”~ Although poor when applied to most ketones, incorporation of deuterium on quenching the reaction mixture of butyl-lithium and camphor tosylhydrazone with deuterium oxide reaches 95%.’3s Another anomaly is that the enol silyl ethers of camphor are not cleaved by ozone, but give 3-silyl ethers (175), probably uia the e p ~ x i d e . ~ ~ ~

Comparison of the action of Grignard and alkyl-lithium reagents on camphor (2) and on fenchone (176) has been made.237Prenyl-lithium reacts normally with fenchone

’’’ 232 233 34

235

236 23‘

C. R. Eck, R. W. Mills, and T. Money, J.C.S. Chem. Comm., 1973, 91 1. D. R. Dimmel and W. Y. Fu, J . Org. Chem., 1973, 38, 3778, 3782. C. J. Love and F. J. McGuillin, J.C.S. Perkin I, 1973, 2509. M. Dedieu and Y .-L. Pascal, Compr. rend., 1974,278, C , 9 ; they report that catalytic reduction is difficult, but see Vol. 3, p. 65. R. H. Shapiro and E. C. Hornaman, J . Urg. Chem., 1974, 39, 2302. R. D. Clark and C. H. Heathcock, Tetrahedron Lerters, 1974, 2027. J. Korvola, Suomen Kem. ( B ) , 1973, 46, 212, 262.

34

Terpenoids and Steroids

(176)(yielding only endo-product), but camphor is like other severely hindered ketones, giving more rearranged borneol (166; R' = OH, R2 = CMe2CH=CH2) than the product of direct addition (166; R' = OH, R 2 = CH2CH=CMe,).238 The Grignard addition product of 4-chloropent-3-enyl-lithium to the ketone (177) undergoes cyclization and rearrangement of a methyl group with formic acid, and the resulting product (178) is readily converted into the ketone (179), which is also obtainable from albene (180)(Vol. 3, p. 8), whose structure is thereby verified.239

(:76) R = Me (177) R = H

(178) R = Hor COMe (179) R = 0

(180) (181)

3-Bromocamphor (173; X = H, Y = Br) with phenylhydrazine yields the 3-phenylhydrazino-2-phenylhydrazone and the phenylhydrazone (18 1 ), with the diphenylhydrazone of camphorquinone (160; R' = Me, R 2 = 0)at higher temperature^.^^' Rate measurements on the iodination of the acid (173; X = H, Y = C 0 2 H )and the methyl ester have been made, but camphor reacts too slowly for reliable values to be obtained. 24' Highlights in a series of papers by Gream et al. on the carboxylic acids (182)and (166; R' = C 0 2 H , R 2 = H) include the behaviour on oxidation either with lead tetraacetate or anodically, a synthesis of (-)-camphene (165) of high optical purity from the tosylate (183) of campholenic alcohol, and a study of the opening of the cyclopropane ring of the main product (184) obtained from camphene (165) and (MeO),SiCH(OMe), .242

(182) R' = COZH, R 2 = H or R' = H, RZ = COzH (186) R' = H . R 2 = OTS

(183)

Carbocamphenilone (185), despite earlier conflicting statements, has a chair conformation (by X-ray crystallography and ~ . d . )Ring-expansion . ~ ~ ~ of the tosylate (186) is more difficult than with the unsubstituted homologue, and since release of ring strain A new was considered to be the same in both cases, an electronic effect was 238 239 240 241

24i

243 244

V. Rautenstrauch, Helc. Chirn. Acta, 1974, 57, 496. P. T. Lansbury and R. M. Boden, Terrahedron Letters, 1973, 5017. A. G. Giumanini, L. Caglioti, and W. Nardini, Bull. Chern. Soc. Japan, 1973, 46, 3319. R. P. Bell and M. I. Page, J . C . S . Perkin II, 1973, 1681. G . E. Gream and C. F. Pincombe, Ausrral. J . Chem., 1974, 27, 543, 589; G. E. Gream, C. F. Pincombe, and D. Wege, ibid., p. 603; G . E. Gream, D. Wege, and M. Mular, ibid., p. 567. B. Lee, J. P. Seymour, and A. W. Burgstahler, J . C . S . Chem. Cornm., 1974, 235. P. I. Meikle and D. Whittaker, J . C . S . Perkin I I , 1974, 322.

Monoterpenoids

35

ring-expansion involves N-bromosuccinimide bromination of the Grignard addition product (166; R' = OH, R 2 = CH2Ph) and reaction of the product (166; R' = OH, R2 = CHBrPh) with isopropylmagnesium bromide. The resulting complex gives the bicyclo[3,2,l]octanones (187) and (188) in benzene.245 Thermolysis of the cyclic endo-sulphite (189) yields camphor (2) and epicamphor (160; R' = Me, R2 = H2),but the more stable exo-isomer undergoes ring fission and rearrangement to the aldehyde (190).246Beckmann fragmentation of the oxime (191)has

been investigated (cf.Vol. 4,p. 51).247Microbial metabolism of camphor was claimed248 to produce a lactone (192; R = Me) with one carbon atom fewer. This lactone (192; R = Me) has now been shown to be a different substance, and the metabolic product is more likely to have retained all ten carbon atoms as in (193).249Some reactions of derivatives of camphanic acid (192; R = C 0 2 H ) are reported.250 Preparation of the ether (194; R = H2) from camphoric anhydride (194; R = 0) is described.251Ring fission to cyclopentanones and cyclohexanones accompanies chromic oxidation of the 1-hydroxybornanes ( 195).252

Thiocamphor (196) usually gives rearranged products (166 ; R ' = CHRCH=CH, , R 2 = SH) with ally1 Grignard reagents; heating converts these into cyclized sulphides (197) (cf. Vol. 4,p. 52).253Unlike camphor, thiocamphor (196) reacts readily with p benzylamines, giving nearly quantitative yields of the corresponding substituted i m i n e ~The . ~ ~dimer ~ (198) formed from thiocamphor with chloramine-T undergoes a hetero-Cope reaction, now shown to be a [3,3] sigmatropic antarafacial process, to give ( 199).25 Reaction of hindered thiones with hindered diazo-compounds gives A3-1,3,4245 246

"'

248

249 250

251 252 253 254

255

A. J. Sisti and G . M. Rusch, J . Org. Chem., 1974, 39, 1182.

R. F. J. Cole, J. M. Coxon, and M. P. Hartshorn, Austral. J . Chem., 1973, 26, 1595. D. Miljkovic, J. Petrovic, M. Stajic, and M. Miljkovid, J . Org. Chem., 1973, 38, 3585. T. Hayashi, M. Sakai, H . Ueda, and C. Tatsumi, Nippon Nogei Kagaku Kaishi, 1969,42, 670. J. Goldman, N. Jacobsen, and K . Torssell, Acta Chem. Scand., 1974, B28,492. V. SunjiC, F. Kajfez, M. OklobdZija, and M. Stromar, Croat. Chem. Acta, 1973, 45, 569. S. Wolff, A. B. Smith, tert., and W. C. Agosta, J. Org. Chem., 1974, 39, 1607. J. J . Cawley and V. T. Spaziano, Tetrahedron Letters, 1973, 4719. M. Dagonneau and J. Vialle, Tetrahedron, 1974, 30, 415. I. Shahak and Y. Sasson, Synthesis, 1973, 535. M. M. Campbell and a.M. Evgenios, J.C.S. Perkin I, 1973, 2866.

36

Terpenoids and Steroids

thiadiazolidines, and these can be pyrolysed to episulphides. Desulphurization of the latter with triphenylphosphine leads to the olefin, (166; R', R2 = =CR2) from camphor and analogous hydrocarbons from fenchone (176) being accessible in this way.256 \/

(196)

(197)

(198)

( 199)

Further papers of interest in the bicyclo[2,2,l]heptane series report the preparation of several new n.m.r. shift reagents from camphoric an investigation into the radical addition of thiols to bornene, yielding only e x o - a d d ~ c t sas , ~does ~ ~ addition to similar substrates of diphenylnitrilimine and benzonitrile oxide,, 59 exchange of the bromine atom in bromotricyclene (readily available) by a phenylsulphonyl group to activate the carbon atom carrying the functional group for metallation,260and addition from the less hindered side (endo)to camphor of trimethylsilyl cyanide in the presence of zinc iodide.261Methylation of camphor with methyl iodide fails in the presence of sodium t-butoxide, but succeeds with sodium amide.262Ethers of borneol and isoborneol have been made.263The reaction of camphorquinone (160; R' = Me, R 2 = 0)with aliphatic aldehydes has been re-investigated using CIDNP.264The stability of the Ni" complexes of camphorquinone dioxime have been investigated by 'H n.m.r.;265further papers on the geometry of the arylidenecamphors (Vol. 4, p. 50)266and on the condensation products of fenchene, camphene, and phenols in the presence of catalysts267 have appeared.

Bicycl@3,1,l]heptanes.-Further discussion of the conformation of pinane derivatives is supported by 'H n.m.r. spectra at 220 and 300 MHz268and an X-ray analysis of cispinocarveyl p-nitrobenzoate (200; R = 0 , C - C,H,N0,-p).269 The 'H n.m.r. spectrum of myrtenol(201; R = CH,OH) has been studied with a shift reagent.270 256

25'

258 259

260 26' 262

16'

264 265

266 26i

268

269 270

D. €1. R. Barton, F. S. Guziec, jun., and I. Shahak, J.C.S. Perkin I, 1974, 1794. M. D. McCreary, D. W. Lewis, D. L. Wernick, and G. M. Whitesides, J. Amer. Chem. SOC., 1974,96, 1038. M. J. Parrott and D. I. Davies, J.C.S. Perkin I, 1973, 2205. W . Fliege and R. Huisgen, Annalen, 1973, 2038. M. Julia and P. Ward, Bull. SOC.chim. France, 1973, 3065. D. A. Evans, G. L. Carroll, and L. K . Truesdale, J. Org. Chem., 1974, 39, 914. E. E. Aringoli and L. E. De Vottero, Rev. Fuc. Ing. yuim. Unit.. nac. Litoral, 1971-2 (publ. 1973), 40/41, 27 (Chem. Abs., 1974, 80, 70 974). K. Nagai, M. Nakayama, A. Matsuo, S. Eguchi, and S. Hayashi, Bull. Chem. SOC.Japan, 1974, 47, 1193. K. Maruyama and T. Takahashi, Chem. Letters, 1974, 467. S. B. Pedersen and E. Larsen, Acta Chem. Scand., 1973, 27, 3291. N. El Batouti and J. Sotiropoulos, Compt. rend., 1974, 278, C , 1109. V. I. Moskvichev and L. A. Kheifits, Zhur. org. Khim., 1973, 9, 1444, 2256; T. F. Gavrilova, 1. S. Aul'chenko, L. A. Kheifits, N. D. Antonova, and 0.A. Subbotin, ibid., p. 2260; cJ Vol. 4, p. 44. R. J. Abraham, M. A. Cooper, H. Indyk, T. M. Siverns, and D. Whittaker, Org. Magn. Resonance, 1973,5, 373. G. F. Richards, R. A. Moran, J. A. Heitmann, and W. E. Scott, J. Org. Chem., 1974,39, 86. J. Paasivirta, H. Hakli, and K.-G, Widen, Org. Magn. Resonance. 1974, 6, 380.

Monoterpenoids

37

CH,OTS

1

T

vi, vii

Reagents: i, Thioacetalize; ii, LiAlH,; iii, acetylate; iv, deacetalize; v, Me,CuLi; vi, O H - ; vii, TsC1-py ; viii, NaH-MeOCH,CH,OMe.

Scheme 17

Total syntheses of pinanes are rare enough to warrant a new one, based on a known cyclization of 5-to~yloxy-ketones,~~~ to be given in full (Scheme 17).272In order to avoid the difficult separation of nopinone (202) and its isomer (203), the scheme was modified by blocking the 6-position of the precursor with benzaldehyde, debenzalating the product with potassium hydroxide in hexamethylphosphoramide and 4-aminobutyric acid. Conversion of (202) into the pinenes followed conventional Whittaker's general piny1 carbonium ion scheme (Vol. 2, p. 50 and Scheme 18) has received much support. Products from the deamination of myrtanylamine (204 ;

(206)

(207)

(210)

(209)

i, Migration of a ; ii, migration of b; iii, removal of H X ; in ref. 260, X = Br.

Scheme 18

17' 272

K. B. Wiberg and G. W. Kline, Tetrahedron Letters, 1963, 1043; S . WolR and W. C. Agosta, J . C . S . Chem. Comm., 1973,771. M. T. Thomas and A. G. Fallis, Tetrahedron Letters, 1973, 4687.

38

Terpenoids and Steroids

X = NH,) are consistent with a ‘hot’ ion (205)273,274 and somewhat different from those arising from carbonium ions produced by the action of potassium hydroxide on pinanols. The unexpected production of the pinan-2-01 (206) in 28% yield from cismyrtanol (204; X = OH) and potassium hydroxide is explained by the capture of a hydroxide ion by the carbonium ion (207; R’ = R’ = H) so fast that the initial cis stereochemistry is retained. trans-Myrtanol yields mostly a-terpineol(17).’7 Substituted piny1 carbonium ions (207), prepared from the pinenes with the calculated amount of hydrogen bromide, rearrange to either bornanes (208) or fenchanes (209)(after dehydrobromination), according to whether the more substituted (a) or less the subtituted (b) bond of the ion (207)migrates, and this is highly dependent on the substituent R’ ; cissubstituents give mostly bornanes (208),whereas up to 100% fenchane (209) rearrangement can be achieved with trans-sub~titution.~~~ Differences in the relative migration of the (a) and (b) bonds have also been observed when the two pinan-2-01s are treated with acid, the one with a P-hydroxy-group [opposite to (206)] yielding more fenchol ion has been gener(210; R’ = R’ = H, X = OH).276The 6,6-dimethylnorpinan-2-yl ated (inter alia) by deamination of the amine (211), when it appeared to be of a highthe myrtanylamine case. energy classical type associated with a c ~ u n t e r i o nas , ~in~ ~ Catalytic reduction of optically active apopinene (201 ;R = H) occurs with racemization, the latter being faster than exchange when deuterium is the reducing agent ; a [1,3] sigmatropic shift is likely.’ 7 8 Catalytic reduction of the hydroperoxide yields pinan-2-01 (206), accompanying ring fission giving the by-product (212).’79

Contrary to the usual cis hydroboration-oxidation of P-pinene (200; R = H) leading to cis-myrtanol (204; R = OH), a large trans-substituent at C-3 causes the reaction to follow the opposite stereochemistry, the substituted pinene (213), for example, giving 85 ”/, of the corresponding trans-myrtanol.280The usual anti approach of the reagent leads to the thermodynamically less stable (cis) isomer, and Wilke et al. showed that reaction of P-pinene with tri-isobutylaluminium followed by oxidation gives cismyrtanol(204; R = OH) at lower temperatures, but trans-myrtanol at higher temperatures, when 2.2% of the diol(214; R = OH) was obtained, the latter leading to the first bridgehead-substituted pinane (214; R = H).,” 273 274

275 *16 277

278 279

28’

E. Chong-Sen, R. A. Jones, and T. C. Webb, J.C.S. Perkin II, 1974, 38. P. I. Meikle and D. Whittaker, J.C.S. Perkin IZ, 1974, 318. M. Barthelemy and Y. Bessiere-Chretien, Bull. SOC.chim. France, 1974, 1703. H . Indyk and D. Whittaker, J.C.S. Perkin ZI, 1974, 313. H. Indyk and D. Whittaker, J.C.S. Perkin I I , 1974, 646. G . V. Smith and D. S. Desai, Ann. New York Acad. Sci., 1973, 214, 20. L. A. Shutikova, V. G. Cherkaev, M. S. Erzhanova, and A. V. Alifanova, Maslob-Zhir. Prom., 1973,23 (Chem. Abs., 1973,79, 115 734). M. Barthelemy and Y. Bessiere-Chretien, Bull. SOC.chim. France, 1974, 600. H . Benn, J . Brandt, and G . Wilke, Annulen, 1974, 189.

39

Mono terpenoids

Various additions of acrolein etc. to P-pinene have been described ; the reaction works at room temperature in the presence of aluminium chloride.282A preliminary report of the radical-induced cyclization of the acrolein adduct to the octalone (215) has ap~ e a r e dAlthough . ~ ~ ~ addition of acrylates to P-pinene does not yield c y c l o b ~ t a n e s , ~ ~ ~ addition of chloroketen gives (216)in 65 % yield.285Labelling studies have shown that the ene reaction between P-pinene and maleic anhydride occurs with transfer of the endoproton via the transition state (217), leading to a product (218) with R-chirality in the

(215 )

(216)

(2 17)

H

(218)

anhydride ring as the main isomer.286The ene reaction with benzyne (Vol. 4, p. 60) and methyl phenylglyoxylate is similar, and in the latter case, since the reaction is reversible, exchange of the product (219) with deuterium oxide followed by thermolysis gives a 8pinene stereospecifically labelled (220) at C-3.287

Afferdecomposition of P-pinene oxonide with dimethyl sulphide there was a violent explosion on distillation, thought to be due to the diperoxide (Vol. 4, p. 57), undecomposed by’this reagent.257The oxide (221) (Vol. 3, p. 64, refers to the methyl analogue) reacts with butyl-lithium and water to give an alcohol (222), or with butyl-lithium followed by methyl iodide to give the alcohol (223); these and other reactions are explained by the unusual concept of a carbodianion located on the carbon atom (C-10) carrying the phenylsulphonyl group.288 Rapid introduction to the 3,7,7-trimethylnorpinane series is by direct reduction of the hydroxymethylene derivative (224; R =

282

283 284

285 186

287 288

B. B. Snider, J . Org. Chem., 1974,39,255; cJ J. Matsubara, T. Kishimoto, H. Yamamoto, and W. Minematsu, Nippon Kagaku Kaishi, 1972, 669. M. M. Chatzopoulos and J. P. Montheard, Actual. chim., 1974, No. 5 , p. 56; CJ Vol. 1 , p. 46. From R. D. Sands, Synth. Comm., 1973,3, 81; such a reaction might appear possible, but the Reporter has found Sands’s work to be erroneous. W. T. Brady and A. D. Patel, J . Org. Chem., 1973, 38, 4106. R. K. Hill, J. W. Morgan, R. V. Shetty, and M. E. Synerholm, J . Amer. Chem. SOC.,1974, 96, 4201. V. Garsky, D. F. Koster, and R. T. Arnold, J. Amer. Chem. SOC.,1974,96, 4207. N. Bosworth and P. D. Magnus, J.C.S. Perkin I, 1973, 2319.

40

Terpenoids and Steroids

OH) catalytically to the 3-aldehyde, or the acetate (224; R = OAc) to the 3,7,7-trimethyln ~ r p i n a n eArylidenenopinones .~~~ (224; R = aryl) are all of E-ge~metry.'~' Photolysis of pinocarvone (225) gives products including the ketones (226)and (227); the mechanism was suggested to involve either a-p bond fission of the @-unsaturated ketone or (as appears more likely) ring-opening to 2-methyl-6-methyleneocta-2,7diene-5-0ne.~~ Photolysis of trans-verbenone epoxide (228) also gives ring-contracted ketones (229) and anhydrides (230).292Labelling has been used to investigate the verbenone-chrysanthenone photochemical rearrangement.293

Ring-opening of pinenes (to the menthane system) occurs with aliphatic aldehydes in the presence of cupric acetate ;294 with various aroyloxy-radicals in the presence of cupric salts, judicious choice of the aryl substituent enables the reaction to be directed towards ring-opening or removal of ally1 hydrogen ;295 ring-opening also occurs with phosphorous and phosporic acids and esters in the presence of peroxides or U.V.light296 and in the decomposition of myrtenal(201; R = CHO) semicarbazone with sulphuric acid (giving cuminaldehyde, p-is~propylbenzaldehyde).~~~ The radical-initiated photoaddition of N-nitrosopiperidine to a-pinene, in contrast, leads to menthanes only above 0 "C(Scheme 19). Below - 40 "C,addition of the nitroxide radical to the initially formed 289

290 291

292

293 294

295 296 29'

A. Yoshikoshi, Y . Takagi, and T. Akiyama, Jap. P., 91 04611973, 91 04711973. G. Feuillerat and J. Sotiropoulos, Compt. rend., 1974, 279, C, 71. T. D. R. Manning, Tetrahedron Letters, 1974, 2669. T. Gibson, J . Org. Chem., 1974, 39, 845. G. W. Shaffer and M. Pesaro, J . Org. Chem., 1974, 39, 2489. M. G. Vinogradov, G. P. Il'ina, and G. I. Nikishin, Zhur. org. Khirn., 1974, 10, 1153. M. Julia and D. Mansuy, Bull. SOC.chim. France, 1974, 1678. H. FranCois and R. Lalande, Compt. rend., 1974, 279, C, 117. M. Villarrubia de Martinez and F. Gonzalo de Venditti, Arch. Bioquim. Quim. Farm., 1971,17, 61 (Chem. A h . , 1973,79, 91 723).

Man oterpeno ids

41

a-pinene

li

n

A Reagents : i, N-Nitrosopiperidine-H +-piperidine (pip)-MeOH, hv; ii, N O ; iii, air; iv, H ,-Pt.

Scheme 19

piny1 radical (231) occurs before ring-opening, but the resulting nitroso-compound undergoes proton transfer with ring-opening to the cyclobutane oxime (232).298 Further papers on the pinane system concern ring-opening of a-pinene epoxide in the presence of S 0 3 2 - (which does not give addition products like ~ a r e n e and ) ~ ~the ~ following known reactions : acid-catalysed addition to phen01,~" reactions of pinonic acid a m i d e ~ , ~ "rearrangement of 2-hydroxypinocamphone,302 ring contraction of pinane-2,3-diol 3-t0sylate,~'~ and reaction with N-bromosuccinimide.304

Bicyclo[4,l,O]heptanes.-The 220 MHz n.m.r. spectrum of car-3-ene (233) supports a planar cyclohexene ring.305 Thermolysis of either cis- or trans-carane at 400°C produces the other isomer, besides many p - and rn-rnenthane~.~'~ The ring-opening by hydrogen chloride on carane is de~cribed,~"and further work of no great novelty concerns the ring-opening of carene epoxides3'* and the direct hydroxylation of ~ a r - 3 - e n e . ~ ' ~ 298 299

300 301

302

303 304

305

306 307

308

309

H. H. Quon, T. Tezuka, and Y. L. Chow, J.C.S. Chem. Comm., 1974,428. E. MySliriski, Roczniki Chem., 1973, 47, 1755; cf: Vol. 4, p. 65. V. I. Moskvichev and L. A. Kheifits, Zhur. org. Khim., 1973, 9, 2256. Z. Bore, F. Avotins, and E. Gudriniece, Latv. P.S.R. Zinar. Akad. Vestis, Kim. Ser., 1973, 583 (Chem. Abs., 1974,80,60 045). T. J. De Pasqual, I. Sanchez Bellido, T. Egido, and M. Grande Benito, Anales. de Quim., 1973, 69, 687; cf: Vol. 2, p. 54, Vol. 4, p. 63. Z. Chabudzidski, Z. Rykowski, and K. Burak, Roczniki Chem., 1973,47, 2505. C. A. N. Catalan, D. J. Merep, and J. A. Retamar, Anafes. SOC.cient. Argentina, 1973, 196, 35. R. J. Abraham, M. A. Cooper, and D. Whittaker, Org. Magn. Resonance, 1973,5, 51 1. I. I. Bardyshev, E. F. Buinova, and B. G. Udarov, Zhur. org. Khim., 1973,9, 1670. I. I. Bardyshev and E. F. Buinova, Vestsi Akad. Naouk Befarusk. S.S.R., Ser. khim. Naouk, 1974, 94 (Chem. Abs., 1973,79, 105 422). B. A. Arbuzov, Z. G. Isaeva, and V. A. Shaikhutdinov, Doklady Akad. Nauk S.S.S.R., 1973, 210, 837; B. A. Arbuzov, Z. G. Isaeva, and E. Kh. Kazakova, Imest. Akad. Nauk S . S . S . R . , Ser. khim., 1973, 2554; Doklady Akad. Nauk S.S.S.R., 1974, 215, 113 (see Vol. 4, p. 64). B. A. Arbuzov, Z. G. Isaeva, R. R. D'yakonova, and G. A. Bakaleinik, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 2543, 2549 (see Vol. 4, p. 64).

42

Terpenoids and Steroids OH

Acetolysis of the tosylates of the alcohols (234), made by reduction of the ozonolysis products of car-3-ene, led to the suggestion that the cis- but not the trans-tosylate forms a non-classical ion (235).31 Various heterocyclic rings fused to caranes have been ~ r e p a r e d . ~ '

'

7 Furanoid and Pyranoid Monoterpenoids Both rose oxides (236) have been found in an insect."' Cantharidin (237; R = Me) and (+)-cantharic acid (238)have been related to palasonin (237; R = H), isolated from Butea Ji.ondosa, the absolute configurations being determined by the Horeau method. Unsuccessful experiments destined to incorporate precursors into palasonin were r e p ~ r t e dl .2~

Full papers on the lilac alcohols (239) and aldehydes have appeared,313and a specific oxidation of dehydrated linalool oxide (240)with 9-borabicyclo[3,3,1]nonane to give a lilac alcohol (239) has been

(239) R' = H, R2 = CH,OH (240) R ' , R Z = CH2

'lo

(24 1)

M. Walkowicz, C. Walkowicz, and H. Kuczynski, Bull. Acad. polon. Sci., ScJr.Sci.chim., 1973, 21, 343.

311

3'2

313

3'4

F. Bondavalli, P. Schenone, and M. Longobardi, Farmaco, Ed. sci., 1974, 29,48. M. G. Peter, G. Snatzke, F. Snatzke, K. N. Nagarajan, and H. Schmid, Helv. Chim.Acta, 1974, 57, 32. S. Wakayarna, S. Narnba, K. Hosoi, and M . Ohno, Bull. Chrrn. Soc. Japan, 1973, 46, 3183; S. Wakayarna and S. Narnba, ihid., 1974, 47, 1293. S. Akutagawa and S. Watanabe, Jap. P., 61 46811973.

Monoterpenoids

43

Dioxins are converted mainly into furans by base, and the method has been applied to the synthesis of perillene (241).3l 5 The dioxin (242) obtained from dehydrolinalool is converted by aluminium oxide into a mixture of the furan (243)and an alcohol (244), which can be readily oxidized to the corresponding lactone and thence to the coumarin (245) from Capnophyllum peregrinum.62

1

three steps

8 Cannabinoids and other Phenolic Monoterpenoids Marihuana chemistry3l 6 and the syntheses of tetrahydrocannabinol (THC), its metabolites, and the a z a - a n a l ~ g u e s ~ have ’ ~ been reviewed. Marihuana might be useful in cancer therapy. l 8 Cannabicitran (citrylidene-cannabis)(246)has been isolated from Lebanese hashish3l 9 (it was not known to be naturally occurring). The relative amounts of certain cannabinoids have revealed three phenotypes of Cannabis.320Contrary to the results with rhesus monkeys, cannabinol(247) can produce a ‘high’ in man, but at much higher doses than Al-THC (248).321 I

I

(246) 315

316 317

31B

319 320 321

(247)

(248)

K. Kondo and M. Matsumoto, 9th I.U.P.A.C. Symposium on Natural Products, Ottawa, 1974, Abstracts, p. 27A. For preparation of dioxins from dienes cf: K. Kondo and M. Matsumoto, J.C.S. Chem. Comm., 1972, 1332; E. Demole, C. Demole, and D. Berthet, H e f v . Chim. Acta, 1973,56, 265. R. Mechoulam, ‘Marihuana’, Academic Press, New York, 1973. D. Bieniek, W. Bau, and F. Korte, Naturwiss., 1974, 61, 117. Chem. and Eng. News, 1974, Aug. 26, p. 6. C. A. L. Bercht, R. J. J. C. Lousberg, F. J. E. M. Kiippers, and C. A. Salemink, Phytochemistry, 1974, 13,619. E. Small and H . D. Beckstead, Nature, 1973, 245, 147. M.Perez-Reyes, M. C. Timmons, K. H. Davis, and E. M. Wall, Experientia, 1973, 29, 1368.

Terpenoids and Steroids

44

A determined attack on methods of detection and purification has made it possible to detect 100 pg ml- of A'-THC as the heptafluorobutyrate with an electron capture detector3,' and as little as 2 ng ml- plasma as the phosphate ester using flame-photometric detection.323 It is possible to predict the retention times of the cannabinoids from those of substituted r e s o r ~ i n o l sMass . ~ ~ ~and n.m.r. spectra of many hydroxylated cannabinoids have been quoted to facilitate the identification of In the mass spectrum of A'-THC, it seems that double-bond isomerization to A6-THC and transfer of the phenolic proton are important before f r a g m e n t a t i ~ n . ~Pyrolysis ,~ of cannabidiol (249; R = H) gives two compounds of molecular weight 314 (C21H3002), the major product being one of the two isomers of decarboxylated cannabielsoic acid (250),327which has been made from cannabidiolic acid (249; R = C0,H) by photooxidation or with manganese

'

R (249)

CO,H (250)

Conditions for the synthesis of A'-THC from mentha-2,8-dienol and olivetol can now be adjusted so that isomerization to A6-THC is prevented or so that the reaction stops at the cannabidiol (249; R = H) stage.329 14C-Labelled A'- and A6-THC have been made from suitably labelled 01ivetol.~~' The full paper on the pyridine-catalysed reaction of unsaturated aldehydes or acetals with phenols (Vol. 4, p. 75) has appeared.331 Epoxidation and photo-oxidation of A6-THC have been investigated. Reduction of the hydroperoxides gives the expected alcohols, the acetates of one pair (251)rearranging to the primary acetate (252; R = CH,OAc) on heating.332 The corresponding acid (252; R = C0,H) is a urinary metabolite of A6-THC and is formed when the alcohol (252; R = CH'OH) is fed to rabbits. The methyl ester (252; R = C0,Me) was made from the aldehyde (252; R = CHO), a selenium oxide oxidation product of A6-THC.333 Reaction of limonene (11) or a-pinene with orcinol in 50% formic acid leads to the same type of cannabinoid structure as prepared by Merlini et al. from piperitol (Vol. 3, 322 323 324 325 326 321

328 329

330

33 1

332 333

D. C. Fenimore, R. R. Freeman, and P. R. Loy, Analyt. C h ~ m .1973,45, . 2331. N. K. McCallum, J. Chromatog. Sci.,1973, 11, 509. K. Bailey, D. Legault, and D. Verner, J. Chromatog., 1973. 87, 263. M. Binder, S. Agurell, K. Leander, and J.-E. Lindgren, Helv. Chim. Acta, 1974, 57, 1626. T. B. Vree and N. M. M. Nibbering, Tetrahedron, 1973, 29, 3849. F. J. E. M. Kuppers, R. J. J. C. Lousberg, C. A. L. Bercht, C. A. Salemink, J. K. Terlouw, W. Heerma, and A. Laven, Tetrahedron, 1973, 29, 2797. A. Shani and R. Mechoulam, Tetrahedron, 1974, 30,2437. R. K. Razdan, H. C. Dalzell, and G. R. Handrick, J. Amer. Chem. SOC.,1974, 96, 5860. Nguyen-Hoang-Nam, J. P. Beaucourt, H. Hoellinger, and L. Pichat, Bull. SOC.chim. France, 1974, 1367. D. Clarke, L. Crombie, and D. A. Whiting, J.C.S. Perkin I, 1974, 1007. T. Petrzilka and M. Demuth, Helv. Chim. Acra, 1974. 57, 121. R. Mechoulam, Z. Ben Zvi, S. Agurell, I. M. Nilsson, J. L. G. Nilsson, H. Edery, and Y. Grunfeld, Experientia, 1973, 29, 1193.

45

Mono terpeno ids

p. 89; Vol. 4, p. 75); the reaction has also been carried out with sesamol (methylene-3,4dioxyphenol), which yields isomers of (253).334At 200 "C,geraniol and triphenyl phosphite give a mixture similar to that obtained from geraniol and phenol in the presence of phosphoric acid (Vol. 2, p. lo), but without the hydrogenated ~ a n t h e n e s . Nor-THC ~~' (252; R = H) has been prepared.336

(253)

Condensation of citral with nitrogen-containing phenols (e.g. hydroxyacridones and hydroxycarbazoles) gives citrylidene compounds similar to the cannabinoid type. In particular, ( f)-mahanimbine (254) and currayazolidine (also known as cyclomahanimbine and curryanine) (255), two alkaloids from Murrayu koenigii, have been made from 2-hydroxy-3-methylcarbazole.Mahanimbine (254) is converted into the cyclic compound with Dowex 50 in benzene.337

334

335

K. L. Stevens, L. Jurd, and G. Manners, Tetrahedron, 1974, 30, 2075. Y.Shigemasa, H. Kuwamoto, C. Sakazawa, and T. Matsuura, Nippan Kuguku Kuishi, 1973, 2423.

R. S. Wilson and E. L. May, J. Medicin. Chem., 1974, 17, 475. W. M. Bandaranayake, M. J. Begley, B. 0. Brown, D. G. Clarke, L. Crombie, and D.A. Whiting, J.C.S. Perkin I , 1974, 998; D. P. Chabraborty, P. Bhattacharayya, and A. R. Mitra, Chem. and Ind., 1974,260.

2 Sesqu iterpenoids BY T. MONEY

1 Introduction The structural classification of sesquiterpenoids outlined in the previous volume’ is used again in this Report, which covers the literature during the period August 1973August 1974.A new review summarizing current biosynthetic theory has been published.2 2 Farnesanes Additional confirmation of the structure of sesquirosefuran (4)has been provided by simple syntheses involving the condensation of geranyl bromide (1) with 2-lithio-3methylfuran (2)3or 2,2’-bis-(3-methylfuryl)mercury(3).4

(3)

J

An interesting feature of a recent synthesis of freelingyne (6)is the coupling reaction between 3-furanylcopper and the iodoalkyne (9.’ In an alternative route,6a flash vacuum pyrolysis ofthe tertiary acetate (8) provided a mixture from which ( k )-freelingyne (6) could be isolated by preparative t.1.c. Dihydrofreelingyne (lo), which also occurs in the heartwood of Eremophilafreelingii, has been synthesized from the same acetylenic ester (9) (Scheme 1).6h

’

R. W. Mills and T. Money, in ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1974, Vol. 4, p. 77. Angew. Chem. Internat. Edn., 1973. 12, 793. Y. Gopichand, R. S. Prasad, and K. K. Chakravarti, Tetrahedron Letters, 1973, 5177. S. Kumazawa, K. Nishihara, T. Kato, Y . Kitahara, H . Komae, and N. Hayashi, Bull. Chem. Soc. Japan, 1974, 47, 1530. D. W. Knight and G . Pattenden, J.C.S. Chem. Cnmm., 1974, 188. C . F. Ingham, R. A. Massy-Westropp, and G . D. Reynolds, ( a ) Austral. J . Chem., 1974, 27, 1477; ( b ) ibid., p. 1491.

‘ G . Rucker,

‘

’

46

47

Sesquiterpenoids

I

(7) R = H (8) R = COMe

vii. viii

I

A

Reagents: i, Bu”Li-CuBr; ii, MnO,; iii, 0A p p h 3 r : vi, A; vii, LiAiH,; viii, PBr,; ix, LiAIH,-THF;

iv, Ph,P=CHCOMe; v, Zn-THF; C r 0 3 . 2 p q ; xi, Ph,P=CMeCO,Et:

X,

Bu, P Scheme 1

The use of vanadium acetylacetonate-t-butyl hydroperoxide [VO(acac),-Bu‘OOH] to epoxidize the known diol (11) stereoselectively is the key feature of a new synthetic route (Scheme 2) to C , , Cecropia juvenile hormone (13)’“

’ (a) S. Tanaka, H. Yamamoto, H. Nozaki, F. B. Sharpless, R. C. Michaelson, and J. D. Cutting, J . Amer. Chem. Soc., 1974, 96, 5254; ( b ) E. J. Corey, J. A. Katzeneilenbogen, N. W. Giiman, S. A. Roman, and B. W. Erickson, ibid., 1968, 90. 5618.

Terpenoids and Steroids

48

c/ ref 7h

ii. Me,CuLi; iii, Me,NCf-I(OMe),; iv. Ac,O. 130 " C ; v,

Reagents: i, VO(acac),-Bu'OOW; HCIO,.

Scheme 2

3 Bisabolanes A revised structure (15) for caespitol [previously (14)'"l has been proposed on the basis

of its chemical correlation with isocaespitol (16).9 Both compounds co-occur with the intercsting e' 1 2 metabolite furocaespitane (17)*' in the marine alga Laurencia caespitosa Larnx. The spectroscopic properties reported" for furocaespitane are also consistent with the alternative structure (18).

Br'

&c,

u%cl

B%Br

C1

Br

Rr (14)

(15)

(16)

Br (17) A. G . Gonzfilez, J. Darias, and J. D. Martin, ( a ) Tetrahedron Lerters, 1973, 2381; ( h ) ihid., p. 3625.

Sesquiterpenoids

49

Three new sesquiterpenoids have been isolated from Douglas fir and identified as dihydropseudotsugona1(19), dihydropseudotsugonol(20),and nr-todomatuic acid (21).'"

A

A

(19) R = CHO (20) R = CHZOH

(21)

Alternative synthetic routes to ( & )-ar-turmerone (22)' ' (Scheme 3), ( k )-a-atlantone (23)12(Scheme 4),and (+)-(E)-nuciferol (24)13have been reported. The synthesis of the keto-acid (25)'& from cyclohexanone has recently been integrated into a stereospecific synthesis of (+)-juvabione (26) (Scheme 5.)14"

Reagents: i, p-MeC,H,CHO:

ii, MeMgI-CuC1: iii, A.

Scheme 3

lo I' I* l3 l4

A. G. Gonzalez, J. Darias, J. D. Martin, and C. Perez, Tetrahedron Letters, 1974, 1249. T. Sakai and Y. Hirose, Chem. Letters, 1973, 825. T.-L. Ho,Synlh. Comm., 1974, 4, 189. J. H. Babler, D. 0. Olsen, and W. H. Arnold, J . Org. Chem., 1974, 39, 1656. J.-C. Depezay and Y. Le Merrer, Tetrahedron Letters, 1974. 2755. (a) J. Ficini and A. M. Touzin, Tetrahedron Letters, 1972, 2093, 2097; ( b )J. Ficini, J. d'Angelo, and J. Noire, J , Amer. Chem. Soc., 1974, 96, 1213.

50

Terpenoids and Steroids

(23) Reagents: i, H,C=CHLi; ii, AcOH-H'; NaO Me-MeOH.

iii, KOH: iv, Cr0,,2py; v, H,C=CMeCH,MgCl;

vi,

Scheme 4

OH

p .':1:3 V

t-

0

RO

A Reagents: i, H,C=CHOEt-H ; ii, LiAlH,: iii, CBr,-Ph,P-py; iv, Me,CHC-(0R)CN(Me,N),PO; v, H'-MeOH; vi, (CH,OH),-H + ;vii, CrO,,py; viii, (MeO),CO-NaH; ix, NaBH,; x, TsC1-py; xi, NaOMe; xii, H,O-H'. +

Scheme 5

51

Sesquiterpenoids

A new method of constructing the isopropylidene group, by thermolysis of p-lactones, has been used in a recent synthesis of (-t)-curcumene (27) (Scheme 6).15

HO

/t\

CO, H

Reagents: i, Me,CHCO,H-LiNPr';;

(27) ii, PhS0,Cl-py; iii, 140 "C.

Scheme 6

4 Cuparane, Laurane, Trichothecane, etc.

A short synthesis of ( k )-cuparene (29), involving BF,-catalysed rearrangement of the epoxide (28), has been published.I6 The related compound b-cuparenone (30) can be obtained by treating the diazo-ketone (31) with anhydrous copper sulphate (Scheme 7)." Cuparene derivatives isolated from plants and fungi generally have R- and S-

%-"/:o-.

HO,C

... .

111,

1v

(29) R (30) R

=

H,

=

0

(31)

Reagents: i, BF,-Et,O-C,H,;

ii, NH,NHCONH,; iii, SOCI,; iv, C H , N , ; v, CuSO,.

Scheme 7

'' l6

A. P. Krapcho and E. G. E. Jahngen, J. Org. Chem., 1974, 39, 1322. C. W. Bird and Y . C. Yeong, Synthesis, 1974, 27. R. B. Mane and G. S. K. Rao, J.C.S. Perkin I , 1973, 1806.

52

Terpenoids and Steroids

configurations respectively. However, the liverworts (Hepaticae) are unique among plants since they produce antipodal sesquiterpenoids (cf. p. 63), and the recent isolation of (S)-2-hydroxycuparene from Marchantia polyrnorpha Linn. is consistent with this genera! observation.’ A non-epimerizing method of ketone methylenation” is the prominent feature of a recent synthesis2’ of ( )-laurene (33) from the known bicyclic alcohols (32)(Scheme 8).21

(33) Reagents: i, BH,-THF; ii, H,O,-NaOH; iii, CrO,,py; iv, PhSCH2Li; v, (PhCO),O; vi, Li-NH,.

Scheme 8

The use of 13Cn.m.r. spectra in biosynthetic studies continues to increase and in the sesquiterpenoid area this technique has recently been used effectively to provide further details regarding the biosynthesis of trichothecanes and helicobasidin.22 Details of these studies are provided in the Specialist Periodical Report dealing with bio~ynthesis.~ Several toxic strains of Fusariurn culrnorum are associated with cereal crops, and a recent has shown that a toxic extract derived from one of these strains contains a trichothecane sesquiterpenoid (34; R = 0)which is closely related to 15-de-0-acetylcalonectrin (34 ; R = H2).Complete details of the first total synthesis of (+) trichoder-

Is

l9 *O

22

23 l4

B. J. Hopkins and G . W. Perold, J.C.S. Perkin I, 1974, 32. R. L. Sowerby and R . M . Coates, J. Amer. Chem. Soc., 1972, 94, 4758. J . E. McMurry and L. A. von Beroldingen, Tetrahedron, 1974, 30, 2027. T. Irie, T. Suzuki, Y.Yasunari, E. Kurosawa, and M. Masamune, Tetrahedron, 1969, 25, 459. ( a ) J. R. Hanson, T. Marten, and M. Siverns, J.C.S. Perkin I, 1974, 1033; (b) R. Achini, B. Muller, and C. Tamm, Heft>.Chim. Acta, 1974,57, 1442; (c) M. Tanabe, K. T. Suzuki, and W. C. Jankowski, Tetrahedron Letters, 1973, 4723. J. R. Hanson in ‘Biosynthesis’, ed. J. D. Bu’Lock (Specialist Periodical Reports), The Chemical Society, London, Vol. 4, in the press. M. M . Blight and J. F. Gr0ve.J.C.S. Perkin I, 1974, 1691.

53

Sesqu it erpeno ids

min (35;R’ = H,, R2 = COMe) have been p~blished.’~ Since allylic oxidation to the corresponding 8-0x0-compound (35; R’ = 0, R 2 = Ac) has previously been accomplished, the synthesis of trichodermin constitutes a synthesis of trichothecolone (35 ; R’ = 0, R2 = H) and trichothecin (35; R’ = 0, R2 = COCH=CHMe). Various synthetic approaches to the trichothecane nucleus have been reported in preliminary form.26 The isolation of a-barbatene (36) and p-barbatene (37) from various liverworts (Barnilophozia species) has been de~cribed.~’ P-Barbatene (37) is identical with a hydro-

K carbon previously isplated from the liverwort Gyrnnornitrion obtusurn.**It is interesting to note that a-pompene, a metabolite of the liverwort Bazzania pornpeana, has been assigned the novel structure (38).29However, the chemical and spectroscopic evidence does not exclude the alternative a-barbatene structure (36): indeed, the chemical shift values for a-pompene and a-barbatene are almost identical. 5 Acorane, Cedrane, etc. An alternative synthetic approach to the acorane-type sesquiterpenoids has recently been used in a new total synthesis of ( )-P-acorenol(39) and ( )-P-acoradiene (40).30As shown in Scheme 9, the spirocyclic skeleton was constructed by a thermal intramolecular ene reaction. Cationic cyclization, involving chloroalkene groups, is a notable feature of a new The required spiro-ketone (43) synthetic route to (+ )-a-cedrene (45) (Scheme was obtained by formolysis of (41) and the subsequent regioselective introduction of alkene functionality into (43) was accomplished by an intramolecular dehydrohalogenation reaction involving alkoxide (44).

+

E. W. Colvin, S. Malchenko, R. A. Raphael, and J. S. Roberts, J.C.S. Perkin I, 1973, 1989. (a) D. J. Goldsmith, A. J. Lewis, and W. C. Still, Tetrahedron Letters, 1973, 4807; (6) Y. Fujimoto, S. Yokura, T. Nakamura, T. Morikawa, and T. Tatsuno, ibid., 1974, 2523; ( c ) N. Masuoka, T. Kamikawa, and T. Kubota, Chem. Letters, 1974, 751. *’N. H. Anderson, C. R. Costin, C. M. Kramer, Y. Ohta, and S. Huneck, Phytochemistry, 1973, 12, 2709. 2 8 J. D. Connolly, A. E. Harding, and I. M. S. Thornton, J.C.S. Chem. Comm., 1972, 1320. 2 9 A. Matsuo, Y. Maeda, M. Nakayama, and S. Hayashi, Tetrahedron Letters, 1973, 4131. 3 0 W. Oppolzer, Helv. Chim. Acta, 1973, 56, 1812. 3 ’ P. T. Lansbury, V. R. Haddon, and R. C. Stewart, J. Amer. Chem. Sor., 1974, 96, 896. 25

26

Terpenoids and Steroids

54

@&bLb+ C'0,Et

C0,Et

C0,Et

1

C0,Et

111

b&+J =_.I, h?&k5h \

C0,Et

C0,Et

OCH,OMe

0

COzEt

I

\

6 OH

/t\

OH

A

(39)

(40)

Reagents: i, H,C =CHCH,CH,Br-LiN(C,H, ,)CHMe,; ii, 280 "C; iii, Na,CrO,-AcOH-Ac,O; iv, MeLi; v, ClCH,OMe; vi, 195 "C; vii, Na-NH,-EtOH; viii, Al,O,-py.

Scheme 9

u

I'

Ac1

Reagents: i, HC0,H-Ac,O; ii, PhICI,; iii, MeLi; iv, H C 0 , H .

Scheme 10

55

Sesquiterpenoids

6 Charnigrane, Widdrane, and Thujopsane Halogenated sesquiterpenoids having a chamigrane or rearranged chamigrane skeleton are common constituents of algae of the marine genus Laurencia. The isolation and structural elucidation of several new compounds of this type have recently been reported : these include acetoxyintricatol (46)32(L. intricata), glanduliferol (47)33"and co-metabolites (48)-(50)33b (L. gianduli$era), and nidificene (51) and nidifidiene (52)34(L. nidifica). OH

6Ac

i

Br

%

B

r

a

:

A new synthesis of (*)-a-chamigrene (55) has been described35 in which the spiro ring system is constructed by a method which should be of general applicability. As shown in Scheme 11 the crucial step in the synthetic sequence is an intramolecular carbene-insertion reaction. Subsequent reduction of the tricyclic product (53) provides an intermediate (54) which can be easily converted into ( f)-a-chamigrene (55). Postulated biogenetic relationships between sesquiterpenoids are often supported by their co-occurrence in nature. In addition it seems reasonable to expect that certain compounds of predictable structure will eventually be found to co-occur with known metabolites of a particular plant or mi~ro-organism.~~ A recent report37supports this viewpoint. Examination of the minor hydrocarbon constituents of Hiba wood oil

32 33 34

'' 36 37

J. A. MacMillan, I. C. Paul, R. H. White, and L. P. Hager, Tetrahedron Letters, 1974, 2039. M. Suzuki, E. Kurosawa, and T. Irie, ( a ) Tetrahedron Letters, 1974, 1807; ( 6 ) ibid., 1974, 821. S. M. Waraszkiewicz and K. L. Erickson, Tetrahedron Letters, 1974, 2003. J. D. White, S. Torii, and J. Nogami, Tetrahedron Letters, 1974, 2879. G. L. Hodgson, D. F. MacSweeney, and T. Money, J.C.S. Perkin I, 1973, 21 13. S. Ito, K. Endo, and H. Narita, Tetrahedron Letters, 1974, 1041.

Terpenoids and Steroids

56

1

i\ -\i

Reagents: i, N a - N H , ; ii, 3 % HCI; iii, ( C H , O H ) , - H i ; iv, NaH-C,H,; v, ( C O c I ) , ; V i , M e C H , N 2 ; vii, Cu": viii, Li-NH,; ix, LiAlH(OBu'),; x, MeSO,CI-py; xi, Me,SO, 60 " C ; xii, HCI0,-THF; xiii, MeLi; xiv, Me,SO, 80 "C. Scheme 11

(57)

1

1

1

(29)

Scheme 12

Sesquiterpenoids

57

(Thujopsis dolobrata) has resulted in the isolation of P-chamigrene (57) and (+)-apseudowiddrene (58).37 These compounds are co-metabolites of thujopsene (59), cuparene (29), and cuprenenes (56) and have structures which are consistent with current biogenetic theory (cf. Scheme 12). A new efficient procedure for converting y-keto-acids into aP-unsaturated ketones has been successfully incorporated into a recent synthesis of (+ )-mayurone (61)and ( & )thujopsadiene (62) (Scheme 13).38 The basic tricyclic framework [cf. (60)] of these compounds was constructed by means of a known intramolecular a-ketocarbene-olefin insertion reaction. Hydrolysis of the product (60) followed by treatment with lead tetra-acetate in the presence of cupric ion provided (+)-mayurone (61), which was subsequently converted into ( k )-thujopsadiene (62) in the usual way. CHO

C0,Me

CO Me VI1 +

Y. VI

0 (60)

Reagents: i, Ag,O; ii, K,CO,-Mel; iii, LiN(C,H, ,)CHMe,-H,C =CHCH,Br; iv, NaI0,-OsO,; v, (COCI),; vi, CH,N,; vii, Cu-CuSO,; viii, NaOH-EtOH; ix, Cu(OAc),- Pb(OAc),py: xi, MeLi; xii, NH,CI.

Scheme 13

7 Sesquicamphane, fi-Santalane, Epi-fi-Santalane, etc. The potential of commercially available (+)-camphor (63) or (-)-camphor (64) as a starting material in sesquiterpenoid synthesis has been exploited in a general synthetic scheme (Scheme 14) which provides (-)-campherenone (68), (-)-camphereno1 (70; endo-OH), ( - )-P-santalene (72), ( + )-epicampherenone (67), ( + )-isoepicampherenol (69 ; exo-OH), ( + )-epi-B-santalene (71), and tricyclic sesquiterpenoids described in J. E. McMurry and L. C. Blaszczak, J . Org. Chem., 1974, 39, 2217.

Terpenoids and Steroids

58

1

i, iii,

5

iv

ii- iv

IsBr

"P-

1

x or

<,

xi

Reagents: i, Brz (1 mole); ii, Br, (2 moles); iii, Br,--ClSO,H; iv, Zn-HBr; v, (CH,OH),-H+; vi, NaILMe,SO; vii, NaI-PO(NMe,),; viii, , J ; ix, HCl--Me,CO; x, LiAlH(OMe),; xi, Na-Pr"0H; xii, TsC1-py. Ni,A B r L .. , , ,

Br

Scheme 14

Section 8 (p. 63). Full details of this synthetic approach have recently been published.39 The simplicity of the general scheme was made possible by the recognition of structural similarities between appropriate monoterpenoids and sesquiterpen~ids~~ and by the development of a three-step stereoretentive procedure for converting camphor into 8bromocamphor. 40 39

C. R. Eck, G . L. Hodgson, D. F. MacSweeney, R. W. Mills, and T. Money, J.C.S. Perkin I,

40

C. R. Eck, R. W. Mills, and T. Money, J.C.S. Chem. Comm., 1973, 91 1 .

1974, 1938.

59

Sesquiterpenoids

The structure of albene (73) has been confirmed by synthesis of the related ketone (74) (Scheme 15).4' It has been suggested that the biosynthesis of albene (73) involves acid-catalysed cyclization of ( + )-epi-P-santalene (71) followed by loss of an isopropyl group.41This proposal is supported, in part, by the unconfirmed formation of (72) when ( )-epi-P-santalene (71) is treated with formic

+

Reagents: i: MeCCI=CHCH,CH,Li;

ii, 97% HCO,H, A: iii, Ac,O-HCIO,;

iv, 0,; v, H C 0 , H .

Scheme 15

8 Amorphane, Cadinane, Copaane, Copacamphane, Ylangocamphane, Sativane, etc. The structures of bicyclosesquiphellandrene (75) (Piper cubeba oil) and l-epibicyclosesquiphellandrene (Ocirnurn basilicum oil) have been assigned on the basis of chemical and spectroscopic evidence.43 Reconsideration of the published evidence has resulted

in the conclusion that (- )-y-amorphene [formerly (76)] is identical with (- )-y-muurolene (77).44 Additional support for the structure of arteannuin B (78)45 has been provided " 42 43 44 45

P. T. Lansbury and R. M. Boden, Tetrahedron Letters, 1973, 5017. G. L. Hodgson and T. Money,unpublished results. S. J. Terhune, J. W. Hogg, and B. M. Lawrence, Phytochemistrv, 1974, 13, 1183. L. H. Briggs and G. W. White, Austral. J. Chem., 1973, 26, 2229. D. Jeremic, A. Jokic, A. Behbud, and M. Stefanovic, Tetrahedron Letters. 1973. 3039.

Terpenoids and Steroids

60

by X-ray crystallographic analysis46and by an independent assessment of spectroscopic e~idence.~' A novel approach to the total synthesis of (+)-a-amorphene (81) utilizes the oxy-Cope rearrangement of the bicyclic alcohol (79) to construct the cis-fused ring system (80) (Scheme 16).4a

(80)

(8 1)

Reagents: i. Pr'CH =CHMgBr-THF; ii, 300 "C;iii, Ph,CK-(EtO),POCl; iv, Li-NH,-Bu'OH.

Scheme 16

Pyrocurzereone (82),49a( k )-mansanone D (83),49band 3-methoxy-7-hydroxycadalenal (84)49c have been synthesized by the routes outlined in Scheme 17. The total synthesis of (&)-oplopanone (85) that was previously reported has recently been described in detail5' A new stereoselective synthesis of (+)-sativene (87) and (+ )-cyclosativene (89) from the known bicyclic ketone (86) (Scheme 18) has confirmed the absolute configuration assigned to these compound^.^^ A notable feature of the synthesis is the use of a regioselective intramolecular 1J-dipolar cycloaddition reaction to provide the pyrazoline (88), which can be photolysed to (+)-cyclosativene (89). 46 47

48 49

50 51

M . R. Uskokovic, T. H. Williams, and J . F. Blount. Helv. Chim. Acta. 1974, 57, 600, D . G. Leppard, M. Rey, A. S. Dreiding, and R. Grieb, Helv. Chim. Acta, 1974, 57, 602. R. P. Gregson and R . N . Mirrington, J.C.S. Chem. Comm., 1973, 598. V. Viswanatha and G. S. K . Rao, ( a ) J.C.S. Perkin I, 1974, 450; ( b ) Tetrahedron Letters, 1974, 247; ( c j ibid., p. 243. D. Caine and F. N. Fuller, J . Org. Chrm., 1973, 38, 3663. E. Piers, M. B. Geraghty, and M. Soucy, Svnrh. Comm., 1973, 3, 401.

61

Sesquiterpenoids

0

h

A

A

A J

J

J

Reagents: i, H,SO,; ii, NaBH,; iii, TsOH, A ; iv, Pt-H,; v, Cr0,-AcOH; vi, SeO,; vii, H', A ; viii, ClC,H,CO,H; ix, H'.

Scheme 17

.i:r3"

0H - -

(85)

62

Terpenoids and Steroids

/I

'I

v, vi

vii, viii

Reagents: i, LiAlH,: ii, SOC1,-py; iii, CrO,,?py; iv, TsNHNH,; v, Bu"Li-THF; vi, 130 "C; vii, TsC1-py; viii, SiO,: ix, h\s.

Scheme 18

B..

y

.(

(92) Reagents: i, m-ClC,H,CO,H; MeS0,Cl-py.

(93)

ii, K0Bu'-Bu'OH; iii, SOC1,-py; iv, H,--Pt; v, LiAlH,; vi,

Scheme 19

Sesquiterpenoids

63

Complete details of the reported synthesis of ( + )-ylangocamphor (90), (- )-sativene (91), (+)-copacamphor (92), and (-)-copacamphene (93) from (-)-camphor (64) have recently been published.39 These transformations (Scheme 19) are an integral part of a general synthetic scheme which illustrates the importance of (+)- or (-)-camphor in sesquiterpenoid synthesis (cf. Scheme 14). and synthesis of the picrotoxane group of Interest continues in the bio~ynthesis~~9’~ sesquiterpenoids and related alkaloids. Dendrowardine, a new alkaloid in this group recently isolated from Dendrobiurn wardianum Wr., has been assigned structure (94) on the basis of its conversion into dihydronobilonine (95) and the similarity of its c.d. curve to that of dendrobine (96).53

NMez

I,

LIH-DMF, 100°C b ii.

H Z-Pt-H

+

H

-Nv H

I

O

8

0-CO

‘H

H * - 0-CO

‘H

n (94)

Another synthetic route to ( 5 )-dendrobine (96) has been described and it is suggested that intermediate (97) in the sequence (Scheme20) could also be used as a precursor of the picrotoxane ~esquiterpenoids.5~

9 Himachalane, Longipinane. Longicamphane, Longifolane, etc. Spectroscopic evidence has been cited in support of structure (98) for ( - )-y-himachalene. The recent isosation of ( + )-a-himachalene (99), ( - )-a-longipinene (loo), ( - )longiborneol (101), and (-)-longifolene (102) from a liverwort [Scapania undulata (L.) Dum] is in keeping with the tendency of this type of plant to produce sesquiterpenoids which are enantiomeric to those found in higher plant^.'^ Unfortunately the authors of the latter report do not indicate that the isolation of (-)-longiborneol and (-)longifolene from S . undulata had previously been recorded. ” An X-ray crystallographic analysis of (kj-isolongifolene epoxide has settled the dispute over the configuration of this compound by confirming the endo formulation (104).58The same group has also studied the D+-catalysed rearrangement of longifolene (102) to isolongifolene (103) and has obtained results at variance with those previously r e p ~ r t e d . ’Thus ~ it has been shown that both methyl groups at C-3 in (103) contain deuterium and that extensive racemization occurs during the rearrangement.

’’

52

53

54

55 56

5’ 58 59

A. Corbella, P. Gariboldi, and G. Jommi, J.C.S. Chem. Comm., 1973, 729. L. Blomquist, S. Brandanage, L. Gawell, K. Leander, and B. Luning, Acta Chem. Scand., 1973, 27, 1439. A. S. Kende, T. J. Bentley, R. A. Mader, and D. Ridge, J. Amer. Chem. SOC., 1974, 96, 4332. R. Tabacchi, J. Garnero, and P. Buil, Helv. Chim. Acta, 1974, 57, 849. A. Matsuo, M. Makayama, and S. Hayashi, Chem. Letters, 1973, 769. S. Huneck and E. Klein, Phytochemistry, 1967, 6, 383. J. A. McMillan, I. C. Paul, U. R. Nayak, and Sukh Dev, Tetrahedron Letters, 1974, 419. G. Mehta and S. K. Kapoor, Tetrahedron Letters, 1973, 497.

64

Terpenoids and Steroids OH

I. 11

A

co

OAc

A

1 F!

tl

ix. x t

CHO

H' Me0

A

A

A

/i (96)

Reagents: i, OH--H,O;

ii, FeCl,; iii, H,C=CH-CH=CH,,

OsO,-Ba(CIO,),; vi, HI0,-THF; vii,

c

110 "C; iv, K,CO,-MeI;

v,

A H 2 OAc; viii, Me&H,Cl--NaCNBH,-

MeOH; ix, LiAIH,; x, H,SO,; xi, (H,C=CH),CuLi; xii, Ru0,-AcOH; xiii, CH,N,; xiv, NaOMe--MeOH ; xv, NaBH,.

Scheme 20

65

Sesquiterpenoids

A full account of the previously reported' synthesis of ( & )-a-longipinene(105)and (k)b-longipinene (105) has been published.60 The bicyclic aldehyde (106), previously has been converted used as an intermediate in the synthesis of ( )-longicyclene(1 into the ketomesylate (107) and thence, by intramolecular alkylation, into (+ )-longicamphor (108)(Scheme 21).61b Longicamphor has not yet been established as a naturally occurring sesquiterpenoid but stereoselectivereduction provides ( +_ )-longiborneol(109), which occurs in both enantiomeric forms in nature.

Reagents: i, Ph,P=CH,-Me,SO; ii, BH,-THF; iii, H,O,-OH - ; iv, MeS0,Cl-Et,N; Cr0,-py; vi, NaN(SiMe,),-C,H,-DME; vii, Ca-NH,-Pr"0H. Scheme 21

10 Humulane, Caryophyllane, Illudane, Hirsutane, etc.

Preliminary results from biosynthetic investigations are consistent with the proposal that a variety of sesquiterpenoids are derived in nature by cyclization of humulene (11l).'*23Recent report^^^,^^ have described attempts to provide laboratory support 6o

62

63

M. Miyashita and A. Yoshikoshi, J. Amer. Chem. SOC.,1974, 96, 1917. S. C. Welch and R. L. Walters, ( a ) Synth. Comm., 1973, 3, 15; (b) ibid.,p. 419. Y. Naya and Y. Hirose, Chem. Letters, 1973, 133, 727. D. Baines, J. Forrester, and W. Parker, J.C.S. Perkin I, 1974, 1598.

66

Terpenoids and Steroids

Scheme 22

for the postulated cyclization processes. Thus treatment of humulene (111)with aqueous acetic acid62 or aqueous sulphuric acid63 in acetone provides humulol (112), a-caryophyllene alchohol (113), and several bicyclic products, (11 4 H l 1 7 ) (Scheme 22), whose structures have been assigned on the basis of spectroscopic e ~ i d e n c e .Moreover, ~~.~~ a time-dependent product analysis indicates that humulol(ll2) is an intermediate in the cyclization reactions.63 The major sesquiterpenoid constituent of the root oil from Artemisia princeps has been identified as y-humulene (1 18), and it is of biosynthetic interest that caryophyllene (1 19) and a-himachalene (120) are also components of the 0iP4

I

(118) 64

(1 19)

K . Yano and T. Nishijima, Phytochemistry, 1974, 13, 1207

67

Sesquiterpenoids

A stereoselective synthesis of ( + )-isocaryophyllene (122), involving cycloaddition of dimethyketen to the optically pure bicyclic allene (121), has been described and is shown in Scheme 23.65

y-

Y =

I

I

Y

O M

1 01 0 2-

t v i L Q

H /

0

0

( 122)

Reagents: i, LiAlH,; ii, TsC1-py; iii, ( B H , ) 2 ; iv, CrO,; v, 360 " C ;vi, Ph,P=CH,.

Scheme 23

Reagents: i, P,O,-DMF; ii, H,SO,-ether

Scheme 24

Further studies on the complex acid-catalysed rearrangements of caryolan-1-01 (123) (Scheme 24) have shown that the intermediate (125) previously postulated to account for the formation of isoclovene (126) also undergoes proton loss to yield (+)epiclovene (127).66The structure of epiclovene (127) rests on the mass spectral fragmentation patterns of the derived acetals (128) and (129) and its conversion into authentic epiclovane. It has also been shown that, in agreement with previous mechanistic proposals by the same group, epiclovene (127)is converted into isoclovene (126)by treatment 65

66

M. Bertrand and J.-L. Gras, Tetrahedron, 1974, 30, 793. D . Baines, C. R. Eck, and W. Parker, Tetrahedron Letters, 1973, 3933.

68

Terpenoids and Steroids

( 1 30)

with sulphuric acid in ether. The absolute configuration of illudin S (130) has been unambiguously established by the Bijvoet X-ray method.67 A variety of sesquiterpenoids have structures which are probably derived in nature by cleavage of a protoilludane (131) or illudane (132) precursor. The term illudalane has been used to describe the parent hydrocarbon framework (133), and pterosin D (134),68 pterosin H (135),69 pterosin I (136),69 pterosin Z (137),69 onotin (138),” and

(131)

OH

HO’ (1 34)

(135) X = C1

(136) X = O M e (137) X = OH

(138) X = H (139) X = OH

onotisin (139)70are new members of this group which have been isolated recently from various species of fern. The conversion of pterosin Z (137) into onotin (138) has also been reported.’ lo A related fern constituent, hypacrone (140), has been assigned a secoilludane structure on the basis of spectroscopic evidence and acid-catalysed cyclization to pterosin 2 (137) (Scheme 25).7’bPterosin E (141), which occurs on bracken leaves, is a C,, member of the illudalane group whose synthesis has recently been de~cribed.’~ Lactaral (144) a new sesquiterpenoid isolated from Lucturius vellereus and L. pergaminus has been structurally elucidated by consideration of 13Cand ‘H n.m.r. e~idence.’~ Isovelleral (142), velleral (143), and the lactones (145) and (146) have also been iso6’

6’)

’O 72

”

A. Furasaki, H . Shirihama, and T. Matsumoto, Chem. Letters, 1973, 1293.

M. Kuroyanagi, M. Fukuoka, K. Yoshihira, and S. Natori, Chem. and Pharm. Bull. (Japan), 1974, 22, 723 and references cited. Y. Hayashi, M. Nishizawa, S. Harita, and T. Saka , Chem. Letters, 1972, 375. A. Banerji, G . Ramakrishnan, and M. S. Chadha, Tetrahedron Letters, 1974, 1369. Y. Hayashi, M . Nishizawa, and T. Sakan, (a) Chem. Letters, 1974, 945; ( b ) ibid., 1973, 63. M . E. N. Nambudiry and G . S. K . Rao, J.C.S. Perkin I, 1974, 317. G . Magnusson and S. Thoren, Tetrahedron, 1974,30, 1431 : CJ J. Froborg, G. Magnusson, and S. Thoren, Acra Chem. Scund., 1974, B28, 265.

Sesqu i t erpeno ids

69

Scheme 25

QQ

HO,C

(141)

lated74.75from this source and it seems possible that a biosynthetic relationship exists between all of these compounds. A closely related compound, lactarorufin A (147), was isolated previously from L. r u f u ~ . ~ ~

0

0

HO

H

Complicatic acid, a new sesquiterpenoid antibiotic isolated from cultures of Stereurn cornplicaturn, has been identified as dehydrohirsutic acid C ( 149).77Labelling studies have shown that hirsutic acid C (148), which also occurs in S . cornplicaturn, is the biological precursor of complicatic acid (149).77Previous work on the biosynthesis of the hirsutane class of sesquiterpenoids was hindered by the general inability to grow the original culture. The isolation of hirsutic acid C and complicatic acid from S . cornplicatum and the coriolins [e.g. 5-dihydrocoriolin C (1SO)] from Coriolus consors has solved this problem and recent studies78a9b have provided significant information

74 75

76 77

G . Magnusson, S. Thoren, and T. Drakenberg, Tetrahedron., 1973, 29, 1621. G. Magnusson and S. Thoren, Acta Chem. Scand., 1973, 27, 1573, 2396. W. M. Daniewski and M. Kocor, Bull. Acad. polon. Sci. Se'r. Sci. chim., 1971, 19, 553. G. Mellows, P. G . Mantle, T. C. Feline, and D. J. Williams, Phytochemistry, 1973, 12, 2717. ( a ) T. C. Feline, G. Mellows, R. B. Jones, and L. Phillips, J . C . S . Chem. Comm., 1974, 63; (b) M. Tanabe, K. T. Suzuki, and W. C. Jankowski, Tetrahedron Letters, 1974, 2271.

Terpenoids and Steroids

70

+--A-

h== (OPP

1

on the biosynthesis of the hirsutane group of sesquiterpenoids. These results, which will be reviewed elsewhere,23are summarized in Scheme 26. A sesquiterpenoid isolated from soft coral (Capnella irnbricata) has been assigned structure (151) on the basis of its chemical and spectroscopic proper tie^.'^ The structure and absolute configuration of this compound have been independently established by X-ray crystallographic analysis and the name capnellane has been coined to describe the parent hydrocarbon s t r ~ c t u r e . ~The ' new compound is therefore named A9(' *)-capnellene-3P,8P,l0a-triol(151).

The structure of africanol (152), a new sesquiterpenoid isolated from a marine invertebrate (Lernnalia ufricana), has been established by X-ray crystallographic analysis.80 It has been suggested" that this new carbon skeleton could be derived in nature by cyclization of humulene (111). 79

8o

M. Kaisin, Y . M. Sheikh, L. J. Durham, C . Djerassi, B. Tursch, D. Daloze, J. C. Braekrnan, D. Losrnan, and R. Karlsson, Tetrahedron Letters, 1974, 2239. B. Tursch, J. C . Braekman, D. Daloze, P. Fritz, A. Kelecom, R. Karlsson, and D. Losman, Tetrahedron Letters, 1974, 747.

71

Sesquiterpenoids

11 Germacrane, Eudesmane, Eremophilane, Vetispirane, etc. The preferred conformations of costunolide (153) and dihydrocostunolide (154) in [2H]chloroform have been determined" by measuring intramolecular internuclear Overhauser effects (n.o.e.'s) in the presence of a lanthanide shift reagent, i2H2,][Eu(fod),]. N.0.e. and c.d. measurements have also been used to determine the absolute configuration and conformation of confertolide (1 55).82 The structure of a new germacranolide, melampodin B (156), has been elucidated mainly by the use of 3Cand 'H n.m.r. data.

% (153)

%H

A&o*c

( 154)

..o

0

(155)

Further studies on the biogenetic-type synthesis of acoragermacrone (157) have revealed that treatment with acid can provide sesquiterpenoids of the cadinane (158) or eudesmane types (159)--(162) (Scheme 27).84Two of the cyclization products, acolamone (159) and isoacolamone (160),are congeners of acoragermacrone (157) in Acorus calarnus and it has been suggested that their biosynthesis involves a similar cyclization process. The conversion ofagerol(l64) into the diepoxide (166)followed by subsequent rearrangement to ageratriol (167) provides laboratory support for the suggested biosynthesis of the latter compound from germacrene A (163).85An alternative biosynthetic route,

83 84

85

K. Tori, I. Horibe, Y . Tamura, and H. Tada, J.C.S. Chem. Comm., 1973, 620. R. Toubiana, M.-J. Toubiana, K. Tori, and K . Kuriyama, Tetrahedron Letters, 1974, 1753. N . S. Bhacca, R. A. Wiley, N . H. Fischer, and F. W. Wehrli, J.C.S. Chem. Comm., 1973, 614. M. Iguchi, M. Niwa, and S. Yamamura, Tetrahedron Letters, 1973, 4367. F. Bellesia, U . M. Pagnoni, and R. Trave, Tetrahedron Letters, 1974, 1245.

72

Terpenoids and Steroids

ir

(161)

(162)

Reagents: i, 0,, hv, methylene blue; ii, NaBH,; iii, m-ClC,H,CO,H;

iv, LiNEt,-C,H,

Scheme 27

( 166)

( 167)

Reagents: i, 0 , , h v , methylene blue; ii, NaBH,; iii, m-ClC,H,C0.3H; iv, LiNEt,-C,H,. Scheme 28

involving oxygenation of agerol (164) and reduction of the intermediate dihydroperoxide (165), has also been accomplished in the laboratory (Scheme 2Qg5 A review of recent studies on the conformations and Cope rearrangement of germacrene-type sesquiterpenoids has been published.86 Related investigations, using model

*,

K . Takeda, Tetrahedron, 1974, 30, 1525.

Sesqu i t e rpenoids

73

cis-trans-cyqlodeca-1,5-dienes, have shown that the abnormal Cope rearrangement of the furanogermacrenes (168) and (169), which provides trans-1,2-divinylcyclohexane derivatives (170) and (171), is probably due to the presence of the furan ring in these

corn pound^.^^

Phantomolin ( 172)88 (Elephantopus mollis), chrysandiol ( 173y9 (Chrysanthemum morifolium), glaucolide-A (174)90 (Vernonia glauca), and glaucolide-B (175)90 (I/. baldwinii) are new biologically active germacranolides whose structures have been established recently by X-ray crystallographic studies. It is interesting to note that OH

Q< H O 0,

0 QR 0

OAc

0 (174) R = COCMe=CH, (175) R = COAc ”

89

90

0 ( 176)

K . Takeda, I . Horibe, and H. Minato, J.C.S. Perkin I, 1973, 2212. A. T. McPhail, K. D. Onan, K.-H. Lee, T. Ibuka, M. Kozuka, T. Shingu, and H.-C. Huang, Tetrahedron Letters, 1974, 2739. T. Osawa, A. Suzuki, S. Tanura, Y. Ohashi, and Y. Sasada, Tetrahedron Letters, 1974, 1569. W. G. Padolina, H . Yoshioka, N. Nakatani, T. J. Mabry, S. A. Monti, R. E. Davis, P. J. Cox, G. A. Sim, W. H. Watson. and I. B. Wu, Tetrahedron, 1974, 30, 1161.

74

Terpenoids and Steroids

phantomolin (172) is the major cytotoxic agent found in plants harvested in winter whereas molephantin (1 76)’3”’ is the compound isolated from spring plants. The structure of cuauhtemone (177), a plant-growth inhibitor isolated from a Mexican medicinal shrub (‘cuauhtematl’) has been determined using the partially relaxed Fourier transform I3C n.m.r. technique.92Certain species of sponge have the remarkable ability to produce sesquiterpenoids containing isocyanide groups. Acanthellin- 1 (178), isolated from Acanthella acuta, is a new member of this group whose structure rests on spectroscopic evidence and on its conversion into 4-epieudesmane ( 179).93 Structure (180) has been proposed for the eudesmane ether isolated from the frontalgland defensive secretion of the West African species of termite (Arniterrnes evuncifer S i l ~ e s t r i ) Isopterocarpolone .~~ (1 8 l), pterocarptriol (1 82), and pterocarpdiolone (183)

(179)

(177)

0

0

HO’ %OH (1 83)

(184)

have been isolated from red sandalwood (Pterocarpus santalinus).’ Recent studies, involving the synthesis of eudesmanones (184) and (185), have shown that the structures previously assigned to canarone are in error.96A general approach to several eudesmanetype sesquiterpenoids has been reported by two g r o ~ p s . ~The ~ *key ~ *intermediate (187) in both routes is synthesized by conjugate addition of a methyl group to the known ketodienol ether (186). Subsequent transformations (Scheme 29) lead to bicyclic ketones, ”

92

93 q4

q5 ‘6

”

”

K. H. Lee, H. Furukawa, M. Kozuka, H. C. Huang, P. A. Luhan, and A. T. McPhail, J.C.S. Chem. Comm., 1973,476. K . Nakanishi, R. Crouch, 1. Miura, X. Dominguez, A. Zamudio, and R. Villarreal, J . Arner. Chem. SOC.,1974, 96, 609. L. Minale, R. Riccio, and G. Sodano, Tetrahedron, 1974, 30, 1341. L. J. Wadhams, R . Baker, and P. E. Howse, Tetrahedron Letters, 1974, 1697. N . Kumar, B. Ravindranath, and T. R. Seshadri, Phytochemistrv, 1974, 13, 633. L. H . Zalkow, S. J. Steindel, N . G. Schnautz, and C. K. Kellog, Tetrahedron Letters, 1973, 3337 and references cited. R. B. Miller and R. D. Nash, J . Org. Chem., 1973, 38, 4424. G. H . Posner and G. L. Loomis, J . Org. Chem., 1973, 38, 4459.

75

Sesquiterpenoids

J

Me0,CO

1

\

\

(189) vii

1 1 1

@C02H 0 H

O H-

Reagents: i, Me.,CuLi-Et,O; ii, NaBH,; iii, (MeO),CO-NaH; iv, (CH,SH),-H + ;v, Raney Ni; vi, LiAlH,; vii, Cr0,-H'; viii, Ph,P=CH,; ix, MeLi; x, SOC1,--py.

Scheme 29

(188)-(190), which have previously been used as intermediates in the syntheses of peudesmol (191),99atractylon ( 192),'0° isoalantolactone (193),'0° alantolactone (194),'" and telekin (195)."' The isolation, structural elucidation, and total synthesis of sesquiterpenoid lactones has been a prominent feature of research in the terpenoid area for several years. Much 99 loo lo*

C. H. Heathcock and T. R. Kelly, Tetrahedron, 1968, 24, 1801. H. Minato and I. Horibe, J. Chem. Soc. (C),1967, 1575 and references cited. J. A. Marshall, N. Cohen, and A. R. Hochstetler, J. Amer. Chem. Soc., 1966, 88, 3408.

76

Terpenoids and Steroids

of the interest has been engendered by the fact that many of these compounds are biologically active and exhibit pronounced allergenic, fungitoxic, antiturnour, and antimitotic effects.In most cases the presence of an a-methylene-y-butyrolactone ring system is considered essential for biological activity. Indeed the parent system (196) has been isolated from white tulips and displays allergenic and fungitoxic activity. A new convenient synthesis of a-methylene-y-butyrolactone (196) has been reported and this procedure

should be generally applicable to the synthesis of sesquiterpenoids containing this ring system.lo2 Full details of a previous report describing the synthesis of cis- and transfused a-met hylene-y-butyrolactone rings have been p~blished."~The methods have been used in the synthesis of ( - )-frullanolide (200) and (+)-arbusculin B (199) from (-)santonin (197) (Scheme 30).'03 An interesting feature of the synthesis of the cis-fused

O V I I I . 1%. 11,

O

x

(199)

Reagents: i, H,-PPh,RhCl; ii, (CH,SH),-BF,,Et20; iii, Raney N i ; iv, Ph,CLi-DME; v, BrCH,CH,Br; vi, DBN-toluene; vii, HCl-DMF; viii, (CH,SH),-H+ ; ix, KOHEtOH; x, HCI; xi, Ph,CLi-TMEDA-DME; xii, A ; xiii, Ph,CLi; xiv, (PhCO,),; xv. 450 "C.

Scheme 30 '02 lo'

P. A. Grieco and C. S. Pogonowski, J . Org. Chem., 1974, 39, 1958. A. E. Greene, J.-C. Muller, and G. Ourisson, J . Org. Chern., 1974, 39, 186.

77

Sesquiterpenoids

unsaturated lactone ring in (-)-frullanolide (200) is the use of 1,Zdibromoethane in the bromination-dehydrobrominationsequence. In the synthesis of the trans-fused lactone system, however, this procedure provided the endocyclic unsaturated lactone (198). Oppositol (201)'04 belongs to a group of halogenated sesquiterpenoids which are found in marine algae of the genus Laurencia (cf. p. 55). Its structure has been established by X-ray crystallographic a n a l y ~ i s "and ~ it is included in this section since it is probably derived in nature by ring contraction of a eudesmane precursor [cf. (202)l. Further Br

examples of this new structural class are axisonitrile- 1 (203)and axisothiocyanate- 1 (204) which have recently been isolated from the marine sponge Axinellu canna bin^.'^^

OH

o - OH

OR

(205)

(206) R = CO

(207)

R

=

CO

Y

Me0

OH

' X (208) X (209) X lo4 lo'

=H = OH

S. S. Hall, D. J. Faulkner, J . Fayos, and J. Clardy, J . Amer. Chem. Soc., 1973, 95, 7187. F. Cafieri, E. Fattorusso, S. Magno, C. Santacroce, and D. Sica, Tetrahedron, 1973, 29, 4259.

Terpenoids and Steroids

78

The structural elucidation of cycloeudesmol (205), an antibiotic compound isolated from a marine alga (Chondria oppositiclada Dawson j, has been reported.' O 6 Eriolangin (206) and eriolanin (207) are new antileukaemic metabolites of Eriophyllurn lanuturn whose unusual 1,lO-seco-eudesmanolidestructures are based on X-ray crystallographic evidence.' O 7 Structures (208)-(21l), suggested for emmotin A-D, represent a skeletal type which is probably derived in nature by methyl migration of a eudesmane precursor."* A structurally related sesquiterpenoid, occidol (212), has been s y n t h e s i ~ e d by ' ~ ~a route which involves transition-metal-catalysed addition of formic acid to a double bond (Scheme 31).' l o Conjugate addition of Grignard reagent (213) and lithium dimethylcuprate to enone systems are the basic features of a simple synthesis of (kj-valerane (215)(Scheme 32).'"

(212) Reagents: i. MeLi; ii, POCI,-py; iii, Ni(CO),-HCI-H,O

Me,CO, h v ; iv, CH,N,

Scheme 31

Two new synthetic routes to the vetispirane sesquiterpenoids have been reported recently."2."3 In one route the spirocyclic system was constructed by means of a Prins reaction involving a suitably substituted cyclopentane derivative (216) (cf. Scheme 33). Subsequent oxidation or dehydration procedures then provided ( & )-Pvetispirene (217), (*)-P-vetivone (218), and (f)-10-epi-P-vetivone (219).'" In the other synthetic route the spirocyclic intermediate (220) was synthesized by intramolecular aldol condensation and subsequently converted into ( )-cr-vetispirene(222)(Scheme 34) and (-t)-P-vetispirene (217), (&)-p-vetivone(218). and (&)-hinesol (223) (Scheme 35). ' ' lo(, lo-

lo8

lo'

''I

'I2

'13

W. Fenical and J. J. Sims, Tctrahedron Letters, 1974, 1137. S. M. Kupchan, R. L. Baxter, C.-K. Chiang, C. J. Gilmore, and R. F. Bryan, J.C.S. Chem. Comm., 1973, 842. A. B. de Oliveira, M. de L. M . Fernandes, 0. R. Gottlieb, E. W. Hagaman, and E. Wenkert, Phytochemistry, 1974, 13, 1199. T.-L. Ho, J.C.S. Perkin I, 1973, 2579. B. Fell and J. M. J. Tetteroo, Angew. Chem. Internat. Edn., 1965, 4, 790. G . H. Posner, C. E. Whitten, J. J. Sterling, and D. J. Brunelle, Tetrahedron Letters, 1974, 2591. P. M. McCurry and R. K. Singh. Tetrahedron Letters, 1973, 3325. K. Yamada, H . Nagase, Y. Hayakawa, K. Aoki, and Y . Hirata, ( a ) Tetrahedron Letters, 4963; ( 6 )ibrd., p. 4967.

Sesquiterpenoids

79

/

(214) X = 0 (215) X = H, Reagents: i, THPO-CH,(CH,),CH,MgCl Me,CuLi.

(213); ii, H'; iii, MeS0,Cl-py; iv, LiBr Me,CO; v,

Scheme 32

HO''%

Reagents: i, Pyrrolidine-H ; ii, MeCH =CHCH,Br; iii, AcOH-AcONa; iv, MeLi; v, NCSMe,S-Et,N; vi, (C,H, ,),BH; vii, H,O,-OH - ;viii, Ac,O-py; ix, SOC1,-py; x, LiAlH,; xi, SnCI,; xii, MeS0,CI-py, A ; xiii, SO,,py-DMSO-Et,N. +

Scheme 33

80

Terpenoids a n d Steroids

'0'

CO,H

I

Reagents: i. L i - N H , B u ' O H ; ii, ( C 0 , H ) 2 - H , 0 ; iii, SM-HCI-DME; iv, (CH,OH),-H + ; v, LiAlH,: vi. 2 M - H C I - D M E ; vii, Ac,O-py; viii, K O H - M e O H ; ix, C r O , , p y ; x, NaHM e 2 C 0 , : xi. N a B H , ; xii, MeS0,Cl-py; xiii, N a O M e - M e O H ; xiv, H C l - D M E ; xv, (PhO),PMeI-BF, ,Et,O; xvi, Zn-AcOH: xvii. (CH,SH),-H ' ; xviii, Raney N i ; xix, M e L - D M E : xx, H +-C,H,, A.

Scheme 34

A well-known photochemical transformation of cross-conjugated dienones has been used in the recent conversion ofnootkatone (224)into P-vetivone (218)and 10-epi-Pvetivone (219)(Scheme 36).' l4 The use of dehydronootkatone (225)in the photochemical sequence provided anhydro-P-rotunol (226). The latter compound and its dihydroderivative (227) have recently been identified as stress metabolites of potato. tubers inoculated with the fungus Phytophthora infestans.' The synthesis of bicyclo[2,2,2]octyl esters by Diels-Alder reaction and their subsequent converion into substituted cis-4,5-dimethylcyclohe~enones~has recently been incorporated into a new stereoselective synthesis of (k)-nootkatone (224) and ( k )-avetivone (228) (Scheme 377.' '' The low-yield synthesis of ( )-nootkatone (224) which was reported last year has recently been superseded by a similar sequence involving the

'

*

D. C i n e a n d C.-Y. C h u , Trtrahrdrori Lertrr.s, 1974, 7 0 3 . D. T. Coxon, K. R . Price, B. Howard, S . F. Osman, E. €3. Kalan, and R. M. Zacharius, Tetrahrclrron Lrttrrs, 91 14, 292 1 . *"' A . J . Birch a n d K . P. Dastur, J.C.S. Perkin I , 1973, 1650 ar,d references cited. '17 K . P. Dastur. J . Amrr. Chvm. Soc., 1974, 96. 2605. 'IJ

I t s

Sesquiterpenoids

81

C0,Me

YQH c02Me\

(223) 4

-

Reagents: i, PtO,--H,; ii, MeLi-DME; iii, POC1,-py; iv, HC1-DME; v, Ph,PBrBr-MeCN; vi, NaI-MeCOEt; vii, Zn---AcOH; viii. (CO,H),-H,O; ix, (PhO),PMel-BF,,Et,O; x, NaBH,; xi, H '-C6Hb, A ; xii, MeLi; xiii, (CH,SH),-H ' ; xiv, Raney Ni.

Scheme 35

keto-acetal(229) as starting material.' * (If: )-Isopetasol(230) has also been synthesized using the conventional Robinson annellation procedure (Scheme 38)'' In a new synthetic route to (k)-eremophilone (232)(Scheme 39) the vicinal cis-methyi groups are generated by conjugate addition of a vinyl group to the enone (231).'203'21 The structure of phornenone (233), a phytotoxic metabolite of Phorna exiguu, has been determined by X-ray crystallographic analysis.' 2 2 Several new furanoeremophilanes have been isolated from Ligularia japonica and Farfugiurn japonicurn and assigned 'I8

12'

H. M. McGuire, H. C. Odom, and A. R. Pinder, J.C.S. Perkin I, 1974, 1879. K. Yamakawa, I. Izuta, H . Oka, and R. Sakaguchi, Tetrahedron Letfers. 1974, 2187. CJ J. Hooz and R. B. Layton. Canad. J . Chem., 1970, 48. 1626. F. E. Ziegler and P. A. Wender, Tetrahedron Letters, 1974, 449. C. Riche, C. Pascard-Billy, M. Devys, A. Gaudemer, M. Barbier, and J.-F. Bouquet, Tetrahedron Lelters, 1974, 2765.

Terpenoids and Steroids

82

(227)

(218)

(2 19)

Reagents: i, DDQ; i i , HBr; iii, Bu,N; iv, hv, dioxan; v. hv, H'-H,O; H ,-Pd/C.

vi, hv, AcOH-H,O; vii,

Scheme 36

(224) Reagents: i, H,C=CHCO,Me; collidine. A.

(228) ii, SeO,; iii, Ph,P=CH,;

Scheme 37

iv, MeLi; v, H C 0 , H ; vi, AI,O,-

83

Sesqu iterpeno ids

1

iv-vi

(230) Reagents: i, H,C=CHCOMe-NaOEt; ii, TsOH-C,H,; v, MeLi; vi, H -MeOH; vii, NaBH,.

iii, (CH,OH),-H

+

; iv, Me,CO,-NaH;

+

Scheme 38

-.,,CHO

iv, xiii, xiv

(232) Reagents: i, (H,C=CH),CuLi-Bu,P; ii, (CH,OH),-H + ; iii, (Sia),BH; iv, H,O,-OH-; v, Cr0,-py; vi, Ph,P=CMeCO,Et; vii, LiAlH,; viii, BuOCH=CH,-Hg(OAc),; ix, 175 "C; x, AcOH-H20; xi, NaOH-MeOH; xii, 250 " C ;xiii, N,H,-H + ;xiv, CrO,.py.

Scheme 39

Terpenoids and Steroids

84

/$om R

'0

[{O,'

0

C'H,OH

(233)

(234) R = OCOC=CMe, (235) R = O H (236) R = H

R'

(237) (238) (239) (240) (241)

R' R' R' R' R'

OK' = O H , R 2 = COC=CMe, = H, R 2 = COC=CMe, = OH, R 2 = H = OH, R 2 = COCH(Me)Et = OH, R 2 = Ac

(24.4)

(243)

(245)

(246)

structures (234H241) on the basis of their spectroscopic characteristics.' 2 3 , 1 24a The latter source has also provided two new furanosesquiterpenoids, farfugin A (242) and farfugin B (243),'24h whose biosynthesis presumably involves ring cleavage of an eremophilane precursor followed, in the case of (242), by re-cyclization in an alternative manner. The structure of ligularenolide (244) has been confirmed by the recent synthesis of its tetrahydro-derivative (245) from the known keto-ester (246).' 2 5 An elegant total synthesis of (&)-bakkenolide-A(249) has been described.' 2 6 The crucial step in the reaction sequence (Scheme 40) is a stereoselective [2,3] sigmatropic rearrangement [(247) -+ (248)]to produce the correct configuration at C-7 in the natural product. It has been suggested that the biosynthesis of the marine sesquiterpenoid (+)-/?gorgonene (251) involves ring cleavage of a tricyclic precursor such as (+)-y-maaliene (250), and the co-occurrence of ( )-P-gorgonene with sesquiterpenoids of this type provides support for this proposal. 1 2 7 A biogenetic-type synthesis of ( - )-/?-gsrgonene has been accomplished by treating maaliol (252) with hydrochloric acid followed by dehydrochlorination. 1 2 7 Alternatively ( k )-fi-gorgonene may be obtained by a more

+

'''

M. Tada. Y . Moriyama, Y . Tanahashi, and T. Takahashi, B u f f . Chem Sor. Japan, 1974, 47, 1999. '" H . Nagano, Y . Tanahashi, Y . Moriyama, a n d T. Takahashi, ( a )B u f f .Chem. Soc. Japan, 1973, 46,2840. ( h ) ihid.. 1974, 47, 1994. 1 2 5 T . Tatee and T. Takahashi, Chem. Lettrrs, 1973, 929. "' D. A. Evans and C . L. Sims, Tetrahedron Letters, 1973, 4691. S. K . Paknikar and V. K . Sood, Totrahedron Letters. 1973, 4853.

85

Sesquiterpeno ids

1

ii. iii

& + & t o &

Sv

H

Br

sMe(247)

NNHTS

Reagents: i, Os0,-NaI0,-Bu'OH; ii, ButOK-Bu'OH; iii, H,- Pd; iv, H,C=CMeLi; v, PBr,; vi. TsNHN=C(SMe)SNa; vii, NaH-THF; viii, HgO-HgC1,; ix, Se0,-H,O -C,H,.

Scheme 40

Reagents: H,C=C(Me)MgCl-THF; ii, Me,SiCH,MgCl; iii, AcOH-H,O.

Scheme 41

86

Terpenoids and Steroids

conventional approach in which the isopropenyl group is introduced by 1,Caddition to the enone (253) (Scheme 41)."*

12 Guaiane, Pseudoguaiane," Seychellane, Aromadendrane, etc. Full details of a synthetic route (Scheme 42) to guaiol(254) have been p u b 1 i ~ h e d .The l~~ final step in the sequence provides a mixture of four compounds, one of which is identical to (k)-guaiol (254). Chemical and spectroscopic evidence has been provided for the C0,Et

at \

C0,Me

(254) Reagents:

1,

Me2NCH,CH2COCH,CH,C0,Et; ii, HCI; iii, PPA, 100 " C ;iv, H,SO,-MeOH; v,

MeLi; vi. NH,Cl; vii, H2-Pd/C. Scheme 42

CH,OH

I

OCOC-CI

I

Me

HOQR

0 HO CH,OH

I/

(257) R = COC

(258) R

=

COC

\

/

I\

Me CH,OH

EtO Me

* The pseudoguaiane IL8 12q

skeleton was incorrectly displayed in Volume 4 (ref. 1, p. 8 I ) .

R. K . Boeckmann and S. M. Silver, Tetrahedron Letters, 1973, 3497. G. L. Buchanan and G. A. R.Young, J . C . S . Perkin I, 1974, 2404.

Sesqu i t erpeno ids

87

HQ

RO--

HO’.

HO”

H

0

“H (259) R = H (260) R = COCMe=CHMe

(261 )

Q/ ‘-0----

CO, H

structure of vanillosmin (255)’ 30 (Vanillosmopsis erythropappa) and for the chlorohys(Centaura hyssopifolia). Single-crystal X-ray analysis sopifolins C-E, (256)--(258),’ has shown that the lactone rings in carolenalin (259) and carolenin (260)are cis-fused.’32 Considerable effort is being devoted to the structural elucidation and stereochemistry of guaianolides and pseudoguaianolides which display cytotoxic activity. Florilenalin

’

H

0H

‘,

OH

H’

(266)

Scheme 43 I30

A. Corbella, P. Gariboldi, G. Jommi, F. Orsini, and G. Ferrari, Phyrochemistry, 1974, 13,459.

131

A. G. Gonzalez, J. Bermejo, J . L. Breton, G. M. Massanet, and J. Triana, Phytochemistry, 1974, 13, 1193. A. T. McPhail, P. A. Luhan, K.-H. Lee, H. Furokawa, R. Meck, C. Piantadosi, and T. Shingu, Tetrahedron Letters, 1973, 4087.

132

88

Terpenoids and Steroids

(261)' 3 3 (Heleniurn autumnale) and plenolin (262j13 4 (Baileya pleniradiata) are new compounds of this type whose structures have been determined by X-ray crystallographic analysis. The X-ray method has also been used to confirm the stereochemistry of ambrosic acid (263)135and the structure of the oxide (266) formed when helanalin (265) or mexicanin A (264)is treated with HC1-CHCI, in the presence of neutral deactivated alumina.' 36 A reasonable mechanism for these transformations has been proposed (Scheme 43). N.m.r. spectroscopic data at 270 MHz have been used to determine the stereochemistry of spathulin (267)13' and the structures of the antileukaemic pseudoguaianolides hymenograndin (268), florigrandin (269), and hymenoflorin (270) (Hyrnenoxys grand[ora).'38 The stereochemistry of the lactone ring in the secoguaianolide parthemollin (271)has been established by X-ray analysis.'39 Ring csntraction of an appropriate guaiane precursor (272) may be involved in the biosynthesis of a new rooting promotor, chlorochrymorin (273), which has recently been isolated from nu

,O Ac

AcO

\

,s

H:,

lr

HO

,

CH,OH

CH,OH (269) R = COCH(Me)Et

13'

(270)

K.-H. Lee, T. Ibuka, M. Kozuka, A. T. McPhail, and K. D. Onan, Tetrahedron Letters, 1974, 2287.

134

135

36

13'

K.-H. Lee, T. Ibuka, A. T. McPhail, K. D. Onan, T. A. Geissman, and T. G. Waddell, Tetrahedron Letters, 1974, 1149. S . Inayama, A. Itai, and Y . Iitaka, Tetrahedron Letters, 1974, 809. A. T. MacPhail, K. D. Onan, K.-H. Lee, H. Furokawa, S.-H. Kim, and C . Piantadosi, Tetrahedron Letters, 1973, 464 1 . W. Herz and A . Srinivasan, Phytochemisrrp, 1974, 13, 1171. W. Herz, K. Aota, A. L. Hall, and A. Srinivasan, J . Org. Chem., 1974, 39, 2013. P. Sundararaman, R. S. McEwen, and W . Herz, Tetrahedron Letters, 1973, 3809.

Sesqu it erpenoids

89

juvenile plants of Chrysanthemum morifoliurn Ram. 140 b-Spathulene (274) is a new member of the aromadendrane class of sesquiterpenoids which has recently been isolated from the essential oil of Schinus molle (California pepper tree).14' A notable feature of a recent synthetic route to (k)-globulol (279) is the use of the boronate fragmentation reaction to produce a 2,7-cyclodecadiene derivative (275) which can be cyclized to the hydroazulenol(276).142 The subsequent conversion of (276)into a tricyclic product (278) with the correct stereochemistry required the use of the Seyferth procedure (PhHgCBr,). In contrast, the Simmons-Smith reagent (CH21,-Zn) provided an adduct (277) whose formation could be explained by the directing effect of the tertiary hydroxy-group. These reactions are summarized in Scheme 44. MeSO, I

cIX

Br

(279)

(278)

(277)

Reagents: i, LiAlH(OBu'),; ii, BH,; iii, NaOMe-MeOH; iv, p-O,NC,H,COCl; v, NaHC0,H,O; vi, CH,I,-Zn; vii, PhHgCBr,; viii, NaBH,; ix, LiCuMe,.

Scheme 44

Complete accounts of two new synthetic routes (Scheme 45) to (k )-seychellene (281) have been p ~ b l i s h e d . ' ~The ~ , 'key ~ ~ step in each sequence is an intramolecular DielsAlder reaction involving cyclohexadienones (280) or (282). Chemical and spectroscopic evidence has been reported for the structure of cycloseychellene(283), a new sesquiter140 141

143

T. Osawa, A. Suzuki, S. Tamura, Y . Ohashi, and Y. Sasada, Tetrahedron Letters, 1973, 5135. S. J . Terhune, J. W. Hogg, and B. M . Lawrence, Phytochemistry, 1974, 13, 865. J . A. Marshall and J. A. Ruth, J . Org. Chem., 1974, 139, 1971. G . Frater, Helu. Chim. Acta, 1974, 57, 172. N. Fukamiya, M. Kato, and A. Yoshikoshi, J.C.S. Perkin I, 1973, 1843.

Terpenoids and Steroids

90

1

ii, iii

H

Reagents: i, 75--80°C; ii, H2-Pd/C; iii, MeLi;

iv,

AcOH-NaOAc; v, H,O,;

VI,

A ; vii, soc12-py.

Scheme 45

penoid isolated from the essential oil of Pogostemon cablin Benth.'45 Seychellene (281) also occurs in the same oil and the biosynthetic relationship between these compounds is presumably similar to that which exists between other pairs of ~esquiterpenoids~~ (e.g. p-santalene, cc-santalene ; sativene, cyclosativene ; longifolene, longicyclene) and monoterpenoids (e.g.camphene, tricyclene).

(283)

13 Mono- and Bi-cyclofarnesanes Independent s t ~ d i e s , ' ~involving ~ , ' ~ ~ the same chemical transformations (Scheme 46), have shown that blumenol A (284), blumenol B (285), and (- )-theaspirone (286) have 145 146

14'

S. J. Terhune, J. W. Hogg, and B. M. Lawrence, Tetrahedron Letters, 1973, 4705. M . N . Galbraith and D. H. S. Horn, J . C . S . Chem. Comm., 1973, 566. G . Weiss, M . Koreeda, and K. Nakanishi, J . C . S . Chem. Comm., 1973, 565.

91

Sesquiterpenoids

1.. 11-1v

(286)

(287)

Reagents: i, H,-PtO,; ii, Cr0,-Me2CO; iii, Ph,P=CHC02Et; iv, H,O-OH-; v, MeS0,Cl-py.

Scheme 46

the same absolute configuration at C-1' as (S)-(+)-cis-abscisic acid (287). The absolute configuration ( R ) at the other chiral centre was deduced by conversion of blumenol B (285) into (-)-theaspirone (286).'47 Dactyloxene-B (288) is one of three new sesquiterpenoid ethers which have been isolated recently from the sea hare (Aplysiadactylomela).14'

It has been suggested that the biosynthesis of this new sesquiterpenoid skeleton involves methyl migration in a monocyclofarnesyl precursor. 14' A biogenetic-type synthesis of grifolin (291)has been achieved by treating a methylene chloride solution of farnesol(2b9) and orcinol(290) with a trace of toluene-p-sulphonic acid.'49 Subsequent treatment of the diacetate (292)with BF,-Et,O followed by hydrolysis and oxidation (Scheme 47) provided a bicyclofarnesane derivative (294) whose structure is very similar to that of tauranin (295).'49 The biosynthesis of tauranin, however, probably involves the intermediate formation of a monocyclofarnesane derivative (cf, siccanin b i o s y n t h e ~ i s ~ ~ ~ ' ~ ~ ) . Two new alcohols isolated from Greek tobacco have been identified as driman-8-01 (298)and driman-8,1l-diol(297) on the basis of spectral evidence and their synthesis from 11-acetoxy-drim-7-ene (296) (Scheme 48).' '

14'

149

IS'

F. J. Schmitz and F. J . McDonald, Tetrahedron Letters, 1974, 2541. K. Ima-ye and H. Kakisawa, J . C . S . Perkin Z, 1973, 2591. K. Y. Suzuki and S. Nozoe, Bioorg. Chem., 1974, 3, 72. J. R. Hlubucek, A. J. Aasen, S . - 0 . Almqvist, and C . R. Enzell, Acta Chem. Scand., 1974, B28, 289.

Terpenoids and Steroids

92

(291) R = H (292) R = Ac

O

n

Ron

o

(294)

(293)

(295) Reagents: i, H'; ii, BF,-Et,O; iii, NaOH-H,O; iv, Fremy's salt.

Scheme 47

J-5 CH,OAc

CH,OH *@oH-&oH H

H

H

(296)

(297)

Reagents: i, rn-CIC,H,CO,H; ii, LiAIH,; iii, MeS0,CI-py.

Scheme 48

(298)

3 Diterpenoids BY J. R. HANSON

1 Introduction This chapter follows the pattern of previous Reports, with sections based on the major skeletal types of diterpenoid. The literature that has been covered was that available to August 1974. The number of naturally occurring diterpenoid substances and the range of their biological activity have continued to increase and a number of new structural types have been reported during the year. Amongst the syntheses reported has been that of the 14-membered ring system of cembrene and the formal total synthesis of the hexacyclic alkaloids. 2 Bicyclic Diterpenoids Labdanes.-A careful chemotaxonomic survey of the oleoresins of Lark (larch) species has been reported.' 13-Epimanool was found in each of the species which were examined whereas larixol and its acetate were confined to L.decidua and Lgrnelini and 13epitorulosol to the remainder. The abietadiene and pimaradiene alcohols, aldehydes, and acids typically found in the Pinaceae were identified from the g.1.c. of the methylated oleoresin. ent-Manool has been found in the liverwort, Jungerrnannia torticalyx.* 13-Epimanool was obtained3 in low yield from the bark of Pinus radiata. The mass spectra of the diterpenoid alcohols related to the abienols have been r e ~ o r d e d . ~ Both cis- and trans-isomers of communic acid (1) and the corresponding equatorial carboxylic acids (2) (i.e. the enantiomers of ozic acid) have been isolated' from Herms villosa (Umbelliferae). ent-Labda-8(17),13(16),14-trien-18-oicacid (3)has been obtained6 from the trunk resin of Kenyan Hyrnenea verrucosa. The same acid occurs' in the seed pod of Hyrnenea courbaril, which also contains the interesting rearranged labdanes ( 4 H 6 ) . Biogenetically these represent an unusual discharge of a carbonium ion in the labdane-clerodane rearrangement (cfi chettaphanin-1). The position of the double bond was located by allylic oxidation to form a 2-ketone and by the mass spectral fragmentation pattern of the diterpenoids. Labda-13-en-8a-ol-15-oic acid has been isolated' from the trunk resin of an Amazonian H . courbaril.

'

'

J. S. Mills, Phytochemistry, 1973, 12, 2407. A. Matsuo, M. Nakayama, J. Ono, and S. Hayashi, Z . Naturforsch., 1972, 27b, 1437. R. J . Weston, Austral. J . Chem., 1973, 26, 2729. P. F. Vlad, K. S. Khariton, M. N. Koltsa, and 0. D. Bordakh, Khim. prirad. Soedinenii, 1974. 8, 30. F. Bohlmann and C. Zdero, Chem. Ber., 1974, 107, 1416. S. S. Martin and J. H. Langenheim, Phytochemistry, 1974, 13, 523. S. F. Khoo, A. C. Oehlschlager, and G. Ourisson, Tetrahedron, 1973, 29, 3379. A. Cunningham, S. S. Martin, and J. H. Langenheim, Phytochemistry, 1974, 13, 294.

93

Terpenoids and Steroids

94

4.. JCO,Me

(5)

(4)

(6)

Communic (l), cupressic, acetylimbricatolic, imbricatolic, and sandaracopimaric acids have been isolated' from Cupressus torulosa stem bark. Examination of the diterpenoid constituents of the oleoresins of the Araucariaceae has continued. Araucaria bidwvlli yields" a complex mixture of bicyclic acids which were separated as their methyl esters. The resin contains ent-labda-8(17),13E-dien1s-oic, ent-clero-3,13-dien-l5-0ic (7), ent-clero-4(18),13E-dien-l5-oic, ent-8P-hydroxylabda-l3E-en- 15-oic, and, in the normal series, agatholic, 19-acetylagatholic, agathalic,

C0,H ,

3 \4 18

HO,C

and agathic acids. An interesting feature is the co-occurrence in this species of labdanes belonging to both enantiomeric series. A . cookii afforded" a mixture of bi- and tricyclic diterpenoids. The acid fraction contained abietic acid, isocupressic acid and its acetate, and the free alcohol and acetate of (13S)-hydroxylabda-8(17),14-dien-19-oicacid (8) and its 8(9)-isomer whilst the neutral fraction contained abietinal, sandaracopimaradienol, 13-epitorulosol, agathadiol, labda-8,14-dien-l3,19-diol,and (13s)hydroxylabda-8( 17),14-dien-19-a1.A. cunninghami contained' * a higher proportion of 15-hydroxy-diterpenoids. The acid fraction gave communic acid, isocupressic acid and acid and its acetate, and 7-0x0-19-acetoxyits acetate, 15-hydroxylabda-8,13-dien-19-oic labda-8,13-dien-15-oic acid. The neutral fraction contained labda-8,13-dien-15,19-diol,

lo I

l2

K. N. Gurudutt, T. R. Seshadri, and T. N. C. Vedantham, Indian J . Chem., 1973,11, 87. R . Caputo and L. Mangoni, Phytochemistry, 1974, 13, 467. R. Caputo, L. Mangoni, P. Monaco, and L. Previtera, Phytochemistry, 1974, 13, 471. R. Caputo, L. Mangoni, and V. Dovinola, Phytochemistry, 1974, 13, 475.

95

Diterpenoids

its diacetate, and its 15-monoacetate together with 15-hydroxylabda-8,13-dien19-a1 and its 15-acetate. The trunk resin of Calocedrus decurrens (Cupressaceae), the incense cedar, contains' four major diterpenoids, lambertianic acid (9), sandaracopimaric acid, dehydroabietic acid, and pinusolide (10). trans-Communic acid, isocupressic acid, isoagatholal, and

(9)

(10)

7-oxodehydroabietic acid were minor components. The diterpenoid constituents of Pinus contorta have been re-examined.l 4 (13S)-Labda-8(17),14-dien-13,18-dioland 18-norlabda-8(17),13-dien-4a,l5-diol were isolated together with 13-epimanool, 13epitorulosol, and some pimaranes. The norlabdadienediol is possibly an autoxidation product of the I 8-aldehyde. Sideritis (Compositae) species have been a fruitful source of diterpenoids. A new derivative of manoyl oxide, borjatriol (ll), has been obtained" from S. rnugronensis. Its structure followed from inter-relationship with manoyl oxide. A labdane triol, gymnospermin (12), has been isolatedI6 from Gymnosperma glutinosa (Compositae). The corresponding enantiomeric dihydroxy-acid had previously been isolated from Dodoneae lobulata. Two further ent-labdanes, (13) and (14), have been recorded in extracts from Dodonaea microzyga. Their structures rest' on spectral evidence and

l6

(13) R = Me (15) (14) R = CH,OH L. J. Gough and J. S. Mills, Phytochemistry, 1974, 13, 1612. T. D. R. Manning, Austral. J. Chem., 1973, 26, 2735. B. Rodriguez and S. Valverde, Tetrahedron, 1973, 29, 2837. M. Miyakado, N. Ohno, H. Yoshioka, T. Mabry, and T. Whiffin, Phytochemistry, 1974, 13,

l7

189. P. R.Jefferies, J. R. Knox, and B. Scaf, Austral. J . Chem., 1974, 27, 1097.

l3

l4

'

96

Terpenoids and Steroids

correlation with the known methyl ent-labda-8,13-dien-l5-oate.The structure (15 ) has been proposed’ for lithofellic acid. The formation of cyclic ethers from the oxidation products of manool and sclareol has continued to attract attention. Instead of the 1,4-dioxan (16), the unusual cyclic acetal(18) was obtainedI9 when the diol(l7) was treated with toluene-p-sulphonic acid. The mass spectra of these acetals have been recorded. Oxidation of manool with aqueous potassium permanganate affords the acetal (19). However, oxidation” of labd-8(17)-en-13-01 (20) gave the 8,13,17-triol and two unusual ethers, 8,12S- and 8,12R-epoxylabdan-l3,17-diols (21) in which an unactivated carbon atom has been

functionalized by the permanganate. The origin of the long-range coupling shown in the n.m.r. spectra by the 17-epoxide protons in some manool derivatives has been established2 using specifically deuteriated analogues. The synthesis has been described22 of the hydrocarbon (22) which was originally obtained by dehydrogenation of sclareol.

(22)

A number of labdanes and other diterpenoids have been isolated from tobacco. The synthesis of a novel constituent, 14,15-bisnor-8-hydroxylabd-ll-en-l3-one from drimenol has been described.’ A series of tetranor-diterpenoids has been isolatedz4 l9

2o 21

22

23

24

D. Albert, C. Hootele, and M. Kaisin, Bull. SUC.chim. belges, 1973, 82, 785. R. C. Cambie, A. F. Preston, and P. D . Woodgate, Austral. J . Chem., 1973,.26, 1821; Org. Mass Spectrometry, 1974, 8 , 161. P. K. Grant and R.T. Weavers, Tetrahedron, 1973, 29, 2769. P. K. Grant and R. T. Weavers, Tetrahedron, 1974, 30, 2385. D. Nasipuri, I. DeDalai, and D . N . Roy, J.C.S. Perkin I, 1973, 1754. J. R. Hlubucek, A. J. Aasen, S . - 0 . Almqvist, and C. R.Enzell, Acta Chem. Scand., 1974, B28, 131. M. Sato, T.-I. Ruo, T. Hayashi, H. Kakisawa, T. Miyaki, H. Yamamoto, and K. Fujisawa, Tetrahedron Letters, 1974, 2 183.

D iterpenoids

97

from an Acrostalagmus species during a study of the biosynthesis of its metabolites. The new fungal metabolites are acrostalic acid (23),acrostalidic acid (24),and isoacrostalidic acid (25).

&

@* >\

%\\

H

/

H

HO,C

HO,C

(23)

(24)

It has been pointed that daniellic acid (26), which was isolated26from Daniellia oliueri, had been isolated2’ many years previously as illurinic acid from African copaiba balsam. This balsam had been obtained from Daniellia oliveri, but owing to confusion over the naming of this plant species this had been overlooked. Two new labdanes, rotundifuran (27)and prerotundifuran (28),have been isolated28from Mtex rotundifolia. Dubiin (29)is a new furanoid diterpenoid which has been isolated29from Leonotis dubia. The relationship of the furan ring and the tertiary hydroxy-group was established by oxidation to the dilactone (30) whilst hydrolysis of the C-6 acetoxy-group, oxidation of the resultant alcohol to a ketone, and deuteriation provided the evidence which established the site of the secondary acetoxy-group.

25 26

*’

J. S. Mills, Phyrochemistry, 1973, 12, 2479. J. Haeuser, R. Lombard, F. Lederer, and G. Ourisson, Terrahedron, 1961, 12, 205. J. C. Umney, Pharm. J., 1891,22,449; 1893,24,215; A. Tschirch and E. Keto, Arch. Pharm., 1901, 548.

la

Y . Asaka, T. Kamikawa, and T. Kubota, Chem. Letters, 1973, 937. G. A. Eagle and D. E. A. Rivett, J.C.S. Perkin I , 1973, 1701.

98

Terpenoids and Steroids

(29)

(30)

C1erodanes.-The rearrangement with boron trifluoride of a number of 8a,9a- and 8P,9fl-epoxy-l4,15-bisnorand 14,15,16-trisnor-labdanederivatives has been examined3' in an attempt to prepare friedolabdanes of the clerodane type. In the event compounds such as (31) were obtained from the a-epoxide and (32) from the P-epoxides. The results show that although rearrangement could occur, leading to the ion (33),further migration of the C-4 P-methyl group was difficult because it led to a 1J-diaxial interaction between the C-5 and C-9 P-methyl groups in the ion (34). One possibility of promoting this migration was explored. This involved the introduction of a P-hydroxy-group at C-3 which might stabilize a neighbouring carbonium ion. The results suggest that the epoxides rearrange in a non-concerted manner in which the carbonium ion can be trapped at various centres. Thus the a-epoxide (36) gave (35) after acetylation whilst the P-epoxide (37) gave ( 3 8 ) and (39) after acetylation.

(37)

(38)

(39)

Solidago (Compositae) species have been the source of a number of bicyclic diterpenoids. The constituents of a variety of S. serotinu include31 the furan (40), its 3a74aepoxide, the cis- and trans-aldehydes (41) and the corresponding 3-ketones, and the butenolide (42), its 3-ketone, and the 3a74j3-truns-diol. Hardwickiic acid has been 30 3L

M. S. Hadley and T. G. Halsall, J . C . S . Perkin I , 1974, 1334. R. McCrindle and E. Nakamura, Canad. J . Chem., 1974, 52, 2029.

D i t erpenoids

99

isolated32 from the blackberry, Ribes nigrum. A full paper describing some kolavenic acid derivatives which were obtained from S. altissirna has appeared.33 Stachysolone, which was isolated from Stachys annua, has been assigned34 the stereochemistry (43). CHO

':"I" OH

'OH

Further details have been given35 on the assignment of absolute stereochemistry to the acetoxy-acid (44),which was isolated from Dodonaea attenuata. The related diene-acid (45) was also isolated from D.attenuata var. linearis. In the course of the structural work the interesting formation of a cyclopropane ring [(46)--+(47)] on hydride reduction was noted. The alcohol (48) and acid (49) have been obtained36from D. boroniaefolia and

CH,OAc

@

HO,C \ CH,OH

HO,C (45)

1 CH~OTS

Me0,C

32 33 34

G. George, Ch. Candela, M. Quinet, and R. Fellows, Helu. Chim. Acta, 1974, 57, 1247 A. Ohsuka, S. Kusumoto, and M. Kotake, Nippon Kagaku Kaishi, 1973, 631. D. P. Popa and T. M. Orgiyan, Khim. prirod. Soedinenii, 1972, 6 , 735. T. G. Payne and P. R. Jefferies, Tetrahedron, 1973, 29, 2575. P. R. Jefferies, J. R. Knox, and B. Scaf, Austral. J . Chem., 1973, 26, 2199.

100

Terpenoids and Steroids

correlated with this diene-acid. A related dihydroxy-acid was obtained3' from Olearia muelleri. The lactone bacchofertin (50) has been isolated3 from Baccharis conferta. The trans-dicarboxylic acid (51) was isolated36from Cyanostegia angustfolia.

HO

@ \

CH,OH

(48)

HO"

CO, H

(49)

&cJ ,

OAc

CH,OCOR (52) R

=

CH,CHMe,, CH(Me)Et, or CMe=CHMe

(53) R = AC (54)

R

=

H

0 (55) R = H (56) R = OH 37 38

P. R.Jefferies, J. R. Knox, K. R. Price, and B. Scaf, Austral. J . Chem., 1974, 27, 221. C. Guerrero and A. Romo de Vivar, Reu. latinoamer. Quim., 1973, 4, 178.

101

Diterpenoids

A group of furanoid esters (52) was isolated39 from Hinterhubera imbricata (Compositae). Their structures were based on mass spectral and n.m.r. evidence in which shift reagents were used to define the ring A stereochemistry. A number of clerodane diterpenoids have been isolated from the Verbenaceae as insect anti-feeding substancesf’ Caryoptin (53)41 and the corresponding alcohol, caryoptinol (54),were obtained42 from Caryopteris diuaricata whilst 3-epicaryoptin was isolated43 from Clerodendron calamitosum. Teucvin is a novel furanoid nor-diterpenoid which was isolated from Teucrium uiscidum. Its structure ( 5 5 ) rests on an X-ray analysis of a brom~-derivative.~~*~’ Teucvin A has been assigned the related structure (56).46Teucrium cubense contains4’ the nor-diterpenoid eugarzasadone (57) which is reported to possess amoebicidal activity. A number of cis-clerodane derivatives, (58) and (59), have been isolated4* from Solidago arguta. Interestingly the trans-clerodane (40)was also isolated from this species. The stereochemistry of these compounds was assigned on the basis of the Cotton effect of the 2-ketones (58 ; R’ = 0). Rearrangement of the 3,4-epoxides of both the cis- and trans-clerodanes afforded the same product (60). The suggestion has been made that cistodioic acid has the stereochemistry (61) and that haplopappic acid is (62).

I

(58)

R‘ R2

R3

H, H, H, H, H,

H H H OH OH

Me CH,OAc CH,OH CH,OAc CH,OH

6 9 HO“

\

(60)

v

&--O 0

(59)

C

C

O

40

H

\

CO, H (61)

(62) 39

2

A13

F. Bohlmann, M. Grenz, and H. Schwarz, Chem. Ber., 1973, 106, 2479. S. Hosozawa, N . Kato, K. Munakata, and Y. L. Chen, Agric. and Biol. Chem. (Japan), 1974, 38, 1045.

41 42 43 44

” 46

47 48

S. Hosozawa, N. Kato, and K. Munakata, Phytochemistry, 1973, 12, 1833. S. Hosozawa, N . Kato, and K. Munakata, Phytochemistry, 1974, 13, 1019. S. Hosozawa, N . Kato, and K. Munukata, Phytochemistry, 1974, 13, 308. E. Fujita, I. Uchida, T. Fujita, N. Masaki, and K. Osaki, J.C.S. Chem. Comm., 1973, 793. E. Fujita, 1. Uchida, and T. Fujita, J.C.S. Perkin I, 1974, 1547. D. P. Popa, A. M. Reinbold, and A. I. Rezvuhkin, Khim. prirod. Soedinenii, 1973, 7, 169. X. A. Dominguez, A. Merijanian, and B. I. Gonzalez, Phytochemistry, 1974, 13, 754. A. B. Anderson, R. McCrindle, and E. Nakamura, J.C.S. Chem. Comm., 1974, 453.

102

Terpenoids and Steroids

Marrubiaside (63) and marrubialactone (64)have been isolated4' from the leaves of Leonurus marrubiastrum. The butenolide ring of marrubiaside was reduced to allow oxidative modifications of ring A such as the formation of a 2-ketone or a 3,4-epoxide. The structure rests on the spectral data of these compounds. Columbin has been isolated5' from Melothria maderospatana (Cucurbitaceae).

3 Tricyclic Diterpenoids

Naturally Occurring Substances.-A number of tricyclic diterpenoids commonly cooccur with bicyclic substances (q.0.). The diterpenoids of h i e s alba (Pinaceae) include5 abieta-8,11,I 3-triene, abieta-8,11,13-trien-7-one,and 13-epimanool. The structure of lagascatriol, isolated from Sideritis angustfolia has been corrected52 to 13-epi-l5,16dihydro-ent-rimuene-1 lR,15S,16-tri01(65). Kirenol(66) is a tetraol which was isolated53 from Siegesbeckia pubescens. The structure was established by correlation with known pimaradiene derivatives. The 15,16-acetonide was prepared and then the C-2 hydroxygroup was removed through the mono-toluene-p-sulphonate. The tentative structure (67) has been proposed54for candicopimaric acid, which was isolated from the roots of Herudeurn candicans.

49 50

51 52

53 54

(67) R. Tschesche and H.-U. Plenio, Chem. Ber., 1973, 106, 2929. Y . P. Chen, H. Y . Hsu, T. I. Ruo, K. Iguchi, and H. Kakisawa, Phytochemistry, 1973,12, 3000. J. M. Ribo, M. R. Mitja, and J. Ramentol, Phytochemistry, 1974, 13, 1614. F. M. Panizo, B. Rodriguez, and S. Valverde, Anales de Quim., 1974,70, 164; cJ ibid., 1972,68, 1461. T. Murakami, T. Isa, and T. Satake, Tetrahedron Letters, 1973, 4991. M. Bandopadhyay, S. B. Malik, and T. R. Seshadri, Indian J . Chem., 1973, 11, 1097.

Diterpenoids

103

Annonalide (68) is an interesting lactone which was isoiated5' along with some clerodanes from Annona coriacea. In one informative degradative sequence the a-ketol was cleaved and the acetal was reduced to afford the h-lactone (69) which was converted in a further series of steps into 13,13-dimethylpodocarp-7-ene(70),an authentic sample of which was prepared from isopimara-8(14),15-diene. The 13C n.m.r. spectrum of annonalide was useds6 to assign the stereochemistry of ring c.

(70)

The momilactones A (71) and B (72) are a pair of growth inhibitors which were isolated5' in trace amounts from Oryza sativa (rice). Their structure was established by an X-ray analysis of (71). The number of nor-diterpenoid dilactones from Podocarpus species continues to increase.'* Some transformations of sellowin A (73), sellowin B (74),and sellowin C (75),including the relationship of the latter to nagilactone, have been described. The light-petroleum extract of Maytenus disperrnus has been shown to contain,60 in addition to pristimerin, maytenone, and sugiol, three new diterpenoids, maytenoquinone (76), 12-methoxytotarol, and 12-hydroxy-7-oxototarol. Their structures were assigned on the basis of their spectral properties and their changes on stepwise reduction. A new dihydroxyabietene (77) has been isolated6' from Nepeta teydea. A number of highly oxygenated abietanes have been obtained from Coleus species. Further study of C. barbathus has led to the isolation62 of a novel diterpenoid cyclobutatusin (78) which contains not only a spirocyclopropane ring as in barbatusin but also a four-membered ring formed by a bond between C-1 and C-1 1. The structure was 55 56

51

58

59

60 61

62

P. Mussini, F. Orsini, F. Pelizzoni, and G. Ferrari, J.C.S. Perkin I , 1973, 2551. P. Mussini, F. Orsini, F. Pelizzoni, B. L. Buckwalter, and E. Wenkert, Tetrahedron Letters, 1973. 4049. T. Kato, C. Kabuto, N. Sasaki, M. Tsunagawa, H. Aizawa, K. Fujita, Y . Kato, and Y . Kitahara, Tetrahedron Letters, 1973, 386 I . M. N. Galbraith, D. H. S. Horn, S. Ito, M. Kodama, and J. M. Sasse, Agric. and B i d . Chem. (Japan), 1972, 36, 2393. K. S. Brown, jun., and W. E. Sanchez L., Tetrahedron Letters, 1974, 675. J. D. Martin, Tetrahedron, 1973, 29, 2553. A. G. Gondlez, F. J. Breton, and C. R. Fagundo, Anales de Quim.,1973,69, 1059. A. H. J. Wang, 1. C. Paul, R. Zelnik, D. Lavie, and E. C. Levy, J . Amer. Chem. SOC.,1974,96, 580.

Terpenoids and Steroids

104

w o 0

,Io

CH,OH

co-0

co-0

,'

& 0

H O

HO'

co--0 (75)

(74)

CH,OH (77)

established by X-ray analysis which also showed that the C-8, C-9, and C-10 substituents were all p. C . somaliensis is the source63of the coleons G (79) and J (80)which also contain the spirocyclopropane ring system. The related hydroquinones, coleons H (81), I (82), and K (83), were isolated from the same source. Galdosol (84) was isolated64 from Salcia canariensis.

0

'OH

0 OAc

(78)

63 64

Me'

'OR

OH

(79) R (80) R

= =

H AC

M. Moir, P. Ruedi, and C. H. Eugster, Helv. Chim.Acta, 1973,56, 2539, 2534. A. G. Gonzalez, B. M. Fraga, J. G. Luis, and A. G. Ravelo, Experientia, 1973, 29, 1471.

D iterpeno ids

105

ROO’’

OH (81) R’ = O H , R2 = R 3 = H , R4 = AC (82) R’ = R2 = R 3 = H, R4 = AC (83) R’ = H, R 2 = OAC,R 3 = Ac, R4 = H

(84)

Isoagatholactone (85), isolated6’ from the sponge Spongia oficinalis, is the first naturally occurring diterpenoid with the carbon skeleton of isoagathic acid. Its structure was established by a correlation with a cyclization product of grindelic acid via the alcohol (86).

88 H

H,OH

H

A number of new alkaloids have been isolated66 from the bark of Erythrophleurn chlorostachys. The esters, such as the 2-methylaminoethanol ester norerythrostachamine, readily rearrange to the amides. Chemistry of the Tricyclic Diterpenoids.-Dehydroabietic acid and podocarpic acid have made useful starting materials for a number of diterpenoid partial syntheses. An interesting reversible C- 10-+C-5 methyl-group migration has been described67 in the en01 acetylation of the 7-oxodehydroabietic acid derivative (87s88). However, this rearrangement is dependent68upon the reaction conditions. Treatment with aluminium trichloride in benzene leads to the ‘retro’ derivative (89). A potential spiranic intermediate is trapped as the y-lactone (90). Ring A-cleavage products [e.g. (91)] are also found in certain cases. The reversible rearrangement permitted69 the introduction of bromine into ring A at C-1, thence affording a A’(*)-olefin and a partial synthesis of teideadiol (92). It has been suggested” that the rearrangement products obtained by treating podocarpic and dehydroabietic acids with phosphorus oxychloride are 18-nor-5,lOfriedopodocarpatrienes (93) and 18-nor-$10-friedoabietatrienes rather than the

’’ G . Cimino, D. De Rosa, S. De Stefano, and L. Minale, Tetrahedron, 1974, 30, 645. 66

67 68

69 ’O

J. W. Loder, C. C. J. Culvenor, R. H. Nearn, G. B. Russell, and D. W. Stanton, Austral. J . Chem., 1974, 27, 179. A. Tahara, H. Mizuno, and T. Ohsawa, Chem. Letters, 1972, 1163. A. Tahara, H. Akita, T. Takizawa, and H. Mizuno, Tetrahedron Letters, 1974, 2837. A. Tahara and H. Mizuno, Tetrahedron Letters, 1974, 523. J. W. Huffman and J. J. Gibbs, J . Org. Chem., 1973, 38, 2732.

Terpenoids and Steroids

106

I

7 L

+

CH,OH

(92)

1-methyl products.’ Their formation nevertheless remains unusual. The pyrolysis of dehydroabietic acid to form 19-norabieta-4,8,11,13-tetraenehas been Preliminary studies on the elaboration of the caged ring system surrounding the nitrogen atom of the diterpenoid alkaloids have centred73on the synthesis of the y-lactam (94) from podocarpic acid methyl ether. A study of the autoxidation of tertiary aldehydes to the nor-alcohols has been extended to dehydr~abietinal.~~ OMe

OMe

(93)

(94)

B. C. Baguley, R. C. Cambie, W. R. Dive, and R. N. Seelye, Austral. J . Chem., 1972,25, 1271. 7 2 R. F. Severson and W. H. Schuller, Canad. J. Chem., 1973,51, 3236. ’’ B. S. Balgir, L. N. Mander, and R. H. Prager, Austral. J . Chem., 1974, 27, 1245. 7 4 R. Caputo, L. Previtera, P. Monaco, and L. Mangoni, Tetrahedron, 1974, 30,963.

Diterpenoids

107

The application of spectroscopic techniques to the elucidation of the stereochemistry of 6-bromo-7-0x0-derivatives produced conflicting stereochemical assignments for the bromine atom. Full details have now been p ~ b l i s h e d 'of ~ the X-ray analysis of 6abromo- 13-hydroxy-14-isopropylpodocarpa-8,11,13-trien-7-one and ofmethyl 6a-bromo13-isopropy1-7-oxopodocarpa-8,11 ,I 3-trien-15-oate in which ring B exists in a boat or half-boat conformation. A synthesis of rosenonolactone from podocarpic acid has been d e ~ c r i b e d .The ~ ~ C-1O x - 9 methyl-group shift with concomitant lactonization on the same face of the molecule was effected by treatment of the a-epoxide (95) with boron trifluoride to generate the lactone (96). This rearrangement is of interest in relation to the studies on the formation of the clerodanes in the bicyclic series.

A number of approaches to the construction of steroidal analogues from podocarpic acid, such as the addition of a five-membered ring to ring c, have been described. A further approach the addition of another ring to positions 3 and 4 of ring A of the diterpenoid to afford a 2-hydroxy-9-methyl ring A-aromatic steroid. A series of heterocyclic derivatives of podocarpic acid has been described.7 8 Methyl dehydroabietate has provided the starting material for syntheses of sempervir01~~ and of 7-0~0-11,12-dirnethoxyabietatriene, a compound which had in turn been converted into taxodione.80 The 8,9-epoxy-7-ketonehas now been identified'' amongst the chromic acid oxidation products (7- and 11-ketones and 7,ll-diketone) of A8,9-pimaranes. The preparation of A8,9-sandaracopimaradienehas been described." An improved synthesis of the unsaturated ketone (97) from dehydroabietanitrile has been de~cribed.'~This was then transformed via the 9(11)-olefin into the 11-epimeric alcohols. Oxidation of the palcohol with lead tetra-acetate and iodine gave the (20-1 1)-y-lactone (98) whilst oxidative cyclization of both the a- and p-epimers with lead tetra-acetate alone gave a mixture of 1,ll- (99) and 20.1 1- (100) ethers with some epimerization at C-11. 75

76 77 78 7y

'' 83

J. F. Cutfield, T. N. Waters, and G. R. Clark, J.C.S. Perkin 11, 1974, 150. W. S. Hancock, L. N. Mander, and R. A. Massey-Westropp, J . Org. Chem., 1973,38,4090. R. C. Cambie, W. A. Denny, T. J. Fullerton, and R. C. Hayward, Austral. J . Chem., 1974, 27, 1317. G . D. Beresford, R. C. Cambie, and K. P. Mathai, Austral. J . Chem., 1973, 26, 1763. T. Matsumoto, I . Sachihiko, T. Matsubayashi, F. Tsunenaga, and K. Fukui, Chem. Letters, 1972, 1159. T. Matsumoto, Y . Ohsuga, and K. Fukui, Chem. Letters, 1974, 297. W. H e n and H . L. Hall, J . Org. Chem., 1974, 39, 1 1 . K. M. D. Do, M. Fetizon, and E. Wenkert, Synth. Comm., 1973, 3, 277. W. Herz and D . H. White, J . Org. Chem., 1974, 39, 1.

Terpenoids and Steroids

108 O

r

(99)

I

(100)

The biogenetically interesting rearrangements of the cation (101) as a potential progenitor of the abietadienes have been examined.84 Rearrangement of the 15Rtoluene-p-sulphonate ( 1 02) derived from pimaric acid afforded the cyclopropane (103), but the isopimaric acid analogue, with a different C-13 stereochemistry, gave no rearrangement.

4 Tetracyclic Diterpenoids

The KaurenePhyllocladene Series.-Kauranoid diterpenoids have previously been obtained from Espeletia (Compositae) species. Examination of E . hurnbertii, E. littlei, and E. timotensis has led to the isolations5 of kaur-9(11),16-dien-19-oic acid from each and in addition 15a-hydroxykaur-16-en-19-oicacid from E. timotensis. Kauranol and 15~-acetoxykaur-16-en-19-oic acid were obtained from E. Iwnhertii. Candol A (entkaur- 16-en-7a-01) and candol B (ent-kaur-16-en-18-01)are new diterpenoids which have been isolateds6 from Sideritis candicans. Leucanthol, isolated from S . leucantha, has been showns7 to be ent-kaur-16-en-3/l,7a,l5/l,l8-tetraol (104) whilst isoleucanthol is

84 85

''

W . Herz and A. L. Hall, J . Org. Chem., 1974, 39, 14. A. Usubillaga, J. de Hernandez, N. Perez, and M. Kiriakidis, Phytochemistry, 1973, 12, 2999. A. G. Gonzalez, B. M. Fraga, M. G. Hernandez, and J. G . Luis, Phytochemisrry, 1973, 12, 2721. T. Garcia de Quesada, B. Rodriguez, and S. Valverde, Anales de Quim., 1972, 68, 1465.

&

Diterpenoids

H

HO" HOCH,

H

. 'OH

109

H

O

s

OH '$

H

-

OH

0

"

H

O

0G

: H HOzC

ent-kaur-15-en-3P,7a,17,18-tetraol. ent-Kauran-2a,6a,l6fi-triol(lO5) has been isolatedg8 from Pteris cretica. Calliterpenone and its monoacetate have been recordeds9 in Callicarpa fongifofia. Atractyligenin as its glycoside has been found" in coffee beans also known as a source of cafestol. A metabolite (106)of atractyligenin has been found" in the urine of coffee drinkers. Two unusual cyclic carbonates, (107) and (108), are formed92 during the oxidation of ring D of atractyligenin with performic acid. The oxidation of ring D of phyllocladene and isophyllocladene and the formation of the using thallium(1) acetate 16-acetoxy-17-iodo- and 17-acetoxy-16-hydroxy-derivatives and iodine has been described.93 The functionalization of ring c by treatlng 16p-entkauran-17-01 and the corresponding C-19 methyl ester with iodine and lead tetraacetate has been studied.94 Reaction occurs at C-11 to give the 11-olefin, the 1 1P-iodo12,17-ether,and minor amounts of the 9(1l)-en-12,17-ether. A number of new kaurenolides have been isolated9' from Gibberellafujikuroi. These include 7P,11a-dihydroxykaurenolide (109) and the corresponding 18-norkaurenolide, 1~,7P-dihydroxykaurenolide, and 18-acetoxy-7~-hydroxykaurenolide.4/3,7@-Dihydroxy-18-norkaurenolide(110) is a further new kaurenolide which was correlatedg6 chemically with 7,18-dihydroxykaurenolidevia its oxidation products.

89

90

91 92

93 94 95

96

(109) (1 10) C.-M. Chen and T. Murakami, Chem. and Pharm. Bull. (Japan), 1973,21 455. S.S. Subramanian, A. G. R. Nair, and T. N. C. Vedantham, Phytochemistry, 1974, 13, 306. H. Ludwig, H. Obermann, and G. Spiteller, Chem. Ber., 1974, 107, 2409. H. Obermann, G. Spiteller, and G. A. Hoyer, Chem. Ber., 1973, 106, 3506. F. Piozzi, G. Savona, and M. L. Marino, Tetrahedron, 1973, 29, 621. R. C. Cambie, R. C. Hayward, J. L. Roberts, and P. S . Rutledge, J.C.S. Perkin I, 1974, 1120. A. J. McAles and R. McCrindle, Canad. J. Chem., 1973, 51, 4103. P. Hedden, J. MacMillan, and M. J. Grinstead, J.C.S. Perkin I , 1973, 2773. H. Yamane, N. Murofushi, and N. Takahashi, Agric. and Biol. Chem. (Japan), 1974,38, 207.

110

Terpenoids and Steroids

lsodon species have been a fruitful source of highly oxygenated diterpenoids. Mebadonin (111) was isolated9' from I . karneba and its structure was determined by X-ray analysis. It is the first example of a kauranoid diterpenoid to be isolated from these species bearing an oxygen function at C-2 and lacking a C-20 oxygen function. Lasiokaurinol ( I 12) and lasiokaurinin (1 13) are two minor diterpenoids isolatedg8 from 1. lasiocarpus. The structure of lasiokaurinol rests on an inter-relationship with lasiokaurin and enmenol. Ponicidin (114) is an interesting member of the series which possesses two hemiacetal linkages whose formation reveals the close proximity of C-20 and C-14." The full paper describing the structures of isodonal, trichodonin, and epinodosin has appeared.'" The structures of the seco-ring B enmein derivatives isodoacetal(ll5) and nodosinin (116) and the tetracyclic odonocin (117)have also been described."' The total synthesis of enmein uia the relay (118),obtained by degradation of enmein,lo2has been described in full.'03 The biosynthesis of enmein from ent-kaur16-en-15-one has been described. O4

AcO

(117) 97 98

99 loo lo' lo* lo'

'04

AcO

(118)

K . Hirotsu, T. Kamikawa, T. Kubota, A. Shimada, and T. Isobe, Chem. Letters, 1973, 255 E. Fujita, M . Taoka, and T. Fujita, Chem. and Pharm. Bull. (Japan), 1974, 22, 280. E. Fujita, M. Taoka, M. Shibuya, T. Fujita, and T. Shingu, J.C.S. Perkin I, 1973, 2277. I. Kubo, T. Kamikawa, and T. Kubota, Tetrahedron, 1974, 30, 615. E. Fujita, M. Taoka, Y. Nagao, and T. Fujita, J.C.S. Perkin I, 1973, 1760. M. Shibuya and E. Fujita, J.C.S. Perkin I , 1974, 178. E. Fujita, M . Shibuya, S. Nakamura, Y. Okada, and T. Fujita, J.C.S. Perkin I , 1974, 165. T. Fujita, S. Takao, Y. Nagao, and E. Fujita, J.C.S. Chem. Comm., 1974, 666.

Diterpenoids

111

Ekyeranes.-A number of beyerene derivatives have been isolated l C 5 from Sideritis pusilla. These include pusillatriol (119), isopusillatriol (120), and pusillatetrol (121). Diazomethane reacts with the C-14 carbonyl group of these diterpenoids to afford'06 an epoxide (1 22). Acetolysis of the sulphonate esters of ent-3/?-hydroxybeyer-15-en2,12-dione and its 3-axial and 1-axial isomers leads"' in each case to ent-la-acetoxybeyer-l5-en-2,12-dione. Treatment of ent-kaur-16-ene or methyl ent-kaur-16-en-19oate with hot formic acid giveslog a mixture of the C-12, C-15, and C-16 ent-beyerane formyl derivatives. The proportion of the 12-substituted compound increases in trifluoroacetic acid. The same mixture is obtained' O 9 from methyl ent-trachyloban-19oate. Cleavage of the cyclopropane ring of methyl ent-trachyloban-19-oate with thallic acetate leads to compounds of the ent-atisane skeleton, including (123) and (124).

(119) R' = H, RZ = OH (120) R' = OH, R2 = H (121) R' = R 2 = OH

C02Me

(123) R

lo' lo6

lo7

Io8 '09

=

Me or CH,OAc

T. Garcia de Quesada, B. Rodriguez, and S. Valverde, Anales de Quim., 1974, 70, 239. T. Garcia de Quesada, B. Rodriguez, and S. Valverde, Anales de Quim., 1974,70, 245. K. H. Pegel, L. P. L. Piacenza, G. P. Gorst-Allman, L. Phillips, and E. S. Waight, Tetrahedron Letters, 1973, 4053. J. C. Fairlie, A. J. McAlees, R. McCrindle, and E. Neidert, Canad. J. Chem., 1974, 52, 706. H . M. Campbell, P. A. Gunn, A. J. McAlees, and R . McCrindle, Canad. J . Cham., 1973, 51, 4167.

1!2

Terpenoids and Steroids

Jativatriol (125) and conchitriol (126) are two new 12-hydroxybeyerene derivatives which have been isolated' ' from Sideritis angustifolia. The hydroxy-groups of jativatrio1 were of sufficiently different reactivity to permit selective hydrolysis of the acetates and stepwise deoxygenation to beyerene.

Gibberellins. ---Recentaspects of the chemistry and biosynthesis of the gibberellins have been reviewed."' A valuable system for the separation of the gibberellins using partition chromatography on Sephadex LH 20 has been described.Il2The full papers have appeared' recording the isolation of gibberellins A,, A, 7 , A,, . A2,, A,, , A,,, A,, , and A,, from Calonyction aculeatum, the evidence for the structures of gibberellins A,,, A,,, A,,, and A,,, and the isolation and structure of gibberellin A,, and its glucoside from the immature seed of Cytisus scoparius. The full paper on the isolation of gibberellins A,, ,A,, ,A,, , A, ,, and A42 from Gibberella.fujikuroi strain TP70 have also appeared. l 4 Gibberellins A,, (127)and A,, (128)are hydration products of gibberellins A 1 3 and A 14 respectively. Gibberellin A,,, 2a-hydroxygibberellin A, (129), has also been isolated" from Gibberella jujikuroi. A detailed analysis of the metabolites from mevalonate in Gibberella fujikuroi has revealed' the presence of more gibberellins to which tefitative structures of 1-hydroxygibberellin A, (130), the lp-epimer of gibberellin A (1 3 1). the 2a-hydroxy-epimer of gibberellin A,, (I 32), and 1,2-epoxygibberellic acid were assigned.

,

HO..

11°

"

I I ' ' I 3

'I4 'I5

' I h

C. von Carsteon-Lichterfelde, S. Valverde, and B. Rodriguez, Austral. J . C h r m . , 1974, 27, 517. J . MacMillan in 'Chemistry and Biochemistry of Plant Hormones', Recent Advances in Phytochemistry, Vol. 7, ed. V . C. Runeckles, E. Sondheimer, and D. C. Walton, Academic Press, New York, 1974, p. 1 . J . MacMillan and C. M. Wels, J . Chromatog., 1973, 87, 271. N . Murofushi, T. Yokota, A. Watanabe, and N. Takahashi, Agric. and Biol. Chem. (Japan), 1973, 37, 1101 ; H. Yamane, 1. Yamaguchi, N . Murofushi, and N. Takahashi, ibid, 1974, 38, 649. J . R . Bearder and J. MacMillan, J . C . S . Perkin I, 1973, 2824. I . Yamaguchi, M. Miyamoto, H . Yamane, N. Takahashi, K . Fujita, and M. Imanari, Agric. and Biol. C h r m . (Japan), 1973, 37, 2453. J . MacMillan and C . M. Wels, Phyrochemistry, 1974, 13, 1413.

Diterpenoids

113

HO

. _

HO

H

C02H

COzH

(131)

(132)

The variation in gibberellin content of pea seed through maturation has been studied.", In addition to gibberellins A,, and A,,, which were identified earlier, gibberellins A,, A l , , A,, , and A,, (13-hydroxygibberellin A15)(1 33) were identified. Gibberellin A, was at a maximum followed by gibberellin A,, and then gibberellin A,,, suggesting a biosynthetic route linking these gibberellins. Pharbitic acid (134) is an interesting diterpenoid related to the gibberellins whose structure was determined' by X-ray analysis. It may arise biogenetically by the addition of mercaptopyruvic acid (or cysteine) to the C-3 keto-derivative of gibberellic acid and, as it is biologically inactive, it may represent a gibberellin regulatory substance.

( I 34)

(133)

The identhcation of known gibberellins in new plant species continues apace. Gas chromatography-mass spectrometry has proved a valuable tool in this, for example in confirming the presence of gibberellins A,, A,, and A, in apple seed.' l 9 Gibberellins A,, A,, A,, and A,, have been characterized in light-grown Phaseolus coccineus12' and gibberellins A, and A, in Corylus avellana.'2'

H

.

.

OH

HO

I

,

HO

CO-0

'" ' I 8

'I9

"'

V. M. Frydman and J. MacMillan, Planfa, 1973, 115, I I ; V. M. Frydman, P. Gaskin, and J . MacMillan, ihid., 1974, 118, 123. T. Yokota, S. Yarnazaka, N. Takahashi, and Y. Iitaka, Tetrahedron Letters, 1974, 2957. I. Sinska, St. Lewak, P. Gaskin, and J. MacMillan, Planfa, 1973, 114, 359. D. H. Bowen, A. Crozier, J. MacMillan, and D. M. Reid, Phyrochemistry, 1973, 12, 2935. P. M. Williams, J. W. Bradbeer. P. Gaskin, and J. MacMillan, Planta, 1974, 117, 101.

114

Terpenoids and Steroids

The partial synthesis from 3P,7P-dihydroxykaurenolide (1 35) of gibberellin A 14 aldehyde (136)-an intermediate in gibberellin biosynthesis-has been described. 22 There has been considerable progress in gibberellin biosynthesis utilizing mutants of Gibberella f ~ j i k u r o i , 'a~cell-free ~ system from Curcurbita maxima,' 24 and pea seedl i n g (see ~ ~pp. ~ 184 ~ and 185). Gibberellu fujikuroi has been used to produce analogues of mould metabolites by microbiological transformation. The full details of the preparation of fluorogibberellic acid and fluorogibberellin A, by this method have now appeared. 126 The microbiological transformation of steviol by Gibberella fujikuroi to a range of 13-hydroxylated gibberellins typical of the higher plants has been r e p ~ r t e d . ' ~ In ' this study and in another study utilizing ent-3P,19-dihydroxykaurenes,'2 8 modifications to the C-19 carboxy-group by, for example, converting it into an ester blocked the ringcontraction step and the formation of the gibberellins. The biological activity of synthetic gibberellin A, and some relatives has been de~cribed.'~, A number of aspects of the chemistry of the gibberellins have received attention. The determination of the configuration at C-1 in the photoaddition products of gibberellic acid 3-ketone has been described.' 30 The solid-state photochemistry of this unsaturated ketone has also been reported.' 3 1 The first products are dimers arising by the addition of the 16,17-double bond across the unsaturated ketone of ring A. Subsequently aromatization reactions occur. The oxidation of gibberellic acid by manganese dioxide to the C-3 ketone has been studied.'32 The products of decarboxylation, (137) and the corresponding C-3 alcohol, together with the (7 -+15)-lactone (1 38), were isolated as byproducts. A number of new intermediates in the aqueous decomposition of gibberellic acid have been isolated. 33 Aromatization proceeds oia the triene (139) and autoxidation cia the 9-hydroperoxide. The mass spectra of the decomposition products have been recorded'34 and the influence of the C-9 stereochemistry on the fragmentation

'

'

(137) IZZ

"' I25

I L z

I "

12*

'

30

I3I 13'

13'

P. Hedden, J. MacMillan, and B. 0. Phinney, J . C . S . Perkin I , 1974, 587. J . R. Bearder, P. Hedden, J. MacMillan, C. M. Wels, and B. 0. Phinney, J . C . S . Chem. Comm., 1973, 777; J. R. Bearder, J . MacMillan, C. M. Wels, M. B. Chaffey, and B. 0. Phinney, Phytochemistry, 1974, 13, 91 1. J . E. Graebe, P. Hedden, P. Gaskin, and J. MacMillan, Phyrochemistry, 1974, 12, 1433. I. D . Railton, N. Murofushi, R. C. Durley, and R. P. Pharis, Phytochemistry, 1974, 13,793; R . C. Durley, I . D . Railton, and R. P. Pharis, ihid., p. 547. J . H . Bateson and B. E. Cross, J . C . S . Perkin I , 1974, 1131. J. R. Bearder, J. MacMillan, C. M. Wels, and B. 0. Phinney, J.C.S. Chem. Comm., 1973, 778. P. R. Jefferies, J . R . Knox, and T. Ratajczak, Phytochemistry, 1974, 13, 1423. Y . Isogai, W. Nagata, T. Wakabayashi, M. Narisada, Y . Hayase, S. Kamata, T. Okamoto, K. Shudo, and M. Somei, Phytochemistry. 1974, 13, 337. E. P. Serebryakov, N . S. Kobrina, and V. F. Kucherov, Izvest. Akad. Nauk S . S . S . R . , Ser. khim., 1972, 2802. G . Adam, Tetrahedron, 1973, 29, 3177. N . S. Kobrina, E. P. Serebryakov, V. F. Kucherov, G. Adam, and B. Voigt, Tetrahedron, 1973, 29, 3425. R . J . Pryce, J . C . S . Perkin I , 1974, 1179. R . T. Gray and R . J. Pryce, J . C . S . Perkin I I , 1974, 955.

D iterpenoids

115

pattern has been discussed. The Cotton effect in the 0.r.d. and c.d. curves of the aromatic gibbane acids at 236 nm also reflects the stereochemistry at C-6 and C-9.I3’ The selectivereduction of the 7-carboxyl group of gibberellic acid to a primary alcohol by treating the anhydride first with disodium tetracarbonyliron and then with sodium borohydride has been described. 136 The determination of the stereochemistry at C-16 of dihydrogibberellin A, methyl ester (140) and its 16-epimer (141)has been re~orded’~’ using shift reagents in the n.m.r. spectrum. The preparation of tritiated gibberellins A1,A3,138A5,A8, andA,,139 has been described. Other Tetracyclic Diterpenoids.-Recently the leucothanes possessing a perhydroanthracene skeleton have been isolated alongside the grayanotoxins from Leucothoe grayanu. A further group of diterpenoids, the grayanols, possibly intermediate between the two, has been de~cribed.’~’In these substances the C-5-C-10 bond has been cleaved to afford a ten-membered ring. The structure of grayanol A (142) was determined by X-ray analysis of the p-bromobenzoate. Grayanol B is the C-6 epimer. Sideritol(143), which was isolated14’ from Sideritis angustifoh. is the first oxygenated diterpenoid of the ent-atisene class which does not contain nitrogen. Its structure was

I 35 136 13’ 138 139

I4O 14’

H. Meguro, K. Hachiya, K. Tuzimurq K. Mori, and M. Matsui, Agric. and Biol. Chem. (Japan), 1973,37, 1035. M. Lischewski and G. Adam, Tetrahedron Letters, 1974, 2835. K . Mori, Agric. and Biol. Chem. (Japan), 1972, 36, 2519. R. Nadeau and L. Rappaport, Phytorhemistry, 1974, 13, 1537. N . Murofushi, R. C . Durley, and R. P. Pharis, Agric. and Biol. Chem. (Japan), 1974, 38,475. S. Fushiya, H. Hikino, and T. Takemoto, Tetrahedron Letters, 1974, 183. W. A. Ayer, J.-A. H. Ball, B. Rodriguez, and S. Valverde, Canad. J . Chem., 1974, 52, 2792.

116

Terpenoids and Steroids

proven by conversion into ent-17-noratisane. It might arise by rearrangement of jativatrio1 (144). The full evidence for the structure and stereochemistry of aphidicolin has appeared.14' Stemodin (145) and the corresponding ketone, stemodinone, were isolated from Sternodia rnaritirna (Scrophulariaceae) and their structures were established by X-ray analysis. The full paper describing the evidence for the structure and stereochemistry of heteratisane has appeared. 4 4

'

5 Macrocyclic Diterpenoids and their Cyclization Products The structures of some cembrene derivatives from a Pacific coral have been elucidated. 145 Nephthenol, isomeric with mukulol, has the structure (146) whilst epoxynephthenol acetate is (147). Sarcophine (148) is an epoxycembranolide which has been isolated'46 from the soft coral Sarcophytum glaucurn and is believed to be a repellant against predators. Its structure rests on detailed spectroscopic evidence and X-ray analysis. The structure of isoincensole oxide has been revised to (149).147

The toxic constituents of Euphorbia species have continued to attract attention. Ingol (1 50) is a new macrocyclic diterpenoid alcohol whose 3,7,12-triacetate-S-nicotinate has been isolated from Euphorbia ingens. The structure of ingol was derived148by a careful analysis of the n.m.r. spectrum. The tricyclic ingenol (151) has been detected'49 in E. drsmondi. Some further esters of ingenol have been i~olated'~'as irritants from E . ingens. These include the C-3 2,4,6-decatrienoate and 16-hydroxyingenol esterified at C-3 with 2,4,6-decatrienoic acid and at C-16 with angelic acid. The C-3 and C-5 benzoate esters of 20-deoxyingenol have been isolated' ' from E. kansui. A 13-oxy-

'

IJ2 14'

145

14' 148

I" lSo I

W. Dalziel, B. Hesp, K. M. Stevenson, and J. A. J. Jarvis, J.C.S.Perkin I, 1973, 2841. P. S. Manchand, J. D. White, H. Wright, and J. Clardy, J . Amer. Chem. Soc., 1973,95, 2705. R. Aneja, D. M. Locke, and S. W. Pelletier, Tetrahedron, 1973, 29, 3297. F. J. Schmitz, D. J. Vanderah, and L. S. Ciereszko, J.C.S. Chem. Comm., 1974, 407. J. Bernstein, U. Schmeuli, E. Zadock, Y. Kashman, and I. Neeman, Tetrahedron, 1974, 30, 2817. M. L. Forcellese, R. Nicoletti, and C. Santarelli, Telrahedron Letters, 1973, 3783. H. J. Opferkuch and E. Hecker, Tetrahedron Letters, 1973, 361 1. F. J. Evans and A. D. Kinghorn, Phytochernistry, 1974, 13, 1011. H. J. Opferkuch and E. Hecker. Tetrahedron Letters, 1974, 261. D. Uemuta. Y. Hirata, H. Ohuaki, Y. P. Chen, and H. Y. Hsu, Tetrahedron Letters, 1974.2527.

D it erpeno ids

117

HO

CH,OH

$ HO

CH,OMe

ingenol dodecanoyl ester has also been obtained' s 2 from this source. 13-0-Acetylhave been 16-hydroxyphorbol and 12-O-palmityl-l3-O-acetyl-l6-hydroxyphorbol as the toxic constituents of Aleurites fordii. Cotylenol (152) is the aglycone of the leaf-growth substances cotylenins A and B, which have been isolated'54 from an unidentified fungus. Its structure rests on the spectral analysis of the products of elimination and glycol fission. These compounds are clearly related to fusicoccin, which has now been shown to be diterpenoid. Full papers describing the structures of cyathin A 3 , cyathin B 3 , allocyathin B3, and cyathin C3 55,1 56 which are metabolites of the bird's nest fungus, Cyathus helenae, have been published. The details of the X-ray structure of baccatin V have been reported.I5'

,'

6 Diterpenoid Synthesis

A new, highly stereoselective synthesis of all-trans-geranylgeraniol has been developed,158based on the coupling of two geraniol units. One of the major synthetic achievements of the year has been the synthesis of cembrene (158).' 5 9 This posed the problem of constructing a 14-membered ring with the correct stereochemistry for four double bonds. The synthesis was based on the preparation of medium-sized-ring 1,5-dienes by the tetracarbonylnickel-induced coupling of terminal allylic bromides. The aldehyde (153) and the phosphonate (154) were coupled together and the product (155) was then converted into the dibromide (156), which was cyclized using tetracarbonylnickel to form (157), which was in turn converted into cembrene (158). The structure (159) was proposed for shonanol. However, the total synthesis of this structure16' and the isomers (160), (161), and (162)I6l gave material which was not identical with the natural product, the structure of which is now in doubt. Two biogenetically patterned syntheses of taondiol (164) have been reported. 6-Tocotrienol and its epoxide (163)occur in Sargassum tortile. Treatment of the naturally occurring epoxide with picric acid gave taondiol.' 6 2 Cyclization of the monomethyl Is*

D. Uemura, Y. Hirata, Y. P. Chen, and H. Y. Hsu, Tetrahedron Leffers,1974, 2529. T. Okuda, T. Yoshida, S. Korke, and N. Toh, Chem. and Pharm. Bull. (Japan), 1974, 22, 971. I s 4 T. Sassa and M. Togashi, Agric. and Biol. Chem. (Japan), 1973,37, 1505. l s 5 L. L. Carstens and W. A. Ayer, Canad. J. Chem., 1973,51, 3157. lsd W. A. Ayer and H. Taube, Canad. J. Chem., 1973,51, 3842. Is' E. E. Castellano and 0. J. R. Hodder, Acta Cryst., 1973, B29,2566. L. J. Altman, L. Ash, and S. Marson, Synthesis, 1974, 129. Is' W. G. Dauben, G. H. Beasley, M. D. Broadhurst, B. Muller, D. J. Peppard, P. Pesnelle, and C. Suter, J . Amrr. Chem. SOC., 1974, 96, 4725. I6O T. Matsumoto, 1. Tanaka, T. Ohno, and K. Fukui, Chem. Lerrrrs, 1973, 321. 16' T. Matsumoto, T. Ohno, H. Fujita, and K. Fukui, Chem. Lrrters, 1973, 1 117. 16' A. Kumanireng, T. Kato, and Y. Kitahara, Chem. Letrers, 1973, 1045. Is3

Terpenoids and Steroids

118

&

&OH H

H

ether (165) gave taondiol methyl ether.'63 When taondiol was heated164 with 5 % methanolic potassium hydroxide, it was smoothly converted into isotaondiol(l66). A free-radical redox mechanism was suggested for the inversion. IhJ lh4

A. G. Gonzalez, J . D . Martin, a n d M . L. Rodriguez, Tetruhedron Lerrrrs, 1973. 3657. A. G . Gonzalez, M. A. Alvarez, J . D . Darias, a n d J . D. Martin, J.C.S. Perkin I. 1973. 2637

119

Diterpeno ids

;;.:-I:::::'..H

0

The synthesis of 3~,17-diacetoxyphyllocladen-1~-one via the tricyclic acetal(167) has )-trachylobane has been completed.'66 An been described.165 A total synthesis of (-t interesting route has been d e ~ i s e d ' ~for ' constructing the cyclopropane ring of this diterpenoid. Treatment of the unsaturated methanesulphonate (168) with methylsulphinyl carbanion in DMSO led to the cyclopropyl ketone (169), which was in turn converted into trachylobane.

(168)

(169)

The total synthesis of gibberellic acid continues to attract attention. A previous report has described the reconstruction of ring A of gibberellic acid (171) from the triene (170). A stereospecific synthesis of the model (175) has now been described,16' based on the cyclization of the propiolic acid ester (172) to form the unsaturated ester (173) which was then methylated to afford (174). Model studies on the synthesis of ring 165

166 16' Ib8

D . M ukherjee. S. K . Mukhopadhyay, K . K. Mahalanabis, A. D. Gupta, and P. C. Dutta, J.C.S. Perkin I , 1973. 2083. R. B. Kelly, J. Eber, and H.-K. Hung, Cunud. J. Chem., 1973, 51, 2534. R. B. Kelly, J. Eber, and H.-K. Hung, J.C.S. Chem. Comm., 1973, 689. E. J . Corey and R. L. Danheiser, Tetrahedron Letters, 1973, 4477.

120

Terpenoids and Steroids

pH

0

0 ’

(173)

@

HO”

0

(177)

(175)

of the gibberellins based169on the cyclization of the aldehyde (175)and its unsaturated analogue gave the equatorial alcohol (176), which could be epimerized to the axial isomer. The synthesis of the ring B/C/D fragment (177) as a potential intermediate has been described. 1 7 0 Portulal (178) is a diterpenoid plant-growth regulator which has a perhydroazulene skeleton with a clerodane substitution pattern. A stereospecific synthesis of the intermediate (179), which has been obtained by degradation of portulal, has been reported.”l A major problem in the synthesis was the introduction of angular functionality into the ketone (180).

A

di::: (-$

CHO

0-co

0

(178) (179)

(180)

The total synthesis of several of the diterpenoid alkaloids represents a major synthetic achievement. some aspects of which have come to fruition during the year. The diene (1 81) adds maleic anhydride stereospecifically to give (1 82). thus generating the C/D ring lh9

I i ‘

L. J . Dolby and C. N . Skold. J . Amrr. Chrm. S o c . . 1974, 96. 3276. D. W . Johnson and L. N . Mander, Austral. J. Chern.. 1974,27. 1277. T . Tokoroyama, K . Matsuo, R. Kanazawa, H . Kotsuki, and T. Kubota. Terrahrdran Letters, 1974, 3093.

121

D iterpen oids

OMe

0

(1 84)

(185)

OH

(186)

system of the alka10ids.l~~ The total synthesis of a hexacyclic relay (185) uia the phenol (183) and the aldehyde (184) has been described.’ The relay has been obtained from lucidusculine and has been converted into the alkaloid napelline (186).’7 4 The first formal total synthesis of an aconite alkaloid has been r e ~ 0 r d e d . The l ~ ~ synthetic ketone (1 87) was converted into the toluene-p-sulphonate (1 88), which underwent a biogenetically patterned rearrangement to afford (189). This relay has been obtained from and reconverted into the delphinine alkaloid talatisamine (190). OMe

AcO-

(189)

(190)

”’ K. Wiesner, P. Ho, and S. Oida, Cunud. J . Chem., 1974, 52, 1042. 174

’”

K. Wiesner, P. Ho, and C. S. J . Tsai, Canad. J . Chem.. 1974, 52, 2353. K. Wiesner, P. Ho, C. S. J. Tsai, and Y . K. Lam, Canad. J . Chem.. 1974. 52. 2355. K. Wiesner, T. Y. R. Tsai, K . Huber, S. E. Bolton, and R . Vlahov. J . Amer. Chem. Soc., 1974, 96, 4990.

4 Triterpenoids BY J. D. CONNOLLY

1 Squalene Group

In an extension of their work on the conformational and mechanistic course of terpenoid terminal epoxide cyclization van Tamelen and his colleagues have investigated' the cyclization in t'itro of the diastereoisomeric dienes (1) and (2) with preformed rings A, B, and D. Under conditions which converted the monocyclic olefin (3) into protostane and lanostane derivatives. the dienes (1) and (2)reacted to give (4)and (5). Compounds with a cyclopentanoid ring D were not detected. These results indicate that the type of

carbonium ion obtained by protonation of C-7 in (1) is not involved in the cyclization of (3). A consequential conclusion is that the formation of rin-gsA, B, and c from acyclic terminal epoxide must be wholly concerted or involve 'frozen', conformationally less stable carbonium ion intermediates. The failure of the cyclase enzyme to accept the labelled bicyclic triene (6) as a substrate tends to support this view.

' E. E.van

Tamelen, R. G.Lees, and A. Grieder, J . Amer. Chem. Soc.. 1974, 96. 2 2 5 5 .

122

Triterpenoids

123

(6)

(5)

The diastereoisomeric dienes (1) and (2) were prepared2 by coupling the racemic bicyclic iodide (7) and the (R)-enantiomer of the monocyclic bromide (8) with excess magnesium in the presence of ethylene dibromide. The diol (6) was assembled in a similar fashion uia the epoxide (9).

(7) dl

(8)

(9)

Radical-induced cyclization of the triene (10) afforded3 the tetracyclic alcohol (11) with truns-anti-trans stereochemistry. The configurational detail of (1 1 ) was established by X-ray analysis.

9& HO

(10)

(11)

It is already known that 2,3-oxidosqualene cyclase has a fairly low substrate specificity and will transform modified squalene oxides into the corresponding lanosterol derivatives. However, the other terminal moiety appears to be significant in determining the R-

I

'

CH,OH

(12) R

=

(13) R

=

(14)

R

=

,+OH

(15)

R

=

.F{

&

E. E. van Tamelen, A. Grieder, and R. G. Lees, J . Amer. Chrm. Sor.., 1974. 96. 2253 Y . Lallemand, M. Julia, and D. Mansuy, Tetrahedron LPtterJ, 1973. 4461.

-' J .

Terpenoids and Steroids

I24

rate of cyclization since 3-hydroxy-l,1',2-trisnorsqualene22,23-oxide (12) is converted faster and squalene 2-3:22.23-dioxide (1 3) and 2-hydroxysqualene 22,23-oxide (1 4)more slowly than squalene 2,3-oxide (15 ) i t ~ e l f . ~ The squalene analogues (16) and (17) have been prepared5 by enzymic coupling of the appropriately modified geranyl pyrophosphate derivatives. Two similar compounds (18) and (19) failed to undergo transformation to squalene-like products. These results suggest that while the terminal double band is obviously not essential for the enzymic reaction the chain length has some importance.

(16) R (17) R

R

=

Bu"

=

iso-C,Hll

......

U OPP

(18) R = Pr" (19) R = n-C,H,,

The long-awaited experimental proof that it is the (3s)-isomer of 2,3-oxidosqualene which undergoes enzymic cyclization to lanosterol has now appeared from two laborat o r i e ~ . ~ .First, ' labelled racemic 2,3-oxidosqualene was incubated6 with a hog liver enzyme preparation. After 10"; conversion into lanosterol the unchanged oxide was recovered and found to have a small positive rotation. Its configuration was established as (3R) by c.d. comparison of the corresponding diol (20) with the enantiomeric 2,5-

dimethylhexane-2,3-diolsin the presence of [Eu(dpm),] . Hence the configuration of the oxide which undergoes cyclization must be (3s).Secondly, labelled antipodal forms of 2,3-oxidosqualene were fed separately to 3j-hydroxy-triterpenoid-producing systems, viz. pig liver microsomes (lanosterol), yeast (lanosterol), and a cell-free homogenate of germinating peas (cycloartenol, P-amyrin, and lupeol). The results provide a convincing demonstration7 of the stereoselectivity of the cyclase enzyme in incorporating only (3S)-2.3-oxidosqualene. The callus tissue of Isodon japonicus retains the ability to synthesize oleanolic acid, maslinic acid (21), and 3-epimaslinic acid (22). Labelling studies have clearly shown* that 3-epimaslinic acid (22)is formed from maslinic acid (21) uia the 3-oxo-derivative (23).

'

T. Shishibori, T. Fukui, and T. Suga, Chem. Letrrrs. 1973, 1289. T. Koyama. K. Ogura, and S. Seto, Chem. Letters, 1974, 529. T. Shishibori, T. Fukui, and T. Suga, Chem. Letters, 1973, 1137. D. H . R. Barton, T. R. Jarman, K . G . Watson, D. A. Widdowson. R . B. Boar, and K . Damps. J.C.S. Chem. Comm., 1974, 861. Y . Tomita and S . Seo. J.C.S. Chem. C o m m . , 1973, 707.

125

Triterpenoids

(21) R = H,B-OH (22) R = Hp-OH (23) R = 0

This excludes alternative mechanisms involving direct cyclization of (3R)-2,3-oxidosqualene. A general high-yield synthesis of 1,5-dienes has been applied to squalene." trans,trans-Farnesyl bromide (24)was converted into the corresponding p-tolyl sulphone (25) by reaction with sodium toluene-p-sulphinate in DMF. The anion of (25) was alkylated with (24) to give the coupled sulphone (26), which was transformed into all-transsqualene with lithium in ethylamine. 2,3-Epiminosqualene (27) has been prepared directly" by reaction of squalene with iodine azide in THF-MeCN followed by reduction with lithium aluminium hydride. /

R

(24) R = Br ( 2 5 ) R = p-MeC,H,SO,

Further contributions to the chemistry of the squalene-derived alkaloids of Daphniphyllum species include the X-ray structure determination of yuzurine (28),a new compound from D. macropodurn which lacks the 2-azabicyclo[3,3,llnonane system,' ' three new compounds from D. teijsmanni,' and a full paper on the alkaloids of the fruits of the Daphniphylla~eae.'~ lo I '

''

"

P. A. Grieco and Y. Masaki, J . Org. Chem., 1974, 39, 2135. L. Avruch and A. C. OehlschIager, Synthesis, 1973, 623. S. Yamamura, K . Sasaki, M . Toda, and Y. Hirata, Tetrahedron Lrrrrrs, 1974. 2023. S. Yamamura and Y . Hirata, Tetrahedron Letters, 1974, 2849. M. Toda, H . Niwa, H . Irikawa, Y. Hirata, and S. Yamamura, Tetruhedron, 1974, 30, 2683.

Terpenoids and Steroids

126

M

e

0

2

C

a

"-Me M

e

O

a

Et

2 FusidaneLanostane Group The oxime (29) of the benzylidene derivative of 2.2-dimethylcyclohexanone underwent an abnormal Beckmann reaction to give the unsaturated nitrile (30) which was hydrolysed to the acid (31). This provide^'^ a facile method for the construction of the characteristic fusidic acid side-chain but suffers from the defect that 2,2-dimethylcyclohexanone fails to condense with a 17-keto-triterpenoid because of steric congestion. The 3C n.m.r. spectra of fusidic acid and of several derivatives have been assigned,15 and the results of feeding experiments with sodium [ 1-l 3C]acetate support current biosynthetic theory.

(30) R = CN (31) R = CO,H

(29)

The degradation of the side-chain of lanosterol continues to attract attention. A Norrish Type I1 photochemical cleavage has been utilized by two groups'63' and results

''

''

'' l 7

(32) R (33) R

=

Ph

=

H

(34) R (35) R

= =

CH, 0

R. K. Hill and R. V. Shetty, Synth. Comm., 1973, 3, 393. T. Riisorn, H . J. Jakobsen, N. Rastrup-Andersen, and H. Lorck, Trrrahedron Lerrers, 1974, 2247. B. Ganern and M . S. Kellogg, J. O r g . Chem., 1974, 39, 575. M. Fetizon. F. J. Kakis, and V. Ignatiadou-Ragoussis, J . O r g . Chem., 1974, 39, 1959.

127

Tr iterpeno ids

in a favourable increase in overall yield. The ketones involved, (32) and (33), were converted by irradiation and subsequent oxidative cleavage of the olefin (34) into 3pacetoxy-4,4,14cr-trimethyl-5a-pregn-8-en-20-one (35). The full details of a general method for the removal of one C-4 methyl group from lanostanes and other triterpenoids have appearedl8 (see Vol. 3, p. 203). The configuration of the C-22 hydroxy-group in inotodiol(36) has been established" as ( R ) by the Horeau method. Inotodiol has been synthesized" in a stereospecific manner from lanosterol via the olefin (37). With N-bromosuccinimide in aqueous THF (37) afforded2' two major bromohydrins (38) and (39). Reaction of either (38) or (39) with base gave the (22s)-epoxide (40), which was converted into inotodiol by reaction with isobutenylmagnesium bromide. OH

,ii---'

HO

lcBr $OH

(39)

(40)

Lanostane 32-nitrates are obtained21 in good yield by photolysis of the corresponding 7a-nitrites in the presence of oxygen. The 32-nitrate group can be readily converted into the alcohol or aldehyde. The previously described route to 32-oxygenated lanostanes, which utilized a nitrogen atmosphere for the photolysis, gives inferior yields. Attempts to form 9-substituted lanostanes by thermolysis of the 7a-azidoformate (41) were unsuccessful. The major products (42) and (43) arose22from insertion into the 52- and 6a-C-H bonds. Thermolysis of the corresponding 7P-azidoformate resulted in the formation of similar products by insertion into the 6a-, 6P-, and 8P-C-H bonds. The lanostane derivative (44)aromatizes to (45) on treatment with toluene-p-sulphonyl chloride.23 The full paper on the ring B-aromatization of tetra- and penta-cyclic triterpenoid dienes has been published.24 I' l9

2o

2z

23 24

K . F. Cohen, R. Kazlauskas, and J. T. Pinhey, J.C.S. Perkin I , 1973, 2076. J . P. Poyser, F. de Reinach Hirtzbach, and G. Ourisson, Tetrahedron, 1974, 30, 977. J. P. Poyser, F. de Reinach Hirtzbach, and G. Ourisson, J.C.S. Perkin I , 1974, 378. J. Allen, R. B. Boar, J. F. McGhie, and D . H. R. Barton, J.C.S. Perkin I , 1973, 2402. 0. E. Edwards and Z . Paryzek, Canad. J . Chem., 1973,51, 3866. J. R. Dias, J. Org. Chrm., 1974, 39, 1767. M . Fukuoka and S. Natori, Chem. and Pharm. Bull. (Japan), 1974, 22, 1035.

128

AcO

Terpenoiih and Steroids

OH

(44)

AcO

(45)

An extensive investigation25 , 2 6 into the mass spectral fragmentation of lanostanes was facilitated by the synthesis of a large number of deuteriated derivatives. The 14amethyl group has a considerable influence26on the fragmentation of 11-ketolanostanes. leading to predominant cleavage of the C-11 -C-12 and C-13-C-14 bonds. During an investigation of the triterpenoid constituents of nine Basidioycetous species a new compound, for which the tentative structure 12~-hydroxymethoxycarbonylacetylquercinic acid (46) is proposed, was isolated from Melanoporia rose^.^' A new

blt'0 C C H ?. CO

''

'' 1 -

R. R . Muccino and C. Djerassi, J. Amer. Chem. Soc. 1 9 7 4 , 9 6 , 556. R . R . Muccino and C. Djerassi, J . A m r r . Chem. Soc., 1973, 95, 8726. A. Yokoyama and S. Natori, Chrm. and Pharm. Bull. ( J a p a n ) , 1974, 22, 877.

Triterpenoids

129

relative of grandisolide, 3a-hydroxylanosta-9(1l)-en-26,23-0lide (47), has been obtained2' from the needles of Abies alba. A potential route for the synthesis of seychellogenin (48) from cycloartenol has been published." The amide (49) was converted into a mixture of C-20 epimers of the y-lactone (50) by irradiation in the presence of lead tetra-acetate and iodine. These epimers were transformed separately by reduction, photolysis of the tertiary nitrite, and oxidation to the alternative y-lactone (51). The C-20 configurations of the epimeric lactones ( 51) were established by comparison with model compounds.

Pollinastanol (52), whose structure was confirmed by X-ray analy~is,~' has been synthesized from cy~loartanol.~ The pure trans-isomer (53) of cucurbitacin Q has been isolated from the fruits of Cucumis p r ~ p h e t a r u r n . ~ ~

'' J.-C. Muller and G . Ourisson, Phytochemistry, 29

-'O "

1974, 13, 1615. A. Milliet and F. Khuong-Huu, Tetrahedron Letters, 1974. 1939. A. Ducruix, C. Pascard-Billy, M. Devys, M. Barbier, and E. Lederer, J.C.S. Chern. Cornrn., 1973, 929. A. Bekaert, M. Devys, and M. Barbier, Tetrahedron Letters, 1974, 1671. Atta-ur-Rahman. V. U. Ahmed, M. A. Khan, and F. Zehra, PhytucherniAtry, 1973, 12, 2741.

Terpenoids and Steroids

130

L

H0

-

HO” (52)

(53)

3 Dammarane-Euphane Group

The hexanordammarane derivative (54) previously synthesized from hydroxyhopane (see Vol. 2, p. 164), was successfully converted33 into dammarenediol I1 (55) on treatment with the Grignard reagent (56). In related studies,33irradiation of the 3-p-nitrophenylacetate (57) of 3-epidammaranediol I1 resulted in remote oxidation at C-12 with formation of the corresponding 12a-hydroxy-compound (58). The C-20 epimer of (57) was oxidized in a similar fashion.

(57) R (58) R

= =

H,H HpOH

Trevoagenins A (59) and B (60), two new dammaranes from Treuoa triner~is,~~ differ in configuration at C-20. Trevoagenin B monoacetate (61) was converted into ocotillol I1 (62) and hence has the (20S724R)configuration. Trevoagenin A is therefore the (20R,24R)-isomer. The monoacetate (63) of trevoagenin A (59) was transformed, via the cyclopropyl intermediate (64) into (20R,24{)-ocotillone whose C-24 configuration must also be (R). Acid-catalysed rearrangement of trevoagenins A and B afforded35 a mixture of the E- and 2-isomers of (65). The structure of each isomer of (65) was confirmed by ozonolysis and methylation to give the same octanormethyl ester, identical with a degradation product of ebelin lactone. 34 ji

R . Kasai. K . S h i n r o , 0. T a n a k a , a n d K. Kawai. (‘hem. and Phurm. Bull. (Japun), 1974, 22, 1213. A. G . Gonzalez, M. Cortes, and E. Suarez, Tvrrahrdron Letters, 1974, 2791. A . G. Gonzalez, M . Cortes, and E. Suarez, J.C.S. Chrrn. Comm., 1974, 425.

Triterpenoids

131

fOH

CH,OH (59) R = H (63) R = AC

(62) R

HO HO

=

(60) R (61) R

(64) R

H

w

=

= =

H AC

H

‘\O ‘\O’

Other new dammaranes include fourquierol (66) and isofouquierol (67) from Fouquiera ~ p l e n d e n sand ~ ~ aglaiondiol (68) and the epimeric agliatriols (69) (24R) and (70) (24s)from Aglaia o d o r ~ t a . ~The ’ structures and configurations of the Aglaia compounds were readily established by interrelation with aglaiol (71), with which they co-occur. Bacogenin A, is a second new sapogenin from Bacopa r n o n n i e r ~and ~ ~ differs from bacogenin A either in the configuration at C-20 or in the position of the vinyl methyl group (see Vol. 4, p. 198). a-Eupaterol acetate, previously reported from Eupatoriurn cannabinurn, has been identified as dammaradienyl a ~ e t a t e . ~ ’ The full paper on the triterpenoids of Japanese White Birch and the C-24 configuration of ocotillol I1 has appeared.40

’‘ D. Butruille and X . A. Dominguez, Trtruhrdrctn Letters, 1974, 639. 57

38 3y 4”

D. Shiengthong, U . Kokpol, P. Karntiang, and R . A. Massy-Westropp, TrJrruhedron, 1974, 30. 2211. D. K . Kulshreshtha and R . P. Rastogi, Phyrochemisrry, 1974, 13, 1205. S. K. Talapatra, D. S. Bhar, and B. Talapatra, Austral. J . Chrm.. 1974. 27, 1 1 37. M . Nagai. N . Tanaka. 0. Tanaka. and S. Ichikawa, Chern. und Phurm. Bull. (Jupun), 1973, 21. 2061.

Terpenoids and Steroids

132

(71)

(70)

Euphenone (72) has been converted41 into A-noreuphenone (75) via the diosphenol (73)(Scheme 1 ). On treatment with acid (75) suffered the normal 'euphenol-isoeuphenol' back bone rearrangement to give A-norisoeuphenone (76). Bacchar-8-en-3-one (77), the equivalent of a D-homoeuphenone, rearranges in a similar manner (see Vol. 4,p. 206). These results are not inconsistent with equilibrium control in the rearrangement.4'

Reagents: i. 0 2 - K O B u ' ; ii, Ba(OH),; i i i , Pb(OAc),.

Scheme 1 * ' J . I.. Zundel. G . Wolff. and G . Ourisson. Bull. Soc. chim. France. 1973, 3206

05x (75)

Triterpenoids

133 H

S’

0

0

Tetranor-triterpenoids.-New compounds isolated this year include vilasinin (78) from the leaves of the neem tree (Azadirachta i n d i ~ a and ) ~ ~heudebolin (79) from Trichilia h e u d e l ~ t i i The . ~ ~ latter is closely related to nimbolin B (80).

HO”

‘-

‘-0 (78)

0

(79) R = AC (SO) R = COCHzCHPh

Irradiation of limonin (81) with a mercury vapour lamp using a pyrex filter afforded44 two photoproducts, (82) and (83), both arising via cleavage of the C-7-C-8 bond. The formation of the aldehyde (82) is reminiscent of the biogenetic pathway to ring Rcleaved tetranor-triterpenoids and the subsequent elaboration to bicyclononanolides. The second photoproduct (83) requires recombination of the biradical intermediate with inversion of the configuration of the C-8 methyl group. Model experiments leading to the synthesis of the ring A features of limonin (81) have been d e ~ c r i b e d . ~The ~ , ~starting ~ compound, 19-hydroxytesterone acetate (84), was (85). transformed4’ into the corresponding 19-hydroxy-4,4-dimethyl-3-oxo-derivative

wo 42 4J

44

‘’ 46

CHO

R . V . Pachapurkar, P. M. Kornule, and C . R . Narayanan, Chrm. Lrrters. 1974. 357 G . A. Adesida and D. A. Okorie. Phytochemisrry, 1973, 12, 3007. D. L. Dreyer and J . F. Rigod, J . Org. Chrm., 1974, 39, 263. H . - R . Schlatter. C . Luthy, and W. Graf, Helo. Chim. Acra. 1974, 57, 1044. C . Luthy. H . - R . Schlatter, and W. Graf. Helo. Chim. Acta, 1974, 57, 1060.

134

Terpenoids and Steroids

:,.,-. 0

0 (84)

An abnormal Beckmann rearrangement of the derived oxime followed by hydrolysis of the nitrile led to the @unsaturated lactone (86), which was subsequently converted into (87)."6 A total synthesis of pyroangolensolide (94) has been reported (Scheme 2).47 C1

0

Reagents: i, CH2=CClCH,C1-NaH; vii, 3-furyl-lithium.

ii, H ' ;

iii, O H - ; iv, Pb(OAc),; v, K,CO,; vi, NBS;

Scheme 2 47

Y . F u k u y a m a , T. Tokoroyama, and T. Kubota, Trrrahedron Lerrers, 1973. ,4869.

135

Triterpenoids

Tentative assignments of the 13C resonances of a range of limonoids have been tabulated and used as a basis for the structure of procerin (95), a complex tetranor. ~ ~ full details of the partial synthesis triterpenoid from the bark of Carapa p r ~ c e r a The of methyl angolensate, andirobin, and mexicanolide have appeared.49

OCOEt

Quassinoids.4uassin (96) gives a split c.d. curve which is due to the interaction of the ring A and ring c chromophores and can be interpreted” in terms of the biogenetically acceptable absolute configuration [as in (96)]. This is the first direct evidence for the OMe

OMe 1

(97) R = H,OH (98) R = 0

absolute configuration of the quassinoids. The methyl signals in a series of nigakihemiacetals and nigakilactones have been assigned and the information has been used to suggest the structure (97) for nigakihemiacetal D from Picrasrna ailanthoides. 5 1 This was confirmed by oxidation to nigakilactone E (98). 4 Shionane Group

Ireland and his colleagues continue on their successful synthetic way with a total synthesis of shionone (107) (Scheme 3).52 The best route for the construction of the key intermediate, the tetracyclic ketone (103), is patterned on the synthesis of alnusenone (see Vol. 2, p. 175) and has as its central feature the triethylaluminium-catalysed con4A 44

51

52

D. A. H . Taylor, J . C . S . Perkin I, 1974, 437. J. D. Connolly, I . M. S . Thornton. and D. A. H . Taylor, J.C.S. Perkin I, 1973, 2407. M. Koreeda, N. Harada, and K. Nakanishi, J . Amer. Chem. Soc., 1974, 96, 266. T. Murae, T. Ikeda, A. Sugie, T. Nishihama, T. Tsuyuki, and T. Takahashi, Bull. C h r m . SOC. Japan, 1973, 46, 3621. R. E. Ireland, C . A. Lipinski, C . J. Kowalski, J. W. Tilley, and D. M . Walba, J . Arner. Chem. SOC.,1974, 96, 3333.

136

Terpenoids and Steroids 0

MCO

m+

OH

\

(99)

Reagents:'i, Et,N; ii, NaBH,; iii, Et,A1-HCN; iv, MeMgI; v, Ac,O-py; vi, SOC1,; vii, BuiAlH; viii, N2H,-KOH; ix, H,CrO,; X, CF,CO,H; xi, POC1,-DMF; xii, Li-NH,-MeI; xv, H,O,-NaOH; xiii [(EtO),-POCHCH=NC,H, I] - N a + ; xiv. Li-NH,-EtOH; xvi, TsNHNH,-HOAc: xvii, MeLi; xviii, CF,CO,H-(CF,CO),O; xix, PriNLiICH,ZnI(Ag); xx, H + ;xxi, CrO,; xxii, Me,C=PPh,.

Scheme 3

jugate addition of cyanide to (101). The transformation of (103) into shionone (107) paves the way for a future and inevitable total synthesis of friedelin. 5 Lupane Group

Photo-oxidation of lupan-28-01 (108) afforded53the 28-nor-olefins (109) and (110) and the 13P,28-oxide (111). Acid cleavage of the oxide (111) provides a route to 12-substituted lupanes via the 12-ene. The physical and spectroscopic properties of a series of (20R)- and (20S)-30-norlupan-20-ol derivative^^^ and 29-substituted lupanes5 have

'' 54 15

A. Vystrcil and J . Protiva, Coll. Czech. Chem. Comm., 1974, 39, 1382. A. Vystrcil and Z. Blecka, Coll. Czech. Chem. Comm., 1973, 38, 3648. A. Vystrcil, V. Pouzar, and V. Krecek, Coll. Czech. Chem. Comm., 1973, 38, 3902.

137

Triterpenoids

been compared. The configuration at C-20 in the epimeric forms of the aldehyde (1 12) was determined5 by Baeyer-Villiger oxidation to the known nor-alcohols. Model experiments for the partial synthesis of the 1P,3a-glycolsystem of glochidiol have been reported.56 Loranthol, a new lupane from Loranthus g r e ~ i n k i i , ~is’ lup-20(29)-en-3/3,7P-diol. Guimarenol (1 13) and lup-18-en-3P-ol have been isolated from Ceropegia ~tichotomu.’~ The former has a novel rearranged lupane skeleton.

6 Oleanane Group Segal and his colleagues have repeated59 their suggestion that the C-16 configuration of a large group of 16-hydroxylated oleananes should be reversed (see Vol. 4, p. 209). They base their proposal solely on the relative rates of acetonide formation of primulagenin A (114) and longispinogenin (115) and fail to take account of the conformational flexibility of rings D and E. They also ignore the mass of contrary chemical and spectro56

K. Waisser, S. Hilgard, A. Zelenka, and A. Vystrcil, Coll. Czech. Chem. Comm., 1973, 38, 3521.

57 58 59

Atta-ur-Rahman, M. A. Khan, and N. H . Khan, Phytochemistry, 1973, 12, 3004. A. G. Gonzalez, F. G . Jerez, and M. L. Escalona, Anales de Quim., 1973, 69, 921. R. Segal, F. Reicher, and R. D. Youssefyeh, J.C.S. Chem. Comm., 1974, 481.

Terpenoids and Steroids

138

flH20 AcO

HO (114) R (115) R

= =

H,a-OH H&OH

x

scopic evidence. The X-ray structure determination6' of the bromo-lactone (116) derived from echinocystic acid diacetate, which places the issue beyond doubt, has been published. The pyridine-induced shifts of the 14a-methyl groups confirm6' the 16ahydroxy configuration in primulagenin A (114) and protoprimulagenin A (1 17). The latter has been prepared directly62 by reduction of the bromo-lactone (116)with lithium aluminium hydride in the presence of boron trifluoride. The 13C n.m.r. spectra of a group of olean-12-ene and urs-12-ene derivatives have been studied63 and the results indicate the potential of 13C n.m.r. in distinguishing between the two series and in stereochemical assignment. New natural products in the oleanane series include caulophyllogenin (1 18) froqthe ,~~ lactone (119) from Centaurium e r y t h r ~ e a , ~ ~ roots of Caulophyllum r o b ~ s t u moleanolic and hederagenic acid (1 20) from Viburnum erubescms.66 The compound (120) was

HO'

60

hl 62

63 64

65

66

C . H. Carlisle, P. F. Lindley, A. Perales, R . B. Boar, J. F. McGhie, and D . H. R. Barton, J.C.S. Chem. Comm., 1974, 284. 1. Kitagawa, M . Yoshikawa, and I . Yosioka, Tetrahedron Letters, 1974, 469. C. R . Narayanan and A. A. Natu, J. Org. Chem., 1974, 39,2639. D. M. Doddrell, P. W. Khong, and K. G . Lewis, Tetrahedron Letters, 1974, 2381. L. I. Strigina, N. S. Chetyrina, V. V. Isakov, A. K . Dzizenko, and G . B. Elyakov, Phytochemistry, 1974, 13, 479. V. Bellavita, F. Schiaffella, and T. Mezzetti, Phyrochemrstry, 1974, 13, 289. S. K . Agarwal and R . P. Rastogi, Phytochemisrry, 1974, 13, 666.

139

Triterpenoids

HOH,C o

w (120)

obtained from hederagenin by oxidation with potassium permanganate. The structures (121) and (122) have been proposed respectively for xanthoxylone from Xanthoxylum r h e t ~ aand ~ ~a new triterpenoid from the leaves and stem of Euphorbia nerifolia.68 The lack of oxygen at C-3 is unusual. Acid hydrolysis of the saponin mixture from the seeds of Careya arborea afforded69 careyagenol D (123), which was readily interrelated with barringtogenol D (124). The interesting observation has been made” that fresh olive

husks (Olea europaea) contain mainly oleanolic acid whereas after storage under humid conditions almost equal amounts of oleanolic and maslinic (2a,3P-diol) acids are obtained. Full details have appeared71 of the formation of protobassic acid (125) by soil bacterial hydrolysis of the saponin from the seed kernels of Madhucb longifoh. A 67

68

69

’O ”

A. Chatterjee, A. Mukherjee, and A. B. Kundu, Phytochernistry, 1974, 13, 623. A. S. R. Anjaneyulu, L. R. Row, C . Subrahmanyam, and K . S. Murty, Tetrahedron, 1973, 29, 3909. S. B. Mahato, N. L. Dutta, and R. N. Chakravarti, J . Indian Chrrn. Soc., 1973, 50, 254. R. Caputo, L. Mangoni, P. Monaco, and L. Previtera, Phytochrrnistry, 1974, 13, 1551. I . Yosioka, A. Inada, and I. Kitagawa, Tetrahedron, 1974, 30, 707.

Terpenoids and Steroids

140

R O HOH,C'

'

W 0 tI (125) R = H

(126) R

=

P-D-glu

prosapogenol. 3-O-~-~-glucopyranosy~protobassic acid (1 26), was also isolated. The molluscicidal saponins of the fruits of Phytofacca dodecandra are glycosides of oleanolic a ~ i d . ' ~ ,Hydrolysis '~ of the saponins from the related P. urnericana yielded74 phytolaccagenin (127), the free acid (128), and a new compound, phytolaccinic acid (129). Acacic acid (130) is the common aglycone in several Albizzia species.75 The full paper

(127) R ' (128) R ' (129) R '

= = =

OH, R 2 = Me OH, R 2 = H H . R 2 = Me

on the photochemical cleavage of triterpenoid glycosides has been published.76 Glycophotolysis has been successfully applied" to desacetyljegosaponin. from the pericarps of Styrux japonica, an uronic acid-containing glycoside of barringtogenol C. The optically pure A/B synthon (1 3 1) for pentacyclic triterpenoid synthesis has been ~ r e p a r e d ' ~ .from ~ " the enone (1 32). The synthesis of [28,28-2H,]-, [29,29-2H2]-,and

''

R. M . Parkhurst, D . W. T h o m a s , W. A. Skinner, a n d L. W. Cary, Canad. J. Chem., 1974, 52,

-'702. R. M. Parkhurst, D . W. T h o m a s , W. A. Skinner, a n d L. W. Cary, Indian J . Chem., 1973, 11, 1192.

-' A. Johnson --

a n d Y. Shimizu, Tetrahedron, 1974, 30, 2033.

' L. C . Comeau a n d J . A . Braun, Bull. S O ~chim. . France, 1974, 716, 721.

I . Kitagawa, M . Yoshikawa, Y. Imakura, a n d I. Yoshioka, Chem. and Pharm. Bull. (Japan), 1974, 22, 1339. " I . Kitagawa, Y. Imakura, T. Hayashi, a n d I. Yoshioka, Chem. and Pharm. Bull. (Japan), 1974, 22, 1675. 7 x J . S. Dutcher, J. G. Macmillan, a n d C . H . Heathcock, Tetrahedron Letters, 1974, 929. "'J . S. Dutcher a n d C . H. Heathcock, Tetrahedron Letters, 1974, 933.

"

Triterpenoids

141

[23,23-'H2]-P-amyrin has made possible the definitive assignment of the methyl signals in the [Eu(dpm),]-shifted spectra of P-amyrin" and P-amyrin acetate.81 The friedelin derivatives from Putranjiva roxburghii have been reviewed.82 Putrone (1 33) and putrol (1 34) are two norfriedelins from P. roxburghii. * They may arise from roxburghonic acid (135). Friedelan-3,28-diol has been reported from Mortonia p ~ l r n e r i . ~ ~

(133) R (134) R

= =

0 H,a-OH

The details have appeared8' of the X-ray analysis of the 2,2-dibromo-derivative of the 25,26-ether (136)from the root bark of Salacia prinoides (see Vol. 4,p. 214). An independent investigation of the root bark of S . prinoides has resulted in the i ~ o l a t i o n *of~ ? ~ ~

8o

'' 82 83

84

*'

86

''

€4. Danieli, G. P. Forni, G. Palmisano, G. Rainoldo, and G. Severini, Chem. und Ind., 1974, 748. T. Shingu, T. Yokoi, M. Niwa, and T. Kikuchi, Chem. and Pharm. Bull. (Japan), 1973, 21, 2252. P. Sengupta, J. Indian Chem. SOC.,1974, 51, 131. V. N. Aiyar, G. R. Chopra, A. C. Jain, and T. R. Seshadri, Indian J. Chem., 1973, 11, 525. X. A. Dominguez and A. Y. Meneses, Phytochemistry, 1974, 13, 1292. D. Rogers, D. J. Williams, B. S. Joshi, V. N. Kamat, and N. Viswanathan, Terrahedron Letters, 1974, 63. N. C. Tewari, K. N. N. Ayengar, and S. Rangaswami, J.C.S. Perkin I, 1974, 146. N . C. Tewari, K. N. N. Ayengar, and S. Rangaswami, Indian J. Chem., 1973, 11, 1334.

Terpenoids and Steroids

142

(138) R' = Me, R2 = H (139) R' = C H 0 , R 2 = H

(140)R '

=

Me, R2

=

OH

friedel-1-en-3-one and the 7&24-ether (137), in addition to the previously reported dione (138), aldehyde (139), and alcohol (140). The rearrangement of friedelan-3a,4a-epoxide under a variety of acidic conditions has been re-investigated.88 In addition to the previously reported glut-5(10)-en-3a-ol (1 41) boron trifluoride etherate in benzene afforded 18a-~-neo-olean-3(5),12-diene (142), 18a-olean-12-en-3a-01(1 43), and olean-13(18)-en-3a-ol (144). Pyridine hydrochloride gave friedel-4(23)-en-3a-o1 (149, and aqueous perchloric acid yielded friedelin. the glutenol(l41). and the diol, surely (146).

Full papers have been published on the unusual photodegradation products of friedelin,'" pachysandiol(3,p,16p-dihydroxyfriedelane) and the corresponding 3-ketone, pachysonol from Pachysandra terminalis,"' and the stereoselective synthesis of alnusenone (147).91 "

")

yo

9'

P. Sengupta, B. Roy, S. Chakraborty, J. Mukherjee, and K . G . Das, ZndranJ. Chem., 1973,11, 1249. R . Aoyagi, T . Tsuyuki, M . Takai. T . Takahashi, F. Kohen, and R. Stevenson, Tetrahedron, 1973, 29, 4331. T . Kikuchi, M. Takayama, T . Toyoda, M. Arimoto, and M. Niwa, Chem. and Pharm. Bull. (Japan), 1973, 21, 2243. R. E. Ireland, M. I . Dawson, S. C. Welch, A . Hagenbach, J. Bordner, and B. Trus, J . Amer. Chem. Sor., 1973, 95, 7829,

143

Triterpeno ids

(149)

(150) (151)

R R

= =

H OH

Dispermoquinone (148) from Maytenus dispermus co-occurs with oleana- 1 1,13(18)dien-3-one (149) and has been correlated92 with pristimerin. The identity of tingenone (tingenin A) (150) and maitenin has been confirmed93(see Vol. 4,p. 217). The structure of tingenone (150) has been the subject of two paper^'^,^^ which include an X-ray analysis.94 20-Hydroxytingenone (151 ) is a related compound from Euonymus tingens.94

7 Ursane Group Larreagenin A, an aglycone from the leaves of Larrea d i ~ a r i c ais, ~3P-hydroxy-29~ norurs- 13(18)-en-20P,28-olide(152). The related acid, larreic acid (153), was isolated from the whole plant and lactonizes to give (152). Other new ursanes include 2a,3adihydroxyurs-12-en-28-oic acid (154) from Prunus serotina and P. l u s i t ~ n i c aeuscaphic ,~~ acid (1 55) from the pericarps of the capsules of Euscaphisj a p ~ n i c a , and ~ * 3P-hydroxyurs20-ene from Eupatoriurn p e r f o l i ~ t u m . ~ ~ 92 93

94

95

96

97

98

99

J. D. Martin, Tetrahedron, 1973, 29, 2997. F. Delle Monache, G. B. Marini-Bettolo, P. M. Brown, M. Moir, and R. H. Thomson, Gazzetta, 1973, 103, 627. P. M. Brown, M. Moir, R. H. Thomson, T. J. King, V. Krishnamoorthy, and T . R. Seshadri, J . C . S . Perkin I , 1973, 2721. F. Delle Monache, G . B. Marini-Bettolo, 0. Goncalves de Lima, I. L. d’Albuquerque, and J. S. de Barros Co&lho, J.C.S. Perkin I, 1973, 2725. G. Habermehl and H . Moller, Annalen, 1974, 169. H. W. A. Biessels, A. C. van der Kerk-van-Hoof, J. J. Kettenes-van den Bosch, and C. A. Salemink, Phytochemistry, 1974, 13, 203. K. Takahashi, S. Kawaguchi, K. Nishimura, K . Kubota, Y. Tanabe, and M. Takani, Chem. and Pharm. Bull. (Japan), 1974, 22, 650. X . A. Dominguez, J. A. G . Quintanilla, and M. P. Rojas, Phytochemistry. 1974, 13, 673.

144

Terpenoids and Steroids

( 1 52)

'1-1

R

(154) R = H (155) R = OH

8 Hopane Group Further chemical evidence for the 21b-H configuration in hydroxyhopanone (156) neatly utilized'00 the C, symmetry of hexanor-A-neohopane. Hydroxyhopanone (156) was dehydrated to give hopenone-a (157) and hopenone-b (158), which were converted into ~-neohop-21 -ene (159) and ~-neohop-3-ene(160) respectively. The compounds (159) and (160) were found to be identical.

(159) loo

K. Sekiguchi, H. Kanemoto, Y . Hirao, T. Tsuyuki, and T . Takahashi, Bull. Chem. SOC.Japan, 1974, 47, 178 1 .

Triterpen oids

145

The structure of spergulagenin A from Mollugo spergula has been established as (161) by X-ray analysis. Spergulagenin A is the first representative with this rearranged hopane skeleton. It was obtained by soil bacterial hydrolysis and is therefore a genuine aglycone. Sebiferic acid (162) is a new 3,4-seco-acid from Sapium seb(ferum.lo2 Its structure was confirmed by partial synthesis cia an abnormal Beckmann rearrangement of moretenone oxime.

OH HO

The widespread occurrence of degraded and extended hopane derivatives in natural sediments has led geochemists to postulate active microbial activity during sedimentation. O 3 Three new fernenes from the lichen Xanthoria resendei' O4 are 12a-acetoxy-3/% hydroxyfern-9(1l)-ene (163), 3P,12P-dihydroxyfern-9(11)-ene(164),and 3,12-diketofern-9(11)-ene (165).

&.-R2

,

I

r

R'

(163) R' (164) R' (165) R'

lo'

lo*

Io3

'04

=

= =

H,P-OH, R2 = H,a-OAc H,P-OH, R2 = H,a-OH R2 = 0

1. Kitagawa, H. Suzuki, I. Yosioka, T. Akiyama, and J. V. Silverton, Tetrahedron Letters, 1974,

1173. B. P. Pradhan and H. N . Khastgir, Indian J. Chem., 1973, 11, 1217. A. Van Dorsselaer, A. Ensminger, C . Spyckerelle, M. Dastillung, 0. Seiskind, P. Arpino, P. Albrecht, G . Ourisson, P. W. Brooks, S. J . Gaskell, B. J. Kimble, R. P. Philp, J. R. Maxwell, and G . Eglinton, Tetrahedron Letters, 1974, 1349. A. G . Gonzalez, J. D. Martin, and C. Perez, Phytochemistry, 1974, 13, 1547.

5 Carotenoids and Polyterpenoids

1 Introduction A considerable number of ‘new’ naturally occurring carotenoids have been described and assigned structures. Notable among these is a series of triterpenoid carotenoids of bacterial origin which present some problems of nomenclature. Interest in the stereochemistry of natural carotenoids and related substances also continues. Very little information has yet been published on I3C n.m.r. spectroscopy despite the obvious potential usefulness of this technique in carotenoid chemistry and biochemistry.

2 Carotenoids New Natural Carotenoids.-Hydrocarhons. A carotene with an unusual absorption spectrum has been isolated from diphenylamine-inhibited cultures of a Phycomyces mutant and identified by its spectroscopic and chromatographic properties and by its 1 l’,12’-tetrahydro-y-carotene (7’,8’,11‘,12’-tetrahydro-P,$-caromass spectrum as 7‘,8‘, tene) (l), a monocyclic isomer of <-carotene (7,8,7’,8‘-tetrahydro-$,$-carotene) (2).’A carotenoid hydrocarbon from Neurospora crassu, previously designated has been separated into two components, [-carotene and its unsymmetrical isomer, 7,8,11,12-tetrahydro-$,$-carotene(3).3

Oxygenated Curotenoids. Acyclic. Three series of acyclic carotenoids have been reported, containing hydroxy-, epoxy-, and 0x0-functions, respectively. The large range of carotenoids accumulated in small amounts by cultures of Rhodospirillum rubrum grown in the presence of diphenylamine includes several monohydroxy-carotenoids, three of which, 1-methoxy-l’-hydroxy-1,2.1’,2’-tetrahydrophytofluene (l-methoxy1,2,7,8,11,12,1’.2’,7’,8’-decahydro-$,$-caroten-l-ol) (4),l‘-hydroxy-3,4,l’,2’,11’,12’-hexahydrospheroidene (1’-methoxy-1,2,7,8,11,12,1‘,2’-octahydro-$,$-caroten-l-ol) (5), and l’-hydroxy-3,4,1’,2’-tetrahydrospheroidene (1’-methoxy-1,2,7,8,1’,2’-hexahydro-$,$-caroten-1-01)(6), have not previously been characterized and two of which, 1-hydroxy-1,2dihydrophytofluene (1,2,7,8,7‘,8’,11’.12’-octahydro-$,~-caroten-l-ol) (7) and l-hydroxy1,2,7’,8’, 1 1’,12’-hexahydrolycopene(1,2,7’,8’, 1 I ’, 12’-hexahydro-I+b,I+b-caraten1-01) (8),are assigned structures for the first time. The structures were deduced mainly from the mass spectra of the compounds and their trimethylsilyl ether^.^

‘

B. H. Davies and A. F. Rees, Phytochemistry, 1973, 12, 2745. F. T . Haxo, Furtschr. Chem. org. Nuturstoffe, 1955, 12, 169. B. H. Davies, C . J. Hallett, R. A. London, and A. F. Rees, Phytuchemistry, 1974, 13, 1209. B. H. Davies and Aung Than, Phytochemistry, 1974, 13, 209.

146

Carotenoids and Polyterpenoids

147

xo

HO \

\

e

f

k

j

0

m

1

n (1) R' = a , R 2 = b (2) R' = R2 = c (3) R' = b, R2 = d (4)R' = e ( X = Me), R 2 = f ( 5 ) R' = e(X = H),R2 = g ( Y (6) R' = f,R2 = g ( Y = Me) (7) R' = f,R2 = b (8) R' = g (Y = H), R2 = b (9) R' = h , R 2 = b (10) R' = h , R 2 = c ( 1 1 ) R' = j , R 2 = b

(12) R' (13) K' =

Me)

(14) R'

= j,R2 = c = k,R2 = d = 1,R2 = d

(15) R' (16) R' (17) R' (18) R' (19) R ' (20) R' (21) R'

m,R2 = d m,R2 = n R2 = m m, R2 = g (Y = m,R2 = b = m,R2 = c = m,R2 = f = = = =

=

H)

148

Terpenoids and Steroids

Mass spectrometry was also the main technique used in the characterization of epoxides of phytoene (1,2-epoxy-1,2,7,8,11,12,7’,8’,11’,12’-decahydro-$,$-carotene)(9), phytofluene [ 1,2-epoxy-1,2,7,8,11,12,7‘,8’-octahydro-$,$-carotene (10) and 1,2-epoxy1,2,7,8,7’,8’,1 1‘,12‘-octahydro-$,$-carotene ( 1 1)], [-carotene (1,2-epoxy-1,2,7,8,7’,8’-hexahydro-$,$-carotene) (12j, and lycopene [ 1,2-epoxy-l,2-dihydro-$,$-carotene(13), and 5,6-epoxy-5,6-dihydro-i).$-carotene(14)],all isolated from tomatoes. The two lycopene epoxides were identical (optical properties not studied) with semi-synthetic samples prepared by epoxidation of lycopene with m-chloroperbenzoic acid. Four aliphatic methoxylated keto-carotenoids (15 H 1 8 ) were isolated from Rhodopseudomonas globformis and three additional related compounds (1 9 H 2 1 ) when the organism was cultured in the presence of diphenylamine.6 All these compounds had a keto-group in the 4 (4’)position and were identified by their spectroscopic (absorption, mass, and H n.m.r.j and chemical properties as 1-methoxy-l,2-dihydro-$,rl/-caroten4-one ( I 5). 171‘-dimethoxy-3’.4’-didehydro1,2,1‘,2’-tetrahydro-$,$-caroten-4-one (16), 1,l’-dimethoxy-1.2,1‘,2‘-tetrahydro-$,$-carotene-4,4’-dione (I 7), 1-methoxy-1’-hydroxy1,2,1’,2’-tetrahydro-$,$-caroten-4-one (1 8), l-methoxy-1,2,7’,8’,11’,12’-hexahydro-$,$caroten-4-one (1 9), 1 -methoxy-l,2,7‘,8’-tetrahydro-$,$-caroten-4-one (20), and 1methoxy-1’-hydroxy-l,2,7’,8’-tetrahydro-$,$-caroten-4-one (21). M o n o c j ~ l i csanthophylls. Aleuriaxanthin, the main xanthophyll of the fungus Aleuria uuruntiu, has been shown to have the novel structure 1’,16’-didehydro-l’,2’-dihydro-j3,$caroten-T-ol (22j, the first example of a methylene-containing acyclic end-group. The location of the hydroxy-group at C-2’ was established by ‘H n.m.r., the methine protons of the free alcohol and acetate resonating as sharp triplets (-I = 6 Hz) at 4.07 and 5.14 p.p.m. respectively. The terminal methylene protons of aleuriaxanthin gave two distinct signals at 4.97 and 4.88 p.p.m. No circular dichroism was observed for aleuriaxanthin, but the c.d. curve of its acetate is recorded. The structure has been confirmed by synthesis.8 Details of the absorption, ‘H n.m.r., and mass spectroscopic data used in the identification’ of 2-hydroxyplectaniaxanthin (3’,4‘-didehydro-l’,2‘-dihydro-P,$-carotene2,1’.2’-triol) (23) from Rhodotorula nurnntiuca have now been presented. l o A new carotenoid, ‘ternstroemiaxanthin’, a major constituent of the red seeds of Ternstroemia juponica has been assigned the structure 3-hydroxy-p,$-caroten- 18’-al (24). The presence of the aldehyde group was deduced from the i.r. and ‘H n.m.r. spectra, and the location of this aldehyde function followed from the absence of the signal at 1.81 p.p.m. characteristic of a methyl group at C-5’. The pigments of Xanthomonas juglandis, previously thought’ to be monocyclic carotenoids because of their characteristic absorption spectra, have now been shown to be brominated aryl polyene esters such as (29).’

‘’

’ A. Ben-Aziz, G. Britton,

and T. W. Goodwin, Phytochemistry, 1973, 12, 2759. K. Schmidt and S. Liaaen-Jensen, Actu Chem. Scand., 1973, 27, 3040. N. Arpin, H. Kjmen, G. W. Francis, and S. Liaaen-Jensen, Yhytochemistry, 1973, 12, 2751. H. Kjosen and S. Liaaen-Jensen, Actu Chem. Scand., 1973, 21, 2495. K. L. Simpson, I.-S. Liu, and C. 0. Chichester, Fed. Proc., 1973, 32, 521. I.-S. LIU,T. H. Lee, H. Yokoyama, K. L. Simpson, and C. 0. Chichester, Phytochemzstry, 1973, 12, 2953. ” K. Kikuchi and M. Yamaguchi, Bull. Chem. Soc. Japan, 1974, 47, 885. l 2 M. P. Starr and W. L. Stephens, J. Bucteriol., 1964, 87, 293. ‘ ’ ~A. G. Andrewes, S. Hertzberg, S. Liaaen-Jensen, and M. P. Starr, Acta Chem. Scand., 1973, 27, 2383.

’ ’

149

Curo t enoids and Poly terpenoids R2

OH

H

b

a

d

(22) (23) (24) (25)

R’ = a ( X = Y = H), R 2 = b R’ = a ( X = OH,Y = H),R2 = c R’=a(X=H,Y =OH),R2=d R’ = f , R 2 = e

C

e (26) R’ = f, R 2 = a (X = Y = H) (27) R ’ = a ( X = OH,Y = H),R2 = e (28) R ’ = a ( X = O H , Y = H ) , R 2 = a ( X = Y = H )

Bicyclic xanthophylls. Chemical characterization’ of the first carotenoids with 2hydroxylated-P-rings has confirmed the structures previously assigned by spectroscopic methods alone. The epoxides 5,6-epoxy-5,6-dihydro-[j,~-caroten-2-01 ( 2 5 ) and 5,6epoxy-5,6-dihydro-P,P-caroten-2-01(26) have been isolated as minor constituents of the green alga Trentepohlia iolithus, and their structures confirmed by comparison with the products of epoxidation of B,c-caroten-2-01 (27) and P,b-caroten-2-01 (28) by mchloroperbenzoic acid.I6 Nitsche has identified fucoxanthinol (5,6-epoxy-3,3’,5’-trihydroxy-6’,7’-didehydto5,6,7,8,5’,6’-hexahydro-~,~-caroten-8-onej (30) as a natural constituent of Fucus vesiculosus’ and has examined two other allenic xanthophylls. Mimulaxanthin from the petals of Mimulus guttatus has been identifiedI8 as the first carotenoid containing two allenic groups. 6,7,6’,7’-tetradehydro-5,6,5’,6’-tetrahydro-~,[~-carotene-3,5,3’,5’-tetraol (31). Treatment with acidic acetone afforded the bis-acetylenic xanthophyll alloxanthin (7,8,7’,8’-tetradehydro-P,B-carotene-3,3’-diolj (32). Consideration of the H n.m.r. and m.s. data has led to revision” of the structure of vaucheriaxanthin to 5’,6‘-epoxy-6.7l4

l6

l9

G. Nybraaten and S. Liaaen-Jensen, Acta Chem. Scand., 1974, B28, 485. H. Kjmen, N. Arpin, and S. Liaaen-Jensen, Acta Chem. Scand., 1972, 26, 3053 G . Nybraaten and S. Liaaen-Jensen, Acta Chem. Scand., 1974, B28, 483. H. Nitsche, Biochim. Biophys. Acta, 1974, 338, 572. H. Nitsche, Z. Naturforsch., 1973, 28c, 481. H. Nitsche, Z. Naturforsch., 1973, 28c, 641.

150

Terpenoids and Steroids

didehydro-5,6,5’,6’-tetrahydro-P,P-carotene-3,5,3’, 19’-tetra01 (33). (One hydroxy-group was previously thought2’ to be at C-19, not C-19’.) Two new keto-carotenoids have been isolated from berries of Lonicera ruprechtiana and L. webbiana.2’ On the basis only of chromatographic and light-absorption properties, and some chemical reactions, these have been given the structures (39)(‘loniceraxanthin’) and (34)(‘webbiaxanthin’). The main pigment of Caltha pulustris (‘calthaxanthin’) is very similar to but not identical with lutein [( 3R,3’R)-fl,~-carotene-3,3‘-diol] (35); in several chemical reactions both gave the same product. It was concluded” that calthaxanthin is stereoisomeric with lutein, differing in the absolute configuration at C-3’. The algal carotenoid variously described as trollein, pyrenoxanthin, or trihydroxy2-carotene (from Chlorella, Chlantydomonas, and CIadophora spp.) has now been identified as loroxanthin (P,~-carotene-3,19,3’-triol)(36 ; stkreochemistry not defined).’

* &,

HO

a

H0 ‘

b

d

e

C

f

I

(1H h

(30) (31) (32) (33) (34)

’” 2’

”

*’

R’ = a, R 2 = b, R 3 = H R’ = R 2 = b , R 3 = H R ’ = R2 = c,R3 = H R ’ = d, R 2 = b, R 3 = OH R’ = R2 = e,R3 = H

(35) R ’ = f, R 2 = g, R 3 = H (36) R ’ = f , R 2 = g , R 3 = OH (37) R’ = H , R 2 = c , R 3 = H (38) R’ = j, R2 = c, R 3 = H

H . Nitsche and K . Egger, Tetrahedron Letters, 1970, 1435. A.-K. Rahman and K . Egger, Z. Naturforsch., 1973, 28c, 434. A . G . Dabbagh and K . Egger, Z. Pflanzenphysiol., 1974, 72, 177. G. W. Francis, K. Knutsen, and T. Lien, Acra Chem. Scand., 1973, 27, 3599; H. Nitsche, Arch. Microbiol., 1974, 95, 79.

Carotenoids and Polyterpenoids

151

Two isomeric carotenoids, mytiloxanthin and isomytiloxanthin, from the edible mussel, Mytilus edulis, have been identified as 3,3’,8’-trihydroxy-7,8-didehydro-fl,~caroten-6’-one (37) and 6,3’-dihydroxy-7’,8’-didehydro-5,6-dihydro-fl,~-carotene-3,8dione (38). Spectroscopic data (ir., m.s., and ‘H and n.m.r.) are presented.24 Comparison of the ‘H and 13Cn.m.r. spectra of isomytiloxanthin with those of model compounds suggests the relative configuration shown (38). Several cyclopentanone carotenoids, including the novel ‘4-ketocapsanthin’, have been reported to be present in anthers and pollen of Aesculus rubicunda.” Zsoprenyluted Curotenoids. Detailed consideration of spectroscopic data, especially ‘H n.m.r., indicates that sarcinaxanthin from Sarcina lutea is probably (40),2-(3-methyl2-butenyl)-2’-(4-hydroxy-3-methyl-2-butenyl)-~,~-caroten-l8-0l, although the alternative structure (41) is not ruled out. The identification of other C,, and C,, carotenoids present in much smaller amounts is only tentative.26

(40)R’ = H, R 2 = R 3 = OH (41)

R’ = R2

=

OH,R3= H

Triterpenoid Carotenoids. In addition to the C30 ‘bacterial phytoene’ previously identified in bacteria,” Taylor and Davies28 have isolated a series of triterpenoid carotenoids from a Streptococcus sp. The hydrocarbons of the series have been identified as the C,, homologues of phytoene, phytofluene, [-carotene, and neurosporene and named 4,4‘-diapophytoene (42), 4,4’-diapophytofluene (43), 4,4’-diapo-[-carotene (44), and 4,4‘-diaponeurosporene (45). The structures were deduced mainly from absorption and mass spectra, though ‘H n.m.r. was used to establish that the diapophytoene was predominantly the 15-cis-isomer(carotene n ~ m b e r i n g ) .Two ~ ~ xanthophylls present in the same organism have been identified3’ as 4-hydroxy-4,4’-diaponeurosporene(46) and its P-D-glucoside. There are considerable difficulties with the nomenclature of these 24

25

26 2’

29 30

A. Khare, G . P. Moss, and B. C. L. Weedon, Tetrahedron Letters, 1973,3921 : B. C. L. Weedon, Pure Appl. Chem., 1973, 35, 113. G. Neamtu and C. Bodea, Stud. Cercet. Biochim., 1973, 16, 3 5 . N. Arpin, S. NorgArd, G . W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1973. 27,2321. G . Suzue, K. Tsukada, and S. Tanaka, Biochim. Biophys. Acta, 1968, 164,88; S. C. Kushwaha, E. L. Pugh, J. K. G . Kramer, and M. Kates, ibid., 1972, 260, 492. R. F. Taylor and B. H. Davies, Biochem. Soc. Trans., 1973, 1, 1091. R. F. Taylor and B. H. Davies, Biochem. J . , 1974, 139, 751. R . F. Taylor and B. H . Davies, Biochem. J . , 1974, 139, 761.

Terpenoids und Steroids

152

b

a

(42) R ' = R 2 = a (43) R ' = a , R 2 = b (44)R' = R 2 = b

(45)R ' (46) R'

c (X = = c (X = =

H), R 2 = b OH), R 2 = b

compounds, which, although they are triterpenoid and appear to be biosynthesized as triterpenoids, have great overall similarity to the conventional C40 carotenoids. These difficulties have been discussed.29 Degraded Carotenoids. Several new compounds have been characterized which, although not carotenoids, have structures similar to the cyclic end-groups of carotenoids, and, in some cases at least, may be derived biologically from carotenoids. Two new tobacco constituents have been identified as (3R)-(- )-3-hydroxy-P-ionone (47)3 and (9R)-9-hydroxy-4-megastigmen-3-one (48)3 ( = blumenol C). The stereochemistry (at C-3 and C-6 respectively) was the same as in the corresponding carotenoids. Several volatile constituents of black tea have been identified by g.c.-m.s. as possible degraded carotenoids.

Details have been given of the spectroscopic data (i.r., u.v., 'H n.m.r., and m.s.) obtained for a component of the volatile hair-pencil secretion of the Monarch butterfly (Dtrnciusp k x i p p u s ) . 3 4 I t was concluded that the compound is a bicyclic a/I-unsaturated ketone with an ether oxygen forming one ring. Two possible structures (49) and (50) were considered, but attempts to prove structure (49) by synthesis were unsuccessful. Several new coumarins from Ferula kopetdaghensis roots include one, kopeolin ( 51), and its glycoside, kopeoside, containing an ether-linked carotenoid-like s~bstituent.~ T. Fujimori, R. Kasuga, M. Noguchi, and H. Kaneko, Agric. and B i d . Chem. (Japan), 1974, 38, 89 1 . A. J. Aasen, J . R. Hlubucek, and C. R . Enzell, Acta Chem. Srand., 1974, B28,285. 33 W. Renold, R. Naf-Miiller, U. Keller, B. Willhalm, and G. Ohloff, Helu. Chim. Acta, 1974, 57, 1301. 3 4 T. E. Bellas, R . G . Brownlee, and R. M. Silverstein, Tetrahedron, 1974, 30, 2267. " K . M . Kamilov and G. K . Nikonev, Khim. prirod. Soedinenii, 1973, 9, 308. 31

32

153

Curo t enoids and Poly terpenoids

0 (49)

Stereochemistry ; Absolute Co&guration.-C-6. Full details have been published36 of the chemical correlations with manool and ambrein used to establish the (6’R)configuration in a-carotene (p,&-carotene)(52)and related compounds. Similar conclusions about

the absolute configuration of (+)-a-ionone (53),(+)-cis-a-irone(54; 6 9 , and (-)-transa-irone (54; 6R) have been reached from details of the c.d. spectra and considerations of exciton interactions. The stereochemistry at C-6 (carotene numbering) of ( +)-cis- and trans-abscisic acid (57) has also been confirmed, and reasons for the failure of Mills’ rule in these cases are discussed.37 The isolation of (+)-a-ionone as a product of oxidative degradation of P,~-caroten-2-01(27) also established the (6’R)configuration in this c a r ~ t e n o i d .The ~ ~ (6’R)configuration in lutein (35) was established by degradation to (+)-(R)-3-oxo-a-ionone (55).39

(53) R’ = H , R 2 = H,H (54) R’ I= Me,R2 = H,H (55) R’ = H , R 2 = 0 (56) R’ = H , R 2 = M e 0 , H

(57)

C-3. Confirmation that natural zeaxanthin (p,,karotene-3,3’-diol) (58) has the (3R,3’R) configuration has been obtained by synthesis of the optically active allenic grasshopper 36

37

38

39

R. Buchecker, R. Egli, H. Regel-Wild, C. Tscharner, and C. H. Eugster, Helv. Chim. Acta, 1973,56, 2548. G . Ohloff, E. Otto, V. Rautenstrauch, and G . Snatzke, Helu. Chim. Acta, 1973, 56, 1874. R. Buchecker, C. H. Eugster, H. Kjrasen, and S. Liaaen-Jensen, Helo. Chim. Acta, 1973, 56, 2899; Acta Chem. Scand., 1974, B28,449. R. Buchecker, P. Hamm, and C. H. Eugster, Helv. Chirn.Acta, 1974, 57, 631.

Terpenoids und Steroids

154

ketone (63) ;40 the correlation between the stereochemistry of the ketone and that of zeaxanthin had previously been e ~ t a b l i s h e d .I~s ~ m e r i z a t i o nof~lutein, ~ however, gave (3R,3'S)-~eaxanthin,"~ confirming that lutein has the (3R,3'R)configuration ( 3 5 ) previously established by H n.m.r analysis and chemical correlation of ( +)-3-methoxy-aionone (56) derived chemically from I ~ t e i n . It ~ ~has , ~been ~ suggested that the main pigment of Caltha palustris may be the (3's)-isomer of lutein.22 C-2. Application of the modified Horeau method45 to 2-acetoxy-/l-cyclocitral (64), derived chemically from P,P-caroten-2-01, P,~-caroten-2-01, and P,P-carotene-2,2'-diol (59) (Trentepohlia iolithus) has e ~ t a b l i s h e dthe ~ ~(2R)stereochemistry for each of these carotenoids, (27), (28), and (59), in agreement with previous deductions from Mills' rule.'

a

b

C

e

d

(58) R ' (59) R' (60) R'

40

4'

42

43 44

4s

= R2 = = R2 = = R2 =

a b

(61) R' (62) R'

= =

c,R2 = d c,RZ = e

c

( a )J. R. Hlubucek, J. Hora, S. W. Russell, T. P. Toube, and B. C. L. Weedon, J.C.S. Perkin I , 1974, 848; ( b ) K. Mori, Tetrahedron, 1974, 30, 1065. L. Bartlett, W. Klyne, W. P. Mose, P. M. Scopes, G . Galasko, A. K. Mallams, B. C. L. Weedon, J. Szabolcs, and Gy. Toth, J. Chem. SOC.(0,1969,2527; R. Bonnett, A. K. Mallams, A. A. Spark, J. L. Tee, B. C. L. Weedon, and A. M c m r m i c k , ibid., p. 429. A. G . Andrewes, Acta Chem. Scand., 1974, B28, 137. A. G. Andrewes, G . Borch, and S. Liaaen-Jensen, Acta Chem. Scand., 1974, B28, 139. R. Buchecker, P. Hamm, and C. H. Eugster, Chimia (Switz.), 1971, 25, 192; 1972, 26, 134. C. J. W. Brooks and J. D. Gilbert. J.C.S. Chem. Comm., 1973, 194.

155

Curotenoids and Polyterpenoids

Carotenoid Epoxides. Examination of the 'H n.m.r. spectra of the furanoid oxides formed (H') from natural violaxanthin (60),lutein epoxide (61),and neoxanthin (62)and from the semi-synthetic products of chemical epoxidation of lutein and zeaxanthin acetates has confirmed the (3S,5R,6S) configuration for the natural epoxides and the (3S,5S,6R)configuration for the principal semi-synthetic With the furanoid oxides of the natural compounds, an axial hydroxy-group at C-3 deshields the axial methyl groups at C-1 and C-5, i.e. the oxygen functions at C-3 and C-5 are trans. This has been confirmed4' in the case of lutein epoxide; treatment of the furanoid oxides with IsoNiO, yielded (-)-loliolide (65), the absolute configuration of which is loliolide (66) was similarly obtained from the semi-synthetic lutein epoxide.

HO H

H'

The natural 5,6-epoxides of fl,B-caroten-2-01 and fl,~-caroten-2-01were identical with the main product of chemical epoxidation of the carotenols.16 Since chemical it was tentatively conepoxidation occurs preferentially cis to the hydroxy-s~bstituent,~~ cluded that the natural epoxides had the epoxide group cis to the hydroxy-group at C-2 [(25)and (26)]. Zsornytiloxanthin. Comparison of the 'H and 13Cn.m.r. spectra of isomytiloxanthin with those of model compounds suggests that isomytiloxanthin has the absolute configuration (38), indicating a close similarity to the natural 5 , 6 - e p o ~ i d e s . ~ ~ Degraded Carotenoids. The absolute configurations of the alienic grasshopper ketone (63) and dehydrovomifoliol (67) have been confirmed by ~ynthesis.~'The volatile tobacco constituent 9-hydroxymegastigma-4,7E-dien-3-one (68) ( = 3-0x0-a-ionol) has been shown to have the ( R ) configuration at C-6 by optical correlation with a-ionone (53) and at C-9 by chemical correlation with lactic acid.50

c::"';."

0

'

Conformation.-Carotenoids. Analysis5' of the electronic spectra of rhodopinal (69) at room temperature and at 77 K indicates a 12-s-rrans,l3-cis conformation, with the C-13 double bond twisted by a dihedral angle of about 20". 46

47 48

49 50

5'

D. Goodfellow, G. P. Moss, J. Szabolcs, G. Toth, and B. C. L. Weedon, Tetrahedron Letters, 1973, 3925. H . Cadosch and C. H. Eugster, Helv. Chim. Acta, 1974,57, 1466. S. Isoe, S. B. Hyeon, S. Katsumura, and T. Sakan, Tetrahedron Letters, 1972, 2517. H. 0. House, 'Modern Synthetic Reactions', 2nd Edn., Benjamin, Menlo Park, 1972, p. 303. A. J . Aasen, B. Kimland, and C. R. Enzell, Acta Chem. Scand., 1973, 27, 2107. C.-A. Chin and P.-S. Song, J . Mol. Spectroscopy, 1974, 52, 216.

156

Terpenoids and Steroids

Retinal and Deriuatives. X-Ray crystallographic data indicate that the polyene sidechain of retinyl acetate (70) is essentially planar but shows marked in-plane bending caused by steric interference between hydrogen atoms and methyl groups on the polyene chain. The torsion angle between ring and side-chain deviates by 58" from that for the s-cis conf~rmation.'~ The conformation ofretinal (71) isomers in solution have also been studied. 'H n.m.r. indicates the polyene chain of all-trans-retinal to have a planar conformation with all the single bonds from C-7 to C-15 in the s-trans conformation. The polyene chain of I

(70) R' = Me, R2 = H, R 3 = C H 2 0 A c (71) R' = M e , R 2 = H , R 3 = C H O

R'

(72) R' = R 2 = Me, R3 = C H O (73) R' = H , R 2 = M e , R 3 = CHO

11-cis-retinal is essentially planar in the regions C-7-C-10 and C - 1 3 4 - 1 5 but is slightly twisted from planarity around the C - 1 M - 1 1 single bond. 11-cis-Retinal exists as an equilibrium between two low-energy conformers, distorted 12-s-cis and distorted 12-s-tr~ns.~At low temperature, the distorted 12-s-trans conformation appears to be referr red.^^.'^ Calculations predict the distorted 12-s-cis conformation for the ground state of 1l - ~ i s - r e t i n a l . Spectroscopic ~~ studies of all-trans- and cisisomers of retinal, 14-methylretinal (72), and 13-desmethyl-14-methylretinal(73) show that in solution 11-cis-retinal exists largely in the 12-s-cis-form, but the 14-methyl homologue probably has a 12-s-trans or very highly twisted 12-s-cisc o n f ~ r m a t i o n . ~ ~ The c.d. spectra of a number of Schiffs bases derived from 1 1 4 s - or all-trans-retinal and simple optically active amines demonstrated that the simple amine moieties are capable of inducing optical activity into the conjugated chromophoric system of the retinal Calculations show that the 490 nm Cotton effect of rhodopsin is not prima facie evidence for the distortion of the retinal chromophore. The retinal transitions could become optically active by coupling with the transitions of aromatic aminoacid side-chains located within a 15 A radius of the c h r ~ m o p h o r e . ~ ~ Zrone. Low-resolution microwave spectroscopic studies have shown that the C-2 and C-6 substituents in cis-a-irone (54; 6s)are both equatorial and that a-ionone (53) and 52

53 54 55 56

"

W. E. Oberhansli, H . P. Wagner, and 0. Isler, A c f a Cryst., 1974, B30, 161. R. Rowan, tert., A. Warshel, B. D. Sykes, and M . Karplus, Biochemistry, 1974, 13,970. W. Sperling, in 'Biochemistry and Physiology of Visual Pigments', ed. H. Langer, Springer, New York, 1973, p. 19. M . Karplus, ref. 54, p. 17. W. K. Chan, K. Nakanishi, T. G . Ebrey, and B. Honig, J . Amer. Chem. SOC.,1974, 96, 3642. E. M. Johnston and R. Zand, Biochemistry, 1973, 12, 4631. E. M. Johnston and R. Zand, Biochemistry, 1973, 12, 4637.

157

Carotenoids and Polyterpenoids

trans-a-irone (54; 6 R ) exist as a mixture of two main conformers. trans-a-Irone is predominantly in the conformation with a pseudo-axial enone ~ i d e - c h a i n . ~ ~ Synthesis.---Carotenoids. Two new methods have been reported for the preparation of p-carotene from Vitamin A and derivatives. In a simple and efficient method, b-carotene was formed in 85 % yield by treatment (reflux,4 h in N,) of retinal with a LiAlH,-TiCl, reagent (1 : 1 in dry THF).60 In the second method, treatment of retinol (74) with NN'-thiodiphthalimide in benzene or dichloromethane at room temperature in the presence of K,CO, or NEt, gave the allylic sulphone (75) in 74 % yield. With n-butyllithium or lithium di-isopropylamide, this gave the @,a'-dianion,which with I2 or Br, afforded a mixture of stereoisomeric /?-carotenes; isomerization yielded all-trans-pcarotene (24 %)."

(75)

(74)

Two recently described6 natural acetylenic carotenoids, 7&didehydro-+,~-carotene (76) and 7,8-didehydro-+,+-carotene(77) have been synthesized by several versions of the C, + C, + C, route. In all cases, except in a low-temperature, low-overall-yield condensation, the products were predominantly the much more stable 9-cis-i~omers.~~ R2

R'

b

a

(76) R ' (77) R '

= =

a,R2 = b RZ = a

The structure assigned7 to aleuriaxanthin (22) has been confirmed by synthesis of the compound and its acetate.' The key step was the photosensitized autoxidation of linalool(78)to produce a mixture of hydroperoxides which were reduced with NaBH, to give a mixture of diols, only one of which gave an acetate (79). Condensation of the ylide (80), generated in situ from the phosphonium salt prepared from (79) with 8'-apo/?-caroten-8'-al (8l), afforded aleuriaxanthin acetate and aleuriaxanthin. Triphasia59

6o

6L 62

63

W. E. Steinmetz, J . Amer. Chem. SOC.,1974, 96, 685. J. E. McMurry and M. P. Fleming, J . Amer. Chem. Soc., 1974, 96, 4708. G . Buchi and R. M. Freidinger, J . Amer. Chem. Soc., 1974, 96, 3332. T. Hamasaki, N. Okukado, and M. Yamaguchi, Bull. Chem. SOC.Japan, 1974, 41, 350. T. Ike, J. Inanaga, A. Nakano, N . Okukado, and M. Yamaguchi, Bull. Chem. SOC.Japan, 1974, 47, 350.

Trrpenoids and Steroids

158

xanthin (3’-hydroxy-5,6-seco-~,~-carotene-5,6-dione) (82) acetate has been prepared by chromic acid oxidation of P-cryptoxanthin (&P-caroten-1-01) (83) acetate.64

.1...[ W”’ .‘. \

\

\

’

e

d

(81) (82) (83) (84)

R’ R’ R’ R’

= a (X = H), R 2 = CHO = b, R 2 =*a(X = OH) = a (X = OH), R 2 = a (X = = R2 = c

H)

(85) R ’ = R2 = d (86) R ’ = e,R2 = c (87) R’ = c, R 2 = CHO

Specifically deuteriated carotenoids are particularly useful in systematic studies of m.s. fragmentations, and syntheses of several deuterium-labelled species have been reported. Three papers by Liaaen-Jensen and c o - ~ o r k e rdescribe s ~ ~ the preparation, by modifications of the standard routes for carotenoid synthesis, of six deuteriated carotenoids, [11,1 l’-2H2]lycopene($,$-carotene) (84), [11,1 l’-2H2]-~-carotene (&,&-carotene) (85),, [7,7’-2H,]lycopene, [7,7‘-2H2]rhodopin (1,2-dihydro-11/,11/-caroten-l-01) (86), [72H,] apo-8’-lycopenal (S’-apo-$-caroten-8’-al) (87), and [19,19,19,19’,19‘,19’-2H6]-~carotene. The preparation of a further eleven deuteriated carotenoids, [4,4,4’,4’-2H4]p-carotene, [7,7’-2H2]zeaxanthin,[7,8,7’,8’-’H4]zeaxanthin, [8,15,8‘,15’-2H4]zeaxanthin, [4,4,8,15,19,19,19,4’,4’,8’,1 5’,19’,19’,19’-2H,4]-/j-carotene, [10,10’-2H2]-P-carotene, [lo, 1 1,15,10,11’.15’-2H,]-/j-carotene, [ 1 1,15,1l’,15’-2H4]-fi-carotene,[ 11,12,1l’,12’-2H4]-P64 65

J . Szabolcs and L. Timar, Acta Chim. Acad. Sci. Hung., 1973, 7 8 , 315. (a) J. E. Johansen and S. Liaaen-Jensen, Acra Chem. S a n d . , 1974, B28, 349; ( b ) ibid., p. 301 ; ( c ) A. Eidem and S. Liaaen-Jensen, ibid., p. 273.

159

Carotenoids und Polyterpenoids

carotene, [l 2,20,20,20-2H,]-fi-carotene, and [ 14-2Hl]-fi-carotene,is given in a paper by who outline methods available for the introduction of deuterium Brzezinka et into carotenoid molecules. Degraded Carotenoids. In the Vitamin A series, a biological preparation of retinyl pyrophosphate by a rat thyroid system has been d e ~ c r i b e d .Chemical ~~ syntheses of 7,s-dihydroretinoic acid (88) and related compounds from 7,s-dihydro-fi-ionone (89)6 and of the (1 12)- and (1 1Z,13Z)-isomers of r e t i n 0 1 ~have ~ been presented. The retinol dimer, kitol(90), was identified as a by-product (10 %) of the cyanide-catalysed oxidative esterification of retin01.~' The preparation of 14-methylretinol(72)from the C1 ketone (91) and of 13-desmethy1-14-methy1retina1 (73) from the C I 7 aldehyde (92) has been reported. 5 6

(91) R = COMe (92) R = CHO

(93)

Details of the synthesis of the allenic grasshopper ketone (63) have been pre~ented.~' Preparation of the optically active intermediate (93)led to the optically active productfoh Isomers of (63) with different stereochemistry were also ~repared.~'" SeO, oxidation of methyl cis-a-ionylideneacetate (94) in ethanol gave a mixture of methyl hydroxyionylideneacetates. One product, the dihydroxy-ester (95) on oxidation (MnO,) gave methyl abscisate (96).71 Several analogues of abscisic acid and its methyl 66

67 68

H . Brzezinka, B. Johannes, and H. Budzikiewicz, Z . Naturforsch., 1974, 29b, 429. K. Gaede and P. Rodriguez, Biochem. Biophys. Res. Comm., 1973,54, 76. L. P. Davydova, L. N. Polyachenko, T. M. Filippova, and G. I. Samokhvalov, Zhur. obschei

Khim., 1913, 43, 2064. V. L. Khristoforov, E. N. Zvonkova, V. P. Varlamov, 0. N. Sorokina, and R. P. Evstigneeva, Zhur. org. Khim., 1973, 9, 1844. 'O M . C. Ghosh, M. Rahman, and S. Ghosh, Indian J . Biochem. Biophys., 1973, 10, 289. " T. Oritani and K. Yamashita, Agric. and Biol. Chern. (Japan), 1974, 38, 801.

69

160

Terpenoids and Steroids

ester labelled with 'H or l8Ohave been prepared.72 The syntheses of a range of quaternary ammonium compounds derived from a- and p-ionones have been reported.73

0

(94) (95) (96) (97) (98)

R' R' R' R' R'

Me, R 2 = H, R3 = H,H Me, R2 = OH, R3 = H,OH = Me, R 2 = OH, R3 = 0 = Et,R2 = H , R 3 = 0 = Et.R2 = O H , R 3 = H,H = =

(99)

Ethyl ( - )-4'-keto-a-ionylideneacetate (97), ethyl ( - )-1'-hydroxy-a-ionylideneacetate (98), ethyl 3'-keto-P-ionylideneacetate(99),and ethyl ( - )-abscisate have been prepared from li ionone one.^^ In a new procedure for the synthesis of dienone derivatives, e.g. ionone and irone, the key step is the pyrolytic rearrangement of ally1 alcohols or acetylenic carbinols and 2,2-dimethoxypropane in the presence of acetic anhydride and phosphoric 3-Isobutyroxy-~-ionone(100) has been synthesized from 3-hydroxy-P-ion01 ( 101).76 The chemical and spectroscopic properties and biological activity of (100) suggest that it may not be identical with quiesone, for which structure (100) has been proposed.77 Dehydrovomifoliol (67) was also prepared. 3-Hydroxy-a-damascone (102) has been prepared by reaction of the tetrahydropyrgnyl ether of ethyl 3,3,5-trimethylcyclohex2-en- 1 -ol-4-carboxylate (1 03) with allyl-lithium, followed by equilibration with dilute

(100) R' (101) R '

= =

0 , R 2 = Me2CHC02 H,0H,R2 = OH

(104) R

72

73

74

75

76 77

=

H or T H P

(102) R (103) R

(105) R (106) R

= =

= =

COCH=CHMe C0,Et

H OH

R. T . Gray, R . Mallaby, G. Ryback, and V. P. Williams, J . C . S . Perkin ZI, 1974, 919. H. Haruta, H. Yagi, T. Iwata, and S. Tamura, Agric. and Biol. Chem. (Japan), 1974, 38, 141, 417, 877. T. Oritani and K . Yamashita, Agric. and Biol. Chem. (Japan), 1973, 37, 1 1 15. T. Ishihara, T. Kitahara, and M. Matsui, Agric. and Biol. Chem. (Japan), 1974, 38, 439. K . Mori, Agric. and Biol. Chem. (Japan), 1973, 37, 2899. R. A. Leppik, D. W. Hollomon, and W. Bottomley, Phytochemistry, 1972, 11, 2055.

Carotenoids and Polyterpenoids

161

alkali." Rupe rearrangement of the appropriate acetylenic alcohols (104) affords dihydro-p-damascone (105) and its 3-hydroxy-derivative (106).79 Chemistry.-Carotenoids. The method" for base-catalysed isomerization of a-carotene into p-carotene or of lutein into zeaxanthin has been improved by the inclusion of dimethyl sulphoxide. Optimum conditions for &-carotene required 20 % KOH in methanol and gave 1 6 2 8 % a-carotene and 1 6 2 1 % p-carotene. Isomerization of lutein required 5 % KOMe in methanol and gave zeaxanthin in l C r l 5 % yield.42 Methods available for 0-methylation of carotenoids have been evaluated, and an improved method is reported.81 Me1 and NaH in THF82 efficiently 0-methylated secondary allylic (aleuriaxanthin), secondary non-allylic (zeaxanthin), sterically hindered [fl,~-caroten-2-oland azafrin (5,6-dihydroxy-5,6-dihydro-lO-apo-p-caroten10'-oic acid) (107)], phenolic [3-hydroxyisorenieratene ($,$-caroten-3-01) (108)], and enolic [astacene (3,3'-dihydroxy-2,3,2',3'-tetradehydro-~,P-carotene-4,4'-dione) (109)] hydroxy-groups in carotenoids.

a

b

d

e

O

C

f

g

(107) R' = a,R2 = C 0 , H (114) R' = e, R2 = d (Y = H) ( 1 15) R' = e, R2 = CH=C(Me)CHO (108) R' = b(X = OH),R2 = b ( X = H) (116) R' = f, R 2 = CHO (109) R' = R 2 = c (117) R' = b(X = H),R2 = g (110) R' = d ( Y = H),R2 = CH=C(Me)CHO (11 1) R' = d (Y = OH),R2 = CH=C(Me)CHO (112) R' = d (Y = H), R2 = CH=C(Me)CH=CHCOMe (113) R' = d ( Y = OH),R2 = CH=C(Me)CH=CHCOMe

79

82

Y. Takei, K. Mori, and M. Matsui, Agric. and Biol. Chem. (Japan), 1973, 37, 2927. K. Mori, M. Ohki, K. Okada, Y. Takei, and M. Matsui, Agric. and Biol. Chem. (Japan), 1973, 37, 2907. P. Karrer and E. Jucker, Helu. Chim. Acra, 1947, 30, 266. G. Nybraaten and S. Liaaen-Jensen, Acta Chem. Scand., 1974, B28, 584. B. A. Stoochnoff and N. L. Benoiton, Tetrahedron Letters, 1973, 21.

162

Terpenoids and Steroids

Chemical reactions of carotenoids with 2-hydroxylated P-rings have been outlined.’“ The expected lower reactivity of the sterically hindered 2-hydroxy-group compared with a 3-hydroxy-group was demonstrated by slower acetylation and hydrolysis of the acetate and less efficient methylation. In purified chloroform slow formation of the furanoid oxides occurred, by a process considered to be a free-radical reaction of a phosgene peroxide complex. Aldol condensation between 8’-apo-/?-caroten-8’-al(llO)or p-citraurin (3-hydroxy-8’apo-p-caroten-8’-al) (1 11) and traces of acetone occurs under basic conditions (e.g. saponification) to yield citranaxanthin (5’,6’-dihydro-5’-apo-1 8’-nor-p-caroten-6’-one) ( 1 12) and reticulataxanthin (3-hydroxy-5’-6‘-dihydro-5’-apo18‘-nor-fi-caroten-6‘-one) (1 13) re~pectively.~~ This throws doubt on previous reports of the natural occurrence of the latter two car~tenoids.~, The oxidation of carotenoid epoxides and furanoid oxides by alkaline KMnO, gives epoxy-apo-carotenals, e.g. mutatochrome (5,8-epoxy-5,8dihydro-P,p-carotene) (1 14) gives 5,8-epoxy-5,8-dihydro-8’-apo-P-caroten-8’-al (115) and violaxanthin gives 1 0‘-apoviolaxanthal (5,6-epoxy-3-hydroxy-5,6-dihydro-l0’apo-fl-caroten-lO’-al) (1 16).85 The preparation of azlactones of 8’, lo’, and 12’-apo-pcarotenals, jj-citraurin, and retinal, by reaction with hippuric acid, and their properties have been described.86 The controlled KMnO, oxidatiofi of chlorobactene ( 4 , ~ carotene) ( J I 7) to yield a mixture of dimethylbenzenedicarboxylicacids has been used in studies of chlorobactene b i o ~ y n t h e s i s . ~ ~ Degraded Carotcrnoids. The reaction of retinylidenephosphorane ( 1 18) with p-nitrosodimethylaniline gives a mixture of products including retinal, p-carotene stereoprepared by isomers, and the hydrocarbon (1 19).8 8 N-All-trans-retinyl-L-amino-acids, condensation of retinal with the amino-acid (alanine, valine, leucine, or isoleucine) in alkaline medium, followed by NaBH, reduction, are more stable than retinyl acetate to oxidative degradation in methanolic solution, but less stable in the crystalline state. Hydrolysis (dilute acid) gives retinal and the amino-acid by an S,1 reaction via the allylic retinyl carbonium ion. 8 9 Schiff s bases have been prepared from all-trans-retinal with (S)-a-phenylethylamine, (S)-a-(1-naphthyl)ethylamine, (R)-(+ )-2,2’-dimethyl-6,6’diaminobiphenyl, or poly-L-lysine and from 1l-cis-retinal with (S)-a-(l-naphthy1)ethylamine.”

(1 18) R = CH=PPh, (119) R = Me 83 84

85 n6

87

89

I. Stewart and T. A. Wheaton, Phytochemistry, 1973, 12, 2947. H. Yokoyama. H . C. Guerrero, and H. Boettger, in ‘The Chemistry of Plant Pigments’, ed. C. 0. Chichester, Academic Press, New York, 1972, p. 1 . P. Molnar and J . Szabolcs, Acta Chim. Acad. Sci. Hung., 1973, 79, 465. V. Tamas, V. Ciudaru, and C. Bodea, Rev. Roumaine Chim., 1973, 18, 1409; V. Tamas and C. Bodea, ibid., 1974, 19, 701. S. E. Moshier and D. J . Chapman, Biochem. J . , 1973, 136, 395. Y. V. Kondukova, L. A. Vakulova, and G. I. Samokhvalov, Khim.-farm. Zhur., 1973, 7 , 29. T . D. Skalaban, E. N. Zvonkova, T. P. Belova, and R. P. Evstigneeva, Khim.-farm. Zhur., 1973, 7 , 17.

Curotenoids and Polyterpenoids

163

In pure acetic acid, anhydroretinol (1 20) was formed from all-trans-retinyl acetate. Addition of water accelerated this process, but led to dimerization as the main reaction." Addition of small amounts of H 2 S 0 4 led to the formation of polymeric products which changed in part to very stable (several hours under N2 at room temperature) carbonium ions." Nucleophiles, such as dihydroflavins, dithiols, di- and tetra-hydrofolate, and dehydroascorbate, promoted the isomerization of all-trans-retinal to the 9-cis- and 13-cisisomers92and of 11-cis- to all-tr~ns-retinal.~~ The surface properties of mixed unimolecular films of retinal and phospholipids at a nitrogen-water interface have been i n ~ e s t i g a t e d The . ~ ~ photois~merization~~ and other physical aspects96 of the photochemistry of retinal and derivatives have been studied. The chemistry (and physiology) of abscisic acid has been re~iewed.~' On treatment with toluene-p-sulphonic acid in chloroform, trans-5,6-dihydroxy-5,6dihydro-P-ionone (121) undergoes a clean rearrangement to give a mixture of the fury1 ketone (122)and the aliphatic triketone (123)in good yield.98 The conversion of a-ionol (124) into a-damascone (127) has been achieved99 by two reaction sequences through

(124) R

=

(125) R

=

OH

+ NMe,-0

(126) R (127) R

= =

H,ONMe, 0

the formation of the NN-dimethylamine oxide (125) and rearrangement of this to the NN-dimethylhydroxylamine (126). Photo-oxygenation of P-damascenone (128) leads to the 3,6-endo-peroxide(129), which can be converted into various oxygenated derivatives in the damascone series. Introduction of oxygen specifically into the 2-position of P-damascenone occurs by SeO, oxidation to give 2-0x0-P-damascenone (130); the preparation of a series of reduction products of this has been described.'" U.V.irradi-

'"L. Pekkarinen and P. Uutela, 91

92

93 94

95

96

97 90 99

loo

Suomen Kern., 1973, €546, 127. L. Pekkarinen and A. Pekkarinen, Finn. Chem. Letters, 1974,53. S . Futterman and M. H. Rollins, J. Biol. Chem., 1973, 248, 7773. A. Futterman and S. Futterman, Biochim. Biophys. Acta, 1974, 337, 390. N. Yckowski and S. S. Brody, Z. Naturforsch., 1974, 29c, 327. F. Fratev, G . Khibaum, and A. Gochev, Izvest. Otdel. Khim. Nauki, Bulg. Akad. Nauk, 1973, 6, 769; T. Rosenfeld, A. Alchalel, and M. Ottolenghi, J. Phys. Chem., 1974, 78, 336. L. Espinoza, M. Trsic, and E. Sanhueza, Chem. Phys. Letters, 1973, 22, 154; T. Rosenfeld, A. Alchalal, and M. Ottolenghi, ibid., 1973, 20, 291. B. V. Milborrow, Ann. Rev. Plant Physiol., 1974, 25, 259. W. Skorianetz and G. Ohloff, Helv. Chim. Acta, 1973, 56, 2025. V. Rautenstrauch, Helv. Chim. Acta, 1973, 56, 2492. K. H. Schulte-Elte, M. Gadola, and G. Ohloff, Helv. Chim. Acta, 1973, 56, 2028.

164

Terpenoids and Steroids

(128) R (130) R

= =

H, 0

(133) R (135) R

=

=

Me,OH CH,

(134) R = Me,OH

(136) R

=

CH,

ation of the hydroxy-enones (131) and (132) in acetonitrile results in cyclization to the unstable isomeric allylic alcohols (133) and (134), which dehydrate easily to the ethers (135) and (136). Similar irradiation of the racemic yd-dihydroxy-enone (121) gave exclusively the furan compound ( 122).'O' U.V. irradiation of trans-p-ionone epoxide (137) in pentane solution gave rise to a number of products, including (122),(123),(138), and (139).' O 2

(137)

(1 39)

A method for the epoxidation of p-ionone by heating it in air in xylene solution to give 5,6-epoxy-P-ionone (137) in 72 % yield has been reported.'03 Cycloisomerization of the trienes (140)and (141) with sodium and propan-2-01 gives rise to bicycloundecadienes (142).'04 Cyclization of cis-isomers of $-ionone (143) by H , S 0 4 gave 25-30% of the benzopyrans (144)and (145),which underwent conversion into (146)and (147).lo5 C-Silylation of a-ionone by Me,SiCl-Li in THF gave the product (148).'06 Lithiation of P-cyclogeraniol vinyl ether (149) by BuLi and rearrangements of the organolithium products are r e ~ 0 r t e d . l ' ~

101

I02 103

I04

105

106

107

B. R. von Wartburg, H . R. Wolf, and 0. Jeger, Hefo. Chim. Acra, 1973, 56, 1956. B. R. von Wartburg, H . R. Wolf, and 0. Jeger, Helv. Chim. Acta, 1973, 56, 1948. H. Hart and P. B. Lavrick, J . Org. Chem., 1974, 39, 1793. J. Barjot, G. Bony, G. Dauphin, P. Duprat, A. Kergomard, and H. Veschambre, Bull. SOC. chim. France, 1973, 3187. N. I . Zacharova, T. M. Filippova, M. A. Miropol'skaya, L. E. Burova, and G. I. Samokhvalov, Zhur. org. Khim., 1974, 10, 514. R. Calas, J. Dunogues, A. Ekouya, G. Merault, and N. Duffaut, J . Organometalfic Chem., 1974, 65, C4. V . Rautenstrauch, G . Biichi, and H . Wiiest, J . Amer. Chem. SOC.,1974, 96, 2576.

165

Carotenoids and Poly terpeno ids

Auto-oxidation of the pyran (144), obtained by photoirradiation of p-ionone, produced dihydroactiniolide (150) and a hemiacetal (151), which could be converted into (150).'08 Photosensitized oxidation of (144) rapidly formed a stable peroxide (152), which could readily be converted into the triones (153) and (154).'09 The catalytic reduction of a-cyclogeranoic acid (155) and the properties of the dihydro-a-cyclogeranoic acid (157) isomers thus formed have been reported.' l o Cyclization of geranyl chloride with BF, etherate gives a-cyclogeranyl chloride (156).'

''

(153)

(154) R

=

H or Me

(155) R = C 0 2 H (156) R = CH2Cl Io8 Io9 ]lo

S. Kurata, Y . Inouye, and H. Kakisawa, Tetrahedron Letters, 1973, 5153. €4. Etoh, K . h a , and M . Iguchi, Agric. and Biol. Chem. (Japan), 1973,37, 2241. R. Buchecker and C. H . Eugster, Helv. Chim. Acta, 1973, 56, 2563. Y . Butsugan, K. Sahaki, T. Bito, and M . Muto, Nippon Kagaku Kaishi, 1973, 1804.

166

Terpenoids and Steroids

Physical Methods.-Chromatographic methods are routinely used in the separation and purification and spectroscopic methods (electronic, i.r., n.m.r., m.s., and often c.d. or 0.r.d.) in the identification and characterization of carotenoids. Details of spectroscopic data etc. for individual carotenoids are given in many of the papers surveyed in previous sections. In this section, only papers dealing solely or largely with physical techniques, or relevant points of more general significance from previously discussed papers, will be considered. Separation Methods. The use of high-pressure liquid chromatography (h.p.1.c.) for separation of Vitamin A isomers and derivatives has been evaluated. This technique has considerable advantages over g.c.' l 2 H.p.1.c. has been used for separation of stereoisomers of 14-methylretinal and 13-de~methyl-14-methylretinal.~~ The separation of the stereoisomeric furanoid oxides obtained from natural or semi-synthetic lutein epoxide elution chromatographic has also been accomplished by l . ~ A. ~concave-gradient ~ method has been used to separate the neutral carotenoids of Neurospora crassa.' l 3 Carotenoids may be separated from steroids by chromatography on lipophilic Sephadex.'

'

Electronic Spectroscopy. The electronic (linear dichroic) spectra of fi-carotene,' rhodopinal (69)," and the Schiff s bases of 8'-apo-P-carotenal (1 lo), citranaxanthin (112), and reticulataxanthin (1 13)' have been analysed in detail. The hypochromicity of the main absorption band and the appearance of a new band at 3 5 G 3 6 0 n m in the absorption spectrum of lycopene in an ethanol-water mixture has been attributed to exciton interactions between two stacked lycopene molecules. p-Carotene does not show this behaviour. The linear dichroism spectra at 77 K can be used for identification ofretinal isomers.' l 8 Fluorescence excitation spectra show that all-trans-retinal has a wavelength-dependent fluorescence quantum yield.' I 9

'

Resonance Raman Spectroscopy. Resonance Raman spectra of ,%carotene in isopentane at low temperature have been obtained and analysed in terms of the Albrecht theory.12' Low-resolution Microwave Spectroscopy. Application of this technique has allowed the conformations and ring orientations of some ionone derivatives to be e s t a b l i ~ h e d . ~ ~ Infrared Spectroscopy. The absorption bands at 920 and 730 cm- in the i.r. spectra of deuteriated carotenoids have been ascribed empirically to out-of-plane deformation of trar~s-CH=CD.~~' N.M.R. Spectroscopy. Characteristic H n.m.r. bands (100 MHz) of carotenoid furanoid oxides have been tabulated46and a table of coupling constants for ring protons of cisand trans-3-methoxy-cr-ionone has appeared. 39 The shift reagent [Eu(dpm),] has been ' I 2

' I 3

'I4 IL5 I l 6

' '' 'I8

Izo

M. Vecchi, J . Vesely, and G. Oesterhelt, J . Chromatog., 1973, 83, 477. A . H . Goldie and R . E. Subden, J . Chromatog., 1973,84, 192. T. Suzuki and K. Hasegawa, Agric. and Biol. Chem. (Japan), 1974,38, 871. T. A. Moore and P.-S. Song, J . Mol. Spectroscopy, 1974,52, 209. T. A. Moore and P.-S. Song, J . Mol. Spectroscopy, 1974, 52, 224. P.-S. Song and T. A. Moore, Photochem. and Photobiol., 1974, 19, 435. J. Heller and J . Horwitz, ref. 54, p. 57. R. L. Christensen and B. E. Kohler, Photochem. and Photobiol., 1974, 19, 401. M. Tasumi, F. Inagaki, and T. Miyazawa, Chem. Phys. Letters, 1973, 22, 5 1 5 ; F. Inagaki, M. Tasumi, and T. Miyazawa, J . Mol. Spectroscopy, 1974, 50, 286.

Carotenoids and Polyterpenoids

167

used in locating the hydroxy-group of aleuriaxanthin.' The 'H n.m.r. spectrum of mimulaxanthin (31) has been determined at 220 MHz.18 Some I3C n.m.r. data for isomytiloxanthin have been reported.24

Mass Spectrometry. Studies12' with deuterium-labelled car0ten0id.s~~ support the postulated mechanisms' * for in-chain elimination of toluene, xylene, and dimethylcyclodecapentaene and the proposed ranges for the sites of these eliminations. Elimination of a cyclopentadienyl radical (common M - 79 fragmentation) appears to be restricted to the C-11-C-11' range for bicyclic carotenoids. Formal loss of methylbenzyne (90 m.u.) instead of toluene may be general for bicyclic 15,15'-didehydrocarotenoids.'21 Carotenoids such as 7,8,11.12-tetrahydro-$,1,b-carotene(3) with a C-1 1,12 (or 11',12') single bond adjacent to the polyene system commonly lose a 94 m.u. fragment ( l-methylcyclohexa-l,3-diene).3~4Hitherto unexplained variations in the ratio of the ( M - 92) and ( M - 106) ions in the mass spectra of C5,, carotenoids have been rationalized through a consideration of steric factors. This ratio may be used to provide information about the positions of the extra prenyl groups relative to the chromophoric system in acyclic C50 c a r ~ t e n o i d s . ' ~ ~ The mass spectra of a number of 5,6- and 5,8-epoxy-derivatives of retinal, retinyl acetate, and trimethylsilyl retinoate have been presented characteristic features of the spectra are discussed. The major fragmentation pathway of methyl abscisate has been elucidated through the use of a range of 2H- and '*O-labelled analogues. Mass spectra of the labelled species are presented.72 The mass spectra of (E)-a-ionone (53), (E)-retro-y-ionone (158), and (E)-retro-y-ionol (159) are markedly different from those of the corresponding (Z)-isomers. The differences are explained in terms of the difference in ability of the molecular ions to undergo intramolecular ring closure and intramolecular hydrogen transfer reactions. The mass spectra can be used for configuration assignment of the isomers.'25

(158) R = 0 (159) R = H , O H

Circular Dichroism. C.d. data for several ionone, irone, and abscisic acid derivatives have been tabulated, and the data have been used to deduce the absolute configurations of ( + )-a-ionone, ( + )-cis-a-irone, (- )-trans-a-irone, (+)-cis-abscisic acid, and (+)-transabscisic acid.37

12'

lZ3 124

125

J. E. Johansen, A.Eidem, and S. Liaaen-Jensen, Acta Chem. Scand., 1974, B28, 385. U. Schwieter, G. Englert, N. Rigassi, and W. Vetter, Pure Appf. Chem., 1969, 20, 365; W. Vetter, G . Englert, N. Rigassi, and U. Schwieter, in 'Carotenoids', ed. 0. Isler, Birkhauser Verlag, Basel, 1971, p. 189; G . W. Francis, Acta Chem. Scand.. 1972, 26, 1443. G. W. Francis, S. NorgArd, and S. Liaaen-Jensen, Acta Chem. Scand., 1974, 828, 244. R. Reid, E. C. Nelson, E. D. Mitchell, M. L. McGregor, G. q. Waller, and K. V. John, Lipids, 1973, 8, 558. A. van Wageningen, H. Cerfontain, and N. M. M. Nibbering, Rec. Trau. chim., 1974, 93, 43.

168

Terpenoids and Steroids

X-Ray Crystallography. The X-ray crystal structure of retinyl acetate has been described.'

3 Polyterpenoids and Quinones Polyterpenoids-The chemical syntheses of the a-D-mannopyranosyl phosphates of ficaprenol (160)'26 and dolichol (162)'27 have been described. A new highly stereoselective synthesis' 2 8 of all-trans-geranylgeraniol (161) is based on a B i e l l m a n r ~ ' ~ ~ coupling of trans-geranyl thiophenyl ether (164) and trans,trans-8-chloro-3,7-dimethyl2,6-octadienyl benzyl ether (165). Brain polyisoprenols [C90--Clos dolichols (163)]give simple 13Cn.m.r. spectra for the repeating unsaturated isoprene units.130

(162) n = 10 (163) n = 17-20

(160) n = 10 (161) n = 3

Quinones.--The synthesis' 31 and properties'32 of ubiquinone have been reviewed, and a review on the synthesis of fat-soluble vitamins includes a consideration of ubiquinone A new intermediate in ubiquinone biosynthesis in rat liver has been and Vitamin K.133 characterized as 5-desmethylubiquinone-9 ( 166).134?-Irradiation of ubiquinone-9 (167) in tributyrin solution gives a main product with an unchanged ring structure but with a hydroxy-group in the side-chain.13'

(166) R = H (167) R = M e 0

The mass spectra are illustrated and some n.m.r. data presented for the partially saturated menaquinones MK-8(II-H2) (168) and MK-9(II-H,) (169) from Breuibacteriurn lZh lZB '29 130 I3l

132 '33 34 135

C. D . Warren and R . W. Jeanloz, Biochemistry, 1973, 12, 5031. C. D . Warren and R . W. Jeanloz, Biochemistry, 1973, 12, 5038. L. J. Altman, L. Ash, and S. Marson, Synthesis, 1974, 129. J. F. Biellmann and J. B. Ducep, Tetrahedron Letters, 1969, 3707; Tetrahedron, 1971, 27, 5861. W. C. Breckenridge, L. S. Wolfe, and N. M. K. Ng Ying Kin, J . Neurochem., 1973, 21, 1311. M. Kawada, M. Watanabe, and I. Imada, Takeda Kenkyusho Ho, 1 9 7 3 , 3 2 , 9 1 . E. A. Obol'nikova, Kofermenry, 1973, 117. G. I . Samokhvalov, Vitam. Vitam. Prep., 1973, 189. R. M. Houser and R. E. Olson, Life Sci., 1974, 14, 121 1 . E. Bancher, J. Washuttl, and R. Schiffauer, Monatsh., 1974, 105, 7 1 .

Carotenoids and Polyterpenoids

169

species.' 36 Mass spectrometry shows that a menaquinone isolated from Propionibacterium arabinosum is a tetrahydro-MK-9, probably MK-9( I-Hz,III-HZ)( 70).137 0

(168) n (169) n (170) n

= = =

1,m = 6 l,m = 7 2,m = 6

By degradation of the dihydromenaquinone MK-9(II-H2)from Mycobacterium phlei and correlation of a side-chain fragment with (R)-(+)-citronello1 the absolute configuration (7's)of the saturated isoprene unit was e ~ t a b l i s h e das ' ~ (171), ~ i.e. identical with that found in the corresponding isoprene units of phytol and phylloquinone.

136

'

37

138

T. Kanzaki, Y . Sugiyama, K . Kitano, Y. Ashida, and I. Imada, Biochim. Biophys. Acra, 1974, 348. 162. N. Sone, J . Biochem. (Japan), 1974,76, 133. R. Azerad and M . - 0 . Cyrot-Pelletier, Biochimie, 1973, 55, 591.

Biosynthesis of Terpenoids and Steroids BY D. V. BANTHORPE AND 6 . V. CHARLWOOD

1 Introduction Biosynthesis in the anabolic sense is here reviewed. The expanding study of microbial degradation and modification of terpenoids (especially steroids) is excluded, as is the large literature on clinical and physiological aspects of steroid metabolism. Hypothetical biogenetic schemes to new (and sometimes not-so-new) compounds are not mentioned unless (as is rarely the case) they incorporate novel features. Little progress has been made on the development from higher plants of tissue cultures and cell-free systems that can sustain terpenoid biosynthesis. The long-hopedfor methodology for such techniques-perhaps the ultimate tools of biosynthetic investigation- seems as distant as ever. Nevertheless much has been achieved with in vivo and limited in vitro systems. However, it is extremely dismaying to observe how often biosynthesized products are not purified to constant specific radioactivity, isotope balances are not established, and the radioactivity in a (often small) fragment of a molecule is measured and conclusions are drawn as to the content and distribution of tracer in the unexamined truncated part. These shortcomings are due to an amazing confidence on the part of many workers that g.1.c. or t.1.c. fractions (often from a single column or plate) are radiochemically pure and, in the last case, to a neglect of the possibility of asymmetric labelling consequent upon compartment effects or differing sizes of endogenous metabolic pools. Duplication of publications and unnecessary splitting of work into parts for periodic release are also rife. The fragmentary nature of much of the work is reflected in apparently unrelated snippets that have to be included in any review of the present type that covers only one year’s work. Guidelines on such matters for editors and referees are surely long overdue. A new textbook with detailed chapters on the biosynthesis of all classes of terpenoids’ and an outstanding review’ of rarely considered aspects of the biochemistry and physiology of lower terpenoids have appeared, as have reviews on stereochemical aspects of the action of certain enzymes involved in steroid~genesis.~.~

2 Acyclic Precursors Although the terpenoids and fatty acids of perfused rat liver are formed exclusively in the cytoplasm and mitochondria respectively, they share a common pool of acetyl

’

‘Phytochemistry’, ed. L. P. Miller, Van Nostrand-Reinhold, New York, 3 vols., 1973.

’ W. D. Loomis and R. Croteau, Recent Ad[,. Phyrochem., 1973, 6, 147 (91 references). J. W . Cornforth, Tetrahedron, 1974, 30, 1515 (44 references). J. W. Cornforth in ‘Biosynthesis and its Control in Plants’, ed. B. V. Milborrow, Academic Press, London, 1973, p. 171 (9 references).

170

171

Biosynthesis of'Terpenoids and Steroids

coenzyme A;5 nevertheless isotopic equilibrium between the two compartmental sites of synthesis is not always achieved.6 The use of specific inhibitors (kynurenate, avidin) coenzyme A (HMGhas confirmed last year's findings that 3-hydroxy-3-methylglutaryl CoA) (1) involved in terpenoid biosynthesis did not arise to any significant extent from the malonyl coenzyme A pathway? The properties of acetoacetyl coenzyme A synthetase have been described.' Part of the carbon skeleton of mevalonate (MVA) (2) has been shown to be utilized for the biosynthesis of fatty acids and ketone bodies in the brain, cord, and skin of rat.*19 It is suggested that label from [2-I4C]MVA is converted into HMG-CoA uia trans-methylglutaconyl coenzyme A (5) (Scheme 1) and that HMG-CoA is then cleaved

-omSCoA L

1

nSCoA 2

CoASH OPP

= coenzyme A = pyrophosphate

Scheme 1

by a specific lyase to yield [14C]acetoacetate (6), which then becomes a precursor for the labelled products in the appropriate tissues. A direct reversal of the step (1)- (2) was considered unlikely. This shunt mechanism links the intermediates of mevalonate and leucine metabolism and may play a role in the regulation of sterol biosynthesis in animals. The incorporation of low but significant amounts of tracer from [2-14C]MVA into a fungal polyketide" also indicates the existence of a pathway for the degradation of MVA to acetate.

'

lo

K. Decker and C. Barth, MoI. CeIIuIar Biochem., 1973, 2, 179. J. M. Dietschy and J. D. McGarry, J . Biol. Chem., 1974, 249, 52. M. M. Dedyukina, E. V. Sharkova, and N. N. Euiyaev, 'Mitokhondrii Biokhim. Ui'trastrukt., Mater. Vses. Simp. Biokhim. Mitokhondrii 7th 1971', ed. S. E. Severin, Nauka, Moscow (publ. 1973), p. 45 (Chem. A h . , 1974, 80, 92474). J. Edmond and G . Popjak, J . Biol. Chem., 1974, 249, 66. J . Edmond, J . Biol. Chem., 1974, 249, 72. J . A. Steele, J . R . Lieberman, and C. J. Mirocha, Canad. J . Microbiol., 1974, 20, 531.

172

Terpenoids and Steroids

The acetate units from which MVA is constructed may be effectively obtained by degradation of the side-chain of endogenous cholesterol' or from citrate by the action of ATP-citrate-oxaloacetate lyase. Tracer from [14C]glycine was appreciably (ca. 0.04%) incorporated into squalene and sterols in yeast or rat liver preparations, presumably as a result of breakdown to one-carbon units.13 This may implicate the protein component of the diet (in addition to the intakes of carbohydrate and fat) in steroidogenesis and hence in cardiovascular disease in higher animals. Clinical interest has stimulated much work on the control of steroidogenesis and in particular on the central role of HMG-CoA ( l).14 Several approaches have convincingly demonstrated that a transient acetyl derivative (possibly a thioester) of HMG-CoA synthetase is an intermediate in the condensation of acetyl coenzyme A with acetoacetyl coenzyme A in yeast,' and this enzyme is apparently specifically inhibited by the antibiotic cerulenin,16 which is known to be a potent inhibitor of steroid synthesis. HMG-CoA synthetases from the cytoplasm and mitochondria of liver (involved in steroidogenesis and ketogenesis respectively)are of similar size (ca. lo5 dalton) and comprise two sub-units, but they are respectively stimulated and inhibited by Mg2+,and are quite distinct immunologically.' A searching study of the substrate stereochemistry of HMG-coenzymeA synthetase from yeast hasappeared.I8 (R)-and(S)-[2H 3Hl]Acetates were converted into coenzyme A thioesters and each of these was enzymically condensed with acetoacetyl coenzyme A. The HMG samples thus formed were chemically reduced to (3R)-mevalonates, which in turn (after admixture with [2-14C]MVA)were converted into cholestrol by a rat liver preparation. The cholesterol was finally degraded microbially to androsta-l,4-diene-3,17-dione.When the synthesis and degradation of cholesterol were carried out with authentic specimens of (2R)- and (2S)-[2-3Hl]MVA it was found that androstadienedione had lost essentially all tritium derived from (2s)-MVA but had retained nearly all the tracer (relative to 14C)from the (2R)-isomer. In the event the androstadienedione derived from the (R)-acetate showed a loss of more than half of the tritium, whereas that obtainkd by the same procedure from the (S)-acetate lost less than half. It was concluded that the reaction on HMG-CoA synthetase was stereospecific and was associated with an intramolecular hydrogen isotope effect ;if this

'

I'

" l4

Is l6 l7

'

R . A. Davis, P. Coan, and F. Kern, Fed. Pror., 1974, 33, 1573. I . Oguni and 1. Uritani, Plant. Cell. Physiol., 1974, 15, 179. A. K . Bose and B. L. Hungund, Experientia, 1973, 29, 939. M. E. Dempsey, Ann. Rev. Biochem., 1974, 43, 967 (169 references). B. Middleton and P. K . Tubbs, Biochem. J., 1974, 137, 15. T. Ohno, T. Kesado, J. Awaya, and S. Omura, Biochem. Biophys. Res. Comm., 1974,57, 1 1 19. K . D. Clinkenbeard and W. D . Reed, Fed. Pror., 1974, 33, 1426. J. W. Cornforth, G. T. Phillips, B. Messner, and H. Eggerer, European J . Biochem., 1974, 42, 591.

173

Biosynthesis of Terpenoids and Steroids

effect was normal (kJJkD > 1) the condensation must have proceeded with inversion of configuration at the methyl group. Thus (4S)-[4-2H1,4-3H,]HMG-coenzyme A (8) and (2S,3R)-[2-2H1,2-3Hl]MVA (9) were the major products from (R)-C2Hf,'H1]acetyl coenzyme A (7). Much interest has centred on HMG-CoA reductase-the enzyme catalysing the essentially irreversible step to form MVA that is believed to be unique to terpenoid synthesis and is probably the rate-limiting step of the sequence. The hepatic enzyme is particulate, but certain solubilized preparations did not show the previously reported property of being inactivated on cooling to 4"C.19 However, other workers have obtained purified samples (molecular weight ca. 2 x lo5 dalton) that were cold' The reductase from Neurospora crassa had similar properties.2 The activity of the hepatic enzyme is subject to feed-back control and its level was depressed in vivo by feeding c h o l e s t e r 0 1 ~ or ~ * bile ~ ~ a c i d ~ , by ~ ~fractions . ~ ~ from serum27 or milk2* (possibly carriers of cholesterol?), and by c - A M P , ~glucagon, ~ and hydroc~rtisone.~' In contrast, and certain drugs21,23,3 stimulated the activity. There was also some evidence for cytoplasmic factors (proteins?) that regulated the enzyme An excellent discussion3 of the significance of feeding experiments in elucidating putative feedback mechanisms in general has much relevance to most of these studies. The general picture is that there must be significant hormonal control of steroidogenesis in vivo, perhaps mediated by the pituitary,32 and it may be significant that hyperinsulinism has been implicated in the incidence of vascular diseases. The two-step reduction of HMG-CoA to MVA mediated by the above reductase involves the notional formation of mevaldate (lo), possibly as its hemithioacetal with

(10)

coenzyme A in an enzyme-bound form. However, mevaldate reductase has been claimed to be present in the cytosol of rat liver and was believed to react uniquely with free l 9

*' 22

23 24

25 26

27

29

30 31

32

33 34

35

M. E. Ackerman, W. L. Redd, and T. J. Scallen, Biochem. Biophys. Res. Comm., 1974, 56, 29. H. Rudney, D . Abramson, D. Brady, J. Chow, and M. J. P. Higgins, Fed. Proc., 1974, 33, 1573. M. J . P. Higgins, D. Brady, and H. Rudney, Arch. Biochem. Biophys., 1974, 163, 271. R . L. Imblum and V. W. Rodwell, J . Lipid Res., 1974, 15, 21 1 . P. A. Edwards and R. G . Gould, J . Biol. Chem., 1974, 249, 2891. M. Higgins and H. Rudney, Nature New Biol., 1973, 246, 60. S. Shefer, S. Hauser, V. Lapar, and E. H . Mosbach. J . Lipid Res., 1973, 14, 400, 573. W. M. Bortz, L. Steele, L. Arkens, and B. Grundhofer, Biochim. Biophys. Acta, 1973, 316, 366. M . S. Brown, S. E. Dana, and J. L. Goldstein, J . Biol. Chem., 1974, 249, 789. W. Boguslawski and J . Wrobel, Nature, 1974, 247, 210. Z. H. Beg, D. W. Allmann, and D. M. Gibson, Biochem. Biophys. Res. Comm., 1973,54, 1362. C. M. Nepokroeff, M. R. Lakshmanan, G. C. Ness, R. E. Dugan, and J. W. Porter, Arch. Biochem. Biophys., 1974, 160, 387. S. J. Bhathena, J. Avigan, and M. E. Schreiner, Proc. Nut. Acad. Sci. U . S . A . , 1974, 71, 2174. R. E. Dugan, G. C. Ness, M. R. Lakshmanan, C. M. Nepokroeff, and J. W. Porter, Arch. Biochem. Biophys, 1974, 161, 499. A. Sanghvi, C. Wight, R. Balachandran, I. Frantz, M . Ener, and L. Taddeini, Life Sci., 1974, 14, 1679. J . Berndt and R. Gaumert, Z . physiol. Chem., 1974, 355, 905. N . Stebbing, Bucferiol. Rev., 1974, 38, 1 (122 references).

174

Terpenoids and Steroids

mevaldate. This protein has now been purified and shown to be a relatively nonspecific aldehyde reductase with NADH and NADPH requirement^.^^ The conclusion was that free mevaldate (which has been reported in certain tissues) is of no direct biosynthetic consequence and is probably formed by salvage breakdown of the enzyme-bound analogues. The level of HMG-CoA in liver may be partly controlled by degradation to acetoacetate (cf. Scheme 1). This step involves a specific lyase, and free HMG must be activated by transfer of coenzyme A from succinyl coenzyme A before degradation ; 3 7 the source of the free HMG was not identified. MVA kinase from bean and maize has been further investigated; kinase activity from chloroplast preparations had a pH optimum of 7.5, whilst the enzyme from leaves showed high activity at pH 5.5. The latter activity was much reduced by endogenous (and ubiquitous) phosphatases and may have been missed in earlier s t ~ d i e s . ~ * , ~ ~ Methods have been described for the isolation of MVA kinase from the chloroplasts of higher plants,40 and the high-pH kinase from Pinus pinaster seedlings utilizes ATP but not other nucleoside triphosphates as phosphate donor.41 An interesting review of enzymic phosphoryl-group transfer has appeared.42 Properties of partially purified All kinase from rubber latex, yeast, liver, and two higher plants have been preparations had molecular weight 95 000-104 000 dalton as determined by gel filtration and sucrose density-gradient centrifugation. MVA-activating enzymes in hazel in iris,45and in homogenates from tissue ~ ~ been studied. cultures46and cell-free preparations of Nepeta ~ a t a r i ahave More details and mechanistic speculations have appeared for the conversion of (1 I), a homologue of isopentenyl pyrophosphate (IPP) (3), into (12), (13), and (14) that is catalysed by IPP-isomerase from pig liver.48 The only IPP homologue of the type (15; n = 1, 3, or 4) that was accepted by prenyl transferase from the same source was 4-methylpent-4-enyl pyrophosphate (15 ; n = 3): this reacted with geranyl pyrophosphate (GPP) to form the cis-isomer of a non-allylic homofarnesyl pyrophosphate (16). Normally the enzyme produces 2-trans-6-trans-farnesylpyrophosphate (FPP), and a model of the geometry of the active site was proposed to accommodate the introduction of the unexpected cis-double bond.49

L - LOPP + L,,,,, + Lpp

/

36 37

38 39

40 41

42

43 J4

" 46 47

4M 49

OPP

A. S. Beedle, H . H . Rees, and T. W . Goodwin, Biochem. J . , 1974, 139, 205. R. Deana, R. Meneghello, L. Manzi, and C . Gregolin, Biochem. J . , 1974, 138, 481. H . M. Hill and L. J. Rogers, Phytochemistry, 1974, 13, 763. P. R. Shewry and A. K . Stobart, Plant. Sci. Letters, 1973, 1, 473. E. Garcia-Peregrin, A. Coloma, a n d F. Mayor, Plant. Sci. Letters, 1973, 1, 367. D . Suarez, E. Garcia-Peregrin, a n d F. Mayor, Phytochemistry, 1974, 13, 1059. J . F. Morrison a n d E. Heyde, Ann. Rev. Biochem., 1972, 41, 29 (239 references). J . C . Gray and R . G . 0. Kekwick, Arch. Biochem. Biophys., 1973, 159.458. P. R. Shewry, N. J. Pinfield, a n d A. K. Stobart, Phyrochemistry, 1974, 13, 341. G . L. Staby, W. P. Hackett, and A. A. de Hertogh, Plant Physiol., 1973, 5 2 , 416. M. R. Downing and E. D . Mitchell, Fed. Proc., 1974, 33, 1446. M. R . Downing and E. D. Mitchell, Phytochernistry, 1974, 13, 1419. T. Koyama, K . Ogura, and S . Seto, J . Biol. Chem., 1973, 248, 8043. K. Ogura, A. Saito, a n d S . Seto, J . Amer. Chem. Soc., 1974, 96, 4037.

Biosynthesis of’ Terpenoib and Steroids

175

Protein fractions from cotton root converted neryl pyrophosphate (NPP) and IPP into 2-cis-6-cis-FPP and (possiblyj 2-trans-6-cis-FPP, whereas condensation of G P P and I P P yielded 2-trans-6-trans-FPP and (possibly) the 2-cis-6-tr~ns-isomer.~Kinetic studies indicated that two enzymes were involved, each specific for one monoterpenoid isomer, and no interconversion of the FPP isomers could be demonstrated. If the products have been correctly assigned this is the first demonstration that all four isomers of F P P can be synthesized in plant tissue. Different skeletal classes of sesquiterpenoid can be formally derived from either 2-trans-6-trans-FPP or its 2-cis-6-trans-isomer. Soluble enzyme systems from tissue cultures of Andrographis panictdata produce both isomers, and previous 14C-3H studies have suggested that the two farnesols* were interconverted via a redox scheme involving their aldehydes. (1R)-[1-3H,]-2-trans-6trans-farnesol and (1R)-[ 1-3H,]-2-cis-6-trans-farnesol have now been prepared by exchange of the appropriate farnesol with 3 H 2 0 using horse liver LADH-NAD+NADH diaphorase, and the corresponding (1s)-isomers were obtained by the same method by exchange of the corresponding [l-3H,]farnesol with H 2 0 . Using these tritiated products it was possible to show that the system from A . paniculata converted 2-trans-6-trans-FPP into its 2-cis-6-trans-isomer with stereospecific loss of the 1 -pro-S hydrogen, whereas the isomerization of the 2-cis-6-trans-isomer into the 2-trans-6-transproduct involved loss of the 1-pro-R hydrogen.’ Incubation of the 2-trans-epoxyfarnesol (1 7) with the fungus Dreschlera sorokiniana yielded the 2-cis-isomer together with small amounts of both 2 4 s - and 2-trans-epoxyfarnesals : this provides more evidence for the redox route of i s o m e r i z a t i ~ n .Stereochemical ~~ details of the ringopening of both enantiomers of the epoxide (17) by the fungus Helminthosporium sativurn have been elucidated using 80-labelled substrates.’

Presqualene alcohol pyrophosphate (1 8) has been detected only in biosynthetic systems that were starved of reduced pyridine nucleotides, and hence the possibility exists that the compound was only an artefact. The time course of formation of (18) and

* In this and other studies of prenol biosynthesis, the free alcohols were recovered for characterization and assay. Presumably in all cases these were initially formed, in uiuo or in vitro, as pyrophosphate esters.

’’ 50 52

53

S. R . Adams and P. F. Heinstein, Phytochemistry, 1973, 12, 2167. K . H. Overton and F. M. Roberts, J.C.S. Chem. Comm., 1974, 385. L. W. Broekhoven, M. W. van Maarschalkerweerd, R. J. J. Lousberg, and C. A. Salemink, Tetrahedron Letters, 1974, 2909. Y. Suzuki, K . Imai, and S. Marumo, J . Amer. Chem. Soc., 1974, 96, 3703.

Terpenoids and Steroids

176

squalene from FPP in intact liver and in a yeast microsomal preparation was, however, entirely in accord with a precursor-product relationship and was considered to suggest strongly that the compound was a normal intermediate in squalene bio~ynthesis.’~ An examination of the stereochemistry of the biosynthesis of presqualene alcohol pyrophosphate was also held to support the view that it is an obligatory intermediate.’ However, the possibility remains that the compound lies on a side-branch of the metabolic pathway. This illustrates a general (and often ignored) problem in the identification of obligate intermediates of metabolism. A compound C could be related to the natural pathway A -+ D as in Scheme 2a or 2b ; proof that C lies on the main pathway (2b) can only be obtained by demonstrating that one enzyme catalyses the step B-+ C and another the step C -+ D and also that the direct step B -+ D is insignificant.

’

A--+B--*D

C

bA-+B--+C+D Scheme 2

The (3S)-isomer of 2,3-oxidosqualene has been shown by circular dichroism to be utilized in the biosynthesis of lano~terol.’~An enzyme system from pig liver is able to accept 8-n-butyl-GPP and 10,ll-dihydro-FPP to give the corresponding squalene analogues, although these substrates are some four-fold less effective than FPP.” Further model systems for the cyclization of terminal epoxides of terpenoids (such as the 2,3-oxidosqualene--+lanosterol conversion) have been studied,’ and similar biocyclizations have been investigated from the viewpoint that the stereospecificity of the process in vico may be controlled by stereoelectronic factors rather than by the geometry of binding of the acyclic precursor to the enzyme surface.59 Model systems have also been studied for the formation of the likely cyclopropyl and cyclobutyl intermediates of terpenoid synthesis ( v i z . chrysanthemyl, presqualene alcohol, and prephytoene pyrophosphates) and for the carbonium-ion rearrangements of such species.60-62 Molecular orbital calculations have been made for both a concerted and a step-wise ‘zipper’ mechanism for the formation of lanosterol from ~ q u a l e n e . ~ ~ 3 Monoterpenoids

The incorporation of radioactivity from acetate and mevalonate into the volatile oil components of S ~ l v i and a ~ ~Pinus6’ seedlings has been demonstrated in a rudimentary 54

55 56

57 58 59

F. Muscio, J . P. Carlson, L. Kuehl, and H. C . Rilling, J . Biol. Chem., 1974, 249, 3746. H . I . Ngan and G. Popjak, Fed. Proc., 1974, 33, 428. T. Shishibori, T. Fukui, and T. Suga, Chem. Letters, 1973, 1137. T. Koyama, K. Ogura, and S. Seto, Chem. Letters, 1974,529. E. E. van Tamelen, R. G. Lees, and A. Grieder, J . Amer. Chem. Soc., 1974, 96, 2255. W. S. Johnson, K. Wiedhaup, S . F. Brady, and G. L. Olson, J . Amer. Chem. Soc., 1974, 96, 3979.

6o 6’

62 63 64 65

T. Cohen, G. Herman, T. M. Chapman, and D. Kuhn, J . Amer. Chem. SOC.,1974, 96, 5627. C . D. Poulter, J . Agric. Food. Chem., 1974, 22, 167. C. D. Poulter, 0. J . Muscio, and R. J. Goodfellow, Biochemistry, 1974, 13, 1530. R. Gleiter and K . Mullen, Helv. Chim. Acta, 1974, 57,823. G . Verzar-Petri and M. Then, Plunta Medica, 1974, 25, 366. A. Machtldo, E. Garcia-Peregrin, and F. Mayor, Plant Sci. Letters, 1974, 2, 83.

Biosynthesis of Terpenoids and Steroids

177

fashion. The formation of geraniol and citronellol from [2-14C]MVA by PeIargoniurn roseurn provides more examples of the well established phenomenon of asymmetric labelling whereby the major part (ca. 80% in these cases) of incorporated tracer resides in the IPP-derived moiety.66 Chrysanthemum monocarboxylic acid (1 9) was formed from (4R)-[4-3H,]MVA by Chrysunthemum cinerariaefolium with 0.4 "/, incorporation of tracer, whereas no label was incorporated after feeding the (4s)-isomer :6 this suggested that the pro-4S hydrogen of mevalonate was lost in the I P P -+ DMAPP conversion here as in other plant systems that have been studied. In addition, partial degradation revealed that most (>95 %)of the incorporated tracer resided in the moiety a of (19). This result contradicts the symmetrical pattern of labelling ( C , moieties carrying equal label) found in 1963 for the same compound formed from [2-l4C]MVA by C. cinerariaefoliurn, and a reinvestigation using the latter precursor (rather than a precursor containing the potentially labile 3H) is urgently needed.

The more recent p ~ b l i c a t i o nsuggests ~~ that fragment b of (19) was derived from 3,3-dimethylacrylic acid, but little evidence has yet been obtained for a role of this acid as a precursor of DMAPP in terpenoid biosynthesis in general. The observation that [14C]leucine was incorporated in a yield of 0.004% into linalool in Cinnamornum camphora such that 80 % of the tracer occurred in the DMAPP-derived moiety was held to be a 'proof of the non-mevalonoid origin of this moiety, and 3,3-dimethylacryl coenzyme A was proposed as the direct precursor of DMAPP.68 These results certainly do not constitute a proof of this hypothesis ;position-specific transfer of 14Cfrom leucine to the DMAPP-derived moiety was not demonstrated, so that these observations may well be the consequence of degradation of the amino-acid to C-2 units followed by their re-incorporation into MVA under conditions (for which there is evidence from other s t ~ d i e s ~ , ~of~compartmentation ,~') of acetate pools. The elegant synthesis of camphor (21) by cyclization of the enol ester (20)71 will undoubtedly stimulate studies using analogues of (20) in uivo, as there is yet no conclusive evidence of the exact nature of the monocyclic precursor (assumed to be the

66 67

68 69 'O 71

T. Suga and T. Shishibori, Bull. Chem. SOC.Japan, 1973, 46, 3545. G . Pattenden and R. Storer, Tetrahedron Lerters, 1973, 3473. T. Suga, T. Hirata, T. Shishibori, and K . Tanga, Chem. Letters, 1974, 189. G . J. Rangi, T. Liang, and J. J. Blum, J . Biol. Chem., 1973, 248, 8064. E. F. Elstner, R . J . Suhadolnik, and A. Allerhand, J. Biol. Chem., 1973, 248, 5385 J . C. Fairlie, G . L. Hodgson, and T. Money, J.C.S. Perkin I, 1973, 2109.

Terpenoids and Steroids

178

biogenetic equivalent of a-terpineol) of the bornane skeleton. The o b ~ e r v a t i o nthat ~~ in Lavandula species fenchone is always produced in an optically pure form whereas the co-occurring camphor has wide variations in specific rotation may mean that the latter is derived directly or in parallel to a-pinene, which (unlike fl-pinene)generally occurs as a mixture of enantiomers. Little progress has been reported in the development of cell-free systems that can sustain monoterpenoid synthesis, but microsomal preparations from Vinca rosea seeds converted geraniol and nerol into their 10-hydroxy-derivatives and thus reproduced one of the first steps in the formation of the monoterpenoid moiety of the indole alkaloids.73 A variety of irregular (i.e.non-isoprenoid) monoterpenoids with novel skeletons have been and a model for the biosynthesis of artemisia ketone involving a bis(dimethylal1yl)sulphonium ylide has appeared. 7 8 More examples have been recorded where the terpenoids of a host can serve as precursors of pheromones in insects : 7 9 8 1 thus 5-hydroxymyrcene, the aggregating pheromone of a beetle species, is produced by the insects from myrcene obtained from their food plant. Another curious finding is that a fractionation of hydrogen isotopes occurred (to the extent of 50 p.p.m.) during biosynthesis of menthol and pulegone.82 4 Sesquiterpenoids

Reviews on the biochemistry of s e s q u i t e r p e n ~ i d sand ~ ~ *of~ sesquiterpenoid ~ lactones in the Cornpositae8' are available. Synthesis of various classes of sesquiterpenoid by cyclization of campherenone (22) may have important implications for intermediacy of bisabolanes in biosynthesis,86 and interesting speculations as to the source of naturally occurring furanoerem~philanes,~cuparanes, and related skeletal types' have appeared.

(22)

Previous conclusions as to the construction of the skeleton (26) of the trichothecane group of fungal metabolites have been confirmed and details of the stereochemistry have been explored. Feeding [6-3H,12,13-* 4C]-2-trans-6-trans-FPPto Myrotheciurn species 72 73

74 75

76 77

" "

83 84 85

Mh 87

R. Granger, J . Passet, and G. Teulade-Arbousset, Compt. rend., 1973, 276, D , 2839. K . M. Madyastha, T. D. Meehan, and C. J. Coscia, Fed. Proc., 1974, 33, 1446. F. Bohlmann, C. Zdero, and U . Faass, Chem. Ber., 1973, 106, 2904. S. J. Torrance and C. Steelink, J. Org. Chem., 1974, 39, 1068. A . F. Thomas and M . Ozainne, J.C.S. Chrm. Comm., 1973, 746. E. H . Hoerger, Proc. Montana Acad. Sci., 1 9 7 3 , 3 3 , 9 7 (Chem. A h . , 1 9 7 4 , 8 1 , 4 9 852). 9. M. Trost and W. G. Biddlecom, J. Org. Chem., 1973, 38, 3438. P. R. Hughes, J. Insect Physiol., 1974, 20, 1271. P. R . Hughes, Nuturwiss., 1973, 60, 261. A. J. Renwick, P. R . Hughes, and T . D. Ty, J. Insect Physiol., 1973, 19, 1735. J . Bricout, L. Merlivat, and M. Koziet, Compt. rend., 1973, 277, D , 885. G . Riicker, Angew. Chem. Inrernat. Edn., 1973, 10, 793 (173 references). G . Riicker, Deut. Aporh.-Ztg., 1973, 113, 139 (62 references). T. A. Geissman, Recent Adv. Phytochem., 1973, 6, 65 (23 references). G . L. Hodgson, D. F. MacSweeney, and T. Money, J.C.S. Perkin I, 1973, 2113. F. Bohlmann, C. Zdero, and M . Grenz, Chem. Ber., 1974, 107, 2730. S. Ito, K . Endo, and H. Narita, Tetrahedron Letters, 1974, 1041.

Biosynthesis of' Terpenoids and Steroids

179

yielded verrucarol (27; R' = H,, R2 = OH, R3 = H, R4 = H), the sesquiterpenoid moiety of the antibiotics verrucarin and roridin, in which the isotope ratio was preserved and the tritium probably resided at C-2. This result indicated an intramolecular hydride shift (24)- (25), such as had been previously proposed in the formation of other trichothecanes, and also proved that the insertion of the oxygen function at C-2 proceeded with retention of c ~ n f i g u r a t i o n . Studies ~~ using model compounds demonstrated that the exo-4P hydrogen of the skeleton (25) was readily exchangeable, and this fact was used to show that the corresponding atom in calonectrin (27; R' = H 2 , R2 = R3 = OAc, R4 = H) was derived from a pro-2R mevalonoid hydrogen and that hydroxylation at C-4 in trichothecolone (27; R' = 0, R2 = R 3 = H, R4 = OH) also involved retention of config~ration.'~These results are consistent with the folding of FPP (23)depicted in Scheme 3. An alternative conformation for the acyclic precursor is

1 1

(28); this had been suggested in early work, but detailed degradation of trichothecolone biosynthesized from (4R)-[4-3H,]MVAhad made the route unlikely (1972) and this alternative has been finally disproved by a 13Cn.m.r. study." The spectrum of trichothecolone biosynthesized from [2-'3 C ] M V A contained enhanced signals corresponding to C-4, C-14, and C-8 which proved that FPP had folded as in (23).

*' 90

91

D. Arigoni, D. E. Cane, B. Muller, and C. Tamm, Helu. Chim. Acta, 1973, 56, 2946. R . Evans, J. R . Hanson, and T. Marten, J.C.S. Perkin I, 1974, 857. J . R . Hanson, T. Marten, and M. Siverns, J.C.S. Perkin I, 1974, 1033.

Terpenoids and Steroids

180

*1R 0 (29)

I R' I1 R ' I11 R'

= = =

0,R2=H H,OH, R 2 = COC,H,, 0 , R 2 = COCH(OH)C,H,,

The tricyclic antibiotics coriolins I, 11, and I11 (29) are generally considered to be formed from FPP uia a humulene-type intermediate (30). However, there are several feasible pathways from (30) to the basic skeleton (31) which differ in the type and degree of concertedness of the cyclizations (Scheme 4),and there are analogies for such pathways in the formation of other sesquiterpenoids. The I3Cn.m.r. spectrum of the coriolins isolated after feeding [ 1,2-' 3C]acetate to Coriolus consors showed six C-C couplings in the tricyclic moiety, and this observation could only be accommodated if

Qr'( H

(31)

I

i H c

1

Scheme 4

/

1

Biosynthesis o j Terpenoids and Steroids

181

route a was followed.92 The closely relatedcompounds complicaticacid(34 ;R', R2= 0) and hirsutic acid C (34; R' = OH, R2 = H) have been found in Stereum cornplicatum and shown to be of mevalonoid origin.93 Analyses of the 13Cn.m.r.spectra of these metabolites biosynthesized from [ 1-' 3C]- and [2-' 3C]-acetate by fungal cultures were consistent with (32) being an intermediate on the pathway ; however, it was pointed out that the latter could arise from (33)via route c as well as by route a, although the sequence (33)-P (32) was considered unlikely on other grounds.94 Partial degradation and determination of the isotope ratios in dendrobine (35) biosynthesized by Dendrobiurn nobile from [2-'4C,5-3H2]MVA led to the proposal that 3H was transferred from C-1 of farnesol to C-8 in the product (Scheme 5).9s These

T

I

Scheme 5

results reinforce previous suggestions that one of the key steps in the formation of picrotoxanes is the cyclization of germacrane (36) to form the muurolane skeleton (37) and appear to exclude the intermediacy of bisabolanes or compounds with cyclopropyl rings. Three other points arise from this work : the incorporation of tracer (1.4%) was extremely large for a higher plant ;no asymmetry of labelling of the IPP- and DMAPPderived moieties was observed ;and either 2-cis-6-trans-FPP was directly formed from

92

93 94 95

M. Tanabe, K. T. Suzuki, and W. C. Jankowski, Tetrahedron Lerters, 1974, 2271. G. Mellows, P. G. Mantle, T. C. Feline, and D. J . Williams, Phytochemistry, 1973, 12, 2717. T. C. Feline, G. Mellows, R . B. Jones, and L. Phillips, J . C . S . Chem. Comm., 1974, 63. A. Corbella, P. Gariboldi, and G. Jommi, J . C . S . Chem. Comm., 1973, 729.

I82

Terpenoids and Steroids

GPP and IPP or its formation from 2-trans-6-trans-FPP did not involve loss of tracer at C-1 (cf: p. 175). Juvenile hormones of insects possess the structure (38; R’, R 2 = Me or Et). As yet no definite information has been available concerning the construction of the skeleton but it is now reported that of two hormones from a moth, one (38 :R’ = R2 = Me) was labelled by exogenous [‘“Clacetate and [‘“C]mevalonate but not by [ 14C]propionate, whereas the other (38 ; R’ = Et, R2 = Me) was labelled by all three additives. [1-14C]Propionate specifically labelled the C-11 of the farnesane skeleton and it is presumed that a unit derived from homomevalonate (39)was involved.96 Prenyltransferases from

tissue of such diverse sources as fruit, liver, and insects readily synthesize the homofarnesane skeleton from exogenous homo-IPP substrate, and the novel aspects of the biosynthesis of these hormones may be the ability of the insects to produce homomevalonate: there is no justification for the view, based only on the failure to detect incorporation of certain precursors, that the synthetic route to these hormones is ‘significantly different from terpenoid pathways’.97 The experiments involving [’ “Clpropionate also excluded alkylation using S-adenosylmethionine as a means of introducing the ethyl group at C-11. Studies of the formation of similar hormones in cell-free systems from a hornworm larva showed that tracer from [3H]-S-adenosylmethionine was exclusively located in the methyl of the ester Time--incorporation studies have revealed that dehydroipomeamarone (40) was reduced in uivo by sweet potato root to form i p ~ m e a m a r o n e . ~ ~ The biosynthesis of abscisic acid (41)has been reviewed. 1o07101 A cell-freepreparation of lysed chloroplasts from avocado fruit efficiently converted [2-3H2]-and [2-14C]-MVA into (41),’02 and bean and tomato shoots converted [2-’4C]-cis,trans-xanthoxin(42) into (41) in 7-1 1 % yields.lo3 The latter results, together with earlier findings that (42)

D. A. Schooley, K. J. Judy, B. J . Bergot, M. S. Hall, and J. B. Siddall, Proc. N a t . Acad. Sci. U . S . A . , 1973, 70, 2921. 97 A. M. Ajami and L. M. Riddiford, Fed. Proc., 1973, 32, 1382. ‘” D. Reibstein and J . H . Law, Binchem. Binphys. Res. Cnmm., 1973, 55, 266. 9 9 I. Oguni and I. Uritani, Plant Physiof., 1974, 53, 649. l o o B. V. Milborrow, Ann. Rev. Plant Physiol., 1974, 25, 259 (82 references). l o ’ B. V. Milborrow, Recent Adv. Phytochem., 1974, 7 , 57 (95 references). l o ’ B. V. Milborrow, Phyfochemisfry. 1974, 13, 131. Io3 H. F. Taylor and R. S. Burden, J. Exp. Bot., 1973, 24, 873. 96

183

Biosynthesis of' Terpenoids and Steroids

is present in the extracts of many seedlings, suggest that the xanthoxin (presumably derived from oxidative degradation of xanthophylls) is a natural precursor of abscisic acid, although the importance of this route is not fully established. Metabolites of abscisic acid in various plants have been reportedlo4 and as have the physiological factors controlling the biosynthesis of the hormonelo8 and its possible effects on the synthesis of gibberellic acid.lo9 5 Diterpenoids

Formation of phytol from [2-l4C]MVA in homogenates of bean leaves was inhibited by phytyl pyrophosphate, but the feed-back effect did not occur when [1-'4C]IPP was substrate : this supports previous conclusions that phytyl pyrophosphate is a potent inhibitor of mevalonate kinase. Evidence for regulatory effects of 6-aminolaevulinate and phytol and its pyrophosphate on the incorporation of tracer from MVA, IPP, and phytol into chlorophyll was also found.' l o A limonoate deliydrogenase was detected in tissue slices of oranges : this may be the initial enzyme of at least one pathway for the degradation of limonoates that occurs during maturation of the fruit.' The C,, lactones (43; R = H or Me) obtained from mould cultures could be theoretically derived from either FPP or geranylgeranyl pyrophosphate. Feeding experiments with [2-' 3C]acetate and [3H,14C]MVA have shown that the compounds were constructed from four molecules of mevalonate with the loss of four pro-S mevalonoid hydrogens and were probably the products of degradation of a diterpenoid of the labdadienol series through oxidative cleavage between C- 12 and C- 13." Micrandrols [(45) is typical member] occur in the trunk wood o f Micrandropsis scleroxylon, and the nature and position of their ring substituents suggest a mevalonoid origin, possibly from a diterpenoid such as sandaracopimaradiene-3P, 18-diol(44),rather than a derivation from shikimate.'13 The metabolism of phytanic acid (46) and its homologues has also been studied.' 14,' l 5

'

(43) '04 lo' 'Oh lo' 'OH

I10 'I'

'I2 'I3

'I4

(4-4)

J. A. McWha and J. R . Hillman, Pfanta, 1973, 110, 345. R. Rudnicki and J. Czapski, Ann. Bot., 1974, 38, 189. D. C. Walton, B. Dorn, and J. Fey, Planta, 1973, 112, 87. D. C. Walton and E. Galson, Plant Physiof., 1974, suppl., 70. B. V. Millborrow and D. R. Robinson, J. Exp. Bor., 1973, 24, 537. I . D. Railton and P. F. Wareing, Planta, 1973, 112, 65. R. B. Watts and R. G. 0. Kekwick, Arch. Biochem. Biophys., 1974, 160, 469. S. Hasegawa, V. P. Maier, and R. D. Bennett, Phytochemisfrj, 1974, 13, 103. H. Kakisawa, M. Sato, T. Ruo, and T. Hayashi, J.C.S. Chem. Comm., 1973, 802. M. A. De Alvarenga and 0. R. Gottlieb, Phytochemistry, 1974, 13, 1283. A. K. Lough, Prop-. Chem. Fats Lipids, 1973, 14, 1. R. E. Cox, J . R. Maxwell, R. G . Ackman, and S. N. Hooper, Biochim. Biophys. Acta. 1974, 360, 166.

Terpenoids and Steroids

184

C02H

The important plant-growth regulators the gibberellins continue to receive much attention. 6 * l 7 The level of gibberellin increases rapidly in barley seedlings but exogenous MVA is not incorporated;'" a pool of kaurene (47) has been identified in barley seeds and this may be the immediate precursor.' l 9 A pathway of gibberellin biosynthesis in a cell-free system from immature seeds of Cucurbita maxima has been established as identical with that observed in fungi.120 The intermediates between mevalonate and 7a-hydroxykaurenoic acid (50)were identified as kaurene (47),kaurenol (48),and kaurenoic acid (49); (50) was further converted into gibberellin A, aldehyde (51) and gibberellin A,, (52). The sequence was confirmed by demonstrating individual conversions of each intermediate. Modification of the cell-free preparation made possible the conversion of GA, aldehyde and GA, into GA, (53), GA,, (54),GA,, ( 5 9 , and GA,, (561,which, with the exception of(56), have not been found previously in higher plants.'20 The conversion of (51) into GA,, (57), GA, ( 5 8 ) , and GA, (59) by Gibberc~llafujikuroi was shown to involve initial 3-hydroxylation,' 2 1 and fifteen gibberellins (many new) were identified from a fast-producer strain of the fungus.' 2 2

''

(47) R ' (48)R' (49) R ' (50) R'

Me, R' = H C H 2 0 H , R' = H C 0 2 H , R2 = H = C 0 2 H , R2 = OH

=

= =

(51) R 1 = H, R 2 = CHO (52) R' = H, R 2 = COZH (57) R ' = OH, R' = C 0 2 H

C02H (53) R = H (56) R = OH

' ' I 7

I"

'"

(54)R (55) R

= =

H OH

J . Macmillan and R. J. Pryce, ref. 1, Vol. 3, p. 283 (50 references). C. A . West, Ann. Proc. Ph.vtochem. Snc., 1972, 9, 143 (37 references). K. F. Faull, B. G. Coombe, and L. G . Paleg, Austral. J . Plant Physiof., 1974, 1, 199. G. J . P. Murphy and D. E. Briggs, Phytochemistry, 1973, 12. 2597. J . E. Graebe. P. IHedden, P. Gaskin, a n d J. MacMillan, Phyrochemistry. 1974, 13, 1433. J . R . Bearder and J . MacMillan, Phytochrmistry, 1973, 12, 2173. J . MacMillan a n d C. M. Wels, Phytochrrnistry, 1974, 13, 1413.

Biosynthesis of' Terpenoids und Steroids

185

A u.v.-mutant of G.fujikuroi has been found that is unable to convert kaurenal into kaurenoic acid although the latter was completely metabolized to give the same gibberellins as the parent strain.'23 The steps beyond the block were examined by feeding to the mutant substrates that occurred beyond this point in the parent strain,12" and the low substrate specificity of the enzymes beyond the block was illustrated by the conversion of the non-fungal diterpenoid steviol (60) and some of its derivatives into gibberel1i11s.I~~This result suggests that many of the fungal enzymes controlling gibberellin biosynthesis are similar to, if not identical with, those in higher plants ;thus a study of fungal mutants may elucidate the situation in the latter. A further mutant is reported that is blocked for GA, and GA, biosynthesis but not for GA, or GA7.126

CO, H

An alternative approach to block the route to gibberellins has been to use a suitably ~ ~ this method promises to yield substituted synthetic derivative of k a ~ r e n e , 'and further information about substrate selectivity of the enzymes of the pathway. A variety of metabolites of gibberellin have been detected in fungi and plants and various more or less plausible pathways of interconversion have been proposed.' 28-13 123

J. R. Bearder, J. MacMillan, C . M. Wels, M. B. Chaffey, and B. 0. Phinney, Phytochemistrv, 1974, 13, 91 I . J. R. Bearder, P. Hedden, J. MacMillan, C . M. Wels, and B. 0. Phinney, J.C.S. Chem. Comm., 1973, 777.

126

130 13' 13*

133 I 34 135

J. R. Bearder, J. MacMillan, C . M. Wels, and B. 0. Phinney, J . C . S . Chem. Comm., 1973. 778. J. R. Bearder, J. MacMillan, and B. 0. Phinney, Phytochemistry, 1973, 12, 2655. P. R . Jefferies, J. R. Knox, and T. Ratajczak, Phytochernistry, 1974, 13, 1423. I . D. Railton, N. Murofushi, R. C. Durley, and R. P. Pharis, Phytochemistry, 1974, 13, 793. R . C . Durley, I . D. Railton, and R. P. Pharis, Phytochemistry, 1974, 13, 547. I. D . Railton, R. C. Durley, and R. P. Pharis, Phyrochemisrry, 1973, 12, 2351. T. Yokota, S. Yamazaki, N. Takahashi, and Y . Iitaka, Tetrahedron Letters, 1974, 2957. R. C. Durley and R. P. Pharis, Planfa, 1973, 109, 357. Y. Asakawa, K. Tamari, A. Shoji, and J. Kaji, Agric. and Biof. Chem. (Japan), 1974, 38, 719. J. H. Bateson and B. E. Cross, J . C . S : Perkin I , 1974, I 131. A. G. McInnes, D. G. Smith, G. P. Arsenault, and L. C . Vining, Canad. J . Biochern., 1973, 51, 1470.

Irvpenoids and Steroids

186 6 Steroidal Triterpenoids

As in previous years this section deals with the biosynthesis of cholesterol, related steriods, and phytosteIols. whereas the following sections cover the further metabolism of these classes and the remaining triterpenoid systems. The flow of reviews is unabated, r . g . on the biosynthesis of steroids'36 and p h y t o ~ t e r o l s , ' ~39 ~ on relevant enzyme systems,'40~'3' and on the regulation of these processes ;1J,142 unfortunately most cover extremely well-trodden ground. 2,3-Oxidosqualene : lanosterol cyclase from rat brain is inhibited by the hypoThe similar enzyme from hog liver cholesteraemic drug N-dodecylimidazole. can effectively convert terminally modified analogues of the natural substrate (e.g. 2-hydroxy-22,23-oxidosqualene)into the appropriate lanosterol d e r i ~ a t i v e s . ' ~The ~ site(s) of cholesterologenesis in mammals'46 15' and its extent in invertebrates'" 15' are of considerable clinical and phylogenetic interest respectively. Sterol carrier protein (SCP)from liver appears to be a single species (molecular weight (*a.16 000 dalton)and probably occurs in all mammalian tissue and even in protozoa. l 5 However, an SCP from liver microsomes that is claimed to be specific for the conversion of 4,4-dimethyl-A8-cholesterol [steroid numbering in (61)] into polar C 2 , sterols has

-'

1437144

136

137 I38 i 39

I40

I41 142 143 1d 4

14s

146 117

I48 I10

I10 1 5 1

152

I53 154

I5Z I56

15-

E. Heftmann, ref. 1. Vol. 2, p. 171 (217 references). G . A . Bean, Adz>. Lipid Res.. 1973, 1 1 , 193 (178 references). T. W. G o o d w i n , Rrcrnt A h > .Phj~tochem.,1973, 6, 97 (42 references). V. A. Paseshchnichenko a n d A. R. Guseva, Uspekhi B i d . Khim., 1973, 14,254 (221 references). J . L. Gaylor in 'Biochemical Lipids', ed. T. W. Goodwin, M T P International Review of Science, Biochemistry Series One, Vol. 4, Butterworths. London. 1974. p. 1. J . L. Gaylor, A h . Lipid Res.. 1972, 10, 89 (128 references). W. M . Bortz. Mrtaholism, 1973, 22. 1507 (171 references). R . G. Dennick a n d P. D. G . Dean, J. Neurochem., 1974, 23, 261. R. G. Dennick. K. J . Worthington, D. R. A. Bramobich, a n d P. D. G . Dean, J . Nrurochem., 1974.22, 1019. T. Shishibori. T. Fukui, a n d T. Suga, Chem. Letters. 1973, 1289. J . H . Gans. A . J. Block, a n d M. R. Cater, Proc. Soc. E.xp. Biol., 1973, 144, 609. P. Raskin a n d M . D. Siperstein. J. Lipid Res., 1974, 15, 20. A. D . Tait. Stt,roid.s. 1973, 22, 239. A . Dcrksen a n d P. Cohen, J. Biol. C'hem., 1973, 248, 7396. c'. D . Goodwin and S. Margolis. J . Biol. Chrm.. 1973. 248. 7610. J . P. Ferezou, M . Devys, J . P. Allais, and M . Barbier, Phytochemistrv. 1974, 13. 593. J . D. Willett a n d W . L. Downcy, Biochem. J . , 1974, 138, 233. P. A . Voogt. Arch. Internat. Physiol. Biochem., 1973, 81, 871. P . A . Voogt a n d J . W . A . van Rheenen. Experientiu. 1974, 29, 1070. A. G . Smith a n d L. J. G o a d . Biochem. J., 1974, 142, 421. G . H. Beastall. A. M . Tyndall, H. H . Rees, a n d T . W. Goodwin, European J . Biochem., 1974, 41, 301. M. E. Dempsey, K . E,. McCoy, T. D . Calimbras, and J. P. Carlson, Fed. Proc., 1974, 33, 1429.

Biosynthesis of Terpenoids and Steroids

187

been partly purihed.'58 Minor details have been filled in for the steps from lanosterol to cholesterol in liver' s 9 and in patients with the rai e disease cerebrotendinous xanthomatosisI6' and for the sequence ofmetabolites in phytosterol formation.1 6 ' ' 6 3 Studies

Scheme 6 159 16*

lb2

lh3

B. Seetharam, E. Hansbury, M. V. Srikantaiah, and T. J. Scallen. Fed. Pror'., 1974, 33, 1573. T. E. Spike, A. H. J. Wang, I. C. Paul, and G. J. Schroepfer, J.C.S. Chenr. Comnz., 1974. 477. G. S. Tint and G. Salen, J . Lipid R e s . . 1974, 15, 256. F. J . Evans, Pkunta, 1973. 111, 33. F. J. Evans, Pluntu, 1974, 116, 99. S. C. Jain and P. Khanna, Jizdian J. Pharm., 1973, 35, 163.

Terpenoids and Steroids

188

of a variety of inhibitors of steroidogenesis in plants,' 64-'68 liver,'69-' 7 4 and microhave enabled, in some cases, a target enzyme to be located, and the pattern of products in the treated tissue has permitted deductions concerning the normal sequence of (often transiently formed) intermediates. A comprehensive scheme (part of which is illustrated in Scheme 6) for the formation of ergosterol (63) from lanosterol (62) in Saccharomyces ceret;isiae has been presented, based on studies with labelled precursors and on trapping experiments :178 the authors carefully point out that the conclusions drawn rest heavily on inference, and that experimental verification at the enzymic level is urgently needed. Some non-natural sterols were converted significantly (ca.4 % yield) into (63)and this was attributed to the lack of specificity of certain enzymes in the metabolic grid. This work has been extended by using nystatin-resistant mutants of yeast :' 7 9 , 1 s 0 analysis of the sterols produced by these strains indicated metabolic blocks in the normal scheme at, inter a h , the steps for C-24transmethylation, A8 + A' isomerization, and formation of A5- and A22-bonds. Many other interesting points emerged from these studies ; for example a A8*"-sterol was isolated, which is in accord with the currently accepted hypothesis for the mechanism of C-14demethylatioii and complements previous (1966) work in which 4,4-dimethylcholesta-8,14-diene-3fi-ol was trapped as an intermediate of cholesterol biosynthesis. The study of unit (enzymatic) transformations by the use of such blocked mutants does not significantly delimit the possible pathways to an end product, but does allow a precise definition of certain unit steps in the pathway and would seem to be a more satisfactory approach than the classical method of feeding potential precursors. Similar but more restricted studies have also been reported on cultures and soluble enzyme systems of yeast and other micro-organisms, and it has been noted that in many cases a large proportion of the sterols are esterified.' 8 1 84 The properties and location of S-adenosylmethionine:A24-sterol methyltransferase(s) in yeast have been reported.' 8 5 * 18 6 Similar methyltransferase activities have ~

Ih4 lh5 Ibh lh7

'

J. M. C . G e m s and J . C. Vendrig, Phytochemistry. 1974, 13, 919. R. J. Olson, T . E. Trumble, and W. Gamble, Biochem. J., 1974, 142, 445. P. R. Shewry and A. K . Stobart. Phytochemistry, 1974, 13, 347. P. Belanger. J . A . Zintel, W. J. Van den Heuval, and J. L. Smith, Canad. J . Chem., 1973, 51. 3294.

lh8

Ih0 'O "I Ii2

I"

1-7

IT"

D. L. Davis and V. C . Finkner, Plant Physiol., 1973. 52, 324. L. Taddeini, I . Frantz, a n d A. Sanghvi, J . Lipid Res., 1974, 15, 84. J . A . Story and D. Kritchevsky, Experientia, 1974, 30, 242. S. Calandra a n d M . Montaguti, Experientia, 1973, 29, 1361. J . H. C a n s , Biochim. Biophj3.7. Acta, 1973, 326, 116. S. Ranganathan and T. Ramascarma, J . Neurochem., 1974, 22. 987. A. A. Kandutsch and H . W. Chen, J . Bid. Chem., 1973, 248, 8408. J . T . Chan and G. W. Patterson, Plant Physiol., 1973. 52. 246. L. G. Dickson and G. W. Patterson, Lipids. 1973, 8, 443. J . T. Chan. G. W. Patterson, S. R. Dutky, and C . F. Cohen, Plant Physiul.. 1974, 53, 244. D. H. R . Barton. J. G. T. Corrie, P. J . Marshall, and D. A. Widdowson, Bioorg. Chem., 1973, 2. 363.

Is'

Is'

183 I Is'

D. H . R. Barton, J . G . T. Corrie. D. A. Widdowson, M. Bard, and R. A. Woods, J.C.S. Chem. Comm., 1974, 30. D. H. R. Barton. J . G. T. Corrie, D. A. Widdowson, M. Bard, and R. A. Woods, J.C.S. Perkin I , 1974, 1326. M . Fryberg. A. C . Oehlschlager, and A. M. Unrau, Arch. Biochem. Biophys., 1974, 160, 83. M . Fryberg, A . C. Oehlschlager, and A. M. Unrau, J . Amer. Chem. Snc., 1973, 95, 5747. L. W. Parks, C . Anding, and G. Ourisson, European J . Biochem., 1974, 43. 451. S . Safe. Biochitn. Broph.1.s A c t n , 1973, 326, 471. E. D. Thompson. R . B. Bailey. and L. W. Parks, Biochim. Biophj.s. Actn, 1974, 334, 116. R. B . Bailey. E. D. Thompson, and L. W. Parks. Bior,him. Biophj,s. A c m , 1974, 334. 127.

189

Biosynthesis of'Terpenoids and Steroids

been demonstrated in vivo or in homogenates of algae,'87 mycobiont of lichen,'88 and a marine diatom.' 8 9 Feeding [Me-2H,]methionine as precursor generally resulted in the incorporation of two atoms of tracer per molecule in accordance with previously postulated schemes for micro-organisms and higher plants involving 24-methylene intermediates. One pathway to phytosterols in higher plants requires the opening of the cyclopropyl ring in the precursor skeleton at the stage of either cycloartenol (64), its 24-methylene

(66)

derivative, or cycloeucalenol (65). Full details have appeared of enzyme systems from tissue cultures of bramble that cleave (65) to form obtusifoliol (66).19' Microsomes of other higher plants could effect similar transformation but systems from liver and yeast' 9 1 could not. 4,4-Dimethyl-steroids were much less effective substrates for the active enzyme systems. Probably cycloartenol is a precursor of steroids only in phyla containing chlorophyll. Alkylation of the side-chain of steroids in various micro-organisms,involves a hydride shift from C-24 to C-25 and formation of a 24-methylene intermediate. However, experiments with doubly labelled mevalonate have shown that in several species of higher plants the 3 H at C-24 is lost during the biosynthesis of stigmasterol (67) and a-spinasterol (68),'92-'9" and Scheme 7 is envisaged. It is also demonstrated in this work'93 that cycloartenol is symmetrically labelled by mevalonate, i.e. no pools of

'''

Z . A. Wojciechowski, L. J. Goad, a n d T . W. Goodwin, Biochem. J . , 1973, 136, 405. R. Lenton, L. J. Goad, and T. W. Goodwin, Phytochemistry, 1973, 12, 2249. I. Rubinstein and L. J. Goad, Phytochernistry, 1974, 13, 485. R. Heintz and P. Beneveniste, J . Biol. Chem., 1974, 249, 4260. C. Anding, L. W. Parks, and G . Ourisson, European J. Biochem., 1974,43, 459. Y . Tomita and A. Uomori, J . C . S . Perkin I , 1973, 2656. W. L. F. Armarego, L. J. Goad, and T. W. Goodwin, Phytochernistry. 1973, 12, 2181. J . Sliwowski and Z . Kasprzyk, Phytochemistry, 1974, 13, 1451.

'** J. 190

19'

'93

190

Terpenoids and Steroids

c

Scheme 7

DMAPP, or any of the other factors that cause the asymmetry of labelling that is so pronounced for monoterpenoids and some sesquiterpenoids, are operative. This is further evidence for the compartmentation of separate sites of mono- and higher terpenoid biosynthesis.

7 Further Metabolism of Steroids The two ‘halves’ comprising the squalene molecule are not equivalent in that one half contains both hydrogens from C-5 of MVA at the central carbon, whereas the other only retains the pro-5R hydrogen, the other hydrogen being derived from NADPH. Whether such asymmetry is retained in subsequent transformation of squalene has been investigated in the case of fusidic acid (69) synthesized by Fusidizrrn coccineum. Cyclization of appropriately labelled squalene would result in tracer being located at HA or HBin (69), depending on whether epoxidation occurred at A 2 or A22 respectively. In the event, tracer was equally divided between the two positions, and this is consistent with the release of squalene from its synthetase into a free squalene pool before its transfer to epoxidase.’ Fucosterol (70) supplies the skeleton of antheridiol (71), a compound controlling sexual reproduction of certain aquatic fungi :l g 6 incorporation studies (Scheme 8) and trapping experiments with a series of potential precursors have indicated the probable sequence of elaboration of the side-chain. 195

R. C . Ebersole, W. 0. Godtfredsen, S. Vangedal, and E. Caspi, J . Amer-. Chem. Soc., 1973, 95, 8 1 3 3 .

C . R . Popplestone and A. M . Unrau, Canad. J . Chem., 1974, 52, 462.

191

Biosynthesis oJ' Terpenoids and Steroids

r

::I:: -+

i

\

HO"

Scheme 8

It has been accepted, with little direct evidence, that the first step in the metabolism of cholesterol to cholestanol in mammals involves the formation of cholest-4-en-3-one (72). Incubation of [ 1,2-3H,]cholesterol with a microscomal fraction from rat liver led to the incorporation of tracer (0.29%) into (72) and it was suggested that this step is rate-limiting for the sequence.197 19'

I . Bjorkhem and K. E. Karlmar, Biochim. Biophys. A c t a , 1974, 337, 129.

Terpenoids and Steroids

192

I n cico studies of the incorporation of MVA into bile acids in toad species have revealed that the main acids are probably derived from dietary phytosterols.' 9 8 Cholesterol can be functionalized by a NADPH-dependent peroxidation system from liver microsomes ; these oxidations appear to involve radical-like processes rather than singlet oxygen.' 99 Cholesterol is dehydrogenated by cultures of Mycobacterium phlei with stereospecific trans-diaxial loss of its la- and 2P-hydr0gens,~" whereas the 2b-hydrogen is only selectively lost (79 %) in the aromatization of 19-nor-steroids by mammalian tissue and micro-organisms.20 Stereospecific 2P-hydrogen elimination also occurs in the C-1,2 dehydrogenation of 5P-androstan-3,17-dione by Nocardia restrictus, but C-4,5 dehydrogenation of the same substrate involves elimination of the 4a-hydr0gen.~'~The stereochemistry of hydrogen transfer has been determined in several other cases : horse liver aldehyde dehydr~genase,~'microbial 20whydroxysteroid dehydr~genase,~'~ and reduction of steroids by rat liver alcohol :NAD oxidoreductase203all involve the 4A-hydrogen of NADH or NADPH, and a yeast reductase catalyses anti-diaxial addition of hydrogen to Sa-androstan- 1 -en-3-0ne.~'~ Intense interest has been aroused206 in cytochrome P450,a mixed-function oxidase from mitochondria that is involved in hydroxylation at C-11 and C-18 of the steroid nucleus and in cleavage (also involving hydroxylation at C-20 and C-21) of the sidechain. Several lines of research, for example involving inhibitor st~dies,~"differential deactivation with phospholipase C,208and biochemical genetics,209indicate that two types of cytochrome may be involved. One type, which is difficult to solubilize, may be associated with phospholipids whereas the other is easily extractable and may not be so conjugated.208.2 The e.s.r. spectra of complexes of P450 with steroids,21 its activation

''

198

199

200 201

'

K . Kurarnoto, S. Itakura, and T . Hoshita, J . Biochem. (Japan), 1974, 7 5 , 853. L. L. Smith and J . I . Teng, J . Amer. Chem. Sac., 1974, 96, 2640. G. T . Phillips and F. P. Ross, European J . Biochem., 1974, 44, 603. T. Nambara, T. Anjyo, M. Ito, and H. Hosada, Chem. and Pharm. Bull. (Japan), 1973, 21, 1938.

202 203 204 205

206 207

208

209

T . Nambara, S. Ikegawa, and H. Hosada, Chem. and Pharm. Bull. (Japan), 1973, 21, 2794. R. Fukuba, Biochim. Biophys. Acta, 1974, 341, 148. F. Hatano-Sato, Y . Takagi, and M . Shikita, J . Biochem. (Japan), 1973, 74, 1065. 0. R. Rodig, P. P. Roller, and A. W. Nicholas, Biochem. Biophys. Res. C o m m . , 1974, 56, 467. H . Schleyer. D. Y. Cooper, and 0. Rosenthal, Ann. New York Acad. Sci., 1974, 222, 102. M . Satre and P. V. Vignais, Biochemistry, 1974, 13, 2201. H . P. Wang, D. R. Pfieffer, T. Kirnura, and T. T. Tchen, Biochem. Biophys. Res. Comm., 1974, 5 7 , 93. G. T. Bryan, A. M. Lewis, J. B. Harkins, S. F. Micheletti, and G . S . Boyd, Steroids, 1974, 23, 185.

'I0 21 I

J. Rarnseyer and B. W. Harding, Biochim. Biophys. Acta, 1973, 315, 306. S. C. Cheng and B . W. Harding, J . Biol. Chem.. 1973, 248, 7263.

Biosynthesis of' Terpenoids and Steroids

193

by ACTH2' and c-AMP,~' and its possible implication in C-15 h y d r ~ x y l a t i o n ~ ' ~ have been investigated. Cholesterol sulphate, a ubiquitous compound, is an effective substrate and is converted into pregnenolone sulphate without cleavage of the ester group.21 A number of closely related compounds possessing insect-moulting hormone activity are widely distributed in plants.216Although several studies have been made the pathways to the phytoecdysones, which seem to be the precursors for ecdysones in insects, are o b ~ c u r el.7 ~ The potential precursor (73) was converted into 8-ecdysone (74) and inolcosterone (75) in leaves of Achyrantherfuuriei in ca. 0.06% yield,218and it was concluded that hydroxylation of the side-chain occurred after the construction of the A/B cis-fused ring system. The stereochemistry of formation of A' in ecdysone and In each case the ecdysterone biosynthesis in insects and in plants was also 7/3-hydrogen was stereospecificalty eliminated (as shown by double-labelling experiments). As the 8P-hydrogen was known also to be involved, the overall reaction is formally a syn-dehydrogenation, but it may well involve two successive anti-processes or alternatively molecular oxygen (i.e. uia hydroxylation-dehydration). R2

(73) R' = R2 = H , R 3 = M e , R 4 = H (74) R ' = R 2 = OH, R 3 = Me, R4 = OH (75) R' = R 2 = O H , R 3 = C H , 0 H , R 4 = H

The route of dealkylation of P-sitosterol (76) to cholesterol (77) in locust larva is thought to involve fucosterol-24,28-epoxide, and Scheme 9 has been suggested,220 involving ring-opened products (78) and (79) of the epoxide. A great mass of work, of varying worth, has appeared on a range of enzymatic modifications to the steroid skeleton. Quite often extracts have been described that transform steroids into ill-characterized products, and doubtful conclusions are drawn concerning the situation in uivo. Several other in uitro studies claim to demonstrate rather obscure clinical points. It is not possible to summarize all of this work here. and 'I2 'I3

'14

'I5 'I6

'I'

'I8 'I9 220

J. Alfano, A. C. Brownie, W. H. Orme-Johnson. and H. Beinert, J . Biol. Chem.. 1973, 248, 7860. M . G . Caron, S. Goldstein, K. Savard, and J. M. Marsh, Fed. Proc., 1974, 33, 1323. G. F. Gibbons and K. A . Mitropoulos, European J. Biochem., 1973, 40, 267. R. B. Hochberg. S. Ladany, M . Wetch, and S. Lieberman, Biochemistry, 1974, 13, 1938. H. Hikino, T. Okuyama, H . Jin, and T. Takemoto, Cliem. and Pharm. Bull. (Japan),1973, 21, 2292. T . Takemoto, T. Okuyama, H. Jin, T. Arai, M. Kawahara, C . Konno, S. Nabetani. S. Arihara. Y . Hikino, and H . Hikino, Chem. and Pharm. Bull. (Japan). 1973, 21, 2336. Y. Tomita and E. Sakurai, J . C . S . Chem. Comm., 1974, 434. I. F. Cook, J. G . Lloyd-Jones, H. H . Rees, and T. W. Goodwin, Biochem. J.. 1973, 136, 135. J. P. Allais, A . Alcaide, a n d M . Barbier, Experientia., 1973, 29, 944.

194

Terpenoids and Steroids

(76)

(79)

(77)

Scheme 9

attention is drawn only to papers of more general interest, on vitamin D, hydroxyland o e s t r o g e n ~ and , ~ ~ ~ ~ ~ ;ise,221the formation and metabolism of bile acids222,223 steroid dehydrogena~es,~ 2-239 reductases,240- 2 4 4 A --+ A' is om erase^,^^^.^^^ and h y d r o ~ y l a s e s . ~ ~ - .2~s 3' -

"'

J . G . G h a z a r i a n a n d H . F. d e Luca. Arch. Biochrm. Biophys., 1974, 160, 63. B. W . Noll, E. A. Doisy, a n d W . H. Elliott, J . Lipid Res.. 1973, 14, 385. F. Hanson, P . D. Klein, a n d G . C. Williams. J . L i p i d Res.. 1973. 14, 50. "' RF.. L. Rellino a n d Y . Oswawa. Bioi,hemisirj,. 1974, 13. 1925. - - K . Einursson. J . Gustafsson. a n d K . Hellstrom, Biochem. J . , 1973. 136, 623. "' I: H . White a n d J . J . Jeffrey, Biocheni. J . , 1974, 137, 349. C. D. Kochakian, D. Stevenson, a n d T . Mayumi, Biochern. Biophys. Res. Comm.. 1973, 54,

"' 'L3

7 7 5

, 7 -

519.

"' P . Gaffney a n d

L. J . Goad. Biochem. J.. 1974. 138, 309. E. H . Charreail a n d M . Tesone, J . Sferoid BiochPm.. 1974, 5, 65. ' 3 0 J . K . F'indlay a n d H . Breuer, Bioc-hPm. J . , 1974. 137, 273. ''I .I. Plassc a n d R. P. Lisboa. Eirropeun J . Biochem., 1973. 39, 449. '" J . .4. Story a n d D. Kritchevsky. E.\-,mrioritiu. 1974. 30. 242. ' 3 3 S. Sulirnovici, R. Bartoov. a n d B. Lunenfeld. Biochim. Biophys. Ac,ta. 1973. 321, 27. -, 7- ' E . R . Lax a n d H . Schriefers. Eirropeun J . Biochern., 1974, 42. 561. ' 3 5 C . H . Blomquist. Ari,h. Biochc~vi.Biophj*s.. 1973. 159, 590. '" H . C . F o r d a n d L . 1.. Engle. J . Biol. Chem., 1974. 249. 1363. '." D. F a n , H . Oshima, B. R . T r o e n , a n d P. T r o e n , Biochim. Biophys. .4ctri, 1974, 360, 88. .'" W. Hcyns a n d P. De M o o r , Biochim. Biophj,s. Acra, 1974, 358. I . 1 3 q G . J . Van der Vusse. M. L. K a l k m a n . a n d H. .I. Van der Molen, Biochirn. Biophys. Acfa. 1974. 348. 404. '" c'. L.e\y. M . Marchiiit. E. F . Baulieu. a n d P. Robel, Sfrroids. 1974. 23, 291. 'I' N o z u a n d B. I . T a m a o k i , Binchim. Biophj.s. A c t a , 1974. 348, 321. "' JK. .Gustafsson a n d A. Pousette. Biochern. J . , 1974, 142, 273. '43 R . Oron. C . Fouchet, a n d F. Perin. Biockim. Biophj..s. Acta, 1974. 348, 425. "' W . Gibb a n d .I. JefYery, Bioc,hrm. J . , 1973, 135. 881. "' A. M . Benson. A . J. Suruda, R . Shaw, a n d P. Talalay. Biochini. Biophys. A c t a , 1974, 348, 317. "" H . Weintraub. F. Vincent, E. E. Baulieu, a n d A. Alfsen, F.E.B.S. Letters, 1973, 37, 82. M. J . G . Brown a n d G . S. Boyd. Europeun J . Biochem., 1974, 44. 37. 'IH K . A . Mitropoulos, S. Balasubramaniam, a n d N. B. Myant. Biochim. Biophys. A c f a , 1973, 326. 428. 'Iy S. Taniguchi. N . Hoshita, a n d K . O k u d a , Eirropearr J . Bioc-hem., 1973. 40, 607. 'jo Y . Y . Lin a n d L.. L. Smith, Biochim. Biophys. Acta. 1974, 348, 189. 2 5 ' J . Gustafsson a n d M. Ingleman-Sundberg. Biochim. Biophj,s. Actu, 1974, 354, 172. "' G. S. Boyd. M . J . G. Brown. N. G. Hattersley. a n d K . E. Suckling, Bioc-him. Biophys. Acta, 337. 132. "' 1.1974, A . E l - K a d y a n d A . M. Allam, J . Geri. Microhiol.. 1973. 77, 465. .'"

Biosynthesis of Terpenoids and Steroids

195

8 Non-steroidal Triterpenoids The formation of oleanolic acid (80), maslinic acid (81), and 3-epimaslinic acid (82) in tissue cultures of Isodon japonicus has been studied using [2-’4C,4R,S-3Hl]MVA.2s4 It was concluded that the conversion (81)--+ (82) involved the 3-0x0-derivative and that

(80) R’ (81) R ’ (82) R’

R3 R2 = R3

=

=

= = =

H,R2 = O H OH,R3 = H OH,R2 = H

mechanisms involving cyclization of (3R)-2,3-oxidosqualene could be excluded as routes to 3cc-hydroxy-compounds in this species. Incubation o f [2-’“C]M\, A in admixture with the (2S,2R,4R)-or (5R,S)-[3HJMVA with flower heads of Calendula qficinalis gave oleanane, ursane, and lupane derivatives with labelling patterns consistent with the generally accepted biogenetic schemes for these corn pound^.^^ The pentacyclic triterpenol tetrahymanol replaces steroids in the membranes of certain protozoa and is an index of, and may even control, growth.2s6 Addition of cholesterol to the culture medium inhibited formation of tetrahymanol, and the additive was taken up, metabolized, and utilized structurally in its place. Inhibition was believed to occur at steps between acetate and MVA and at the level of squalene syntheta~e.~” A novel series of triterpenoid analogues of carotenoids has been isolated from Streptococcusf~ecitrm.~~~ No Cd0carotenoids occur in this species, and it is suggested that a new biosynthetic pathway is operative involving the condensation of two molecules of FPP to give 4,4’-diapophytoene (83) which undergoes a dehydrogenation sequence analogous to that in the formation of tetraterpenoid carotenes.

X \

\

\

Y \

\

Y

(83)

9 Carotenoids

Previous work (1973) had suggested that two routes were available for the biosynthesis of phytoene (86) from prephytoene alcohol pyrophosphate (84),one direct and the other involving lycopersene (85) (Scheme 10). It has now been shown that trans-phytoene biosynthesized by a mycobacterium species retained one pro-S and one pro-R hydrogen 254

255 256

257 258

Y . Tomita and S. Seo, J.C.S. Chem. Comm., 1973, 707. J. Sliwowski and Z. Kasprzyk, Phytochrmistry, 1974, 13, 1441. A. S. Beedle, K. A. Munday, and D . C. Wilton, Biochem. Soc. Truns.. 1973. 1. 1319 A. S. Beedle, K . A . Munday, a n d D . C. Wilton, Biochem. J . , 1974, 142, 57. R. F. Taylor and €3. H . Davies, Biochem. J . , 1974, 139, 751.

Terpenoids and Steroids

196 Ht

R

R R

trans-(86)

Scheme 10

from C-1 of the two molecules of GGPP that constitute the molecule2s9 and that hydrogen from NADPH was not incorporated. This complements reports (1967) that two pro-R hydrogens were retained in cis-phytoene. On the basis of these results a penetrating stereochemical analysis259 revealed that lycopersene could only be a precursor of cis-phytoene if two special and unlikely assumptions were made. It was concluded that lycopersene was not an intermediate in carotenoid biosynthesis (in those micro-organisms at least). The pathway from (84)to cis- or trans-(86)is presumed to involve removal of the appropriate epimeric hydrogen from a common tertiary cyclopropylcarbinyl cation (87) (Scheme 10). The previous results favouring lycopersene as an obligate intermediate were attributed to the demonstrable presence of squalene synthetase in the system : this can form lycopersene from endogenous GGPP and the former can then be non-specifically dehydrogenated. However, to resolve the problem of the role of lycopersene as an intermediate it will be necessary to purify phytoene synthetase. free of squalene synthetase, and examine it for ability to synthesize lycopersene. Soluble enzyme systems from plastids of various tomato fruits converted [ 14C]-cisand trans-phytofluene and trans-5-carotene into a range of all-trans acyclic, monocyclic, and bicyclic carotenoids (e.g. neurosporene, lycopene, a- and #?-carotene)260or their ’59

lh0

D. E. Gregonis and H . C . Rilling, Biochernrsrry, 1974, 13, 1538. A. A. Qureshi. A. G. Andrewes, N. Qureshi, and J. W. Porter, Arch. Brochem. Biophys., 1974, 162. 93.

Biosynthesis oJ Terpenoids and Steroids

197

all-cis analogues [proneurosporene, prolycopene, (poly)cis-~arotenoids].~~' Kinetic characteristics and cofactor requirements of the systems were determined and experimental proof was obtained for enzymic conversions that have been postulated in widely accepted biogenetic pathways. cis-(-Carotene was identified as an intermediate en route to (po1y)cis-carotenoids,and enzyme systems metabolizing it were isolated from tangerine tomatoes.262 Chloroplasts isolated in organic solvents were able to convert [2-14C]MVAinto phytoene in excellent yield,263and the biosynthesis of p-carotene in the photochromogen Mycobacterium kansasii has been Routes from p-carotene to more complex carotenoids in goldfish265 and bacteria266have been indicated by isolation and inhibition studies. Tracer from [Me-'4C]methionine and S-adenosyl[Me- 14C]methionine was specifically and efficiently incorporated into the methoxy-groups of certain microbial methoxy-carotenoids in vivo. The methylation of the presumed precursors must have been rapid and complete since hydroxy-carotenoids were present in only trace Partial degradation of the aryl carotenoid chlorobactene (88), formed in Chloropseudomonasethylica from [2-14C]MVA,indicated the labelling pattern shown. This suggested that ( a ) the aromatic ring was of mevalonoid origin, (b) stereospecific migration of methyl occurred, and (c) this methyl was derived from the C-3' position of MVA.268

(88)

= 14C

CPTA [2-(4-chlorophenylthio)triethylaminehydrochloride], nicotine, and related compounds have been confirmed to inhibit the cyclization of straight-chain carotenoids with the resultant accumulation of lycopene and its Th is effect is now known to occur in leaf and fruit tissue and in fungi. CPTA is also a powerful inhibitor of chlorophyll synthesis in greening pumpkin cotyledon^.^^ Studies with antibiotics have shown that carotenogenesis appears independent of chloroplastic DNA but is directed by nuclear DNA, although the sites of synthesis are in the c h l ~ r o p l a s t . ~ ' ~ 26'

262

263 264

26s 266 267

268 269 270

271 272 273 27J

275

17' 271 278

A. A. Qureshi, M. Kim, N. Qureshi, and J. W. Porter, Arch. Biochem. Biophys., 1974, 162, 108. A. A. Qureshi, N. Qureshi, M. Kim, and J. W. Porter, Arch. Biochem. Biophj,s., 1974, 162, 117. M. J. Buggy, G. Britton, and T. W. Goodwin, Phytochemistry, 1974. 13, 125. H. L. David, J . Bacteriol., 1974, 119, 527. D. B. Rodriguez, K . L. Simpson, and C. 0. Chichester, Infernat. J . Biochem., 1974, 5, 157. L. K. Hsieh, T. C. Lee, C. 0. Chichester, and K. L. Simpson, J. Bacteriol., 1974, 118, 385. R. K. Singh, G. Britton, and T. W. Goodwin, Biochem. J., 1973, 136, 413. S. E. Moshier and D. J. Chapman, Biochem. J . , 1973, 136, 395. S. M . Poling, W . J . Hsu, and H. Yokoyama, Phytochemistrj, 1973, 12, 2665. H. Kleinig, Arch. Microhiol., 1974, 97, 217. B. H. Davies and A . F. Rees, Phytochemistry, 1973, 12, 2745. W. Hsu, S . M . Poling, and H. Yokoyama, Phytochemistry, 1974, 13, 415. E. P. Hayman, C. 0. Chichester, and K. L. Simpson, Phytochemistry, 1974, 13, 1123. J. Fortino and W. E. Splittstoesser, Plant Cell Physiol., 1974, 15, 59. D. J. Simpson, F. M. M. Rahman, K. A. Buckle, and T. H. Lee, Austral. J . Plant Physiol., 1974, 1, 135. C . D. Howes, Phytochemistry, 1974, 13, 1469.

D. J. Simpson, C. 0. Chichester, and T. H. Lee, Austral. J . Plant Physiol., 1974, I , 1 1 9. R. Sirevag and R. P. Levine, Planta, 1973, 111, 73.

Terpenoids and Steroids

198

Various studies of the genetic control of carotenoid biosynthesis in Phycomyces blakesleeanus have been r e p ~ r t e d . ~ ~ ~ . ~ ~ ' The isomerization of all-trans-retinal to 1I-cis-retinal and the coupling of the latter with opsin to yield rhodopsin has been demonstrated in rat retina.281 Retina that had been bleached by high-intensity light produced isorhodopsin from all-trans-retinal, giving rise to the suggestion that the isomerization-regeneration sequence is carried out by a membrane-bound enzyme complex whose specificity is dependent on the structural integrity of the membrane. Molecular orbital calculations have shown that the C-11 -C-12 bond is the weakest double bond in the excited triplet state of all-transretinal,282and this partly explains why the most hindered 11-cis configuration of retinal is involved in the natural reaction sequence in the retina. The trisporic acids (89), which stimulate the development of the sex cells of many mucoraceous fungi, require the collaborative effect of (+) and ( - ) mating types of mycelia for their biosynthesis. Extracts of each type separately produce different precursors but these have not been fully identified.2R3Efficient (up to 39 %) incorporation of [ 10-''Clretinol, [ l0-'4C]-3-methyl-l-(2,6,6-trimethylcyclohexenyl)octa-1,3,5trien-7-one, and the hydroxy- and acetoxy-derivatives of the latter into (89) suggested the pathway from carotenoids depicted in Scheme 11, although the later steps may be in

bt:0H

Scheme 11

"' A.

P. Eslava and E. Cerda-Olmedo, Plant Sci. Letters, 1974. 2, 9. W. Hsu, D. C. Ailion, and M. Delbruck, Phvtochemisfry, 1974, 13, 1463. S. Amer a n d M. Akhtar, Nature New Biol., 1973, 245, 221. lX B.z O'Leary. B. Duke, J . E. Eilers, a n d E. W. Abrahamson, Nature, 1973, 246, 166. ''' R. P. Sulter. T. L . Harrison, a n d G. Galasko, J . Biol. Chem., 1974, 249, 2282.

'*'"'

Biosynthesis oj’Terpenoids and Steroids

199

variable order owing to the probably low specificity of the enzymes involved.284 Enzymes from bovine tissue can also cleave p-carotene to retinal.28 10 Meroterpenoids

This class (Cornforth, 1968) comprises compounds of partly mevalonoid origin. Only topics in which the terpenoid moiety is involved are included here. Reviews are available on indole steroidal Solanum alkaloids,288and the steroidal alkaloid a-tomatine.2 8 Verrucarinic acid (90), derived by hydrolysis of the antibiotics of the verrucarin and roridin classes [cf: (91), verrucarin A], closely resembles (3R)-MVA (92) and has been demonstrated, by a variety of double-labelling experiments, to be derived from it with an inversion at C-3 promoted by a 1,2-shift of the pro-2R hydrogen.290 Sideramines are also believed to contain a C5 unit derived from MVA, and this, together with cis-A2anhydro-MVA (93) and its trans-isomer, is formed by cell-free systems from certain fungi.29

H HO

(90)

HO

)

CO,H

(92)

HO

h02 H

(93)

Degradation of the furanocoumarin (94) biosynthesized from [5-3H2]M [A revealec tracer at the position indicated,292which is in complete accord with Seshadri’s hypothetical scheme (1958) for the formation of such compounds by the prenylation of the coumarin skeleton (Scheme 12). Others had previously claimed unspecific labelling 284

285

286 287

289 291

292

J. D. Bu’lock, B. E. Jones, D. Taylor, N. Winskill, and S. A. Quarrie, J . Gen. Microbinl., 1974, 80, 301. A. M. Gawienowski, M. Stacewicz-Sapuncakis, and R. Longley, J . Lipid Res., 1974, 15, 375. G. A. Cordell, Lloydia, 1974, 37, 219 (413 references). A. I. Scott, P. B. Reichardt, M. B. Slaytor, and J. G. Sweeney, Recent Adc. Phytochern., 1973, 6, 117 (28 references). K. Schreiber, Biochem. Soc. Trans., 1974, 2, 1. J. G . Roddick, Phytochemistry, 1974, 13, 9. R. Achini, B. Muller, and C. Tamm, Helv. Chim. Acra, 1974, 57, 1442. H. Anke and H. Diekmann, Arch. Microbiol., 1974, 95, 213. J. P. Kutney, P. J. Salisbury, and A. K . Verma, Tetrahedron, 1973, 29, 2673.

200

Terpenoids and Steroids

OMe

I

of the furan poiety by ["CIMVA, but had not located the site of tracer. In the present work much tritium occurred in the methoxy-group, and this provides one of the few available examples of MVA contributing to the C1 pool as well as being involved in terpenoid biosynthesis. [5- 14C]MVA was specifically incorporated into the skeleton of alizarin (95) by Rubia tinctorurn, and a prenylation and cyclization sequence is presumed (Scheme I 3).293 The anthraquinone (96) from Streptocarpus dunnii is

pCO, H

;:e-c,jC02H

+

\

\

0

OH

OH

\

0 (95)

Scheme 13

293

E. Leistner. Phytochemisrry, 1973, 12, 337

Biosynthesis o f Terpenoids and Steroids

20 1

probably formed by a similar route since oxidation of the hydroxymethyl group followed by decarboxylation resulted in loss of all tracer from the compound that had been biosynthesized from [2-' 4C]MVA.294 This particular route to the anthraquinones is now known to occur in leaf and root tissue and in micro-organisms.

fl+w+p HO'

I

Scheme 14

The fungal prenylphenol ascochlorin (97) has been shown by incorporation of [1,2-I3C]acetate and 13Cn.m.r. analysis of the product to result from a route involving migration of a C-14 methyl group (Scheme 14).295Similar compounds, the paniceins [cf: (98), panicein A] from the sponge Hatichondria panicea have been suggested to be derived from reaction of FPP with quinol residues, and this theory has been supported by isolation of (99)from the same source.296 a-Tomatine has been demonstrated to be synthesized from [2-14C]MVAin root tissue of tomatoes both in vivo and in and the biosynthesis of other steroidal alkaloids appears to be enhanced in necrosing leaves.298 A full report on the 294 295

296 29' 298

J. Stockigt, U . Srocka, and M . H . Zenk, Phytochemisrry, 1973, 12, 2389. M. Tanabe and K. T. Suzuki, J . C . S . Chem. Comm., 1974, 445. G . Cimino, S. de Stefano, and L. Minale, Experientia, 1973, 29, 1063. J . G . Roddick, Phytochemisrry, 1974, 13, 1459. A. R. Guseva, V. A. Paseshchnichenko, and M. G. Borikhina, Priklad. Biokhim. Mikrobiol., 1973, 9 , 764.

202

Terpenoids and Steroids

biosynthesis of iridoid glucosides in various higher plants has appeared.299Incorporations were often high : e.g. [ 10-3H,]loganin was converted into gentiopicroside in Gentianu trifrora in 4.504 yield. Two possible routes were considered for the ring cleavage involved between loganin (100)and the oleuropein-type secoiridoids [e.g. (101), oleuropein]. Route u of Scheme 15 was demonstrated by the incorporation of [ ‘‘C]secologanin (102) into oleuropein in Olea europaea in 0.34 % yield. Although the potential intermediate of route b, 8-epikingiside (103), was also incorporated into (101) in 0.2% yield, it was shown that there was no preference for (103) when it was fed in admixture with its isomer 8-kingiside (104), which should not be involved in this route. These results were held to indicate that route a was operative, although the authors state that this cannot be a definite conclusion.299

( 102)

7 C0,Me HO

0-Glu 0-g1u

( 100)

0 0-Glu

0-g1u

(103) Scheme 15

0-Glu (104) 299

€3. Inouye, S. Ueda, K. Inoue, and Y . Takeda, Chem. and Pharm. Bull. (Japan), 1974, 22,676.

20 3

Biosynthesis of Terpenoids and Steroids 11 Polyterpenoids

An enzyme system from Lactobacillus has been partially purified that converts FPP and IPP into polyprenyl pyrophosphate, especially C5 isoprenyl pyr~phosphate.~"This complements previous work in which enzymes that sustained synthesis of C,, and C,, isoprenyl pyrophosphate were solubilized from extracts of Micrococcus lysodeikticus. [14C]MVA was incorporated into C,, prenols by Lactobacillus p l ~ n t a r u r nand ~~~ Streptococcus r n u t ~ n sand , ~ ~the ~ distribution of some of the intermediates of peptidoglycan biosynthesis was determined.301 The role of the C,, pyrophosphate as a membrane-bound carrier of lipids in the biosynthesis of peptidoglycan of bacterial cell walls has been assessed.303 Dolichols (105). in which most of the isoprene units are cis-linked,

,

(105) n

=

16-22

play a similar role in rat liver and other tissues. In uiuo administration of [4S-3H,]MVA to rat led to 0.02% incorporation into the fraction containing dolichols, but steroids and other terpenoids containing trans-linked units were also labelled :,04 this was unexpected since the pro-4S mevalonoid hydrogen has been shown to be eliminated in the construction of a rrans-A linkage in other polyterpenoids. Again it is likely that MVA is contributing to a C, metabolic pool under these conditions.

12 Methods

A rapidly developing technique305 that has been mentioned in several of the previous sections is the deduction of labelling patterns (in a non-destructive manner) by analysis of the Fourier transform 13Cnn.m.r. spectrum of a product biosynthesized from an appropriate precursor labelled with 13C. Incorporations of ca. 1 % of a precursor (containing 100% atoms excess 13C) are required in order to obtain interpretable spectra, and this restricts the method, at present, to metabolites of micro-organisms, as incorporations in higher plants rarely approach this figure.306 The general feasibility of the technique has been demonstrated by deducing the accepted labelling pattern in fusidic acid (69) biosynthesized in the fungus Fusidiurn coccineum from [ 1-' ,C]acetate307 and by the use of paramagnetic reagents to enhance signals and interpret the spectrum of the fungal sesquiterpenoid helicobasidin (106)."0s A very useful handbook on techniques has appeared.309A short review306deals with the problems associated with the non-permeability of added precursors in the meta300

30' 302

303 304

305 306

307 308 309

M . V. Keenan and C. M . Allen, Arch. Biochem. Biophjjs., 1974, 161, 375. K. J . I . Thorne, J. Bacteria/., 1973, 116, 235. K. J . I . Thorne, Biochem. J., 1973, 135, 567. J . L. Strominger, Biochem. Soc. Trans., 1973, 1, 1026. H . G . Martin and K . J . I . Thorne, Biochem. J., 1974, 138, 277. H . Seto, T. Sato, and H . Yonehara, J. Amer. Chem. Soc., 1973, 95, 8461. A . I . Scott, Science, 1974, 184, 760. T. Riisom, H. J . Jakobsen, N. Rastrup-Anderson, and H . Lorck, Tetrahedron Letters, 1974, 2247. M . Tanabe, K . T. Suzuki, and W. C. Jankowski, Tetrahedron Letters, 1973, 4723. J . B. Harborne, 'Phytochemical Methods'. Chapman and Hall, London, 1973.

204

Terpenoids and Steroids

(104)

bolizing tissue and possible complications due to compartmentation effects and the occurrence of metabolic pools. Use of a viable seed source for biosynthetic studies on higher plants is recommended wherever this is possible, and it is suggested that studies can be carried out with greatest advantage under two sets of conditions : (i) short-time incubation coupled with trapping experiments to identify precursors and (ii) long-time (months if necessary) studies to allow equilibration of precursor with endogenous pools, the by-passing of possible compartmentation effects, and (perhaps) the induction of appropriate synthetases. Another review deals with methods of disrupting cells to obtain soluble enzyme systems.310 A technique of great potential is implied in the claim3" that rapid freezing of plant tissue with liquid nitrogen renders cells permeable to substrates of various enzymes, especially when the latter are introduced by vacuum infiltration. Enzymic activities obtained are said to compare well with those obtained by conventional methods. New assay methods for the key enzyme HMG-coenzyme A reductase (see Section 2) have been devised, 2p3 l5 and also for microsomal steroid-7a-hydro~ylase.~ The syntheses of tritiated GA,, GA, , and t e t r a h ~ d r o - G A , ~and ' ~ of specifically deuteriated carotenoids3l 7 have been described. The study of chemical taxonomy has become more widespread and many such investigations related to terpenoids have appeared. Several reports deal with qualitative analyses of individual or groups of species, but a few investigations go beyond this to seek answers to questions concerning introgression of species, gene flow, clonal variations, etc. or deal with the incidence of marker compounds specific to species or genera. Reviews on general principle^,^ 8 , 3 l 9 the chemistry of geographical races,32o the geographical variation of leaf oils of Abies species,32 and comparative biosynthetic pathways in higher plants322have appeared. Significant studies have taken place on clonal patterns in Juniper323and Abies species324.325 and on the chemotaxonomy of 31n 311

312

313 314

Is 316

I' 31R

'I9 320 321 322 323 324 325

L. Edebo and K. E. Magnusson, Pure Appl. Chem., 1973, 36, 325. D. Rhodes and G . R. Stewart, Plunta. 1974, 118, 133. J . Huber. S. Latzin, and B. Harnprecht, Z . physiol. Chem., 1973, 354, 1645. G . Nicolau. S. Shefer, G . Salen, and E. H. Mosbach, J . Lipid Res., 1974, 15, 94. F. H . Hulcher and W. H . Oleson, J . Lipid Res., 1973, 14, 625. I. Bjorkhem and H . Danielsson, Anu/.vf.Biochern., 1974, 59, 508. R . Nadeau and L. Rappaport, Phytochemisrry, 1974, 13, 1537. H . Brzezinka, B. Johannes, and H . Budzikiewicz, Z . Naturforsch., 1974, 29b, 429. D . S. Seigler, Chem. in Britain, 1974, 339 (29 references). V. Heywood, Pitrc Appl. Chem., 1973, 34, 355 (75 references). T. J . Mabry, Pure Appl. Chem., 1973, 34, 377 (44 references). E. von Rudloff, Pure Appl. Chem., 1973, 34, 401 (35 references). H. Grisebach, Pure Appl. Chem., 1973, 34, 487 (69 references). R. H. Flake, E. von Rudloff, and B. L. Turner, Recenr Adr. Phytochern., 1973, 6, 215. R . S. Hunt and E. von Rudloff, Canad. J . But., 1974, 5 2 , 477. E. Zavarin. K . Snajberk, and W. B. Critchfield, Biochem. System., 1973, I, 87.

Biosynthesis of Terpenoids and Steroids

205

the L e g ~ m i n o s a e the , ~ ~P~i n a ~ e a e , ~C1 ~ ’ lac tone^,^^^ c a r o t e n o i d ~ and ,~~~ iridoid g l u c o ~ i d e s .A~particularly ~~ interesting i n v e ~ t i g a t i o n dealt ~ ~ with the chemical taxa of Mentha arvensis : four chemotypes (rich in pulegone, linalool, isopulegone, and ocimene respectively)were isolated that were not correlated with morphological variations in the species. The designation of a specific taxon depended on the presence of the particular marker monoterpenoid rather than on qualitative differences in the composition of the essential oils. Genetic analyses of the factors governing the formation of mono, ~ ~H~e d e ~ r n species a ~ ~ ~ have also been reported. terpenoids in pi nu^,^^' T ~ n a c e t u r nand Reviews are available on the production of secondary metabolites by plant cell cultures335and on biotransformations in tissue culture.336

326

327 328 32q

330

33’ 332

333 334

335 336

J. B. Harborne in ‘Chemotaxonomy of Leguminosae’, ed. J. B. Harborne, D. Boulter, and B. L. Turner, Academic Press, London, 1971, p. 257 ( 1 17 references). Y. A. Polyavchenko and E. A. Rudakov, Rust. Resur., 1973, 9, 481 (Chem. Abs., 1974, 80, 105 850). M . W. Bierner, Biochem. System., 1973, 1, 95. T. Ignasiak, Biochem. System., 1973, 1, 97. P. J. Grayer-Barkmeijer, Biochem. System., 1973, 1, 101. L. S. Gill, B. M . Lawrence, and J. K. Morton, Bot. J . Linn. Soc., 1973, 67, 213. P. Baradat, C. Bernard-Dagan, C. Fillon, A. Marpeau, and C. Pauly, Ann. Sci. Forest, 1972, 29, 307 (Chem. Abs., 1974,80, 35 116). J. Lokki, M. Sorsci, K. Forsen, and M. von Schantz, Hereditas, 1973, 74, 225. R . S. Irving and R. P. Adams, Recent Adtl. Phytochem., 1973,6, 187. F. Constabel, 0. L. Gamborg, W. G . W. Kurz, and W. Steck, Planta Medica. 1974. 25. 158. W . Steck and F. Constabel, Lloydia, 1974, 37, 185.

Naturally Occurring Terpenoids whose Structures have been Determined by X - Ray Analysis

This summary lists either a heavy-atom derivative or, in more recent analyses, the naturally occurring substance itself. 1 Monoterpenoids

+ )-trans-chrysanthemate 6-bromo-2,4-dinitrophenylhydrazone.M. J. Begley, L. Crombie, D. J. Simmonds, and D. A. Whiting, J.C.S. Chem. Comm., 1972, 1276.

+

( )-Allethronyl (

Irido ids Loganin penta-acetate monomethyl ether bromide. P. J . Lentz, jun. and M. G. Rossmann, Chem. Comm., 1969, 1269; P. J. Lentz, jun., Diss. Abs. Internut. (B), 1971, 32, 715. Tecomanine methoperchlorate and alkaloid C methoperchlorate., G. Jones, G. Ferguson, and C. Wayne, Chem. Comm., 1971,944. Acyclic Monoterpenoid (3R,4S,7S)-trans,trans-3,7-Dimethyl-1,8,8-tribromo-3,4,7-trichloro-octa1,5-diene. D. J. Faulkner, M. 0. Stallard, J. Fayos, and J. Clardy, J. Amer. Chcm. Soc., 1973, 95, 341 3. Menthunes cis-Carvone tribromide. R. W. Schevitz and M. G. Rossmann, Chem. Comm., 1969, 71 1 ; R. W. Schevitz, Diss. Abs. Internat. (B), 1971, 31, 4533. trans-Menth-1(7)-ene-2,8-diol. W. E. Scott, D i n . Abs. Internat. ( B ) , 1970, 31, 170; W. E. Scott and G. F. Richards, J . Org. Chem., 1971, 36, 63. 0-Menthyl S-methyl phenylphosphonothiolate. K. Mislow, J. Donohue, N. Mandel, W. B. Farnham, R. K. Murray, and H. P. Benschop, J . Amer. Chem. Soc., 1971, 93, 3792. ( -)-Menthy1 phenyl glyoxylate. R. Parthasarathy, J. Ohrt, A. Horeau, J. P. Vigneron, and H. B. Kagan, Tetruhedron, 1970, 26,4705. (-t )- 1 -Naphthyl(phenyl) (methoxy)[( - )-menthoxylsilane. J. Vidal, J. L. Galigne, and J. Falgueirettes, Compt. rend., 1970, 270, C, 690. Platinum complex of dithiocumate. J . P. Fackler, jun., J . Amer. Chem. Soc., 1972, 94, 1009. Fe(CO), complex of pulegone. E. Korner von Gustorf, F. W. Grevels, C. Kriiger, G. Olbrich, F. Mark, D. Schulz, and R. Wagner, Z . Natuforsch., 1972, 27b, 392. 206

Terpenoid Structures Determined 641 X - R q Analysis

207

Bornanes (+)-3-Bromocamphor. F. H. Allen and D. Rogers, Chem. Comm., 1966, 837; J. Chem. SOC.( B ) , 1971,632. Salts of (+)-3-bromocamphor-9-sulphonicacid. W. H. Pirkle, R. L. Muntz, and 1. C. Paul, J. Amer. Chem. Soc., 1971, 93, 2817; J. A. Wunderlich, Acta Cryst., 1967, 23,846; S. M. Johnson, I. C. Paul, K. L. Rinehart, jun., and R. Srinivasan, J. Amer. Chem. Soc., 1968, 90,136; see also the imide in D. J. Cram, J. Day, D. R. Rayner, D. M. von Schriltz, D. J. Duchamp, and D. C. Garwood, J. Amer. Chem. Soc., 1970, 92, 7369. 2-Bromo-6-(dimethylaminomethyl)-l,3,3-trimethylnorbornane hydrobromide. G . Reck, 2. Chem., 1969, 9, 30; L. Kutschabsky and G. Reck, J. prukt. Chem., 1971, 312, 896. A-( +),,,-trans-Tris-[( +)-3-acetylcamphorato]chromium(rrr). W. D. Horrocks, jun., D. L. Johnston, and D. MacInnes, J . Amer. Chem. Soc., 1970,92, 7620. 2-exo-Bromo-2-endo-nitro-1,3,3-trimethylnorborane. J. Berthou, Y. Brunel, A. Laurent, A. Rassat, and C. Rerat, Compt. rend.. 1967, 264, C, 292; C. Rerat, ibid., 1968, 266, C, 612. (+)-3-Diazocamphor. A. F. Cameron, N. J. Hair, and D. G. Morris, J.C.S. Perkin 11, 1972, 1331. Pinanes. 3-(Dimethylaminomethyl)pin-2(10)-ene. L. Kutschabsky and G. Reck, J. prakt. Chrrn.. 1971, 312, 896. Fe(CO), complex of pinocarvone. E. Korner von Gustorf, F. W. Grevels, C. Kruger, G. Olbrich, F. Mark, D. Schulz, and R. Wagner, 2. Naturfursch., 1972, 2%. 392. Bis-(n-pineny1)nickel. C. Kriiger, Angew. Chem. Internat. Edn.. 1972, 11, 387. Cantharidin. U. C. Sinha, Indian J. Phys., 1971, 45, 432.

2 Sesquiterpenoids Carotane. Daucyl-DL-alaninate hydrobromide. C. D. Green, Diss. Abs. ( B ) , 1967, 28, 100; R. B. Bates, C. D. Green, and T. C. Sneath, Tetrahedron Letters, 1969, 3461. Cuparane, Laurane, Trichothecane. Trichodermol p-bromobenzoate. S. Abrahamsson and B. Nilsson, Actu Chem. Scand., 1966, 20, 1044. Laurinterol acetate. A. F. Cameron, G. Ferguson, and J. M. Robertson, Chem. Cornm.. 1967, 271 ; J . Chem. Soc. (B), 1969, 692. Dihydrofomannosin-p-bromobenzolurethane.A. T. McPhail and G. A. Sim, J. Chern. Soc. (B), 1968, 1104. Pacifenol. J. J. Sims, W. Fenical, R. M. Wing, and P. Radick, J. Amer. Chem. Soc.. 1971,93, 3774. Opposital. S. S. Hall, D. J. Faulkner, J. Fayos, and J. Clardy, J . Amer. Chem. Soc.. 1973, 95, 7187. Acetoxyintricatol. J. A. McMillan, I. C. Paul, R. H. White, and L. P. Hager, Tetrahedron Letters, 1974, 2039.

208

Terpenoids und Steroids

Ac*orcint..Ctdrlycirie

Shellolic broniolactone monohydrate. E. J. Gabe, Acta Crjst., 1962, 15, 759. Bromogetgertn acetate. J. A. Hamilton, A. T. McPhail. and G. A. Sim, J. Chem. Soc., 1962, 708. Acorone p-bromophenylsulphonylhydrazone. C. E. McEachen, A. T. McPhail, and G. A. Sim, J . Chem. SOC.(0, 1966, 579. Acorenone-B 4-iodo-2-nitrophenylhydrazone.R. J. McClure, K. S. Schorno, J. A. Bertand, and L. H. Zalkow, Cliem. Comm., 1968, 1 1 35. Khusimol p-bromobenzoate, R. M. Coates, R. F. Farney, S. M. Johnson, and I. C. Paul, Chew. Cornm.. 1969, 999. Cedryl chromate. V. Amirthalingam, D. F. Grant, and A. Senol, Acta Cryst., 1972, B28, 1340. ( + )-2,5-Diepi-P-cedrene. T. Norin, S. Sundin, B. Karlsson, P. Kierkegaard, A.-M. Pilotti, and A.-C. Wiehager, Tetrahedron Letters, 1973, 17. A n 1 c wphut ic . Ctrdinunr , Cubrbunr . Cadinol dihydrobromide. F. Hanic, Coll. Czech. Chein. Comm., 1958, 23, 1751. lresin di-p-bromobenzoate. M. G . Rossmann and W. N . Lipscomb, Tetrahedron, 1958, 4,275. (k)-Cadinene dihydrochloride. N. V. Mani, 2. Krwr.. 1963, 118, 103. Bulgarene dihydrobromide, A. Linek, R. Vlahov. M. Holub, and V. Herout, Tetrahedron Lettcrs. 1968, 23. Nor-jl-cubebone. W. E. Thiessen, Actu Cryst., 1969, A25, S144. Arteannuin B. M. Uskokovic, T. H. Williams, and J. F. Blount, Helv. Clzim. Acta, 1974. 57, 600.

Himnt ~Iiulune,Longifolune. Himachalene monohydrochloride. B. Nilsson, Arkit.. Kerni, 1968, 29, 41 5. Longifolene hydrochloride. R. H. Moffett and D. Rogers, Clzem. and Ind., 1953, 916. Longifolene hydrochloride. A. F. Cesur and D. F. Grant, Acru Cryst., 1965, 18, 55. 7-Bromo-3,15-cyclolongifolane. J.-C. Thierry and R. Weiss, Tctmhedron Letters, 1969, 2663. 3x-Bromolongifolene. J.-C. Thierry and R. Weiss, Tetrahedron Letters, 1969, 2663. 3r-Bromo-7[jH-longifolane. J.-C. Thierry and R. Weiss, Tetruhedron Letters, 1969, 2663. 7-Bromo-3,15-cyclolongifolane. J.-C. Thierry and R. Weiss, Acta Cryst., 1972, B28, 3228. c+Bromolongifolene. J .-C. Thierry and R. Weiss, -4ctu Cryst., 1972, B28, 3249. 31x-Bromolongifolene. J.-C. Thierry and R. Weiss. Actu Crjst. 1972, B28, 3249. 3r-Rromo-7/,’H-longifolene. J.-C. Thierry and R. Weiss, Acta Cryst., 1972, B B ,3234. 15-7/3H-l,ongifolyl p-bromobenzoate. J.-C. Thierry and R. Weiss, Acta Cryst., 1972, 1328, 3241. lsolongifolene epoxide J. A. McMillan, 1. C. Paul, U. R. Nayak, and S. Dev, TetraIicdrron Letters. 1974. 41 9. Htir tiukane, Curjvplzj ~llune . Illudune. 11-Caryophyllene chloride. J. M. Robertson and G. Todd, J . Clzcin. Sw.. 1955, 1254. lsoclovene hydrochloride. J . S. Clunie and J. M. Robertson. J . Chem. S o c ~ . 1961,4382. .

Terpenoid Structures Determined by X-Ray Analysis

209

Caryophyllene chlorohydrin. D. Rogers and Mazhar-ul-Haque, Proc. Chem. Soc.. 1963, 371. a-Caryophyllene alcohol p-bromobenzenesulphonate. K. W. Gemmell, W. Parker, J. S. Roberts, and G. A. Sim, J . Amer. Chem. Soc.. 1964, 86, 1438. Hirsutic acid cr-bromophenacyl ester. F. W. Comer and J. Trotter, J. Chem. Sue. (B), 1966, 11. Humulene-silver nitrate complex. A. T. McPhail and G. A. Sim, J. Chem. SOC. (B), 1966, 112. Pseudoclovene A mono-p-bromobenzenesulphonate. G. Ferguson, D. M. Hawley, T. F. W. McKillop, J. Martin, W. Parker, and P. Doyle, Chem. Cumm., 1967, 1123. Humulene bromohydrin. F. H. Allen and D. Rogers, J. Chem. SOC.(B), 1968, 1047. Caryophyllene iodonitrosite. D. M. Hawley, G. Ferguson, and J. M. Robertson, J. Chem. SOC.(B), 1968, 1255. Photocaryophyllene A bromoketone. R. B. Bates, G. D. Forsythe, G. A. Wolfe, G. OhloR, and K.-H. Schulte-Elte, J. Org. Chem., 1969, 34, 1059. Photocaryophyllene D bromoketone. R. B. Bates, G. D. Forsythe, G. A. Wolfe, G. Ohloff, and K.-H. Schulte-Elte, J. Org. Chem., 1969, 34, 1059. Pseudoclovene-A-diol mono-p-bromobenzenesulphonate. D. M. Hawley, G. Ferguson, T. F. W. McKilop, and J. M. Robertson, J. Chem. Soc. (B), 1969, 599. r -Caryophyllene alcohol p-bromobenzenesulphonyl ester. K. W. Gemmell, W. Parker, J. S. Roberts, J. M. Robertson, and G. A. Sim, J. Chem. Sue. (B), 1970, 947. Chlorodehydroxymarasmic acid. P. D. Cradwick and G. A. Sim, Chem. Comm., 1971, 431. Illudol. P. D. Cradwick and G. A. Sim, Chem. Comm., 1971,431. Pseudoclovene-B dibromide. R. I. Crane, C. Eck, W. Parker, A. B. Penrose, T. F. W. McKillop, D. M. Hawley, and J. M. Robertson, J.C.S. Chem. Comm., 1972, 385. Humulene diepoxide. M. E. Cradwick, P. D. Cradwick, and G. A. Sim, J.C.S. Perkin IZ, 1973,404. Illudin S. A. Furusaki, H. Shirahama, and T. Matsumoto, Chem. Letters, 1973, 1293. Cuauhtemone. R. A. Ivie, W. H. Watson, and X. A. Dominguez. Actu Cryst., 1974, B30. 2891. Germacrane, Eudesmane, Eremophilune. Hydroxydihydroeremophilone. D. F. Grant and D. Rogers, Chem. and Iizd., 1956, 278. 2-Bromo-a-santonin. J. D. M. Asher and G. A. Sim, J. Chem. Such., 1965, 6041. 2-Bromodihydroisophoto-a-santoniclactone acetate. D. M. Asher and G. A. Sim, J. Chem. Sue., 1965, 1584. Elephant01 p-bromobenzoate. S. M. Kupchan, Y. Aynelchi. J. M. Cassady, A. T. McPhail, G. A. Sim, H. K. Schnoes, and A. L. Burlingame, J. Amer. Chem. Suc., 1966,88,3674; A. T. McPhail and G. A. Sim, J.C.S. Perkirz IZ, 1972, 1313. p-Bromobenzoyl-laserol. A. Linek, C. Novak, L. Vesela, and V. Kupcik, Coll. Czech. Chem. Comm., 1967, 32, 3437. 2-Bromo-( -)-P-desmotroposantonin. A. T. McPhail, B. Rimmer, J. M. Robertson, a n d G . A. Sim, J. Chem. Soc. (B), 1967, 101. Gemacratriene-silver nitrate adduct. F. H. Allen and D. Rogers, Chem. Comm., 1967, 588.

210

Terpenoids and Steroids

2-Bromolumisantonin. C. P. Huber and K. J. Watson, .I. Chem. Soc. (CJ, 1968, 2441. 2-Bromo-/j-santonin. P. Coggon and G. A. Sim, J . Clzem. Soc. ( B ) , 1969, 237. Chamaecynenol 4-bromo-3-nitrobenzoate. H. Shimanouchi and Y. Sasada, Bull. Chem. Soc. Japan. 1969,42, 334. Costunolide bis(si1ver nitrate). F. Sorm, M. Suchy, M. Holub, A. Linek, 1. Hadinec, and C. Novak, TetrahedronLetters, 1970, 1893. 0-(Bromoacety1)tetrahydrodouglanine. Mazhar-ul-Haque, C. N. Caughlan, M. T. Emerson, T. A. Geissman, and S. Matsueda, J. Chem. Soc. (B), 1970, 598. Fukinolidol bis(bromoacetate). C. Katayama, A. Furusaki, I. Nitta, M. Hayashi, and K. Naya, Bull. Chern. SUC..Japan, 1970. 43, 1976. Hydroxypelenolide p-bromobenzoate. R. B. Bates, C. J. Cheer, and T. C. Sneth, J. Org. Cheni.. 1970, 35. 3960. Shiromodiol acetate p-bromobenzoate. R. J. McClure, G. A. Sim, P. Coggon, and A . T. McPhail, Chem. Comun., 1970, 128. Pregeijerene silver nitrate complex dihydrate. P. Coggon, A. T. McPhail, and G. A. Sim, J . Chem. SOC. ( B ) , 19’70, 1024. Vernolide x -iodobenzoate. C. Pascard, Tetrahedron Letters, 1970, 41 3 1. Germacratriene-silver nitrate adduct. F. H. Allen and D. Rogers, J. Chem. Soc. (B), 1971, 257. Vernolepin p-bromobenzenesulphonate. A. T. McPhail and G. A. Sim, J. C‘hem. Soc. ( B ) , 1971, 198. Pyrethrosin 3-o-chlorophenylisoxazolinederivative. E. J. Gabe, S. Neidle, D. Rogers, and C. E. Nordman, Chem. Cumm., 1971, 559. Liatrindiol mono-o-bromobenzoate. S. M. Kupshan, V. H. Davies, T. Fujita. M. R. Cox, and R. F. Bryan, J . Amer. Chem. Soc.. 1971, 93, 4916. Maytoline methiodide methanol solvate. R. F. Bryan and R. M. Smith, J . Chem. Sot. (B), 1971, 2159. Melampodin. S. Neidle and D. Rogers, J.C.S. Chem. Comm., 1972, 140. Isocollybolide. C. Pascard-Billy, Acta Crj’sr., 19’72, B28, 33 1. Dihydrofukinolidol sulphite (stereoisomer S-2). A. Furusaki and T. Watanabe, Bull. Chem. Soc. Jupan. 1972. 45, 2288. Dihydrofukinolidol sulphite (stereoisomer S- 1). A. Furusaki and T. Watanabe, Bull. Chem. Soc. Jupan. 19’72, 45, 2288. Enhydrin bromohydrin. G. Kartha, K. T. Go, and B. S. Joshi, J.C.S. Chem. Comm., 1972, 1327. Miscandenin. P. J. Cox, G. A. Sim, J. S. Roberts. and W. Herz, J.C.S. Chem. Comvvr., 1973, 428. Dihydromikanolide. P. J . Cox, G. A. Sim, J. S. Roberts, and W. Herz. J.C.S. Chem. Comm.. 1973, 428. Molephantin p-bromobenzenesulphonate. K .-H. Lee. H. Furukawa, M. Kozuka, H.-C. Huang. P. A. Luhan, and A. T. McPhail, J.C.3’. Chem. Comnz.. 1973, 476. Eupacinin, Eupacunoxin. S. M. Kupchan, M. Maruyama, R. J . Hemingway. J. C. Hemingway, S. Shibuya, and T. Fujita, J . Org. C1hem.. 1973, 38,2189. Liatrin. S. M. Kupchan, V. H. Davies, T. Fujita, M. R. Cox, R. J. Restivo, and R. F. Bryan, J . Org. Chem., 1973. 38, 1853. Eremophilenolide. C. Kabuto, N. Takada, S. Maeda, and Y . Kitahara, Chem. Letters, 1973, 371.

Tcrpenoid Structures Determined by X-Ray Analvsis

21 1

Eriolangin, Eriolanin. S. M. Kupchan, R. L. Baxter, C.-K. Chiang, C. J. Gilmore, and R. F. Bryan, J.C.S. Chem. Cornrn., 1973,842. Tetradymol. P. W. Jennings, S. K. Reeder, J. C. Hurley, C. N. Caughlan, and G. D. Smith, J. Org. Chem., 1974, 39, 3392. Dihydrophytuberin. D. L. Hughes and D. T. Coxon, J.C.S. Clzem. Comm., 1974, 822. Eupaformonin. A . T. McPhail, K. D. Onan, K.-H. Lee, T. Ibuka, and H.-C. Huang, Tetruhedron Letters, 1974, 3203. Phomenone. C. Riche, C. Pascard-Billy, M. Devys, A. Gaudemer, and M. Barbier, Tetrahedron Letters, 1974, 2765. Chrysandiol. T. Osawa, A. Suzuki, S. Tamura, Y. Ohashi, and Y . Sasada. Tetrahedron Letters, 1974, 1569. Phantomolin. A. T. McPhail, K. D. Onan, K.-H. Lee, T. Ibuka, M. Kozuka, T. Shingu, and H.-C. Huang, Tetrahedron Letters. 1974, 2739. Glaucolide-A. W. G. Padolina, H. Yoshioka. N. Nakatani, T. J. Mabry, S. A. Monti, R. E. Davis, P. J. Cox, G. A. Sim, W. H. Watson, and I. B. Wu, Tetrahedron, 1974, 30, 1161. Guaiane. Cyperane. Bromoisotenulin. D. Rogers and Mazhar-ul-Haque, Proc. Chem. Soc., 1963, 92. Patchouli alcohol diester of chromic acid. M. Dobler, J. D. Dunitz, B. Gubler, H . P. Weber, G. Buschi, and J. 0. Padilla, Proc. Chem. Soc., 1963, 383. Bromohelenalin. M. T. Emerson, C. N. Caughlan, and W. Herz, Tetrahedron Letters, 1964,621. Mazhar-ul-Haque and C. N. Caughlan, J. Chem. SOC. (B), 1969,956. Bromoambrosin. M. T. Emerson, W. Herz, C. N. Caughlan, and R. W. Witters, Tetrahedron Letters, 1966, 615 1. Euparotin bromoacetate benzene solvate. S. M. Kupchan, D. C. Hemingway, J. M. Cassady, J. R. Know, A. T. McPhail, and G. A. Sim, J. Amer. Chem. Soc.. 1967, 89, 465. Bromomexicanin-E. Mazhar-ul-Haque and C. N. Caughlan, J. Chem. Soc. (B), 1967, 355. p-Gorgonene-silver nitrate complex. M. B. Hossain and D. van der Helm, J. Amer. Chem. Soc., 1968, 90,6607. Deacetyldihydrogaillardin p-bromobenzoate. T. A. Dullforce, G. A. Sim, D. N . J. White, J. E. Kelsey, and S. M. Kupchan, Tetrahedron Letters. 1969, 973. Monobromogaillardin. T. A. Dullforce, G. A. Sim, D. N. J . White, J. E. Kelsey, and S. M. Kupchan, Tetrahedron Letters, 1969, 973. Bromoanhydrotetrahydropulchellin, C, 5H,,BrO,. Mazhar-ul-Haque, C. N. Caughlan, and M. T. Emerson, Acta Cryst., 1969, A25, S142. 4-Bromo- 1,2,7.7-tetramethyltricyc10[6,2,1,02,6]undecan-3-one: bromo-ketone derived from cyperene epoxide. H. Dreyfus, J.-C. Thierry, R. Weiss, 0. Kennard, W. D. S. Motherwell, J. C. Coppola, and D. G. Watson, Tetrahedron Letters, 1969, 3757. Isocyperene glycol phosphobromidate. H. Dreyfus, J.-C. Thierry, R. Weiss, 0. Kennard, W. D. S. Motherwell, J. C. Coppola, and D. G. Watson, Tetrahedron Letters, 1969, 3757. Isocyperene glycol phosphochloridate. H. Dreyfus, J .-C. Thierry, R. Weiss, 0. Kennard, W. D. S. Motherwell, J. C. Coppola, and D. G. Watson, Tetrahedron Letters. 1969, 3757.

212

Terpenoids and Steroids

3-Bromoanhydrodehydrodihydropulchellin.K. Aota, C. N. Caughlan, M. T. Emerson, W. Herz, S. Imayama, and Mazhar-ul-Haque, J . Org. Chem., 1970, 35, 1448. Solstitialin. W. E. Thiessen and H. Hope, Actu Cryst.. 1970, B26, 554. 1 1,13-Dibromopulchellin hemihydrate. T. Sekita, S. Imayama, and Y. Iitaka, Actu Cryst., 1971, B27, 877. Bromogaillardin. T. A. Dullforce, G. A. Sim, and D. N. J. White, J. Chem. Soc. (B), 1971, 1399. Deacetyldihydrogaillardin p-bromobenzoate. T. A. Dullforce, G. A. Sim, and D. N. J. White, J . Chem. Soc. (B), 1971, 1399. Centaurepensin. J. Harley-Mason, A. T. Hewson, 0. Kennard, and R. C. Pattersen, J.C.S. Chem. Comm., 460, 1972. Axivalin. G. D. Anderson, R. S. McEwen, and W. Herz, Tetrahedron Letters, 1972, 4423. Centaurepensin. A. T. Hewson, R. C. Pattersen, and 0. Kennard, Cryst. Struct. Comm., 1972, 1. 383. Pseudoivalin bromoacetate. G. D. Anderson, R. Gitany, R. S. McEwen, and W. Herz, Tt7trulzcdron Lctters. 1973, 2409. 13p-p-Bromophenylthio-1 1~,13-dihydropulchellin-C diacetate. M. Currie and G. A. Sim, J.C.S. Perkin 11, 1973, 400. Euparotin. A. T. McPhail and G. A. Sim, Tetrahedron, 1973. 29, 1751. Helenalin oxide. A. T. McPhail and K. D. Onan, Tetrahedron Letters, 1973, 4641. Parthemollin. P. Sundararaman, R. S. McEwen, and W. Herz, Tetrahedron Letters, 1973, 3809. Chlorochrymorin. T. Osawa. A. Suzuki, S. Tamura, Y. Ohashi, and Y. Sasada, Tctruliedron Letters. 1973, 5 135. Carolenalin monoacetate. A. T. McPhail, P. A. Luhan, K.-H. Lee, H. Furukawa, R. Meck, C. Piantadosi, and T. Shingu, Tetruhedron Letters, 1973, 4087. Ambrosic acid. S. Inayama, A. Itai, and Y. Iitaka, Tetrahedron Letters, 1974, 809. Plenolin. K.-H. Lee, T. Ibuka, A. T. McPhail, K. D. Onan, T. A. Geissmann, and T. G. Waddell, Tetrahedron Letters, 1974, 1149. Florilenalin. K.-H. Lee, T. Ibuka, M. Kozuka, A. T. McPhai1, and K. D. Onan, Tetrulredron Letters, 1974, 2287. Pseudoivalin bromoacetate. R . Gitany, G. D. Anderson, and R. S. McEwan, Acta Cryst.. 1974, B30, 1900. Miscrlluncwus. Deoxynupharidine hydrobromide. K . Oda and H. Koyama, J. Chem. Soc. (B), 1970, 1458.

Isocollybolide. C. Pascard-Billy, Chem. Comm., 1970, 1722. Chanootin. B. Karlsson, A.-M. Pilotti, and A.C. Wiehager, Actu Cryst., 1973, B29, 1209. Breynolide. K. Sasaki and Y. Hirata, Tetrahedron Letters, 1973, 2439. Purpuride. T. J. King, J. C. Roberts, and D. J . Thompson, J.C.S. Perkin I , 1973, 78. Pinguisone. A. Corbella, P. Gariboldi, G. Jommi, F. Orsini, A. DeMarco, and A. Immirzi, J.C.S. Perkin I , 1974, 1876. Capnellane. M. Kaisin, Y. M. Sheikh, L. J . Durham, C. Djerassi, B. Tursch, D. Daloze, J. C. Braekman, D. Losman, and R. Karlsson, Tetrahedron Letters, 1974, 2239.

Terpenoid Structures Determined by X-Ray Analysis

21 3

Africanol. B. Tursch, J. C. Braekman, D. Daloze, P. Fritz, A. Kelecom, R. Karlsson, and D. Losman, Tetrahedron Letters, 1974,747.

3 Diterpenoids Bicyclic Diterpenoids Clerodin bromolactone. I. C. Paul, G. A. Sim, T. A. Hamor, and J. M. Robertson, J . Chem. Soc., 1962,4133. adduct. K. K. Cheung, D. Melville, Isocolumbin 1-p-iodophenyl-3-phenylpyrazoline K. H.Overton, J. M. Robertson, and G. A. Sim, J. Chem. Snc. (B), 1966,853. Deacetylcascariilin acetal iodoacetate. C. E. McEachan, A. T. McPhail, and G. A. Sim, J. Chem. Soc. (B), 1966,633. Aplysin-20. H. Matsuda, Y. Tomile, S. Yamamura, and Y. Hirata, Chem. Comm.,

1967, 898. p-Bromophenacyl labdanolate. K. Bjamer, G. Ferguson, and R. D. Melville, Act0 Cryst., 1968,B24,855. Isoeremolactone. Y. L. Oh and E. N. Maslen, Acta Cryst., 1968,B24, 883. Dibromoplathyterpol ketone. T. J. King, S. Rodrigo, and S. C. Wallwork, G e m . Comm., 1969,683. Chettaphanin-11. A. Sato, M. Kurabayashi, A. Ogiso, and H. Mishima, Tetruhedron Letters, 1971,839. Clerodendrin Ap-bromobenzoate chlorohydrin. N. Kato, S. Shibayama, K . Munakata, and C. Katayama, Chem. Comm., 1971, 1632;J.C.S. Perkin 11, 1973,69. Gutierolide. W. B.T. Cruse, M. N. G. James, A. A. AlShamma, J. K. Beal, and R. W. Doskotch, Chem. Comm.. 1971, 1278. 2-Keto-3-bromotetrahydroisobulbin A. K. Kamiyama, Y. Wada, T. Komori, M. Arita, and T. Kakisawa, Tetrahedron Letters, 1972, 1869. Concinndiol. J. J. Sims, G. H. Y. Lin, R. M. Wing, and W. Fenical, J.C.S. Chem. Comm., 1973,470. Teucvin A. E. Fujita, I. Uchida, T. Fujita, N. Masaki, and K. Osaki, J.C.S. Chem. Comm., 1973,793;J.C.S. Perkin I, 1974, 1547. Tricyclic Diterpenoids Dibromorosololactone. A. I. Scott, S. A. Sutherland, D. W. Young, L. Guglielmetti, D. Arigoni, and G. A. Sim, Proc. Chem. Soc., 1964, 19. 1,2-Deacetyl-~-caesalpin2-p-bromobenzoate. A. Balmain, K. Bjamer, J. D. Connolly, and G. Ferguson, Tetrahedron Letters, 1967,5027;K. N.Birnbaum and G. Ferguson, Acta Cryst.. 1969,B25,720. Methyl 6cr-bromo-12-rnethoxy-7-oxopodocarpa-8,11,13-trien-l6-oate. R. C. Cambie, G. R. Clark, D. R. Crump, and T. N. Waters, Chem. Cornm.. 1968,183;G.R. Clark and T. N. Waters, J. Chem. Soc. (C), 1970,887. Rosein 111. R. Guttormson, P. Main, A. J. Allison, and K. H. Overton, Chem. Comm.,

1970,719. Rimuene. B. F.Anderson, D. Hall, and T. N. Waters, Acta Cryst. 1970,B26,882. Levopimaric acid. I. L. Karle, Acta Cryst., 1972,B28, 2000. Nagilactone A diacetate. Y. Hayashi, T. Sakan, K. Hirotsu, and A. Shimada, Chem. Letters, 1972, 349.

214

Terpenoids and Steroids

Barbatusinp-bromobenzoyl ester. A. H. J . Wang, 1. C. Paul, R. Zelnik, K. Mizuta, and D. Lavie, J. Amer. Chem. Soc.. 1973, 95, 598. Triptolide. C. J. Gilmore and R. F. Bryan, J.C.S. Perkin 11, 1973, 816. Momilactone. T. Kato, C. Kabuto, N. Sasaki, M. Tsungawa, H. Aizawa, K. Fujita, Y. Kato, and Y. Kitahara, Tetrahedron Letters, 1973, 3861. J. F . Cutfield, T. N . 6cc-Bromo-I3-hydroxy-14-isopropylpodocarp-8,11,13-trien-7-one. Waters, and G. R . Clark, J.C.S. Perkin IZ, 1974, 150. Cyclobutatusin. A. H . J. Wang, I . C. Paul, R. Zelnik, D. Lavie, and E. C . Levy, J . Amer. Cllem. Soc., 1974, %, 580.

Tetruc.yciic.Diterpenoids Bromoepoxynorcafestanone. A. 1. Scott, G. A. Sim. G. Ferguson, D. W. Young, and F. McCapra, J . Amer. Chem. Soc., 1962, 84, 3197. Methyl gibberellate di-p-bromobenzoate. J. A. Hartsuck and W. N. Lipscomb, J. Amer. Chem. Soc.., 1963, 85, 3414. Acetylbromoacetyldihydroenmein. M. Natsume and Y. Iitaka, Acta Cryst., 1966, 20, 197. Reyerol monoethylidene iodoacetate. A. M. O’Sonnell and E. N. Maslen, Acta Cryst., 1966, 21, 744. Methyl bromogibberellate. F. McCapra, A. T. McPhail, A. I. Scott, G. A. Sim, and D. W. Young, J. Chem. Sue. (0, 1966, 1577. 16-Methyl- 1 5-bromoacetoxyenmein. P. Coggon and G. A. Sim, J . Chem. Soc. (B), 1969, 413. Grayanotoxin I. P. Narayanan, M. Rohrl, K. Zechmeister, and W. Hoppe, TetraI i r h w i Lettcrs, 1970, 3943. Aphidicolin. K. M. Brundret, W. Dalziel, B. Hesp, J. A. J. Jarvis, and S. Neidle, J.C.S. Chrm Comm.. 1972, 1027. Grayanotoxin XV. N. Hamanaka, H. Miyakoshi, A. Furusaki, and T. Matsumoto, Chem. Letters. 1972, 779. Leucothol A. A. Furusaki, N. Hamanaka, H. Miyakoshi, T. Okuno, and T. Matsumoto, Chem. Letters. 1972, 783. Leucothol B. N. Hamanaka, H. Miyakoshi, A. Furusaki, and T. Matsumoto, Chern. Letters. 1972, 787. 70-Hydroxykaurenolide and beyeran-3a-01p-bromobenzenesulphonates. J. R. Hanson, G. M. McLaughlin, and G. A. Sim, J.C.S. Perkin 11. 1972, 1124. (-)-Kaur-15-en-l9-al. I. L. Karle, Acta Cryst., 1972, B28, 585. Mebadonin. K. Hirotsu, T. Kamikawa, T. Kubota, A. Shimada, and T. Isobe, Chern. Letters, 1973, 255. Grayanol A. S. Fushiya, H. Hikino, and T. Takemoto, Tetrahedron Letters, 1974, 183. Pharbitic acid. T. Yokota, S. Yamazaka, N. Takahashi, and Y. Iitaka, Tetrahedron Lc.tters, 1974, 2957. hlucwcyclic Diterpenoids and Related Cyclization Products. Cembrene. M. G . B. Drew, D. H . Templeton, and A. Zalkin, Acta Cryst., 1969, B E , 261. Eunicin iodoacetate. M. B. Hossain, A. F. Nicholas, and D. van der Helm, Chem. Comm.. 1968. 385.

Terpenoid Structures Determined by X - Ray Analysis

215

Eunicellin dibromide. 0. Kennard, D. G. Watson, L. Riva di Sanseverino, B. Tursch, R. Bosmans, and C. Djerassi, Tetrahedron Letters, 1968, 2879; 0. Kennard, D. G. Watson, and L. Riva di Sanseverino, Acta Cryst., 1970, B26, 1038.

Phorbol and its Derivatives Phorbol bromofuroate. R. C . Pettersen, G. Ferguson, L. Crombie, M. L. Games, and D. J. Pointer, Chem. Comm., 1967,716; R. C. Pettersen, G. I. Birnbaum, G. Ferguson, K. M. S. Islam, and J. G. Sime, J. Chem. SOC.(B), 1968, 980. Neophorbol- 13,20-diacetate 3-p-bromobenzoate. W. Hoppe, F. Brandl, I. Strell, M. Rohrl, J. Gassmann, E. Hecker, H. Bartsch, G. Kreibich, andCh. von Szczepanski, Angew. Chem., 1967,79, 824 (Angew. Chem. Internat. Edn., 1967,6,809);W. Hoppe, F. Brandl, M. Rohrl, and K. Zechmeister, Acta Cryst., 1971, B27, 1718. 12,13,20-Lumiphorbol triacetate 4-p-bromobenzoate. E. Hecker, E. Harle, H. U. Schairer, P. Jacobi, W. Hoppe, J. Gassmann, M. Rohrl, and H. Abel, Angew. Chem., 1968,80,913 (Angew. Chem. Internat. Edn., 1968,7, 890). Phorbol. W, Hoppe, K. Zechmeister, M. Rohrl, F. Brandl, E. Hecker, G. Kreibich, and H. Bartsch, Tetrahedron Letters, 1969,667; F. Brandl, M. Rohrl, K. Zechmeister, and W. Hoppe, Acta Cryst., 1971, B27, 1718. Ingenol triacetate. K. Zechmeister, F. Brandl, W. Hoppe, E. Hecker, H. J. Opferkuch, and W. Adolf, Tetrahedron Letters, 1970, 4075. 6,20-Epoxylathyrol phenylacetate diacetate. K. Zechmeister, M. Rohrl, F. Brandl, S. Hechtfischer, W. Hoppe, E. Hecker, W. Adolf, and H. Kubinyi, Tetrahedron Letters, 1970, 3071. Daphnetoxin. G. H. Stout, W. G. Balkenhol, M. Poling, and G. L. Hickernell, J . Amer. Chem. SOC.,1970,92, 1070. Huratoxin. K. Sakata, K. Kawazu, T. Mitsui, and N. Masaki, Tetrahedron Letters, 1971, 1141. 7-Hydroxylathyrol 3,5,7-triacetate. P. Narayanan, M. Rohrl, K. Zechmeister, D. W. Engel, W. Hoppe, E. Hecker, and W. Adolf, Tetrahedron Letters, 1971, 1325. 12-Hydroxydaphnetoxin. J. Coetzer and M. J. Pieterse, Acta Cryst., 1972, B28, 620.

Taxanes 2,5,9,1O-Tetra-acetyl-14-bromotaxinol. M. Shiro, T. Sato, H. Koyama, K. Nakanishi, and S. Uyeo, Chem. Comm., 1966,97; M. Shiro and H. Koyama, J . Chem. Soc. (B), 1971, 1342. Taxa-4( 16)-1l-diene-5,9,10,13-tetraolp-bromobenzoate. K. Bjamer, G. Ferguson, and J. M. Robertson, J. Chem. SOC.(B), 1967, 1272. Baccatin V. D. P. Della Casa de Marcano, T. G. Halsall, E. Castellano, and 0. J. R. Hodder, Chem. Comm.-, 1970, 1382; Acta Cryst., 1973, B29, 2566. 'Taxinine. M. Shiro and H. Koyama, J. Chem. Soc. (B), 1971, 1342. Taxol. M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggan, and A. T. McPhail, J . Amer. Chem. SOC.,1971,93,2325. Jatrophonedihydrobromide. S. M. Kupchan, C. W. Sigel, M. J. Matz, J. A. S. Renauld, R. C. Haltiwanger, and R. F. Bryan, J. Amer. Chem. SOC.,1970, 92, 4476; R. C. Haltiwanger and R. F. Bryan, J. Chem. Soc. (B), 1971, 1598.

216

Terpenoids and Steroids

Miscelluneous Diterpenoids Ginkgolide-A mono-p-bromobenzoate. N. Sakabe, S. Takada, and K. Okabe, Chem. Comm., 1967. 259. Portulal p-bromophenylsulphonylhydrazone. S. Yamazaki, S. Tamura, F. Marumo, and Y . Saito, Tetrahedron Letters, 1969, 359; Acta Cryst., 1971, B27, 2097. Cyathin A,. W. A. Ayer and H. Taube, Tetrahedron Letters, 1972, 1917. Pachydictyol. D. R. Hirshfeld, W. Fenical, G. H. Y. Lin, R. M. Wing, P. Radlick, and J. J. Sims, J . Amer. Chem. Soc., 1973, 95,4049. Sarcophine. J. Bernstein, U. Schmeuli, E. Zadock, Y . Kashman, and I. Neeman, Tetrahedron, 1974, 30, 28 17.

4 Sesterterpenoids Ophiobolin methoxybromide. M. Morisaki, S. Nozoe, and Y . Iitaka, Acta Cryst., 1968, B24, 1293. Methyl cephalonate bromoacetate. A. Itai, S. Nozoe, S. Okuda, and Y. Iitaka, Acta Cryst., 1969, B25, 872. Ceroplastol I p-bromobenzoate. Y. Iitaka, 1. Watanabe, and I. T. Harrison, Acta Cryst., 1969, B25, 1299. Derivative of Ophiobolin D. S. Nozoe, A. Itai, and Y. Iitaka, Chem. Comm., 1971,872. Retigeranic acid p-bromoanilide. M. Kaneda, Y. Iitaka, and S. Shibata, Acta Cryst., 1974, B30, 358. Fusicoccin A p-iodobenzenesulphonate. M. Brufani, S. Cerrini, W. Fedeli, and A. Vaciago, J . Chem. Soc. (B), 1971, 2021. Fusicoccin deacetyl aglycone mercuribromide. E. Hough, M. B. Hursthouse, S. Neidle, and D. Rogers, Chem. Comm., 1968, 1197. 5 Triterpenoids Squalene Group. Daphniphylline hydrobromide. N. Sakabe and Y. Hirata, Tetrahedron Letters, 1966, 965. Yuzurimine hydrobromide. H. Sakurai, N. Sakabe, and Y. Hirata, Tetrahedron Letters, 1966, 6309. Methyl N-bromoacetylhomosecodaphniphyllate. Y. Sasaki and Y. Hirata, J. Chem. Soc. (B), 1971, 1565. Daphnilactone A. K. Sasaki and Y. Hirata, J.C.S. Perkin 11, 1972, 1411. Daphnilactone B. K. Sasaki and Y. Hirata, Acta Cryst., 1973, B29, 547. Yuzurine. S. Yakamura, K. Sasaki, M. Toda, and Y. Hirata, Tetrahedron Letters, 1974, 2023. Daphnimacropine. N. Kamijo, T. Nakano, Y. Terao, and K. Osaki, Tetrahedron Letters, 1966, 2889. Macrodaphnine hydrobromide. T. Nakano and B. Nilsson, Tetrahedron Letters, 1969, 2883. Daphmacrine. C. S. Gibbons and J. Trotter, J . Chem. Soc. (B), 1969, 840. Fusidane Lunostane Group Fusidic acid methyl ester p-bromobenzoate. A. Cooper and D. C. Hodgkin, Tetrahedron, 1968, 24, 909.

Terpenoid Structures Determined by X-Ray Analysis

217

Lanostenyl iodoacetate. J. Fridrichsons and A. McL. Mathieson, J. Chem. Soc., 1953, 2159. 3P-Acetoxy-7a,1la-dibromolanostane-8a,9a-epoxide.J. K. Fawcett and J. Trotter, J. Chem. SOC.(B), 1966, 174. (23R)-3a-Methoxy-5a,9~-lanosta-7,24-diene-26,23-lactone (abieslactone). F. H. Allen, N. W. Isaacs, 0. Kennard, and W. D. S. Motherwell, J.C.S. Perkin II, 1973, 498. (24S),25-Dibromolanostenyl acetate. C. H. Carlisle and P. A. Timmins, J. Cryst. Mol. Structure, 1974, 4, 31. Bis-p-bromobenzoate derivative of cyclograndisolide [3or-methoxy-9,l9-cyclo-9~lanost-24-en-26,(23R)-olide]. F. H. Allen and J. Trotter, J . Chem. Soc. ( B ) , 1971, 1079. Pollinastanol acetate. A. Ducruix, C. Pascard-Billy, M. Devys, M. Barbier, and E. Lederer, J.C.S. Chem. Comm., 1973, 929. Datiscoside bis-p-iodobenzoate. R. J. Restivo, R. F. Bryan, and S. M. Kupchan, J.C.S. Perkin II, 1973, 892.

Dammurane-Euphane Group. Bromo-derivative of betulafolienetriol. 0.Tanaka, N. Tanaka, T. Ohsawa, Y. Iitaka, and S. Shibata, Tetrahedron Letters, 1968, 4235. 3~,12~-O-bis-p-bromobenzoylpyxinol. H. Yamauchi, T. Fujiwara, and K. Tomita, Tetrahedron Letters, 1969, 4245. Bacogenin A, dibromoacetate. K. Kawai, Y. Iitaka, S. Shibata, D. K. Kulshreshtha, and R. P. Rastogi, Acta Cryst., 1973, B29, 2947. Euphenyl iodoacetate. M. F. C. Ladd and C. H. Carlisle, Acta Cryst., 1966, 21, 689. 24,25-Dibromokulactone. K. W. Ma, F. C. Chang, and J. C. Clardy, Chem. Comm., 1971, 424. Glabretal. G. Ferguson, P. A. Gunn, W. C . Marsh, R. McCrindle, R. Restivo, J. D. Connolly, J. W. B. Fulke, and M. S. Henderson, J.C.S. Chem. Comm., 1973, 159. Epilimonol iodoacetate. S. Amott, A. W. Davie, J. M. Robertson, G. A. Sim, and D. G. Watson, J. Chem. SOC.,1961,4183. Dihydrogedun-3B-yl iodoacetate. S. A. Sutherland, G. A. Sim, and J. M. Robertson, Proc. Chem. SOC.,1962,222. Cedrelone iodoacetate. I. J. G. Grant, J. A. Hamilton, T. A. Hamor, J. M. Robertson, and G. A. Sim, J. Chem. SOC.,1963,2506. Detigloylswietenine p-iodobenzoate. A. T. McPhail and G. A. Sim, J. Chem. Soc. (B), 1966, 318. Mexicanolide derivative. S. A. Adeoye and D. A. Bekow, Chem. Comm., 1965, 301. Utilin. H. R. Harrison, 0. J. R. Hodder, C. W. L. Bevan, D. A. H. Taylor, and T. G. Halsall, Chem. Comm., 1970, 1388. Phragmalin. R. R. Arndt and W. H. Baarchers, Tetrahedron, 1972, 28, 2333. Fraxinellone. P. A. Coggon and A. T. McPhail, J. Chem. Soc. (B), 1970, 1521. Simarolide 4-iodo-3-nitrobenzoate. W. A. C. Brown and G. A. Sim, Proc. Chem. SOC., 1964, 293. Glaucarubin p-bromobenzoate. G. Kartha, and D. J. Haas, J. Amer. Chem. Soc., 1964,86, 3630. Bisnorquassin. H. Lynton, Cnnad. J. Chem., 1970, 48,307.

218

Terpenoids and Steroids

Baccharane Group Baccharis Oxide. F. Mo, Acta Cryst., lY73, B29, 1796. Lupune Group. 3~-Acetoxy-20-hydroxylupane.W. H. Watson, H.-Y. Ting, and X. A. Dominguez, Actu Cryst., 1972, B28, 8. Oleanane Group Methyl oleanate iodoacetate. A. M. A. El Rahim and C. H. Carlisle, Structure Reports, 1956, 20, 645. Phytolaccagenin 2-oxazoline derivative. G. H. Stout, B. M. Malofsky, and V. F. Stout, J . Amrr.. Chem. Soc., 1964, 86, 957. Methyl melaleucate iodoacetate. S. R. Hall and E. N. Maslen, Acta Cryst., 1965, 18, 265. Eupteleogenin iodoacetate. M. Nishikawa, K. Kamiya, T. Murata, Y. Tomiie, and I. Nitta, Tetrahedron Letters, 1965, 3223. Protoaescigenin-2 1-tiglate-22-acetate. W. Hoppe, A. Gieren, N. Brodherr, R. Tschesche, and G. Wulff, Angew Chem., 1968,80, 563. Platicodigenin bromolactone. T. Akiyama, Y. Iitaka, and 0. Tanaka, Acta Cryst., 1970, B26, 163. Genin D. J.-P. Mornon, Compt. rend., 1970, 270, C, 926. I ( 10+5)abeo-3p-Methyl-24B-nor-25a, 1 8a-oleanane. G. W. Smith, Acta Cryst ., 1970, B26, 1746. 18a-Oleanane. G. W. Smith, D. T. Fowell, and B. G. Melsom, Nature, 1970,228, 355. Katonic acid ketoacetate. W. E. Thiessen, H. A. Levy, W. G. Dauben, G. H. Beasley, and D. A. Cox, J. Amer. Chem. Soc., 1971, 93,4312. Echinocystic acid bromolactone diacetate. C. H. Carlisle, P. F. Lindley, A. Perales, R. B. Boar, J. F. McGhie, and D. H. R. Barton, J.C.S. Chem. Cornrn., 1974, 284. Gymnemagenin. R. Hoge and C. E. Nordman, Acta Cryst., 1974, B30, 1435. Bromolactone of 3P,27-diacetoxyoleanolic acid. T. G. D. van Schalkwyk and G. J. Kruger, Acta Cryst., 1974, B30, 2261. Friedelan-3~-01chloroacetate. E. J. Corey and J. J. Ursprung, J. Amer. Chem. SOC., 1956, 78, 504 1. 3-0-Acetyl- 16-0-bromobenzoylpachysandiol-B.T. Kikuchi, M. Niwa, and N. Masaki, Tetruhedron Letters, 1972, 5249. Dendropanoxide. J . D. White, J. Fayos, and J. Clardy, J.C.S. Chem. Cornm., 1973, 357. Friedelan 25,26-oxide. D. Rogers, D. J. Williams, B. S. Joshi, V. N. Kamat, and V. Viswanathan, Tetrahedron Letters, 1974, 63. Pristimerol bis-p-bromobenzoate. P. J. Ham and D. A. Whiting, J.C.S. Perkin I , 1972, 330. Tingenone. P. M. Brown, M. Moir, R. H. Thomson, T. J. King, V. Krishnamoorthy, and T. R. Seshadri, J.C.S. Perkin I, 1973, 2721. Hopantc Group. 6-Ketoleucotyiine- 16P-0-p-bromobenzoate. T. Nakanishi, T. Fujiwara, and K. Tomita, Tetrahedron Letters. 1968, I49 1 .

Terpenoid Structures fhtermincd by X - Ray Analysis

219

Motiol iodoacetate. Y. Nishi, T. Ashida, Y. Sasada, and M. Kakudo, Bull. Chem. SOC. Jupan, 1968, 41, 1308. Adiantol B bromoacetate. H. Koyama and H. Nakai, J. Chem. SOC.(B), 1970, 546. 6-0-p-Bromobenzoylzeorin. T. Nakanishi, H. Yamauchi, T. Fujiwara, and K. Tomita, Tetrahedron Letters, 197 I , 1 157. p-Bromophenacyl retigerate. A. R. Takahashi and Y . Iitaka, Acta Cryst., 1972, B28, 764. Spergulagenin A. I . Kitagawa, H. Suzuki, I. Yosioka, T. Akiyama, and J . V. Silverton, Tetrahedron Letters, 1974, 1 173. Davallol iodoacetate. Y. L. Oh and E. N. Maslen, Actu Cryst., 1966, 20, 852. Tetrahymanone. J. T. Gordon and T. H. Doyne, Act0 Cryst., 1966, 21, A1 13. Ursane Group Methyl ursolate bromoacetate. G. H. Stout and K. L. Stevens, J. Org. Chem., 1963, 28, 1259. 23-Hydroxy-2.3-secours-12-ene-2,3,28-trioicacid 2.23-lactone 3,28-dimethyl ester. H. R. Harrison, 0. J. R. Hodder, S. Brewis, and T. G. Halsall, J . Chem. Soc. (C), 1971. 2525. Arborinane Group. 2cr-Bromoarborinone. 0. Kennard, L. Riva di Sanseverino, and J. S. Rollet, Tetrahedron, 1967, 23, 131. Serrutanr Group. Bromoindole derivative of 3fi-methoxy-21-keto-A 13-serratene. F. H. Allen and J. Trotter, J. Chem. Soc. (B), 1970, 721.

6 Carotenoids

p-Carotene. C. Sterling, Acta Cryst., 1964, 17, 1224. 15,15’-Didehydro-fi-carotene. W. G. Sly, Acta Cryst., 1964, 17, 51 1. Canthaxanthin. J. C. Bart and C. H. MacGillavry, Acta Cryst., 1968, B24, 1587. 15,15’-Didehydrocanthaxanthin.J. C. Bart and C. H. MacGillavry, Aczu Crysf., 1968, B24, 1569. Crocetindial. J. Hjortih, Acta Cryst., 1972, B28,2252. 11-cis-Retinal. R. Gilardi, I. L. Karle, J. Karle, and W. Sperling. Nature, 1971, 232. 187; R. D. Gilardi, I. L. Karle, and J. Karle, Actu Cryst., 1972, B28, 2605. all-trans-Retinal. R. Gilardi, I. L. Karle, J. Karle, and W. Sperling, Nature, 1971, 232, 187; T. Hamanaka, T. Mitsui, T. Ashida, and M. Kakudo, Acta Cryst., 1972, B28, 214. Retinoic acid. C. H. Stam, Actu Cryst., 1972, B28, 2936; C. H. Stam and C. H. MacGillavry, ibid., 1963, 16, 62. Retinyl acetate. W. E. Oberhansli, H. P. Wagner, and 0. Isler, Acta Cryst., 1974, B30, 161. trans-p-Ionylidenecrotonic acid. E. L. Eichorn and C. H. MacGillavry, Actu Cryst., 1959, 12, 872.

220

Terpenoids and Steroids

9-cis-P-Ionylidenecrotonic acid. B. Koch and C . H. MacGillavry, Acta Cryst., 1963, 16, A48. Retro-/I-ionylideneacetyl-p-bromoanilide. S. Paul-Roy. H. Schenk, and C. H. MacGillavry, Chem. Comm., 1969, 1517.

Part 11

STEROIDS

1 Steroid Properties and Reactions BY D. N. KIRK

1 Structure, Stereochernistry,and Conformational Analysis The calculation of molecular structures and enthalpies of steroids and related molecules by the ‘force-field’ method (‘molecular mechanics’) was reported in earlier volumes.l a A critical evaluation for a wide variety of hydrocarbons (not steroids), ranging from ethane to complex bridged-ring hydrocarbons, gives strong support to the validity of the procedure.lb The accuracy of calculated bond lengths and angles rivals data obtained by experimental methods. A new development in this field which challenges one of the fundamental concepts of conformational analysis therefore demands serious attention. Since the pioneering work of Barton over twenty years ago, the observed preference of cyclohexane derivatives for the conformation which puts a bulky substituent in an equatorial position has been attributed to the avoidance of 1,3-diaxial interactions. Wertz and Allinger2 now propose, with strong support from force-field calculations and other data, that the conformational preference has its origin largely in the tertiary hydrogen atom avoiding the equatorial conformation, where it is considered to suffer unfavourable interactions with vicinal hydrogen atoms. A substituent, even the rather bulky methyl group, is then forced to occupy the equatorial position by default. The basis of this revision of previous theory is that the van der Waals radius of hydrogen has been grossly under-estimated, so that two vicinal hydrogens in the gauche conformation (dihedral angle ca. 60”) are in a state of mutual compression and repulsion. An equatorial hydrogen in a cyclohexane system is subject to two such interactions, compared with only one in the axial configuration. The magnitude of the resulting destabilization is estimated as 0.9 kcal mol-I (the ‘equatorial hydrogen effect’).2 The 1,3-interaction of an axial methyl group with axial hydrogens, in contrast, is considered to contribute only some 25-30 % of the total conformational free energy difference; 1,3-diaxialinteractions between methyl and hydrogen, which are of ‘gauche-butane’ (‘skew-butane’) type, have apparently been very much over-estimated. The paper putting forward these new ideas appeared too late in the period under review for the Reporter to assess its full significance for steroid chemistry, but many of the interpretations placed upon steroid phenomena will need reconsideration in terms of the equatorial hydrogen effect if this new proposition should find general acceptance. The authors themselves2comment upon only a limited number of features ( a) ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1974, Vol. 4, p. 311; 1973, Vol. 3, p. 279; 1971, Vol. I , p. 263; ( 6 ) E. M. Engler, J. D. Andose, and P. von R. Schleyer, J . Amer. Chem. SOC.,1973, 95, 8005. D. H. Wertz and N. L. Allinger, Tetrahedron, 1974, 30, 1579.

223

224

7erpenoids und Steroids

pertaining to steroid chemistry. These include the stereochemistry of reduction of unhindered cyclohexanones by hydride donors, where the preference for formation of the equatorial alcohol follows from the need to minimize compression between the approaching hydride and the vicinal hydrogen atoms. The new interpretation differs only in detail from Felkin's explanation in terms of torsional strain. (For further discussion of cyclohexanone reductions see p. 246.) The small size of the '3-axial ketone effect' and the faster oxidation of axial compared with equatorial alcohols also find novel explanations.2 The new hypothesis, if valid, must be seen as one of those rare advances demanding substantial revision of much that has been written in its field of application. Differences in steric energy between a series of Sa-steroidal3-ketones and the corresponding A2-olefins,computed by the force-field method, show a significant correlation with observed rates of formation of the 2-benzylidene derivatives from the ketone^.^ Although the authors have deliberately omitted from their calculations such complicating features as solvation and entropy effects, the result is an encouraging step towards the prediction of reaction rates and supports the concept of conformational transmission as an important contributor to reaction rates. Calculations4 of the conformational strains in methyl-substituted trans-2-decalones should aid understanding of the distortion of ring A in 4,4-dimethyl-3-oxo-5a-steroids. A new study5 of the equilibration of 5a- and S~~-cholestan-4-ones, using carefully authenticated and purified samples, has essentially confirmed the recently revised6 composition of the equilibrium mixture (87 k 1 ":, of the 5cl-isomer in ethanol at 25 "C). The present data are consistent with experimental and computed ('molecular mechanics') conformational free energy differences in the 1-decalone series, as well as for 5a- and S[&cholestan-6-ones. Conformational studies on A-homo-steroids have been extended to a series of 4a-0x0-derivatives7 and to the ~-homo-6-ketone(l),which prefers the 5fi- to the Sa-configuration, the ratio being 4 : 1 at equilibrium,8 unlike the analogous normal steroids; the c.d. curves for these ketones are also unusual in that the Sa-isomer in the A-homo-series gives the larger negative value of Ac.

Spectroscopic Methods-N.M. R. Spectroscopy. Measurement of chemical shift differences for the solvent pairs DMSO-pyridine or CDCI,-pyridine permits estimation of the dihedral angle between OH and Me groups attached to adjacent carbon atoms. The method is reported to have been used successfully for a variety of hydroxy-steroids N . L. Allinger and G. A. Lane, J. Amer. Chem. SOC.,1974, 96, 2957. W. Schubert, L. Schafer, and G. H. Pauli, J . C . S . Chem. Comm., 1973,949. N. L. Allinger, G. A. Lane, and G. L. Wang, J. Org. Chem., 1974, 39, 705. ' Ref. la, 1972, Vol. 2, p. 231. H. Velgova, V. Cerny, and F. Sorm, CON. Czech. Chem. Comm., 1973, 38, 2751. H. Velgova and V. Cernp, CON.Czech. Chem. Comm., 1973,38, 2976.

Steroid Properties and Reactions

225

and -terpenoids and also for aliphatic alcohols and phenols. An 0x0-group close to methyl may disturb the results.' A preliminary communication' gives magnetic anisotropies and electric field effects for hydroxy-, amino-, chloro-, and bromo-substituents. 5a-Androstane derivatives were among those studied, but full details of this work are not yet available. 'H N.m.r. spectra of 78 steroids of the 10a- and 9P,10apregnane series, derived from the cucurbitacins, give evidence of preferred conformations and show that some of the compounds have deformed rings." 'H N.m.r. spectra (also optical rotation data and i.r. spectra) have been discussed for a collection of steroidal 5a,6a-diols.' 15416a-Methylene-steroids are distinguished from the 15/3, 16P-isomers by 'H n.m.r. spectroscopy, or in the case of the 17-0x0-derivatives by the signs of their Cotton effects, where the methylene group has an apparently dissignate (anti-octant) effect.' Low-temperature n.m.r. study of solutions of steroid ketones and boron trifluoride has made it possible to observe separate proton signals for free and complexed ketone molecules, as well as 19Fsignals for BF, bound at different sites in dike tone^.'^ Poor agreement between lanthanide-induced shifts of proton signals in some ketones and those predicted by the McConnell-Robertson equation is considered to suggest the need for an additional term, with non-axial symmetry.I5 The implications for steroid spectra have still to be explored. Another author,I6 concerned with the same problem, considers that the lanthanide atom in complexes of the type ketone-[Pr(dpm),] may occupy either of two positions, on either side of the C=O axis, rather than the position along the axis normally assumed: induced shifts calculated on this basis appear to support the hypothesis. The complex (2), derived from dihydrolanosterone, has been

examined as a chiral reagent for inducing different shifts in enantiomeric compounds, but was much less effective than complexes based upon camphor and related compounds.' Fourier-transform 13C n.m.r. spectra have been assigned for a series of 0x0-5asteroids (androstanes and cholestanes), including representative compounds with oxofunctions at each of the skeletal positions.'* The parent hydrocarbons were also B. P. Hatton, C. C. Howard, and R. A. W. Johnstone, J.C.S. Chem. Comm., 1973, 744. A. K. Davis, D . W. Mathieson, P. D. Nicklin, J. R. Bell, and K. J. Toyne, Tetrahedron Letters, 1973, 413. I ' J. R. Bull, A. J. Hodgkinson, and A. Tuinrnan, Tetrahedron, 1973, 29, 2415. l 2 M. Fetizon, M. Golfier, and J. Rens, Ann. Chim. (France), 1973, 8, 161. l 3 G.-A. Hoyer, G . Cleve, and R. Wiechert, Chem. Ber., 1974, 107. 128. l 4 R . E. Schuster and R. D . Bennett, J . Org. Chem., 1973, 16, 2904. l 5 R. H. Newman, Tetrahedron, 1974, 30, 969. l 6 D . J. Chadwick, Tetrahedron Letters, 1974, 1376. l 7 M. D . McCreary, D. W. Lewis, D. L. Wernick, and G. M. Whitesides, J . Amer. Chem. SOC., 1974, 96, 1038. '* H. Eggert and C. Djerassi, J . Org. Chem., 1973, 38, 3788. lo

Terpenoids and Steroids

226

examined, and signal assignments were made with the aid of specific deuterium labelling : the replacement of hydrogen by deuterium at a particular carbon atom decreases the intensity of the 3C n.m.r. signal dramatically. By taking an overall view of the data, the chemical shifts for the a- (carbonyl) carbon atom and for the p- and y-carbon atoms were found to vary in regular manner with the local substitution pattern. Some characteristic isotope effects of deuterium on chemical shifts were also noted.' * A detailed analysis of the 3C n.m.r. spectra of progesterone, deoxycorticosterone, corticosterone, cortisol, and other hydroxy-progesterone derivatives provides a valuable insight into the factors which may contribute to chemical shifts in such c o m p ~ u n d s . ' ~ The assignment of signals to individual carbon atoms for each of the compounds has allowed the recognition of substituent effects operating at the a-, p-, y-, and even in some cases the &carbon atoms. Significant effects may occur at even greater range when the influence of a substituent is transmitted through conformational distortion involving buttressing. As an example, a 17a-hydroxy-group in (3) induces an upfield shift at C-7, the mutual compression of the 17a-OH and 14a-H apparently resulting in significant distortion at the adjacent C-7. Shifts due to specific deuterium substitution were valuable in the assignment of signals.'

'

'

3C N.m.r. spectra permit the assignment of configuration to epoxy-steroids. Of several characteristic effects noted, the most useful appears to be a pronounced shielding ( 3 . 5 4 p.p.m.) of the carbon atom described as 'homoallylic', or ' y from oxygen' if this atom carries an axial hydrogen atom which is cis to the epoxide oxygen.20 The corresponding trans relationship leads to little change in the carbon chemical shift. By way of illustration, C-5 in a 2~,3a-epoxy-5a-steroid(4)is shielded by 5 p.p.m. compared with the same carbon atom in the [j-epoxide.

(4)

C N.m.r. spectra of cholic, deoxycholic, chenodeoxycholic, and lithocholic acids, and some of their derivatives, have been analysed with use of lanthanide shift reagents.21 13

l9

N. S. Bhacca, D. D. Giannini, W. S. Jankowski, and M. E. Wolff, J . Amer. Chem. SOC.,1973, 95, 8421.

' O

''

K. Tori, T. Komeno, M. Sangare, B. Septe, B. Delpech, A. Ahond, and C . Lukacs, Tetrahedron Letters, 1974, 1157. D. Leibfritz and J. D. Roberts, J . Amer. Chem. Sor., 1973, 95, 4996.

Steroid Properties and Reactions

227

Distinctive features of 5u- and 5/?-isomersare noted. Spectra have also been recorded for D 2 0 solutions containing p-xylene or 2-methylnaphthalene, rendered soluble by sodium deoxycholate, with which the hydrocarbons form inclusion complexes in solution.2 3C N.m.r. data have been analysed for a series of ergostadiene derivatives22and for a variety of polyhydroxypregnan-20-one derivative^.^^ Lanthanide-induced shifts of a-carbon atoms in the I3C n.m.r. spectra of ketones include significant contact as well as pseudo-contact contribution^.^^ Circular Dichroisrn. The most comprehensive empirical analysis of c.d. data ( n + n*) so far reported for steroidal ketones, and related compounds of the decalone class, has confirmed the long-assumed additivity of contributions due to separate parts of the ) to individual rings and alkyl hydrocarbon framework.25 Contributions ( ~ A Eassigned substituents allow the prediction of AE values for a wide variety of ketones based upon structures of either trans- or cis-decalone types, in any of four common solvents (hexane, MeCN, dioxan, and MeOH). Further analysis of data has suggested that the sign and magnitude of the c.d. curve are largely determined by the number of C-C bonds in the ketone molecule which form part of a particular planar zig-zag of bonds (the so-called ‘primary zig-zag’), exemplified for an all-trans structure of the 4-0x0-5a-steroid type in Figure 1. The only other C-C bonds found to make major contributions to AE are

Figure 1 4-0x0-5cc-steroid and octant projection, illustrating a ‘primary zig-zug’ of C-C bonds

those of a-axial and 8-axial alkyl substituents, and certain ‘front-octant’ groups. Some other regularities are noted, including structural features which regularly exhibit d i ~ s i g n a t ebehaviour ~~ and instances of enhancement of c.d. contributions when exceptionally strained C-C bonds form part of a primary This work complements earlier findings by H ~ d e cconcerning ,~~ the c.d. effectsof heteroatom substituents. A 19-acetoxy-group has a significant effect on the chiroptical properties of a 4,4dimethyl-5a-3-oxo-steroid, which is thought to reflect increased distortion of ring A by steric strain. The effect is absent in the analogous S/i’-compounds, where C-19 is not compressed by the 4,4-dimethyl system.28 The c.d. curves for 2a- and 28-acetoxysteroidal 4-en-3-ones and their 19-nor analogues obey Snatzke’s ‘reverse-octant’ 22

23

24

25

26

2’

R. J. Abraham and J. R. Monasterios, J.C.S. Perkin I I , 1974, 662. T. Yamagishi, K. Hayashi, H. Mitsuhashi, M. Imanari, and K. Matsushita, Tetrahedron Letters, 1973, 3527, 3 5 3 1 , 4735. D. J. Chadwick and D. H. Williams, J.C.S. Chem. Comm., 1974. 128. D. N. Kirk and W. Klyne, J.C.S. Perkin I, 1974, 1076. W. Klyne and D. N. Kirk, Tetrahedron Lefters, 1973, 1483. Ref. la, 1972, Vol. 2, p. 235. G. Snatzke, W. Graf, H.-D. Schlatter, and C. Luthy, Helo. Chim. Acta, 1974. 57, 1055.

Terpenoids and Steroids

228

rule29for the n + n* transition (330 nm) in transoid enones, when the unusual conformation of ring A in the 2P-isomers is taken into account.30 The Cotton effects at ca. 240 nm (z-+ n*) follow the helicity rule,31 but disagree with predictions based upon the chirality contributions of allylic axial s u b ~ t i t u e n t s .The ~ ~ third c.d. band for these enones (210-220 nm) likewise fails to follow the suggested dependence upon a'-axial in the case of the 2P-i~orners.~~ The need for further study of the low-wavelength c.d. of enones is evident. The isomeric (2)- and (E)-3-ethylidene-Sa-cholestanes[(5) and (6), respectively] give c.d. curves of enantiomeric type. reflecting the chirality of the rigid ethylidenecyclohexane component.33 Comparison of the oestr-4-ene structure (7) with the (E)ethylidene compound (6) reveals the broad similarity of the local environments of the olefinic bonds, which results in a close resemblance between their c.d. curves. The authors point out that signs of c.d. curves of other steroidal olefins which include a A'(9)-octalin unit [ef (711 [e.g. oestr-5-enes, and steroidal 7-enes or 9(1l)-enes] are also dominated by the chirality of the 'ethylidenecyclohexane' c o r n p o n e n t ~ . ~ ~

1

i

H

Me

I

H

H (5)

z

(6) E

H (7)

C.d. spectra for pure samples of 6a- and 6P-hydroxyoestradiols conform to the patterns established for the 6P-hydroxyoestriol derivatives (6a, two negative Cotton effects ; 68, two positive).34 Earlier data for 6P-hydroxyoestradiol appear to refer either to different or to impure material. The electronic interactions between the 170x0-function and the aromatic ring in oestrone and related compounds have been investigated by U.V. and c.d. studies.35 Exciton splitting of c.d. curves has been observed for compounds with two separate chromophores absorbing in the 230-260 nm range, which include benzoate esters and aP-unsaturated ketones.36 The c.d. curve then exhibits two maxima of opposite sign, the one at higher wavelength showing the sign corresponding to the chirality defined by the directions of the electric transition moments of the two chromophores. Compounds exa'mined include the benzoates and 6a- and 6/3-hydroxycholest-4p-chlorobenzoates of 3fl-hydroxycholest-5-en-7-one, en-3-ones (opposite chiralities), and 7a-hydroxycholest-4-en-3-0ne.~~ The chiroptical properties of steroidal ally1 sulphoxides show a complicated dependence upon the stereochemical relationship of the sulphoxide and olefinic groups and 29 30 31

32

33 34

35 36

G . Snatzke, Tetrahedron, 1965, 21, 413. R. D. Burnett and D. N. Kirk, J . C . S . Perkin I , 1973, 1830; ibid., 1974, 284. A. Moscowitz, E. Charney, U. Weiss, and H. Ziffer, J . Amer. Chem. Soc., 1961, 83, 4661; C. Djerassi, R. Records, E. Bunnenberg, K. Mislow, and A. Moscowitz, ibid., 1962, 84, 870. A. W. Burgstahler and R. C . Barkhurst, J . Amer. Chem. SOC.,1970, 92, 7601; Ref. l a , 1972, Vol. 2, p. 234. D. N. Kirk and R. J. Mullins, J.C.S. Perkin Z, 1974, 14. E. P. Burrows, S. L. Jones, and H . E. Smith, J . Org. Chem., 1973, 38, 3797. G. A. Kogan, A. V. Zakharychev, T. N. Deshko, V. V. Egorova, and S. N. Ananchenko, Zhur. obshchei Khim., 1973, 43, 2321. M. Koreeda, N. Harada, and K. Nakanishi, J . Amer. Chem. Soc., 1974, 96, 266.

229

Steroid Properties and Reactions

upon the solvent.37 C.d. and U.V.data are reported for 17/?-acetoxy-2,3-dithia-5aandrostane, among a series of d i t h i a d e ~ a l i n s . ~ ~ Further progress is reported in the use of induced c.d. in metal complexes for the assignment of configuration to polar l i g a n d ~ . ~Copper ~" hexafluoroacetylacetonate interacts with optically active alcohols to give a c.d. band near 333 nm (and others at shorter wavelengths). Examples, which include several steroids and terpenoids, show that the sign of the Cotton effect at 333 nm is related to the bulk of structural features near the hydroxy-group. Viewed down the HO-C bond, the sequence depicted in Figure 2 corresponds to a negative Cotton effect. Either [Ni(acac),] or [Pr(dpm),] may Small

Large -.A

Medium

Figure 2 Projection of an alcohol down HO-C bond: substituent sequence giving a negative Cotton eflect with copper hexajuoroacetylacetonate

be used to assign chirality to a-glycols or a-amino-alcohols. The nickel reagent gives two c.d. maxima, near 3 15 and 615 nm, respectively. Circular dichroism has been induced in achiral substances in a cholesteric liquidcrystalline m e ~ o p h a s e . The ~ ~ mechanism of the phenomenon is complicated, the sign and intensity of c.d. depending upon the detailed structure of the liquid crystalits helicity and pitch - and other features. Hydrocarbons such as benzene and substituted benzenes, pyrene, and anthracene display c.d. in mixtures of cholesteryl chloride and nonanoate. The technique of linear dichroic spectroscopy in oriented polyethylene films has been employed to determine the conformations of acetyl substituents at the 6a-, 68-, and 178-positions in steroid^.^'

Mass Spectrometry. Recent systematic studies of the mass spectra of simple oxygenated androstanes and pregnanes have been extended to the isomeric 3,ll -dihydroxypregnan20-0nes,~lthe 5a- and 5P-isomers of 17P-hydroxyandrostane-3,6-diones,3P-hydroxy6-hydroxyandrostane-3, androstane-6,17-diones, 3,17P-dihydroxyandrostan-6-0nes,~~ 17-diones, and 6,17P-dihydroxyandrostan-3-0nes.~~ Characteristic fragmentations within each class have been recognized. Mass spectra of androstane-12q 17fl-diols reveal the loss of the 12a-OH and 17a-H as H 2 0 but this fragmentation is impossible for steric reasons in 12/3,17fi-diol~.~~ Fragmentations of a series of 3,12,17-trisubstituted androstanes are discussed.45 37

38

38

39

40 41

42 43 44 45

D. N. Jones, J. Blenkinsopp, A. C. F. Edmonds, E. Helmy, and R. J. K. Taylor, J . C . S . Perkin Z, 1974, 937. S. Hagishita and K. Kuriyama, J . C . S . Perkin ZZ, 1974, 686. ( a ) J. Dillon and K. Nakanishi, J . Amer. Chem. Soc., 1974, 96, 4055, 4057, 4059. F. D. Saeva, P. E. Sharpe, and G. R. O h , J . Amer. Chem. Soc., 1973,95, 7656, 7660; F. D . Saeva and G. R. Olin, ibid., p. 7882. A. Yogev, J . Sagiv, and Y . Mazur, J . C . S . Chem. Comm., 1973, 943. M. Ende and G. Spiteller, Tetrahedron, 1973, 29, 2457. F. J. tiammerschmidt and G. Spiteller, Tetrahedron, 1973, 29, 3995. F. J . Hammerschmidt and G. Spiteller, Tetrahedron, 1973, 29, 2465. E. Zietz and G. Spiteller, Tetrahedron, 1974, 30, 5 8 5 . E. Zietz and G. Spiteller, Tetrahedron, 1974, 30, 597.

Terpenoids and Steroids

230

t

H . transfer from 8 p o r 15a

(12) m/r 112 (11)

Scheme 1

The synthesis of specifically deuteriated (68, 8/J, or 15a) 3,3-ethylenedioxy-steroids (8) has shed new light on the mechanisms of fragmentation to give characteristic ions.46 Scheme 1 depicts the likely mechanisms. Rotation about the 5,6-bond in the intermediate radical-cation (9) leads to loss of specificity in the transfer of hydrogen from C-6 to C-10, indicating that the fragmentation leading to the ion (10) of m/e 125 is non-concerted. The C-6 radical (1I ) may fragment with transfer of hydrogen to C-6, either from the 8P-position (preferred) or from 15a, through a six-membered cyclic transition state to give the ion (12) of m/e 112. 4-Alkylcholest-5-en-3~-ols undergo an unusual rearrangement and fragmentation to give an ion (m/e 331) which is thought to have the hydroxy-group transferred to C-6, with loss of the carbon atoms of ring A : the mesomeric structure (13) is proposed for the ion.47

Characteristic ions at M - 111 and M - 85 have been recognized in the mass spectra of a variety of sterols with the 3P-hydroxy-A5 structure, irrespective of the nature of the ~ide-chain.~'Mass spectra are also reported for 5a- and 5P-cholestan-546

H. E. Audier, J. Bottin, M. Fetizon, J. C . Gramain, and G. Sozzi, Bull. Soc. chim. France,

47

1973, 2408. F. F. Knapp and G. J. Schroepfer, J.C.S. Chem. Comm., 1974, 537. S. H. M. Naqvi, Steroids, 1973, 22, 285.

48

Steroid Properties and Reactions

23 1

01s and -3,5-di0ls,~~ A' 7(20)- and A20(22)-unsaturated5a-cholestane-3[j,6a-diol derivatives related to products recently isolated from ~tarfish,~'5,6a-methano-5a-cholest a n e ~ , and ~ 1- and 4-dimethylamin0-steroids.~~The effect of a 14a-methyl group on the fragmentation of 11- and 7-0x0-steroids has been examined.53 The elimination of acetic acid from molecular ions of 17-acetoxy-androstanes has been investigated with the use of deuterium labelling.59 The direct analysis of 'daughter' ions (DADI) resulting from the decomposition of metastable molecular ions shows considerable promise as a method for the analysis of mixtures of steroids.55 Use of a double-focusing mass spectrometer of reversed geometry affords the desired spectrum by allowing the ions under study to be focused while those of the conventional mass spectrum are defocused. The method is demonstrated for example, by the analysis of mixtures of oestrone, oestradiol, and o e ~ t r i o l . ~ ~ Chemical ionization mass spectra can distinguish between isomeric 1,3-, 2,3-, and 3,4-amino-alcohols in the steroid series.56 Loss of water from the 0-protonated MH' ion occurs only when the ion cannot derive stabilization from hydrogen-bonding with the amino-group, as a consequence of a large 0 . e - N distance. A detailed study is reported of the gas chromatography-mass spectrometry of the so-called 'catechol oestrogens' (2-hydroxy- and 4-hydroxy-derivatives of the natural oestrogens) and their methyl and trimethylsilyl ethers.57 Miscellaneous. Infrared absorption spectra have been recorded for a series of acetoxysteroids and steroidal ketones in the region between 600 and 300 cm-'. Band assignments are proposed.58 Fluorescence spectra have been recorded for some cholestad i e n e ~ . The ~ ~ triplet lifetime of cholesta-4,6,8(14)-triene has been measured and compared with that of allo-ocimene.60

2 Alcohols and their Derivatives, Halides, and Epoxides Substitution and Elimination.-A new and efficient method for replacing hydroxygroups by halogen, with inversion of configuration, comprises reaction with the appropriate N-halogenosuccinimide (Cl, Br, or I) and either triphenylphosphine or triphenyl phosphite in THF. Yields are said to be high for reactions of either equatorial or axial alcohols at C-3, or for the conversion 17P-OH+ 17a-Br. Even cholesterol gave 3abromocholest-5-ene as the major product.61 Reaction with triphenylphosphine and carbon tetrachloride also converts alcohols into alkyl chlorides : cholesterol afforded a mixture including 3P-chlorocholest-5-ene, with lesser amounts of the 3a-isomer and cholesta-3,Sdiene. These products result from breakdown of an intermediate alkoxychlorotriphenylphosphorane.but other products, the 3,5-cyclo-6-ene (I 4) and 49

50 5 1 52

53 54 55 56 57

58 59

6o

''

J. Jovanovic and G. Spiteller, Tetrahedron, 1973, 29, 4017. Y . M. Sheikh and C . Djerassi, J . Org. Chem., 1973, 38, 3545. J. F. Templeton and C . W. Wie, Canad. J. Chem., 1974, 52, 517. C . Marazano and P. Longevialle, Compt. rend., 1973, 277, C , 175. R. R. Muccino and C . Djerassi, J . Amer. Chem. Soc., 1973, 95, 8726. R. Robbiani and J. Seibl, Helv. Chim. Acra, 1974, 57, 674. D. H. Smith, C . Djerassi, K. H. Maurer, and U . Rapp, J . Amer. Chem. Soc., 1974, 96, 3482. P. Longevialle, G. W. A. Milne, and H. M. Fales, J. Amer. Chem. Soc., 1973, 95, 6666. H.-0. Hoppen and L. Siekmann, Steroids, 1974, 23, 17. M. Mailloux, J. Weinman, and S. Weinman, Bull. SOC.chim. France, 1974, 203. J. Pusset and R . Beugelmans, J.C.S. Chem. Comm., 1974, 448. R. S. H. Liu, Y. Butt, and W. G. Herkstroeter, J.C.S. Chem. Comm., 1973, 799. A. K . Bose and B. Lal, Tetrahedron Letters, 1973, 3937.

232

Terpenoids and Steroids

the phosphorane (15), provide the first evidence of rearrangement accompanying such a reaction.62

I

OPCIPh,

Magnesium iodide in ether is highly effective for the conversion of tosylates into iodides, the reaction conditions being milder than with sodium iodide-acetone. 5aCholestan-3P-yl tosylate gave 3a-iodo-Sa-cholestane in 95 % yield.63 Sa-Androstan3p-01, -7p-01, and -1 6p-01 have been converted directly into the corresponding a-alcohols in ca. 90 % yields by heating their tosylates with tetra-n-butylammonium hydroxide in either DMSO or N-methylpyrr~lidone.~~ A survey of the pathways of reaction between numerous monohydroxy-5a-androstanes and SOCI,, SOBr,, PCI, , or PBr, indicates which of these reactions are likely to have, use in syntheses.64 Nucleophilic substitution of Scr-[3a -2H]cholestan-3~-olor its mesylate occurred without loss of deuterium, to give 5a-[3~-2H]cholestan-3a-01.6s Lithium dimethylcuprate converts cholesteryl tosylate into a mixture of 3P-methylcholest-5-ene and 6p-methyl-3a,Scyclo-Sa-cholestane (16), indicating the intermediacy of a non-classical 3a,S-cyclo5a-cholestanyl cation or a related species. The question of a possible organocopper(rI1) intermediate is discussed."

The four isomeric 3-tosyloxy-5,10-secocholest1(10)-en-5-ones (1 7 ) (isomeric at C-3, and about the olefinic bond) solvolyse at different rates and give different mixtures of products, depending upon the ease of homoallylic participation by the olefinic nelectron^.^' 1.3-Cyclo-derivatives(cyclopropanes) were among the products from the two tosylates of ( E ) configuration. Acetolysis of 4-bromocholest-4-en-3-ones apparently proceeds through the unstable A5-isomer to give a mixture of products of the types indicated (Scheme 2), in yields dependent upon the solvent (KOAc in HOAc or EtOH). S,2' substitution via the h2

63 O4

h5

" "

R. Aneja, A. P. Davies, and J. A. Knaggs, Tetrahedron Letters, 1974, 67. J. Gore, P. Place, and M. L. Roumestant, J . C . S . Chem. Comm., 1973, 821. D. B. Cowell, A. K. Davis, D. W. Mathieson, and P. D. Nicklin, J . C . S . Perkin I , 1974, 1505. J. E. Herz and L. A. Marquez, J.C.S. Perkin I , 1974, 1438. G . H. Posner and J.-S. Ting, Tetrahedron Letters, 1974, 683. L. Lorenc, M. J. GaSiC, I. Juranic, M. DaboviC, and M. Lj. Mihailovic, Tetrahedron Letters, 1974. 395.

233

Steroid Properties and Reactions

@

0

Br

R

=

OR

R

=

HorAc

Ac or Et

Scheme 2

4-bromo-2,5-dien-3-01 would explain attack at C-2, whereas 6P-substitution can be rationalized as an allylic (S,2') substitution of the bromo-substituent in the 4-bromoA5-isomer.h* The acetolysis (KOAc-HOAc) of 6/3-bromoandrost-4-ene-3,17-dione gives the 6p-acetoxy- as well as the previously reported 2a- and 2P-acetoxy-derivati~es,~~ 5a-Bromo-6P-hydroxy-steroids are more unstable than had previously been realized. The 3P-acetoxy-derivative (18) suffers rather rapid methanolysis at 45 "C, giving the 5a-methoxy-derivative (19), or under buffered conditions the 5/3,6&epoxide (20). The 3P-methoxy-bromohydrin (21) is even more reactive, and could not be isolated : reaction of 3P-methoxycholest-5-ene, for example, with N-bromoacetamide and perchloric acid gave a crude product which afforded the 5a,6a-, and SP.6P-epoxides and the 6abromo-5fl-a.icohol(22).69 These and related observations help to explain the sometimes poor reproducibility of 5,6-bromohydrin formation, a key step in the syntheses of several classes of steroid derivatives.

R'O

@

*co@

OH (18) R' = Ac, R2 = Br (19) R' = Ac, R2 = OMe (21) R' = Me, R2 = Br

(23) R (24) R (25) R 68

69

= = =

Br CH(CN)CO,Et CH,CN

T. Koga and M. Tomoeda, J.C.S. Perkin I, 1973, 1848. B. W. Cubberley and B. A. Marples, J.C.S. Perkin I, 1974, 9 .

234

Terpenoids and Steroids

A 7P-cyanomethyl substituent has been introduced by treating the 7-bromo-A5compound (23) with ethyl cyanoacetate and potassium carbonate. Hydrolysis and decarboxylation of the product (24) led to the cyanomethyl compound (25), which was transformed into a variety of products retaining the 7fi-s~bstituent.~' Nitrates (26) of 2 1-acetoxy-17a-hydroxypregnan-20-ones,prepared by the action of acetyl nitrate (Ac20-HNO,), give the A16-derivatives (28) on heating above 100 "C with potassium acetate in DMF.71 The reaction is more complicated than this result alone would suggest, for the enol acetate-aldehyde (27) can be isolated as an intermediate if the reaction is performed initially below 80°C.The primary product (27) rearranges to the A'"-compound on further heating. Other substituents, including the nitrate of an ll[l-alcohol, survive this reaction sequence: the llfi-alcohol can be regenerated by reducing the nitrate with zinc The free enol-aldehyde (29) can be C H ,OAc I

(26)

CHO I

CH ,OAc I

(27) R = AC (29) R = H

obtained by rearrangement of a 17a,21-dihydroxy-20-ketonewith zinc acetate-acetic acid, and the derived 20-acetate (27) can then be isomerized to give the AI6-unsaturated 21-acetoxy-20-ketone (28), either as above or by use of lithium carbonate in DMF.72 6fi-Acetoxy-5a-cholest-2-en-5-01 (31) was obtained from the 3fi-mesylate (30) on heating in triethylamine, but potassium t-butoxide instead gave the 6fi-hydroxy-3a,Saoxide (an oxetan; 32), which on further reaction rearranged to give the 3a-hydroxy-5fi, 6P-epoxide (33), by attack of a 6fi-alkoxide ion on C-5.73

24-Hydroxycholesteryl acetate was dehydrated by P20, in benzene to give the A24-unsaturated derivative (desmosterol acetate) with negligible formation of the A2 3-isomer.74 Dehydration of 25-hydroxycholestery1 acetate with phosphoryl

70 71

T. T. Thang and F. Winternitz, Compt. rend., 1974, 278, C , 809. H. Laurent, G . - A . Hoyer, and R. Wiechert, Chem. Ber., 1974, 107, 1235. H. Laurent, and R . Wiechert, Chem. Ber., 1973, 106, 2263. P. Tsui and G. Just, Canad. J. Chem., 1973, 51, 3502. M. Morisaki, J. Rubio-Lightbourn, N. Ikekawa, and T. Takeshita, Chem. and Pharm. Bull. (Japan), 1973, 21, 2568.

Hofmeister, '' H. H. Hofmeister, l 3 74

Steroid Properties and Reactions

235

chloride-pyridine gave the A24- and A25-unsaturated derivatives in 2 : 1 ratio ; separation was achieved by chromatography (Si02-AgN0,).75 Ring-opening of Epoxides-A systematic study of the reaction of epoxides with lithium dimethylcuprate included 2a,3a-epoxy-5a-cholestane,which was opened to give the 2fl-methyl-3a-alcohol : 7 6 the nucleophilic opening of oxygen-substituted epoxycyclohexanes with lithium dimethylcuprate appears to be subject to conformational control (diaxial product) rather than control by polarity effect^.^' Reaction of the 5a,6aepoxide (34) with allylmagnesium bromide gave the 6~-allyl-Sa-alcohol(35),which was oxidized by ruthenium tetroxide-sodium metaperiodate to give the 6P-carboxymethyl derivative (36).78 After conversion by standard reactions into 6a- and 6fl-carboxymethyl-progesterones, the acidic group provided a coupling site to bovine serum albumin for studies on the radioimmunoassay of progesterone.

(35) R = CH2CH=CH2 (36) R = CH2C02H

(34)

Nucleophilic opening of the epoxide ring in 4a,5a-epoxycholestan-7a-ol(37) with azide ion to give the product (38) derives assistance from intramolecular association with the hydroxy-group. The presence of other substituents at C-7, or none, resulted in very much slower reactions.79

Esters, Ethers, and Related Derivatives of Alcohols.-Steroid hydrogen sulphates are known to be hydrolysed with astonishing facility in moist ether or dioxan, although they are fairly resistant to hydrolysis in aqueous solutions : the ether oxygen has been considered to act as a nucleophile, displacing the steroidal oxygen by attack upon the 75

76 7i

78 79

M. Seki, J. Rubio-Lightbourn, M. Morisaki, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 2783. C. R. Johnson, R. W. Herr, and D. M. Wieland, J. Org. Chem., 1973, 38, 4263. B. C. Hartmen, T. Livinghouse, and B. Rickborn, J. Org. Chem., 1973, 38, 4346. C. D. Jones and N. R. Mason, Steroids, 1974, 23, 323. D. H. R. Barton and Y . Houminer, J.C.S. Chem. Comm., 1973, 839.

236

Terpenoids and Steroids

sulphur atom.” A new study” shows that the neutral salt (e.g.cholestan-3P-yl potassium sulphate) is stable in purified moist dioxan containing less than 1% water unless a trace of an electrophilic species is present to initiate hydrolysis. Rapid reaction follows the addition of even a minute trace of electrophile (e.g. I , , H2S04,ZnCl,, NH,Cl, or hydrazine sulphate) or under the influence of a glass surface. When a clean Teflon vessel was used, the ester salt was stable even under reflux and could be recovered on cooling. Initiation of reaction by an electrophile releases acid and results in accelerated hydrolysis. Rates of acetylation of 12~-hydroxy-steroids are more sensitive to side-chain branching at C-20 than to the length of the side-chain. The 21-methyl group of cholanes and related structures is mainly responsible for slowing the acetylation.82 Numerous reagents are now available for trimethylsilylation of alcohols, but their reactivities differ widely. By proper choice of reagents, alone or as mixtures, it is possible to transform all common hydroxy-steroids into their silyl ethers, or 0x0-steroids into enol trimethylsilyl ethers.83 The potential value of the t-butyldimethylsilyl protecting group in steroid chemistry is well illustrated by selective silylation at C-3 in androst-5ene-3P,17P-diol (71 % yield). The protecting group is stable to Cr0,-pyridine and may be cleaved by either aqueous acetic acid or tetra-n-butylammonium The bis-trimethylsilylation of pregnane- 17~,20~-diols and the mass spectral fragmentation of the products are unexpectedly c o m p l i ~ a t e d . ~ Stepwise ~ silylation with unlabelled and perdeuterio-reagents showed that the first trimethylsilyl group, introduced at the 20~-oxygen,is transferred to the 17a-OH group during attack by a second mole of the reagent. The mass spectrum of the labelled derivative (39) exhibited ions at m/e 117 (40) and m/e 126 (41), in ratio depending upon the energy of the ionizing electrons, indicating that scrambling occurs between the two silyl groups during fragmentation. MC

+ MeCH=OSi(CH,),

(40) m/e I17 + M e C H =OSi(CD,), (41) m/r 126 (39)

Contradicting a recent report, selective tritylation of 3/,’,19-dihydroxyandrost-5-en17-one is now shown to give the 3-trityl ether, rather than the C-19 derivative. A column of silica gel selectively hydrolysed the 3,19-ditrityl ether to give the authentic 19-trityloxy-compound.86 The 2.3-methylenedioxy-derivatives have been prepared from 2-hydroxyoe~trogens.~~

*I

’*

R3

84

*‘

”

D. N. Kirk and M. P. Hartshorn, ‘Steroid Reaction Mechanisms’, Elsevier, Amsterdam, 1968, pp. 29, 439. M. B. Goren and M. E. Kochansky, J . Org. Chem., 1973, 38, 3510. K. F. Atkinson and R.T. Blickenstaff, Steroids, 1974, 23, 895. H. Gleispach, J. Chromatog., 1974, 91, 407. H. Hosoda, D. K . Fukushima, and J. Fishman, J . Org. Chem., 1973, 38, 4209. P. Vouros, J . Org. Chem., 1973, 38, 3 5 5 5 . D. R. Baigent and K . G. Lewis, Austral. J . Chem., 1974, 27, 323. A. M. Femino, C . Longcope, J. E. Patrick, and K. I . H. Williams, Steroids, 1974, 23, 869.

237

Steroid Properties and Reactions

The problems encountered in the synthesis of steroid glycosides have been reviewed.88 Particular attention is paid to methods which permit stereochemical control in the sugar component. Several hydroxy-steroids have been converted into anomeric glucosides by use of 2,3,4,6-tetra-0-acetyl-~-glucopyranosyl bromide.89 Characteristic n.m.r. differences distinguish a- from P-anomers. The 3- and 19-monoglucuronosides 17-one are both accessible by conventional methods of 3P, 19-dihydroxyandrost-5-enfrom the diol when one or other of its hydroxy-groups is protected by acetylation, but the free diol formed the 3-monoglucuronoside selectively, indicating differential reactivity of the hydroxy-group~.~~

Oxidation.-An attractive new oxidant for the conversion of primary and secondary alcohols into aldehydes and ketones, respectively. comprises a mixture of DMSO, hexamethylphosphoramide (as solvent), and any of a variety of acid chlorides or anhydrides. When the mixture containing methanesulphonic anhydride was allowed to react with testosterone at - 20 “C, followed by addition of triethylamine, androst-4ene-3,17-dione resulted in 99% yield. Somewhat lower yields resulted from use of TsC1, Ts,O, or BzC1, but cyanuric chloride led to a 99 ”/, yield.” Chlorine with pyridine in CHCl, oxidizes alcohols to aldehydes or ketones, and shows useful selectivity for secondary alcohols in the presence of a primary hydroxy-function. Scr-Cholestane3P, 19-dio1, for example, gives 19-hydroxy-5a-cholestan-3-one with one molar proportion of chlorine.92 Complexes formed from either chlorine and DMSO, chlorine and thioanisole, or N-chlorosuccinimide and dimethyl sulphide offer smooth oxidation of sec,tert-1,2-diols to a-hydroxy-ketones, without C-C bond ~ l e a v a g e , ~ and should prove useful for converting pregnane- 17,20-diols into 17-hydroxypregnan-20-ones. Iodobenzene dichloride in the presence of pyridine provides another novel and mild oxidant for primary and secondary alcohols.94 Examples include 5cr-cholestan-3~and ~ P - o ~which s, gave 5a-cholestan-3-one in 72 7; and 81 % yields, respectively. The mechanism is thought to involve decomposition of an iodo-alkoxy-chloride (42).

R’

H

\ C /’ R2/

\OH

R’

R’ \

H)Ph

+ PhICl, 3 R2

c1

+ R2/c=o

+

Phl

Unfortunately the reagent is not suitable for unsaturated alcohols as the olefinic bond is chlorinated (p. 240). The complex (43) of chromium trioxide with 3,S-dimethylpyrazole is a convenient selective oxidant for alcohols, possibly having advantages 88

89

90 91

92 93 94

G . Wulff and G. Rohle, Angew. Chem. Internat. Edn., 1974, 13, 157; G. Wulff, Cronache Chim., 1973, 42. P. KoEovsky, K. K. Koioev, a n d Z . Prochazka, Coll. Czech. Chem. Comm., 1973, 38, 3273. S. H. Nicholson, D. S. H. Smith, and A. B. Turner, J . C . S . Perkin I , 1973, 2887. J. D. Albright, J . Org. Chem., 1974, 39, 1977. J. Wicha and A. Zarecki, Tetrahedron Letters, 1974, 3059. E. J. Corey and C. U. Kim, Tetrahedron Letters, 1974, 287. J. Wicha, A. Zarecki, and M. Kocor, Tetrahedron Letters, 1973, 3635.

Terpenoids and Steroids

238

i

0,CrOH

over the pyridine complex.95 Its application to steroids deserves study. Oxidation of S[j-cholest-2-en-1/3-01with chromic acid gave mainly the allylic rearrangement product, the l-en-3-0ne.~~ Full particulars have appeared97 of the mechanistic study of the Fetizon oxidation (Ag,CO,<elite), reported in outline last year.98 The Fetizon oxidant has been used to oxidize sec,tert-a-diols to a-hydro~y-ketones.~~ Examples include a pregnane- 17a,20a-diol, which gives the 17a-hydroxypregnan-20-one,but a 17a,20/3diol was slowly degraded to the corresponding androstan-17-one. 5a-Androstane3P,5,6b-triol is oxidized by Fetizon's reagent with different selectivity according to the solvent. The 6fi-hydroxy-group was oxidized preferentially in benzene, and the 38group in chloroform, although a total of five products resulted in each case. The 3b,5,6a-triol was oxidized selectively at C-3, giving the 5a,6a-dihydroxy-3-oxo- and 6a-hydroxy-A4-3-0x0-derivatives. loo Reduction.-Lithium dimethylcuprate is an efficient reducing agent for a-acetoxyand a-bromo-ketones,' giving the unsubstituted ketones, as indicated briefly last

95 96

97

98 99 100

101

E. J . Corey and G . W. J. Fleet, Tetrahedron Letters. 1973, 4499. J . Y . Satoh, K . Misawa, T. T. Takahashi, M. Hirose, C . A . Horiuchi, S. Tsujii, and A . Hagitani, Bull. Chem. Soc. Japan., 1973,46, 3155. F. J. Kakis, M. Fetizon, N. Douchkine, M. Golfier, P. Mourgues, a n d T . Prange, J. Org. Chem., 1974, 39, 523. Ref. l a , 1974, Vol. 4, p. 327. J. Bastard, M. Fetizon, and J. C. Gramain, Tetrahedron, 1973, 29, 2867. M. Fetizon and P. Mourgues, Tetrahedron, 1974, 30, 327. J. R. Bull and A . Tuinman, Tetrahedron Letters, 1973, 4349.

Steroid Properties and Reactions

239

year.' O 2 Deacetoxylation was successful even where other reagents failed : the 2,16diacetate (44) in the cucurbitacin series gave the reduced compound (45). Other 2acetoxy-3-ketones were similarly reduced, but a 5a-acetoxy-6-ketone gave the 6-0x05or-steroid accompanied by the hydroxy-lactone (46), resulting from proton abstraction from the acetoxy-group followed by internal condensation at C-6.lo' Chromous acetate selectively debrominated 2~,4~-dibromo-5~-cholestan-3-one ta give the 2/3-monobromo-ketone, which afforded 5P-cholest-1-en-3-one on dehydrob r ~ m i n a t i o n .A ~ ~high-yielding transposition of oxygen from C-3 to C-2 involves conversion of Sa-cholestan-3~-01oia the 2-ene, and iodo-acetoxylation (12-KI03AcOH), into the iodohydrin acetate (47). Reduction with LiAlH, then afforded 5orcholestan-2P-o1(48)in at least 95 % yield (ca. 7&75 % ~verall)."~Lithium aluminium deuteride reduces a 3-iodo-oestra- 1,3,5(10)-triene to give the 3-deuterio-derivative.'O4

X(47)

H

R

(48) R

= =

Ac, X = I X=H

Lithium in dimethoxyethane reduces some phenolic ethers to give aromatic hydroc a r b o n ~ . ' ~ 'The methoxymethyl and tetrahydropyranyl ethers of oestra- 1,3,5(10)trien-3-01 gave only the hydrocarbon, but some other ethers gave mixtures of the hydrocarbon and the phenol. Miscellaneous.-The products of pyrolysis of some allylic alcohols and hydroperoxides (5a-OH and -O,H, A 6 ; 7a- and 7P-OH and -O,H, A') have been identified."" When a mixture of cholesterol and sodium ethoxide was heated in ethanol (180 "C; sealed tube) the products included the four isomeric (at C-3 and C-5) cholestanols and small proportions of four isomeric 2-ethylcholestanols (Guerbet -Markovnikoff reaction). O 7

'

3 Unsaturated Compounds

Electrophilic Addition.-The conversion of olefins into cis-diols by the iodo-acetoxylation procedure (Prevost reaction) does not require the use of silver acetate. 5a-Cholest2-ene is readily converted into the 2P-acetoxy-3a-iodo-derivative (47) by iodine with potassium iodate in acetic acid."* The iodo-acetate (47) is transformed via an acetoxonium ion into monoacetates of the 2P,3P-diol by silver acetate in aqueous acetic acid, but comparable yields may be obtained by the use of cupric acetate or potassium acetate, or even by longer treatment with refluxing aqueous acetic acid. The 2P,3pdiol could be obtained in 70 % yield from the 2-ene without isolation of intermediates ; the new iodo-acetoxylation procedure is suggested as a convenient route to the 2/3,3/3lo* lo'

lo4 lo5 lo6 lo'

lo'

Ref. l a , 1974, Vol. 4, p. 329. M. Adinolfi, M. Parrilli, G. Barone, and G . Laonigro, Steroids, 1974, 24, 135. K. I. H. Williams and T. A. Wittstruck, Steroids, 1974, 23, 731. A. N. Cherkasov, L. E. Golubovskaya, and K. K. Pivnitsky, Zhur. org. Khim., 1974, 10, 320. L. L. Smith, M. J. Kulig, and J. I. Teng, Steroids, 1973, 22, 627. J. Wicha, Chem. and Ind., 1973, 954. L. Mangoni, M . Adinolfi, G. Barone, and M . Pariilli, Tetrahedron Letters, 1973, 4485.

240

Terpenoids and Steroids

epoxide by alkaline hydrolysis of the intermediate product.'08 A systematic study of thallium(1)carboxylates has shown that these too are useful alternatives to the silver salts for iodo-acyloxylation. 5a-Cholest-2-ene gave the iodo-acetate (47) in 80 % yield. O9 The 5,6-diacetoxy-A2-derivative (49) reacted abnormally with hypobromous acid because of steric hindrance by the 5a-acetoxy-group. the major product being the 2[j-bromo-3~-01(50). but epoxidation occurred normally on the ~c-face.'~Either the bromohydrin (50) or the 2a,3a-epoxide reacted with HBr to give the 2a,5a-epoxide (51), with migration of the 5a-acetoxy-group to the 3~r-position.~~

Iodobenzene dichloride in the presence of pyridine converts cholest-5-ene rapidly into the -5a,6P-dichloro- (trans) adduct, although, both 5c(,6a- and 5a,6P-dichlorides result when no pyridine is present.94 The A22-olefin (52) derived by degradation of lanosterol reacts with hypobromous acid to give two major bromohydrins, which both afford the 22S,23-cpoxide (53) on reaction with base.' l o One of the bromohydrins was used as a source of the 22-0x0- and 22-hydroxy-compounds.

Cholesteryl acetate with sodium nitrite and nitric acid in acetic acid gives the 3P,5adiacetoxy-6-nitrimino-derivative (54),'11 contrary to an earlier report' l 2 that the (55). product was the 3[~-acetoxy-5a-nitrito-6-acetoximino-derivative , Pregnenolone reacted with PbF,(OAc), to give an insoluble product, believed to be the steroid-lead compound (56)on the basis of its chemical and i.r. characteristics.'13 Phenylselenenyl acetate (PhSeOAc), conveniently generated by first forming the bromide (from PhSeSePh + Br2--HOAc)and adding potassium acetate, adds directly on to reactive olefins, to give trans-adducts ; oxidation of the latter leads to elimination of phenylselenenic acid to give the allylic acetate in high yield.' l 4 5a-Cholest-2-ene,

loo ' l o

'I1 I" I"

R. C. Cambie, R. C. Hayward, J . L. Roberts, and P. S. Rutledge, J.C.S. Perkin I , 1974, 1858. J. P. Poyser, F. de R. Hirtzbach, and G. Ourisson, J.C.S. Perkin I , 1974, 378. C . R . Narayanan, M. S. Parkar, and P. S. Ramaswamy, Chem. and Ind., 1974, 208. Ref. 10, 1972, Vol. 2, pp. 254. 255. M. Ephritikhine and J. Levisalles. J.C.S. Chem. Comm., 1974, 429. K. B. Sharpless and R. F. Lauer, J. Org. Chem., 1974, 39, 429.

24 1

Steroid Properties and Reactions

Pb

(54) R' ( 5 5 ) R'

Ac, R2 = NO, = NO, R2 = OAC

=

F'

I 'OAc OAc

unfortunately, gave a mixture of the two possible diaxial phenylseleno-acetoxy-products (~P-OAC, 3a-SePh and 3a-OAc, 2/&SePh),leading finally to a mixture of 2fl-acetoxy-5acholest-3-ene and 3a-acetoxy-5a-cholest-1-ene ; cholesterol failed to react under the conditions described. The bromination of cholest-4-en-3-one (57) has been known to occur in various ways,' depending upon the reagents and reaction conditions. Possible products include the 2a-, 4-, 68-, and 6a-monobromo-, or the 2a,6P-, 2a,6a-, and 4,6fl-dibromoderivatives. New work' l 6 has helped to clarify these reactions; the introduction of bromine at C-4 (60) may occur either by addition to give an unstable 4,5-dibromo-3ketone (58), followed by dehydrobromination, or by addition of the elements of acetyl hypobromite or hypobromous acid (59),followed by an elimination step. The bromination of cholest-5-en-3-one has also been investigated.'

'

mzo@%* I\\

0 (57)

Br (58) X = Br (59) X = OH o r OAc

Br

(60)

Epoxidation.-Cholesterol is oxidized by hydrogen peroxide in the presence of iron(111) acetylacetonate to give the 58,6fl-epoxide: an optimum yield of 8504 is reported in acetonitrile as solvent. The contrast with predominant a-epoxidation by peroxy-acids is noteworthy. Steroidal 4-enes similarly gave P-epoxides as major products, irrespective of substitution at (2-3. The mechanism is not yet understood."7 Similar reactions catalysed by either iron(r1) or titanium(Ir1)ions in acetonitrile gave mixed 5,6-epoxides, and products of their ring-opening, along with by-products.' These latter reactions in their present form do not appear to have preparative utility. t-Amy1 hydroperoxide with MoCl, converts A5-unsaturated steroids into 5,6epoxides, the proportion of P-epoxide being higher than with perbenzoic acid: the 8-epoxide was the major product when 3P-acetoxy-A5-steroids reacted with the C . Djerassi, G. Rosenkrantz, J. Romo, S. Kaufmann, and J. Pataki, J . Amer. Chem. S O C . , 1950,72,4534; D. N. Kirk, D. K. Patel, and V. Petrow, J . Chem. Soc., 1956, 627. ''I7l 6 P. B. D. de la Mare and B. N. B. Hannan, J . C . S . Perkin II, 1973, 1586. M. Tohma, T. Tomita, and M . Kimura, Tetrahedron Letters, 1973, 4359. ' I BM. Kimura, M. Tohma, and T. Tomita, Chem. and Pharm. Bull. (Japan), 1973, 21, 2521.

'I5

7-erpenoids and Steroids

242

molybdenum reagent. ‘Thecomplex of M o o , and HMPA, in contrast to MoCl,, caused highly stereoselective a-epoxidation. Unsaturated alcohols are epoxidized with exceptional stereospecificity by a mixture of t-butyl hydroperoxide with either vanadyl acetylacetonate or hexacarbonylmolybdenum, in refluxing benzene. 2 o Cholest-5ene-3P,4O-diolgave the SP,6P-epoxide in 95 ‘’4yield, being superior to the reaction with and a-epoxides in 2 : 1 ratio. Other extn-chloroperbenzoic acid, which gave the /Iamples’ 2 o support the impression that epoxidation by these reagents occurs with assistance from neighbouring hydroxy-groups. Further examples of the epoxidation of As-unsaturated steroids with hydroperoxides catalysed by molybdenum compounds include the formation of a- and P-epoxides in a wide variety of proportions according to the nature of the reactants.121 t-Amy1 hydroperoxide with MoCl, converts A7unsaturated steroids into 8P-hydroxy-7-ketones. 2 2

’

’

Miscellaneous Additions-Dichlorocarbene generated from chloroform and sodium hydroxide in the presence of benzyltriethylammonium bromide is highly reactive towards unsaturated steroids, even in cases where dichlorocarbene from the pyrolysis of sodium trichloroacetate was ineffective. Cholesteryl acetate gave the 5B,6b-dichloromethylene adduct, which afforded the 5p,6/?-methylenederivative on reduction with sodium-liquid ammonia. A 7-ene afforded the 7a,8a-adduct, and an ergost-22ene gave a 22,23-adduct, though in low ~ i e 1 d . l ’ ~The reactivity of difluorocarbene towards various steroidal olefins has been studied by use of some similar model compounds.’ 2 4

(61)

(62)

The isomeric ~-norcholest-4-en-3-01~ (61) have been converted by Simmons-Smith methylenation into isomeric 4.~-cyclo-~-homo-~-norcholestane derivatives (62); further transformatiocs gave ketones, bromohydrins, and other derivatives of this novel skeleton.’2s The stereochemistry of methylene addition on to the 6,7-olefinicbond of a 4.6-dien-3-one, by use of dimethylsulphonium methylide, shows wide variations depending upon substitution pattern.’26 Hydroboration of the 18-1101- steroidal 13-ene (63) gave a mixture of products. Thermal isomerization of the adduct at 50°C or above gave 12-substituted products, transformed by oxidation and acetylation into the 12-acetoxy-compounds (64) and (65). The c/D-trans-isomer (65) predominated from higher-temperature reactions. A steroidal ‘I9

12’

”’

‘22

’” lZ4

125

12‘

G. A. Tolstikov, V. P. Yur’ev, I. A. Gailyunas, a n d S . R. Rafikov, DokladqAkad. Nuuk S . S . S . R . , 1974, 214, C , 120. K. B. Sharpless a n d R. C. Michaelson, J . Amer. Chem. Soc., 1973, 95, 6136. G. A. Tolstikov, V. P. Yur’ev, I. A. Gailyunas a n d U. M. Dzhemilev, Zhur. obshchei Khim., 1974, 44, 215. G. A. Tolstikov, U . M. Dzhemilev, a n d V. P. Yur’ev, Zhur. obshchei Khim., 1973, 43, 2076. Y. M . Sheikh, J . Leclercq, a n d C. Djerassi, J.C.S. Perkin I , 1974, 909. R. A. Moss a n d D. J. Smudin, Tetrahedron Letters, 1974, 1829. J . Joska, J. FajkoS. a n d M. BudeSinsky, Colt. Czech. Chem. Comm., 1974, 39, 1914. G. E. Arth, G. F. Reynolds, G. H. Rasmusson, A. Chen, a n d A. A. Patchett, Tetrahedron Letters, 1974, 291.

Steroid Properties und Reactions

243

8( 14)-ene will react with diborane at 50-60 "C, the main products, after oxidation and acetylation. being the 15-acetoxy-compounds (66) and (67). In the ergostane series, the c/D-truns-product predominates (73 %) after reaction at 130 0C.127

(63)

(64) I~E-OAC, 13~-H (65) 12P-OAc. 13P-H

(66) 14a-H, 15a-OAc (67) 14P-H. ISP-OAC

Hydroboration-oxidation of cholesta- 1,5-dien-3D-ol gave the 5-ene- 1 a,3D-diol and the 5-ene-2~,3P-diol,each in 15-20 % yield : the former diol was used for the preparation of la-hydroxy-vitamin D, 2 8 Trialkylboranes are reported to react with 3P-acetoxypregna-5,16-dien-2O-one in THF to give the corresponding 16a-alkyl 20-ketones (68), often accompanied by the 16~-tetrahydrofurylderivative (69).' 29 Formonitrile oxide (HC-N 0),generated in situ from sodium fulminate and aqueous H,SO,, adds to a pregn- 16-en-20-one to give the isoxazolidino-steroid (70), along with heterocyclic products of more complex structure.'30

.'

-+

(68) R = Et, Bu,etc.

-0

(69) R = ... Dicyanoacetylene takes part in either ene addition or Diels-Alder diene addition with suitable ergostadienes. Three such steroids (As*7-diene,A5.7.9(1')-triene, and A7.I4-diene)are examined as substrates for comparative study of dienophiles, and the results of their reactions with an extensive list of dienophiles (or enophiles) are tabulated.'31 The preparation of 0-alkylated ketones by conjugate addition of lithium dialkylcuprates on to UP-unsaturated ketones has been reviewed, along with some related reactions.'32

Reduction.--The catalytic hydrogenation of steroidal 4-en-3-ones of the aldosterone series, like that of other 11P-substituted pregn-4-en-3-oneq gives 5a-dihydro-products 3 3 Exceptional stereochemical and the 3a- and 3P-hydroxy-5a-terrahydro-derivatives.' control of reduction of 4-en-3-ones has been achieved by reaction of the derived iminium 12'

12'

129

13' 13' 132 133

E. Mincione and F. Feliziani, J.C.S. Chem. Comm., 1973, 942. C. Kaneko, S. Yamada, A. Sugimoto, Y. Eguchi, M. Ishikawa, T. Suda, M. Suzuki, S. Kakuta, and S. Sasaki, Steroids, :974, 23, 75. A. A. Akhrem, I. S. Levina, Yu. A. Titov, V. A. Khripach, Yu. N . Bubnov, and B. M. Mikhailov, Zhur. obshchei Khim., 1973, 43, 2565. J. Fajikos and J. A. Edwards, J . Hetrrucix-lir Chem., 1974, 11, 6 3 . A. Abramovitch and P. W. Le Quesne, J . Org. Chem., 1974, 39, 2197. W. Carruthers, Chem. and ivd., 1973, 931. Y . Lederman, R. Szpigielman, M . Bendcovsky, J. Herling, and M. Harnik, Anafyt. Biochem., 1973, 51, 193.

& Eto?yyo Terpenoids and Steroids

244

CI;

Me

ClO,

H

(71)

(72)

perchlorates (71) with the Hantzsch ester (72) (a dihydropyridine) in refluxing acetonitrile : the products were 3-oxo-5~-steroids(70%) apparently uncontaminated by the Sa-isomers. 34 The olefinic bond in Ah-unsaturated 5/3-steroids, prepared by novel application of a series of known reactions, is reduced by deuterium with either soluble or heterogeneous catalysts to give mixtures of 6a,7a- and 6/3,7/3-dideuteriated species. Lanthanide shift reagents were employed in the analyses of n.m.r. spectra which revealed the deuterium configurations. 35 The hydrogenation of androsta-3,5-dien-7-one in ethanol to prepare 5a-androstan-7-one was complicated by extensive formation of 7b-ethoxy-5a-androstane, unless traces of acid were rigorously excluded.64 The olefinic bond in A'- or A9(' ')-unsaturated aromatic ethers can be reduced selectively by electrolysis to give products with the normal (Sp,9a) configuration.' 36

'

Oxidation.-Oxygenation of ergosteryl acetate to give the 5a,Sa-epidioxide is catalysed by a variety of Lewis acids. Some of these, (AlCl,, SnCl, - diphenylpicrylhydrazyl, VOCl,, SbCl, - anthracene, MoCl,, FeCl,, etc.) are effective even in the dark, and the reactions are all attributed to ground-state (triplet) oxygen.' 37 Possible mechanisms are discussed briefly, but further work is required to clarify the details. Cholesta-3,5dien-7-one is one of several conjugated dienones which are found to react with molecular oxygen in a hydrocarbon solvent (e.g. xylene) at 12&130°C; the product was the 3r,4a-epoxide (73). A free-radical mechanism is proposed, but the details are still being studied.'

0,'

(7 3)

5~~,7/3-Cyclo-~-homocholest-2-ene (74)is oxidized by t-butyl chromate to give a mixture of the 2-en-4-one (75) and the 3-en-2-one (76), but the isomeric 5cr,7acyclo-olefin gave only the corresponding 3-en-2-one derivative. 39 The ozonolysis of cholest-4-en-3-one at - 15 "C in acetic acid-ethyl acetate has afforded a crystalline I34

U. K. Pandit, F. R. M. Cabre, R. A. Gase, and M. J. de Nie-Sarink, J.C.S. Chem. Comm.,

135

D. N. Kirk and D. R. A. Leonard, J.C.S. Perkin I , 1973, 1836. K . Junghans, Chem. Ber., 1973, 106, 3465. D. H. R. Barton, R. K. Haynes, P. D. Magnus, and I. D. Menzies, J.C.S. Chem. Comm., 1974,

1974, 627. 136

137

511. 138

139

H. Hart and P. B. Lavrik, J. O r g . Chem., 1974, 39, 1793. L. Kohout, Coll. Czech. Chem. Comm., 1973, 38, 2760.

245

Steroid Properties and Reactions

@ R 1

(74) R (75) R

= =

L'

H, 0 (A,,

222 nm)

o&

H CHO 4 - -OAc - - t y

.,-

! I .

(77) (76) (A,,

267 n m )

5-acetoxy-3,5-peroxy-derivative,probably having the structure (77). The 5-hydroxyanalogue resulted when an aqueous solvent was used.'4o Precise experimental conditions are described for the allylic bromination of Assterols (at C-7) and dehydrobrominations of the bromides to give 5,7-dienes in high yield : earlier procedures are not always reliable. Hydrogenation of the 5,7-dienes can be controlled to give the A'-sterols, uncontaminated by the rearranged olefins, by using Raney nickel as catalyst in the presence of trieth~larnine.'~'Byproducts from the allylic bromination of cholesteryl benzoate have been identified : the 7fl-bromo-derivative is unstable to chromatography on a l ~ m i n a . ' ~ ' Miscellaneous.-Phenols of the oestrogen series undergo selective deuteriation at C-4 in alkaline D,O : the location of deuterium was established by an n.m.r. study. Phenol itself incorporates deuterium at both the ortho and the para positions under similar though milder conditions, so the reason for the absence of isotopic exchange at C-2 in the steroid is not obvious. Contact with deuterium and a palladiumsarbon catalyst effected labelling of oestrone at both C-6 and C-9.'43 Oestrogen derivatives with additional hydroxy-groups in ring A have been obtained via diazotization of the corresponding nitro-derivative~.'~~ Oxidation of the aromatic ether (78) with H,O,-trifluoroacetic acid affords the quinones (79) and (80) in low yields. The quinones exhibit circular d i c h r ~ i s r n . ' ~ ~

(78)

0 (79) R (80) R

= =

Me0 H

3-Methoxy- 19-nor-17a-pregna-1,3,5(lO)-trien-20-yn-17s-01 acetate ('mestranol' ; 81) rearranged in part to give the 17-epimer (82), along with the dehydration product (83) and the aldehyde (84),when left on a column of alumina. A carbonium ion mechanism is proposed.'46 14* 14'

14*

143

144 145 146

G. Lefebvre, Bull. SOC.chim. France, i974, 173. H. W. Kircher and F. U. Rosenstein, J. Org. Chem., 1973, 38, 2259. R. I. Yakhimovich, E. S. Kotlyar, L. K. Kurchenko, and V. A. Boguslavsky, Khim. Farmatmet. Zhur., 1973, 7, 33. J. H. Block and C. Djerassi, Steroids, 1973, 23, 591. K. Kovacs, Z. Rakonczay, and B. Matkovics, Acru Phys. er Chem. (Szeged.), 1973, 19, 287. J.-F. Biellmann and G. Branlant, Buff.Soc. chim. France, 1973, 2086. R. M. Kanojia, L. Yarmchuck, and I. Scheer, J. Org. Chem., 1974, 39, 2304.

246

Terpenoids and Steroids H

H

I

C

Ill

C

CHO

I

The properties and stereochemistry of 17~~-‘alkoxypropargyl’-androstan17p-01s have been studied. 4 7 Hydrogenolysis of 17P-acetoxy-1a,5-cyclo-5a,lOa-androstan-2one (85) required forcing conditions and gave a mixture of products of cyclopropyl ring-opening, with the 5a,l0~~-configuration.~~~

’

4 Carbonyl Compounds

Reduction of Ketones.-New light on the perennial problem of the mechanism of reduction of cyclohexanones by borohydride comes from a detailed study of the kinetics and stereochemistry of reduction of a series of 2-alkylcyclohexanones. Numerical values for the increased enthalpies of activation due to 2-axial and 2-equatorial methyl substituents will be useful to chemists interested in the factors controlling reduction of steroid ketones. 149 A preliminary report of the quantitative evaluation of ‘steric congestion’ suggests that it may soon become possible to estimate quantitatively the contributions of steric effects to the control of reduction of steroidal ketones and other reactions. 5 0 A further interesting contribution proposes that the predominant formation of equatorial alcohols from unhindered cyclohexanones is a consequence of deformation of the carbonyl antibonding n*-orbital by its interaction with C-C antibonding orbitals of the +bonds of the cyclohexanone ring. The effect is to favour approach of nucleophiles (e.g.H -) from the quasi-axial direction.’ If the formation of 3P-hydroxy-SLY-steroids from the corresponding ketones, for example, is really the consequence of orbital deformation, earlier theories’ 5 2 based upon thermodynamic control or steric or torsional effects may become superfluous (see also p. 224). 14-

’49 lso

”

H. Chwastek, N. Le Goff, R. Epsztein, and M. Baran-Marszak, Tetrahedron, 1974, 30, 603. R . L. Augustine and E. J. Reardon, J . Org. Chem., 1974, 39, 1627. D. C. Wigfield and D. J. Phelps, J. Amer. Chem. Soc., 1974, 96, 543. W. T. Wipke and P. Gund, J. Amer. Chem. Sor., 1974, 96, 299. J . Klein, Tetrahedron Lefters, 1973, 4307. Ref. 10, 1973, Vol. 3, p. 336; ref. 80, p. 134; J.-C. Jacquesy, R . Jacquesy, and J. Levisalles, Bull. Sor. rhim. France, 1967, 1649; M. Cherest, H. Felkin, and N. Prudent, Tetrahedron Letters, 1968, 2199; M . Cherest and 13. Felkin, ibid., p. 2205.

247

Steroid Properties and Reactions

Reduction of the 1-, 2-, 3-, and 4-0x0-derivatives of D-homo-Sa-androstane with sodium borohydride proceeds with essentially the same stereochemistry as in the corresponding 5a-androstanones. ' Sodium cyanoborohydride (NaBH,CN) is stable to weak acids, and has now been shown to reduce steroidal ketones in acidified THF, with stereochemical consequences hardly distinguishable from those of reactions with NaBH,. Differences between the reactivities of ketones (cyclohexanones > methyl ketones > cyclopentanones) allow selective reductions of androstane-3,17-diones and pregnane-3,20-diones at C-3. The 0x0-group is presumably activated to reduction by protonation, for ketones are rather unreactive to NaBH,CN in neutral media.' 5 4 The reduction of a series of cholestenones with NaBH,CN has also been examined. Both 1,2- and 1,4-addition of hydrogen were observed, in proportions depending upon the particular enone and the pH of the solution.' A new reducing agent, lithium dimesitylborohydride bis(dimethoxyethane), shows remarkable stereoselectivity for the reduction of cyclohexanones to axial alcohols, as well as widely differing reaction rates according to steric hindrance.'56 The stable crystalline reagent offers interesting possibilities in steroid chemistry. 'Disiamylborane', and other highly hindered dialkylboranes reduce cycloalkanones with high 5aselectivity for approach from the more exposed side of the carbonyl Cholestan-6-one gave only the 6P-alcohol, whereas the 3a,Sa-cycl0-6-ketone gave the 6a-alcohol. Stereochemical control reported for 2-alkylcyclohexanones implies that other suitable steroid ketones should afford the less stable of the possible alcohol products. Further study of the reduction of ketones by either ethanol or propan-2-01, with soluble iridium complexes as catalysts, has shown varied stereoselectivity according to the associated ligands and other factors. Experiments with 5a-cholestan-3-one, using amines or DMSO as ligands, afforded up to 69% of the axial but for preparative purposes none of these modifications equals the original method for preparing the axial alcohol, by use of trimethyl phosphite. 5 9 Sa-Cholestan-3-one is reduced in the presence of various precipitated metals, with water as hydrogen donor. The 3ccand 3P-ols are formed in ratios dependent upon the metal and solvent system, the axial (3a) alcohol predominating in some cases.' 6 o Aminoiminomethanesulphinic acid (thiourea SS-dioxide) is another reducing agent for 3-0x0-%steroids. In a strongly alkaline solution (sodium n-propoxide-n-propanol) it gives the 3P-alcohols as major products. 5a-Pregnane-3,20-dione was reduced only at C-3.I6'

'

153

15' 155 156

15'

159

I6O 16'

L. E. Conteras, D. de Marcano, L. Marquez, M. Molina, and L. Ternpestini, J . Org. Chem., 1974, 39, 1550. M.-H. Boutigue and R. Jacquesy, Compt. rend., 1973, 276, C , 437. M.-H. Boutigue, R. Jacquesy, and Y. Petit, Bull. SOC.chim. France, 1973, 3062. J . Hooz, S. Akiyama, F. J. Cedar, M. J. Bennett, and R. M. Tuggle, J. Amer. Chem. Soc., 1974, 96, 274. H. C. Brown and V. Varma, J. Org. Chem., 1974, 39, 1631. Y. M. Y. Haddad, H. B. Henbest, J. Husbands, T. R. B. Mitchell, and J. Trocha-Grimshaw, J.C.S. Perkin I , 1974, 596. Y. M. Y. Haddad, H. B. Henbest, J. Husbands, andT. R. B. Mitchell, Proc. Chem. Soc., 1964, 361 ; D. N. Kirk and P. A. Browne, J. Chem. SOC.(0,1969, 1653. M. Ishige, M. Shiota, and Y. Ideno, Canad. J. Chem., 1973, 51, 3923. J. E. Herz and L. A. de Marquez, J.C.S. Perkin I , 1973, 2633.

248

Terpenoids and Steroids

A new procedure for deoxygenation of ketones to give olefins may find applications in steroid chemistry : the ketone is stirred in ether with chlorotrimethylsilane and zinc dust. 1 6 2 The mechanism of reduction of the sapogenin side-chain (a masked 22-oxo-compound) with LiAID,-AlCI, has been elucidated : 6 3 the resulting dihydrosapogenin (86) contained one deuterium atom, specifically at the C-22-position in the (22R)configuration.

Other Reactions at the Carbonyl Carbon Atom.--The Wittig reaction of 5wcholestan3-one with ethylidenetriphenylphosphoranegives a mixture of (2)-and (E)-3-ethylideneSa-cholestanes [ ( S ) and (6);see p. 2281, which were separated by fractional crystallization and chromatography on activated charcoal. Configurations were assigned on the basis of hydroboration-oxidation and a c.d. study of the acetates and o-nitrobenzoates of the derived alcohols (87).33 The characteristic olefinic c.d. curves of the 3-ethylidene isomers are discussed on p.228. Suitable Wittig reagents have been used to convert the bisnorcholan-22-a1 (88) into mixed cis- and trans-isomers of the corresponding cholest-22-ene (89) and its 24-nor-analogue (90), re~pectively.'~~

\ CH =C H ( C H 1°CHM e

(89) n = 1 (90) n = 0

A 21-hydroxypregnan-20-onereacts with 0-ethoxyvinyltriphenylphosphoniumsalts (or suitable precursors) in the presence of a base to give the furan (91).'65 A review of

applications of organic phosphonate carbanions (Wittig-Homer reaction) includes a

Ih2 lh3

'

b4 I b 5

W. B. Motherwell, J . C . S . Chem. Comm., 1973, 935. A. H. Albert, G . R. Pettit, and P. Brown, J . Org. Chem., 1973, 38, 2197. A. Metayer. A. Quesneau-Thierry, a n d M. Barbier, Tetrahedron Letters, 1974, 595. M. E. Garst and T. A. Spencer, J . Org. Chem., 1974, 39, 584.

t

Steroid Properties and Reactions

249

number of steroidal examples, including conversions of the types \

' /c=o 1 , /------C=CHCo2Et

/C=CHCN

and applications of the products in synthesis'66 The immonium salt (92), formed by reaction of 17P-hydroxy-5a-androstan-3-0ne with 3-pyrrolinium perchlorate, is converted by diazomethane into the spiro-salt (93); butyl-lithium causes fragmentation of the latter compound to give the 3-methylenederivative (94)in 82 yield, a significant improvement on yields claimed from the Wittig reaction. Other ketones and aldehydes react similarly.' 6 7

x)

(92)

(93)

(94)

Tosylmethyl isocyanide (TsCH,NC) adds onto ketones under basic conditions to give oxazolines or derived products. Use of thallium(]) ethoxide as base gave a 4-ethoxy-2oxazoline, which was readily hydrolysed by acid to give an a-hydroxy-aldehyde. Applied to 5a-cholestan-3-one, the two-step process afforded the 3a-hydroxy-3Baldehyde (99,which was found to exist partly in dimeric form.'68 Trimethylsilyl cyanide is an efficient reagent for the conversion of ketones into the trimethylsilyl ethers (96) of cyanohydrins, even in cases where hydrogen cyanide addition to the ketone is unsuccessful. The cyanohydrin ether (96) may be reduced and hydrolysed to give the aminomethyl alcohol (97). 69 Although no steroidal examples have yet been described, the importance of aminomethyl alcohols (97) for Demjanov ring expansion "O suggests applications in steroid chemistry.

(95)

n-(2-Methoxyallyl)nickel bromide (98),a new and reasonably stable reagent, converts ketones (e.g. 5a-cholestan-3-one) into 3-hydroxy-3-(2-oxopropyl) derivatives (99).'

'

166

16' i68

lh9

J. Boutagy and R. Thomas, Chem. Rev., 1974, 74, 87. Y. Hata and M. Watanabe, J. Amer. Chem. SOC.,1973, 95, 8450. 0. H. Oldenziel and A. M. van Leusen, Tetrahedron Letters, 1974, 167. D. A. Evans, G . L. Carroll, and L. K. Truesdale, J. Org. Chem., 1974, 39, 914. Ref. 80, pp. 323, 324; Ref. la, 1971, Vol. 1, p. 353; ibid., 1974, Vol. 4, p. 370. L. S. Hegedus and R. K. Stiverson, J. Amer. Chem. SOC., 1974, 96, 3250.

250

Terpenoids and Steroids

(99)

(98)

Steroidal 19-methyl 3.19-diketones (100) readily undergo internal cyclization with (101),a compound belonging to the bicyclobase to give the 3,lO-(2'-oxoethano)-system [2,2,2]octanone class. Huang-Minlon reduction under forcing conditions removed the oxo-group. C.d. data are reported for compounds of the type (101).'72

H -

H

In continuation of study of A'(")-unsaturated 5,10-seco-5-oxo-steroids (102), the trans-isomer has been shown to react with hydroxylamine or N-methylhydroxylamine to give cyclized derivatives (isoxazolidines) (103) or (104), respectively. The cis-isomer of (102) failed to react, apart from simple formation of the 5-oximino-derivative.' 7 3

R (103) R = H (104) R = Me

Steroidal nitrones [e.g. (105) and (106)]have been prepared by treating suitable aldehydes and ketones with N-alkylhydroxylamine salts and sodium bicarbonate : the products were stable crystalline solids. i 4

17*

F. M. Hauser, A. Philip, and F. I . Carroll, J. Org. Chem., 1973, 38, 3696. M. Lj. Mihailovic, Lj. Lorenc, Z. Maksimovic, and J. Kalvoda, Tetrahedron, 1973, 29, 2683. P. M. Weintraub and P. L. Tiernan, J . Org. Chem.. 1974, 39, 1061.

25 1

Steroid Properties and Reactions

I

CH=N

Me

\

t 105)

R

Reactiom of Enols and Enolate Ions.-Although all previous work involving enolization of 1l-oxo-steroids (107) has indicated the 9(1 1)-en-11-01 structure, lithium di-isopropylamide gives the kinetically controlled product, the 1 l-en-11-01,which was trapped as its trimethylsilyl ether (108). Use of lithium as cation minimizes rearrangement to the more stable 9(11)-enol. The lithium A' '-enolate reacted with perchloryl fluoride to give the 1 2 ~ and l2p-fluoro-ketones (109). Similar reactions in the 9~-fluoro-l l-oxo-series (110) proceeded through the A' '-en01 (1 1 1) to give the novel 9~,12\j-difluoro-(1 12) 75 and 9~!,12,12-trifluoro-ketones.' F

(107) R = H

(108) R = H

(110) R

(111)

=

F

R

=

F

(109) R (112)

R

= =

H F

Methylation of the 1l-oxo-oestrone derivative (113) gave the 9cr-methyl compound (1 14); the stereochemistry of alkylation was confirmed by an independent synthesis, involving aromatization of a 9a-methylandrosta-l,4-dien-3-one derivative. 7 6

'

(113) R = H

(114) R

=

Me

The hemiacetal form (115) of an 18-hydroxypregnan-20-onereacts smoothly with lead tetra-acetate in acetic acid to give the 21-acetoxy-derivative (116),or with sources of electrophilic bromine (e.g. Ph,Me,N+ Br, -) to give the 21-bromo-hemiacetal (117).

176

D. H. R. Barton, R. H. Hesse, M. M . Pechet, a n d T. J . Tewson, J . C . S . Perkin I , 1973, 2365. R. V. Coombs. J. Koletar, R . D a n n a , H. Mah, a n d E. Galantay, J.C.S. Perkin I , 1973, 2095.

Tcrpenoids and Steroids

252

R R (117) R (119) R (115) (116)

=

H

= = =

OAC

Br OH

These reactions. like the rapid substitution of hydrogen at C-21 by deuterium when the hemiacetal was treated with deuterioacetic acid, suggest the rapid and reversible formation of the vinyl ether (118) in acidic media, allowing electrophilic attack at C-21. These reactions led to the first convenient synthesis of 18.21-dihydroxypregn-4-ene3,20-dione, which exists in the hemiacetal form (1 19).17’ Boron trifluoride was found to be an effective catalyst for the bromination of methyl 3a,7a-diacetoxy-12-oxo-5~-cholanate (120) with bromine and acetic acid.’ 7 8 The 1 la-bromo-derivative (121) was formed in high yield, although reaction was only slight when HBr was used as the catalyst, even at 70 “C. This situation contrasts with the ready bromination of the corresponding 12-oxo-derivative lacking a 7a-acetoxysubsti tuen t .

H

(120) (121)

R R

= =

H Br

The 2-acetoxylation of 4-en-3-ones with lead tetra-acetate is improved by using a four-fold excess of reagent at 6&70 0C.30Stereospecific bromination of the 4-en-3-one at the 6P-position with N-bromosuccinimide requires intensively dried solvent for optimum yields.30 4.4-Dimethyl 5a-steroidal 2-ones undergo acetoxylation, bromination. or formylation at C-3; the latter reaction is slow and ineffi~ient.”~The 2a.3fi-diol (1 22), a metabolite of ‘chlormadinone acetate’. the corresponding 4.6-dien-3-one. has been obtained along with the 2/1,3[Gisomer by acetoxylation at C-2 [Pb(OAc),], followed by reduction with sodium borohydride. Both diols form acetonides.’ 80 Ring-D bromination of the steroid-like 17-oxocyclopenta[a]phenanthrene (123) has been studied.’ The lithium A3-enolate obtained by reduction of testosterone with lithium-ammonia reacts with l-iodo-3-trimethylsilylbut-2-eneto give the 4-alkylated derivative (124). ”’

‘‘I

D. N . Kirk and M . S. Rajagopalan, J.C.S. Chem. Camm., 1974, 145. Y. Yanuka and G . Halperin. J. Org. Chem., 1973, 38, 2587. A. D. Boul, R . Macrae, and G. D. Meakins, J.C.S. Perkin I, 1974, 1138. T. Abe and A. Kambegawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1295. M . M. Coombs. M.Hall, and C. W. Vose, J.C.S. Perkin I, 1973, 2236.

253

Steroid Properties and Reactions

(1 23)

Epoxidation and treatment with acid converted the vinylsilane component into the 4-(3’-oxobutyl)derivative (125), a suitable intermediate for construction of an additional ring.’82 Reductive alkylation (Li-NH,, then MeI) of cholesta-4,6-dien-3-one gives 4,4-dimethylcholest-5-en-3-one rather than a 4-monomethyl derivative. 8 3

Enolizable ketones (or aldehydes) react with phenylselenenyl chloride in ethyl acetate at room temperature to give a-phenylseleno-derivatives. Oxidation in situ with H,O,, peracetic acid, or sodium metaperiodate is followed by spontaneous elimination of the selenoxide to give the ap-unsaturated ketone or aldehyde. 5aCholestan-3-one gave the 1-en-3-one in high yield, with only minor contamination by the 4-en-3-one and 1-4-dien-3-0ne.l~~ A kinetic study of the enzyme-modelled isomerization of cholest-5-en-3-one by phenol-triethylamine mixtures has revealed complex behaviour, interpreted in terms of a transition state (126) involving a mole of the phenol and a phenol-triethylamine complex. rn-Nitrophenol was the most effective of a series of substituted phenols investigated.

\

ArO-H’

i:&c:-

,.o

H

c?.,..H--NEt,

o&

0I

A1

G . Stork and M . E. Young, J. Amer. Chem. SOC.,1974, 96, 3682. K . P. Dastur, Tetrahedron Letters, 1973, 4333. lE4 K . B. Sharpless, R. F. Lauer, and A. Y. Teranishi, J. Amer. Chem. Sac., 1973, 95, 6137. 1 8 5 A . Fauve, A. Kergomard, and M. F. Renard, Tetrahedron, 1973, 29. 2903. 18’

183

254

Terpenoids und Steroids

The well-known enolization-protonation procedure has been employed to deconjugate cholesta-l,4,6-trien-3-one,giving the 1,5,7-trien-3-one (127), which was found to be very unstable. Reduction with Ca(BH,), gave the 1,5,7-trien-3P-ol,which was used in a new synthesis of la-hydroxy-7-dehydrocholesterol.' 86 The concept of stereoelectronic control of deprotonation of a ketone, first proposed to account for the reactions of a 7-oxo-steroid, receives new support from a demonstrated kinetic preference for deuterium exchange of 2-axial protons in 4-t-butylcyclohexanone. 8 7 Steroidal 7-en-6-ones may be converted into their 6,8(14)-dien-6-01acetates (128) without change of configuration at C-5. The n.m.r. spectra of these derivatives provide reliable evidence of the C-5 configuration, depending upon the presence or. absence of allylic coupling between the C-5 and C-7 protons.'88

'

Reactions of Enamines and Enol Derivatives.-3-Pyrrolidino-3.5-dienes ( 1 29) react with formaldehyde to give 6-hydroxymethyl-4-en-3-ones (1 30) as major products.'89 Depending upon the reaction conditions, the product may be predominantly in the 6a- or the 6P-configuration, but both isomers are dehydrated by acid to give the 6methylene-4-en-3-one (13 l), a known intermediate for the preparation of 6-methylated s t e r ~ i d s . ' ' ~Dienamines of the 19-nor and 9P,10a ('retro') series react in a similar manner. 189

The dienamine (129) reacts with either crotonaldehyde or methyl vinyl ketone to give the benz[4,5,6]-steroids (1 33) or (134), respectively, after hydrolysis and chromatography. Condensation probably proceeds through a Michael-type addition at C-6, to give the keto-enamine (132),followed by electrophilic attack by the carbonyl group at C-4. A dehydrogenation step, required to aromatize the initial cyclohexadiene,

"'

'" I9O

C. Kaneko, A. Sugimoto, Y. Eguchi, S. Yamada, M. Ishikawa, S. Sasaki, and T. Suda, Tetrahedron, 1974, 30, 2701. G. B. Trimitsis and E. M. Van Dam, J.C.S. Chem. Comm., 1974, 610. W. B. Smith and G. P. Newsoroff, Steroids, 1974, 23, 579. F. Schneider, A. Boller, M. Muller, P. Muller, and A. Fiirst, Hefv. Chim. Acta, 1973, 56, 2396. D. Burn, G. Cooley, M. T. Davies, J. W. Ducker, B. Ellis, P. Feather, A. K. Hiscock, D. N. Kirk, A. P. Leftwick, V. Petrow, and D. M. Williamson, Tetrahedron, 1964, 20, 597.

255

Steroid Properties and Reactions

(133) R' (134) R'

(1 32)

= =

H, R 2 = Me Me, R2 = H

may occur by air oxidation, or possibly through disproportionation, since yields never reached 50 %.' Dichlorocarbene generated by thermolysis of sodium trichloroacetate converted 3-pyrrolidyl-3,5-dienes (129) directly into 4-chloro-~-homo-4(4a),5-dien-3-ones(1 35). Chlorofluorocarbene gave the corresponding 4-fluoro-derivative.' 9 2 O-Carboxymethyl-oximes (1 36) of steroidal 4-en-3-ones, required for binding to proteins for

H02CCH20N

c1

( 136)

(135)

radioimmunoassay studies, are readily prepared from monoketones, but selective condensation of 0-(carboxymethy1)hydroxylamine at C-3 in progesterone and its oxygenated derivatives has required indirect routes, to avoid formation of the 3,20bis-oxime derivative. The 3-pyrrolidyl-3,5-diene (129), which is formed selectively from progesterone with pyrrolidine in methanol, has been found to react with 0(carboxymethy1)hydroxylamine preferentially at C-3, giving the required C-3 derivative (1 36) in acceptable yield.' 9 3 Attempts to deconjugate 4-en-3-ones by careful protonation of the 3-pyrrolidyl dienamine derivative (129) gave poor results except in the case of oestr-9(11)-ene ~~ analogues, which afforded the 5( 10),9(1 l)-dien-3-ones in reasonable ~ i e 1 d s . I A detailed study of the hydrolysis of a 3-pyrrolidino-3,5-dienehas revealed an unexpectedly complex mechanism ;195 the transition state for protonation of enamines is thought to be more reactant-like than for the corresponding reaction of enol ethers.' 96

H

i137) 19* 193 194

i138)

i139)

P. Houdewind, J. C . L. Armande, and U. K. Pandit, Tetrahedron Letters, 1974, 591. S. A. G . de Graaf and U. K. Pandit, Tetrahedron, 1974, 30, 1 1 15. A. H. Janoski, F. C. Shulman, and G . E. Wright, Steroids, 1974, 23, 49. R . Bucourt and J. Dube, Bull. SOC.chim. France, 1974, 479. P. Bolla and M. Legrand, Bull. SOC.chim. France, 1973, 2143. P. W. Hickmott and K. N. Woodward, J.C.S. Chem. Comm., 1974, 2 7 5 .

256

Terpenoids and Steroids

An androst-15-en-17-one (137) is most effectively converted into the A' 4-compound (139) by reduction of the enol acetate (138)with sodium borohydride.' 9 7 17,!?-Acetoxy-3-methoxyoestra-2,5(10)-diene (140) reacts with perchloryl fluoride to give a 2-fluoro-5(10)-en-3-one(141). The configuration at C-2 is considered likely to be ,!? on the basis of some reactions of derivatives.19*

(1 40)

(141)

The enol acetates of cyclohexanone and cyclopentanone react with phenylselenenyl bromide and silver trifluoroacetate to give the 2-phenylselenoketones. Oxidation with NaIO, affords the 2-en-l-one7 by smooth collapse of an intermediate selenoxide, suggesting a potentially useful route for the regioselective dehydrogenation of steroidal ketones, when the required enol acetates are available (c$ p. 253).' 99 Alkylations and formylations of enol ethers with the Vilsmeier reagent have been reviewed.200 Dehydrogenation and Oxidation.-The dehydrogenation of a 4-en-3-one with dichlorodicyanobenzoquinone (DDQ) has been known for many years to give the 1,4-dien-3one, invariably contaminated by some 15% of 1,4,6-trien-3-one. Removal of the trienone from the residues left after direct isolation of as much dienone as possible has been achieved by selective reaction of the trienone with sodium metabisulphite to give a water-soluble adduct. The trienone could be recovered by decomposition of the complex with alkali2' The p-nitrophenylhydrazones of 5a-cholestan-3-one and lanost-8-en-3-one are dehydrogenated by iodine and potassium t-butoxide to give the corresponding 1,4-diene (142), requiring two molar proportions of reagent, and the 1-ene (143),requiring one mole of reagent, respectively.202 Nitrobenzene, or more conveniently p-nitrobenzoic acid, is a useful alternative to iodine as the oxidant. Yields are excellent (85-92"/,), so these processes will be seen as attractive alternatives to

(142)

(143)

DDQ or selenium dioxide if the p-nitrophenylhydrazone groups can be removed with equal efficiency to give the 174-dien-3-oneand 1-en-3-one: this requirement has not yet been discussed. Mechanisms are considered, a point of additional interest being the formation of the (E)-isomer of the A'-compound (143)by use of iodine, or the less stable G. H. Rasmusson a n d G. E. Arth, Steroids, 1973, 22, 107. J. Pataki, Tetrahedron, 1973, 29, 4053. lYY D. L. J. Clive, J . C . S . Chem. Comm., 1973, 695. D. Burn, Chem. and Ind., 1973, 870. 201 A. K. Lala a n d A. B. Kulkarni, Steroids, 1973, 22, 763. 2 0 2 D. H. R. Barton, J. C. Coll, J. F. McGarrity, a n d D. A. Widdowson, J.C.S. Perkin I, 1973, 1565. I"

lY8

Steroid Properties and Reactions

257

(2)-isomer when a nitroaryl oxidant was employed.202 A new method for the introduction of unsaturation ap to an ester group comprises generation of the a-carbanion by means of lithium N-cyclohexyl-N-isopropylamide, a-sulphenation by reaction with dimethyl disulphide, oxidation of the 01-methylthio-ketoneto the sulphoxide, and final pyrolysis of the latter at ca. 120 0C.203Yields are high, and ketone enolates are unaffected, allowing the selective conversion illustrated in Scheme 3. Diphenyl disulphide is more reactive than the dimethyl reagent, offering an analogous route to ag-unsaturated ketones. Lactones can also be dehydrogenated by these procedures (cc similar reactions using phenylseleno-ketones as intermediates, pp. 253 and 256).

0

C0,Me

1 0 H Scheme 3

A Nocardia species can be used either to reduce a 4-en-3-one to give the 501 saturated ketone or to dehydrogenate the enone, giving the 1,4-dien-3-one, according to the incubation conditions.204 Enzymic conversion of oestr-4-ene-3,17-dione into oestrone proceeds through loss of the 2P-proton, as revealed by tritium labelling.205

'03 '04 '05

B. M. Trost and T. N . Salzmann, J . Amer. Chem. SOC., 1973,95, 6840. G. Lefebvre, F. Schneider, P. Germain, and R. Gay, Tetrahedron Letters, 1974, 127. T. Nambara; T. Anjyo, M. Ito, and H. Hosoda, Chem. and Pharm. Bull. (Japan), 1973,21, 1938.

Terpenoids and Steroids

258

Autoxidation of 5a-cholestan-3-one in t-butyl alcohol with potassium t-butoxide proceeds beyond the known 2,3-dione by hydroperoxide attack on (2-4 (144) and loss of the C-3 carbon atom ; the product, the aldehyde-carboxylate (145), was reduced by sodium borohydride and afforded the lactone (1 46). Comparable reactions converted Sfl-cholestan-3-one into the lactones (147)and ( 148).206 A1(9)-Octal-2-oneand A '(*'-indan-2-one have been used as models for a detailed study of the Baeyer-Villiger oxidation: they can be regarded as bicyclic analogues of steroidal 4-en-3-ones and ~-nor-3(5)-en-2-0nes.~'~ Reactions of Oximes and Related Compounds.-A reaction sequence recently developed for the selective removal of a methyl group from 4,4-dimethyl steroids has now been adapted for the preparation of 18-nor-17-0x0-steroids. Abnormal Beckmann fission of the oxime (149) was followed by epoxidation of the unsaturated nitrile (150) and cyclization of the epoxide (151) with BF, to give the ketone (152). The product was assigned the 13P-configuration from n.m.r. evidence.208

The Beckmann cleavage of an cehydroxy-ketoxime (153) has been used to open ring reaction with tosyl chloride-pyridine gave the unstable cyano-aldehyde (154).209 The 5-hydroxy-6-acetoximino-5a-cholestane(1 5 5 ) undergoes Beckmann fragmentation under exceptionally mild conditions, or even on storage, to give the cyano-ketone (1 56),210 whereas the corresponding h i t r i t e is converted by alumina into a mixture of products.21 D:

OH

(155)

( I 56)

Further studies on Schmidt and Beckmann rearrangements have concerned 6-0xo-, ~-oxo-,and A5-7-0x0-steroids2l 2 and oestrone.21 The oxime of an a$-epoxy-ketone is fragmented by hydroxylamine-0-sulphonic acid in alkaline solution to give an acetylenic ketone214(cf:the analogous tosylhydrazone ?06 207 208 'OY

210

"'

2 L 2

R. Sandmeier and C . Tamm, Helv. Chim. Acta, 1973, 56, 2238. A. DeBoer and R . E. Ellwanger, J. Org. Chem., 1974, 39, 77. M. M. Coombs and C . W. Vose, J.C.S. Chem. Comm., 1974, 602. D. MiljkoviC, J. Petrovic, M. Stajic, and M. Miljkovic, J. Org. Chem., 1973, 38, 3585. C . R . Narayanan and M. S. Parkar, Chem. and Ind., 1974, 163. M. Onda and K. Takeuchi, Chem. and Pharm. Bull. (Japan), 1973, 21, 1287. B. Matkovics and Z . Tegyey, Acta Chim. Acad. Sci. Hung., 1974, 80, 21 1. B. Matkovics, B. Tarodi, and L. Balaspiri, Acta Chim. Acad. Sci. Hung., 1974, 80, 79. P. Wieland and H . Kaufmann, Helv. Chim. Acta, 1973, 56, 2044.

259

Steroid Properties and Reactions

C

I

H

cleavage215). The new reaction has been applied to the oxime of a 9a,lla-epoxy-12ketone, a compound which is resistant to the tosylhydrazone method of cleavage. A 4,5-epoxy-3-ketone gave the 4,5-seco-3-yn-5-one(157), which reacted with 4N-H2S04 in dioxan, undergoing ring closure to give the 4-en-3-0ne.~l 4 The mechanism of hydrolysis of the 3-oxime of 17cr-acetoxy-6cr-methylpregn-4ene-3,20-dione, and some derivatives, has been studied.2l 6 The reaction of hydrazoic acid and boron trifluoride with a 4-en-3-one to form a tetrazole has been extended to a

(158)

R

N GN,

= I

,.’

N

0’

T, Me

(159) R = NHCOMe

5-en-7-one and to progesterone. Reactions with the 20-0x0-function afforded two recognizable products, the bis-tetrazole (158) and the acetamido-tetrazole ( 159).2l 7 The phenylhydrazones (160) of 5cr-cholestan-3-one or cholest-4-en-3-one react with arsenic trichloride to give the corresponding arsadiazole derivatives (1 61).2

Carboxylic Acids, Nitriles, and Aldehydes.-A novel degradation of the lanosterol sidechain (162) has provided the corresponding pregnan-20-one derivative (1 66) without damage to the sensitive A8-olefinic system. Selective ozonolysis of a lanosteryl ester first provided the trisnor-acid (163). Two routes were then developed for further degradation : (a) bromination of the acid ester at C-23 via the enolate anion, followed by dehydrobromination, gave the ap-unsaturated ester (164), which isomerized in a

*l5 217

M. Tanabe, D. F. Crowe, R. L. Dehn, and G. Detre, Tetrahedron Letters, 1967, 3739. R. E. Huettemann and A. P. Shroff, J. Pharm. Sci.,1974, 63, 74. H. Singh, R. K. Malhotra, and N. K. Luhadiya, J.C.S. Perkin Z, 1974, 1480. G. Markl, H. Baier, and C. Martin, Tetrahedron Letters, 1974, 1977.

Terpenoids and Steroids

260

basic medium to the fill-unsaturated (A20(22))ester (165),and a second selective ozonolysis generated the required 20-0x0-group (166); (b)the acid chloride (167) was converted by means of lithium diphenylcuprate into the phenyl ketone (168), which underwent photochemical cleavage to give the 20-methylenepregnane (169); again the degradation was completed by selective ozonolysis.2

(163) R (167) R

= =

OH C1

7a-Cyanotestosterone acetate (1 70), prepared by reaction of the 4,6-dien-3-one with HCN and Et,Al, was incompletely hydrolysed by methanolic HC1, the amide intermediate being trapped by conjugate addition on to the 4-en-3-one to give the lactam (171). Suitable conditions were found for completion of the hydrolysis uia the N-nitroso-lactam (172), to give 7a-carboxytestosterone acetate (173). Sulphur tetrafluoride converted the carboxy-group into a trifluoromethyl group (174)without damage to the enone system.220

(170) R (173) R (174) R

= = =

CN CO,H CF,

(171) R = H (172) R = N O

Methyl deoxycholate and esters of other steroidal acids are readily hydrolysed by enzymes present in potato tubers. Several other plants, including apple and pineapple, contain similar esterases, although potatoes exhibited the highest activity. A crude cell-free extract of the enzyme was also effective.221The iodo-aldehyde (175) underwent a remarkable reductive cyclization when its hexane-benzene solution was passed through chromatographic alumina, giving the oxepan (176). The same product was *lo 220

3.Ganem and M. S. Kellogg, J . Org. Cham., 1974, 39, 515. G. H. Rasmusson, A. Chen, and G . E. Arth, J. Org. Chern., 1973, 38, 3670. N. G. Chan and Z . Prochazka, Coll. Czech. Chern. Comrn., 1973, 38, 2288.

Steroid Properties and Reactions

26 1

formed from the iodo-aldehyde by reduction with NaBH, in boiling THF, or with NaBH, in methanolkther at room temperature followed by passage through alumina. In the absence of any other obvious reducing agent in the direct cyclization on alumina, it is suggested that the reacting steroidal species is able to abstract a hydride ion from the hydrocarbon solvent.2 2 2

Titanocene (from the dichloride and sodium) deoxygenates aldehydes, esters, and epoxides to hydrocarbons with the same carbon skeleton : methyl 5P-cholanate gave SP-~holane.~~~ 5 Compounds of Nitrogen and Sulphur

The 22-tosylates of 22R- and 22s-hydroxycholesteryl 3-benzoates gave 22-azides of inverted configuration with sodium azide in HMPA : the corresponding 22-aminocholesterols were obtained by reduction of the azides. No difficulty was encountered in converting 22-oxocholesterol into its oxime, which afforded the mixed amines on reduction.224The amino- and acetamido-derivatives at (2-3, C-4, C-6, C-7, C-1 1, C-16, and C-17 in the Sa-androstane series have been prepared by conventional methods, and their configurations have been assigned from n.m.r. spectra.64 2-Azido- and 4-azidoderivatives of oestrogens have been prepared from the corresponding phenolic amines by diazotization and reaction with sodium azide, and the diazoacetates of oestradiol and oestrone were obtained by reaction with the tosylhydrazone of glyoxylic acid chloride (TsNHN=CHCOC1).22s Reaction of some 17P-acetamido-androstanes with nitrous acid gave the 17pacetoxy-derivatives in only low yields. a/?-Unsaturated E-lactams merely gave the N nitroso-lactams, and enamine-lactams [e.g. (177)] suffered nitrosation to give oximinolactams (1 78).226

222 223 224 225

226

H. Suginome and K . Kato, Tetrahedron Letters, 1973, 4143. E. E. van Tamelen and J. A. Gladysz, J. Amer. Chem. SOC.,1974, 96, 5920. Q. Khuong-Huu, Y. Letourneux, M. Gut, and R. Goutarel, J. Org. Chem., 1974, 39, 1065. J. A. Katzenellenbogen, H. N. Myers, and H. J. Johnson, jun., J . Org. Chem., 1973, 38, 3525. M. Kobayashi and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1973, 21, 1069.

262

Terpenoids and Steroids

The reaction between p-carboxybenzenesulphonyl azide and a 16-diethylaminomethylene- 17-ketone [e.g. (179)] provides a synthesis of the 16-diazo-17-ketone (1 80) which is claimed to be superior to the more usual chloramine oxidation of the oximinoketone. Photolysis of the diazo-ketone (180)gave a mixture of isomeric 16-carboxy-~nor-1 3a-androstane derivatives ( 181).227

(179) X = CHNEt, (180) X = N,

(181)

A 16-aminomethy1ene-17-oxo-steroid(182), obtained by ammonolysis of the 16methoxymethylene derivative, condenses with 4-aminouracils (183) to give the novel heterocyclic structures ( 184).228

& X

CHNH, +

0 H-NH, N (182)

(183) X

=

NH

~

0. S, or N H

1

/

( 184)

The water-soluble steroidal imidazole (1 85) has been studied as a model for an enzyme system, and is found to catalyse the hydrolysis of esters of 3-arylpropionic acid and related compounds229and of phenolic acetates.230 Hydrophobic interaction between the ester molecule and the body of the steroid (cc-face)is thought to stabilize the transition state for attack of the imidazole residue on the ester group. The related imidazolyldiamine with C-3 and C-17 substituents interchanged is even more effectiveas a catalyst for hydrolysis of aryl esters.231 H

I

H, N

22’

228 229 230

231

J. Meinwald and A. J. Taggi, J . Amer. Chem. SOC.,1973, 95, 7663. G. Bouchon, H. Pech, and E. Breitmaier, Chimia (Swirz.), 1973, 27, 212.. J . P. Guthrie and Y. Ueda, J.C.S. Chem. Comm., 1973, 898. J. P. Guthrie and Y. Ueda, J . C . S . Chem. Comm., 1974, I 1 1 . J. P. Guthrie and Y. Ueda, Canad. J . Chem., 1973, 51, 3936.

263

Steroid Properties and Reactions

The oxidation of pseudosolasodine diacetate, as a key step in the degradation of has received a detailed study leading solasodine to 3/I-acetoxypregna-5,16-dien-20-one, to the identification of intermediates and b y - p r o d u ~ t s . ’ Criteria ~~ for the assignment of stereochemistry to steroidal indolizidines (186) have been reported; the rate of quaternization with methyl iodide is more useful than spectroscopic methods.233

( 186)

A kinetic and product study of the ally1 sulphoxide-sulphenate rearrangement (Scheme 4) in the steroid series indicates that the reaction is a normal suprafacial [2,3] sigmatropic process. Rate differences were used to assign configurations at sulphur in the sulphoxides, on the basis of the degree of steric strain in the transition state for rearrangement. 234

@

7 L

...

04s

o,..

SMe

The 2cr,3cr-anti-(R)-episulphoxide(187) reacts with acidified alcohol to give the bissteroidal disulphide S-mono-oxides (188) ; reactions leading to assignment of configuration at sulphur in these products are described.235

( 187)

232 233

* 34 23s

S

H

(188) G . G . Malanina, L. I. Klimova, L. M. Morozovskaya, 0. S. Anisimova, L. M . Alexeeva, and N. N. Suvorov, Khim. Farmatseot. Zhur., 1974, 8, 18. V. M . Kolb and M. StefanoviC, Tetrahedron, 1974, 30, 2233. D. N. Jones, J. Blenkinsopp, A. C . F. Edmonds, E. Helmy, and R. J. K . Taylor, J.C.S. Perkin I , 1973, 2602. M. Kishi, S. Ishihara, and T. Komeno, Tetrahedron, 1974, 30, 2135.

264

Terpenoids and Steroids

5a-Cholestan-3-one 2a-ethylxanthate reacted with HCl in benzene to form the novel heterocycle (189), although in ether the product was the 3-0x0-2a-thiol. Either the xanthate or the thiol, with malononitrile and a catalytic amount of morpholine, afforded the thiophen derivative ( 190).236 Steroidal thiophenylacetates are desulphurized by deactivated Raney nickel to give jj-phenylethenyl ethers.237

6 Molecular Rearrangements Contraction and Expansion of Rings.-A new homologation procedure comprises the addition of difluorocarbene on to an enol acetate, followed by hydrolysis of the resulting difluorocyclopropyl acetate; some of the many examples are outlined in Scheme 5.

1

Scheme 5

Difluorocarbene is readily produced by pyrolysis of sodium chlorodifluoroacetate. Mechanisms for opening of the difluorocyclopropane ring are

’”

”’ 23x

S. K . Roy, J . Org. Chem., 1973, 38, 4211. J . Ellis and R. A. Schibeci, Austral. J . Chem., 1974, 27, 429. P. Crabbe, A. Cervantes, A. Cruz, E. Galeazzi, J. Iriarte, and E. Velarde, J . Amer. Chem. Soc., 1973, 95, 6655.

Steroid Properties and Reactions 265 Cyanogen azide (hazard warning !) reacts with alkylidenecycloalkanes to give, after hydrolysis, ring-expanded cyclic ketones. Examples in the steroid field include the conversion of a 3-methylene-5a-steroid (191) into A-homo-ketones (192) and (193), or of a 3-ethylidene-A4-compound into mixed methyl-enones with an enlarged ring. The

proposed mechanism is very similar electronically to the Tiffeneau and diazomethane reactions, which afford comparable mixtures of ring-enlarged ketones.239 Solvolytic rearrangements of D-nor-steroids in the 13a-series are interpreted on the basis that a leaving-group at the 16a- or 16b-position has the quasi-equatorial c ~ n f o r m a t i o n . ~ ~ ’

No special strain is involved in the 16a-series (194), but a 16b-substituent appears to force a boat-like conformation on ring c (195). The reader is referred to the original

OH Reagents: i, Li(Bu‘O),AlH; ii, H + ;iii, Jones’ reagent

Scheme 6 239

J. E. McMurray and A. P . Coppolino, J . O r g . Chem., 1973, 38, 2821.

266

Terpenoids and Steroids

paper for details of the complex reactions undergone, which appear to involve nonclassical cationic intermediates. Diagrams (194) and (195) illustrate only the initial geometries of the reactants. Reactions of the 5a.7a-cyclo-~-homo-4-ketone(196) and related compounds exhibit interesting features. some of which are illustrated in Scheme 6.240 ‘Backbone’ and Related Rearrangements.--The ‘backbone’ and ‘Westphalen’ rearrangement products (198) and ( 199) from 4~-acetoxy-5-hydroxy-5cc-cholestane ( 197) with D2S04-DOAc-Ac20 contained no detectable deuterium, 2 4 1 showing that

AcO

AcO

the rearrangement under these conditions occurs without the intermediacy of olefinic or cyclopropane-like structures. This finding contrasts with evidence for some analogous reactions, including the backbone rearrangements (in H2S04) of the steroidal amines holamine (200) and methylholaphylline (201). Reaction of samples bearing 8P-deuterium labels resulted in extensive but not total loss of deuterium, indicating that the stage involving conversion of a C-9 into a C-8 carbonium ion proceeds mainly uia deprotonation to a A’-olefin, followed by reprotonation. Direct hydride shift (8p --+9p) occurs to a small extent. The authors comment briefly on the unresolved features of this mechanistic

R d (ZOO) P R C= E-NH, O M (201) R

=

e

fi-NHMe

A new example of the backbone rearrangement appears at first sight to contravene the accepted principle of thermodynamic equilibration of products.243The 2a-hydroxyA8-unsaturated compound (202), with the 14P-configuration, rearranged with formic acid in refluxing dichloromethane to give, after removal of formate groups, a mixture containing the A5- and A4-unsaturated isomers (203) with the 1 4 a - c o n f i g ~ r a t i o n . ~ ~ ~ Although some examples of ‘retro-Westphalen’ rearrangements (5P-Me -P 10P-Me) 240 241

242

243 244

L. Kohout and J. FajkoS, Coll. Czech. Chem. Camm., 1974,39, 1613. E. T. J. Bathurst and J. M. Coxon, J . C . S . Chem. Comm., 1974, 131. J.-C. Thierry, F. Frappier, M. Pais, and F.-X. Jarreau, Tetrahedron Letfers, 1974, 2149. Ref. la, 1972, Vol. 2, pp. 304, 305; 1973, Vol. 3, pp. 378-381. A. Ambles, J.-C. Jacquesy, and R. Jacquesy, Bull. Soc. chim.France, 1973, 2865.

Steroid Properties and Reactions

267

(203) A4 or As

(202)

are known,245the simultaneous isomerization from the 148- to the 14a-configuration is unprecedented. Without the 2a-hydroxy-substituent, a full backbone rearrangement would occur, leading to a A'3('7)-isomer [cf: (198)], so the 2a-hydroxy-group seems to be responsible for the unusual reaction. Two points may be noted: (a) the 2a-OH (or OCHO) group is originally axial, but becomes equatorial in the products ; (h) the 17p-side-chain in cholestane derivatives has been said to stabilize the 14a- more than the 14fl-configuration,by virtue of torsional interaction across the C-13-C-17 bond.Z46 Nevertheless, the apparent absence of any 14p-or A13(l')-product is not readily explained. Further examples of backbone rearrangement under thermodynamic control have been reported for compounds of the euphol series.z47 The 6~-cyano-Sa-hydroxy-compound (204) gives a normal 'Westphalen' product (205), the cyano-group being similar to a 6P-fluoro-substituent in its effect on the rate of reaction. A 6P-azido-group (206), however, leads to the unrearranged 3,5-diacetate as major product, behaviour which indicates neighbouring-group participation by the azido-group attacking C-5 (207) in the initial step.248

(204) R' (206) R'

= =

Me, R2 = CN Ac, RZ = N,

(205)

The 5a-hydroxy-7-en-6-one (208) rearranges with acid to give dienones (209) and (210) and minor third compound, probably the lOP-isomer of (210). The reactions

AcO

245

246

247

*"

0

Ac 0

E.g. Ref. la, 1972, Vol. 2, p. 303. Ref. la, 1971, Vol. 1, p. 362. J. L. Zundel, G. Wolff, and G. Ourisson, Buff. SOC.chim. France, 1973, 3206. B. A. Marples, B. M. O'Callaghan, and J. L. Scottow, J . C . S . Perkin I , 1974, 1026.

Terpenoids and Steroids

268

are of 'Westphalen' type, but remarkable in that the saturated hydroxy-ketone corresponding to (208) is inert under similar conditions.249 A partial backbone rearrangement occurs when a C-9 carbonium ion (212) is generated in 5P-pregnane-3,20-dione by the action of concentrated sulphuric acid on either the 9(1 1)-ene (211) or its 1 la-hydroxy precursor.250 Conjugation in the 13(17)-en-20-one (213) probably accounts for the stability of the product. Epoxidation of the olefinic bond, followed by reaction of the epoxide (214) with formic acid, reversed the migration of C- 18 to give 17a-hydroxy-9p-pregn-8(14)-ene-3,20-dione (215). Using known methods, the pregnane side-chains of compounds (213) and (215)were degraded to afford the corresponding 17-oxoandrostane derivatives.25o

(2 15)

Aromatization of Rings.-Some further interesting isomerizations in the hyperacidic solvent HF-SbF, imply that both dienon-phenol and phenol-dienone interconversions are possible. Androsta- 1,4,6-triene-3,17-dione(2 16) is aromatized to give a 'pura' phenol, while also being isomerized at C-14 and suffering double-bond migration, to give the compound (217). This reaction, and a similar isomerization of androsta1,4-diene-3,17-dione, requires backbone rearrangements to explain the inversion at C-14 and probably occurs through transient dearomatization of the initial product of a normal dienone-phenol rearrangement.2

249 250

251

R. Hanna, Tetrahedron Letters, 1973, 3349. J. Schmitt, A. Hallot, P. J . Cornu, and A. Costes, Bull. Soc. chim. France, 1973, 2035. J.-C. Jacquesy, R. Jacquesy, and Ung Hong Ly, Tetrahedron Letter.$, 1974, 2199.

Steroid Properties and Reuctions

269

A further group of steroids with functional groups equivalent to triple unsaturation in rings A and B has been shown to give a 4-methyloestra-l,3,5(10)-triene on reaction with HBr-AcOH. The 3- and 6-monoacetates (218) and (219) of a 4-ene-3P,6P-diol, however, gave the 4-en-6-one (220) and 4-en-3-one, respectively, although the 3,6diacetate aromatized normally.252 The mechanism of enone formation has not yet been defined in detail, but seems likely to involve initial elimination of acetic acid to give the dienol corresponding to the product enone.

(218) R' = A c ; R 2 = H (219) R' = H ; RZ = AC

(220)

Other examples of the aromatization of steroids with triple functionality in rings A and B include 3,4,5- and 3,5,6-triol derivatives.253A 3~-acetoxy-4ct,5a-epoxyandrostane was similarly aromatized in HBr-AcOH via a spiro-cation intermediate, but the corresponding oestrane derivative aromatized without skeletal rearrangement, as revealed by use of 3a-deuterio-labelled material. When C-4 was blocked by a methyl substituent, the androstane derivative (221) aromatized to give mainly the 1P-dimethyloestratriene (222), accompanied by a little of the 3,4-dimethyl derivative. The 1,4dimethyl product arises by a simple migration of the C-19 methyl group to C-1. The effect of 2,2-dimethyl substitution on the aromatization was also The 5,6-epoxyandrostan-7-01~ (223) were unexpectedly found to give the 4-methyloestraA ~kinetic study of the dienone-, 1,3,5(10)-triene on heating with H B ~ - A c O H . ~ ~ phenol rearrangement of androsta-1,4-diene-3,17-dione, and other model dienones, includes measurements of their basicities.' 56

2~-Hydroxy-3,17-dioxoandrost-4-en19-a1 (224), prepared by a novel sequence of conventional reactions, is converted rapidly and quantitatively into oestrone in neutral aqueous The hydroxy-aldehyde is suggested as the immediate biosynthetic precursor of oestrone, implying that the final step in uiuo may not require enzymic assistance. 252

253 254

255 256

257

D. Baldwin, J. R. Hanson, and A. M . Holtom, J.C.S. Perkin I, 1973, 1704. D. Baldwin, J. R. Hanson, and A. M. Holtom, J.C.S. Perkin I, 1973, 2687. J. R. Hanson and H. J. Wilkins, J.C.S. Perkin I, 1974, 1388. D. Baldwin and J. R. Hanson, J.C.S. Chem. Comm., 1974, 21 1 . M. J. Hughes and A. J. Waring, J.C.S. Perkin I / , 1974, 1043. H. Hosoda and J. Fishman, J.C.S. Chem. Comm., 1974, 546.

270

Terpenoids and Steroids

Reduction of the adduct (225) with LiAlH, gave the aromatic steroid analogue (226). The suggested mechanism of this unusual reaction involves the intermediate reduced compound (227), which appeared (n.m.r.) to be formed under mild conditions. The aromatization step may involve deprotonation at nitrogen and expulsion of a lithiumco-ordinated methyl carbanion, as illustrated. The A8(I4)-isomerof (225) afforded a 7,7’-dimericsteroid under similar reaction conditions.’

(228)

(229)

The reaction between the 7p-hydroxylanost-8-en-11-one (228) and toluene-psulphonyl chloride in pyridine also proceeded in part by ejection of the C-19 methyl ~ reaction, ~ ~ under ionizing group, giving the product (229) with an aromatic ring B . This conditions, is in sharp contrast to the more usual formation of anthrasteroids when ring B is aromatized. 17,17-Disubstituted-18-norandrost13-enes have been aromatized in ring c by brominationdehydrobromination to give the 7,13-diene, followed by a repetition of these two steps.260 Other steroid analogues with a phenolic ring c (231) have been obtained by treating l7~-hydroxy-l7cr-methylandrost-8-en-ll-ones [e.g. (230)] with formic acid. Dehydration at C-17, with Wagner-Meerwein migration of the 13pmethyl group to C- 17, provides the necessary third unsaturated linkage. Treatment of the 1 1-acetate (232) with DDQ gave the corresponding 1,4-dienone,accompanied by 258

*”

H. de Nijs and W. N. Speckamp, Tetrahedron Letters, 1973, 3631. J . R. Dias, J . O r g . Chem., 1974, 39, 1767. C . L. Hewett, I. M . Gilbert, J. Redpath, D. S. Savage, J. Strachan, T. Sleigh, and R. Taylor, J.C.S. Perkin I, 1974, 897.

27 1

Steroid Properties and Reactions H+

0

AcO

(230)

(231) R (232) R

= H = AC

(233)

the phenanthrene derivative (233), resulting from dienone+phenol rearrangement and further dehydrogenation.26 Chromogenic Reactions-The essential structural features for a positive Kober reaction have been closely defined from study of a wide variety of steroids: a steroidal ring system with a phenolic ring A is necessary, together with unsaturation or an oxygen function in ring D, an angular methyl group at C-13, and angular hydrogen atoms (rather than unsaturation or substitution) along the ‘backbone’ of the molecule. Several of the products of the Kober reactions of oestradiol and oestrone 3-methyl ether have been identified as 17-methyl-18-noroestrane derivatives, with varying levels of unsaturation up to and including that of a phenanthrene derivative.262 Further indicate that benzylic cations of the type (234), resulting from cationic migration from ring D, are key intermediates in the Kober reaction sequence. A series of papers describes new studies of the chromogenic reactions between steroids and strong acids. A solution of testosterone in 70 % perchloric acid deposits a crystalline 1 : 1 complex of its components within 30 minutes, but heating a chloroform solution of testosterone (235) and the with the acid affords isomeric 17-methyl-18-norandrost-4-en-3-ones corresponding 4,13(14)- (236) and 4,13(17)-dien-3-ones (237). Colour development appears to be associated with cationic species [e.g.(238)]derived from these die none^."^

(235) Ring D saturated (236) A13 (237) A r 3 ( 1 7 )

Epitestosterone (l7a-OH) generates the same dienones in formic acid. The KagiMiescher reaction (HOAc-H,SO,, then Br,-HOAc) of epitestosterone appears to 261

C . L. Hewett, S. G . Gibson, I. M. Gilbert, J. Redpath, and D. S . Savage, J.C.S. Perkin I , 1973, 1967.

262

263 2h4

M. Kimura, M. Kawata, K. Akiyama, K. Harita, and T. Miura, Chem. and Pharm. Bull. (Japan), 1973, 21, 1720, 1741. M. Kimura, K. Akiyama, and T. Miura, Chem. and Pharm. Bull. (Japan), 1974, 22, 643. M. Kimura and K . Harita, Chem. and Pharm. Bull. (Japan), 1973, 21, 1205.

272

Terpenoids and Steroids

involve formation and further reactions of similar cations derived from the dienones to generate the characteristic c o l o ~ r The . ~ ~absorption ~ spectra of products resulting from the chromogenic reactions of testosterone depend upon the particular acidic species employed. Sulphuric, phosphoric, or perchloric acids and the Lewis acids SbCI,, SbCl, , ZnCI,, or AlC1, all give distinguishable spectra, as well as characteristic gas-chromatograms of isolated products.266 Miscellaneous Rearrangements-The hydrolysis of Sfl-pregnane-3a,20a-diol20sulphate with boiling hydrochloric acid causes elimination with rearrangement to give the olefinic product (239), in contrast to the 208-isomer which gives ‘uranediol’, a D-homoandrostane d e r i ~ a t i v e . ~These ~’ rearrangements follow the pattern already recognized in the solvolysis of the corresponding 2O-tosylo~ypregnanes.~~~

(239)

Concentrated sulphuric acid transforms 2 1-acetoxypregnan-20-ones (240) into rearranged products, either the 17P-methyl-18-nor-17a-pregn-13-en-20-0ne (243) or the 13-hydroxy-derivative (242), which readily dehydrates to give the 13-ene on heating.26’ Although similar rearrangements are well known to occur in 17%-hydroxypregnane derivative^,^^' the present reaction requires an unusual preliminary step to generate a C- 17 carbonium ion. Allylic displacement of the 21-acetoxy-substituent from the enol (241) is proposed.269 CH,OAc CO

P FH,-OAc

iH2

SH 1

265

‘‘’‘ 2h7

2hX

‘‘’ ‘’O

M. Kimura and K . Harita. Chem. and Pharm. Bull. (Japan), 1973, 21, 1235. M. Kimura and K. Harita, Chem. and Pharm. Bull. (Japan). 1973, 21, 1261. 1. Yoshizawa, T. Miura, M. Kimura, K. Anzai, and S. Matsuda, Chem. and Pharm. Bull. (Jupun), 1973, 21, 1622. H. Hirschmann, F. B. Hirschmann, and A. P. Zala, J . Org. Chem.. 1966, 31, 375. J . Schmitt, A . Hallot, P. J. Cornu, A. Costes, and P. Comoy, Bull. SOC.chim. France, 1973,2032. Ref. 80, p. 271.

27 3

Steroid Properties und Reactions

Pregnane-3,20-diones (244) are isomerized by the hyperacidic media HF-SbF, or HS03F--SbF, to give mixtures containing the 13a,17a- (246; major product), 130,17a-, and 13aJ 7P-analogues. The simultaneous equilibration of configurations at both C-13 and C-17 is thought to proceed through the 13,17-ssco-enol(245),for samples labelled with deuterium at C-17 and C-21 lost none of the

0 ti

The 9a,l la-epoxide (247) rearranged with boron trifluoride to give the related 9,B-11ketone and the novel 9-methyl- 19-nor-9P-pregn-5(10)-en-11a-01 derivative (248).27 This result contrasts with a recent report273of rearrangement of 9a,l la-epoxy-5aandrostane-3,17-dione to give 1la-hydroxy-90-androst-8( 14)-ene-3,17-dione.,Evidently the nature of substituents at C-3 and/or C-17 controls the reaction path. Epoxidation of the A5(l')-olefin (248) gave first the SP,lOP-epoxide,which rearranged in the presence of acid to give the Sa,lla-epoxy-lO[j-oI (249), a compound of curious and unprecedented structure which owes its existence to the unusual proximity of C-5 and C-1 1 permitted by the 90-configuration. Further simple transformations of the 5a,l la-epoxy-compound afforded the 90-methyl product (250) with a phenolic ring A.272

21 1 272 273

J.-C. Jacquesy. R. Jacquesy, S. Moreau, and J.-F. Patoiseau, J.C.S. Chem. Comm., 1973, 785. A. C. Campbell, C . L. Hewett, M. S. Maidment, and G. F. Woods, J . C . S . Perkin 11974, 1799. J. W. ApSimon, R. R. King, and J. J. Rosenfeld, Canad. J . Chem., 1969,47, 1989.

274

Terpenoids and Steroids Me

Me

(255)

-+ (253)

(2541

The curious reactions whereby the 20a- and 20j-acetoxy- 16417a-epoxypregnanes (251) and (253) react with methylmagnesium iodide to give the isomeric 20-methyl-l6a,20-diols (252) and (254) are explained by a mechanism [see (255)] involving hydride transfer (20 -+ 17), as revealed by deuterium labelling. The stereochemistry of hydride migration in each isomer depends upon the side-chain conformation required to bring the C-20 and C-16 oxygen substituents into close proximity, for complexing with magnesium.274 The Serini reaction (rearrangement of a diol monoacetate by zinc dust-toluene) occurs in ring D with suitably alkylated derivatives. A 16a-alkyl 16P,17j-diol 17acetate (256) gave the 16~-alkyl-17-ketone(257) in good yield. A similar trans-diol derivative failed to react, in accordance with the suggested involvement of an orthoacetate of the diol. The l6a-vinyl compound (258) reacted to give the (Z)-16-ethylidene17-ketone (259) in high yield. Reactions with 17a-deuteriated diol derivatives showed that a hydride migration step is involved.275

(256) R = Et, Ph. etc. (258) R = CH=CH,

(257)

(259)

The reactions of 5,6cc-dibromo-5~-cholestan-3~-ol and of its Sa,6j-isomer with aqueous silver fluoride give complex mixtures including small amounts of rearrangement products, apparently resulting from initial ionization of the C-5-Br bond in each case.27 h Aluminium chloride catalyses the isomerization of a 3-methoxyoestra-2,5(10)diene to the 3,5(6)-diene.277 Mechanistic details of the formation of 5a- and SP-azidoderivatives from 5a-pregnan-6/50] (with HN,-BF,) have been elucidated by deuterium labelling. A key feature is hydride migration from C-5 to C-6, which is followed by T. V. Ilyukhina, A. V. Kamernitzkii, a n d I. I. Voznesenskaya, Tetrahedron, 1974, 30, 2239. G. Goto, K . Yoshioka, a n d K . Hiraga, Tetrahedron, 1974, 30, 2107. 2 7 h A. Kasal a n d A. Trka, Coll. Czech. Chrm. Comm., 1974, 39, 603. "' A. J. Birch a n d K . P. Dastur, J.C.S. Perkin I, 1973, 1650. 274

275

Steroid Properties and Reactions

275

kinetically controlled formation of the 5a-azide, later converted into an equilibrium mixture of 501- and 5 f l - i ~ o m e r s .The ~ ~ ~step involving electrophilic addition of the elements of hydrazoic acid across an olefinic bond has been demonstrated in a series of separate experiments with a variety of steroidal 0 1 e f i n s . ~ ~ ~ Buffered acetolysis of the 19-mesyloxy-3-thioacetal (260) gave the 5,19-cyclo-3,5dieno[3,4-b]dithian (261), with migration of sulphur following attack of the A4-olefinic bond upon C-19.Desulphurization of the dithian gave the 5,19-cyclo-A3-derivative (262).28 o

7 Functionalization at Non-activated Positions

A detailed study of ‘remote oxidation’ by photochemically excited benzophenone groups has shown the scope and limitations of the method.281 Suitable esters of 5acholestan-3a-01, 5a-androstan- 17/3-01, and 5/3-cholan-24-01gave oxidation products, but esters of 5a-cholestan-3P-01and 5IJ-cholestan-3a-01 (with equatorial OH groups) failed to react. Benzophenone 3- and 4-carboxylic acids and some of their homologues were employed for esterification. In general, oxidation by the excited benzophenone will occur if the benzophenone carbonyl oxygen can easily contact remote hydrogens on the steroid; photographs of space-filling models illustrate the shape of a reactive molecule, 5a-cholestan-3a-yl benzophenone-4-propionate, where the carbonyl oxygen can reach the 7a-, 12a-, and 14a-hydrogen atoms, and also that of the benzophenone-4carboxylate, which is a V-shaped molecule, so that the necessary proximity of the benzophenone carbonyl group and a remote hydrogen atom cannot be attained. Reactive esters show strong circular dichroism, induced in the benzophenone by the adjacent chiral steroid. whereas unreactive esters show only weak c.d. effects. Phosphorescence lifetimes are also a sensitive indicator of molecular packing. The products of ‘remote oxidation’, some of which have been described in earlier Reports,282comprise olefins and also macrocyclic benzophenone-steroid insertion products which can be converted into olefins at the point of benzophenone insertion.281 Many of the products are not readily accessible by other methods. The principle of ‘remote oxidation’ at tertiary centres, directed by proximity effects, has been combined with that of chlorination of steroids at the 5a-, 9a-, and 14a-positions with iodobenzene d i ~ h l o r i d e by , ~ ~employing ~ the iododichloride (263) derived from 278

219

280 28 1

282

283

Q. Khuong-Huu, A. Pancrazi, and I. Kabore, Tetrahedron, 1974, 30, 2579; CJ ref. la, 1973, Vol. 3, p. 369. A. Pancrazi and Q . Khuong-Huu, Tetrahedron, 1974, 30, 2337. J. R. Williams and G. M. Sarkisian, Tetrahedron Letters, 1974, 1109. R. Breslow, S. Baldwin, T. Flechtner, P. Kalicky, S. Liu, and W. Washburn, J . Amer. Chem. SOC.,1973, 95, 325 1. Ref. la, 1971, Vol. 1, p. 390; 1972, Vol. 2, p. 317; 1973, Vol. 3, p. 396; 1974, Vol. 4, p.386. Ref. la, 1973, Vol. 3, p. 396.

276

Terpenoids and Steroids

5a-cholestan-3a-yl p-i~dophenylacetate.~~~ The reagent delivered chlorine selectively to the 14a-position, giving the AI4-unsaturated derivative in 53 yield after dehydrochlorination. The dichloro-derivative of the rn-iodobenzoate attacked C-9 in preference to C-14, affording a route to the A9(' ')-isomer. As in the analogous reactions with benzophenone derivatives, the site of attack is predictable from the geometry of the steroid ester.284

'Remote oxidation' has also been achieved by the use of a photoexcited nitrobenzene derivative.285 Sa-Androstan-3cc-yl P-(p-nitropheny1)propionate (264), irradiated in Pyrex, gave a mixture which was subjected to the action of iodine-acetic acid to dehydrate any tertiary alcohols formed. 5a-Androst- 14-en-3-one was isolated in 26 % yield after Jones oxidation of the products. The residue contained a little of the 3,12dione, indicating that the excited nitro-group can abstract hydrogen from either C- 12 or C-14, which are roughly equidistant from C-3.285 Direct hydroxylation at tertiary centres can be achieved by irradiation of a cholestane derivative and peracetic acid in acetic acid. 3/l-Acetoxy-5a-cholestane gave the 5ahydroxy- (30 ",) and 25-hydroxy- (37.5"6)derivatives, along with small amounts of the 14-, 17-, and 20-hydroxycholestan-3[~-yl acetates. Use of 5a-cholestan-3/l,5-diol 3acetate gave the 5a,25-diol, transformed in three steps into 25-hydroxycholester01.~~~ k variation of the Barton reaction (photolysis of a nitrite287)provides a nitrate instead of the usual oxime.288When oxygen was bubbled through an irradiated solution of the 7%-nitrite(265) in benzene, the 7~,32-diol32-nitrate (266) resulted. The nitrate group could be reduced by Zn-AcOH as a convenient route to the 32-alcohol. The suggested mechanism of formation of the nitrate involves capture of an alkyl radical by oxygen and reaction of the peroxyl radical with nitric oxide (Scheme 7). Sa-Pregnane-3fi,4fi,20/l-triol 3,20-diacetate was converted by lead tetra-acetate into the 4/3.19-epoxy-derivative(267);further transformations led to 19-norproge~terone.~~~ R. Breslow, R. Corcoran, J. A. Dale, S. Liu, and P. Kalicky, J . Amer. Chem. SOC.,1974, 96, 1973. Z H 5 P. C. Scholl and M . R. van de Mark, J . Org. Chem., 1973, 38, 2376. A. Rotman and Y. Mazur, J.C.S. Chem. Comm., 1974, 15. "' Ref. 80, p. 398. 2 8 M J. Allen, R. B. Boar, J. F. McGhie, a n d D. H. R. Barton, J . C . S . Perkin I , 1973, 2402. 2 8 9 R. E. Gall. J. E. Nemorin, a n d L. Tarasoff, J . C . S . Perkin I , 1974, 881.

284

277

Steroid Properties and Reactions

+ NO Scheme 7

Irradiation of the N-iodo-derivative (268) of a cholan-24-amide afforded the 24,20lactones (269), epimeric at C-20.290

The furost-25-ene (270), prepared by application of conventional reactions to the furostan-26-01, has been hydroxylated (OsO,) and acetylated to give the diol monoacetates (271); the hypoiodite-photolysis process [ Pb(OAc),-I, , hv] transformed these products into isomeric 22,25-epoxyfurostan-26-01 derivatives (272).291

Thermolysis of the 1 1-0xo1anostan-7a-yl azidoformate (273) gave the oxazolidinone (274) resulting from nitrene insertion into the 6a-CH bond. The Sa-CH insertion 290 291

P. Hodge, G . M. Perry, and M. Pollard, Steroids, 1974, 24, 79. A. G. Gonzalez, C. G. Francisco, R. Freire Barreira, R. Hernandez, J. A. Salazar, and E. Suarez, Tetrahedron Letters, 1974, 2681.

278

Terpenoids and Steroids

*cOJ$YY

A c Op OCN, S H N d H

0

(274)

(273)

product was also formed, but none of the desired 9a-CH insertion compound was obtained. The 7(3-yl azidoformate similarly gave products of nitrene attack at C-6 and at the 8/?-po~ition.’~~ The 6-0x0, 7-0x0, 11-0x0, and ll-oxo-9(3-derivatives have been isolated in small amounts from among the products of oxidation of 3fl-acetoxy-5a-androstan-17one with chromium trioxide in acetic A possible clue to the mechanism of 15a-hydroxylation of deoxycholic acid by iron(r1) ions and oxygen or H , 0 2 2 9 4 comes from the observation that cyclohexanol affords a mixture of diols. An oxidized iron species bound by the hydroxy-group of cyclohexanol is considered to effect the hydroxylation : binding by the 12a-hydroxy-group may serve to direct hydroxylation to the 1 Sa-position in the steroid.295 8 Photochemical Reactions

Olefinic Compounds.--Quantum transformation yields have been estimated for the reversible reactions indicated in Scheme 8.29hThe effect of wavelength on the production of previtamin D, has been evaluated ; 2 9 7 methods are described for the thinlayer,298gas,299and column chroma tog rap hi^^^^ separation of the various isomers ,olqA

Toxisterol, A

Lumisterol,

Scheme 8

produced by the irradiation of ergosterol. U.V. spectra are reported for the various products obtained by photoisomerization of vitamin D, . 3 0 1 Irradiation of 7-dehydrocholesterol in the presence of eosin gave a mixture of isomeric 7,7’-dimers, the separate 292

293 294

295 29h 297

298 299

300 30’

0. E. Edwards and Z . Paryzek, Canad. J . Chem., 1973, 51, 3866. J . Jovanovic, M. Spiteller-Friedmann, and G . Spiteller, Annalen, 1974, 693. Ref. la. 1971, Vol. 1, p. 391; 1974, Vol. 4, p. 385 J. T. Groves and M. Van Der Puy, J . Amer. Chem. Soc., 1974,96, 5274. R. Mermet-Bouvier and E. Abillon, J . Pharm. Sci.,1973, 62, 891. E. Abillon and R. Mermet-Bouvier, J . Pharm. Sci., 1973, 62, 1688. R. Mermet-Bouvier, J . Chromatog., 1971, 59, 226. R. Mermet-Bouvier, J . Chromatog. Sci.,1972, 10, 733. R. Mermet-Bouvier, Analyt. Chem., 1973, 45, 584. R. Mermet-Bouvier, Bull. SOC.chim. France, 1973, 3023.

279

Steroid Properties and Reuctions

components having either the 5,8(9)- or 5,8(14)-diene structure.302 The chemistry of the Vitamin D series of compounds has been reviewed briefly.302" Cholest-5-ene is partially isomerized on irradiation in t-butyl alcohol with water and o-xylene (as sensitizer) to give a 7 : 3 mixture of the 4-ene and 5-ene, accompanied by the 5a- and 5p-01s. Use of deuterium oxide instead of water gave products with inclusion of from one to four deuterium atoms.303 Phatochemical cycloadditions of ethoxycarbonylnitrene to olefinic bonds of tesgave the aziridines (275) and tosterone acetate and 3~-acetoxypregna-5,16-dien-20-one (276), re~pectively.~'~

"\

C0,Et

(276) (two isomers)

U.V. irradiation of the 18,18-dimethoxypregn-16-en-20-one (277) gave a mixture of the cyclic ether (278) and the rearranged product (279).305 Acetone-sensitized photolysis of a 6-en-5a-01 (280) ruptured the 5,6-bond, giving the 5-oxo-5,6-seco-steroid (281). Other conditions for the irradiation were ineffective.306

Carbonyl Compounds.-Photoisomerization of the 14p,17a-pregnan-1 1-one derivative (282) proceeded normally to give the 11,19-cyclo-compound(283),but lead tetra-acetate 302

F. Boomsma, H. J. C . Jacobs, E. Havinga, and A. van der Gen, Rec. Tratl. chim., 1973,92,1361.

302

( a ) E. Havinga, Experientia, 1973, 29, 1181.

303 304

305 306

J. A. Waters, Steroids, 1974, 23, 259. R. P. Gandhi, S. Garg. and S . M. Mukherji, J. Indian Chem. Soc., 1974, 51, 324. F. Marti, H. Wehrli, and 0. Jeger, Helv. Chim. Acta, 1973, 56, 2698. H. A. C . M. Keuss and J. Lakeman, J . C . S . Chem. Comm., 1973, 480.

Terpenoids and Steroids

280

7

H

oxidation of the latter gave the unusual 9.1 l-seco-ether (284),along with the 19-hydroxy14p,17a-pregnan-11 Photolysis of the 23,24-diphenylcholan-24-onesystem (285) in t-butyl alcohol gave the corresponding 20-methylenepregnane derivative (286) (Norrish Type TI process). Ozonolysis of the product (286) completed a novel degradation of cholanic acids to give pregnan-20-ones (287).308 An analogous degradation was successful in the lanostane series309(see also p. 259).

(285)

(286) R (287) R

= =

CH, 0

Photolysis of 5-vinyl-~-nor-5cc-cholestan-3-one (288) in t-butyl alcohol gave the 5P-isomer (289) as the only product detected. The biradical(290) is envisaged as the key intermediate. The 5-vinyl compound also resulted from irradiation of the A-homoenone (28l), through cc-cleavage (3,4-bond) to give the biradical (290).310

‘A Chapter on Ketone Photochemistry’, in the Van’t Hoff-Le Be1 commemorative issue of Tetrahedron, includes reviews of a variety of reactions drawn from the steroid fieid.311 307

308 309

3‘0 311

P. Gull, Y . Saito, H . Wehrli, and 0. Jeger, Helt.. Chim. Acta, 1974, 57, 863. M. Fetizon, F. J. Kakis, and V. Ignatiadou-Ragoussis, J. Org. Chem., 1973, 38, 4308. M . Fetizon, F. J. Kakis, and V. Ignatiadou-Ragoussis, J. Org. Chem., 1974, 39, 1959. J. I. Seeman and H. Ziffer, Tetrahedron Letters, 1973, 4409. K. Schaffner and 0. Jeger, Tetrahedron, 1974, 30, 1891.

Steroid Properties and Reactions

28 1

Miscellaneous.-Photosensitized oxidation of cholesterol affords the 6a- and 6phydroperoxy-A4-compounds (292) in 1-2 % yields, along with the known 5a-hydroperoxy-6-ene (293). Reaction with singlet oxygen by the ene mechanism seems likely to account for all the p r o d ~ c t sl .2~

Photo-oxygenation (singlet oxygen) converted the 5( 10),9( 11)-diene (294) first into 5a- and 5~-hydroperoxy-l(lO),9(1l)-dienes(295), and then into a mixture of isomeric

'

5-hydroperoxy- 1,ll-epidioxy-9-enes (296).3

\

NOH

(30 1) Scheme 9 312

313

M. J. Kulig and L. L. Smith, J . Org. Chem., 1973, 38, 3639. M. Maumy and J. Rigaudy, Bull. SOC.chim. France, 1974, 1487

282

Terpenoids and Steroids

The demethylation of dimethylamino-steroids and other tertiary amines by photosensitized oxidation has been ~ t u d i e dl 4. ~ The photo-Beckmann rearrangements of androsterone and 13a-androsterone oximes give product mixtures (Scheme 9) which have not yet been fully explained. The formation of both 13p and 13a isomeric lactams from the 13P-oxime (297) seems to imply separation of C-13 from C-17 before C-13-N bonding occurs, but the 13aoxime (300) afforded no detectable 13P-lactam, giving instead the isomeric 13a-lactams (299) and (301),both of which could be envisaged as rearrangement products from an intermediate oxaziridine (302).3' A version of the hypoiodite reaction (irradiation in the presence of HgO and I,) converted cholesterol or its 3a-epimer into a mixture of products which included the 3,4seco-4-iodo-3-aldehyde (303), as well as two oxetans (305) derived by photoaddition of the aldehyde group to the 4,5-olefinic bond in intermediate products (304)."'

(304) 6a

(303)

+ 6p

(305) 6a

+ 68

Photolysis of the 19-nitrite (306) caused elimination of the angular 10P-substituent, giving a mixture of the 6-oximino-5(10)-ene (307) with a lesser amount of the 1(10),5diene (308).3l 7

(306)

Cholesteryl O-thiobenzoate gave cholesta-3,5-diene on photolysis, with stereospecific removal of the (cis) 4P-hydrogen atom. Prolonged irradiation caused readdition of the thiobenzoic acid to the diene to give a mixture of the 3a- and 3P-S-

c> H

WCH (309)

'14

3'5 3'6 3 ' 7

I

OH ( 3 10)

D Herlem, Y . Hubert-Brierre, F. Khuong-Huu, and R. Goutarel, Tetrahedron, 1973, 29, 2195. H. Suginome and T. Uchida, Bull. Chem. SOC.Japan, 1974, 47, 687. H. Suginome and K. Kato, Tetrahedron Letters, 1973, 4139, 4143. Y. Watanabe and Y. Mizuhara. J . C . S . Chem. Comm., 1973, 7 5 2 .

283

Steroid Properlies and Reactions

’

(309) in propan-2thioben~oates.~ Irradiation of a 17r-ethynyl-17P-hydroxy-steroid 01 gives the cis- and trans-adducts (310j.319

9 Miscellaneous The search for cholesteric mesophases with low transition temperatures has led to with transition temperatures some long-chain alkanoates of 5a-cholest-8(14)-en-3~~-ol, 30 “C lower than those of the corresponding cholesteryl esters. The transition temperatures of the decanoate, for example, to the smectic, cholesteric, and isotropic phases, are 44.4,58.9, and 71.8 “C,re~pectively.~~’ The smectic phases of cholesteryl nonanoate and myristate have been characterized as ‘type A’ by miscibility studies with known smectic liquid ~rystals.~”p-Methoxycinnamates of a series of 17/?-alkyl-5a-androstan3p-01~give cholesteric me so phase^.^^^ A cholesteric mesophase comprising cholesteryl chloride and nonanoate (2 : 3) confers optical activity on dissolved hexacarbonylmolybdenum. 3 2 Plates of silicic acid impregnated with iron(Irr), nickel(II), or chromium(m) salts, which were originally developed for the separation of prostaglandins, have received limited study for steroids. 3,7,12-Trioxocholanic acid is more strongly retarded by iron(m) plates than by untreated or silver nitrate plates, but ergosterol was only slightly more retarded than cholesterol. It would seem to follow that iron(rI1) interacts with ketones and so may prove useful for the separation of polar ~ t e r 0 i d s . jBenzoylation ~~ of hydroxy-steroids to confer U.V.absorption is a useful aid to detection in high-resolution liquid c h r ~ m a t o g r a p h y . ~ ~ ~ Solubilities of some steroids in water and in saline have been determined by use of l4C-labe1led materials.326Lecithin has been shown to retard the dissolution of cholessterol in bile acid The steroidal nitroxide radical (311) forms a gel on dissolution in c y ~ l o h e x a n e . ~ ~ ~ The stereochemistry of oxazolidinyloxy-radicalsattached to a steroid at C-3 has been established.329 0. I

318

31y

320 321 322 323

324 325

326 327 328

329

S. Achmatowicz, D. H. R. Barton, P. D. Magnus, G . A. Poulton, and P. J. West, J.C.S. Perkin I , 1973, 1567. L. M. Kostochka, E. P. Serebryakov, and V. F. Kucherov, Zhur. org. Khim., 1973, 9. 1611. J. Y . C . Chu, J.C.S. Chem. Comm., 1974, 374. D. Coates and G. W. Gray, J . C . S . Chem. Comm., 1974, 101. J. Malthiete, J. Billard, and J. Jacques, Bull. Soc. chim. France, 1974, 1199. S. F. Mason and R. D. Peacock, J.C.S. Chem. Comm., 1973, 712. R. L. Spraggins, J. Org. Chem., 1973, 38, 3661. F. A. Fitzpatrick and S. Siggia, Analyt. Chem., 1973, 45, 2310. D. K. Madan and D. E. Cadwallader, J . Pharm. Sci., 1973, 62, 1567. W . 1. Higuchi, S. Prakongpan, V. Surpuriya, and F. Young, Science, 1972, 178, 633. R. Ramasseul and A. Rassat, Tetrahedron Letters, 1974, 2413. P. Michon and A. Rassat, J . Org. Chem., 1974, 39, 2121.

284

Terpenoids and Steroid

20R-p-Tolylpregn-5-ene-3[j,20-diol has been used as an alternative substrate for studies on the biosynthetic degradation of cholesterol to pregnenolone, with positive results.330 A review of the uses of potassium t-butoxide in synthesis includes many examples of applications in the chemistry of steroids and other alicyclic molecules : reactions include the base-catalysed alkylation or nitrosation of ketones, eliminations, condensations, and rearrangement^.^ 3 1 Further to last year’s warning, methyl iodide and benzyl chloride are added to the list of potentially carcinogenic alkylating agents, which already includes dimethyl sulphate and other reagents with applications in steroid chemistry : precautions against skin contact or inhalation of the vapour are strongly re~ommended.~

330 331

332

R. B. Hochberg, P. D. McDonald, M. Feldman, and S . Lieberman, J . Biol. Chem., 1974, 249, 1277. D. E. Pearson and C. A. Buehler, Chem. Ret.., 1974,14, 45. G. W. Gribble, Chem. in Britain, 1974, 10, 101.

Steroid Synthesis BY P. J. SYKES AND J. S. WHITEHURST

1 Total Synthesis Much skill and ingenuity continues to be displayed in the synthesis of steroids. Oestrone has been synthesized' (Scheme 1) starting from 6-methoxy-l-vinyl-3,4dihydronaphthalene (1). The key reaction is the Diels-Alder addition of (1) to 2,6dimethylbenzoquinone (2), which is directed by boron trifluoride etherate to give as the major product the desired intermediate (3) (69yd) and relatively little (1404)of the undesired compound (4). However, the undesired compound is the only product isolated in the purely thermal addition of (1) and (2). Isomerization of ( 3 ) to ( 5 )followed by conversion of the two carbonyl groups into methylenes, ring fission [to (13)], and alkaline re-closure yielded compound (14); Beckmann rearrangement of its oxime gave racemic oestrone methyl ether (15). 19-Nor-steroids have been synthesized from glutaraldehyde by way of the lactones (16),2which by the action of vinylmagnesium chloride give the ketones (17) from which the Mannich bases (18; X = NR', or NHR') or the ketones (19) can be obtained. under mildly acid Condensation of (18) or (19) with 2-methylcyclopentane-1,3-dione conditions yields the dienol ethers (20),readily transformed into the unsaturated ketones (21). Catalytic reduction of these can be induced stereoselectively to give either the aor the fl-configuration at C-9 (steroid numbering), the final products being 19-norsteroids with stereochemistry 9a,lOP or 9P,lOc~.~ In extending this approach to form oestrone, m-methoxyacetophenone was converted by three steps into the nitrile (22) which was resolved4 The dextrorotatory lactone (23; Ar = m-methoxyphenyl),however, consumed two moles of vinyl Grignard reagent [cf: (16)]; the difficulty was overcome by reduction of (23) to (24),followed by reaction of the latter with vinylmagnesium chloride (Scheme 2). Manganese dioxide oxidation of the product (25) (preferential oxidation of the allylic hydroxyl) in the presence of diethylamine gave (26). Condensation of this with 2-methylcyclopentane-1,3-dione yielded a diketone (27) rather than a dienol ether [cJ (1 S)]. Dehydration of (27) followed by partial catalytic reduction produced (28), a compound which is readily converted into oestrone methyl ether. The racemic form of (27) was transformed into racemic equilenin methyl ether. Compounds such as

' *

R . A . Dickinson, R . Kubela, G . A. McAlpine, Z. Stojanac, and Z . Valenta, Canad. J . Chem., 1972,50,2377. 'Terpenoids and Steroids', ed. K . H . Overton (Specialist Periodical Reports), The Chemical Society, London, 1973, p. 409. J. W. Scott, E. Widmer, W. Meier, L. Labler, P. Muller, and A. Furst, J . Org. Chem., 1972,37, 3183. N. Cohen, B. L. Banner, J. F. Blount, M. Tsai, and G . Saucy, J . Org. Chem., 1973, 38, 3229.

285

Tcrpcnoids and Steroids

286

(9)

(6) R = OH

I

iv: (7) R = OMS V:

(8) R

=

vii

H

R = H

H

(10) R = OH viii: (11) R = OAC ix: (12) R = H

I

Me0

&

0

Reagents: i, Ether-BF, etherate: ii, NaHC0,-MeOH ; iii, LiAIH(OBu'),-THF: iv, MsCI-py; v, Zn-MeOH; vi, H,-PdiCaCO,; vii, NaAIH,(OCH,CH,OMe),; viii, Ac,O-py: ix, Li-THF-NH,; x, Os0,-py; xi, Pb(OAc),-THF: xii, 5 aq. HCI-THF; xiii, Beckmann rearrangement.

Scheme 1

Steroid Synthesis

287

0

0 OH

H (20)

(21)

(17) react with thiourea in glacial acetic acid to form the compounds (29); however, these substances are inferior to the Mannich bases (18) in their condensation with 2-methylcyclopentane-1,3-dioneto form the dienol ethers (20).5 In a study of the

Reagents: i, Acid phthalate-(R)-( + )-a-methylbenzylamine; ii, hydrolysis; iii, AIH(Bu’),-toluene; iv, C H , =CHMgCl; v, Mn0,-benzene-Et,NH; vi, 2-rnethylcyclopentane-1,3-dionetoluene-AcOH ; vii, toluene-p-sulphonic acid-toluene ; viii, H ,-Pd/C-toluene.

Scheme 2

N . Cohen, B. L. Banner, J. F. Blount, G. Weber, M. Tsai, and G. Saucy, J . O r g . Chem., 1974, 39, 1824.

Terpenoids und Steroids

288

R2

non-reductive methylation of (30) (R1 = suitable ring A precursors: R2, various) the best ratio of [j- to a-face methylation was achieved6 by use of THF as solvent at - 78 "C. The asymmetric ( i e . unilateral) cycli~ation'.~ of the ketone (31 ; n = 5 ) by (S)-proline in acetonitrile at room temperature has produced (97.373 the ketol (32; n = 5); dehydration of this by toluene-p-sulphonic acid in benzene gave (99 :(,) the dione (33 ; n = 5 ) of 87",, optical purity.8 The homologue (31 ; n = 6) the compound (33; n = 6) in 83 ",, yield and 71 y o optical purity. The compounds (33; n = 5 or 6) are obviously attractive intermediates for the total synthesis of steroids. Compound (33; n = 6) by the successive action of lithium acetylide and hydrogen-palladium yielded the vinyl alcohol (34), which with phosphorus tribromide formed the allylic bromide (35; X = Br). This condensed' with the sodium salt of 2-methylcyclopentane1,3-dione to form (+)-(36). However, cyclization to (37) was only slightly stereoselective, the product being a mixture of C-13 epimers. Interestingly too, neither the

0

(36)

0

(37)

' J. W . Scott, P. Buchschacher, L. Labler, W . Meier, and A . Furst, Helv. Chim. Acta, 1974,57, '

1217. U . Eder, G. Sauer, and R. Wiechert, Angew. Chrm. Internat. Edn., 1971, 10, 496. Z . G. Hajos and D. R. Parrish, J . Org. Chem., 1974, 39, 1615. J. Ruppert, U . Eder, and R. Wiechert, Chem. Ber., 1973, 106, 3636.

Steroid Synthesis

289 + alcohol (34) nor the isothiouronium salt [35; X = S=C(NH,), -OAc] could be induced to react with 2-methylcyclopentane-1,3-dione. The bromide derived from 6-methoxy-1-tetralone by the successive action of vinyl Grignard reagent and phosphorus tribromide has an endocyclic double bond; it is therefore a substituted ethyl bromide and not an analogue of (35) as had been assumed in earlier work." The racemate (38) has been converted" into (+)-19-nortestosterone (42) by the reactions shown in Scheme 3. The stereoselective hydrogenation of (39) to (40)doubtless

(39)

(39a)

I

I

i"

v-

i

C02Et

VI-viii

Reagents: i, NaH-DMSO; ii, - D M S O ; iii, Et,O-CO,; iv, H,-Pd/BaSO,-EtOH; v, H C H O aq.piperidine, HCl-DMSO; vi, NaOMe-MeOH-(41); vii, HCl aq.-MeOH; viii, toluene, reflux ; ix, H ,-Pd/C-EtOH-NEt ; x, HCl-MeOH.

Scheme 3

proceeds through the dienol (39a). Decarboxylation produces a negatively charged carbon at the site of the carboxy-group, thereby selectively directing electrophilic attack to this centre. Compound (38) has also been transformed into compound (45) (Scheme 4),which is of value in the synthesis of fusidic acid (46).12 The stereoselective methylations are notable, as is the Westphalen-type rearrangement (43) -+ (44). lo l1

M. H. Tankard and J. S. Whitehurst, J.C.S. Perkin I, 1973, 615. Z. G. Hajos and D. R. Parrish, J. Org. Chem., 1973,38, 3239, 3244; cf. G . S. Grinenko, E. V. Popova, and V. I. Maximov, Zhur. obshchei Khim., 1971,7,935; G . Nomine, G. Amiard, and V. Torelli, Bull. SOC.chim. France, 1968, 3664. W. G. Dauben, G. Ahlgren, T. J. Leitereg, W. C. Schwarzel, and M. Yoshioko, J . Amer. Chem. SOC.,1972, 94, 8593.

290

Terpenoids and Steroids OBu'

0

(38) bi-iv

OBu'

(ii-viii

0

I&= O

A 0

'

0 0 H

o & ' /

(43)

(44)

(45)

Reagents: i, NaH--DMSO; ii, Bu'OK-Mel; iii, aq. M e C O , H ; iv, Triton B; v, KOH-Bu'OH-MeI; vi, N a O H : vii, (COCl),; viii, LiCuEt,; ix. Triton B ; x, m-chloroperbenzoic acid; xi. BF,.Et ,O; xii, toluene-p-sulphonic acid-benzene: xiii, Li-NH ,-Bu'OH.

Scheme 4

The well-known oestrone intermediate (47)on partial reduction and optical resolution gave the enantiomers (48) and (49).13 Compound (48) on cyclization formed the ether (50) and thence, via (51), natural oestrone. A neat way of converting the 'unnatural' isomer (49) into natural oestrone (apart from oxidation and re-cycling) is conversion l 3

C. H . Kuo, D. Taub, a n d N . L. Wendler, J . Org. Chem., 1968.33, 3126; H . Gibian, K. Kieslich, H.-J. Koch, H . Kosmol, C . Rufer, E. Schroder, and R. Voslich, Terrahedron Letrers, 1966, 2321.

29 1

Steroid Synthesis

0

m OH

"0

Me0

-0

Me0

OAc

1

into the acetate and sodium borohydride reduction. The product (52) on treatment with toluene-p-sulphonic acid in benzene yielded (53), which by hydrolysis and oxidation produced (50).14 Compound (47)on peracid oxidation gives a mixture of the compounds (54) and (55). Treatment of this mixture with triethyloxonium fluoroborate has given the compounds l4

T. Asako, H . Hiraga, and T. Miki, Chem. and Phurm. Buff. (Japan), 1973,21, 107, 697, 7 0 3 .

292

Terpenoids and Steroids 0

0

0

0

H

Me0

Me0

OH

\

(56) (ca. 2596) and (57) (ca. 75‘1~3’~ (C-9 epimers in both cases). Compound (57) was transformed into ( +)-13-isoestrone methyl ether. A stereoselective total synthesis of oestrone by a cationic olefin cyclization method has been achieved16(Scheme 5). Condensation of the aldehyde (58) with (59) followed by sequential treatment with acid and base gave (60: R’ = H, R2 = 0). Reduction to the alcohol followed by stannic chloride-methylene chloride cyclization at - 100 “C produced the racemic compounds (63) (major component) and (64). The proportions of these compounds depended on several factors and varied strikingly according to the nature of R’, R2, and the cyclizing agent and conditions. The a-epoxide (65) was obtained from (63) by way of the chlorohydrin and was rearranged to oestrone (67). Direct epoxidation of compound (63) gave the unwanted P-epoxide (66). Johnson’s group has also synthesized natural progesterone (Scheme 6) by a cationic cyclization route.” Starting from Hagemann’s ester (68) the acid (69) was obtained in racemic as well as in both optically active forms (resolution by a-methylbenzylamine) and these in turn provided the corresponding forms of (70). Wittig coupling of this with the acetylenic aldehyde (71) produced compound (72). Release of the carbonyl group” followed by its reduction gave an epimeric mixture of alcohols (73) from all three forms of (72). Cyclization of the alcohols (73) formed an 85 : 15 mixture of the 17j3- and 17%-epimersof (74), the 17P-epimer being secured in 95% optical purity. Elaboration to progesterone (75)was carried out on the racemic form by two oxidations (t-butyl chromate to introduce the C-3 carbonyl group and DDQ to introduce a A4-double bond) and a homogeneous catalytic reduction. (+-)-Testosterone was also obtained” from compound (73). Cyclization with trichloroacetic acid in 2-nitropropane formed the oxime ether (76). Lithium aluminium l5 l6 I’

A. R . Daniewski, M. Guzewska, and M . Kocor, J. Org. Chem., 1974, 39, 2193. P. A . Bartlett and W . S. Johnson, J. Amer. Chem. Soc., 1973,95, 7501. R . L. Markezich, W. E. Willy, B. E. McCarry, and W. S. Johnson, J . Amer. Chem. SOC.,1973, 95, 4414, 4416. M . Fetizon and M . Jurion, J.C.S. Chem. Comm., 1972, 382. D . R . Morton, M . B. Gravestock, R . J . Parry, and W . S. Johnson, J. Amer. Chem. SOC.,1973, 95, 4417, 4419.

293

Steroid Synthesis

Ph,; I(58)

I

/

R2

0

1

R'O (60) R = H, R2 = 0 i v : (61) R' = H, R 2 = H,OH v : (62) R' = Me& R 2 = H,OH

I

(59)

H

HO

I H

HO

\

viii.

IX

H

HO

Reagents: i, PhLi-ether, MeOH; ii, MeOH-H,SO,; iii. aq. N a O H ; iv, NaAlH,(OCH,CH,OMe),; v, CF3CON(SiMe3)~;vi, SnC14-CH2C12 ( - 100 "C); vii, MeOH; viii, p TsNC1,; ix, Me,NOH-Me,CO; x, BF,,Et,O.

Scheme 5

hydride reduction gave the glycol (77), which on sodium periodate cleavage produced the ketone (78), which was transformed into testosterone benzoate. Interestingly, the cyclization'' of compound (79) does not give a 17-isopropenyl-steroid. Instead, the product is the olefin (80);in this connection Japanese workers have found that compound (81) rearranges to (82) on treatment with hydrochloric acid.21 2o

"

K . A. Parker and W . S. Johnson, J . Amer. Chem. SOC.,1974,96, 2556. I . Yoshizawa, T. Miura, M. Kimura, K . Anzai, and S. Matsuda, Chem. and Pharm. Bull. (Japan). 1973, 21, 1622.

Terpenoids and Steroids

294

viii-xi

I

xv

(72)

(73)

1

XVI

Reagents: i , HOCH,CH,OH-H +,LiAlH,; i i , HC1-THF; iii, CH,(CO,Me),-MeOH-NaOMe; iv, MeC0,H-HC1; v, MeOH-H ; vi, HSCH,SH-BF,,Et,O-CHCl,; vii, KOHM e O H ; viii, NaAlH,(OCH,CH,OMe),-THF; ix, TsC1-py; x, NaI-Me,CO-Pr;NEt ; xi, PPh,-MeCN-Pr',NEt ; xii, PhLi-ether; xiii, MeI-DMF-H,O-CaCO,; xiv, NaAlH ,(OCH ,CH,OMe),-THF; xv, C F , H Me-ethylene carbonate-CF,CO,H ; xvi, ButOCrO,OH-C1,C =CCl,-AcOH-Ac,O; xvii, DDQ-toluene; xviii, H ,-Rh(PPh,),It oluene-Et OH. +

Scheme 6

Steroid Synthesis

295

.d

-_.I-:’

HO-’ HO.’

H

H (80)

(81)

H

(82)

Starting from cyclopentane 1,3-diones having suitable substituents at the 2-position (e.g. ally1 and ethoxycarbonylmethyl), aromatic and 19-nor-gonanes have been syn-

thesized.22 Also, starting from cyclopentanones, analogues of 16-methyloestrone and 16-methyl-19-nortestosterone have been ~ynthesized.’~The compound (83) by addition of rn-methoxyphenylethylmagnesium bromide yielded the lactone (84). When this was cyclized (AIC13-HCI in benzene) the product was the racemic 9PH-marrianolic acid derivative (85) from which ( +)-9P-oestrone was ~ r e p a r e d . ’ Likewise, ~ the action of rn-methoxyphenylethylmagnesium bromide on (86) followed by cyclization, hydrolysis, and oxidation yielded racemic 9P,13a-oe~trone.’~Triethylsilane-trifluoroacetic acid is a useful variant of the known methods for the reduction of the compound (87) (or its 8PH-A9(’‘)-isomer) to the 8P,9a-dihydro-c0mpound.’~

”

23 24

25

K . Yoshioka, T. Asako, G. Goto, K . Hiraga, and T. Miki, Chem. and Pharm. Bull. (Japan), 1973, 21, 2195, 2202, 2427; M. Harnik, R. Szpigielman, Y . Lederman, J. Herling, and Z . V. I. Zaretskii, J . O r g . Chem., 1974, 39, 1873. D. K . Banerjee and P. R . Srinivasan, Indian J . Chem., 1972, 10, 891. V. A . Andryushina, E. V. Popova, 0. S. Anisimova, and G . S. Grinenko, Zhur. org. Khim., 1974, 10, 222; V. A. Andryushina and G . S. Grinenko, ibid., p. 519. T. A. Serebryakova, S. N. Ananchenko, and I. V. Torgov, Izuest. Akad. Nuuk S.S.S.R., Ser. khim., 1973, 1917.

Terpenoids and Steroids

296 ,CO,Me

0

H

CH,CO, Me Me0

(83)

(84)

OAc

2 Halogeno-steroids Methods for introducing fluorine adjacent to carbonyl are being actively pursued. With the aim of preparing 12-fluoro-corticosteroids26 the bis-methylenedioxy-compound (88; R ' = F) was treated with sodium bistrimethylsilylamide in THF and the enolate quenched with trirnethylsilyl chloride or benzoic anhydride. However, neither of the products (89; R' = F, R2 = H, X = SiMe,) and (89; R' = F, R2 = H, X = Bz) could be induced to react with trifluorofluoro-oxymethane (CF,OF). Attention was turned to the use of metal enolates. The sodium enolate (89; R' = F, R 2 = H, X = Na) reacted violently with CF,OF but quite smoothly with perchloryl fluoride to form (90 ; 12p-F) (equatorial fluorine). For large-scale preparations the necessarily longer reaction times militate against the use of sodium enolates as these tend to equilibrate with unreacted ketone: the problem was solved by the use of lithium enolates, best prepared from the sodium enolates by exchange with lithium chloride in THF. Compound (88 ; R' = H) could be smoothly converted into (88 ; R' = F). However, if the base was lithium di-isopropylamide, (88; R' = H) was converted into the 11,12-enolate (89; R' = H, R2 = H, X = Li), which with perchloryl fluoride produced the 12fluoro-ketones (90: 12P-F) (65 and (90; 1 2 ~ - F(23 ) %). The nature of the base used is therefore of paramount importance in deciding whether the product is formed kinetically or thermodynamically.

x)

26

D. H. R. Barton, R. H. Hesse, M . M. Pechet, and T. J. Tewson, J . C . S . Perkin I , 1973, 2365.

St ero id Synthesis

297

The addition of difluorocarbene to a variety of steroid enol acetates and enol ethers has been studied27(see p. 313). ~ - N o r - s t e r _ o i d ssuch ~ ~ -as ~ ~(91) undergo reaction to form (92; X = Y = F), readily transformed by hydrolysis, oxidation, and treatment with base into the fluoro-ketone (93). Interestingly, chlorofluorocarbene, CClF (generated from PhHgCC1,F) adds to (91) to give both the compounds (92; X = C1, Y = F) and (94; X = F, Y = Cl), whereas dichlorocarbene yields only (94; X = Y = C1).28 The addition of difluorocarbene to side-chain unsaturated linkages has been used to generate, ultimately, steroids containing allenic substituents, as well as orally active progesterone analogues.

The action of perchloryl fluoride in aqueous dioxan on compound (95) has given the highly unstable 2P-fluoro-compound (96), which readily loses hydrogen fluoride, 27

28 29

P. Crabbe, A. Cervantes, A. Cruz, E. Galeazzi, J. Iriarte, and E. Velarde, J . Amer. Chem. SOC., 1973,95, 6655. P. Rosen, A. Bovis, and R . Karasiewicz, J . Medicin. Chem., 1974, 17, 182. P. Crabbe, H . Carpio, E. Velarde, and J. H. Fried, J . Org. Chem., 1973, 38, 1478; H . Carpio, P. Crabbe, and J. H . Fried, J.C.S. Perkin I , 1973, 227.

Terpenoids and Steroids

298

generating an aromatic ring A . ~ ’ Much use has been made of the epoxide (98) of the ketone (97) as a source of fluorine- and bromine-containing ring-a aromatic steroids.3 1 Epoxide opening of (98) by HBr leads to the corresponding 4-bromo-ketone (99; X = H, Y = Br) whereas HF yields the 2a-fluoro-ketone (99; X = F, Y = H), which was transformed into 2-fluoro-oestrone. Perchloryl fluoride in methanol introduced a 4-fluoro-substituent into the pyrrolidine enamine of a 19-n0r-A~-3-ketone,~~ which was converted into 4-fluoro-oestrone.

(95)

0

0 0’

I[:”

0 Y

(97)

(99)

Much of the interest in halogeno-steroids centres on their use as progestational agents. Even a brief survey shows the concentration of effort made to produce 6possessing a 17a-acetoxyhalogeno-A4-3-keto- or 6-halogeno-A4~6-3-keto-systems pregnan-20-one system or 17fi-hydroxy-17a-ethynyl unit. Additional structural elements that have been added include a 16-methylenegroup and a la,2a-cyclopropane unit. The appropriate papers should be consulted for these compounds.33 In a new synthesis34 of the potent progestational agent chlormadinone acetate (104) (see also p. 252) the starting material (100) (available from the 16a,l7a-epoxide or 16-dehydropregnenolone acetate) was treated with N-bromosuccinimide and the 7a-bromo-derivative produced was converted, by treatment with potassium hydroxide in methanol, into the acid-sensitive 7a-methoxy-compound (101). Alkaline hydrolysis gave the 3-hydroxy-derivative, which on perbenzoic acid oxidation formed the epoxide (102), itself transformed by hydrogen chloride in water-free solvents into the chlorohydrin (103). Chromic acid oxidation and treatment with lithium chloride-hydrogen 30 31

32

33

34

J . Pataki, Tetrahedron, 1973, 29, 4053. M. Neeman, T. Mukai, J. S. O’Grodnick, and A. L. Rendall, J.C.S. Perkin I , 1972, 2300: M. Neeman, J. S. O’Grodnick, and K . Morgan, ibid., p. 2302; M. Neeman and J. S . O’Grodnick, Tetrahedron Letters, 1972, 4847; M. Neeman, Y. Osawa, and J. Mukai, J.C.S. Perkin I , 1973,1462; M. Neeman and J. S. O’Grodnick, Canad. J . Chem., 1974,52,2941. M. Neeman, Y . Osawa, and T. Mukai, J . C . S . Perkin I , 1972,2297; M. Neeman and Y . Osawa, Tetrahedron Letters, 1963, 1987. E . g . , A . L. Johnson, J . Medicin. Chem., 1972, 15, 854; S. J. Halkes and J. Hartog, ibid., p. 1288; J. Hartog, J. J. G . M. Wittelaar, L. Morsink, and A . M. de Wachter, ibid., p. 1292; E. L. Shapiro, L. Weber, G. Teutsch, H . Harris, R. Neri, and H . L. Herzog, ibid., 1973, 16, 649; R. Mickova, Coll. Czech. Chem. Comm., 1973, 38, 2492. G. Langbein, E. Menzer, M. Meyer, and R. Weseman, J . prakt. Chem., 1973, 315, 8.

299

Steroid Synthesis

AcO &Me

e

M

:HO &

HO C1

fl

0

C1

chloride in DMF gave 17~-acetoxy-6-chloropregna-3,5-diene-3,2O-dione (chlormadinone acetate) (104). The metabolism of this compound has been studied in the rabbit and one of the urinary compounds is a 2,3-dihydroxy-compound. The configuration of this has been e ~ t a b l i s h e d .Lead ~ ~ tetra-acetate oxidation of (104) led to the 2a- and 2~-acetoxy-compounds(105). These were distinguished from each other by the conversion of one into the other by the action of potassium acetate in acetic acid. The stable epimer, therefore, was the equatorial 2rx-compound. On sodium borohydride reduction this produced the expected 2a,3P-dio1(106),identical with naturally produced material. Interestingly, although the compound is a trans-diol, it gave an acetonide (see also p. 252). 35

T. Abe and A. Kambegawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1295.

300

Terpenoids and Steroids

3 Oestranes The synthesis of 9-methyl-19-nor-steroids has received attention. 3 6 , 3 7 11-0x0-oestrone methyl ether (107) on reaction in methyl iodide solution with potassium t-butoxide in t-butyl alcohol yielded stereoselectively the 9cc-methyl derivative, which was readily converted into 9a-methyloestrone (108). This was also obtained by methylation of the 1 l - e n ~ l a t eof ~ compound ~’~~ (109) and reductive removal of the C-10 methyl group by lithium-biphenyl-diphenylmethane and of the C- 1 1 carbonyl group by Wolff-Kishner reduction. Compound (108) was converted into 9a-methyl-19-norprogesterone(1 10). The stereochemistry at C-10 was settled unequivocally by X-ray analysis. 9P-Methyl steroids were prepared from the totally synthetic optically active compounds (1 1 1). Compound (1 1 la) underwent m e t h ~ l a t i o nby ~ ~ lithium dimethylcuprate to form, stereoselectively, the 9P-methyl compound (112a). Though a cis-2-decalone, this underwent further alkylation at position 6 (steroid numbering). Perforce the requisite side-chain had to be introduced by alkylation of the pyrrolidine enamine to form (111b) : this was then followed by conjugate addition of methyl to form (112b). Lithium dimethylcuprate also converted37 (1 1lc) into (112c). Subsequent cyclization gave, from both 0

Me0

R

@

R

&p

0 (111) a ; R = H

b; R

=

MeCCI=CHCH,

c ; R = MeC(-OCH,CH,O-)CH,CH, 3h 37

38

”

(112) a ; R = H b ; R = MeCCl=CHCH, c ; R = MeC(-OCH,CH,O-)CH,CH,

J. R. Bull and A. Tuinman, Tetrahedron, 1973, 29, 1101. R . V. Coombs, J. Koletar, R. Danna, H. Mah, and E. Galantay, J . C . S . Perkin I , 1973, 2095. M.Tanabe and D. F. Crowe, Chem. Comm., 1969, 1498. D. H. R . Barton, R . H . Hesse, G. Tarzia, and M. M. Pechet, Chem. Comm., 1969, 1497.

30 1

Steroid Synthesis OH

(112b) and (112c),the 19-nor-steroid (113), which had 9P,lOa-stereochemistry (as in the cucurbitacins). Conjugate addition of cyanide to (11lc) yielded the 9a-cyano-deri~ative~~ (112c; 9a-CN in place of 9P-Me). Lithium dimethylcuprate induced (114) to form a 5-methyl rather than a 9-methyl compound.36 Some of the most fascinating reactions being discovered in the steroid field involve the use of superacids. Oestrone, its methyl ether, and its acetate on treatment with HF-SbF, are all smoothly converted into oestra-4,9-diene-3,17-dione (1 15) in ca. 80% yield.40 With FS0,H-SbF, the products are compounds (116) (62%) and (115) (ca. 10%). 19-Norandrostenedione (117) in contact with HF-SbF, for 10 minutes at 0°C produced the isomer (117; 14P-H) in 75% yield.41 Using the system DF-SbF,, up to 12 deuterium atoms could be incorporated into the molecule. In the androstane series some highly unsual products have been obtained by using HF-SbF, to promote dienone-phenol rearrangement^.^^

&*

0

’

H

(115)

HO \

H

(116)

& *

/

( 1 17)

The methylation of 19-nor-A4-3-keto-steroids (118 ; R = H) to produce 2a-methyl derivatives (118 ; R = Me) has been made possible by the action of lithium hexamethyldisilazane and the trapping of the A2~4-enolatewith methyl iodide.43 5aH- 19-Norketones of type (119) very readily undergo conjugate addition of methyl (coppercatalysed Grignard reagent) to give the la-methyl compounds, even in the presence of an 1lP-hydroxy-group which might have been expected to induce P-attack of the reagent by complex f0rmation.4~ In 19-nor-steroids (118; R = H) ring A becomes aromatized and C-6 oxidized by the action of oxygen in DMS0.45 The products, 3-hydroxy-6-ketones, are formed by

40 41

42 43 44 45

J. P. Gesson, J.-C. Jacquesy, and R . Jacquesy, Bull. SOC.chim. France, 1973, 1433. J.-C. Jacquesy, R. Jacquesy, and G. Joly, Tetrahedron Letters, 1972, 4739. J.-C. Jacquesy, R . Jacquesy, and Ung Hong Ly, Tetrahedron Letters, 1974, 2199. M . Tanabe and D. F. Crowe, J.C.S. Chem. Comm., 1973, 564. C. C. Bolt and F. J. Zeelan, Rec. Trav. chim., 1973, 92, 1267. H. Hofmeister, H. Laurent, and R. Wiechert, Chem. Ber., 1973, 106, 723.

Terpenoids and Steroids

302

(1 18)

(1 19)

sequential oxygenation at C-6 followed by aromatization and not in the reverse order. 2~-Hydroxy-3,17-dioxoandrost-4-en19-a1(12l), which is quite possibly the penultimate steroid in the androgen-oestrogen bioconversion, has been ~ y n t h e s i z e dfrom ~ ~ (120; R' = R2 = R3 = H, R4 = OAc). N-Bromosuccinimide introduced a 6P-bromine atom, to afford (120; R 1 = R 2 = H, R3 = Br, R4 = OAc), and the action of glacial acetic acid-potassium acetate on the latter replaced the bromine with rearrangement ; one of the products (120; R' = R4 = OAc, R2 = R3 = H) on hydrolysis and treatment with dimethyl-t-butylsilyl chloride-imidazole yielded (120; R 1 = OSiMe,Bu', R 2 = R 3 = H, R4 = OH), which on oxidation and hydrolysis formed (121). Compound (121) in a phosphate buffer at pH 7 was converted rapidly and quantitatively into oestrone. If indeed (121) is the penultimate link in the biological sequence, the last step might well be non-enzymatic. 0

0

I

R3

The a-epoxide (122) gave the 10P-hydroxy-compound (123) when treated with either potassium t-butoxide or lithium di-is~propylamide.~~ The or-epoxide (124) by contrast yielded compound (125) with potassium t-butoxide (loss of the 12-axialproton) and (126) with lithium di-isopropylamide. These results have been rationalized in terms of orbital symmetry.48 Compound (125) was quantitatively converted on deacetalization into (127). The ketone (128) on peroxidation with rn-chioroperbenzoic acid gave the l0a-hydroxy-compound (129) in addition to the known 10~-compound.30 Compounds of type (130) have been and have contraceptive properties. On catalytic hydrogenation they produce 9PH-compounds, but on metal-ammonia reduction the normal 9ctH-stereochemistry ensues. A three-step procedure for converting 17-keto-steroids into their 18-nor-derivatives has been worked out in the oestrane series (see p. 258).51 Dehydroabietic acid has been 46 4'

48 49 50

5L

H . Hosoda and J . Fishman, J.C.S. Chem. Comm., 1974, 546. G . Teutsch and R . Bucourt, J . C . S . Chem. Comm., 1974, 763. J. Mathieu, Bull. SOC.chim. France, 1973, 807. H . J. Kooreman, D. van der Sijde, and A. F. Marx, Rec. Trav. chim., 1972,91, 1095. D. van der Sijde, H . J . Kooreman, K. D. Jaitly, and A. F. Marx, J. Medicin. Chem., 1972, 15, 909; 1973, 16, 1302. M. M. Coombs and C. W. Vose, J.C.S. Chem. Comm., 1974, 602; cf. R . Anliker, M. Miiller, M. Perelman, J . Wohlfahrt, and H. Heusser, Helv. Chim. Acta, 1959, 42, 1071.

Steroid Synthesis

303

304

Terpenoids and Steroids

transformed into the 14a-methyl-19-nor-compound( 131).52 The best route so far known to A14-17p-olsis that of sodium borohydride reduction of the 14,16-diene-17acetates (132).5 3 Compound (1 33) on reaction with Grignard reagent, acetylation, and treatment with zinc in toluene (Serini-type reaction) produced in high yields the 168alkyl compounds (134)? Starting from the 16-hydroxy-17-keto-isomer of (133) the products were the 17~-alkyl-16-ketones.Methods for the construction of ethers of type (135) have been devised;55 the compounds are orally active oestrogens, the 17cycloalkenyl ether grouping being a variant of the more usual 17a-ethynyl-typegrouping. OAc

I

Me0

p \

(133)

(135)

4 Androstanes

A new synthesis56 of A2-steroids is exemplified by the conversion of 17D-acetoxy-5aandrostan-3-one into 17P-hydroxy-5a-androst-2-ene. Initial conversion of the 3-ketone + into its 2a-hromo-derivative is accomplished by reaction with PhNMe, Br, - ; reaction of the bromo-ketone with triethyl phosphite affords the enolate [136; R = (EtO),P(O)O], which on reduction with lithium in ammonia-propan-2-01 yields the olefin (136; R = H). The remote oxidation of unactivated C-H bonds by photoexcited nitrobenzene derivatives has been r e p ~ r t e d , ~and ’ the procedure is illustrated by the conversion of 5a-androstan-3a-ol into 5cc-androst-14-en-3-one. Ring-D dehydrogenation is accomplished by irradiation of the P-(pnitropheny1)propionate ester [137; R = 0,C(CH2),C,H,N0,-p] ; saponification and chromatography of the resultant neutral fraction yields a mixture of 5a-androstan-3cc-01and 5a-androstan-14-en-3a-o1? which is oxidized to the respective ketones for ease of separation. A 26% yield of the 52

T. Wirthlin, H . Wehrli, and 0. Jeger, H e h . Chim. Acta, 1974, 57, 368.

54

G. Goto. Y . Yoshioka, K . Hiraga, and T. Miki, Chem. and Pharm. Bull. (Japan), 1973. 21,

’’ G. H . Rasmusson and G. E. Arth, Steroids, 1973, 22, 107. 55 56

5’

1393; Tetrahedron, 1974, 30, 2107. R . Gardi, R. Vitali, G. Falconi, and A. Ercoli, J. Medicin. Chem., 1973, 16, 123. M . Fetizon, M . Jurion, and A . Nguyen Trong, Org. Prep. Proced. Internat., 1974,6, 31. P. C. Scholl and M . R. Van der Mark, J. Org. Chem., 1973,38, 2376.

Steroid Synthesis

305

H (1 37)

A14-3-ketone can be achieved. The yield of well defined remote-oxidation product is, however, lower by this method than that reported58 for the photolysis of the benzophenone derivatives ( 1 38). Irradiation of androsterone 3wtrifluoroacetate (137 ; R = O,CCF,) in the presence of PhICI, yields a product which upon dehydrochlorination and saponification is shown5' to be androst-9(1l)-en-17-one (49 %) (see also p.275). Interest has continued in reactions which lead to aromatization in steroids, and it is reported that the action of hydrogen bromide on 17~-acetoxy-4P,5a-dihydroxyandrost2-ene, 5a,6a- and 5cr,6P-dihydroxyandrost-2-en-l 7-one, and 4P-acetoxy-3P-hydroxyandrost-5-en-17-one is to convert them into their respective 17-substituted-4-methyloe~tra-l,3,5(10)-trienes.~~ SimiIar treatment of 6~,17P-diacetoxy-3P-hydroxyandrost4-ene gives a mixture of 17P-acetoxy-4-methyloestra-1,3,5( 10)-triene and testosterone acetate. Selective ring-c aromatization has been accomplished by treating 17P-hydroxy17-methylandrost-4,6,9(1l)-trien-3-one with refluxing formic acid.6' The reaction furnishes 17,17-dimethy1-18-norandrosta-4,8,1 lJ3-tetraen-3-one (139; R = H) in 45';/,, yield ; dehydrogenation of this tetraene gives the corresponding A4,6,8,' -pentaene. The formic acid rearrangement reaction has also been used to convert 3P-acetoxy-17Phydroxy-17-methyl-5c-androst-8-en-ll-one and 9cc-bromo-l7~-hydroxy-l7-methylandrost-4-ene-3,ll-dione into 3P-acetoxy-1l-hydroxy-17,17-dimethyl-l8-nor-5a-androst8,11,13-triene and 1l-hydroxy-l7,17-dimethyl-18-norandrosta-4,8,11,13-tetraen-3-one (139; R = OH) respectively.62 Application of this aromatization procedure to 38acetoxy-l7~-hydroxy-l7-methyl-5~-androst-9( 1l)-en-12-one in an attempt to obtain the corresponding 12-phenol resulted only in the formation of 3P-acetoxy-17-methyl-

59

(139) R. Breslow, S. Baldwin, T. Flechtner, P. Kalicky, S. Liu, and W. Washburn, J . Amer. Chem. SOC.,1973, 95, 3251. R. Breslow, R. Corcoran, J. A. Dale, S. Liu, and P. Kalicky, J . Amer. Chem. SOC.,1974, 96, 1973.

6o 61 62

D. Baldwin, J. R. Hanson, and A. M. Holton, J.C.S. Perkin I, 1973, 1704. A. B. Turner, Chem. and Ind., 1972, 932. C. L. Hewett, S. G . Gibson, I. M. Gilbert, J. Redpath, and D. S. Savage, J . C . S . Perkin I , 1973, 1967.

306

Trrpenoids and Steroids

5a-androsta-9(1 1),16-dien-l2-one, presumably since aromatization of ring c would involve an unstable tertiary carbonium ion adjacent to the C-12 carbonyl group. The scope of the available reactions to ring-c aromatic steroids has been extended to include a route via bromination and dehydrobr~mination~(Scheme 7). Initial bromination of the A ' 3-steroids (140) followed by dehydrobromination leads to the 7,13-dienes (141) as expected; these on further bromination yield, in the main, the dibromides (142),of which (142b and c) were sufficientlystable to be isolated. Dehydrobromination of the crude dibromides (142) results in the direct formation of the 8,11,13trienes (143), generally in good yields. This aromatization procedure has also been and the correapplied to 3a-benzoyloxy-17,17-dimethyI-18-nor-S~-androst-l3-ene, sponding SP-ring-c-aromatic steroid was isolated in good yield. , J H 2 RMe 2 ,&H2R2

Br

I

(140) a : R ' = Ac, R 2 = H b : R' = Rz, R 2 = H C : R ' = Bz, R 2 = OBZ d : R ' = Ac. R 2 = Ph e : R ' = Bz, R 2 = Ph

Po-

J.

&Ll

iii

4

H (143)

Reagents: i , B r ? . - 6 0 ° C ; ii. N a I L M e 2 C O ; iii, B r ? , - 6 0 ° C ; iv, stir with silica in benzene.

Scheme 7

4,4-DimethyI-Scc-androstan-2-one has been prepared for the first time.64 The into its synthesis commences with the conversion of 4,4-dimethyl-5a-androstan-3-one 2-arylidene derivative by reaction with p-methoxybenzaldehyde ; the 3-keto-group is then reduced and acetylated prior to ozonolysis of the 2-arylidene group. The resulting 3[$acetoxy-2-ketone on treatment with zinc in acetic acid affords the required 2-ketone. Conversion of the 3-ketone directly into the 2a-acetoxy-3-ketone by lead tetra-acetate seems to offer a shorter route, but the subsequent isomerization (2a-OAc.3-C=0 -+ 3P-OAc,2-C=0) results in the formation of an equilibrium mixture of both steroids. Thus although the route first described is longer, the overall yield of 2-ketone is higher. The preparation of four D-homoandrostanes has been d e s c r i b ~ d(Scheme ~~ 8), via the ring expansion of the intermediate amino-alcohols (144). Subsequent oxidation of C . L. Hewett, I. M. Gilbert, J. Redpath, D. S. Savage, J. Strachan, T . Sleigh, and R. Taylor, J . C . S . Perkin I . 1974, 897. "'A . D. B o d . R. Macrae. and G . D. Meakins, J . C . S . Perkin I , 1974, 1138. h5 L. E. Contreras, J. M. Evans, D. de Marcano, L. Marquez, M. Molina, a n d L. Tempestini, J . O r g . Chem., 1974, 39, 1550.

63

Steroid Synthesis

a ; R' b ; R' C ; R' d ; R'

= =

= =

307

1

iv

a-OH, R 2 = H b-OH, R 2 = H H, RZ = p-OH H, RZ = b-OH, As

c>

Reagents: i. Trimethylsulphonium ylide; ii, NaN,-boric acid; iii, Zn-HCI; iv, NaN0,-HCl; v, Huang-Minlon reduction.

Scheme 8

the D-homo-alcohol (145c) furnished the 3-keto-derivative and this was converted into 2-keto-~-homoandrostaneby a group-transposition sequence similar to that outlined Oxidation of the alcohol (145d) allowed above for 2-keto-4,4-dimethyl-5a-androstane. which was reduced to the A4-~-homo-steroid, the isolation of the ~-homo-A~-3-ketone, and this in turn on hydroboration and oxidation furnished a route to ~-homo-Scxandrostan-4-one. Oxidation of either of the derivatives (145a) or (145b) provided a simple way to ~-homo-5cx-androstan-l -one. A novel route to D-homoandrostanes has been described, based upon the reaction of the trio1 (146) with base.66 The reaction involves elimination of the acetylene with consequent ring-D homologation to form 3p, 1 7afi-dihydroxyandrost-5-en17-one.

( 1 46)

( 1 47)

The published route67 from Sa-androstan-17-one to the corresponding 15-ketone has been improved and adapted to large-scale preparations of this hitherto not readily with available ketone.68 Reaction of 16a-bromo-17,17-ethylenedioxy-5a-androstane base yields a A' 5-acetal which on hydrolysis affords the A' 5-17-ketone; peroxidation h6 67

68

H . Chwastek, R . Epsztein, and N . LeGoff, Tetrahedron Letters, 1973, 179. C. Djerassi, G . von Mutzenbecker, J. FajkoS, D. H. Williams, and H . Budzikiewicz, J . Amer. Chem. SOC.,1965,87, 817. I . M. Clark, W . A . Denny, E. R . H . Jones, G . D. Meakins, A. Pendlebury, and J. T. Pinhey, J . C . S . Perkin I , 1972, 2765.

308

Terpenoids and Steroids

then affords the keto-epoxide (147). The key step in this improved synthetic route is the reaction of the epoxide (147) with hydrazine and toluene-p-sulphonic acid in the presence of air to yield 5%-androstan-15P-01. Surprisingly, if this latter reaction is carried out in nitrogen, the allylic alcohol 5a-androst-16-en-15P-ol is obtained. Oxidation of the saturated 15fi-alcohol affords the desired 15-keto-steroid. A convenient high-yield conversion of androst-5-ene-3P, 17P-diol into the 3P-hydroxyA5- 17-ketone (dehydroisoandrosterone) has been devised, in particular for small-scale radioactive preparation^.^^ The method depends on selective reaction at the C-3 hydroxy-group between the 3fi~7P-dioland dimethyl-t-butylsilyl chloride in the presence of imidazole : androst-5-ene-3P,17P-diol3-dimethyl-t-butylsilyl ether is formed in 71 yield. Oxidation at C-17 is then accomplished with chromium trioxidepyridine and cleavage of the protecting group is carried out with aqueous acetic acid. The reaction of formaldehyde with a series of dienamines (148) and (149) has been shown to establish a synthesis of the corresponding 6-hydroxymethyl-steroids (150) and (151)respectively. 'O The latter could be dehydrated to their 6-methylene analogues and thence by palladium-carbon isomerization to their 6-methyl-A4~6-derivatives. ''()

R

R2

Me, R2 = 0 R2 = P-Ac,r-H c: R' R2 = B-Ac,cr-OAc d : R ' = H.R2 = 0 e : R' = H, R 2 = B-OH,cr-Me

(148) a ; R' b : R'

=

= Me, = Me,

(149) a ; R b; R C:

R

d; R

= =

0 P-Ac,a-H

= B-Ac,u-OAC ==

P-OH,a-Me

A route to 6P-methyi derivatives of €3-norandrostanes has been illustrated by the reaction of 3fi-acetoxy-~-nor-5x-androsta-6,17-dione with methylmagnesium bromide.' The initial dimethylated steroid can be dehydrated to 3P-hydroxy-6,17~ dimethyl-~-nor-androst-5-en-l7-01, which on oxidation yields the corresponding 6P-methyl-A4-3-ketone; the preparation of the corresponding 6/3-methyl-~-norcholest4-en-3-one is also described. A procedure for the 2-alkylation of A4-3-keto-steroids h9

'O

"

H . Hosoda, D. K . Fukushima, and J . Fishman, J . Org. Chem., 1973, 38, 4209. F. Schneider, A . Boller, M. Muller, P. Muller, and A . Furst, Helu. Chim. Actu, 1973,56, 2396. J . Joska, J . FajkoS, and F. Sorm, Coll. Czech. Chem. Comm., 1973,38, 2121.

Steroid Synthesis

309

via the corresponding 2,4-dienolate ion has been p~blished.~,Thus when the 17tetrahydropyranyl ether of testosterone or 19-nortestosterone is treated with lithium hexamethyldisilazane, the 2,4-dienolate ion is produced in high yield and can be trapped as the hitherto unknown ring-A homoannular 2,4-dienol silyl ether (152 ; R = Me or H) by reaction with t-butyldimethylchlorosilane. Alkylation of the dienol ether (152 ; R = Me) with methyl iodide in hexamethylphosphoramide gave an 800/0 conversion into a mixture of the 2a- and 2P-methylated-A4-3-ketones, which on base equilibration gave the 2a-methyl-steroid. Acid-catalysed removal of the C- 17 protecting group afforded 2a-methyltestosterone. Michael addition of nitromethane to 17/?-propionyloxyhas been shown to yield the or 17fi-hydroxy-l7-methylandrosta-l,4,6-trien-3-one corresponding la-(nitr~methyl)-dienones~~ (153; R = CH,NO,). Reduction of the nitromethyl group with titanous chloride yields the la-formyl derivative (153; R = CHO), whilst hydrogenation of the nitromethyl steroid affords la-(nitromethyl)-17Ppropionyloxy-5~-androstan-3-one.

Me (1 53)

(152)

An improved route to a-diazoketo-steroids has been published. 7 4 Formylation of the 17-ketone (154: R = H,) with ethyl formate and sodium hydride gave the 16-formyl derivative (154; R = CHOH), which on reaction with diethylamine was converted into the enamine (154; R = CHNEt,). Reaction of the latter with p-carboxybenzenesulphonyl azide afforded the diazo-ketone (154; R = N,) in an overall yield of 627; based upon the 17-ketone. This method avoids the erratic results encountered in the chloramine oxidation of oximino-ketones. Irradiation of the diazo-ketone (90 ; R = N,) and -1 68gave a mixture of two acids, 3P-hydroxy-~-l3a-norandrost-5-ene-l6acarboxylic acids. 0

154)

Benzyl alcohol has been used as a hydrogen donor in the selective hydrogenation of unsaturated steroid^'^ with heterogeneous catalysts such as 10 Pd-C. Seven examples are given amongst which are the reduction of 17fi-hydroxy-5a-androst-1-en-3-one to the saturated 5a-androstan-3-ketone (quantitative) and 17P-hydroxy-1,4-androstadienl2

l3

74

l5

M . Tanabe and D. F. Crowe, J.C.S. Chem. Comm., 1973, 564. M . Kocor, M . Gumulka, and T. Cynkowski, Bull. Acad. polon. Sci., Ser. Sci. chim., 1973, 21, 721. J. Meinwald and A. J. Taggi, J. Amer. Chem. Soc., 1973, 95, 7663. R . Vitali, G. Caccia, and R. Gardi, J. Org. Chem., 1972, 37, 3745.

Terpenoids and Steroids

310

3-one to a mixture of 17P-hydroxy-S/?-androstan-3-one (25 %) and 17p-hydroxyandrost4-en-3-one (72 ?<). The homogeneous catalytic hydrogenation of androsta-1,4-dien3,17-dione with dichlorotris(tripheny1phosphine)ruthenium has been investigated in the presence of various bases. Addition of triethylamine reduces the formation of 5a-androstan-3,17-dione, thereby increasing the selectivity in formation of androst4-ene-3,17-di0ne.~~ It is reported77 that the 4,5P-dihydro-derivatives of testosterone and androst-4-en-3,17-dione are formed when these compounds are treated with Et,SiH in the presence of CF,CO,H ; the yields are in the region of 85 5",. There have been two accounts of synthetically useful methods for the protection of steroidal keto-groups. The first7* involves selective mono-thioacetal formation when the androstenediones (155; R = H or OH) are treated with ethanedithiol in methanol catalysed by boron trifluoride etherate. The yields of 3,3-dithioacetals are 73 and 85 'i1 respectively. The second method involves acetalization with o-nitrophenylethylene glycol ; regeneration of the ketone is accomplished upon irradiation at 3500 A and takes place under anhydrous and chemically inert condition^.'^ The acetal (156)

0

formed from androst-5-en-3p-ol-l7-one, when photolysed, gives a 74 <; yield of the 17-ketone, comprising a mixture of 13p- and 13%-steroids(2 : I), but irradiation of the acetal formed from testosterone gives only 31 y;) of the A4-3-ketone, since the initially generated deconjugated ketone is not photochemically stable. Improved synthetic methods have been presented for the introduction of 2a- and 2p-acetoxy-groups into androst-4-ene-3,17-dioneand 19-norte~tosterone.~~ The routes discussed are the direct acetoxylation of 19-nortestosterone with lead tetraacetate. where the yield of mixed 2a- and 2p-acetates has been raised from the previously reported 24 "~~to 43 and the acetolysis of 6fi-bromoandrost-4-en-3,17-dione, where it is now shown that three acetoxy-derivatives (6p-, 2a-, and 2p-) are formed in varying yields depending on the experimental conditions. An improved synthesis of 2phydroxytestosterone involves the direct acetoxylation of testosterone 17-chloroacetate using an excess of lead tetra-acetate ; a 2 1 yield of 2~-acetoxy-l7~-chloroacetoxytestosterone is obtained along with a similar quantity of the 2a-is0mer.~~ The 2- and 1 7-chloroacetoxy-groups are both easily hydrolysed by base to afford the 2,8,17/?-diol. A simple, high-yield synthesis for 5a-androstan- 17p-01has been achieved by borohydride "(),

S. Nishimura, T. Ichino, A . Akimoto, and K . Tsuneda, Bull. Chem. SOC.Japan, 1973,46, 279. T. A. Serebryakova. A. V. Zakharychev, S. N . Ananchenko, and I . V. Torgov, tzuest. Akad. Nauk S . S . S . R . .Ser. khim.. 1974, 742. '' J. R. Williams and G. M. Sarkisian, Svnrhesis, 1974, 32. - " J . Herbet and D. Gravel, Canad. J . Chem., 1974, 52, 187. R . D. Burnett and D. N . Kirk, J.C.S. Perkin I , 1973, 1830. " R. D. Burnett and D. N . Kirk, J . C . S . Perkin t, 1974, 284. 7h

31 I

Steroid Synthesis

reduction of the tosylhydrazone of the required 3-ket0ne.*~A route to 15a,16a,17Ptrihydroxyandrost-4-en-3-one (163) has been outlinedg3(Scheme 9) commencing from the acetal (157). The A4-bond was first converted via the oxide (158) into the 5/?hydroxy-steroid (1 59) prior to bromination in ring D. Dehydrohalogenation of steroid (160) furnished 3fl,5/?-dihydroxyandrost-15-en-17-one ethylene acetal (161), which was hydrolysed and the resultant 17-ketone reduced and acetylated to give the unsaturated acetate (162). Osmium tetroxide oxidation at the A15-bond, followed by regeneration of the A4-bond uiu thionyl chloride dehydration of the 5p-alcohol, gave the 3P, 15c(,l6a,l7/?-tetrol,which was selectively oxidized at C-3 by N-bromoacetamide to yield the required keto-trio1 (163).

1

iv

OAc

I

OAc vi, vii

I

I

I

BBr

(163) Reagents: i , LiAI(OBu'),H; i i , m-CIC,H,CO,H; i i i , LiAIH,; iv, P h M e , N + B r , - ; v, 1,Sdiazabicyclo[5,4,0]undec-5-ene;vi, p-TsOH-H ,O; vii, LiAlH,, followed by re-acetylation; viii, OsO,; ix, SOCl,, hydrolysis; x, N-bromoacetamide.

Scheme 9

The preparation of some 14-functionalized 19-hydroxyandrostanes has been reported.84 When the 8,19-oxide (164)is reduced the main product is the corresponding 19-hydroxy-A'4-analogue. Hydrogenolysis proceeds with retention of configuration, i.e. the isomer with an 8a-hydrogen is not detected. Epoxidation of the 19-hydr0~y-A'~A steroid yields 14a,l5a-epoxy-19-hydroxy-3-acetoxy-l7~-pivaloyloxy-5a-androstane. similar zinc reduction of the oxide ring in 5-bromo-6,19-epoxy-5a-androsta-3,17-dione

'* 83

'4

L. Cagliotti, U r g . Synth., 1972, 2, 122. T . Nambara, M. Ito, M . Ito, J. Mori, J. Goto, and H . Hosoda, Chem. and Pharm. Bull. (Japan), 1973, 21, 2452. G . Kruger and G . I . Birnbaum, Tetrahedron Letters, 1973, 1501.

312

Terpenoids and Steroids OCOCMe, 1

( 164)

has been shown to lead to a mixture of 19-hydroxyandrost-4-en-3,17-dione and 19hydro~yandrost-5-en-3,17-dione.~~ The thermal rearrangements of some a-halogenoepoxides have been studied.g6 When the 3P-acetoxy-5a-androstane epoxides (165; R = Br or C1) are heated to just above their melting points they rearrange to the corresponding 16-halogeno-17-ketones; the proportions are 26 of the 16a-bromo-17ketone and 68 (’;, of the 16P-bromo-17-ketone. Reaction of the bromo-epoxide (165 ; R

165)

R = Br) with sodium iodide in acetone affords a high yield of 3~-acetoxy-l6a-iodo-5aandrostan- 1 Tone. A high-yield route to 3P-acetoxy-4~,5~-epoxpandrostan-6-one has been p~blished.~’ It is based upon the reaction of alkaline hydrogen peroxide with the corresponding 3P-acetoxy-A4-6-ketone. Similar oxidation with perbenzoic acid leads only to mixtures of the 4a,5a- and 4P,S/?-epoxides. A comparison of the expoxidation reaction amongst a series of androst-4-en-6-ones indicates that the presence of a 3-hydroxy-group facilitates the reaction. Several synthetic routes to cyclopropyl-containing androstanes have been documented. The intermediate from the Simmons-Smith methylenation of the 5-double bond of 3/?-acetoxyandrost-5-en-l7-one was treated with perphthalic acid to yield 3~-acetoxy-5,7~-cyclo-~-homo-5~-androstan-l7-one and the corresponding 5a,7aepimer ;8s yields were, however, only 3 :, and 8 7; respectively. The 3-acetates were hydrolysed and the resulting alcohols oxidized to the corresponding 5,7-cyclo-~homoandrostan-3,17-diones. The addition of dihalogeno-carbenes to the 5-double is reportedg9 to take place in higher bond of 3P-acetoxy-~-norandrost-5-en-17-one yields than for the 5-double bond of normal steroids. For example, when difluorocarbene is added to the ~-norandrost-5-enesystem the adduct (166) is formed in 65 7; yield ; addition is from the a-face rather than from the /I-face as is the case in normal A5-steroids. Attempts to add dichlorocarbene to the B-nor-olefin resulted in effective addition, but the adduct underwent spontaneous rearrangement to a 5,6a-dichloro-A5steroid (167). The synthesis of 15a,l6a-methylenetestosteronehas been described” G . S. Grinenko, V . I. Bayunova, and S. D. Shuvalova, Khim. prirod. Soedinenii, 1973,9, 48. P. Catsoulacos and A . Hassner, Bull. Soc. chim. France, 1973, 717. ” D. Baldwin and J. R. Hanson, J.C.S.Perkin I , 1972, 2051. L. Kohout and J. FajkoS, Coll. Czech. Chem. Comm., 1973, 38, 1415. ” P. Rosen and R. Karasiewicz, J . Org. Chem., 1973, 38, 289. ‘” R. Wiechert, D. Bittler, and G . A. Hoyer, Chem. Ber., 1973, 106, 888

313

Steroid Synthesis

and commences with the Simmons-Smith methylenation of 3/3-acetoxy-l7a,205dihydroxypregn-5,15-dieneto yield the 15a,l6a-cyclopropano-steroid(75 7;). Periodate oxidation of the 17a,20<-diol,saponification of the 3P-acetate, and Oppenauer oxidation of the resulting alcohol furnishes 15a,l6a-methyleneandrost-4-en-3,17-dione, reduction of which with lithium tri-t-butoxyaluminium hydride yields 15a,16a-methylenetestosterone. The addition of difluorocarbene to the triple bond of 3a-ethynyl-3,17P-diacetoxy-5aandrostane readily affords a novel difluorocyclopropenyl derivative” (1 68 ; R = OAc). Reaction of the 3/3-hydroxy-derivative(168 ; R = OH) with N-(2-chloro-l,l,2-trifluoroethy1)diethylamine (fluoramine) provided a mixture containing three steroids. The major compound (25 was the fluoro-steroid (168 ; R = F), the second compound (15 was shown to be the conjugated cyclopropenyl ketone (169), and the third (3 %) and most interesting was the steroidal allene (170). In a similar series of experiments 17a-ethynyl-3~,17-diacetoxy-5a-androstane was converted in 25 ;4 yield into its allene 17-(2’-cr-trifluoromethylvinylidene)-3~-acetoxy-~a-androstane.

x)

x)

HC=C

K

F F

HC=C

K 0

H

i170)

There have been a number of reports concerning the synthesis of heterocyclicanalogues and heterocyclic derivatives of androstanes. Some of the more important are described below, commencing with synthetic routes to steroids which include the heteroatom within the skeleton. A synthesis of the 15-oxa-steroid system (176)is outlined in Scheme 1 0.92 The reaction between 3P-hydroxy-Sa-androstan-17-0ne(171) and o-nitrobenzaldehyde leads to the known 15,17-dioic acid 17-methyl ester (173) uia the intermediate (172). Oxidation of this acid-ester furnishes the 14P-acetoxy-14,17-~ecoandrostane (174) in 60% yield, accompanied by a small amount of the 14-epimer. Hydrolysis of the ester affords the dihydroxy-acid (175; R’ = R2 = OH), which was acetylated to yield the 3P,14B-diacetate(175; R’ = OH, R2 = OAc) prior to its conversion into the diazo-ketone (175; R’ = CH2N,, R2 = OAc) via the corresponding acid chloride. Reaction of the diazo-ketone with boron trifluoride etherate led directly to the 15-oxa91

92

P. Crabbe, H . Carpio, E. Velarde, and J . H. Fried, J . Org. Chem., 1973, 38, 1478 P. Rosen and G . Oliva, J. Org. Chem., 1973, 38, 3040.

314

Tcrpenoids and Steroids

Reagents: i. o-02NC,H,CHO; i i , CrO,; iii. Pb(OAc),; iv, KOH-MeOH; v, (COCl),. C H 2 N 2 ; vi, BF, ,Et ,O.

Scheme 10

androstane (176), which was converted by a standard chemical route into 15-oxaoestrone. There have been several reports of the synthesis of steroidal lactams. Beckmann rearrangement of the 0-acetyl-oximes of 3,!l-hydroxy-5a-androstan-l7-one and 3phydroxyandrost-5-en-17-0neyielded steroidal lactams of type (177 ; 5a-H and A5 re~pectively).~~ After esterification of the 3P-alcohol function in the steroids (177) with monochloroacetic anhydride, the resulting chloroacetates were heated with piperidine or morpholine to yield the 3~-aminoacetoxy-derivatives. Beckmann rearrangement catalysed by boron trifluoride of the oxime acetate of 3/j-acetoxy-5a-androstan-17-one etherate resulted in the expected lactam (177) and also in the formation of the secosteroid (178; R 1 = CH,, R 2 = CN) in 40:;;) yield.94 This same D-homo-lactam type (177) has also been observed to be a reaction product from the photolysis of 17o x i m e ~ .The ~ ~ reaction is illustrated by photolysis of 0-acetylandrosterone oxime to H

yield a mixture of O-acetyl-~-homo-Sa17a-aza-androsterone and its 13a-epimer, albeit in yields of only 3 and 1 respectively. The same mixture of lactams could be obtained in higher yield from the photolysis of NO-diacetylandrosterone h y d r a ~ o n e . ~ ~

:/:

y3

"

:/,:

P. Catsoulacos, Chirn. Ther., 1972, 7 , 578. P. Catsoulacos and L. Boutis, Chirn. Ther., 1973, 8, 215. H . Suginorne and T. Uchida, Bull. Chern. Sor. Japan, 1974, 47, 687 H. Suginorne and T Uchida, Tetrahedron Letters, 1973, 2289.

Steroid Synthesis

315

Thionyl chloride-catalysed rearrangement of 3cc-(trifluoroacetamido)-5a-androstan17-one oxime gave the familiar lactam (177 : 3a-NHCOCF3),hydrolysis and reduction of which furnished 3P-amino-~-horno-Sa17a-aza-andro~tane.~~ Reaction of 3aacetoxy-5a-andros tan- 17-one oxime with dicyclohexy lcarbodi-imide afforded the secoandrostane (178; R 1 = CH,, RZ = CN), which was subsequently ozonized to yield a 13-ketone prior to hydrolysis and oximation to form the intermediate oxime (178; R' = NOH, R2 = C0,H). Sodium-propan-2-01 reduction of the latter allowed the isolation of 3a-hydroxy-18-nor-~-homo-l7a-aza-5a-androstane.~' Oxidation by permanganate-periodate of the lactam D-homo-17a-aza-androst-4-en-3,17-dione leads to the corresponding ~-nor-3,5-secoandrostan-3-oic acid, which on conversion into its 5-oxime gives the dilactam (179) by means of a Leuckart rea~tion.~'The dilactam (1 79) on reduction with sodium in pentanol afforded the 4,17a-diaza-steroid, which was quaternized in two stages to yield 4,17a-dirnethyl-4,17a-diaza-~-homo-.5a-androstane, a steroid with potential neuromuscular blocking activity.

A novel reaction is reported to take place between androst-4-en-3,17-dione and excess hydrazoic acid in the presence of boron trifluoride etherate.99 The major product (27"() is a bistetrazolo-steroid (180) and is accompanied by a minor product (181) which by heating is converted into the same bistetrazolo-derivative (1 80).

Turning now to steroids which have added heterocyclic moieties or additional fused heterocyclic systems, the steroidal quinoxaline (182)has been prepared from the reaction of either 3~-hydroxy-l6a-bromo-5a-androstan-l7-one or 3b-acetoxy-1Ga-bromoandrost-Sen- 17-one with 4,5-dimethyl-o-phenylenediamine.O0 Condensation of the same 16a-bromo-steroids with a variety of aminopicolines led to the corresponding 97

'*

y9

L. Diatta and P. Longevialle, Bull. Soc. chim. France, 1973, 1159. H . Singh, D . Paul, and V. V. Parashar, J . C . S . Perkin I, 1973. 1204. H . Singh, R . V . Malhotra, and V. V. Parashar, Tetruhedron Lctfers, 1973, 2587. P. Catsoulacos, J . Heterocyclic Chem., 1973, 10, 933.

Terpenoidsand Steroids

316

imidazopyridines (183; R = 6'-, 7'-, or 8'- Me).'" The condensation of epiandrosterone with ethyl formate yields 3~-hydroxy-16-(methoxymethylene)-5cr-androstan-l7-one, which has been shown to react with ammonia to furnish the corresponding 16-(aminomethylene) derivative.' O 2 Condensation of the latter with various aminopyrimidines gave 4'3'-( 16,17-epiandrosteno)pyrido[2',3'-d]pyrimidines (184 ; R = S, 0, or NH). The same type of condensation reaction between 2-(hydroxymethy1ene)- or 2-(aminomethy1ene)-testosteroneand various uracils leads to the formation of pyridopy rimidines (185: R = 0, S, or NH) in 50--60"/: yields.'03

The synthesis of an androstane fused to a pyrazole ring at positions 4 and 6 (187) has been published and starts with the reaction of 5~,6~-epoxy-3fl,17fl-dihydroxy-l7methylandrost-6-one and phenylhydrazine to produce the phenylazo-steroid (186).

OH

lo' lo'

lo4

N=NPh

Ph-N-N

P. Catsoulacos a n d E. Souli, J . Hererocyclic Chem., 1974, 11, 87. G . Bouchon, H. Pcch, and E. Breitmaier, Chimia (Switz.).1973, 27, 212. H. Pech. G. Bouchon, a n d E. Breitmaier, Chem. Ber., 1974, 107, 1389. A . V . Kamernitskii, I z v e s f . Akad. Nauk S.S.S.R., Ser. khim.. 1974. 190.

Steroid Synthesis

317

Cyclization of the latter with strong acid yields the pyrazole (187). The water-soluble imidazoyl steroid (188) has been prepared from adrenosterone via the intermediate 3P-acetyl-5a-androstan-1 ia,l7P-dio!. ' 0 5 Oxidation of this 1la,l7P-diol by lead tetra-acetate afforded the 3P-acetoxyacetyl derivative, which was converted into the 3P-imidazole grouping. Oxidation of the two hydroxy-groups, oximation of the resultant keto-groups, and subsequent reduction gave the diamino-steroid (188). The Wittig-Horner reaction using (EtO),POCHR (R = 2-pyridyl or 2-quinolyl) and sodium hydride as the ylide-generating reagent has been used to gain access to either pyridylmethylene- (189) or quinolylmethylene-androstanes.106 Steroids so converted are 17-methyltestosterone, 3/?-acetoxyandrost-5-en-l7-one, and 3/?-hydroxy-h-androstan17-one.

( 1 89)

Four 17~-acetoxy-5a-androstane[3,2-b]indo!es(190) have been synthesized by reaction of the 3-ketoandrostane with each of the four arylhydrazines phenylhydrazine, p-tolylhydrazine, and 2- and 1-naphthylhydrazine and cyclizing the resultant hydrazones with strong acid.' O 7 3~-Acetoxy-Sa-androstan-l7-one was likewise converted into four androstano[l7,16-b]indolesby using the same four arylhydrazines. Condensation of 2-(hydroxymethy1ene)testosterone or 16-(hydroxymethy1ene)epiandrosteronewith a variety of aminopyrazoles has afforded the lH-pyrazol0[3,4-b]pyridine steroids (191) and (192) (R' = H or Me, R 2 = Me, Et, or Ph).Io8 The 2-(hydroxymethylene)derivative of 17~-hydroxy-17-methy!-l6a-acetoxy-5a-androstan-3-one has been condensed with hydroxylamine to yield 16a,l 7P-dihydroxy-17-methyl-5a-androstano[3,2-c]isoxazole(193); the isomeric 16,17-dihydroxy-derivativewas also synthe~ized.'~'

Io5

P. J . Guthrie and Y . Ueda, Canad. J. Chem., 1973, 51, 3936. W. Gustowski, M. Kocor, and J. Michalski, Bull. Acad. polon. Sci.,Ser. Sci. chim., 1973, 21, 887. P. Jacquignon, M. Croisy-Delcey, and A. Croisy, Bull. SOC.chim. France, 1972, 4251. J. Haeufel, H . Pech, and E. Breitmaier, Chem.-Ztg., 1973, 97,658. T. Nambara, K . Shimada, S . Iwamura, M. Mori, and M. Nokubo, Chem. and Pharm. Bull. (Japan), 1973, 21, 2474.

lob

lo'

'09

318

Terpenoids and Steroids 5 Pregnanes and Corticoids

Selective conversion of a ketone into its metal enolate is a convenient method for Thus the bismethylenedioxyprotecting it during metal hydride reductions. derivative of prednisone (194) with sodium or lithium bistrimethylsilylamide or trityllithium afforded the enolate (195);this, reduced in situ at - 78 "C with lithium aluminium hydride produced prednisolone BMD (196). The method can be applied to the conversion (1 97a) + (197b), thereby saving two steps in the industrial synthesis' " of cortisol. Yields of 1 I,!?-hydroxy-compoundsare of the order 4&75 %.

''

( 194)

(195) M

=

Li or Na

(197) a ; R' = 0, R 2 = C 0 , M e b ; R' = ,!l-OH,a-H, R2 = CH,OH

Treatment' l 2 of the 5a- and 5P-epimers of (198; R = H,) with either HF-SbF, or FS0,H-SbF, yields a separable mixture of (198) (ca. 23%), (199a) (ca. 6873, (199) (ca. 8%), and (199c) (ca. 1%). The proportions of the products remain substantially the same starting from (199a) or (199b), so presumably they represent equilibrium mixtures. The stereochemical integrity at C-5 is maintained throughout. Using deuterium labels at C-17 and C-20 in (198) it was found that no deuterium was lost. It is presumed therefore that the reaction occurs by C-13-C-17 bond fission in (200) to form (201) followed by a recombination. Compound (198; 1 I-CO, 5P-H) does not undergo the conversion. This may be due to positive charge on C-11 (the oxygen being protonated) making C-13-C-17 fission more difficult. Aldosterone 18-benzoate-21-acetate (202; R' = Me, R2 = Ph), when treated with a catalytic quantity of sodium methoxide in methanol, formed the 18-monobenzoate 'lo

'I'

' I 2

D. H . R . Barton. R. H. Hesse, M. M. Pechet, and C. Wiltshire, J.C.S. Chem. Cornm., 1972, 1017. J. A. Hogg, P. F. Beal, A. H . Nathan, F. H . Lincoln, W. P. Schneider, B. J. Magerlein, A . R. Hanze, and R. W. Jackson, J. Amer. Chem. SOC., 1955, 77,4436. J.-C. Jacquesy, R. Jacquesy, S. Moreau, and J. F . Patoiseau, J.C.S. Chem. Comm., 1973, 785.

3 19

Steroid Synthesis

(199) a; 13a, 17cr b ; 13p, 17a c ; 1301,17/3

S products

(203) and then the 21-benzoate (204) by acyl migration. The configuration of R2 was retained when this group was a a-phenylpropyl (S-enantiomer) ; also by proper choice of R2 the reaction could be stopped at compound (203).'13 Acid hydrolysis of (202) yields the 21 -monoesters (205).

(203)

(202)

wOCH20zCR2

\

H

~

CH20,CR'

\",H

The structure of stapelogenin was presumed114 to be (206), the position and stereochemistry of the ring-c hydroxy-group being the uncertain feature. The compound on 'I3 '14

R. Vitali and R . Gardi, Chem. and Ind., 1973, 584. U. Eppenberger, W. Vetter, and T. Reichstein, Helv. Chim. Acta, 1966, 49, 1505.

320

Terpenoids and Steroids

'

hydrogenation' l 4 gives a tetrahydro-compound, presumably (207). Its synthesis' leaves no doubt that structure (206) is correct. The lactone (208)' l 6 (Scheme 1I), which is also the starting point in the partial synthesis of the steroidal alkaloid batrachatoxinin, was reduced to the ScrH-compound (209),which on acetalization and reduction yielded the 208- (20R)-compound(210). Introduction of a 12-carbonylgroup, catalytic reduction, protection of the C-12 carbonyl, and alkaline hydrolysis then produced the diacetal diol (21 11, the 18-monoacetate of which was deacetalized to form (212). The action of dimethyl sulphoxide in the presence of acetic anhydride-acetic acid on (212) gave, principally, the methyl thiomethyl ether (213), which was reduced to the 3fl,12fl-diol. Acetylation followed by release of the 20,!?-OHand oxidation gave the 20-ketone (214). The introduction of two double bonds in ring D led to (215),the epoxide (216) of which, on treatment with Pd-BaSO, in methanol containing cyclohexene, gave the 148hydroxy-compound (217) ; this on catalytic reduction yielded the 17cr-acetyl compound (218). Alkali hydrolysed the acetoxy-groups, isomerized the side-chain at C-17, and brought about intramolecular ketol formation to produce dihydrostapelogenin (219), which on hydrogenolysis afforded tetrahydrostapelogenin (207). A sapogenin from at least five species of starfish has been identified as (220); on oxidation it gives the 3,6-diketone (221). The latter has been synthesi~ed"~from pregn-4-en-3,11,20-trione.The sapogenin itself has also been synthesized' * from 1la-hydroxyprogesterone (222). Conversion of this into the 3,S-dienol diacetate, acetalization at C-20, and sodium borohydride reduction gave (223). Subsequent hydroboration-hydrogen peroxide oxidation gave a separable mixture of 6p- and 6cr-alcohols. The latter, by protection of the 3P- and 6a-hydroxy-groups, conversion of the 11-oxygen function into tosylate, introduction of the A'("')-bond, and hydrolysis then produced 3,!?,6wdihydroxy-Sa-pregn-9(1l)-en-20-one (220) identical with material from natural sources. The action of formaldehyde on the pyrrolidine enamines (224; 9cr-H,lOfl-Me or 9,!?-H,lOa-Me)have been investigated. Hydroxymethyl groups are introduced at position 68 and the reaction is of preparative value for the formation of 6-methyl Efficient syntheses of 3-0xo-A~*~-steroids possessing azide, thiocyanate, compounds.

'

I

''

' I h

B. P . Schaffner a n d H . Wehrli, Helv. Chzm. Acra, 1972, 55, 2563. K. Heusler, J . Kalvoda, P. Wieland, and A. Wettstein, H e h . Chim. Acra, 1961, 44. 179, 1374; Ch. Meystre;K Heusler, J . Kalvoda, P. Wieland, G . Anner, and A. Wettstein, Experientia,

1961, 17. 475. J. W . ApSimon, J. A . Buccini, and S. Badripersand, Canad. J . Chem., 1973, 51, 850. ' I B D. S. H . Smith and A. B. Turner, Tetrahedron Letters, 1972, 5263. "' F. Schneider, A . Boller, M . Miiller, P. Miiller, and A . Fiirst, Helc. Chim. Acra, 1973, 56, 2396. 'I'

32 1

Steroid Synthesis

X

t

wo m='OAc

XIX

xv-

XYIII,

OAc

I

M0 w ACO

1

Reagents: LiAlH,-py complex; ii, HOCH,CH,OH-H ; iii, LiAIH,; iv, Ac,O-py; v, Bu'OCr0,OH; vi, H,-Pd/C-EtOH; vii, saponification; viii, Ac,O-py; ix, H ' ; x, DMSOAc,O-AcOH; xi, LiAlH(0-t-amyl),; xii, Ac20-py-4-dimethylaminopyridine; xiii, Chloramine-T; xiv, CrO, ; xv, pyridine hydrobromide perbromide; xvi, DMF ; xvii, NBS; xviii, Li,CO,-LiBr-DMF; xix, p-0,NC,H4C03H ; xx, cyclohexene-Pd/BaS04MeOH; xxi, H,-Pd; xxii, MeOH-KOH; xxiii, H,-Pt. +

Scheme 11

322

Terpenoids and Steroids

g2 AcO..

HO

(223)

and isothiocyanate groups at C-4 have been achieved. 2 o Ring-opening of the epoxide (225) yields the compounds (226; X = Br, N,, or SCN; R = H). The action of tetramethylammonium fluoride in acetonitrile on (226; X = N,, R = Ac) yielded (227; X' = H, X2 = N3). The 6-thiocyanate was prepared from (226; X = SCN, R = H) by perchloric acid-acetic acid. Compound (226; X = Br, R = Ac) by reaction with

U (224)

'lo

H . L. Herzog, J . Korpi, E. L. Shapiro, G. Teutsch, and L. Weber, J.C.S. Chem. Comm., 1973, 7 2 ; G. Teutsch, L. Weber, G. Page. E. L. Shapiro, H. L. Herzog, R. Neri, and E. J . Collins, J. Medicin. Chem., 1973, 16, 1370.

Steroid Synthesis

323

sodium azide in DMF or DMSO yielded (227 ; X' = N,, X2 = H) and only a little of the azide (227; X1 = H, X2 = NJ. Thermally induced allylic rearrangement of (226; X = N,, R = Ac) gave (227; X' = N,, X2 = H). Compound (226; X = Br, R = Ac) by reaction with potassium thiocyanate in DMF gave (227; X' = SCN, X2 = H). The 4-isothiocyanate (227; X' = NCS, X2 = H) was prepared in good yield by thermolysis of the 6-thiocyanate (226 ; X = SCN, R = H). The somewhat unstable analogue (228) of cortisone has been prepared.' 2 1

.:--i-""" CH,OH

I

H (228)

Functionalization of methyl groups by existing methods, lead tetra-acetate, lead tetra-acetate-iodine, and nitrite photolysis, has been used in a variety of syntheses. Progesterone has been converted into 19-norprogesterone' 2 2 and 18-hydroxyprogesterone into 18-hydroxydeoxycorticosterone (18,2l-dihydroxypregn-4-ene-3,20dione),' 2 3 a hypertensive agent. A 17a-methyl group was functionalized smoothly by utilizing a 12a-hydroxy-group.'24 The compound (229) obtained from the 18-methyl analogue by a lead tetra-acetate-iodine reaction gives on oxidation the 20-ketone ; this latter on silver acetate-methanol oxidation forms a mixture of the epimers (230), both of which undergo hydrogenolysis to form the (20s)-compound (231).'25 The (20R)-epimer is available by a mild base (DMF) cyclization of (229).

(231)

Pyrolysis of the diazo-alkane adducts (232) of A'6-20-oxo-steroids yields cyclopropanes (233)when R is unsaturated and not 16-substituted-A' 6-20-oxo-compounds.'26 The compound (234) has been ~ y n t h e s i z e d 'as ~ ~well as the compounds (235H237). "

''' 12'

125

126 12'

J. J. Schneider, J.C.S. Perkin I , 1973, 1361. R. E. Gall, J. E. Nemorin, and L. Tarasoff, J.C.S. Perkin I , 1974, 881. D. N. Kirk and M. S. Rajagopalan, J.C.S. Chem. Comm., 1974, 145. Ch. R. Engel, D. Mukherjee, and G. J. Beaudoin, Sjerords, 1973, 21, 857. P. Choay, C. Monneret, and Q. Khuong-Huu, Bull. SOC.chim. France, 1973, 1456. P. Bladon, D. R . Rae, and A . D. Tait, J . C . S . Perkin I , 1974, 1468. A. J. Solo, S. Eng, and B. Singh. J . Org. Chem., 1972, 37, 3542; A . J. Solo and J. N . Kapoor, J . Medicin. Chem., 1973, 16, 270.

Terpenoids and Steroids

324

(234)

(235)

(236)

(237)

Me OSiMe,

::1 (238)

The last compound (A4-3-ketone) has high progestational activity. The reduction of A' 4*'6-dien-20-ones (238) to A14-ene-20-ones (240) has been reinvestigated.' 28 The trialkylsilanes were slow reducing agents, the reagents of choice being Et,(EtO)SiH and (Me,SiH),O : the intermediate silyl ethers (239) could be isolated. The reacti01-1'~~ between phosgene and 1 1 -deoxycorticosterone yields the chlorine-containing carbonate (241)and only a little of the 21-chloro-compound (242). In the presence of an 11-carbonyl function the relative proportions are reversed. The 20-0x0-21-hydroxy side-chain has been incorporated in a number of small-ring systems.' 30 Hydroxy-ketones of type (244) without loss of the (243)can be transformed into 21-acyloxy-20-oxo-A16-steroids 1 1P-hydroxy-group by Mattox rearrangement and subsequent isomerization. A similar sequence of reactions employing 17-nitrate esters was also successful.' 3 1 170!,20a-Diols are smoothly oxidized to 17a-hydroxy-20-ketones (yields ca. 75 by the action of silver carbonate on celite. 17-Keto-steroids are also formed but in low (3-10%) yields. By contrast 17a,20,!3-diols are transformed exclusively into the 17-ketones.' 3 2 The action of trialkylboraqes (in the presence of oxygen) on Al6-2O-

x)

'' '"

'" 13'

3'

E. Yoshii, H. Ikeshima, and K . Ozaki, Chem. and Pharm. Bull. (Jupan), 1972, 20, 1827. M. L. Lewbart, J . O r g . Chem.. 1973, 38, 2328, 2335. R. Wiechert, M. Maikowski, G . A . Hoyer, and H. Laurent, Chem. Ber., 1973, 106, 882. H. Hofmeister, H . Laurent, and R. Wiechert, Chem. Ber., 1973, 106, 2263; H . Hofmeister, H. Laurent, G. A. Hoyer, and R. Wiechert, ihid., 1974, 107, 1235. J . Bastard. M. Fetizon, and J. C . Gramain, Tetrahedron, 1973, 29, 2867.

325

Steroid Synthesis CH,OH

I

CH,O,CR

ketones (245) yields the 16a-alkyl compounds (246).' 3 3 By-products of this reaction are the compounds (246) in which the group R is derived from the solvent (e.g. cr-tetrahydropyranyl). After some unsuccessful attempts to move a C-10 fl-methyl group to the 9P-position this was achieved134by the action of nitrous acid on the amine (247). In the process the bismethylenedioxy-grouping suffered selective hydrolysis and oxidation to yield the acid (248).

6 Seco-steroids The products obtained from the ozonlysis of cholest-4-en-3-one have been shown to be dependent on the solvent used; in acetic acid-ethyl acetate at - 15 "C a peroxysecocholestane (249) is produced whereas in acetic acid-ethyl acetate-water a mixture of (249) and the hemiacetal (250) r e s ~ 1 t s . I Testosterone ~~ and progesterone give analogous results. Thermal decomposition of the seco-derivative (249) yields the expected 5-keto-~-nor-3,5-secocholestan-3-oic acid. The latter seco-acid has been converted acid methyl ester and thence by reduction and into its 5,5-ethylene-dioxyacetal-3-oic hydrolysis into 5-oxo-3,5-seco-~-norcho~estan-3-ol, which exists almost completely in the tautomeric ring form (251).'36 It was noted that hydrolysis of the intermediate 133

134 135

136

A. Akhren, I . S. Levina, Yu. A. Titov, V. A. Khripach, Yu. N. Bubnov, and B. M. Mikhailov, Z . obshchei Khim., 1973,43, 2165. L. P. Makhubu, Z. G. Hajos, and G. R. Duncan, Canad. J . Chem., 1974, 52, 1744. G. Lefebvre, P. Germain, and R. Gay, Bull. SOC.chim. France, 1974, 173. J . T. Edward, M. Kaufmann, and R. K . Wojtowski, Canad. J . Chem., 1973, 51. 1610.

326

Terpenoids and Steroids

OHC (249)

(252)

5,5-ethyleneacetal with insufficient water led to the dimer (252). The same 5,5-ethyleneaceta~-~-nor-3,5-secocho~estan-3-oic acid methyl ester has been subjected to BarbierW ieland degradation to obtain the dinor-acid 5,5-ethylenedioxy-2,5-seco-~-norcholestan-2-oic acid,' 37 which was converted into the mixed anhydride (253) by hydrolysis of the acetal and treatment with ethyl chloroformate. Reaction of ammonia with the

anhydride (253) yields a hydroxy-lactam (254). The same 2,5-seco-acid was also converted into its acid chloride by reaction with triphenylphosphine in carbon tetrachloride, and the action of ammonia upon this acid chloride was to form either 5-oxo-2,5-seco-~-dinorcholestan-2-amide or the hydroxy-lactam (254), depending on the reaction conditions. The seco-spirostan (255) has been prepared by a standard procedure, and reaction with benzylamine converts it into the 4-aza-spirostan analogue (256). Sodium-alcohol reduction of the oxime of the keto-acid (255) yields the expected lactam, which was degraded by a conventional series of reactions to 4-aza-5a-pregn-16en-3,20-dione.' 3 8 Oxidation of cholesterol with hypoiodite (HgO and I,, under irradiation) leads to along with 10 each of the two oxetans the known 3,4-seco-4-iodocholest-5-en-3-al 13'

13'

G . H . Cooper and L. E. J. Moir, J.C.S. Perkin I, 1972, 2755. H . Singh, P. P. Sharma, and R. B. Mathur, I n d i a n J . Chem., 1973, 1 1 , 1254.

327

Steroid Synthesis H Me &75)

I

CHzPh

(255)

(256)

(257 ; 6a-iodo and 6p-i0do).'~~ Absorption of the 4-iodo-3,4-seco-steroid on to alumina gave, after elution, a single compound, namely 4-oxa-~-homocholest-5-ene.40 Treatment of the 1,2-epoxy-3-ketocholestanes(258; R = H, or CH,) with tosylhydrazine and sodium borohydride has been shown to lead to A-seco-acetylenic alcohols (259) The corresponding in 2204 (R = CH,) and 327! (R = H,) yields re~pective1y.l~~ la,3~-dihydroxy-2~-methoxy-4-substituted steroids accompany the seco-derivatives. The preparation of similar ene-yne-seco-derivativesfrom 1cr,2a-epoxycholest-4-en-3-one and 4~,5/3-epoxycholest-l-en-3-one was attempted but no clean products could be isolated. The formamido-2,3-seco-5a-cholestan-2,3-diones (260; R' = CHO, R 2 =

PhCH,; R' = CHO, R2 = Me; R' = Ac, R2 = PhCH,) have been synthesized from 2-(hydroxymethylene)-5or-cholestan-3-one,via the intermediates 2-formyl-5a-cholest2-ene and 2-(aminomethyl)-5a-cholest-2-ene. 42 Acetone-sensitized mercury-lamp irradiation of the 17a-ethynyl-17,5-dihydroxy-19nor-5a-androst-6-enes (261 ; R = H or OAc) leads to the corresponding B-seco-steroids ~ seco-derivative (262; R = OAc) was shown readily to (262; R = H or O A C ) . ' ~The

'

140 14'

14' 143

H. Suginome and K . Kato, Tetrahedron Letters, 1973, 4139. H. Suginome and K . Kato, Tetrahedron Letters, 1973, 4143. M. Weissenberg, D. Lavie, and E. Glotter, Tetrahedron, 1973, 29, 353. K. Oka and S. Hara, Tohoka Yakka Daigaku Nempo, 1973,255 (Chem. A h . , 1974,81,63 863). H. A. C . M . Keuss and J. Lakeman, J . C . S . Chem. Comm., 1973,480.

Terpenoids and Steroids

328

lose the elements of acetic acid to furnish the corresponding A3.'-5-ketone. A series of 9,ll-seco-steroids has been prepared commencing from oestradiol3-methyl ether. Oxidation of oestradiol 3-methyl ether with chromic anhydride leads to the 9-0XO9,ll-seco-derivative (263),reduction of which with borohydride affordsa mixture of the 9-hydroxy-analogues. The latter were not separated but were treated with selenous acid to yield the naphthyl-seco-steroid, 3-methoxy-17~-acetoxy-9,1 l-seco-oestra1,3,5(10),6,8-pentaen-ll-oic acid. The 170-acetyl group of this acid was further hydrolysed and oxidized to give the 17-keto-analogue, and this in turn was treated with ethynylmagnesium bromide to furnish the ethynyl-seco-derivative (264). Reduction of (264) with hydrogen and palladium led to the corresponding 17a-ethyl derivative. The D-seco-steroid (265) has been prepared by oxidation of 140-oestrone methyl ether it was identical with (+)-cis-doisynolic acid, thus confirming that the latter has the natural 8/3H,9ctH-~onfiguration. Oxidation was accomplished by converting 14a-oestrone into its enol acetate, which on periodate oxidation furnished a lactonol (266), reaction of which with diazomethane afforded a ~-seco-16-aldehydo-l7-ester. Electrochemical reduction of this aldehyde led to the 14a-ethyl function and hydrolysis gave the required acid (265). HO,C

OAc

(265)

The Beckmann rearrangement of oestrone-17-oxime brought about by heating the steroid in pyridine with 4-AcNHC,H4SO,Cl has been reported to yield the expected 1 7a -aza-o-homo-oestratriene along with the D-seco-nitrile (178; R1 = CH,, R2 = 144

145

J. H. Dygos and J. Chinn, J . Org. Chem., 1973, 38, 4319. J. Iriarte and P. Crabbe, J.C.S. Chem. Comm., 1972, 1 1 10.

Steroid Synthesis

329

CN).146 Other Beckmann fragmentations resulting in D-seco-steroids include the reaction of 3p,170-dihydroxy-16-oxaminoandrost-Sene with toluene-p-sulphonyl chloride in pyridine to give an almost quantitative yield of the unstable cyano-aldehyde (267), isolated as its dinitrophenylhydrazone. 14' The structure of the aldehyde (267) follows from its ready transformation into the known lactone (268; R = H,, X = 0). The photolysis of 3~-acetoxy-16,17-secoandrost-5-en-16,17-imide (268; R = 0, X = NH) yields the 13,16-seco-17-nor-derivative (269),148whilst photolysis of 3P-acetoxy-14flhydroxy-20-0~0-5a-pregn-16-ene in t-butyl alcohol affords the novel 14,15-secosteroid (270) whose structure was confirmed by an independent synthesis.149 R

COMe

Solvolysis of (E)-3~-tosyloxy-5,10-seco-l( lO)-cholesten-5-one (271 ; R = Ts) by sodium acetate in aqueous acetone has been shown to result in a novel cyclopropanyl5,lO-seco-steroid (272) in 32 % yield, along with the 3p-acetate (271 ; R = Ac) in 35 "/, yield and the corresponding alcohol (271 ; R = H) in 30'x yield. The solvolysis of the corresponding (E)-cholest-l(lO)-en-3a-tosylate also proceeds with cyclopropane ring formation but affords a 10-hydroxy-derivative (273) in 64 "/, yield. The solvolysis of the corresponding (2)-3a-tosyloxy-ester yields only the analogous 3a-acetoxy-derivative (274) in 90% ~ie1d.l~'The reaction of the seco-steroid (271 ; R = Ac) with hydroxylamine yields an interesting heterocyclic derivative with the isoxazolidine structure (275) in quantitative yield. The seco-steroid corresponding to (271; R = Ac), but with the (2)-configuration, does not undergo this reaction but merely yields the 5-oximinoderivative, since the trigonal C-5 carbon and the l(l0)-olefinic group are now too far apart to permit analogous internal cyclization.

146 147 148

14'

B. Matkovics, B. Tarodi, and L. Balaspiri, Acta Chim. Acad. Sci.Hung., 1974, 80, 79. D. MiljkoviC, J. PetroviC, M. StajiC, and M. MiljkoviC, J . Org. Chem., 1973, 38, 3585. R. P. Gandi, M. Singh, T. D. Sharma, and S . M. Mukherji, Tetrahedron Letters, 1973, 657. F. Marti, H. Wehrli, and 0. Jeger, Hefv. Chim. Acta. 1973, 56, 1078. L. Lorenc, M . J. GaSid, I. JuraniC, M. DaboviC, and M. Lj. MihailoviC, Tetrahedron Letters, 1974, 395. M. Lj. MihailoviC, L. Lorenc, Z . MaksimoviC, and J. Kalvoda, Tetrahedron, 1973, 29, 2683.

Terpenoids and Steroids

330

(273)

(274)

(275)

7 Cholestane and Analogues There have been several syntheses reported recently for la-hydroxycholesterol. In the first, 6~-hydroxy-Sa-cholest-l-en-3-one was treated with alkaline hydrogen peroxide to yield its corresponding 1r,2a-epoxide, borohydride reduction of which gave the diol (276 ; R = OH), partial acetylation furnishing the 3P-acetate (276; R = OAc). Dehydration with phosphorus oxychloride of the 6b-hydroxy-function gave the expected As-steroid, which upon lithium aluminium hydride reduction gave la-hydroxycholester01.'~~Further reaction of this diol, as its diacetate, with N-bromosuccinimide gave the corresponding 7-bromo-derivative7 which without isolation was dehydroIrradiation of this brominated with collidine to yield la,3~-diacetoxycholesta-5,7-diene. ring-B diene followed by thermal isomerization and saponification led to la-hydroxycholecalciferol (277; R = H). A similar procedure'53 has been used to convert 6pacetoxy-5a-cholest-l-en-3-oneinto la-hydroxycholesterol, again via the acetoxyalcohol (276; R = OAc), the overall yield for the transformation being 30"/,.

152

153

A . Fuerst, L. Labler, W . Meier, a n d K.-H. Pfoertner, Heit.. Chim. Acta, 1973, 56, 1708. M. Morisaki, K. Bannai, and N . Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1853.

Steroid Synthesis

33 1

A different approach to the synthesis of la-hydroxycholesterol is illustrated by the route commencing from the readily available cholesta- 1,4-dien-3-0ne.l~~ Deconjugation of this cross-conjugated dienone, using potassium t-butoxide in DMSO, yields the expected A1y5-3-ketone,which is subsequently reduced to yield A'-cholesterol. Diborane reduction of the A'-function yields the required la-hydroxy-steroid. However, by far the most attractive route to la-hydroxycholesterol combines the deconjugation and epoxide ring-opening steps into one reaction.' 5 5 Cholesterol is first converted (45 which upon reaction with a large excess yield) into la,2a-epoxycholesta-4,6-dien-3-one, of lithium and ammonium chloride in ammonia-THF is converted directly into 1a-hydroxycholesterol(60 :<) ;the reaction proceeds via the intermediate (278). Bromination of la-hydroxycholesterol diacetate, in this case by dibromodimethylhydrantoin, followed by dehydrobromination with trimethyl phosphite in xylene leads, as before, to la,3P-diacetoxycholesta-5,7-diene, which was converted into la-hydroxy-vitamin D, (277 ; R = H) by the usual route.

This latter synthetic sequence (eight steps) has also been used to convert 25-hydroxycholesterol into la,25-dihydroxy-vitamin D, (277 ; R = OH).'56 The sequence involves prior dehydrogenation of 25-hydroxycholesterol to its corresponding 1,4,6-trien-3-one (282), which is then epoxidized to yield la,2a-epoxy-25-hydroxycholesta-4,6-dien-3-one (283); reaction of this with lithium and ammonium chloride in liquid ammonia yields directly 1a,25-dihydroxycholesterol(284), the key intermediate for the synthesis of (277 ; R = OH). A more conventional route to la,25a-hydroxycholesterol commencing from 6P,25-dihydroxycholesterol has been reported ; l 57 this proceeds via the intermediate A'-3-keto-6-acetoxy-steroid along the lines already described above. Perhaps the most practical route to large quantities of la,25-dihydroxycholesterol,however, is from fucosterol (279), an abundant sterol in brown algae."' The route (Scheme 12) transforms fucosterol(279) into desmosterol(280) and thence by the elegant Barton' 5 5 procedure into the final product (284). A twenty-four step sequence has been described'59 for the conversion of isohomocholanic acid methyl ether (285) into la,25-dihydroxycholecalciferol(277; R = OH). The retro-cyclo-steroid reaction with (285) resulted in the As-3P-hydroxy-derivative, which, after conversion into its ethyl ester, was subjected to the nitration-reduction 154 155

156 157

158

159

C. Kaneko, S. Yamada, A . Sugimota, and M. Ishikawa, Tetrahedron Letters, 1973, 2339. D. H. R. Barton, R . H . Hesse, M. Pechet, and E. Rizzardo, J. Amer. Chem. Soc., 1973, 95, 2748. D. H . R . Barton, R . H . Hesse, M. Pechet, and E. Rizzardo, J.C.S. Chem. Comm., 1974, 203. J . Rubio-Lightbourn, M. Morisaki, and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1973, 21, 1854. M. Morisaki, J . Rubio-Lightbourn, N. Ikekawa, and T. Takeshita, Chem. and Pharm. Bull. (Japan), 1973,21, 2568. E. J. Semmler, M. F. Holick, H. K. Schnoes, and H . F. De Luca, Tetrahedron Letters, 1972, 4147.

Terpenoids and Steroids

332

1“

Reagents: i, 0 , ;ii, NaBH,; iii. P,O,; iv, Hg(OAc)?-NaBH,; v, dichlorodicyanobenzoquinone; vi, H 2 0 2 - N a O H ; vii, Li-NH,.

Scheme 12

I

OMe

sequence to introduce the 6-keto-function. This was subsequently acetalized, and reaction of the ester function with Grignard reagent then resulted in the formation of 3P,25-dihydroxy-5a-cholestan-6-one ethylene acetal. Oxidation of this 3P-alcohol to its 3-ketone was followed by conversion into the A’-3-keto-steroid via the 2P-bromoderivative, and epoxidation led to the corresponding ln.3P-diol. Thereafter this synthesis follows the conventional route to the vitamin D, derivative (277; R = OH) via the intermediates 1a,3P-diacetoxy-6~,25-dihydroxy-5a-cholestane and la,3Pdiacetoxy-25-hydroxycholest-5,7-diene.More recently the introduction of the lahydroxy-group into 25-hydroxycholesterol has been accomplished160 by a reaction sequence commencing with hydroboration-oxidation at A5, Jones oxidation, and acetalization to yield the intermediate 25-hydroxy-3,3-dimethoxy-5a-cholestan-6-one. Borohydride reduction of the 6-keto-functioq acetal hydrolysis, bromination, and 160

T. A. Narwid, J. F. Blount, J. A. Iacobelli, and M. R. Uskokovic, H e h . Chim.Acta, 1974, 57, 781.

Steroid Synthesis

333

1

OMS

(286)

dehydrobromination afforded a A'-3-ketone, which was epoxidized and mesylated to yield the intermediate (286). Epoxide-ring cleavage with aluminium amalgam gave the la-hydroxy-3-keto-steroid, which was reduced and treated with lithium carbonate in DMF to yield the lc(,3P,25-triol(284). A synthesis of 24,25-dihydroxycholecalciferol has been reported,I6' also commencing from desmosterol (280). Successive hydroxylation, acetylation, bromination, and dehydrobromination led to the isolation of the intermediate 24,25-dihydroxy-38acetoxycholesta-5,7-diene, which was irradiated, isomerized, and saponified to yield a 1 : 1 mixture of (24R)- and (24S)-24,25-dihydroxycholecalciferol.In a similar sequence of reactions 3P,25,26-trihydroxycholest-5,7-diene, prepared from 3fl-acetoxy-5a-cholest25-ene, was converted into 25,26-dihydroxychoIecaIciferol.1 6 * A simple synthesis of 25-hydroxy-5a-cholestanyland 25-hydroxycholesteryl 38acetates has been reported.' 6 3 Irradiation of a solution of 3P-acetoxy-Sa-cholestane in peracetic acid yields a mixture of the 25-hydroxy- and 5a-hydroxy-cholestanes (287 ; R' = OH, R 2 = H) and (287; R' = H, RZ = OH). Subsequent irradiation in peracetic acid solution of the steroid (287; R' = H, R2 = OH) affords the 5al25-diol (287;

I

OMe

I6I L62

163

J. Redel, P. Bell, F. Delbarre, and E. Kodicek, Compt. rend., 1974, 278, D , 529. J . Redel, P. Bell, F. Delbarre, and E. Kodicek, Compt. rend., 1973, 276, D , 2907. A. Rotman and Y . Mazur, J.C.S. Chem. Comm., 1974, 15.

334

Terpenoids and Steroids

R' = R 2 = OH), which after trichloroacetylation, elimination of the 5a-trichloroacetate by reaction with toluene-p-sulphonic acid, and saponification yields 25-hydroxycholesterol. This latter steroid has also been prepared in an overall yield of 30% from s t i g m a ~ t e r o l ,the ' ~ ~key transformations being the ozonolysis and reduction of cyclostigmasteryl-6-methyl ether to yield the (hydroxymethy1)cyclopregnane (288 ; R = OH) ; conversion of this steroid into its iodide (288; R = I), followed by reaction with (R = tetrahydr0-2H-pyranyl)~yielded the cyclopregnyne (289). LiC?C-CMe,OR' Reduction of (289) followed by retro-i-steroid rearrangement afforded 25-hydroxycholesterol. A simple, one-step synthesis of(25S)-16~,26-dihydroxycholesterol has been achieved' 6 5 by the Clemmensen reduction of the spirostane yamogenin (290; R1 = OH, R 2 = H); further reduction with platinum oxide leads to (25s)-16P,26-dihydroxy-5a-cholestan3P-01. The supposed route to 3~-methoxy-5a-cholestane-4~,5-diol, based upon the acid-catalysed cleavage of 4a,5-epoxy-3~-methoxy-5a-cholestane, has been shown not to be valid;'66 the product from this reaction is the allylic alcohol 3P-methoxycholest5-en-4a-01. A valid synthesis of the 3~-methoxy-4P75a-diol is reported. H

I Me

A novel method of inverting sterol configurations has been described;'67 it is based upon reaction of the alcohol with triphenylphosphinediethyl azodicarboxylate in THF in the presence of an acid such as benzoic or formic. Transformations reported include 5a-cholestan-3~-01to the 3a-01 formate (97 %) or to the 3a-01 benzoate (100 %) and methyl 3a,l2a-dihydroxycholanateto the corresponding 3P-formyloxy-derivative (97 " ,)). Under these reaction conditions 5a-cholestan-3a-01 does not react. The reaction of sterols with N-halogeno-imides in the presence of triphenylphosphine or triphenyl phosphite allows for the replacement of hydroxyl by halogen, also with stereochemical inversion.'68 Thus 3P-hydroxy-5a-cholestaneyields 3a-bromo-5aand 3a-hydroxy-5a-cholestane can be converted into its 3P-bromocholestane (98 derivative (80 whilst 5~-androstan-3P-01-17-one yields its 3%-chloro-analogue in 92 yield. O,,),

x),

"(>

lh4

Ih5 lh6 lh7

lh8

J . J . Partridge, S. Faber, and M. R. Uskokovic, Hela. Chim. Acra, 1974, 57, 764. R. Tschesche, Y. Saito, and A. Topfer, Tetrahedron Letters, 1974, 967. T. H . Campion and G . A. Morrison, Tetrahedron, 1973, 29, 239. A . K . Bose, B. Lal, W. A. Hoffman, and M. S . Manhas, Tetrahedron Letters, 1973, 1619. A. K . Bose and B. Lal, Tetrahedron Letters, 1973, 3937.

Steroid Synthesis

335

A selective bromination of ctp-unsaturated ketones has been described monobromination of cholest-4-en-3-one with 2,4,4,6-tetrabromocylcohexan-2,5-dienone gives a mixture of two products, 2a-bromocholest-4-en-3-one in the chair conformation (major) and the 2ct-bromo-enone in the boat conformation (minor). The structure of the minor product was supported by its strongly negative Cotton curve, and conformational change from boat to chair form was observed to take place in solution, even in the absence of acid. Bromination of 5,6a-cyclo-5a-cholestan-3-onewith phenyltrimethylammonium perbromide has been shown to afford the corresponding 2a-bromo-steroid, but similar bromination of 3ct,5-cyclo-5a-cholestan-7-oneresults in the formation of 3P-bromocholest-5-en-7-0ne.'~~In the latter case the bromine atom is forced to take the aposition adjacent to the cyclopropyl ring, and this unstable ct-bromo-ketonedecomposes. Allylic bromination of stigmasteryl acetate with N-bromosuccinimide followed by collidine dehydrobomination has been shown to result in a 25 % yield of 7-dehydrostigearlier methods report only 1-2 % yields for this synthesis. mastery1 acetate The reaction of 5a-cholestan-3-one with ethyl cyanoacetate has been shown' 72 to yield an alkylidene cyanoacetate which upon reduction yields a chromatographically separable mixture of the 3a- and 3P-substituted steroids (291) in the ratio of 5 : 1. Alkaline hydrolysis followed by re-esterification leads to the corresponding 3a- or 3P-methyl acetates or the 3a- or 3P-dimethyl malonates, depending on the reaction conditions used.

HC

I

C0,Et

(291)

Work has continued on the remote oxidation of steroids by photolysis of attached benzophenone groups (see p. 275). 5 8 Steroid esters of benzophenonecarboxylic acid (138; II = 0), benzophenoneacetic acid (138; n = l), and other homologues (138;

16'

170 17'

V . Calo, L. Lopez, G. Pesce, and P. E. Todesco, Tetrahedron, 1973, 29, 1625. V. Cerneg, Coll. Czech. Chem. Comm., 1973, 38, 1563. H . W. Kircher, W. Henry, and F. U . Rosenstein, J . Org. Chem., 1973,342259. D. Kontonassios, C. Sandris, and G . Tsatsas, Bull. SOC.chim. France, 1973, 622.

Terpenoids and Steroids

336

n = 2 or 4) have been prepared, and on photolysis various of these esters undergo intramolecular attack by the benzophenone on the steroidal hydrogens. The derivative (138;n = 0)does not functionalizethe steroid at all whereas irradiation of the homologue (138; n = 1) yields 55:/; of the A14-steroid. With the benzophenone-4-propionic acid (138: n = 2), a new process emerges in that direct irradiation yields 35"/:',of the A14olefin, but this product is accompanied by a 50"; conversion into a product mixture (292), formed by direct insertion of the benzophenone carbonyl into the steroidal C-H bonds. Cleavage of the mixture (292)by lead tetra-acetate gives A8(14)-cholesten3m-01 (30 ')()) and a mixture of A6- and A'-cholesten-3a-01s. Functionalization of C-14 can also be effected upon irradiation of the steroidal derivative (293), itself formed by treating the p-iodophenylacetate of 3a-cholestanol with chlorine.59 The reaction mixture contains A14-cholestenyl-3a-acetate (53 :/;J, the corresponding A9(' ')-isomer ( 5 %), and A5-isomer (0.8 %), along with unreacted cholestan-3a-01 acetate (20%). Remote oxidation using the derivatized cholestanol (294)affords A9(l ')-cholestenyl-3macetate (43 'A) and only a 9 "{) yield of the isomeric A14-steroid.

(293)

(294)

An improved synthesis of 5m-cholest-8(14)-en-7-onehas been reported ;'7 3 treatment of 5x-cholest-7-ene with a peracid gave a chromatog1aphically separable mixture of 7x-hydroxy-5a-cholestan-8a,9a-oxide and the isomeric Q S I ,1 4m-oxide. Acid-catalysed rearrangement of the epoxide mixture yielded, again after chromatography, 5a-cholest8( 14)-en-7-one (25 ",) and 9a-hydroxy-5a-cholestan-7-one.A small quantity of the previously unobserved 5a-cholest-8(14)-en-15-one was also isolated. Reduction of the 8(14)-en-7-onewith lithium in liquid ammonia was shown unexpectedly to generate the saturated 7-ketone with the unnatural 14P-configuration. A synthetic route to other 8(14)-en-15-oneshas been recorded' 7 4 and involves the reaction of mercury(I1) acetate with A14-steroids. Thus when 5m-ergost-14-ene and 3fi-hydroxy-5a-ergost-14ene acetate are treated with mercury(r1)reagent they are converted into 5cc-ergost-8(14)en- 1 5-one and 3P-hydroxy-5a-ergost-8(14)-en-15-one respectively. An investigation has been ~ n d e r t a k e n 'of ~ ~the reaction of thallium salts with the carbonyl function of steroids. Thus when thallium triacetate reacts with either A'-3keto- or A4-3-keto-steroids the corresponding 1,4-dien-3-ones result (seven examples are given) in yields of 43-78 %. The action of this reagent upon 5a-cholestan-3-one, however, results in the formation of 2a-methoxycarbonyl-~-nor-5a-cholestane (after esterification of the initially formed acid). A novel synthesis of 5a-cholestan-1,3-dione has been accomplished by oxidation of the enol ester 3-benzoyloxy-5a-cholest-2-ene, using a mixture of sodium chromate in

"' 175

I . Midgley and C . Djerassi, J.C.S. Perkin I , 1973, 155. E. C . Blossey and P. Kucinski, J.C.S. Chem. Comm., 1973, 56 A . Romeo and G . Ortar. Tetrahedron, 1972, 28, 5337.

337

Steroid Synthesis

acetic acid, acetic anhydride, and carbon tetrach10ride.l~~Hydrolysis of the intermediate 3-benzoyloxy-5ax-cholest-2-en-l-one leads directly to the 1,3-dione. The structure previously assigned to cholestane-3,4,6-trione has been reinvestigated,' and this compound is now shown to consist of a mixture of the 3-ethyl ethers of the and 3-ethoxycorresponding dienols, i.e. 3-ethoxy-4-hydroxycholesta-2,4-dien-6-one 6-hydroxycholest-2,5-dien-4-one. Slow hydrolysis of the two enol ethers leads to the 'triketone', isolated again as a tautomeric mixture of two dienols. The tautomers may be separated by fractional crystallization. As an alternative method of reducing 3- and 6-ketones to their corresponding 3pand 6p-alcohols, the reagent aminoiminomethanesulphonic acid (thiourea SS-dioxide) has been investigated ;l 7 8 yields are ca. 84-90 7;. Reaction of cyanoborohydride in the presence of ammonium acetate, methylamine, or dimethylamine is reported to reduce 5a-cholestan-3-one to the 5a-cholestan-3~-amineshaving 3P-NH2, 3p-NHMe, and 3P-NMe2 respectively 7 9 cyanoborohydride used alone has been shown to reduce the and 5a/5bunsaturated steroids cholest-4-en-3-one, 3~-acetoxycholest-5-en-7-one, cholest- 1 -en-3-one to mixtures of their saturated and allylic the proportion of product from 1,2-addition increasing as the pH of the reaction is lowered. An evaluation of the synthetic routes to As-3-keto-steroids (variously substituted at C-17) has been made.18' The reagent of choice for the oxidation of the A5-3,!3-alcohol function has been shown to be dipyridinechromium trioxide in methylene chloride ; I s 2 eight examples of this oxidation are given and purities of greater than 99 % are recorded for the resulting As-3-ketones. A synthetically useful reaction has been noted to take place when cholesta-3,5-dien-7one is heated in the presence of air in a solvent (e.g.xylene) that has readily abstractable Free-radical autoxidation leads directly to 3a,4a-epoxycholesthydrogen atoms. 5-en-7-one (31%) by oxidation of the $-bond. A novel procedure for converting epoxides into allylic alcohols involves reaction of the oxide with a selenium anion (e.g. PhSe-); the nucleophile opens the oxide ring to yield a hydroxyselenide, which is not isolated but is further oxidized by hydrogen peroxide to an unstable selenoxide, which in turn decomposes to the (E)-allylic Thus 5a-cholestane 2a,3a-oxide is converted into 3a-hydroxy-5a-cholest-1-ene and the corresponding 2p,3P-oxide is converted into 2~-hydroxy-5ax-cholest-3-ene (40 and 50 c:yields respectively) A synthesis of the 19-nor-enone (295; R = 0)has been described185via hydrolysis of the corresponding oxime (295 : R = NOH), itself obtained in 45 o', yield from photolysis of 3~-acetoxycholest-5-en-19-olrlitrire. A 20 7; yield of 3p-acetoxy-19-norcholesta1(10),5-diene is obtained during the initial photolysis reaction. The photolysis of 0-cholesteryl thiobenzoate has been shown to afford a quantitative yield of cholesta-

;'

'

"' R. Mechoulam, K . Lutcher, and A. Golabaum, Synthesis,

1974, 363. 1972, 1358. J. E. Herz and L. A. de Marquez, J.C.S. Perkin I , 1973, 2633. M. H . Boutigue and R. Jacquesy, Bull. SOC.chim. France, 1973, 750. M . H. Boutigue, R . Jacquesy, and Y . Petit, Bull. Soc. chim. France, 1973, 3062. J . B. Jones and K . D. Gordon. Canad. J . Chem., 1972, 50, 2712. J . C. Collins, W. W. Hess, and F. J. Frank, Tetrahedron Letters, 1968, 3363. H . Hart and P. B. Lavrick, J . O r g . Chem., 1974, 39, 1793. K . B. Sharpless and R . F. Lauer, J . Amer. Chem. Snc., 1973, 95, 2697. Y . Watanabe and Y-.Mizuhara, J.C.S. Chem. Comm., 1973, 752.

"' J. T. Pinhey and E. Rizzardo, J.C.S. Perkin I , ln0 la'

In2 la3 la4

lR5

338

Terpenoidsand Steroids

AcO

R

3,5-diene but similar photolysis of 0-cholestanyl thiobenzoate proceeded only slowly to give a mixture of S-cholestan-3a-yl and S-cholestan-3P-yl thiobenzoates.ls6 In connection with the large number of papers recently published dealing with novel naturally occurring marine sterols, there has been a major effort to improve synthetic routes to variously elaborated cholestane side-chains. Syntheses of 5a-cholesta-7,24dien-3P-01 (300) and cholesta-5,7,24-trien-3fi-ol (304) have been devised according to Schemes 13 and 14 respectively.'*' The hydrogenation of ergosteryl benzoate (296)

\ B

7

0

M

1

iii. iv

(297)

(296)

V

t

Reagents:

H,-(Ph,P),RhCI; ii. O,, reductive work-up; iii, NaBH,; iv, CBr,-PPh,; Me,C =CHCH,Br-Mg.

I,

v,

Scheme 13

yields the 7,22-diene (297), in near quantitative yield, and ozonolysis of this diene produces the 23,24-dinor-22-aldehyde (298). Reduction and bromination furnish the 22-bromo-steroid (299), which on coupling to ?,it-dimethylallyl bromide results in the required 7,24-diene (300). The final coupling reaction also results in the formation of some 20-methyl-5a-pregn-7-en-3P-01. Cholesta-5,7,24-trien-3fl-ol (304) was prepared from the 26-nor-25-ketone (301) according to Scheme 14. The critical step in this route is the dehydration of the tertiary alcohol (303) without disturbing the homoannular diene in ring B ; dehydration by (methyl carboxysulphamoy1)trimethylS. Achmatowicz, D. H . R. Barton, P. D. Magnus, G. A . Poulton, and P. J . West, J.C.S. Perkrn I , 1973. 1567. J. P. Moreau, D. J. Aberhart, and E. Caspi, J . O r g . Chem., 1974, 39, 2018.

Steroid Synthesis

339

(304)

(305)

(303)

Reagents: i , NBS-collidine; ii, M e M g l , reacetylation; iii, Me0,CNS02NMe3

Scheme 14

ammonium hydroxide inner salt gave a mixture of the trienes (304)and (305),which were chromatographically separable. New syntheses of the A5,22-cis-and A5’22-trans-C,,and -C27 sterols dimethyl-24cholesta-5,22-dien-3/J-o1(307) and (308) and cholesta-5,22-dien-3P-ol (309) and (310) have been formulated,’ commencing from 3~-acetoxycholenicacid (306). Decarboxylation of the acid (306) by reaction with lead tetra-acetate and cupric acetate led to the 5,22-diene, in which the 5-double bond was protected by conversion into the 6b-acetoxy3,s-cyclo-steroid prior to ozonolysis of the 22-double bond to yield a 22-aldehyde of type (298). Two separate Wittig reactions of the 22-aldehyde with isobutyltriphenylphosphonium bromide and isoamyltriphenylphosphonium iodide led respectively to the cis- and trans-steroids (307), (308) and (309), (310). Each isomer could be obtained pure after chromatography. The retrocyclo-steroid reaction applied to each yielded the four parent A5,22-sterols.A similar sequence of reactions has been employed in the

’’

0

(309) 188

(310)

A. Metayer, A . Quesneau-Thierry, a n d M . Barbier, Tetrahedron Letters, 1974, 595.

340

Terpenoids and Ster0id.y

synthesis of asterosterol(31 l),a marine sterol isolated from asteroids. Wittig condensation of isobutyltriphenylphosphoniumbromide with (20S)-3fi-acetoxypregn-7-ene-20carboxaldehyde results in the formation of a chromatographically separable mixture of the trans-7,22-diene (311) and its corresponding cis-7,22-isomer.' 89 The C,, marine sterol trilns-24,24-dimethp1-5a-chol-22-en-3P-o1 (311 ; ring B saturated) has been synthesized for the first time. 90 3/j-Hydroxychol-5-en-24-oic acid (306)was acetylated and reduced to yield 3/~-acetoxy-5r-cholan-24-oicacid, which was oxidatively decarboxylated with lead tetra-acetate-cupric acetate to form the corresponding 22-olefin. Ozonolysis of this olefin and Wittig reaction between the resultant aldehyde and isobutyltriphenylphosphonium bromide afforded trans-24,24-dimethyl-5a-chol-22-en-3~01 ; 1 9 " again the major product of this reaction is the corresponding AZ2-cis-isomer, which has also been fully characterized. 19'

'

(312)

(313)

liii

Reagents : i, EtC ECH-Et MgBr; ii, Lindlar catalyst-H, ; iii, I-(dimethylamino)-I -methoxypropI-ene; iv. LiAlH,; v, H , O , .

Scheme 15

A synthesis of the naturally occurring plant steroid (24S)-24-ethylcholest-5,22.25trien-3p-01 (317) and its (24R)-epimer has been described'92 (Scheme 15). Reaction of

''I

M. Kobayashi, K . Todo, and H . Mitsuhashi, Chem. and Phurm. Buff.(Japan), 1974, 22, 236. A. Metayer and M . Barbier, Campt. rend., 1973, 276, C , 201. A . Metayer and M . Barbier. J . C . S . Chem. Comm., 1973, 424. W . Sucrow. P. P. Caldeira, and M . Slopianka, Chcm. Ber., 1973, 106, 2236.

Steroid Synthesis

34 1

the aldehyde 3P-acetoxy-22,23-dinorchol-5-ene aldehyde (312) with 1-butynylmagnesium bromide gave a chromatographically separable mixture of the (22s)- and (22R)-butynyl carbinols (313), and further reaction of the (22s)-isomer with Lindlar catalyst and hydrogen resulted in the A5,23-diene(314). Reduction of the (22R)-isomer of (313) with lithium aluminium hydride furnished (22S)-27-norcholesta-5,23t-diene3P,22-diol. Claisen rearrangement of the intermediate (314) with 1-(dimethylamino)-1methoxyprop- 1-ene gave two epimeric amides, the (24S,25R)-(315)and (24S,25S)-isomers, which after separation and further reduction afforded the corresponding amines (316). Oxidation to the amine oxide followed by a Cope rearrangement resulted in the formation of the required triene (317). Hydrogenation of this triene using triphenylphosphinerhodium catalyst leads to selective hydrogenation of the A2'-bond and formation of porifasterol. Similar hydrogenation of the (24R)-isomer of (317) leads to stigmasterol. Routes to three steroidal 4,22,25-trien-3-ones (318) have been described by way of Wittig reactions on 3-oxo-23,24-dinorcho1-4-en-22-a1.'"3 Using the reagents (R = H, Me, or Et), access is obtained to the cholestane MeC(=CH,)CH,C(=PPh,)R series (318: R = H), the ergostane series (318; R = Me), and the stigmastane series (3 18 ; R = Et), respectively.

Two new syntheses for desmosterol (280) have been recorded. In the first,'94 38acetoxychol-5-en-24-oic acid (306) was converted into its diazo-ketone and thence by Wolff photochemical rearrangement to the homologue, 3P-acetoxychol-5-ene-24carboxylate. Reaction of the latter with methylmagnesium iodide followed by dehydration resulted in a high yield of pure desmosterol(280). The second route'95 commences from methyl 3-hydroxybisnorcholenate (319). Initial protection of the 3P-hydroxy-A5system by the cyclo-steroid reaction was followed by reduction to the 21-alcohol, which was in turn converted into its 21-iodo-derivative via a 21 -tosyloxy-intermediate. Reaction of the 21-iodide with (~r-dimethylallyl)nickelbromide and retrocyclo-steroid reaction completes the route to desmosterol (280). Desmosterol, stigmasterol, and lanosterol have each been treated with dichlorocarbene (generated from chloroform in the presence of strong alkali in the presence of catalytic amounts of triethylbenzylammonium chloride) and the initial adducts then reduced with lithium in t-butyl alcohol.'94 The reaction products were 24,25methylenecholest-5-en-3P-01, 22,23-methylenestigmast-5-en-3P-o1, and 24,25-methylenelanost-8-en-3P-01respectively. The reaction of stigmasteryl acetate with dichlorocarbene, however, has been reported by other workers'96 to give only the 5P,6P-adduct, the 22-double bond remaining intact after the reaction. Dichlorocarbene has beea 193 194

196

R . Ikan and R . Gottlieb, Synth. Comm., 1973, 3, 407. R . Ikan, A. Markus, and Z . Goldschmidt, J.C.S. Perkin I , 1972, 2423. S. K . Dasgupta, D. R . Crump, and M . Gut, J . Org. Chem., 1974, 39, 1658. Y . M. Sheikh, J . Leclercq, and C. Djerassi, J . C . S . Perkin I , 1974, 909.

342

Terpenoids and Steroids

shown to react similarly with the 5,6-double bond of cholesteryl acetate '(from the fi-face) and with the 7,g-double bond of both Sa-cholest-7-en-3P-yl acetate and 5aergost-7,22-dien-3P-yl acetate (from the a-face). In the latter case the 22-double bond was again unaffected by the dichlorocarbene. Reaction of 24-methylcholest-5,22-dien3P-yl acetate (brassicasterol) with dichlorocarbene followed by reduction with lithium in ammonia gave four compounds, Sfi,6P-methylene-ergost-22-en-3p-01, 24,24-dimethylcholesta-5,22-dien-3~-ol, 5/l,6P : 22,23-dimethylene-ergostan-3P-o1,and the mono-addition product (320). The 22,23-cyclopropano-steroid(320) was found to differ from the naturally occurring marine sterol (22R,23R,24R)-demethylgorgosterol in its stereochemistry at C-22 and C-23.

A synthesis of 26-methyl-24-methylenecholesterol(321 ; R = CH,) has established this structure for 24,28-didehydroaplysterol, isolated from the sponge uerongia aerophoba. 9 7 The reaction between 3P-acetoxycholenyl chloride and di-s-butylcadmium afforded the ketone (321; R = 0),which was converted into its methylene analogue (321 : R = CH,) by a Wittig reaction. The presence of an 'extra' carbon atom in the normal cholesterol skeleton at C-26 is without previous parallel among naturally occurring sterols.

(321)

(322)

,

The Wit tig reaction bet ween Bu P =CMeCH CO, Me and 3fi,16a-diacetox y- 5aandrostan-17-one has been successfully used to obtain the 16-0x0-24-norcholanate (322; R' = CO,Me, R 2 = 0),the synthesis being completed by hydrogenation of the initially formed olefin and oxidation of the 16-hydroxy-group.' 98 An improved synthesis of 3r,7~,12a-triacetoxy-5~-cholan-23-al (322; R' = CHO, R2 = H,) has been described ;'99 the reaction between methyl cholate and phenylmagnesium bromide gives the intermediate (322: R' = CH=CPh ,, R - H,), which upon subsequent "' P. De Luca, M . de Rosa, L. Minale, R . Puliti, G. Sodano, F. Giordano, and L. Mazzarella, J.C.S. Chem. Comm.. 1973, 825. I Y R A . Scettri. E. Castagnino, and G. Piancatelli, Gazzerta, 1974, 104, 437. '" Y . Shalon and W. H. Elliot, S y n f h . Comm., 1973, 3, 287.

Steroid Synthesis

343

oxidation with ruthenium tetroxide in carbon tetrachloride yields the desired 23aldehyde (322 : R' = CHO, R2 = H2). The highly functionalized side-chain of antheridiol(323), a mould sex hormone, is an example in which the side-chain of the most probable precursor, fucosterol (279), has been extensively modified. It has been synthesized2" in 20% overall yield by a route involving the aldol condensation of 3P-acetoxy-22,23-bisnor-A5-cholenaldehyde (3 12) and the carbanion of P-isopropylbut-2-enolide (324), ihereby yielding 7-deoxy-7dihydroantheridiol. Photo-oxidation and rearrangement completes the synthesis of I

antheridiol(323). The major product from the initial aldol condensation reaction is in fact the (22R,23S)-isomerof 7-deoxy-7-dihydroantheridio1, but this can be converted into the desired (22S,23R)-isomerby Jones oxidation to the (23S)-22-ketone.followed by autoxidation and borohydride reduction. A synthesis of the 23-hydroxy-&lactonic isomer (329) of antheridiol is outlined in Scheme 16.201 The initial epoxidation of the A5.22-24-ketone(325) leads only to the (22S,23R)-epoxide(326), and Wittig reaction of this 24-ketone with the carbanion of diethyl(ethoxycarbony1methyl)phosphonategenerates the 24-ethoxycarbonylmethylene side-chain (327), with the (E)-configuration. The d-lactone (328) is rapidly formed in quantitative yield by treating (327) with aqueous perchloric acid. The synthesis of the final product (329) is completed by haematoporphyrin-sensitized photo-oxygenation and oxidative rearrangement. A stereoselective synthesis of 5~,6[~-epoxy-l-oxocholest-2-en-4~-ol has appeared as a model of the steroid withaferin A (330), a member of a new series of naturally occurring C,, steroidal lactones.202 Acetylation at C-3 of 1a-hydroxycholesterol followed by Jones oxidation led to isolation of cholesta-2,5-dien-1-one in 55 "/, yield. Peroxidation of this dienone gave the 5a,6a-oxide accompanied by some undesired 5P,6P-oxide, but the latter could be converted into the former by opening to the 5a,6P-diol and then ringclosing the 5a-hydroxy-6fl-mesylate. Base-catalysed opening of the 5a,6fl-epoxidegave 6a-hydroxycholesta-2,4-dien-l-one which was converted into its 6~-mesylateprior to oxidation with osmium tetroxide to yield 4a,5~,6a-trihydroxycholest-2-en-l-one 6-mesylate. Ring closure of the latter derivative by base gave the desired 58,6P-epoxy-loxocholest-2-en-4P-01. 2oo 202

T. C . McMorris, R. Seshadri, a n d T . Arunachalam, J . O r g . Chem., 1974, 39, 669. C . R.Popplestone and A. M . Unrau, Canud, J . Chem., 1973,51, 1223. M. Ishiguro, A. Kajikawa, T. Haruyama, M. Morisaki, and N. Ikekawa, Tetrahedron Letters, 1974. 1421.

344

Terpenoidr and Steroids 0

C0,Et

&

(325)

jiii

HO (329) Reagents:

1. H,O,-NaOH; 11, Et,POCH,C02Et-NaNH,; sensitized photo-oxidation; v, cupric acetate.

iii HClO,, aq.; lv, haematoporphyrin-

Scheme 16

w OH

(330)

Finally, a convenient synthesis of 5a-cholest-2-en-6-one has been described ;'03 reaction between cholesterol and diborane, followed by refluxing in triglyme prior to hydrogen peroxide oxidation, affords 5cr-cholest-2-en-6cr-01, which is readily oxidized to the required A2-6-ketone. Many syntheses have been reported leading to heterocyclic derivatives of cholestanes. truns-Diaxial ring-opening of N-cyanoaziridines has been studied204with a variety of '04

E. B. Byall and F. T. Bond, Sl.nth. Comm., 1972, 2, 357. K . Ponsold and W. Ihn, Teirczhedron Letters, 1972, 4121.

345

Steroid Synthesis CN

l

(331)

nucleophiles ; thus when 2~,3p-(cyanoirnino)-5a-~holestane reacts with thiocyanate ion the heterocyclic derivative (331) is produced by ring closure of the intermediate 3athiocyanato-2~-cyanoamino-steroid. The condensation of oxindole or 1-methyloxindole has been d e m o n s t ~ a t e d ~to~ ' give rise with 2-hydroxymethylene-5~-cholestan-3-one to the pyrano[2,3-b]indolium salt systems (332; R = H) or (332; R = Me) respectively. Direct oxygenation of 5a-cholestan-3-one in the presence of t-butoxide, followed by reduction with borohydride, results in the formation, in 557; yield, of 3-oxa-5crcholestan-2-one ; similar autoxidation of SP-cholestan-3-one yields a mixture of 4-oxaThe reaction between 7-dehydro5a-cholestan-3-one and 3-0xa-5~-cholestan-4-one.~~~ (azido lead acetate) has been shown207 cholesteryl benzoate and Pb(O+), -n(N3)n (50%) and 3pto give a mixture of 3fi-benzoyloxy-5a,l4a-diazidocholest-7-en-6-one benzoyloxy-5a-azidocholest-7-en-6-one (25 %). Under the same conditions cholesta3,5-diene is converted into 3a,6fi-diazidocholest-4-ene (40 %) and 6p-azidocholest-4en-3-one (6%) whereas similar treatment of cholesterol itself results in the seco-steroid (333; R = H). 3fi-Methoxy-7a-azidocholest-5-ene is transformed into the seco-steroid (333; R = N3) under these reaction conditions and is itself converted either into the heterocyclic steroid (334) or into (335) upon hydrogenation,208 depending on the conditions used.

Three side-chain degradation procedures are worthy of mention. In the first, a fourstep sequence enables methyl cholanate or methyl lithocholate (306; methyl ester) to be converted into their corresponding 5P-pregnan-20-ones in yields of 35 and 27 % respectively ;'09 these yields are significantly higher than those previously reported. Initial reaction of methyl cholanate with phenylmagnesium bromide followed by acetic which is subseanhydride dehydration furnishes 24,24-diphenyl-5P-cholan-23-ene, quently rearranged to 23,24,diphenyl-5fi-cholan-24-one by reaction of its dibromide with alcoholic silver nitrate. Norrish Type I1 photoelimination conditions when 2n5

2ob

'07 '08 2n9

G . I . Zhungietu, B. P. Sukhanyuk, F. N. Chukrii, and L. N . Volovel'skii, Khim. gererotsikl. Soedinetzii, 1973, 219. R . Sandmeier and C. Tamm, Helv. Chim. Acta, 1973, 56, 2238. H. Hugl and E. Zbiral, Tetrahedron, 1973, 29, 753. H. Hugl and E. Zbiral, Terraheclron, 1973, 29, 759. M . Fetizon, F. J. Kakis, and V. Ignatiadou-Ragoussis, J . Org. Chem., 1973, 38, 4308.

346

Terpenoids and Steroih

applied to this 24-ketone yield 20-methylene-5/j-pregnene, ozonolysis of which affords directly the required 5ij-pregnan-20-one. The other two degradation methods concern the lan.xtero1 side-chain. L,anosterol acetate or benzoate is first oxidized with ozone followed by Jones reagent to produce the trisnor-acid (336; R' = R 2 = H). Addition of lithium isopropylcyclohexylamide in THF-HMPA to the methyl ester results in the formation of the enolate anion and addition of bromine gives the bromo-ester (336; R' = Br. R 2 = Me), which was

(336)

dehydrobrominated to the aP-unsaturared ester. Base treatment of this ester produced the ll;i-isomer, ozonolysis of which produced 3fi-acetoxy-4,4,14a-trimethyl-5a-pregn-8en-20-one.210 The latter pregnenone can also be obtained from lanosterol in a six-step sequenw2' Epoxidation of lanosteryl acetate leads to the 24,25-epoxide7which is rearranged to the 24-ketone by treatment with boron trifluoride etherate. Bromination of this ketone with two molar equivalents of bromine furnishes a dibromo-ketone, formulated as 3~~-acetoxy-23,25-dibromolanost-8-en-24-one; dehydrobromination then leads to an 8,22.25-trien-24-oneand oxidation to a pregn-8-en-20a-carboaldehyde. Further oxidation of this aldehyde using oxygen and 2,2'-dipyridylcopper(11)diacetate in pyridine results in the formation of 3~-acetoxy-4,4,14x-trimethyl-Sa-pregn-8-en-20one. The epoxidation reaction of 5cc-lanost-8,24-dien-3P-ylacetate used as the first step in the above degradation sequence has been separately investigated.212 Recrystallization of the C-24 stereoisomeric oxides from methanol allows the isolation of the insoluble (24R)-24,25-epoxy-Sa-lanost-8-en-3/~-yl acetate, whilst the methanol-soluble fraction yields the corresponding (24s)-isomer. Bromination of the 24-double bond in lanosteryl acetate has been shown to yield two 24,2S-dibromides in equal amounts under conditions of kinetic control.213 Thermodynamically controlled equilibration results in a preponderance ( 5 : 1) of the dibromoderivative with the (24s)-configuration (337); the driving force for this transformation is considered to be the interaction between the C-20 methyl group and the (24R)bromine atom. The oxidation of 5a-lanost-8-en-3P-yl acetate with chromium trioxide (first reported by Marker in 1937) has been rein~estigated.~'~ The reaction is now shown to yield a chromatographically separable mixture of 7,l l-dioxo-5a-lanost-8-en-3P-yl acetate and 7-oxo-5a-lanost-9(1l)-en-3/3-yl acetate in equal amounts. The C-8 epimer of the latter 'Io 11' 212 'I3

'I4

B. Ganem and M . S. Kellogg, J . O r g . Chem., 1974, 39, 575. L. H. Briggs, J . P. Bartley, and R. S . Rutledge, J . C . S . Perkin I , 1973, 806. R . B. Boar, D. A . Lewis, and J. F. McGhie, J.C.S. Perkin I , 1972, 2231. D. H . R. Barton, H. MacGrillen, P. D. Magnus, C. H. Carlisle, and P. A . Timmins. J.C.S. Perkin I , 1972, 1584. R. B. Boar, J. F. McGhie, and D. A . Lewis, J.C.S. Perkin I , 1972, 2590.

Steroid Synthesis

347

(337)

sterol, namely 7-oxo-5a,8cr-lanost-9(1l)-en-3B-y1 acetate, has been prepared ria the reaction of 5cr-lanost-7,9(1l)-diene-3P-yl acetate with acetic acid-hydrogen peroxide. An efficient synthesis2 of agnosterol(338) commences from lanosterol. Bromination of lanosterol results in a mixture of the 24,25-dibromides [(337) and the corresponding (24R)-isomer], which need not be separated but which upon reaction with perbenzoic acid yields the expected 24,25-dibromo-8a,9-epoxides. The latter can be readily debrominated and dehydrated (in either order) to yield pure agnosterol(338). The product from the reaction between methylmagnesium bromide and 3P-acetoxy-8a,9a-oxido-5alanostane is formulated as dihydroagnosterol (338; but saturated side chain).2l 6 When the same 8~,9-epoxidewas treated with allylmagnesium bromide the resulting product was found to be 3P,9a-dihydroxy-Sa-lanost-7-ene.

8 Steroidal Insect and Plant Hormones In work directed towards a synthesis of antheridio12” the compound (339), readily available from diosgenin, was converted by way of the 23t-bromo-derivative into the unsaturated ketone (340). Dimethyl malonate in the presence of tetramethylguanidine

215

R. B. Boar, D. A. Lewis, and J. F. McGhie, J.C.S.PerkinI, 1973, 1583.

”‘ G. R . Pettit

and W. P. Jones, J. Org. Chem., 1972, 37, 2788. G. A. Smith and D. H. Williams, J.C.S. Perkin I, 1972, 281 1.

Terpenoids and Steroids

348

O

C H 2 C 0 2Me

Y

I

(341)

(342)

underwent conjugate addition to compound (340) to form the crystalline adduct (341 ; = Me, R2 = H). Hydrolysis and bromination to yield (341; R' = H, R2 = Br) was then followed by a further hydrolysis to produce the ylactone (342). Selective reduction of the C-22 carbonyl group was achieved by use of lithium borohydride in the presence of methyl acetate as solvent (to prevent the reduction of the methoxycarbonyl group), and the 3,22-diol produced was converted into its bistetrahydropyranyl ether and treated with calcium carbonate, lithium iodide, and iodine in DMF. This oxidative decarboxylation procedure introduced the desired double bond into the lactone ring and the product (343) was then photo-oxidized to introduce the carbonyl group at C-7. The crystalline compound produced had about one tenth the biological activity of antheridiol(344) and was probably the C-22 epimer of that compound. The compound (345) has been synthesized from stigmasterol.21

R'

(343)

?I8

(344)

C. R . Popplestone and A . M . U n r a u , Canad. J . Chem., 1973,51, 1223.

349

Steroid Synthesis

The experimental details of a previously announced synthesis of antheridiol have The compounds (346; R = H or OH), possible biological precursors of ecdysone, have been synthesized.220

9 Steroidal Alkaloids The full paper has appeared221of the partial synthesis (44 steps) of batrachatoxinin A (348) from 1 la-hydroxyprogesterone by way of the lactone (347). A total of 2 kg of the 3-ethylene acetal of this lactone was made available for the purpose. The salamander alkaloid (353)222has been synthesized223by a ring-expansion procedure224 starting

(347)

(349) 219

220

221

222

223 224

(350)

T. C. McMorris, R. Seshadri, and T. Arunachalam, J . Org. Chem., 1974,39, 669; Tetrahedron Lecters. 1972, 2673; Chem. Comm., 1971, 1646. M. N . Galbraith, D. H . S. Horn, E. J. Middleton, and J. A. Thomson, J.C.S. Chem. Comm., 1973, 203; Austral. J. Chem., 1974, 27, 1087. R. Imhof, E. Gossinger, W. Graf, L. Berner-Fenz, H. Berner, R. Schaufelberger, and H . Wehrli, Helc. Chim. Acta, 1973, 56, 139; see ref. 2, p. 498. S. Hara and K . Oka, J . Amer. Chem. SOC., 1967, 89, 1041 ; Y . Shimizu, Tetrahedron Letters, 1972, 2919; see ref. 2. p. 491. M. H. Benn and R. Shaw, J . C . S . Chem. Comm., 1973, 288; Canad. J. Chem., 1974,52, 2936. G . Habermehl and A. Haaf, Annalen, 1969, 722, 155.

350

Terpenoids and Steroids

from the trienone (349). Epoxidation of this gave (350),which on hydrogenation yielded (351). Hydrazoic acid in chloroform converted this into the hydroxy-amide (352) as the major product. Finally, treatment of (352) with lithium-thylamine-t-butyl alcohol gave (353). In a synthesis of ~ a m a n i n e(357) ~ ~ ~the cyano-aldehyde (354) (from the corresponding ring-A 3-ketone) on reduction (sodium borohydride) and tosylation yielded (355), which on further reduction (diborane) and treatment with one molar equivalent of benzoic anhydride in pyridine yielded (356); the uncyclized amide is not an intermediate in the reaction. Transposition of the oxygen function from C-17 to C-16 was achieved by way of the 16-benzylidine-17-ketone.

OHC

4

NC&

Tos$ NC

H

H

&

(355)

(354)

Ho *NH

PhCON

H

€3

(356) 225

R. B. R a o a n d L. Weiler, Tetrahedron Letters, 1973, 4971.

(357)

Steroid Synthesis

35 I

(358)

Me,N

)n&p Me

(359)

Me,N

9 Me

Methylparavallarine (358; R' = R2 = Me) with concentrated sulphuric acid gives isomethylparavallarine (359) ; the 14p stereochemistry has been proved by relating it to the compound (360). Moreover (359) has been correlated with isoconessine (361), which therefore, like (359), must possess a 1 4 p - h ~ d r o g e n .Paravallarine ~~~ itself (358; R' = H, R2 = Me) has been transformed into conessidine (364). In this sequence paravallarine was converted by three steps into (362) and thence to the oxime (363). Reduction (sodium-propanol) and deacetylation (lithium-ethylamine) gave an NOH

226

J. Thierry, F. Frappier, M. Pais, F.-X. Jarreau, and R . Goutarel, Bull. SOC.chirn. France, 1972, 4753.

Terpenoids and Steroid7

352

approximately 1 : 1 mixture of (20s)- and (20R)-amines; the former yielded conessidine (364) quantitatively on gentle chromic acid oxidation.227 The same paper discusses the general problem of retaining or inverting the stereochemistry at C-20 in similar steroidal alkaloids with particular reference to the use of an 18-methoxycarbonyl group. The functionalization of the methyl group in the nitrone system (365) can be achieved228by the action of benzoyl chloride and dilute alkali, which gives (366). The action of toluenep-sulphonyl chloride -alkali on (365) yields (367). The hydrogen atoms of the methyl group in (368) are replaced by chlorine on treatment with sodium hypochlorite; the trichlorometh yI compound so formed when reduced by lithium aluminium hydride gives the ring-expanded product (369). Many examples are givenzz8of the functionalization of the pyrroline ring in the systems (364) and (368). The conversion NMe, to NHMe was achieved in yields of up to 70:4 in a steroid example229by a photosensitized oxygenation.

c, I

cNS_

tNF

10 Sapogenins

The structure assigned to isoplexigenin B has now been confirmed by synthesis to be (23S,25R)-spirost-5-ene-3P,23-diol (290; R' = R 2 = OH).230 In the sequence of reactions used diosgenin (290: R' = OH, R2 = H) was firstly converted into its 23-ketone (290; R' = OH, R2 = 0) and thence by hydride reduction into isoplexigenin B. Syntheses of the closely related sapogenins sceptrumgenin (370; R = CH,) and isonuatigenin (370; R = P-OH,cc-Me) have been described.231 Michael addition of nitromethane to but-3-en-l-ol-2-one acetate gave the key intermediate (371) required

(370) L27

'"

229

"'

230

(371)

J . Einhorn. C . Monneret, and Q. Khuong-Huu, Bull. Soc. chim. France, 1973, 301, 303. J . P. Alazard. B. K hernis, and X . Lusinchi, Tetrahedron Letters, 1972,4795; J. P. Alazard a n d X . Lusinchi. Bull. Sot,. d i m . France, 1973, 1814; P. Milliett. and X . Lusinchi, Tetrahedron Letters, 1974, 2825. 2833; A. Picot and X . Lusinchi, ibid., p. 679. D. Herlem, Y . Hubert-Brierre, F.Khuong-Huu, and R . Goutarel, Tetrahedron, 1973,29,2195. Y . P. G u p t a and R. K . Mehra, Indian J . Chem., 1972, 10. 451. S. V . Kassar, M. Lal, R. K . Mehra, and Y . P. Gupta, Tetruhedron, 1973, 29, 3169.

Steroid Synthesis

353

for this synthesis. Condensation of the acetal (371) with (E)-5,17(20)-pregnadien-3P-o116-one afforded the intermediate (370; R = OCH,CH,O), which after deacetalization secured the ketone (370; R = 0);Wittig reaction completed the synthesis to spectrumgenin (370; R = CH,). The 3P-acetate of the ketone (370; R = 0)was further treated with dimethyloxosulphonium methylide and the resulting oxirans were reduced to yield, after chromatography, isonuatigenin (370; R = P-OHp-Me) and the isomeric 25-alcohol. A synthesis of the C-23-spiro-acetal sapogenin (372) has been reported commencing from 3fl,16a-diacetoxy-5a-pregnan-20-0ne.~~~ Wittig reaction of this 20-ketone with (EtO),P(CH,CN gave an intermediate which on hydrogenation over Raney nickel followed by diazotization-hydroxylation, chromic anhydride oxidation, and further hydrogenation (H2-Pd/C) afforded the norcholanal (373). Condensation of this

(372)

Me

OH

(373)

(374)

Me

aldehyde with CH,=CHCH(Me)CH,MgBr led to the homocholestene (374), which after chromic anhydride oxidation, ozonolysis, and hydride reduction cyclized to the spiro-acetal system (372). A simple method of converting the 5cc-spirostan (290 ; R' = R2 = H ; 5cr-H) into the (25s)- and (25R)-stereoisomers of (20S,22S)-furostan22,25-epoxy-26-01, (375; R' = H, R2 = OH) and (375; R' = OH, R2 = H), has been described ; 2 3 3 yields are overall 60 "/,. Reduction of (25R)-spirostan (290: R' = R2 = H ; SLY-H) with hydride-aluminium chloride yields the intermediate (376; R = OH), which via tosylation and iodination can be transformed into the iodo-derivative (376 ; R = I). Elimination of the iodine from this molecule by alkali afforded a A25-olefin,which on treatment with osmium tetroxide gave a mixture of diols which were partially acetylated and cyclized to yield the mixture of spiro-sapogenins (375; R' = H, R2 = OAc) and (375; R 1 = OAc, R2 = H). Saponification and column chromatography gave the isomeric 26-alcohols. The novel sapogenin funchaligenin (375; R' = OH, R 2 = H ; 232

233

G. Piancatelli and A . Scettri, Gazzettn, 1974, 104, 343. A. G. Gonzalez, C. G. Francisco, R. Freire Barreira, R. Hernandez, J. A. Salazar, and E. Suarez, Tetrahedron Letters, 1974, 268 1 .

354

Terpenoids und Steroid

(375)

(376)

2c(,3P-diol) has been synthesized from didehydrogitogenin, (370; R = CH, : 2a,3Pd i ~ l ) . 'The ~ ~ latter sapogenin was first epoxidized and then reduced and acetylated to yield the intermediates (370; R = a-OH,P-Me or a-Me$-OH ; 2a,3/?-diacetate). Oxidation of the isomer (370: R = Z-OH,P-Me) led to the expected acid, which underwent reduction and cyclization to yield funchaligenin. A degradation of ring F of neoruscogenin (370: R = CH, : lP,3P-diol; A5)has been reported.235 The 1[1,3P-diacetate of neoruscogenin was oxidized with osmium tetroxide to yield the spirostenetriols (370; R = CH,OH,OHj which were further oxidized with periodate to the 25-ketone (370: R = 0 ; lP,3fi-diacetate: A5). Reaction of the latter with excess periodate led to the 26,27-dinorspirostene (377).

(377)

11 Cardenolides

An improved synthesis of digitoxigenin (378 ; R = H) has been published ;236 the overall yield is 21 9: based upon the starting material, 15c(,21-dihydroxypregn-4-en-3-one (379: R' = R2 = H). The route commences by converting 1%-hydroxycortexone (379: R' = R2 = Hj into its dimesylate and thence by reaction with the potassium salt of malonic half ester into the intermediate ester (379; R1 = MeSO,, R2 = COCH,CO,Et), reaction of which with piperidinium acetate formed the butenolide (380). Reaction of the latter with collidine' afforded the A4,14,20(22)-trieno1ide, which was stereospecifically hydrogenated to 3-0~0-5~-carda-l4,20(22)-dienolide, itself being reduced to the corresponding 3P-hydroxy-derivative in 85:( yield by the action of hexachloroiridic acid and trimethyl phosphite in aqueous propan-2-01. Conversion of the 3b-hydroxy-group into its 3P-formyloxy-derivativeprior to reaction of the 14,20(22)dienolide with NN-dibromoebenzenesulphonamide allowed the isolation of an intermediate I4P-hydroxy- 15a-bromo-cardenolide, which on reductive removal of the bromine and subsequent hydrolysis afforded digitoxigenin (378; R = H). A route has 234

235 j3'

A . G . Gonzalez, R. Freire Barreira, R . Hernandez, J. A. Salazar, and E. Suarez Lopez, A n d e s de Quim., 1973. 69, 1031. F. Rdnchetti and G . Russo, Gurzettu, 1974, 104, 245. W. Fritsche, W . Haede, K. Radscheit, U . Staches, and H . Ruschig, Annufen, 1974, 621.

355

Steroid Synthesis

CH20R2

'OS0,Me

been described for the conversion of digitoxigenin into its 5aH isomer, uzarigenin : 2 3 7 the key step is the transformation of 3-keto-5P-digitoxigenin into 3-keto-5cc-uzarigenin by refluxing with 10:d Pd-C in triglyme. Under these conditions, however, inversion of the butenolide (C-17P to C-17a) usually also occurs, so that the yield of uzarigenin is only ca. 3 %. The synthesis of 5a,l3a-cardenolides epimeric at C-17 has been described.238 Condensation of 3fl-acetoxy-5cc,l3cc,17a-pregnan-20-one with lithium ethoxyacetylide yields the expected 20-t-alcohol, which is rearranged to the up-unsaturated ester (381) under acid catalysis. Subsequent acetylation and selenium dioxide oxidation was followed by intramolecular condensation to give 3P-hydroxy-5a,l3a,l7a-card-20(22)enolide, after hydrolysis of the 3P-acetate function. This reaction sequence was also used to convert 3~-acetoxy-5a,l3a,l7~-pregnan-20-one into the corresponding 38hydroxy-5a,13rx-card-20(22)-enolide. Me

I

C=CHCO,Et

OH (382)

(383)

3fi-Acetoxypregna-5,14-dien-20-one has been used as the starting material for the synthesis of xysmalogenin (382).239 Acetoxylation of the 20-ketone with lead tetraacetate led to the 2 1-acetoxy-20-keto-steroid which underwent a Reformatsky reaction to yield the lactone (383): this when dehydrated furnished the A5,'4.20(22)-trienolide. N-Bromoacetamide treatment of this afforded the 14p,15cc-bromohydrinand reductive debromination furnished xysmalogenin acetate (382). The simultaneous oxidation and chlorination of digitoxigenin (378 ; R = H) during its reaction with t-butyl hypochlorite affords the corresponding 4P-chloro-3-ketone, which upon dehydrohalogenation yields canarigenone (384; R = H).240 Careful reaction of this ap-unsaturated ketone with lithium tri-t-butoxyaluminium hydride 237 238 239

M . Okada and J . Anjyo, Chem. and Pharm. Bull. (Japan), 1974, 22, 464. T. Nambara and J . Goto, Chem. and Pharm. Bull. (Japan), 1973, 21, 2209. E. Yoshii and K.Ozaki, Chem. and Pharm. Bull. (Japan), 1972,20, 1585. Y . Kamano, G . R . Pettit, and M . Tozawa, J. Org. Chem., 1974, 30, 2319.

356

Terpenoids and Steroids 0

R (384)

affords canarigenin, the 3P-hydroxy-analogue of the ketone (383 ; R = H), whilst reduction of the enone (384; R = H) with borohydride affords a route to uzarigenin (378; R = 5a-H). Oxidation of the enone (384; R = H) with rn-chloroperoxybenzoic acid leads to the expected 4b,5p-epoxy-3-ketone, which on reduction with chromium(I1) acetate yields the 5b-hydroxy-3-ketone, which can be further reduced by Urushibara nickel A to periplogenin (378; R = OH). A synthetic route to 4-chlorocanarigenone (384: R = C1) has been described commencing with the reaction of 3-oxocarda-4,14, 20(22)-trienolide with thionyl chloride to yield the 4,145,l 5<-trichloro-A4-3-ketone, which on treatment with Raney nickel yields 4-chloro-3-oxocarda-4,14,20(22)-trienolide.241Conversion of the 14-ene into the 14~-alcoholwas achieved by reduction of the corresponding 14,15-bromohydrin. A synthesis of 4-chloro-14~,15~-epoxy-3-oxocarda4,20(22)-dienolide is also reported,241 as is the synthesis of 3~-hydroxy-6-chloro-l4acarda-4,6.20(22)-trienolide (385),the first cardenolide bearing chlorine at position 6. The 6-chloro-cardenolide was synthesized from 3-OXO14a-carda-4,20(22)-dienolide in five stcps uia the corresponding A4*6-3-ketone and the A4-6a,7a-epoxy-3-ketone. Reaction of the latter with hydrogen chloride afforded the A4*6-6-chloro-3-ketone, which was reduced to the chloro-cardenolide (385).

61 (385)

(3x6)

Reaction of anhydrous hydrogen chloride with the oxide 3~-hydroxy-l4a,i5a-epoxySP-card-20(22)-enolidehas been shown to result in the formation of the 15a-hydroxy-14chloro-5p, 14/kardenolide (386; R' = OH, R 2 = H), whereas borohydride reduction of the corresponding chloro-ketone (386; R', R2 = 0)yields the epimeric l5p-alcohol (386; R' = H, R 2 = OH).242 On the other hand, borohydride reduction of the four possible 14-deoxy-l5-oxocardenolides(148,17p: 14,!3,17sr; 14a,17P; and 14a,17a) has shown that the 15-oxo-group in the 14~-cardenolidesis reduced to the 15a-hydroxy242

U . Stache, K . Radscheit. W . Fritsch, and W. Haede. Annulem, 1974, 608. M Okada. K . Kimura, and Y . Saito. Chem. and Pharm. Bull. (Japan), 1972, 20, 2729.

Steroid Synthesis

357

derivative, whereas predominant formation of the 1SP-hydroxy-epimer was observed with the 14a-carden01ides.~~~ These results were found to be independent of the configuration at C-17. The introduction of halogen, alkyl, and alkoxy-substituents into the lactone ring at C-22 of several cardenolide glycosides by way of intramolecular PO-activated cyclization of 14P-hydroxy-c/~-cis-steroid aglycones and glycosides derived from digoxin, digitoxin, ouabain, evomonosid, and convallatoxol has been The method is typified by the reaction of 2-chloro-2-(diethyl phosphono)acetic acid with 3P, 12pdiacetoxy-l4P,2 1-dihydroxy-SP-pregnan-20-one to yield the intermediate (387), which on reaction with base cyclizes to give 22-chloro-3~,12~,14~-trihydroxycard-20(22)enolide (388). A synthetic route to isocardenolides (389) is reported.245 Reduction of digitoxigenin with di-isobutylaluminium hydride resulted in the production of the corresponding furfuryl derivative (390), which was oxidized with hypohalous acid to the isomeric cardenolide (389);during this oxidation the 3P-alcohol was protected as its chloroacetate. The P-D- and a-L-glycosides of the isocardenolide (389) are reported, and isocardenolides were similarly prepared commencing from gitoxigenin, digoxigenin, and strophanthidin. CH,OCOCHP(O)(OEt),

( O k o

OH

OH

OH

Oxidation of digitoxigenin followed by oxime formation and subsequent reduction allowed the isolation of 3cr- and 3P-amin0-3-deoxydigitoxigenin.~~~ The same 3amino-derivatives could also be prepared by tosylation of the appropriate 3-alcohol, reaction of the tosylate with azide, and reduction of the 3-azides. Both of these routes have led to the epimeric 3-amino-3-deoxy-derivativesof uzarigenin, oleandrigenin, gitoxigenin, and d i g ~ t i g e n i n .The ~ ~ ~3-adamantoates of digitoxigenin, oleandrigenin, and gitoxigenin have been prepared; they result from reaction of the cardenolides with adamantanecarbonyl 12 Bufadienolides

A method for the direct conversion of 14-dehydrobufalin (391; R = H) into bufalin (392; R = H) has been described.249 The 14-olefin (391 ; R = H) was easily converted into its 14P-hydroxy-1Sa-halogeno-derivative by the action of N-iodo-, N-bromo-, or 243 244

245 246 247 248 249

M. Okada and Y. Saito, Chem. and Pharm. Bull. (Japan), 1973,21, 388. W. Eberlein, J. Nickl, J. Heider, G . Dahms, and H. Machleidt, Chem. Ber., 1972, 105, 3686. J. M . Ferland, Canad. J . Chcrn., 1974, 5 2 , 1652. L. Sawlewicz, E. Weiss, H . H. A . Linde, and K . Meyer, Helri. Chim. Acta. 1972, 55, 2452. E. Hauser, U. Boffo, L. Meister, and K . Meyer, Helu. Chim. Acra. 1973, 56, 2782. H . Just, G. Baumgarten, and R. Reissbrodt, Pharmazie, 1973, 28, 336. Y. Kamano and G. R., Pettit, J . Org. Chem., 1973, 38, 2202.

358

Terpenoids and Steroids

R

OH

(392)

H (391)

N-chloro-succinimide, and careful hydrogenolysis using Urushibara nickel A readily afforded bufalin (392; R = H) in good yield. The same 14~-hydroxy-15a-chlorohydrin could also be obtained by the action of hydrogen chloride upon resibufogenin (393 ; R = H) whereas the isomeric 14B-chloro-15cr-hydroxy-5fl-bufa-20,22-dienolide-3fl-ol is obtained by the action of hydrogen chloride on the corresponding 14.~,15a-epoxide.~~~ Reduction of resibufogenin (393 ; R = H) with lithium aluminium hydride is reported25 to yield the hemiacetal(394) rather than bufa!in as had been previously However, it is not necessary to use this route to bufalin since Raney nickel reduction of the corresponding l4P-hydroxy-15a-bromohydrin has been confirmed to be the route of choice.254 Treatment of resibufogenin 3P-acetate (393; R = H) with boron trifluoride etherate results in the formation of 14a- and l4P-artebufogenins (395), which are chromatographically ~eparable.~’ Similar ring-opening of 3P-acetoxy-l4a,15aepoxy-5fi-bufa-20,22-dienolide again results in a mixture of the same two 14-epimeric 15-ketones (395). The cis-c/D-ring of the 14P,15-ketone is more stable than the transc/D-ring of the 1 4 a - e ~ i m e r . ~ ~ ~

’

0

R

(393)

A synthesis of scillarenin (396) has been described using 14-dehydrobufalin (391 ; R = H) and resibufogenin (393; R = H) as relays.257 Bufalin was easily oxidized to ’‘O

”*

2 5 2

254

L55 2’6

”’

Y . Kamano and G. R. Pettit. Chem. and Pharm. Bull. (Japan), 1973,21, 895. E. Hauser, H. H . A. Linde, and S. Spengel, Help. Chim. Acra, 1972, 55, 3026. F. Sondheimer, W. McCrae, and W. G . Salmond, J . Amer. Chem. Soc., 1969,91, 1228. G. R. Pettit, L. E. Houghton, J. C . Knight, and F. Bruschweiler, J. Org. Chem., 1970,35,2895. F. Sondheimer and R . L. Wife, Tetrahedron Letters, 1973, 765. Y . Kamano and G. R. Pettit, Canad. J . Chem., 1973, 51, 1973. Y. Kamano, S. Kumon, T. Arai, and M. Komatsu, Chem. and Pharm. Bull. (Japan), 1973, 21, 1960. Y . Kamano and G . R . Pettit. J . Org. Chem., 1974. 39. 2629.

359

Steroid Synthesis

the SP-3-ketone, which was brominated at C-4 and subsequently dehydrobrominated to yield its A4-3-keto-analogue (scillarenone). Lithium tri-t-butoxyaluminium hydride reduction of the latter enone afforded scillarenin (396). Oxidation of scillarenin with rn-chloroperbenzoic acid led to the isolation of the 4P,SP-epoxide, which on oxidation with N-bromosuccinimide gave the 4~,SIJ-epoxy-3-keto-analogue. Reduction of this ketone with chromium(1r)acetate afforded telocinobufagone (397) and further reduction (telocinowith Urushibara nickel A gave the 3P,5P,14P-trihydroxybufa-20,22-dienolide b~fagin).'~

O As(392; R

(396)

=

H)

As(392; R

=

H)

(397)

Y

Ha.*

(398)

A synthetic method has been developed for transforming bufotalin (392 ; R = OAc) into cinobufagin (393; R = OAc). Dehydration of the 3p-acetate of bufotalin with thionyl chloride led to the expected A 14-olefin. Direct epoxidation with rn-chloroperbenzoic acid gave as exclusive product the 14a,15or-epoxide,a new isomer of cinobufagin acetate. However, addition of hypobromous acid to 14-dehydrobufotalin (391 ; R = OAc) followed by treatment of the resulting bromohydrin with alumina afforded the 14P,lSP-epoxide, cinobufagin acetate (393; R = OAc; 3D-OAc). Selective hydrolysis of the 3P-acetate group led to the isolation of cinobufagin itself, and oxidation of the 3-alcohol led to the corresponding 3-ketone. Borohydride reduction of this ketone provided a sample of 3a-hydroxy-16~-acetoxy-l4~,15~-epoxybufa-20,22-dienolide (3-e~icinobufagin).~~~ The sequence of reactions leading from the 14P,l5/3-epoxide (393; R = H) to the 14P-hydroxy-bufadienolide (392; R = H) has also been applied to the conversion of gamabufotalin (3P,1lor, 14~-trihydroxy-5~-bufo-20,22-dienolide into the corresponding 14P,15P-epoxide (11cr-hydroxyresibufogenin).260 As before, Arenobufagin (398) oxidation afforded also the 1la,l4~-dihydroxy-3-keto-analogue. has been converted into argentinogenin [A9(' "-analogue of (398)] by oxidation with bismuth trioxide, and 3P, 12fl-diacetoxy-14-hydroxy- 1l-ket0-5~-bufa-20,22-dienolide has also been prepared by successive borohydride reduction, partial acetylation, and Kiliani oxidation of arenobufagin.26' Dehydrogenation of the enol lactone (399) using sulphur in boiling p-cymene leads to the bufa-l4,20,22-trienolide, reduction of which at C-3 with hexachloroiridic acid15* 259

O'' 26'

G . R . Pettit and Y . Kamano, J . O r g . Chem., 1974,39, 2632. G. R . Pettit and Y . Kamano, J . Org. Chem., 1972, 37, 4040. G. R . Pettit and Y . Kamano, J . C . S . Perkin I , 1973, 725. S. Spengel and H . H . A . Linde, Helc. Chim. Acta, 1973, 56, 2827.

Terpenoids and Steroih

360

H (399)

trimethyl phosphite gave 14-dehydrobufalin (391 ; R = H). Using the hypobromous acid route (PhSO,NBr,) the formate, acetate, and rhamnopyranoside were each converted into the respective derivative of resibufogenin (393 ; R = H).262 Finally, it is reported that treating proscillaridine A [the L-rhamnosyl derivative of scillarenin (396)] with amalgamated aluminium sheet leads to an 85 : 15 mixture of bufadienolides (400) and (401). Other selective hydrogenation catalysts were shown to reduce the A4-double bond leaving the pyrone ring intact.263

I:;$ OH

262

263

OH

W . Haede. W . Fritsch, K. Radscheit, and U . Stache, Annalen, 1973, 5. P. Berlin and K. R. H . Repke, Z . Chem., 1973, 13, 13.

Reviews on Steroid Chemistry

The following list of reviews on steroid chemistry covers the period 1969-1974.

1 General

B. A. Marples, ‘Terpenoids and Steroids’, Ann. Reports (B), 1971, 68, 467 (162 references) ; 1972, 69. 509 (144 references) ; 1973, 70, 549 ( 139 references). G . F. Woods and A. C. Campbell, ‘Progress in Applied Chemistry and Medicinal Substances-Steroids’, Reports Progr. Appl. Chem., 1972, 57, 598 (1 79 references). L. J. Chinn, ‘Conformational Analysis of the Steroids’, Zntra-sci. Chem. Reports, 1969, 3, 23 (18 references). R. Bucourt, ‘Conformational Transmission in Steroids’, Conform. Anal. Pap. Znt. Symp., ed. G. Chiurdoglu; Academic Press. New York, 1959, p. 59. R. Wiechert, ‘Modern Steroid Problems’, Angew. Chem. Internat. Edn., 1970, 9, 321 (195 references). J. Mizon, ‘Sterols: (I) Cholesterol’, Pharm. biol., 1970, 6, 629. F. Hartley, ‘Steroids and Hormone Products’, ‘Modern Chemical Industry’, Proceedings of the I.U.P.A.C. Symposium, ed. J. G. Gregory, Society of Chemical Industry, London, 1968, p. 281. H. Selye, S. Szabo, P. Kourounakis, and Y. Tache, ‘Tentative Rules for the SSS (Symbolic Shorthand System) Designation of Steroids’, Adv. Steroid Biochem. Pharmacol., 1972, 3, 1. D. Taub and T. B. Windholz, ‘Steroids’, ‘Kirk-Othmer Encyclopedia of Chemical Technology’, 2nd Edn., 1969, Vol. 18, p. 830. 2 Steroid Synthesis and Steroid Reactions ‘Steroids’,ed. W. F. Johns, M.T.P. International Review of Science, Organic Chemistry, Series One, Vol. 8, Butterworths, London, 1973. This volume contains the following review chapters: G. Saucy and N. Cohen, ‘Total Synthesis of Steroids’ (90 references); W. Nagata and S. Uyeo, ‘General Synthetic Transformations’ (319 references); D. J. Marshall and Y. Lefebvre, ‘Estranes and Gonanes’ (170 references) ; B. Pelc, ‘Androstanes’ (219 references); R. Wiechert and H. Laurent, ‘Pregnanes and Corticosteroids’ (196 references); R. H. Ode, Y. Kamano, and G. R. Pettit, ‘Cardenolides and Bufadienolides’ (143 references) ; H. Mori, ‘Metamorphosis Hormones and Steroid Antibiotics’ (100 references) ; P. J. Sykes, ‘Cholestane Derivatives and Sapogenins’ (1 83 references) ; H. 0. Huisman, ‘Total Synthesis of Heterocyclic Steroidal Systems’ (99 references); H. R. Race, ‘Nor, Homo and Abeo Steroids’ (66 references). 36 1

362

Terpenoids und Steroids

‘Organic Reactions in Steroid Chemistry’, ed. J. H. Fried and J. A. Edwards, Vols. 1 and 2, Van Nostrand-Reinhold, New York, 1972. This contains the following review chapters : H. L. Dryden, ‘Reduction of Steroids by Metal-Ammonia Solutions’ (95 references): D. M. S. Wheeler and M. M. Wheeler. ‘Reduction of Steroidal Ketones’ (274 references); R. L. Augustine, ‘Steroid Hydrogenation’ (170 references); L. Tokes and L. J. Throop, ‘Introduction of Deuterium into the Steroid System’ (187 references): G. H. Rasmusson and G. E. Arth, ‘Selective Oxidations of Hydroxy Steroids’ (271 references); C. C. Beard, ‘Introduction of Double Bonds into the Steroid System’ (373 references); R. Gardi and A. Ercoli, ‘Protection of Carbonyl Groups and Hydroxyl Groups’ ( 1 90 references) : J. Fried and N. A. Abraham, ‘Introduction of Fluorine into the Steroid System’ (144 references): G. J. Matthews and A. Hussner, ‘Synthesis of Oxiranes, Aziridines and Episulphides’ (162 references); H. Laurent and R. Wiechert, ‘Selective Introduction of Alkyl and Methylene Groups into the Steroid System’ (248 references) ; E. P. Oliveto, ‘Synthesis and Degradation of the Pregnane Side-chain’ (299 references) ; K. Heusler and J. Kalvoda, ‘Selective Functionalisation of the Angular Methyl Group and Further Transformation t o 19-Norsteroids’ (1 30 references) ; K. Schaffner, ‘Photochemical Rearrangements and Cycloadditions’ ( 1 10 references) ; G. A. Boswell, ‘Ring Expansion and Simultaneous Ring ContractionRing Expansion’ (62 references) ; R. M. Scribner, ‘Ring Contractions’ (75 references). ‘The Total Synthesis of Natural Products’. ed. J. W. ApSimon, Vol. 2, Wiley-Interscience. New York, 1973. D. N. Kirk and M. P. Hartshorn, ‘Steroid Reaction Mechanisms’, Elsevier, Amsterdam, 1968. ‘Protective Groups in Organic Chemistry’, ed. J . F. W. McOmie, Plenum Press, London, 1973. I. T. Harrison and S. Harrison, ‘Compendium of Organic Synthetic Methods’, WileyInterscience, New York and London, 1971. E. Zbiral, ‘Organic Synthesis Using Lead(1v) Acetate Azides Pb(OAc), - 4(N3)n’, Synthesis, 1972, 285 (74 references). D. Burn, ‘Alkylation with the Vilsmeier Reagent’, Chem. and Ind., 1973, 870 (19 references). J. Kalvoda and K. Heusler, ‘The Hypoiodite Reaction. A Method for Intramolecular Substitution on Non-activated Carbon Atoms’, Synthesis, 1971, 501 (152 references). J. A. Waters, Y. Kondo, and B. Witkop, ‘Photochemistry of Steroids’, J . Phurm. Sci., 1972, 61, 321 (128 references). R. H. Hesse, ‘The Barton Reaction’, Adt,. Free-radical Cllern., 1969, 3, 83 (1 10 references). D. H. R. Barton, ‘Use of Photochemical Reactions in Organic Synthesis’, Mod. Sviluppi. Sin. Org. Corso. Estico Chim. loth, 1967, 15. J. Weill-Raynal, ‘The Torgov Reaction’, BuII. Soc. chim. France, 1969, 4561 (49 references). G. Stork, ‘Some Developments in Annelation Methods’, in ‘Hormonal Steroids’, Proceedings of the 3rd International Congress, 1970, ed. V. H. T. James, Excerpta Medica, Amsterdam, p. 101. D. K. Banerjee, ‘Dieckmann Cyclisation and Utilisation of the Products in the Synthesis of Steroids’, Proc. Indian Acad. Sci. Serf. A , 1974,79. 282 (44references). D. N. Kirk, ‘Selectivity in Reactions of Epoxides’, Chem. and. Ind., 1973, 109 (24 references).

Reuiews on Steroid Chemistr?)

363

D. K. Banerjee, ‘Synthetic Investigations on Steroids’, J . Indian Chem. Soc., 1970, 47, 1 (70 references). N. K. Chaudhuri and M. Gut, ‘Synthesis of Isotopically Labelled Steroids of High Specific Activity’, Methods Enzymol., 1969, 15, 305. R. Wiechert, ‘Synthesis of Antiandrogenic Steroids’, A&. Biosci., 1967, 1. 54 (20 references). A. A. Akhrem, T. V. Ilyukhina, and Yu. A. Titov, ‘Alkyl Steroids’. Uspekhi Khim., 1969, 38,1852 (255 references). T. Kobayashi, ‘Chemistry of Vitamin D and its Related Compounds 11. Total Synthesis of Vitamin D, and Syntheses of Vitamin D, Active Metabolites’, Vitamins, 1973,47, 38 I (37 references). R. Pappo, ‘Progress in the Total and Partial Synthesis of Steroids’, Intra-sci. Chem. Reports. 1969, 3, 123 (49 references). M. P. Rappoldt, ‘Retrosteroiden’, Chem. Weekhlad, 1971, 67, S 18 (1 3 references). L. Starka and R. Hampl, ‘Steroid Allylic Alcohols’, in ‘Hormonal Steroids’, Proceedings of the 3rd International Congress, 1970, ed. V. H. T. James, Excerpta Medica, Amsterdam, p. 150. R. C. Jenkins and E. C. Sandberg, ‘Preparation and Properties of Steroid Sulphate Esters’, Methods Enzymol., 1969, 15, 351. D. Onken and D. Heublein, ‘Acetylenated Steroids’, Pharmuzie, 1970, 25, 3. W. Nagata, ‘Synthesis of Natural Products by the Use of a New Hydrocyanation Process. Introduction of Various Carbon Substituents and Bridged Kings of Angular Positions’, Nippon Kuguku Zusshi, 1969, 90,837. I. L. Shapiro, ‘Preparation and Characterisation of Cholesterol’, Ultrupurity, 1972, 193 (28 references). A. S. Narula, ‘Modification ofTetracyclic Triterpenes into Steroid Hormone Analogues’, J. Sci. Ind. Res., India, 1972, 31, 423 (143 references).

3 Steroidal Alkaloids Y. Sato, ‘Steroidal Alkaloids’, in ‘Chemistry of the Alkaloids’, ed. S. W. Pelletier, Van Nostrand-Reinhold Co., New York, 1970, p. 591 (185 references). J. Tomko and Z. Voticky, ‘Steroid Alkaloids. Verutvum and Buxus Groups’, Alkaloids (New York), 1973, 14, 1 (128 references). G. G. Habermehl, ‘Steroid Alkaloids’, in ‘Alkaloids’, ed. K. F. Wiesner, M.T.P. International Review of Science, Organic Chemistry, Series One, VoI. 9, p. 235, Butterworths, London. 1973 (1 50 references). F. Khuong-Huu and R. Goutarel, ‘Steroidal Alkaloids of the Apocynaceae and the Buxaceae’, in ‘The Alkaloids’, ed. J. E. Saxton, Specialist Periodical Reports, The Chemical Society, London, 1972, Vol. 2, p. 259 (42 references). W. Turowska and V. Wrzeciono, ‘Buxus Alkaloids with the 9p, 19-Cyclo-14amethyl5a-pregnane Skeleton’, Wiudomosci Chem., 1973, 27, 869 (41 references). R. B. Herbert, ‘Solanurn and Verutuurn Steroidal Alkaloids’, in ‘The Alkaloids’, ed. J. E. Saxton, Specialist Periodical Reports, The Chemical Society, London, Vol. 3, 1973 (76 references). K. Schreiber, ‘Synthesisand Biogenesis of Steroidal Solanum Alkaloids’. Biochem. Soc. Trans., 1974, 2, 1 (126 references).

Terpenoids and Steroids

364 4 Physical Methods

‘Hormonal Steroids’, Proceedings of the 3rd International Congress, 1970, ed. V. H. T. James, Excerpta Medica, Amsterdam. This contains the following review chapters : A. E. R. Talaty, G. A. Russell, and P. R. Whittle, ‘Application of Electron Spin Resonance Spectroscopy to Structure Determination in Steroids’, p. 184; A Cooper, ‘Application of X-ray Diffraction to the Determination of Molecular Structure of Steroids’. p. 194 ; K. Tori, ‘Application of Intramolecular Nuclear Overhauser Effects in Steroid Chemistry’, p. 205 ; P. S. H. Kuppens and E. B. M. De Jong, ‘High Resolution Gas Chromatography in Steroid Analysis’, p. 214. G. Adam. ‘Applications of Physical Methods for Solution of Natural Chemical Product Structure Problems’, 2. Chem., 1970, 10, 241 (47 references). R. von Ammon and R. D. Fischer, ‘Shift Reagents in N.M.R. Spectroscopy’, Angmy. Chem. Internat. Edn., 1972, 11, 675 (169 references). M. Spiteller-Friedmann and G. Spitteller, ‘Mass Spectra of Steroids’, Fortschr. chem. Forsch., 1969, 12, 440 (184 references). A. M. Duffield, ‘Utilization of Mass Spectrometry in Natural Product Chemistry’, Recent. Adt. Phytochem., 1969.2, 107 (17 references). N. Morisaki, ‘Mass Spectra of Natural Steroids’, Yuki Gosei Kzigaku Kyokai Shi,1973, 31, 573 (26 references). N. S. Vul’fson and V. G. Zaikin, ‘Mass-spectrographic Determination of the Position of the Double Bond in Unsaturated Steroids’, Uspekhi Khim., 1973, 42, 1379 (86 references). P. Crabbi., ‘Optical Rotary Dispersion and Circular Dichroism Studies in the Steroid Field’. in ‘Modern Methods of Steroid Analysis’, ed. E. Heftmann, Academic Press, New York, 1973, p. 331 (11 references). A. W. Burgstahler, R. C. Barkhurst, and J. Gawronki, ‘Cotton Effects and AllylicHomoallylic Chirality of Steroidal Olefins, Conjugated Dienes and Enones’, in ‘Modern Methods of Steroid Analysis’, ed. E. Heftmann, Academic Press, New York, 1973, p. 349 (44 references). G. Snatzke and F. Snatzke, ‘Cotton Effects of Acid Derivatives, Aromatic Steroids and Nitrogen, Sulphur and Halogen-containing Steroids’, in ‘Modern Methods of Steroid Analysis’, ed. E. Heftmann, Academic Press, New York, 1973, p. 381 (72 references). W. Klyne and D. N. Kirk, in ‘Fundamental Aspects and Recent Developments in Optical Rotatory Dispersion and Circular Dichroism’, ed. F. Ciardelli and P. Salvadori, Heyden, London, 1973. L. Velluz and M. Legrand, ‘L’Etude du Dichro’isme Circulaire Optique (1961-1 969)’, Bull. Soc. chim. France, 1970, 1785. F. Hodoson, V. Cuirdaru, and H. H. Nantsch, ‘C-OH Valence Vibration of Hydroxysteroids’, Studii Cercetari Chim. (Bucharest), 1972 20, 587 (44 references). B. Schrader and E. Steigner, ‘Raman Spectroscopy of Steroids’, in ‘Modern Methods of Steroid Analysis’, ed. E. Heftmann, Academic Press, New York, 1973, 231 (25 references). A. T. Christensen, ‘X-Ray Analysis of Steroid Structure and the Automated Diffractometer’, in ‘Modern Methods of Steroid Analysis’, ed. E. Heftmann, Academic Press, New York, 1973, p. 281 (24 references).

Reviews on Steroid Chemistry

365

J. Karle, ‘Applications of Direct Methods of X-Ray Structure Analysis to Steroids’, in ‘Modern Methods of Steroid Analysis’, ed. E. Heftmann, Academic Press, New York, 1973, p. 293 (28 references). R. Zalewski, ‘Electronic Spectra of Steroids’, Pr. Zakresu. Tow-arozn. Chem. Wyzsza. Szk. Ekon. Poznaniu Zesz. Nauk. Ser. I, 1969, 29, 47. B. P. Lisboa, ‘Thin-layer Chromatography of Steroids, Sterols and Related Compounds’, Methods Enzymol., 1969, 15, 3 (365 references). 5 Heterocyclic Steroids H. 0. Huisman, ‘Approaches to the Total Synthesis of Heterocyclic Steroid Systems’, Angew. Chem. Internat. Edn., 1971, 10,450 (64 references). G. I. Zhungetu, G. N. Dorofrenko, and B. M. Sarin, ‘ ‘Steroids Containing Heteroatoms in the Nucleus or Side Chain of the Molecule’, Uspekhi Khim., 1970, 39, 646 (79 references). H. Singh, V. V. Parashar, R. B. Mathur, and R. K . Malhotra, ‘Heterosteroids’, Indian. J . Pharm., 1972, 34, 1 (90 references) H. Singh, V. V. Parashar, S. Padmanabhan, and R. B. Mathur, ‘Azasteroids-Synthesis and Significance’, Indian J . Pharm. Educ., 1970, 4, 2. 1. Ninomiya, ‘Aza Steroids. Their Synthesis and Biological Activity’. Yuki Gosei Kugaku Kyokiu Shi, 1972, 30,318 (155 references). J. A. Zderic, ‘Steroidal Oxepins’, Chem. Heterocyclic Compounds, 1972, 26, 467 (75 references). 6 Natural Products and Biological Aspects

T. Tamura and T. Iida, ‘Isolation and Identification of Natural Steroids’, Yukagaku, 1973, 22, 581 (107 references). D. Taub, ‘Naturally Occurring Aromatic Steroids’, in ‘Total Synthesis of Natural Products’, ed. J. W. ApSimon, Wiley-Interscience, New York, 1973, p. 641 (122 references). D. B. Gower, ‘1 6-Unsaturated-C,, Steroids. A Review of their Chemistry, Biochemistry and Possible Physiological Role’, J . Steroid Biochem., 1972, 3, 45 (1 59 references). D. F. Morrow and D. Gallo, ‘Steroids and Biologically Related Compounds’, Ann. Reports Medicin. Chem., 1972, 7, 182 (127 references). C. W. J. Chang, ‘Marine Natural Products other than Pigments’, J . Chem. Educ., 1973, 50, 260 (29 references). Y. Kamano, ‘New Plant Bufadienolides’,Kagaku N o Ryoiki, 1973,27,984 (37 references). H. H. A. Linde and K. Myer, ‘Bufadienolides’,‘1st International Congress on Pharmacognosy and Phytochemistry’, ed. H. Wagner, Springer, Berlin, 1970, p. 239 (75 references). Y. Kamano, ‘Total Synthesis of Toad Poisons. Recent Advances in Synthesis of Bufadienolides’, Yushi Kagaku Kyokaishi, 1973, 31, 202 (80 references). B. Matkovics, ‘C-2 and C-4 Enzymic and Chemical Hydroxylation of Phenolic Steroids’, Steroids and Lipids Res., 1973, 4, 153 (29 references). Sir Ewart R. H. Jones, ‘Microbiological, Hydrdxylation of Steroids and Related Compounds’, Pure Appl. Chem., 1973, 33, 39 (16 references).

Terpenoids and Steroids

366

7 Miscellaneous D. Lavie, ‘Steroidal Lactones of the Withanolide Type’. Bol. Inst. Quim. Univ. nac. aunton. Mexico, 1970, 22, 181 (21 references). A. A. Akhrem, I. S. Levina, and Yu. A. Titov, ‘Chemistry of Ecdysones’, Uspekhi Khim., 1971,40, 162I (193 references).

ERRATA Vol. 4, 1974 Page 23. For

Read

I

Isoprene

[Ni(cod) ]

(127)

Page 77, ref. 1, Add: p. 197; ref. 2, Add: 1973, Vol. 2, p. 7. Page 8 I . The structure for pseudoguaiane should be

Page 101. The arrow from formula (129) to formula ( 1 28) should be complete and be accompanied by the reagent numbers iv, ii, iii. Page 114. Formula (203) should have an extra asterisk:

367

368

Terpenoids and Steroids

Page 144. Formula (421) should be

Page 206. Replace ‘CH’ at the top of formula (128), ( 1 29) by ‘OH’ Page 21 2, line 10. For ‘[23,23-2H2]-b-amyrin’read ‘[22,23-2H2]-P-amyrin’. Page 269, second block of formulae. Insert ‘(44)’ before the second arrow; i.e. the block depicts two separate incorporations. Page 303. In the articles by Hanson on terpenoid biosynthesis, although the total numbers of references are as stated, the numbers of references relevant to sesquiterpenoids are 21 in Vol. I and 14 in Vol. 2.

Author Index Aasen,A. J.,7,91.96,152,155 Abe, T., 252, 299 Abel, H.. 215 Aberhart, D. J., 338 Abillon, E., 278 Abraham, N. A.. 362 Abraham, R. J., 30,36,41,227 Abrahamson, E. W., 198 Abrahamsson, S., 207 Abramovitch, A., 243 Abramson, D., 173 Accrombessy, G., 5 Achini, R., 52, 199 Achmatowia, S., 283,338 Ackerman, M.E., 173 Ackman, R. G., 183 Adam, G., 114, 115,364 Adams, D. R., 8 Adams, R. P.,205 Adams, S. R., 175 Adeoye. S. A., 217 Adesida, G. A., 133 Adinolfi, M.,239 Adolf, W., 21 5 Agarwal, S. K., 138 Agosta, W. C., 35, 37 Agostini, A., 17 Agurell, S., 44 Ahlgren, G., 289 Ahmed, V. U., 129 Ahond, A., 226 Ailion, D. C., 198 Aiyar, V. N., 141 Aizawa, H., 103,214 Ajami, A. M.,182 Akhmedov, A. I., 7 Akhrem, A. A., 243,325.363, 366 Akhtar, M.,198 Akimoto, A., 310 Akita, H., 105 Akiyama, K., 271 Akiyama, S., 247 Akiyama, T., 40, 145,218,219 Akutagawa, S., 42 Alazard, J. P.,352 Albert, A. H., 248 Albert, D..96 Albrecht, P.,145 Albright, J. D., 237 A b i d e , A., 193 Alchalel, A., 163 Alexander, J., 23, 25 Alexeeva, L. M.,263 Alfano, J., 193

Alfsen, A., 194 Alifanova, A. V., 38 Allais, J. P.,186, 193 Allam, A. M.,194 Allen, C. M., 203 Allen, F. H., 207, 209, 210, 217,219 Allen, J.. 127, 276 Allerhand, A., 177 Allinger, N. L., 223, 224 Allison, T. J., 213 Allmann, D. W., 173 Almqvist, S.-O., 7, 91, 96 AI Shamma, A. A., 213 Altman. L. J., 13, 117, 168 Alvarez, M.A., 118 Ambles, A., 266 Amer, S., 198 Amiard, G., 289 Amirthalingam, V., 208 Ananchenko, S. N., 228, 295, 310 Anderson, A. B., 101 Anderson, B. F., 213 Anderson, G. D., 212 Anderson, N. H., 53 Anding, C., 188, 189 Andose, J. D., 223 Andrewes, A. G., 148, 154 196 Andryushina, V. A., 295 Aneja, R., 116, 232 Anisimova, 0. S., 263, 295 Anjaneyulu, A. S. R., 139 Anjyo, T., 192, 257,355 Anke, H., 199 Anliker, R., 302 Anner, G., 320 Antonova, N. D.. 36 Anzai, K., 272,293 Aoki, K., 78 Aota, K., 88, 212 Aoyagi, R., 142 ApSimon. J. W., 273, 320 Arai, T., 193, 358 Arbuzov, B. A., 41 Arigoni, D., 23, 179, 213 Arihara, S., 193 Arimoto, M.,142 Aringoli, E. E., 36 Arita, M.,213 Arkens, L., 173 Armande, J. C. L., 255 Armarego, W. L. F., 189 Arndt, R. R.,2 17

3 69

Arnold, R. T., 39 Arnold, W. H., 49 Arnott, S., 217 Arpin, N., 148, 149, 151 Arpino, P., 145 Arsenault, G. P., 185 Arth, G. E., 242,256,260,304, 362 Arunachalam, T., 343,349 Asaka, Y., 17,97 Asakawa, Y., 185 Asako, T., 291,295 Ash, L., 13, 117, 168 Asher, J. D. M.,209 Ashida, T., 219 Ashida, Y.,169 Atkinson, K. F., 236 Atta-ur-Rahman., 129, 137 Audier, H. E., 230 Augustine, R. L., 246, 362 Aul'chenko, I. S., 36 Aung Than., 146 Avigan, J., 173 Avotins, F., 4 1 Avruch, L., 125 Awaya, J., 172 Ayengar, K. N. N., 141 Ayer, W.A., 16, 115, 117,216 Aynelchi, Y., 209 Azerad, R., 169 Baarchers, W. H., 217 Babler, J. H., 12,49 Bachhawat, J. M.,6 Badripersand, S., 320 Baguley, B. C., 106 Baier, H., 259 Baigent, D. R., 236 Bailey, K., 44 Bailey, R. B., 188 Baines, D., 65,67 Bakaleinik G. A., 41 Baker, R., 74 Balachandran, R., 173 Baliispiri, L., 258, 329 Balasubramanian, S., 194 Balavoine, G., 4 Baldwin, D., 269, 305, 312 Baldwin, S., 275, 305 Balgir, B. S., 106 Balkenhol, W. G., 215 Ball, J.-A. H., 115 Balmain, A., 213 Bambagiotti, A. M.,23

370 Bancher, E., 168 Bandaranayake, W. M.,45 Bandopadhyay, M., 102 Banerjee, D. K.,295, 362,363 Banerji, A , , 68 Bannai, K., 330 Banner, B. L., 285, 287 Banthorpe, D. V., 10,20 Baradat, P., 205 Baran-Marszak, M., 246 Barbier, M.,81, 129, 186, 193, 2 11 , 2 17,248, 339,340 Bard, M., 188 Bardyshev, I. I., 5. 22, 27, 41 Barjot, J., 164 Barkhurst, R. C., 228, 364 Barnes, J. M., 16 Barone, G., 239 Bart, J. C., 2 19 Barth, C., 171 Barthelemy, M., 38 Bartlett, L., 154 Bartlett, P. A., 292 Bartley, J. P., 346 Barton, Sir D. H. R., 36, 124, 127, 138, 188,218,235,244, 25 1,256,276,283,296,300, 318,331,338,346,362 Bartoov, B., 194 Bartsch, H., 215 Basselier, J.-J., 11 Bastard, J., 238, 324 Bates, R. B., 207, 209, 210 Bateson, J. H., 114, 185 Bathurst, E. T. J., 266 Bau, W., 43 Baulieu. E. E., 194 Baumgarten, G., 357 Bax, H.-J., 9 Baxter, R. L., 78, 21 1 Bayunova, V. I., 312 Bazyl'chik. V. V., 27 Beal, J. K.. 213 Beal, P. F., 3 18 Bean, G. A., 186 Bearder, J. R., 112, 114, 184, 185 Beard, C. C., 362 Beasley, G. H., 117, 218 Beastall, G. H., 186 Beaucourt, J. P., 44 Beaudoin, G. J., 323 Beckstead. H. D., 43 Beckwith, A. L. J., 23 Beedle. A. S., 174, 195 Beg, Z. H., 173 Begley, M. J., 15, 45, 206 Behbud, A., 59 Beinert, H., 193 Bekaert, A,, 129 Bekow, D. A., 217 Belanger, P.. 188 Bell, J. R.. 225 Bell, P.. 333 Bell, R. P., 34

A u t ho r Index Bellas, T. E., 152 Bellavita, V., 138 Bellesia, F., 71 Beliino, F. L., 194 Belova, T. P., 162 Ben-Aziz, A., 148 Bendcovsky, M., 243 Beneveniste, P., 189 Benezet, L., 23 Benn, H., 38 Benn, M.H., 349 Bennett, M. J., 247 Bennett, R. D., 183, 225 Benoiton, N. I,., 161 Benschop, H. P., 206 Benson, A. M., 194 Bentley, T. J., 63 Ben Zvi. Z., 44 Bercht, C. A. L., 43.44 Beresford, G. D., 107 Beresnevich, L. B., 23 Berg, W., 18 Bergot, B. J., 182 Berlin, P., 360 Bermejo, J., 87 Bernard-Dagan, C.. 205 Berndt, J., 173 Berner, H., 349 Berner-Fenz, L., 349 Bernstein, J., 116, 216 Berthet, D., 43 Berthou, J., 207 Bertrand, C., 25 Bertrand, J. A., 208 Bertrand, M., 27, 67 Bessiere-Chretien, Y.,38 Beugelmans, R., 23 1 Bevan. C. W. L., 217 Beyer, K., 3 Bhacca, N. S., 71,226 Bhar, D. S., 131 Bhathena, S. J., 173 Bhatnagar, S. P., 8 Bhattacharayya, P., 45 Bianchi, C., 7 Biddlecom, W. G., 15, 178 Biellrnann, J.-F., 168, 245 Bieniek, D., 43 Bierner, M. W.. 205 Biessels, H. W. A., 143 Billard, J., 283 Binder. M., 44 Birch, A. J., 21, 80, 274 Bird, C. W., 51 Birnbaum, G. I., 215,311 Birnbaum, K. N., 213 Bito, T., 28, 165 Bittler, D., 312 Bjamer, K.. 213, 215 Bjorkhem, I., 191, 204 Bladon, P., 323 Blakitnyi, A. N., 21 Blanchard, M.,5 Blaszczak, L. C., 57 Blaycock, B. T., 16

Blazhin, Yu. M., 8 Blecka, Z., 136 Blenkinsopp, J., 229, 263 Blickenstaff, R. T., 236 Blight, M.M., 52 Block, A. J., 186 Block, J. H., 245 Blomquist, C. H., 194 Blomquist, L., 63 Blossey, E. C., 336 Blount, J. F., 60,208,285,287, 332 Blum, J. J., 177 Boar, R.B., 124,127,138,218, 276,346,347 Bodea, C., 151, 162 Boden, R. M., 34,59 Boeckmann, R. K., 86 Boelens, H., 29 Boettger, H., 162 Boffo, U., 357 Boguslavsky, V. A.. 245 Boguslawski, W., 173 Bohlmann, F., 9, 28, 93, 101, 178 Boiko, V. N., 21 Bolla, P., 255 Boller, A., 254, 308, 320 Bolt, C. C., 301 Bolton, S. E., 121 Bonadies, F., 17 Bond, F. T., 344 Bondavalli, F., 7, 42 Bonnett, R., 154 Bonsignori, 0.. 14 Bony, G., 164 Boomsma, F., 279 Booth, A. B., 21 Borch, G., 154 Bordakh, 0. D., 93 Bordner, J., 142 Bore, Z., 41 Borikhina, M. G., 201 Bortz, W. M., 173, 186 Bose, A. K., 3, 172, 231, 334 Bosmans, R., 215 Boswell, G. A., 362 Bosworth. N., 39 Bottin, J., 230 Bottini, E., 32 Bottomley, W., 160 Bouchon, 262,316 B o d , A. D., 252,306 Boullier, P. A., 20 Bouquet, J. F., 81 Boust, C., 30 Boutagy, J., 249 Boutigue, M.-H., 247, 337 Boutis, L., 3 14 Bovis, A., 297 Bowen, D. H., 113 Boyd, G. S., 192, 194 Bradbeer, J. W., 113 Brady, D., 173 Brady. S. F., 176

Author Index Brady, W. T., 39 Braekman, J. C., 70,212,213 Bramovich, D. R.A., 186 Brandanage, S., 63 Brandl, F., 215 Brandt, J., 38 Branlant, G., 245 Braun, J. A., 140 Breckenridge, W. C., 168 Breitmaier, E., 262,316,317 Breslow, R.,275,276,305 Breton, F. J., 103 Breton, J. L., 87 Breuer, H., 194 Brewis, S., 219 Bricout, J., 178 Brieskorn, C. H., 27 Briggs, D. E., 184 Briggs, L. H., 59,346 Britton, G., 148,197 Broadhurst, M. D., 117 Brodherr, N.,218 Brody, S. S., 163 Broekhoven, L. W., 175 Brooks, C. J. W., 154 Brooks, P. W., 145 Brown, B. O., 45 Brown, H. C., 6,247 Brown, K. S., jun., 103 Brown, M. J. G., 194 Brown, M. S., 173 Brown, P., 248 Brown, P. M., 143,218 Brown, R.T., 18 Brown, W. A. C., 217 Browne, L. M., 16 Browne, P. A., 247 Brownie, A. C., 193 Brownlee, R. G., 152 Brufani, M., 216 Brundret, K. M., 214 Brunel, Y., 207 Brunelle, D. J., 78 Brunner, H., 4 Bruschweiler, F., 358 Bryan, G. T., 192 Bryan, R.F., 16,78,210,211,

214,215.217 Brzezinka, H., 159,204 Bubnov, Yu. N.,243,325 Buccini, J. A., 320 Buchanan, G. L., 86 Buchecker, R.,28, 153, 154,

165 Buchschacher, P., 288 Buckle, K. A., 197 Buckwalter, B. L., 103 Bucourt, R.,255,302,361 Bude'Sinsky, M., 242 Budylina, V. V.,22 Budzikiewin, H., 159,204,307 Buchi, G., 29,157,164 Buehler, C. A., 284 Buthe, I., 32 Buggy, M. J., 197

Buil, P., 63 Buinova, E. F., 41 Bukala, M., 5 Bull, J. R., 225,238,300 Bullivant, M. J., 15 Bu'lock, J. D., 199 Bunnenberg, E., 228 Burak, K., 41 Burden, R. S., 182 Burgstahler, A. W., 34, 228,

364 Burlingame, A. L., 209 Burn, D., 254,256,362 Burnett, R.D., 228,310 Burova, L. E., 164 Burrows, E. P., 228 Buschi, G., 21 1 Butruille, D., 131 Butsugan, Y., 28,165 Butt, Y.,14,231 Byall, E. B., 344 Cabre, F. R. M., 244 Caccia, G., 309 Cadosch, H., 155 Cadwallader, D. E., 283 Cafieri, F.. 77 Caglioti, L., 34,31 1 Caine, D., 60, 80 Calandra, S., 188 Calas, R , 26,164 Caldeira, P. P., 340 Calimbras, T. D., 186 Calo, V., 335 Cambie, R. C., 96, 106, 107,

109,213,240 Cameron, A. F., 207 Campbell, A. C., 273,361 Campbell, H. M., 11 1 Campbell, M. M., 35 Campion, T. H., 334 Candela, Ch., 99 Cane, D. E., 179 Caputo, R., 94,106,139 Cardillo, G., 12 Carlini, C., 14 Carlisle, C. H., 138,217,218,

346 Carlson, J. P., 176,186 Carman, R.M., 21,22,24 Caron, M. G., 193 Carpio, H., 297,313 Carroll, F. I., 250 Carroll, G. L., 36,249 Carruthers, W., 243 Carstens, L. L., 11 7 Cary, L. W., 140 Casey, C. P., 12 Casida, J. E., 7 Caspi, E., 190,338 Cassady, J. M.. 209,21 1 Castagnino, E., 342 Castanet, Y., 31 Castellano, E., 215

371 Castellano, L. L., 117 Catalan, C. A. N., 41 Cater, M. R.,186 Catsoulacos, P., 312,314,315,

316 Caughlan,C.N.,210,211,212 Cawley, J. J., 35 Cedar, F. J., 247 Cense, J.-M., 6 Cerda-Olmedo, E., 198 Cerfontain, H., 167 Cerneg, V., 335 t e r n $ , V.,224 Cerrini, S., 216 Cervantes, A,, 264,297 Cesur, A. F., 208 Chabardes, P., 14 Chabudu'nski, Z., 41 Chadha, M. S., 68 Chadwick. D. J., 225,227 Chaffey, M. B., 114,185 Chakraborty, D. P.,45 Chakraborty, S., 142 Chakravarti, K. K., 46 Chakravarti, R. N.,139 Chan, J. H. H., 14 Chan, J. T., 188 Chan, N.G., 260 Chan, W. K., 156 Chang, C. W. J., 365 Chang, F. C., 217 Chapman, D. J., 162.197 Chapman, T. M., 176 Chapple. C. L.. 18 Charney, E., 228 Charreau, E. H., 194 Chatterjee, A., 139 Chatzopoulos, M. M., 39 Chaudhuri, N.K., 363 Cheer, C. J., 210 Chen, A., 242,260 Chen, C.LM., 109 Chen, H. W., 188 Chen, Y. L., 101 Chen, Y. P., 102,116,117 Cheng, S. C., 192 ChCrest, M., 246 Cherkaev, V.G., 38 Cherkasov, A. N.,239 Chetyrina, N.S., 138 Cheung, K. K., 213 Chiang, C.-K., 78,21 1 Chichester, C. O., 148,197 €hilds, R.F., 29 Chin, C.-A,, 155 Chinn, J., 328 Chinn, L. J., 361 Choay, P.,323 Chogovadze, Sh. K.,7 Chong-Sen, E., 38 Chopra, G, R.,141 Chow, J., 173 Chow, Y. L., 41 Christensen, A. T., 364 Christensen, R.L., 166

372 Chu, C.-Y.. 80 Chu, J. Y.C., 283 Chukhrii, F. N., 345 Chwastek, H., 246,307 Ciereszko, L. S., 116 Cimino, G., 105,201 Ciudaru, V., 162 Clardy, J., 77, 116,206,207,

217.218 Clark, G. R.,107,213,214 Clark, I. M., 307 Clark, R.D., 33 Clarke, D., 44,45 Cleve, G., 225 Clinkenbeard, K. D., 172 Clive, D. L. J., 256 Clunie, J. S., 208 Coan, P., 172 Coates, D., 283 Coates, R.M..52,208 Cocker, W., 15, 28 Coetzer, J., 215

Coggon,P.,210,214,215,217 Cohen, C. F., 188 Cohen, J. F., 16 Cohen, K.F., 127 Cohen, N.,75,285,287,361 Cohen, P., 186 Cohen, T., 176 Cole, R.F.J., 35 Coll, J. C.. 256 Collins, C. J., 31 Collins, E. J., 322 Collins, J. C., 337 Coloma, A., 174 Colvin, E. W., 53 Comeau, L. C., 140 Comer, F. W., 209 Comoy, P., 272 Connolly, J. D., 53, 135,213, 217 Constabel, F., 205 Contento, M.,12 Contreras, L. E., 247,306 Cook, I. F., 193 Cookson, R.C., 8 Cooley, G., 254 Coombe, B. G.. 184 Coombs, M.M., 252,258,302 Coombs, R. V.,251,300 Cooper, A., 216,364 Cooper, D. Y., 192 Cooper, G. H., 326 Cooper, M.A,, 36,41 Coppola, J. C., 21 1 Coppolino, A. P., 265 Coran, S. A.. 23 Corbella, A., 63,87,181,212 Corcoran, R.,276,305 Cordell, G. A., 199 Corey, E. J., 47,119,218,237, 238 CornClis, A., 29 Cornforth, J. W., 170,172 Cornu, P.J., 268,272

Author Index Corrie, J. G. T., 188 Cortes, M.,130 Coscia, C. J., 178 Costes. A., 268,272 Costin, C. R.,53 Cowell, D. B., 232 Cox, D. A., 218 Cox, M. R.,210 C o x , P. J., 73,210,21 1 Cox, R.E., 183 Coxon, D. T., 80,21 1 Coxon, J. M., 35,266 Crab&, P., 27,264,297,313,

328,364 Cradwick, M. E., 209 Cradwick, P. D., 209 Cram, D. J., 207 Crane, R.I., 209 Critchfield, W.B., 204 Croisy, A., 317 Croisy-Delcey, M., 317 Crombie, L., 15,44,45,206,

215 Cross, B. E., 114,185 Croteau, R.,170 Crouch, R.,74 Crowe, D. F., 259, 300,301,

309 Crowley, K. J., 21,28 Crozier, A., 113 Crump, D. R., 213,341 Cruse, W.B. T., 213 Cruz, A., 264,297 Cubberley, B. W., 233 Cuillier, P.,25 Cuirdaru, V., 364 Culvenor, C. C. J., 105 Cunningham, A., 93 Currie, M..212 Cutfield, J. F., 107,214 Cuthbertson, E., 29 Cutting, J. D., 47 Cynkowski, T., 309 Cyrot-Pelletier, M.-O., 169 Czapski, J., 183 Dabbagh, A. G., 150 Dabovii, M..232,329 Dagonneau, M., 35 Dahms, G., 357 d'Albuquerque, 1. L., 143 Dale, J. A., 276,305 Daloze, D., 70,212,213 Dalzell, H. C., 44 Dalziel, W., 116,214 Damaskin, B. B., 4 Damps, K., 124 Dana, S.E., 173 d'Angelo, J., 49 Danheiser, R.L., 119 Danieli, B., 141 Danielsson, H., 204 Daniewski, A. R.,292 Daniewski, W.M., 69

Danna, R.,251,300 Darias, J. D., 48,49,118 Das, K.G., 142 Dasgupta, S. K.,341 Dastillung M.,145 Dastier, K.P., 80,253,274 Dauben, W.G., 117,218,289 Dauphin, G., 164 David, H. L., 197 Davie, A. W., 217 Davies, A. P., 232 Davies, B. H., 146, 151, 195,

197 Davies, D. I., 36 Davies, M. T., 254 Davies, V. H., 210 Davis, A. K.,225,232 Davis, D. L., 188 Davis, K.H., 43 Davis, R.A., 172 Davis, R.E., 13,73,211 Davydova, L. P., 159 Dawson, M. I., 142 Day, J., 207 De Alvarenga, M.A., 183 Dean, P.D. G., 186 Deana, R.,174 de Barros Coelho, J. S., 143 De Bernardi, M., 16 De Boer, A., 258 Decker, K., 171 De Dalai, I., 96 Dedieu, M., 33 de Dartan, D., 23 Dedyukina, M. M., 171 De Graaf, S. A. G., 255 de Hernandez, J., 108 de Hertogh, A. A., 174 Dehn, R. L., 259 De Jong, E. B. M., 364 de la Mare, P. B. D., 241 Delbarre, F., 333 Delbruck, M., 198 Della Casa de Marcano, D. P.,

215 Delle Monache, F., 143 Delpech. B., 226 de Luca, H. F., 194,331 De Luca, P.,342 de Marcano, D., 247,306 De Marco, A., 212 de Marquez, L. A., 247,337 Dembitskii, A. D., 7 Demole, C.. 43 Demole, E., 43 De Moor,P., 194 Dempsey, M.E., 172,186 Demuth, M., 44 de Nie-Sarink, M.J., 244 de Nijs, H., 270 Dennick, R.G., 186 Dennis, R.,9 Denny, W.A., 107,307 de Oliveira, A. B.. 78 De Pasqual, T. J., 41

Author Index Depezay, J.-C., 49 de Reinach Hirtzbach, F., 127 Derksen, A., 186 De Rosa, D., 105 de Rosa, M., 342 Desai, D. S., 38 Deshko, T. N., 228 Dessertine, A. L., 16 De Stefano, S., 105, 201 Detre, G., 259 Dev, S., 208 De Vottero, L. E., 36 Devys, M., 81, 129, 186, 211, 217 de Wachter, A. M., 298 Dias, J. R., 127, 270 Diatta, L., 315 Diaz, E., 3 Dickinson, R. A., 285 Dickson, L. G., 188 Dieckmann, H., 199 Dieckmann, R.H.. 11 Dietsche, T. J., 6 Dietschy, J. M., 171 Dillon, J., 4, 229 Dimmel, D. R.,33 Dive, W. R.,106 Djerassi,C., 70, 128, 212,215, 225,228,231,241,242,245, 307,336,341 Do, K. M. D., 107 Dobler, M., 21 1 Doddrell, D. M., 138 Doisy, E. A., 194 Dolby, L. J., 120 Dominguez, X. A., 74, 101, 131,141, 143,209,218 Donohue, J., 206 Dorn, B., 183 Dorofrenko, G. N., 365 Dorschel, C., 18 Doskotch, R. W., 213 Douchkin, N., 23,238 Dovinola, V., 94 Downey, W. L., 186 Downing, M. R., 174 Doyle, P., 209 Doyne, T. H., 219 Drakenberg, T., 69 Dranishnikov, G. L., 11 Dreiding, A. S., 60 Drew, M. G. B., 214 Dreyer, D. L., 133 Dreyfus, H., 2 11 Dryden, H. L., 362 D u k , J., 255 Ducep. J. B., 168 Duchamp, D. J., 207 Ducker, J. W., 254 Ducruix, A., 129, 2 17 Duffaut. N., 26, 164 Duffield, A. M., 364 Dugan, R.E., 173 Duke, B., 198 Dul, M., 5

Dullforce, T. A., 21 1, 212 Duncan, G. R., 325 Dunitz, J. D., 21 1 Dunogues, J., 26, 164 Duprat, P., 164 Durham, L. J., 70,212 Durley, R. C., 114, 115, 185, 186 Dutcher, J. S., 140 Dutky, S. R., 188 Dutta, N. L., 139 Dutta, P. C., 119 D’yakonova, R. R., 41 Dyatkina, S. L., 4 Dygos. J. H., 328 Dzhemilev, U. M., 242 Dzizenko, A. K., 138 Eachan, C. E.. 213 Eagle, G. A., 97 Eber, J., 119 Eberlein, W., 357 Ebersole, R. C., 190 Ebrey, T. G., 156 Eck, C. R.,33,58.67, 209 Eckell. A., 21 Edebo, L., 204 Eder, U., 288 Edery, H., 44 Edmond, J., 171 Edmonds. A. C. F., 229,263 Edward, J. T., 325 Edwards, J. A., 243 Edwards, 0.E., 278 Edwards, P. A., 173 Egger, K., 149, 150 Eggerer, H., 172 Eggert. H., 225 Edigo, T., 4 1 Egli, R.,28, 153 Eglinton, G., 145 Egorova, V. V., 228 Eguchi. S., 16, 36 Eguchi, Y., 243,254 Ehrenfreund, J.. 28 Eichhorn, E. L., 219 Eidem, A., 158, 167 Eigtved, P., 17 Eilers, J. E., 198 Einarsson, K., 194 Einhorn, J., 352 Ekouya, A., 26, 164 El Batouti, N., 36 El-Kady, I. A.. 194 Elliott, M., 16 Elliott, W. H., 194, 342 Ellis, B., 254 Ellis, J., 264 Ellwanger, R. E., 258 El Rahim, A. M. A., 218 Elstner. E. F., 177 Elyakov, G. B., 138 Emerson, M. T., 210,211, 212 Ende, M., 229

373 Endo, K., 55, 178 Ener, M., 173 Eng, S., 323 Engel, Ch. R., 323 Engel, D. W., 215 Engle, L. L., 194 Engler, E. M., 223 Englert, G.. 167 Enriquez, R.,3 Ensminger, A., 145 Enzell, C. R., 7, 91, 96, 152, 155 Ephritikhine, M., 240 Eposito, P., 17 Eppenberger, U., 319 Epsztein. R., 246, 307 Ercoli, A., 304, 362 Erickson, B. W., 47 Erickson, K. L., 21, 55 Erlanger, B. F., 7 Erm, A. Yu.,8 Erzhanova, M. S., 38 Escalona. M. L., 137 Eschchenko, L. S., 5 Eslava, A. P., 198 Espinoza, L., 163 Etoh, H.. 165 Eugster, C. H.. 28, 104, 153, 154, 155,165 Eulyaev, N. N., 171 Evans, D. A., 36,84,249 Evans, F. J., 116, 187 Evans, J. M., 306 Evans, R., 179 Everett, G. W., jun., 3 1 Evgenios, D. M., 35 Evrard, M., 31 Evstigneeva, R. P., 159, 162 Faass, U., 178 Faber, S., 334 Fackler, J. P., jun., 206 Fagundo, C. R.,103 Fairlie, J. C., 31, 11 1, 177 FajkoS, J., 242, 243, 266, 307, 308,312 Fakis, F. J.. 238 Falconi, G.. 304 Fales, H. M., 23 1 Falgueirettes, J.. 206 Fallis, A. G., 37 Fan, D., 194 Farney, R. F., 208 Farnham, A. W.. 16 Farnham, W. B.. 206 Fattorusso, E., 77 Faulkner, D. J., 13, 77, 206, 207 Faull. K. F., 184 Fauve, A., 253 Fawcett, J. K., 217 Fayos, J., 7, 206, 207, 218 Feather, P., 254 Fedeli, W., 2 16

3 74 Fedorov, P. I., 27 Feldman, M., 284 Feline, T. C., 69, 181 Feliziani, F., 243 Felkin, H.,246 Fell, B., 78 Fellows, R., 99 Femino, A. M., 236 Fenical, W., 78, 207, 213,216 Fenimore, D. C., 44 Ferezou, J. P., 186 Ferguson, G., 206, 207, 209, 213,214,215,217 Ferland, J. M., 357 Fernandes, M. de L. M.,78 Ferrari, G., 87, 103 Ferro, A,, 5 Fetizon, M., 23, 107, 126, 225, 230,238,280,292,304,324, 345 Feuillerat, G., 40 Fey, J., 183 Fialkov, Yu. A., 21 Ficini, J., 27, 49 Filippova, T. M.,159, 164 Fillon, C., 205 Findlay, J. K., 194 Finkelhor, R. S., 31 Finkner, V. C., 188 Fischer, N. H., 71 Fischer, R. D., 364 Fisher, G. S., 5 Fishman, J., 236, 269,302,308 Fitton, H., 10 Fitzpatrick, F. A., 283 Flake, R. H., 204 Flechtner, T., 275, 305 Fleet, G. W. J., 238 Fleming, M. P., 157 Fliege, W.. 36 Flood, C. T., 4 Fonseka, 9. D., 7 Forcellese, M.L., 116 Ford, H. C., 194 Fordham, W. D., 10,20 Forni, G. P., 141 Forrester, J., 65 Forsen, K., 205 Forsythe, G. D., 209 Fortino, J., 197 Fouchet, C., 194 Fowell. D. T., 2 18 Fraga, 9. M., 104, 108 Frages, G., 23 Francis, G. W., 148, 150, 151, 167 Francisco, C. G., 277, 353 Franwis, H., 40 Frank, F. J., 337 Frantz, I., 173, 188 Frappier, F., 266, 35 1 Frater, G., 89 Fratev, F., 163 Freeman, R. R., 44 Freidinger, R. M.,157

Author Index Freire Barreira. R., 277, 353, 354 Fridrichsons, J., 2 I7 Fried, J. H., 297, 313, 362 Fritsch, W., 354, 356, 360 Fritz, P., 70, 2 13 Froborg, J., 68 Frohlich, H. H., 27 Fryberg, M., 188 Frydman, V. M., 113 Fu, W. Y., 33 Fiirst, A., 254, 285, 288, 308, 320,330 Fujihara, Y., 9 Fujimori, T., 152 Fujimoto, K., 16 Fujimoto, Y., 53 Fujisawa, K., 96 Fujita, E., 101, 110, 213 Fujita, H., 117 Fujita, K., 103, 112, 214 Fujita, S., 6 Fujita, T., 8, 9, 10,11, 101,110, 210,213 Fujita, Y.,6 Fujiwara, T., 5,217, 218, 219 Fukamiya, N., 89 Fukuba, R., 192 Fukui, K., 107, 117 Fukui, T., 124, 176, 186 Fukuoka, M.,68, 127 Fukushima, D. K.,236,308 Fukuyama, Y., 134 Fulke, J. W. B., 217 Fuller, F. N., 60 Fullerton, T. J., 6, 107 Furasaki, A., 68,209,210,214 Furukawa, H., 74, 87, 88, 210, 212 Fushiya, S., 115, 214 Futterman, A., 163 Futterman, S., 163 Gabe, E. J., 208,210 Gadola, M., 163 Gaede, K., 159 Gaffney, P., 194 Gailyunas, I. A., 242 Galbraith, M. N., 90, 103, 349 Galantay, E., 25 1,300 Galasko, G., 154, 198 Galeazzi, E., 264, 297 Galigne, J. L., 206 Gall, R. E., 276, 323 Gallazzi, A., 32 Gallo, D.; 365 Galson, E., 183 Gamble, W., 188 Gamborg, 0. L., 205 Games, M. L., 215 Gandhi, R. P., 279, 329 Ganem, B., 126,260,346 Gans, J. H., 186, 188 Garcia de Quesada, T., 108, 111

Garcia-Peregrin,E., 174, 176 Gardi, R., 304, 309,3 19, 362 Garg, S., 279 Gariboldi, P., 63. 87, 181,212 Garnero, J., 23, 63 Garsky, V., 39 Garst, M.E., 20,248 Garwood, D. C., 207 Gase, R. A., 244 GaSiC, M. J., 232, 329 Gaskell, S. J., 145 Gaskin, P., 113, 114, 184 Gassmann, J., 215 Gaudernar, M., 25 Gauderner, A., 81,211 Gaumert, R., 173 Gavrilova, T. F., 36 Gawell, L., 63 Gawienowski, A. M., 199 Gawronki, J., 364 Gay, R., 257,325 Gaylor, J. L., 186 Geissman, T. A., 88, 178,210, 212 Gemmell. K. W., 209 George, G., 99 Geraghty, M.B., 60 Germain, J.-E., 5 Germain, P.. 257, 325 Gesson, J. P., 301 Geuns, J. M.C., 188 Ghazarian, J. G., 194 Ghosh, M. C., 159 Ghosh, S., 159 Ghozland, F., 25 Giannini, D. D., 226 Gibb, W., 194 Gibbons, C. S., 216 Gibbons, G. F., 193 Gibbs, J. J., 105 Gibian, H., 290 Gibson, D. M.,173 Gibson, S. G., 27 1,305 Gibson, T., 40 Gieren, A., 218 Gilardi, R. D., 219 Gilbert, I. M.,270, 271, 305 Gilbert, J. D., 154 Gill, L. S., 205 Gill, S. S., 7 Gilman, N. W., 47 Gilmore, C. J., 78, 211. 214 Giordano, F., 342 Gitany, R., 2 12 Giumanini, A. G., 34 Gladysz, A., 261 Gleispach, H., 236 Gleiter, R.. 176 Glotter, E., 327 Go, K. T., 210 Goad, L. J., 186, 189, 194 Gochev, A., 163 Godtfredsen, W. O., 190 Gossinger, E., 349 Goldbaum, A., 337

Author Index Goldie, A. H.. 166 Goldman, J., 35 Goldschmidt, Z., 34 1 Goldsmith, D. J., 53 Goldstein, J. L., 173 Goldstein. S., 193 Golfier, M.. 23, 225, 238 Golubovskaya, L. E., 239 Gonplves de Lima, O., 143 Gondlez, A. G., 48, 49, 87, 103, 104, 108, 118, 130,137, 145,277,353,354 Gonzalez, B. I., 101 Gonzalo de Venditti, F., 40 Goodfellow, D.. 155 Goodfellow, R. J., 176 Goodwin, C. D., 186 Goodwin, T. W., 148,174,186, 189, 193, 197 Gopichand, Y., 46 Gordon, K. D., 337 Gordon, J. T., 219 Gore, J., 232 Goren, M. B., 236 Gorst-Allman, G. P., 1 1 1 Goryaev, M. I., 7 Goto, G., 274, 295, 304 Goto, J., 3 11, 355 Gottlieb, 0. R., 78, 183 Gottlieb, R., 341 Gough, L. J., 95 Gould, R. G., 173 Goutarel, R.. 261, 282, 351. 352,363 Gower, D. B., 365 Graebe, J. E., 114, 184 Graf, W., 133,227, 349 Gramain, J. C., 230, 238, 324 Grande Benito, M., 4 1 Grandguillot, J.-C., 16 Granger, R., 178 Grant, D. F., 208, 209 Grant, H. G., I8 Grant, I. J. G., 217 Grant, P. K., 96 Gras, J.-L., 67 Gravel, D., 3 10 Gravestock, M. B., 292 Gray, G. W., 283 Gray, J. C.. 174 Gray, R. T., 114, 160 Grayer-Barkmeyer, P. J., 205 Gream, G. E., 34 Green, C. D., 207 Greene, A. E., 76 Gregolin, C., 174 Gregonis, D. E., 196 Gregson, R. P., 60 Grenz, M., 101, 178 Grevels, F. W., 206, 207 Gribble, G. W., 284 Grieb, R., 60 Grieco, P. A., 12,31,76 Grieder, A,, 122, 123, 176 Grimshaw, J., 27

Grinenko, G. S., 289, 295, 312 Grinstead, M. J., 109 Grisebach, H., 204 Gross, D.. 18 Grove, J. F., 7, 52 Groves, J. T.. 278 Grundhofer, B., 173 Grunfeld, Y., 44 Gubler, B.. 2 1 1 Gudriniece, E., 4 1 Guerrero, C., 100 Guerrero, H. C., 162 Guglielmetti, L., 2 13 Guiso, M., 17 Gull, P., 280 Gumulka, M., 309 Gund. P., 246 Gunn. P. A., 111,217 Gupta, A. D., 119 Gupta, Y. P., 352 Gurudutt, K. N., 94 Guseva, A. R., 186, 201 Gustafsson, J., 194 Gustowski. W., 317 Gut, M., 261, 341, 363 Guthrie, J. P., 262, 317 Guttormson, R.,2 13 Guzewska, M., 292 Guziec, F. S., jun., 36 Haaf, A., 349 Haas, D. J., 217 Habermehl, G., 143, 349, 363 Hach, V., 7 Hachiya, K., 115 Hackett, W. P., 174 Haddad, Y. M. Y.,247 Haddon, V. R., 53 Hadinec. I., 210 Hadley, M. S., 98 Haede, W., 354, 356. 360 Hakli, H., 36 Haeufel, J., 317 Haeuser, J., 97 Hagaman, E. W., 78 Hagenbach, A., 142 Hager, L. P., 55, 207 Hagishita, S., 22Y Hagitani. A., 238 Hahn, R. C., 23 Hair, N.J., 207 Hajos, Z. G., 288,289,325 Halkes, S. J., 298 Hall, A. L., 88, 107, 108 Hall, D., 2 13 Hall, M., 252 Hall, M. S., 182 Hall, S. R., 218 Hall, S. S., 77, 207 Hallett, C. J., 146 Hallot, A., 268, 272 Halperin, G., 252 Halsall, T. G.. 98. 215, 217, 219

375 Haltiwanger, R. C., 2 15 Ham, P. J., 218 Hamanaka, N., 2 14 Hamanaka, T., 2 19 Hamasaki, T., 157 Hamilton, J. A., 208. 2 17 Hamm, P., 153, 154 Hammerschmidt, F. J., 229 Hammock, B. D., 7 Hamor, T. A,, 213,217 Hampl, R., 363 Hamprecht, B., 204 Hancock, W. S., 107 Handrick, G. R., 44 Hanic, F., 208 Hanna, R., 268 Hannan, B. N. B., 241 Hansbury, E., 187 Hanson, J. R., 52, 179, 214, 269,305.3 12 Hanson, R. F., 194 Hanze, A. R., 318 Hara, H.. 7 Hara, S., 327, 349 Harada. N., 135, 228 Harborne, J. B., 204, 205 Harding, A. E., 53 Harding, B. W., 192 Harita, K.. 271, 272 Harita, S., 68 Harkins, J. B., 192 Harle, E., 2 15 Harley-Mason, J.. 2 12 Harnik, M.. 243. 295 Harris, H., 298 Harrison, H. R., 217, 219 Harrison, I. T.. 2 16. 362 Harrison, S., 362 Harrison, T. L., 198 Hart, H.. 164, 244. 337 Hartley, F., 361 Hartmen, B. C., 235 Hartog, J., 298 Hartshorn. M. P., 35, 236, 362 Hartsuck, J. A,, 214 Haruta, H., 160 Haruyama, T., 343 Hasegawa, K., 166 Hasegawa, S.. 183 Hassner. A., 312 Hata. C., 9 Hata, Y., 249 Hatano-Sato, F., 192 Hattersley, N. G., 194 Hatton, B. P., 225 Haumesser, W., 29 Hauser. E., 357. 358 Hauser. F. M., 250 Hauser, S., 173 Havinga, E., 279 Hawley, D. M., 209 Haxo, F. T., 146 Hayakawa, Y., 78 Hayano, T., 17 Hayase, Y., 114

3 76 Hayashi, K., 26, 227 Hayashi, M.,210 Hayashi, N., 46 Hayashi, S., 5,7, 14,36,53,63, 93

Hayashi, T., 35,Y6, 140, 183 Hayashi, Y., 68, 213 Hayman, E. P.. 1Y7 Haynes, R. K., 244 Hayward, R. C., 107, 109, 240 Heathaxk, C. H., 33, 75, 140 Hechtfischer, S., 215 Hecker, E., 116, 215 Hedden, P., 109,114,184.185 Heerma, W., 44 Heftmann, E., 186 Hegedus, L. S., 249 Heider, J., 357 Heinstein, P. F.. 175 Heintz, R., 189 Heitmann, J. A., 36 Heller, J., 166 Hellstrom, K., 194 Helmy, E., 229, 263 Hemingway, D. C.. 21 1 Hemingway, J. C., 210 Hemingway, R. J., 210 Henbest, H. B., 247 Henderson, M. S., 2 17 Henkels, W. D., 17 Henry, W., 335 Herbert, J., 3 10 Herbert, R. B., 363 Herkstroeter, W. G., 14. 231 Herlem, D., 282, 352 Herling, J., 243, 295 Herman, G., 176 Hernandez, M.G., 108 Hernandez, R., 277,353,354 Herout, V., 208 Herr, R. W., 235 Hertzberg, S., 148 Herz, J. E., 232, 247,337 Herz, W., 88, 107, 108, 210, 211,212

Herzog, H. L., 298, 322 Hesp, B., 116, 214 Hess, W. W.. 337 Hesse, R. H., 251, 296, 300, 318,331,362

Heublein, D., 363 Heusler, K., 320, 362 Heusser, H., 302 Hewett, C. L., 270, 271, 273, 305,306 Hewson, A. T., 2 12 Heyde, E., 174 Heyns, W., 194 Heywood, V., 204 Hibino, K., 11 Hickernell, G. L., 215 Hickmott, P. W., 255 Higgins, M.J. P., 173 Higuchi, W. I., 283 Hikino, H., 115, 193, 214

Author Index Hikino, Y.,193 Hilgard, S., 137 Hill, H. M.,174 Hill, R. K., 39, 126 Hillman, J. R., 183 Hine, K. E., 29 Hiraga, H., 291 Hiraga, K., 274, 295, 304 Hirao, Y., 144 Hiraoka, M., 5 Hirata, T., 177 Hirata, Y., 78, 116, 117, 125, 212,213,216

Hiroi, M.,7 Hirose, M., 238 Hirose, Y., 49,65 Hirotsu, K., 110,213, 214 Hirschfeld, D. R., 216 Hirschmann. F. B., 272 Hirschmann, H.. 272 Hirtzbach, F. de R., 240 Hiscock, A. K., 254 HjortHs, J., 219 Hlubucek, J. R., 7. 91.96, 152, 154

Ho, P., 121 Ho, T.-L., 49,78 Hochberg, R. B., 193,284 Hochstetler, A. R., 75 Hodder, O.J.R., 117,215,217, 219

Hodge, P., 277 Hodgkin, D. C., 216 Hodgkinson, A. J., 225 Hodgson, G. L., 31, 55,58,59, 177, 178

Hodoson. F., 364 Hoellinger, H., 44 Hoerger, E. H., 178 Hoffman, W. A., 334 Hofmeister, H., 234, 301, 324 Hoge, R.. 218 Hogg, J. A., 318 Hogg, J. W., 22, 23, 59, 89, 90 Holden, C. M., 30 Holick, M.F., 331 Hollomon, D. W., 160 Holton, A. M., 269, 305 Holub, M., 208, 210 Holzwarth. G., 3 1 Honig, B., 156 Hooper, S. N., 183 Hootele, C., 96 Hooz, J., 81, 247 Hope, H., 212 Hopkins, B. J., 52 Hoppe, W., 214,215,218 Hoppen, H.-O., 231 Hoppmann, A., 21 Hora, J., 154 Horeau, A., 206 Horibe, I., 71, 73, 75 Horiuchi, C. A.. 238 Horn, D. H. S., 90, 103, 349 Horn, R. R., 31

Hornaman, E. C., 33 Horrocks, W. D., jun., 207 Horwitz, J., 166 Hosada, H., 192 Hoshita, N., 194 Hoshita, T., 192 Hosoda, H.,236,257,269,302, 308,311

Hosoi, K., 42 Hosozawa, S., 101 Hossain, M.B., 21 1, 214 Houdewind, P., 255 Hough, E., 216 Houghton, L. E., 358 Houminer, Y., 235 House, H. O., 155 Houser, R. M.,168 Howard, B., 80 Howard, C. C., 225 Howes, C. D., 197 Howse, P. E., 74 Hoyer, G. A., 109, 225, 234, 312,324

Hsieh, L. K., 197 Hsu, E. C., 31 Hsu, H. Y.,102, 116, 117 Huang, H.-C., 73, 74, 210, 21 1

Huber, C. P., 210 Huber, J., 204 Huber, K., 121 Hubert-Brierre, Y.,282,352 Huckin, S. N., 12 Huettemann, R. E., 259 Huffman, J. W., 105 Hughes, D. L., 21 1 Hughes, M.J., 269 Hughes, P. R.,178 Hugl, H., 345 Huisgen, R., 36 Huisman, H. O., 361.365 Hulcher, F. H., 204 Huneck, S., 53, 63 Hung, H. K., 119 Hungund, B. L., 172 Hunt, R. S., 204 Hurley, J. C., 21 1 Hursthouse, M.B.,216 Husbands, J., 247 Hussner, A.. 362 Hyeon, S. B., 155 Iacobelli, J. A., 332 Ibuka, T., 73,88, 211, 212 Ichikawa, S., 131 Ichino, T., 310 Ideno, Y.,247 Idriss, N., 25 Ignasiak, T., 205 Ignatiadou-Ragoussis, V.,126, 280,345

Iguchi, K., 102 Iguchi, M.,71, 165 Iguchi, T., 6

377

Author Index Ihn, W., 344 Iida, H., 3 Iida, T., 365 Iitaka, Y., 88, 113, 185, 212, 214,216,217,218,219 Ikan, R.,341 Ike,T., 157 Ikeda, T., 135 Ikegawa, S., 192 Ikekawa, N., 234, 235, 330, 331,343 Ikeshima, H., 324 Il’ina, G. P., 40 Ilyukhina, T. V., 274, 363 Imada, I., 168, 169 Imai, K., 175 Imakura, Y., 140 Imanari, M.,112,227 Ima-ye, K., 91 Imblum, R.L., 173 Imhof, R.,349 Immirzi, A,, 212 Imoto, Y.,14 h a , K., 165 Inada, A., 139 Inagaki, F., 166 Inanaga, J., 157 Inayama, S., 88,212 Indyk, H., 36,38 Ingham, C. F., 46 Ingleman-Sundberg, M., 194 Inoue, K., 17,202 Inouye, H., 17, 18, 202 Inouye, Y., 165 Ipatieff, V. N.,5 Ireland, R.E., 135, 142 Iriarte, J., 264, 297, 328 Irie, T., 52, 55 Irikawa, H., 125 Irving, R.S., 205 Isa, T., 102 Isaacs, N. W., 217 Isaeva, Z. G., 41 Isakov, V. V., 138 Ishige, M.,247 Ishiguro, M.,343 Ishihara, S., 3, 263 Ishihara, T., 160 Ishikawa, M.,243, 254, 33 1 Ishino, R.,14 Islam, K. M.S., 215 Isler, O., 156, 219 Isobe, T., 110,214 Isoe, S., 155 Isogai, Y., 114 Itai, A., 88,212,216 Itakura, S., 192 Itaya, N., 16 Ito, M.,192, 257,311 Ito, S., 55, 103, 178 hie, R.A., 209 Iwamura, S., 317 Iwata, T., 160 Izuta, I., 81

Jackson, R. W., 318 Jacobi, P., 215 Jacobs, H. J. C., 279 Jacobsen, N., 35 Jacques, J., 283 Jaquesy, J. C., 246, 266, 268, 273,301,318 Jacquesy, R., 246, 247, 266, 268,273,301,318,337 Jaquignon, P., 317 Jahngen, E. G. E., jun., 20,49 Jain, A. C., 141 Jain, S. C., 187 Jaitly, K. D., 302 Jakobsen, H. J., 126,203 James, M.N. G., 213 Janes, N. F., 16 Jankowski, W. C., 52, 69, 181, 204,226 Janoski, A. H., 255 Jarman, T. R.,124 Jarreau, F.-X., 266, 35 1 Jarvis, J. A. J., 116, 214 Jayewardene, A. L., 7 Jeanloz, R.W., 168 Jefferies, P. R., 95, 99, 100, 114, 185 Jeffery, J., 194 Jeffrey, J. J., 194 Jeger, O., 164, 279, 280, 304, 329 Jenkins, R.C.. 363 Jenner, G., 8 Jennings, P. W., 21 1 Jennings, R.C.,7 . , 23 Jensen, H. P Jensen, S. R., 16, 17 Jeremic, D.. 59 Jerez, F. G., 137 Jin, H., 193 Johannes, B., 159, 204 Johansen, J. E., 158, 167 John, K. V., 167 Johnson, A., 140 Johnson, A. L., 298 Johnson, A. W., 7 Johnson, C. K., 31 Johnson, C. R.,235 Johnson, D. W., 120 Johnson, H. J., jun., 261 Johnson, S. M.,207,208 Johnson, W. S., 176,292,293 Johnston, D. L., 207 Johnston, E. M.,156 Johnstone, R.A. W., 225 Jokic, A., 59 Joly, G., 301 Jommi, G., 63,87, 181,212 Jones, B. E., 199 Jones, C. D., 235 Jones, D. N., 229,263 Jones, Sir E. R.H., 307, 365 Jones, G., 206 Jones, J. B., 337 Jones, R.A., 38

Jones, R.B., 69, 181 Jones, S.L., 228 Jones, W. P., 347 Josey, A. D., 8 Joshi, B. S., 141, 210, 218 Joshi, G. D., 25 Joska, J., 242, 308 Jovanovit, J., 231, 278 Jucker, E..161 Judy, K. J., 182 Julia, M.,36, 40, 123 Julia, S., 15 Junghans, K., 244 JuraniC, I., 232, 329 Jurd, L., 45 Jurion, M.,292,304 Just, G., 234 Just, H., 357 Kaal, f.A., 8 Kabore, I., 275 Kabuto, C., 103,210, 214 Kadota, T., 16 Kagan, H. B., 4,206 Kaisin, M.,70, 96, 212 Kajfez, P., 35 Kaji, J., 185 Kajikawa, A., 343 Kakis, F. J., 23, 126, 280, 345 Kakisawa, H.,91,96, 102, 165, 183 Kakisawa, T., 2 13 Kakudo, M.,2 19 Kakuta, S.,243 Kalan, E. B., 80 Kalicky, P., 275, 276, 305 Kalkman, M.L., 194 Kalvoda, J., 250,320,329,362 Kal’ya, I. A., 8 Kamano, Y., 355, 357, 358, 359,361,365 Kamat, V. N., 141,218 Kamata, S., 114 Kambegawa, A., 252,299 Kamernitzkii, A. V., 274, 316 Kamijo, N., 216 Kamikawa, T., 17,53,97, 110, 214 Kamilov, K. M.,152 Kamiya, K., 218 Kamiyama, A. K., 213 Kanazawa, R., 120 Kandutsch, A. A., 188 Kaneda, M.,216 Kaneko, C., 243,254,331 Kaneko, H., 152 Kanemoto, H., 144 Kanojia, R.M.,245 Kanzaki, T., 169 Kapoor, J. N., 323 Kapoor, S. K.,63 Kappeler, H., 15 Karasiewin, R.,297,312 Karle, I. L., 213,214,219

378 Karle, J., 219, 365 Karlmar, K. E., 191 Karlsson, B., 208, 2 12 Karlsson, R., 70, 212, 213 Karntiang, P., 131 Karplus, M., 156 Karrer, P., 161 Kartha, G., 210, 217 Kasai, R.. 130 Kasal, A., 274 Kasano, M., 14 Kashman, Y., 116, 216 Kasprzyk, Z., 189, 195 Kassar, S. V., 352 Kasuga, R., 152 Katagiri, T., 8 Katayama, C., 2 10, 2 13 Kates, M., 15 1 Kato, K., 261, 282, 327 Kato, M., 8 9 Kato, N., 101, 213 Kato, T., 4, 13, 46, 103, 117, 214 Kato, Y., 103, 214 Katsumura, S., 155 Katzenellenbogen, J. A,, 11, 47,261 Kaufmann, H., 258 Kaufmann, M., 325 Kaufmann, S., 241 Kaur, J., 10 Kawada, M., 168 Kawaguchi, S., 143 Kawahara, M., 193 Kawai, K., 130, 2 17 Kawata, M., 271 Kawazu, K., 215 Kazakova, E. Kh., 41 Kazlauskas, R., 127 Keenan, M. V., 203 Kekwick, R. G . O., 174, 183 Kelecom, A , 70, 213 Keller, U., 152 Kellog, C. K., 74 Kellogg, M. S., 126, 260, 346 Kelly, R. B., 119 Kelly, R. C., 18 Kelly, T. R., 75 Kelsey, J. E.. 2 11 Kende, A. S., 6 3 Kennard, 0.. 211, 212, 215, 217,219 Kennedy, R. L., 5 Kergomard, A,, 22, 164, 253 Kern, F., 172 Kesado, T., 172 Keto, E., 97 Kettenes van den Bosch, J . J., 143 Keuss, H. A. C. M., 279, 327 Khan, M. A., 129, 137 Khan, N. H., 137 Khanna. P., 187 Khare, A., 151 Khariton. K. S., 9 3

Author Index Khastgir, H. N., 145 Kheifits, L. A,, 36, 41 Khemis, B., 352 Khibaum, G., 163 Khong, P. W., 138 Khoo, S. F., 9 3 Khripach, V. A,, 243, 325 Khristoforov, V. L., 159 Khuong-Huu, F., 129, 282, 352,363 Khuong-Huu, Q., 261, 275, 323,352 Kierkegaard, P., 208 Kieslich, K., 290 Kikuchi, K., 148 Kikuchi,T., 141, 142, 218 Kim, C . U., 237 Kim, M., 197 Kim, S.-H., 88 Kimble, B. J., 145 Kimland, B., 7, 155 Kimura, K., 356 241.27 1,272,293 Kimura, M., Kimura, T., 192 Kimura, Y.,6 King, R. R., 273 King,T. J., 143, 212, 213, 218 Kinghorn, A. D., 116 Kircher, H. W., 245, 335 Kiriakidis, M., 108 Kirk, D. N., 227,228,236,241, 244,247,252,254,310,323, 362,364 Kiryushkina, G. V., 25 Kishi, M., 263 Kishimoto, T., 14, 39 Kitagawa, I., 138, 139, 140, 145,219 Kitahara, T., 160 Kitahara, Y., 4, 13, 46, 103, 117,210,214 Kitano, K., 169 Kjaer. A., 16 Kjosen, H., 10. 148, 149, 153 Klein, E., 6 3 Klein. J., 246 Klein, P. D., 194 Kleinig, H., 197 Klimova, L. I., 263 Kline, G. W., 37 Kloss, P., 17 Klyne, W., 154, 227, 364 Klyuev, Yu. P., 5 Knaggs, J. A., 232 Knapp, F. F., 230 Knight, D. W., 4 6 Knight, J. C., 358 Know, J. R., 21 1 Knox, J. R., 95, 99, 100, 114, 185 Knutsen, K., 150 Kobayashi, M., 26 1, 340 Kobayashi, T., 363 Kobnna, N. S., 114 Koch, B., 220

Koch, E., 6 Koch, H.-J., 290 Kochakian, C. D., 194 Kochansky, M. E., 236 Kocdr, M., 69, 237, 292, 309, 317 K&vsky, P., 237 Kodama, M., 103 Kodicek, E., 333 Konst, W. M. B., 29 Korner von Gustorf, E., 206, 207 Kornig, D., 9 Koga, T., 233 Kogami, K., 25 Kogan, G. E., 228 Kohen, F., 142 Kohler, B. E., 166 Kohout, L., 244, 266, 312 Kokke, W. C. M. C., 26.31 Kokpol, U., 131 Kolb, V. M., 263 Koletar, J., 251, 300 Koltsa, M. N., 93 Komae, H., 4 6 Komatsu, M., 358 Komeno, T., 2 2 6 , 2 6 3 Komori, T., 213 Kondo, K., 4 3 Kondo, T., 27 Kondo, Y.,362 Kondukova, Y. V., 162 Konno, C., 193 Konovalov, E. V., 2 1 Kontonassios, D., 335 Kooreman, H. J.. 302 Koreeda, M., 90, 135, 228 Korke, S., 117 Kornule, P. M., 133 Korpi, J., 322 Korte, F., 4 3 Korvola, J., 32, 33 Kosmol, H., 290 KoSoev, K. K., 237 Kossanyi, J., 11 Koster, D. F., 3 9 Kostochka, L. M., 283 Kotake, M., 99 Kotlyar, E. S., 245 Kotsuki, H., 120 Koul, A. K., 6 Kourounakis, P., 361 Kovacs, K., 245 Kowalski, C. J., 135 Koyama, H., 2 1 2 , 2 1 5 , 2 1 9 Koyama, T., 124, 174, 176 Kozhin, S. A,, 22 Koziet, M., 178 Kozuka, M., 73, 74, 2 10, 2 11, 212 Kramer, C. M., 5 3 Kramer, J. K. G., 151 Krapcho, A. P., 2 0 , 4 9 Kravchenko, L. V., 3 Krecek, V., 136

Author Index Kreibich, G., 215 Kreiser, W., 29 Krishnamoorthy, V., 143, 218 Kritchevsky, D., 188, 194 Kriiger, C., 206, 207 Kruger, G., 3 11 Kruger, G. J., 2 18 Kubela, R., 285 Kubinyi, H., 215 Kubo, I., 110 Kubota, K., 143 Kubota, T., 17, 53, 97, 110. 120, 134,214 Kucherov, V. F., 114, 283 Kucinski, P., 336 Kuczynski, H., 42 Kudryavtsev, I. B., 8 Kudryavtseva, M. I., 22 Kuehl, L., 176 Kiippers, F. J. E. M., 43,44 Kuhn, D., 176 Kuhnert-Brandstatter, M., 24 Kulig, M. J.. 239, 281 Kulkarni, A. B., 256 Kulkarni, S. N., 25 Kulshreshtha, D. K., 131, 217 Kumanireng, A., 117 Kumanotani, J., 14, 25 Kumar, N., 74 Kumazawa. S., 4, 13,46 Kumon, S., 358 Kundu, A. B., 139 Kuo, C. H., 290 Kupchan, S. M., 16, 78, 209, 210,211,215,217 Kupcik, V., 209 Kupletskaya, N. B., 31 Kuppens, P. S. H., 364 Kurabayashi, M., 2 13 Kuramoto, K., 192 Kurata, S., 165 Kurchenko, L. K., 245 Kuriyama, K., 71,229 Kurosawa, E., 52, 55 Kuroyanagi, M., 68 Kurz, W. G. W., 205 Kushwaha. S. C., 151 Kusumoto, S., 99 Kutney, J. P., 199 Kutschabsky, L., 207 Kuwamoto, H., 45 Laats, K. V., 8 Labler. L., 285, 288,330 Ladany, S., 193 Ladd, M. F. C., 217 Ladwa, P. H., 25 Lakeman, J., 279,327 Lakshmanan, M. R., 173 Lal, B., 231,334 Lal, M., 352 Lala, A. K., 256 Lalande, R., 40 Lallernand, J. Y., 123

Lam, Y. K., 121 Lane, G. A., 224 Langbein, G . . 298 Langenheim, J. H., 93 Langhammer, L., 24 Lansbury, P. T., 34, 53, 59 Laonigro, G., 239 Lapar, V., 173 Larsen. E., 36 Laszlo, P., 29 Latzin, S., 204 Lauder, H. St. J., 15 Lauer, R. C., 7 Lauer, R. F., 240, 253, 337 Laurent, A., 207 Laurent, H., 234, 301, 324, 364,362 Laven, A., 44 Lavie, D., 103, 214, 327, 366 Lavrik, P. B., 164. 244, 337 Law, J. H., 182 Lawrence, B. M.,22,23,59,89, 90,205 Lax, E. R., 194 Layton, R. B., 81 Leander. K., 44,63 Leclercq, J., 242, 34 1 Lederer, E., 129, 2 17 Lederer, F., 97 Lederman, Y., 243,295 Lee. B., 34 Lee, K.-H., 73,74,87,88,210, 21 1,212 Lee, T. C., 197 Lee, T. H., 148, 197 Lees, R. G., 122, 123, 176 Lefebvre, B., 11 Lefebvre, G., 245, 257, 325 Lefebvre, Y., 361 Leffingwell, J. C., 20 Leftwick, A. P., 254 Legault, D.. 44 Le Goff, N., 246,307 Legrand, M., 255, 364 Leibfritz, D., 226 Leistner, E., 200 Leitereg, T. J., 289 Le Merrer, Y.,49 Lenox, R. S., 11 Lenton, J. R., 189 Lentz, P. J., jun., 206 Leonard, D. R. A., 244 Leppard, D. G., 60 Leppik, R. A., 160 Le Quesne, P. W., 243 Leriverend, P., 30 Le Roux, J. P., 11 Lester, D. T., 7 Letourneux, Y., 261 Levina, I. S., 243, 325, 366 Levine, R. P., 197 Levisalles, J., 240, 246 Levy, C., 194 Levy, E. C., 103,214 Levy, H. A., 218

3 79 Lewbart, M. L., 324 Lewis, A. J., 53 Lewis, A. M., 192 Lewis, D. A., 346,347 Lewis, D. W., 36, 225 Lewis, J., 10 Lewis, K. G., 138,236 Liaaen-Jensen, S., 10, 148, 149, 151, 153, 154, 158,161, 167 Liang, G., 31 Liang, T., 177 Lieberman, J. R., 171 Liberman. S., 193, 284 Lien, T., 150 Lietzke, M. H., 3 1 Lin, G. H. Y., 213,216 Lin, Y. Y., 194 Lincoln. F. H., 318 Linde, H. H. A., 357,358,359, 365 Lindgren, J.-E., 44 Lindley, P. F., 138. 218 Linek, A,, 208, 209, 210 Linstrumelle, G., 15 Lipinski, C. A., 135 Lippmaa, E., 3 Lipscomb, W. N., 208, 214 Lisboa, B. P., 194, 365 Lischewski, M., 115 Liu, I.-S., 148 Liu, R. S. H., 14,231 Liu, S., 275, 276, 305 Livinghouse, T., 235 Lloyd-Jones, J. G.. 193 Locke, D. M.,116 Loder, J. W., 105 Loftus, P.. 30 Loiko, Zh. F., 5 Lokki, J., 205 Lombard, R., 97 London, R. A., 146 Longcope, C., 236 Longevialle, P., 23 1, 3 15 Longley, R., 199 Longobardi, M., 7,42 Loomis, G. L., 74 Loomis, W. D., 170 Lopez, L., 335 Lorck, H., 126, 203 Lorenc, L., 232,250, 329 Losman, D.. 70,2 12,2 13 Lough, A. K.. 183 Lousberg, R. J. J. C., 43, 44, 175 Love, C. J., 33 Loy. P. R., 44 Ludwig, H., 109 Luhadiya, N. K., 25Y Luhan, P. A., 74, 87, 210, 212 Luis, J. G., 104, 108 Luk, C. K., 31 Lukacs, G., 226 Lunenfeld, B., 194

380 Luning. B., 63 Lusinchi, X., 352 Lutcher, K., 337 Luthy, C., 133, 227 Lynton, H., 217 Ma, K. W., 217 Mabry, T. J., 73, 95, 204, 211 Mc Alees, A. J., 109, 11 1 Mc Alpine, G. A., 285 McCallurn, N. K., 4 4 McCapra, F., 214 McCarry, B. E., 292 McClure, R. J., 2 0 8 , 2 1 0 McCormick, A., 154 McCoy, K. E., 186 McCrae, W., 358 McCreary, M. D., 36, 225 McCrindle, R., 98, 101, 109, 111,217 McCurry, P.M., 78 McDonald, E. C., 7 McDonald, F. J., 91 McDonald, P. D., 284 McEachen, C. E., 208 McEwen, R. S., 8 8 , 2 1 2 McGarrity, J. F., 256 McGarry. J. D., 171 McGhie. J. F., 127, 138, 218, 276,346,347 MacGillavry, C. H., 219 McGregor, M. L., 167 MacGrillen, H., 346 McGuire, H. M., 8 1 Machado, A., 176 Machleidt, H., 357 McInnes, A. G., 185 Maclnnes, D., 207 MacKellar, F. A., 18 McKillop, T. F. W., 209 McLaughlin, G. M., 214 MacMillan, J., 109, 112, 113, 114, 184, 185 MacMillan, J. A., 55, 63, 207, 208 Macmillan, J. G., 140 McMorris, T. C., 343, 349 MCMUKY,J. E., 52, 57, 157, 265 MacNicol, D. D., 29 McPhail, A. T., 73, 74, 87, 88, 2 0 7 , 2 0 8 , 2 0 9 , 2 10.2 1 1 , 2 12, 213,214,215,217 McQuillin, F. J., 9, 33 Macrae, R., 2 5 2 , 3 0 6 MacSweeney, D. F., 55,58,178 McWha, J. A., 183 Madan, D. K., 283 Mader, R.A., 63 Madyastha, K.M., 178 Maeda, S., 210 Maeda, T., 5 3 Malkonen, P., 32

Author Index Markl, G., 259 Magerlein, B. J., 318 Magno, S., 77 Magnus, P. D., 39, 244, 283, 338,346 Magnusson, G., 6 8 , 6 9 Magnusson, K. E., 204 Mah, H., 2 5 1 , 3 0 0 Mahalanabis, K. K., 119 Mahato, S. B., 139 Maidment, M. S., 273 Maier, V. P.,183 Maikowski, M., 324 Mailloux, M., 231 Main, P., 213 Makayama, M., 63 Makhubu, L. P., 325 Maki, Y., 32 Maksimovic, Z., 250, 329 Malanina, G . G., 263 Malchenko, S., 5 3 Malhotra, R. K., 259, 315, 365 Malik, S. B., 102 Mallaby, R., 160 Mallams. A. K., 154 Malofsky, B. M., 2 18 Malthiete, J., 283 Manchand, P. S., 116 Mandel, N., 206 Mander, L. N., 106, 107, 120 Mane, R. B., 51 Mangoni, L., 94,106, 139,239 Manhas, M. S., 334 Mani, N. V., 208 Manners, G., 45 Manning, T. D. R., 40, 9 5 Mansuy, D., 40. 123 Mantle, P. G., 69, 181 Manzi, L., 174 Marazano, C., 231 Marchuit, M., 194 Marnal. G., 7 Margolis, S., 186 Mariani, E., 7 Marini-Bettolo, G. B., 143 Marino, M. L., 109 Mark, F., 206, 207 Markezich, R. L., 292 Marks, K., 32 Markus, A., 341 Maroni, P., 25 Maroni-Barnaud, Y., 25 Marpeau, A., 205 Marples, B. A., 233, 267, 361 Marquez, L. A,, 232, 247, 306 Marsh, J. M., 193 Marsh, W. C., 217 Marshall, D. J., 361 Marshall, J. A., 75, 8 9 Marshall, P. J., 188 Marson, S., 13, 117, 168 Marten. D. F.. 12 Marten, T., 52, 179 Marti, F., 279, 329 Martin, C., 259

Martin, H.-G., 203 Martin, J., 209 Martin, J. D., 48, 49. 103, 1 18, 143, 145 Martin, S. S., 93 Martini-Bettolo, T., 17 Martynov, A. A., 22 Marumo, F., 216 Marumo, S., 175 Maruyama, K., 36 Maruyama, M., 210 M a n , A. F., 302 Marx, J. N., 29 Masaki, N., 101,213, 215, 218 Masaki, Y., 12, 125 Masamune, T., 52 Mash’yanov, I. P., 11 Maslen, E. N., 213, 214, 218, 219 Masler, W. F., 4 Mason, N. R., 235 Mason, S. F., 283 Massanet. G. M., 8 7 Massy-Westropp, R. A., 46. 107, 131 Masugi, T., 32 Masuoka, N., 5 3 Mathai, K. P., 107 Mathieson, A. McL., 217 Mathieson, D. W., 225,232 Mathieu, J., 302 Mathur, N. K., 6 Mathur, R. B., 326, 365 Matkovics, B.. 245, 258, 329, 365 Matsubara, J., 39 Matsubara, Y., 5 , 9, 14 Matsubayashi, T., 107 Matsuda, H., 213 Matsuda, S., 272, 293 Matsueda, S., 210 Matsui. M., 16, 115, 160, 161 Matsumoto, M., 4 3 Matsumoto, T., 68, 107, 117, 209, 214 Matsumura, H., 17 Matsumura, Y., 11 Matsuo, A., 5 , 7 , 3 6 , 5 3 , 6 3 , 9 3 Matsuo, K., 120 Matsushita, K., 227 Matsuura, T., 45 Matthews, G . J., 362 Matz, M. J., 215 Maumy, M., 281 Maurer, K. H., 231 Maximov. V. I., 289 Maxwell, J. R., 145, 183 May, E. L., 4 5 Mayor, F., 174, 176 Mayumi, T., 194 Mazhar-ul-Haque, 209, 2 10, 211,212 Mazur, Y., 229,276, 333 Mazzarella, L., 342 Meakins, G. D., 252, 306,307

Author Index Mechoulam, R., 4 3 , 4 4 , 3 3 7 Meck, R.,87, 212 Meehan, T.D., 178 Meguro, H., 115 Mehra, R. K., 352 Mehta, G., 32, 63 Meier, W., 285, 288, 330 Meikle, P. I., 34, 38 Meinwald, J., 2 1, 262, 309 Meister, L., 357 MeSlows, G., 69, 181 Melsom, B. G., 218 Melville, D., 213 Melville, R. D., 213 Meneghello, K.,174 Meneses. A. Y., 141 Menzer, E., 298 Menzies, I. D., 244 Merault, G., 26, 164 Merep, D. J., 41 Merijanian, A., 101 Merlivat, L., 178 Mermet-Bouvier, R.,278 Messner, B., 172 Metayer, A., 248,339, 340 Metge, €., 25 Meyer, K., 357 Meyer, M., 298 Meystre, Ch., 320 Mezzetti, T., 138 Michaelson, R. C., 6 , 4 7 , 242 Michalski, J., 3 17 Micheletti, S. F.. 192 Michelot, D., 15 Michon, P., 283 Mickova, R.,298 Middleton, B., 172 Middleton, E. J., 349 Midgley, I., 336 Mihailovik, M. Lj., 232, 250, 329 Miki, T., 291,295, 304 Miklailov, B. M., 243. 325 Milborrow, B. V., 163,182,183 MiljkoviC, D., 35, 258, 329 MiljkoviC, M., 35, 258, 329 Miller, R. B., 74 Milliet, A., 129 Milliett, P.,352 Mills, D. L., 4 Mills, J. S.,93, 95, 9 7 Mills, R. W., 33, 46, 5 8 Milne, G. W. A., 231 Minale, L., 74, 105, 201, 342 Minardi, G., 32 Minato, H., 73, 7 5 Mincione, E., 243 Minematsu, W., 14, 39 Mirocha, C. J., 171 Miropol'skaya, M. A., 164 Mirrington, R. N., 60 Misawa, K., 238 Mishima, H., 213 Mislow, K., 206, 228 Mitchell, E.D., 167, 174

Mitchell, T. R. B., 247 Mitja, M. R.,102 Mitra, A. R.,45 Mitropoulos, K. A., 193, 194 Mitsuhashi, H., 26, 227, 261, 340 Mitsui, T., 215,219 Miura. I., 74, 271, 272, 293 Miyakado, M., 9 5 Miyaki, T., 96 Miyakoshi, H., 214 Miyamoto, M., 112 Miyashita, M., 6 5 Miyawaki, S., 11 Miyazawa, T., 166 Mizon, J., 361 Mizuhara, Y., 282, 337 Mizuno, H.,105 Mizuta, K., 214 Mo, F., 218 Moffett, R. H., 208 Moir, L. E. J., 326 Moir, M., 104, 143, 218 Molina, M., 247, 306 Moller, H., 143 Molnar, P., 162 Monaco, P.,94, 106, 139 Monasterios, J. R.,227 Money, T., 31, 33, 46, 55, 58, 59,177, 178 Monneret, C., 323,352 Montaguti, M., 188 MonthCard, J. P., 3 9 Monti, S. A,, 73, 21 1 Moore, T. A., 166 Moradpour, A,. 4 Moran, R. A.. 36 Moreau, J. P., 338 Moreau, S., 273, 318 Morgan, J. W., 3 9 Morgan, K., 298 Mori, H.. 361 Mori, J., 31 1 Mori, K., 115, 154, 160, 6 1 Mori, M., 317 Morikawa, S., 5 Morikawa, T., 5 3 Morisaki, M., 216, 234 235, 330,331,343,364 Moriyama, Y., 8 4 Mornon. J.-P.. 218 Morozovskaya, L. M., 263 Morris, D. G., 207 Morrison, G. A., 334 Morrison, J. D., 4 Morrison, J. F., 174 Morrow, D. F., 365 Morsink, L., 298 Morton, D. R.,292 Morton, J. K., 205 Mosbach, E. H., 173, 204 Moscowitz, A., 228 Mose, W. P., 154 Moshier, S.E., 162, 197 Moskvichev, V. I., 3 6 , 4 1

38 1 Moss, G. P., 151, 155 Moss, R.A., 242 Motherwell, W. B., 248 Motherwell, W. D. S., 211,217 Mourgues, P., 23, 238 Mourier, E., 14 Muccino, R.R., 128,231 Miiller, M.. 254, 302, 308, 320 Miiller, P., 254, 285, 3 0 8 , 3 2 0 Mukai, T., 298 Mukhamedova, L. A., 22 Mukherjee, A., 139 Mukherjee, D.. 119. 323 Mukherjee, J., 142 Mukherji, S. M., 275). 329 Mukhopdhyay, S. K., 1 19 Muks, E. A., 8 Mular, M., 34 Mullen, K., 176 Muller, B., 52, 117, 179, 199 Muller, J.-C., 76, 129 Mullins, R. J., 228 Munakata, K., 101, 213 Munday, K. A., 195 Muntz, R. L., 207 Murae, T., 135 Murakami, T., 102, 109 Murata, T., 2 18 Murayama, E., 22 Murofushi, N., 109, 112, 114, 115, 185 Murphy, G. J. P., 184 Murray, R. K., 206 Murty, K. S., 139 Muscio, F., 176 Muscio, 0.J., 176 Mussini. P., 103 Muto, M., 28, 165 Myant, N. B., 194 Myer, K., 365 Myers, H. N., 261 MySlinski, E., 41 Nabetani, S., 193 Nadeau, R., 115,204 Naf-Miiller, R., 152 Nagai, K., 1 4 , 3 6 Nagai, M., 131 Nagano, H., 84 Nagao, Y., 110 Nagarajan, K. N., 42 Nagase, H., 78 Nagata, W., 1 1 4 , 3 6 1 , 3 6 3 Nair, A. G. R., 109 Nakai, H., 219 Nakamura, E.. 98, 101 Nakamura. H., 26 Nakamura, S., 110 Nakamura, T., 5 3 Nakamura, Y ., 17 Nakanishi, K.,4,7,74, YO, 135, 156,215,228 Nakanishi, T., 218,219 Nakano, A., 157

382 Nakano. T., 2 16 Nakano, Y., 13 Nakatani, N., 73, 21 1 Nakayama. M.,5.7, 14,36,53, 93 Namba, S., 42 Nambara, T., 192, 257, 311, 317,355 Nambudiry, M.E. N., 6 8 Nantsch, H. H., 364 Naqvi, S. H. M., 230 Narang, C. K., 6 Narayanan, C. R., 133, 138, 240.258 Narayanan, P., 214, 215 Narayanaswamy, M.,27 Nardini, W., 34 Narisada, M.,114 Narita, H., 55, 178 Narula, A. S., 363 Narwid, T. A., 332 Nash, R. D., 74 Nasipuri, D., 96 Nathan, A. H.. 318 Natori, S., 68, 127, 128 Natsume, M.,214 Natu, A. A,, 138 Naves, Y.-R., 5 Naya, K., 2 1 0 Naya, Y., 65 Nayak, U. R., 6 3 , 2 0 8 Neamtu, G.. 151 Nearn, R. H., 105 Needham, P. H.. 16 Neeman, I., 116,216 Neeman, M.,298 Neidert, E., 111 Neidle, S., 210, 214, 216 Nelson, E. C., 167 Nemorin, J. E., 276, 323 Nepokroeff, C. M.,173 Neri, R., 298, 322 Ness, G. C., 173 Neuenschwander, P., 14 Newman, R. H., 3 , 2 2 5 Newsoroff, G. P., 254 Ngan, H. I., 176 Nguyen-Hoang-Nam, 44 Nguyen Trang, A., 304 Ng Ying Kin, N. M.K., 168 Nibbering, N. M.M.,44, 167 Nicholas, A. F., 214 Nicholas, A. W., 192 Nicholas, H. J., 7 Nicholson, S. H., 237 Nickl, J., 357 Nicklin, P. D., 225, 232 Nicolau, G., 204 Nicoletti, R., 116 Nielsen, B. J., 16, 17 Nikishin, G. I., 4 0 Nikoner, G. K., 152 Nilsson, B., 207, 208. 216 Nilsson, I. M.,4 4 Nilsson, J. L. G., 44

Author Index Ninomiya, I., 365 Nishi, Y., 219 Nishihama, T., 135 Nishihara, K., 46 Nishijima, T., 6 6 Nishikawa, M.,2 18 Nishimura, K., 143 Nishimura, S., 310 Nishioka, T., 18 Nishizawa, M.,68 Nishizaki, T., 5 Nitsche, H., 149, 150 Nitta, I., 210, 218 Niwa, M.,71, 125, 141, 142, 218 Nogami, J., 55 Noguchi, M.,152 Noguchi, T., 9 Noire, J., 49 Nokubo, M.,317 Noll, B. W.,194 Noma, Y., 24 Nomine, G., 289 Nonomura, S., 24 Nordman, C. E., 210, 218 Norgird. S., 151, 167 Norin, T., 30, 208 Novak, C., 209,210 Nozaki, H., 47 Nozoe, S., 91, 216 Nozu, K., 194 Nybraaten, G., 149, 161 Oberhansli, W. E., 156, 219 Obermann, H., 109 Obol’nikova, E. A., 168 O’Callaghan, B. M.,267 O’Connell, A. M.,214 Oda, K.. 212 Ode, R. H., 361 Odom, H. C.. 8 1 Oehlschlager, A. C., 93, 125, 188 Oesterhelt, G., 166 Ogiso, A., 213 Ogorodnikov, S. K., 8 O’Grodnick, J. S., 298 Oguni, I., 172, 182 Ogura, K., 124, 174, 176 Oh, Y. L., 213,219 Ohashi, Y., 73, 89, 211, 212 Ohki, M.,161 Ohloff, G., 28, 152, 153, 163, 209 Ohnishi, R., 5 Ohno, M.,1 6 , 4 2 Ohno, N., 9 5 Ohno, T., 117, 172 Ohrt, J., 206 Ohsawa, T., 105,217 Ohsuga, Y., 107 Ohsuka, A., 9 9 Ohta, Y., 53 Ohuaki, H., 116

Oida, S., 121 Oka, H., 8 1 Oka, K., 327,349 Okabe, K., 216 Okada, K., 16, 161 Okada, M., 3 5 5 , 3 5 6 , 3 5 7 Okada. Y., 110 Okamoto, T., 114 OklobdMja, M.,35 Okorie, D. A., 133 Okuda, K., 194 Okuda, S., 216 Okuda, T., 117 Okukado. N., 157 Okuno, T., 214 Okuno, Y.. 16 Okura, H., 6 Okuyama, T., 193 Olah, G. A., 31 Olbrich, G., 206,207 Ol’dekop, Yu. A., 23 Oldenziel, 0. H., 249 O’Leary, B., 198 Oleson, W. H., 204 O h , G. R., 229 Olsen, D. O., 1 2 , 4 9 Olson, G. L., 176 Olson, R. E., 168 Olson, R. J., 188 Oliva, G., 313 Oliveto, E. P., 362 Omura, S., 172 Onan, K. D., 7 3 , 8 8 , 2 1 1 , 2 1 2 Onda, N., 258 Onken, D., 363 Ono, J., 93 Oosterhoff, L. J., 31 Opferkich, H. J., 116, 215 Oppolzer, W., 5 3 Orgiyan, T. M.,9 9 Oritani, T., 4, 5, 159, 160 Orme-Johnson, W. H., 193 Orsini, F., 87, 103, 212 Ortar, G., 336 Osaki, K., 101, 213, 216 Osawa, T., 73, 8 9 , 2 1 1 , 2 1 2 Osawa, Y., 1 9 4 , 2 9 8 Oshima, p.,194 Osman, S. F., 8 0 Otto, E., 153 Ottolenghi, M.,163 Ourisson, G., 76, 93, 97, 127, 129, 132. 145, 188,189,240, 267 Overton, K. H., 175, 213 Ozainne, M.,178 Ozaki, K.,32,324, 355 Ozon, R., 194 Paasivirta, J., 3, 36 Pachapurkar, R.V.,133 Padilla, J. O., 2 11 Padmanabhan, S., 365 Padolina, W. G., 73. 21 1

383

Author Index Page, G., 322 Page, M.I., 34 Pangnoni, U. M., 71 Pais, M., 266, 351 Paknikar, S. K., 84 Palamand, S. R., 11 Paleg, L. G., 184 Palmisano, G., 141 Pancrazi, A., 275 Pandit, U. K.. 244, 255 Panizo, F. M., 102 Panova, G. V., 31 Pansard, J., 25 Pappo, R., 363 Parashar, V. V., 315, 365 Parkar, M. S., 240,258 Parker, D. G., 9 Parker, K. A., 293 Parker, W.. 65,67, 209 Parkhurst. R. M., 140 Parks, L. W., 188, 189 Parrilli, M., 239 Parrish, D. R., 288, 289 Parrott, M. J., 36 Parry, R. J., 292 Parthasarathy, R., 206 Partridge, J. J., 334 Paryzek, Z., 278 Pascal, Y.-L., 33 Pascard, C., 210 Pascard-Billy, C., 8 1, 129,210, 211,212,217 Paseschnichenko, V. A., 186, 20 1 Pasquet, C., 29 Passet, J., 178 Pataki, J., 241, 256, 298 Patchett, A. A., 242 Patel, A. D., 39 Patel, D. K.,241 Patoiseau, J.-F., 273, 318 Pattenden, G., 15, 46, 177 Patrick, J. E., 236 Pattersen, R. C., 212 Patterson, G. W., 188 Paul, D., 315 Paul. I. C., 55. 63, 103, 187, 207,208,213.214 Pauli, G. H., 224 Paul-Roy, S., 220 Pauly, C., 205 Pavan, M., 16 Payne, T. G., 99 Peacock. R. D., 283 Pearson, D. E., 284 Pech, H., 262,316,317 Pechet, M.M., 251, 296, 300, 318,331 Pechkovskii, V. V., 5 Pedersen, S. B., 36 Pegel, K. H., 111 Pehk, T., 3 Pekkarinen, A., 163 Pekkarinen, L., 163 Pelc, B., 361

Pelizzoni, F., 103 Pelletier, S. W., 116 Pendlebury, A., 307 Penrose, A. B., 209 Peppard, D. J., 117 Perales, A., 138, 218 Perelman, M., 302 Perez, C., 49, 145 Perez, N., 108 Perez-Reyes, M., 43 Perin, F.. 194 Perold, G. W., 52 Perry, G. M., 277 Perry, M., 25 Pesaro, M., 40 Pesce, G., 335 Pesnelle, P.,117 Peter, M. G., 42 Peterson, H. F., 8 Petit, F., 5 , 3 1 Petit, Y..247, 337 Petrashen, I. V., 5 Petrov, G. M., 5 PetroviC, J., 35, 258, 329 Petrow, V., 241,254 Petrzilka, T., 44 Pettersen, R. C., 215 Pettit, G. R., 248, 347, 355, 357,358,359,361 Peyron, L., 23 Pfieffer, D. R., 192 Pfoertner, K.-H., 330 Pharis, R. P., 114, 115, 185, 186 Phelps, D. J., 24, 246 Philip, A., 250 Phillipou, G., 23 Phillips, G. T., 172, 192 Phillips, L., 69, 111, 181 Philp, R. P., 145 Phinney, B. O., 114, 185 Piacenza, L. P. L., 111 Piancatelli, G., 342, 353 Piantadosi, C., 87, 88, 212 Pichat, L., 44 Picot, A., 352 Piers, E., 60 Pierson, G. O., 28 Pieterse, M. J.. 215 Pilotti, A.-M., 208, 212 Pincornbe, C. F., 34 Pinder, A. R., 81 Pines, H., 5 Pinfield, N. J.. 174 Pinhey, J. T., 127, 307, 337 Pini, D., 14 Piozzi, F., 109 Pirkle, W. H., 207 Pivnitsky, K. K., 239 Place, P., 232 Plasse. J., 194 Plenio, H. U., 102 Pogonowski, C. S., 76 Pointer, D. J., 215 Poling, M., 215

Poling, S . M.,197 Pollard, M., 277 Polyachenko, L. N., 159 Polyakova, N. P., 27 Polyavchenko, Y. A., 205 Ponsold, K., 344 Popa, D. P., 99, 101 Popjlk, G., 171, 176 Popova, E. V., 289,295 Popova, L. A., 5 Popplestone, C. R.. 190, 343, 348 Porter, J. W., 173, 196, 197 Posner, G . H., 74,78, 232 Potapov, V. M., 25, 31 Poulter, C. D., 14, 176 Poulton, G. A., 283, 338 Pousette. A., 194 Pouzar. V., 136 Poyser, J. P., 127, 240 Pradhan, B. P., 145 Prager, R. H., 106 Prakongpan, S., 283 Prange, T., 23, 238 Prasad, R. S., 46 Prashad, B., 6 Preston, A.-F., 96 Previtera, L., 94, 106, 139 Price, K. R.,80. 100 Prochhzka, 237, 260 Protiva, J., 136 Prudent, N., 246 Pryce, R. J., 114, 184 Pugh, E. L., 151 Puliti, R., 342 Pulman. D. A., 16 Pusset, J., 23 1

z.,

Quarrie, S. A., 199 Quesneau-Thierry, A., 248, 339 Quinet, M., 99 Quintanilla, J. A. G., 143 Quon, H. H., 41 Qureshi, A. A., 196, 197 Qureshi, N.. 196, 197 Raaen, V. F., 31 Race, H. R., 361 Radlick, P., 207, 216 Radscheit, K., 354, 356, 360 Radushnova, I. L., 25 Rae, D. R., 323 Rae, I. D., 26 Rafikov, S. R.,242 Ragonnet, B., 27 Ragozzino, L., 16 Rahrnan, A.-K., 150 Rahman, F. M.H., 197 Rahman, M., 159 Railton, I. D.. 114, 183, 185 Rainoldo, G., 141 Ragjagopalan, M. S., 252, 323

384 Rakonczay, Z., 245 Ram, B., 10, 11 Ramakrishman, G., 68 Raman, H. H., 32 Ramascarma, T., 188 Ramasseul, R., 283 Ramaswamy. P. S., 240 Ramegowda, N. S., 6 Ramentol, J.. 102 Ramsden, H. E., 15 Ramseyer. J.. 192 Ranganathan, S., 32, 188 Rangaswami, S., 14 1 Rangi, G. J.. 177 Rani, U., 10 Rao, A. S., 27 Ra0,G.S. K.,23,25.51,60,68 Rao, R. B., 350 Raphael, R. A,, 53 Rapp, U., 23 I Rappaport, L., 115, 204 Rappoldt, M. P., 363 Raskin, P., 186 Rasmussen, G. H., 242, 256, 260, 304, 362 Rassat, A., 207 Rassat, R., 283 Rastogi, R. P., 131, 138, 217 Rastrup-Andersen, N.. 126, 203 Ratajczak, T., 114, 185 Rautenstrauch. V., 12, 2Y, 34, 153, 163, 164 Ravelo, A. G., 104 Ravindranath, B., 74 Rayner, D. R.. 207 Razdan, R. K., 44 Reardon, E. J.. 246 Reck, G., 207 Records. R., 228 Redd, W. L., 173 Redel, J., 333 Redpath, J., 270, 271,305,306 Redwood, A. M., 26 Reed, W. D., 172 Reeder, S. K., 21 1 Rees, A. F., 146, 197 Rees, H. H., 174, 186, 193 Regel-Wild, H., 28, 153 Reibstein, D., 182 Reichardt, P. B., 199 Reicher, F., 137 Reichstein, T., 319 Reid, D. M., 113 Reid, R., 167 Reinbold, A. M., 101 Reissbrodt, R., 357 Renard, M. F., 253 Renauld, J. A, S., 215 Rendall, A. I., 298 Renold, W., 152 Rens, J., 225 Renwick, A. J., 178 Repke, K. R. H., 360 Rerat. C., 207

Author Index Restivo, R. J., 210, 217 Retamar, J. A,. 41 Rey, M., 60 Reynolds, G. D., 46 Reynolds, G. F., 242 Rezvuhkin, A. I., 101 Rhodes, D., 204 R i b , J. M., 102 Riccio, R.. 74 Richards, G . F., 36, 206 Richardson, F. S., 3 1 Riche, C., 81, 211 Rickborn, B., 235 Riddiford, L. M., 182 Ridge, D., 63 Rigassi, N., 167 Rigaudy, J., 28 1 Rigod, J. F., 133 Riisom, T., 126, 203 Rik, G. R., 3 Riley, R. G., 11 Rilling, H. C., 176, 196 Rimpelin, J., 8 Rimrner, B., 209 Rimpler, H., 17 Rinehart, K. L., jun., 207 Riva di Sanseverino, L., 215, 219 Rivett, D. E. A., 97 Rizzardo, E., 331, 337 Robbiani, R., 31, 231 Robel, P., 194 Roberts, F. M., 175 Roberts, J. C., 212 Roberts, J. D., 226 Roberts, J. L., 109, 240 Roberts, J. S., 53, 209, 210 Robertson, J. M., 207, 208, 209,213,215,217 Robinson, D. R., 183 Rocquet, F., 27 Roddick, J. G., 199, 201 Rodig, 0. R., 192 Rodrigo, S., 213 Rodriguez, B., 95, 102, 108, 111, 112, 115 Rodriguez, D. B., 197 Rodriguez, M. L., 118 Rodriguez, P., 159 Rodwell, V. W., 173 Rohle, G., 237 Rohrl, M., 214, 215 Rogers, D., 141,207,208,209, 210,211,216,218 Rogers, L. J., 174 Rojas, M. P., 143 Roller, P. P., 192 Rollet, J. S., 219 Rollins, M. H., 163 Roman, S. A,, 47 Romeo, A,, 336 Romo, J.. 24 1 Romo de Vivar, A., 100 Ronchetti, F., 354 Rosen, P., 297,312, 313

Rosenfeid, J. J., 273 Rosenfeld, T., 163 Rosenkratz, G., 241 Rosenstein. F. U., 245, 335 Rosenthal, O., 192 Ross, F. P., 192 Rossmann, M. G., 206,208 Rotman, A., 276,333 Rouessac, F., 16 Roumestant, M. L., 232 Row, L. R., 139 Rowan, R., tert., 156 Roy, B., 142 Roy, D. N., Y6 Roy, S. K., 264 Rubinstein, I., 189 Rubio-Lightbourn, J., 234, 235,331 Rucker, G., 46 Rudakov, E. A., 205 Rudney, H.. 173 Rudnicki, R., 183 Rucker, G., 178 Ruedi, P., 104 Rufer, C., 290 Rundquist, 0. A., 28 Ruo, T. I., 96, 102, 183 Ruppert, J., 288 Ruppert, J. F., 25 Rusch, G. M., 35 Ruschig, H., 354 Russell, G. A.. 364 Russell, G. B., 105 Russell, S. W., 154 Russo, G., 354 Ruth, J. A,, 89 Rutledge, P. S., 109, 240, 346 Ryabushkina, N. M., 27 Ryback. G., 160 Rykowski, Z., 41 Sachihiko, I., 107 Saeva, F. D., 229 Safe, S., 188 Sagiv, J., 229 Sahaki, K., 28, 165 St. Lewak, 113 Saito, A., 174 Saito, Y.,216, 280, 334, 356, 357 Sakabe, N., 216 Sakaguchi, R., 81 Sakai, M.,35 Sakai, T., 49 Sakamoto, H., 17 Sakan, T., 68, 155,213 Sakata, K., 215 Sakazawa. C., 45 Sakurai, E., 193 Sakurai, H., 216 Salazar, I., 3 Salazar, J. A., 277, 353, 354 Salemink, C. A., 43, 44, 143, 175

Author Index Salen, G., 187, 204 Salisbury, P. J., 199 Salmond, W. G., 358 Salzmann, T. N., 257 Samitor, Yu. Yu., 22 Samokhvalov, G. I., 159, 162, 164, 168 Sanchez L., W. E., 103 Sanchez Bellido, I., 4 I Sandberg, E. C., 363 Sandmeier, R., 258, 345 Sandri. S., 12 Sandris, C., 335 Sands, R. D., 39 Sangare, M., 226 Sanghvi, A., 173, 188 Sanhueza. E., 163 Santacroce, C., 77 Santarelli, C . , 1 16 Santelli, M., 27 Sarin, B. M., 365 Sarkisian, G. M., 275, 310 Sasada, Y., 73, 89, 210, 21 1, 212,219 Sasaki, K., 12.5, 212, 216 Sasaki, N., 103, 214 Sasaki, S., 243, 254 Sasaki, T., 16 Sasaki, Y., 2 16 Sassa, T., 1 17 Sasse. J. M., 103 Sasson, Y., 35 Satake, T.. 102 Sathe, V. M., 27 Sato, A., 2 13 Sato, M., 96, 183 Sato, T., 22, 203, 2 15 Sato, Y., 363 Satoh, J. Y.,238 Satre, M., 192 Saucy, G., 285, 287, 361 Sauer, G., 288 Savage, D. S., 270, 271, 305, 306 Savard, K., 193 Savich, T. O., 8 Savona, G.. 109 Sawlewicz. L.. 357 Scaf, B., 95, 99, 100 Scallen, T. J., 173, 187 Scettri, A,, 342, 353 Schafer. L., 224 Schaffner, B. P., 320 Schaffner, K., 280,362 Schairer, H. U., 2 15 Schaufelberger, R., 349 Scheer, I., 245 Schenk, H., 220 Schenone, P., 7, 42 Schetter, I., 18 Schevitz, R. W., 206 Schiaffella. F., 138 Schibeci. R..A.. 264 Schiffauer, R., 168 Schindler, H. D.. 4

Schlatter, H.-R.. 133. 227 Schleyer, H., 192 Schleyer, P. von R., 223 Schmeuli, U., 116, 215 Schmid, H., 42 Schmidt, K., 148 Schmitt, J., 268, 272 Schmitz, F. T., 91, 116 Schnautz, N. G., 74 Schneider, F., 254, 257, 308, 320 Schneider, J. J., 323 Schneider, W. P., 318 Schnoes, H. K., 209, 331 Scholl. P. C., 276. 304 Schooley, D. A., 182 Schorno, K. S., 208 Schrader, B., 364 Schreiber, K., 199, 363 Schreiner, M. E.. 173 Schriefers, H., 194 Schroder, E., 290 Schroepfer, G. J., 187, 230 Schubert, W., 224 Schutte, H. R., 18 Schuller, W. H., 106 Schulte-Eke, K. H., 163, 209 Schulz, D., 206, 207 Schuster, R. E., 225 Schwieter, U., 167 Schwarz, H., 101 Schwarzel, W. C., 289 Scopes, P. M.. 154 Scott, A. I., 199. 203, 213, 214 Scott, J. W., 285, 288 Scott, W. E., 36, 206 Scottow, J. L., 267 Scribner, R. M., 362 Seelye, R. N.. 106 Seeman, J. I., 26, 280 Seetharam, B., 187 Segal, R., 137 Seibl, J., 3 1, 23 1 Seigler, D. S., 204 Seiskind, O., 145 Seki, M., 235 Sekiguchi, K., 144 Sekita, T., 2 12 Selye, H.. 361 Semmler, E. J.. 33 1 Sengupta, P., 141, 142 Senol, A., 208 Seo, S., 124, 195 Septe, B.. 226 Serebryakov, E. P., 114, 283 Serebryakova, T. A., 295, 310 Seshadri, R., 343, 349 Seshadri. T. R., 74, 94, 102, 141, 143, 218 Seto, H., 203 Seto, S., 124, 174, 176 Sevast'yan, A. P., 21 Severini, G., 14 1 Severson, R. F., 106

385 Sevin, A., 6, 27 Seymour, J. P., 34 Shackelford, R. E., 20 Shaffer, G. W.. 40 Shagidullin, R. R., 22 Shahak, I., 35, 36 Shaikhutdinov, V. A,, 4 1 Shalon, Y., 342 Shani, A.. 44 Shannon, P. V. R., 15 Shapet'ko, N . N., 25 Shapiro, E. L., 298, 322 Shapiro, I. L.. 363 Shapiro. R. H., 33 Sharkova, E. V., 17 1 Sharma, P. P., 326 Sharma, T. D., 329 Sharpe, P. E., 229 Sharpless, K. B., 6,23,47.240, 242,253,337 Shavyrin, V. S., 22 Shaw, R., 194, 349 Shchegrov, L. N., 5 Shefer, S., 173, 204 Sheikh, Y. M., 70, 212, 231, 242,341 Shetty, R. V., 39, 126 Shewry, P. R., 174, 188 Shibata, H., 22 Shibata, S., 216, 217 Shibayama, S., 213 Shibuya, M., 110 Shibuya, S., 210 Shiengthong, D., 13 I Shigemasa, Y., 45 Shikita, M.. 192 Shimada, A.. 110, 213, 214 Shimada, K., 317 Shimanouchi, H., 210 Shimizu, S., 22 Shimizu, Y., 140, 349 Shingu,T., 18,73,87,110,141, 211,212 Shinzo. K., 130 Shiota, M., 247 Shirahama, H., 68, 209 Shiro, M., 2 15 Shishibori, T., 124, 176, 177, 186 Shoji, A., 185 Shono, T., 11 Shroff, A. P., 259 Shudo, K., I14 Shulman, F. C., 255 Shutikova, L. A., 38 Shuvalova, S. D., 312 Shveidel, L. Ya., 23 Sica, D., 77 Siddall, J. B., 182 Siekmann, L., 231 Sigel, C. W., 215 Siggia, S., 283 Silver, S. M., 86 Silverstein. R. M.,11, 152 Silverton, J. V., 145, 219

386 Sim, G. A,, 73, 207, 208, 209, 210.21 1,212,213,214,217 Sime, J. G., 2 15 Simmonds, D. J.. 15, 206 Simpson, D. J., 197 Simpson, K.L.,148, 197 Sims, C. L.. 84 Sims, J. J., 78. 207, 213, 216 Singaram, B., 24 Singh, B., 323 259, 315, 326. 365 Singh, H., Singh, M., 329 Singh, R. K., 78, 197 Sinha, U. C., 207 Sinska, I., 113 Sionskaya, L. V.. 5 Siperstein, M. D., 186 Sirevag, R., 197 Sisti. A. J., 35 Siverns, M., 52, 179 Siverns, T. M., 36 Skalaban, T. D.. 162 Skinner, W. A,, 140 Skold, C. N.,120 163 Skorianetz, W., Slaytor, M.B.. 199 Sleigh, T., 270, 306 Sliwowski, J., 189, 195 Slopianka, M., 340 Sly, w. G., 2 19 Small, E., 43 Smith, A. B.. tert., 35 Smith, A. G., 186 Smith, D. G., 185 Smith, D. H., 231 Smith, D. S.H.. 237, 320 Smith, G. A., 347 Smith, G. D., 21 1 Smith, G. V., 38 Smith, G. W., 218 Smith, H.E.. 228 Smith. J. L., 188 Smith, L. L., 192, 194. 239. 28 1 Smith, R. M., 2 10 Smith, W.B., 254 Smudin, D. J., 242 Snajberk, K., 204 Snatzke, F., 42. 364 Snatzke, G.. 42, 153. 227. 228, 364 Sneath, T. C.. 207, 2 10 Snider, B. B., 39 Sobti, R.,15 Sodano, G., 74.342 Solo, A. J., 323 Solodar, A. J., 24 Solomon, P.H., 7 Somei, M., 114 Sondheimer, F.. 358 Sone, N.,169 Song. P.-S., 155, 166 Sood, V. K., 84 Sorm, F., 2 1 0 , 224, 308 Sorochinskaya, E. I., 22

Author Index Sorokina, 0. N., 159 Sorsci, M..205 Sotiropoulos, J., 36, 40 Soucy, M., 60 Souli, E., 316 Sou Phouti., 14 Sowerby, R. L., 52 Sozzi, G., 230 Spark, A. A., 154 Spaziano, V. T., 35 270 Speckamp, W. N., Spencer, T. A., 20,248 Spengel, S., 358, 359 Sperling, W., 1.56, 219 Spike, T. E., 187 Spiteller, G., 109, 229, 231. 278,364 Spiteller-Friedmann, M., 278, 364 Splittstoesser. W. E., 197 Spraggins, R. L., 283 Spyckerelle, C., 145 Srikantaiah, M.V., 187 Srinivasan, A,, 88 Srinivasan, K., 28 Srinivasan, P. R., 3, 295 Srinivasan. R., 207 Srocka. U., 201 Staby. G. L., 174 Stacewicz-Sapuncakis, M., 199 Stache, U., 354, 356, 360 StajiC, M..35, 258, 329 Stallard, M.O., 13, 206 Stam, C. H., 219 105 Stanton, D. W., Starka, L., 363 Starr, M.P., 148 Stebbing, N., 173 Steck, W., 205 Steele, J. A.. 171 Steele, L., 173 Steelink, C., 28, 178 59, 263 Stefanovik, M., Steigner, E., 364 Steindel, S. J., 74 SteinmetL, W.E., 157 Stephens, W. L., 148 Sterling, C., 2 19 Sterling, J. J., 78 Stevens, K. L., 45, 219 Stevenson, D.. 194 Stevenson. J. H.. 16 Stevenson, K.M., 116 Stevenson, R..142 Stewart, G. R., 204 Stewart, I., 162 Stewart, R.C., 53 Still. W.C., 53 Stiverson, R. K., 249 Stobart, A. K., 174, 188 Stockigt, J., 201 Stojanac, Z., 285 Stoochnoff. B. A., 161 Storer, R., 177 Stork, G.. 16, 253, 362

Story, J. A., 188, 194 Stout, G. H., 215, 218,215, Stout, V. F., 218 Strachan, J., 270, 306 Strack, D. L., 23 Strell, I., 215 Strigina, L. I., 138 Stromberg, S.. 30 35 Stromar, M.. Strominger, J. L., 203 Suarez, D., 174 Suarez Lopez, E., 130, 277, 353,354 Subbotin, 0. A,, 36 Subden, R.E., 166 Subrahmanyam, C., 139 Subramanian, S. S., 109 Suchy, M., 2 1 0 Suckling, K. E., 194 340 Sucrow, W., Suda, T., 243, 254 Suemitsu, R.,6 8, 9, 10, 11 Suga, K., Suga, T., 124, 176, 177, 186 Sugie, A., 135 Sugimoto, A.. 243, 254, 33 I Suginome, H.,261, 282, 314, 327 Sugiyama, Y., 169 Suhadolnik, R. J., 177 Sukhanyuk, B. P., 345 Sukh Dev, 15, 63 Sulimovici, S., 194 Sulter, R. P., 198 Sumimoto, M., 27 Sundararaman, P., 88,2 12 Sundin, S., 208 SunjiC, V., 35 Surpuriya, V., 283 Suruda, A. J., 194 Suter, C., 117 Sutherland, M.D., 18 Sutherland, S. A., 213, 217 Suvorov, N.N.,263 Suzue, G., IS1 Suzuki, A., 73, 89, 211, 212 Suzuki, H., 145, 219

Suzuki,K.T..69,181,201,204 Suzuki, M., 55,243 Suzuki, T., 27, 52, 91, 166 Suzuki, Y., 175 Sweeney, J. G., IVY Sycheva. V. M., 5 Sykes, B. D., 156 Sykes, P. J.. 361 Synerholm, M.E.. 39 Szabo, S., 361 Szaboln, J., 154, 155, 158, 162 Szkoda, M.,32 Szpigielman, R., 243, 295 Tabacchi, R., 63 Taboada, J., 3 Tache, Y., 361

Author Index Tada, H., 71 Tada, M.. 84 Taddeini, L., 173, 188 Taggi, A. J., 262,309 Tahara, A.. 105 Tait, A. D., 186, 323 Takabe, K., 8 Takada, N., 210 Takada, S., 2 16 Takagi, A., 40 Takagi, Y., 192 Takahashi, A. R., 219 Takahashi, K., 143 Takahashi, N., 109, 117, 113. 185, 214 Takahashi, O., 25 Takahashi,T., 36,84, 135, 142, 144 Takahashi, T. T., 238 Takai, M.,142 Takani, M., 143 Takaoka, D., 7 Takayama, M., 142 Takei, Y., 161 Takeda, K., 10, 72.73 Takeda, Y., 202 Takemoto, T., 115, 193, 214 Takeshita, T., 234, 33 1 Takeuchi, K., 258 Takizawa, T., 105 Talalay, P., 194 Talapatra, B., 131 Talapatra, S. K., 131 Talaty, A. E. R., 364 Talebarovskaya, I. K., 25 Tali, M. A,, 8 Tamaoki, B. I., 194 Tamari, K., 185 Tamas, V., 162 Tamm, C., 52, 179, 199, 358, 345 Tamura, S., 89, 160, 211, 212, 216 Tamura, T., 365 Tamura, Y., 7 1 Tanabe, A., 201 Tanabe, K., 5 Tanabe, M., 52, 69, 181, 204, 259,300,301,309 Tanabe, Y., 143 Tanahashi, Y., 84 Tanaka, I . , 117 Tanaka, J., 8 Taaaka, K., 5 , 18 Tanaka, N., 131,217 Tanaka, 0..130, 131,217, 218 Tanaka, S., 8, 47, 151 Tanga, K., 177 Taniguchi, S., 194 Tankard. M. H., 289 Tanura, S., 73 Taoka. M., 110 Tarasoff, L., 276, 323 Tarodi, B., 258, 329 Tarzia, G., 300

Tasumi, M., I66 Tatee, T., 84 Tatsumi, C., 24. 35 Tatsuno, T., 53 Taub, D., 290,361,365 Taube, H., 117,216 Taylor, D.. 199 Taylor, D. A. H., 135,217 Taylor, H. F., 182 Taylor, H. L.. 2 15 Taylor, R., 270, 306 Taylor, R. F.. 151, 195 Taylor, R. J. K., 229, 263 Tchen, T. T., 192 Tee. J. L., 154 Teegarden, D. M., 32 Tegyey, Z., 258 Tempestini, L., 247, 306 Templeton. D. H., 214 Templeton. J. F., 23 1 Teng, J. I., 192, 239 Teng, S. E.. 8 Teranishi, A. Y., 253 Terao, Y., 216 Terhune,S. J., 22,23,50,89,90 Terlouw, J. K.. 44 Tesone, M., 194 Tetteroo, J. M. J., 78 Teulade-Arbousset, G.. 178 Teutsch, G., 298, 302, 322 Tewari, N. C., 141 Tewson, T. J., 251, 296 Tezuka, T., 41 Thang, T. T., 234 Then, M.. 176 Thierry, J.-C., 208, 2 11, 266, 35 1 Thies, P. W., I8 Thiessen, W. E., 208, 212, 218 Thomas, A. F., 22, 29, 178 Thomas, D. W., 140 Thomas, M. T., 37 Thomas, R.. 249 Thompson, D. J., 21 2 Thompson, E. D., 188 Thompson, W. W., 5 Thomson, J. A., 349 Thomson, R. H., 143,218 Thoren, S., 68, 69 Thorne, K. J. I., 203 Thornton, 1. M. S., 53, 135 Throop, I>. J., 362 Tiernan, P. L., 250 Tietze, L.-F., 18, 20 Tilley, J. W., 135 Timar, L., 158 Timm, H., 17 Timmins, P. A., 217, 346 Timmons, M. C., 43 Ting, H.-Y., 218 Ting. J.-S., 232 Tint, G. S., 187 Titov, Yu. A,. 243, 325. 363, 366 Tobita, S., 18

387 Toda, M., 125,216 Todd. G., 208 Todesco, P. E., 335 Todo, K., 340 Tokes, L., 362 Togashi, M., 117 Toh, N., 117 Tohma, M., 241 Tokoroyama, T., 120. 134 Tolstikov, G. A,. 242 Tomile, Y.. 2 13. 2 1 X Tomita, K., 2 17, 2 18, 2 19 Tomita, T., 241 Tomita, Y.. 124. 189, 193, 195 Tomko. J., 363 Tomoeda, M., 233 Topfer, A.. 334 Torelli, V., 289 Tori, K., 7 1 , 226, 364 Torii, S., 55 Torgov, I. V., 205, 3 I 0 Torrance, S. J.. 28, 178 Torssell, K.. 35 Toth. G., 154, 155 Toube, T. P., 154 Toubiana, R.. 7 1 Tnuzin. A. M., 27. 49 Toyne, K. J., 225 Toyoda, T.. 142 Tozawa, M., 355 Trainor, G. L., 3 Trave. R.. 71 Triana, G., 87 Trimitsis, G. B.. 254 Trka, A., 274 Trocha-Grimshaw, J., 27,247 Troen, B. R., 194 Troen, P., 194 Trost, B. M., 6, 15, 178, 257 Trotter, J., 209, 216, 217, 219 Trsic, M., 163 Truesdale, L. K., 36, 249 Trumble, T. E., 188 Trus, B., 142 Tsai, C. S. J.. 12 1 Tsai, M., 285, 287 Tsai, T. Y. R., 121 Tsatsas, G.. 335 Tscharner, C., 28, 153 Tschesche, R., 102, 218, 334 Tschirch, A., 97 Tsui, P.. 234 Tsujii, S., 238 Tsukada, K., 151 Tsunagawa, M., 103. 214 Tsuneda. K., 3 10 Tsunenaga, F., 107 Tsuyuki, T., 135, 142, 144 Tubbs, P. K., 172 Tuddenham, R. M., 8 Tuggle, R. M., 247 Tuinman, A., 225, 235, 300 Turner, A. B., 237, 305, 320 Turner, B. L., 204 Turner, J. O., 8

388 Turowska, W., 363 Tursch, B., 70,212,213,215 Tuzimura, K., 115 Ty, T. D., 178 Tyndall, A. M., 186 Uchida, I., 101, 213 Uchida. T., 282, 314 Udarov, B. G., 41 Ueda. H., 24, 35 Ueda, S., 17, 18, 202 Ueda, Y.,262,3 17 Uemura, D., 116, 117 Uesato, S., 18 Uhde, G., 28 Ulmer, R., 24 Umemura, T., 16 Umney, J . C., 97 Ung Hong Ly, 268,301 Unrau, A. M., 188, 190, 343, 348 Uomori, A., 189 Uritani, I., 172, 182 Ursprung, J. J., 218 Uskokovic, M. R.,60,208,332, 334 Usubillaga, A., 108 Uutela, P., 163 Uyeo, S., 215, 361 Uzarewicz, A,, 22 Vaciago, A., 2 16 Vakulova, L. A,, 162 Valenta, 2.. 285 Valverde, S., 95, 102, 108, 11 1, 112, 115 Van Dam, E. M., 254 van de Mark, M. R., 276 Van den Heuval, W. J., 18d Vanderah, D. J., 116 van der Gen, A,, 279 van der Helm, D., 21 1, 214 van der Kerk-van-Hoof, A. C., 143 van der Linde, L. M., 29 Van der Mark, M.R., 304 Van der Molen, H. J., 104 Van Der Puy, M., 278 van der Sijde, D., 302 Van der Vusse, G. J., 194 Van Dorsselaer, A,, 145 Vangedal, S., 190 van Leusen, A. M., 249 van Maarschalkerweerd, M. W., 175 van Rheenen, J. W. A., 186 van Schalkwyk, T. G. D., 218 van Tamelen, E. E.. 18, 122, 123, 176,261 van Wageningen, A., 167 Varkevisser, F. A,, 26 Varlamov, V. P., 159 Varma, V.. 6, 247

Author Index Vasella. A., 23 Vasirian, K., 17 Vaughan, W. R., 32 Vecchi, M., 166 Vendantham, T. N. C., 94, 109 Velarde, E., 264, 297, 313 Velgova, H., 224 Velluz. L., 364 Vendrig. J. C., 188 Venzke, B. N., 21,22 Verghese, J., 20, 24 Verma. A. K., 199 Verner, D., 44 Verschoyle, R. D., 16 Verzar-Petri, G., 176 Veschambre, H., 22, 23, 164 Vesela, L., 209 Vesely, J., 166 Vetter, W., 167, 319 Vialle, J., 35 Vidal, J., 206 Vidari, G., 16 Vig. B., 11 Vig, 0. P., 10, 11 Vignais, P. V., 192 Vigneron, J. P., 206 Vikulova, N. K., 3 1 Villarreal, R., 74 Villarrubia de Martinez, M., 40 Vincent, F., 194 Vincieri, F. F., 23 Vincze, M. V., 7 Vining, L. C., 185 Vinogradov, M. G., 40 Viswanathan, N., 141 Viswanatha, V., 60,218 Vitali, R., 304, 309, 319 Vlad, P. F., 93 Vlahov, R., 12 1,208 Voslich, R., 290 Voigt, B., 114 Volovel’skii, L. N., 345 von Ammon, R., 364 von Beroldingen, L. A., 52 von Carstenn-Lichterfelde, C., 112 von Mutzenbecker, G., 307 von Rudloff, E., 204 von Schantz, M., 205 von Schriltz, D. M., 207 von Szczepanski, Ch., 215 von Wartburg, B. R., 164 Voogt, P. A., 186 Vose, C. W., 252, 258, 302 Voticky, Z., 363 Vouros, P.. 236 Vowinkel, E., 32 Voznesenskaya, I. I., 274 Vree, T. B., 44 Vul’fson, N. S., 364 Vystrcil, A,, 136, 137 Wada, Y., 213 Waddell, T. G.. 88, 212

Wadhams. L. J., 74 Wagner, H., 17 Wagner, H. P., 156,219 Wagner, R., 206,207 Waight, E. S., 11 1 Waisser, K., 137 Wakabayashi, T., 114 Wakayama, S.. 42 Walba, D. M., 135 Walkowin, C., 42 Walkowicz, M., 42 Wall, E. M.. 43 Wall, M. E., 215 Wallach, O., 24 Waller, Ci. R..167 Wallwork, S. C., 2 13 Walters, R. L., 65 Walton, D. C., 183 Wang, A. H. J., 103, 187,214 Wang, G. L.. 224 Wang, H. P., 192 Wani, M. C., 215 Waraszkiewicz, S. M.,55 Ward, P., 36 Wareing, P. F., 183 Waring, A. J., 269 Warren, C. D., 168 Warshel, A., 156 Washburn, W., 275, 305 Washuttl, J., 168 Watanabe, A., 112 Watanabe, I., 216 Watanabe, M., 168, 249 Watanabe, S., 8, 9, 10, 11, 42 Watanabe, T., 210 Watanabe, Y.,282, 337 Waters, J. A,, 279, 362 Waters, T. N., 107,213.214 Watson, D. G., 21 1, 215, 217 Watson, K. G., 124 Watson, K. J., 210 Watson, W. H., 73, 209, 21 1, 218 Watts, R. B., 183 Wayne, C., 206 Weavers, R. T., 96 Webb, T. C., 38 Weber, G., 287 Weber, H. P., 21 1 Weber, L., 298,322 Weber, M., 30 Weedon, B. C. L., 151, 154, 155

Wege, D., 34 Wehrli, F. W., 71 Wehrli, H., 279, 280.304, 320. 329,349 Weickgenannt, G., 28 Weiler, L., 12, 350 Weill-Raynal, J., 362 Weinges, K., 17 Weinman, J., 23 1 Weinman, S., 23 1 Weiritraub, H., 194

Author Index Weintraub, P. M., 250 Weiss, E., 357 Weiss, G., 9 0 Weiss, R., 208, 21 1 Weiss, U., 228 Weissenberg, M., 327 Welch, M., 193 Welch, S. C., 65, 142 Wels,C. M., 112, 114,184,185 Wender, P. A., 81 Wendler, N. L., 290 Wenkert, E., 78, 103, 107 Wernick, D. L.. 36, 225 Wertz, D. H., 223 Weseman, R., 298 West, C. A., 184 West, P. J., 283, 338 Weston, R. J., 93 Wettstein, A,, 320 Weyerstahl. P., 21 Wheaton, T. A.. 162 Wheeler, D. M. S., 362 Wheeler, M. M., 362 Whiffin, T.. 95 White, A. F., 7 White, A. H., 194 White, D. H., 107 White, D. N. J., 21 1, 212 White, G., 5 9 White, J. D., 25, 55, 116, 218 White, R. H., 55. 207 Whitehurst, J. S., 289 Whitesides, G. M., 36, 225 Whiting, D. A., 15.44,45.206, 218 Whittaker, D., 30, 34. 36, 38, 41 Whitten, C. E., 78 Whittle, P. R., 364 Wiberg. K. B., 37 Wicha, J., 237, 239 Widdowson, D. A., 124, 188, 256 Widen, K.-G., 36 Widmer, E.. 285 Wie, C., 231 Wiechert. R., 225, 234. 288. 301,312,324,361,362,363 Wiedhaup, K., 176 Wiehager, A.-C., 208, 212 Wieland, D. M.. 235 Wieland, P., 258, 320 Wiesner, K., 121 Wife, R. L., 358 Wigfield, D. C., 24, 246 Wight, C., 173 Wijesekera, R. 0. B., 7 Wild, J., 15 Wiley, R. A., 71 Wilke. G., 38 Wilkins, H. J., 269 Willcott, M. R., 13 Willett, J. D., 186 Willhalm, B., 152 Williams, D. H., 227, 307, 347

Williams, D. J., 69, 141, 181, 218 Williams, G. C., 194 Williams, J. R.,275, 310 Williams, K. I. H., 236, 239 Williams, P. M.,113 Williams, T. H.. 60, 208 Williams, V. P., 160 Williamson, D. M.. 254 Willy, W. E., 292 Wilson, R. S.. 45 Wilton, D. C., 195 Wiltshire, C., 3 18 Windholz, T. B., 361 Wing, R. M.. 2 0 7 , 2 1 3 , 2 1 6 Winskill, N., 199 Winternitz, F., 234 Wipke, W. T., 246 Wirthlin, T., 304 Witkop, B., 362 Wittelaar, J. J. G. M., 298 Witters, R. W.. 21 1 Wittstruck, T. A,, 239 W J-Hsu., 197, 198 Wohifahrt, J., 302 Wojciechowski, Z. A., 189 Wojtowski, R. K., 325 Wolf. €4. R.,28. 164 Wolfe, G. A., 209 Wolfe, L. S., 168 Wolff, G., 132, 267 Wolff, M. E., 226 Wolff, s., 35, 37 Woodgate, P. D., 96 Woods. G. F.. 273, 361 Woods, H. A., 188 Woodward, K. N., 255 Worthington, K. J., 186 Wright, G. E., 255 Wright, H., I16 Wrobel, J.. 173 Wrzeciono, V., 363 Wu, I. B., 73, 2 1 1 Wiiest, H., 29, 164 WurtT, G . , 218,237 Wunderlich, J. A., 207 Yagi, H., 160 Yagupol'skii, L. M., 2 1 Yakamura, S., 2 16 Yakhimovich, R. I., 245 Yakubovich, V. B., 5 Yamada, K., 3 , 7 8 Yamada, S., 243,254, 331 Yamagishi, T., 227 Yamaguchi, I., 112 Yamaguchi, M., 148, 157 Yamaguchi, T., 16 Yamakawa, K., 81 Yamamoto, H.. 39,47. 96 Yamamura, S., 71, 125, 213 Yamane, H., 109, 112 Yamashita. K., 4, 5, 159, 160 Yamauchi, H., 217, 219

389 Yamazaki, S., 113, 185, 214, 216 Yanai, T., 25 Yano, K., 66 Yanuka. Y., 252 Yarmchuck, L., 245 Yasuhara, F., 21 Yasunari, Y.. 52 Yeong, Y. C., 5 1 Yogev, A,, 229 Yokoi, T., 141 Yokota, T., 112, 113. 185, 214 Yokowski, N., 163 Yokoyama, A., 128 Yokoyama, H., 148, 162, 197 Yokura, S., 53 Yonehara. H., 203 Yoshida, T.. 18, 117 Yoshihira, K., 68 Yoshii, E.. 324, 355 Yoshikawa, M., 138. 140 Yoshikoshi, A,, 4 0 , 6 5 , 8 9 Yoshioka, H.. 73. 95, 21 1 Yoshioka, K., 274, 295 Yoshioka, Y., 304 Yoshioko, M., 289 Yoshizawa, I., 272, 293 Yosioka,I.. 138, 139. 140. 145, 219 Young, D. W., 213, 214 Young, F., 283 Young, G. A. R., 86 Young, M. E., 253 Young, M. R., 1 0 Youssefyeh, R. D., 137 Yur'ev, V. P., 242 Zacharius, R. M.,80 Zacharova, N. I., 164 Zadock, E., 116,216 Saidlewicz, M., 22 Zaikin, V. G., 364 Zakharychev, A. V., 228. 310 Zala, .A. P., 272 Zalewski, R., 365 Zalkin, A., 214 Zalkow, L. H., 208 Zalkow, Z. H., 74 Zamudio, A,, 74 Zand, R.,156 Zarecki, A., 237 Zaretskii, Z. V. I., 295 Zavarin, E.. 204 Zbiral, E., 345. 362 Zderic, J. A,, 365 Zdero, C., 93, 178 Zechmeister, K., 2 14, 2 15 Zeelan, F. J., 301 Zehra, F.. 129 Zelenka, A., 137 Zelnik, R., 103, 214 Zenk, M. H.. 201 Zhungietu, G. I., 345, 365 Ziegler. F. E.. 81

Zieti. E., 223 Ziffer. H.. 26. 228. 280

Zink, M.P., 28 Zintel, J. A.. 188

Zundel. J. L., 132, 267 Zvonkova, E. N.,159, 162