Terpenoids and Steroids: Volume 7 (SPR Terpenoids and Steroids (RSC))

A Specialist Periodical Report

Terpenoids and Steroids Volume 7

A Review of the Literature Published between September 1975 and August 1976 Senior Reporter J. R. Hanson, School of Molecular Sciences, University of Sussex Reporters D. V. Banthorpe, University College, London G. Britton, University of Liverpool 6. V. Charlwood, King's College, London J. D. Connolly, University of Glasgow N. Darby, University of British Columbia, Vancouver, Canada D. N. Kirk, Westfield College, London T. Money, University of British Columbia, Vancouver, Canada J. S. Whitehurst, University of Exeter

R. B. Yeats, Bishop's University, Lennoxville, Quebec, Canada

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

ISBN: 0 85186 316 7

ISSN: 0300-5992 Library of Congress Catalog Card No. 74-61 5720

Copyright 0 1977 The Chemical Society All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means - graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems - without written permission from The Chemical Society

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

In trod uc tion The terpenoids and steroids have continued to provide a fascinating wealth of chemistry. Over the past few years the availability of spectroscopic instrumentation has led to many structures being proposed utilizing plausible analogies based partly on potential biogenetic relationships with compounds of known structure but without a firm inter-relationship. However, each year new skeletal types of terpenoid are discovered. There are many examples now of terpenoids with differing carbon skeleta co-occurring or at least occurring in related plants. Thus, although biogenetic analogy forms a powerful tool for focusing attention on likely structures, the need for either a definitive X-ray analysis or an unambiguous chemical correlation is an ever-present one. A substantial amount of 13C n.m.r. data has now been obtained for the various major groups of terpenoid and this method has now taken its place alongside 'H n.m.r. as a structural tool. It has found considerable application in biosynthesis in determining the origin of carbon skeleta. Stereochemical studies in biosynthesis have also been a major area of interest during the year. The steroids have remained valuable substrates for studying the scope of physical methods and of new reactions. The number of highly oxygenated plant steroids, such as the withanolides and the Nicundru products, has continued to increase. In this Report, we have included the section on the partial synthesis of steroids within the chapter on steroid properties and reactions in an effort to reduce the overlap between the steroid reactions and steroid synthesis chapters. July 1977

J. R. HANSON

Contents Part I Terpenoids 3

Chapter 1 Monoterpenoids By R. B. Yeats 1 Physical Measurements: Spectra efc.; Chirality

3

2 General Synthetic Reactions

5

3 Biogenesis, Occurrence, and Biological Activity

8 10 10 12 18

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

20

5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, Iridoids p-Menthanes o-Menthanes m-Menthanes Tetrame thylcyclohexanes Dimethylethylcyclohexanes Cycloheptanes

22 22 22 29 34 35 35 35 36

6 Bicyclic Monoterpenoids Bicyclo[3,l,0]hexanes Bicyclo[2,2,1Jheptanes Bicyclo[3,1,llheptanes Bicyclo[4,1,OJheptanes

36 36 37

7 Furanoid and Pyranoid Monoterpenoids

45

8 Cannabinoids and other Phenolic Monoterpenoids

48

41 44

V

Terpenoidsand Steroids

vi

Chapter 2 Sesquiterpenoids By N. Darb y and T. Money 1 Farnesanes

52 52

2 Mono- and Bi-cyclofarnesanes

54

3 Bisabolane, Sesquicarane, Sesquithujane

58

4 Sesquipinane, Sesquifenchane

62

5 Carotane, Acorane, Cedrane

62

6 Cuparane, Trichothecane

65

7 Chamigrane

69

8 Amorphane, Copaane, Ylangocamphane, Copacamphane, etc.

71

9 Himachalane, Longipinane, Longicamphane

75

10 Humulane, Caryophyllane, Protoilludane, Illudane, Marasmane, Hirsutane

77

11 Germacrane

83

12 Eudesmane, Vetispirane, Eremophilane

87

13 Guaiane, Psesidoguaiane

102

14 Miscellaneous

105

Chapter 3 Diterpenoids By J. R. Hanson 1 Introduction 2 Bicyclic Diterpenoids Labdanes Clerodanes

107 107 108 108 111

3 Tricyclic Diterpenoids Naturally Occurring Substances The Chemistry of the Tricyclic Diterpenoids

112 112 115

4 Tetracyclic Diterpenoids

117 117 118 119 121 121

Naturally Occurring Substances The Chemistry of the Tetracyclic Diterpenoids Gibberellins Grayanotoxins Diterpenoid Alkaloids 5 Macrocyclic Diterpenoids and their Cycclization Products

121

6 Miscellaneous Diterpenoids

123

7 Diterpenoid Total Synthesis

125

vii

Contents

Chapter 4 Triterpenoids By J. D. ConnolJy 1 Squalene Group

130 130

2 Fusidane-Lanostane Group

132

3 Dammarane-Euphane Group Tetranortri terpenoids Pentanortriterpenoids Quassinoids

138 139 140 140

4 Shionane-Baccharane Group

14 1

5 Lupane Group

141

6 Oleanane Group

143

7 Ursane Group

149

8 Hopane Group

150

9 Stictane-Flavicane Group

153

Chapter 5 Carotenoids and Polyterpenoids By G.Britton

155

1 Introduction

155

2 Carotenoids New Structures Monocyclic Carotenoids Bicyclic Carotenoids Isoprenylated Carotenoids Triterpenoid Carotenoids Degraded Carotenoids Stereochemistry Geometrical Isomerism Absolute Configuration Synthesis and Reactions Carotenoids Retinol Derivatives Other Degraded Carotenoids Physical Methods and Physical Chemistry Separation and Assay Methods Mass Spectrometry 13 C N.M.R. Spectroscopy Optical Rotatory Dispersion and Circular Dichroism Electronic Absorption Spectroscopy Miscellaneous Physical Chemistry Retinal as Visual Pigment Model: Spectroscopy and Physical Chemistry

155 155 155 156 158 158 158 159 159 159 161 161 167 168 170 171 171 171 172 172 172 173

...

Terpenoids and Steroids

Vlll

3 Polyterpenoids and Quinones Polyterpenoids Quinones

Chapter 6 Biosynthesis of Terpenoids and Steroids By 0.V. Banthorpe and B. V. Charlwood

173 173 174

176

1 Introduction

176

2 Acyclic Precursors

176

3 Hemiterpenoids

183

4 Monoterpenoids

183

5 Sesquiterpenoids

187

6 Diterpenoids

200

7 Steroidal Triterpenoids

202

8 Further Metabolism of Steroids

208

9 Non-steroidal Triterpenoids

213

10 Carotenoids

216

11 Meroterpenoids

219

12 Methods

221

13 Chemotaxonomy and Genetics

222

Part I/ Steroids Chapter 1 Steroid Properties, Reactions, and Partial Synthesis By 0.N. Kirk

227

Section A : Steroid Properties and Reactions 1 Structure, Stereochemistry, and Spectroscopic Methods N.M.R. Spectroscopy Chiroptical Methods Mass Spectra Miscellaneous Techniques

227 229 23 1 233 234

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

235 235 239 240 242

ix

Contents

3 Unsaturated Conpounds Electrophilic Addition Other Addition Reactions Other Reactions of Olefinic Steroids Acetylenic compounds Aromatic Compounds

244 244 247 253 256 257

4 Carbonyl Compounds Reduction of Ketones Other Reactions at the Carbonyl Carbon Atom Reactions involving Enols or Enolic Derivatives Oximes, Tosylhydrazones, and Related Derivatives of Ketones Carboxylic Acids and Derivatives

258 258 259 263

5 Compounds of Nitrogen and Sulphur

270

6 Molecular Rearrangements Backbone Rearrangements Aromatization of Rings Miscellaneous Rearrangements

273 273 275 276

7 Functionalization of Non-activated Positions

279

8 Photochemical Reactions

28 1

9 Miscellaneous

286

267 270

Section B : Partial Synthesis of Steroids 10 Cholestane Derivatives and Analogues

288

11 Vitamin D and its Metabolites

291

12 Pregnanes Miscellaneous Pregnanes Pregnanes Substituted at C-18

296 296 298

13 Lactones and Cardenolides

302

14 Heterocyclic Steroids

305

15 Steroid Radioimmunoassay and Labelled Steroids Haptens Labelling with Isotopic Hydrogen 0ther Is0topes

309 3 10 3 12 315

16 Miscellaneous Syntheses

3 16

X

Terpenoidsand Steroids

Chapter 2 Steroid Total Synthesis By J. S. Whitehurst

320

Erratum

329

Author Index

330

Part I TERPENOIDS

1 Monoterpenoids BY R.

B. YEATS

This Report covers the primary literature from August 1975 up to August 1976; literature available only as a Chemical Abstract after September 1st 1976 is not included. Two useful supplementary volumes’a32aupdate the corresponding chapters in the second edition of Rodd3 on acyclic and monocyclic monoterpenoids, on bicyclic monoterpenoids,*’ and on the biogenesis of mevalonate, hemiterpenoids, and monoterpenoids.2“ A useful textbook on natural plant constituents includes some biochemistry and chemistry of mon~terpenoids.~

’’

1 Physical Measurements: Spectra etc.; Chirality 13

C N.m.r. assignments for campholenic aldehyde, car-3-ene, P-cyclocitral, three lavandulyl derivatives, and nerol oxide, as well as for 24 acyclic, 39 p-methane, six bicyclo[3,1,0]hexane, twelve bicyclo[2,2, llheptane, and eight bicyclo[3,1,l]heptane monoterpenoids are recorded.’ The use of trichloroacetyl isocyanate to generate carbamates in situ can be used to identify methyl groups adjacent to a tertiary alcohol (downfield shift of 0.29-0.44 p.p.m.) and to assign the geometry of double bonds in allylic alcohols.6 Similarities in the ‘H n.m.r. and infrared spectra of monoterpenoids may be valuable in identifying new sesquiterpenoid analogue^.^ Mass spectral papers include another compilation of monoterpenoid alcohol spectra,8 a comparison of fragmentation patterns for camphor and menthone with their oxime, semicarbazone, and nitrophenylhydrazone derivatives,’ and a comparison of collisional activation mass spectra of ten related acyclic, monocyclic, and bicyclic monoterpenoid hydrocarbons together with derived C7H9+ions. l o 1

2

3

4

5

6 7 8 9

10

( a )‘Rodd’s Chemistry of Carbon Compounds’, Second Edition Supplement, Vol. 11, Parts A and B, ed. M. F. Ansell, Elsevier, Amsterdam, 1974; ( b ) S. H. Harper, ibid., Chapter 6, p. 175. (a) ‘Rodd’s Chemistry of Carbon Compounds’, Second Edition Supplement, Vol. 11, Parts C, D, and E, ed. M. F. Ansell, Elsevier, Amsterdam, 1974; ( 6 ) R. T. Brown, ibid., Chapter 12, p. 53; (c) T. W. Goodwin, ibid., Chapter 19, pp. 237-247. ‘Rodd’s Chemistry of Carbon Compounds’, Second Edition, Vol. 11, Part B and Vol. 11, Part C , ed. S. Coffey, Elsevier, Amsterdam, 1968 and 1969. T. Robinson, ‘The Organic Constituents of Higher Plants’, 3rd edn., Cordus Press, North Amherst, Massachusetts, 1975. F. Bohlmann, R. Zeisberg, and E. Klein, Org. Magn. Resonance, 1975,7,426. D. R. Taylor, Canad. J. Chem., 1976,54,189. S . J. Terhune, J. W. Hogg, A. C. Bromstein, and B. M. Lawrence, Canad. J. Chern., 1975,53, 3285. J. Iwamura, K. Beppu, and N. Hirao, Bunseki Kiki,1976,14, 162 (Chem. Abs., 1976,85, 63 172). J. Cassan, R. Camain, and M. Azzaro, Analysis, 1975, 3, 323. H. Schwarz, F. Borchers, and K. Levsen, Z . Naturforsch., 1976,31b, 935.

3

4

Terpenoids and Steroids

The c.d. spectra of N-salicylidene derivatives of p-menthane, thujane, and fenchane amines correlate with known absolute configurations, I ' and a new octant rule for nitramines is illustrated with N-nitrocamphidine. l 2 In measuring the fluorescent-detected c.d. spectrum of camphor, differences in the fluorescence intensity of the chromophore may result from restricted Brownian rotation during the lifetime of the excited state rather than from the circular dichroism of the c h r o m o p h ~ r e . 'Differences ~ in the absorption and fluorescence c.d. spectra of a number of bicyclo[2,2, llheptanones have been e ~ p 1 a i n e d . The l ~ greater sensitivity of vibrational c.d. to structural changes than absorption spectra should make it a valuable tool for determining molecular stereochemistry; some C-H data are provided for borneol, camphor, menthol, and the pinenes.l' and Alkylation of the Schiff base derived from (lS,2S,SS)-2-hydroxypinan-3-0ne glycine t-butyl ester has yielded D-amino-acids in high optical purity (e.g.D-alanine, 83'/0),'~ and asymmetric hydrogenolysis of the chiral hydrazone derived from (2s)-bornylamine and ethyl pyruvate yields L-alanine in 46.5% optical purity. l7 In another model system for the action of NAD(P)H, (-)-menthy1 benzoylformate is reduced with (- )-menthy1 Hantzsch ester, catalysed by Zn2' under Reformatskytype conditions, in 77% optical yield to (-)-menthy1 (2R)-mandelate (cf. Vol. 6, p. 6).'* (+ )-8-Phenylmenthyl acrylate is dramatically superior to (- )-menthy1 acrylate in chiral directing ability in Diels-Alder cycloaddition reactions." The substituted caprolactam available from (- )-menthone oxime by Beckmann rearrangement is used to oxidize sulphides in low optical yields2' Other syntheses of chiral sulphur compounds based upon (- )-menthol include the synthesis of 0-substituted diary1 sulphilimines, sulphonium ylides, and sulphoxides from the corresponding (0)-( - )menthoxydiarylsulphonium salts,21the synthesis of thiirans in low optical yield using S-lithiomethyl 0-(-)-menthy1 dithiocarbonate,22 and the straightforward diastereomeric preparation of chiral benzyl thiols from sodium 0 - ( -)-menthy1 d i t h i ~ c a r b o n a t e Other . ~ ~ asymmetric induction reactions involving monoterpenoids include the synthesis of a chiral D e w a r - b e n ~ e n ea, ~one-step ~ synthesis of S - ( +)2,2,2-trifluorophenylethanolof sufficient purity for direct use as a chiral n.m.r. ~ o l v e n t , ~two ' routine investigations using chiral lithium aluminium hydride

'1

l2

13 1J 15

16 l7

18

19

20 21

22 23 24 25

H. E . Smith, E. P. Burrows, E. H. Massey, and F.-M. Chen, J. Org. Chem., 1975, 40, 2897. T. Polonski and K. Prajer, Tetrahedron L,etters, 1975, 3539; N-camphidine is structure 3 and not 2 as reported. D. Ehrenberg and I. Z. Steinberg, J. Amer. Chem. SOC.,1976, 98, 1293. H. P. J. M. Dekkers and L. E. Closs, J. Amer. Chem. SOC.,1976, 98, 2210. L. A. Nafie, T. A. Keiderling, and P. J. Stephens, J. Amer. Chem. SOC.,1976,98, 2715. S.-I. Yamada, T. Oguri, and T. Shioiri, J.C.S. Chem. Comm., 1976, 136. S.-I. Kiyooka, K. Takeshima, H. Yamamoto, and K. Suzuki, Bull. Chem. SOC.Japan, 1976, 49, 1897. K. Nishiyama, N. B a t a , J. Oda, and Y. Inouye, J.C.S. Chem. Comm., 1976, 101. E. J. Corey and H. E. Ensley, J. Amer. Chem. SOC., 1975,97, 6908. Y. Sato, N. Kunieda, and M. Kinoshita, Chem. Letters, 1976, 563. M. Moriyama, S. Oae, T. Numata, and N. Furukawa, Chem. and I d . , 1976, 163. C. R. Johnson and K. Tanaka, Synthesis, 1976, 413; formula 2 is incorrect. M. Isola, E. Ciuffarin, and L. Sagramora, Synthesis, 1976, 326. J. H. Dopper, B. Greijdanus, D. Oudman, and H. Wynberg, J.C.S. Chem. Comm., 1975, 97'2. D. Nasipuri and P. K. Bhattacharya, Synthesis, 1975, 701.

Monoterpenoids

5

c o m ~ l e x e s ,and ~ ~ a’ report ~ ~ of acetophenone reduction with monoterpenoid glycollithium aluminium hydride complexes.28 Chromatography of radiochemically homogeneous terpenoids has been reviewed;29 useful gas-chromatographic techniques reported include the use of polyphenyl ether in g.c.-m.s. of 23 monoterpenoid hydrocarbon^,^' the use of 3,4,5-trimethoxybenzylhydrazine for pre-column removal of aldehydes and ketones,31and the resolution of some bicyclic alcohols and ketones by co-injection with a volatile chiral resolving agent.32

2 General Synthetic Reactions Some useful reviews which discuss applications from, or are of value to, monoterpenoid chemistry include applications of singlet oxygen,33 manganese dioxide,34 di-isobutylaluminium and tri-isobutylaluminium h y d r i d e ~ c, a~t~e ~ h o l b o r a n eand ,~~ chlorosulphonyl i~ocyanate,~’ discussions of functional group selectivity of complex hydride reducing agents,38 h y d r o z i r ~ o n a t i o nselenium ,~~ reagent^,^' and the photochemistry and spectroscopy of &unsaturated carbonyl compound^;^' an interesting, but non-novel, account of industrial terpenoid synthesis has also appeared.42 Epoxidation of tetrahydropyranyl ethers (e.g. isopentenyl tetrahydropyranyl ether) produces readily detonatable peroxides which are stable to many commonly used methods of d e s t r ~ c t i o n . ~ ~ and mercury(~~)-catalysed~~ [3,3]sigmatropic rearangement of allylic trichloroa~etimidates~~ and allylic p ~ e u d o - u r e a (e.g. s ~ ~ geraniol, linalool) are useful for the 1,3-transposition of hydroxy- and amino-groups; the former is synthetically preferred. The [2,3]sigmatropic rearrangement of allylic sulphoxides has been used to effect an alkylative 1,3-carbonyl transposition of enones (e.g. carv~ne).~~ 26 27 28

29

30

31 32 33 34 35 36 37 38 39 40

41 42 43 44

4s

46

U. Valcavi, P. Balzano, and V. Monterosso, Ann. Chim. (Italy), 1975,65, 91. U. Valcavi, P. Balzano, and V. Monterosso, Ann. Chim. (Italy), 1975, 65, 543. E. D. Lund and P. E. Shaw, 172nd A.C.S. Meeting, San Francisco, August 1976, Abstracts ORGN, No. 169. C. J . Coscia, in ‘Chromatography’, ed. E. Heftmann, 3rd. edn., Van Nostrand-Reinhold, New York, 1975, p. 571. B. J. Tyson, J. Chromatog., 1975, 111, 419. B. P. Moore and W. V. Brown, J. Chromatog., 1976,121, 279. P. D. Maestas and C. J. Morrow, Tetrahedron Letters, 1976, 1047. G. Ohloff, Pure Appl. Chem., 1975, 43.481. J. J. Fatiadi, Synthesis, 1976, 65, 133. E. Winterfeldt, Synthesis, 1975, 617. C. F. Lane and G. W. Kabalka, Tetrahedron, 1976,32, 981. J. K. Rasmussen and A. Hassner, Chem. Rev., 1976,76, 389. E. R. H. Walker, Chem. SOC.Rev., 1976, 5, 23. J. Schwartz and J. A. Labinger, Angew. Chem. Internat. Edn., 1976,15, 333. K. B. Sharpless, K. M. Gordon, R. F. Lauer, D. W. Patrick, S. P. Singer, and M. W. Young, Chem. Scripta, 1975,8A, 9. K. N. Houk, Chem. Rev., 1976,76, 1. H. Pommer and A. Nurrenbach, Pure Appl. Chem., 1975,43, 527. A. I. Meyers, S. Schwartzman, G. L. Olson, and H.-C. Cheung, Tetrahedron Letters, 1976, 2417. L. E. Overman, J. Amer. Chem. SOC.,1976,98,2901; an earlier communication, ibid., 1974,96,597, was omitted from these Reports. S. Tsuboi, P. Stromquist, and L. E. Overman, Tetrahedron Letters, 1976, 1145. B. M. Trost and J. L. Stanton, J. Amer. Chem. SOC., 1975,97,4018; this paper was inadvertently omitted from last year’s Report.

6

Terpenoids and Steroids

A 1,3-hydroxy-transposition[e.g.geraniol to linalool, (+ )-cis-carveol to (- )-ciscarve011 has been accomplished via the previously reported (Vol. 5, p. 6) metalcatalysed epoxidation and sodium-ammonia reduction of the corresponding a epoxyme~ylate.~’The full paper (Vol. 6, p. 7) on bromine-trialkyltin alkoxide oxidation of alcohols has appeared and includes a one-step procedure using related work using N-bromosuccinimide reports bromine-bis(tributy1tin) oxidation of primary allylic alcohols (e.g. geraniol) to aldehydes, but in the presence of aldehydes, non-allylic alcohols yield Chromyl chloride oxidation of alcohols (citronellol, geraniol, pinocarveol) to aldehydes is difficult to control and led to a new method of preparing pure di-t-butyl ~ h r o m a t e , ~the ’ use of which is also reviewed (with only four references post- 1969!);51oxidation of allylic alcohols is less satisfactory than with Collins oxidation because of double-bond isomerization and allylic oxidation.” Chromium trioxide in hexamethylphosphoramide (HMPA) readily oxidizes geraniol to geranial although menthol oxidation proceeds only in moderate yield;52geranial is also obtained in high yield from geranyl bromide by the use of chromate ion as a nucleophile in HMPA in the presence of dicyclohexyl-18crown-6.s3 Corey has used potassium superoxide as a nucleophile in DMSO-DMF in the presence of polyether- 18-crown-6 to convert geranyl bromide directly into gerani01;~~ in benzene, potassium superoxide-18-crown-6 readily cleaves a -keto(e.g. camphorquinone), a-hydroxy-, and a-kalogeno-ketones (e.g. 3-bromocamphor), -esters, and -carboxylic acids to the corresponding carboxylic acids.” In connection with atmospheric pollution by monoterpenoids, a -pinene, @ pinene, and ( + )-limonene have been shown to be extremely reactive towards O ( 3 P ) atoms, with rate constants an order of magnitude higher than that for the reaction of O ( 3 P )with p r ~ p y l e n ea; ~ second ~ paper reports the Arrhenius expression^.^^ Acidcatalysed oxidation of borneol to camphor using rn-chloroperbenzoic acid5* is less efficient than the corresponding nitroxide-catalysed ~ x i d a t i o n .Two ~ ~ very mild method? for oxidizing alcohols to aldehydes or ketones without double-bond isomerization or epimerization are the use of N-methylmorpholine N-oxide, catalysed by [RUCI,(PP~,),],~~ and photochemical cleavage of pyruvate esters.61 The ‘forbidden’insertion of triplet oxygen into cis- 1,3-dienes by photochemical irradiation in the presence of trityl cation gives 1,4-peroxido-cis-2-enes (e.g.a-terpinene to 47 48 49

51

s2 53

54

s5 fih

s7

58 59

60 61

A. Yasuda, H. Yamamoto, and H. Nozaki, Tetrahedron Letters, 1976, 2621, K. Saigo, A. Morikawa, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1976, 49, 1656. T. Ogawa and M . Matsui, J. Amer. Chem. Soc., 1976,98, 1629. K. B. Sharpless and K. Akashi, J. Amer. Chem. SOC.,1975, 97, 5927. A. K. Lala and A. B. Kulkarni, J. Sci. Znd. Res., India, 1975, 34, 605. G. Cardillo, M. Orena, and S. Sandri, Synthesis, 1976, 394. G . Cardillo, M. Orena, and S . Sandri, J.C.S. Chem. Comm., 1976, 190. E. J. Corey, K. C. Nicolaou, M. Shibasaki, Y. Machida, and C. S . Shiner, TetrahedronLetters, 1975,3183; see J. San Filippo, C.-I. Chern, and J. S. Valentine, J. Org. Chem., 1975,40, 1678, and R. A. Johnson and E. G. Nidy, ibid., 1975, 40, 1680 for earlier reports of this reaction. J. San Filippo, C.-I. Chern, and J . S. Valentine, J. Org. Chem., 1976, 41, 1077. J. S. Gaffney, R. Atkinson, and J . N. Pitts, J. Amer. Chem. Soc., 1975, 97, 5049. J. S. Gaffney, R. Atkinson, and J . N. Pitts, J. Amer. Chem. Soc., 1975, 97, 6481. J. A. Cella, J. P. McGrath, and S . L. Regen, Tetrahedron Letters, 1975, 4115. J . A. Cella, J. A. Kelley, and E. F. Kenehan, J. Qrg. Chem., 1975,40, 1860. K. B. Sharpless, K. Akashi, and K. Oshima, Tetrahedron Letters, 1976, 2503. R. W. Binkley. Synth. Comm., 1976, 6, 281.

7

Monoterpenoids

ascaridole) in high yield.62 Hydroxylation of (1) with ozone on silica gel proceeds in low yield but with high retention of configuration to yield dihydrolinalool (2) after debr~mination.~~

52 I

Br

Further investigations of selective reductions include 1,4-reduction of enones (e.g. carvone) as well as reductive alkylation, using Li- and K - S e l e ~ t r i d e sand , ~ ~the use of 9-borabicyclo[3,3,1]nonane, which in the case of camphor yields only 75% of the exo -isoborne01~~ compared with 99.3% using the very sterically hindered lithium trisiamylborohydride;h6 bornan-2-em-yloxyaluminium dichloride reduces (-)menthone to a 95:5 mixture of (+)-neomenthol(3; X = S-OH) and (-)-menthol (3;X = R-OH).67Silver-ion-induced oxidation of acyclic and cyclic organoboranes is a useful method for cyclizing dienes; geranyl acetate, after &-elimination, yields (4; X = cis-H), and linalyl acetate yields (4; X = &-OH) and (4; X = t r a n ~ - O H ) . " ~ Non-rearranged allylic ethers [e.g. ( 5 ) ] are formed in good yield on treating the

p-tosylhydrazones of a@-unsaturated aldehydes and ketones with sodium borohydride-methanol owing to decreased C=N reactivity favouring basecatalysed e l i m i n a t i ~ n Only . ~ ~ the olefinic bond in a@-unsaturated carbonyl compounds (e.g. carvone) is reduced in high yield using Na[HFe,(C0),],70 whereas only the carbonyl group in citral (the formula is incorrect in this paper) is reduced using propan-2-01 on dehydrated alumina.'l 62

63 64 65

66 67

68 69

70

D. H. R. Barton, R. K. Haynes, G. Leclerc, P. D. Magnus, and I. D. Menzies, J.C.S. PerkinI, 1975,2055; D. H. R. Barton, P. D. Magnus, and I. D. Menzies, Brit. P. 1 4 1 0 483 (Chem. A h . , 1976,84,16 917); an earlier report. of this reaction, D. H. R. Barton, G. Leclerc, P. D. Magnus, and I. D. Menzies, J.C.S. Chem. Comm., 1972, 447, was omitted from these Reports. E. Keinan and Y. Mazur, Synthesis, 1976,523. J. M. Fortunato and B. Ganem, J. Org. Chem., 1976, 41, 2194. H. C. Brown, S. Krishnamurthy, and N. M. Yoon, J. Org. Chem., 1976,41, 1778. S. Krishnamurthy and H. C. Brown, J. Amer. Chem. SOC.,1976,98, 3383. D. Nasipuri, P. R. Mukherjee, S. C. Pakrashi, S. Datta, and P. P. Ghosh-Dastidar, J.C.S. Perkin Z,1976, 321. R. Murphy and R. H. Prager, Tetrahedron Letters, 1976, 463. R. Grandi, A. Marchesini, U. M. Pagnoni, and R. Trave, J. Org. Chem., 1976, 41, 1755. J. P. Collman, R. G. Finke, P. L. Matlock, R. Wahren, and J. 1. Brauman, J. Amer. Chem. SOC., 1976,98, 4685. G. H. Posner and A. W. Runquist, Tetrahedron Letters, 1975, 3601.

Terpenoidsand Steroids

8

Other synthetically useful reactions are allylic amination using TsN=Se=NTs7’ and TsN=S=NTS,~~photolysis of ap-unsaturated ketones in the presence of U02C1,-methanol [e.g. to give ( 6 ) ; cf. Vol. 6, p. halogenation of enol silyl ether^,'^ terminal double bond (e.g. geranyl cyanide, carvone) bromination with (7)

.tTBr Br

Br

in CH2C12,7hchlorination of tertiary alcohols with PC15,77an improved synthesis of alkyl iodides via hydroboration and reaction with iodine-sodium m e t h o ~ i d which e~~ proceeds by inversion ,79 regeneration of ketones from tosylhydrazones, arylhydrazones, and oximes,80 ether cleavage using di-iodomethyl methyl ether in acetonitrile,’l and the protection of hydroxy-groups as methylthiomethyl ethers” and as 6-methoxyethoxymethyl ethers.83

3 Biogenesis, Occurrence, and Biological Activity A monograph on fragrance raw materials has been publisheds4as well as two useful, if dated, collections of papers on essential (2- 13C]Mevalonolactone is synthesized in two steps from [2-13C]acetic acid and 4-benzyloxybutan-2-one although a longer route is required for [3,413C2]mevalono1actone.s7The structure of the hemiterpenoid mustelan (8) from the anal glands of the mink (Mustela vison) and the polecat (Mustela putorius) has been

72 73 74 75

76 77

78 79 80 81

82

83 84

85

Xh 87

K. B. Sharpless, T. Hori, L. K. Truesdale, and C. 0. Dietrich, J. Amer. Chem. Soc., 1976,98, 269. K. B. Sharpless and T. Hori, J. Org. Chem., 1976, 41, 176. T. Sato, 0. Ito, and M. Miyahara, Chem. Letters, 1976,295. L. Blanco, P. Amice, and J . M. Conia, Synthesis, 1976, 194. Y. Kitahara, T. Kato, and I. Ichinose, Chem. Letters, 1976, 283. R. M. Carman 2nd I. M. Shaw, Austral. J. Chem., 1976, 29, 133. N. R. de Lue and H. C. Brown, Synthesis, 1976, 114. H. C. Brown, N. R. de Lue, G. W. Kabalka, and H . C. Hedgecock, J. Amer. Chem. SOC.,1976,98,1290. S. R. Maynez, L. Pelavin, and G . Erker, J. Org. Chem., 1975,40, 3302. C. A. Smith and J. B. Grutzner, J. Org. Chem., 1976,41, 367. E. J . Corey and M. G . Bock, Tetrahedron Letters, 1975, 3269; K. Yarnada, K. Kato, H. Nagase, and Y. Hirata, Tetrahedron Letters, 1976. 65. E. J. Corey, J.-L. Gras, and P. Ulrich, Tetrahedron Letters, 1976, 809. D . L. J. Opdyke, ‘Food and Cosmetics Technology, Vol. 13 Supplement: Monographs on Fragrance Raw Materials’, Pergamon, 1975. W h International Congress on Essential Oils [Papers]’, Allured Publ. Corp., Oak Park, Illinois, 1974. Anais Acad. brasil, Cienc., 1972, 44 (suppl.). J. A. Lawson, W. T. Colwell, J. I. DeGraw, R. H. Peters, R. L. Dehn, and M. Tanabe, Synthesis, 1975, 729.

Monoterpenoids

9

confirmed by X-ray analysis of the corresponding thietan 1,l-dioxide and by synthesis.88 There has been considerable progress in the study of monoterpenoid b i o s y n t h e ~ i s . ' ~ -This ~ ~ ~is reviewed in Chapter 6. Fungal metabolism of methyl geranate by Colletotrichum nicotianae affords methyl R-f + )-6,7-dihydroxygeranate in 85% yield via methyl S - ( - )-6,7epoxygeranate.lo5 Pseudomonas aeruginosa converts a -terpineol into p -mentha1,4(8)-diene and borneol. lo6 Further oxygenated monoterpenoids have been reported from pine beetles. 107*108 It is suggested that micro-organisms introduced by Dendroctonus frontalis may be responsible for the conversion of the aggregation pheromone trans -verben01 into verbenone which inhibits further attack by the pine bark beetle (cf. Vol, 6, pp. 13, 179, 180).'0' Fourteen anticipated mammalian metabolites of ( +)-limonene may result from allylic oxidation or epoxide formation.' l o Essential oil analyses of note this year are of Buchu leaf (some p-menthane Hyssopus officinalis (methyl myrtenate, 2sulphur derivatives),"' hydroxyisopinocamphone, pink acid, and pinonic acid), Laggera auritu ( mmenth-6-en-S-01),~'~some Cymbopogon species (up to 89% of unusual p m e n t h a d i e n ~ l s ) , and ~ ' ~ Trichosterna lanceolatum (55 YO p-menthen-4-01).' l5 There H. Schildknecht, I. Wilz, F. Enzmann, N. Grund, and M. Ziegler, Angew. Chem. Internat. Edn., 1976,15, 242. 89 D. V. Banthorpe, G. A. Bucknall, H. J. Doonan, S. Doonan, and M. G. Rowan, Phytochemistry, 1976, 15,91. 90 K . G. Allen, D. V. Banthorpe, B. V. Charlwood, 0.Ekundayo, and J. Mann, Phytochemistry, 1976,15, 101. 91 D. V. Banthorpe and 0. Ekundayo, Phytochemistry, 1976,15, 109. 9* D. V. Banthorpe, E. CardemiI, and M. D. C . Contreras, Phytochemistry, 1976, 15, 391; reference 11 should read (1976) Phytochemistry, 15, 91. 93 A. Hatanaka, J. Sekiya, an0 T. Kajiwara, Phytochemistry, 1976, 15, 487. 94 C. D. Poulter, D. M. Satterwhite, and H. C. Rilling, J. Amer. Chem. SOC., 1976, 98, 3376. 95 C. D. Poulter and H. C . Rilling, Biochemistry, 1976, 15, 1079. 96 H. Itokawa, K. Takeya, and M. Akasu, Chem. and Pharm. Bull. (Japan), 1976,24, 1681. 97 Y. Shoyama, M. Yagi, I. Nishioka, and T. Yamauchi, Phytochemistry, 197.5, 14, 2189. 98 A. Saito, K. Ogura, and S . Seto, Chem. Letters, 1975, 1013. 99 M. Gleizes, Compt. rend., 1976, 283, D, 97. loo Y.Fujita, S.-I. Fujita, and T. Hasegawa, Nippon Kagaku Kaishi, 1975,711 was omitted from last year's Report; the identical paper is also published as Y . Fujita, S.-I. Fujita, and T. Hasegawa, Osaka Kogyo Gijutsu Shikensho Kiho, 1975, 26, 238. Io1 D. G. Rhoades, D. E. Lincoln, and .I. 13. Langenheim, Biochem. Syst. Ecol., 1976,4, 5 102 T. Nagasawa, K. Urnemoto, T. Tsuneya, and M. Shiga, Nippon Nogei Kagaku Kaishi, 1976, 50, 287. 1O3 H. Hendriks and F. H. L. Van Os, Phytochemistry, 1976,15, 1127. 104 J. Bricout and C. Paupardin, Compt. rend., 1975, 281, D, 383. 105 K. Imai, S. Marumo, alid T. Ohtaki, Tetrahedron Letters, 1976, 1211. 106 K. Tadasa, S.Fukazawa, M. Kunimatsu, and T. Hayashi, Agric. and Biol. Chem. (Japan), 1976,40,1069. lo7 J. A. A. Renwick and P. R. Hughes, Insect Biochem., 1975,§, 459. 108 D. A. Evans and M. D. Higgs, Tetrahedron Letters, 1975, 358.5. lo9 J.M.Brand, J. W. Bracke, L. N. Britton,A. J. Markovetz, andS. J. Barras,J. Chem. Ecor'.,1976.2,195. J. W. Regan and L. F. Bjeldanes, J . Agric. Food Chem., 1976,24,377; see references therein for earlier work. l l 1 R. Kaiser, D. Lamparsky, and P. Schudel, J. Agric. Food Chem., 1975, 23, 943. I l 2 D. Joulain and M. Ragault, Rivista Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1976, 58, 129. 113 S . K . Zutshi, B. K. Bamboria, and M. M. Bokadia, Current Sci., 197.5, 44, 571. lI4 D. V.Banthorpe, R. J. H. Duprey, M. Hassan. L. F. Janes, and B. M. Modawi, Planta Medica, 1976,29, 10. l I 5 T. H.Schultz, D. R. Black, T. R. Mon, and G . E. Connolly, J . Agric. Food Chem., 1976,24, 862. 88

10

Terpenoids and Steroids

have been repor:s of wide variations of composition within a species, for example, Majorana hortensis ' l 6 and Hungarian Tanacetum vulgare (e.g. 82% artemisia ketone, 64% piperitone, 94% thujone, 84% thujyl alcohol, 8 1'/o umbellulone, and in some samples such high percentages of unidentified c o m p ~ n e n t s ) . ~ ~ ' The crystal structures of three pyrethroid insecticides have been The syntheses of phenothrin analogues of lower insecticidal activity12' and of other chrysanthemate esters12' have been reported. Further pyrethroid papers concern the relationship between insecticidal toxicity and cyclopropane substituents in pyrethroids,'22 the photochemistry of the most potent known pyrethr~id,"~and the metabolism of permethrin in rats (cf. Vol. 6, p. 13).124 Further papers on monoterpenoid ether juvenoids have appeared'2s and metabolic investigation now extends to steers (cf. Vol. 5, p. 7, ref. 48).126

4 Acyclic Monoterpenoids Tergenoid Synthesis from Isoprene.-Co-oxidation of thiophenol and isoprene with oxygen yields the synthons (9) and (10) in useful yields'27 and the isoprene epoxide (1l)"* is a useful hemiterpenoid synthon with car bani on^.'^^ The full paper on Cookson's syntheses of ocimenones, filifolene, and the tagetones has appeared (Vol. 5, p. 8).130 One-pot syntheses of the predominantly transisomers (>go%) of (12; X = CH,OH) and (13; named lavandurol), (12; X = C02H), and (12; X = CHO) result from [ (~5-C,H,)2TiCl,]-catalysed regioselective isoprene I

11'7 11X

119

12"

121

122

123 124

12s

126

'"

129 130

OH

I

R. Granger, .I. Passel, and J. Lamy, Rivista Ital. Essenze-Frofumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1975, 57, 446. P. Tetcnyi, P. Kaposi, and E. Hethelyi, Phytochemistry, 1975, 14, 1539. J. D. Owen. J.C.S. Perkin I, 1975, 1865. J. D. Owen, J.C.S. Perkin I, 1976, 1231. T. Matsuo, N. Itaya, T. Mizutani, N. Ohno, K. Fujimoto, Y. Okuno, and H. Yoshioka, Agric. and Biol. Chem. (Japan), 197640,247. F. Mori, Y. Ornura, T. Nishida, and K. Itoi, Ger. Offen. 2 544 150 (Chem. Abs., 1976,85, 62 724); T. Mizutani, N. Itaya, N. Ohno, T. Matsuo, S. Kitamura, and Y. Okuno, U.S.P. 3 862 174 (Chem. Abs., 1976,84, 5199). T. Sugiyama, A. Kobayashi, and K. Yamashita, Agric. and Biol. Chem. (Japan), 1975, 39, 1483. I-. 0. Ruzo, R.I,.Holmstead, and J. E. Casida, Tetrahedron Letters, 1976, 3045. M. Elliott. N . F. Janes, D. A . Pulman. L. C. Gaughan, T. Unai, and J. E. Casida, J. Agric. Food Chem., 1976,24, 270. F. M. Pallos and C. K. Tseng, U.S.P. 3 914 321 (Chem. Abs., 1976, 84, 44 458); W. S. Bowers, U.S.P. 3 913429 (Chem. Abs., 1976, 84, 44459); F. M. Pallos, U.S.P. 3928616 (Chem. Abs., 1976, 84, 105 848); W. S. Bowers, U.S.P. 3 936 474 (Chem. Abs., 1976,84, 180 434); G. P. Nilles, M. J. Zabik, R. V. Connin, and R. D. Schuetz, J. Agric. Food Chem., 1976, 24, 699. G. W. Ivie, J. E. Wright, and H. E. Smalley, J. Agric. Food Chem., 1976, 24, 222. P. J. Nederlof, M. J. Moolenaar, E. R. de Waard, and H. 0.Huisrnan, TetrahedronLetters, 1976,3175. G. Eletti-Bianchi, F. Centini, and L. Re, J. Org. Chem., 1976, 41, 1648. G. C. M. Aithie and J. A. Miller, Terrahedron Letters, 1975, 4419. D. R. Adams, S. P. Bhatnagar, R. C. Cookson, and R.M. Tuddenham, J.C.S. Perkin I, 1975, 1741.

Monoterpenoids

11

insertion into 2-methylallyl Grignard reagent, followed by appropriate elaborat i ~ n . 'A~ report ~ of geraniol, nerol, and 3,7-dimethyloct-2-ene- 1,7-diol synthesis simply combines previously reported telomerization and amino-oxide rearrangement reactions (Vol. 4, p. 10; Vol. 5, p. 12)132and an earlier paper in the same series has come to light - the sodium-initiated telomerization with NN-diethylallylic amines to yield NN-diethyl-lavandulylamineand NN-diethylnerylamine (cf.Vol. 6, p. 15).133 Dimerization of isoprene with TiC1,-Et3Al-sulpholan gives a 2 : 1 ratio of (14) and (15).13, Electronic and steric factors have been examined in the amine[NiC12(PPh3)2]-NaBH4dimerization of isoprene to both linear and cyclic dimers; for example, (15) is favoured with n-propylamine but cyclic dimers are preponderant with 0 - p i ~ o l i n e . 'In ~ ~a similar system, Baker reports 61% head-to-tail dimerization [e.g. (16)] using NiC12-PPh3-NaBH4,'36 reporting the same results again in a communication including isoprene dimerization with cyclododecatriene(tripheny1phosphine)nickel and acetaldehyde (the preferred reaction is at the u-ally1 site of the nickel complex). 137 Exclusive head- to- head dimerization of isoprene occurs with (17) in the presence of [(PPh3)2PdC12]to give (18); reaction with the homologue of (17) proceeds similarly but in lower yield, and acyclic organodisilanes again give

(16)

head-to-head linking but with trans-double Isoprene dimerization over lithium (or sodium) followed by oxidation to give CIo-alcoholsand -diols is similar to that reported earlier [Vol. 1, p. 18; formula (71) is- obviously incorrect]'39 and formation of carboxylic acids by quenching with carbon dioxide is of little novelty.'40 Telomerization of l-chloro-3-methylbut-2-ene with 2-methylbut-2-ene in the presence of SnCl4l4land of isoprene with its hydrochlorides (to give linalool, a -terpineol, Isoprene and m -menth-6-en-8-01 after saponification) have been re-in~estigated.'~~ 131

S. Akutagawa and S. Otsuka, J. Amer. Chem. SOC., 1975,97, 6870; formula 2 is obviously incorrect and

there is an error in Table I. K . Takabe, T. Katagiri, and J. Tanaka, Chem. Letters, 1975, 1031; see G . Hata, Jap. P. 04 109/1976 (Chem. Abs., 1976,84, 165 074) for an improved synthesis of the octadienylamine. 133 K. Takabe, K. Hashimoto, T. Katagiri, and J. Tanaka, Asahi Garusu Kogyo Gijutsu Shoreikai Kenkyu Hokoku, 1 9 7 4 , 2 5 1 6 3 (Chem. Abs., 1 9 7 6 , 8 4 , 4 4 376). 134 F. Imaizumi, S. Hirayanagi, and K. Mori, Nippon Kagaku Kaishi, 1975, 1771. 135 I. Mochida, S. Yuasa, and T. Seiyama, J. Catalysis, 1976, 41, 101. 136 R. Baker, A . Onions, R. J. Popplestone, and T. N. Smith, J.C.S.Perkin 11, 1975, 1133. 137 R. Baker, A. H. Cook, and M. J. Crimmin, J.C.S. Chem. Comm., 1975, 727. 138 H. Sakurai, Y. Kamiyama, and Y. Nakadaira, Chem. Letters, 1975, 887. 139 ( a ) J. Brossas, R. Rupprecht, and F. Clouet, Fr. P. 2 266 682 (Chem. A h . , 1976, 85, 62 639); ( b ) R. Rupprecht and J . Brossas, J. Polymer Sci., Part C, Polymer Symposia, 1975, 52, 67. 140 S. Bormann, J. Brossas, and F. Clouet, Makromol. Chem., 1976, 177, 673. 141 K. B. Leets, V. 0.Chernyshev, K. A. Rang, A . Y. Erm, andM. N. Koel, J. Org. Chem. (U.S.S.R.), 1975, 11,2491; it seems that K. Laats, K. B. Leets, and K. V. Leets in all these reports are the same author. 142 T. Kaal and K. Laats, EestiNS. V. Teaduste Akad. Toimetised, Keem., Geol., 1975,24,263 (Chem.Abs., 1976, 84, 74 443); cf. Vol. 6, p. 14-it seems unnecessary to call isoprene 2-methylbuta-1,3-diene! 132

12

Terpenoids and Steroids

telomerization with acetic acid is rep01-ted.l~~ Further papers in this section report quantitative cyclodimerization [catalyst: Ni(a~ac)~-P(OPh)~-perhydro-9b-alumophenalene] to (19; 95%) (cf. Vol. 3, p. ,,),I4' head-to-tail dimerization (80%) with mesityl oxide [catalyst: Ni(a~ac)~-PPh~-AlEtJ,'~' and the formation of (20; 62%) [catalyst: Mg-(Ph,P)2NiC1,],'46 allo-ocimene (95%) (catalyst: Ni napht hena te-P h2PH-LiA1H4),147 2,7-dime th ylocta- 1,3,7-triene or 2,7-dimethylocta- 1.,4,6-triene (catalyst: Pd acetonylacetonate-tricyclohexylphosphineH3P04),'48and a mixture of myrcene (21; 39%) and cis- and trans-ocimene (22; 52% ) (Pd catalysts-NaOPh). 149

2,6-Dimethyloctanes.-Minor components in Cinnarnonzurn carnphora are reported to be 3,7-dimethylocta- 1,7-dien-3,6-diol and 3,7-dimethylocta-1,5-dien3,7-dio1,I5' and in Mentha X gentilis nm. Izirtella, tetrahydrogeranyl a ~ e t a t e . ' ~ ' Electron-impact and photo-ionization mass spectra of geraniol, linalool, and nerol have been r e p ~ r t e d . ' ~Enantiomeric ' composition studies using chiral europium shift reagents include data on ipsdien01'~~ and citronellic acid. 154 Base-catalysed cleavage of N-alkenyldialkylamines may yield ocimene (22) and myrcene (21) mixtures or pure myrcene;lS5Vig reports another synthesis of myrcene (cf. Vol. 4, p. 13), this time by y-alkylation of a c e t ~ a c e t a t e . ' ~ ~ ' . ' ~ ~ for the thermal inter1,7-Hydride shifts in the allo-ocimene ~ e r i e s ~ ~account conversions (below 300°C) of the trienes (23) and (24) and also the cis-trans isomerism (24) + (25). probably via (26), whereas at higher temperatures (25)yields 14?

144

146

147 148

I49

15* IT3

lz4

155

157 15x

A. Erm, M. Kaljurand, and K. Laats, Eesti N.S. V. Teaduste Akad. Toimetised, Keem., Geol., 1975,24, 246 (Chern. Abs., 1 9 7 6 , 8 4 , 4 4 372). U. M. Dzhemilev. G. E. Ivanov, and G. A. Tolstikov, J. Org. Chem. (U.S.S.R.),1975,11, 1623; Chem. Abs., 1976, 84, 5155 gives an incorrect structure for formula 111: it should be (19). Takasago Perfumery Co. Ltd., Dutch P. 13 655/1973 (Chem. Abs., 1976, 84, 31 272). K. Yamamoto, K. Ueda, S. Akutagawa, and A. Komatsu, Jap. P. 24 927/1975 (Chem. .4bs., 1976,84, 31 271). M. Yagi, S. Akutagawa, and A. Komatsu, Jap. P. 24 92411975 (Chem. Abs., 1976, 8 4 , 4 4 460). K. J. Ploner, Ger. Offen. 2 458 392 (Chem. Abs., 1975,83, 193 5 5 0 ) . T. Sometani, I. Sato, T. Moriya, S. Akutagawa, and A. Komatsu, Jap. P. 24 925/1975 (Chem. Abs., 1976,84, 44 461). D. Takaoka and M. Hiroi, Phytochemistry, 1976, 15, 330. M. von Schantz, K.-G. Widen, and L. Granqvist, Phytochemistry, 1975,14,2025. L. V. Kravchenko and G. R. Rik, Chem. Natural Compounds, 1974,10,746. E. L. Plummer, T. E. Stewart, K. Byrne, G. T. Pearce, and R. M. Silverstein, J. Chem. Ecol., 1976,2,307. D. Valentine, jun., K. K. Chan, C. G . Scott, K. K. Johnson, K. Toth, a n d G . Saucy, J. Org. Chem., 1976, 41, 62. M. Tanaka and G . Hata, Chem. and Ind., 1976, 370; G. Hata and M. Tanaka, Jap. P. 123 605/1975 (Chem. Abs., 1976,84, 122 077). 0. P. Vig, A. K. Vig, and S. D. Kumar, Indian J. Chem., 1975, 13, 1244. K. J. Crowley and S. G . Traynor, Tetrahedron Letters, 1975, 3555. W. Cocker, K. J. Crowley, and S. G. Traynor, '6th International Congress on Essential Oils [Papers]', Allured Publ. Corp., Oak Park, Illinois, 1974; Chem. Abs., 1976, 84, 135 828 is incomplete.

Monoterpenoids

13

a-pyronene (27) by electrocyclic reaction as well as (28) [via (26)];15' similar reactions account for the conversion of 4-trans -64s-allo-ocimene (29) into the corresponding trans,trans-isomer and into (27) and (28), both of which are transformed by [1,5]hydride shifts, e.g. a-pyronene (27) into @-pyronene (3).158Cyclodimerization of myrcene (21) with 1 , 3 - d i e n e ~ and ' ~ ~ with methyl acrylate'60 is

reported (cJ Vol. 1, p. 10). The photochemical conversion of citronellyl iodide into (31) and trans-p-menth-8-ene is reported via a 'hot' carbonium ion.i61 The regiospecificity of sensitized photo-oxygenation (e.g. of myrcene) is correlated with ene and diene ionization potentials in a frontier molecular orbital treatment of attack by singlet oxygen (cf. Vol. 6 , p. 16).162Wittig reaction of 3,7-dimethylocta-2,6dienyltriphenylphosphonium bromide maintains the stereochemical integrity of its E- or Z-double bond.163Oxidation of (31) with RhCl3,3H20-FeCI3-O2 gives the ketone (32) in 80% yield but with RhC13,3H20alone results in progressive isomerization to E-(33; X=Me), to 2-(33; X=Me), and finally to 1,2,3,3tetramethylcyclohexane; (33; X = Me) is incorrectly named in this paper.164

lS9

160

161

162

163 164

G. A. Tolstikov, U. M. Dzhemilev, G . E. Ivanov, and L. M. Zelenova, Zhur. obshchei Khim., 1976,46, 189. G . A. Tolstikov, U. M. Dzhemilev, and R. I. Khusnutdinov, Bull. Acad. Sci. U.S.S.R.,Diu. Chem. Sci., 1975,24, 1447. P. D. Gokhale, A. P. Joshi, R. Sahni, V. G. Naik, N. P. Damodaran, U. R. Nayak, and S. Dev, Tetrahedron, 1976, 32, 1391. L. A. Paquette and D . C. Liotta, Tetrahedron Letters, 1976, 2681. L. Barlow and G. Pattenden, J.C.S. Perkin I, 1976, 1029. F. J. McQuillin and D . G. Parker, J.C.S. Perkin I, 1975, 2092.

Terpenoids and Steroids

14

Hydroformylation of (3 1) using [RhH(CO)(PPh,),] is again accompanied by some isomerization to (33; X = Me) and preliminary results on oxidation of (31) with T1(NO3),,3H,O in methanol show a complex mixture, e.g. (34) and (35; X = Y = OMe).164Manganese(rI1) acetate oxidation results in free-radical addition to (3 1) at the 6,7-double bond, under kinetic control, when an adjacent hydroxy-group will stabilize the resulting radical [e.g. to give (36) from acetic acid] but at the 1,2-double bond [e.g. to give (35; X = H, Y = cyclopentyl) from cyclopentanone] under thermodynamic control when there is no adjacent hydroxy-group, implying a reversible free-radical addition to the 6,7-double bond in such cases.'65 The tricarbonyldieneiron complex of myrcene (2 1) undergoes annelation with oxalyl chloridealuminium trichloride to give (37) together with what is probably an unidentified diastereoisomer.166

(34)

(35)

Cuprous salts of dienolate dianions derived from ap-unsaturated carboxylic acids show a greater tendency to undergo y-alkylation than the corresponding lithium salts or the cuprous salts of the corresponding esters. The regioselectivity varies markedly with reagent homogeneity, temperature, and solvent; for example, y-alkylation of the cuprous salt of the dienolate dianion of 3-methylbut-2-enoic acid (senecioic acid) with prenyl bromide is reported to yield a 2 : 1 y : a ratio'67 and a 9 : 1 y : a ratio (cf. a 1 : 9 9 y : a ratio with the dilithio-salt).'68 The stereochemical homogeneity of the y-products [after methylation, (33; X = C0,Me)E : Z 5 5 :45,16' E :Z 2.2 : 1,167 E :2 4 : 1167]is also dependent upon the method of preparation. In contrast, the dilithium anion of senecioic acid with 3-methylbut-2-enal gives, after basic elimination, esterification, and reduction (cf. Vol. 4, p. 236), exclusively the dehydronerol (38) in a synthesis of the known isovalerate ester [Vol. 4, p. 11; structure (4 1)is The regiospecific syn -addition of lithium organocuprates [e.g. (39)] to alkynes [e.g. (40)] is used to synthesize geranial acetal 133; X = E-CH(OMe),] in high yield,17' and the syn-addition of the monoalkenyl-copper (41) to propyne provides an alternative route to the vinyl-copper (33; X = Z - C u ) used previously by this group in a synthesis of nerol (Vol. 6 , p. 9; cf. Vol. 6, p. 17).

'65

166

167 168 169

i70

F. J. McQuillin and M . Wood, J.C.S. Perkin I, 1976, 1762; for a preliminary communication see J.C.S. Chem. Comm., 1976,65. A. J. Birch and A. J . Pearson, J.C.S. Chem. Cornm., 1976, 601. B. S. Pitzele, J. S. Baran, and D. H . Steinman, Tetrahedron, 1976, 32, 1347. J. A. Katzenellenbogen and A. L. Crumrine, J. Amer. Chem. SOC., 1976, 98, 4925. G. Cardillo, M. Orena, and S . Sandri, Tetrahedron, 1976, 32, 107. A. Alexakis, A. Commercon, J. VilliCras, and J. F. Normant, Tetrahedron Letters, 1976, 2313.

Monoterpenoids

15

The vinyl-lithium (33; X = 2-Li) is readily formed by iodine-lithium exchange and thus the synthesis of nerol (33; X = 2-CH,OH) in 85% overall yield is straightforward.’71 Prenol addition to l-ethoxy-3-methylbuta-1,3-diene, catalysed by Hg(OAc),-NaOAc, yields ~ i t r a 1 . lThe ~ ~ 1,4-dialdehyde monoacetal (42)is readily available by alkylating ihe carbanion of propionaldimine with the corresponding cyclic acetal of a -bromoacetaldehyde and selective hydrolysis. Its conversion into a dihydrotagetone (43) is straightforward. 173 Stereornutation accompanies Wittig rearrangement of the ether carbanion (44) to (45).”‘ A synthesis of R-( -)-ipsdienol (46)175 is very similar to that reported previously for S - ( -)-ipsen01’~~ (Vol. 6, p. 19)

A fi

O

0

i

i

0

A (43)

A (44)

(45)

except that the epoxide (47) is synthesized from R -( + )-glyceraldehyde. 17’ Skattebol utilized a [3,3]sigmatropic rearrangement-alkylation sequence to racemic (46)and to ipsenol but failed in rearranging (48)to (46)[cf. Mori’s rearrangement of (48)-acetate, Vol. 6, p. 181.”’ Condensation of isopentenyl acetate with senecioic anhydride yields, inter alia, (49). Pyrolysis of this gave the corresponding myrcenone which was reduced to racemic (46).17’ Kossanyi et al. now use a Norrish Type I reaction to cleave 2-ethoxycarbonyl-2-methylcyclopentanone to (50) (cf. Vol. 5, pp. 11, 12); straightforward reactions yield the diol ( 5 1)reported on the hair pencils of G.Cahiez, D.Bernard, and J. F. Normant, Synthesis, 1976, 245; see A. Alexakis, J. Normant, and J. Villikras, J . Organometaflic Chem., 1975, 96, 47 1 for a discussion of regioselectivity in alkyl-copper additions. 17* F. Mori, T.Nishida, and K. Itoi, Jap. P. 50 301/1975 (Chem. A h . , 1976, 84,5203). 173 J. F. Le Borgne, T. Cuvigny, M. Larcheveque, and H. Normant, Terrahedron Letters, 1976, 1379. 174 C. F. Garbers and F. Scott, Tetrahedron Letters, 1976, 507; formula 6 is incorrect. 175 K. Mori, Tetrahedron Letters, 1976, 1609. 176 For the full paper, see K. Mori, Tetrahedron, 1976, 32, 1101. 177 S. Karlsen, P.Froyen, and L. Skattebol, Acta Chem. Scand., 1976, B30,664. 178 C. F. Garbers and F. Scott, Tetrahedron Letters, 1976, 1625.

171

Terpenoids and Steroids

16

II A

0

ql

OH

A

OH

(47)

iCHO

+OH

'>I

'-1

C0,Et

OH

the African monarch butterfly [Vol. 3, p. 17; formula (42) has one double bond too many].'79 Alkylation of the dilithiosulphone (52) with prenyl chloride followed by reductive cleavage of the sulphone group may lead to the ocimenes (22), geraniol (33; X = E-CH,OH), and the A2-isomer of geraniol; similar reaction of dihydro-(52) leads to citronellol in good yield. Linalool is obtained similarly from phenyl prenyl sulphone and the isoprene epoxide (11).ls' R-( +)-Epoxygeraniol (53) has been synthesized via the lactone (54) and the mesylate ( 5 5 ) (Scheme 1).lS2 The syntheses

L-glutamic acid

i--iv* MeCO (54)

HO

0

1

vi, vii

Reagents: i, HNO2; ii, SOC12; iii, CH2N2; iv, 57% aq. HI; v, piperidine; vi, MeMgI; vii, acetone-p-TsOH; + viii, Me3PCH2C02Me-NaH-THF; ix, LiAIH4, separation; x, AczO-py ; xi, 90% HOAc; xii, MeS02C1-py, -20 "C; xiii, NaOMe-MeOH.

Scheme 1

181 182

J. P. Morizur, G. Bidan, and J. Kossanyi, Tetrahedron Letters, 1975,4167. It is disturbing that referees have passed two major errors in this paper: the text refers to reducing a Z-ester and Scheme 2 refers to the final product as an N-heterocycle! M. Julia, D. Uguen, and A. Callipolitis, Bull. Soc. chim. France, 1976, 519. M. Julia and D. Uguen, Bull. Soc. chim. France, 1976, 513. S. Yamada, N. Oh-hashi, and K. Achiwa, Tetrahedron Letters, 1976, 2557.

Monoterpenoids

17

of lavandulol and its esters by [3,3]sigmatropic rearrangement,ls3[9- 14C]geranio1,184 citronellol by alkylations from p r o p i ~ n i t r i l e and ,~~~ isogeranyl methyl ether from isoprene 186 are straightforward. Studies of boron trifluoride etherate-catalysed ether formation from acyclic monoterpenoid alcohols now include data on nerol (33; X = 2-CH,OH) and (cf. Vol. 2, p. 11) and a full report on citronellol (Vol. 5, p. 14)."' linalo01'~~ l,2-Dehydiolinalool is rearranged to citral (E :2 1: 1)by (Ph3Si0)3VQ189and by polymeric silylvanadates (stated to give the E-isomer only, with no supporting evidence);190 corresponding tungsten or molybdenum catalysts give the pyran (56; 47%) or the cyclopentene (57; 12%) respectively."' Cyclization of 1,2dehydrolinalyl acetate with zinc chloride yields (58) along with the corresponding

enol acetate and 2-acetoxycar-2-ene.191 Tetraisobutyldialuminoxan in methylene chloride cyclizes neryl diethyl phosphate [33; X = Z-CH,OPO(OEt),] to limonene and minor amounts of t e r p i n ~ l e n e , 'in ~ ~contrast to substitution using other aluminium reagents in hexane,lg2 and on treating the corresponding acetate with aluminium alkyls a -alkylation predominates. lg3 The mechanism of acetolysis of 2,4-dinitrophenyl ethers is The full paper on the cyclization of methyl 6,7-epoxycitronellate has been published (Vol. 2, p. 19)19' and the thermolysis of geranate and citronellate derivatives is also reported from the same laboratory. 196 Electrochemical reduction of geranial(33 ;X = E-CHO) favours p -radical-carbonyl radical coupling over carbonyl-carbonyl radical coupling by 2 : 1 .197 Geranyl tetrahydropyranyl ether undergoes cyclic hydroboration with thexylborane and conversion into cis- and truns-(59; 2 3 : 1) by electrophilic rearrangement of the K. von Fraunberg, Ger. Offen. 2 432 235 (Chem. Abs., 1976,85,21669). S. J. Rajan and J. Wemple, J. Labelled Compounds, 1975, 11, 467. 185 E. Debal, T. Cuvigny, and M. Larcheveque, Synthesis, 1976, 391. 186 T. Sato, H. Kise, M. Seno, and T. Asahara, Yukagaku, 1975,24,607. K. Nagai, Bull. Chem. SOC.Japan, 1975,48, 2317. 188 K. Nagai, Bull. Chem. SOC.Japan, 1976,49, 265. For an earlier paper on isopulegol ethers omitted last year, see K. Nagai, J. Sci. Hiroshima Uniu., Ser. A : Phys. Chem., 1974,38, 141. 189 H. Pau!ing, D. A . Andrews, and N. C. Hindley, Helu. Chim. Acta, 1976, 59, 1233. 190 M. B. Erman, I. S. Aul'chenko, L. A. Kheifits, V. G. Dulova, Yu. N. Novikov, and M. E. Vol'pin, Zhur. org. Khim., 1976, 12, 921; also accepted for publication as a communication after the fuli paper was published: M. B. Erman, I. S. Aul'chenko, L. A. Kheifits, V. G. Dulova, Ju. N. Novikov (sic), and M. E. Vol'pin, Tetrahedron Letters, 1976, 298 1. 191 H. Strickler, J. B. Davis, and G. Ohloff, Helu. Chim. Acta, 1976, 59, 1328. 192 Y. Kitagawa, S. Hashimoto, S. Iemura, H. Yamamoto, and H. Nozaki, J. Amer. Chem. S ~ C .1976,98, , 5030. 193 S. Hashimoto, Y. Kitagawa, S. Iemura, H. Yamamoto, and H. Nozaki, Tetrahedron Letters, 1976,2615. 194 K. B. Astin and M. C. Whiting, J.C.S. Perkin f I , 1976, 1160. 195 J. Wolinsky, P. Hull, and E. M. White, Tetrahedron, 1976, 32, 1335. 196 R. H. Bedoukian, Diss. Abs. Internat. (B), 1976, 36, 4477. 1g7 J . C. Johnston, J. D . Faulkner, L. Mandell, and R. A. Day, J. Org. Chem., 1976, 41, 2611. 183 184

Terpenoids and Steroids

18

cyanoborate and peroxide oxidation; cyclic hydroboration of geranyl acetate with diborane followed by bromine-water photolysis and oxidation yields (60).198In contrast. hydroboration of geraniol(33; X = E-CH,OH) and linalool to acyclic diols and triols has been r e ~ 0 r t e d . l ~ ~

-41

ip

OH

Halogenated Monoterpenoids.-The structures of some halogenated monoterpenoids previously reported are in error. From Aplysia californica and Plocarniurn coccineum, two compounds reported have structures (61; X = CHBr,) [not as Vol. 4, p. 12, formula (44)I2Ooand (62) [not as Vol. 4, p. 12, formula (42)];20'*202 one previously reported compound has not in fact been isolated to date [Vol. 4, p. 12, formula (43)I2O1and base treatment of compound (62) yields the epoxide (63) [not Vol. 5 , p. 13, formula (53)].'02 CI. Br "

(611

x

BQ

Br

A c1

(62)

(53)

A new halogenated monoterpenoid from Aplysia californica is (64) which is related to the previously reported (65) (Vol. 6, p. 20), although the latter probably has a different stereochemistry; the previously reported (Vol. 6, p. 20) dibromotrichloro-monoterpenoid can now be assigned the structure (6 1; X = CH2Br)and a third new compound may tentatively be assigned the structure (66).203

1')s 199 *O0

201 *(I2

2u3

R. Murphy and R. H. Prager, Austral. J. Chem., 1976, 29, 617. J. Wolinsky and R. H. Bedoukian, J. Org. Chem., 1976, 41, 278; see also ref. 196. D . J. Faulkner, M. 0. Stallard, J. Fayos, and J. Clardy, J. Amer. Chem. Soc., 1973,95, 3413. D. J. Faulkner and M. 0. Stallard, Terruhedron Letters, 1973, 1171. M. R. Willcott, R. E. Davis, D . J. Faulkner, and M. 0. Stallard, Tetrahedron Letters, 1973, 3967. C . Ireland, M. 0. Stallard, D. J. Faulkner, J. Finer, and J. Clardy, J. Org. Chem., 1976, 41, 2461.

Monoterpenoids

19

Desmia (Chondrococcus) japonicus yields the IabiIe (67; E-Br, X = C1) and (67; 2 - B r , X = Cl)204which are the progenitors of the four methoxy artefacts (68; E - or 2 - B r ) and (67; X = OMe; E - or 2 - B r ) reported earlier;’05 the presence of the known (69) was also determined.205The presence of the new compounds (70; X = Y = C1, Z = Br), (70; X = H, Y = C1, Z = Br), (70; X = H, Y = Br, Z = Cl), (70; X = Z = C1, Y = Br), (71; X = Y = Cl), (71; X = C1, Y = H), and (72) in Hawaiian Chondrococcus hornemanni suggests that the biogenesis of halogenated myrcenes results from enzymatic addition of BrCl to myrcene (2 1) in Markovnikov and anti-Markovnikov fashion, followed by elimination of halogen acid, and prompts the search for corresponding chloromethyl derivatives; the synthesis of (73; X = C1, Y = Z = Br), (73; X = H, Y = Z = Cl), and (73; X = Y = C1, Z = Br) is also reported.206 Sri Lanka Chrondrococcus hornemanni contains (71; X = Y = H) but no halogenated myrcene~.~’~

New cyclic halogen-containing monoterpenoids include plocamene C (74)208(cf. Vol. 6, p. 33). No structural details were available in the abstract. This compound is closely related to violacene 2 (75) which was isolated from Plocamium violaceum; the structure, determined by X-ray analysis, was inadvertently omitted from last year’s Report.*09 Chondrococcus hornemanni has also yielded chondrocole C (76), and the related tentative structure (77) has been assigned to a second component.206 2 04 205

206

207 208

209

Y. Naya, Y. Hirose, and N. Ichikawa, Chem. Letters, 1976, 839. N. Ichikawa, Y. Naya, and S. Enomoto, Proc. Japan A c a d , 1975,51, 562; Y. Naya, Y. Hirose, and N. Ichikawa, 10th International Symposium on the Chemistry of Natural Products, Dunedin, New Zealand, 1976, Abstract E32. 9.J. Burreson, F. X. Woolard, and R. E. Moore, Chem. Letters, 1975, 1111. F. X. Woolard, R. E. Moore, M. Mahendran, and A . Sivapalan, Phytochemistry, 1976, 15, 1069. P. Crews and E. Kho-Wiseman, 172nd A.C.S. Meeting, San Francisco, August 1976, Abstract ORGN, No. 82. J. S. Mynderse, D. J. Faulkner, J. Finer, and J. C. Clardy, Tetrahedron Letters, 1975, 2175; J. S. Mynderse, Diss.Abs. Internat. ( B ) , 1975, 36, 2567.

20

Terpenoids and Steroids

CI

Jj , / ' CI

Br

@

Br

clL Br

(74)

CI

(77)

Treatment of geranyl acetate with bromine and silver fluoroborate in nitromethane yields (78) as a model for bromonium-ion induced biosynthesis; dehydration yields two alkenes (79).210

Br

a0k aoA Hr

Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-In the yomogi alcohol synthesis (Vol. 6, p. 21, Scheme 7) another reagent, CuC1,-CuO-EtOH, 25"C, after reagent i, was omitted. 13C N.m.r. data for the naturally occurring pyrethrin esters, chrysanthemic acid, pyrethric acid, and the synthetic allethrin have been reported.21' The mass spectra and g.c. retention time data for nineteen irregular monoterpenoids, including nine possible biosynthetic intermediates, have been reported.212 The X-ray analysis of (+ )-trans-chrysanthemic acid-pbrornoanilide derivative has been carried Further work on the chrysanthemyl model for squalene biogenesis from Poulter's group has been published (cf. Vol. 3, pp. 2 0 - 2 2 ) . ~ ~ ~

21" 211

212

213 214

L. E. Wolinsky and D. J. Faulkner, J. Org. Chem., 1976,41, 597. L. Crombie, G. Pattenden, and D. J. Simmonds, J.C.S. Perkin I, 1975, 1500. W. W. Epstein, L. R. McGee, C. D. Poulter, and L. L. Marsh, J. Chem. and Eng. Data, 1976, 21, 500. This paper makes reference to a naturally occurring compound, arthole (80), which is unknown to this Reporter; only the mass spectrum is recorded. A. F. Cameron, G. Ferguson, and C Hannaway, J.C.S. Perkin ZI, 1975, 1567. J. M. Hughes, Dim. A h . Internat. ( B ) ,1976,36.4440; two papers, C. D. Poulter, 0.J. Muscio, and R. J. Goodfellow, Biochemistry, 1974, 13, 1530 and J. Org. Chem., 1975, 40, 139, were omitted from last year's Report.

Monoterpenoids

21

The efficient addition of allylic bromides to carbonyl compounds in a heated zinc column has been used to synthesize (*)-artemisia alcohol (81; R = H, X = CH,) in 91% yield.215 Artemisia ketone was synthesized efficiently from 3-methyl-ltrimethylsilylbut-2-ene and 3-methylbut-2-enoyl chloride in the presence of A1C1,.216 Racemic methyl santolinate (82) was synthesized (along with the C-3 epimer; ratio 8 : 1) via Claisen rearrangement, according to Scheme 2 (cf. Vol. 6 , p. 7).217 OSiMe,Bu'

lvii-ix H (82) Reagents: i, NaCH(CO,Et)PO(OEt),; ii, LiAIH,; iii, (EtCO)20-py; iv, lithium isopropylcyclohexylamideTHF, -78 "C; v, HMPA-Bu'SiMezC1-THF; vi, NaCI, 0 "C; vii, 65 "C; viii, AcOH-H20; ix, CH2N2.

Scheme 2

Hydroxymethylation of 6-chloro-2,6-dimethylhept-2-ene with benzyloxymethyl chloride and dehydrochlorination yields the lavandulols (83).218 Base-promoted cyclization of (84; R = H , X=CO,Et) to (85; R = H , X = C02Et)219leads to (*)-trans-chrysanthemic acid by known methods (Vol. 1, p. 16); similarly, cyclization of (84; R = Pr', X = C0,Et) yields (85; R = Pr', X = C0,Et) but dehydration only results in ring-opening to the lavandulyl skeleton, making it necessary to us2 base-promoted cyclization of the allylic benzoate (81; R = Bz, X = H,C02Et) to synthesize (*)-trans-chrysanthemic acid after epimerization and hydrolysis.220 (lR,3R )-Chrysanthemic acid is synthesized via similar cyclization of

HOCHR (85)

2l5 216

217 218

219

220

J. F. Ruppert and J. D. White, J. Org. Chem., 1976, 41, 550. J. P. Pillot, J. Dunoguks, and R. Calas, Tetrahedron Letters, 1976, 1871. J. Boyd, W. Epstein, and G. Friter, J.C.S. Chem. Comm., 1976, 380. C. F. Garbers, J. A. Steenkamp, and H. E. Visagie, Tetrahedron Letters, 1975, 3753. J. H. Babler and A. J. Tortorello, J. Org. Chem., 1976,41, 885. J. Ficini and J. d'Angelo, Tetrahedron Letters, 1976, 2441.

X

22

Terpenoids and Steroids

the nitrile (4R)-(84; R = H, X = CN), available from (2s)-pantolactone, to (3R)(85; R = H, X = CN).221 Other related papers from this Japanese group report the syntheses of (*)-trans-chrysanthemic acid from (86)222and of chiral pyrocin (87) by asymmetric hydrogenation223(cf. Vol. 1, p. 17); the asymmetric decomposition of the diazoacetate (88) by chiral copper complexes (cf. Vol. 6, p. 21) to dihydrochrysanthemolactone is also reported.224Photochemical di-n-methane rearrangement of (89) gave a 15% yield of methyl chrysanthemate (cis : trans 1 : 2), probably via a singlet excited A similar rearrangement of the corresponding cis- and trans -nitriles was reported to give good yields of cis- and trans-chrysanthemic nitriles.226

P il’-

OzCCHNl

COzH

0

(86)

(87)

(88)

-Co2Me

(89)

5 Monocyclic Monoterpenoids

C7clobutane.-Further reports of grandisol (90) synthesis include Magnus’s full paper (Vol. 6, p. 22)227and an almost identical Japanese report of an earlier synthesis (Vol. 3, p. 25) based upon a dihydropyranone-ethylene cycloaddition.228 A third synthesis utilizes cyclopropanation of 4-methoxy-3,6,6-trimethylcyclohexa-2,4dienone to yield (91) followed by rearrangement of the Q -oxycyclopropylcarbinyl cation of (91) to (92). After reduction of the cyclobutanone, second-order Beckrnann cleavage of the cyclopentanone oxime gave (93) from which grandisol(90) was readily

Cyclopentanes, 1ridoids.-A very useful review of the biosynthesis of the known sweroside-, morroniside-, and oleuropein-type secoiridoid glucosides, together with the biosynthesis of alkaloidal glucosides which can be regarded as secoiridoid 221 222

*z3 224

2z5 226 22’ 22* 229

T. Matsuo, K. Mori, and M. Matsui, Tetrahedron Letters, 1976, 1979. H. Hirai, K. Ueda, and M. Matsui, Agric. and Biol. Chem. (Japan), 1976, 40, 153. H. Hirai and M. Matsui, Agric. and Biol. Chem. (Japan), 1976,40, 161. H. Hirai and M. Matsui, Agrrc. and B i d Chem. (Japan), 1976.40, 169; see also ref. 434. M. J. Bullivant and G. Pattenden, J.C.S. Perkin I, 1976, 256. P. Baeckstrom, J.C.S. Chem. Comm., 1976. 476. P. D. Hobbs and P. D. Magnus. J. Amer. Chem. SOC., 1976.98, 4594. H. Kosugi, S. Sekiguchi, R. Sekita, and H. Uda, Bull. Chem. SOC. Japan, 1976, 49, 520. N. F. Golob, Diss. Abs. Internat. ( B ) , 1975, 35, 4835.

23

Monoterpenoids

derivatives, has appeared.230A review of the chemical structures and biosynthesis of the Loganiaceae alkaloids has also appeared; the structures of gentianine and cantleyine are in error.231I3C N.m.r. data for swertiamaroside and related secoiridoid glucosides confirm their structures (which were not in The essential oil from Lippia citriodora (oil of verbena) has yielded the four cyclopentanes (94; X = M e b ( 9 6 ) as minor components;233Teucriurn rnururn yields the two known dialdehydes (94; X = CHO) together with dolicholactone (97) and allodolicholactone (98) which may arise by biogenetic-type Cannizzaro reactions from (94; X = CHO).234

(94)

(95)

Thirty-three known iridoid and secoiridoid glucosides have been analysed by gas chromatography of their trimethylsilyl derivatives. G.c.-m.s. analysis of several representative compounds (e.g.4-CO2H,4-C02Me, 4-unsubstituted) demonstrated the feasibility of iridoid-containing plant extract analysis and resulted in the identification of secologanoside 11-methyl ester (99; R = H, X = CH,) from Loniceru r n ~ r r o w i i the ; ~ ~sixth ~ paper in a series of chemotaxonomic studies on iridoids illustrates the need for accurate analysis of minor components.236

..;.;-ire X H

0 - p - Glu-

(99)

New C,, iridoid glucosides are scutellariosides I and I1 from Scutellaria altissima, which are 10-cinnamoylcatalpol and l0-(4-hydroxycinnamoyl)catalpol, respect i ~ e l y . ~The ~ ’ full paper concerning gluroside from Galeopsis tetrahit (Vol. 6 , p. 23) has been a new report of melampyroside (Vol. 6, p. 23) from Odontites rubru and Euphrasia rubra has appeared,239and the presence of harpagide and its acetate in various Labiatae species is 230 231 232

233 234 235 236 237 238 239 240

H. Inouye, S. Ueda, and Y. Takeda, Heterocycles, 1976, 4, 527. N . G . Bisset, Pharm. Weekblad, 1975, 110, 425. A. Cornelis and J. P. Chapelle, Pharm. Actu Helv., 1976, 51, 177. R. Kaiser and D. Lamparsky, Helv. Chim. Acta, 1976, 59, 1797. U . M. Pagnoni, A. Pinetti, R. Trave, and L. Garanti, Austral. J. Chem., 1976,29, 1375. H . Inouye, K.Uobe, M. Hirai, Y. Masada, a4d K . Hashimoto, J. Chromatog., 1976,118, 201. P. Kooiman, Actu Botan. Need., 1975, 24, 459. K. Weinges, K. Kiinstler, G . Schilling, and H. Jaggy, Annalen, 1975, 2190. 0. Sticher and A. Weisflog, Pharm. Actu Helv., 1975, 50, 394. J. L. G . Bilbao, M. M. Lomas, B. Rodriguez, and S. Valverde, Anales de Quim., 1976,72, 494. N. F. Comissarenko, A. I. Derkach, I. P. Sheremet, and D. A. Pakaln, Khim. prirod. Soedinenii, 1976, 109.

24

Terpenoids and Steroids

Stilbericoside (loo), which was omitted from last year’s report, from Stilbe e r i ~ o i d e s , and ~ ~ ’ deutziol (101), the new minor component from Deutzia scabra (cf. Vol. 5, p. 17),242are of interest in adding t o the small number of known iridoids lacking a C-10 carbon atom; other examples are ~ n e d o s i d e whose , ~ ~ ~ structure is now to be (102), mentzeloside (deutzioside) (Vol. 4, p. 24; Vol. 5, p. 17), decaloside (Vol. 4, p. 24), the previously unreported scabroside (103),244and feretoside (Vol. 6, p. 24). In this connection, the structure for linarioside was incorrectly reported previously (Vol. 3, p. 26); it should be (104) which does possess a C-10 carbon atom.245

The straightforward syntheses of onikulactone (105; X = S-Me) and mitsugashiwalactone (105; X = R-Me) are New C,, iridoid glucosides include ixoside (106; X = O H , Y = C 0 2 H ) and ixoroside (107) from Ixora c h i n e n ~ i s , and ~ ~ ’ tarennoside (106; X = H, Y = CH20H) along with ixoside (106; X = O H , Y = C 0 2 H ) and the known (Vol. 4, p. 24) geniposidic acid (106; X = OH, Y = CH,OH) from Tarenna k u t ~ e n s i sto , ~provide ~~ an anticipated biogenetic sequence. Another report of duranotoside derivatives

241 242

2-43 244 245 246 247

248

H. Rimpler and H. Pistor, Z . Naturforsch., 1974, 29c, 368. P. Esposito, M. Guiso, M. Nicoletti, and C . dz Luca, Gazzettu, 1976,106, 57. T. A. Geissman, W. F. Knaak, and J. 0. Knight, Tetrahedron Letters, 1966, 1245. P. Esposito and M. Guiso, Gazzetta, 1973, 103, 517. See also I. Kitagawa, T. Tani, K. Akita, and I. Yosioka, Chem. and Pharm. Bull. (Japan),1973,21,1978. T. Fujisawa, T. Kobori, and H. Ohta, J.C.S. Chem. Comm., 1976, 186. Y. Takeda, H. Nishimura, and H. Inouye, Phytochemistry, 1975,14,2647. Y. Takeda, H. Nishimura, and H. Inouye, Chem. and Pharm. Bull. (Japan), 1976,24, 1216.

Monoterpenoids

25

from Duruntu repens has been published (Vol. 5, p. 17).24yThe structures of (Vol. 6, p. 25), along with other valepot~ a l e c h l o r i nand e ~ ~7-epideacetylisovaltrate ~ without reference to the earlier riates from Vuleriunu oficinulis, are work and appear to be based upon incorrect structures for valtrate (108; R' = R2= H),252isovaltrate ( 109),252and didrovaltrate (I (Vol. 6, p. 25). Valechlorine should be (111; R' = R2 = H, X = C1) and it appears that 7-epideacetylisovaltrate may be 7-deacetylisovaltrate. Without further comment, a second paper reports

cH 2

CH,OAc

Me,CR'CH,CO,

~

,

~

~

u

ACO*O

0,CCH2CR2Me,

O,CBui

(108)

(109) CH~OAC Me,CR 1CH2C02@0

0,CBu' (110)

XH,C

OH

0,CCH,CR2Me,

(111)

correct structures for the biogenetic sequence, valechlorine (111; R' = R2 = H, X = Cl)+vaitrate (108; R' = R2 = H)-+acevaltrate (108; R' = H, R2 = OAc, or R' = OAc, R 2 = H ) in the same species.253 Two new valepotriates from Valeriana tiziaefolia are (111; R' = R2 = H, X = 02CBui) and (111; R' = R2 = H, X = OAc), and a third compound is either (111; R' = H, R2 = OH, X = 02CBu') or (111; R' = OH, R2 = H, X = 0,CBu') (cf. acevaltrate above); in vivo labelling experiments confirmed that these compounds were not formed from valtrate during isolation.254 A second paper now reports the isolation of syringoxide from Syringa vulgaris (Vol. 6, p. 24) and suggests the stereochemistry (112); a minor component is syringenone

(113).*"

(112) ( 1 13) Y. H. Kuo and T. Kubota, Experientia, 1976,32,968;reference 7 should read H. Rimpler and H. Timm, 2.Nufurforsch.,1974, 29c, 1 1 1. n o S. Popov, N. V. Handjieva, and N. Marekov, Compt. rend. Acad. bulg. Sci., 1973, 26, 913. N. Marekov, S. Popov, and N. Handjieva, Izvest. Khim. (Bulgaria), 1975, 8, 115. 252 P. W. Thies, E. Finner, and F. Rosskopf, Tetrahedron, 1973, 29, 3213. 253 S. S. Popov, N. L. Marekov, and D . N. Dimitrov, Compt. rend. Acad. bulg. Sci., 1975,28,651. Popov is not clear on what acevaltrate is; however, see Chemical Abstracts Registry Number 25 161-41-5. 2s' J. Holzl, V. M. Chari, and 0.Seligmann, Tetrahedron Letrers, 1976, 1171; J . Holzl, Planta Med., 1975, 28,301 (Chem. Abs., 1976,84, 102 380). zss S. S . Popov, N. L. Marekov, and N. L. Evstatieva, Compt. rend. Acad. bulg. Sci., 1975, 28, 1509.

149

i

26

Terpenoids and Steroids

&,cis-Nepetalactone is present in Nepeta mussini and has been converted into (3S)-methylcyclopentane-(1R,2S)-dicarboxylicacid (cf. Vol. 2, p. 18).256 The synthesis of (*)-isodihydronepetalactone (1 14) is dependent upon the highly stereoselective hydrolysis of the cyclo-adduct (1 15) to (1 16) which on reductive cleavage of the cyclobutanone ring yields, after hydrolysis, (114) accompanied by minor amounts of the two lactones (1 17).257 Selective monohydroboration-

oxidation of (19) leads to the mesylate (118) which is converted into (*)iridomyrmecin (1 19) according to Scheme 3.258Partridge’s syntheses of loganin and its analogues are not very different from Biichi’s synthesis (cf.Vol. 1, p. 20; Vol. 4, p. 26).259

(119)

(118)

Reagents: i, H20-dioxan-Na2C03; ii, dehydration; iii, B2H6-oxidation; iv, Jones oxidation; v, LiNPriTHF; vi, Me3SiCI; vii, 03-MeOH-CH2C12; viii, NaBH,; ix, aq. HCI.

Scheme 3

The structure of naucledal (Vol. 3, p. 28) is now firmly established as (120).260New oleuropein-type secoiridoids include 10-acetoxyligustroside (121; R = H)and 10acetoxyleuropein (121; R = OH) from Osmanthus fragrans,261the related aldehyde [99; X = H,CHO, R = 2-(3,4-dihydroxyphenyl)ethyl]from Ligustrurn japonicum,262 and two complex esters from Fraxinus americana based upon the oleoside moiety ( ~ 2 2 ) both ; ~ ~esters ~ are bis-secoiridoids, contain two and three glucose units, respectively, together with a single 2-(p-hydroxyphenyl)ethanolunit, and are related to the known nuzhenide (Vol. 3, p. 28) with which they C O - O C C UThe ~ . ~mild ~~ isolation conditions used suggest a re-examination of other iridoid-containing species for similzr complex esters which are readily solvolysed. E. J. Eisenbraun, R. L. Irvin, and D. J. McGurk, ‘6th International Congress on Essential Oils [Papers]’, Allured Publ. Corp., Oak Park, Illinois, 1974, p. 149 (Chern.Abs., 1976,84, 135 829). 257 J. Ficini and J. d’Angelo, Tetrahedron Letters, 1976, 687. 2 5 8 R. S. Matthews and J. K. Whitesell, J. Org. Chem., 1975,40, 3312. 259 J. J. Partridge and M. R. Uskokovic, U.S.P. 3 907 772 (Chem.A h . , 1976,84, 74 104); cf. J. J. Partridge and M. R. Uskokovic, U.S.P. 3 755 188 (Chern. Abs., 1973,79, 146 397). 260 J. Purdy and S. McLean, Tetrahedron Letters, 1976, 2511. 261 H. Inouye, K. Inoue, T. Nishioka, and M. Kaniwa, Phytochemistry, 1975, 14, 2029. 262 H. Inouye, K. Inoue, T. Nishioka, and T. Tanahashi, unpublished data. Z 6 3 R. T. LaLonde, C. Wong, and A. I.-M. Tsai, J. Amer. Chem. SOC.,1976,98, 3007.

256

Monoterpenoids

27

H

New sweroside-type glucosides include grandifloroside (123; R = 3,4dihydroxycinnamyl) and methylgrandifloroside (123; R = ferulyl) from Anthocleista g r a n d i f l ~ r a vogeloside ,~~~ (7-methoxysweroside) from Anthocleista v ~ g e l i iand ,~~~ centapicrin [2'-(rn-hydroxybenzoyl)-3'-acetylsweroside] from Erythraea cen taurium.266 The stereochemistry of alcoholysis of the structurally related swertiamarine, lamiide, and ipolamiide is shown, (124) to (125).267 In the secoiridoid series,

hydrolysis of secologanin (126) with buffered p -glucosidase is thought to proceed without ring-opening to yield (127) by backside displacement of water from C-1 by a C-7 oxygen atom (the authors use a deplorable numbering system), although inversion at C-1 by ring-opening and recyclization before attack by the (2-7 oxygen atom cannot be ruled out.268A related naturally occurring compound of interest is sarracenin (128) from Sarracenia flava whose X-ray crystal structure has also been determined;269the authors make no mention of the fact that this compound is identical with the known emulsin-cleavage product of morroniside (129)270-no rotation is given, but the melting point and spectroscopic data are almost identical. The existence of sarracenin may provide an important biosynthetk link between loganin, secologanin (126), and the monoterpenoid indole alkaloids in which ringopening before condensation with tryptamine may account for the corresponding known trans stereochemistry in a number of them; for example Scott's recent ax J.-P.Chapelle, Phytochemistry, 1976,15, 1305. ZCJ J.-P. Chapelle, Planta Med., 1976, 29, 268 (Chem. Abs., 1976, 85, 74 898). +66 K. Sakina and K. Aota, Yakugaku Zasshi, 1976,96683. 267 S. S. Popov and N. L. Marekov, Compt. rend. Acad. bulg. Sci.,1975, 28, 775. 2ex1 R. T. Brown and C. L. Chapple, Tetrahedron Letters, 1976, 787. asD. H. Miles, U. Kokpol, J. Bhattacharyya, J. L. Atwood, K . E. Stone, T. A . Bryson, and C. Wilson, J. Amer. Chem. SOC.,1976,98, 1569. I. Souzu and H. Mitsuhashi, Tetrahedron Letters, 1969, 2725.

Terpenoids and Steroids

28

OHC

-’-.*-

\--,

O-p-Glu (129)

(126) (127)

(128)

cell-free biosynthesis of ajmalicine (130) may well involve (13 1).271 Further papers on the more complex monoterpenoid alkaloids lie outside the scope of this Report; the reader is referred to the Specialist Periodical Reports on the Alkaloids.

Further work on secoiridoid biosynthesis has now shown, using [7,EL3H2]-7deoxyloganic acid, that the C-8 proton as well as the C-7 proton is retained in the sequence loganin -+ secologanin (126) -+ morroniside (129) (cf. Vol. 3, p. 28) in Lonicera morrowii, Cornus officinalis, and Gentiana t h ~ n b e r g i i . ~ ~ ~ Full details of the previously unreported absolute stereochemistry of tecomanine (132) and alkaloid C (133) from Tecoma stans have been published.273 Cantleyine (134) and tetrahydrocantleyine (135) from Lasianthera austrocaledonica are artefacts from reaction with ammonia, possibly on a ‘bis-terpenic h e t e r o ~ i d e ’ , ~ ~ ~ although in Strychnos nux-uomica cantleyine (134) is reported to be formed from loganin on treatment with ammonia;275the suggestion that the nitrogen is incorporated before hydrolytic cleavage of the sugar must be Incorporation

Z71 272 z73

274

275

A. I. Scott and S.-L. Lee, J. Amer. Chem. SOC.,1975,97,6906.

Y. Takeda and H. Inouye, Chem. and Pharm. Bull. (Japan), 1 9 7 6 , 2 4 , 7 9 . G. Ferguson and W. C. Marsh, J.C.S. Perkin 11, 1975,1124; theX-ray analysisis, however, listed in Vol. 5, p. 206. Th. Sevenet, A. Husson, and H.-P. Husson, Phytochemistry, 1976,15, 576; J. P. Foucher, A. Husson, H.-P. Husson, Th. Sevenet, C. Thal, and J.-P. Vidal, 10th International Symposium on the Chemistry of Natural Products, Dunedin, New Zealand, 1976, Abstract, E10. N. G. Bisset and A. K. Choudhury, Phytochemistry, 1974,13, 265 (omitted from previous Reports).

Monoterpenoids

29

of nitrogen into secologanin (126)by reductive amination gives rise to two reports of bakenkosin (136)

q H

C0,Me I

I (135)

11

0 - 6 -Glu

(136)

p-Menthanes.-Reviews on y - t e ~ p i n e n e , ~piperitenone, '~ isopiperitenone, and their and on some less well-known p-menthadienes (only two references p0st-1970!)~~'have been published. Bohlmann has isolated another naturally occurring thymol epoxy-ester (cf.Vol. 1, p. 34; Vol. 3, p. 46),this time from Wedeliafursteriana.281Compound (137)has been isolated282from Pluchea odorata. Pseudomonas fluorescens converts (-)-menthone into cis- and t r a n ~ - ( 1 3 8 ) . ~In' ~addition to known (Vol. 2, p. 31) p-menthane-8thiol-3-ones in Buchu leaf oil, S-methyl And S-acetyl derivatives have been isolated

together with 4-hydroxydiosphenol and the two (lS)-2-acetoxypulegones. l 1 The latter have been subjected to a conformational as have isornenth01~~~ and The X-ray structure of (&)-carvoxime is reported the 1,8-dinitro-p-menthanes.286 again.287 The nomenclature and absolute stereochemistry of monobromoisodehydrobispulegone and dibromodehydrobispulegone have been clarified (cf. Vol. 4 , p. 36).28813CN.m.r. data are recorded for the menthols and their acetates.289 The 276

27' 278

279

H. Inouye, S. Tobita, and M. Moriguchi, Chem. and Pharm. Bull. (Japan), 1976,24, 1406. L.-F.Tietze, Tetrahedron Letters, 1976, 2535. J. Verghese, Indian Perfumer, 1974, 18, 53. Y. R. Naves, Rivista Ital. Essenze-Profumi, Piante Offic.,Aromi, Saponi, Cosmet., Aerosol., 1976, 58, 136.

J. Verghese, J. Sci. Ind. Res., India, 1975, 34,487. F. Bohlmann and C. Zdero, Chem. Ber., 1976, 109, 791. 282 F. Bohlmann and C. Zdero, Chem. Ber., 1976,109,2653. 283 N. Sawamura, S. Shima, and H. Sakai, Agric. and Biol. Chem. (Japan), 1976,40,649. 284 K . Imamura, T. Shishibori, and T. Suga, J. Sci. Hiroshima Univ., 1975,39A, 273. 2s5 G. Kartha, K. T. Go, A. K. Bose, and M. S. Tibbetts, J.C.S. Perkin ZI, 1976, 717. m6 C. Morat, A. Rassat, and P. Rey, Tetrahedron, 1975,31,2927. m7 H. A. J. Oonk and J. Kroon, Acta Cryst., 1976, B32, 500; see F. Baert and R. Fouret, Cryst. Structure 281

Comm., 1975, 4, 307.

D. Rogers, J. M. Franco, S. Martinez-Carrera,and S. Garcia-Blanco, Acta Cryst., 1975, B31, 2742. zng Y. Senda and S. Imaizumi, Tetrahedron, 1975, 31, 2905.

Terpenoids and Steroids

30

unusually high binding potential of the r-bond in the photoelectron spectrum of ascaridole may be due to electronegativity Kinetic data are reported for acid-catalysed addition of acetic acid to l i m ~ n e n e . ~ ~ ’ Alkylation of isovaleramide with 1,3-dichlorobut-2-ene yields (139) after methylation; acid-catalysed hydrolysis and internal aldol condensation gives ( )~ i p e r i t o n e . ~The ” ~ value of piperitenone and isopiperitenone formation, probably uia electrocyclic reaction of the pyrolytic acetic acid-elimination product from A5- and A6-isomersof (49), cannot be assessed in the absence of reaction yields.”’ (S)-( -)-Pulegone is obtained in good yield from (-)-citronello1 by oxidation with pyridinium chlorochromate followed by double-bond i s o m e r i ~ a t i o n . ~Low~’~~~ temperature reduction of (-)-carvone to (-)-&-carved (140) and oxymercuration-reduction provides an efficient synthesis of ( + )-pin01( 141).2”4Two more syntheses of diosphenol and isodiosphenol (7: 3 ) (cf. Vol. 6, p. 28) are one by acid-catalysed rearrangement of pulegone oxime.296

*

A (139)

(140)

Other useful p-menthane syntheses of n o great novelty are of cis- and transpiperitol from 2a,3a -epoxycarane (silica-catalysed rearrangement to cis-p-menth2-en- 1,8-diol is also of (*)-dihydrocarvone, isopulegone, and p menthofuran uia p - k e t o - s u l p h ~ x i d e s , ~of~ ~ p-mentha-l,4(8)-diene via a bromination-dehydrobromination sequence,299and of trans-carveol by benzoyl peroxide-CuC1 oxidation of a -pinene.3”0 Further details for the conversion of (-)-(142) into (+)-(142), uia its epoxide, are reported (Vol. 5 , p. 25; cf. Vol. 3, p. 44).3(’1 I

R. S . Brown, Canad. J. Chem., 1976, 54, 805. T. Yamanaka, Bull. Chem. SOC.Japan, 1975,48, 3107; 1975,48, 3471. 2y2 P. Hullot, T. Cuvigny, M. Larcheveque, and H. Normant, Canad. J. Chem., 1976, 54, 1098. 2y3 Experimental details have appeared in E. J. Corey, H. E. Ensley, and J. W. Suggs, J. Org. Chem., 1976, 41, 380. 2g4 L. Garver, P. van Eikeren, and J. E. Byrd, J. Org. Chem., 1976, 41, 2773. 295 M. Ohashi, S. Inoue, and K . Sato, Bull. Chem. SOC.Japan, 1976, 49, 2292. L90 C. Maignan and F . Rouessac, Bull. SOC.chim. France, 1976, 550. 297 R. S. Prasad and S . Dev, Tetrahedron, 1976, 32, 1437. 2y8 0. P. Vig, M. L. Sharma, R. C. Anand, and S. D. Sharma, J. Indian Chem. Soc., 1976, 53, 50. my C. P. Mathew and J. Verghese, J. Indian Chem. SOC.,1975, 52, 997; see also B. Singaram and J. Verghese, Indian J. Chem., 1976, 14B, 479. 300 C. T. Walling and C. R. Willis, Canad. P. 981 695 (Chem. A h . , 1976, 85, 33 220). 301 T. Shono and Y. Takagi, Jap. P. 69 049/1975 (Chem. A h . , 1975,83, 193 551). 290

29l

Monoterpenoids

31

Last year's Report of (+)-limonene hydroboration (Vol. 6, p. 30) did not refer to the earlier Report (Vol. 3, p. 35) which, in the case of Brown's work, is a repetition of earlier Bacdyshev reports the salicylic acid-catalysed rearrangement of isoterpinolene to various p-methadienes (cf. Vol. 3, p. 71, ref. 314).303Lewis acid-catalysed rearrangement of methyl perillate is reported in an investigation of the acylation of the exocyclic double bond.304 Pyrolysis of limonene diacetate yields perillyl acetate as the major The full paper on the oxidation of cis- and trans-p-menth-2-ene with t-duty1 perbenzoate-cupric octanoate has appeared (Vol. 5, p. 23); t-butoxy radicals abstract secondary allylic pseudo-axial hydrogen atoms preferentially to give (143) and (144) via a cyclic transition state involving ligand transfer and the formation of a copper(1)-olefin complex.3o6 The poor quality of the Chemical Abstract makes it difficult to assess the value of a report of peracetic acid oxidation of /3~ h e l l a n d r e n e . ~ ' Dye-sensitized ~ allylic photo-oxygenation of LY -terpineol is Additional papers in the series (Vol. 6, p. 30) on the investigation of selenium dioxide oxidation of 'ene-acetates' include allylic oxidation of cis - and tran~-(145),~O~ dihydrocarveyl acetate (146; X = R - O A C ) , ~and ~ ' neodihydrocarveyl

acetate (146; X = S - O A C ) . ~ ~Epoxidation ' of limonene and of other p-menth-lenes, using t-amyl hydroperoxide, catalysed by Mo(CO)~,favours the trans -1,2e p ~ x i d e . ~Rearrangement ~' of the limonene cis - and trans -monoepoxides over variously prepared aluminas may yield dihydrocarvone (147), (148), or (149) as the major product, along with the cyclopentane aldehyde (150).312A further paper reports rearrangement over various solid acids and bases.313 See H. C. Brown and C. D. Pfaffenberger, J. Amer. Chem. Soc., 1967,89, 5475; in addition ref. 170 in Vol. 3, p. 35 is incorrect: it should be H. C. Brown and E. Negishi, J.Amer. Chem. Soc., 1972,94,3567. I. I. Bardyshev, L. A. Popova, E. F. Buinova, B. G. Udarov, and Zh. F. Loika, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1975, 85 (Chem. Abs., 1976,84, 165 038). 304 B. V. Burger, C. F. Garbers, H. S. C. Spies, and H. E. Visagie, J. S. African Chem. Inst., 1975,28,328. 305 H. R. Ansari and P. E. Fido, Ger. Offen. 2 513 910 (Chem. A h . , 1976,84, 122 072). 306 A. L. J. Beckwith and G. Phillipou, Austral. J. Chem., 1976, 29, 1277. 307 M. Y. Shashkina and G. P. Shergina, Izuest. Vyssh. Uchebn. Zaved., Lesn. Zhur., 1975,18, 121 (Chem. Abs., 1976,84, 150 758). 308 Y. S. Cheng, M. D. Tsai, J. M. Fang, and S. S. Hsu, Hua Hsueh, 1975,8 (Chem.Abs., 1976,84,105 816; it seems unnecessary to specify the stereochemistry of the C-8 hydroxy-group!). 309 T. Tahara and Y. Sakuda, Yukagaku, 1976,25, 161; ambiguities in the English abstract are resolved by reference to Table 1. 310 T. Tahara and Y. Sakuda, Yukagaku, 1 9 7 5 , 2 4 , 4 4 6 . 331 ( a ) V. P. Yur'ev, 1. Gailyunas, L. V. Spirikhin, and G. A. Tolstikov, Zhur. obshchei Khim., 1975, 45, 2312; ( 6 )cf. E. E. Royals and J. C. Leffingwell, J. Org. Chem., 1966,31, 1937, and Vol. 1, p. 26, ref. 91. See also Vol. 4, p. 57, ref. 269. 312 K. Arata and K. Tanabe, Chem. Letters, 1976, 321. 313 K . Arata, S. Akutagawa, and K. Tanabe, J. Catalysis, 1976, 41, 173. 3O* 303

$1

Terpenoids and Steroids

32

QP

(147)

QOH

(148)

P

O

(149)

H

(150)

m -Chloroperbenzoic acid epoxidation of (-)-a - terpineol has been re-examined; a 2 : 2 : 1 ratio of the cis- and trans-epoxides (1 : 4) and the ethers (151) and (152) is Piatkowski's interesting work on the metal hydride reduction of carvone epoxide (153) has become accessib1e3l5and, along with a discussion of the reduction of carveol epoxides (Vol. 4, p. 34),316has made an important contribution to the knowledge of 1 -hydroxydihydrocarveols and 1 -hydroxycarvomenthols (cf. ref. 31 lb); the formation of (-)-dihydrocarveol (146; X = R-OH) during lithium aluminium hydride reduction of limonene cis -monoepoxide is also Having discussed reduction of the monoepoxides of y - t e ~ p i n e n e Kozhin , ~ ~ ~ ~has now reduced the two diepoxides (Vol. 6, p. 30).3176Lead tetra-acetate oxidation of carvone to (154; X = C H 2 0 H ) and (154; X = CH20Ac) has been described.318

Lithium-ethylamine reduction at one or both double bonds of carvone, and of carvenone (58) to carvomenthone only, is reported.319 The effect of solvent on the lithium oi'potassium amide-reduction of p-cymene to menthenes and menthadienes has been examined.320 Hydrogenation of carvone (Vol. 4, p. 32), using palladiumpolysaccharide exchange resin, favours endocyclic over exocyclic double-bond reduction, more so than with Pd-C or Pd-BaS04,321whereas platinum or rhodium on exchange resins exhibit no special selectivity.322 Optimum conditions for the catalytic hydrogenation of thymol, and the catalytic dehydrogenation of menthol, to menthone have been determined.323 Cathodic reduction of carvomenthone (to 314 315

316 317

318 319 320 32 1 322 323

C. W. Wilson and P. E. Shaw, Austral. J. Chem., 1975, 28, 2539. K. Piatkowski, A. Siemieniuk, and H. Kuczynski, Bull. Acad. polon. Sci., Sir,Sci. chim., 1975,23,883. K. Piatkowski, D . Mrozinska, and H. Kuczynski, Bull. Acad. polon. Sci., Sir.Sci. chim., 1975,23,503. (a)See Vol. 5, p. 22; ref. 149 should be to Zhur. obshchei Khim., 1974,44,944; ( b ) E. I. Sorochinskaya and S. A. Kozhin, Zhur. obshchei Khim., 1975, 45, 2537; Chem. Abs., 1976, 84, 105 786 incorrectly refers to a-terpinene dioxides. J. de P. Teresa and I. S. Bellido, Anales de Quim., 1976, 72, 76. D . Sedzik-Hibner, Roczniki Chem., 1976,50, 265. V. V. Bazyl'chik and P. I. Fedorov, Zhur. obshchei Khim., 1976,46, 199. G. Descotes and J. Sabadie, Bull. SOC.chim. France, 1975, 2133. J . Sabadie and G. Descotes, Bull. SOC.chim. France, 1976, 911. N . E. Kologrivova, I . V. Shumskaya, and L. A. Kheifits, J. Appl. Chem. (U.S.S.R.),1975, 48, 1704; Chem. A h . , 1975,83, 193 520 incorrectly refers to dehydration of menthol.

Monoterpenoids

33

carvomenthols) and of menthone (ta p-menthane) in neutral solution has been examined .324 Photochemical or oxygen-initiated 1,4-free-radical addition of trialkylboranes to (+)-carvone and (-)-perillaldehyde occurs trans to the isopropyl The full paper on the TiC1,-catalysed photochemical addition of methanol to pulegone (VoI. 6, p. 10) has been published.326Photoenolization of pulegone via an n-T* singlet excited state has been used to deuteriate the y-methyl groups.327 Beckwith has examined base-catalysed elimination from menthyl (3; X = R-OTs) and neoisomenthyl tosylates, interpreting his results in terms of an antiperiplanar transition state; using t-butoxide-DMSO, methyl tosylate gives trans-p-menth-2ene exclusively, whereas neoisomenthyl tosylate yields cis - p -menth-2-ene as the major Raney cobalt hydrogenation is reported to give cis-p-menth-3one (96%) from p i p e ~ i t o n e .Further ~ ~ ~ work from Posner’s group (Vol. 3, p. 45) implicates some syn - 1,2-elimination in alumina-catalysed elimination from menthyl (3; X = R -0Ts) and neomenthyl tosylates (3; X = S - O T S ) . ~Preliminary ~~ on lithium aluminium hydride reduction of carvone and piperitone oximes to aziridines has been extended to the use of Reda1330band to the corresponding saturated ketone oximes and hydrazonium iodides;330cpiperitone oxime yields only saturated aziridines using lithium aluminium hydride and with little solvent effect, but unsaturated aziridines become the major product using Redal whereas with carvone oxime the proportions of aziridines, as well as primary and secondary amines, are sensitive to both solvent and reducing agent.3306 2-Ethoxymethylenementhone is responsible for the observed mutarotation of 2-hydroxymethylenementhone and 2-hydroxymethyleneisomenthone (cf.Vol. 5, p. 25).331Acetylation and benzoylation of menthone and some 4-substituted isomenthones are reported.332 Robinson ring annelation of (-)-menthone and (-)carvomenthone with methyl vinyl ketone, which is very similar to unacknowledged and previous work (Vol. 3, p. 41), has been used to synthesize octalones without an angular isopropyl group;334similar annelation of enamines gives the expected octalones with no angular methyl group using menthone but a surprising result is the exclusive formation of the non-angular-methyl octalone from dihydrocarvone when the fully saturated carvomenthone gives a 3 : 7 ratio of angularmethyl octalone to a non-angular-methyl o ~ t a l o n e . ~The ~ ’ structures of the a phellandrene-P -naphthol adducts have been 324

325 326

327 328 329 330

331 332 333 334 335 336

R. J. Holman and J. H. P. Utley, J.C.S. Perkin ZZ, 1976, 884. A . Arase, Y.Masuda, and A. Suzuki, Bull. Chem. SOC.Japan, 1976,49, 2275. T. Sato, G . Izumi, and T. Imamura, J.C.S. Perkin I, 1976, 788; cf. ref. 74. M. Tada and K. Miura, Bull. Chem. SOC.Japan, 1976,49, 713. A. L.J. Beckwith and G. A . Phillipou, Austral. J. Chem., 1976, 29, 877. G. H. Posner and G . M. Gurria, J. Org. Chem., 1976, 41, 578. ( a ) L.Ferrero, S. Geribaldi, and M. Azzaro, Rev. Roumaine Chim., 1976, 21, 49; (6) L. Ferrero, S. Geribaldi, M. Rouillard, and M. Azzaro, Canad. J. Chem., 1975,53,3227; (c)Y. Girault, M. Decouzon, and M. Azzaro, Tetrahedron Letters, 1976, 1175. V. M. Potapov, G . V. Grishina, and I. K. Talebarovskaya, J. Org. Chem. (U.S.S.R.),1976,12,458. C.Metge and C. Bertrand, Bull. SOC.chim. France, 1975, 2178. C.Metge and C. Bertrand, Bull. SOC.chim. France, 1976, 957. C.Metge and C. Bertrand, Compt. rend., 1975, 281, C, 551. W. M. B. Konst, J . G. Witteveen, and H. Boelens, Tetrahedron, 1976, 32, 1415. B. Singaram and J. Verghese, J.C.S. Perkin I, 1976,1254; it is difficult to see why this paper refers to the authors’ earlier work,which gives an incorrect structure, without correction, CurrentSci., 1975,44,583.

Terpenoids and Steroids

34

Phase-transfer addition (cf. Vol. 6, p. 31) of dibromocarbene to carvone and reduction to a monobromo-ketone by tributyltin hydride, or to a dibromo-alcohol with lithium aluminium hydride, is 1,3-Dipolar cycloaddition of acetonitrile oxide occurs exclusively at the exocyclic double bond in limonene to give (155; R = Me, X = Hz), whereas isoxazoline formation with carvone yields (155; R = Me, X = 0) and the isomeric product from attack at the C-6 double bond; benzonitrile oxide, however, only yields (155; R = P h , X = O or NOH).33s A re-investigation of aqueous chlorination of a -terpineol indicates that the diequatorial chlorohydrin (156) and the corresponding diaxial chlorohydrin are the major

xkN R

(155)

products from which most of the minor products are derived.”’ The bisnitrosomenthone from (-)-menthone is racemic and that from (*)-menthone has a meso ~tructure.”~ The decomposition of E-pulegone tosylhydrazone by methyl-lithium usually gives p-mentha-2,4(8)-diene exclusively, whereas the corresponding Z isomer yields p-mentha-3,8-diene.341 The structures of two minor products first isolated during the reaction of the chloromagnesium enolate of (+)-pulegone with p-substituted benzaldehydes (Vol. 5 , p. 25) correspond to 174-additionof the enolate to pulegone itself as well as to the major reaction product.342Further papers in this section concern oxymercuration-demercuration of piperitone and ~ a r v o n e , ~ ~ ~ the structure of the piperitone sodium bisulphite addition and the Beckmann rearrangement of (+)-2-keto-anti-3-oximino- 1,8-cineole to the expected tetrahydropyran carboxylic o -Menthanes.-Cleavage

of a number of pin-2-ene derivatives (157) to o menthenes, e.g. (158) and (159), has been The o-menthane lactone (160) has been synthesized although the recorded properties differ somewhat from those previously reported (Vol. 6, p. 31).346Ficini has further extended her work in NN-diethylaminopropyne cycloaddition (cf.ref. 257; Vol. 5 , p. 27; Vol. 3, p. 39) to synthesize (161) with a high degree of 33’

338 339 340

341

342

343 344

345 346

347

L. Sydnes and L. Skattebol, Tetrahedron Letters, 1975,4603; see Vol. 4,p. 59 for similar pinane work. C.-Y. Shiue, R. G. Lawler, and L. B. Clapp, J. Org. Chem., 1976, 41, 2210. H. L. Kopperman, R. C. Hallcher, A. Riehl, R. M. Carlson, and R . Caple, Tetrahedron, 1976,32,1621. R. M. Carman, G. N. Saraswathi, and J . Verghese, Austral. J. Chem., 1976, 29, 453. W. G. Dauben, G. T . Rivers, W. T. Zimrnerman, N. C. Yang, B. Kim, and J. Yang, Tetrahedron Letters, 1976, 2951. F. Ghozland, Y . Maroni-Bernaud, and P. Maroni, Bull. SOC.chim. France, 1976, 978, 983. S. C. Misra and G. Chandra, Indian J. Chem., 1975, 13, 1239. T.-J. Huang and S.-R. Zhang, Hua Hsueh Tung Pao, 1975,297 (Chem. Abs., 1976,84, 30 505). F. Bondavalli, P. Schenone, and M. Longobardi, Gazzerta, 1975,105, 1317. N. Lander and R. Mechoulam, J.C.S. Perkin I, 1976, 484. J. Ficini, A. Ernan, and A. M. Touzin, Tetrahedron Letters, 1976, 679.

Monoterpenoids R

35

II

C0,Me I

II

C0,Me

I

I

I

LJ rn -Menthanes.-Bardyshev has succeeded in isolating m -mentha-6,8-diene and rn mentha- 1,3(8)-diene from Russian turpentine new esters of ferulol (162) have been detected in Peucedanum luxurians 349 and spectroscopic evidence is provided for the presence of (163) as an ether group in the two new coumarins, iselin and iliensin, from Seseli ilien~e.’~ A~ halogenated member of this class is discussed in the halogenated monoterpenoids section.210 The biogenetic-type cyclization of citral-pyrollidine enamine yields, after hydrolysis, a -cyclocitral (164) exclusively;351(*)-a-cyclocitral is partly resolved by partial hydrolysis of the oxazolidine formed from (S)-(+)-pr~linol.~~* p -Cyclocitral is formed in high yield by ozonolysis of p-ionone or, anomalously, by ozonolysis of the trimethylsilyloxytriene derivative of p - i ~ n o n e The . ~ ~synthesis ~ of (165) is ~traightforward.~~’ Diels-Alder reactions of a -pyronene (27) and p -pyronene (30) are

Tetramethylcyc1ohexanes.-Six

Dimethylethylcyc1ohexanes.-Halogenated members of this class have already been reported. 206,208,209 Another synthesis of the boll weevil pheromones (166; X = 2-CH20H), (166; X = 2-CHO), and (166; X = E-CHO) in 80% overall yield is reported (cf.Vol. 6, p. 348

I. I. Bardyshev, R. I. Zen’ko, A. L. Pertsovskii, and E. N. Manukov, Chem. Natural Compounds, 1974, 10,325.

349 350

351

352 353

F.Bohlmann and M. Grenz, Chem. Ber., 1976,109,788. L.I. Dukhovlinova, M. E. Perel’son, Y. E. Sklyar, and M. G. Pimenov, Chem. Natural Compounds, 1974, 10,316;an earlier paper, Y. N. Sheinker, G. K.Nikonov, M. E. Perel’son, G. P. Syrova, G. Y. Pek, N. S. Vul’fson, V. 1. Zaretskii, and V. G. Zaikin, Chem. Natural Compounds, 1969,5,301,reports this group as an alkyl group in peucenol, which is incorrectly named in Chemical Abstracts, Registry Number 52 5 15-76-1,as a 1,4,4-trimethylcyclohex-2-en-l-yl derivative; the earlier paper, however, does not unambiguously identify the group. M.Shibasaki, S.Terashima, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1975,23,272(omitted from last year’s Report). M. Shibasaki, S.Terashima, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1976,24,315. N. Miiller and W. Hoffmann, Synthesis, 1975, 781;Ger. Offen. 2432231 (Chem. Abs., 1976,84,

180 433). 354

355 356

R. D. Clark and C. H. Heathcock, J. Org. Chem., 1976,41,1396. Y. BessBre and F. Ouar, J. Labelled Compounds, 1975,11,3. Y.Matsubara and M. Kasano, Kinki Daigaku Rikogakubu Kenkyu Hokoku, 1975,10,53(Chem. Abs., 1976,84,31 259); ibid., p. 61 (Chem. Abs., 1976,84,31 260;this abstract is in error).

Terpenoids and Steroids

36

33); Meyer-Schuster-type rearrangement of the ethynyl acetate (167) to yield (166; X = E-CHO) and (166; X = 2-CHO) shows little stereo~electivity.~~' Atmospheric oxidation products of (1 66; X = CHO) are as expected.35s

Cyc1oheptanes.-The structure of the Ni" complex of P -thujaplicin, and of its amine adducts, has been described.359Photochemical irradiation of a,P -epoxyeucarvone (cf.Vol. 6, p. 35) at 254 nm yields (168), but by n-r* excitation above 280 nm yields (168), the photodecarbonylation products (169) and the corresponding (YPunsaturated isomer, and (170), the photoisomer of (169); the photochemical conversion of eucarvol (171) into the epimeric alcohols (172) is also

6 Bicyclic Monoterpenoids formylation of (Y -thujene to give (1 73; A3) is less efficientthan that of sabinene, and p-thujene does not form (173; A'), reflecting the known reactivities of vinylcyclopropane~.~~~ A useful synthesis of (173; A2)involves treating thuj-3-one tosylhydrazone with butyl-lithium in """-tetramethylethylenediamine foilowed by DMF and hydrolysis.362Improved methods of preparation of pure (-)-neoisothujan-3-01, (-)-isothujan-3-01, (*)-isothujan-3-01, (-)-isothuj-3-one7 and (+)-isothuj-3-one are the antinociceptive activity of (-)-isothuj-3-one is codeine-like and equipotent with A'-THC in mice.363The Sorensen reports that a mixture of sulphuration of thuj-3-one is thujan-3-01 and neothujan-3-01(174) (called isothujol) does not give the ion (175) as suggested earlier (Vol. 5, p. 30; Vol. 6, p. 35) but the cyclopentyl cation (176)

Bicyclo[3,1,0]hexanes.-Vilsmeier

357 358 359

360 361 362 363

364

S. W. Pelletier and N. V. Mody, J. Org. Chem., 1976, 41, 1069. R. D. Henson, D. L. Bull, R. L. Ridgway, and G. W. Ivie, J. Agric. Food Chem., 1576, 24, 228. B. Matai and R. M. Sathe, J. Inorg. Nuclear Chem., 1976,38, 1748. B. Frei and H. R. Wolf, Helv. Chim. Acta, 1976, 59, 82. P. C. Traas, H. Boelens, and H. J. Takken, Rec. Trav. chim., 1976, 95, 57. P. C. Traas, H. Boelens, and H. J. Takken, Tetrahedron Letters, 1976, 2287. K. C. Rice and R. S. Wilson, J. Medicin. Chem., 1976, 19, 1054. C. Fournier, D. Paquer, and M. Vazeux, Bull. SOC.chim. France, 1975, 2753; cf. Vol. 4, p. 60 for the unquoted synthesis of thioverbenone.

Monoterpenoids

A

37

A

A

A

resulting from acid cleavage of the cyclopropane ring before heterolysis of the C-OH bond.365 Some very old chemistry is re-reported; thuj-3-one is converted into 2,3-dimethyl-4-isopropylcyclopent-2-enone.366

Bicyclo[2,2,l]heptanes.-Reviews of interest in this section include Brown’s on non-classical carbonium ions,367Sorensen’s on monoterpenoid rearrangements in s u p e r a c i d ~ , ~and ~ ’ a discussion by Yates of the photochemical ring expansion of cyclic ketones, with particular emphasis on his own An extensive examination of the minor components of East Indian sandalwood oil has revealed as one component (177),370which is also synthesized from teresantalic acid by oxidative decarboxylation and cyclopropylmethylhomoallylic rearrangement. Electron-impact mass spectral data have been recorded for the trifluoromethanesulphonates (178; X = OS02CF3,Y = H) and (178; X = H, Y = OSO,CF,).”’ An X-ray crystal structure determination372of a minor product from the conversion of 3-bromocamphor into ( + ) - 9 - b r o m o ~ a m p h o rconfirms ~~~ the structure (179). The

HO

u

reagent (180) is useful for the alkoxybromination of alkenes in the presence of alcohols although little asymmetric induction is Racemic camphor- 10sulphonic acid is resolved efficiently with carnitine itri rile.^^^ The rates of quaternization and the base strengths of some 3-aminoborneols and their corresponding esters 365 366

367

368 369 370

371 37* 373 374 3’5

T.S.Sorensen, J.C.S. Chem. Comm., 1976, 45. C. A . N.Catalan and J. A . Retamar, ‘6th International Congress on Essential Oils [Papers]’, Allured Publ. Corp., Oak Park, Illinois, 1974, p. 138 (Chem. A h . , 1976,84, 105 789); cf 0. Wallach, Annalen, 1902,323,335. H. C. Brown, Tetrahedron, 1976, 32,179. T.S. Sorensen, Accounts Chem. Res., 1976, 9, 257. P. Yates, J. Photochem., 1976,5, 91. E. Demole, C. Demole, and P. Enggist, Helv. Chim. Acta, 1976, 59, 737. A . G. Martinez, M. G. Marin, R. Perez-Ossorio, and M. Hanack, Anales de Quim., 1976, 72, 670. D . F. Rendle and J. Trotter, Acta Cryst., 1975, B31,2512. P. Cachia, N.Darby, C. R. Eck, and T. Money, J.C.S. Perkin I, 1976, 359. G. Dauphin, A. Kergomard, and A. Scarset, Bull. SOC.chim. France, 1976, 862. D. M. Muller, E. Strack, and I. Lorenz, J. prukt. Chem., 1975, 317,689.

38

Terpenoids and Steroids

have been measured; cis -compounds are stronger bases than trans -compounds, as expected, differences between cis-exo and cis-endo examples being due to the steric effect of the C-8 methyl group.376 In this connection, the full report of the stereospecific reduction of (lR)-3-endo -aminocamphor hydrochloride (Vol. 4, p. 49) to (181) in over 90% yield using aluminium chloride and tri-isobutylaluminium has appeared.377

A synthesis of [ 10-*H]camphor from camphene has been reported (see Vol. 3, p. 67).378Nojigiku alcohol (Vol. 6, p. 35) has been synthesized, albeit in low yield, by reaction of (+)-camphene with t-butyl benzoate in acetonitrile in the presence of cupric chloride and cupric benzoate, thus excluding a non-classical radical intermediate and also establishing the absolute configuration of nojigiku alcohol (182).379 The scope of the problem of systematic synthesis design by non-rearrangement routes can be examined via what Hendrickson has called construction grids; the The ironcamphor, pinane, and tricyclene carbon skeletons are carbonyl-promoted cyclocoupling of polybromo-ketones with 1,3-dienes (cf.Vol. 6, p. 33) has been used to synthesize carbocamphenilone (183) from the corresponding adduct (184; X = H2)which, after double-bond reduction, is oxidized quantitatively to (183) with selenium dioxide.”’ Selenium dioxide oxidation of (184; X = H2)gives the homoconjugated a-diketone (184; X = 0),which exhibits characteristic T-T* absorption in the ultraviolet and C-6 vinylic deshielding in the ‘H n.m.r. due to ground-state h o m o c ~ n j u g a t i o n Isocamphenilenic .~~~ acid derivatives (185) are now readily available3’* from the ketone (185; X = COMe).”’ 3-Diazocamphor rearranges to the tricyclanone (186) in 97% yield in the presence of silver heptafluorobutanoate, presumably uia a ketocarbene (cf.Vol. 4, p. 46).384

376

177

37R

379

3 ~ 38 1

382 3x3

384

A. H. Beckett, A. A. AI-Badr, and A. Q . Khakhar, Tetrahedron, 1975, 31, 3103. H . Pauling, Helu. Chim. Acta, 1975,58, 1781; this paper reports improved yields over those previously reported. A. Nickon, J. L. Lambert, J. E. Oliver, D. F. Covey, and J. Morgan,J. Amer. Chem. Soc., 1976,98,2593. M. Julia, D. Mansuy, and P. Detraz, Tetrahedron Letters, 1976, 2141; last year’s Report erroneously names this molecule nojiguki alcohol. nJ. B. Hendrickson, J. Amer. Chem. Soc., 1975, 97, 5763. R. Noyori, T. Souchi, and Y. Hayakawa, J. Org. Chem., 1975,40, 2681. G. W. Hana, G. Buchbauer, and H. Koch, Monatsh., 1976,107, 945. G. Buchbauer, G. W. Hana, and H. Koch, Monatsh., 1976,107, 387. F. C. Brown, D. G. Morris, and A. M. Murray, Synth. Comm., 1975,5, 477.

Monoterpenoids

39

Chrysanthenone (187) is reported to rearrange to (188) on treatment with hydrogen chloride (cf. Vol. 4, p. 53)!385The full paper on the homoenolization of camphor and the endo- and em-isocamphanones has been published (Vol. 4,p. 48;cf. Vol. 6, p. 40).378 A useful discussion of the preparation and solvolyses of the 6-fenchene

hydrochloride (189), camphene hydrochloride (190), and cy -fenchene hydrochloride (19 1)and the corresponding p-nitrobenzoates (no endo -chlorides reported)386may be read profitably in conjunction with Brown’s review.367 The rearrangement of

(189)

(190)

I

(191)

camphor, in HF-SbF5, to (192) and (193) provides easy access to 1’4dimethylbicyclo[2,2,2]octanes;rearrangement of (192) gives (194).387In SbF5-S0,, camphene hydrochloride (190) and the endo- and em-bornyl chlorides react with carbon monoxide or acetonitrile to yield the em-products (195; X = C0,H) or (195; X = N H A C ) . ~ Hydrolytic ’~ cleavage of the toluene-p-sulphonate (196; X = OTs) on silica gel, or in THF in the presence of boron trifluoride and a trace of water, as well as the treatment of (196; X = NH,) with nitrosyl bromide in acetic acid, results in (197) as one product; yields, however, were not recorded.”’ Rearrangement of (196; X = OTs) in trifluoroacetic acid gave (197), after reduction, in 29% yield along with em-4-methylsantenol (198; 39%) and some presumed isocyclene (1 99).”’

385

386 387 388

389

390

D. J. Merep and J. A. Retamar, Anais A c a d . brasil. Cienc., 1972,44 (Suppl.), 355 (Chem.Abs., 1975,83, 131 763). W. Hiickel, H.-J. Schneider, and H . Schneider-Bernohr, Annalen, 1975, 1690. J.-C. Jacquesy, R. Jacquesy, and J.-F. Patoiseau, Terrahedron, 1976, 32, 1699. N. Kitagawa, M. Nojima, and N. Tokura, J.C.S. Perkin I, 1975, 2369; this paper incorrectly refers to (19.5; X = C02H) as (19.5; X = OH) and Table 1 refers to CO instead of C 0 2 . R. Antkowiak and W. Z . Antkowiak, Bull. A c a d . polon. Sci., Sir. Sci. chim., 1976, 24. 291; the corresponding ketone may have been formed by Bardyshev as ketone X, I. I . Bardyshev, 1., V. Kosnikova, A. L. Pertsovskii, and L. M. Krezo, Doklady A k a d . Nauk S.S.S.R., 1969,186, 1325 (Chem. Abs., 1969,71, 102 022). R. Antkowiak and W. Z. Antkowiak, Bull. A c a d . polon. Sci., Sir. Sci. chim., 1976, 24, 299; cf. Vol. 2, p, 43 for the formation of (198) via acetolysis of fenchyl toluene-p-sulphonate.

40

Terpenoids and Steroids

(200)

Chelotropic addition of dichlorocarbene to bornadiene gave (200; X = C1) whereas with difluorocarbene the syn -adduct was favoured over the anti-adduct (200; X = F) (cf. Vol. 3, p. 59).391A thio-Claisen rearrangement has been reported with the allylic enethiolic ether of t h i ~ c a m p h o r . Flash ~ ~ ~ thermolysis of ally1 exo -2-bornyl sulphide to thiocamphor and propene has been examined.393 Cerium ammonium nitrate oxidation of camphorquinone gives (201 ;X = C0,Me) as the major product along with the exo-double-bond isomer, methyl 3-methoxy2,2,3-trime t hylcyclopen tane- 1- carboxy late, and dimethy1 camphorate.394 Chlorohydroboration-oxidation of camphene yields a 3 : 1 endo :ex0 mixture of (185; X = CH,OH), and bornylene is converted into a mixture of borneols and epiborneols, the endo-isomers predominating in each case.395 Photoaddition of N-nitrosopiperidine to camphene gives the oxime (202) and provides a simple way of recovering tricyclene from commercial ~ a m p h e n e . ~ ~ ~

(202)

Br

& Br

Further observations on the bromination of camphor (Vol. 6, p. 39; Vol. 5, p. 32) include the isolation of 3,9,9-tribromocamphor (179) during the synthesis of (+)-9bromocamphor from 3-endo -bromocamphor, the isolation of (203) as a second minor component (Vol. 6, p. 39) on treating 3,3-dibromocamphor with bromine in chlorosulphonic acid, the characterization of 3,3,8-tribromocamphor, and the remarkable conversion of 3,3-dibromocamphor into 3,3,8-tribromocamphor (50% yield) in chlorosulphonic acid by ~elf-bromination.~’~ Another sterically hindered alkene [e.g. (204)] (cf. Vol. 6, p. 40) has been synthesized, this time in diastereoisomeric forms, by reductive dimerization of (+)-camphor with LiA1H4-TiC13-THF;397 configurational assignments are consistent with the olefin octant rule.”’ 39’ 392 3y3

.79* 3y5 3y6

397

398

C. W. Jefford, W. D. Graham, and U. Burger, Tetrahedron Letters, 1975,4717. L. Morin and D. Paquer, Compt. rend., 1976, 282, C, 353, H. G. Giles, R. A . Marty, and P. de Mayo, Canad. J. Chem., 1976,54,537; in figure 1 thiocamphor and the sulphide both lack the C-10 methyl group. R . Danieli and G. Palmisano, Chem. and Znd., 1976, 565. I. Uzarewicz and A. Uzarewicz, Roczniki Chem., 1976, 50, 1315. H. H. Quon and Y. L. Chow, Tetrahedron, 1975,31,2349. H. Wynberg, K. Lammertsma, and L. A. Hulshof, Tetrahedron Letters, 1975,3749; see ref.379 for some ‘camphene-camphene’ dimers. A. I. Scott and A. D. Wrixon, Tetrahedron, 1972, 28, 933.

Monoterpetzoids

41

Nitrosolysis of camphor ethyl acetal with ethanolic ethyl nitrite in sulphur dioxide yields the orthoester oxime (205) which is rapidly dehydrated by excess acetal to the orthoester nitrile which then reacts with sulphur dioxide to form the ester nitrile and diethyl s ~ l p h i t e Further . ~ ~ ~ papers in this section include the full paper on ozonolysis of silyl ethers (Vol. 5 , p. 33),354another synthesis of camphor-en01 trimethylsilyl ether (cf. Vol. 6, p. 41),400the conversion of camphor oxime with Grignard reagents of (206) into the corresponding imine with no aziridine f ~ r r n a t i o n ,the ~ ~ preparation ' by treating bornylene with trichloroacetyl isocyanate,402the oxidation of thiocamphor to the S-oxide and alkylation in the presence of thallium(1) ethoxide to cup -unsaturated s u l p h ~ x i d e s , ~and " ~ the free-radical C-3 alkylation of camphor with a1kenes. 404

i.r. and Raman spectral bands have been assigned for a - and p-pinene405and the Raman circular intensity differential spectrum has been recorded for (-)-a - ~ i n e n e . ~ O ~ (-)-a-Pinene is converted exclusively into (+)-cis-verbenol [4S-(157; R = Me, X = H,OH)], and (+)-a-pinene into (+)-trans-verbenol (207), by the pine bark beetle I p s p a r a ~ o n f u s u salthough , ~ ~ ~ the claim for optical purity, at least in the case of (+)-trans-verbeno1(207), must be questioned in the light of Mori's routine synthesis of the optically pure antipodes (e.g. [a]L4 = +141", c = 0.65%, CHC1,).408

Bicyclo[3,1,1]heptanes.-Some

The rearrangement of the piny1 carbonium ion obtained from (208), using hydrogen bromide, .to the corresponding fenchyl and bornyl bromides confirms earlier observations (Vol. 5, p. 38).409Many papers reporting the rearrangement of 399 *OO 401 402

403 *04

405 406

407

408

M. M. RogiC, K. P. Klein, J. M. Balquist, and B. C. Oxenrider, J. Org. Chem., 1976, 41, 482. G. Simchen and W. Kober, Synthesis, 1976, 259. K. Imai, Y. Kawazoe, and T. Taguchi, Chem. and Pharm. Bull. ~Jupan),1976,24, 1083. B. Byrne, C. A. Wilson, and W. C. Agosta, Tetrahedron Letters, 1976, 2189. G. E. Veenstra and B. Zwanenberg, Rec. Trav. chim., 1976, 95, 37. M. Chatzopoulos, B. Boinon, and J.-P. Montheard, Compt. rend., 1975,281, C , 191; cf. ref. 418. H. W. Wilson, A p p l . Spectroscopy, 1976, 30, 209. W. Hug, S. Kint, G . F. Bailey, and J. R. Scherer, J. Amer. Chem. SOC.,1575, 97, 5589. J. A. A. Renwick, P. R. Hughes, and I. S. Krull, Science, 1976, 191, 199; the formula given for (+)-trans-verbenol is actually that of the (-)-enantiomer. K. Mori, Agric. and Biol. Chem. (Japan), 1976,40,415; in this connection Devon and Scott (Vol. 3, p. 5 , ref. 1) quote +168" but the paper referred to, J. Insect Physiol., 1969,15,363, makes no mention of this ["ID!

409

M. BarthCICmy, A. Gianfermi, and Y. Bessibre, Helu. Chim. A m , 1976, 59, 1894.

42

Terpenoids and Steroids

pinenes into other monoterpenoids are of little novelty and/or provide limited data, e.g. the use of kaolin4" and vermiculite411 catalysts; one, at least, attempts to examine the action of a number of simple fatty acids with a-pinene over a range of Dehydration of (209; R = H-)with toluene-p-sulphonic acid or zinc bromide (when 6-endo-bromoisoborneol was an additional product) gave the expected rearrangement products, viz. campholenic aldehyde (201;X = CH,CHO), isopinocamphone and pinocamphone [cis- and truns-(210; R = Me, X = 0)respectively], and pinol(141); dehydration of the acetate (209; R = Ac) gave the acetate of (140), (211; R = M ) , and (211; R=Ts), in addition t o p - ~ y r n e n e . ~ ' ~

Photo-oxidation of a - and P-pinene in the presence of magnesium phthalocyanine or methylene blue gave (212) and (213; X = OOH) respectively ('H n.m.r. identification Although von Rudloff oxidation (sodium periodate-potassium permanganate) of p -pinene to nopinone proceeds in high yield, the presence of t-butyl alcohol is essential. In its absence the yield of nopinone drops dramatically and, surprisingly, up to 16% of (214) is formed.415Reduction of 2a,3a-epoxypinane in ethanol is complex because of rearrangements by the catalyst alone [e.g. to (141)]; in hexane, isocarvomenthol (215) and isopinocampheol (216; X = OH) are each formed in 45% yield.416 Photochemical irradiation of P -pinene with thioacetic acid confirms the earlier observation of free-radical addition (using benzoyl peroxide initiation) to the double bond without ring-opening to give cis- and trans-(210; R = CH2SAc, X = H2) (3 : 1),417and another non-rearrangement example is provided by di-t-butyl peroxide-initiated addition of hex-1-ene to cis-verbanone (217;

(2 16) (214) 410

411

412 413

414 415 416 417

(215)

(2 17)

(218) *%

A. U. De and S. P. Srivastava, J. Indian Chem. Soc., 1975,52,164; cf. S. Battalova, A. A. Likerova, and T. R. Mukitanova. Izuest. A k u d . Nauk kazakh. S.S.R., Ser. khim., 1975,25,70 (Chem. A b s . , 1976,84, 105 785). S. B. Battalova and T. R. Mukitanova, Izuest. A k a d . Nauk kazakh. S.S.R., Ser. khim., 1975, 25, 49 (Chem. Abs.. 1975,83,206 429); cf. M. I. Goryaev, A . F. Artarnonov, L. P. Petelina, R. Suleeva, and V. A. Yugai, Vestnik A k u d . Nauk kazakh. S.S.R., 1975, 59 (Chem. Abs., 1975,83, 4 3 5 0 5 ) . G. N. Valkanas, J. Org. Chem., 1976, 41, 1179. J. de P. Teresa, I. S. Bellido, and J. F. S. Barrueco, Anules de Quim., 1976,72,560; cf. Vol. 4, p. 61, ref. 297. H. Kropf and B. Kasper, Annalen, 1975, 2232. C. W. Jefford, A. Roussel, and S. M. Evans, Helv. Chim. Acta, 1975, 58, 2151. Z. Rykowski, K. Burak, and Z . Chabudzinski, Roczniki Chem., 1975, 49, 1335. J. C. Richer and C. Larnarre, Cunad. J. Chem., 1975,53,3005; cf. Vol. 1,p. 43 which only refers to thiols although thioacetic acid is discussed in the original paper; see also F. G. Bordwell and W. A. Hewett, J. Amer. Chem. SOC., 1957, 79, 3493.

Monoterpenoids

43

R = H) to give (217; R = n-hexyl) and to isopinocamphone [cis-(210; R = Me,

K = O)] to yield (218).""*' Ring-opening is, however, observed in the oxidative addition of cyclopentanone to P -pinene, promoted by cupric oxide-acetic acid, when contrary to observathe sole product is 2-(p-menth-l-en-7-yl)~yclopentanone,~~~" tions with cupric acetate (Vol. 6, p. 43) but identical with the reported result using t-butyl The full paper on radical-initiated photoaddition of N nitrosopiperidine to a-pinene (Vol. 5 , p. 40) notes that reaction with P-pinene at -40 "C gives syn- and anti-nopinone oximes (6 : 1) in 84% yield, although ring cleavage predominates at higher Hydroformylation of (-)-a -pinene with hydrogen-carbon monoxide in the presence of cyclo-octa-l,5-dienylrhodiumchloride favours the formation of (2 16; X = CHO), which is readily obtained optically pure via the (-)-tripinyltrioxan; with p -pinene, the preferred product is 10-formyl-cis -~inane.""~O P -Pinene is converted into the azide (213; X = N3) using Tl(OAc),-Me,SiN, (cf. Vol. 4, p. 59).421 A number of papers this year are full reports of earlier communications; they include Fallis's synthesis of a - and /3 -pinene (Vol. 5 , p. 37),422Bessikre-ChrCtien's pyridine hydrochloride cleavage of the ether (219) (Vol. 3, p. 76),423and the rearrangement of 2-chloro-3-nitrosopinane in benzene solution, catalysed by silica, to give 6-endo-chlorocamphor ~ x i m e , ~ *in" "contrast to the corresponding 6-ex0 cyanocamphor oxime produced by treatment with potassium cyanide.425A related paper examines base treatment of the red-brown oily by-product from 2-chloro-3nitrosopinane formation which yields CY -fenchen-&one oxime (220).426

Papers of no great novelty concern the attempted synthesis of isopinothiocam"~~ phone [cis-(210; R = Me, X = S)],"""lead oxide oxidation of P - ~ i n e n e , "peroxidathe formation of 2a,3a -epoxypinane and tion of a-pinene over glass hydration into sobrer01,""~~ reduction of chrysanthenone (~ 7 ) , " "the ~ 'stereospecific chlorohydroboration-oxidation of P -pinene to cis-myrtanol and of a -pinene to (216; X = OH),395and the conversion of nopinone into [3-2H]myrtena1.355 418 419

420

421 422

423 4Z4

425 426

427 428 429

430

M. Chatzopoulos, B. Boinon, and J. P. Montheatd, Compt. rend., 1975, 281, C, 1015; cf. ref. 404. (a)M. Hajek and J. Malek, Synthesis, 1976,315; ( b )last year's Report erroneously ascribes this result to Lallemand; this work was done by M. Cazaux, Thesis, Bordeaux, 1969. W. Himmele and H. Siegel, Tetrahedron Letters, 1976, 907, 91 1; W. Hirnmele, H. Siegel, S. Pfohl. J. Paust, W. Hoffmann, and K. von Fraunberg, Ger. Offen. 2 404 306 (Chem. Abs., 1976,84,59 78 I). E. Maxa, E. Zbiral, G. Schulz, and E. Haslinger, Annalen, 1975, 1705. M. T. Thomas and A. G. Fallis, J. Amer. Chem. Soc., 1976,98, 1227. Y. Bessikre-ChrCtien and C. Grison, Bull. SOC.chim. France, 1975, 2499. C. H. Brieskorn and E. Hemmer, Chem. Ber., 1976, 109, 1418. V. P. Papageorgios, Chem. Chron., 1974,3, 149 (Chem. Abs., 1976,84, 5160). S. W. Markowicz, Roczniki Chem., 1975,49, 2117. Y. Fujihara and Y. Matsubara, J. Synth. Org. Chem., Japan, 1976,34, 243. J. de P. Teresa, A. S. Gonzalez, and I. S. Bellido, Anales de Quim., 1976,72, 181. A. M. Rornanikhin and N. I. Popova, Izvest. Vyssh. Uchebn. Zaved., Khim. khim. Tekhnol., 1975, 18, 1967 (Chem. Abs., 1976,84, 150 762; the abstract uses the name sorberol). D. J. Merep, C. A. N. Catalan, and J. A. Retamar, Rivista Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol, 1975,57, 197; ref. 85, p. 144.

Terpenoids and Steroids

44

Bicyclo[4,1,0]heptanes.-Molecular rearrangements in the carane series have been reviewed (in Russian).431 The enthalpies of combustion, formation, and vaporization of cis- and trand13C N.m.r. shifts have been recorded for carane have now been car-3-ene, car-4-ene (named car-2-ene!), and the related derivatives (221; X = a-H, P-OH), (221; X = a - H , P-OAc), (221; X=O), (222; X=H,OH), and (222; X =

o)*433

P

Px

A useful synthesis of (+)-car-2-ene (223) utilizes the copper-catalysed decomposition of (S)-2-cyclohexenyl2-diazopropionate(224), which is readily available from L-alanine, to yield the lactone (225); conversion of the carbonyl group into a methyl group was achieved via the corresponding lactol followed by reduction of the derived tosylhydrazone to yield (226). Methoxycarbonylation at C-3 then leads to (+)-car-2ene (223) by standard

Work in this area continues to be repetitious with results eked out into an unnecessary number of publications; examples this year include acid isomerization of cis- and trans -~aranes,'~' trans ring-opening of 3P,4p epoxycarane with hydrogen chloride and with 3,5-dinitrobenzoyl and, in English translation (Vol. 6, p. 46), the rearrangement of a carane to a bicycl0[3,1,0]hexane.~~~ Permanganate oxidation of car-2-ene gives (227) and (228), and hence (229).438 It 431 432

413

434

435

436

437

43R

B. A. Arbuzov and Z. G. Isaeva, Uspekhi Khim., 1976,45, 1339. M. P. Kozina. V. A. Aleshina. G. L,. Gal'chenko. E. F. Buinova. and I. I. Bardvshev. Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1976, 14 (Chem. Abs., 1976, 85, 33 19j). F. Fringuelli, H. E. Gottlieb, E. W. Hagaman, A. Taticchi, E. Wenkert, and P. M. Wovkulich, Gazretta, 1975, 105, 1215; Chem. Abs., 1976, 85, 46 864 is unsatisfactory. S.-I. Yamada. N. Takamura, and T. Mizoguchi, Chem. and Pharm. Bull. (Japan), 1975,23, 2539; see also ref. 224. I. I. Bardyshev and G. V. Deshits, Vestsi Akad. Navuk belarusk. S.S.R.,Ser. khim. Navuk, 1975, 89 (Chem. Abs., 1976,84, 165 039); cf. Vol. 3, p. 82; Vol. 5, p. 41; for related work see ref. 439a. B. A. Arbuzov, Z . G. Isaeva, G. Sh. Bikbulatova, and V. A. Shaikhutdinov, Bull. Acad. Sci., U.S.S.R., Div. Chem. Sci., 1975, 24, 887; cf. Vol. 2, p. 56; Vol. 4,pp. 63-65. B. A. Arbuzov, Z. G. Isaeva, and R. R. D'yakonova, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1975, 24, 890; cf. Vol. 4, pp. 64, 65. B. A. Arbuzov, V. V. Ratner, Z. G . Isaeva, and N. Kh. Abaeva, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1974, 23, 2665.

Monoterpenoids

45

appears that both possible allylic oxidations accompany epoxidation of (+ )-car-3ene439ato yield four products [e.g. (230) and (231)] which were readily reduced, in these cases, to the diols (227) and (229).4396Fifteen products from the autoxidation of (+)-car-3-ene in the presence of cobalt stearate are described in proportions H

O

(227)

P

op (228)

H

O

op

P

(229)

(230)

(231)

varying with the reductive work-up of the initial hydroperoxides; the air-sensitive (-)-m-mentha-4,6-dien-8-01 and (+)-p-mentha-l,5-dien-8-01, (-)-car-3-en-5one, (+)-car-3-en-2-one, (- )-car-4-en-3a -01, ( -)-car-4-en-36-01, and (+ )-car-2en-4-one are major products; autoxidation with oxygen alone and selenium dioxide oxidation are described.440 The tosylhydrazone (222; X = NNHTs, unspecified stereochemistry) is converted into the Vilsmeier product (232) as previously Chlorohydroborationoxidation of car-3-ene yields (233) as the major

7 Furanoid and Pyranoid Monoterpenoids A halogenated member (76) of this class has already been discussed in the halogenated monoterpenoid section.206 The acetates (234) have been isolated from Bursera delpechiana (cf. Vol. 4, p. 68),441and the alkaloid gentiananine (235; R1,R2= OMe,Me) has been reported from Pedicularis r n a c r ~ c h i l a . ~ ~ ~ R2

AcoQ (234)

439 440 441 442

W. Cocker and D. H. Grayson, ( a )J.C.S. Perkin I, 1975, 1217; ( b ) ibid., 1976, 791. D. A. Baines and W. Cocker, J.C.S. Perkin I, 1975, 2232. D. R. Adams and S. P. Bhatnagar, Internat. Flavours Food Addit., 1975,6, 185. A. Abdusamatov, A. Samatov, and S. Yu. Yunusov, Khim.prirod. Soedinenii, 1976, 122.

Terpenoids and Steroids

46

Further details of Kondo's perillene (236) synthesis (Vol. 5 , p. 43; Vol. 6, p. 16) have been published;443another synthesis was based (Scheme 4) upon photochemical isomerization-lactonization of (237).444 Reduction and alkylation of 3-methyl2-furoic acid with 1-bromo-3-methylbut-2-ene gave (238) which was oxidatively decarboxylated with lead tetra-acetate-cupric acetate to rosefuran (239).445 C0,Et <

- / \ EtO

OEt

OEt

(237) Reagents: i, EtOH-HCI, h v ; ii, NaBH,; iii, Bui2A1H-THF, -30 "C.

Scheme 4

(238)

(239)

,Rose oxide (240) (32% cis, 68% trans) and dihydrorose oxide were synthesized efficiently by the action of isobutenylmagnesium bromide or isobutylmagnesium bromide o n the ether (241)."' Synthesis of dehydrorose oxide, rose oxide (240), and

dihydrorose oxide isomers based upon reduction-cyclization of (49), dihydro-(49), or tetrahydro-(49), respectively, have also been r e p ~ r t e d . 'A ~ ~third synthesis of dihydrorose oxide is only significantly different in the formation of 3,7-dimethyl-5keto-octanal by TiC1,-Ti(OCEt,),-catalysed Michael addition of 4-methyl-2~ unusual trimethylsiloxypent- 1-ene to crotonaldehyde dimethyl a ~ e t a l . , ~The monoterpenoid a -pyrone nectriapyrone (242) (Vol. 6, p. 47) has been synthesized (Scheme 5 ) although it is not clear why the bromination step is apparently stereospecific.448 The of dihydroactinidiolide" (243) from p -ionone via K. Kondo and M. Matsumoto. Tetrahedron Letters, 1976, 391. S. Takahashi, Synth. Comm., 1976,6, 331. A. J. Birch and J. Slobbe, Tetrahedron Letters, 1976, 2079. 4J6 H. Ishikawa, S. Ikeda, and T. Mukaiyama, Chem. Letters, 1975, 1051; a reaction scheme confusingly implies that rose oxide reacts with isobutylmagnesium bromide to yield dihydrorose oxide, and Current Abstracts of Chemistry and Index Chemicus, Abstract No. 238 491, perpetuates this! 44l K. Narasaka, K. Soai, Y . Aikawa, and T. Mukaiyama, Bull. Chem. Soc. Japan, 1976, 49, 779. 44x T. Reffstrup and P. M. Boll, Tetrahedron Letters, 1976, 1903; (242) is incorrectly named nectiapyrone in VOl. 6, p. 47. 4 4 y S. Kurata, T. Kusumi, Y. Inouye, and H. Kakisawa, J.C.S. Perkin I , 1976,532; a preliminary report, S. Kurata, Y. Inouye, and H. Kakisawa, Tetrahedron Letters, 1973,5 153, wasomitted from these Reports.

443

444

445

* The authors449use the name dihydroactiniolide

Monoterpenoids

’o*-/

C0,Et

Y C H O

47

i, ii

, &o

ili

~

do

&o/

Br

(242) Reagents: i, base; ii, CHzN2; iii, NBS; iv, Zn-AcOH-ether.

Scheme 5

photochemical irradiation to (244), autoxidation to (245), and periodate cleavage, hydrolysis, and oxidation provides a more thorough investigation of earlier w ~ r k ; ~ ” an efficient (74%) peroxy-acid oxidation of 6-ionone to (243) is also reported.451

(243)

(245)

Acid-catalysed cyclization of (246) (cf. Vol. 4, p. 5) yields cis- and trans-(247) together with some (248) (cf.Vol. 6, p. 32) from which the more stable cis-(247) may be readily obtained; reductive desulphurization of cis- and trans 4247) gives cis- and trans-tetrahydroactinidiolide respectively, whereas thermal desulphurization gives (243).452The structure of gentiocrucine (Vol. 6, p. 47) has been confirmed by

\ /

SO,Ph I

(246,

450

451 452

453

P. de Mayo, J. B. Stothers, and R. W. Yip, Canad. J. Chem., 1961,39,2135; M. Mousseron-Canet, J . C. Mani, and J. P. Dalle, Bull. SOC.chim. France, 1967, 608. Y. Takagi, K. Kogami, and K. Hayashi, Jap. P. 69 062/1975 (Chem. A h . , 1 9 7 6 , 8 4 , 4 3 820). S. Torii, K. Uneyama, and M. Kuyama, Tetrahedron Letters, 1976, 1513; in Vol. 2, p. 59 franstetrahydroactinidiolide is incorrectly referred to as trans-actinidiolide (line 1) and on line 5 for actinidiolide read dihydroactinidiolide. B. Ganem, J. Amer. Chem. SOC.,1976,98, 224.

Terpenoids and Steroids

48

8 Cannabinoids and other Phenolic Monoterpenoids New brominated monoterpenoids from Cymopolia barbata include cymopol [ E (249; X = H2)], the bromonium-ion-catalysed cyclization product, cyclocymopol (250), whose X-ray structure has been determined, cymopolone and isocymopolone [ E - and 2-(249; X = 0)respectively], and cymopochromenol (251).454 OH

OH

The full paper on the structure and synthesis of alliodorin (Vol. 4, p. 69) has been published455and bakuchiol methyl ether (cf. Vol. 4, p. 70) has been synthesized again.456The synthesis4” of the previously unreported trimethyl ether of flemiwallichin A,458from Flemingia wallichin, [it differs from flemingin B (Vol. 2, p. 63) in having a C-7 rather than a C-8 hydroxy-group] by the previously reported citralphloroglucinol route (Vol. 2, p. 63; Vol. 3, p. 90) may not be as straightforward as the authors presume in view of Crombie’s that the chromene obtained from phloroacetophenone and citral in pyridine at 40°C is (252) and not (253). Compound (252) in pyridine at 110 “C, however, yields the minor citran (254) via intramolecular Diels-Alder reaction of the corresponding trienone whereas the formation of the previously reported major citran (255), whose structure is now established by X-ray analysis,46o first involves the unexpected rearrangement of (252) to (253),459thus confirming the structure of rubranine (Vol. 3, p. 91).

454

455 456

457 458

459 460

H.-E. Hogberg, R. H. Thompson, and T. J. King, J.C.S. Perkin I, 1976, 1696. K. L. Stevens and L. Jurd, Tetrahedron, 1976,32, 665. 0. P. Vig, A. K. Vig, 0. P. Chugh, and K. C. Gupta, J. Indian Chem. SOC.,1976, 53, 368. S. Y. Dike and J. R. Merchant, Tetrahedron Letters, 1976, 1529. J. M. Rao, K. Subrahmanyam, and K. V. J. Rao, Zndian J. Chem., 1975,13, 1000. L. Crombie, D. A. Slack, and D. A. Whiting, J.C.S. Chem. Comm., 1976, 139. M. J. Begley, L. Crombie, R. W. King, D. A. Slack, andD. A. Whiting,J.C.S. Chem. Comm., 1976,138.

Monoterpenoids

aOoMe nu

0

49 OH

R

\

Re-examination of Crombie’s earlier work (Vol. 2, p. 62, ref. 252) in the light of these observations leads to a reassignment of deoxybruceol (256).461 Two reviews of ~ a n n a b i n o i d s ~and ~ ~ .another ~~~ have appeared; Mechoulam’s excellent review updates his book (Vol. 5, p. 43, ref. 316) with references from mid-1972 to early 1975.463 Two new propyl-side-chain cannabinoids are propyl homologues of cannabichromene and cannabiger01.~~~ Butyl homologues of A’-THC, cannabinol, canThe structure nabidiol, and A’-tetrahydrocannabinolic acid have been of cannabispiran (257) has been determined by X-ray analysis.467 By observing the

solvent shift of the ‘H n.m.r. signals of the metu-coupled aromatic protons in deuteriochloroform and in hexadeuteriobenzene, it is possible to distinguish between ‘normal’ and ‘abnormal’ synthetic tricyclic cannabinoids; in ‘normal’ isomers the chemical shifts of these protons are different in both solvents but they are almost identical in hexadeuteriobenzene for the ‘abnormal’ isomer.468 The mass spectral fragmentation of h6-THC has been re-investigated using [9,9,9,10,10,10*H6]-h6-THC,partly confirming and partly revising earlier observations with regard to the most prominent fragment ion [Cl,Hl,02]+;469mass spectral fragmentation 461 462 463 464

465

466 467 468 469

M. J. Begley, L. Crombie, D . A . Slack, and D . A. Whiting, J.C.S. Chem. Comm., 1976, 140. M. E. Wall, Recent Adv. Phytochem., 1975,9; 29. R. Mechoulam, N . K. McCallum, and S. Burnstein, Chem. Rev., 1976, 76, 75. ‘Marihuana: Chemistry, Biochemistry and Cellular Effects’, ed. G. G. Nahas, Springer-Verlag. New York, 1976. Y. Shoyama, H. Hirano, M. Oda, T. Somehara, and 1. Nishioka, Chem. and Pharm. Buff (Japan),1975, 23, 1894. D . J. Harvey, J. Pharm. Pharmacof., 1976,28, 280. T. Ottersen, A . Aasen, F. S. El-Feraly, and C. E. Turner, J.C.S. Chem. Comm., 1976, 580. A. Arnone, R. Bernardi, L. Merlini, and S. Servi, Gazzetta, 1975, 105, 1127. E. G. Boeren, W. Heerma, and J. K. Terlouw, Org. Mass Spectrometry, 1976,11,659; cf. J. K. Terlouw, W. Heerma, P. C. Burgers, G . Dijkstra, A . Boon, H. F. Kramer, and C.A . Salemink, Tetrahedron,1974, 30,4243; see.also ref. 463.

50

Terpenoids and Steroids

patterns for the trimethylsilyl derivatives of A'-tetrahydrocannabinolic acids, cannabidiolic acid, and the propyl homologues have also been e ~ a m i n e d . ~ " The camphane cannabinoid (258) is probably formed from cannabidiolic acid by acid-catalysed cyclization during photo-oxygenation."' Three unambiguous syntheses of cis-A6-THC (259) are reported from the corresponding cis-A'-THC, the

HO' C0,Me

(258)

more complex using chemistry from previously reported cannabielsoin work (Vol. 6, p. 49).472A'-THC, labelled in the pentyl side-chain with deuterium or tritium, or at C-7 with deuterium or 14C,and A6-THC, labelled in the side-chain only, have been ~ynthesized.'~~ Other syntheses, reviewed by M e ~ h o u l a mare , ~ of ~ ~A4-THCfrom p menth-4-ene-3,8-di01,~~~ of (-)-Ah-THC from (+)-trans-car-3-ene epoxide (cf.Vol. 2, p. 62),"' and of (+)-7-hydroxy-A1-THC (cf. Vol. 6, p. 50) from (-)perillaldehyde, as well as the 6cu - and 6P-hydroxycannabidiols, ' - / - h y d r o ~ ~ cannabidiol, and 1 O-hydroxy~annabidiol.~~~ In a series of six papers Razdan et af.discuss the synthesis and activity of nitrogen, sulphur, aromatic, and carbocyclic analogues of ~ a n n a b i n o i d sand , ~ ~another ~ group has synthesized thiocannabinol via reaction of pulegone and 3-metho~y-5-pentylthiophenol.~~~ Reductive removal of the phenolic group from A6-THC again confirms its necessity for pharmacological activity (cf.Vol. 6, p. 49).479 Microbiological hydroxylation of A'-THC using Cunninghamelfa bfakesfeeana results in 6cu - and/or 4'-hydroxylation; some 7-hydroxylation occurs in combination with 4'-hydr0xylation,"'~ in contrast to metabolism in dog lung when the major metabolites are 3'-hydroxy- and 4'-hydroxy-A'-THC in addition to small amounts of 7-hydroxy, &-hydroxy-, and 6P-hydro~y-Al-THC.~''In liver tissue, the proportions of these metabolites are reversed.481 This less common C-4' side-chain 470 J7 1 472 473

474 47s 476 477

478 479

480 481

S. Billets, F. El-Feraly, P. S. Fetterman, and C. E. Turner, Org. Mass Spectrometry, 1976, 11, 741.

J . K. Kirtany and S. K. Paknikar, C'hem. and Ind., 1976, 324. D. B. Uliss, R. K. Razdan, H. C. Dalzell, and G. R. Handrick, Tetrahedron Letters, 1975, 4369. C . Ci. Pitt, D. T. Hobbs. H. Schran, C. E. Twine, and D. L. Williams, J . LabeffedCompounds, 1975,11, 551. A. Arnone, L. Merlini, and S. Servi, Tetrahedron, 1975, 31, 3093. J.-L. Montero and F. Winternitz, Compt. rend., 1975, 281, C, 197. N. Lander, Z. Ben-Zvi, R. Mechoulam, B. Martin, M. Nordqvist, and S. Agurell, J.C.S. Perkin I, 1976,s. For example, M. Winn, D. Arendsen, P. Dodge, A. Dren, D . Dunnigan, R. Hallas, K. Hwang, J. Kyncl, Y.-H. Lee, N. Plotnikofi, P. Young, H. Zaugg, H. Dalzell, and R. K. Razdan, J. Medicin. Chem., 1976, 19, 461; R. K. Razdan and H. C. Dalzell, ibid., 1976,19, 719; see references therein for four earlier papers. H.-J. Kurth, U. Kraatz, and F. c o r t e , Chem. Ber., 1976, 109, 2164. U . Kraatz and F. Korte, Tetrahedron Letters, 1976, 1977. M. Binder, Helv. Chim. Actu, 1976, 59, 1674. M. Widman, M. Nordqvist, C. T. Dolleiy, and R. H. Briant, J. Phurm. Pharmacol., 1975, 27, 842.

Monoterpenoids

51

hydroxylation is also observed with Syncephalustrum rucemosum and A1-THC, In vitro metabolism of cannabinol in rat A6-THC, cannabinol, and cannabidi01.~~~ liver results in only minor amounts of C-2', C-3', C-4', and C-5' side-chain hydroxyet ul. observed the same minor side-chain hydroxylation with l a t i ~ n . ~Martin '~ cannabidiol, also isolating 6a -,6p -, and 1'-hydroxycannabidiol, in addition to the known major metabolite, 7-hydro~ycannabidiol;~~~ in a second paper they also report eight dihydrocannabidiol~.~'~ In contrast, similar in vitro experiments with cannabinol and rabbit liver enzymes show a 2 : 3 ratio of 4'-hydroxycannabinol: 7-hydroxy~annabionol.~'~ Photochemical irradiation of cannabinol produces (260), which is converted into the hydroxyphenanthrene (261).486Attempts to form A'-THC co-ordination compounds failed, which suggests that the physiological action of A'-THC is unrelated to transition-metal complexes.487

482 483 484

485 486

487

L. W. Robertson, M. A . Lyle, and S. Billets, Biomed. Mass Spectrometry, 1975, 2, 266. M. Widman, J. Dahmen, K . Leander, and K. Peterson, Acta Pharm. Suec., 1975, 12, 385. B. Martin, M. Nordqvist, S. Agurell, J.-E. Lindgren, K . Leander, and M. Binder, J. Pharm. Pharmacol., 1976,28, 275. B. Martin, S. Agurell, M. Nordqvist, and J.-E. Lindgren, J. Pharm. Pharmacol., 1976,28, 603. A. Bowd, D. A . Swann, and J. H. Turnbull, J.C.S. Chem. Comm., 1975, 797. G. W. Watt and J. R. Paxson, J. Inorg. Nuclear Chem., 1976,38,627.

2 Sesqu iterpenoids _____~____

~~~

BY N. DARBY AND T. MONEY

This chapter follows the pattern of previous Reports with the various sesquiterpenoids considered in structural groups based on their postulated or established biosynthesis. Interest in sesquiterpenoid structure, synthesis, and biosynthesis has continued at a high level during the period covered by the present Report. Two excellent reviews have been published: one provides an up-to-date account of sesquiterpenoid biosynthesis' while the other provides an authoritative description of studies on sesquiterpenoid stress compounds.2 Stress metabolites are produced by plants after infection with fungi, bacteria, and viruses or after mechanical wounding, irradiation with U.V. light, dehydration, cold, or treatment with phytotoxic agents.

1 Farnesanes Recent investigations in the new important area of stress metabolites (cf. Vol. 6, p. 80) have revealed the presence of various nerolidol derivatives (l)--(5) and bicyclic sesquiterpenoids (cf. p. 94) in eggplant fruit which has been incubated with fungi.3

(1) R = O (2) R=H,OH

(3) R = H (4)R = E t

Another dehydronerolidol derivative (6) (cf.Vol. 1,p. 52) has been isolated from the genus Bri~kellia.~" The same research group has also reported the isolation of the sesquiterpenoid quinone (7) from three species of S e ~ e l i . ~ ~ Nickel-catalysed trimerization of isoprene has been shown to provide a mixture of natural PLtruns-farnesene (8) (cf.Vol. 1, p. 82) and the isomeric compound (9).5 1 2

3 4 5

G. A. Cordell, Chem. Rev., 1976, 76,425. A. Stoessl, J. B, Stothers, and E. W. B. Ward, Phytochemistry, 1976, 15, 855. A. Stoessl, J. B. Stothers, and E. W. B. Ward, Canad.J. Chem., 1975, 53, 3351. F. Bohlmann and C. Zdero, (a)Chem. Bet-., 1976,109, 1436; ( b j ibid., 1975,108, 2818. S. Akutagawa, T. Tzketomi, and S. Otsuka, Chem. Letters, 1976,485.

52

Sesquiterpenoids

53

/ \

/

(8)

/

(9)

Alternative synthetic routes (Schemes 1 and 2) to dendrolasin (10) have been developed by two research g r o u p ~ . One ~ ' ~ of the synthetic sequences6 was also adapted to provide neotorreyol(11) and torreyal(l2) (cf.Vol. 4, p. 84; Vol. 5, p. 46).

A

i,ii

OH

OH

OH

CI

vii

SPh

&

SPh

X

viii

X=HorOH

1

(10) X = H (11) X = O H Reagents: i, '0,; ii, (NH,),CS; iii, 0 2 , hv, Rose Bengal; iv, Bu'OCI-THF; v, H2SO4; vi, SOCI,; vii, Bu"Li; viii, Li-EtNH,; ix, MnO,.

Scheme 1 K. Kondo and M. Matsumoto, Tetrahedron Letters, 1976, 391. S. Takahashi, Synth. Comm., 1976,6, 331.

Terpenoids and Steroids

54

1.i (10) Reagents: i, NaOEt; ii, NaOH; iii, (Et0),PO(CH2CO2Et); iv, Hf,h v ; v, NaBH,; vi, BuiAlH.

Scheme 2

Biosynthetic studies on juvenile farnesol") are described in Chapter 6.

and the cis-trans isomerization of

2 Mono- and Bi-cyclofarnesanes The predicted involvement of brominated monocyclofarnesane derivatives in the biosynthesis of halogenated chamigrane sesquiterpenoids (cf.Vol. 4, p. 96; Vol. 5 , p. 55 ;Vol. 6 , p. 64) has received considerable support by the recent isolation of a - (13) and P-snyderol (14) from species of marine red alga (Laurencia obtusa and L.

(13)

(14)

sn yderiae ) which also produce bromochamigranes. ' Simple biogenetic-type syntheses of P-snyderol (14) have been accomplished in low yield by treating nerolidol (15) with the dienone (16)" or methyl trans,trans-farnesate (17) with NBSCu(OAc), followed by reduction, bromination, and hydr01ysis.l~ Of biosynthetic interest is the reported isolation of the alcohols (19) and (20) from the Hawaiian marine alga Laurencia n i d i f i ~ a , 'Compounds ~ of this type have previously been isolated from other marine organisms (cf.Vol. 5, p. 91; Vol. 6, p. 93) 8

lo 11

l2 13 14

M. G. Peter and K. H. Dahm, Helc. Chirn. Actu, 1975, 58, 1037. R. C. Jennings, K. J . Judy, and D. A. Schooley, J.C.S. Chem. Comm., 1975, 21. C. Capellini, A . Corbella, P. Gariboldi, and G . Jommi, Bioorg. Chem., 1976, 5 , 129. R. M. Howard and W. Fenical, Tetrahedron Letters, 1976, 41. T. Kato, I. Ichinose, A. Karnoshida, and Y . Kitahara, J.C.S. Chem. Comm., 1976, 518. A. G. Gonzalez, J . D. Martin, C. Pkrez, and M. A. Ramirez, Tetrahedron Letters, 1976, 137. H. H. Sun, S . M. Waraszkiewicz, and K. L. Erickson. Tetrahedron Letters, 1976, 585.

Sesquiterpenoids

55

& \

\

OH

+ (14)

+

Br

T

Br

wet silica

(14)

(15) i, NBS-Cu(OAc)z ii, LiAIH4

' Br

(18)

(17)

and it is assumed that their biosynthesis involves methyl migration in a monocyclofarnesane precursor. The facile conversion of (19) into (20) has prompted the suggestion that the latter compound may be an artefact.14

(19)

(20)

An alternative stereoselective synthesis of (k)-abscisic acid (25) (cf.Vol. 4, p. 142) has been a ~ h i e v e d by ' ~ the route outlined in Scheme 3.

h,

ii

iii, iv

CO,H

OH

Reagents: i, NaAIH2(0CH2CH20Me)2; ii, H+; iii, MnO,; iv, A g 2 0 .

Scheme 3

(*)-Caparappi oxide (29) and its 8-epimer (30) have been obtained by acidcatalysed cyclization of the diol(28) derived from dihydro-a -ionone (26)16 (Scheme 4). l6

H. J. Mayer, N. Rigassi, U. Schwieter, and B. C. L. Weedon, Helu. Chim.Acta, 1976,59, 1424. P. Lombardi, R. C. Cookson, and H. P. Weber, Helu. Chim. Acta, 1976,59,1158; cf. R. C. Cookson and P. Lombardi, Gattetra, 1975, 105, 621.

Terpenoids and Steroids

56

\

i,ii,&

0

OH

(29)

(30)

(28)

Reagents: i, CH2=CHMgBr; ii, rn -CIC6H4C03H; iii, LiAIH4; iv, HC104.

Scheme 4

A further example of the use of phenyl sulphones in prenylation reactions is provided in the recent synthesis of deoxytrisporone (37) (Scheme 5)." An interesting feature of this synthesis is the regiospecific acylation of the diol (35) with isobutyric anhydride.

c

S

0

2

P

h

&S02Ph

(31)

@SO2Ph

(32)

(33) iiil

& & &

C0,Me

&oH.iv,v

S02Ph

(35)

(34)

pi

OCOPr'

vii, viii

OH

~

(37)

(36) Reagents: i, H+; ii, SeO,; iii, BrCH2CMe=CHCOzMe-LiPr;; vii, CrO,-py; viii, KOH-MeOH.

Scheme 5 K. Utieyama and S . Torii, Tetrahedron Letters, 1976, 443.

iv, NaOMe; v, EiAlH4; vi, (Pr'CO),O-py;

57

Sesq u iterpenoids

A group of isomeric furanosesquiterpenoids isolated from a marine sponge (Microciona toxystila) has been assigned structures (38)-(41) on the basis of their chemical and spectroscopic properties. l 8 Microcionin-2 (39) and microcionin-4 (41) have structures which are presumably derived by rearrangement (1,2-methyl shift) of a monocyclofarnesane precursor (cf.Vol. 6, p. 92). It has been suggestedI8 that the biosynthesis of microcionin- 1 (38) involves cyclization of a rearranged monocyclofarnesane intermediate and the chemical feasibility of this proposal is indicated by the reported conversion of (39) into (38).18

BF3-EtzO t---

0

Alternative structures have been assigned to the sponge metabolites spiniferin-1, (42) or (43), and spiniferin-2, (44) or (45).19 It has been suggested that the unique

Or

/

(44)

(45)

bicyclic skeleton of spiniferin- 1 is formed by cyclization of a cis-farnesyl precursor [cf. (46)] followed, in the case of spiniferin-2, by methyl migration. The cooccurrence of the spiniferins and pleraplysillin (47) in the same species of sponge

(46) 18

19

(47)

G . Cimino, S. DeStefano, A. Guerriero, and L. Minale, Tetraheron Letters, 1975, 3723. G. Cimino, S. DeStefano, L. Minale, and E. Trevillone, Tetrahedron Letters, 1975, 3727.

Terpenoids and Steroids

58

(Pleraplysilla spinifera) (cf.Vol. 4, p. 143) and the cyclization of ethyl y-geranate (48) to (49) (cf. Vol. 6, p. 33) provide indirect support for these biosynthetic proposals.

(49)

(48)

Another component of the essential oil of the pepper tree (Pseudowintera colorata ) has been isolated and assigned the rearranged bicyclofarnesane structure (50).20 Cyclonerotriol (52) has recently been isolated2' from Fusarium cuZmorum where it co-occurs with cyclonerodiol (51) (cf.Vol. 1,p. 58; Vol. 2, p. 72; Vol. 3, p.

LR

HO

(51) R = H (52) R=OH

102). In structural terms these fungal metabolites are analogous to the iridoid monoterpenoids (cf. Chapter 1). Recent studies on the biosynthesis of cyclonerodiol,22cyclonerotriol,22 and abscisic acid (25)23are described in Chapter 6.

3 Bisabolane, Sesquicarane, Sesquithujane Characterization of (E)-y-bisabolene (55a) has recently been accomplished for the first time by its synthesis from a P-hydroxy-acid (53a) whose absolute configuration was established by X-ray crystallographic analysis.24 The g.1.c. and spectral characteristics of (2)-y-bisabolene (55b), produced from the diastereomeric acid (53b), were also r e c ~ r d e d . 'Thus ~ it can be concluded that the previous synthetic route to y-bisabolene (Vol. 6, p. 57) produced a 3 : 2 ratio of (E)-and (2)-isomers. As a result of these definitive the proper identification of y-bisabolene in natural systems can now be made.

2' 22

23 24

R. E. Corbett and T. L. Chee, J.C.S. Perkin I, 1976, 850. J. R. Hanson, P. B. Hitchcock, and R. Nyfeler, J.C.S. Perkin I, 1975, 1586. R. Evans, J.R.Hanson,andR.Nyfeler,J.C.S. Chem. Comm., 1975,814; J.C.S. PerkinZ, 1976,1214. B. V. Milborrow, Phytochemistry, 1975, 14, 123, 2403. L. E. Wolinsky, D. J. Faulkner, J. Finer, and J . Clardy, J . Org. Chem., 197641,697.

59

Sesquiterpenoids

A simple and efficientsynthesis of juvabione (58) (cf. Vol. 1, p. 60; VoI. 5 , p. 49; Vol. 4, p. 88), a sesquiterpenoid possessing juvenile hormone activity, has been achieved using a combination of hydroboration and carbonylation reactionsz5(cf. Scheme 6 ) . A new efficient synthesis of (f)-a-curcumene (59) (cf.Vol. 5, p. 51) involves reduction in situ (Li-NH,) of the alkoxide produced from p-tolylmagnesium bromide and 6-methylhept - 5-en-2-one. 26 Full details of a previously reported synthesis (Vol. 6, p. 88) of cis- and trunsatlantones (60)and a related trisnor-sesquiterpenoid (61) have been p ~ b l i s h e d . ~ ~ " , ~

H

A

H (58)

(57)

Reagents: i, Me2CHCMe2BHz-THF; ii, CO-HzO; iii, H20-HOAc.

Scheme 6

(59) 25 26

2'

(60)

(61)

E. Negishi, M. Sabanski, J.-J. Katz, and H. C. Brown, Tetrahedron, 1976, 32, 926. S. S. Hall, F. J. McEnrose, and H.-J. Shue, J. Org. Chem., 1975, 40, 3306. ( a ) D. R. Adams, S. P. Bhatnagar, R. C. Cookson, and R. M. Tuddenham, J.C.S. Perkin I, 1975,1741; ( b )D. R. Adams, S. P. Bhatnagar, and R. C. Cookson, ibid., p. 1502.

Terpenoids and Steroids

60

These compounds co-occur in the essential oil of Cedrus atlantica and it is interesting to note that a-caryophyllene alcohol (62) (obtained for the first time as a natural product) and the epimeric himachalene epoxides (63a and b) have also been identified as c o - r n e t a b o l i t e ~ . ~ ~ ~

4:) *p (62)

(63a and b)

The first total synthesis of the marine seaweed metabolite isocaespitol (71) has been achieved by the synthetic route outlined in Scheme 7.28 In the final step of the

vi-viil

Br o@OAc'H

/t\ OH

1-

@b

Br

C0,Me

1 ix'x -

@OAc

Ac

Me0,C

Reagents: i, 0,; ii, (Me0)2PO(CH2C02Me)-NaH; iii, LiAlH,; iv, Ac20-py; v, Ac20-Me3N; vi, K,CO,; vii, PBr3; viii, MeCOCH2C02Et-NaOEt; ix, CuBr,-LiBr-NaH-DMF; x, Ba(OH),-EtOH; xi, alumina; xii, BrCI.

Scheme 7 28

A. G. Gonzblez, J. D. Martin, and M. A. Melian, Tetrahedron Letters, 1976, 2279.

Sesquiterpenoids

61

synthesis a mixture of isocaespitol (71) and caespitol (72) was obtained in a ratio of 1:3. Stereoselective dialkylation of 7,7 -dichloronorcaran-2-one ethylene acetal (73) forms the basis of a new synthetic route (Scheme 8) to ( f)-sesquicarene (76) and (*)-sirenin (77).29 Transformation of the bicyclic ketone (75) into the natural

R (73)

(74)

(76) R = H (77) R = O H

(75)

Reagents: i, C12C:; ii, (Me2C=CHCH2CH2)2CuLi; iii, MeI; iv, H20-H+

Scheme 8

products was accomplished by reactions developed previously by another research In an alternative synthesis31 (Scheme 9) of sirenin (77) and sesquicarene (76) the basic bicyclo[4,l,O]heptane framework was constructed by an adaptation of the normal synthetic route to the carane system.

C02Me

C02Me I

I

(81)

(80)

+ exo -methyl isomer Reagents: i, ClCH20CH&H=CH2-BF3,Et20; TsC1-py; vi, (Me2C=CH)2CuLi.

ii, KOBU'; iii, AczO-BF,;

iv, NaOMe-MeOH; v,

Scheme 9 29 3O 31

K. Kitatani, T. Hiyama, and H. Nozaki, J. Amer. Chem. SOC.,1976,98, 2362. ( a ) Cf. U. T. Bhalerao, J. J. Plattner, and H , Rapoport, J. Amer. Chem. Soc., 1970, 92, 3429; (b) E. J. Corey and K. Achiwa, Tetrahedron Letters, 1969, 1837, 3257. C. F. Garbers, J. A. Steenkamp, and H. E. Visagie, Tetrahedron Letters, 1975, 3753.

62

Terpenoidsand Steroids

A further example of the structural similarity between many monoterpenoids and s e s q ~ i t e r p e n o i dis s ~provided ~ in a recent paper describing the isolation and structural elucidation of zingiberenol (82), sesquisabinene (83), sesquisabinene hydrate (84), and sesquithujene (85).33

(82)

(83)

(84)

(85)

The biosynthesis of (2)-y-bisabolene (55b) and paniculide B (86) in callus cultures of Androgruphic p u n i ~ u l u t uis~ described ~ in Chapter 6. A new compound (87) structurally similar to paniculide (86) has recently been isolated from a Senecio species (cf.p. 72).

(87) R’ = COCMerCHMe R2 = COCHMeCH=CH2

4 Sesquipinane, Sesquifenchane A series of simple transformations (Scheme 10) from endo-dicyclopentadiene has provided alternative synthetic routes to (k)-sequifenchene (97) and (k)-epi-Psantalene (98).3’ The suggested intermediacy of P-bergamotene (99) in ovalicin (100) biosynthesis has been supported by recent ~ t u d i e susing ~ ~ , [~1,2-13C]acetate ~ and [4-’3C]mevalonate as precursors (cf. Chapter 6).

5 Carotane, Acorane, Cedrane Further studies (cf.Vol. 6, p. 61) on the formic acid-catalysed conversion of carotol (101) into daucene (102) and acoradienes (103) have shown that prolonged exposure to 90% HC0,H results in the disappearance of (103) and (103) and the formation of a mixture of at least five Two of these compounds have been identified 32

33

34

35

16 37 38

Cf. G. L. Hodgson, D. F. MacSweeney, andT. Money, J.C.S. Perkin I, 1973,2113; J.C.S. Chem. Comm., 1973,236. S . J. Terhune, J. W. Hogg, A. C. Bronstein, and B. M. Lawrence, Canad. J.”Chem., 1975, 53, 3285. K. H. Overton and 11). J. Picken, J.C.S. Chem. Comm., 1976, 105. P. A. Grieco and J. J. Reap, Synth. Comm., 1975, 5 , 347. M. Tanabe and K. T. Suzuki, Tetrahedron Letters, 1974, 4417. D. E. Cane and R. H. Levin, J. Amer. Chem. SOC., 1975, 97, 1282; ibid.. 1976,98, 1183. L. H. Zalkow, M. G. Clower, M. G. J. Smith, D. VanDerveer, and J. A. Bertrand, J.C.S. Chem. Comm., 1976,374.

63

Sesquiterpenoids

LkQ+kpAkQ 0

0

0

viii-xi,

/ iii

\ xii

Reagents: i, Hz-Ni-B; ii, B H ;iii, Cr03-H'; iv, m-ClC6H4CO3H;v, BuiAlH; vi, Me2C=PPh3-DMSO; vii, Ph3CLi-Me; vii, LiAlH,; ix, TsC1-py; x, AcO-; xi, HO--H20; xii, CH2=PPh3-DMSO.

Scheme 10

(99)

as the ether (104) and the racemic tricyclic alcohol (106).38It has also been shown3' that separate treatment of the acoradienes (103) with formic acid also yields racemic (106). A new stereocontrolled synthetic route to acorenone-B (108) (cf. Vol. 6, p. 62) has been developed by using a combination of spiroannelation, secoalkylation, and

Terpenoids and Steroids

64

(106)

(105)

carbonyl transposition reactions39(Scheme 11). In an alternative synthesis4' of (k)acorenone-B (108) the spiro[4,5]decane system is constructed by the intramolecular ene reaction (Scheme 12) used previously in the synthesis of ( )-P-acorenol (cf.Vol. 5 , pp. 53, 54).

*

p-* 0

SPh

(108) Reagents: i, b i P h 2 - K O H : ii, LiBF4-C6H6; iii, HC02Et-NaH; iv, T s O H - C ~ H ~v,; AIHBu;; vi, Cr03H +; vii, (CH2SH)-BF3,Et20; viii, C5HS&-S03-Et3N; ix, HgC12-MeCN; x, KOH-MeOH; xi, LiNPr;; xii, PhSSPh; xiii, MeLi.

Scheme 11 39 4"

B. M. Trost, K. Hiroi, and N. Holy, J. Amer. Chem. SOC.,1975, 97, 5 8 7 3 . W. Oppolzer and K. K. Mahalanabis, Tetrahedron Letters, 1975, 3411.

Sesquiterpenoids

65

Reagents: i, 280 "C; ii, MeLi; iii, A1203-py, 220 "C; iv, [(Ph3P),RhCI]-H2; v, Na2Cr04-Ac20-HOAc; vi, Pb(OAc),; vii, TSOH-C6H6.

Scheme 12

:'rr""

4-Ketocedrol(l lo),* and isocedrolic acid (111)42have been identified as metabolites of Juniperus squamata and their structures established by chemical correlation

R2 (110) R ' = M e , R 2 = 0 (111) R' = C02H, R2 = H2

with LY -cedrol (113). ( f)-Cedrene (114)and ( f)-cedrol (113)have been synthesized by a new synthetic sequence in which the tricyclic skeleton is constructed by an intramolecular Diels-Alder reaction on (112)43(cf. Scheme 13). ( -)-Prezizaene (119) and the related tricyclic sesquiterpenoids (120)-(122) have been isolated from Eremophila georgii4, The absolute stereochemistryof these compounds is antipodal to that of the zizaene sesquiterpenoids found in vetiver oil (cf.Vol. 3, p. 123; Vol. 4, pp. 94-96) and their biosynthesis probably involves cyclization of p -acoradiene (115) and rearrangement of the intermediate allocedryl (116) or cedryl (117) carbonium ions or their biological equivalents (cf. Scheme 14).44

6 Cuparane, Trichothecane Halogenated sesquiterpenoids are now recognized as common constituents of marine organisms (cf.pp. 69 and 7 1) and a recent report describes the isolation of 41

42 43 44

T. H. Kuo, I. C. Yang, C. S. Cheng, and Y. T. Lin, Experientia, 1976, 32, 686. Y. H. Kuo, S. H. Hsieh, S. T. Kao, and Y. T. Lin, Experientia, 1976, 32, 827. E. G. Breitholle and A. G . Fallis, Canad. J. Chem., 1976, 54, 1991. P. J . Carrol, E. L. Ghisalberti, and D. E. Ralph, Phytochernistry, 1976, 15, 777.

66

Terpenoids and Steroids

a ao m0*

+

N Na

H

i,

H

H

\

iil

.% ,,

2-epimer +

H Reagents: i; B2H6-DME; SOCl2-py .

H

ii, Cr03-Hf; iii, Me,SiCN-ZnI,;

Scheme 13

a H

(120) R' = H, R2 = OH (121) R ~ R ~ = O

(122)

Scheme 14

iv, LiAIH,; v, HNO,; vi, MeLi; vii,

67

Sesquiterpenoids

(123) R1 = Br, R2 = H (124) R'=H, R * = B ~

a -bromocuparene (123)and a -isobromocuparene (124)from seaweeds of the genus L a ~ r e n c i a An . ~ ~alternative synthesis of P-cuparenone (129)(cf.Vol. 5,p. 51) has been accomplished using the reaction sequence outlined in Scheme 15.46 CN

0

0

(129)

(128)

(127)

Reagents: i, Me;?C=CHCOMe-LiNPri; ii, H2S04-HOAc-THF; iii, NaOH-MeOH-H2O; iv, NaBH,; v, ICHZZnI; vi, Cr03-H+; vii, Li-NH3.

Scheme 15

12,13-Epoxytrichothec-9-ene(138)(cf. Vol. 4,p, 90),a metabolite of T. roseurn and a proposed intermediate in the biosynthesis of trichothecene sesquiterpenoids (cf. Chapter 6), has recently been synthesized (Scheme 16).47 The final cyclization step [(136)+ (137)] in the synthesis is identical to that proposed in the biosynthesis of this compound. Two new trichothecene sesquiterpenoids have been isolated from the culture filtrates of Fusarium sp. K-5036and assigned structures (139)and (140) on the basis of their chemical and spectroscopic proper tie^.^^ A further report on the I3C n.m.r. of the trichothecenes has recently been published49 and recent s t u d i e ~ ~on~ the - ~ ~biosynthesis of this group of sesquiterpenoids are described in Chapter 6. 45 46

47 48

49

51

52

53 54

T. Suzuki, M. Suzuki, and E. Kurosawa, Tetrahedron Letters, 1975, 3057. A. Casares and L. A. Maldonado, Synth. Comm., 1976,6, 11. N. Musuoka and T. Kamikawa, Tetrahedron Letters, 1976, 1691. K. Ishii, Phytochemistry, 1975,14, 2469. R. A. Ellison and F. N. Kotsonis, J. Org. Chem. 1976,41, 576. B. Muller, R. Achini, and C. Tamm, Helu. Chim. Acta, 1975, 5 8 , 4 7 1 . B. Muller and C. Tamm, Helv. Chim. Acta, 1975, 58, 483. W. Knoll and C. Tamm, Helu. Chim. Acta, 1975, 58, 1162. R. Evans and J. R. Hanson, J.C.S. Chem. Comm., 1975, 231; J.C.S. Perkin I, 1976, 326. R. Evans, J. R. Hanson, and T. Marten, J.C.S. Perkin I, 1976, 1212.

Terpenoids and Steroids

68

h i , viii

(1 34a)

(134b)

ix,

'0PoAc x

xi,viii

,H

O

-

0

P O H

(135)

(138)

(137)

Reagents: i, (CH*SH),-BF3,Et20; ii, Et2C03-NaH; iii, HCHO-Et2NH; iv, H,BO,; v, NaBH,; vi, Ac2O-p~;vii, HgCI*-CdCO,; viii, HO--H20; ix, MsC1-py; x, Et4NOAc; xi, MeMgI; xii, H+.

Scheme 16

(139) R = H (140) R = OH

69

Sesquiterpenoids 7 Chamigrane

Further studies on the halogenated sesquiterpenoids of marine algae (cf.p. 65 and also Vol. 4, p. 96; Vol. 5 , p. 55; Vol. 6, p. 64) have revealed the presence of 10bromo-a -charnigrene (141) in Californian L a ~ r e n c i acompounds ,~~ (142)-(146) in Laurencia o b t u ~ a and , ~ ~ nidifocene (147) in Lafirencia nidifi~a.~'According to

Br

L43

hC'

(145) X = H (146) X = B r

(147)

current biosynthetic theory the chamigranes and halogenated derivatives could be derived by cyclization of an appropriate monocyclofarnesane [cf. (148)] or bisabolene intermediate [cf.(149)]. A biomimetic approdch to the synthesis of 10-

bromo-a -chamigrene (141) based on the suggested monocyclofarnesane route has recently been achieved (Scheme 17) by bromonium-ion-induced cyclization of geranylacetone (150)58(cf. synthesis of a - and p-snyderol, p. 54). Conversion of cyclization products into an isomer (153) of a-snyderol (cf. p. 54) followed by acid-catalysed cyclization yielded 10-brorno-a -chamigrane (141) as the major product. A recent investigation of the chemical constituents of the digestive gland of the sea hare (Aplysia californica) has resulted in the isolation of prepacifenol epoxide (154) and the related compounds (155) and (156).59 Unlike previous halogenated mono- and sesqui-terpenoids isolated from this source, the latter compounds (155) and (156) have not yet been identified as metabolites of the 55 56

'5 58 59

B. M. Howard and W. Fenical, Tetrahedron Letters, 1976, 2519. A. G. Gonzfilez, J . Darias, A. Diaz, J. D. Fourneron, J. D. Martin, and C. PCrez, Tetrahedron Letters, 1976,3051. S . M. Waraszkiewicz and K. L. Erickson, Tetrahedron Letters, 1976, 1443. L. E. Wolinsky and D. J. Faulkner, J. Org. Chem., 1976,41, 597. C. Ireland, M. 0. Stallard, and D. J. Faulkner, J. Org. Chem., 1976, 41, 2461.

Terpenoids and Steroids

70

Reagents: i, Br2-AgBF4-MeN02; ii, TsOH-C6H6; iii, CH2=CHMgBr.

Scheme 17

OH (154)

'

H

(155)

I

I

(156)

Laurencia species which form a major portion of the sea hare's diet. Perforene (160), a new metabolite detected in the marine alga Laurencia perforata, has been assigned the unusual structure (160) and it has been suggested that the biosynthesis of this compound involves rearrangement (Scheme 18) of a chamigrane intermadiate.") It is interesting that three other metabolites of this species of Laurencia also have rearranged chamigrane structures (cf.Vol. 6, p. 65).

60

A. G. Gonzalez, J. M. Aguiar, J. D. Martin, and M. L. Rodriguez, Tetrahedron Letters, 1976, 205.

Sesquiterpenoids

71

8 Amorphane, Copaane, Ylangocamphane, Copacamphane, etc. Recent studies61have confirmed that the phytoalexin isolated from species of cotton (Gossypiurn)infected with the fungus Verticilliurn dahliae is hemigossypol(l61) (cf. Vol. 6, p. 66) and not, as previously reported,62 isohemigossypol (162). A related compound, p-hemigossypolone (163) has been identified as one of the compounds which inhibits the growth of tobacco budworm (Heliothisvirescens) in cotton CHO OH

CHO OH

HO

CHO 0

HO

(161)

(162)

(163)

Although comparatively rare, sesquiterpenoids containing isocyanide, isothiocyanate, and formamide, groups have been isolated from species of marine sponge (cf.Vol. 5, p. 74; Vol. 6, pp. 65,87,89). Included in this small group are the previously reported amorphane derivatives (164a-4, and a complete account of

(164) a; X = N C b; X=NCS c; X = NHCHO

their isolation and structural elucidation has recently been published.64 Three new metabolites of the marine sponge Aninella cannabina have been assigned structures (165a) (axisonitrile-3), (165b) (axisothiocyanate-3), and (16%) ( a ~ a n i d e - 3 ) . ~ ~

A (165) a; X = N C b; X=NCS c; X = NHCHO 61

J. A. Veech, R. D. Stipanovic, and A. A. Bell, J.C.S. Chem. Comm., 1976, 144.

A. S. Sadykov, L. R. Metlitskii, A. K. Karindzhonaev, A. I. Ismailov, R. A. Mukhamedova, M. K. Avazkhodzhaev, and F. G. Karnaev, Doklady Akad. Nauk S.S.S.R., 1974,218, 1472. 63 J. R. Gray, T. J. Mabry, A. A. Bell, R. D. Stipanovic, and M. J. Lukefahr, J.C.S. Chem. Comm., 1976, 109. 64

65

B. J. Burreson, C. Christophersen, and P. J. Scheuer, Tetrahedron, 1975, 31, 2015. B. Di Blasio, E. Fattorusso, S. Magno, L. Mayol, C. Pedone, C. Santacroce, and D. Sica, Tetrahedron, 1976, 32,473.

Terpenoids and Steroids

72

These compounds have rearranged amorphane structures and co-occur with axisonitrile-1 (166a) and -2 (167a), axisothiocyanate-1 (166b) and -2 (167b), and axamide- 1 ( 166c) and -2 (167c) (cf. Vol. 5, p. '77; Vol. 6, p. 89) in the same species of sponge.

% Q

(166) a ; X = N C

(167) a; X = N C

b: X = N C S c; X = NHCHO

b; X = NCS c; X = NHCHO

Several new sesquiterpenoids having normal (168) and rearranged (169-172) cadinane structures have been isolated from the aerial parts of the plant Heterotheca

WH \

/

I

OR

(169) R = M e (170) R = H

HO'

/p

9;

inuloides.66 The same group has also that the triester (173), related to oplopanone (174) (cf. Vol. 3, p. 117; Vol. 5, p. 61), is a metabolite of Senecio abrotanifolius (cf. p. 62).

Ho@ o -

R 0.. R'O"

OAc

0

(1 73) R' = COCH(Me)Et R' = COCH=C(Me)Et

(174)

An alternative synthesis of cubebol(l75) is very similar to that previously reported by another research group (cf. Vol. 4,p. 102) and utilizes the same intramolecular ('(1

67

F. Bohlmann and C. Zdero, Chem. Ber., 1976,109, 2021. F. Bohlmann and A. Suwita, Chem. Ber., 1976, 109, 2014.

Sesquiterpenoids

73

carbene insertion reaction, (176) + (177), to construct the basic tricyclic framework.68

&
A

C)i-1....; - bO A

A (175)

(176)

(177)

Chemical and spectroscopic evidence has been used to establish the structure of a new compound (178) (cis-a, -copaen-8-01) isolated from the root oil of Angelica archangelica.69

(178)

Full details of the previously reported synthetic routes to (-)-copacamphene (179), (-)-cyclocopacamphene (180) (Vol. 2, p. 77), (+)-sativene (181), and (+)-cyclosativene (182) (Vol. 5 , p. 60) have been published.'" The bicyclic inter-

mediate (183)70*7'used in the synthesis of (+ )-sativene (181)and (+)-cyclosativene (182) has also been used in a new total synthesis (Scheme 19)of (+)-cis-sativenediol (186) and its (+)-trans-isomer (187).'* The enantiomeric forms of these compounds have previously been reported (Vol. 6, p. 67) as biologically active fungal metabolites although a more recent paper73 has shown that the so-called trans-compound actually possesses the isosativenediol structure (188). The synthesis of authentic (+)-trans-sativenediol (187) by the route outlined in Scheme 19 has indirectly confirmed that the co-metabolite of ( - )-cis -sativenediol in Helrninthosporium sativum is (-)-isosativenediol (188). 68 69

70 71

'* 73

S. Torii and T. Okarnoto, Bull. Chem. SOC.Japan, 1976,49, 771. J. Taskinen, Acta Chem. Scand., 1975, B29, 999. E. Piers, M. B. Geraghty, R. D. Srnillie, and M. Soucy, Canad. J. Chem., 1975, 53, 2849. An alternative synthesis of this compound has recently been described: H. Hagiwara, M. Miyashita, H. Uda, and A. Yoshikoshi, Bull. Chem. SOC. Japan, 1975, 48, 3723. E. Piers and H.-P. Isenring, Synrh. Comm., 1976, 6, 221. F. Dorn and D. Arigoni, Experientia, 1975, 31, 753.

74

Terpenoidsand Steroids

(186) R' (187) R'

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

Reagents: i, Cr03-py-CF3C02H; ii, LiNPri-THF; iii, MooS-py-HMPA; iv, LiAlH4.

Scheme 19

(188)

An intramolecular Diels-Alder reaction, involving prior isomerization of the central double bond in (189),has provided a bicyclic intermediate (190)which can be converted into (*)-8-epidendrobine (193) (cf. Scheme 20).74

(189)

(190)

(191)

1v1

%lc H

*

a(<

E t O b N

/

,

v, vi

H

0

0

(193)

(192)

Reagents: i, 170 "C; ii, m-CIC,H4C03H; iii, Cr03-H+; iv, SnC12-HC1-EtOH; v, MeSO3F; vi, NaCNBH3.

Scheme 20 74

R. F. Borch, A. J. Evans, and J. .I. Wade, J. Amer. Chem. SOC.,1975, 97, 6282.

Sesquiterpenoids

75

9 Himachalane, Longipinane, Longicamphane Two new himachalane sesquiterpenoids, centdarol (194)75" and isocentdarol (195),75b have been isolated from the wood of Cedrus deodora and assigned structures (194) and (195) on the basis of their chemical and spectroscopic properties.

"o& \

H

HO (194)

(195)

Some new longipinane derivatives (196a and b) and (197a and b) have been identified as constituents of the roots of Polypteris t e ~ a n a .The ~ ~ structure of

OR2 OH

OH

(196a and b)

(197a and b)

a; R' = R2 = COCH(Me)CH=CH2 b; R1= COCH(Me)CH=CH2, R2 = COCH2CHMe2

vulgarone (199), a constituent of the essential oil of Chrysanthemum uulgare, has been deduced from spectroscopic data and chemical e~idence.~'This compound represents a new sesquiterpenoid skeleton which may be derived in nature by rearrangement of a longipinene precursor (198) [cf.conversion of verbenone (200) into chrysanthenone (201)] or cyclization and oxidation of a -cis-bergamotene (202).

/-J+J=@ H

75 76

77

0

0

D. K. Kulshreshtha and R. P. Rastogi, (a)Phytochemisby, 1975, 44, 2237; (6) ibid.,l976, 15, 557. F. Bohlmann and C. Zdero, Chem. Ber., 1975,108, 3543. Y. Uchio, A. Matsuo, M. Nakayama, and S. Hayashi, Tetrahedron Letters, 1976, 2963.

Terpenoidsand Steroids

76

The complete absence of reduced products has prompted the suggestion that a carbonium ion intermediate is involved in the photochemical transformation of longibornyl iodide (203) into longiborn-8-ene (204), longicyclene (205),and longifolene (206).78 It has been known for some time that treatment of longifolene (206)

A

h v , n-heptane-NEt3

(204)

(205)

(206)

with peroxy-acid produces longicamphenilone (2 10) and the hydroxy-ketone (2 11). These transformations have been rationalized as shown in Scheme (21) and the proposed hydroxy-aldehyde intermediate (209) has recently been isolated by using carefully purified solvents in the reaction.79

Scheme 21

Recent studiesx0on the biosynthesis of culmorin (217) are described in Chapter 6. The results are consistent with the proposal that culmorin (217) is derived from '8

79 8~

P. D. Gokhale, A. P. Joshi, R. Sahni, V. G. Naik, N. P. Damodaran, U. R. Nayak, and S. Dev, Tetrahedron, 1976, 32, 139. A. P. Joshi, U. R. Nayak, and S . Dev, Tetrahedron. 1976, 32, 1423 and references cited therein. J. R. Hanson and R. Nyfeler, J.C.S. Chem. Comm., 1975, 171, 824; cf. D. Arigoni, Pure A p p l . Chem., 1975, 41, 219; F. Dorn, P. Bernasconi, and D. Arigoni, Chimia (Switz.), 1975.29, 25.

77

Sesquiterpenoids

trans,truns -farnesyl pyrophosphate ( 212) by the sequence of cyclization reactions depicted in Scheme 22. At one stage in the biosynthetic route a 1-pro-S hydrogen of farnesyl pyrophosphate (originally a 5-pro -S hydrogen of mevalonic acid) migrates to provide an intermediate (2 15) capable of cyclizing to the longicamphane skeleton [e.g. (216)]. It is interesting to note that at a corresponding point in the biosynthesis of the copacamphane and ylangocamphane skeletons the 1-pro-R hydrogen (i.e. 5 pro -R of mevalonic acid) migrates.

*

OPP

(2 12)

(213) 2 = enzymic group

(214)

1 H OH

10 Humulane, Caryophyllane, Protoilludane, Illudane, Marasmane, Hirsutane The proposed intermediacy of humulene ( 2 18)-in the biosynthesis of sesquiterpenoids belonging to various structural groups (caryophyllane, protoilludane, etc.)

(218)

has stimulated numerous efforts (cf. Vol. 5, p. 65; Vol. 6, p. 71) to duplicate the proposed cationic cyclization processes in the laboratory. Until recently all of these reported cyclizations provided products resulting from initial electrophilic attack at the most reactive double bond (A"', farnesane numbering). The problem of involving the least reactive A9-10-do~ble bond in the initial cyclization step may have been solved by a recent investigation in which regiospecific functionalization at this position was accomplished.*' Thus hydroboration-oxidation of humulene bisepox81

A. Sattar, J, Forrester, M. Moir, J. S. Roberts, and W. Parker, Tetrahedron Letters, 1976, 1403.

78

Terpenoidsand Steroids

ide (2 19) followed by acetylation, deoxygenation (WC1,-Bu"Li), and reduction (LiAlH,) provided the alcohol (220). Subsequent cyclization studies using this

compound as substrate could be of considerable significance in the viosynthesis of humulene-derived sesquiterpenoids. Other investigators have shown that the A9*'Odouble bond is involved in the conversion of humulene (2 18)into the bicyclic ethers (223) and (224).82 It is proposed, however, that the mechanism of this reaction involves initial acetoxymercuration of the A6y7-doublebond (Scheme 23).

Hg(OAc), 2>

, \

HgOAc

Scheme 23

A protoilludane intermediate (225) (cf.Vol. 4, p. 113) has been implicated in the biosynthesis of protoilludane, illudane, illudalane, and marasmane sesquiterpenoids

(225)

(cf.Chapter 6) and a recent report describes the synthesis (Scheme 24) of compounds (226) and (227a and b) which may be regarded as laboratory equivalents of this intermediate (225).83 Subsequent studies have shown that treatment of the protoilludane derivatives (226) and (227a and b) with formic acid results in rearrangement 83

S. Misumi, Y. Ohfune, A. Furusaki, H. Shirahama, andT. Matsumoto, Tefmhedron Letters, 1976,2865. Y. Ohfune, H. Shirahama, and Y . Matsumoto, Tetrahedron Letters, 1975,4377.

79

Sesquiterpenoids

(230)

(229)

+ iii

cis -syn -cis-isomer

I

H

(227b)

(224)

(227a)

Reagents: i, C2H4, h v ; ii, Ph3P=CH2; iii, Ti(C104)3-ButOH-H20; iv, MeMgI; v, Hg(OAc)2-H20-THF; vi, NaBH4.

Scheme 24

to (233) and (234) and not to compounds of the illudane or hirsutane group.84 The tricyclic ketone (232) used in the synthesis of compounds (226) and (227) has also been employed in a biogenetic-type synthesis of (*)-hirsutene (239)85(Scheme 25).

1

1

J H

(233) R=CHO 84

85

Y. Ohfune, H. Shirahama, and T. Matsumoto, Tetrahedron Letters, 1976, 2869. Y. Ohfune, H. Shirahama, and T. Matsumoto, Tetrahedron Letters, 1976, 2795.

H

(234)

Terpenoids and Steroids

80

Reagents: i, NaBH4; ii, T s O H - C ~ H iii, ~ ; Cr03-Ht; iv, Ph-,P=CH,; MsC1-py.

v, rn-CIC6H4CO3H;vi, LiAIH,; vii,

Scheme 25

The suggested intermediacy of hirsutene (239) in the biosynthesis of the hirsutane sesquiterpenoids has been supported by its recent isolation from Coriolus consors.86 In addition an alternative synthesis of this compound has been accomplished86by the route outlined in Scheme 26.

m 4q ?% q’ vi, vii

COCl

CHO

4iv’v

lviii

H

ix-xi,

H

0 Reagents: i, CH2=CHCH2Cl-NaH-DME; ii, Ph3P=CH2; iii, 240°C; iv, OsO,; v, NaIO,; vi, Ag20; vii, (C0CI)z; viii, SnCl4-CS2; ix, Li-NH,; x, Cr03-py; xi, Ph3P=CH2-DMSO.

Scheme 26 86

S. Nozoe, J . Furukawa, U. Sankawa, and S. Shibata, Tetrahedron Letters, 1976, 195.

81

Sesquiterpenoids

A revised structure (242; R = OH) has been proposed for lactarorufin B as a result of X-ray crystallographic analysis of a derivative (241).87 The new structure (242) differsfrom the previous one in the position of the lactone carbonyl group and it has been that a similar revision in the structure of the related sesquiterpenoid lactarorufin A (242; R = H) may also be required. Compounds of this type (cf. Vol. 5, p. 68; Vol. 6, p.' 74) are included in this section since their biosynthesis probably involves ring cleavage of a marasmane intermediate (243) derived by rearrangement of a protoilludane precursor (225). OH

(241) R = OCOC6H4Br

(225)

(242)

(243)

A complete account of the experimental evidence leading to the structural elucidation of the first members (244a-d) of the capnellane group of sesquiterpenoids has been provided in a recent paper" (cf.Vol. 5, p. 70). These compounds (244a-d) are found in soft coral (Capnella imbricata) and it has been suggested" that their biosynthesis involves cyclization of humulene followed by methyl migration from C-5 to C-4 [cJ (245)j. Wallichoside, a new C14 member of the illudalane group of sesquiterpenoids, has been isolated from the rhizomes of an Indian fern (Pteris wallichiana) and assigned structure (246) on the basis of chemical and spectroscopic evidence.89 OGlu

%-/OH

(244) a; R' = R2= R3= H

b;R'=R3=H,R2=OH c;R'=R2=H,R3=OH d;R2=R3=H,R1=OH 87

88

89

(245)

M. Bogucka-Led6chowska, A. Hampel, Z. Dauter, A. Konitz, E. Borowski, W. Daniewski, and M. Kocbr, Tetrahedron Letters, 1976, 2267. Y. M. Sheikh, G. Singy, M. Kaisin, H. Eggert, C. Djerassi, B. Tursch, D. Daloze, and J. C. Braekman, Tetrahedron, 1976, 32, 1171. P. Sengupta, M. Sen, S. K. Niyogi, S. C. Pakrashi, and E. Ali, Phytochernistry, 1976, 15, 995.

Terpenoidsand Steroids

82

An alternative synthesis of (f)-isocaryophyllene (253) has been achieved by the reaction sequence outlined in Scheme 27.” The conversion of the bicyclic ketone (250) into isocaryophyllene (253) has previously been reported (cf. Vol. 5 , p. 67) by another research group.”

0”’ dOH Q Br

iL

\

--*

(247)

(248)

0

A

1 0

(249)

(250) iii, i v l

(253)

(251 )

(252)

Reagents: i, AgC1O4-H20-Me2CO; ii, hv, Me2C=CH2; iii, CH212-Zn/Cu; iv, KOBut-DMSO; v, 360 “C; vi, Ph3P=CH2.

Scheme 27

Recent studies on the biosynthesis of illudin M (254)’* (cf. Vol. 4, p. 114), fomannosin (255),93and pteroside B (256)94are reported in Chapter 6. In each case the results are consistent with biosynthetic routes involving a protoilludane intermediate (225).

(225)

1

d

1

*o$p d

o b /

&O

\

OH OH

(254) YO

91

92

93 94

1

’ (255)

1

)qQ \

1 GluO

(256)

A. Kumar and D. Devaprabhakara, Synthesis, 1976,461; A. Kumar, A. Singh, and D. Devaprabhakara, Tetrahedron Letters, 1976, 2177. M. Bertrand and J.-L. Gras, Tetrahedron, 1974, 30, 793. J . R. Hanson, T. Marten, and R. Nyfeler, J.C.S. Perkin I, 1976, 876. D. E. Cane and R. B. Nachbar, Tetrahedron Letters, 1976, 2097. H. Hikino, 7’.Miyase, and T. Takemoto, Phytochernistry, 1976, 15, 121.

83

Sesquiterpenoids

11 Germacrane The isolation and structure determination of goyazensolide (257), a new germacranolide responsible for the schistosomicidal properties of Eremanthus goyazensis, has been reported.95 An ester analogue of (257), budlein-A (258), co-occurs with budlein-B (259) in Viguiero buddlei~eformis.~~ A combination of spectroscopic and 0

/

OH

RO 0H

(257) R = COC(Me)=CH2 (258) R = COC(Me)=CHMe

(259)

X-ray evidence has been used to determine the structure and configuration of eupahyssopin (260), an antitumour agent isolated from Eupatorium hyssopifoli~rn.~~ As part of their ongoing study of cytotoxic constituents of plants (cf.Vol. 6, pp. 75, 76) the Herz group has identified eupassopin (260), eupassofilin (261), and eupassopilin (262) as new metabolites of this plant.98 From the data provided it seems obvious that e ~ p a s s o p i nand ~ ~e ~ p a h y s s o p i nare ~ ~identical and it is hoped that the respective research groups will decide on the name to be applied to structure (260). Other germacranolides whose structures have been determined recently include eleganin (263), liscundin (264), liscunditrin (265), liatripunctin (266), chapliatrin

0

(260) R1= OH, R2 = H (261) R' = H, R2 = COCH2CH(OH)(CH2)14Me (262) R' = R2 = H

95

96

97

98

(263) R = COC(Me)=CHCH20Ac (264) R = COC(Me)=CHMe (265) R = COC(CH20Ac)=CHMe

W. Vichnewski, S. J. Sarti, B. Gilbert, and W. Herz, Phyrochernisrry, 1976, 15, 191. A. Romo de Vivar, C. Guerrero, E. Diaz, E. A. Bratoeff, and L. Jimknez, Phytochemistry, 1976,15,525. K.-H. Lee, T. Kimura, M. Okamoto, and C. M. Cowherd, TetrahedronLetters, 1976, 1051. W. Herz and R. P. Sharma, J. Org. Chem., 1976, 41, 1015.

Terpenoids and Steroids

84

(267), isochapliatrin (268), and acetylchapliatrin (269) (Liatris melampodin-A acetate (270), leucanthin-A (27 l), leucanthin-B (272), melampodin-B (273), 4(5)-dihydromelampodin-B, cinerenin (274), and melampodin-C (275) (Melampodium species),'00",6acanthaspermal A (276) and B (277) fAcanthaspermum species),1n' and tifruticin (278) and deoxyfruticin (279) (Tithahia species).ln2

R'O-'

w o---h,

:

R20/

0

(267) R' = H, R2 = Ac (268) R' = Ac, R2 = H (269) R' = R2 = Ac

(270) 2,3-epoxide (27 1) 4,5-epoxide (272) 2,3:4,5-bisepoxide

fl

O R 2 OR3

R'

(273) R = A c (274) R = M e (275) R = COCHMe2

*H o

(276) R1 = H, R2= COC(OH)Me2 R3= COCHMe2 (277) R' = OH, R2 = COMe R3= COCH(Me)Et

y.. y.. OCOC(Me)=CHMe

OCOCH(Me)CH=CH2

0

0

(278)

(279)

A tentative structure (280) has been proposed for periplanone-B, one of the sex pheromones of the American cockroach (Periplanata americana ). A recent paper v9

100

101 102

103

( a )W. Herz and R. P. Sharma, Phytochemistry, 1975,14, 1561; (b) W. Herz, I. Wahlberg, C . S . Stevens, and P. S. Kalyanaraman, ibid., 1975, 14, 1803. ( a )D. L. Perry and N. H. Fischer, J. Org. Chem., 1975,40,3480; (b) N. H. Fischer, R. A. Wiley, H.-N. Lin, K. Karimian, and S . M. Politz, Phytochemistry, 1975, 14, 2241. W. Herz and P. S. Kalyanaraman, J. O r g . Chem., 1975, 40, 3486. W. Herz and R. P. Sharma, J. Org. Chem., 1975, 40, 3118. C. J. Persoons, P. E. J. Verwiel, F. J. Ritter, E. Talman, P. J. F. Nooijen, and W. J. Nooijen, Tetrahedron Letters, 1976, 2055.

Sesquiterpenoids

85

dealing with antitumour constituents of Liatris species includes a full account of the isolation and structural elucidation of pycnolide (28 l),* the first secogermacranolide found in nature.lo4

The postulated involvement of germacrane-type intermediates in the biosynthesis of eudesmane and guaiane sesquiterpenoids (cf. p. 102) has prompted considerable interest in the cyclization of appropriate germacrane derivatives (cf.Vol. 4, p. 118; Vol. 5 . p. 71). Recently a full account of the acid-catalysed cyclization of acoragermacrone (282) has been publishedlo5 and because of printing errors in a previous Report (Vol. 5 , p. 72) a summary of these results is repeated here (Scheme 28). Treatment of acoragermacrone (282) under a variety of acidic or thermal conditions produces isocalamenediol (284), shyobunone (289), epishyobunone (290), acolamone (285), isoacolamone (286), and the bicyclic formates (287) and (288). Compounds (285) and (286) co-occur with acoragermacrone (282) in Acorus calamus L. and it has been suggestedlo5that their biosynthesis involves formation and cyclization of a germacrene intermediate. Closely related studies by the same research group have shown that the isoacoragermacrone epoxide (29 1)is converted into a variety of products, (292)-(294), when treated with acetic acid or A1C1,.106 Treatment of costunolide (295) with Amberlite IR- 120 cation-exchange resin produces a - (296) and p-cyclocostunolide (297) in good yield.lo7 In contrast, the photochemical cyclization of 11,13-dihydrocostunolide produces a guaianolide, photunolide (298). lo' Although this type of reaction has been reported p r e v i o ~ s l y ' ~ ~ (Vol. 1, p. 83) the recent study"' has shown that an intramolecular shift of hydrogen from C-14 to C-4 probably takes place during the cyclization process. Cyclization of agerol (299) (cf. Vol. 4, p. 119) with 80% aqueous acetic acid yields an isovetivane 104

lo5 lo6 lo7

Io8

W. Herz and R. P. Sharrna, J. Org. Chem., 1976, 41, 1248. M. Niwa, A. Nishiyama, M. Iguchi, and S. Yamamura, Bull. Chem. SOC.Japan, 1975,48,2930 M. Niwa, M. Iguchi, and S. Yamamura, Tetrahedron Letters, 1975, 3661. T. C. Jain and J. E. McCloskey, Tetrahedron, 1975, 31, 221 1. R. E. K. Winter and R. F. Lindauer, Tetrahedron, 1976, 32, 955. H. Yoshioka, T. J. Mabry, and A. Higo, J. Amer. Chem. SOC.,1970, 92,923.

* Owing to typographical errors in Volume 6 (p. 76) pycnolide was referred to as 'pyrenolide' and the reference year as '1974' instead of 1975.

86

Terpenoidsand Steroids

,

+ (289)

; : : H (290)

Reagents: i, 80% HOAc-H20, 75 "C; ii, AICI,-Et20,0 "C; iii, 80% HCOzH-H*O, 20 " C ; iv, 110 "C.

Scheme 28

80% 60°C HOA;

@

Ho*.

HO

Sesquiterpenoids

rQ+Q 87

0

0

0

0

(298)

derivative (300).110aNaturally occurring sesquiterpenoids with this carbon skeleton are unknown. However, it is of historical interest that a- and p-vetivene were originally considered as isovetivane derivatives before the synthetic work of Marshall and deMayo established that their structures were based respectively on the eremophilane and vetispirane skeletons.' lob

(299)

(300)

Dihydrocostunolide (305) has recently been synthesized from a santonin derivative (301) by the sequence of reactions outlined in Scheme 29."' A new synthetic approach to the synthesis of germacrane sesquiterpenoids involving cyclization of 10,11-epoxy-truns,trans -farnesyl phenyl sulphide (306) provides a mixture of hedycaryol(307) and the isomeric alcohols (308) and (309)."* Studies' 13,'14 on the biosynthesis of germacrane sesquiterpenoids have appeared recently.

12 Eudesmane, Vetispirane, Eremophilane The structural elucidation and total synthesis of sesquiterpenoid lactones such as the germacranolides [cf.(310)] and eudesmanolides [cf. (311)] continues to be a very 110

111 112

113

( a )F. Bellesia, U. M. Pagnoni, and R. Trave, J.C.S. Chem. Comm., 1976,34; ( b ) cf. 'Natural Products Chemistry', Vol. 1, ed. K. Nakanishi, T. Goto, S. Ito, S. Natori, and S. Nozoe, Academic Press, New York, 1974, pp. 108-1 10. Y. Fujimoto, T. Shimizu, and T. Tatsuno, Tetrahedron Letters, 1976, 2041, M. Kodarna, Y. Matsuki, and S. Ito. Tetrahedron Letters, 1976, 1121. F. Bellesia, R. Grandi, A. Marchesini, U. M. Pagnoni, and R. Trave, Phytochemistry, 1975, 14, 1737. S. S. Martin, J. H. Langenheim, and E. Zavarin, Phytochemistry, 1976, 15, 113.

88

Terpenoidsand Steroids

J

(305)

(304)

Reagents: i, Zn-NaI; ii, h v ; iii, H,-Pd; iv, NaBH,; v, MsC1-py; vi, Bu4N02CC02NBu4.

Scheme 29

+q OH

(310)

(311)

active area of research. Most of this interest is associated with the fact that many of these lactones display fungitoxic, antitumour, antimitotic, allergenic, or schistosomicidal activity. Further investigation of the allergenic (contact dermatitis) agents of Frullania species has revealed the presence of a new lactone (312) and a bicyclic aldehyde (313) which may act as a biosynthetic precursor of the various eudesmanolides found in this plant."' 115

Y. Asakawa, G. Ourisson, and T. Aratani, Tetrahedron Letters, 1975, 3957.

89

Sesquiterpenoids

HO (312)

(313)

Cyperol4,5-epoxide (314) has been identified as a co-metabolite of a -cyperol in the rhizomes of nutgrass (Cyperus rotundus).'16 Single-crystal X-ray analysis has shown that vernodesmine (315) has a unique eudesmanolide structure with a phenyl

(3 14)

(315)

substituent at C-4.l" The recent suggestion that the stereochemistriesof dihydro-a agarofuran (316) and dihydro-P-agarofuran (317) should be interchanged (cf. Vol.

(316)

(317)

6 , p. 77) has been disputed on mechanistic grounds and on the basis of 13Cand 'H n.m.r. spectroscopic data."' It has also been established that irradiation of aagarofuran (318) in methanol provides @ -agarofuran (319) and the rearrangement products (320) and (321).l19 Cathidine D (322),'*' cathedulin-2 (323), and

+ 0

116

117 118

120

H. Hikino and K. Aota, Phytochemistry, 1976, 15, 1265. A. T. McPhail, R. W. Miller, B. Mompon, and R. Toubiana, Tetrahedron Letters, 1975, 3675. A. F. Thomas and M. Ozainne, Tetrahedron Letters, 1976, 1717. A. F. Thomas and M. Ozainne, Helv. Chim. Acta, 1976, 59, 1243. M. Cais, D. Ginsburg, A. Mandelbaum, and R. M. Smith, Tetrahedron, 1975, 31, 2727.

90

Terpenoidsand Steroids

cathedulin-8 (324)'*' are biologically active constituents of the narcotic plant Catha edulis, and recent spectroscopic and chemical evidence has shown that these

,OR'

(322) R' = nicotinyl, R2 = COPh or COMe, R3 = COMe or COPh

(323) R1= R2 = nicotin 1 (324) R' = nicotiny1,R2= H

compounds are agarofuran derivatives. 120*121 Cauhtemone (326), a plant-growth inhibitor isolated from the Mexican medicinal shrub 'Cauhtematl' (cf. Vol. 5 , p. 74), has been synthesized'22 in racemic form by the sequence of reactions outlined in Scheme 30. A new method of synthesizing a-methylene-y-lactones (cf. Vol. 5 , p.

(326) Reagents: i, EtCOCH=CH,-KOH-MeOH; ii, pyrrolidine-C6H6; iii, Li-NH,; iv, (Et0)zPOCl; v, LiEtNH2; vi, HOAc-H20; vii OsO,; viii, Me2CO-CuS0,; ix, (EtO),CO-NaH; x, MeLi; xi, SOCl;?-py.

Scheme 30

76) via a -phenylselenolactone interrnediate~'~~ has been used in the reported transformation of (- )-a-santonin (327) into (+ )-tuberiferine (330),124a (+)121

123

*z4

R. L. Baxter, L. Crombie, D. J. Simmonds, and D. A. Whiting, J.C.S. Chem. Comm., 1976, 465. D . J. Goldsmith and I. Sakano, J. Org. Chem., 1976, 41, 2095. P. A. Grieco and M. Miyashita, J. Org. Chem., 1974,39,120 and references cited therein; cf. H. J. Reich, I. L. Reich, and J . M. Renga, J. Amer. Chem. Soc., 1973,95,5813;D . B. Sharpless, R. F. Lauer, and A. Y. Teranishi, ibid., 1973, 95, 6137; B. M. Trost and T. N. Salzmann, ibid., 1973,95, 6840. ( a ) K. Yamakawa, K. Nishitani, and T. Tominaga, Tetrahedron Letters, 1975, 2829; ( 6 ) ibid., p. 4137.

91

Sesqu iterpenoids

/

1

iiil

HO 0 (332)

(331)

vl

(330)

ixl

qQH

HOq

o (333)

O (336)

O

vi, viil

R r

0I vii, x, xi

HO' (334)

(337)

I

0

Ph

(338)

/

iii, viiil

iii

OH

r(

0Qo (335)

(339)

Reagents: i, LiNPri; ii, (PhSe)2; iii, H202-Hf-THF; iv, LiAIH4-THF, - 10 "C; v, [VO(a~ac)~]-Bu'00H; vi, LiNPr&(PhSe)2; vii, M n 0 2 ; viii, Zn-Ht-C6H6; ix, EtOH-H+-NH2NH2; x, (CH20H),-Ht; xi, 02-Hf-H20.

Scheme 31

Terpenoids and Steroids

92

artecalin (335),1 2 4 a arglanine (339), 124h santamarine (343),1246and yomogin (35O)lz5 (Schemes 3 1-33). The extension of this procedure to a bis-selenide intermediate (356) has also been used in a recent synthesis of tuberiferine (330)126(cf.Scheme 34).

q

o

-

i, ii

0 (340)

(336)

iv

/

(341)

v, vi

(342)

(343)

Reagents: i, Cr03-H+; ii, HOCH2CH(OH)CHzBr-H+; iii, Zn-MeOH; iv, NaBH4; v, LiNPr&(PhSe)2; vi, H~O~-H+-THF.

Scheme 32

0

C0,Me ii

/

m-.. oqxJ&.

(327)

0

CQ2Me

C02Me

(346)

(347) iii-"1

iii-"1

0~

o (350)

~ (348)

o

~ (349)

Reagents: i, (Bu'0)2Cr0z; ii, [(Ph3P)3RhC1]-Hz; iii, NaBH,; iv, HzO-HO-; v, HzO-H+; vi, DDQ; vii, (PhSe)z-base; viii, HzO-H+-THF.

Scheme 33 125

126

K. Yarnakawa, K. Nishitani, and A. Yamamoto, Chem. Letters, 1976, 177. P. A. Grieco and M. Nishizawa, J.C.S. Chem. Comm., 1976, 582.

93

Sesquiterpenoids

(351)

phseq x-xiil

o+o

0

O (356)

*

o

O

(330)

Reagents: i, (CH20H)2-H+; ii, BH,-THF; iii, CrO,-py; iv, Na0Me:MeOH; v, LiNPr&BrCH2C02Me;vi, Li-NH3-THF; vii, CHzN2; vii, p-TSOH-C&6; ix, LiNPri-MeI; x, LiNPri-(PhSe)2; xi, HCl; xii, LiNPri-PhSeC1; xiii, @-CH2C12.

Scheme 34

A new synthetic route to @-cyperone(360) (Scheme 35) uses 1,3-dibromopent-2ene as an ethyl vinyl ketone equivalent.”’

SBu

0

Br

Br

(357)

SBu (358) iil

Reagents: i, LiNPri; ii, Pr‘MgBr-CuCN; iii, HC104-HC02H.

Scheme 35 127

R. B. Gammill and T. A. Bryson, Synth. Comm., 1976,6, 209.

Terpenoids and Steroids

94

Treatment of humulene (2 18)with concentrated HzS04provides S -selinene (361) in -60% yield and it is hoped that further studies will provide a mechanistic explanation for this remarkable transformation.'28 Increasing attention is being given to the study of 'phytoalexins', i.e. stress metabolites (p. 52) which act in defence of the plant against disease. Recent studies in this area have shown that incubation of eggplant fruit (Sofanurn rnefongena) with spore suspensions of Monilinia fructicofa resulted in the production of several nerolidol derivatives (p. 52), the eudesmane derivative (362), and the

(36 1)

(218)

(362)

known vetispirane phytoalexin lubimin (367).3 Germacrane-2,3-diol(364),lubimin (367), and 3-hydroxylubimin (368)129are stress metabolites of diseased potato tubers (cf. Vol. 6, p. 80) and the results of recent biosynthetic using [ 1,2-"C]acetate as precursor are consistent with the proposed biosynthetic relationship between these compounds [cf.(363) --+ (368)l. The structure and configuration of 3-hydroxylubimin (368) has also been confirmed by X-ray crystallographic analysis.130

H

o

r

n

-HI&

R (363) R = H (364) R = OH

(365)

I -H

(367) R = H (368) R = OH

The known tricyclic ether (370) derived from (- )-p-pinene (369) has been used as an intermediate in a new synthetic route (Scheme 36) to (+)-hinesol (379) and 1012x

129 1x1

G. Mehta and B. P. Singh, Tetrahedron Letters, 1975, 3961. In a previous paper (J.C.S. Chem. Comm., 1975,431) this compound was named 4-hydroxylubimin. G. I. Birnbaum, C. P. Huber, M. L. Post, J. B. Stothers, J. R. Robinson, A. Stoessl, and E. W. B. Ward, J.C.S. Chem. Comm., 1976, 330.

Sesqu iterpe noids

95

Reagents: i, LiAlH4; ii, TsC1-py; iii, NaCN-DMSO; iv, NaOH-MeOH; v, Ac20-BF3,Et20; vi, MeOHH + ; vii, Me2CO-CuSO,; viii, LiNPr&(PhSe)2-NaI04; ix, Me2CuLi; x, MeS02Ph-NaH; xi, H+-H20; xii Cr03-py; xiii, NaH-DMSO; xiv, Al-Hg; xv, MeMgI; xvi, m-ClC6H4C03H; xvii, Me02CNS026Et3.

Scheme 36

epi-( +)-hinesol13' [natural hinesol is the (-)-enantiomer]. A full account of the synthesis of the spirodecenone (380) and its subsequent use in previous an alternative synthesis of (*)-a-vetispirene (382) (cf. Vol. 5, p. 78) has been described in a recent paper.'32b Chemical and spectroscopicevidence has been cited in support of the structure and absolute configuration of cybullol(383), a metabolite of Cyanthus bulleri Brodie. 133 It has been ~ u g g e s t e d 'that ~ ~ the trisnor-sesquiterpenoid structure of cybullol is produced in nature by elimination of an isopropyl group from a eudesmane precursor, and the structural elucidation of a bicyclic sesquiterpenoid trio1 which co-occurs with cybullol could eventually provide indirect support for this proposal.133 131

132

133

D. Buddhsukh and P. D . Magnus, J.C.S. Chem. Comm., 1975, 952 (correction: ibid., 1976, 304). (a)D. Caine and J. B. Dawson, Chem. Comm., 1970,1232; (b)D. Caine, A. A. Boucugnani, S. T. Chao, J. B. Dawson, and P. F. Ingwalson, J. Org. Chem., 1976, 41, 1539. W. A. Ayer and M. G. Paice, Canad. J. Chem., 1976,54,910.

Terpenoids and Steroids

96

(383)

A new annelation process involving photochemical cycloaddition of a -formy1 ketones to symmetrical alkenes has provided alternative synthetic routes (Scheme 37) to valerane (385) and isovalerane (386)134(cf. Vol. 5, p. 78; Vol. 6, p. 87).

a+ J

Reagents: i, h v ; ii, H+; iii, Ph3P=CMe2; iv, H2-Pd.

Scheme 37

Further studies on the emmotin group of sesquiterpenoids (cf. Vol. 5, p. 78) has resulted in the structural elucidation of emmotin-F (387), -G (388), and -H (389).'35 Compounds of this type are probably biosynthesized by methyl migration in a eudesmane precursor. The antitumour activity of the elemanolides vernolepin (393) and vernomenin (394) has stimulated several research groups to solve the problems associated with 135

S. W. Baldwin and R. E. Gawley, Tetrahedron Letters, 1975, 3969. A. B. De Oliveira, G . G. De Oliveira, C. T. M. Liberalli, 0. R. Gottlieb, and M. T. Magalhaes, Phytochemistry, 1976, 15, 1267.

Sesq u iterpenoids

97

their total synthesis. Various synthetic routes to the a -methylene-y -1actone functionality' 36-1 38 (cf. p. 90) and A/B ring s y ~ t e m ' ~of~these " ~ ~compounds have been devised (cf.Vol. 5, p. 76; Vol. 6, p. 831and the extension of these investigations has resulted in the first total synthesis (Scheme 38) of (&)-vernolepin (393) and (f)-vernomenin (394).141 In an alternative total ~ y n t h e s i s 'the ~ ~ lactone intermediates, (391) and (392), are produced by the reaction sequence outlined in Scheme 39. A full account of the previously reported (cf.Vol. 1,p. 94) conversion of costunolide (395) into dehydrosaussurea lactone (398) has been published. '43 Melitensin (399). '44a 11(1 3)-dehydromeliten~in,'~~~ and the ester (400)144bare new elemanolides which have recently been identified as metabolites of the plant Centaurea melitensis. Further investigations of Senecio '45a and Othonna 1456 species have revealed the presence of several furanoeremophilanes whose structures [cf. (401)] differ little from those previously isolated from these sources (cf. Vol. 5, p. 127; Vol. 6, p. 85). Three additional eremophilane sesquiterpenoids, (403)-(405), have been isolated from cultures of Penicillium roquefortii and their structures deduced from spectroscopic evidence and from their correlation with a previously reported metabolite (402)146(cf. Vol. 6, p. 84). X-Ray crystallographic analysis has confirmed the structure of epoxydecompostin (406). 14' A full account of the structural elucidation of flourensic acid (407) (cf.Vol. 2, p. 108) and flourensadiol(408), co-metabolites of the common Western shrub Flourensia cernuu, has been p u b l i ~ h e d . 'The ~ ~ development of a new synthetic route to the known bicyclic ketone (410)149and the subsequent use of this compound in an alternative synthesis of (*)eremophilenolide (411) (cf.Vol. 4, p. 129) and (&)-furanoeremophilane(412) has recently been described (Scheme 41).150 136 137 138 139 140 141 142 143 144

145

146 147 148

149 150

P. A. Grieco, J. A. Noguez, and Y. Masaki, Tetrahedron Letters, 1975,4213 and references cited therein. C. G. Chavdarian and C. H. Heathcock, J. Org. Chem., 1975,40,2970. C. G. Chavdarian, S. L. Woo, R. D. Clark, and C. H. Heathcock, Tetrahedron Letters, 1976, 1769. S. Danishefsky, P. Schuda, and K. Kato, J. Org. Chem., 1976,41, 1081. R. D. Clark and C. H. Heathcock, J. Org. Chem., 1976,41, 1396. P. A. Grieco, M. Nishizawa, S. D. Burke, and N. Marinovic, J. Amer. Chem. Soc., 1976, 98, 1612. S. Danishefsky, T. Kitahara, P. F. Schuda, and S. J. Etheridge, J. Amer. Chem. Soc., 1976, 98, 3028. T. C. Jain, C. M. Banks, and J. E. McCloskey, Tetrahedron, 1976,32, 765. A. G. Gonzblez, J. M. Arteaga, and J. L. Breton, ( a )Analesde Quim., 1974,70,158; ( b )Phytochemistry, 1975,14,2039. ( a )F. Bohlmann and C. Zdero, Chem. Ber., 1976, 109, 819; (b) F. Bohlmann and A. Suwita, ibid., p. 1230. S . Moreau, A. Gaudemer, A. Lablache-Combier, and J. Biguet, Tetrahedron Letters, 1976, 833. B. L. Flamm, J. A. Pettus, J. J. Sims, J. P. Springer, and J. Clardy, Tetrahedron Letters 1976, 2671. D. G. I. Kingston, M. M. Rao, T. D. Spittler, R. C. Petterson, and D. L. Cullen, Phytochemistry,1975,14, 2033. Cf.J. A. Marshall and G. M. Cohen, J. Org. Chem., 1 9 7 1 , 3 5 , 8 7 7 . I. Nagakura, S. Maeda, M. Ueno, M. Funamizu, and Y. Kitahara, Chem. Letters, 1975, 1143.

98

Terpenoids and Steroids

Ixvii. xviii

A

f/

// 0

0

0 OH

0

A 0

0

0 0 (393)

H . OH (394)

Reagents: i, LiNPri-PhSeC1-THF; ii, LiNPri-MezC=CHCHzBr; iii, HzOZ-THF; iv, Bu'OOH-Triton B; v, Li-NH,; vi, AczO-py; vii, 03,-78 "C;viii, CrO,-H+; ix, CH2N2; x, HCI; xi, AcOCMe=CHzTsOH; xii, O,-CH?CIz; xiii, NaBH,; xiv, MsCI-py; xv, o-O2NC6H4SeCN-BH,-DMF; xvi, BBr3-CHzC12;xvii, Kz03-MeOH; xviii, TsoH-C&,; xxi, DBU; xxii, HOAc-HzO.

Scheme 38

xix,

-

H'; xx, LiNPri-HCHO;

Sesquiterpenoids

99

O

H

a CO -0

co-0 C p vii, viii

m

H

/

n

0

*.

- CO2H * O

,v,vi

v

C02Me

xi,xii

0

/

O-0

0O .

H

xiii xiv

~

b

aH

L

'.O

o

H

..O

xv-xvii

(393) cf Scheme 38 (391) xviii + a + 0 (394) (392) H OH C 0 2 M e

Reagents: i, NaOH-H20; ii, NaHC03-K13; iii, DBU; iv, NaOCH-H20-THF; v, rn -CIC6H4C03H; vi, NaOAc-H20; vii, Os04-Ba(C10&; viii, P ~ ( O A C ) ~ - M ~ Oix,HLi,AlH(OBu')3; ; x, Amberlite IR- 120; xi, (CH30H)z-TsOH; xii, Mgs04-C~H6; xiii, AIHBu~;xiv, Ph3P=CH2; xv, LiCH2C02Li; XVi H -H20; xvii, CH2N2; xviii, TsOH-C6H6.

wo pro Scheme 39

(395)

(398)

iil

iv, v l

Reagents: i, A; ii, Me2NH-MeOH; iii, MeI; iv, NaHC03.

Scheme 40

Terpenoids and Steroids

100

(399) R = H (400) R = COCH(Me)CH20H

AcO

R4 (401) R’ and R 2 = H 2or 0 R3 and R4 = H or OCOR

HO

Q3.f (404)

mR (402) R = C H O (403) R = M e

AcO

rn (405)

Recent studieslS1 on the biosynthesis of eremophilane sesquiterpenoids have confirmed the suggestion that the basic carbon skeleton [cf. (414)] of this group is derived by rearrangement (1,2-methyl shift) of an unknown eudesmane intermediate [cf. (413)l. These result^''^ are described more fully in Chapter 6 . Biogenetic-type transformations in this area have previously been described (cf.Vol. 4,p. 128) and a recent investigation has shown that the cyclopropyl ketone (415) (potentially equivalent to a eudesmane system with a carbonium ion or leaving group at C-9) can be converted into 11,12-dihydronootkatone (416) by treatment with BF3.l S 2 Six new compounds (418)-(423) have been isolated from Cacalia species and identified as derivatives of the co-metabolites cacalol (417) and the norsesquiterpenoid maturinone (424)’53(cf.Vol. 1,p. 102). Compounds of this type are lS1

152

lS3

F. C. Baker, C. J. W. Brooks, and S. A. Hutchinson, J.C.S. Ched. Comm., 1975,293; F. C. Baker and C. J. W. Brooks, Phytochemistry, 1976,15,689. D. Caine and S. L. Graham, Tetrahedron Letters, 1976, 2521. K. Naya, Y . Miyoshi, H. Mori, K. Takai, and M. Nakanishi, Chem. Letters, 1976, 7 3 .

101

Sesquiterpenoids

ix-xi

(411)

I

(412)

Reagents: i, MeLi; ii, Hg(OAc)2-THF-H20; iii, NaC1; iv, NaBH4; v, MeCOCl; vi, H20-HO-; vii, Cr03-Hf; viii, (CH,OH),-H+; ix, B2H6; x, Cr03-py; xi, NaOMe-MeOH; xii, TsNHNH2; xiii, O ~ ;Red-Al. Zn-MeCHBrC02Et; xiv, SOC12-py; xv, ( B U ' O ) ~ C ~ xvi,

Scheme 41 H

-----+

H

Enz

I

(415)

(416)

probably derived in nature by methyl migration of an eremophilane precursor. The structure of cacalol (417) has been confirmed by synthesis (Scheme 42)154while chemical evidence has recently been for the structure of a co-metabolite and autoxidation product, cacalone (425). 154 155

Y. Inouye, Y. Uchida, and H. Kakisawa, Chem. Letters 1975, 1317. A. Casares and L. A. Maldonado, Tetrahedron Letters, 1976, 2485.

Terpenoids and Steroids

102 OR

OH

(417) R*= R~ = H (418) R' = Ac, R2= H (419) R' = H, R2 = OCOCHMe2

(420)

0

(421) R' = OH, R2= H (422) R' = H, R2 = OMe

13 Guaiane, Pseudoguaiane Confirmatory evidence has been provided for the revised structure of a guaiadiene (428) present in geranium Another component of costus oil has been identified as the triene acid (429)15' and an isomer (430) of guaioxide (cf.Vol. 1, p. 111) has been isolated from the roots of a Ligularia species.'58 Further studies on the chemistry of patchoulol (431) have shown that treatment with Pb(OAc), provides a 1 : 2 : 2 mixture of (432), (433), and (434).'59 The subsequent conversion of (433) into a -bulnesene (436) was also accomplished by c f l O M e

i ,N

O

M /

\

(426)

e

a; /

v, v i l

OCH,CO, H

\

(427) R = CH2C02Me

(417)

Reagents: i, P205-MeS03H; ii, HZ-Pd; iii, MeCOCI-AIC1,; iv, Me2S0,; v, BBr3; vi, BrCH2C02MeK,C03; vii, NaOH-H20; viii, NaOAc-Ac20; ix, LiAIH,; x, TsC1-py; xi, NaBr-DMSO; xii, BuLi.

Scheme 42 Is6

Is9

Y. Nagahama, H. Naoki, and Y. Naya, Bull. Chem. SOC.Japan, 1975,48,3706. E. Klein and F. Thomel, Tetrahedron,1976, 32, 163. H. Hirota, Y. Tanahashi, and T. Takahashi, Tetrahedron Letters, 1975, 4579. G. Mehta and B. P. Singh, Tetrahedron Letters, 1975, 4495.

Sesquiterpenoids

103

H

C O ,H

{a _____* ii,i,NaBH4 TsCI-py

/

H

/

H

1

KOAC-HOAC

(434)

rearrangement of the corresponding tosylate (435). 159 Structures have also been assigned to the guaianolides hypochaerin (437)160(Hypochaeris setosus) and artecanin (438)161 (Artemisia cana) and a revised structure has been proposed for canin (439) (A.cana). The biological activity of certain pseudoguaianolides has evoked considerable interest in the isolation and structural elucidation of sesquiterpenoids of this type162

0 (437) 160

161

162

(438)

(439)

A. G. Gonzalez, J. Bermejo, G. M. Massanet, J. M. Amaro, B. Dominguez, and A. Morales, Phytochemistry, 1976, 15; 991. N. R. Bhadane and F. Shafizadeh, Phytochemistry, 1975,14,2651. Cf. Y. Yoshioka, T. J. Mabry, and B. N. Timmerman, ‘Sesquiterpene Lactones’, University af Tokyo Press, Tokyo, 1973.

Terpenoids and Steroids

104

(cf. Vol. 1, p. 114-119; Vol. 4, p. 135; Vol. 5, p. 87; Vol. 6, p. 90). Recent X-ray crystallographic studies have shown that microlenin (442), an antitumour metabolite of Helenium microcephalum, has a novel dimeric structure which is presumably constructed by a biological Diels-Alder-type reaction between helenalin (440) (a co-metabolite) and the enol form of an unknown norpseudoguaianolide (441).163

>

>

(44 1)

The structure of autumnolide (443), an anticancer agent isolated from Helenium autumnale. has been determined by X-ray analysis.'64 Autumnolide co-occurs with the antineoplastic agent helenalin (440), and although the compounds have very similar structures their conformations in the solid state are different. Thus only in autumnolide does the preferred conformation permit hydrogen-bonding between the C-4 and C-6 hydroxy-groups. Carbon-13 n.m.r. spectra of tenulin (444) and derivatives indicate that the natural compound actually occurs as a mixture of C-16 epimers.lhS

"O

0

OH OH (443)

(444)

Further studies on the synthesis of psuedoguaianolides (cf. Vol. 6, p. 90) have resulted in the total synthesis of the cytotoxic compounds (*)-damsin (447) (Scheme 43)lh6and (*)-confertin (449) (Scheme 44).16' The realization that many sesquiterpenoids containing a-methylene-y-lactone rings display important biological activity'" (cf. pp. 88 and 96) has prompted the development of several procedures Io3 Iha 165

'6' IhX

K.-H. Lee, Y. Imakura, D. Sims, A. T. McPhail, and K. D. Onan, J.C.S. Chem. Comm., 1976,341. R. B. VonDreele, G. R. Pettit, G . M. Cragg. and R. H. Ode, J. Amer. Chem. SOC., 1975,97, 5256. W. Herz and R. P. Sharma, J. Org. Chem., 1975, 40, 2557. R. A. Kretchmer and W. J. Thompson, J. Amer. Chem. SOC.,1976,98, 3379. J. A. Marshalland R. H. Ellison, J. Amer. Chem. SOC.,1976, 98,4312. S. M. Kupchan, D. C. Fessler, M . A. Eakin, and T. J. Giacobbe, Science, 1970,168,376; S. M .Kupchan, M. A. Eakin, and A. M. Thomas, J. Medicin. Chem., 1971,14, 1147.

Sesq uiterpenoids

105

___*

____)

R'

Me0

O

0

0

K-

(446) a; R' = CH2C02Me,R' = H b; R' = H, R' = CH2C02Me

(445)

ii, xi, xii

q 9 ,x

0

b i i i , ix, xiv

xv, xvi

0

0

0

(447) Reagents: i, BrCH2C02Et-Zn; ii, HZ-Pd; iii, KOH-EtOH; iv, Li-NH,; v, CH N ; vi, 0 3 ;vii, (Me0)3P; viii, MeI-KZCO,; ix, NaBH4; x, Pt-02; xi, Cr03-HC; xii, (CH,OH)2?&; xiii, HC02Et-NaH; xiv, HCl; xv, TsC1-py, 0 "C; xvi, py, A.

Scheme 43

for synthesizing this structural (cf.Vol. 5, p. 76). Recently a new general synthetic route to cis -fused a -methylene-y-lactones has been accomplished by cyclization of an appropriate (2)-bromo-aldehyde (450). 17'

14 Miscellaneous A recent i n ~ e s t i g a t i o n into ' ~ ~ the biosynthesis of botrydial(452) and dihydrobotrydial (453)(cf.Vol. 6, p . 95) is described in Chapter 6. The unusual carbon skeleton (455)of these compounds is probably constructed in nature by ring contraction and ring cleavage of an appropriate tricyclic intermediate [cf. (454)] derived from farnesyl pyrophosphate. 169

170 171 172

For a review see P. A. Grieco, Synthesis, 1975, 67. B. M. Trost and C. H. Miller, J. Aner. Chern. Soc., 1975, 97, 7182 and references cited therein. M. F. Semmelhack and E. S. C. Wu, J. Amer. Chem. Soc., 1976,98, 3384. J. R. Hanson and R. Nyfeler, J.C.S. Chem. Comm., 1976, 72.

106

Terpenoids and Steroids

(448)

pi-viii

Lxii, xiii

XIV. xv

xvi-xvitt

0

0 -

0 Bu'O (449)

C0,Me

Reagents: i, LiNPri-CH2=CHCH2Br; ii, LiAIH,; iii, m-CIC6H4CO3H; iv, MsCl; v, Li-NH3; vi, CH212Zn-Cu; vii, 0 3 ;viii, AgzO; ix, HC104-H20; x, LiNPr;-(PhSe)2; xi, H202; xii, Hz-Pd; xiii, KH-(Me0)2CO; xiv, KH-LiAIH4 xv, MnO2; xvi, CF3C02H; xvii, NaOH; xviii, Cr03-py.

Scheme 44

'

w@

(-----JBr

C0,Me

Zn-Cu-THF

A

cHo CHO

OAc

OAc

(452)

(453)

(454)

(455)

3 Diterpenoids BY J. R. HANSON

1. Introduction This chapter follows the-pattern of the previous Reports, with sections based on the major skeletal types of diterpenoid. The literature which has been covered is that available to August 1976. Some useful reviews of diterpenoid chemistry have appeared.' During the year the 13C n.m.r. resonances of a number of groups of diterpenoids have been assigned.* These include the l a b d a n e ~ , ~ podocarpanes,6 -~ kauranoids,' beyeranes,8 gibberellins,' and aconitine alkaloids." In addition 13C n.m.r. has played a major role in the elucidation of the structure of many new diterpenoids during the year and this is discussed in the relevant sections. Marine organisms have afforded a number of interesting diterpenoids. Arnongst the simpler derivatives that have been isolated" are crinitol (9-hydroxy1-01), geranylgeraniol) and oxocrinol (11-oxo-3,7-dimethyldodeca-2,6-dienwhich were obtained from the brown alga Cystoseiru crinitu. Caulerpol (1) is a relative of vitamin A which has been isolated12 from Caulerpu brownii. The full paper on the structure of geranyl-linalool isocyanide, isolated from Halichondria sp., has appeared.I3 I

(1) 1

2

5

6

* 9 10 11

12

13

E. Fujita, K. Fuji, Y. Nagao, and M. Node, Bull. Inst. Chem. Res., Kyoto Univ., 1974,52,519; 1975,53, 319. 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 6, p. 96. S. 0. Almquist, C. R. Enzell, and F. W. Wehrli, Actu Chem. Scand., 1975, B29, 695. B. L. Buckwater, I. R. Burfitt, A. A. Nagel, E. Wenkert, andF. Naf, Helv. Chim.Actu, 1975,58,1567. A. G. Gonzilez, C. G. Francisco, R. Freire, R. Hernindez, J. A. Salazar, and E. Suirez, Tetrahedron Letters, 1976, 1897. I. Wahlberg, S. 0. Almquist, T. Nishida, and C. R. Enzell, Acra Chem. Scand., 1975, B29, 1047. J. R. Hanson, M. Siverns, F. Piozzi, and G. Savona, J.C.S. Perkin I, 1976, 114. C. von Carstenn-Lichterfelde, C. Pascual, J. Pons, R. M. Rabanal, B. Rodriguez, and S. Valverde, Tetrahedron Letters, 1975, 3569. R. Radeglia, G. Adam, and Ph. D. Hung, Tetrahedron Letters, 1976, 605. S. W. Pelletier and Z. Djarmati, J. Amer. Chem. SOC.,1976, 98, 2626. E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, D. Sica, V. Amico, G. Oriente, M. Piattelli, and C. Tringali, Tetrahedron Letters, 1976, 937. A. J. Blackman and R.J. Wells, Tetrahedron Letters, 1976, 2729. B. J. Burreson, C. Christopherson, and P. J. Scheuer, Tetrahedron, 1975, 31, 2015.

107

Terpenoids and Steroids

108 2 Bicyclic Diterpenoids

Labdanes,-Investigations have continued on the occurrence of diterpenoids in the oleoresin of Larix species.I4 4-Epicommunic acid [labda-8( 17),E-12,14-trien-18whilst the bark of Hymenea oic acid) has been isolated from Pinus den~iflora'~ coubaril has been shown" to contain ent-labda-8(17),13-dien-15-oic acid and entlabda- 13-en-8P -01- 15-oic acid and its dihydro-analogue. 3-Oxocativic acid, the ring A seco-acid (2), and the angeloyl esters (3) have been isolated17 from Brickellia corymbosa, B. squarrossa, and B. veronicaefolia and the clerodane derivative hardwickiic acid was obtained from B. annulosa. The structures of four stereoisomeric 8,12-epoxylabda-l4-en-13-ols (4), isolated18 from Nicotiana tabacum, were determined by conversion into 12-norambreinolide. The biogenesis of these compounds from abienol has been discussed.

(3) R' = H, R2 = Ang R1 = Ang, R2 = H

(4)

Four new diterpenoid oxides have been obtained" from Sideritis gomerae. They are gomeraldehyde (ent-8,13-epoxylabdan-15-a1)and gomeric acid (ent-8,13epoxylabdan-15-oic acid) and their 13-epimers. ent-Labda-13-en-8&15-diol was also isolated. 3 p -Hydroxymanoyl oxide and the 18-benzoyloxy-derivative have been obtained" from Palafoxia rosea. The structure of 7-hydroxyhedychenone (9,extracted from Hedychium spicatum, was derived2' by spectroscopic methods. The butenolide corresponding to daniellic acid has been obtained22from Pamburus missionis (Rutaceae). Potamogetonin ( 6 )is a new furanoid diterpenoid which has been from Potamogeton ferrugineus E. N. Schmidt and V. A. Pentegova, Khim. prirod. Soedinenii, 1974, 698. D . F. Zinkel, Phytochemistry, 1976, 15, 1073. A. J. Marsaioli, H. de Freitas Leitao Filho, and J. de P . Campello, Phytochemistry, 1975,14, 1882. F. Bohlmann and C. Zdero, Chem. Ber., 1976,109, 1436. A. J. Aasen, J. R. Hlubucek, and C. R. Enzell, Acra Chem. Scand., 1975, B29, 589. A. G. Gonzilez, B. IM. Fraga, M. G. Hernandez, F. Larruga, and J. G. Luis, Phyrochemistry, 1975, 14, 2655. X. A. Dominguez. C. Cisneros, E. Guajardo, R. Villarreal, and A. Zamudio, Phyrochemisrry, 1975,14, 1665 S. C. Sharma, J. S. Tandon, and M. M. Dhar, Phytochemistry, 1976, 15,827. D. L. Dreyer and Kyong-Hwi Park, Phyrochemistry, 1975,14, 1617. C . R. Smith, R. V. Madrigal, D . Weisleder, K. L. Mikolajczak, and R. L. Highet, J. Org. Chem., 1976,41, 593.

Diterpenoids

109

(Potamogetonaceae). The structure was elucidated mainly by comparison of the ‘H and I3Cn.m.r. spectra with those of sciadin and nepetaefuran. Ballotinone, which was from Balluta nigra (Labiatae), has been assigned the structure of 7-oxomarrubiin (7) by comparison of its 13C n.m.r. spectrum with those of some derivatives of marrubiin. A useful review of the naturally occurring 9,13epoxylabdanes has been published. The structure ( 8 ) was assigned to lasiocoryin on the basis of an X-ray analysis.*’ The stereochemistry, particularly that of the spiranic centre, of nepetaefolin (9)was also assigned26by X-ray analysis.

A number of partial syntheses have been described in the bicyclic series. The synthesis of methyl (12s)-and (12R)-hydroxylabda-8(17)-en-19-oateutilized2’ the aldehyde (10)as an intermediate. This was obtained from podocarpic acid. The synthesis of the furan methyl lambertianate (11)from dimethyl agathate has been described.28 Examination of the I3Cn.m.r. spectra of the levantenolides (12)has led’ to a revision of their C-12stereochemistry. a-Levantenolide has the (12R)configuration whereas p -1evantenolide has the (12s)configuration. The functionalization at C-12of labdanes by oxidation of C-15alcohols with iodine and lead tetra-acetate has been described.29 24

25

26

27 28

29

G. Savona, F. Piozzi, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1976, 1607. D. E. A. Rivett, J. S. African Chem. Inst., 1975,28,305; Chem. in S. Africa, 1976,7 (Chem.Abs., 1976, 85, 33 193). R. B. von Dreele, G. R. Pettit, R. H. Ode, R. E. Perdue, J. D. White, and P. S . Manchand, J. Amer. Chem. SOC.,1975, 97, 6236. R. A. Bell, M. B. Gravestock, and V. Y. Taguchi, Canad. J. Chem., 1975,53, 2869. R. A. Bell and M. Fetizon, Canad. J. Chem., 1976, 54, 141. A. G. Gonzalez, C. G. Francisco, R. Freire, R. Hernandez, J. A. Salazar, and E. Suirez, Tetrahedron Letters, 1976, 2725.

Terpenoids and Steroids

110

@T

@o C0,Me

C0,Me (11)

(10)

(12)

The cyclization of agathic acid by formic acid to afford the tricyclic isoagathic acid has been known for many years. The stereochemistry of the comparable cyclization products (15) and (16) of methyl E-anticopalate (13) and methyl 2-anticopalate (14)

802M fl 70,Me

H

1

1 &:02Me H H

@C02Me H

(15)

(16)

respectively has been determined.30 The stereochemistry of hydrogenation, hydroboronation, and osmylation of the 12,13-double bond in these tricyclic products is dependent31 on the stereochemistry at C-14. Amongst the products of irradiation of 15,16-dinorlabd-8(17)-en-13-one(17) were the ethers (18) and (19) and the cyclopentanol (20).32These compounds were thought to have arisen by prior iso-

30

31 32

S. Bory, D. Do Khac Manh, M. Fetizon, M. Kone, and N. Trong Anh, Bull. SOC.chim. France, 1975, 2347. D. Do Khac Manh, M. Fetizon, and N. Kone, Bull. SOC.chim.France, 1975, 2351. G. Ohloff, Ch. Vial, H. R. Wolf, and 0. Jeger, Helv. Chim. A d a , 1976, 59, 75.

111

Diterpenoids

merization to the 8(9)-olefin. There have been on the selenium dioxidehydrogen peroxide oxidation of exocyclic olefins in the labdane series. Manool, for example, gave labda-8( 17),14-dien-7q 13-diol. C1erodanes.-The full paper has appeared34on the group of cis-clerodanes (21) and (22) and the trans-clerodane C-5 epimer of (21; R' = Me, R2= H) which were

(21) R' = Me, R2= H R' =CH20Ac, R2= H R' = CH,OH, R2 = H R' = CH20H, R2 = OH R' = CHZOAc, R2 = OH

isolated from Solidago arguta. This paper discusses in detail methods for assigning the stereochemistry to members of the clerodane series. Confirmation of the stereochemistry of marrubiaside has been achieved by interrelationship within this series. Columbin and isocolumbin have been isolated3' from Dioscoreophyllum cumminsii (Menispermaceae). Floridiolic acid (23)36and floribundic acid (24)" are CH20H

YHzoH CO, H

C0,I.l

(23)

(24)

constituents of Evodia floribunda. Whereas the structure of the former rests on an X-ray analysis, the structure of the latter was assigned by examination of its 13C n.m.r. spectrum and by a correlation with the C-2 ketone, tinophyllone. The cis -clerodane stereochemistry (25) has been assigned38to annuanone. The structure for a clerodane obtained from Cascarilla oil. (26) has been 33 34 35

36

37 38 39

M. J. Francis, P. K. Grant, K. S. Low, and R. T. Weavers, Tetrahedron, 1976,32, 95. R. McCrindle, E. Nakamura, and A. B. Anderson, J.C.S. Perkin I, 1976, 1590. E. Ramstad, J. W. Powell, B. J. Wilson, S. K. Adesina, J. D. Higginbotham, and J. B. Harborne, Phytochemistry, 1975,14, 2719. D. Billet, M. Durgeat, S . Heitz, J. P. Brouard, and A. Ahond, Tetrahedron Letters, 1976,2773; R. Bally, D. Billet, M. Durgeat, and S . Heitz, ibid., p. 2777. D. Billet, M. Durgeat, S. Heitz, and A. Ahond, Tetrahedron Letters, 1975, 3825. D. P. Popa, T. M. Orgiyan, and Kh. Sh. Kharitov, Khim. prirod. Soedinenii, 1974, 331. A. Claude-Lafontaine, M. Rouillard, J. Cassan, and M. Azzaro, Bull. Soc. chim. France, 1976, 88.

Terpenoids and Steroids

112 OH

(26)

(25)

trans-Clerodane structures have been assigned4' to the minor diterpenoids of Teucrium chamaedrys, teucrins B (27), E (28), F (29), and G (30), and a study of the circular dichroism of a C-6 ketone derived from teucrin A has established the absolute stereochemistry of rings A and B in the series. An X-ray analysis has been published4' of methyl barbascoate (31).

OH

OH

Me0,C (30)

3 Tricyclic Diterpenoids Naturally Occurring Substances.-A A9'l ')-isomer of pimaric acid has been from Othona cylindrica and 0. floribunda (Compositae). en#-Pimara-8(14),15dien- 19-oic acid and thermarol (ent-pimara- 1Sen@, 19-diol) were isolated43from 40 41

42 43

D. P. Popa and A. M. Reinbol'd, Khim. prirod. Soedinenii, 1974, 328, 600. S. R. Wilson, L. A. Neubert, and J. C. Huffman, J. Amer. Chem. SOC.,1976,98, 3669. F. Bohlmann and K. H. Knoll, Phyrochemistry, 1976, 15, 1072. A. Matsuo, S. Uto, M. Nakayama, S. Hayashi, K. Yamasaki, R. Kasai, and 0. Tanaka, Tetrahedron Letters, 1976, 2451.

Diterpenoids

113

the liverwort Jungermannia thermarurn (Hepaticae). Halloltetrol, which was from Podocarpus hallii, has been assigned the structure (32). In both these cases the 13C n.m.r. spectra played a signficant role in the elucidation of the structure. In the latter paper useful correlations are given between the stereochemistry at C-4 and C-13 and the I3C chemical shift of the substituent carbons. The pimarane acids (33) have been isolated4' from Dimorphotheca pluvialis

"--& -=TCH20H OH

'<

111 CH,OH (32)

(33) R = H or OH; A' or

(Compositae). The tetracyclic beyer- 15-en-19-oic acid with the normal configuration was also present. The phenol sugiol and a number of bicyclic relatives of agathic acid have been from Araucaria angusfifolia. The more highly oxygenated abietanes royleanone (34), 6,7-dehydroroyleanone, horminone (35), taxoquinone (36), 7-oxoroyleanone (37), 6&7a -dihydroxyroyleanone (38), and 7 a -acetoxy-6@-hydroxyroyleanone (39) have been obtained4'

OH (34) (35) (36) (37)

R=Hz R = a - O H , P-H

(38) R = H (39) R = Ac

R=a-H, P-OH R=O

from two Abyssinian Plectranthus species. Treatment of horminone, taxoquinone, a mixture of rearranged or 6,7-dehydroroyleanone with 80% sulphuric acid products including the 20(10 + 9)-abeo-abietane (40) and the phenalone (41). Coleons C, D, I, and I' have been isolated49from a Madagascan Plectranthus species. Coleons I and I' are the C-3 0-formyl derivatives of coleons C and D. The X-ray analysis of coleon D (42) has been de~cribed.~' The diterpenoid quinone conacytone 44

45 46 47 48

49 50

R. C. Cambie, I. C. Burfitt, T. E. Goodwin, and E. Wenkert, J. Urg. Chem., 1975,40, 3789. F. Bohlmann and Le Van Ngo, Chem. Ber., 1976,109, 1446. J. de P. Campello and S. F. Fonseca, Phytochemistry, 1975, 14, 2299. M. Hensch, P. Ruedi, and C. H. Eugster, Helv. Chim. Acra, 1975, 58, 1921. M. Hensch, C. H. Eugster, and H. P. Weber, Helv. Chim. Actu, 1975, 58, 1934. P. Ruedi, and C. H. Eugster, Helu. Chim. Actu, 1975, 58, 1899. H. P. Weber, T. J. Petcher, P. Ruedi, and C. H. Eugster, Helv. Chim. Actu, 1976,59, 1221.

& 114

\

Terpenoids and Steroids

& o

H : ; &3

\

/

/

0 H O

(40)

(41)

(42)

(43) and the novel rearranged lactone icetexone (44) have been isolateds1 from Salvia ballotaeflora (Labiatae). The absolute stereochemistry and X-ray structure of stemolide (45), which is unusual in possessing an 18(4-+ 3)-abeo-abietane skeleton, has now been determined.52

(43)

(45)

(44)

The structures of a number of norditerpenoid lactones from Podocarpus species have been revised as a result of some X-ray analyses. Inumakilactone A (46) has 0

(46)

been shown to have a 1 , 2 P - e p o ~ i d eand ~ ~this affects the structure of a number of related lactones such as nagilactone C which have the same ring A hydroxy-epoxide. Podolactone A (47) also been showns4to possess a 2,3P-epoxide. X-Ray analysis of sellowin B bromohydrin acetate has likewise led55to a revision of the structure of sellowin B to (48). A useful summary of the distribution of the diterpenoid furans of Pterodon species has appeared.56 51

52 53 54

55

56

W. H. Watson, Z. Taira, X. A. Dominguez, H. Gonzales, M. Guiterrez, and R. Argon, Tetrahedron Letters, 1976, 2501. P. S. Manchand and J. F. Blount, Tetrahedron Letters, 1976, 2489. J. E. Godfrey and J. M. Waters, Austral. J. Chem., 1975,28, 745. B. J. Poppleton, Cryst. Structure. Comm., 1975, 4, 101. S. K. Arora, R. B. Bates, P.-C. C. Chou, W. E. Sanchez, K. S. Brown, and M. N. Galbraith, J. Org. Chem., 1976,41,2458. M. Fascio, W. B. Mors, B. Gilbert, J. R. Mahajan, M. B. Monteiro, D. Dos Santos Filho, and W. Vichnewski, Phytochemistry, 1976, 15, 201.

115

Diterpenoids

'I/CH,OH OH

(48)

(47)

The Chemistry of the Tricyclic Diterpenoids.-Analysis of the I3C n.m.r. spectra of the y-lactone (49) derived from dihydroisopimaric acid has shown5' that it possesses a cis A/B ring fusion rather than the trans fusion which has hitherto been accepted. The reactions of the C-8 carbonium ion are of interest in relation to the biogenesis of the tetracyclic diterpenoids. The BF,-catalysed rearrangement of the a - and ,B-epoxides (50) might be expected to generate this carbonium ion, However, the products were the pimara-7(8),9( 11)- and -6(7),8( 14)-dienes and the 7-ketone rather than tetracyclic compounds."

The conversion of dehydroabietic acid into the steroid skeleton (52) by way of the The effect of ring c substituents on the unsaturated ketone (51) has been

(51)

(52)

deisopropylation reactions of methyl dehydroabietate have been examined.60 The have been acid-catalysed rearrangements of the ring c aromatic A5'6)-7-ketone~ further studied.61 In the presence of a C-4 methoxycarbonyl group (53) reaction with aluminium trichloride affords rearrangement via a spiranic intermediate to compounds such as (54) and (55). On the other hand reaction with acetic anhydride 57 58 59

60 61

J. W. ApSimon, A . W. Holmes, H. Beierbeck, and J. K. Saunders, Canad. J. Chem., 1976, 54,418. J. W. Blunt, G. S. Boyd, M. P. Hartshorn, and M. H. G. Munro, Austral. J. Chem., 1976,29, 987. A . Tahara, Y. Harigaya, and M. Onda, Chem. and Pharm. Bull. (Japan), 1976,24,427; 1975,23,1989, 1996. A , Tahara and H. Akita, Chem. and Pharm. Bull. (Japan), 1975, 23, 1976, 1984. A , Tahara and H. Akita, Chem. and Pharm. Bull. (Japan), 1975,23, 2660; 1976, 24, 706, 995.

Terpenoids and Steroids

116

containing sulphuric acid affords the products of methyl group migration, e.g. (56). When the C-4 substituents are two methyl groups, cleavage of ring A occurs to afford products such as (57)in which rings B and C are both aromatic.

qt? C02Me

(53)

1

Attention has been directed over a number of years at the conversion of derivatives of abietic acid into compounds related to the gibberellins. The stereochemistry shown in (58) has been assigned62 to the ring-contraction product of methyl 6,7dioxo-5a,l0a-podocarpa-8,1 1,13-trien-l9-oate and details have been given63 of the functionalization of ring A in this series using transannular iodo-ether formation. The syntheses of gibberellin AI2and of kaurene and phyllocladene from abietic acid have been d e ~ c r i b e d The . ~ ~ key to the construction of ring D involves the carbene addition of the diazo-ketone (59) to afford the cyclopropyl ketone (60). Subsequent

isomerization affords the cyclopentanone of ring D related to the tetracyclic diterpenoids. Rearrangement of the bromohydrin (61) afforded65the methyl ketone (62) in a partial synthesis of the beyerene ring system. 62 63 64

65

T. Nakata, Y . Ohtsuka, A. Tahara, and S. Takada, Chem. and Pharm. Bull. (Japun), 1975, 23, 2318. T. Nakata and A. Tahara, Chern. and Pharm. Bull. (Japan), 1975, 23, 2 3 2 3 . T. Nakata and A. Tahara, Tetrahedron Letters, 1976, 1515; A. Tahara, M. Shimagaki, S. Ohara, T. Tanaka, and T. Nakata, Chern. and Pharm. Bull. (Japan), 1976,24, 2329. M. Shimagaki and A. Tahara, Tetrahedron Letters, 1976, 1103.

Diterpenoids

117 HO

'

'OH

\'

C0,Me

4 Tetracyclic Diterpenoids

Naturally Occurring Substances.-ent-Kauran- 16p-01, ent-kaur- 16-en- 19-oic acid, and ent-kaura-9(11),16-dien- 19-oic acid have been isolated66 from Annona senegalensis root bark, which also contains a hitherto unidentified diterpenoid tumour-inhibitory substance. ent-Kaur- 16-en- 19-01, and the corresponding aldehyde and acid have been isolated67 from Cacalia bulbifera (Compositae). entKaur-16-en-19-oic acid and the 9(11),16-diene have been isolated6' from Verbesina angustifoh and V. onocophora (Compositae) whilst ent-kaur- 16-en-18-oic acid and its 19-angeloxy-derivative were from Melampodium perfoliatum (Compositae). ent- 1l a , 15a -dihydroxykaur-16-en-19-oic acid, its 15-oxo-derivative, and ent- 1la -hydroxy- 15-oxokauran-19-oic acid, together with 1la,12a, 15a trihydroxykaur-16-en-19-oicacid, have been isolated7* from Eupatorium album. The location of the functional groups on rings c and D was facilitated by the use of 13 C n.m.r. spectroscopy. 19-Carboxyatractylagenin has been identified7' as the hypoglycaemic agent of Xanthium strumarium (Compositae). A number of new sweet glucosides have been isolated7' from Stevia rebaudiana (Compositae). Rebaudioside A is 13-O-[p-glucosyl-( 1-2)-~-glucosyl-(l-3)]~glucosylsteviol and rebaudioside B is its p -glucosyl ester. The aglycones from S. paniculatu are ent-15a-hydroxykaur-16-en-19-oicacid, ent-16&17dihydroxykauran-19-oic acid, and ent-1 la,l5a-dihydroxykaur- 16-en-19-oic acid and its 15-0x0-derivative. ent-6a,7a, 13-Trihydroxykaur- 16-en- 19-oic acid, ent-6a,7a,17-trihydroxy-16/3H-kauran-19-oic acid, 6a,7a, 16@,17-tetrahydroxykauran- 19-oic acid, and 7p, 13-dihydroxykaurenolide have been from the seeds of the bean Phaseolus coccineus (Leguminosae). The rastronols A-H, (63)-(67), are a series of ent-kaur-16-en-15-one bitter principles which have been isolated75from Englerastrum scandens (Labiatae). The structures of these highly oxygenated compounds were determined by careful 'H n.m.r. 66

67 68 69 70

71 7*

'3 74

75

E. K. Adesogan and J . I. Durodola, Phytochemistry, 1976,15, 1312. A . A . El-Emary, G. Kusano, and T. Takemoto, Phytochemisny, 1975,14, 1660. F. Bohlmann and C. Zdero, Phytochemistry, 1976,15, 1310. F. Bohlmann and C. Zdero, Chem. Ber., 1976,109, 1670. W. Herz and R. P. Sharma, J. Org. Chem., 1976,41, 1021. J. C. Craig, M. L. Mole, S. Billets, and F. El-Feraly, Phytochemistry, 1976, 15, 1178. H. Mitsuhashi, J. Ueno, and T. Sumita, J. Pharm. SOC.(Japan), 1975,95, 127; H. Kohda, R. Kasai, K. Yamasaki, K. Murakami, and 0.Tanaka, Phytochemistry, 1976,15,981. H, Kohda, 0.Tanaka, and K. Nishi, Chem. and Pharm. Bull. (Japan), 1976,24,1040; K. Yamasaki, H. Kohda, T. Kobayashi, R. Kasai, and 0. Tanaka, Tetrahedron Letters, 1976, 1005. P. Gaskin and J. MacMillan, Phytochemistry, 1975, 14, 1575. K. Nomoto, P. Ruedi, and C. H. Eugster, Helv. Chim. Acra, 1976, 59, 772.

Terpenoids and Steroids

118

(63) A; R~ = R~ = H B; R * = H , R ~ = O H C; R' = AC,R~ = O H

(64) D; R = A c E; R = H

experiments on the parent compounds and a number of related ethers. The C-20 aldehydes rastronols D and E exist in equilibrium with their 7-20-hemiacetals. Confirmatory evidence has been for the unusual 13P-kaurane (phyllocladene) skeleton of calliterpenone. The examination of Sideritis species (Compositae) has continued to provide further diterpenoids. S. reverchunii the tricyclic lagascol and lagascatriol, the beyerenes tobarrol, benuol, jativatriol, 12-acetyljativatriol, and conchitriol, and the atisenes serradiol and sideritol. The X-ray analysis of isosideritol (ent-atis-13en-7a,16a,17-triol), which was a minor diterpenoid from S. angustifulia, has been de~cribed.'~ The Chemistry of the Tetracyclic Diterpenoids-The reaction of ent-kaur- 16-ene with thallium(II1) nitrate ent-kaur-16-en-15P-01 nitrate which undergoes a ready [3,3] sigmatropic rearrangement to ent-kaur-15-en-17-01 nitrate. The reactions of phyllocladene and of labda-8( 17)-en-13-01 with sodium azide and iodine chloride have been examined.80 The synthesis of 13-hydroxylated ent-kaur-16-ene derivatives such as steviol using an acyloin-like cyclization of keto-esters has been developed.81 A detailed analysis was mades2 of the products arising from the use of sodium in liquid ammonia in this reaction. Acetolysis of methyl ent- 1 2 p-tolyl-p-sulphonyloxybeyeran19-oate gaveg3 products resulting from a single 1,2-shift [ent-14(13 -+ 12)-abeu-beyeranes]. O n the other hand formolysis and trifluoroacetolysis gave the products of further skeletal 76 77

78 79

80

E. Fujita, M. Ochiai, I. Uchida, A. Chatterjee, and S . K. Desmukh, Phytochemistry, 1975, 14, 2249. C. Mirquez, F. M. Panizo, B. Rodriguez, and S . Valverde, Phytochemistry, 1975, 14, 2713. I. Carrascal, B. Rodriguez, S. Valverde, and J. Fayos, J.C.S. Chem. Comm., 1975, 815. M. Ochiai and E. Fujita, J.C.S. Chem. Comm., 1975, 967. R. C. Cambie, R. C. Hayward, P. S. Rutledge, T. Smith-Palmer, and P. D. Woodgate, J.C.S. Perkin I, 1976, 840.

81

82 83

I. F. Cook and J. R. Knox, Tetrahedron, 1976, 32, 363. I. F. Cook and J. R. Knox, Tetrahedron, 1976, 32, 369. A. J. McAlees, R. McCrindle, and S . T. Murphy, J.C.S. Perkin I, 1975, 1641.

Diterpenoids

119

rearrangement, including 12-methyl- 17-noratisanol and ent-beyeranols. Buffered formolysis of (16S)-ent- 1 2 a -tolyl-p -sulphonyloxykaurane gaves4 mainly the corresponding alcohol together with smaller amounts of the ent-atisan-13- and - 16-01s and traces of ent-kauranol and ent-14(13 + 12)-abeo-kauranol. The structures of some of the solvolysis products have been confirmed by X-ray analy~is.'~The structure (68), assigned to a thallium(II1) acetate oxidation product of methyl enttrachyloban-19-oate, has been determined" by an X-ray analysis. A ring-contraction sequence has been applied87to an oxidation product (69) of epicandicandiol to afford the gibbane hydroxy-acid (70). The microbiological

(68)

(70)

(69)

hydroxylation of 3p,7p -dihydroxykaurenolide by Rhizopus arrhizus affords a low yield of l l a - and 13-hydroxylated derivatives.'8 The conversion of enmein uia (71) into the methanesulphonate (72), the gibbane aldehyde (73), and thence the methyl esters of gibberellin AI5and gibberellin A37is a remarkable partial synthesis which has been achieved" during the year.

Me0 Me0,C

CHO

OTHP

(73)

Gibberellins.-Details of a purification system for plant hormones using gel permeation chromatography have been given.9o The mass spectra of the TMS derivatives of 84

8s 86

88 *9

90

A. J. McAlees, R. McCrindle, and S. T. Murphy, J.C.S. Perkin I, 1976, 1042. G. Ferguson and W. C. Marsh, Acta Cryst., 1975, B31, 1684,2278; 1976, B32, 24. G. Ferguson, W. C . Marsh, and R. McCrindle, Acta Cryst., 1976, B32, 123 1. A. G. Gonzalez, B. M. Fraga, M. G. Hernandez, F. Larruga, and J . G. Luis, A n d e s de Quim., 1975,71, 733 (Chem. Abs., 1976,85,45 876). G. Ellames and J. R. Hanson, J.C.S. Perkin I, 1976, 1666. M. Node, H. Hori, and E. Fujita, J.C.S. Chem. Comm., 1975, 898. D. R. Reeve and A. Crozier, Phytochemistry, 1976, 15, 791.

120

Terpenoids and Steroids

gibberellin glucosides and glucosyl esters91 and the fragmentation pattern of 3 a hydroxy- and 3-keto-deri~atives~~ have been described. The isolation of gibberellins A3,A4,and A7from Pinus a t t e n ~ a t and a ~ ~of gibberellin A9glucosyl ester94from the needles of Picea sitchensis has been described. Full details have appeared95of the isolation of gibberellins As, A32, and A32acetonide from Prunus persica and of the structural elu~idation~, of gibberellin A32. A useful method has been developed97 for converting the readily accessible 3hydroxy-gibberellins into 2-hydroxy-gibberellins and it has been applied to the partial synthesis of two new gibberellins, A,, (74), isolated from Echinocystis macrocarpa (Cucurbitaceae), and A47 ( 7 9 , isolated from the fungus Gibberella

~ ~ conversion by Gibberella fujikuroi of fujikuroi. Full details have a p p e a ~ e d ~of' . the steviol into 13-hydroxylated gibberellins and kaurenes and of isosteviol and steviol acetate into gibberellin analogues. The microbiological hydroxylation of gibberellin A9 and its conversion into gibberellins A2, and A4, by Rhizopus nigricans has been described. loo An interesting biomimetic chemical conversion of the C2, gibberellins into the CI9 gibberellins by decarboxylation of C-20 acids with lead tetra-acetate has been described."' The selective reduction of the C-7 carboxy-group of the gibberellins has been achieved"* by the reduction of the dimeric anhydrides with sodium borohydride. A number of amides of gibberellins A, and A3have been described.lo3 Photolysis of 3 -0xogibberel1ic acid in the solid state gives phenolic products whereas the methyl ester affords cyclobutane dimers. An X-ray analysis has revealed1O4the different geometrical arrangements of the acid and the ester in the crystals which lead to this behaviour. A full paper describing the [2 + 21 photoaddiT. Yokota, K. Hiraga, H. Yamane, and N. Takahashi, Phytochemistry, 1975, 14, 1569. E. P. Serebryakov, N. S. Kobrina, and B. V. Rozynov, Khim. prirod. Soedinenii, 1975,11,486. 9? A. Kamienska, R. C. Durley, and R. P. Pharis, Phytochemistry, 1976, 15, 421. 94 R. Lorenzi, R. Horgan, and J. K. Heald, Pfanru, 1975, 126,75; Phytochernistry, 1976, 15, 789. 95 I. Yamaguchi, T. Yokota, N. Murofushi, N. Takahashi, and Y. Ogawa, Agric. and Biol. Chem. (Japan), 1975,39, 2399. 96 I. Yamaguchi, T. Yokota, N. Murofushi, and N. Takahashi, Agric. and Biol. Chem. (Japan), 1975, 39, 2405, 97 L. J. Beeley, and J. MacMillan, J.C.S. Perkin I, 1976, 1022. y R J. R. Bearder, J. MacMillan, C. M. Wels, and B. 0. Phinney, Phytochemistry, 1975, 14, 1741. 9') J. R. Bearder, V. M. Frydman, P. Gaskin, J. MacMillan, C. M. Wels, and B. 0. Phinney, J.C.S. Perkin I, 1976, 173. loo J. R. Bearder, V. M. Frydman, P. Gaskin, 1. K. Hatton, W. E. Harvey, J. MacMillan, and B. 0. Phinney, J.C.S. Perkin I, 1976, 178. lol J. R. Bearder and J. MacMillan, J.C.S. Chern. Cornm., 1976, 421. 1*2 M. Lischewski and G. Adam, Tetrahedron Letters, 1975, 3691. G. Adam, M. Lischewski, F. J. Sych, and A. Ulrich, J. prukt. Chem., 1976, 318, 105. 104 L. Kutschabsky, G. Reck, and G . Adam, Tetrahedron, 1975,31, 3065. 91

92

Diterpenoids

121

tions of olefins to the ring A unsaturated gibberellins has appeared."' The 3-ketone of gibberellin A, on irradiation undergoes a Norrish Type I fragmentation to afford (76).lo6 Reduction of the olefin affords a saturated aldehyde (77) which undergoes an internal aldol condensation with the regeneration of ring A (78). This parallels the mechanism for the epimerization of the 3-hydroxy-group in gibberellin chemistry.

Grayanotoxins.-Grayanotoxins XVI and XVII have been i~olated"~from Leucothoe grayana and shown to be 6-0-acetylgrayanotoxin I1 and 3,6didehydrograyanotoxin I11 respectively. Diterpenoid Alkaloids.-The alkaloids of Delphinium staphisagria include"' some bisditerpenoid alkaloids such as staphidine, staphinine, and staphimine. The full paper has appearedlogon the structure and stereochemistry of delphisine, neoline, chasmanine, and homochasmanine. The application of I3Cn.m.r. measurements to these alkaloids has led to the revision of the structure of the alkaloid A from D. bicolor. l o 5 Macrocyclic Diterpenoids and their Cyclization Products

The absolute stereochemistry of mukulol(79) has been determined."' The variation in 4,8,13-duvatrienediol content of tobacco leaves has been studied."' Young plants contain the highest concentration. Many terpenoid degradation products of these macrocyclic diterpenoids have been i ~ o l a t e d ~ ' ~from . " ~ tobacco leaves. The absolute configurations of some of these, e.g. (SO), have been determined."4-' l6 Ovatodiolide (81) and anisomelic acid (82) are two diterpenoid lactones which have been i ~ o l a t e d "from ~ Anisomeles malabarica (Labiatae). Pukalide (83) is a furanocemtranolide which has been obtained''' from the soft coral Sirnularia 105

106 lo' lo8

109 110 111

112

Il3

114 115 116

117 118

B. Voigt and G. Adam, Tetrahedron, 1976, 32, 1581. G. Adam and T. V. Sung, Tetrahedron Letters, 1976, 247. S. Gasa, R. Ikeda, N. Hamanaka, and T. Matsumoto, Bull. Chem. SOC.Japan, 1976,49, 835. S. W. Pelletier, N. V. Mody, Z. Djarmati, I. V. MiCoviC, and J. K. Thakkar, Tetrahedron Letters, 1976, 1055, 1749. S. W. Pelletier, Z. Djarmati, S. LajSiC, and W. H . Decamp, J. Amer. Chem. SOC.,1976, 98, 2617. S. W. Pelletier, N. V. Mody, A . J. Jones, and M. H. Benn, Tetrahedron Letters, 1976, 3025. R. S . Prasad and S. Dev, Tetrahedron, 1976,32, 1437. S. Y . Chang and C. Grunwald, Phytochemistry, 1976, 15, 961. C. Demole and E . Demole, Helv. Chim.Acta, 1975,58,1867; T. Fujimori, R. Kasuga, H. Matsushita, H. Kaneko, and M. Noguchi, Agric. and Biol. Chem. (Japan), 1976,40,303; T. Chuman, H. Kaneko, T. Fukuzumi, and M. Noguchi, ibid., p. 587. A . J. Aasen, T. Chuman, and C. R. Enzell, Agric. and Biol. Chem. (Japan), 1975, 39, 2085. A. J. Aasen, J. R. Hlubucek, and C. R. Enzell, Acta Chem. Scand., 1975, B29, 677. A . J. Aasen, T. Nishida, C. R. Enzell, and M. Devreux, Acta Chem. Scand., 1976, B30, 178. K. K. Purushothaman, R. B. Rao, and K. Kalyani, Indian J. Chem., 1975,13, 1357. hl. G. Missakian, B. J. Burreson, and P. J. Scheuer, Tetrahedron, 1975,31, 2513.

Terpenoids and Steroids

122

0

I

(79)

C0,Me

(81)

(83)

(82)

abrupta. Its structure was assigned on the basis of a detailed analysis of its 'H n.rn.r. spectra. The full paper on the structure and stereochemistry of the tumourinhibitory substance jatrophone (84) has appeared."' The reactivity of the 8,9double bond of the unsaturated ketone with thiols has been discussed in terms of its biological activity. Jatrophatrione (85), which lacks this grouping, has nevertheless

(84)

(85)

been described12' as an antitumour agent from Jatropha macrorhiza (Euphorbiaceae). The crystal structure of a bertyadionol derivative has been published. 12' 6,20-Epoxylathyrol 5,lO-diacetate 3-phenylacetate, which had previously been found in the Euphorbiaceae, has been isolated122 from Castanopsis lamontii (Fagaceae). 3,12-Di-O-acetylingol8-tiglate ( 8 6 )and the 3,5,16,20-tetra-acetate of 16-hydroxyingenol (87) have been isolated123from the irritant latex of Euphorbia lactea. Resiniferatoxin, tinyatoxin (88), and 12-deoxy-4/3-hydroxyphorbol 13119

120

121

122 123

S. M. Kupchan, C. W. Sigel, M. J . Matz, C. J . Gilmore, and R. F. Bryan, J. Amer. Chem. Soc., 1976,98, 2795. S. J. Torrance, R. M. Wiedhopf, J. R. Cole, S. K. Arora, R. B. Bates, W. A. Beavers, and R. S. Cutler, J. Org. Chem., 1976,41, 1855. E. N . Maslen, R. F. Toia, A . H. White, and A . C. Willis, J.C.S. Perkin 11, 1975, 1684. Wai-Haan Hui and Man-moon Li, Phytochemistry, 1976, 15, 1313. R. R. Upadhyay and E. Hecker, Phyrochemistry, 1975,14,2514.

Diterpenoids

123

phenylacetate are toxins which have been from the latex of Euphorbia poisonii. 12-0-Dodecanoylphorboll3-acetateand the corresponding 20-linolenate are irritants which have been detected'25 in the seeds of Croton sparciflorus (Euphorbiaceae). Prostratin (89) is a highly toxic substance which has been isolatedlz6from Pimelea prostrata. Its structure was determinedI2' by X-ray analysis. Full papers have appeared128on the structure of the cotylenins.

CH,Ph

I

kH,0CCH2C,H40H-p II 0 (88)

CH,OH (89)

6 Miscellaneous Diterpenoids As with other classes of terpenoid, the investigation of marine organisms has yielded a diversity of novel structural types. Dictyol A (90) and dictyol B (91) have been isolated'29 from the brown alga Dictyota dichotoma and from the sea hare, Aplysia

125

lz6

127 128

129

F. J. Evans and R. J. Schmidt, Phytochemistry, 1976, 15, 333. R. R. Upadhyay and E. Hecker, Phytochemistry, 1976, 15,1070. A. R. Cashmore, R. N. Seelye, B. F. Cain, H. Mack, R. Schmidt, and E. Hecker, Tetrahedron Letters, 1976, 1737. I. R. N McCormick, P. E. Nixon, and T. N. Waters, Tetrahedron Letters, 1976, 1735. T. Sassa, A. Takahama, and T. Shindo, Agric. and Biol. Chem. (Japan), 1975, 39, 1729; T. Sassa, M. Togashi, and T. Kitaguchi, ibid., p. 1735. E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, D. Sica, V. Amico, G. Oriente, M. Piatelli, and C. Tringali, J.C.S. Chem. Comm., 1976, 55.

124

Terpenoids and Steroids

depiluns, which feeds on these algae.'30 Dollabelladiene (92) hzs been obtainedI3' from Dollubellu californica. A plausible biogenesis may involve the folding of geranylgeranyl pyrophosphate shown in (93). Dolatriol and its 6-acetate (94) are cytotoxic compounds which have been obtained13*from D. auricularia. The name dolestane has been proposed for the parent hydrocarbon. Sphaerococcenol-A (95) is a bromo-diterpenoid which has been from the red alga Sphaerococcus coronopifolius, and irieol (96) and iriediol (97) are bromo-diterpenoids which have been isolated134from Laurencia spp.

(93) OPP = pyrophosphate

(92)

% % Pr

'%%

H

- -Br

(96)

<.'

H

-

- -Br

(97)

The crystal structure of 18-hydroxydecipia-2(4),14-dien-1-oic acid (98) has been published.'35 The structure and absolute stereochemistry of a novel tetracyclic diterpenoid, stemarin (99), has been described.'36 Eremantholide A(100) is a tumour-inhibitory compound which has been from Eremanthus eleugnus (Compositae) and is possibly a nor-diterpenoid. The structure of colletotrichin (formerly known as acetylcolletotrichin) (101), which has been determined by an 130 131 132

L. Minale and R. Riccio, Tetrahedron Letters, 1976, 2711. C. Ireland, D. J. Faulkner, J. Finer, and J. Clardy, J. Amer. Chern. Soc., 1976,98, 4664. G. R. Pettit, R. H. Ode, C . L. Herald, R. B. von Dreele, and C. Michel, J. Amer. Chem. Soc., 1976,98, 4677.

133 134 135

I36 137

W. Fenical, J. Finer, and J. Clardy, Tetrahedron Letters, 1976, 731. W. Fenical, B. Howard, K. B. Gifkins, and J . Clardy, Tetrahedron Letters, 1975, 3983. E. N. Maslen, P. N. Sheppard, A. H. White, and A. C. Willis, J.C.S. Perkin 11, 1976, 263. P. S . Manchand and J. F. Blount, J.C.S. Ckem. Comm., 1975, 894. R. F. Raffauf, P.-K. C. Huang, P. W. LeQuesne, S. B. Levery, and T. F. Brennan, J. Amer. Chem. Soc., 1975,97,6884.

Diterpenoids

125

X-ray analysi~,'~'contains a possible nor-diterpenoid fragment. A curious diisocyanide, di-isocyanoadociane (102), which has been from a sponge, is also possibly diterpenoid.

$ 0 O

+

EN:%

N-C

0

7 Diterpenoid Total Synthesis In a biogenetically patterned synthesis, the cyclization of epoxygeranylgeraniol with boron trifluoride etherate has been shown 140 to afford the compounds (103) and the pimaradienols (104). The cyclization of epoxygeranylgeranyl pyrophosphate by kaurene synthetase the epimeric 3-hydroxykaurenes. A cyclization of olefinicp-keto-esters (105) to the bicycliccompound (106) has formed'42the basis of a novel synthesis of A8(14'-podocarpen-13-one (107), a compound which is an intermediate in several diterpenoid total syntheses. Synthetic approaches to the

(103) 138

139 140

141

142

(104)A' or

R. Goddard, I. K. Hatton, J. A. K. Howard, J. MacMillan, and C. J. Gilmore, J.C.S.Chem. Comm., 1976, 408. J. T. Baker, R. J. Wells, W. E. Oberhansli, and G. B. Hawes, J. Amer. Chem. Soc., 1976,98,4010. E. E. van Tamelen and S. A. Marson, J. Amer. Chem. SOC.,1975,97, 5614. R. M. Coates, R. A, Conradi, D. A. Levy, A. Akeson, J. Harada, S.-C. Lee, and C. A. West, J. Amer. Chem. Soc., 1976,98,4659. R. W. Skeean, G. L. Trammell, and J. D. White, Tenuhedron Letters, 1976, 525.

126

c?.”

do Terpenoids and Steroids

@

\

H

(105)

H

(106)

(107)

stemodin ring system have been deve10ped.I~~Some improvements have been in the synthesis of 13-methoxypodocarpatrienes which are intermediates in diterpenoid total synthesis. The rings A -+B -+c approach to diterpenoid total synthesis has been successfully e ~ p l o i t e d ’ ~in’ syntheses of sugiol, ferruginol, and nimbiol. This method the construction of diterpenoids with angular group functionality as in the synthesis of carnosic acid dimethyl ether. The synthesis of some further angularly substituted intermediate acids has also been described.147 A stereoselective synthesis of callitrisic acid has been reported.14* A new synthesis of sempervirol has utilized the c ~ n d e n s a t i o nof l ~p~ -cyclocitral with 4-isopropyl-3-methoxybenzyl chloride to afford (108). Cyclization of the corresponding ketone gave the tricyclic system (109) which was converted into sempervirol. A novel rearrangement of the angularly fused cyclobutanone (110) to (111)forms the basis of a synthesis of potential intermediates for conversion into the diterpenoid alkaloids.

(110) 143 144

145 146

147 148

I49 150

(111)

P. K. Ghosal, D. Mukherjee, and P. C. Dutta, Tetrahedron Letters, 1976, 2997. U. R. Ghatak and S. Chakrabarty, J. Org. Chem., 1976, 41, 1089. W. L. Meyer, G. B. Clernans, and R. A. Manning, J. O r g . Chem.. 1975,40, 3686. W. L. Meyer, R. A. Manning, E. Schindler, R. S. Schroeder, and D. C. Shew, J. Org. Chem., 1976,41, 100s. A. S. Sarrna, A. K. Banerjee, and P. C. Dutta, J.C.S. Perkin I , 1976, 722. S. C. Welch and J. H. Kim, Synth. Cumm., 1976, 6 , 27. T. Matsurnoto, S. Usui, and K. Fukui, Chem. Letters, 1976, 241. U. R. Ghatak, B. Sanyal, and S. Ghosh, J. Amer. Chem. Soc., 1976, 98, 3721.

Diterpenoids

127

The conversion of the tricyclic keto-ester (112) via the bromohydrin (113) into methyl 7,16-dioxo-17-norkauran-19-oate a formal total syn(114) thesis of gibberellin A12.

The application of the reductive methylation sequence to the 7-methoxyhexahydrofluorene derivative (1 15) leads'52 to (116) in which, the methyl group enters trans to the 9-carboxy-group. The synthesis of (117; R = H ) has been de~cribed.'~ Various ~ methods have been explored154for the stereospecific introduction of the ring B carboxy-group (117; R = C 0 2 H ) . The use of 2ethoxycarbonylmethyl-6-methoxyindenone(1 18) as a dienophile in a Diels-Alder reaction has been explored155in the preparation of the ester (119) which was then cyclized to (120). H

Me0 Me02C

C0,Me

C0,Me

M e 0m

Me0

C

H ,CO, Et

0

Me0

a II

0 CH,CO,Et

151

152

153 154 155

I. Takemoto, K. Mori, and M. Matsui, Agric.and Biol.Chem. (Japan), 1976,40,25 1; Tetrahedron, 1976, 32, 1497. H. 0. House, R . C. Strickland, and E. J. Zaiko, J. Org. Chem., 1976, 41, 2401. H. J. E. Loewenthal and S. Schatzmiller, J.C.S. Perkin I, 1975, 2149. H. J. E. Loewenthal and S. Schatzmiller, J.C.S.Perkin I, 1976, 944. G. Jammaer, H. Martens, and G . Hoornaert, Tetrahedron, 1975,31, 2293.

Terpenoids and Steroids

128

Casbene (123) may be biogenetically related to the diterpenoids of the lathyrol, phorbol, and ingenol series. The synthesis1s6of casbene represents one of the major achievements of the year. The aldehyde (121), obtained from methyl cischrysanthemate, was converted in a series of steps into the dibromide (122) which was cyclized with tetracarbonylnickel to afford casbene (123) and a geometrical

(121)

( 122)

(123)

isomer. The full paper on the synthesis of cembrene has a p p e a ~ e d . ' ~The ' synthesis and pheromone activity of DL-neocembrene have been described.158 The synthesis has been described'59 of the tricyclic compound (124) related to isoeremolactone. The total synthesis of portulal (125) has been completed.'60 ,CH,OH

(124)

(125)

The conversion of the relay (1 28) into grayanotoxin I1 has been described earlier. The synthesis of this relay has been achieved16' utilizing the photochemical rearrangement of the dienone (126) to the cyclopentanone (127). The conversion of

(126)

(127)

(128)

the model compound (129) into the chasmine fragment (130) has been described earlier. Now the stereospecific total synthesis of the aromatic intermediate (131) has been completed.162 L. Crombie, G . Kneen, and G. Patterlden, J.C.S. Chem. Comm., 1976, 66. W. G. Dauben, G. H. Beasley, M. D. Broadhurst, B. Muller, D. J. Peppard, P. Pesnelle, and C. Suter, J. Amer. Chem. SOC., 1975, 97, 4973. 158 Y. Kitahara, T. Kato, T. Kobayashi, and B. P. Moore, Chem. Letters, 1976, 219. 159 G. I. Feutrill and R. N. Mirrington, J.C.S. Chem. Comm., 1976, 589. 160 R. Kanazawa, H. Kotsuki, and T. Tokoroyama, Tetrahedron Letters, 1975, 3651. 1 6 1 S . Gasa, N. Hamanaka, S. Matsunaga, T. Okuno, N. Takeda, and T. Matsumoto, Tetrahedron Letters, 1976, 553. 162 S. F. Lee, G . M, Sathe, W. W. Sy, P. T. Ho, and K. Wiesner, Canad. J. Chem., 1976, 53, 1039.

156

157

129

Diterpenoids OMe

HO" Me0

4 Triterpenoids BY J. D. CONNOLLY

1 Squalene Group The work of Johnson and his colleagues on biomimetic polyene cyclization has been reviewed.’+2 A convenient synthesis of optically active squalene 2,3-oxide from L-glutamic acid has been r e p ~ r t e d . The ~ ’ ~ (S)-acetonide (l), derived from glutamic acid,3 was converted by standard methods into the C30compound (2). The corresponding diol (3) was tran~formed,~ via the mesylate (4),into (3R)-squalene 2,3-oxide (5). Hydrolysis of (9,mesylation, and displacement afforded the enantiomeric (3s)oxide (6).

(3) R = H (4) R = M s

1-trans - 1‘-Norsqualene 2,3-oxide is cyclized by a cell-free system of corn embryos to 3 1-norlanosterol in addition to the expected 3 1-norcy~loartenol.~2Methylfarnesyl pyrophosphate and 3-desmethylfarnesyl pyrophosphate are utilized only as co-substrates by yeast enzyme and are incorporated into 11-methylsqualene and 10-desmethylsqualene re~pectively.~” During the course of this work the 1 2

3 4 5

6

7

W. S. Johnson, Bioorg. Chem., 1976, 5, 51. W. S. Johnson, Angew. Chem. Internat. Edn., 1976, 15, 9. S. Yamada, N. Oh-hashi, and K. Achiwa, Tetrahedron Letters, 1976, 2561. S. Yarnada, N. Oh-hashi, and K. Achiwa, Tetrahedron Letters, 1976, 2557. L. Cattel, C. Anding, and P. Benveniste, Phytochernistry, 1976,15, 931. P. R. Ortizde Montellano, R. Castillo, W. Vinson, and J. S. Wei, J. Arner. Chern. Soc., 1976,98,2018. P. R. Ortiz de Montellano, R. Castillo, W. Vinson, and J. S. Wei, J. Arner. Chern. Soc., 1976,98,3020.

130

Triterpenoids

131

all-E-isomers of 11-methylsqualene,6 11,14-dimethyl~qualene,~and 10desmethylsqualene' were prepared for reference purposes. The methyl phosphonophosphate derivative (7) of presqualene alcohol is a highly efficient inhibitor of the presqualene alcohol to squalene step in the biosynthesis of squalene by the liver enzyme system.8 It does not, however, prevent the formation of presqualene alcohol pyrophosphate from tritiated mevalonate, and this suggests that presqualene alcohol is a mandatory intermediate in the biosynthesis of squalene. The full details of the incorporation of [6,6,6-2H3]mevalonate into squalene and p -amyrin in Pisum sativum have a ~ p e a r e d . ~

-v..H

Me CHzCH2P020P033-

R'

3Bu36H

,I--\ H

A cell-free system from the prokaryotic bacterium Acetobacter rancens converts squalene into hop-22(29)-ene (8) and hopan-22-01 (9).1° Incubation of (3R,S)[ 12,l 3-3H2]squalene 2,3-oxide under the same conditons afforded the corresponding 3a- and 3P-hydroxyhopane derivatives (10)-(13) (see p. 151). The failure to detect ketonic intermediates in the incubation leads to the conclusion that the 30hydroxy-compounds are formed directly from (3R)-squalene 2,3-oxide (see Vol. 1, p. 162 and Vol. 5, p. 124).

(8) R=H,H (10) R=H,P-OH (11) R=H,a-OH

(9) R=H,H (12) R=H,B-OH (13) R = H,a -OH

The fungus Sclerotinia fruticola produces squalene 1 0 , l l-oxide, whose structure was confirmed" by comparison with a synthetic sample. The results of a 13Cstudy of squalene suggest12 that the conformation and intramoleculai motion do not vary greatly with the polarity of the medium. Five new alkaloids, daphnigracine (14), daphnigraciline (15), oxodaphnigracine (16), oxodaphnigraciline (17), and epioxodaphnigraciline (18), have been isolated13

* lo

12 l3

E. J. Corey and R. P. Volante, J. Amer. Chem. SOC.,1976,98, 1291. T. Suga and T. Shishibori, Phytochemistry, 1975,14, 2411. C. Anding, M. Rohmer, and G. Ourisson, J. Amer. Chem. SOC.,1976,98, 1274. M. Katayama and S. Marumo, Tetrahedron Letters, 1976, 1293. M. E. van Dommelen, A. R. N. Wilson, J. W. de Haan, and H. M. Buck, Rec. Truv. chim., 1975,94,206. S. Yamamura, J. A. Lamberton, H. Irikawa, Y. Okomura, and Y. Hirata, Chem. Letters, 1975, 923.

Terpenoids and Steroids

132

from the leaves of Duphniphyllum gracile. The zwitterionic compound (19) from D . teijsrnunni l4 is closely related to daphnilactone B.

-02c

(14) (15) (16) (17) (18)

R1 = OH, R2 = Pri, R3 = H,H R1= OH, R2 = Et, R3 = H,H R' = OH, R2 = Pri, R3= 0 R' = OH, R2 = Et, R3 = 0 R'=Et, R2=OH, R 3 = 0

2 Fusidane-Lanostane Group Regiospecific oxidation of the 3-hydroxy-group of methyl fusidate has been accomplishedI5 by use of the Corey reagent (one equivalent of N-chlorosuccinimidedimethyl sulphide complex). Thermolysis of lanostanol 38 -azidoformate (20) provides a method for functionalization of the 4a-methyl group.l6 Two compounds (21) and (22) were produced in addition to lanostanone. I3CN.m.r. data identified the involvement of the 4a-methyl group in the formation of (21). A recent report i n d i c a t e ~that ' ~ nitroxide photolysis results in functionalization of the 4p-methyl group. A modified method for the removal of the C-4 methyl groups of lanosterol has been published.'* The methods for degrading the side-chain of lanosterol continue to be i m p r ~ v e d . ' ~ .A ~ ' series of degraded lanost-8-en-7,ll -diones (23) has been prepared.21 No attack at C-12 was observed under conditions which afforded the disophenols (24)21and the a-oximino-ketones (25).22 The full details of the structural e!ucidation of eucosterol(26), a novel spirocyclic norlanostene from several Eucomis species, have a ~ p e a r e d . Two ~ ' additional compounds from the same source are 16p-hydroxyeucosterol (27) and the carboxylic acid (28).23The latter was prepared from (26) by base-catalysed elimination and l4

l6

l9

2o 21 2*

23

S. Yarnarnura, M. Toda, and Y. Hirata, Bull. Chem. SOC. Japan, 1976, 49, 839. S. S. Welankiwar and W. S. Murphy, J.C.S. Perkin I, 1976, 710. A. J. Jones, P. F. Alewood, M. Benn, and J. Wong, Tetrahedron Letters, 1976, 1655. J. A. Nelson, S. Chou, and T. A. Spenser, J. Amer. Chem. SOC., 1975, 97, 648. K. F. Cohen and J. T. Pinhey, Austral. J. Chem., 1975, 28, 2659. J.-M. Bernassau and M. Fetizon, Synthesis, 1975, 795. W. Kreiser and W. Ulrich, Annalen, 1976, 1199. W. Kreiser and W. Ulrich, Annalen, 1976, 1206. W. Kreiser and W. Ulrich, Annalen, 1976, 1214. R. Ziegler and C. Tamm, Helu. Chim. Actu, 1976, 59, 1997.

Triterpenoids

133

(24)

(23)

(25)

oxidative cleavage. One of the metabolites of the fungus Mucor rouxii is E-24ethylidene-5a -1anost-8-en-3P -yl acetate (29) whose structure was confirmed by synthesis.24 Bosistoin from Bosistu euodiformisz5 and 0-methylpertyol from the roots of Pertyu robustuz6have been assigned the same structure (30). Comparison of the published physical and spectroscopic data confirms their identity. Bosistoin was synthesizedz5from the degraded acid (3 1). Mallotin from Mullotus stenanthus is 24,24-dimethyl-5a -lanosta-7,25-dien-3a -01 (32).” 4a -Methyl and 4 p -methyl ‘C0,H

(26) R = H (27) R = O H

/

(29) 24

2s 2h

27

S. Safe and L. M. Safe, Canad. J. Chern., 1975, 53, 3247. J. A. Croft, E. Ritchie, and W. C. Taylor, Austral. J. Chern., 1975,28, 2019. M. Nagai, S. Nagumo, and K. Izawa, Tetrahedron Letters, 1975, 3655. R. Pal, D. K. Kulshreshtha, and R. P. Rastogi, Phytochernistry, 1975,14, 2253.

Terpenoidsand Steroids

134

(32)

(31)

derivatives of cholestane and 24-methyl- and 24-ethyl-cholestane have been isolated from a bituminous shale.28 A stereoselective synthesis of (33), a possible intermediate for synthetic approaches to lanostanes, has been published.*’ Treatment of the thioacetal (34) with phosphoryl chloride in pyridine gave the expected dehydration product and, with longer reaction times, the 2,3-dihydro- 1,4benzodithiin (35). Photolysis of the latter afforded ethylene and the compound (36), the stable dithiet tautomer of a dithio-o -quinone, whose structure was established3’ by X-ray analysis.

AcO

Me0

(35)

(36)

The structure and stereochemistry of passiflorine (37), a glucoside from the leaves of PassifEora edulis, have been confirmed by X-ray analysis.31 An interesting transposition of the cyclopropane ring, to (39), was observed on reaction of the aglucone methyl ester (38) with acid. Ananasic acid, a trihydroxy-acid from pineapple stems (Ananas comosus), has been assigned the structure (40).32 Three 29 3*

3’

3*

I. Rubinstein and P. Albrecht, J.C.S. Chem. Comm., 1975, 957. R. A. Packer and J. S . Whitehurst, J.C.S. Chem. Comm., 1975, 757. R. B. Boar, D. W. Hawkins, J. F. McGhie, S . C. Misra, D. H. R. Barton, M. F. C. Ladd, and D. C. Povey, J.C.S. Chem. Comm., 1975, 756. E. Bombardelli, A. Bonati, B. Gabetta, E. M. Martinelli, G. Mustich, and B. Danieli, Phytochemistry, 1975,14,2661. R. H. Takata and P. J . Scheur, Tetrahedron, 1976, 32, 1077.

Triterpenoids

135

related compounds, acerinol (4l), acerionol (42), and 25-0-methylacerinol, have been reported from Cimifuga a c e ~ i n a .Other ~ ~ new cycloartanes include cycloneolitsol (43) from Polypodium juglandifolium 34 and cycloartanone from the latex of Euphorbia b a l s a m i f e ~ a . ~ ~

(37) R = P-D-G~u (38) R = M e

un

(41) R = H,OH (42) R = O

HO

(43)

In the presence of D 2 0 microsomes of maize embryos

cycloeucalenol

(44)into [ 19-2H]obtusifoliol(45). This reaction is the biochemical equivalent of an acid-catalysed opening of the cyclopropane ring. The 13Cresonances of some actein and cimigoside derivatives have been as~igned.~’ 33 34

35 36 37

G . Kusano, M. Uchida, Y. Murakami, N. Sakurai, and T. Takemoto, J. Pharm. SOC.Japan, 1976,96,321. R. Sunder, K. N. N. Ayengar, and S. Rangaswami, J.C.S. Perkin I, 1976, 117. A. G . Gonzdlez, B. M. Fraga, P. Gonzilez, and A. G . Ravelo, Phytochernistry, 1976,15, 427. A. Rahier, P. Benveniste, and L. Cattel, J.C.S. Chem. Comm., 1976, 287. L. Radics, M. Kajtar-Peredy, S. Corsano, and L. Standoli, Tetrahedron Letters, 1975, 4287.

136

Terpenoidsand Steroids

(44) (45 1 On treatment with N-bromoacetamide followed by alkali the olefin (46), a pyrolysis product of N-isobutyrylcyclobuxidine F, afforded the corresponding l P , l O P - e p o ~ i d e The . ~ ~ latter was readily transformed into (47) which was found to be identical with N-isobutyrylbuxaline F, an alkaloid from B u m s balearica. p Nitroperbenzoic acid converted (48) into the l a , l O a -epoxide (49). Successive treatment of (49) with triphenylphosphine and sodium methoxide afforded the novel cyclopropane derivative (50). /

(46) R = H (48) R = M e

OH

The full details of the work on the antifungal glycosides, holotoxins A and B,39of s ~ ~ appeared. the sea cucumber Stichopus japonicus and their a g l y c ~ n e have The first successful transformation of a lanostane into a cucurbitane by a cationic process has been reported.41 O n exposure to acid 3P-acetoxy-9a -hydroxy-11-keto5a -1anostane afforded two rearranged products (5 1) and ( 5 2 ) with a cucurbitane 38

39

41

M. Benechie and F. Khuong-Huu, Tetrahedron, 1976,32, 701. I. Kitagawa, T. Sugawara, and I. Yosioka, Chem. and Pharm. Bull. (Japan), 1976,24, 275. I. Kitagawa, T. Sugawara, I. Yosioka, and K. Kurijama, Chem. and Pharm. Bull. (Japan),1976,24,266. 0. E. Edwards and 2. Paryzek, Canad. J. Chem., 1475, 53, 3498.

137

Triterpenoids

skeleton. Interrelation with an authentic cucurbitacin was achieved by conversion of (52) and 24-deoxybryogenin acetate (53)into the same aromatic product (54) with anhydrous toluene-p -sulphonic acid. Under different acid conditions the starting compound followed an alternative rearrangement pathway to give (55). &17

p

l

y

AcO

AcO

(52)

(51)

C8H 1 7

@

AcO

\

9'' (53)

&GH*,

\

AcO

(54)

(55)

New compounds in this series include cucurbitacin S (56)42 and bryoamaride (57) and its 25-0-acetyl derivative (58)43 from Bryonia dioica. Cucurbitacin S reacted . with acidic methanol to form the acetal (59).

{POM (58) R = M e

- -0

j 42 43

(59)

P. J. Hylands and A. M. Salama, Phytochemistry, 1976, 15, 559. H. Ripperberger, Tetruhedron, 1976,32, 1567.

138

Terpenoids and Steroids

3 Dammarane-Euphane Group The full details of the remote oxidation at C-12 of the p-nitrophenylacetate of 3-epidammaranediol I1 to the triol (60) have appeared.44 This triol has been converted into betulafolienetriol (6 1) and (20S)-protopanaxadiol (62), thus com~ l e t i n gtheir ~ ~ formal syntheses. New dammaranes include 25-acetoxy-20(S),24(R )-epoxy-3-oxodammarane (63) and the related alcohol (64) from the lichen Pyxine ~ o c c i f e r aand ~ ~ 3&20(R)dihydroxydammar-24-ene (65) and the corresponding ketone (66) from Barbacenia bic~lor.~' The structures of chikusetsusaponins 1 (ginsenoside Rg,) and l a have been el~cidated.~~ HO

(61) R = H,a -OH (62) R = H,P -OH OH

(63) R = O (64) R = HJ-OH

(65) R=H,@-OH (66) R = O

The absolute configuration of sapelin B (67) has been shown to be (23R, 24S), as expected on biogenetic grounds, by interrelation with sapelin D (68)7of established stereochemistry, and from the c.d. of the tribenzoate (69).48 Boron trifluorideinduced rearrangement of sapelin B epoxide gave sapelin D (68) in addition to the expected aposapelin B. The determination of the absolute configuration of a -glycols from the c.d. spectrum in the presence of shift reagent may require caution since both sapelin B and 4,6-O -ethylidene-a -D-glucopyranoside gave Cotton effects with signs opposite to prediction. Two new natural products from Simarouba amara are 3,21dio~otirucalla-7~24-diene (70) and 3-oxotirucalla-7,24-diene (71).49 The latex of Antiaris africana is a good source of b u t y r o ~ p e r m o lwhich , ~ ~ has always been difficult to obtain in quantity. 44

45

46 47

4R 49 50

R. Kasai, K. Shinzo, and 0. Tanaka, Chem. and Pharm. Bull. (Japan),1976,24, 400. S. Huneck, Phytochemistry, 1976, 15, 799. P. M. Baker, E. J. L. Barriero, and B. Gilbert, Phytochemistry, 1976, 15, 785. T. D. Lin, N. Kondo, and J. Shoji, Chem. and Pharm. Bull. (Japan), 1976,24, 253. C. W. Lyons and D. R. Taylor, J.C.S. Chem. Comm., 1976,647. J . Polonsky, Z. Baskevitch-Varon, and B. C. Das, Phyrochemistry, 1976,15, 337. J. I. Okogun, A. I. Spiff, and D. E. U. Ekong, Phyrochemistry, 1976, 15, 826.

osR.oR 139

Triterpenoids

(67) R = H (69) R = B z

(70) R = CHO (71) R = M e

Tetranortriterpen0ids.-The structure of sendanin (72), from the bark of a Japanese variety of Melia azedarach, has been confirmed by X-ray analy~is.'~The novel enol-ether (73) has been i ~ o l a t e d 'from ~ the heartwood of Khaya anthotheca along and (75).52 Zinc-copper couple is a with 11p- and 1la -acetoxyazadirone (74)52753 very convenient reagents3 for reduction of epoxides, a,@-epoxy-lactones, ap unsaturated ketones, and a-ketols. The full details of the X-ray analysis of prieurianin have appeared.54

OAc

--..

/

"OH

H

0

'

0

(73)

51

s2

s3 54

"OAc

OH (74) R = H,P - 0 A c

(75) R = H,CX -0Ac

M. Ochi, H. Kotsuki, K. Hirotsu, and T. Tokoroyama, Tetrahedron Letters, 1976, 2877. T. G. Halsall and J. A. Troke, J.C.S. Perkin I, 1975, 1758. D. E. U. Ekong, J. I. Okogun, and B. L. Sondengam, J.C.S. Perkin I, 1975, 2118. A. F. Cameron and F. D. Duncanson, Acra Crysr., 1976, B32, 1841.

Terpenoids and Steroids

140

Pentanortriterpen0ids.-Recently a fascinating group of highly cleaved Czs terpenoids has been isolated from the Cneoraceae (for a review see ref. 55). Initially these compounds, e.g. cneorin C (76), were considered to be sesterterpenoids, but with the structural elucidation of cneorin B (77)56the biogenetic relationship with tetranortriterpenoids became more apparent. The carbon framework (78) helps to emphasize this relationship. It has now been that the cneorins and related compounds are pentanortriterpenoids with the same biogenetic origins as tetranortriterpenoids with which they co-occur.

(76)

(77)

Quassinoids.-The full paper on the structural elucidation of picrasins A-G has been published.57 Two new compounds, nigakihemiacetals E (79) and F (go), have been isolated'' from Picrasma ailanthoides.

OH

Me0

Me0 '0

@

55 56

57 58

(79)

OH '

(80)

H. Straka, F. Albers, and A. Mondon, Biol. Ppanzen, 1976,52,267. A. Mondon and B. Epe, Tetrahedron Letters, 1976, 1273. H. Hikino, T. Ohta, and T. Takemoto, Phytochemistry, 1975,14, 2473. T. Murae, A. Sugie, T. Tsuyuki, and T. Takahashi, Chem. and Pharm. Bull. (Japan), 1975,23,2188.

Triterpenoids

141

4 Shionane-Baccharane Group The full details of the backbone rearrangement of 3a,4a -epoxyshionane into bacchar-12-en-3a -01 have appeared.59 A second product of this reaction, previously assigned structure (81), has now been to be (82) by comparison with an authentic sample prepared6* from 4 a -bromoshionan-3-one (83) via the dienone

5 Lupane Group A re-examination61 of the acid treatment of betulinic acid has shown that (85),(86), and (87) are formed depending on the conditions. Dlmethyl dihydroceanothate (88) has been synthesized6*from methyl dihydrobetulonate via the seco-ester (89).

CO, Me Me0,C..

HO

Meo2C2

Me0,C

S. Yamada, K. Tachibana, Y. Moriyama, Y. Tanahashi, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC. Japan, 1976,49, 1134. K. Tachibana, S. Yamada, S. Yamada, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC.Japan, 1975,48, 3425. B. Achari and S. C. Pakrashi, Tetrahedron, 1976, 32, 741. T. K. Ray, D. R. Misra, and H. N. Khastgir, Indian J. Chem., 1975, 13, 948.

Terpenoids and Steroids

142

Lantabetulic acid, from the Common Pink taxon of Lantana camara, is 3&25epoxy-3a -hydroxylup-20(29)-en-28-oic acid (90).63 Other new lupanes include glochidol (91), from Glochidion e v i o c a ~ p u mand , ~ ~lup-20(29)-en-3&27-diol, from Lithocarpus cornea .65

&

HO" &C02H

HO

(90)

(91)

Reaction of the lupan-20-01 derivatives (92)-(94) with lead tetra-acetate aff orded66mainly the corresponding 12&20-oxides whereas the (20R )-nor-alcohol (95) gave the trisnor-derivatives (96) and (97). Lead tetra-acetate-iodine treatment of the amide of 3p -hydroxy- or 3p -acetoxy-lupan-28-oic acid resulted only in formation of the corresponding i ~ o c y a n a t e .The ~ ~ mass spectral fragmentation of lup- 12-ene67and 12-0xolupane~~ derivatives has been studied. The results are at variance with the published data69used to support the structure of thurberin (98) and thurberodione (99). Bornan-2-exo -yloxyaluminium dichloride is a highly stereoselective reducing agent for the preparation of 3a (axial) alcohols from triterpenoid 3-ket0nes.~' Me

&OH

Me HO+H

64 65

66 67

68 69

70

Me

Me+OH

CH20H

AcO .

N. K. Hart, J. A. Lamberton, A. A. Sioumis, and H. Suares, Austral. J. Chem., 1976, 29, 655. W.-H. Hui and M.-M. Li, Phytochemistry, 1976,15, 561. W.-H. Hui and M.-M. Li, J.C.S. Perkin I, 1976, 23. V. Pouzar, J. Protiva, E. Lisi, E. Klinotovi, and A. VystrEil, Coll. Czech. Chem. Comm., 1975,40,3046. J. Protiva and A. VystrEil, Coll. Czech. Chem. Comm., 1976, 41, 1200. J . Protiva, V. Pouzar, and A. VystrEil, Coll. Czech. Chem. Comm., 1976,41, 2225. S. D . Joland and C. Steelink, J. Org. Chem., 1969, 34, 1367. D. Nasipuri, P. R. Mukherjee, S. C. Pakrashi, S. Dutta, and P. P. Ghosh-Dastidar, J.C.S. PerkinI, 1976, 321.

Triterpenoids

143

The first singlet electronic c.d. band of several steroidal and triterpenoid olefins, including A : B-neolup-9-ene (loo), has been assigned71 as the 7rX + 3s Rydberg transition.

I

(98) R = H,P -OH (99) R = O

(100)

6 Oleanane Group A careful of several taxa of Lantana camara has resulted in the isolation of 22~-hydroxy-3-oxo-olean-12-en-28-oic acid (101), 22~-dimethylacryloyloxy-3Phydroxyolean- 12-en-28-oic acid (102), 24-hydroxy-3-0x0-olean- 12-en-28-oic acid (103), and a mixture of the dimethylacrylate (104) and angelate (105) of 22phydroxylantanolic acid. Other workers have also obtained (104) from L . camara and have called it lantanilic A possible alternative structure for lantanolic acid (106) with the potential ketone at C-2 has been excluded on chemical grounds by converting it into the acetal of oleanonic acid methyl ester.73

\

Of=(

HO

eoZ

0

HO"

(104) R = OCO (105) R = OCO

(106) R = H 71 72

73

)=/

A. F. Drake, J.C.S. Chem. Comm., 1976, 5 1 5 . A. K. Barua, P. Chakrabarti,M. K. Chowdhury, A. Basak, and K . Basu, Phytochemistry, 1976,15,987. A. K. Barua, P. Chakrabarti, K. Basu, A. Basak, S. Chakravarti,and S. K . Banerjee, J. Indian Chem. SOC. 1975,52, 1112.

144

Terpenoids and Steroids

Arjungenin (107) from Terminalia arjuna is the C - 19 epimer of tomentosic A new nortriterpenoid, norarjunolic acid (108), has been isolated7' from Akebia quinata where it occurs with arjunolic acid. The structure of the ketol (109), from the stems of Castanopsis lamontii, was confirmed by its partial synthesis from 14a,l5a-epoxytaraxeran-3-one(l10).76 Other new oleananes include phytolac-

MOzH H O . . A

HO..

acid ,~~ coside B (11l),a glucoside from the root of Phytolacca a r n e r i ~ a n avergatic (112) from Salvia ~ i r g a t a acetylmorolic ,~~ acid from Lithocarpus cornea,7y and papyriogenin A (113), the aglycone of papyrioside L-I1 from the leaves of Tetrapanax papyferum, whose structure was established" by X-ray analysis.

74

75 76 77

78 79

8o

T. Honda, T. Murae, T. Tsuyuki, and T. Takahashi, Chem. and Pharm. Bull. (Japan), 1976, 24, 178. R. Higuchi and T. Kawasaki, Chem. and Pharm. Bull. (Japan), 1976,24, 1314. W.-H. Hui and M.-M. Li, Phytochemistry, 1976, 15, 1313. W. S . W-00 and S . S . Kang, Phytochemistry, 1976,15, 1315. A. Uhubelen and E. Ayanoglu, Phytochemistry, 1976, 15,309. W.-H. Hui and M.-M. Li, Phytochemistry, 1976,15, 336. S . Amagaya, M. Takai, Y. Ogihara, and Y. Iitaka, J.C.S. Chem. Comm., 1975, 991.

Triterpenoids

145

The structure of barringtogenol B (sapogenol A) from Cureya arborea has been revised” from (1 14) to (115). Barringtogenol Al 22-angelate (116), camelliagenin A 16-angelate (117), and the corresponding 22-angelate (1 18) have been isolated” from the bark of Harpullia pendulu. Attempts to form an isopropylidene acetal of (118) resulted in facile acyl migration to give (1 17) and (119). Acyl migration and isopropylidene acetal formation in primulagenin A and other 16-hydroxyoleanenes have received detailed

(114)

b=-/

(116) R1 = OH, R’ = CO’

HO

,R3 = H

w w

(117) R ’ = R ’ = H , R ~ = C O (118) R ’ = R 3 = H , R’=CO

Another method for the selective cleavage of uronic acid-containing saponins has been reporteds5 (see Vol. 4, p. 218). Treatment of the permethylated glucuronide, containing a free carboxy-group, with lead tetra-acetate afforded the epimeric acetates (120) which underwent facile alkaline hydrolysis to give the sapogenol. This method has been successfully applied to several saponins including acid-labile OAc systems.

0

RO

81 82 83 84

-Sap

A. K. Barua, A. Basak, and S. Chakravarti, J. Indian Chem. SOC.,1976, 53, 209. P. W. Khong and K. G. Lewis, Austral. J. Chem., 1976,29, 1351. D. R. Baigent, 0. D. Hensens, and K. G. Lewis, Austral. J. Chem., 1976.29, 1341. 0. D. Hensens, P. W. Khong, and K. G. Lewis, Austral. J. Chem., 1976,29, 1549. I. Kitagawa, M. Yoshikawa, Y . Ikenishi, K. S. Irn,and I. Yosioka, Tetrahedron Letters, 1976, 549.

146

Terpenoids a n d Steroids

Structural assignments have been published for the following saponins: desacylboninsaponin A from the bark of Schima mertensiana,86saponins A and B (chikusetsusaponins IV and IVa)47from Panax p ~ e u d o g i n s e n g platicodin ,~~ D from the root of Platycodon grandiflorum,88 mi-saponins A and B fromthe seed kernels of Madhuca A and D from Acacia c o n c i n n ~ lebbekanin , ~ ~ ~ ~ ~ D from the l ~ n g i f o l i a ,acacinins ~~ flowers of Albizzia lebbek," and saponins from Fatsia j a p o n i ~ aA, ~kebia ~ q~inata,~~ and Bupleurum f a l ~ a t u m . ~ ' Olean- 12-enes are converted into the corresponding 12-chloro-derivatives, e.g. (121), on reaction with a gaseous mixture of nitrosyl chloride and chlorine in pyridine ~ o l u t i o nThis . ~ ~ method has been used to separate natural mixtures of oleanenes and ursenes since the latter are inert under these conditions. The glycyrrhetic acid derivative (122) affordedg7the fluorinated product (123) on treatment with CF30F at -70 "C. (123) decomposed readily in polar solvents to give a rearranged product which has been assigned the novel structure (124).

Me

The ring A conformation of a series of 2,3-disubstituted 24-noroleananes has been in~estigated.~' The rates of oxidation with chromic acid of a series of 1-, 2-, and 3hydroxy- (both a and p ) oleananes, -24-noroleananes, and -1upanes have been I. Kitagawa, K. S. Im, and Y. Yosioka, Chem. and Pharm. Bull. (Japan), 1976,24, 1260. N. Kondo and J. Shoji, Chem. and Pharm. Bull. (Japan), 1975,23,3282. 8 8 A. Tada, Y. Kaneiwa, J. Shoji, and S. Shibata, Chem. and Pharm. Bull. (Japan), 1975, 23, 2965. *9 I. Kitagawa, A. Inada, and I. Yosioka, Chern. and Pharm. Bull. (Japan), 1975.23, 2268. 9 0 I. P. Varshney, G. Handa, and R. Pal, Indian J. Chem., 1976, 14B, 228. 91 I. P. Varshney and R. Pal. J. Indian Chem. SOC.,1976, 53, 153. 92 I. P. Varshney, G. Handa, and R. Pal, J. Indian. Chem. SOC.,1975, 52, 1202. 'n T. Aoki, Y. Tanio, and T. Suga, Phytochemisrry, 1976, 15, 781. 94 R. Higuchi and T. Kawasaki, Chem. and Pharm. BuU. (Japan), 1976,24, 1021. 95 A. Shimaoka, S. Seo, and H. Minato, J.C.S. Perkin I, 1975, 2043. 96 C. D. Bannon, K.A. Eade, H. 3. Samaan. and J,. J. H. Simes, Austral. J. Chem., 1975, 28, 2649. Y7 S. Rozen, I. Shahak, and E. D. Bergmann, J. Org. Chem., 1975,40, 2966. Y 8 J. Klinot, M. HoiejSi, M. BudESinsky, and A. Vystrtil, Coll. Czech. Chem. Comm., 1975, 40, 3712. Y Q M. S.Nair, S . Hilgard, 3. Klinot, K. Waisser, and A. VystrEil, Coll. Czech. Chem. Comm., 1976,41,770. 86

e7

Triterpenoids

A

147

The full details of the synthesis of the bicyclic intermediates corresponding to rings and B (125)''' and rings D and E (126)'" of P-amyrin have appeared.

Several taraxerane derivatives have been reported. These include taraxer- 14ene-3P,29-diol (127), the diacetate (128), 29-hydroxytaraxer- 14-en-3-one (129), the acetate (130), 14a-hydroxytaraxeran-3-one(13 l),and taraxerane-3/3,14a -diol and epitaraxeryl acetate from (132) from the stems of Lithocarpus Melaleuca leucadendron.'02

(127) (128) (129) (130)

R' = H,@-OH,R2 = H R' = H,@-OAc, R2 = Ac R'=O, R2=H R' = 0, R2 = Ac

(131) R = O (132) R = H , P - O H

Ireland has e-:taded his list of synthetic successes in the triterpenoid field with a total synthesis of friedelin (133) uia the pentacyclic ether (137).'03 Strategy dictated that the introduction of the cis D-E ring junction, a principal source of steric strain, be left to the later stages and hence, unlike the alnusenone synthesis (see Vol. 2, p. 175), ring A was modified first. This required interchange of the ethoxy- and methoxy-groups of the pentacyclic ether (134) which had been used in the alnusenone synthesis. The synthetic route is outlined in the Scheme. 2 la -Hydroxyfriedel-4(23)-en-3-one(143) and 3cu,4a -epoxyfriedelane are new natural products from Phyllanthus reticulatus '04 and Castanopsis lamontii7" respectively. The structure (144) has been for a new quinonemethide from the root bark of Salacia macrosperma.

loo

lo1 lo* 103 104

Io5

J. S. Dutcher, J. G . MacMillan, and C . H. Heathcock, J. Org. Chem., 1976, 41, 2663. J. E. Ellis, J. S. Dutcher, and C . H. Heathcock, J. Org. Chem., 1976, 41, 2670. W.-H. Hui and M.-M. Li, Phytochemistry, 1976,15, 563. R. E: Ireland and D . M. Walba, Tetrahedron Letters, 1976, 1071. W.-H. Hui, M.-M.Li, and K.-M. Wong, Phytochemistry, 1976, 15, 797. G . C . S. Reddy, K. N. N. Ayengar, and S. Rangaswami, Indian J. Chem., 1976,14B, 131.

Terpenoids and Steroids

148

EtO (135)

/ I-iv

'

R'O &OR*

(134) R' =Me, R2 = Et (137) R1 = Et, R2 = M e

v-vii _ I )

Reagents: i, PhZPLi-THF; ii. Li-NH3-DME-EtOH; iii, MeI-DME; iv, 5N HCI-EtOH-C6H6; v, H202aq. NaOH-MeOH; vi, p-TsNHNH2-HOAc-CH2CI2; vii, MeLi-Et20; viii, CF3C02H-(CF3C0)20; ix, LDA-THF; x, Zn-Ag-CH212-THF; xi, L~(OBU')~AIH-THF-C&, 0 "C; xii, DHP-POC13-CH2C12; xiii, Li(OBut)3AIH-THF-C6H6, reflux; xiv, Cr03-2py-CH2C12; xv, K0Bu'-MeI-THF; xvi, Li-NH3-THFBu'OH; xvii, C1PO(NMe2)2-DME-HMPA-BuLi; xviii, Li-EtNH2-Bu'OH; xix, p-TsOH-MeOH-THF.

Scheme

Triterpenoids

149

7 UrsaneGroup A second friedo-ursane derivative, cymbopogenol (145), has been isolated from lemongrass, Cymbopogen citralis.'06 The structures (146) and (147) have been assigned to two closely related ursenes from the leaves of Mallotus h o ~ k e r i a n u s . ' ~ ~ Extraction of the bark of Schinus terebenthifolius has yielded terebenthifolic acid (148) and bauerenone (149).lo8 Taraxastenone has been reported from Melaleuca leucadendron.lo2

(146) R' = 0, R2 = C 0 2 H (147) R1 = H,@-OH,R2 = CH20H

(148) R = C 0 2 H (149) R = M e

Several 21,22-seco-diacids (150) have been prepared"' in the 200,28-epoxy18a,190 H-ursane series by oxidation of the corresponding 22-hydroxymethylene21-ketones (151). Reaction of the 21-ketone (152) with oxygen in an alkaline medium afforded the cy -hydroxy-acid (153) and the seco-diacid (150). 'lo Several interesting reactions were observed during this work.'1° While pyrolysis of the aacetoxy-acid (1 54) yielded the ketone (1 55) pyrolysis of the seco-diacid anhydride resulted in loss of carbon monoxide and formation of the lactone (156). Lead tetra-acetate oxidation of the ketone (155) [or the hydroxy-acid (153)] followed a Baeyer-Villiger pathway to the lactone (156). The ketone (155) was very susceptible to reduction in the presence of alcoholic alkali. The mass spectral fragmentation of a series of compounds based on 200,28-epoxy-18a,19PH-ursane has been examined. lo6 lo' lo*

lo9

S. W. Hanson, M. Crawford, M. E. S. Koker, and F. A. Menezes, Phytochemistry, 1976,15, 1074. W.-H. Hui and M.-M. Li, Phytochemistry, 1976, 15, 985. J. de P. Campello, and A. J. Marsaioli, Phytochemistry, 1975, 14, 2300. E. Klinotovi, J. BeneS, and A. VystrCil, Coll. Czech. Chem. Comm., 1975, 40, 2861. E. Klinotovs, J. BeneS, J. Vokoun, and A. VystrEil, Coll. Czech. Chem. Comm., 1976, 41, 271. J. Vokoun, E. Klinotovi, and A. VystrEil, Coll. Czech. Chem. Comm., 1976, 41, 1590.

Terpenoids and Steroids

150

Some 13Cresonances in the ursene series have been reassigned.'12 The labelling pattern in ursolic acid and 2a -hydroxyursolic acid isolated from tissue cultures of Isodon japonicus fed with sodium [ 1,2-13C]acetate conforms with the original Ruzicka hypothesis for the biogenesis of pentacyclic triterpenoids.Il2

, U l \'

(153) R' =OH, R2 = COzH (154) R' = OAc, R2 = C02H (155) R ' R 2 = 0

(156)

8 Hopane Group In 1973 the structure (157) or (158) was proposed113 for a C35hopane derivative, bacteriohopanetetrol, from the bacterium Acetobacter xylinurn. Structure (157) is attractive as a precursor for the extended hopane derivatives obtained from geological sources (see Vol. 3, p. 228 and Vol. 5, p. 145). Rohmer and Ourisson have now confirmed114the validity of (157) and have shown the presence of both (22R)- and (22s)-epimers. Periodate cleavage of the tetrol followed by sodium borohydride reduction and acetylation afforded the epimeric acetates (159) identical with synthetic samples prepared from diploptene (160). A range of Acetobacter species and

llZ lJ3 114

S. Seo, Y. Tomita, and K. Tori, J.C.S. Chem. Comm., 1975, 954. H. J. Forster, K. Biemann, W. G. Haigh, N. H. Tattric, and J. R. Colvin, Biochem. J., 1973, 135, 133. M. Rohmer and G. Ourisson, TetrahedronLetters, 1976, 3633.

Triterpenoids

151

other prokaryotic bacteria has been e ~ a m i n e d " ~and the results indicate the structural variation and widespread occurrence of the bacteriohopanes. Oxygenation patterns (161) and (162) have been found in addition to the presence of double bonds. A bacteriohopanetetrol has been isolated from Bacillus A6 and/or acido~aldariurn.~'~~'~~ OH

OH

OH

OH

OH

OH

Homologous components of the bacteriohopane-tetrol mixture from A . rancens and A . xylinium have been identified as 3-methylhopane derivatives.'" The structure (163) of the product of the periodate-borohydride reaction sequence was confirmed by reduction to (22R)-3-methyl-29-ethylhopane(164) identical with a synthetic sample. The 3-methylhopanes can arise either by direct cyclization of squalene initiated by S-adenosylmethionine or by formation of 3-methylsqualene and subsequent cyclization by the cyclase enzyme. Rohmer and Ourisson favour the latter course in view of the low substrate specificity of the cyclase enzyme of A . rancens (see p. 131).

(163) R=CH20H (164) R = M e

The aromatic derivatives (165) and (166) have beenisolated from several geological sources. l 9 They probably arise by progressive geochemical aromatization of hopane precursors. The structures were confirmed by synthesis.

llS 116 117 118 119

M. Rohmer and G. Ourisson, Tetrahedron Letters, 1976, 3640. T. A. Langworthy, W. R. Mayberry, and P. F. Smith, Biochim. Biophys. Acta, 1976, 431,5 5 0 . T.A. Langworthy and W. R. Mayberry, Biochim. Biophys. Acta, 1976, 431,570. M. Rohmer and G. Ourisson, Tetrahedron Letters, 1976, 3641. A. C. Greiner, C. Spyckerelle, and P. Albrecht, Tetrahedron, 1976, 32, 257.

152

Terpenoids and Steroids

Enzymic hydrolysis of the saponin mixture from the root of Mollugo spergula afforded a new bisnorhopane, spergulatriol (167), together with spergulagenin A (168).12' Acidic hydrolysis of the saponin or acid treatment of (167) gave isoanhydrospergulatriol (169). Cleavage of the acetyl group of spergulagenin A (168) occurred under photochemical conditions with the formation of (167). Spergulagenin A has been inter-related chemically with hydroxyhopane via the alcohol (17O).l2l It is interesting to note that the carbonyl function of (168) is reduced stereospecifically under alkaline conditions.'21 The details of the X-ray analysis of (168) have appeared.'22

# OH

{fl OH

New hopane natural products include 29-nor-2laH-hopane-3,22-dione (17 1) from Mallotuspaniculatus,'0222-hydroxy-2laH-hopan-3-one (172) from Lithocarpus cornea,65hop-17(2 l)-en-3a -01 (173) from Castanopsis species,'23 and dryocrassol (174) and its acetate from the leaves of Dryopteris crassirhizorna and other (see Vol. 6, p. 140). The C-22 configuration of dryocrassol has been assigned as S . A hopan-29-01 of unspecified C-22 configuration has been reported from Polypodium j ~ g l a n d i f o l i u r nThe . ~ ~ conversion of mollugogenol A (175) into 6-keto21aH-hopane confirms the p orientation of the hydroxyisopropyl group in mollugogenols A and E (176).12' The tentative structure (177) has been proposed for

(171) R = O 120

lZ1 lZ2 123 124 125

(172) R = O

(173) R = H p - O H

I. Kitagawa, H. Yamanaka, T. Nakanishi, and I. Yosioka, Tetrahedron Letters, 1976, 2327. I . Kitagawa, H. Suzuki, and I. Yosioka, Chem. and Pharm. Bull. (Japan), 1975, 23, 2087. T. Akiyarna and J. V. Silverton, A c f a Crysf., 1976, B32, 58. W. H. Hui and M.-M. Li, Phytochemisfry, 1976, 15, 427. M. Ageta, K. Shiojima, Y.Arai, T. Kasama, and K. Kajii, Tetrahedron Lefters, 1975, 3297. M. K. Choudhury and P. Chakrabarti, Phytochemistry, 1976, 1 5 , 4 3 3 .

153

Triterpenoids

(174) R = H , H

HO

R (175) R=H,a-OH (176) R = O

(177) R = H , H

(1 78) R = H,P -OH (179) R=H,(u-OH

mollugogenol F, a new sapogenol from Mollugo hirta.'26 The structure of mollugocin A, one of the saponins from this source, has been Two new rearranged hopanes, alangidioi (178) and isoalangidiol(179), with a D-E cis fusion have been reported from the leaves of Alangium l a m a r ~ k i i . 'New ~~ fernene derivatives which have appeared this year include fern-9(1 l)-en-6a -01 (180) and fern-9(1 l)-en-206 -01 (181) from the rhizomes of Polypodium juglandifoliurn34 and hortensol (182) from the leaves of Evodia horten~is.'~~ The structure of (182) was confirmed by X-ray analysis.

(180) R1 = OH, R2 = H (181) R' = H, R2 = OH

9 Stictane-Flavicane Group The chemical shifts and lanthanide-induced shifts of the methyl resonances of a series of stictane and related flavicane triterpenoids have been examined131 and provide supporting evidence for previous structural assignments (see Vol. 4, p. 219). lZ6

lZ7 128 129 l3O 131

M. K. Choudhury and P. Chakrabarti, Indian J. Chem., 1975,13, 947. A. K.Barua, S. Chakravarti, A. Basak, A. Ghosh, and P. Chakrabarti, J. Indian Chem. SOC.,1976,53, 598. A. K.Barua, S. Chakravarti, A. Basak, A. Ghosh, and P. Chakrabarti, Phytochemistry, 1976,15,831. B. Achari, A.Pal, and S. C. Pakrashi, Tetrahedron Letters, 1975, 4275. L. E. McCandlish and G. H. Stout, Acta Cryst., 1976, B32, 1788. R. E. Corbett and A. L. Wilkins, J.C.S. Perkin I, 1976, 857.

Terpenoids and Steroids

154

Further support comes from comparison of the 'H n.m.r. and mass spectral data of the diols (183) and (184) obtained by oxidative cleavage, followed by reduction, of the 17(21)-double bond in the hopene and flavicene series.132

(184)

132

R. E. Corbett and A. L. Wilkins, J.C.S. Perkin I, 1976, 1316.

5 Carotenoids and Polyterpenoids BY G. BRllTON

1 Introduction A highlight of 1975 was the Fourth International Symposium on Carotenoids, held at Bern, Switzerland. Although the plenary lectures have not yet appeared, many of the short communications have now been published in detail. The second edition of ‘The Chemistry and Biochemistry of Plant Pigments’ has appeared.’ The first volume includes chapters on the chemistry,’” distribution,lb biosynthesis,“ functional aspects,ld and metabolism’‘ of carotenoids, and in Volume 2 an exhaustive survey of analytical methods used in carotenoid work is given.’’ The increasing interest in 13Cn.m.r. spectroscopy of carotenoids is reflected by two publications which give extensive tabulated data (see refs. l a and 93). In this Report only the briefest consideration will be given to ‘degraded carotenoids’, i.e. those compounds that are structurally and possibly biogenetically related to fragments of the carotenoid molecule, except for particular cases where the chemistry is considered directly relevant to the chemistry of carotenoids themselves.

2 Carotenoids New Structures.-Monocyclic Carotenoids. A poly-cis-isomer of y-carotene [p,$carotene (l)], isolated from Tangerine tomato fruits,* may be similar to pro-yTwo compounds from the Delta tomato carotene from Pyracantha ang~stifolia.~ mutant have been identified as 1‘,2’-epoxy-1’,2’-dihydro-/?,$-carotene (2) and 1’,2’epoxy-l‘,2’-dihydro-~,$-carotene (3), epoxides of y- and 6-carotene re~pectively.~ Evidence has been presented for the structure (4)(l’-methoxy-3’,4’-didehydro-1’,2’dihydro-&$-carotene) for a minor carotenoid of Rhodomicrobium ~unnielii.~ On the basis of its light absorption spectrum and chemical reactions, a minor compound from the yeast Phufia rhodozyrna has been assigned structure (5), 3-hydroxy-3’,4’didehydro-p,$-caroten-4-0ne.~ ‘The Chemistry and Biochemistry of Plant Pigments’, ed. T. W. Goodwin, 2nd Edn., Academic Press, London and New York, 1976: ( a )G. P. Moss and B. C. L. Weedon, Vol. 1, p. 149; ( b )T. W. Goodwin, Vol. 1, p. 225; (c) G . Britton, Vol. 1, p. 262; ( d )C . P. Whittingham, Vol. 1, p. 624; 3. H. Burnett, Vol. 1, p. 655; (e) K. L. Simpson, T.-C. Lee, D. B. Rodriguez, and C. 0. Chichester, Vol. 1, p. 780; cf)B. H. Davies, Vol. 2, p. 38. R. W. Glass and K. L. Simpson, Phytochemistry, 1976,15, 1077. L. Zechmeister and W. A. Schroeder, J. Amer. Chem. Soc., 1942,64, 1173. G. Britton and T. W. Goodwin, Phytochemistry, 1975,14, 2530. G . Britton, R. K. Singh, T. W. Goodwin, and A . Ben-Aziz, Phytochemistry, 1975,14, 2427. A. G. Andrewes, H. J. Phaff, and M. P. Starr, Phytochemisrry, 1976, 15, 1003.

155

Terpenoids and Steroids

156

Bicyclic Carorenoids. Re-investigation' of the carotenoids of Anacystis nidulans has confirmed the presence of P,P-carotene-2,3,3'-triol(6),8 and the previously unknown P,P-carotene -2,3,2',3'-tetrol (7) was also isolated. These compounds are considered to be identical with caloxanthin and nostoxanthin, for which allenic structures have previously been The main carotenoid of CoccoZithus

k

1

m

n

(1) R 1= a, R 2 = b (2) R ' =a, R 2 = c (3) R'=d,R2=c (4) R' = a , K 2 = e 8

9 10

(5) R'=f, R 2 = g ( 6 ) R ' = h (X=OH), R 2 = h ( X = H ) (7) R ' = R * = h ( X = O H ) (8) R' = j, R 2 = k

(9) R' = 1, R2 = k (10) R 1 = f , R 2 = m (11) R ' = h (X=H), R 2 = m (12) R' = n , R 2 = p

R. Buchecker, S. Liaaen-Jensen, G. Borch, and H. W. Siegelman, Phyrochemisfry, 1976, 15, 1015. R. L. Srnallidge and F. W. Quackenbush, Phytochemisrry, 1973,12, 2481. A. Hager and H. Stransky, Arch. Mikrobiol., 1970,71, 132. H. Stransky and A. Hager, Arch. Mikrobiol., 1971,72, 84.

Carotenoids and Polyterpenoids

157

huxleyi has been shown’’ to be 19’-hexanoyloxyfucoxanthin [5,6-epoxy- 19’hexanoyloxy-3, 3’,5’-trihydroxy-6’, 7’-didehydro-5, 6, 7, 8, 5’, 6’-hexahydro-P, pcaroten-8-one 3’-acetate (13)]. A minor component had the properties of the apo-carotenoid 19-hexanoyloxyparacentrone [3,5,19-trihydroxy-6,7-didehydro-7‘apo-P-caroten-8’-one 19-hexanoate (14)]. Full details have been of the spectroscopic and chemical evidence that led to the a~signmenf’~ of the structure hexanoyloxy-3, 3’, 5’-trihydroxy-6’, 7’-didehydro-5,6, 7,8, 5‘,6’-hexahydro-P, p P,P-caroten-19’, 11’-olide 3-acetate (15 ) to peridinin. Re-examination” of the original taraxanthin samples has confirmed that taraxanthin is a mixture containing lutein 5,6-epoxide [5,6-epoxy-5,6-dihydro-P,~ -carotene-3,3’-diol (S)] as the main component. These studies revealed the presence in extracts of Ranunculus acer of a new carotenoid identified as 5,6-dihydro-P,~-carotene-3,5,6,3’-tetrol(9). Papilioerythrinone, a new ketocarotenoid of animal origin, has been assigned the (10) although no m.s. or n.m.r. data structure 3-hydroxy-P,~-carotene-4,3‘-dione were obtained.16 The related 3’-dehydrolutein [3-hydroxy-P,~ -caroten-3’-one (1 l)] has been isolated from two insects and characterized by its chemical, chromatographic, light absorption, and m.s. properties and by comparison with a semisynthetic sample.” This structure was previously proposed” for ‘philosamiaxanthin’, a carotenoid isolated from another insect species but incompletely characterized.

CO

I

CSHll

l2

l3

l4

l5 l6

l7 l8

N . Arpin, W. A. Svec, and S. Liaaen-Jensen, Phytochemistry, 1976,15, 529. H. H. Strain, W. A . Svec, P. Wegfahrt, H. Rapoport, F. T. Haxo, S. NorgHrd, H. K j ~ s e n ,and S. Liaaen-Jensen, Acta Chem. Scand., 1976, B30, 109. H. K j ~ s e nS. , NorgQrd,S. Liaaen-Jensen, W. A. Svec, H. H. Strain, P. Wegfahrt, H. Rapoport, and F. T. Haxo, Acta Chem. Scand., 1976, B30, 157. H. H. Strain, W. A. Svec, K. Aitzetmiiller, M. C. Grandolfo, J. J . Katz, H. K j ~ s e n S. , Norgird, S. Liaaen-Jensen, F. T. Haxo, P. Wegfahrt, and H. Rapoport, J. Amer. Chem. SOC., 1971,93, 1823. R. Buchecker, S. Liaaen-Jensen, and C. H. Eugster, Helo. Chim. Acta, 1976,59, 1360. K. Harashima, J.-I. Nakahara, and G. Kato, Agric. and Biol. Chem. (Japan), 1976, 40, 711. H. Kayser, J. Comp. Physiol., 1975, 104, 27. K. Harashima, Internat. J. Biochem., 1970, 1, 5 2 3 .

158

Terpenoids and Steroids

Isoprenylated Carotenoids. The main carotenoid of the bacterium Arthrobacter glacialis has been identified” as the previously unknown monocyclic CSocarotenoid 2-(4-hydroxy-3-methylbut-2-enyl)-2’-(3-methylbut-2-enyl)-3’, 4’-didehydro-1’, 2’dihydro-&,$-caroten-1‘-01(12). The location of the hydroxy-groups was established unequivocally by use of the n.m.r. shift reagent [Eu(dpm),]. Triterpenoid Carotenoids. Two novel triterpenoid xanthophylls from Streptococcus faeciurn have been identified2’ as 4,4’-diapo-7’,8’-dihydro-$,$-caroten-4-a1 (16) carotenoids, p-citraurinene*’ and 4,4’-diapo-$,JI-caroten-4-a1(17). Two other {S’-apo-P-caroten-3-01 (1S)] and p -citrauro122[S’-apo-P-carotene-3,8’-diol (19)], both isolated from citrus fruits, are likely to be derived from Cd0 carotenoids. Spectroscopic data were presented for both compounds.

H c>

(18) R = M e (19) R=CHZOH

Degraded Curotenoids. Two papersz3 report the full characterization of a series of acid (20)] isolated from glycosyl esters of crocetin [8,8’-diapocarotene-8,8’-dioic Saffran naturalis. The compounds identified were the di-(P-D-gentiobiosy1)-ester (crocin), the mono-(p-D-gentiobiosyl)-mono-(P-D-glucosyl)-ester,the di-(P-Dglucosy1)-ester, the mono-(@-D-gentiobiosyl)-esterand the mono-(~-D-glucosyl)ester, Caulerpol (21), a new diterpenoid alcohol from the alga Caulerpa brownii, is related structurally to the vitamin A series.24The new acetylenic diol, 3-hydroxy7,8-didehydro-P-ionol (22), from Burley tobacco is considered to be a carotenoid degradation product.25

I

l9

2o 21

*2 23 24

25

N. Arpin, J.-L. Fiasson, S. Norgird, G. Borch, and S. Liaaen-Jensen, A c f a Chem. Scand., 1975, B29, 921. R. F. Taylor and B. H. Davies, Biochem. J., 1976, 153, 233. U. Leuenberger and I. Stewart, Phytochemistry, 1976, 15, 227. U. Leuenberger, I. Stewart, and R. W. King, J. O r g . Chem., 1976,41, 891. H. Pfander and F. Wittwer, Helv. Chim. Acta, 1975, 58, 1608, 2233. A. J. Blackman and R. J. Wells, Tetrahedron Letters, 1976, 2729. T. Fujimori, R. Kasuga, H. Kaneko, and M. Noguchi, Phytochemistry, 1975,14,2095.

159

Curotenoids and Polyterpenoids

Stereochemistry.-Geometrical Isomerism. Details of the synthesis and the spectroscopic and stereomutation properties of the all-trans- and 15-cis-isomers of phytoene [7,8,11,12,7’,8’,11’,12’-octahydro-$,$-carotene(23)] have been

(23)

published.26 13C N.m.r. data obtained for a series of synthetic isomers of a C20 analogue of phytoene2’ suggest that a phytoene isomer from Rhodospirillum rubrum may have the 13-cis,l5-truns,l3’-cis (Z,E,Z)configuration rather than 13-truns,l5trans, 1 3 ‘ 4 s (E,E,Z)originally proposed.28 Other studies, largely with 13Cn.m.r., have revealed that violeoxanthin is the 9-ci.s-isomer of violaxanthin [5,6,5’,6’diepoxy--5,6,5‘,6’-tetrahydro-@,P -carotene-3,3’-diol 24)]29 and that the neo -A isomers of zeaxanthin [p,p -carotene-3,3’-diol(25)] and capsorubin [3,3’-dihydroxyK,K -carotene-6,6’-dione (26)] have the 13-cis configuration, whereas their neo-B isomers are 9-~is.~O Absolute Configuration. Astaxanthin (3,3’-dihydroxy-P,P-carotene-4,4’-dione) isolated from Phufia rhodozyma has been shown31by c.d. and ‘H n.m.r. to have the

i3T

HO

HO”

(24) (25) (26) (27) 26 27

28 29

3O 31

w

p.. .

HO

C

H

0 d

R’ = R2 = a R 1 = R 2 = b (X=H, Y=OH) R‘=R~=c R’=R2=d

(28) R’ = R2= b (X=OH, Y = H ) (29) R’ = e, R2 = f (30) R ’ = b ( X = Y = H ) , R 2 = g

N. Khan, D. E. Loeber, T. P. Toube, and B. C . L. Weedon, J.C.S. Perkin I, 1975, 1457. L. Barlow and G. Pattenden, J.C.S. Perkin I, 1976, 1029. P. Granger, B. Maudinas, R. Herber, and J. Villoutreix, J. Magn. Resonance, 1973, 10, 43. G. P. Moss, J. Szabolcs, G. T6th, and B. C . L. Weedon, Acta Chim. Acad. Sci. Hung., 1975,87, 301. M. Baranyai, J. Szabolcs, G. Tbth, and L. Radics, Tetrahedron, 1976, 32, 867. A. G. Andrewes and M. P. Starr, Phytochemistry, 1976,15, 1009.

160

Terpenoids and Steroids

(3R,3‘R) configuration (27), i.e. opposite to that of astaxanthin from all other natural sources so far i n ~ e s t i g a t e d This . ~ ~ is the first example of the occurrence of a carotenoid in different optical forms. The p,P-carotene-2,3,3’-triol (6) and P,pcarotene-2,3,2’,3’-tetrol (7) from Anacystis nidulans have the (2R,3R) configuration (31). ‘H N.m.r. data proved the trans-diol structure, and the (2R,3R) chirality

(31)

then followed from c.d. studies.’ It is noteworthy that the configuration at C-2 in these compounds is opposite to that previously determined33 for P,p -carotene2,2’-diol (28). The p r o v i ~ i o n a l ~(5R,6S) ~ assignment for the 5,6-epoxide group ;f fucoxanthin [(3S,5R,6S,3‘S,5’R,6’R)-5,6-epoxy-3,3’,5’,-tri hydroxy-6’,7’didehydro-5,6,7,8,5’,6’-hexahydro-P,P-caroten-8-one 3’-acetate (29)] has been c~nfirmed.~’ The modified Horeau method has been used to show that aleuriaxanthin [ l’,16’-didehydro-1’,2’-dihydro-P,4-caroten-2’-01(30)] from the fungus Aleuria aurantia has the (2’R) c o n f i g ~ r a t i o n . ~ ~ In the Cso series, the absolute configuration of bacterioruberin [(2S,2’S)-2, 1,2,1’,2’-tetrahydro-+,$2’-bis- (3- hydroxy-3 -methylbutyl)-3,4,3’,4’-tetrahydrocarotene-1,l’-diol (32)] has been determined by synthesis of the derivative (2S,2’S)-tetra-anhydrobacterioruberin (33) from (-)-(R)-lavandulol (36).37 Samples of (33) obtained by synthesis and prepared from natural bacterioruberin or bisanhydrobacterioruberin [2,2’-bis-(3-methylbut-2-enyl)-3,4,3’,4‘-tetradehydro1,2,1‘,2’-tetrahydro-t,!~,$-carotene1,1’-diol(34)lhad the same c.d. properties. That c.d. data for carotenoids must be interpreted with caution was indicated by the fact that a direct comparison of the c.d. properties of (32) and (34) with those of a synthetic octahydro model (35) led to the erroneous opposite conclusion. In a similar

HoL... ”%.. L a

...

b

d

(32) R’ = a , R’= b (33) R’ = c, R2 = d 32 33 34

35 36 37

(34) R’ = c, R’ (35) R’ = e, R’

=b

=f

A , Veerman, G . Borch, R. Pedersen, and S. Liaaen-Jensen, Actu Chem. Scund., 1975, B29, 525. H. Kjosen, N. Arpin, and S. Liaaen-Jensen, Actu Chem. Scund., 1972,26, 3053. D. Goodfellow, G . P. Moss, J. Szabolcs, G . T6th, and B. C. L. Weedon, TetruhedronLetters, 1973,3925. K. Bernhard, G . P. Moss, G . Toth, and B. C. L. Weedon, Tetrahedron Letters, 1976, 115. R. Buchecker, N. Arpin, and S. Liaaen-Jensen, Phytochemistry, 1976, 15, 1013. J . E. Johansen and S. Liaaen-Jensen, Tetrahedron Letters, 1976, 955.

Carotenoids and Polyterpenoids

161

way the striking similarity between the c.d. curves of decaprenoxanthin [2,2’-bis-(4hydroxy-3-methyl-2-butenyl)-~,~ -carotene (37)] and the synthetic 2,6-truns model dimethyl-P,P -car0 tene (38) suggested the (2SY6R,2‘S,6’R ) configuration for (37). The ‘H n.m.r. spectrum of (37), however, favoured a 2,6-cis substitution pattern, and this, together with consideration of the fact that the chiral centre at C-2 does not contribute significantly to the c.d., led to the conclusion that decaprenoxanthin is in fact (2R,6R,2’R,6‘R) (39).38

Chemical reactions wiih TiC14 and the sulphurane (40), leading to the production of 5,6- and 5,8-epoxidesYhave allowed the assignment of the (5R,6R) configuration to azafrin [5,6-dihydroxy-5,6-dihydro-l0’-apo-~-caroten10’-oic acid (4 l)].” Ph

O-C(CF3)zPh

\s/ Ph/

\0-C(CF3),Ph (40)

Synthesis and Reactions.-Curofenoids. A synthetic route via polyene sulphones has been used to prepare the apo-carotenoids 8’-apo-P-caroten-8’-al(42) and ethyl 8’-apo-P-caroten-8‘-oate (43) and also torularhodin ethyl ester [ethyl 3’,4’didehydro-P,$-caroten- 16’-oate (44)] (Scheme 1) and P-carotene [P,P-carotene (45)] (Scheme 2).40 38

39 4O

A. G. Andrewes, S. Liaaen-Jensen, and 0. B. Weeks, Actu Chem. Scand.,1975,B29,884. W. Eschenmoser and C. H. Eugster, Helu. Chim. Actu, 1975,58,1722. A. Fischli and H. Mayer, Helu. Chim. Acta, 1975,58,1492,1584.

162

Terpenoids and Steroids

(42) R=CHO (43) R=CO,Et

(42)

iii. iv. i

,

1

ii

(R= C02Et)

Reagents: i, NaS02PhOPh; ii, BrCHzCH=C(Me)CH=CHCH=C(Me)R NaBH4; iv, Ac20-py.

Scheme 1

1

Scheme 2

(R = CHO or C02Et); iii,

Carotenoids and Polyterpenoids

163

Several other carotenoids have been synthesized by standard routes involving condensation of Wittig salts with the Cloand CZ0dials (46) and (47). Thus the Wittig salts (48), (49), and (50) were used to prepare the acyclic 1,2-dihydrocarotenes

$CHzi.ph,

Br-

\

u

C

H

,

h

P

h

, Br-

(49)

(48) Br

-CH,bPh,

(50)

1,2,7,8,1’,2’,7’,8’-octahydro-$,$-carotene(5 l), 1,2,7,8-tetrahydro-@,$-carotene (52), 1,2,1’,2’-tetrahydro-$,$-carotene (53), 1,2-dihydro-$,$-carotene (54), 3,4,3’,4‘-tetradehydro-l,2,1’,2’-tetrahydro-$,$-carotene ( 5 5 ) , and 3,4-didehydro1,2-dihydro-$,$-carotene (56),41 and P,P-carotene-2,2’-diol (28) has been pre-

a

b

C

d

(51) R 1 = R 2 = a (52) R’= a , R2 = b (53) R’ = R~= C

(54) R’ = c, R2 = b (55) R ’ = R 2 = d (56) R 1 = d , R 2 = b

pared from (46) and the Wittig salt (57).42Wittig salts obtained from the optically active irones (58) and (59) were in the synthesis of the model compounds (2R,6R,2’R,6’R)-2,2’-dimethyl-~,~-carotene (60) and (2R,SS,2’R,6’S)-2,2’dimethyl-&,€-carotene (61). Optically inactive tetra-anhydrobacterioruberin (33) was synthesized from racemic lavandulol via the Wittig salt (62). Use of optically active (-)-(R)-lavandulol (36) gave the chiral (2S,2’S)-tetra-anhydroba~terioruberin.~~ The model octa-anhydrobacterioruberin (35) was also prepared. In several syntheses of the 2,2’-dinor-~arotenoidsactinioerythrol [3,3’-dihydroxy2,2’-dinor-P,P-carotene-4,4’-dione (63)] and violerythrin [2,2’-dinor-P,P-carotene3,4,3’,4’-tetrone (64)], the cyclopentenone ring system was built up from acetylene and acetone and the carotenoids were then produced by the Wittig or sulphone 41 42 43

A. Eidem, R. Buchecker, H. Kjosen, and S. Liaaen-Jensen, Actu Chem. Scund., 1975,B29, 1015. K.Tsukida, K. Saiki, M. Ito, I. Tomofuji, and M. Ogawa, J. Nutr. Sci. Vituminol., 1975,21,147. A. G. Andrewes, G. Borch, and S. Liaaen-Jensen, Actu Chem. Scund., 1976,B30,214.

Terpenoidsand Steroids

164

(58) R’ = CH=CHCOMe, R2 = H (59) R’ = H, R2 = CH=CHCOMe

(62)

methods.44 Dehydroflexixanthin [3,1’-dihydroxy-2,3,3’,4’-tetradehydro-l’,2’dihydro-P,$-caroten-4-one (65)] and deoxyflexixanthin [ 1’-hydroxy-3‘,4’didehydro- 1’,2’-dihydro-&!~-caroten-4-one (66)] have been prepared by condensation of the Wittig salt (73) with the C30aldehydes (67) and (68) re~pectively.~’ In addition to phytoene (23), prepared as a mixture of the all-trans- and 1 5 4 s isomers by Wittig condensation, several model compounds with a similar triene chromophore have been produced.26 A range of poly-cis (poly-2) isomers of the Czo phytoene analogue has been ~ y n t h e s i z e d . ~ ~ Autoxidation of 4-0x0-carotenoids in the presence of potassium t-butoxide gives the corresponding diosphenols (3,4-didehydro-3-hydroxy-4-ones). These on reduction with KBH, gave the 3,4-dihydroxy-compounds which, on carefully controlled oxidation, yield the 3-hydroxy-4-ones (Scheme 3). Astaxanthin (27; racemic), phoenicoxanthin [3-hydroxy-@,@-carotene-4,4‘-dione (69)], and hydroxyechinenone [3-hydroxy-@,@-caroten-4-one (70)] have been prepared in this way from canthaxanthin [P,P-carotene-4,4’-dione (71)] and echinenone [P,P-caroten-4one (72)] and their 15,15’-acetylenic analogue^.^^ The in situ acylation of nucleophiles generated cathodically from canthaxan thin provided a novel and convenient route to the retro-diacetate (74) and the corresponding retro-monoacetate. On hydrolysis these gave the 5 3 ’ - and 7,7’-dihydro-derivativesof canthaxanthin, (75) and (76).47 The efficient hydroxylation of @-carotene to isocryptoxanthin [P,P44

45 46

47

F. Kienzle and R. E. Minder, Helv. Chim. Acta, 1976, 59, 439. R. E. Coman and B. C. L. Weedon, J.C.S. Perkin I, 1975, 2529. R. D. G. Cooper, J . B. Davis, A. P. Leftwick, C. Price, andB. C. L. Weedon, J.C.S. Perkin I, 1975,2195. E. A. H. Hall, G . P. Moss, J. H. P. Utley, and B. C. L. Weedon, J.C.S. Chem. Comrn., 1976, 586.

165

Carotenoids and Polyterpenoids

e (63) (64) (65) (66) (67)

R1=R2=a R1=R2=b R' = c, R2 = d R ' = e (X=H), R 2 = d R' = e (X = H), R2 = CHO

@. 0

HO

(68) (69) (70) (71) (72)

R' = c, R2 = CHO R 1 = e (X=OH), R 2 = e ( X = H ) R' = e $X= OH), R2 = f R'=R = e ( X = H ) R' = e (X = H), R2 = f

0% HO

0

OH

Reagents: i, KOBU'; ii, KBH4; iii, A1OBut-Me2CO benzoquinone.

HO 0

or M n 0 2 or 2,3-dichloro-5,6-dicyano-p

Scheme 3

caroten-4-01 (77)] on the chromatographic adsorbent Microcell C has been

A technical synthesis of (4R,6R )-4- hydroxy - 2,2,6- trime thy lcyclo hexanone (85) starting from the readily available 0x0-isophorone (86) has been described. (85) is an ideal precursor for the synthesis of optically active hydroxylated carotenoids (e.g. zeaxanthin). Chirality was introduced at C-6 (C-3, carotene numbering) by a stereoselective reduction of the double bond by baker's yeast.49 The reaction of xanthophylls such as zeaxanthin (25)' isozeaxanthin [&pcarotene-4,4'-diol ( 7 8 ) ] ,and lutein [&e-carotene-3,3'-diol (79)] with CHC1,-HCl 48

A9

D. B. Rodriguez, Y. Tanaka, T. Katayama, K. L. Simpson, T.-C. Lee, and C. 0. Chichester, J. Agric. Food Chem., 1976,24,819. H. G . W. Leuenberger, W. Boguth, E. Widmer, and R. Zeli, Helu. Chim. A d a , 1976,59,1832.

Terpenoids and Steroids

166

has led to the isolation of the chlorinated carotenoids (80)--(83)."' O,P-Caroten-201 (84) does not undergo dehydration by CHC1,-HCl, but treatment with 0.1MBF3,Et20 gave a product for which the retro structure (87) was proposed.'l Treatment of the Csocarotenoid (12) with KOMe-MeOH-DMSOs2 resulted not in E - to O-ring isomerization but in an elimination reaction to give (88).19 Details of the

I

a

X

b

C

(77) R' = a iX= OH, Y = Z = H), R2 = a (X = Y = Z = H) (78) R ' = R = a ( X = O H , Y = Z = H ) (79) R ' = a ( X = Z - H , Y = O H ) , R 2 = b (80) R ' = a (X=C1, Y = Z = H ) , R 2 = a ( X = Y = Z = H ) (81) R ' = a $ X = C l , Y = Z = H ) , R 2 = c (82) R ' = R = a ( X = C l , Y = Z = H ) (83) R 1 = a ( X = Z = H , Y=C1), R 2 = a ( X = Z = H , Y = O H ) (84) R ' = a ( X = Y = H , Z = O H ) , R 2 = a ( X = Y = Z = H )

51 52

H. Pfander and U. Leuenberger, Chimia ( S w i f t . ) ,1976,30, 71. H. Kayser, Tetrahedron Letters, 1975, 3743; 2. Naturforsch., 1976, 31c, 121. A. G. Andrewes, Actu Chem. Scand., 1974, B28, 137.

167

Carotenoids and Polyterpenoids

chemical reactions of peridinin (15) have been published. l 2 * I 3 Treatment of azafrin methyl ester (89) with TiCl, gave the furanoid oxide (90), whereas the 5,6-epoxide (91) was furnished by reaction with the sulphurane (40).39 Reaction of azafrinaldehyde (92) with [(Ph,P),RhCl] led to a mixture of (93) and (94), the latter arising probably through elimination of acetylene, and r e ~ a r b o n y l a t i o n Under . ~ ~ standard conditions (89) forms only a monomethyl ether. The site of methylation has been proved to be the C-5 h y d r o ~ y - g r o u p . ~ ~

a (89) R' = a, R2 = CH=CHC02Me (90) R' = c, R2 = CH=CHC02Me (91) R' = b, R2 = CH=CHC02Me

b

C

(92) R' (93) R' (94) R'

= a, = a, = a,

R2 = CH=CHCHO R2 = CH=CH2 R2 = CHO

Retinol Derivatives. The sulphone method forms the basis of three new synthetic routes to vitamin A (retinol; 95), involving condensation of the p -ionylidene-ethyl (C,,) phenyl sulphone (96) with the epoxide (97)", or the chloride (98)55 or condensation of the 0-ionyl phenyl sulphone (99) with the allylic chloride Conditions have been developed under which the elimination of the sulphone group from the reaction intermediate (101) occurs e f i ~ i e n t l y . ~In' another stereospecific

wcH

(96) R = Ph, variously substituted

53 54

55

56

U. Vogeli, W. Eschenrnoser, and C . H. Eugster, Helv. Chim. Acta, 1975, 58, 2044. M. Julia and D. Uguen, Bull. SOC. chim. France, 1976, 513. P. S. Manchand, M. Rosenberger, G. Saucy, P. A. Wehrli, H. Wong, L. Chambers, M. P. Ferro, and W. Jackson, Helv. Chim. Acta, 1976,59, 387. A. Fischli, H. Mayer, W. Simon, and H.-J. Stoller, Helv. Chim. Acta, 1976, 59, 397.

Terpenoids and Steroids

168

synthesis of retinol from 2,2,6-trimethylcyclohexanone(102) the key step is the transformation of the intermediate (103) to the unsaturated ketone (104) by a novel vanadium@)-catalysed rea~rangement.’~ Retinol has also been synthesized by a scheme involving condensation of P-ionylideneacetaldehyde dimethylacetal (105) with 3-methyl- 1-trimethylsiloxybuta-1 ,3-diene.58

(102)

(103)

Other compounds, related to retinol, which have been prepared by standard methods include the allenic isomer (106) (all-trans-, 9-cis-, 13-cis-, and 9,13-di-cisforms obtained),” the all-trans- and various cis-isomers of 11,12-didehydro-15demethyl-P-axerophtene ( 107),60 and 14-methylretina! (108), 15-methylretinal (109), and 13-demethyl-14-methylretinal (1

1

H

(108) R’= R2 =Me, R’ = H (109) R’= R’ =Me, R2 = H (110) R 1 = R 3 = H , R 2 = M e

Other Degraded Curotenoids. The chemistry of abscisic acid (111) has been reviewed.h2 In a stereoselective synthesis of (1 1l), 2-cis-3-methylpent-2-en-4-yl-101 (112) was used to introduce the 2-cis,4-trans geometry (abscisic acid 57

58

59

60

h1

62

G. L. Olson, H.-C. Cheung, K. D. Morgan, R. Borer, andG. Saucy, Helv. Chim. Actu, 1976,59,567. T. Mukaiyama and A. Ishida, Chem. Letters, 1975, 1201. K. Nakanishi, A. P. Yudd, R. K. Crouch, G . L. Olson, H.-C. Cheung, R. Govindjee, T. G. Ebrey, and D. J . Patel, J. Amer. Chem. SOC.,1976, 98, 236. V. Ramamurthy and R. S. H. Liu, J. Org. Chem., 1975, 40, 3460. T. Ebrey, R. Govindjee, B. Honig, E. Pollock, W. Chan, R. Crouch, A. Yudd, and K. Nakanishi, Biochemistry, 1975, 14, 3933. T. Oritani and K. Yamashita, Kugaku To Seibutsu, 1975, 13,351 (Chem. A h . , 1976, 84, 17 560).

169

Carotenoids and Polyterpenoids

n ~ m b e r i n g ) The . ~ ~ preparations of the j3-D-glUCOpyranOSyl ester64and of the diethylarnin~ethylamide~' of (111) have been described. Alkaline methanolic conditions can lead to the isolation of the methyl ester of (111) as an artefact.66 Syntheses have been reported for several other natural products related structurally to carotenoids, uiz. (*)-carrapi oxide (113) and its 8 - e ~ i m e r ,8-damascone ~~ (114) and pdamascenone (1 15),68deoxytrisporone (116),69dihydroactiniolide (1 17),70edulans I and 11 (118) and (119),7'and strigol (120).72 Optically active (+)-(S)-6-hydroxy-a-

v rii-qo \0

Ho

(120)

Ho

(120)

1

cyclocitral (12 l), prepared by hydrolysis of the oxazolidine derivative (122), has been used to synthesize (+)-(S)-dehydrovomifoliol (123).73 a-and j3-Ionones, (124) and (125), have been prepared from cyclocitral phenyl sulphides and ~ u l p h o n e s . ~ ~ 63 64

65

66

67 68

69 70 71

72 73 74

H. J. Mayer, N. Rigassi, U. Schwieter, and B. C. L. Weedon, Helv. Chim. Acta, 1976, 59, 1424. H. Lehmann, 0. Miersch, and H. R. Schiitte, Z. Chem., 1975,15,443. J. Sadet, P. Rumpf, and C. Gausser, European J. Med. Chem.-Chim. Ther., 1975,10, 91. B. V. Milborrow and R. Mallaby, J. Expt. Bot., 1975, 26, 741. R. C. Cookson and P. Lombardi, Gazzetta, 1975, 105, 621. K. S. Ayyar, R. C. Cookson, and D. A. Kagi, J.C.S. Perkin Z, 1975, 1727. K. Uneyama and S. Torii, Tetrahedron Letters, 1976, 443. S. Kurata, T. Kusumi, Y. Inouye, and H. Kakisawa, J.C.S. Perkin I, 1976, 532. D. R. Adams, S. P. Bhatnagar, and R. C. Cookson, J.C.S. Perkin I, 1975, 1736. J. B. Heather, R. S. D. Mittal,. and C. J. Sih, J. Amer. Chem. SOC., 1976,98, 3661. M. Shibasaki, S. Terashima, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1976,24, 315. S. Torii, K. Uneyama, and M. Isihara, Chem. Letters, 1975, 479.

170

Terpenoids and Steroids

Several of the products of acid-catalysed (as. HC0,H) rearrangement of P ionone epoxide (126)75 and 5-0x0-cu-ionone (127)76have been identified. Compound (127) was obtained by oxidation of LY -ionone (124) with t-butyl Selective asymmetric reduction of the carbonyl group of P-ionone has been achieved with dihydrosilane-chiral rhodium(1) complex Some derivatives of 2methyl-4-(2,2,6-trimethylcyclohexyl)butane-1-carboxylic acid (128) have been pre~ pared from hydrogenated P - i ~ n o n e .The ~ ~ photolysis of ( E ) - P - i ~ n o n e , ’ isomethyl-(E)-P-ionone epoxide (129),80and (E)-P-ionylidene epoxide ( 130)81have been investigated, and sigmatropic hydrogen migration and electrocyclization processes brought about by direct irradiation of a number of ionone and ionylidene derivatives have been described.82The different photochemical behaviour of dienes, trienes, and higher polyenes in the ionone, ionylidene, and vitamin A series has been

Physical Methods and Physical Chemistry.-Electronic absorption, ‘H n.m.r., and m.s. data for many carotenoids are presented in the papers discussed in earlier sections of this Report. As in previous years, this section will concentrate mainly on those papers that are devoted to systematic studies involving physical techniques, or 75

76 77 78

79

81

82 83

K. L. Stevens, R. Lundin, and D. L. Davis, Tetrahedron, 1975,31, 2749. D. L. Davis, K . L. Stevens, and L. Jurd, Agric. Food Chem., 1976,24, 187. I. Ojima, T. Kogure, and Y. Nagai, Chem. Letters, 1975, 985. T. Zawisza, Acta Polon. Phurm., 1975, 32, 15. A. van Wageningen, H. Cerfontain, and J. A. J. Geenevasen, J.C.S. Perkin ZZ, 1975, 1283. B. R. von Wartburg, H. R. Wolf, and 0.Jeger, Helv. Chim. Actu, 1976, 59, 727. A. P. Alder, H. R. Wolf, and 0. Jeger, Helv. Chim. Actu, 1976,59, 907. V. Ramamurthy and R. S. H. Liu, J. Org. Chem., 1976,41, 1862. V. Ramamurthy and R. S . H. Liu, J. Amer. Chem. SOC., 1976,98, 2935.

Carotenoids and Polyterpenoids

171

in which techniques such as 13Cn.m.r. or c.d., which are not in routine use, have been employed. Particularly useful is the review by Moss and Weedon,la which includes extensive tabulationof i.r., ‘Hn.m.r., l3Cn.m.r.,rn.s.,ando.r.d. datafor awiderange of carotenoids. Separation and Assay Methods. In his general review of carotenoid analytical methods, Davieslf gives a comprehensive survey of separation techniques. A warning has been given that chromatography on Microcell C can result in efficient hydroxylation of some c a r o t e n o i d ~ .A~ ~review of methods for the separation of photosynthetic pigments, including carotenoids, has been published.84 A gelchromatographic separation of retinol, retinyl esters, and other fat-soluble vitamins has been de~cribed.’~ H.p.1.c. procedures have been developed for the separation and and analysis of retinal isomers,“ for the determination of phytoene in for analysis of abscisic acid in plant extracts.88 A spectrophotometric method for the simultaneous deteimination of a - and ,&carotenes in mixtures89 and an improved colorimetric procedure for the analysis of vitamin A have been reported.”

Mass Spectrometry. A review” on biochemical applications of mass spectrometry deals largely with carotenoids. Field-desorption m.s. of carotenoids gives the molecular ion as the base peak, with very few fragment ions. Eighteen carotenoids were examined by this technique.92 A fragment ion at M - 68 on electron impact seems to be characteristic for acyclic carotenoids with a 1,2,7,8-tetrahydro endgroup.4’ 13 C N.M.R. Spectroscopy. Two papers have presented a large amount of tabulated information from the I3C n.m.r. spectra of carotenoids and related compounds. Englert93 gives data for P-carotene (45), &-carotene [&,&-carotene (131)], isozeaxanthin (78), zeaxanthin (25), canthaxanthin (71), astaxanthin (27; configuration not stated), astacene [3,3'-dihydroxy - 2,3,2’, 3’-te trade hydro-P,P -car0tene-4,4’dione (132)], and phoenicoxanthin (69) and some of their derivatives, a number of synthetic allenic carotenoids and apo-carotenoids, and a wide range of cis- and trans-isomers of retinol and related compounds. Detailed lanthanide-induced shift data are also presented. The general review by Moss and Weedon’= includes tabulated 13Cn.m.r. data for P-carotene, isozeaxanthin, zeaxanthin, canthaxanthin, lutein (79), violaxanthin (24), fucoxanthin (29), phytoene (23; 15,15’-cis), alloxanthin [7,8,7’,8’-tetradehydro-P,P-carotene-3,3’-diol (13 3)], isomytiloxanthin [6,3’dihydroxy-7’,8’-didehydro-5,6-dihydro-P,~-carotene-3,8-dione (134)], methyl bixin [dimethyl-6,6’-diapocarotene-6,6’-dioate, (1331, and crocetindial(47). Other , ~ ~ and cis-isomers of zeaxanpapers report 13Cn.m.r. data for v i ~ l e o x a n t h i ntrans-

84 85

86

88 89

90 91

92 93

Z. Sestak, J. Chromatog. Libr., 1975, 3, 1039. M. Holasov6 and J. Blattn6, J. Chromatog., 1976,123, 225. J. P. Rotmans and A. Kropf, Vision Res., 1975, 15, 1301. C. V. Puglisi and J. A . F. D e Silva, J. Chromatog., 1976, 120, 457. P. B. Sweetser and A. Vatvars, Analyt. Biochem., 1976,71, 68. C. AndrC and A. Vercruysse, Acta Botan. Need., 1975, 24, 225. J. A. Blake and J. J. Moran, Canad. J. Chem., 1976,54, 1757. H. Budzikiewicz, Adv. Mass Spectrometry, 1974,6, 163. C. D. Watts, J. R. Maxwell, D . E. Games, and M. Rossiter, Org. Mass Spectrometry, 1975, 10, 1102. G. Englert, Helv. Chim. Acta, 1975, 58, 2367.

Terpenoids and Steroids

172

b

(131) R' (132) R' (133) R'

= R2 = a = R2 = b = R2 = c

(134) R ' = d , R 2 = c (135) R' = R2 = CH=CHC02Me

thin and capsorubin (26),") the 5- O-monomethyl ether of azafrin methyl ester (89),53 and some synthetic poly-2-isomers of the C20analogue of p h y t ~ e n e . ~ ~ The I3C n.m.r. spectra of some retinal derivatives as visual pigment models have also been ~ e p o r t e d . ~ ~ . ~ '

Optical Rotatory Dispersion and Circular Dichroism. 0.r.d. data for several carotenoids have been tabulated.'" C.d. data have been recorded for astaxanthin (27; 3R and 3S),31P,P-carotene-2,3,3'-triol (6) and P,@-carotene-2,3,2',3'-tetrol (7),7 decaprenoxanthin (37),38 the synthetic 2,2-dimethyl-~,~ -carotenes (60) and (61),43and the novel monocyclic C50carotenoid (l2).I9 In the last case only very rough agreement was obtained between the observed spectrum and that calculated on the basis of the additivity h y p o t h e ~ i s . ~ ~ Electronic Absorption Spectroscopy. Extensive tables of light absorption maxima and extinction coefficients for naturally occurring carotenoids are included in the review by Davies." Miscellaneous Physical Chemistry. Various aspects of the physical chemistry of P -carotene and related carotenoids have been reported, including several theoretical calculations related to spectroscopic p r ~ p e r t i e s , ~ investigations '-~~~ of carotenoid triplet stateslo1 and triplet energies,lo2 studies of carotenoid radical ions,'03 and examination of electron-transfer reactions between carotenoids and chlorophyll a.lo4 Two reviews offer brief surveys of the year's literature on the photochemistry of 94

Y.Tokito, Y. Inoue, R. Chujo, and Y. Miyoshi, Organic Magn. Resonance, 1975,7, 485.

y6

J. Shriver, E. W. Abrahamson, and G. D. Mateescu, J. Amer. Chem. SOC.,1976, 98, 2407. L. Bartlett, W. Klyne, W. P. Mose, P. M. Scopes, G. Galasko, A. K . Mallams, B. C. L. Weedon, J.

y7

V. R. Salares, R. Mendelsohn, P. R. Carey, and H. J. Bernstein, J. Phys. Chem., 1976,80, 1137.

95

Szabolcs, and G. T6th, J. Chem. Soc. ( C ) ,1969, 1527. y8

9y

loo

lo3

F. Inagaki, M. Tasumi, and T. Miyazawa, J. Raman Spectroscopy, 1975,3, 335. B. Mallik, K. M. Jain, K. Mandal, and T. N. Misra, Indian J. Pure A p p l . Phys., 1975, 13, 699. M. A. Al'perovich and I. I. Zil'berman, Ukrain. khim. Zhur., 1975, 41, 1182 (Chem. Abs., 1976, 84, 165 067). R. Bensasson, E. J. Land, and B. Maudinas, Photochem. and Photobiol., 1976,23, 189. W. G. Herkstroeter, J. Amer. Chem. SOC.,1975, 97, 4161. E. A. Dawe and E. J. Land, J.C.S. Furaduy I, 1975,71, 2162. J. Lafferty, E. J. Land, and T. G. Truscott, J.C.S. Chem. Comm., 1976, 70.

Carotenoids and Polyterpenoids

173

p01yenes'~~ and on excited states of biomo1ecules,'06both including carotenoids and related compounds.

Retinal as Visual Pigment Model: Spectroscopy and Physical Chemistry. As in previous years, several theoretical, spectroscopic, and photochemical studies of retinal (136) and related compounds, especially Schiff's bases, have been repOrted,59,61,94,95,107-125 and in many cases the main aim was to obtain information relevant to the functioning of rhodopsin and related visual pigments. Particularly valuable are surveys of the year's literature on the photochemistry of p o l y e n e ~ , ' ~ ~ excited states of biomo1ecules,106and recent developments in the molecular biology of vision.126

3 Polyterpenoids and Quinones Po1yterpenoids.-Needles of Juniperus communis contain a range of polyprenols up to ca. Cll0, a major component being the Cg5alcohol (137).'*' The series of syntheses of polyisoprenyl sugar phosphates has been extended to dolichyl p-Dmannopyranosyl phosphate (138).12' A simple procedure for the preparation of

(137) 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121

122 123

124

125 126 127 128

(138) X = p -D-mannopyranosyl phosphate

E. J. Land, Photochem. and Photobiol., 1975, 22, 286. P.-S. Song and R. D. Fugate, Photochem. and Photobiol., 1975,22, 277. R . R. Birge, M. J. Sullivan, and B. E. Kohler, 1 Amer. Chem. SOC.,1976, 98, 358. P.-S. Song, Q. Chae, M. Fujita, and H. Baba, J. Amer. Chem. SOC, 1976,98, 819. R. E. Cookingham, A. Lewis, D. W. Collins, andM. A. Marcus, J. Amer. Chem. SOC.,1976,98,2759. E. L. Menger and D. S. Kliger, J. Amer. Chem. SOC.,1976,98, 3975. W H. Waddell, R. Crouch, K. Nakanishi, and N. J. Turro, J. Amer. Chem. SOC., 1976,98,4189. R. S. Knox and V. J. Ghosh, Photochem. and Photobiol., 1975, 22, 149. P. E. Blatz, L. Lane, and J. C. Aumiller, Photochem. and Photobiof., 1975, 22, 261. S. Hotchandani and R. M. Leblanc, Photochem. and Photobiol., 1976,24, 59. R. H. Callender, A. Doukas, R. Crouch, and K. Nakanishi, Biochemistry, 1976,15, 1621. R. Crouch, V. Purvin, K. Nakanishi, and T. Ebrey, Proc. Nat. Acad. Sci. U.S.A., 1975,72, 1538. R. Mathies and L. Stryer, Proc. Nut. Acad. Sci. U.S.A., 1976,73, 2169. A. D. Greenberg, B. Honig, andT. G. Ebrey, Nature, 1975, 257, 823. L. Salem and P. Bruckmann, Nature, 1975,258, 526. S. Georghiou, Nature, 1976,259.423. M. R. Fransen, W. C. M. M. Luyten, J. van Thuijl, J. Lugtenburg, P. A. A. Jansen, P. J. G. M. van Breugel, and F. J. M. Daemen, Nature, 1976,260, 726. J. H. Parkes, J. H. Rockey, and P. A. Liebman, Biochim. Biophys. Acta, 1976,428, 1. L. J. Weimann, G. M. Maggiora, and P. E. Blatz, Znternat. J. Quanturn Chem., Quantum Biol. Symp., 1975,2, 9. Pham Van Huong, R. Cavagnat, and F. Cruege, Lasers in Physical Chemistry and Biophysics, Proceedings of the 27th International Meeting of the Socittt de Chimie Physique, 1975, 425. A. L. Capparelli and 0. M. Sorarrain, 2.phys. Chem. (Leipzig), 1975,256,497. H. Shichi, Photochem. and Photobiol., 1975,21, 457. W. Sasak, T. Mankowski, T. Chojnacki, and W. M. Daniewski, F.E.B.S. Letters, 1976,64, 55. C. D. Warren, I. Y. Liu, A. Herscovics, and R. W. Jeanloz, J. Biof. Chem., 1975, 250, 8069.

Terpenoids and Steroids

174

tritiated polyprenols has been described.129 An h.p.1.c. method for the separation of polyprenols has been developed,13’ and hydroxyalkoxypropyl Sephadex has been used to separate individual polyprenols from naturally occurring mixtures. 13’ Quinones.-Four menaquinone (13 9) homologues from Sarcina lutea have been identified’32as dihydromenaquinones-6, -7, -8, and -9. A novel quinone from bulbs and leaves of Iris is thought to be related to plastoquinone-9 (140) but to have a modified ring methylation pattern.133 N o chemical data were reported. The distribution of ubiquinone (14 1) homologues in a number of Gram-negative bacteria has been surveyed.134 The biosynthesis of menaquinones and related quinones has been reviewed. 135 The molecular structure and electronic properties of ubiquinone have been studied by semi-empirical molecular orbital

%;:?opy-q; (139)

(140)

(141)

0 BF:sf&L

A novel approach to the problem of effecting regiospecific quinone-isoprene coupling has been r e p ~ r t e d ’ ’(Scheme ~ 4). Addition of the allylic bromide (142) to the masked quinone (143) gave the epimeric masked quinol(l44). Cope rearrangement of the latter, followed by oxidation gave 2-isopentenyl-p-benzoquinone(145). TMSO CN

+

(142)

0 (143)

\

HO (144)

0

(145)

Rcagents: i, Mg-NH4CI aq.; ii, NaF aq.

Scheme 4 R. W. Keenan and M. Kruczek, Aqalyt. Biochem., 1975,69, 504. P. L. Donnahey and F. W. Hemming, Biochem. SOC. Trans., 1975,3, 775. 13l T. Chojnacki, W. Jankowski, T. Mankowski, and W. Sasak, Analyt. Biochem., 1975,69, 114. 1 3 2 G. H. Dialameh, Internat. J. Vit. Nutr, Re$., 1976, 46, 105. 133 C. Etman-Gervais, Compt. rend., 1976, 282, D, 1171. 13‘ F. A. Denis, P. A. D’Oultremont, J . J . Debacq, J . M. Cherel, and J . Brisou, Compt. rend. SOC.biol., 1975, 169, 380. R. Bentley, Pure Appl. Chem., 1975, 41,47. 1 3 h D. L. Breen, J. Theor. B i d . , 1975, 53, 101. 1 3 7 D. A. Evans and J. M. Hoffman, J. Amer. Chem. SOC.,1976,98, 1983.

175

Carotenoids and Polyterpenoids

The method could be applied to the synthesis of many natural benzo- and naphthoquinones. The masked quinone (146), which may serve as a general precursor to the menaquinones, was prepared and isoprenylated by a similar series of reactions.

aoM TMSO CN

Me

0

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

1 Introduction This Report follows the pattern of previous years, leaving aside aspects of steroidal metabolism that are of clinical interest and the microbiological modification of terpenoids and steroids. It is our impression that this has not been a vintage year for the study of isoprenoid biosynthesis and that the pace of significant discovery is slowing down. A few reports have appeared concerning the difficult problems associated with the development of cell-free systems and tissue cultures from higher plants that can sustain terpenoid biosynthesis. Such systems could well assume paramount importance for studies involving 13C-labelling techniques, in the search for factors that control the biosynthesis of secondary metabolites and as source material for the purification of enzymes associated with terpenoid metabolism. The outstanding work of the year has, in our opinion, been the ingenious stereochemical studies carried out at Zurich on the biosynthesis of sesquiterpenoids. ’ ~ on the General reviews have appeared on aspects of terpenoid b i o s y n t h e ~ i sand use of biogenetic arguments in the elucidation of the structure of naturally occurring

2 Acyclic Precursors Differences in incorporation of radioactivity from the C-1 and C-2 carbons of propionate into cholesterol and bile acids by biliary fistula rats have been d e m o n ~ t r a t e d .It~ appears that incorporation of propionate via HC03- is not the major pathway. Feeding experiments with sodium [ 14C]bicarbonate produced no labelled cholesterol or bile acids. There has been continued interest in the formation of 3-hydroxy-3methylglutaryl-CoA [HMG-CoA, (2)] and the reduction of this to mevalonate (MVA), a step that is essentially irreversible and rate-limiting in terpenoid

2

3

4 5

6

R. B. Boar and D. A. Widdowson, Ann. Reports (B),1974,71,455. 0.Cori, E. Cardemil, L. Chayet, A. Jabalquinto, R. Vicuna, and R. Deves, Cienc. Invest., 1974,30,95. J. R. Hanson, in ‘Biosynthesis’, ed. T. A. Geissman (Specialist Periodical Reports), The Chemical Society, London, 1975, Vol. 3, p. 1. M. Gleizes, A n n i e Biol., 1976, 15, 101. A.J. Birch, in ‘Some Recent Developments in the Chemistry of Natural Products’, ed. S. Rangaswame and N. V. Subba Rao, Prentice-Hall, New Delhi, 1972, p. 6. S. Dev, ref. 5, p. 308. R. A. Davis, J. P. Showalter, and F. Kern, Steroids, 1975, 26,408.

176

177

Biosynthesis of Terpenoids and Steroids

biosynthesis. On carrying out the condensation of acetoacetyl-CoA with acety1-Senzyme at -25 "C in 25% ethanol the novel protein-bound intermediate (1) accumulated.' Purified HMG-CoA synthetase was found to carry out both a rapid transacetylation from acetyl-CoA to 3'-dephospho-CoA and a slow hydrolysis of the for me^.^ It appears that an acetyl-enzyme intermediate is involved in these minor reactions as well as in the overall condensation. The ability of the acetylated enzyme, upon addition of acetoacetyl-CoA, to yield (2) indicated that the acetylated residue was at the active site. Cysteine was the receptor for this group. SCoA

(21

A review on the regulation of HMG-CoA reductase has appeared" and the enzyme from rat liver has been purified 1000-fold with respect to the original microsome preparation: '' the latter study involved novel solubilization procedures for the particulate enzyme and yielded a protein with subunits of molecular weight 47 000 dalton. In contrast, others'* have reported the solubilized enzyme to be a dimer of units of 120 000 dalton and to contain bonded cholesterol (five moles per subunit). A previous finding that oleic acid stimulated secretion of cholesterol in isolated perfused rat liver has been rationalized by the finding that levels of HMG-CoA reductase were increased by this additive. l 3 Injection of triglyceride, carried in inert lipoprotein or an artificial fat emulsion, into rat liver led to an increase in the activity of HMG-CoA reductase but this was not reflected in an increase in the rate of cholesterologenesis. This uncoupling was believed to result from the detergent effect caused by the unphysiological levels of the carrier.I4 With isolated rat hepatocytes the presence of serum in the medium resulted in a seven-fold increase in HMG-CoA reductase activity. Addition of high-density lipoproteins and lecithin dispersion also increased reductase activity, and the latter also produced an increase in the rate of efflux of cell cholesterol to the medium;15on the other hand, low-density lipoprotein and cholesterol-lecithin dispersions inhibited the reductase, and it was concluded that in normal rat hepatocytes the relative rates of efflux and influx of cholesterol may play a fundamental role in the regulation of HMG-CoA reductase activity and formation of cholesterol. The administration of adenosine compounds to starved rats led to an increase in the activity of microsomal HMG8

9 10

11

12

13 14 15

H. M. Miziorko, D. Shortle, and M. D. Lane, Biochem. Biophys. Res. Comm., 1976,69,92. H. M. Miziorko, K. D . Clinkenbeard, W. D. Reed, and M. D. Lane, J. Biol. Chem., 1975,250,5768. V. W. Rodwell, J. L. Nordstrom, and J. J. Mitschelen, Adv. Lipid Res., 1976,14, 2 . C. D. Toemanen, W. L. Read, M. V. Srikantaiah, and T. J. Scallen, Biochem. Biophys. Res. Comm., 1976, 68, 784. R. A. Heller and M. A. Shrewsbury, J. Biol. Chem., 1976,251, 3815. E. H. Goh and M. Heimberg, F.E.B.S. Letters, 1976,63, 209. F. 0. Nervi, M. Carrella, and J. M. Dietschy, J. Biol. Chem., 1976, 251, 3831. P. A. Edwards, Biochim. Biophys. Acfa, 1975,409, 39.

178

Terpenoidsand Steroids

CoA-reductase16 and an increased incorporation of [ 1 -I4C]acetate into sterols in liver slices, but similar stimulatory effects were not obtained with either adenine or guanosine derivatives. Patients with familial hypercholesterolaemia exhibit lower levels of plasma cholesterol after an operation for portacaval anastomosis, and it has now been shown in rats that such an operation causes an increase in HMG-CoA reductase and cholesterol 7 a -hydroxylase activities. l 7 Many transplantable human and rodent hepatomas do not control the rate of sterol biosynthesis and HMG-CoA reductase levels in response to dietary cholesterol as normal liver cells do. However, certain hepatoma cells have now been found that, although lacking feedback regulation of cholesterologenesis in viuo, retain their regulatory ability in ~ i t r 0 . l ~It thus appears that malignant transformation is not necessarily linked to the loss of regulation by the cell of HMG-CoA reductase activity or sterol synthesis. For obvious clinical reasons most interest has centred on factors that decrease the activity of HMG-CoA reductase. Levels of ingested cholesterol are known critically to affect the activity of this enzyme and it has been suggested'' that it is controlled by the permeability of the cells to the sterol. A unique lipoprotein from serum characteristic of experimentally induced hypercholesterolaemia strongly inhibited the enzyme."' This protein probably contains bonded cholesterol and may be the same as a species that regulates cholesterologenesis after the ingestion of large amounts of dietary cholesterol.*' Whole serum and the low-density-lipoprotein fraction from controls suppressed cholesterologenesis and reduced HMG-CoA reductase activity in human cell cultures, but the corresponding fractions from subjects with homozygous familial hypercholesterolaemia failed to do so, although 7-ketocholesterol did suppress the reductase activity in both systems.22 Delipidated human serum enhanced the incorporation of [2-'"C]acetate but not of [2-l4C1MVA into sterols in isolated pigeon lymphocytes, a result that that the whole serum contains an inhibitor of HMG-CoA reductase. 7-Ketocholesterol or 7 a - and 25-hydroxycholesterol suppressed the reductase in hepatoma cell cultures more efficiently than did cholesterol supplied as a lipoprotein complex.24 Kinetic analysis indicated that the reductase activity was modulated in two distinct ways: serum and cholesteryl succinate specifically decreased the rate of synthesis of the enzyme, whereas the 0x0- and hydroxy-derivatives of cholesterol increased its rate of inactivation. Some uncertainties in this field may be due to the great difficulty in establishing the factors which control enzyme activity in these in v i m and in v i m systems. Thus recent studies of enzymic activities of preparations from neonatal rats fed on a cholesterol-rich diet have led to the conclusion that the decarboxylation of mevalonic acid pyrophosphate lh 1'

18

l9

2o 21

22 *?

24

G, Subba Rao, R. George, and T. Ramasarma, Biochern. J., 1976,154,639. S. Balasubramaniam, C. M. Press, K . A . Mitropoulos, A . A . Magide, andN. B. Myant, Biochim. Biophys. Actu, 1976, 441, 308. 0. R. Beirne and J. A. Watson, Proc. Nut. Acud. Sci. U.S.A.,1976, 73, 2735. P. A. Edwards, A. M. Fogelman, and G. Popjak, Biochem. Biophys. Res. Comm., 1976,68,64. G. Assmann, R. G. Brown, and R. W. Mahley, Biochemistry, 1975,14,3996. J. L. Breslow, D. R. Spaulding, D. A . Lothrop, and A . W. Clowes, Biochem. Biophys. Res. Comm., 1975, 67, 119. H . J . Kayden, L. Hatam, and N. E. Beratis, Biochemistry, 1976,15, 721. V. K. Kalra and D. H. Blankenhorn, Biochim. Biophys. Actu, 1976,441, 334. J. J. Bell, T. E. Sargeant, and J. A. Watson, J. Biol. Chem., 1976, 251, 1745.

Biosynthesis of Terpenoids and Steroids

179

(MVAPP) to isopentenyl pyrophosphate (IPP) can be another rate-limiting step in hepatic cholesterologenesis.” When the plasma lipoprotein level in rats was reduced ca. 90% by administration of the adenine analogue 4-aminopyrazolopyrimidine up to a 30-fold increase in HMG-CoA reductase activity was observed in kidney and lung tissue,26coupled with a three-fold increase in the rate of cholesterol synthesis from acetate or octanoate: removal of the drug then produced an increase in plasma cholesterol level and a decrease of reductase activity to the levels normally found in these tissues. Thus the low rates of cholesterol synthesis in non-hepatic tissues are due to feedback inhibition mediated by the liver and not because of intrinsically low enzymic activity. The finding that the brain of 7 day old rat possessed greater HMG-CoA reductase activity than adult brain has led to the suggestion2’ that this might account for the higher levels of cholesterol biosynthesis observed in rapidly growing brain when compared with mature tissues. The arteriosclerotic response that can be brought about by large doses of vitamin D2is reduced by the presence of hydroxymethylglutaric acid;28the additive leads to a regression of the arterial lesions and a reduction in serum lipoprotein levels. MVA is now known to be metabolized by routes other than those which give rise to terpenoids and steroids. The breakdown occurs predominantly in the kidneys to give C2 units that can be utilized in fatty-acid synthesis.” The ‘sterol’ and the ‘shunt’ pathways have been evaluated in nine different tissues of rat: previous conclusions that the kidneys are the predominant site of both types of metabolism have been ~onfirmed.~’ MVA is known to accumulate, at a low level, in the blood, and these results suggest that impairment of renal clearance of serum MVA by either route may account for the hypercholesterolaemia associated with some kidney disorders. A study of the effects of possible antimetabolites of MVA (for example the 2,3anhydro-compound) on the formation of cholesterol in cell-free systems from liver has been reported.31 Although there is much evidence to suggest that the envelopes of photosynthetically competent plastids are relatively impermeable to MVA, the origin of the MVA required for chloroplastidic terpenoid biosynthesis in plastids that are not able to fix CO, is not yet certain. Studies3’ using silicone-oil centrifugal filtration have shown that etioplasts and 1-2 h etiochloroplasts have envelopes that are permeable to acetate and MVA, but plastids from etiolated tissues that have been illuminated for periods of 4 h or longer show progressive impermeability to these precursors. Novel findings are still to be had from even well-studied systems. Highly purified prenyltransferase from porcine liver that catalysed the formation of geranyl pyrophosphate [GPP, (3)J or farnesyl pyrophosphate (FPP) from IPP also feebly catalysed the hydrolysis of its allylic substrate.33 This hydrolysis is stimulated by 25

26

27

2s 29

30

31 32

33

C. K. Ramachandran and S. N. Shah, Biochem. Biophys. Res. Comm., 1 9 7 6 , 6 9 , 4 2 . S . Balasubramaniam, J. L. Goldstein, J. R. Faust, and M. S. Brown, Proc. Nut. Acad. Sci. U.S.A., 1976, 73, 2564. M. M. Sudjic and R. Booth, Biochem. J., 1976, 154, 559. S. Y. K. Yousufzai and M. Siddiqi, Experientia, 1976,32, 1033. J. Edmond, A . M. Fogelman, and G. Popjik, Science, 1976,193, 154. M. Righetti, M. H . Wiley, P. A . Murrill, and M. D. Siperstein, J. Biol. Chem., 1976, 251, 2716. J. Kitamura, M. Shima, K. Hiratuka, and S. Asano, J. Pharm. SOC.Japan, 1976, 96, 732. A . R. Wellburn and R. Hampp, Biochem. J., 1976,158, 231. C. D. Poulter and H. C. Riiling, Biochemistry, 1976, 15, 1079.

Terpenoids and Steroids

180

inorganic pyrophosphate (PPi) in an autocatalytic fashion, but its significance in uivo (where the concentration of PPi is very low) is obscure. Competition experiments involving 2-fluoro-IPP and PPi were interpreted to indicate that PPi was exerting its effect by binding at the IPP-site. Previously it had been claimed that PPJ inhibited liver prenyltransferase by binding at both IPP and allylic sites. Studies using H2"0 and (lS)-[3HI]GPP showed that the C-0 bond. was broken on hydrolysis and inversion at C-1 of GPP occurred. The C - 0 bond fission must occur in the prenylation of GPP to form FPP, where it is known that an analogous inversion occurs. In contrast, phosphatases usually cause P-0 cleavage. These results implied a common active site for prenylation and hydrolysis and a carbonium-ion route for the former (Scheme 1 ; route a). This contrasts with the previous (1968) SN2-like proposal (Scheme 1; route b ) , which had to invoke an 'X-group' to

uopp OP+ a,

OPP-

R

R

Y O OPPP P +

FipPP

yp (3)

OPP

OP+P-

R (3 )

Scheme 1

accommodate the observed stereochemistry of elimination. If the R group on the allylic substrate in Scheme 1 is trifluoromethyl, the strong electron-withdrawing effect of the substituent should retard the formation of the ionic species of route a but have little effect on the rate of the nucleophilic displacement of route b. In the event34when E-3-trifluoromethylbut-2-en-1-01 and IPP were incubated with prenyltransferase from porcine liver the reaction rate was 1.5 X lo6 less than that observed with substrates IPP and GPP, a result that supports the carbonium-ion route. The substrate specificity of porcine prenyltransferase has been reinvestigated:35 previously (1974) it had been reported that 4-methylpent-4-enyl pyrophosphate coupled with GPP to give cis-homo-FPP and it has not been shown that the same substrate reacted with DMAPP to give exclusively the analogous 2-cis -homoneryl pyrophosphate. Further study36of the crystalline prenyltransferase from avian liver has revealed that it consists of two identical subunits (molecular weight 43 000 dalton per subunit) but contains no lipid or carbohydrate moiety. Detailed binding data were interpreted 34

35 36

C. D. Poulter, D. M. Satterwhite, and H. C. Rilling, J. Arner. Chem. Soc., 1976, 98, 3376. A. Saito, K . Ogura, and S. Seto, Chem. Letters, 1975, 1013. B. C. Reed and H. C. Rilling, Biochrrnistry, 1976,15, 3739.

181

Biosynthesis of Terpenoids and Steroids

to indicate that each subunit has a single allylic binding site, able to accommodate dimethylallyl pyrophosphate (DMAPP), GPP, or FPP together with a site for IPP: in the absence of an allylic pyrophosphate, or an analogue thereof, IPP can also bind to the allylic site. It has been demonstrated previously that in several plant species the interconversion of 2-trans-FPP into its cis-isomer involves dephosphorylation and a redox system involving the corresponding aldehydes. A similar redox pathway apparently occurs for the conversion of geraniol into nerol in Menyanthes trifoliat~.~'The initial formation of geraniol from its pyrophosphate involved inversion of configuration at C- 1, and hence presumably alkyl-oxygen bond fission. The kaurene synthetase from Echinocystsis macrocarpa (wild cucumber) seed is able to cyclize both R - and S-enantiorners of 14,15-oxidogeranylgeranylpyrophosphate to give 3a - and 3P-hydroxykaurene respectively in good yields.38 The degree of flexibility of substrate revealed by the diterpenoid cyclase makes more plausible previous proposals that naturally occurring axially hydroxyIated terpenoids might arise by direct cyclization of appropriate epoxide precursors. A series of analogues, (4)and ( 5 ) , of the precursors of squalene, in which the carbinol oxygen is replaced by a methylene group, inhibited the formation of squalene from [2-I4C]- and [5-3H2]-MVAby rat liver squalene ~ y n t h e t a s e .These ~~ phosphonophosphates also inhibited the biosynthesis of kaurene from MVA in a cell-free system from Ricinus communis, but the corresponding phosphonates were only weakly inhibitory. The formation of labelled squalene from a mixture of [2-I4C]MVA and [ l-3H]presqualene alcohol pyrophosphate by the squalene synthetase preparation was completely inhibited by the addition of ( 5 ) to the incubation CH2CH2P020P033-3Bu3NH+ RCH2P020P033-3Li'

__

(4) R = isopentenyl, dimethylallyl, geranyl, or farnesyl CH,R

(5) R = geranyl

system, and under these conditions presqualene alcohol pyrophosphate accumulated. No inhibition of squalene biosynthesis from presquaiene alcohol pyrophosphate was observed when the other substrate analogues were used, showing that effective inhibition requires a close correspondence of the carbon structure between substrate and inhibitor. The results were held to indicate that presqualene alcohol pyrophosphate is an obligate intermediate in the formation of squalene from MVA. A detailed stereochemical analysis (briefly reported in 1974) of the biosynthesis of presqualene alcohol has led to the deduction of the mode of linkage of the CIS moieties4' and has confirmed that the pyrophosphate is not an artefact of terpenoid biosynthesis as has been suggested. Generally the distinction as to whether an experimentally determined precursor is an obligate intermediate or lies 37

38

39 40

D. Arigoni, Pure A p p l . Chem., 1975,41, 219. R. M. Coates, R. A . Conradi, D. A. Ley, A . Akeson, J. Harada, S. C. Lee, and C. A . West, J. Amer. Chem. Soc., 1976,98,4659. E. J. Corey and R. P. Volante, J. Amer. Chem. SOC.,1976,98, 1291. G . Popjbk, N. L. Ngan, and W. Agnew, Bioorg. Chem., 1 9 7 5 , 4 2 7 9 .

Terpenoids and Steroids

182

on a side path of metabolism that has access to the normal pathway is rarely considered in biosynthetic studies and is, indeed, extremely difficult to elucidate in any convincing fashion without extensive studies using highly purified enzyme preparations. Squalene synthetase has binding sites for two molecules of FPP but the pyrophosphate group of the farnesyl residue which is first bound to the enzyme is released before the second molecule is bound, and one proton at C-1 of the first molecule of FPP only is exchanged with the medium during the formation of presqualene pyrophosphate. When tritiated 2-methylfarnesyl pyrophosphate (6) was incubated with the synthetase radioactive 11-methylsqualene (7) was f ~ r r n e d , ~but ' when the substrate was an equimolar mixture of [l-2H2]farnesol and (6) the product (7) contained only one atom of deuterium. The results indicate that (6) can only function as substrate at the second binding site although inhibition studies with the analogue show that it is able to bind at the first site. Similar studies with the 3-desmethyl analogue of FPP (8) gave the same results and this has led to the that the 3-methyl group of the first FPP residue may be essential in 'anchoring' the substrate by specific binding to the synthetase.

G R MfiR OPP

(6 1

(7) R = geranyl

OPP

(8)

A phytoene synthetase that converts IPP into phytoene has been partially purified from tomato plastids. The complex, which had a molecular weight of ca. 200 000 dalton, was devoid of squalene synthetase activity and required Mn2' as a cofactor. ATP caused a six-fold stimulation in activity, and, as there was no evidence that it was otherwise involved, it may act as an aliosteric effector.43 A comparison of the efficiency of the 2,3-oxidosqualene cyclase from human placenta microsomes with that from rat liver microsomes has led to the conclusion44 that in human placenta the conversion of squalene into lanosterol is limited by the rate of squalene epoxidation. Tracer from [ l-'4C]-2,3-oxidosqualenewas incorporated into cycloartenol (1% yield) by a cell-free system from Alnus glutinosa but none of the triterpenoid glutinone was synthesized from the labelled precursor.45 When 2,3-oxidosqualene was incubated with cell-free extracts from corn embryos the only product was cycloartenol, whereas when l-trans-l'-nor-2,3-oxidosqualene (9) was the substrate both 3 1-norcycloartenol and 3 1-norlanosterol were formed;46 1-cis- l'-nor-2,3-oxidosqualene(10) gave rise to no detectable cyclization products 41 42

43

44

45 46

P. R. Ortiz de Montellano, R. Castillo, W. Vinson, and J. S. Wei, J. Amer. Chem. Soc., 1976,98,2018. P. R. OrtizdeMontellano, R. Castillo, W. Vinson, and J. S . Wei,J. Amer. Chem. Soc., 1976,98,3020. B. Maudinas, M. L. Bucholtz, C. Papastephanou, S. S. Katiyar, A. V. Briedis, and J. W. Porter, Biochem. Biophys. Res. Comm., 1975,66, 430. C. Tabacik, M. Astruc, B. Descornps, and A. Crastes de Paulet, Biochirn. Biophys. Actu, 1975,398,490. A. Nicolas, J. Bascoul, A. Crastes de Paulet, and P. D. G . Dean, Phytochemistry, 1975, 14, 2407. L. Cattel, C . Anding, and P. Benveniste, Phytochemistry, 1976, 15, 931.

183

Biosynthesis of Terpenoids and Steroids

when incubated under the same conditions. Addition of unlabelled 31norcycloartenol failed to trap any radioactivity from [4-3H]-(9)and the formation of 3 1-norlanosterol was not inhibited, whereas the same additive considerably inhibited the conversion of labelled cycloeucalenol into obtusifoliol by the same preparation. It is concluded that both 3 1-norcycloartenol and 3 1-norlanosterol are formed directly by the 2,3-oxidosqualene cyclase through an intermediate (11) where the absence of a 4P-methyl group produces sufficient molecular freedom at the active site of the enzyme to permit either the 19-H or 8P-H to be abstracted respectively. A similar intermediate (12) is postulated in the isomerization of cycloeucalenol into obtusifoliol.

(9) R’= M e , R2= H (10) R’ = H, R2 = M e

(11) R =

(12) R =

3 Hemiterpenoids

+

The role of 3,3-dimethylacrylate in terpenoid biosynthesis has never been adequately defined although it has often been proposed as the source of the DMAPP moiety. In the plant Senecio rnikanioides it has been found that [14CJleucineis a more effective precursor of this acid than is [14C]MVA.47

4 Monoterpenoids An excellent review of the biosynthesis and metabolism of this class has a p p e a ~ e d . ~ ’ Labelling studies with [ 1-”C]- and [2-13C]-acetate have shown that the antibiotic rosellisin (13) found in the fungus Hypomyces rosellus is an acetogenin and not an i ~ o p r e n o i din , ~contrast ~ to the biosynthesis of another (Y -pyrone nectriapyrone. CO,Me

HOCH,

47

48 49

D. O’Donovon and D. J. Long, Proc. Roy. Irish Acad., 1975,75B, 465. R. Croteau and W. D. Loomis, Internat. Flavours Food Additives, 1975,6, 292. M. S. R. Nair, Phytochemistry, 1976, 15,1090.

Terpenoids and Steroids

184

The majority (82-92%) of the tracer incorporated into (+)-car-3-ene (14) biosynthesized from [2-14C]MVA in Pinus palustris or P. sylvestris was located at C-4." It is argued that the main route of formation of (14) from the a -terpinyl cation (15) involves a shift of the double bond (Scheme 2, route a ) whereas the pathway originally proposed by Ruzicka (Scheme 2, route 6) is quite unimportant. The pro-2s hydrogen of MVA is stereospecifically eliminated in the formation of the A3-bondof (14), and one-half of the 3H is lost from [5-3H2]MVAduring the synthesis of that part of (+)-car-3-ene that had been derived from IPP. This latter result may indicate that one hydrogen at C-5 of MVA is lost during the conversion of GPP into NPP although one hydrogen must be lost during the cyclization step to form the carane skeleton. I

I

represents

I

14c

Scheme 2

The phenomenon of asymmetric labelling of monoterpenoids biosynthesized in higher plants is well established and further examples have been reported." Thus ( + )-isothujone, biosynthesized in Tanaceturn vulgare after feeding [4-'4C]IPP, and geraniol and (+)-pulegone, [4-14C]DMAPP,or [Me-'4C]-3,3-dimethylacrylate, formed in Pelargoniurn graveolens and Mentha pulegiurn respectively after uptake of [Me-'4C]-3,3-dimethylacrylate,contained the bulk of the tracer in that part of the molecule that had been derived from IPP. In contrast, geraniol biosynthesized from [ U-'4C]glucose by P. graveolens had label in both the IPP- and DMAPP-derived units, whereas [ U-14C]-~-valineand [ U-'4C]-~-leucinewere not significantly incorporated into monoterpenoids in any of the systems studied. These results have led to the proposal that two metabolic pools of intermediates of monoterpenoid biosynthesis exist in the plant, the smaller pool A (Scheme 3) being sparsely filled whereas pool B is well filled and essentially irreversibly bound to protein. Exogenous precursors would thus be channelled into pool A, IPP from which condenses with bound DMAPP from pool B to give rise to the asymmetry of labelling normally observed. When terpenoid synthesis is more rapid or metabolism times are longer 50 51

D. V. Banthorpe and 0. Ekundayo, Phytochernistry, 1976,15, 109. K . G . Allen, D. V. Banthorpe, B. V. Charlwood, 0. Ekundayo, and J. Mann, Phytochemistry, 1976,15, 101.

Biosynthesis of Terpenoids and Steroids

185

Acetate + MVA + IPP 6 DMAPP) Pool A

C 0 2 -+ Glucose

7 + Pyruvate \

Acetate + MVA --+ IPP

I

Enz

I

Enz

DMAPP) Pool B

I

I

Enz

Enz

Clo

t

GPP

Scheme 3

both pools fill with tracer and symmetrically labelled products result. In support of this proposal it was shown that a cell-free system prepared from T. vulgare that had been exposed to 14C02for 20 days yielded, after incubation with isotopically normal IPP, geraniol which was almost exclusively labelled in the DMAPP-derived unit. When the experiment was repeated with plants that had been exposed to 14C02for only 3 days, the geraniol produced was only slightly labelled, indicating that the bound C5 pool had not taken up significant tracer during this short exposure. Little is known of the biosynthetic routes to the irregular monoterpenoids. It has been suggested that chrysanthemyl alcohol is a parent of the class that includes artemisia ketone, lavandulol, and santolinatriene, and stereochemical considerations have indicated that the (lR, 3R)-isomer (16) of this alcohol would be the required precursor. The alcohol (16) occurs in Artemisia Zudoviciana, and this is the first identification of the alcohol from a natural source.52 The santolinyl compound (17) also occurs in Artemisiu tridentata and the S-stereochemistry at C-3 is as expected if (16) (presumably as its pyrophosphate ester) is a precursor.s3

A cell-free extract from 7'.vulgure has been prepared that synthesized geraniol and nerol from [2-14C]MVA and [4-'4C]IPP in high yield (2.4% and 11.9% re~pectively).~~ Dimethylvinylcarbinol was also incorporated efficiently into monoterpenoid alcohols by the system and this raises the important issue as to its role in monoterpenoid biosynthesis. Both dimethylvinylcarbinol pyrophosphate and DMAPP inhibited the formation of monoterpenoids from (3R)-[2-14C]MVA by the cell-free preparation, and the marked change in the proportioiis of geraniol and nerol produced in the presence of these additives led to the conclusion that two prenyltransferases were present in the system. The cell-free extract also incorporated [9,10-'4C2]-a-terpineoland [7-'4C]terpinen-4-ol into isothujone. The cyclase activity appeared to be associated with a particulate fraction. 52 s3 54

K. Alexander and W. W. Epstein, J. Org. Chem., 1975, 40, 2576. J. Shaw, T. Noble, and W. W. Epstein, J.C.S. Chem. Comm., 1975, 591. D. V. Banthorpe, G. A . Bucknall, H. J. Doonan, S. Doonan, and M. G. Rowan, Phytochemistry, 1976, 15,91.

186

Terpenoids and Steroids

An alcohol oxidase that is able to accept primary aliphatic alcohols in the range C6-Clo has been purified cu. 5000-fold from T. vulgare,” The enzyme (molecular weight ca. 180 000 dalton) comprises two subunits of 94 000 and 75 000 dalton and is thought to be responsible for the formation of leaf aldehyde (trans-hex-2-en-1-al) although geraniol and nerol were also effective substrates for this enzyme, On the other hand Thea sinensis contains an alcohol dehydrogenase (molecular weight 95 000 dalton) that accepts geraniol, nerol, citronellal, and citra1.s6 It is believed that geraniol is converted into nerol in some plants via a redox system involving the corresponding aldehydes and, presumably, geraniol dehydrogenase. No alcohol dehydrogenase has been found in 7’. uulgure and it is perhaps significant that in this plant nerol is believed not to be formed from geraniol (or vice versa). A preliminary report (1973) on a cytochrome P450-dependent hydroxylase from Vinca rosea has been expanded.57 The system, which could be reconstituted from the separable components of cytochrome P450, a NADPH-cytochrome c reductase, and a lipid, converted geraniol and nerol into their C- 10-hydroxy-derivatives, which are the accepted precursors for loganin and its relatives. Hydroxylase activity was enhanced by dithiothreitol but was inhibited by thiol reagents, metyrapone, and cytochrome c and other inhibitors of cytochrome P450-containing systems. The acid protons at C-7 and C-8 were incorporated intact from [7,8-3H2]-7-deoxyloganic during the synthesis of loganin, secologanin, and morroniside by Lonicera rnorrowii, Cornus oficinalis, and Gentiana t h ~ n b e r g i i .An ~ ~ unusual enol diacetal monoterpenoid sarracenin (18) found in the insectivorous plant Sarracenia &va may be an intermediate in the pathway to the indole alkaloids.59 Sarracenin might arise from loganin. Acid-catalysed cleavage yields an enol aldehyde (19) in which rotation about the central bond might explain the transformation from the cis ring-junction of the monoterpenoid precursors to the trans stereochemistry found in the indole a1kaloids. loganin

+L OHC COzMe

COzMe

&02Me

(19)

(18)

Several new fascinating halogenated monoterpenoids, e.g. (20) and (21), have been isolated from red algae of Chondroccus species: their structure suggests formation by enzymic addition of BrCl to myrcene followed by dehydrohalogenation. /Br I

I

I

I

‘ i Br

-

I

CI

v

(21)

D. V. Banthorpe, E. Cardemil, and M. del C . Contreras, Phytochemistry, 1976, 15, 391. A. Hatanaka, 3 . Sekiya, and T. Kajiwara, Phytochemistry, 1976, 15, 487. 57 K. M. Madyastha, T. D. Meehan, and,C. 3 . Coscia, Biochemistry, 1976, 15, 1097. 5 8 Y. Takeda and H. Inouye, Chem. and Pharm. Bull. (Japan), 1976,24, 79. s9 D. H. Miles, U. Kokpol, J. Bhattacharyya, J. L. Atwood, K . E. Stone, T. A: Bryson, and C. Wilson, J. Amer. Chem. SOC., 1976,98, 1569. 6o B. J. Burreson, F. X . Woolard, and R. E. Moore, Chem. Letters, 1975, 1111.

s5 56

187

Biosynthesis of Terpenoids and Steroids

Adult male and female bark beetles (Ips paraconfusus) convert (- )-a-pinene into (+)-cis-verbenol and (- )-myrtenol whereas (+)-trans-verbenol and (+ )-myrtenol are produced from ( +)-a-pinene.61 Since (+ )-cis-verbenol is the aggregation pheromone for this beetle it would appear that production of the pheromone is controlled by the host tree.

5 Sesquiterpenoids An excellent review containing extensive tables of sesquiterpenoids that have been studied by tracer methods has appeared62 and another concerns sesquiterpenoid stress metabolite^."^ Two summaries of brilliant work carried out at the E.T.H. Zurich are now these suggest that a unifying stereochemical concept for C1, biosynthesis, such as has been successfully developed for C,, and C30biosynthesis, may at last be emerging. A feature of the work is the elegantly conceived chemical and microbial degradations that were used to determine the position of the labelled atoms, and in some examples the stereochemistry of C-H bonds. These reviews may be briefly summarized under five headings. 1. The fungal metabolite avocettin (23) may be derived from antipodal y cadinene (22) by three plausible routes (Scheme 4). Feeding of [2-14C]MVA in

(22)

P Scheme 4 61

63 64

J. A. A. Renwick, P. R. Hughes, and I. S. Krull, Science, 1976,191, 199. G. A. Cordell, Chem. Rev., 1976,76, 425. A. Stoessl, J. B. Stothers, and E. W. B. Ward, Phytochernistry, 1976,15, 8 5 5 . F. Dorn, P. Bernasconi, and D. Arigoni, Chimia (Swirz.), 1975, 29, 25.

1

188

Terpenoids and Steroids

conjunction with (4R)-[4-3Hl]-, (3R,5R)-[5-3Hl]-, and (3R,5S)-[5-3H,]MVA followed by degradation showed that (a) (3R)-MVA was the specificprecursor; (6) the folding of the farnesyl skeleton was as in (24) rather than (25); (c) no loss of tritium occurred from the terminal C-1 of FPP; ( d ) the route involving a 1,3-hydride shift was followed; and ( e ) the (5s)-hydrogen of MVA underwent 1,3-shift whereas the andpodal hydrogen was retained. Scheme 4 shows 2-cis-FPP (26) as precursor and there indeed is some evidence (from other sources) to suggest that this can be formed from the initially formed 2-trans-FPP (27) with the loss of a hydrogen at C-1 (uia a redox system). However, it was suggested that in the present instance (27) could be the initial precursor in a scheme that by-passes formation of the 2-cis-isomer (Scheme 5). The key idea was that enough conformational flexibility occurred in the diene systems containing the Cloring (germacrene D) to permit the conformational change (28)-+(29) necessary to allow cyclization. This had been proposed by others (1973) to accommodate the formation of dendrobine from 2-trans-FPP via an intermediate with a germacrene-type ring without the prior interconversion of 2-cis-FPP.

pH i , ,

Scheme 5

In a parallel investigation, the origin of the methyl groups of the isopropyl unit of (23) was explored to determine whether the side-chain could rotate after cyclization but before transfer of hydride ion. Feeding of [2-'4C]MVA (30) followed by degradation yielded the tracer pattern shown in (31), and ultimately (32) contained 85% of the activity expected for one label equivalent, i.e. the tracer was located at the p r o 4 methyl group of the side-chain. As the absolute configuration of avocettin is known, and as it was very reasonably presumed that only the E-methyl group of the isopropylidene moiety of the aliphatic precursor was labelled in this experiment, it was inferred that the overall addition to the C=C bond was a syn-process and that hydride-ion transfer was faster than rotation of the charged side-chain (Scheme 6 ) . 2. Another group of studies of the biosynthesis of (-)-sativene (33) by Helminthosporium sativum and H. victoriae made use of the known patterns of fungal degradation of this and of the related alkaloid victoxinine in order to elucidate.the Iabelling pattern without extensive chemical manipulation. Uptake of [3H,14C]MVAgave the pattern shown (in part) and in particular ( a )all hydrogens linked to C-5 of MVA were retained; ( b )a stereospecific 1,3-hydride shift occurred but in contrast to the previous example the epimeric hydrogen migrated; (c) the biogenetic individuality of the methyl groups of the side-chain was retained; and ( d ) the carbon atom at C-2 of the precursor occupied the dotted position (33) of the Cz bridge. This last observation was crucial since two plausible routes to (-)-sativene

Biosynthesis of Terpenoids and Steroids

HO

Qo

% 'H

(30)

189

H

CO2H

(31)

+

Scheme 6

and (-)-copacamphene (38) from the CISprecursor may be postulated, namely (34)+(35)+(33) or (36)+(37)+(35)+(33). The latter pathway, although longer, is quite feasible since copacamphene derivatives co-occur with sativene as metabolites of Helminthosporium species, and the interconversion (35)+(37) (uia 1,3-migration of the C3 bridge) has been demonstrated in model systems. The origin of the two carbon atoms in the lower bridge and the previously outlined result showed that in both fungal species the shorter of the two routes was followed.

1

(35)

(37)

1

1

190

Terpenoids and Steroids

3, Information on the direct route to the copacamphane skeleton has been obtained by studies on the biosynthesis of dendrobine (39), an alkaloid found in the orchid Dendrobium nobile, and related compounds (1969, 1972, 1973). The presumed route to (39)is shown in Scheme 7 and studies with (3K,SS)-[S-3H,]MVA and its (5R)-isomer have now revealed that a 1,3-hydride shift to the side-chain (previously demonstrated in 1973) involved the same epimeric hydrogen at C-5 of MVA as shifted in the formation of sativene.

+ 0 Scheme 7

(39)

4. Longifolene, the (+)-isomer (40) of which occurs in higher plants and the (-)-enantiomer (41) in fungi and liverworts, was also studied. The (-)-enantiomer co-occurred with ( - )-sativene in Helminthosporium species. Routes to both compounds, linked by a 1,2?shift of a C, bridge, can be proposed (Scheme 8). In the present work the use of [3H,'4C]MVA as precursor showed that, as for sativene, (+)-longifolene was assembled by the shorter route in Pinus ponderosa; in particular, feeding of (5R)-[5-3H,,2-'4C]MVA and its (SS)-isomer revealed that all the hydrogens at C-5 of MVA were again retained and that a 1,3-hydride shift to C-3 occurred with the same epimeric hydrogen in ( + )-longifolene undergoing migration as in (-)-sativene and dendrobine. This in turn uniquely defined the si direction of attack on the relevant C=C bond during generation of the C,, ring system in (42). Preliminary studies also indicated that it is the epimeric hydrogen that shifts in the formation of the (-)-isomer of longifolene. 5 . As a result of the studies outlined above, additional stereochemical conclusions can be drawn. Firstly, folding of the acyclic chain of the CI5precursor is as in (24) rather than (25) in all cases [as has been previously demonstrated in other examples (1974, 1975)]. Secondly the labelling pattern favours the intermediacy of the Cll ring system (42) rather than bisabolene-like (43) or sesquicamphane-like (44) intermediates as has been suggested by other workers. Thirdly a penetrating stereochemical analysis led to the conclusion that formation of (- )-longifolene and

191

Biosynthesis of Terpenoids and Steroids (+)-

1

p

(-1-

Scheme 8

(431

(441

(- )-sativene (same enantiomeric series) in the fungi both involved re-anti cyclization of 2-cis-FPP to give initially CI1 and Clo ring-intermediates respectively that involved 1,3-shift of epimeric hydrogens derived from C-5 of MVA; the corresponding antipodal hydrogens in each case migrated when the antipodal (+)sesquiterpenoids were formed in higher plants. Similar analyses were carried out for the formation of dendrobine and avocettin although here the situation was not unequivocal as 2-trans-FPP could not be ruled out as the species that underwent cyclization. If, however, 2-cis-FPP was the immediate precursor (see above) then it was considered that it could be formed from 2-trans-FPP (27) without loss of hydrogen at C-1 by a sequence (Scheme 9; a represents suprafacial anionotropic rearrangement and b conformational rotation) involving the formation of nerolidyl pyrophosphate and resulting in inversion of configuration at C- 1. M

R

A

+

,oh*H hoPp

0 opH-% A Me Me R

Me

R

R

Q\IH

O

(27) Scheme 9

(26)

192

Terpenoids and Steroids

In summary, these important investigations have rationalized the stereochemistry of the 1,3-hydride shift (which transfers a positive centre from C-10 or C-11 at the distal end of FPP to C-1 and so allows initiation of further isomerization or a second cyclization of the C l oor C I ring) on the basis of the ring size of the products. This presumably results from fixation of specific conformations of the intermediates on a hypothetical enzyme surface. The larger diversity of structure for sesquiterpenoids than for di- or tri-terpenoids could then reflect the larger conformational flexibility of a C l oor Cll ring (which are often involved in the formation of the former) than of the c6 rings that are usually implicated in the latter. The labelling pattern of culmorin (45) biosynthesized by Fusariurn culrnorurn, indicated that the endo-C- 10 proton originated from the 2s-position of MVA, whereas the C-11-hydroxy-group displaced a pro-5R hydrogen of MVA, and a pro-5s hydrogen (equivalent to the 1s hydrogen of FPP) was inferred to migrate, It was noted that a probably to C-5, at an early stage in the process (cf.Scheme

Scheme 10

C1, ring is formed in the intermediate whereas the epimeric hydrogen of FPP had been previously reported to migrate when intermediates with a Clo ring were believed to be involved. The proposal was made that initial attack of C-1 of FPP on the distal C=C yielded a non-classical cyclopropyl ion which could collapse to give a C I l ring intermediate (involving formation of C - 1 4 - 1 1 bond) by transfer of the appropriately orientated pro-1s hydrogen of FPP, whereas collapse to a Clo ring (C-1-C- 10bond formation) would necessarily involve the migration of the epimeric pro-1R hydrogen atom. Either procedure would result in the positive centre being relocated at the former C-1 atom of FPP in a position to be involved in further reactions. This idea, which is equivalent to the occurrence of 1,3-hydride shifts within classical carbonium ions (see previous work of the Zurich group), has been more fully developed in a study (partly reported in preliminary form in 1973) of the biosynthesis of illudin M (46) in Clitocybe illudens66using a variety of doubly labelled MVA precursors. Results from feeding experiments with [5-3H]MVA and [l3H]FPP suggested that a hydride shift occurred between the atoms that were C-1 and C-9 in FPP, and incorporation of [2-3H]MVA indicated that hydrogen was lost from C-4 of FPP during cyclization. Again a scheme was proposed wherein the pro-1s hydrogen of FPP migrated during the formation of the C l l ring system (Scheme 11). Further studies have been made concerning the formation of the mycotoxin trichothecin (47) produced by Trichotheciurn roseurn. Earlier reports of 3H/14C ratios obtained after feeding [2-3H2]-or [5-3H2]-MVA(together with [2-I4C]MVA) that had supported the involvement of the co-metabolite crotocin (50) as an 65

66

J. R. Hanson and K. Nyfeler, J.C.S. Chem. Comm., 1975, 824. J. R . Hanson, T. Marten, and R. Nyfeler, J.C.S. Perkin I , 1976, 876.

193

Biosynthesis of Terpenoids and Steroids

Enz

Enz t

1

c-

+H Scheme 11

intermediate were corrected and it was concluded that this diepoxide was not on the direct pathway from trichodiene (48) to (47).67 In order to take account of problems arising from the reversibility of IPP-isomerase which ‘washed out’ tracer from [2-3H]MVA, the atom ratios in the experiments using this precursor were normalized to those of the diterpenoid deoxyrosenonolactone which is also produced in the fungus and whose biosynthetic route was well established. The compounds (49b) and (49c) were incorporated into (47) in yields of ca. 6% and 27% respectively and this is consistent with the sequence (48)+(49a)+(49b)+(49~)+(47). Previous studies (1975)on cell-free systems from 7’. roseurn had indicated that 2-trans-FPP was a precursor of trichodiene (48) and that cyclization took place with the loss of a pro-1s hydrogen of this with its ultimate replacement by a pro-4s hydrogen of

q- Rq/ - oq/(48)

OH

(49)a; R = H,H b; R = OH,H c;R=O

67

R.Evans, J. R. Hanson, and T.Marten, J.C.S. Perkin I, 1976, 1212

0

194

Terpenoids and Steroids

NADPH. In a number of examples it has been demonstrated that cyclic sesquiterpenoids result from 2-trans-FPP by dephosphorylation and conversion into 2 4 s farnesol (and hence presumably 2-cis-FPP) uia a redox system. However, in the present case6*farnesol was not a substrate and no tracer could be demonstrated to be associated with the farnesals. The fact that the added hydrogen came from the opposite face of NADPH to that utilized in common redox systems (e.g. liver alcohol dehydrogenase) may indicate that a totally different type of mechanism occurs from that previously proposed for the trans to cis conversion, and the occurrence of a novel cyclopropyl intermediate was suggested (Scheme 12). OPP

*-q-y-F+q Scheme 12

A similar hypothetical intermediate may occur in the formation of cyclonerodiol (5 1)and cyclonerotriol(52) in T. roseum and Fusarium ~ u l r n o r u r n The . ~ ~incorpo~~~ ration of various doubly labelled MVA precursors, including [4,5-'3C2]MVA,were consistent with the folding of 2-trans-FPP as shown. Whereas 2-trans-FPP was efficiently incorporated, nerolidol (an alternative notional precursor) was not,

pox+

-0q

OPP

-

\

\ -0T

(51) R = H (52) R = O H

X=HorEnz

p

although this did not rule out nerolidyl pyrophosphate or an enzyme-bound form of this as a precursor. The fact that tritium was lost from [2-'4C,2-3H2]MVAbefore the construction of the parent C,, compound was demonstrated by the finding that 2trans-FPP biosynthesized from [2-3H,,2-'4C]MVA in liver preparations was incorporated into the fungal product with the expected isotope ratios. It is noteworthy that these novel sesquiterpenoids were found in degenerating cultures that had lost 60

69

7o

R. Evans and J. R. Hanson, J.C.S. Perkin I, 1976, 326. R. Evans, J. R. Hanson, and R . Nyfeler, J.C.S. Chem. Comm., 1975, 814. R . Evans, J. R. Hanson, and R.Nyfeler, JC&. C k m . Comm., 1975, 1214.

195

Biosynthesis of Terpenoids and Steroids

their capacity to form the normal pattern of sesquiterpenoids. It is possible that the reversibility of IPP-isomerase could then be important as prenyltransferase activity could well be low. The construction of the fungal metabolites botrydial (53) and dihydrobotrydial (54) produced by the plant pathogen Botrytis cinerea has been defined by the use of [4,5-13C2]MVA together with 2Hlabelling.71 These compounds do not obey the simple isoprene rule, but of the several possibilities for linkage of C, units followed by rearrangement and bond fission the results were consistent only with skeletal assembly as shown in (55). CHO

Cell-free preparations from callus cultures of the plant Andrographis paniculata under anaerobic conditions yielded y-bisabolene which was shown to have the 2-configuration (56); previously it had not been fully demonstrated whether this notional intermediate of various sesquiterpenoid classes occurred as the 2- or the E-isomer.’* (3R)-[5-3H2,2-14C]MVAwas incorporated into (56) with the loss of one-sixth of the tritium label and this indicated that 2-cis-6-trans-FPP rather than 2cis-6-cis-FPP was a precursor (the tritium in the former being lost, presumably, in a redox process concerned with its formation from 2-trans-6-trans-FPP; the intermediacy of the 2-cis-6-cis-isomer wouId involve the loss of two atoms of tritium). The result was confirmed by the demonstration that 2-cis-6-trans-FPP was incorporated into y-bisabolene in good yield (1.2%) under conditions where the 2-cis-6-cisisomer was poorly utilized (0.02%). The callus cultures accumulated paniculides and uptake of [1,2-13C2]acetate gave rise to the labelling pattern shown (57) for paniculide B. These experiments illustrate some of the particular advantages of plant tissue cultures in biosynthetic studies, the ready preparation of an active cell-free system and high precursor incorporations permitting the use of 13Cn.m.r. for location of label in a case where the tracer pattern from [2-l4C]MVA could not be determined.

,....-

(57) :.-----.I delineates an intact C2 unit derived from acetate 71

’*

J. R. Hanson and R. Nyfeler, J.C.S. Chem. Comm., 1976,72. K. H. Overton and D. J. Picken, J.C.S. Chem. Comm., 1976, 105.

196

Terpenoids and Steroids

Studies on the biosynthesis of ~ a p s i d i oby l ~ Capsicum ~ frutescens and of ovalicin (58) in Pseudorutium o v a l i ~reported ,~~ last year, have now appeared in expanded form. In the latter case a route to ovalicin involving the intermediacy of pbergamotene has been confirmed by feeding experiments with [3,4-13Cz]MVA which yielded labelling as in (58). Feeding of [ 1,2-13C2]acetateto the fungus Fumes annosus revealed75 the labelling pattern of fomannosin (59), consistent with previHO

0 , m, and A represent the labelled atoms in three separate molecules of [3,4-

l3Cz]MVA 0

0

1

Me OQ0

ilr t

73 74 75

F. C. Baker and C. S. W. Brooks, Phytochemistry, 1976,15,689. D. E. Cane and R. H. Levin, J. Amer. Chem. Soc., 1976,98, 1183. D. E. Cane and R. B. Nachbar, Tetrahedron Letters, 1976,2097.

11

% 5 1

12

.13

197

Biosynthesis of Terpenoids and Steroids

ous speculations on its biosynthesis. Another study using 13Cn.m.r. was on the stress metabolites of Datura strurnoniurn : 7 6 fungal infection of fruit capsules led to the formation of germacrene-2,3-diol (60), lubimin (6 l),and hydroxylubimin (62) and analysis of the products after feeding [ 1,2-13C2]acetatewas consistent with the pathway shown.

(61) R = H (62) R=OH

A brief report records the incorporation of 2-truns-FPP, biosynthesized by a prenyltransferase preparation from (4R)-[4-3Hl,2-'4C]MVA,into germacrene D in . ~ ~ incorporation of [2-14C]MVA into pterosides of seeds of Kudsuru j ~ p o n i c u The Japanese bracken Pteridiurn uquilinum was maximal (0.7%)in early the route shown in Scheme 13 was proposed and requires that acetic acid produced by

1 Pteroside A Pteioside B Pteroside C Pteroside D Pteroside Z

R1 = H R2 = Me, R3 = OH R' = R.I= R3= H R' = OH, R2= R3= H R' = OH, R2 = Me, R3= H R1= R3 = H, R2 = Me Scheme 13

'6

77

'8

G. I. Birnbaum, C. P. Huber, M. L. Post, J. B. Stothers, J . R. Robinson, A . Stoessi, and E. W. B. Ward, J.C.S. Chem. Comm., 1976,330. K. Morikawa, S. Nozoe, and Y. Hirose, 6th International Congress on Essential Oils, Allured Publishing Company, Oak Park, Illinois, 1975, p. 167 (Chem. A h . , 1976, 84, 105 807). H. Hikino, T. Miyase, and T. Takemoto, Phytochemistry, 1976, 15, 12 1.

198

Terpenoids and Steroids

Kuhn-Roth degradation of the radioactive pteroside should have a specific activity one-ninth of that of the precursor MVA. In the event the ratio was 1.41:9. The authors claim that since this type of degradation of an aromatic methyl is inefficient this evidence supports their scheme, although there may be other interpretations of these data. has been The formation of halogenated sesquiterpenoids in Laurencia intri~ata’~ the subject of speculation and the finding of a - and P-snyderol (63) and (64) in several Laurencia species was helds0 to support the involvement of a brominated monocyclofarnesol intermediate €or chamigrane derivatives [e.g. elatol (65)]. The latter and caespitol (66) co-occur in L . obtusa*’ and it was proposed that a bisabolonium ion (67) may be the common precursor for these two skeletal types.

4a,5cr-Oxidoeudesm- 11-en-3a -01 (69), cyperol (68), and cyperolone (71) cooccur ir Cyperus rotundus,**and a route to the latter involving formation of a ketone (70) has been suggested. Coriolin (72), complicatic acid (73), and hirsutic acid (74) may be derived from hirsutene (75),which was found in Coriolus cons or^.^^

-jq

82

83

R. H. White and L. P. Hager, Phys. Chem. Sci. Res. Reports, 1975, I, 633 (Chem. Abs., 1976,84,71 504). B. M. Howard and W. Fenical, Tetrahedron Letters, 1976, 41. A. G. Gonzalez, J . Darias, A. Diaz, J. D. Fourneron, J. D. Martin, and C. Pkrez, Tetrahedron Letters, 1976, 305 1. H. Hikino and K. Aota, Phytochemistry, 1976, 15, 1265. S. Nozoe, Tetrahedron Letters, 1976, 195.

Biosynthesis of Terpenoids and Steroids

199

Degradation of abscisic acid (76), biosynthesized from [3-3H,3’-’4C]MVA by avocado fruit, gave results consistent with the accepted view that the methyl groups at C-3, C-2’, and pro-S C-6’ all originate from the methyl group at C-3 of MVA.84 Levels of abscisic acid in Phaseolus vulgaris leaves subjected to water stress were increased by up to 16-fold over controls. The major metabolites were dihydrophaseic acid and phaseic a ~ i d . ~ The ’,~~ metabolism of exogenous abscisic acid by bean shoots is not identical with that of the endogenous compound:” thus [2-14C](76) was metabolized to dihydrophaseic acid and epidihydrophaseic acid, the amount of the latter being some 18-42% of the former in the free form and up to 200% of the former in the conjugated form.

(76) R = pro-6‘-S-methyl

Corpora allata, from the cockroach Blaberus giganteus, and extracts thereof were able to convert 2-trans-6-trans-methyl farnesoate (77) into juvenile hormone 111 (78) in up to 6% yield.88 The epoxidase, which was membrane bound, was associated with the 100 000 g precipitate of the corpora allata homogenates and required NADPH and molecular oxygen; only trace amounts of the corresponding juvenile hormone diol (79) were formed. A mammalian epoxide hydratase capable of converting (78) and similar terpenoid epoxides into the corresponding diols has been

84 85

86

B. V. Milborrow, Phytochemistry, 1975, 14, 2403. M. A. Harrison and D. C. Walton, Plant Physiol., 1975, 56, 250. D. C. Walton, M. A. Harrison, and P. Cote, Planta, 1976, 131, 141. J. A. D. Zeevaart and B. V. Milborrow, Phytochemistry, 1976, 15, 493. B. D. Hammock, Life Sci., 1975, 17, 323.

Terpenoids and Steroids

200

purified.89 Details of the kinetics, heat stability, and inhibition by organophosphates of juvenile hormone carboxyesterase from Schistocerca gregaria are available.”

6 Diterpenoids The labelling pattern in fusicoccin (80), biosynthesized in Fusicoccum amydali from [1-13C]- and [2-“C]-acetate, implies that it is formed by direct cyclization of geranylgeranylpyrophosphate (GGPP),’l supporting suggestions that it is a diterpenoid rather than a degraded sesterterpenoid. Exposure of Ricinus communis seedlings to Rhizopus, Aspergillus, or Fusarium species resulted in a 2 0 4 0 - f o l d increase in the formation of casbene from mevalonate by cell-free extracts of the plant,” suggesting that it was a phytoalexin.

w

H.

OH

Ac

L O M e

(80)

Much interest has again been focused on the gibberellins and their biosynthetic intermediates. Typical of the difficulties experienced in cell-culture work, extracts of cell cultures of tomato converted” [ ‘‘C]copalyl pyrophosphate (81) but not [14C]GPPinto ent-kaurene (82), whereas extracts from seeds utilized MVA and the prenyl pyrophosphates. On the other hand, although isolated plastids from developing Echinocystis macrocarpa endosperm could convert both copalyl pyrophosphate and GGPP into ent-kaurene, preparations of organelles from pea shoots and castor bean endosperm have either no or very limited ability to metabolize GGPP:94thus the step from this to copalyl pyrophosphate may be limited to certain stages of plant development. A cell-free system from pea cotyledon was able to convert [14C]MVA into FPP and GGPP in the presence of Mn2’, ATP, and the drug A M 0 1618. The GGPP was efficiently converted into ent-kaurene by the same system when the drug was omitted.” The conversion of GGPP into ent-kaurene by extracts from pea shoot tips was enhanced by the addition of an enzyme preparation from sonicated chloroplasts, and this is held as the first evidence that kaurene is synthesized in the chloroplast. The conversion of ent-kaurene into gibberellic acid (83) involves loss of hydrogen from C-3. Feeding ent-[3@-3H,17-14C]kaureneto Gibberellafujikuroi gave (83) that had retained 93% of the tritium Thus 3-hydroxylation occurs with retention of configuration. Since the pro-4R hydrogen from MVA is lost in the conversion of xy

90 91

92 97 94 y5

96

B. D. Hammock, S. S. Gill, V. Stamoudis, and L. I. Gilbert, Comp. Biochem. Physiol., 1976,53B, 263. G. E. Pratt, InsectBiochem., 1975, 5 , 595. K. D. Barrow, R. B. Jones, P. W. Pemberton. and L. Phillips, J.C.S. Perkin I, 1975, 1405. D. Sitton and C. A. West, Phytochemistry, 1975, 14, 1921. Y. Ybtin and I . Shechter, Plant Phvsiol., 1975, 56, 671. P. D. Simcox, D. T Dennis, and C. A. West, Biochem. Biophys. Res. Comm., 1975, 66, 166. T. C. Moore and R. C. Coolbaugh, Phytochernistry, 1976,15, 1241. R. M. Dawson, P. R. Jefferies, and J. R. Knox, Phytochemistry, 1975, 14, 2593.

Biosynthesis of Terpenoids and Steroids

20 1

(82) into (83) it follows that this hydrogen must be in the 3P-position in (81). As the C-18 atom of (83) is derived from the C-2 of MVA this would support proposals that the cyclization of GGPP results from antiplanar addition to the distal C=C bond with the polyene in a chair conformation. The oxidation of ent-kaurene is inhibited by the plant-growth regulator ancymidol: at 10-6mo11-1 the drug blocks the formation of ent-kaurenol and at 10-3mo11-1 it stops the conversion of MVA into ent-kaurene. These effects are completely reversed by the addition of gibberellic acid." Isosteviol(84) and steviol acetate (85) are effectively metabolized by cultures of mycelia of a G. fujikuroi

CO,H

(84)

mutant;98(84) is converted, inter aha, into derivatives, with the ring C-D rearranged, of GA,7, GAI9,GA2,,, and 13-hydroxy-GAI,, and (85)is metabolized mainly to 7P hydroxy- and 6p,7@-dihydroxy-derivatives and the 13-acetates of GA17 and GA,,. These results provide further evidence that the fungal enzymes responsible for biosynthesis of gibberellin from ent-kaurenoic acid lack rigid substrate specificity. They also reveal that structural changes in the C-D ring system of ent-kaurenoids as substrate suppress the 3-hydroxylating system. As in past years several studies of +he metabolism of exogenous gibberellins in higher plants have a p p e a ~ e d ; ~ ~ -some " ~ of this work is of little value as the R. C. Coolbaugh and R. Hamilton, Plant Physiol., 1976, 57, 245. J. R. Bearder, V. M. Frydman, P. Gaskin, J. MacMillan, C. M. Wels, and B. 0.Phinney, J.C.S. Perkin f, 1976, 173. 99 G . W. M. Barendse and G . J . M. de Klerk, Planta, 1975,126, 25. *Ofl R. C. Durley and R. P. Pharis, Plunta, 1975, 126, 139. lo1 A. W. Brown, D. R. Reeve, and A. Crozier, Pluntu, 1.975, 126, 83. Io2 R. L. Wample, R. C. Durley, and R. P. Pharis, Physiol. PIant., 1975, 35, 273. 103 I. D. Railton, R. C. Durley, and R. P. Pharis, Plant Cell Physiol., 1975, 16, 943. lo4 V. M, Frydman and J. MacMillan, Planta, 1975,125, 181. 105 L. J. Nash and A. Crozier. Pluntu, 1975, 127, 221. '9

98

202

Terpenoids and Steroids

metabolites were not identified. The seasonal variation of levels of gibberellins in Pinus species'"' and the influence of the growth retardant (2-chloroethy1)trimethylammoniuni chloride on gibberellin biosynthe~is'~'have been recorded. Although abscisic acid is a strong inhibitor of germination of chilled hazel seeds, it had little effect on the biosynthesis of gibberellic acid."'

7 Steroidal Triterpenoids The biosynthesis of cholesterol, related steroids, and phytosterols is dealt with in this section whereas the further metabolism of these classes and the remaining nonsteroidal triterpenoids are covered in the following two sections. Reviews have appeared on the biosynthesis of sterols and higher terpenoid~,'~'the in vivo metabolism of steroids in primates"" and in plant tissue culture,"' and dietary feedback control of cholesterol synthesis.l12 The latter contains a reasoned defence of the hypothesis that HMG-CoA reductase is controlled by alterations to its supporting microsomal membrane. Abstracts of a symposium on all aspects of steroid biosynthesis have appeared."3 The major site of steroid synthesis in animals has been considered to be the liver, but recently (1975) this has been disputed and detailed studies now show that sterol synthesis in guinea pig occurs more readily in ileum and lung than in liver under a variety of conditions' 1 4 3 1 ' s and a brief study indicates similar sites of biosynthesis in swine.'" All tissues of guinea pig studied had an active feedback system controlling cholesterol biosynthesis and the results of feeding cholesterol and ~holestyramine''~ showed that both the former and possibly bile acids suppress cholesterol synthesis in the liver to a far lesser extent than in the small intestine. For obvious reasons, inhibitors of cholesterol biosynthesis have aroused intense interest. Studies on a variety of species (mostly rats) have been made using 1-alkylimidazoles,'I8 c01chicine,~'~ and chenodeoxycholic acid,12' the last work being particularly interesting as the metabolite affected HMG-CoA reductase but not cholesterol 7a -hydroxylase, the steps believed to be rate-limiting for the biosynthesis of sterols and of bile acids respectively. Arsenite, p -mercaptoethanol, dithiothreitol, and ethanethiol all inhibited the biosynthesis of cholesterol from MVA in rat liver homogenates. The accumulation12' of 4,4-dimethyl-5a-cholest-8en-36-01 together with the corresponding A8724-dienesupported the view that R. Lorenzi, R. Horgan, and J. K. Heald, Planta, 1975, 126, 75. I. Shir and B. Kessler, Plantu, 1975. 125,73. I. Arias, P. M. Williams, and J. W. Bradbeer, Plantu; 1976, 131, 135. l o g H. H. Rees and T. W. Goodwin, in 'Biosynthesis', ed. T. A. Geissmari (Specialist Periodical Reports), The Chemical Society. London, 1975, Vol. 3. p. 14. L 1 O K. Schubert and K. Schade, Endokrinologie. 1975,66, 228. S . J. Stohs and H. Kosenberg, Lfoydiu, 1975, 38, 181. 3. R. Sabinr and hf. J. James, Life Sci., 1976. 18, 1185. J. Steroid Riochem., 1975, 6. 291-4.53. S. D. Turley. C. E. West. and B. 3. Horton, Lipid.7, 1976, 11,281. A . Swanri, hf. H. Wilet, and M. D. Siperstein, J. Lipid R e x , 1975, 16, 360. ] I 5 W. Y. Huang and F. A . Kummerow, Lipids, 1976, 11, 34. : I 7 S. D. Trirlzy and C. E. West, Lipids, 1976,11, 571. K. 11. Raggaley, S. D. Atkin, P. D. English, R. M. Hindley, B. Morgan, and J. Green, Biochem. Pharrntzcol., 1975.24, 1902. F. D. Ottery and S . Goldfarb, F.E.B.S. Letters, 1976,64, 346. lZc) S. Shefer, G. Salen, T. Fedorowski, H. Dyrszka, and E. H. Mosbach, J. Steroid Biochem., 197.5.6.1563. ! 2 1 D. Abernethy, C. Hignite, and D. L. Azarnoff, Steroids, 1976, 27, 297.

iOh

Ioi

Biosynthesis of Terpenoids and Steroids

203

cytochrome P450 was involved in the 14a -demethylation of ianosterol. Incubation of [2-14C]MVA with rat liver fractions in the presence of triarimol led to the inhibition of cholesterol formation, and ['4C]lanoster.ol and [14C]-24,25dihydrolanosterol accumulated:122 apart from a slight inhibition of A7-stero1-A5dehydrogenase, the drug did not affect the activity of any enzyme in the cho!esterol pathway from acetate apart from lanosterol 14a-demethylase. 5a -Cholest-8(14)en-3P-ol-15-one depressed the incorporation, in viva, of tracer from [14C]acetate, but not from [14C]MVA,into liver sterols by rat;123this confirms recent observations that a number of 15-oxygenated sterols are potent inhibitors of sterol synthesis and act at the level of HMG-CoA reductase. Previously held views, based on incorporation of acetate in uitro, concerning the diurnal changes in the rate of cholesterol synthesis in the rat have been challenged:124-126 it is claimed that incorporation experiments carried out in vivo using 3 H 2 0as substrate are more representative of the actual situation in viuo, and such experiments reveal no effect of feeding on cholesterologenesis. The effects of stress, fasting, light, and feeding of cholestyramine, p-sitosterol, and cholesterol in various combinations on hepatic cholesterologenesis127and of the thyroid state on chblesterol turnover have been reported,12' and it has been demonstrated that rats maintained on a diet in which water was replaced by skim milk have plasma cholesterol levels that are significantly lower than controls.129 In adrenocortical cells Ca2+can replace ACTH in a hormone-like action on adrenal s t e r o i d o g e n e ~ i s .A' ~ ~ lipogenic diet inhibits cholesterol biosynthesis between lanosterol and cholesterol A regulator but no evidence could be found for inhibition at any other here, rather than at the HMG-CoA level, would allow inhibition of C27 sterols without affecting the biosynthesis of other essential pathways to ubiquinones and dolichols. Detailed studies of the kinetics of cholesterol formation from MVA in man have been made133and it has been discovered that sub-lines of Ehrlich ascites tumours that did not produce glycogen had a very low rate of s t e r o i d o g e n e ~ i s . ~ ~ ~ Details of cholesterol biosynthesis continue to be explored. Further details of work concerning the stereochemistry of the rearrangement of the methyl group at C-15 of squalene (which migrates to C-13 of lanosterol) during the biosynthesis of cholesterol by rat liver are a ~ a i l a b 1 e . ICholesterol, ~~ biosynthesized independently 122

123

125

lZ6 127

lZ8 129

130 131

132 133

134

135

K. A. Mitropoulos, G. F. Gibbons, C. M. Connell, and R. A . Woods, Biochem. Biophys. Res. Comm., 1976, 71,892. D . L. Raulston, C. 0. Mishaw, E. J. Parish, and G . J . Schroepfer, Biochem. Biophys. Res. Comm., 1976, 71,984. R.Fears and B. Morgan, Biochem. J., 1976,158, 53. R. Fears and €3. Morgan, Biochem. SOC.Trans., 1976, 4, 58. R. Fears and B. Morgan, Biochem. SOC.Trans., 1976,4, 60. H. J. Weis and J. M. Dietschy, Biochim. Biophys. Acra, 1975, 398, 315. D. Mathe and F. Chevallier, Biochim. Biophys. Actu, 1976,441, 155. M. R. Malinow and P. McLaughlin, Experientia, 1975, 31. 1012. R. Neher and A. Milani, Experientia, 1976, 32, 773. 0. Wiss, Biochem. Biophys. Res. Comm., 1976,68, 350. 0. Wiss, Biochem. Biophys. Res. Comm., 1976,68, 353. G . C. K. Liu, E. H. Ahrens, P. H . Schreibman, P. Samuel, D . J. McNamara, and J . R. Crouse, Proc. Nur. Acad. Sci. U.S.A.,1975, 72,4612. C. Granzow, J. Weber, and D. Werner, Biochem. Biophys. Res. Comm., 1975,66, 53. G . T. Philips and K. H. Clifford, European J. Biochem., 1976,61, 271.

204

Terpenoids and Steroids

from (6R )-[6-2H1,6-3H1,6-14C]- and (6S)-[6-2Hl,6-3Hl,6-14C]MVA, was converted into androsta-1,4-diene-3,17-dione by incubation with Mycobacterium phlei. The latter was converted chemically into oestrone in which the C-18 methyl group contained the only carbon atom that originated from C-6 of MVA. Oxidation of oestrone from (6R)-[6-2H1,6-3H1,614C]MVA gave acetic acid which had the R configuration, and likewise the (6s)-precursor gave (S)-acetic acid. The results indicate that the intramolecular rearrangement of the methyl group from C-15 of squalene to C-13 of lanosterol is stereospecific and involves overall retention of configuration. The 1 4 a -methyl group of 24,25-dihydrolanosterol was lost as formic acid during the biosynthesis of ergosterol by cell-free preparations of Saccharomyces cereuisiae and of cholesterol by rat liver, and the 14a-demethylase from both systems was inhibited by carbon monoxide, providing further evidence in favour of the participation of cytochrome P450 in this The substrate specificity in enzymic demethylation at C-4 of steroid precursors has been explored137by assay of logical precursors with rat liver systems. 4a-Formyl4~-methylcholestan-3~-01was very effectively metabolized and was a possible direct intermediate en route from 4,4-dimethylsterolsYbut 4-methylcholest-3-ene, 3P,4p -epoxy-4a -me thylcholestane, 3a,4a -epoxy-4P -methylcholestane, and others were ineffective. 5a -Cholesta-7,14-dien-3P-o1 is known to be converted into cholesterol on incubation with rat liver homogenates under anaerobic conditions: study of enzymic isornerization of the former to the 8,14-diene by microsomal fractions under nitrogen indicated ready conversion into cholesterol and possible relevance for its biosynthesis. 13* However, there appears to be no information as to the occurrence or formation of the 7,14-diene in uiuo. In the biosynthesis of sterols in Calendula oficinalis the pro-2R hydrogen from MVA was retained at the 15a-position whereas the pro-2s hydrogen was lost from C-15 in the formation of the A14(15)-b~nd,139 and previous reports that both the pro-2R and the pro-2s hydrogens were retained are in error. The dichotomy of sterol biosynthesis whereby the pathway in plants and algae involves the intermediacy of cycloartenol whereas that in animals and fungi involves lanosterol has been employed to confirm that the Oomycete Saprolegnia ferax, which was shown to utilize the cycloartenol pathway, is better classified with the algae than with the higher fungi.140 Unexpectedly, however, [3H]lanosterol was more effectively incorporated into the sterols of the alga Chlorella ellipsoidea than was labelled cycloarten01,~~~ but this may have been due to compartmentation effects. Cycloeucalenol (86), which is considered to be one of the intermediates of sterol biosynthesis in the photosynthetic eukaryotes, on incubation in D 2 0 with microsomes from Zea mays gave [19-2Hl]obtusifoliol (87),142a result that was to be expected since it has previously (1975) been shown that peas germinated in D 2 0 produced cycloartenol deuteriated specifically at C- 19, presumably by a similar route. 136 13’ 13*

139 140

141

14*

K. A. Mitropoulos, G. F. Gibbons, and B. E. A. Reeves, Steroids, 1976, 27, 821. J. A. Nelson, S. Kahn, T. A. Spencer, K. B. Sharpless, and R. B. C!ayton, Bioorganic Chem., 197.5,4,363. H. M. Hsiung, T. E. Spike, and G . J. Schroepfer, Lipids, 1975, 10, 621. J . K. Sliwowski and E. Caspi, J.C.S. Chem. Comm., 1976, 196. J. D. Bu’Lock and A. U . Osagie, Phytochemistry, 1976, 15, 1249. L. B. Tsai and G . W. Patterson, Phytochemistry, 1976,15, 1131. A. Rahier, P. Benveniste, and L. Cattel, J.C.S. Chem. Comm., 1976, 287.

Biosynthesis of Terpenoids and Steroids

205

It has previously been reported that 3H and 14Cfrom methionine were transferred to cholesterol in rat liver preparations uia a process involving degradation and reincorporation (and not by a methylation step): similar incorporations into the side-chain and possibly into the tetracyclic moieties of sitosterol and /3-amyrin have now been demonstrated in Pisum s ~ t i u u m Formation .~~~ of 24-ethyl-5a -cholest-7and 24-ethylcholest-5-en-3Pen-3P-01, (24S)-24-ethyl~holesta-5,22-dien-3/3-01, 01 by Cyathula capitatu was accompanied by loss of tritium at C-24 of cycloartenol during alkylation of the side-chain. However, this atom was retained, probably at C-25, in (24Z)-5a-stigrnasta-7,24(28)-dien-3/3-01,'~~ and such a 1,2-shift, which has been previously demonstrated in the formation of sterols in Phycomyces blukesleeanus (1975), was also shown to occur in the formation of 24-methylene-24,25dihydrolanosterol, obtusifoliol, 22-dihydroergosterol, and ergosterol by Mucor pusillus;145in the latter case methylation at C-24 of the side-chain occurred at the lanosterol level. Side-chain methylation in Chlorella ellipsoidea is completely dependent on the presence of a A24-bondin the sterol precursor, and this organism, unlike Ochromonas m ~ l h a r n e n s i sis, ~unable ~ ~ to introduce unsaturation at C-24to allow further alkylati~n.'~'Reduction of a 24-methylene side-chain appears not to be a major pathway in the formation of the CZssterols (ergost-5-en01 and brassicasterol) in the Chlorellu species.'41 The methyltransferase that catalyses the formation of 24-ethylidene sterols from 24-methylene precursors in bean rust uredospores (Uromyces phaseoli) can also alkylate lanosterol, 24-methylenecholesterol, zymosterol, and desmosterol to produce C29ster01s.l~~ [28-3H]-24-Methylenecholesterol was efficiently (ca. 3% yield) incorporated into withaferin A (88) and withanolide D (89) by Withania somnifera,149whereas [28-3H]-24-methylcholesterol did not act as a precursor in this system. However, since feeding experiments with [28-3H]-24-methylcholesta-5,24dien-3/3-01gave ambiguous results it was not possible to rule out other 4-desmethyl sterols (with c28) as intermediates in withanolide biosynthesis. Several studies are available concerning the metabolism of steroids by insects. It is generally assumed that the Insecta do not synthesize steroids de nouo but accumulate them from food: this was neatly confirmed for the housefly as ['4C]cholesterol recovered from larvae had the same specific activity as that added to their diet."' A 143 144 145 146

14' 148 149

I5O

E. Caspi and B. L. Hungund, J. Steroid Biochem., 1975,6, 1285. R. Boid, H. H. Rees, and T. W. Goodwin, Biochem. Physiol. Pflanzen, 1975, 168, 27. E. I. Mercer and D. J. R. Carrier, Phytochernistry, 1976, 15, 283. J. H. Adler and G. W. Patterson, Lipids, 1976, 11, 634. L. B. Tsai, J. H. Adler, and G. W. Patterson, Phytochemistry, 1975, 14, 2599. H. K. Lin and H. W. Knoche, Phytochemistry, 1976, 15, 683. W. J. S. Lockley, H. H. Rees, and T. W. Goodwin, Phytochernistry, 1976, 15, 937. A . K. Dwivedy, J. ZnsectPhysioL, 1975, 21, 1685.

Terpenoidsand Steroids

206

(88) R1 = H, R2 = C H 2 0 H (89) R' = OH, R2 = Me

unique pathway of sterol metabolism was claimed in the phytophagous Mexican bean beetle:'" precursors were coated on to the leaves of the host plant and CZ9 cholestanols were dealkylated to cholesterol, but AS-C2, phytosterols, stigmasterol, and sitosterol were insignificantly converted into cholesterol, in contrast to the situation for other insects. The accepted route of conversion of phytosterols into cholesterol involves the intermediacy of fucosterol24,28-epoxide [Scheme 14; (90)],

-

v

Scheme 14

and the stereochemistry of this intermediate has now been determined.lS2When [33H]-(24S,28S)-(90) was incubated with supernatant from the homogenate of gut of Bombyx mori a 3796 conversion into desmosterol was observed (the homogenate lacked the enzyme that catalysed the reduction of desmosterol to cholesterol) whereas the (24R,28R)-isomer was only converted in a yield of 0.9%. Steroidal allenes affect the metabolism of the silkworm by specifically inhibiting the stigmast5-en-3p-ol to stigmasta-5,14(28)-dien-3p-oi onv version.''^ 3a-(P,P-Dimethylaminoethoxy)androst-5-en-17-one,its methyl oxime, and 3P-(P,P-dimethyl aminoethoxy)cholest-5-ene all blocked the conversion of p-sitosterol into cholesterol in silkworm larvae and led to accumulation of d e s m ~ s t e r o l . 'A ~ t~higher 151

lS2

153 154

J . A . Swoboda, M. J. Thompson, W. E. Robbins, andT. C. Elden, Lipids, 1975,10,524. S. M. L. Chen, K. Nakanishi, N. Awata, M. Morisaki, N. Ikekawa, and Y. Shimizu, J. Amer. Chem. SOC., 1975,97,5297. N. Awata, M. Morisaki, Y. Fujirnoto, and N. Ikekawa, J. Insect Physiol., 1976, 22, 403. H. Hikino, Y. Ohizurni, T . Saito, E. Nakamura, and T. Takemoto, Insect Biochern., 1976,6 , 21.

Biosynthesis of Terpenoids and Steroids

207

concentrations the androstene derivatives blocked the initial step in the conversion of 6-sitosterol. The first step in the conversion of cholesterol into insect moulting hormones is the formation of cholesta-5,7-dien-3~-oi,arid this transformation occurs directly in Calliphora erythrocephala larvae and not via Sm-cholestan-3~-ol and .5a-cholest-7-en-3~-01.~~~ Formation of the 5,7-diene was accompanied by partial stereospecific elimination of the 76-hydrogen atom of cholesterol during the formation of the A'-bond, and this is consistent with the intermediacy of cholesta5,7-dien-36-01 on the pathway to the ecdysones. Large amounts of C28and C29sterols occur in asteroids and other echinoderms but it seems that they cannot be synthesized from C27 sterols by transmethylation as is the case in plants (but not in other animals). This was confirmed with the starfish Laiaster leechii, which could convert MVA into A'-cholesterol but could not alkylate this at C-24 or introduce a A22-bond.156Similarly the starfish Asterias rubens can only synthesize C,, sterols de novo, but here there is evidence15' that a A22-bondcan be introduced into both cholesterol and A'-cholesterol. This starfish can also synthesize A5-sterolsand there is some indication that cholesterol itself may be synthesized even though it was previously concluded that the family could not perform the final steps in this biosynthesis. This species also rapidly metabolized dietary steroids and such A5-sterols could be converted into A'-products, but it was considered unlikely that the organism had the ability to dealkylate CZ8and C,, 19-Norcholesterol in the sponge Axinella polypoides has been shown to be derived from dietary and a series of unusual C,, sterols, claimed to be formed from 24-epibrassicasterol, has been found in the scallop Patinopecten yessoensis.'60 The pattern of sterols in commercial yeast concentrates and in cultures suggested that 4,4-dimethylzymosterol was an important intermediate on the pathway from lanosterol to ergosterol and this was confirmed by feeding experiments using [2-'H]lanosterol. There was no evidence for any 4,4-dimethylfucosterol as intermediate, and incubation of mixtures of [3H]zymosterol and ['4C]lanosterol with yeast cultures indicated that in the initial stages of aerobic growth the major route to ergosterol passed via zymosterol, but that as this accumulated 4a-methyl-24methylenezymosterol assumed equal importance.'" Several strains of baker's yeast accumulate only C2, sterols and have been shown to lack sterol methyltransferase. Cholesta-5,7,22,24-tetraen-3~-01 has now been isolated from such mutants.162 This compound was not a substrate for the methyltransferase from the parent strain and it inhibited the enzyme when incubated in admixture with the normal substrate (zymosterol). If such inhibition occurs in vivo then on the normal pathway to ergosterol 22(23)-unsaturation must occur after alkylation. Ergosterol peroxide (9 1)occurs widely in yeast and fungi and although incorporation studies have indicated that it is a possible intermediate in the oxidative metabolism of ergosterol there have been reservations that it could be an artefact. A 155

157

ls9 160 161 lh2

P. Johnson, 1. F. Cook, H. H. Rees, and T. W. Goodwin, Biochem. J., 1975, 152, 303. S. I. Teshima and A. Kanazawa, Comp. Biochem. Physiol., 1975, 52B, 437. P. A. Voogt and J. W. A. van Rheenan, Comp. Biochem. Physiol., 1976,54R, 479. P. A. Voogt and J. W. A . van Rheenan, Comp. Biochem. Physiol., 1976,54B, 473. M. De Rosa, L. Minale, and G . Sodano, Experientia, 1975, 31, 758. M. Kobayashi and H. Mitsuhashi, Steroids, 1975, 26, 605. M. Fryberg, L. Avruch, A. C. Oehlschlager, and A. M. Unrau, Cunad. J. Biochem., 1975, 53, 881. R. B. Bailey, L. Miller, and L. W. Parks, J. Bucteriol., 1976, 126, 1012.

Terpenoids and Steroids

208

careful has now revealed that the peroxide is formed by simultaneous non-enzymic photo-oxidation and enzymic pathways in Penicillium rubrum and Gibberella fujikuroi ; this work removes most of the previous ambiguities. This report also; incidentally, assigns a functional role to the pigment found in these two unrelated species of fungi.

(91)

Homogenates from leaves of a number of cardenolide-producing plants were able to convert [ 16,17-3H]-3P-hydroxy-5a-pregnan-20-oneefficiently into 5apregnane-3,20-dione, the corresponding 3@,20@-diol,and, to a lesser degree, progesterone, 20P-hydroxy-Sa-pregnan-3-0ne,and 5a-pregnane-3/3,2Oa-di01.'~~ On the other hand, labelled 3P-hydroxy-SP-pregnan-20-onewas metabolized in very poor yield to 5P-pregnane-3,20-dione and, in the case of Digitalis purpurea, to the corresponding 3P,20p -diol; this indicates that cardenolide biosynthesis is not a major metabolic route in the plants investigated. Two strains of tissue cultures of Digitalis purpurea (one of which required auxins and cytokinins whereas the other did not) were able to convert 5/3-pregnane-3,20-dione into 3P-hydroxy-SPpregnan-20-one, 3a-hydroxy-SP-pregnan-20-one,and the glucosides of the hydroxylated derivatives, but metabolism did not continue further along the pathway to the carden01ides.l~~ Since the metabolic pathways followed in both strains of callus tissue were the same it was concluded that cardenolide biosynthesis is not regulated by exogenous hormone, and such compounds were thought to play only a minor role in the control of diosgenin production in cultures of Dioscorea deltoidea. 166 The use of plant tissue cultures, in which metabolic events are modified compared with the intact plant organs from which they were derived, in order to study the The effect of growth medium on function of steroids in plants has been ad~0cated.l~' the production of sterols by the fungus Leptosphaeria typhae has also been reported. '"

8 Further Metabolism of Steroids Reviews on the biosynthesis and metabolism of pr~gesterone'~'and the vitamins D17'*171have appeared. 163 164 165

166 167

169 170

17'

M. L. Bates, W. W. Reid, and J. D. White, J.C.S. Chem. Cornrn., 1976, 44. S. J. Stohs, Phytochemistry, 1975, 14, 2419. M. Hirotani and T. Furuya, Phytochemistry, 1975, 14, 2601. J. G . Marshall and E. J. Staba, Phytochernistry, 1976, 15, 53. M. R. Heble, S. Narayanaswamy, and M. S. Chadha, Phytochemistry, 1976, 16, 681. J. Alais, A. Lablache-Combier, L. Lacoste, and G . Vidal, Phytochemistry, 1976, 15, 49. M. B. Aufrere and H. Benson, J. Pharm. Sci., 1976, 65, 783. H. F. D e Luca, Ann.Rev. Biochem., 1976, 4 5 , 6 3 1 . H. F. De Luca, Life Sci., 1975, 17, 1351.

Biosynthesis of Terpenoids and Steroids

209

The control exerted by ACTH over steroidogenesis and cleavage of the steroid side-chain in the adrenals may be centred on hydroxylation at C-21 as a consequence of perturbation of the hexose monophosphate or, alternatively, by modification of the structure of the enzyme system responsible for cleavage of the side-chain so as to decrease the susceptibility of the system to an i n h i b i t ~ r . ' Evidence ~~ has been presented for a novel sex-linked hypophyseal factor that effects steroid 5a -reductase in cultured hepatoma cells.'74 Prostaglandins may inhibit androgen biosynthesis in testis by affecting cholesterol e s t e r a ~ e ,but ' ~ ~the picture is complex and in human placenta it has been suggested that these same compounds mainly affect oestradiol-17P - d e h ~ d r o g e n a s e . 'These ~ ~ inhibitors were not found in vitro. This is not surprising as it is generally held that prostaglandins act on membranes: if they do indeed have the claimed effects in vivo they may do so by release of a second messenger such as c -AMP. Progesterone formation in mitochondria from placenta is stimulated by citrate but inhibited by Mn2+: several rationalizations are possible. 177 Detailed exploration of the mechanism of cleavage of the side-chain of sterols en route to sex hormones continues. Conversion of cholesterol into its 22-hydroxy- and 20,22-dihydroxy-derivativesand pregnenolone by bovine adrenocortical preparations in an "0,-enriched atmosphere resulted in all three compounds containing label, and the distribution of this in the dihydroxy-compounds proved the hydroxygroups of the side-chain to be derived from two different molecules of oxygen. This is consistent with sequential hydroxylation and eliminates certain previously proposed mechanisms involving oxetans as intermediates. 178 A claim that formation of pregnenolone in the adrenal cortex initially involved dihydroxylation of cholesterol at (2-20 and C-22 followed by dehydration, epoxidation, and hydration could not be substantiated by experiments using the proposed intermediates as substrates for acetone powders from adrenal An anaerobic route for degradation of the pregnenolone side-chain provides a possible new pathway to androgens: metabolism of ['80]-17a-peroxypregnenoloneby rat testicular microsomes under argon led to a route involving dioxetan intermediates rather than a previously suggested BaeyerVilliger-type mechanism (Scheme 15).180

Scheme 15

172 173 174 175

176 177

1'8 179 180

A. F. de Nicola, J. Steroid Biochem., 1975,6, 1219. S. B. Koritz and A, M. Moustafa, Arch. Biochem. Biophys., 1976, 174, 20. J. A. Gustafsson, A. Larsson, P. Skett,and A. Stenberg, Proc. Nat. Acad. Sci. U S A . ,1975,72,4986. L. C. Ellis, D. K. Sorenson, and L. E. Buhrley, J. Steroid Biochem., 1975,6, 1081. M. A. Shaw and J. Jeffery, Biochem. SOC.Trans., 1975, 3, 889. W. Boguslawski, J. Klimek, B. Tialowska, and L. Zelewski, J. Steroid Biochem., 1976, 7, 39. S. Burstein, B. S. Middleditch, and M. Gut, J. Biol. Chem., 1975, 250, 9028. S. Burstein, C. Y. Byon, H. L. Kirnball, and M. Gut, Steroids, 1976, 27, 691. L. Tan and J. Rousseau, Biochem. Biophys. Res. Comm., 1975,65, 1320.

210

Terpenoids and Steroids

At the distal end of the hormone skeleton, it has been suggested as a result of studies on model systems that ring A may be aromatized in vivo by epoxidation rather than by simple hydroxylation (Scheme ~C-I).'~' This work may stimulate biochemical studies o n the role of unsaturation in ring A of androgen precursors.'82

Scheme 16

Tracer studies support the latter mechanism as a likely route for the operation of A43-oxo-steroid-5cu,5~-red~ctases in the formation of non-aromatic mammalian steroid hormones. '" Other studies of steroid hormone biosynthesk cover a variety of subjects. Reduction of 2 1-dehydrocortisol by the appropriate dehydrogenase involves transfer of hydrogen from the 4s-position of NADH,Ig4and the same hydrogen is utilized by 3P-hydroxy-steroid dehydrogenase of Pseudomonas testosteroni.'*' The latter is especially noteworthy as liver alcohol dehydrogenase transfers the epimeric hydrogen of the reduced coenzyme to the same substrate; this is an exception to the Alworth-Bentley rule that the stereospecificity of removal of the paired methylene hydrogens at C-4 of reduced pyridine nucieotides is fixed and does not vary with the source of the enzyme preparation. It appears that for these two enzymes the selection of the face of NADH from which hydride is transferred cannot be dictated by the 'best fit' of substrate and cofactor. Various corticosteroids were oxidized to steroidal-21-oic acids by a metalloenzyme of molecular weight ca. 74 000 daltonlB6 and sitosterol is converted into steroid hormones by rat testis in vitro. lB7A detailed study of the action on cholesterol of dioxygenases has demonstrated that 7cu- and 7 0 -hydroperoxides are formed by both plant and animal preparations.'" IU1

Ih? 1X.t 184 1U S

I86 1 87

188

P. iblorand, M. Kalapurackal, L. Lompa-Krzymien, and A. van Tongerloo, J. Theoret. Biol., 1976, 56, 503. M. Ganguly, K. L. Cheo, and H. J. Brodie, Biochim. Bzophys. Acru, 1976, 431, 326. D. C. Wilton, Riochem. J., 1976, 155, 487. J. C. Orr and C. Monder, J. Biol. Chem., 1975, 250. 7547. E. V. Groman, R. M. Schultz, L. L. Engel, and J. C. Orr, European J. Biochem., 1976,63,427. K. 0. Martin and C. Monder, Biochemistry, 1976, 15,576. M. T. R. Subbiah and A. Kuksis, Experientia, 1975, 31, 763. J. I. Teng and L. L. Smith, Bioorg. Chern., 1976, 5, 99.

Biosynthesis of Terpenaids and Steroids

21 1

Intense interest still surrounds the cytochrome P450-dependent systems that are responsible for many nuclear and side-chain hydroxylations of steroids.1*9-193 Studies on the hydroxylation of cholesterol at C-7 indicate that there is probably not a cholesterol-specific type of cytochrome P450: it is thought that the enzyme complex functioning as the steroid 7 a -hydroxylase contains an additional component that binds cholesterol and competes for the 0,-activated site with other The 15phydroxylases that are subject to separate regulatory hydroxylating system of Bacillus rnegateriunz has been resolved into (i) an NADPHdependent FMN-flavoprotein, (ii) an iron-sulphur protein, and (iii) cytochrome P450, which could be recombined to regenerate full activity."* Antibodies raised to adrenal ferredoxin in goat inhibited side-chain cleavage in bovine, rat, and other adrenal mitochondria1 systems. 196-198 Details of the hydroxylations and subsequent modifications that convert cholesterol into bile acids continue to be explored. The overall conversion depends on '~~ as a consequence of effects on the cytochrome ascorbate levels in ~ i v o , perhaps P450 forming part of the microsomal7a -steroid hydroxylase.200 This liver enzyme system, which is believed to initiate the first step in bile acid formation from cholesterol, is a mixed-function oxidase and unlike hydroxylases that occur in the mitochondria and mediate the side-chain cleavage is highly substrate 7a Hydroxy-4-cholesten-3-onehas been proposed to be the last common intermediate for cholic and chenodeoxycholic acids but tracer experiments in bile-fistula rats suggest that this might not be so202as do studies on metabolism of this proposed precursor in man.203 Although current theories have suggested that chenodeoxycholic acid is not converted into cholic acid under normal conditions there appears to be a definite but limited capability for this transformation in perfused rat liver.*04 In the same experimental system, potential precursors of chenodeoxycholic acid may be hydroxylated at the C- 12a-position either before or after hydroxylation in the side-chain at C-25 or C-26. This implies that cholic acid may be formed via the classical pathway of hydroxylation at C-26 or via (2-25 hydroxylation.20' Previously it had been concluded that hydroxylation at C- 12 preceded attack in the side-chain, but apparent discrepancies of order of functionali189

19'

I9l

192 193

*94

195 196 197

198 1g9

201 202

203

204

205

Q. P. Lee, P. K. Zachariah, and M. R. Juchau, Steroids, 1975,26, 571. E. G . Hrycay, J. A. Gustafsson, M. Ingelman-Sundberg. and L. Ernster, European J. Biochem., 1976,61, 43. G. Betz, P. Tsai, and R. Weakley, Steroids, 1975, 25, 791. R. H. Menard, F. C. Rartrer, and J. R. Gillette, Arch. Biochern. Biophys., 1976, 173, 395. S. D. Nelson. J. R. Mitchell, E. Dyborg, and H. A. Sasame, Biochem. Biophys. Re5. Comm., 1976, 70, 1157. S. Balasubrarnaniam and K. H. Mitropoulos, Biochem. Soc. Trans.. 1975, 3, 964. A. Berg, J. A. Gustafsson, M. Ingelman-Sundberg, and K. Car!strom, J. Biol. Chem., 1976.251,2831. J. Baron, Arch. Biochem. Biophys., 1976, 174, 226. J. Baron, Arch. Biochem. Biophys., 1976, 174, 239. G . Kapke and J. Baron, Biochem. Biophys. RPS.Cornm., 1976,70, 1097. D. Hornig and H . Weiser, Experientia, 1976, 32, 687. 1. Bjorkheim and A. Kallner, J. Lipid Res., 1976, 17.360. J. R. Arthur, H . A. F. Blair, G . S. Boyd, J. I. Mason, and K. E. Suckling, Biochern. J., 1970, 158, 47. C. A. Sherman and R. F. Hanson, Steroids, 1976,27, 145. R. F. Hanson, P. A. Szczepanik, P. D. Klein, E. A. Johnson, and G .C. Wilhams, biochrm. Biophys. Acta, 1976,431,335. I. M. Yousef and M. M. Fisher, Lipids, 1975. 10, 5 7 i . B. I. Cohen, T. Kurarnoto, M. A. Rothschild, and E H. Mosbach, J Riol. Chem., 1976, 251, 2709.

212

Terpenoids and Steroids

zations such as this may merely reflect the operation of metabolic grids comprising enzymes of group, rather than substrate, specificity. Rat liver microsomes hydroxylate 5 p -cholestane-3a,7a712a-trio1 at C-25 and C-26: both activities are dependent on cytochrome P450 and there is some evidence A mitochondria1 steroid 24that different types of the latter are hydroxylase that accepts 3a,7a, 12a-trihydroxy-5~-cholestanoic acid has been extracted from rat liver:2o7apparently this is not a mixed-function oxidase although the presence of oxygen was obligatory for its action, Bile acids hydroxylated at C-23 have been formed from sodium cholate and deoxycholate in preparations from Viperinae specieszosand a steroid- 12a-hydroxylase from liver microsomes has been studied.209Sitosterol has been confirmed to be a precursor of CZ4and C29 bile acids in mammalian liver, and here hydroxylation at C-26 precedes that at C-7.210*211 The biosynthesis of the ecdysones (moulting hormones) from steroids has been briefly reviewed.212 a - and P-Ecdysones are formed from cholesterol in the Y-organs of the pre,moult crayfish Orconectes limosus and presumably these are the moulting glands.213 In larva of the housefly Musca domestica the same compounds are synthesized in oenocytes from the abdominal region:214this work confirms previous suggestions that the prothoracic glands are not the only moulting glands in insects. Investigations of the conversion of [3H]-a-ecdysone into its p-isomer in Calliphora erythrocephalu during larval development suggest that in vivo the hydroxylation at C-20 is not important in the regulation of the latter isomer but rather that inactivation of this plays a key role in determining the titre of moulting hormone.' 15216 In contrast, the high p :a-ecdysone level in the fly Sarcophagu bullata has been assigned to high levels of activity of the appropriate 20h y d r ~ x y l a s e and ~ ' ~ the enzyme has been partially purified from the midgut of the tobacco hornworm where again it is suspected to have a regulatory Other studies of the levels of ecdysone in larval-pupal development have appeared.219 The detailed mechanism of the formation of ecdysones in insects continues to be explored. [3~x-~H]-3P, 14a-Dihydroxy-S~-cholest-7-en-6-one is metabolized in Calliphora stygea at puparium formation via the keto-trio1 (92) to a - and pecdysones and so the diol(93) is a likely precursor in vivo.220In another Calliphora species a 3H-14C study of the interconversion of cholest-5-en-3P-01 into cholesta5,7-dien-3P-ol showed that cis-7(3- and -8P-hydrogens were removed. The same stereochemistry has been previously found in the biosynthesis of ecdysone and for 2*6

I. Bjorkheim, H. Danielsson, and K. Wikwall, J. Biol. Chem., 1976, 251,3495.

J. Gustafsson, J. Biol. Chem., 1975, 250,8243. 208 S. Ikawa and A. R. Tarnmar, Biochem. J., 1976,153,343. *09 S.S. Ali and W. H. Elliott, J. Lipid Res., 1976, 17,386.

2n7

210 211 212

213 214

215

21h 217 *l*

21y

220

L. Aringer, P. Eneroth, and L. Nordstrom, J. Lipid Res., 1976, 17. 263. L. Aringer, J. Lipid Res., 1975. 16, 426. H. H. F,ees and T. W. Goodwin, Biochem. SOC.Trans., 1974, 2, 1027. A. Willig and R. Keller, Experientia, 1976, 32,936. G.Studinger and A. Willig, J. Insect Physiol., 1975, 21, 1793. N. L. Young, InsectBiochem., 1976, 6 , 1. N. L. Young, J. InsectPhysiol., 1976, 22, 153. W.E. Bollenbacher, W. Goodman, W. V. Vedeckis, and L. I. Gilbert, Steroids, 1976, 27, 309. N. N. Nigg, J. A. Svoboda, M. J. Thompson, S. R. Dutky, J. N. Kaplanis, and W. E. Robbins, Experientia, 1976, 32,438. B. Largueux, J . M. Perron, and J. A. Hoffmann, J. Insect Physiol., 1976, 22,57. M.N. Galbraith, D. H. S. Horn, E. J. Middleton, J. A. Thompson, and J. S. Wilkie, J. Insect Physiol., 1975, 21,23.

Biosynthesis of Terpenoids and Steroids

213

analogous reactions in protozoa and in a cockroach species. A feature of the present work was the strict adherence to aseptic conditions: in non-sterile regimes the contribution of the associated microflora to the total metabolism of the insect could be considerable. ’”

Some thirty phytoecdysones occur in higher plants where their biological function is presumably to interfere with the hormonal metabolism of phytophagous insects. The detoxification of such compounds by the silkworm Bornbyx rnori222and their formation in tissue culture of Achyranthes species have been r e p ~ r t e d . ” In ~ a study of the formation of cyasterone (94) in the plant CyathuZu cupitutu, conventional use of doubly labelled precursors showed that a C-24-ethylidene sterol was a precursor without the necessary involvement of a C-24-ethyl sterol. Certain pathways involving ethylidene sterols could be ruled out and an earlier detailed mechanistic proposal (1968) was consistent with the result^.''^ Feeding [4-3H1,2-’4C]MVA to the same plant’44 proved that the 3H at C-24 in cycloartenol was eliminated during side-chain alkylation to form 24-ethyl-5a -cholest-7-en-3P -01, (24S)-24-ethylcholest-5,22dien-3P-01, and 24-ethylcholest-5-en-3P-01, but was retained (probably at C-25) in (242)-5a -stigmasta-7,24(28)-dien-3P-o1. In the co-occurring cyasterone, all 3H from the mevalonoid precursor was retained in the nuclear fragment (at C-17) after cleavage of the side-chain and a negligible amount was found in the latter. Significant incorporation of [ ‘‘C]sitosterol and [3H]fucosterol into cyasterone could not be detected under these conditions. These findings were discussed in terms of the stage in phytosterol biosynthesis where the cyasterone pathway branches but it remains possible that compartmentation effects did not allow passage of the labelled waterinsoluble precursors to the biosynthetic sites. 9 Non-steroidal Triterpenoids More details of work, reported in 1972, on the stereospecificity of biosynthesis of P-amyrin (95) in Pisurn sutivurn are a~ailable.”~The cis-terminal methyl groups of squalene and the 4p-, 8-, lo-, 14-, 17-, and 20a-methyl groups of P-amyrin were all formed from C-6 of MVA. This is in accord with a ‘chair’ form of 2,3-oxidosqualene zz1 P. Johnson, H. H. Rees, andT. W. Goodwin, Biochem. SOC.Trans., 1974,2, 1062. 222 223 2z4 225

H. Hikino, Y.Ohizumi. and T. Takemoto, J. Insect Physiol., 1975, 21, 1953. H. Hikino, H. Jin, andT. Takemoto, YukugukuZusshi,1975,95,581 (Chem.A h . , 1975,83,93 91 1). R. Boid, H. H. Rees, andT. W. Goodwin, Biochem. SOC.Trans., 1974, 2, 1066. T. Suga and T. Shishibori, Phytochemistry, 1975.14, 2411.

Terpenoids and Steroids

2 14

in the cyclization. The distribution of cycloartenol and P-amyrin in P. sativum has led to the conclusion that the cotyledon, which synthesizes the triterpenoid but not sterols, either lacks oxidosquaiene-cycloartenol cyclase or contains an inhibitor for this.226 A cell-free system from Acetobacter rancens converted [ 12,13-'HH]squalene into hop-22(29)-ene (96) and hopan-22-01 (97), whereas (3RS)-[ 12,13-3H]-2,3oxidosquaiene was transformed into the 'unnatural' 3-hydroxyhopane derivatives 1 This confirms previous findings in Tetrahymena and Polypodium (98)-(10 species that squalene, and not 2,3-oxidosqualene, is the precursor of the 3-deoxytriterpenoids and shows that the cyclase in the prokaryote is able to accept both squalene and its 2,3-epoxide as well as the unnatural 3s-isomer of the latter.

. (96) R ' = R2 = H (981 R' = H, R'= OH ( I 00) R' = OH, R~ = H

(95)

(97) R' = R ~ = H

(99) R' = H, R2 = OH (101) R' =OH, R'= H

The profile of the incorporation of 14Cfrom acetate into medicagenic acid (102) in Medicago media suggested that it is the first saponin synthesized in the germinating seeds ,? Investigations with tissue cultures of Isodon japonicus using [ 1,2-13C]acetate have been extended2'' to the study of the formation of ring E of ursolic acid. Ruzicka's hypothesis for the cyclization of 2,3-oxidosqualene appears to hold for the ursanes (103) and (104) as indicated in Scheme 17, and routes involving the carbonium ion (1 0 5 ) can be excluded. The hydroxylation of triterpenols to the corresponding diols in the flowers of Culendula oficinalis apparently occurs exclusively in the chromoplasts,23" and the triterpenol ester is substrate. The formation of triterpenoid analogues of carotenoids T. Y. Fang and D. J. Baisted, Bmchewt. J., 1975, 150, 323. C. Anding, M . Rohmer, and G. Ourisson, J. Amer. Chem. Soc., 1976. 98, 1274. E. Nowacki, M. Jurzysta, and D. Dietrych-Szostak, Biochem. Physiol. Pflanzen, 1976,169, 183. no S. Seo, Y. Tomita. and K. Tori, J.C.S. Chem. Comm., 1975, 954. 21(J G. Acfler and Z.Kasprzyk, Phyrochemisfry. 1976, 15, 205. Zz6

227

215

Biosynthesis of Terpenoids and Steroids

HO HO

1

e-

R HO (103) R = H (104) R = OH

Scheme 17

(105)

in Streptococcus fuecium has been further investigated: 23 1,232 the C: N ratio in the growth medium is an important factor in the regulation of carotenogenesis. The routes of biosynthesis of the diapocarotenoids (cf. the routes to the C40carotenoids) were confirmed. 231

232

R. F. Taylor and B. H. Davies, J. Gen. Microbial., 1976,92, 325. R. F. Taylor and B. H. Davies, Biochern. J., 1976, 153, 233.

Terpenoids and Steroids

216 10 Carotenoids

Reviews of the b i o ~ y n t h e s i s ’ ~ and ~-~~~ of carotenoids are available. Carotenoid biosynthesis by a cell-free system from Flavobacterium species has been briefly Interest in the action of various chemicals on carotenoid biosynthesis has been maintained: in Phycornyces blakesleeanus and its mutants, diphenylamine caused increased levels of phytoene and phytofluene and reduced levels of coloured carotenes, whereas dimethyl sulphoxide reduced both types.238 The drug A M 0 1618 increased the levels of all types of carotenoids in all strains, probably by preventing cyclization of GGPP and so increasing the amount of this precursor available for dimerization. The Et,NCH2 group in the amines (106)-(108) was Me(CH2), NEt2

Ph(CH2),NEt2

(106) n = 4-8

(107) n = 1-5

RC~H~OCH~CH~NE~Z (108) R = H, p-Me, p-Et, p-Pr’, or p-But

essential for the stimulation of carotenogenesis in g r a p e f r ~ i t . ~Those ~ ’ compounds that did not contain an aromatic nucleus gave less inhibition of the cyclases, but (107; n = 4 or 5) caused increased accumulation of lycopene precursors. It appears that the action of these amines is similar to that previously found for 2-(4chlorophen yl t hio)triethylamine. 4- [p - (Diethy1amino)ethoxylbenzophenone inhibited hydroxylation at C-1 and C-1’ and induced carotenoid accumulation in Rhodospirillum rubrum, presumably by derepression of the gene level for car0te nogenesis. 240 Various studies on carotenoid biosynthesis in higher plants are available, i.e. concerning the influence of light on carotenogenesis in tomatoes241and on radish the evidence for a phytochrome-mediated pathway in the former,243 and carotenoid synthesis at four levels of maturity in fruit of the bitter melon Momodica c h ~ r a n t i a , ’in~ ~ and during ripening in oranges.246 Confirmatory evidence that spinach chloroplasts are capable of total synthesis of pcarotene has also been A multienzyme aggregate of four identical dehydrogenases (copies of the car B gene product) that act sequentially in the conversion of phytoene into lycopene has been proposed to account for the formation of acyclic carotenoids in P. blukesleeunus 233

234

235 236 237 238

239 240 241

242 243 244

245

246 247

E. D. Beytia and J. W. Porter, Ann. Rev. Biochem., 1976, 45, 113. G. Britton, in ‘Chemistry and Biochemistry of Plant Pigments’, ed. T. W. Goodwin, 2nd Edn., Academic Press, London, 1976, p. 1. B. H. Davies, Ber. deut. botan. Gesellschaft, 1975, 81, 7. T. W. Goodwin, in ref. 234, p. 262. D. J. Brown, G . Britton, andT. W. Goodwin, Biochem. SOC.Trans., 1975, 3,741. T. C. Lee, D. B. Rodriguez, I. Karasawa, T. H. Lee, K. L. Simpson, and C . 0. Chichester, A p p l . Microbiol., 1975, 30, 988. S. M. Poling, W. J . Hsu, and H. Yokoyama, Phytochemistry, 1975, 14, 1933. E. P. Hayman and H. Yokoyama, J. Bacteriol., 1976, 127, 1030. L. C. Raymundo, C. 0. Chichester, and K. L. Simpson, J. Agric. Food Chem., 1976,24, 59. H. K. Lichtenthaler, Physiol. Plant., 1975, 34, 357. R. L. Thomas and J. J. Jen, Plant Physiol., 1975, 56, 452. D. B. Rodriguez, L. C. Raymundo, T. C. Lee, K. L. Simpson, and C. 0.Chichester, Ann. Bot., 1976,40, 615. D. Laval-Martin, J. Quennemet, and R. Moneger, Phytochemistry, 1975, 14, 2357. S. K. Eilati, P. Budowski, and S. P. Monselise, 2. Expt. Bot., 1975, 26, 624. H. Bickel and G. Schultz, Phylochernistry, 1976, 15, 1253.

Biosynthesis of Terpenoids and Steroids

217

A similar enzyme complex of four dehydrogenases and two identical , ~ ~it~was considered that the cyclases has been invoked in Ustilago ~ i o l a c e aand white and co!oured mutants are the result of structural mutations that alter the conformations of these aggregates. Study of the biosynthesis of carotenoids by Myxococcus fulvus in the presence of nicotine and 4-chloro-5-dimethylamino-2(Q,Q,CY-trifluoro-m -tolyl)-3(2H)-pyridazinone has led to the hypothesis that there are four sites of regulation. The results suggested that the enzymes responsible for the conversion of phytoene into the main end-product, myxobacton ester, are arranged in an assembly line, the sequence of which is, however, not in~ariable.~” A genetic map of a region concerned with carotenoid production in Rhodopseud omonas capsulata has been deduced.251 In the photosynthetic bacteria Rhodomicrobium uannielii, which normally contains acyclic carotenoids with tertiary hydroxy- and methoxy-groups at C-1 and C-1’, phytoene only accumulated when diphenylamine was present, but the occurrence of hydroxy-derivatives of phytofluene, 7,8,11,12-tetrahydrolycopeneYneurosporene, and lycopene in the presence of the inhibitor252indicated that hydroxylation could take place at any level of desaturation although only the more desaturated half of the molecule was so substituted. Isolated lettuce chloroplasts could epoxidize zeaxanthin in the presence of reduced pyridine nucleotides and oxygen and the process was stimulated by bovine serum albumin (which protected the epoxidase system from inhibition by fatty Detailed study led to the conclusion that the epoxidase was an ‘external monoxygenase’ and that the violaxanthin cycle (of which epoxidation of zeaxanthin is a part) was a trans-membrane system wherein de-epoxidation took place on the loculus side and epoxidation on the stroma side of the membrane. This arrangement requires migration of the carotenoids of the violaxanthin cycle across the membrane in a type of shuttle. The possible role of this cycle in some regulatory mechanism of photosynthesis at the membrane level was also discussed. In some species of green algae keto-carotenoids were synthesized when growth was halted by environmental conditions and these compounds may be formed either by the catabolism of chlorophyll or by the result of de nouo synthesis. The profile of incorporation of tracer from [2-14C]acetate by Haematacoccus lacustris into carotenoid and keto-carotenoids indicated that the latter was the major pathway to the keto-compounds, but some breakdown of chlorophyll did occur and the relative contributions of these two pathways varied with the external In the marine isopod Idotea resecata incorporation of [14C]-P-car~teneinto hydroxycarotenoids was very low and it was not possible to decide whether the ketocarotenoids present were formed by direct oxidation of @-caroteneto canthaxanthin via echinenone or via h y d r o x y - c o m p ~ u n d s . ~ ~ ~ Carotenoids of the crustacea have attracted attention because of the colour that they impart to the animals. It is generally accepted that, like other animals, this class 248

249

250 251

252

253 z54 255

C. M. G. Aragon, F. J. Murillo, M. D. de la Guardia, and E. Cerda-Olmedo, EuropeanJ. Biochem., 1976, 63, 71. E. D. Garber, M. L. Baird, a n d D . J. Chapman, Botan. Guz., 1975, 136, 341. H. Kleinig, European J. Biochem., 1975, 57, 301. H. Yen and B. Marrs, J. Bacreriol., 1976, 126, 619. G. Britton, R. K. Singh, T. W. Goodwin, and A. Ben-Aziz, Phytochemistry, 1975,14, 2427. D. Siefermann and H. Y. Yamamoto, Arch. Biochem. Biophys., 1975, 171, 70. P. Donkin, Phytochemistry, 1976,15, 711. B. M. Gilchrist and W. L. Lee, Comp. Biochem. Physiol., 1976, 54B, 343.

Terpenoids and Steroids

218

does not carry out de novo synthesis but rather modifies and stores dietary pigments. Astaxanthin (109) was the predominant (> 70% of the total) carotenoid of seven common crustacean species (prawn, crab, lobster, e t ~ . )Carotenoids . ~ ~ ~ that possess chiral centres have hitherto always been of the same optical form irrespective of their source but now (3R,3’R)-astaxanthin has been isolated from the yeast Phafia rhodozyma whereas Haematococcus and Homarus species contained the (3S,3’S)isomer.257It was argued that carotenoid hydroxylases have the same stereochemical specificities regardless of organism but that this specificity is related to the structure of the precursor of the chiral carotenoid. Of the possible routes of biosynthesis of astaxanthin (Scheme 18) that involving initial hydroxylation at C-3 (route a ) would

1

1

e

0

1

1

0

(3S,3’9( 109)

(3R,3’R)-(109) Scheme 18

256

257

Y. Tanaka, H. Matsuguchi,T. Katayama,K. L. Simpson, and C. 0.Chichester, Cornp.Biochern. Physiol., 1976,54B, 391. A. G. Andrewes and M. P. Starr, Phyfochernistry, 1976, 15, 1009.

Biosynthesis of Terpenoids and Steroids

219

be expected to yield the (3S)-carotenoid whereas hydroxylation of a preformed 40x0-carotenoid (route b ) might yield the (3R)-isomer. A detailed study of the carotenoids in P.rhudozyma258has provided evidence that this latter pathway might be that operative in the yeast.

11 Meroterpenoids The biosynthesis of the isoprenoid moiety of terpenoid alkaloids has been reviewed.259 It has been found260that catharanthine (which accumulates in Vinca rosea) inhibited a membrane-bound monoxygenase that oxidized geraniol at C- 10. The inhibition was reversible and non-competitive in solubilized preparations of the enzyme and hence was probably not due to disruption of membranes. Other alkaloids that were produced as end-products were less inhibitory and catharanthine may mediate feed-back control of alkaloid biosynthesis in uiuo. The steroidal alkaloid tomatine accumulated mainly in the vacuoles and the soluble phase of the cytoplasm of the pericarp tissue of green tomato fruit and it was believed that the microsomal organelles were responsible for its synthesis.261(25s)[2,4,2',4'-3H4]-5a-Cholestan-3P,26-diol (110) was incorporated into both neotigogenin (1 11) and tomatidine (1 12) in Lycopersicon pimpinellifolium whereas under similar conditions tracer from (25S)-[2,4,2',4'-3H4]-5a-furostan-3@,26-diol (113) was incorporated only into the sapogenin (111).262 Since 26aminodihydrodiosgenin (1 14) is efficiently incorporated into solasodine (1 15) it is reasonable to assume that introduction of nitrogen at C-26 must have occurred before the tetrahydrofuran ring was formed. Isolated chloroplasts from green potato peelings could incorporate tracer from 14C02, ['4C]formate, [2-'4C]glycine, [2''C]pyru~ate, [2-14C]acetate, [2-14C]MVA, or [ U-14C]serine into the solanidine , ~ ~ ~addition of inactive formate, serine, or moiety of the toxic alkaloid ~ o l a n i n ewhilst pyruvate to the chloroplast preparation caused a decrease in tracer incorporated into MVA from I4CO2;these results were taken to indicate the pathway from CO, to mevalonate in these organelles. A cell-free system from Aspergillus terreus catalysed the transfer of C5 units to both aryl rings of dihydroxypulvinone (116), giving a possible precursor (117) of the fungal metabolites (118) and (1 19).264,265 Synthesis of key intermediates indicated that prenylation occurred first at ring A and this was followed by prenylation and cyclization at the distal ring.266 [2-14C]MVA, [l-3H]geraniol, and [ l-3H]nerol were all incorporated into cannabichromenic acid (120) and tetrahydrocannabinolic acid (12 1) by Cannabis ~ a t i v aand , ~ [~arboxy-'~C]cannabigerolic ~~ acid (122) labelled these two compounds and also cannabidiolic acid (123). The results probably show that cannabigerolic 258

259

260 261 262 263 264

z66 267

A . G. Andrewes, H. J. Phaff, and M. P. Starr, Phytochemistry, 1976,15, 1003. B. Gabetta, Fitoterapia, 1975,46, 147. J. McFarlane, K. M. Madyastha, and C. J. Coscia, Biochem. Biophys. Res. Comm., 1975,66, 1263. J. G. Roddick, Phytochemistry, 1976, 15, 475. F. Ronchetti, G . Russo, G. Ferrara, and G. Vecchio, Phytochemistry, 1975, 14, 2423. N. K. Ramaswamy, A . G. Behere, and P. M. Nair, European J. Biochem., 1976,67,275. N. Ojima, K. Ogura, and S. Seto, J.C.S. Chem. Comm., 1975, 717. N. Ojima, I. Takahashi, K. Ogura, and S. Seto, Tetrahedron Letters, 1976, 1013. D. W. Knight and G. Pattenden, J.C.S. Chem. Comm., 1976, 635. Y. Shoyama, M. Yagi, 1. Nishioka, and T. Yamauchi, Phytochemistry, 1975,14, 2189.

220

Terpenoids and Steroids

R'

(111) R' =Me, R2 = H, X = 0 (112) R'=Me, R 2 = H , X = N H (1 15) R' = H, R2 = Me, X = NH; As R'. I

&

F

R

2

HO

Q/yyJa:: ' R'

HO (113) R' = Me, R2 = CHzOH (114) R' = CH2NH2,R2 = Me; A5

(116) R ' = R ~ = H (117) R ' = R 2 =

(1 19)

acid was the initial intermediate formed from the coupling of the isoprenoid and polyketide precursors and that this compound was converted directly into (120) and (121) as in Scheme 19. A review of the biosynthesis of Vitamin K and other naturally occurring naphthoquinones268and an outline of recent work on the induction of biosynthesis, metabolic turnover, and kinetics of formation of this vitamin and other prenyl lipids have a p p e a ~ e d . ~ ~ ~ -The ' ~ ' prenylation of 4-hydroxybenzoate has been further A cell-free extract of Euglena gracilis could synthesize nona- and octa-prenyltoluquinol from homogentisate and a Micrococcus luteus extract that had been pre-incubated with IPP.273The same system produced 2-deca-, 2-nona-, and 2-octa-prenyl forms of 4-carboxy-2-polyprenylphenolwhen p-hydroxybenzoate 268 269

270 271 272

273

R. Bentley, Pure A p p l . Chem., 1975,41, 47. H. K. Lichtenthaler and K . H. Grumbach, Proceedings of the international Congress on Photosynthesis, ed. M. Avron, Elsevier, New York, 1975, Vol. 3, p. 2007. H. K. Lichtenthaler and H. K. Kleudgen, ref. 269, p. 2017. H. H. Anigk and H. K. Lichtenthaler, ref. 269, p. 2021. S. S. Aiam, A . M. B. Nambudiri, and H. Rudney, Arch. Biochem. Biophys., 1975,171, 183. G . Thomas and D. R. Threlfall, Phytochemistry, 1975, 14, 2607.

+p

22 1

Biosynthesis of Terpenoids and Steroids

Isoprenoid precursor (Clo)} Polyketide precursor (CIS)

C 502H H1 I

1 C 0

%co2~

,A

(122’1

~

.--+

0

2

’

(120)

Scheme 19

CSH,,

0 H

’

CSH,,

ck(3c0 ’

H

CSHII

>OH

(121)

was the substrate. The prenyltransferase was fairly substrate specific. The polyprenyltoluquinols may be obligate intermediates on the route from homogentisate to plastoquinone. In Euglena the 3-polyprenyltoluquinols were synthesized in the etioplasts and chloroplasts whereas the 4-carboxy-2-polyprenylphenolswere synthesized mainly in the mitochondria. Distribution studies in Calendula officinalishave shown that the side-chain of plastoquinone is synthesized in the cytoplasm and transported to the Although it is generally accepted that insects are unable to synthesize sterols de novo, aseptic larvae of Calliphora erythrocephala synthesized ubiquinones 8, 9, and 10, dolichols-17, -18, and -19, and farnesol from [2-’4C]MVA.275A brief study oftRNA-isopentenyl transferase from a Lactobacillus species has appeared.276Certain furanosesquiterpenoids are known to be produced in response to infection of sweet potato by micro-organisms. The activity of the MVA-PIPP system, especially of pyrophosphomevalonate decarboxylase, was increased up to ten-fold in the infected tissues over control, but the levels were also elevated in tissue adjacent to the infected region and the increase preceded the formation of the stress metabolite in the infected region. Physical wounding did not produce the furanoterpenoid and had only a slight effect on the activity of these enzyme systems. Mercuric chloride and other inorganic compounds were also inducers of furanoterpenoids and the response was inhibited by application of cycloheximide and so may have involved protein synthesis de n 0 v 0 . ~ ~ ’

12 Methods New, or more efficient, syntheses have been reported for [ 1-13C]-and [2-’3C]-acetic aCidS278.279 and chiral acetate,280 [3-14C]HMG-CoA,281 [4,5-’3C2]MVA,71 [9274 275

276

277 278

279 280 2R1

W. Janiszowska, W. Michalski, and Z. Kasprzyk, Phytochemistry, 1976,15, 125. A . S. Beedle, M. J. Walton, and T. W. Goodwin, Insect Biochem., 1975, 5, 465. J . Holtz and D. Klambt, 2.physiol. Chem., 1975,356, 1459. K. Oba, H. Tatematsu, K. Yamashita, and I. Uritani, Plant Physiol., 1976, 58, 51. D. L. Fitzell, D. P. H. Hsieh, C. A. Reece, and J. N. Seiber, J. Labelled Compounds, 1975,11, 135 D. G. Ott and V. N. Kerr, J. Labelled Compounds, 1976,12, 119. C. A. Townsend, T. Scholl, and D. Arigoni, J.C.S. Chem. Comm., 1975, 921. H. Suzuki, K. Oba, and I. Uritani, Agric. and Biol. G e m . (Japan), 1975, 39, 1675.

Terpenoids and Steroids

222

14C]gerani01,~~~ [ 11,12-2H2]-and [ 11,12-'H2]- chenodeoxycholic and -1ithocholic acids,283 ( R ) - e p ~ x y g e r a n i o l ,(R)~ ~ ~1 0 , l l-epoxyfarnesol and ( R ) - and (S)-2,3~ x i d o s q u a l e n e and , ~ ~ ~variously labelled cannabinoids.286Commercially available [3H]-17a-hydroxypregnenolone has been shown to contain a major (40-50°/0) this has important implications since this intermediate has been used in many studies of steroidogenesis. Improved methodology for the rapid assay of hepatic HMG-CoA reductase has been describedZ8* and new and simplified assays are available for cholesterol 7 a - h y d r o ~ y l a s e ,4-methylsterol ~~~ o x i d a ~ e , ~3P-hydroxy-steroid ~' dehydrogenase,291the biosynthesis of bile and microsomal cholesterol levels.294The rate of biosynthesis of gibberellins has been monitored by a bioassay based on P-amyrin production of Amaranthus The use of polyethylene oxide-bound oestradiol for purifying i\"4-3-oxo-steroid isomerase has been described,296 as has apparatus suitable for the production of radiolabelled metabolites in tobacco from 14C02.297Useful reviews are availon the use of "C-labelled compounds in biosynthesis. Tissue cultures ' ~ been established that are from Mentha p~legium''~and Dioscorea d e l t ~ i d e a ~have able to support the synthesis of secondary metabolites.

13 Chemotaxonomy and Genetics This section reviews phytochemical studies concerned with geographical and clonal variation of terpenoid content, variation during the growing season, taxonomic and evolutionary implications, hybridization, and genetics of terpenoid development. The geographical variability of monoterpenoid content in Abies concofor and A . grandis appears i m p ~ r t a n t , " ~ *although ~ * ~ variations found in the leaf oil of the latter species were indicative of introgression with the former. There was little evidence of geographic differentiation in the cortical monoterpenoids of Pseudotsuga mac 282 283

284 285

2R6

287 288

289 ZYO

291

*92 293 2q4

295

296 297

298

299 300 301

302 303

S. J. Rajan and J. Wemple, J. Labelled Compounds, 1975, 11,467. A. E. Cowen, A. F. Hofmann, D . L. Hachey, P. J. Thomas, D. T. E. Belobaba, P. D . Klein, and L. Tokes, J. Lipid Res., 1976, 17, 231. S. Yamada, N. Oh-Hashi, and K. Achiwa, Tetrahedron Letters, 1976, 2557. S. Yamada, N. Oh-Hashi, and K. Achiwa, Tetrahedron Letters, 1976, 2561. C. G. Pitt, D . T. Hobbs, C. E. Twine, and D. L. Williams, J. Labelled Compounds, 1975, 11, 551. M. I. Shapiro and B. R . Bhavani, J. Labelled Compounds, 1975, 11,81. C. D . Goodwin and S . Margolis, J. Lipid Res., 1976, 17, 297. D. B. Johnson, M. P. Tyor, and L. Lack, J. Lipid Res., 1976,17, 353. D . R . Brady, T. W. Mattingly, and J. L. Gaylor, Analyt. Biochem., 1976, 70, 413. J. P. Berchfold, Compt. rend., 1976, 282, D, 1533. R. F. Hanson, H. L. Sharp, and G. C. Williams, J. Lipid Res., 1976, 17, 294. R. A. Davis, J. P. Showalter, and F. Kern, Steroids, 1975, 26, 408. G. Nicolau, S. Shefer, and E. H. Mosbach, Analyt. Biochem., 1975, 68, 2 5 5 . L. T. Kinsman, N. J. Pinfield, and B. K. Stobart, Planta, 1975, 127, 149, P. Hubert, E. Dellacherie, J. Neel, and E. E. Baulieu, F.E.B.S. Letters, 1976, 65, 169. R. T. Bass, R . W. Jenkins, G . C. Newell, a n d T . S. Osdene, Internat. J. A p p l . RadiationIsotopes, 1975,12, 753. A. C. McInnes and J. L. C. Wright, Accounts Chem. Res., 1975, 8, 313. T. J. Simpson, Chem. SOC.Rev., 1975,4, 497. J. Bricout and C. Paupardin, Compt. rend., 1975,281, D, 383. H. C. Chaturvedi and S . N. Srivastava, Lloydia, 1975, 39, 82. E. Zavarin, K. Snajberk, and J. Fisher, Biochem.System. Ecol., 1975, 3, 191. E. von Rudloff, Canad. J. Bot., 1976, 54, 1926.

Biosynthesis of Terpenoids and Steroids

223

r o ~ a r p aand , ~ ~there ~ was no gene exchange between this species and P. men~iesii.~” Similar ~ t ~ d icarried e ~ out ~ on ~ stands ~ * of~Pinus ~ ~sylvestris in Finland produced no clear-cut geographical trend on monoterpenoid variation. The infraspecific variation308and sex differentiation”’ in the volatile oil from species of Juniperus have been studied, and a survey of the quantitative composition of the oil from young and old leaves of J. scopulorum led to a warning that taxonomic implications from phytochemical studies might only be valid if the tissues analysed were at the same stage of Seasonal variations in the monoterpenoid content of oils from P i ~ e a , P~ ’i ~n ~ sand , ~ A4entha3l3 ~ ~ have been reported. Two distinct chemical types of Satureja douglusii have been e ~ t a b l i s h e d ; ~one ’~ type contained large quantities of limonene and carvone with only small amounts of piperitenone, piperitone, pulegone, and isomenthone, whereas in the second type the situation was reversed and the percentage of 3-0x0-compounds in this type varied greatly with environmental conditions. Chemical races have been reported in species of T ~ u g a , ~ Tanacetum ~’ ~ u l g a r eand , ~ ~Ocimum ~ b a ~ i l i c u m . ~No ~ ’ correlation was established between morphological detail and three sesquiterpenoid races of Psidium g ~ a j a v a , ~and ’ * similarly there was no relationship between chromosome number and sesquiterpenoid lactone content in various races of Artemisia triden tata. ’’ Analysis320of the monoterpenoid composition of oils from Pinus aristata and P. longaeva has provided further evidence that these species should be in subsection Balfourianae of the pines along with P. balfouriana. Species of Juniperus that were but some species that morphologically very similar were chemically quite were only distantly related with respect to their morphology were quite similar in terms of their volatile oil content. The systematic implications of the iridoid glucosides present in species of V e r b e n a ~ e a eand ~ ~ ~L o a ~ a c e a eand ~ ~ ~of the ~ t e r o 1and ~ c~a ~r o~t e*n o~i d~~ found ~~ ~ ~in species of red algae have been discussed. A primitive angiosperm ‘magnolian pattern’ of carotenoids has been found in the seed K. Snajberk and E. Zavarin, Biochem. System. Ecol,, 1976,4, 159. E. Zavarin and K. Snajberk, Biochem. System. Ecol., 1976,4, 93. 306 R. Hiltunen, S. Juvonen, andP. M. A . Tigerstedt, Farm. Aikak., 1975, 84, 75 (Chem. Abs., 1976, 84, 28 136). 307 R. Hiltunen, Planta Med., 1975, 28, 315. 308 R. P. Adams, Biochem. System. Ecol., 1975, 3, 71. 309 R. P. Adams and R. A . Powell, Phytochemistry, 1976, 15, 509. 3 1 0 R. P. Adams and A . Hagerman, Biochem. System. Ecol., 1976,4, 75. 311 E. von Rudloff, Canad. J. Bot., 1975, 53, 2978. 312 M. Zafra and E. Garcia-Peregrin, J. Agric. Sci., 1976, 86, 1. 3 1 3 H. Hendriks and F. H. L. van Os, Phytochemistry, 1976,15, 1127. 314 D. G . Rhoades, D. E. Lincoln, and J. H. Langenheim, Biochem. System. Ecol., 1976, 4, 5 . 315 E. von Rudloff, Canad. J. Bot., 1975, 53, 933. 316 K. Forsen, Ann. Acad. Sci. Fennicae, 1975,207A, 54. 31’ P. Pushpangadam, S. N. Sobti, and R. Khan, Indian J. Exp. Bot., 1975, 13, 520. 318 R. M. Smith and S. Siwatibau, Phytochemistry, 1975,14, 2013. 319 R. G. Kelsey, J. W. Thomas, T. J. Watson, and F. Shafizadeh, Biochem. System. Ecol., 1975,3,209. 320 E. Zavarin, K. Snajberk, and D. Bailey, Biochem. System. Ecol., 1976, 4, 81. 321 T. A . Zanoni and R. P. Adams, Biochem. System. Ecol., 1976,4, 147. 322 P. Kooiman, Acta Botan. Need., 1975, 24, 459. 323 P. Kooiman, Acta Botan. Need., 1974, 23, 677. 324 E. Fattorusso, S. Magno, C. Santacroce, D. Sica, G. Impellizzeri, S. Mangiafico, M. Piattelli, and S. Sciuto, Biochem. System. Ecol., 1976,4, 135. 325 I. Chardon-Loriaux, M. Morisaki, and N. Ikekawa, Phytochemistry, 1976, 15, 723. 326 T. Bjornland and M. Aguilar-Martinez, Phytochemistry, 1976, 15, 291. 304 305

224

Terpenoidsand Steroids

coats of various c y c a d ~ and ~ * ~this is held to confirm previous theories with regard to cycad evolution. The relationship between the New and Old World populations of Xanthium strumarium has been probed by a ~ t ~ dof ythe~sesquiterpenoid ~ ~ * ~ ~ lactone content of various hybrids. The hybrids from a cross of Eucalyptus crenulata and E. ovata were found to have intermediate morphology or intermediate monoterpenoid composition, and sometimes both, but there was little correlation between these characteristic^.^^' and of The genetic aspects of the biosynthesis of odoriferous oils in monoterpenoids in Mentha have been reviewed: of the 14 or 15 genes that control the major rnonoterpenoid components in mint, genetic analysis has given fairly complete information on five genes, and five others are still under close study. Consideration of genetic inheritance of car-3-ene production by Pinus sylvestris has ~ h o ~thatngenetic ~ ~control ~ , is basically ~ ~ ~simple and involves a single locus and one dominant-recessive allele pair. Details are available of the genetic control of the biosynthesis of @-carotenein fruits of orange and red and Reports are available on the discovery of insect anti-feeding anti-juvenile on the homology of biosynthetic routes and its basis in ~ h e m ~ t a ~ ~ and n ~ on m the y , role ~ ~ of~ terpenoids in chemical ecology.339Further speculations have been made about the biosynthesis of various classes of sesquiterpenoid based on the results of a of the quantitative co-occurrence of these in the genus Hymenaea.

327 328

329 330

331 33* 333 334

335 336 33’ 338 339 340

A. J. Bauman and H. Yokoyarna, Biochem. System. Ecol., 1976,4, 73. C. McMillan, P. I. Chavez, andT. J. Mabry, Biochem. System. Ecol., 1975, 3, 137. C. McMillan, T. J. Mabry, and P. I. Chavez, Amer. J. Bot., 1976, 63, 317. D. Simmons and R. F. Parsons, Biochem. System. Ecol., 1976, 4, 97. F. W. Hefendehl and M. J. Murray, Lloydia, 1976, 39, 39. M. J. Murray, Anais Acad. hrasil. Cienc., 1972, 44, 24. F. W. Hefendehl, ref. 77, p. 15. R. Hiltunen, P. M. A. Tigerstedt, S. Juvonen, and J. Pohjola, Farm. Aikak., 1975,84,69 (Chem. Abs., 1 9 7 6 , 8 4 , 4 0 847). A. Ognyanova and K. Moinova, Genet. Sel., 1973,6, 3 (Chem. Abs., 1976,85, 59 774). K. Munakata, Pure Appl. Chem., 1975, 42, 57. W. S. Bowers, T. Ohta, J. S. Cleere, and P. A. Marsella, Science, 1976, 193, 542. P. Tetenyi, Herba Hung., 1975, 14, 37. H. Schildknecht, Angew. Chem. Internat. Edn., 1976, 15, 214. S. S. Martin, J. H. Langenheim, and E. Zavarin, Phytochernistry, 1976, 15. 113.

~

Part II STEROIDS

1 Steroid Properties, Reactions, and Partial Synthesis BY

D. N. KIRK

As an innovation, this year’s Report combines the usual section on ‘Properties and Reactions’ with the subject of ‘Partial Synthesis’ into a single chapter. In earlier volumes, selection of subject matter for two separate chapters has perforce been somewhat arbitrary, and has not infrequently resulted in some duplication of material, where authors chose to emphasize different facets of the same piece of work. The present chapter retains the classification of ‘Properties and Reactions’ used in previous volumes, but groups into additional sections the work which was concerned in particular with aspects of synthesis. Section A: Steroid Properties and Reactions

1 Structure, Stereochemistry, and Spectroscopic Methods Force-field calculations have given the atomic co-ordinates for 3a -hydroxy-5& androstan- 17-one (‘androsterone’) with abcyt the same accuracy as X-ray measurements, the errors being no greater than 0.1 A.’ The value of this method lies partly in its speed (10 minutes of IBM 360 computer time) and partly in the fact that no crystal is required. Variations of energy with conformation can also be computed. The authors stress the likely dangers in using Dreiding models, which may differ markedly in shape from actual molecules because they fail to simulate torsional and ,van der Waals effects. A monograph2 concerned with the configurations and conformations of corticosteroids provides detailed information particularly on mass spectra and ‘H and I3C n.m,r., and discusses side-chain conformations of corticosteroids both with and without C- 18 oxygen functions; the relationships between biological activity and conformation are discussed. The structural features and conformations compatible with anaesthetic activity in pregnane derivatives have also been r e ~ i e w e d . ~ The lactone ring in 17p -hydroxy- 17a -methyl-2-oxa-5a-androstan-3-one (1) has a flattened chair-like conformation, with a torsion angle of 11-12’ about the 2,3-b0nd.~ Clearly this structure represents an energetic compromise between the normal preferences for a chair ring and a coplanar ester group, and may have some 2

3 4

N. L. Allinger, M. T. Tribble, and Y. Yuh, Steroids, 1975, 26, 398. P. Genard, ‘Contribution h la determination de la configuration et de la conformation moleculaire des corticosttroids’, Masson et Cie, Paris, 1974. G. H. Phillipps, J. Steroid Biochem., 1975,6, 607. D. F. Rendle and J. Trotter, J.C.S. Perkin 11, 1975, 1361.

227

Terpenoids and Steroids

228

H

(1)

relevance to the interpretation of chiroptical data for lactones. Absolute configurations at C-19 previously assigned to some 19-substituted 19-hydroxy-steroids appear to be incorrect.’ X-Ray crystallography and other studies establish that oestrogen biosynthesis occurs by removal of the pro-R hydrogen from 19-hydroxyandrostane precursors. Methyl-lithium converts a 19-aldehyde into a mixture of 19hydroxy-19-methyl derivatives rich in the (19-R)-isomer, rather than the single isomer as reported previously. The present work covers a variety of other reactions at C-19; X-ray data give the preferred conformations about the 10,19-bond for several 19-substituted steroids.’ X-Ray analysis of (E)-3/3-hydroxy-5,10secocholest-l( lO)-en-5-one ( 2 ) , as the p-bromobenzoate, confirmed the E configuration and established the extended crown conformation (2) of the cyclodecenone ring. In solution, however, some 15% of the material appears to exist in the alternative conformation (3), as shown by ‘A and 13Cn.m.r. spectra of the 3-acetate. These conformations help to explain the stereochemistry of known reactions at the olefinic bond.6

(2 1

(3 )

Some new transformations, accompanied by n.m.r. studies, confirm the structures of the lop-alcohol (4)and the epoxy-ketone ( 5 ) in the ‘Westphalen’ series of

OAc

(41

compounds.’ Compounds in this group show marked variations in the conformation of ring B, depending upon the substitution pattern, confirming earlier suggestions regarding ‘Westphalen’s diol’ and its derivatives. 6

Y. Osawa, K. Shibata, D . Rohrer, C . Weeks, and W. L. Duax, J. Amer. Chem. Soc., 1975,97,4400. H.-C. Mez, G. Rist, 0.Ermer, L. Lorenc, J. Kalvoda, and M. Lj. Mihailovic, Helv. Chim. Acta, 1976,59, 1273. E.Glotter, Y.Rabinsohn, and Y. Ozari, J.C.S. Perkin I, 1975,2104.

229

Steroid Properties, Reactions, and Partial Synthesis

The 9(10 -+ 19)-abeo analogue (6) of oestrone methyl ether has been shown by X-ray crystallography to have the normal 9 a -configuration, but because of the chair conformation of the enlarged ring B the molecule differs considerably in shape from oestrone methyl ether.8 X-Ray, n.m.r., and 0.r.d. data establish the structures and absolute configurations of a series of insect-repellent steroids isolated from Nicandra physaloides.' The structure and conformation of the 6-sila-steroid (7) have been determined. l o

Me

Me (7)

N.M.R. Spectroscopy.-The systematic tabulation and analysis of 13Cn.m.r. spectra has now been extended to a series of hydroxy- and acetoxy-steroids." The thirtyone steroidal alcohols examined include androstanols and cholestanols with the OH group at each of the secondary ring positions. Secondary carbon atoms Q to hydroxy-groups show downfield shifts ranging from 32.7 to 51.4 p.p.m. Earlier impressions that axial and equatorial hydroxy-groups may be distinguished by means of these chemical shifts have not been confirmed. C , Shifts are a function of steric relationships, and for most of the compounds studied are given approximately (*2 p.p.m.) by the empirical expression ha(p.p.m.)=45.0+3.5p-3.5n

where p is the number of skew-pentane interactions of the hydroxy-group with carbon atoms and n is the number of y-gauche carbon atoms with hydrogen atoms compressing the hydroxy-group. The mechanisms of these shift effects are discussed. Shifts of P-carbon signals are smaller (2.3-13.5 p.p.m. downfield), and their origins are less clear, but many of the P-carbon shifts can be reproduced reasonably well by the equation A,(p.p.m.) = 9.3 - 2.4q

q being the number of y-gauche interactions between the hydroxy-group and

y-carbon atoms attached to C,. One consequence is that the P-carbon is more shielded by an axial than by an equatorial hydroxy-group. Shifts of y-carbon may be either up- or down-field, more usually the former. There appears to be some correlation with 1,3-syn -diaxial OH-Me interactions. The conformation dependence of 6 -carbon shifts is also discussed; they lie in the range 2-4 p.p.m. when the groups concerned are in a 1,3-syn-diaxial relationship, but are smaller or may even be negative for other patterns of bonding."

lo

l1

C. M. Weeks, D. C. Rohrer, and W. L. Duax, Steroids, 1976, 27; 261. M. J. Begley, L. Crombie, P. J. Ham,and D. A. Whiting, J.C.S. Perkin I, 1976, 296. A. T. McPhail, R. W. Miller, and P. M. Gross, J.C.S. Perkin 11, 1975, 1180. H. Eggert, C. L. Van Antwerp, N. S. Bhacca, and C. Djerassi, J. Org. Chem., 1976,41, 71.

230

Terpenoids and Steroids

Other authors1*give empirical rules and reference values for the prediction of 13C chemical shifts for X-substituted carbon ( X = O H , NH2, or C1) and the p- and y-carbon atoms for a series of compounds which include decalols and steroidal analogues, where the relevant conformations are of gauche type (torsion angles ca. 60"). Data for other conformations (torsion angles 4 between 0" and 90") were best accomodated by an angular dependence of cos 4 type.12 Spectra of a series of 6P-substituted 5 a -cholestane-3/3, 5-diols revealed significant 13Cshifts, depending upon the size and nature of the 6P-substituent, at the positions which are either y - or 6-related to the substituent." Although some regularities have been discerned, these effects are not yet sufficiently well-defined or understood to permit their routine application for the assignment of signals in steroid spectra. 13 C N.m.r. spectra for thirteen steroidal unsaturated ketones, including compounds of the 4-en-3-one, 4,6-dien-3-one, 1,4-dien-3-0ne, 5-en-7-one, and 3 3 dien-7-one types, show some regularities in chemical shift. l4 The protonated forms of some steroidal 4-en-3-ones in sulphuric acid give 13C spectra which have been compared with those of simple ketones in the same medium. The magnitudes of chemical shifts over a range of acid concentrations were interpreted as indicating that C-5 carries the larger part of the cationic charge.15 Syntheses of the 2- and E-isomers of 20(22)-didehydrocholesterol and the four isomeric 20,22-epoxides have allowed study of their 13Cn.m.r. spectra, which show distinctive differences related to conformations.l6 13CN.m.r. spectra are reported for a series of 17a-oxa-D-homoandrostan-17-ones (6-lactones)." The 160- and 160 -acetoxy-derivatives of these lactones appear each to prefer the conformation which permits the acetoxy-group to be quasi-equatorial, where it almost eclipses the lactone carbonyl group. 13C N.m.r. spectra, with assignments of all signals, are reported for eight sapogenins, including the parent compound (25R)5a-~pirostan,'* and for some 17/3-(2,5-dihydr0-5-0~0-3-furyl)-3P,5a,6trihydroxy-derivatives (cardenolides). l 9 Large shifts in I3C n.m.r. signals resulting from methoxycarbonylation or mesylation of alcohols should prove useful in the analysis of steroid spectra.20 Experiments with 3~-chlorocholest-5-ene and two other unsaturated compounds indicate that chemical shift anisotropy can make a significant contribution to I3C relaxation of unsaturated carbon atoms not bonded to hydrogen, although dipole-dipole and to a lesser extent spin-rotation mechanisms are generally the dominant contributors to spin-lattice relaxation times 'H N.m.r. studies show that ring A of vitamin D, exists in solution as an equimolar mixture of chair conformers, with the 3-hydroxy-group axial and equatorial, respectively." The conformational equilibrium is not appreciably different in l a hydroxy-vitamin D3,and is unaffected by variations in side-chain structure. Added '2

14

l5 l6

18

l9

2o 21

22

H. Beierbeck and J. K . Saunders, Canad. J. Chem., 1976, 54, 632. J. W. Blunt, Austral. J. Chem., 1975, 28, 1017. J. R. Hanson and M. Siverns, J.C.S. Perkin I, 1975, 1956. A. R. Butler and H. A . Jones, J.C.S. Perkin 11, 1976, 963; A. R. Butler, ibid., p. 959. W. G. Anderson, C. Y. Byon, M. Gut, and F. H. Bissett, Tetrahedron Letters, 1976, 2193. M. J. GaSik, Z. Djarmati, and S. W. Pelletier, J. Org. Chem., 1976, 41, 1219. H . Eggert and C. Djerassi, Tetrahedron Letters, 1975, 3635. V. Wray and S. Lang, Tetrahedron, 1975, 31, 2815. Y. Terui, K. Tori, and N. Tsuji, Tetrahedron Letters, 1976, 621. G . C. Levy and U. Edlund, J. Amer. Chem. SOC.,1975, 97, 5031. R. M. Wing, W. H. Okamura, A. Rego, M. R. Pirio, and A . W. Norman, J. Amer. Chem. SOC., 1975,97, 4980.

Stereid Properties, Reactions, and Partial Synthesis

23 1

lanthanide shift reagents, however, disturb the equilibrium in favour of the axialhydroxy conformer. This rather surprising result was confirmed by a study of competitive binding of [ E ~ ( d p m ) by ~ ] cis- and trans-4-t-butylcyclohexanols,when the axial (cis) alcohols exhibited preferential complexing (axial : equatorial ratio 1.29 : 1). A converse conformational preference was reported recently23in a study of the behaviour 1-methylcyclohexanol with lanthanide shift reagents. The relative magnitudes of ‘H shifts at the lop- and 13P-methyl groups caused by an l l p hydroxy function correlate well with the selectivity of hydrogen abstraction during photolysis of nitrites or hypoiodites: greater deshielding by the hydroxy-group implies closer proximity and, therefore, preferred reaction of the more-deshielded methyl group.24 Configurations of 16,17-disubstituted androstanes can be determined from n.m.r. spe~fra.~’16P,17a -Disubstituted compounds exhibit a very small coupling constant (J16.17 s 2 Hz), whereas the other isomers give J values of between 5 and 8 Hz. Distinctions are possible on the basis of chemical shifts of the 136 -methyl proton signals, and other features.

Chiroptical Methods.-A new theoretical (CNDO/S) study of c.d. in the carbonyl n -+ v* transition has succeeded in deriving rotatory strengths close to experimental values for a variety of cyclohexanone and decalone derivatives.26 The results substantiate the importance of ‘primary’ zig-zags of anti-coplanar C-C bonds, postulated on the basis of an empirical analysis based largely on steroid ketones. New conclusions2‘ about the ‘front octant’ region indicate a boundary surface which is sharply concave towards the oxygen of the carbonyl group, with small ‘pockets’where sign reversal occurs even in the rear octants. These may help to explain the known dissignate (‘anti-octant’) contributions of ‘P’-axial methyl groups in some cyclohexanones and their steroid analogues. C.d. data for steroidal ~ ~ - o x o - , l 6 - 0 ~ 0 -and , 17-oxo-compounds, as well as the quasi-enantiomeric A-nor-ketones, have been analysed as part of a comprehensive study of ketones of the hexahydroindan-1 -one and -2-one types2’ The main features of the relationships between structures and Cotton effects have been established, as they were earlier27 for compounds with the ketonic group in a six-membered ring. Tables of increments ( ~ A E associated ) with common structural features now permit the calculation of A& values for a wide range of steroid-like compounds with the ketonic group in a five-membered ring. The likely error does not exceed 0.5 units unless polar substituents or strongly distorting substituents lie close to the oxo-group. Some compounds containing a fused cyclobutanone ring are also included in the study.28 Fresh evidence is presented that the lowest-energy singlet electronic c.d. band in several chiral mono-olefins is associated with the .rr, -B 3s Rydberg t r a n ~ i t i o n . ~ ~ Inadequacies of the diene chirality rule have become apparent from recent data. C.d. effects of cyclohexa-1,3-dienes seem to be due as much to allylic axial substituents as to the diene ~hirality.~’The effect is well illustrated by the series of 23 24 25

26 27 28

29 30

J. Bouquant, M. Wuilmet, A. Maujean, and J. Chuihe, J.C.S. Chem. Comm., 1974, 778. R. B. Boar, J.C.S. Perkin I, 1975, 1275. B. Schonecker, D. Tresselt, and K. Ponsold, Tetrahedron, 1975,31. 2845. T. D. Boumann and D. A. Lightner, J. Amer. Chem. SOC.,1976,98, 3145. D. N. Kirk and W. Klyne, J.C.S. Perkin I, 1974, 1076. D. N. Kirk and W. Klyne, J.C.S. Perkin I, 1976, 762. A. F. Drake, J.C.S. Chem. Comrn., 1976, 515. A. W. Burgstahler, L. 0. Weigel, and J. K. Gawronski, J. Amer. Chem. SOC.,1976,98, 3015.

232

Terpenoidsand Steroids

5a -steroidal 1,3-dienes (8)-(10). The diene system itself, with M-chirality, would be expected to contribute a negative Cotton effect, but the oestra-1,3-diene (8) instead exhibits a positive Cotton effect. Allylic axial methyl substitution (5a or lop) results in a shift to negative Cotton effects. The 5(10),6-diene (11) similarly exhibits a negative Cotton effect, contrary to the diene-helicity rule: the conformation, confirmed by an X-ray study, imposes right-handed helicity on the diene system in ring B.31 Sa-Androsta-l4,16-diene (12)’ synthesized from the 16-ene via the 15-bromoderivative, provides one of several examples of near-planar dienes whose c.d. behaviour provides further evidence for chirality contributions of allylic bonds3*

(8) R’ = R2 = H; 4 . ~ 2 6 0= +3.8 (9) R‘ = Me, R2= H; 4 . = -2.7 ~ (10) R‘=R2=Me; 4&264=-11.1

~

~

(11)

~

~

The signs of Cotton effects (n + r*)of seven-membered ring lactams of the Aaza-A-homo-type [e.g. (13) and (14)] show a simple correlation with the conforma-

0

H

H (13)

(14)

tion of the lactam ring (Figure l);33 the C-NH-CO-C system is essentially planar. Neither the ketone ‘Octant Rule’ nor sector rules which have been proposed for

1

c.d. (-)

\

c.d. (+)

Figure 1 Signs of c.d.for chiral seven -membered ring lacrams

lactams or amides can correctly predict the observed signs. N-Salicylidene derivatives of steroid amines give c.d. spectra exhibiting up to three maxima above 200 nm; signs have been correlated with amine configurations by a chirality rule based upon the coupled-oscillator mechanism.34 31 32 33 34

H. Paaren, R. M. Moriarty, and J. Flippen, J.C.S. Chem. Comm., 1976, 114. A. W. Burgstahler, D. L. Boger, and N. C. Naik, Tetrahedron, 1976, 32, 309. H. Ogura, H. Takayanagi, and K. Furuhata, J.C.S. Perkin I, 1976, 665. H. E. Smith, E. P. Burrows, and F.-M. Chen, J. Org. Chem., 1976, 41, 704.

Steroid Properties, Reactions, and Partial Synthesis

233

A full account has appeared3’ of the study of absolute configurations of vicinal diols and amino-alcohols by c.d. measurements in solutions containing nickel acetylacetonate [Ni(acac)J or the n.m.r. ‘shift reagent’ [ P r ( d ~ m ) , ] .Examples ~~ of steroidal derivatives examined include 2,3-, 3,4-, 5,6-, 16,17-, 17a,20/3-, and side-chain diols. A c.d. study of 18-hydroxydeoxycorticosteroneconfirms that the compound exists in the hemiacetal form (15) in ~olution.~’Addition of the complexing reagent [Pr(dpm),] caused the appearance of a bisignate c.d. curve centred near 325 nm, with signs which were correlated with the (20R)-configuration in the 20,21-diol system by comparison with the behaviour of the corresponding diol (16) in the 18,2O-cyclo series. The (20R)-configuration is consistent with the formation of the diol by Os04 attack on the rear face of the vinyl ether (17). It is not clear from a model whether the

(15)

(16)

(17)

(20R)-configuration is the more stable or merely the kinetically favoured form: equilibration of (20R)- and (20s)-isomers via opening and reclosure of the hemiacetal ring may explain the observed changes when the material is dissolved in polar solvents. A full report of the c.d. of steroidal diol bis-(p -dimethylaminobenzoates) confirms the reliability of theoretical calculations of the coupled Cotton effects of the remote ester groups (exciton chirality method). The c.d. curves show two maxima of opposite signs, separated by some 27 nm, and with intensity inversely proportional to the square of the interchromophore distance. The profile of the observed c.d. curve results from the superimposition of two component curves, each of asymmetric A review39of the uses of chiroptical techniques for structural and conformational studies includes examples of the assignment of stereochemistry to steroids and terpenoids, among a wide variety of natural products. The ‘Octant Rule’ for carbonyl compounds and the ‘rules’ applicable to other chromophoric systems are discussed critically. Mass Spectra.-A computer analysis of mass spectra of progesterone and twentynine of its stereoisomers and alkylated derivatives has established the main fragmentation pathways and their dependence on configurations, particularly at C-10 and C-17, and on the substitution pattern.40 Mass spectra of 17a-acetoxy-, 17ahydroxy-, and 17a-methoxy-progesterones are dominated by fragmentations 35 36

37 38

39 40

J. Dillon and K. Nakanishi, J. Amer. Chem. SOC., 1975,97, 5409, 5417. See ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1975, Vol. 5, p. 229. M. P. Li, M. K. Birmingham, andT. H. Chan, J. Org. Chem., 1976,41,2552. N. Harada, S. L. Chen, and K. Nakanishi, J. Amer. Chem. SOC., 1975,97,5345. P. M. Scopes, Fortschr. Chem. org. Naturstoffe, 1975,32, 167. S. Hamrnerum and C. Djerassi, Tetrahedron, 1975,31,2391.

234

Terpenoids and Steroids

involving ring D and the side-chain.,' Androst-5-en-3P-01 has been prepared with deuterium labels in a variety of positions ( l a -2H1, 2,2,4,4-'H4, 3a-'H1, 6-2H1, 7,7-2HZ,9 i ~ - ~ H 16,16-'H2, ~, 17,17-2H2, 19,19-2H2,e t ~ . ) ; these ~' derivatives were used to elucidate the details of its mass-spectral fragmentation^.^^ Steroids labelled with deuterium (by CD30D-D20-DzS04) have been used as internal standards for quantitative analysis of intermediates in testosterone biosynthesis, using g . l . ~ . - m . s . ~ ~ Mass spectra are reported for 3,17p -dihydroxy-5a -androstane- 11,16-diones and the related 3-0xo-cornpound,"~for 4,4-dimeth~l-A~-steroids,~~ and for 6 - o x a - ~ homo-5a -cholestan-7-0nes.~~ A review of hydrogen transfer processes in the mass spectral fragmentations which result in loss of small neutral molecules (H,O, HCN, keten, hydrocarbons, etc.) includes reference to a wide variety of steroidal comp o u n d ~ .G.1.c.-m.s. ~~ allowed the resolution of androst-16-ene derivatives which occur as porcine pheromones; various cholestenes were also ~ e p a r a b l e . , ~ Miscellaneous Techniques.-The limitations of i.r. spectroscopy for the study of non-conjugated olefinic steroids are well known; bands are generally weak or unobservable. Laser-Raman spectra, in contrast, give very strong and sharp olefinic bands in the C-H stretching (3000-3100 cm-I) and C=C stretching (16001700 cm-') regions. The first extensive survey covering unsaturation in almost all possible locations in rings A-c lists characteristic bands which should have value in locating olefinic bonds. Ethynyl groups also give pronounced Raman bands, but 0 - H and C=O vibrations, which are strongly i.r.-active, give relatively weak Raman spectra. Modern instrumentation allows the use of 3-15 mg samples, either as solids or in solution (CHC13or CCl,).'" Fluorescence data have been reported for thirty-one corticosteroids in sulphuric acid, allowing identification of the structural features necessary for strong fluorescence." The U.V.absorption maxima of 4-en-3-ones are red-shifted by amino or quaternary ammonium functions in compounds such as (18) or (19).'2

(18) Z = y M e (19) Z = NMe2 C104-

J1 42 43 44

4s 46

47 48

49

51 52

S. Hammerum and C. Djerassi, Steroids, 1975,25, 817. W. Ockels and H. Budzikiewicz, Tetrahedron, 1975, 32, 135. H. Budzikiewicz and W. Ockels, Tetrahedron, 1975, 32, 143. A. Ruokonen, Actu Endocrinol., 1975,80, Suppl., 199, 293. H. Richter and G . Spiteller, Monutsh., 1976,107, 459. E. Flaskamp, H. J. Kesterke, and H. Budzikiewicz, Monatsh., 1976, 107, 815. M. S. Ahmad, M. Mushfiq, M. Asif, and G. A . S. Ansari, J. prakt, Chem., 1975,317, 1049. D. G. I. Kingston, B. W. Hobrock, M. M. Bursey, and J. T. Bursey, Chem. Reu., 1975,75, 693. C. G. Edmonds and C. J. W. Brooks, J. Chromatog., 1976,116, 173. J. E. D . Davies, P. Hodge, and M. N. Khan, J.C.S. Perkin IZ, 1976, 841. C. Monder and J. Kendall, Analyt. Biochem., 1975, 68, 248. M. Sharma and V. Georgian, Steroids, 1976, 27, 225.

235

Steroid Properties, Reactions, and Partial Synthesis

The dinitroxide (20) is one of several nitroxide biradicals used to test the point-dipole approximation for electron-electron dipolar interaction^.'^ C8H 17

&

2 Alcohols and their Derivatives, Halides, and Epoxides an interSubstitution, Elimination, and Solvolysis.-7a-Hydroxycholesterol, mediate in the enzymic formation of bile acids from cholesterol, has been difficult to obtain by chemical methods. It is now available from the accessible 7P-isomer by reaction with HBr at -78 "C, which affords 7 a -bromocholesteryl benzoate (21), followed by acetolysis (KOAc-HOAc) to form the 7 a -acetoxy-derivative (22).

(21) X = B r (22) X= O Ac

Reduction of the diester (LaAlH4)liberates 7a -hydroxy~holesterol.~~ The cholest5 -ene-3&7-diols, isomeric at C-7, are interconverted in acidified alcohols; the 7a-isomer gives the 7a -alkoxycholesterol, which may subsequently equilibrate to a

mixture rich in the 7 p -alko~y-derivative.~'This series of reactions apparently accounts for the detection of 7-alkoxy-derivatives as artefacts in extracts of mammalian tissues. Attempts to prepare 3a-chlorocholest-Sene by substitution of some suitable 3p -precursor with inversion have achieved only partial success.56 Cholesteryl tosylate was useless in this respect, but the 3p -iodo-compound reacted with Bu4N+C1--acetone to give 3a-chlorocholest-5-ene with a 40% conversion; the other main product was cholesta-3,5-diene, which could be removed by preparative layer c h r ~ m a t o g r a p h y .Potassium ~~ superoxide (KO,) in DMSO-DME containing 18-crown-6 provides an exceptionally effective nucleophile, which converts cholesteryl tosylate in 56% yield into cholest-5 -en-3a -01, unaccompanied by either cholesterol or 3,5-cyclo-deri~atives.~~Substitution of halides with inversion and the quantitative formation of cyclohex-2-en-1-01 from truns-1,2dibromocyclohexane suggest other applications of KO2 in steroid chemistry. 53 54 55 56

57

W. B. Gleason and R. E. Barnett, J. Amer. Chem. Soc., 1976, 98, 2701. D. B. Johnson and L. Lack, J. Lipid Metabolism, 1976, 17,91. M. J. Kulig, J. I. Teng, and L. L. Smith, Lipids, 1975, 10,93. D. N. Kevill, C. R. Degenhardt, and R. L. Anderson, J. Org. Chem., 1976,41, 381. E. J. Corey, K. C. Nicolaou, M. Shibasaki, Y. Machida, and C. S. Shiner, Tetrahedron Letters, 1975,3183.

Terpenoids and Steroids

236

The preparation of 19-iodocholesterol (24) by nucleophilic substitution of the 'neopentyl' 19-tosyloxycholesterol (23) with NaI-propanol resulted in partial isomerization to 6P-iodomethyl- 19-norcholest-5(10)-en-3~-ol(25)' which could not be removed completely by crystallization. The pure 19-iodo-compound (24) was obtained by using the 3-acetate 19-tosylate of cholest-5-ene-3P, 19-diol for the substitution reaction, and was found to isomerize to the 6P -iodomethyl compound (25) in refluxing Nucleophilic substitution of the 19-tosylate (26) could similarly be effected by lithium bromide or chloride in propan-2-01 to give the 19-halide (27) without rearrangement.59 After hydrolysis of the 3@-acetate,heating either of the 19-halogeno-derivatives in acetic acid or acetonitrile gave the corresponding 6P-halogenomethyl- 19-nor-5( 10)-ene.

(23) R' = H, R2 = OTs R' = H, R~ = I (26) R' = Ac, R2= OTs (27) R' = Ac, R2= C1 or Br

(25)

(24)

H.p.1.c. analysis of the product from reaction of 5a -cholestan-6a -01 with PC15 disclosed the presence of the 6P-chloro-compound (15%) as well as the 6a-chloroisomer (64%),previously reported as the only product. Thionyl chloride gave 6achloro-5a -cholestane (80%), with none of the 6P -chloro-compound, cholest-5-ene being th;: major by-product in this case.6o Traces of other products were identified from both reactions.61 Details of the use of magnesium halides for nucleophilic substitution of sulphonate esters show that this efficient reaction has wide applicability. Androstan-17P-yl tosylate or mesylate derivatives gave 17a -bromo- or 17aiodo-compounds in 50-57% yields.62 Some novel alternatives to tosylates and mesylates as leaving groups are described; the pyridine-3-sulphonate of an 1 l a hydroxy-steroid, for example, is replaced by azide ion to give the 11P-azidoderi~ative.~~ The conditions necessary for rearrangement of 2&3a -(diaxial) iodohydrin esters [e.g. (28)] to the transposed diequatorial isomers [e.g. (29)] have been further Me

ACO

I

H (28)

58

59

61

62 61

Me

H (29)

M. Maeda, h4. Kojima, H. Ogawa, K. Nitta, and T. Ito, Steroids, 1975, 26, 241. M. Maeda, H. Komatsu, M. Kojirna, and H. Ogawa, Chem. and Pharrn. Bull. (Japan), 1976,24, 1398. C. W. Shoppee and R. D. Lundberg, J.C.S. Perkin I, 1975. 2205. C. W. Shoppee and R. D. Lundberg, Steroids, 1975, 26, 470. P. Place, M.-L. Rournestant, and J. Gore, Bull. SOC.chim. France, 1976, 169. U. Zehavi, J. Org. Chem., 1975, 40, 3870.

Steroid Properties, Reactions, and Partial Synthesis

237

explored.64 3 a -Acetoxy-2/3-iodo-3~-methyl-5a-cholestane (30) reacts with silver acetate in wet acetic acid uia the 2a,3a-acetoxonium ion (31) to give the 2a,3a-diol (32), after hydrolysis. The isomeric iodo-acetate (33) failed to react through an acetoxonium ion, probably for steric reasons. Elimination products were formed in~tead.~’

I

H (33)

Fluorination of steroids at C-5 can be achieved by reaction of 5-hydroxycompounds either with HF-CH2C12 at -60 “C or with HF-pyridine. The relative effectiveness of these reagents depends upon structural features of the steroid.66 4-Bromocholest-4-en-3-one reacts with sodium methoxide to give a mixture containing 4-methoxycholest-4-en-3-one,3,3-dimethoxy-cholest-5-en-4~-ol, and a each in ca. 20% product thought to be a 3-methoxy-5-hydroxycholest-2-en-4-one, yield.67 5-Bromo-6~-chloro-5a-cholestan-3~-ol suffered a complicated set of reactions with aqueous silver perchlorate, giving a variety of rearranged as well as unrearranged products.68 Some vicinal dibromo-steroids react with silver salts in the presence of water to give e p o x i d e ~ .Some ~ ~ uncertainty has surrounded the detailed mechanism of allylic substitutions (SN2’),’’ which are-well known in steroid chemistry. A recent study demonstrates that orbital symmetry strongly favours the syn mechanism when the nucleophile is an electrically neutral species. Electrostatic repulsion between an anionic nucleophile and the leaving group, or strong steric compression of the nucleophile during syn attack, however, may result in a preference for anti approach of the n ~ c l e o p h i l e . ~ ~ Deuterium isotope effects in the solvolysis of 5a -cholestan-3a-y1 and -3p-yl brosylates are interpreted as evidence for a rate-determining ionization step, with ring A in a fairly rigid chair conformation. Product analyses, however, suggest a conformational change towards ‘half-chair’ in the transition state leading from the carbocation to products of inverted configuration. There is also evidence of a 64

6s 66

67 68

69 7”

71

M. Adinolfi, M. Parrilli, G . Barone, G . Laonigro, and L. Mangoni, Gazzetta, 1975, 105, 1259. M. Adinolfi, M. Parrilli, G . Barone, and L. Mangoni, Gazzetta, 1975, 105, 1021. A . Ambles and R. Jacquesy, Tetrahedron Letters, 1976, 1083. A. Enger and J. P. Pete, Bull. SOC.chim. France, 1975, 1681. A. Kasal and M. BudtSinskf, Coll. Czech. Chem. Comm., 1975, 40, 1231. A . Kasal, Coll. Czech. Chem. Comm., 1976,41, 140. ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1976. Vol. 6, p. 228. R. L. Yates, N. D. Epiotis, and F. Bernardi, J. Amer. Chem. Soc., 1975,97, 6615.

238

Terpenoids and Steroids

competing reaction path involving a hydrogen-bridged intermediate when the axial 3a -brosylate is solvolysed.72 Similar studies on the solvolysis of cholesteryl tosylate provide support for the early concept of a simple 3,5-cyclocholestanyl cation, rather than for alternative arrangements of delocalized bonding which have been discussed more recently. A small inverse isotope effect ( k H / k D= 0.974) in the solvolysis of [5,6a - 2 H 2 ] - 5 a-cholestan-3P-yl brosylate is attributed to a difference in the inductive effects originating from hydrogen or deuterium.73 The 12a-mesyloxy-group is eliminated efficiently (80-85O/0) from the cholic acid derivative (34) to give the All-compound (35), by heating with sodium or potassium acetate in HMPA.74

,&

&O,Me

AcO"

0,Me

'OAc

AcO'

'

H

OAc

H

(35)

(34)

Formolysis of the 17aa -methyl-D-homo- 17p-tosylate (36), followed by deesterification with LiAlH4, gave the 16-ene (37) as the major product, with small amounts of the two pairs of alcohols epimeric at C-16 (38) and C-17 (39). Predomi-

1 5 H

H

Me

DOH (39)

(37)

nant retention of configuration at C- 17, despite steric compression, requires a special explanation: several possibilities are discussed. The expected product of migration of the 17aa-methyl group to C-17 could not be detected, although a little of the AI3-olefin (40) was ~ b t a i n e d . ' ~The elimination of tosylates to give olefins proceeds readily on alumina which has been dehydrated at 400°C in vacuo: 5acholest-2-ene was formed without any cholestanols from 5a -cholestan-3P-yl tosylate.76 Palladium tetrakis(tripheny1phosphine) dehydrobrominates some alicyclic

(40) 72 71 74

75

76

M. Tarle, S. BorEiC, and D. E. Sunko, J. Org. Chem., 1975, 40, 2949. M. Tarle, S. BorEiC, and D. E. Sunko, J. Org. Chem., 1975, 40, 2954. C. H. Chen. Synthesis, 1976, 125. S. S. Deshmane and H. Hirschmann, J. Org. Chem., 1975, 40, 3469. G. H. Posner and G. M. Gurria, J. Org. Chem., 1976,41,578.

Steroid Properties, Reactions, and Partial Synthesis

239

a-bromo-ketones to give a@-unsaturatedketones, but reacted only inefficiently with 2a-bromo- or 4a-bromo-5cu-cholestan-3-ones, giving useless mixtures of prod u c t ~ Intramolecular .~~ 1,3-elimination of bromine from the 2a,4a-dibromo-3aand -36-alcohols (41) with zinc-copper couple gave the cyclopropanols (42) and (43).78 The 3P-hydroxy-isomer (42) was formed from both the 3a- and 3pdibromo-alcohols, implying the existence of an inversion mechanism which is thought to involve transient cleavage of the cyclopropanol by zinc acetate; an intermediate of type (44) is proposed. The stereochemical assignments of the cyclopropanols are supported by the relative rates of solvolysis of their tosylates. The 3p -alcohol derivative (45) was stable to attempted acetolysis over 20 h, but the 3a-compound (46) reacted in 15 min, consistent with its being the endo-alcohol. The major product from the acetolysis was the 2,4-diene.78

(42) R = H (45) R = T s

(43) R = H (46) R = T s

Ring-opening of Epoxides.-Epoxide ring opening by halogen acids, a familiar reaction in steroid chemistry, may proceed through a tight oxonium-halide ion pair, whose dissociation by solvent is rate determining in some cases.79 Although epoxide opening by HBr or HI normally gives diaxial halohydrins in the steroid series, neighbouring hydroxy-groups often cause abnormal behaviour, giving diequatorial adducts or other products. New examples,80 involving the four types of epoxyalcohol (47)-(50), illustrate the variability of stereochemical control by neighbouring groups, depending upon competition between polar and steric effects. The proportions of a - and p -epoxides obtained by peracid reactions of cholest-4ene and its 7 a - and 7@-hydroxy-, 7@-acetoxy-, and 7-0x0-derivatives have been compared with data for similar 3-substituted ~holest-5-enes.~~ The derived 4a,5aand 5a,6a -epoxides all reacted smoothly with sodium azide to give azido-alcohols, with maximum reaction rates when a hydroxy-group was suitably placed to provide 77

78 79

J. M. Townsend, I. D. Reingold, M. C. R. Kendall, and T. A. Spencer, J. Org. Chem., 1975,40,2976. J. F. Templeton and C. W. Wie,.Canad. J. Chem., 1975, 53, 1693. G. Lamaty, R. Maloq, C. Selve, A. Sivade, and J. Wylde, J.C.S. Perkin I& 1975, 1119. E. Glotter, P. Krinsky, M. Rejto, and M. Weissenberg, J.C.S. Perkin I, 1976, 1442. Y. Houminer, J.C.S. Perkin I, 1975, 1663.

Terpenoids and Steroids

240

(47) 3a,4ff,5a (48) 3P,4B95P

(49)

(50) R = H o r A c

intramolecular catalysis by complexing with the reacting epoxy-oxygen atom.81 Nucleophilic opening of a 17p-hydroxy- 15p,16p-epoxide (oestradiol 3-methyl ether series) with a variety of reagents gave the corresponding 16a -substituted 15@,17@-diols. In some cases the 15a-substituted 16p,17P-diols were also formed. 8 2 16P,17P-Epoxy-l7a -pregnan-20-ones react with pyridine thiocyanate to give thiocyano-alcohols, which readily cyclize to afford cyclic thiocarbonates (51).83 COMe

(51)

Sitosterol (24-ethylcholesterol) is degraded to desmosterol (A24-cholesterol) in the siikworm Bombyx mori, through the (24S,28S)-epoxide. The stereochemical features of the isomeric 24,28-epoxides and the derived 24,28-glycols have been worked out by a combination of physical and chemical a$-Epoxyoximes give trans -a-alkyl-p -hydroxy-ketones by reaction with lithium dialkylcuprate and deoximation, a procedure with potentialities for alkylation in steroid ~hemistry.~’ Oxidation and Reduction.-Alkyl chloroformates (5 2) react with dimethyl sulphoxide to give unstable carbonates which lose carbon dioxide to form alkoxydimethylsulphonium salts (53). Addition of triethylamine breaks the sulphonium salt down to

(52)

(53)

dimethyl sulphide and a ketone (or aldehyde). This reaction sequence was found to be unsatisfactory for steroidal chloroformates, but gave reasonable yields of ketones 83

84

K. Ponsold and G. Schubert, J . prakt. Chem., 1976,318, 279. A . I. Terekhina, Z. I. Istomina, A. V. Kamernitsky, L. I. Lisitsa, I. V. Sotskova, and A. M. Turuta, Khim. Farm. Zhur., 1975,9, 14. S.-M. L. Chen, K. Nakanishi, N. Awata, M. Morisaki, N. Ikekawa, and Y. Shimizu, J. Amer. Chem. SOC., 1975,97,5297. E. J. Corey, L. S. Melvin, jun., and M. F. Haslanger, Tetrahedron Letters, 1975, 3117.

24 1

Steroid Properties, Reactions, and Partial Synthesis

when 1,2-epoxypropane was present as a non-basic acid scavenger. A low yield in the oxidation of 1la -hydroxyprogesterone suggested that hindered alcohols are relatively unreactive. Another novel and high-yielding oxidation (e.g. of 5a cholestan-3P-01) comprises reaction with nitrosyl tetrafluoroborate in CH2C12MeCN containing hexamethyldisiloxane as scavenger.86 5a-Cholestan-3P-01 was oxidized to the ketone by a mixture of the 2,2,6,6Rates of tetramethylpiperidin- 1-yloxyl radical and rn -chloroperoxybenzoic oxidation of 3P-hydroxy-A5-steroidsby cholesterol oxidase show wide variations according to 17P-substit~tion.~~ 3-Bromo-4,4-dimethyloxazolidin-2-one (54) is a brominating and oxidizingagent comparable with N-bromosuccinimide. Cholic acid was oxidized selectively at the 7a -hydroxy-group, and cholesteryl benzoate was brominatcd at C-7 under free-radical condition^.^' Oppenauer oxidation of a pregnane-18,20-diol ( 5 5 ) is accompanied in part by a hydride shift from C-18 to C-20. Use of the 18,18-dideuterio-derivative (56) led to the lactone (57) with 18.2% D at C-20.90 A review, in two parts, deals with oxidations by activated manganese dioxide. Numerous steroid examples are included.’* HO

Me I

I

Br

(55) R = H (56) R = D

(54)

(57) R = H or D

Active Tio metal powder (prepared from TiC13and K in THF) couples ketones to give olefins [e.g.5a-cholestan-3-one -+ 3-(5a-cholestan-3-ylidene)-5a -cholestane] or riduces uic-diols [e.g.(58)] to give olefins (59); reactions generally proceed in high yield.92

(58)

(59)

Epoxides (e.g. ‘cholesterol oxide’) are smoothly reduced to olefins by the Ti” species formed when TiC13is reduced by LiAlH, (0.25 moles) in THF.936P-Bromo5a -cholestane-3P,S-diol is among bromohydrins reduced to olefins (cholesterol) by the same reagent^.'^ 86 87

89

91

92 93 94

D. H. R. Barton and C. P. Forbes, J.C.S. Perkin I, 1975,1614. B. Ganem, J. Org. Chem., 1975,40,1998. C. J. W. Brooks and A. G. Smith, J. Chromatog., 1975,112,499. J. J. Kaminski and N. Bodor, Tetrahedron, 1976,32,1097. L.Eignerova and A. Kasal, Coll. Czech. Chem. Comm., 1976,41,1056. A.J. Fatiadi, Synthesis, 1976,65, 133. J. E. McMurry and M. P. Fleming, J. Org. Chem., 1976,41,896. J. E.McMurry and M. P. Fleming, J. Org. Chem., 1975,40,2 5 5 5 . J. E. McMurry and T. Hoz,J. Org. Chem., 1975,40,3797.

242

Terpenoids and Steroids

5a-Cholestan-3P-01 has been used as a model alcohol to examine a variety of reactions with free-radical character, aimed at devising a convenient deoxygenation procedure which could be applied to alcoholic groups in sugar chemistry.95 The desired reaction occurred when 0-cholestanyl thiobenzoate (60) was treated with tributylstannane in refluxing toluene, giving 5a -cholestane in yields of up to 7 5 % . 0-Cholesteryl S-methyl dithiocarbonate (61) similarly afforded cholest-5-ene; the

S

I1

(60) 5a-H, R=Ph-C-O (61) A5, R = MeS-C-0

II

S

free-radical mechanism avoids the normal cationic rearrangement of cholesteryl derivatives. A novel synthesis of the red crystalline 0-cholesteryl selenobenzoate is described, but this ester was inferior to the thiobenzoate for deoxygenation by means of t r i b ~ t y l s t a n n a n e .6a,7cu ~ ~ -Epoxyandrost-4-ene-3,17-dione (62) is reduced selectively to give 7a-hydroxyandrost-4-ene-3,17-dione(63) by aluminium amalgam; this reagent is superior to chromous acetate for the purpose.96

(62)

(63)

6P-Deuterio-3a,5-cyclo-5cu -cholestan-6a -01 is hydrogenolysed (LiA1H4-AlCl3) to give the corresponding 6 a -deuterio-hydr~carbon.~’Allylic alcohols are hydrogenolysed to the corresponding olefins by LiAlH4-TiC1, or LiA1H4-AlC13.98 3P Tosyloxy-groups at C-3 are cleaved to the parent alcohols by irradiation in the presence of sodium b ~ r o h y d r i d e . ~ ~ Ethers, Esters, and Related Derivatives of Alcohols.-Oestrogens are effectively methylated at the phenolic oxygen by extraction from alkaline solution into dichloromethane containing iodomethane, with a tetra-n-hexylammonium salt as a phase-transfer reagent (‘extractive alkylation’). Conditions are mild, and the reaction is very rapid. In combination with g.1.c. analysis of the methyl ethers, it provides a simple and convenient method for the analysis of oestrogen mixtures.’’’ 3H95

96 47

98

99 loo

D. H. R. Barton and S. W. McCombie, J.C.S. Perkin I, 1975, 1574. A. M. M. Hossain, D. N. Kirk, and G. Mitra, Steroids, 1976, 27, 603. M. P. Paradisi, Gatzetta, 1975, 105, 451. Y. Fujimoto and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1976,24, 825. Y . Kondo, K. Hosoyama, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1975,23,-2167. J . D. Daley, J. M. Rosenfeld, and E. V. Younglai, Steroids, 1976, 27, 481.

Steroid Properties, Reactions, and Partial Synthesis

243

Labelled silylating agents have been used in a study of specific reaction rates and equilibria in the silylation of steroid hormones: the derivatives are suitable for mass spectrometry. lo' Rates of formation, chromatographic properties, and mass spectra are reportedlo2for the useful t-butyldimethylsilyl ethers of steroid alcohols. Some of the chemical characteristics of the t-butyldimethylsilyloxy-group have been examined using derivatives of a variety of steroids. The group serves as protection during either reduction (LiA1H4)or acetylation of other functional groups. Selective hydrolysis of the 3@,17@-dietheraffected only C-3.1°3 Compounds of the ecdysone series may be converted into trimethylsilyl derivatives at various positions by choice of appropriate reagents.lo4 2'-O-Tetrahydrofuranyl (THF)ethers are reported to be useful alternatives to tetrahydropyranyl (THP) ethers for the protection of alcohols (and t h i o l ~ ) . 'THF ~~ ethers are easily formed, and are more sensitive to acidic hydrolysis than are THP ethers. We are warned that hydroboration-oxidation or peracid oxidation of simple unsaturated compounds containing a hydroxy-group protected as its THP ether has led to violent detonations.lo6 The danger comes from the ready formation of peroxides from THP ethers, and presumably also from THF ethers: these peroxides, though very sensitive, are not easily removed by ordinary chemical methods. Pregnane- 17cu,20p,21-trio1 derivatives react with acidified acetone to give separaX-Ray analysis has established the ble mixtures of 17,20- and 20,2 l-acet~nides.~~)' six-membered ring structure (64) for the p-bromophenylboronate ester derived @B :+-

\

(64)

from a pregnane-17a,20P,21-tri01.~~* SP-Cholestane-3P,S-diols form separable cyclic sulphites in which the S=O oxygen is axial and equatorial, respectively, in a boat-like heterocyclic ring.lo9 The glucuronic acid derivative (65) with SnCl, has been used in a modified synthesis of 3-P-glucuronides of oestradiol and oestriol.l10 The a-anomer is formed as a minor product. Glucuronides of some 2-methoxy- 16-substituted oestrogens have been prepared by the conventional method, using the 1-bromo-sugar derivative."' The novel p-methoxyethoxymethyl (MeOCH2CH20CH2)protecting group 101 102 103

1°4 105 106 107

108

lo9 110 111

H. F.Struckmeyer, 2.analyt. Chem., 1976,279, 147. G. Phillipou, D.A. Bigham, and R. F. Seamark, Steroids, 1975, 26, 516. H. Hosoda, K. Yamashita, H. Sagae, and T. Nambara, Chem. and Pharm. Bull. (Japan), 1975,23,2118. E. D. Morgan and C. F. Poole, J. Chromatog., 1976, 116, 333. C. G. Kruse, N. L. J. M. Broekhof, and A. van der Gen, Tetrahedron Letters, 1976, 1725. A . I. Meyers, S. Schwartzman, G. L. Olson, and H.-C. Cheung, Tetrahedron Letters, 1976, 2417. E. G. Balashova, K. N. Gabinskaya, L. M. Alekseeva, V. F. Shner, 0.V. Massinova, and N. P. Suvorov, Khim. prirod. Soedinenii, 1975, 360. P. J. Cox, P. D. Cradwick, and G. A. Sim, J.C.S. Perkin 11, 1976, 110. D.M. Bleile, C. E. Malmberg, and A. T. Rowland, Steroids, 1975, 26, 29. K. Honma, K. Nakazima, T. Uematsu, and A . Hamada, Chem. and Pharm. Bull. (Japan), 1976,24,394. T. Nambara and Y. Kawarada, Chem. and Pharm. Bull. (Japan), 1976,24,421.

Terpenoids and Steroids

244

OAc

(65)

for alcohols"* would appear to have applications in steroid chemistry. The 0alkylation of 20-ethynylpregnan-20-01sis described.ll3 The 3-carboxy-2,2,5,5tetramethylpyrrolidin- 1-yloxyl free radical (66) has been used for spin-labelling of

d2H I

0-

(66)

cortisol and testosterone. l4 Condensation of the carboxy-group with steroidal hydroxy-groups was achieved by use of NN'-thionyldi-imidazole as coupling reagent. Cholesteryl esters of o -(9-anthryl)alkenoic acids of different chain lengths have been prepared as fluorescent-labelled derivatives. '15 The formation of some other derivatives of hydroxy-steroids is described on p. 317. 3~,16~-Diacetoxyandrost-5-en-17-one is readily available, but its hydrolysis to the parent dihydroxy-ketone has only been achieved by use of enzymes, because of the instability of the ketol system to alkali. Protection of the 17-0x0-group as the semicarbazone is now shown to permit alkaline hydrolysis of the ester groups. The 0x0 function was successfully regenerated by aqueous pyruvic acid-acetic acid.' l 6

3 Unsaturated Compounds Electrophilic Addition.-5a -Cholest-2-ene (67), on reaction with iodine, potassium iodate, and sulphuric acid in aqueous dioxan, gave the 2P,3a-diol (69) as the main product.''' The intermediate 2,3-epoxide (68) can be isolated by using a modified procedure, with iodine in aqueous dioxan in the presence of silver oxide to trap liberated hydrogen iodide.l18 The 2-methyl and 3-methyl derivatives of S c y -cholest-

(67) 112

113

*I5 116 117

11*

(68)

E. J. Corey, J.-L. Gras, and P. Ulrich, Tetrahedron Letters, 1976, 809. Z. G. Hajos and G. R. Duncan, Canad. J. Chem., 1975,53,2971. J. R. Dodd and A. J. Lewis, J.C.S. Chem. Comm., 1975,520. W. Stoffel and G. Michaelis, Z. physiol. Chem., 1976, 357, 7 . V. R. Mattox and A. N. Nekon, Steroids, 1976, 27, 845. M. Parrilli, M. Adinolfi, G. Barone, G. Laonigri, and L. Mangoni, Gazzetta, 1975, 105,1301. M. Parrilli, G. Barone, M. Adinolfi, and L. Mangoni, Tetrahedron Letters, 1976, 207.

Steroid Properties, Reactions, and Partial Synthesis

245

2-ene also gave 2/3,3P-epoxides as major products (ca. 70%) in a single operation. Cholesterol gave a mixture rich in the a-epoxide (54%a : ~ S O / O P ) . ~ ' ~ 3a-Methyl-5a -cholestane-2P,3P-di01(70) could not be obtained from 3-methyl5a -cholest-2-ene by the Woodward cis-hydroxylation procedure, but was prepared by a straightforward four-step sequence from 2a,3a -epoxy-5a -cholestane.'19 3-Methyl-5a -cholest-2-ene as normally prepared is contaminated by the A3isomer.l19

(70)

The 5a -configuration of the 5-chlorocholestane which results from hydrochlorination of cholest-5-ene has been confirmed by X-ray analysis.120The residue from hydrochlorination of cholest-5-ene appeared to contain another compound which could not be isolated or identified as the unknown 5 P - i s 0 m e r . ~ Perhaps ~~ the possibility of its being a 'backbone-rearranged' isomer (p. 273) should be investigated. The stereochemistry of electrophilic attack upon a As-steroid may depend critically upon subtle conformational features. Cholest-5-en-3-one, for example, reacts with bromine chloride to give products of both a - and p-attack, whereas cholesterol is attacked almost wholly from the a -face.'" Discussion centres on conformational features, without reference to possible electronic differences when 3-0x0- and 3P-substituted cholest-5-enes are compared, but the authors mention further experiments in progress. The Reporter suggests that inductive and ?r-type interactions of the C-3 substituents with the olefinic bond should be included in discussion of any fresh experimental results, even if only to exclude their possible role. The unreliable and hazardous nitration of cholesteryl acetate at C-6 has been modified to afford a procedure which is claimed to be safe and efficient for large-scale (500 g) ork king."^ The trick is to use unrecrystallized cholesteryl acetate in nitric acid-ether wth potassium nitrite, under specified conditions. Trifluoro(fluoro-oxy)methanetends to convert simple unsaturated steroids into complex mixtures of products, but reacts with allylic alcohols or acetates to give only two products, corresponding to cis-addition of either CF,OF or F2, the former ''9

120

l21 l22 123

M. Adinolfi, M. Parrilli, G. Barone, and L. Mangoni, Steroids, 1975, 26, 169. J. F. Griffin, M. G . Erman, W. L. Duax, D. S. Watt, and F. A . Carey, J. Org. Chem., 1975,40, 2956. C. W. Shoppee and R. D . Lundberg, J.C.S. Perkin I, 1975, 2208. P. B. D . de la Mare and R. D . Wilson, Tetrahedron Letters, 1975, 3247. A. T. Rowland, Steroids, 1975, 26, 251.

Terpenoids and Steroids

246

~ r e d 0 m i n a t i n g . lTwo ~ ~ examples of addition are illustrated (Scheme 1). The 16methylene- 17a -hydroxypregnan-20-one derivative (75) formed the 16pfluoromethyl-16a,17a -epoxide (76), as the result of electrophilic fluorination by the reagent. HO 1

(72) X = OCF3or F

(74)

(73)

CH,OAc

CH,OAc

I

I

CH, -!-+

CH,F

Reagent: i, CF-,OF or F2.

Scheme 1

Thallium(1) azide and iodine converted 5a -cholest-2-ene into a mixture of three isomeric iodo-azides. 1*5 Reaction of either a 17-methyleneandrostane (77) or a 17methylandrost- 16-ene (78) with thallium triacetate gave mixtures of the allylic acetates (79), (80), and (8 1). Oxyrnercuration-demercuration was more selective in giving, after acetylation, the 16p-acetoxy-17-methylene compound (80) as the main product. 12'

(77) X = H (79) R = a-OAc (80) R = P - O A c

(78) R = H (81) R = OAc

Reaction of steroidal olefins and allylic or homoallylic alcohols with lead Unsatutetra(trifluor0acetate) generally gives mixtures of oxidation 12J

l25

lZ6 lZ7

D. H. R. Barton, L. J. Danks, A. K. Ganguly, R. H. Hesse, G. Tarzia, and M. M. Pechet, J.C.S. Perkin I, 1976, 101. R. C. Cambie, R. C. Hayward, P. S. Rutledge, T. Smith-Palmer, and P. D. Woodgate, J.C.S. Perkin I, 1976,840. G. Ortar, M. P. Arpiani, and A. Romeo, Steroids, 1976. 27, 197. D. Westphal and E. Zbiral, Annalen, 1975, 2038.

247

Steroid Properties, Reactions, and Partial Synthesis

rated alcohols may simply give their trifluoroacetates. Examples of transformations, generally not in high yield, include the oxidation of 5a-cholest-2-ene to give 5acholestane-2a,3a-diol diacetate (after hydrolysis and acetylation of the initial product), cholest-4-ene to the 4p,SP-diol 4-trifluoroacetate, and 3 p acetoxycholest-5-ene to the 5a,6a -diol6-trifluoroacetate. A A9(")-steroid gave the allylic 12a -trifluoroacetoxy-derivative. **' The stereoselectivity of electrophilic additions to the stigmast-22-ene side-chain (82) shows similarities to the corresponding reactions of an ergost-22-ene (83), being controlled mainly by the configuration at C-20, which decides the position of the bulky steroid nucleus in relation to the A22-bond. The difference in stereochemistry at C-24 has relatively little effect. Electrophilic attack comes mainly from the side occupied by the C-21 methyl group in the preferred conformation of the side-chain. The stereochemistry of some of these addition reactions is illustrated in Scheme 2.

St

St

St

(82)

\

(22R,23R)

/

(22S23.S)

St = steroid nucleus Reagents: i, m-CIC6H4C03H;ii, 12-AgOAc; iii, NaOH.

Scheme 2

The bromohydrins, bromoketones, ketones, and alcohols derived from the 22,23epoxides were also characterized. 129 Stereochemical features of the reactions between the 24-norchol-22-ene system (84) and rn -chloroperbenzoic acid, hypobromous acid, and osmium tetroxide have also been s t ~ d i e d . ' ~ '

(84)

Other Addition Reactions.-Full details are now available on the preparation and use of polymer-supported peroxy-acids: some olefins are epoxidized smoothly, but lZ8 Iz9 130

D. Westphal and E. Zbiral, Monatsh., 1975, 106, 679. M. Nakane, M. Morisaki, and N. Ikekawa, Tetrahedron, 1975, 31, 2755. M. Ishiguro and N. Ikekawa, Chem. and Pharm. Bull. (Japan), 1975,23,2860.

248

Terpenoids and Steroids

cholesteryl acetate reacted inefTi~ient1y.l~~ Esters of cholesterol and p-sitosterol are oxidized directly to their 5 q 6 p -dihydroxy-derivatives by hydrogen peroxide in dioxan containing sulphuric acid. '32 Chlorination of cholest-5-enes with iodobenzene dichloride has been reinvestigated, with emphasis on the effects of 3psubstituents. A free-radical mechanism accounts for the low stereoselectivity in forming the 5a,6a - and 5a,6/3 -dichloro-adducts. 133 5a -Cholest-2-ene is among olefins which exemplify a new cis-oxamination reaction: 'chloramine T' (85), with a catalytic amount of osmium tetroxide, affords a mixture of the toluene-p-sulphonamido-alcohols (87) and (88), probably through addition of the osmium(vII1) derivative (86).'34 0

NTs

Nos// TsNClNa,3H20 + Os04 + // No 0

(87)

(88)

A partial synthesis of canarigenin (89) includes the hydroxylation of the corresponding 3,5-diene with oso4to give mixed A53,4-cis-diols; these afford the 4-en3-one with toluene-p-sulphonic acid in refluxing benzene. '35 Osmium tetroxide converted androsta-5,15-diene-3P,17P-diol into androst-S-ene-3P,15a,16a,l7@tetrol and the 3p,l5P,16&17P-tetr01.'~~ N-Methylmorpholine N-oxide can be used with only a catalytic amount of osmium tetroxide for the economical cishydroxylation of alkenes. The pregn- 17(20)-ene derivative (90) gave the 17a,20a diol (91) in 78% yield.'" CH,OAc \

C H ,OAc

131 132

I33 134 135

136 137

C . R. Harrison and P. Hodge, J.C.S. Perkin I, 1976, 605. V. G. Atabekyan, M. V. Mukhina, and A . S. Sopova, Zhur. org. Khim., 1976,12, 1231. A. Zarecki, J. Wicha, and M. Kocbr, Tetrahedron, 1976, 32, 559. K . B. Sharpless, A. 0 . Chong, and K. Oshima, J. Org. Chem., 1976,41, 177. H. P. Albrecht and P. Reichling, Annalen, 1975, 2211. E. M. Chambaz, G. Defaye, and H. Buffet, Compt. rend., 1976, 282, C, 133. V. Van Rheenen, R. C. Kelly, and D . Y. Cha, Tetrahedron Letters, 1976, 1973.

Steroid Properties, Reactions, and Partial Synthesis

249

Hydroboration of the 17,17-dimethyl-18-norandrost-13-ene (92) gives a mixture of adducts, but equilibration with rearrangement at 60 "C favours the 12a,13aadduct (93) whereas at 130°C the 12p,13p-adduct (94) becomes almost the sole product. Each adduct affords the corresponding 12-hydroxy-derivative (95) on oxidation. Spectroscopic properties and chemical transformations of the novel series of 12-oxygenated 18-nor-steroids are de~cribed.'~' An attempt to prepare 15a -hydroxyoestradiol(96) via hydroboration-oxidation of a 17p-butyldimethylsilyloxyoestr- 15-ene (97) derivative gave predominantly the 16a -hydroxy-compound, but use of the 14-ene (98)gave satisfactory conversion

Fi (92)

(93) 12a,13a, X = B

/ \

(97) At; (98) A

(96)

/

(94) 12@,13p,X = B ' (95) X = O H

\

into the 15a -hydroxy-deri~ative.'~~Syntheses of isomeric 5a -androstane3,15,17p-triols employed the conjugate addition of benzyl alcohol on to 15-en-17ones or the hydroboration-oxidation of 14-en- 17p-oh, respectively, as key steps in the stereospecific preparation of 15p-hydroxy- and 15a-hydroxy-derivati~es.~~~ Hydroboration of a cholest-25-ene (99), followed by oxidation to give the 26-hydroxycholestane, proceeds with a slight preference for formation of the (25s)-isomer (100). An authentic (25R)-isomer is available in kryptogenin; a microbial hydroxylation of cholesterol gave the pure ( 2 5 S ) - i ~ o r n e r . ~ ~ ~

,p ,;g CH,OH

H

(99)

(100)

Some 2-substituted derivatives of 17p-hydroxyoestra-4,9-dien-3-one have been prepared by the routes outlined in Scheme 3, with conjugate additions to the reactive 2-methylene group of the 2-methylene-4,9-dien-3-one(101) as the key Conjugate methylation of A4-3-0x0-steroids to give 5p-methyl-3-ketones can be achieved in moderate yield by the action of either trimethylaluminium-nickel acetylacetonate or lithium dimethy1~uprate.l~~ Steroidal 4,6-dien-3-ones react with lithium dimethylcuprate to give the 7 a - and 7P-methyl-5-en-3-ones, which may be 13*

139 140 141 142

143

E. Mincione and F. Feliziani, Ann. Chim. (Italy), 1975,65, 209. H. Hosoda, K. Yamashita, and T.Nambara, Chem. and Pharm. Bull. (Japan), 1975, 23, 3141. M. Matsui and Y. Kinuyama, J.C.S. Perkin I, 1976, 1429. R. K. Varma, M. Koreeda, B. Yagen, K. Nakanishi, and E. Caspi, J. Org. Chem., 1975,40, 3680. A. A. Shishkina, T. I. Ivanenko, and K. K. Pivnitsky, Khim. Farm. Zhur., 1975, 9, 10. L. Bagnell, A. Meisters, and T. Mole, Austral. J. Chem., 1975, 28, 817.

Terpenoids and Steroids

250

Reagents: i, CH2O; ii, H~-[(Ph3P)~Rhcl]; iii, CH2N2;iv, A; v, R2NH.

Scheme 3

isomerized to the corresponding conjugated 7-methyl-4-en-3-0nes.l~~HCN addition to the dienone (102) gave the 7a-cyano-derivative (103),which was used as a source of other 7a -substituted 0

(102)

(103)

Testosterone acetate is converted by dichlorocarbene (CHC1,-NaOHBzEt,N’Cl-) into the isomeric 4,5-dichloromethylene adducts (104) and the ‘tetrachlorospiropentane’analogues (105).14‘

c1 (104)

(105)

Difluorocarbene adds to 3,3-ethylenedioxycholest-5-eneselectively from the P-side of the olefinic bond. The reaction has been compared with those of simpler 144 145 146

J. F. Grunwell, H. D. Benson, J. 0”. Johnston, and V. Petrow, Steroids, 1976, 27, 759. R. M. Weier and L. M. Hofmann, J. Medicin. Chem., 1976,19, 975. E. V. Dehmlow and G . C. Ezimora, 2. Nufurforsch, 1975,30b, 825.

Steroid Properties, Reactions, and Partial Synthesis

25 1

olefinic compounds: chlorofluorocarbene addition was also e~arnined.’~’SimmonsSmith methylenenation of 3p -acetoxy-5a -cholest-6-ene gave the 6P,7ap -cyclo-~homo-5cu -cholestane derivative (106).’48

(106)

Olefin cleavage under non-oxidizing conditions has been achieved through a cycloaddition-cycloreversion sequence. Addition of the nitrile oxide (107) on to a 3methylene-5a -steroid gave the 3-ethoxycarbonylisoxazoline (108). Hydrolysis and thermal decarboxylation then gave the 3-0x0-steroid (109), along with the cyanohydrin (1 lo), in proportions depending upon the reaction conditions. Use of triphenylacetonitrile oxide (111) gave the corresponding isoxazolines (112), which broke down under irradiation to give the 3-0x0-steroid (109) in ca. 45% yield.’*’ O+NrC-CO,Et (107)

(108) R = COzEt (112) R=CPh3 (and C-3 epimer)

(109)

OtNrC-CPh, (111)

Maleic anhydride adds to androst- 14,16-diene to give the 14p,17p Diels-Alder adduct. A pregn- 16-en-20-one undergoes cycloadditions with the nitronic esters (113) to give the tetrahydro-oxazoles (114), which lose methanol with a trace of boron trifluoride to give the dihydro-oxazoles (1 15). The remarkable feature of the

(113) R = M e or Et R. A. Moss and D. J . Smudin, J. Org. Chem., 1976, 41, 611. L. Kohout and J. FajkoS, Coll. Czech. Chem. Comm., 1975,40, 3924. 149 J. Kalvoda and H. Kaufmann, J.C.S. Chem. Comm., 1976,209. lSo J.-C. Beloeil, C. Pascard-Billy, and T. Prange, J.C.S. Chem. Comm., 1976, 214.

14’

148

Terpenoids and Steroids

252

cycloaddition step is that it proceeds efficiently only under high pressure (14 000 atm), having a large negative activation volume.151 The addition of oxygen to ergosteryl acetate (116) to give the epidioxide (1 17) is catalysed by a variety of substances, including triphenylmethylium (trityl) salts and various Lewis acids. A full report of this work makes it clear that the reaction is a formally 'forbidden' addition of triplet oxygen. The trityl cation-catalysed reaction is photochemically activated, but is not a radical-chain process. The more effective of the Lewis acids (e.g. FeCl,, FeBr,) function in the dark. The various catalytic systems are considered to overcome a kinetic barrier to the addition of triplet oxygen to cisoid dienes, the barrier being one of spin-pairing. The possible roles of the various catalysts are discussed in terms of two distinct mechanisms.152 When titanium tetrachloride was used as the catalyst for the dark reaction, the titanium compound was consumed and an abnormal product, the 6a -chloro-h -hydroxy-7ene (118) resulted. An intermolecular reaction involving the epidioxide (1 17), the 5,7-diene, and TiC1, is proposed to account for chlorohydrin f0rmati0n.l~~ The formation of the 5a,8a-epidioxide (119) from ergosterol in fungi is partly enzymic and partly a chemically photosensitized process, probably promoted by natural pigments. 154 Cerium(1v) oxide with hydrogen peroxide generates singlet molecular oxygen, which can be trapped by ergosterol or lumisterol acetates to form the 5,8-epidioxide~.'~~ Trapping by cholesterol has been used to demonstrate the formation of singlet molecular oxygen in the base-catalysed disproportionation of hydrogen p e r 0 ~ i d e . lSinglet ~~ oxygen attacks the A'-bond in 17P-hydroxyoestra4,9-dien-3-one (120) to give the mixed 9 a - and 9P-hydroperoxyoestradiols (121), which afford the 9,lO-seco-derivative (122) with acid. Further acid treatment effects ring closure to give oestra- 1,3,5(10),9(1l)-tetraene- 1,4,17P-triol (123) through formation of a bond from C-4 to C-9."'

(116) R = A c (119) R = H

"o&H

0'& O H

(1 20) 151

152

153 lS4

lS5 156

157

(117)

(121)

A. V. Kamernitzky, I. S. Levina, E. I. Mortikova, and B. S . El'yanov, TetrahedronLerters, 1975,3235. D. H. R. Barton, R. K. Haynes, G. Leclerc, P. D. Magnus, and 1. D. Menzies, J.C.S. Perkin Z,1975,2055. D, H. R. Barton and R. K. Haynes, J.C.S. Perkin Z, 1975, 2065. M. L. Bates, W. W. Reid, and J. D. White, J.C.S. Chem. Comm., 1976, 44. D. H. R. Barton, P. D. Magnus, and J. C . Quinney, J.C.S. Perkin Z, 1975, 1610. L. L. Smith and M. J. Kulig, J. Amer. Chem. SOC.,1976, 98, 1027. M. Maurny and J. Rigaudy. Bull. SOC.chim. France, 1975, 1879.

Steroid Properties, Reactions, and Partial Synthesis

253

Other Reactions of Olefinic Steroids.-Experimental conditions are described for the efficient conversion of cholesteryl acetate into its 7-0x0-derivative (by Cr03-pyCH2C12).158Oxidation of 3~,19-diacetoxycholest-5-ene with t-butyl chromate provided entry into a series of 3&7,19-trioxygenated cholestane derivatives. 1 5 9 Chromic acid oxidizes terminal olefins and some cycloalkenes to give ketones when Hg" salts are added as activators; 5a -cholest-2-ene, however, was unaffected. 16' 3-Methoxyoestra-l,3,5(10),8-tetraen-l7/?-01(124) was aromatized in ring B by either oxygen or hydrogen peroxide (in H2S04-Bu'OH), but DDQ aromatized ring c and cleaved ring D to give the 9,lO-dihydrophenanthrenederivative (125).161

The selective hydrogenation of androsta-1,4-diene-3,17-dione to the 4-ene-3,17dione with [RuC1,(Ph3P),] also gave variable proportions of the 5a -saturated diketone, depending upon hydrogen pressure.'62 A mechanism is proposed. The corresponding catalyst with tris-( p -methoxyphenyl)phosphine ligands achieved a more selective reduction, giving the 4-ene-3,17-dione as 90% of the Selective reduction of the A22-olefinicbond in ergosterol or its esters (126) requires the protection of the more reactive 5,7-diene system. This has now been achieved in a variety of ways, which include formation of the azo-adduct (127) before a three-step chemical reduction of the side-chain double bond (Scheme 4), or formation of the tricarbonyliron adduct (120), followed by hydrogenation. The 5,7-diene is easily regenerated from either a d d u ~ t . ~ ~ ~ A new version of the mechanism of hydrogenation of a@-unsaturated ketones over palladium proposes formation of a Pd complex of the enone, which is 158

159 160 161 162 163 164

D . S. Fullerton and C. M. Chen, Synrh. Comm., 1976,6, 217. J. FajkoS and J. Joska, Coll. Czech. Chem. Comm., 1976,41,923. H. R. Rogers, J. X. McDermott, and G. M. Whitesides, J. Org. Chem., 1975,40, 3577. K. Junghans, Chem. Ber., 1975,108,2824. S . Nishimura, T. Ichino, A . Akimoto, K. Tsuneda, and H. Mori, Bull. Chem. SOC.Japan, 1975,48,2852. S. Nishimura, 0. Yumoto, K. Tsuneda, and H. Mori, Bull. Chem. SOC.Japan., 1975,48, 2603. D. H. R. Barton, A . A . L. Gunatilaka, T. Nakanishi, H. Patin, D. A . Widdowson, and B. R. Worth, J.C.S. Perkin I, 1976, 821.

254

Terpenoidsa n d Steroids

RO

rn (127) -OAc, -SPh\

... .

Y

111, I\.

t-

t

Reagents: i, 4-Phenyl-1,2,4-triazoline-3,5-dione; ii, Hg(OAc)z-PhSCl; iii, CF3COzH-PhCH2SiHMe2; iv, Raney Ni; v, H2-Adams Pt-PhCH2SiHMe2.

Scheme 4

hydrogenolysed at the @-carbon atom in the product-determining Sa,14@-Cholest-7-en-3P-ol,with the unnatural cis-C/D ring junction, is obtained by reduction of either the 8(14)-en-7-oneor the 8a,l4a-epoxy-7-ketone with zinc dust in methanolic sulphuric acid.166 Cholesterol, on reaction with dibenzoyl peroxide followed by trichloroacetic acid, gave a blue colour attributed to cations with conjugated unsaturated structures. Cholesta-2,4,6-triene and 3-(cholest-5-en-3~-yl)cholesta-2,4,6-trienewere isolated from the product mixture. Some other sterols gave diverse c010urs.~~'The coioured solutions formed from cholesterol or oestrone with antimony trichloride give e.s.r. spectra suggesting the presence of radical-cations.'" Cholesta-3,5diene and 3,3'-bicholesta-2,4-diene were isolated from the reaction of cholesterol, and the hexaene (131) from oestrone. Dimeric and trimeric products have been Me

AcO

16s

166 16' 168

@

M. J . F. Burman, D. R. Elliott, M. H. Gordon, R. G. Peck, and M. J. T. Robinson, Tetrahedron Letters, 1976, 1535. M. Anastasia, A. Fiecchi, and A. Scala, J.C.S. Perkin I, 1976, 378. Y. Kurasawa, A. Takada, and T. Ueda, Chem. and Pharm. Bull. (Japan), 1976,24, 375. Y. Kurasawa, A. Takada, and T. Ueda, Chem. and Pharm. Bull. (Japan), 1976,24,487, 1268.

255

Steroid Properties, Reactions, and Partial Synthesis

isolated from among the products of Liebermann-Burchard reaction of steroidal 3,5-dienes. 169 Cyclizations of the 4-substituted-4,5-secocholest-5-enes(132) and (134), with stereospecific labelling of deuterium at C-7, afforded 5/3-cholest-6-enes (133) and (133, respectively. Loss of 7a-deuterium but retention of 7P-deuterium established that for this SE2' reaction the bond-forming (4,5-bond) and bond-breaking processes (C-7-H) occur in the syn relationship illustrated, as required by orbital symmetry

P Me

H' 0'

- OSnCl,

(132)

1 Me

(134)

(1 33) R = OCH;?CH;?OH (135) R = H

Thermal rearrangement of a 2Q-vinylpregnane-17a,20-diolat 230 "C provides a high-yielding degradation to an androstan-17-0ne.l~' The 7r-allylpalladium complexes (136) derived from 4-en-3-ones, which are readily prepared, react with the anions of malonic esters in DMSO to give the 6P-ylmalonates (137), which may be decarboxylated to give the 6 a - and 6P-yl acetates (138) in good ~ie1d.l~'Earlier

routes to these compounds, required for use in radioimmunoassay (p. 309) have been tedious and less efficient. C. H. Brieskorn and G. Greiner, Arch. Pharm., 1975, 308, 375. I. M. Cunningham and K. H. Overton, J.C.S. Perkin I, 1975, 2140. 171 J.-P. Barnier and J.-M. Conia, Bull. SOC.chim. France, 1975, 1659. r72 D. J. ColIins, W. R. Jackson, and R. N. Timms, Tetrahedron Letters, 1976,495.

169

170

Terpenoids and Steroids

256

Acetylenic Compounds.-The reductive cyclization of acetylenic ketones with naphthalene radical-anions has been studied for a variety of 4,5-secocholest-3-yn-5one analogues (139). Products vary with structural type; three examples are illustrated in Scheme 5. Results are interpreted in terms of initial electron transfer from the reagent to form a ketyl radical-anion, followed by intramolecular radical attack on the triple bond.'73

(139)

H

Me

Reagent: i, CloH8Na.

Scheme 5

Tris(triphenylsily1) vanadate with triphenylsilanol is an efficient catalyst for the rearrangement of a 17a -ethynyl- 17p -hydroxy-steroid (140) to give the pregn17(20)-en-21-al (142).174 A vanadate ester (141) is assumed to transfer oxygen as illustrated. ,CHO

(140)

(141)

(142)

Di-isobutylaluminium hydride reduces the 17a -ethynyl- 17p-hydroxy-system (140) to give the saturated hydrocarbon (pregnane) side-chain (143) although AlH, gives the allene ( 144).17' Reduction of the 17a -ethynyl-17@-hydroxy-system (140) or its acetate with lithium or sodium in liquid ammonia can afford a variety of products, depending upon the reaction condition^.^'^ The acetylenic alcohols (145) derived from 24-oxocholesterol gave the allene (146) on reduction with LiAlH4. 173

175

S. K. Pradhan, T. V. Radhakrishnan, and R. Subramanian, J. Org. Chem., 1976,41, 1943. G. L. Olson, K. D. Morgan, and G. Saucy, Synthesis, 1976, 25. J. C. Hilscher, Chem. Ber., 1976, 109, 1208. 0. I . Fedorova, 0. S. Anisimova, and G . S. Grinenko, Khim. prirod. Soedinenii, 1976, 180.

257

Steroid Properties, Reactions, and Partial Synthesis

II

OH

C

(145)

(146)

Similar reaction of the cholest-23-yn-25-01(147)gave the 23-en-25-01 (148), but use of LiA1H4-A1Cl3 gave the required cholesta-23,24-diene (149) in 13% yield, along with the 23-en-25-01 (148).177

A

*

OH

YOH

(147)

(148)

(149)

Aromatic Compounds.-Oestradiol is smoothly brominated at C-4 (50%) and C-2 (20%) by 2,4,4,6-tetrabromocyclohexa-2,5-dienone, although other methods give low yield^.^'' The 11-0x0-derivative (150) has been detected as an intermediate in the oxidation of 3-methoxyoestra-l,3,5(10)-triene, which ultimately gives the 9 p hydroxy-11-ketone (15 1) and other products. The precise position of compound (150)in the reaction sequence is uncertain.17’ Oxidation of 17a -(3’-furyl)oestradiol 3-methyl ether (152) gives butenolides: N-bromosuccinimide in aqueous dioxan attacks the furan ring at C-2’, giving butenolide (153), whereas peracid gives mainly the hydroxy-lactone (154), which may be reduced to the lactone (155) or oxidized to the maleic anhydride derivative (156).

(150)

(151)

Y. Fujimoto, M. Morisaki, and N. Ikekawa, J.C.S. Perkin I, 1975, 2302. 178 V. N. Zontova, V. N. Rzheznikov, and K. K. Pivnitsky, Steroids, 1975, 25, 827. 179 P. Aclinou and B. Gastambide, Compt. rend., 1975,23, C, 1423. 180 Y. Lefebvre and C. Revesz, J. Medicin. Chem., 1975,18, 581. 177

Terpenoids and Steroids

258

(153)

(154) R = OH,H

(155) R = H 2 (156) R = 0

4 Carbonyl Compounds Reduction of Ketones.-A review of the functional group selectivity of complex hydride reducing agents includes a number of useful selective transformations in the steroid series.181 Bornan-2-exo-yloxyaluminium dichloride reduces 0x0-steroids and triterpenoids stereoselectively to form axial alcohols (e.g. 5a -cholestan-3one -+-3a -01; 85%).lg2 Cholest-4-en-3-one is reduced by either tetrabutylammonium or sodium cyanoborohydride in acidic HMPA to give mainly saturated alcohols, although several other aP -unsaturated ketones gave allylic alcohols or hydrocarbons. 183 The mechanistic details of the reduction of ketones by hydride donors present a continuing challenge. Stereochemical control of attack on cyclic ketones, exemplified by 3-0x0- and 7-oxo-5a-steroids, has been correlated with the relative ease of attainment of a transition state in which the nucleophile (hydride) This hypothesis approaches from the direction anti-periplanar to C,- H rests upon an orbital-symmetry analysis of the relative energies of transition states resembling those proposed by Felkin. The anti-periplanar mode of approach is considered to be assisted by favourable overlap of the &, (T&,and H- orbitals (Figure 2); ring A of a steroid, being relatively flexible, would tolerate the necessary partial flattening in the transition state for reduction of a 3-0x0-group by attack from the ‘axial’ a -direction, whereas the relative rigidity of ring B would resist flattening and therefore retard ‘axial’ approach of the nucleophile. This argument would account for the predominant formation of the 3P-alcohol; the low stereoselectivity of reduction at C-7 is explained without invoking steric hindrance, which is regarded as failing to provide a satisfactory rati0na1e.l~’

Figure 2 Favourable and unfauourable interactions of hydride orbital with .lrz0 and u& orbitals lA*

185

E. R. H. Walker, Chem. SOC. Rev., 1976, 5 , 23. D . Nasipuri, P. R. Mukherjee, S. C. Pakrashi, S. Datta, and P. P. Ghosh-Dastidar, J.C.S. Perkin I, 1976, 321. R. 0. Hutchins and D. Kandasamy, J. Org. Chem., 1975, 40, 2530. J. Huet, Y. Maroni-Barnaud, Nguyen Trong Anh, and J. Seyden-Penne, TetrahedronLetters, 1976,159. Nguyen Trong Anh and 0. Eisenstein, TetrahedronLetters, 1976, 155.

Steroid Properties, Reactions, and Partial Synthesis

259

Continued practical studies on the reductions of ketones, including 0x0-steroids, with NaBH4, show that entropy constitutes a major part of the barrier to reduction, although differences in enthalpies of activation are largely responsible for variations in rates and stereochemical outcome between different ketones.lg6 Construction of isokinetic plots involving nineteen ketones led to the suggestion of variations in mechanism or in transition-state structure according to the degree of steric hindrance. For any one ketone, however, even if one face of the carbonyl group is subject to strong hindrance, there is no indication of any significant mechanistic difference between the ‘axial’ and ‘equatorial’ modes of attack.’“ The mystery deepens! A new study of the catalytic hydrogenation of 5a -cholestan-3-one has produced wide variations in the ratio of 3a- and 3/3-alcohols, depending upon the catalyst, solvent, and conditions of reaction. Optimum conditions, using a particular nickel catalyst, gave the axial 3a-alcohol in an isolated yield of 80%. Even cholest-5-en-3one afforded the 3a-alcohol (epicholesterol) with this catalyst, the A5-bond being ~naffected.’~’ Other Reactions at the Carbonyl Carbon Atom.-Grignard reactions of a pregnan20-one (157) with 4-methylpentylmagnesium bromide, or of a 21 -norcholestan-20one (158) with methylmagnesium bromide, gave the (20s)- and (20R)-cholestan20-01s (159) and (160), respectively as major products, in accordance with the known conformational preference of the side-chain, with a-face attack by the reagent. The 21-norcholestan-20-one side-chain has a more marked conformational preference than the pregnan-20-0ne.~~~ The stereochemistry of Grignard attack on a pregnan20-one (157) is modified in the presence of a 13/3-methoxycarbonyl group. The product was a mixture of (20R)- and (20s)-lactones of types (161), depending upon the reagent emp10yed.l~~

(157) R = M e

(159) (20s)

(158) R=C6H13 Oestrone methyl ether reacts at the 17-0x0-group with methoxyvinyl-lithium, giving the 17a -adduct (162). Hydrolysis afforded the 20-0x0-derivative (163), whereas oxidation (OsO,) generated the dihydroxyacetone system (164), albeit in the wrong configuration at C-17 for a corticosteroid ~ynthesis.”~ Experiments with mono- and bi-cyclic ketones show that methyl-lithium with lithium dimethylcuprate gives methyl carbinols, very largely with the axial-hydroxy lS6 lS7 ls8

lS9

D. C. Wigfield and D. J. Phelps, J. Org. Chem., 1976,41, 2396. M. Ishige and M. Shiota, Canad. J. Chem., 1975, 53, 1700. W. R. Nes and T. E. Varkey, J. Org. Chem., 1976,41, 1652. A. Milliet and F. Khuong-Huu, Bull. SOC.chim. France, 1975, 2266. J. E. Baldwin, 0. W. Lever, jun., and N. R. Tzodikov, J . Org. Chem., 1976, 41, 2312.

Terpenoidsand Steroids

260

(163) R = H (164) R = O H

config~ration,'~'although the reaction with methyl-lithium alone (or with methylmagnesium halides) is less stereoselective, as exemplified by several steroid reactions. The combined reagents ('dilithium t r i m e t h y l ~ u p r a t e ' ) 'seem ~ ~ likely to find applications in steroid chemistry. Cholest-4-en-3-one gives the adduct (166) with the vinylcuprate (165).193 The C-17 thiiran (167) is one of several prepared from the corresponding ketone by treatment with the lithio-derivative (168) of the 2methylthio-oxazoline (169).'94

(167)

(168) R = L i (169) R = H

The reaction of 2a-bromo-5cu-cholestan-3-one with zinc and allyl bromide in benzene-DMSO failed to produce the expected 2a -ally1 derivative, giving instead a complex mixture having the A-nor allyl ketone (170) as its major component. The isolation of a 3-allyl-3-hydroxy-derivative (17 1) in low yield suggests that reaction occurs first at C-3, with subsequent semipinacolic contraction of ring

191 192

Iq3 194

Iq5

T. L. Macdonald and W. C. Still, J. Amer. Chem. SOC.,1975, 97, 5280. W. C. Still and T. L. Macdonald, Tetrahedron Letters, 1976, 2659. J. P. Marino and D. M. Floyd, Tetrahedron Letters, 1975, 3897. A. I. Meyers and M. E. Ford, J. O r g . Chem., 1976,41, 1735. P. D. Woodgate, B. R. Davis, a n d M . H . Lee, Austral. J. Chem., 1975, 28, 1785.

Steroid Properties, Reactions, and Partial Synthesis

261

Androsta- 1,4-diene-3,17-dione reacted selectively at C- 17 with potassium acetylide to give the 17a-ethynyI- 17p-alcohol: the dihydroxyacetone side-chain was then elaborated by use of known transformations, without interference from the 1,4-dien-3-0ne Ethynylation of a [ 16-3H]- or [ 16-2H2]-17-oxo-steroid proceeds without loss of label. 19’ Some further examples of the condensation of carbonyl compounds with phosphonate carbanions (Wittig-Horner reaction) include the transformations illustrated in Scheme 6. The failure of some related reactions is not properly

HO‘.

&cHo

0

Hzoc s \

~

’

Reagents: i, (Et0)2POCHC02Et, hydrolysis; ii, (Et0)’POCHCN.

Scheme 6

The recently described sulphur ylide diphenylsulphonium cyclopropylide (172), which converts saturated ketones into spirocyclobutanones, reacted with a steroidal 4,6-dien-3-one in a more complex manner. Two moles of the reagent were incorporated to give the spiro[2,4]heptan-4-one (173) and the epimer at the C-3 position of the steroid. Scheme 7 illustrates the likely reaction path.199 Diazocyclopropane converts the 16-bromo- 17-0x0-compounds (174) into isomeric spiro-oxirans (175); rearrangement with boron trifluoride gave the corresponding spirocyclobutanones (176), which could be debrominated with Raney H. Sakarnoto and M. Kato, Chem. and Pharm. Bull. (Japan), 1976,24828. A. I. A. Broess, J . S . Favier, N. P. van Vliet, and D. C . Warrell, J. Labelled Compounds, 1975,11,223. l Y 8E. D. Bergrnann and A. Solornovici, Steroids, 1976, 27, 431. 199 M. J. Green. H.-J. Shue, A. T. McPhail, and R. W. Miller, Tetrahedron Letters, 1976, 2677. 2oo D. R. Rae, J.C.S. Perkin I , 1975, 2460. 196

19’

Terpenoids and Steroids

262

1

2-o i

(173)

h lo

Scheme 7

H (175)

(174)

Methylthiotrimethylsilane converts aldehydes and ketones into bis(methy1thio)acetals under very mild conditions, without the need for an acidic catalyst. 5aAndrostane-3,17-dione reacted selectively at C-3.The reaction appears to depend upon the high affinity of silicon for oxygen.2o1 2-Methylenepropane-l,3-diolprotects ketone< as acetals from which the ketones can be regenerated without resort to acidic treatment, if required.202Hypophosphorous acid adds on to 3-0x0-steroids to give 3-yl phosphonous acids. 5u -Cholestan-3-one gives the 3-hydroxy-derivative (177), but a 4-en-3-one gives the 3,5-dien-3-yl phosphonous acid (178).203

(177)

(178)

17a-Hydroxypregnan-20-ones react with excess phosgene (in CH,C12-py) to give 20-chloro- 17a,20-cyclic carbonates (179); the chlorine can be displaced by acetoxy201 202 203

D. A. Evans, K. G. Grirnm, and L. K. Truesdale, J. Amer. Chem. Soc., 1975,97, 3229. E. J. Corey and J. W. Suggs, Tetrahedron Letters, 1975, 3775. M. Zkches. G. Ledouble, 0. Albert, and M. Wiczewski, European J. Med. Chem., 1975, 10,309.

Steroid Properties, Reactions, and Partial Synthesis

263

or methoxy-substituents without attack on the carbonate ring. The 2 1-acetoxy analogue (180) is reduced by zinc to give the pregn-20-ene 17a,20-diol carbonate (181).204 CH ,R

(179) R = H (180) R=OAc

Lactone formation, by intramolecular condensation of a -acetoxy-ketones in strongly basic media, has been examined systematically. Lithium di-isopropylamide in ether is effective as the base; conditions must be chosen according to the reactant. Scheme 8 illustrates successful reactions, which afforded either the P -hydroxy- ylactone or the butenolide, depending upon the ease of adoption of the conformation necessary for elimination of water. The method appears to be limited to tertiary a acetoxy-ketone~.~~~

0

0

0

Scheme 8

Reactions involving Enols or Enolic Derivatives.-Polyhalogenation studies on 5P cholestan-2-one show that chlorination occurs in the order 1P,3a,3P, followed in the case of chlorination by the highly hindered la -position. Attempted bromination beyond the 1/3,3,3-tribromide gave only 1,1,3-tribromo-5~-cholest-3-en-2-one.206 Acid-catalysed bromination of la -methyl and la-phenyl-5a-cholestan-3-ones occurred normally to give 2 a -bromo-derivatives. The bromination of 5 P cholestan-3-one at the 4P-position is also unaffected by the presence of a la-methyl 204

205

206

M. L. Lewbart, J. Org. Chem., 1976, 41, 78. J. R. Bull and A. Tuinman, J.C.S. Perkin I, 1976, 212. J. Y. Satoh, C. A. Horiuchi, and A. Hagitani, Bull. Chem. SOC.Japan, 1975,48, 1282.

264

Terpenoids and Steroids

sub~tituent.~'~ A new procedure for the bromination of 4-en-3-ones gives the 6Pbromo-derivatives in high yield. The eaone and molecular bromine are irradiated in CCI4, with cyclohexene oxide as acid scavenger, to ensure that reaction proceeds only through a free-radical mechanism.208 A series of 16a -alkyl- 17a -methylpregnan-20-ones has been prepared by conjugate addition of various Grignard reagents on to the 16-en-20-one system, followed by immediate in situ alkylation of the A17(20)-eno1ate with methyl iodide. Byproducts formed along with the 16a,17a-dimethyl derivative include the 16amethyl and 1 6 q 21-dimethyl corn pound^.^'^ 2 1-Methylated corticosteroids have been obtained by base-catalysed methylation of the 17,21-acetonide (182). Acidic hydrolysis of the methylated acetonide (183) gave the product (184). 21Trifluoroacetyl(l85) and 2'-nitroethyl (186) derivatives were prepared similarly, as well as several other compounds with extended side-chains.*l'

(182) R = H (183) R = M e

(184) R = M e (185) R=COCF3 (186) R = CH2CH2N02

Two procedures have been devised for the synthesis of a novel class of cyclosteroids, the 4ru,6a -cyclo-SP -derivatives (190). Carbenoid decomposition (NaOMe; 160°C) of the tosylhydrazone (187) gave the unsaturated acid (188). Copper-catalysed decomposition of the derived diazo-ketone (189) gave the desired 4a,6a-cyclo-ketone (190) by a keto-carbene addition to the 5,6-double bond. A more satisfactory synthesis proceeded from the 6P-tosylate (191), which gave the 4a,6a -cyclosteroid in high yield on reaction with base (KO'Bu-HO'Bu). Several hormone analogues with the 4a,6a -cyclo modification were devoid of biological activity."' An 18-acetoxypregnan-20-one (192) forms the A'7(20)-eno1acetate (193) even with isopropenyl acetate, in contrast to A2'-enolization in the absence of the C-18 substituent. Forced acetylation of the 18 -+ 20-hemiacetal (194) may give an anhydro-dimer (195) along with the 18-acetoxy-20-ketone (192).*12 An 18iodopregnan-20-one (196) reacts with base to give the 17& 18-cyclo-17a-pregnan20-one (197), which could be acetoxylated normally at C-21. Cleavage of the 17P,18-cyclo-ketone (197) with hydrogen iodine appears to generate the 18-iodo17a-pregnan-20-one, rather than the normal 17P-isomer (196).212 207 208 209

21n 211 212

T. T. Takahashi and J. Y. Satoh, Bull. Chem. SOC.Japan, 1976,49, 1089. V. Calo, L. Lopez, and G. Pesce, J.C.S. Perkin II, 1976, 247. J. Cairns, C. L. Hewett, R. T. Logan, G. McGarry, D. F. M. Stevenson, and G. F. Woods, J.C.S. Perkin Z, 1976, 1558. M. Tanabe, B. B. Sockolov, and D. F. Crowe, Chem. and Pharm. Bull., (Japan), 1975,23,2728. F. T. Bond, W. Weyler, B. Burnner, and J. E. Stemke, J, Medicin. Chem., 1976, 19, 255. D. N. Kirk and M. S. Rajagopalan, J.C.S. Perkin I, 1976, 1064.

Steroid Properties, Reactions, and Partial Synthesis

O

OTs W

.d:s

\

265

\

Me

&-OH

(192) R = O A c (196) R = I

(193)

(195)

(194)

(197)

The preferred sequence for preparing 3P-hydroxy-5a -androstan-16-one from the 3-hydroxy-17-ketone is illustrated in Scheme 9. Overall yields were 5156% .213

Reagents: i, PhCHO-KOH; ii, LiAlH4; iii, AqO-py; iv, 0,; v, Zn-HOAc.

Scheme 9 213

I. Ghilezau, Sir E. R. H. Jones, G . D. Meakins, and J. 0. Miners, J.C.S. Perkin I, 1976, 1350.

Terpenoidsand Steroids

266

Thallium(I1I)acetate in acetic acid can react with ketones to provide acetoxylated, dehydrogenated, or rearranged products. An investigation of the behaviour of all the common types of steroid ketones provided examples of each mode of reaction, although products were always Few if any of the reactions appear to offer any advantages over alternative routes to the same products. Formamide and perchloric acid are reported to react with 3-0x0- or 17-0x0-steroids to give isoxazolines (198) or (199).’15 The reaction of a (25R)-spirostan (200) with BF3-Ac20 gives the E-seco-23-acetyl derivative (201) in 90% yield, contrary to earlier indications. Hydrolysis, accompanied by intramolecular conjugate addition, give the 23-acetyl-(25R)-spirostan (202). Use of BBr, instead of BF3 gave the normal F-SeCO ‘pseudosapogenin’ derivative (203), whereas BCl, gave a mixture of the E-seco- and F-seco-compounds.216

x

AcOCH

(200) R = H (202) R = COMe

Pseudosolasodine diacetate (204), derived as the first degradation product of solasodine, reacts quantitatively with iodine. Chromatography of the solution on silica gel gave the product (205) of 23,N-cyclization. Oxidation by the usual

>14

*16

G. Ortar and A . Romeo, J.C.S. Perkin 1, 1976, 111. L. N. Volovelsky, N. V. Popova, M. Y. Yakovleva, and 1‘.G. Khukhryansky, Zhur. obshchei Khim., 1975,45, 2090. A . G . Gonzalez, C. G. Francisco, R. Freire, R. Hernandez, J. A. Salazar, and E. Suirez,-Tetrahedron Letters, 1976, 1325.

267

Steroid Properties, Reactions, and Partial Synthesis

procedure for degradation of a furost-20(22)-ene gave the ester (206) and the pregn16-en-20-one (207).217 Microbial 4,5-di-dehydrogenation of 5a -androstane-3,17-dione involves abstraction of 4p-H.218 COMe

Oximes, Tosylhydrazones, and Related Derivatives of Ketones.-The reaction between oximes and refluxing acetic anhydride-pyridine affords enimides and e n a r n i d e ~The . ~ ~oxime ~ of a 17-0x0-steroid reacts with inversion at C-13, through a radical mechanism, to give the 1 3 a -steroidal enamide (208) after chromatography on alumina.22o This route to 130-androstanes is said to be superior to the usual photochemical method. The oxime (209) of testosterone acetate reacts with acetic anhydride-pyridine-acetyl chloride at 80 "C to give the NNO-triacetyl compound (210), which can be hydrolysed to give the 4-hydroxy-derivative (21 1). The reaction is apparently a general one for ketoximes: the C-acetoxylation step is thought to proceed in tramolecularly .221

OAc

L

(208)

(209)

(210)

OH (211)

Oximes (212) of pregnan-20-ones give both 20,21-imino-derivatives (213) and 20-aminopregnanes (2 14) on reduction with lithium aluminium hydride. Grignard reagents similarly afford the corresponding 20-alkyl or 20-aryl-20,2 1iminopregnanes (2 15). Some transformations involving the aziridine ring are described.222 Hydroxylamine converts a 16a-bromoandrostan- 17-one (216) cleanly into the , ~ ~ ~ paralleling the action of 17-oxime (217) of the 16a- h y d r ~ x y - k e t o n e closely h y d r a ~ i n e .Reduction ~~~ of the oxime-acetate (218) with diborane gave the 17pacetamido- 16a -acetoxy-derivative (2 19).223 217 21B

219 220

221 222

223 224

G. G . Malanina, Khim. Farm. Zhur., 1976, 10, 90. T. Nambara, S. Ikegawa, and C. Takahashi, Chem. and Pharm. Bull. (Japan), 1975,23,2358. Ref. 70, p. 254. R. B. Boar, F. K. Jetuah, J. F. McGhie, M. S. Robinson, and D. H. R. Barton, J.C.S. Chem. Comm., 1975, 748. M. V. Bhatt, C. G. Rao, and S. Rengaraju, J.C.S. Chem. Comm., 1976, 103. A. Tzikas, Ch. Tamm. A. Boller, and A. Furst, Helu. Chim. Acta, 1976, 59, 1850. P. Catsoulacos, Bull. Soc. chim. France, 1976, 642. P. Catsoulacos and A. Hassner, J. Org. Chem., 1976,32, 3723.

Terpenoids and Steroids

268

(213) R = H (215) R = Me, Et, or Ph HONH? $JH]+/flR

NHAc

--OR

(217) R = H (218) R = Ac

--OAc

+

(219)

20P-Hydroxypregnan-2 1-als (223) have been prepared from the 20,2 1-dioxocompounds (220) by forming the 21-aldoxime (221), reducing at C-20 with NaBH4, and hydrolysing the oxime (222) with aqueous-ethanolic sodium hydrogen sul~hite.~” CHO I

CH=NOH

YH=NOH

THO

(220) R = H or OH

2-Chloroethoxyamine (224) and w -chloro homologues form 0-0 chloroalkyloximes with steroidal 0x0-groups at all the usual positions except C- 11. These derivatives are very sensitive to electron-capture detection, and have been used for g.1.c.-m.s. studies.226 ClCH2CH20NHZ (224)

Cleavage of tosylhydrazones, arylhydrazones, and oximes to their parent ketones simply by exchange in acetone is said to offer a mild and convenient method under non-acidic conditions. Hexadeuterioacetone affords a -deuteriated ketones.227 Although tosylhydrazones of saturated ketones are reduced by borohydride in methanol to give hydrocarbons, similar treatment of the tosylhydrazone of cholest4-en-3-one gave a mixture of 3a - and 3~-methoxycholest-4-enes, apparently through a diazonium alkoxide ion pair.228 The reduction of tosylhydrazones of 225

226 227 228

S.-W. O h and C. Monder, J. Org. Chem., 1976, 41, 2477. T. Nambara, T. Iwata, and K. Kigasawa, J. Chromatog., 1976, 118. 127. S. R. Maynez, L. Pelavin, and G . Erker, J. Org. Chem., 1975, 40, 3302. R. Grandi, A. Marchesini, U. M. Pagnoni, and R. Trave, J. Org. Chem., 1976, 41, 17.55.

269

Steroid Properties, Reactions, and Partial Synthesis

a@-unsaturatedketones with NaBH,CN (or NaBD,CN) and acid may also be more complicated than earlier publications had implied. Cholest-4-en-3-one tosylhydrazone, for example, gave a mixture containing 5a- and 5@-cholestanes and cholest-3-enes (227), but the 5a -cholest-l-en-3-one derivative gave essentially 5a -cholestane with only a trace of ~lefin.,,~cisoid Enone derivatives, in contrast, give olefins as major products [e.g. 8(14)-en-7-one -P 14a-7-ene; 4-en-6-one + 5ene]. Two competing mechanisms were deduced from deuterium-labelling experiments, Alkene (227) formation results from hydride reduction of an iminium intermediate (225), followed by an intramolecular hydrogen transfer from nitrogen to the @-carbon atom as part of a fragmentation of the tosylhydrazine derivative (226). Alternative Michael-type conjugate reduction gives the ene-tosylhydrazines (228), which tautomerize to the saturated tosylhydrazones (229); further protonation-reduction then gives the saturated hydrocarbons (230). The former of these mechanisms is particularly favourable in compounds of cisoid type.229

I

H- attack at C-5

&' &'-&' TsNH-N

TsNH-NH

H

(228)

H (229)

H

(230)

Tosylhydrazone stereochemistry may influence the regioselectivity of decomposition of enone derivatives to give dienes.,,' The new hydrazone nitroxyl (231) has been used for spin-labelling of ketones, including 5a -cholestan-3-one, by azine formation.231 A 20-semicarbazone (232) reacts with Se0,-HOAc to give the selenadiazolyl steroid (23 3); thermal decomposition of this heterocycle afforded the pregn-20-yne (234).,,, The rearrangement of ketone nitrones with tosyl chloride in pyridine has been described in full.233The reaction has resemblances to the Beckmann rearrangement of oximes, but does not depend upon nitrone stereochemistry, and gives N-alkyl(usually N-methyl) lactams. 229

23"

231

232 233

E. J. Taylor and C. Djerassi, J. Amer. Chem. Soc., 1976,98, 2275. W. G . Dauben, G. T. Rivers, W. T. Zimmerman, N. C. Young, B. Kim, and J. Yang, Tetrahedron Letters, 1976,2951. H. Schlude, Tetrahedron Letters, 1976, 2179. H. Golgolab and I. Lalezari, J. Heterocyclic Chem., 1975, 12,801. D. H. R. Barton, M. J. Day, R. H. Hesse, and M. M. Pechet, J.C.S. Perkin I, 1975, 1764.

Terpenoids and Steroids

270 Me I

C=NNHCONH,

.o-

H,

(231)

(232)

(233)

(234)

Carboxylic Acids and Derivatives.-Esters may be reduced to ethers in low yield by This reaction would not norlithium aluminium hydride-aluminium mally be used for preparative purposes, being more effectively carried out with sodium borohydride-boron trifluoride, but could complicate the use of LiA1H4AlCI, for other purposes such as the reductive cleavage of the spiroacetal system in sapogenins. Formation of the 3P-acetoxyeti-5-enic esters has been used to obtain optically pure samples of (+)- and ( - ) - t ~ u n ~ - v e r b e n oand l ~ ~ to ~ resolve an alcohol intermediate in the synthesis of the witchweed seed germination stimulant (+)-strig01.~~~ A general synthesis of thiol esters from carboxylic acids, exemplified by the formation of the n-propylthio-, isopropylthio-, and t-butylthio-esters of cholic acid, comprises reaction with diethyl chlorophosphate-triethylamine, followed by the thallium(1) salt of the appropriate thi01.~~’ 5 Compounds of Nitrogen and Sulphur

Oxidative deamination of a secondary amine to the ketone can be effected by formation of the imine with 2-pyridinecarboxaldehyde, reaction of the imine with peroxy-acid to form the oxaziridine, and alkaline hydrolysis (KOH-H,O-DMFMe2CO). The steps are illustrated for 3 a -amino-5a -cholestane (235), leading to (239); a 17a-aminoandrostane also gave the corresponding ketone.238

at-

0

H

(239) 234 235 236

237 23R

A. M. Maione and I . Torrini, Chem. and Ind., 1975, 837. K. Mori, Agric. and Biol. Chem. (Japan), 1976, 40, 415. J. B . Heather R. S. D . Mittal, and C. J. Sih, J. Amer. Chem. Soc., 1976, 98, 3661. S. Masarnune, S. Karnata, .I.DLakur, Y. Sugihara, and G. S. Bates, Cunad. J . Chem., 1975, 53,3693. S. E. Dinizo and D. S. Watt, J. Amer. Chem. SOC.,1975, 97, 6900.

Steroid Properties, Reactions, and Partial Synthesis

27 1

The kinetics of opening of the aziridine ring in 5a,6a-iminocholestan-3p- and -3a-01s by azide ion suggest a reaction more complex than the opening of the corresponding epoxides. The 3 a -hydroxy-substituent causes slight rate acceleration, apparently resulting from internal 'solvation' of protonated The oxaziridine (240) derived from conanine has been methylated at nitrogen by methyl fluorosulphonate to give the first reported oxaziridinium salt (241). The salt was stable in the crystalline state, but decomposed in solution to give the iminium ion

(240)

(24 1)

(242)

2a -Azido-Sa-cholestan-3-0ne(243) reacts with acyl halides and triphenylphosphine to give oxazoles (244).241

The immediate product (246) of 1,3-dipolar cycloaddition of a 16diazoandrostan- 17-one (245) on to an acetylenic carbonyl compound rearranged spontaneously to give a pyrazole derivative (247).242

+ (245) HCGC-COR

(247)

R = Me or OMe

Lanostan-3P -yl azidoformate (248)243and its A8-unsaturated are thermolysed or p h ~ t o l y s e d *to~ ~give the oxazolidinones (249) and the products (250), functionalized in the 4a -methyl group. Other reactions leading to heterocyclic derivatives of steroids are described on p. 305. 239 240 241

242 243

244

Y. Houminer, J.C.S. Perkin I, 1976, 1037. A . Milliet, A . Picot, and X. Lusinchi, Tetrahedron Letters, 1976, 1573. A. Wolloch and E. Zbiral, Tetrahedron, 1976, 32, 1289. M. Franck-Neumann and C. Dietrich-Buchecker, Tetrahedron Letters, 1976,2069. A . J. Jones, P. F. Alewood, M. Benn, and J. Wong, Tetrahedron Letters, 1976, 1655. J. J. Wright and J. B. Morton, J.C.S. Chem. Comm., 1976, 668.

Terpenoids and Steroids

272

+ 0

N,-C-O

It

0 H

(248) A*, or 8,9-saturated

(249)

(250)

The regioselective thermolysis of diastereoisomeric steroidal sulphoxides (25 1)to give olefins has been made regiospecific by use of the 1-adamantylsulphinyl derivatives. The (R)-and (S)-isomers at sulphur of 3a -(l-adamantylsulphinyl)-5a cholestane gave only 5a -cholest-3-ene and -2-ene, respectively, as a consequence of

H

the bulk of the adamantyl group; corresponding compounds of the 5P-series gave SP-cholest-2-ene and -3-ene regioselectively, and at markedly different rates, in boiling benzene.245 The exceptionally stable dithiet (254) has been prepared from 3~-acetoxy-7,7-ethylenedithio-5a-lanost-8-en-l1~-01 (252) by reaction with phosphoryl chloride-pyridine under reflux to give the aromatized product (253), which lost ethylene with ring contraction on photolysis in heptane at -20 0C.246

AcO

/

AcO

S’

245 246

D. N. Jones, A. C . F. Edmonds, and S. D. Knox, J.C.S. Perkin I, 1976,459. R. B. Boar, D. W. Hawkins, J. F. McGhie, S. C . Misra, D. H. R. Barton, M. F. C. Ladd, and D. C. Povey, J.C.S. Chem. Comm., 1975, 756.

273

Steroid Properties, Reactions, and Partial Synthesis

Vicinal phenylthio-alcohols are cleaved by lead tetra-acetate with insertion of oxygen, The 16p-phenylthio-derivative (255) of oestrone methyl ether, for example, was reduced to the thio-alcohol (256): treatment with lead tetra-acetate then gave the cyclic hemithioacetal acetate (257), which could be methanolysed to give the derivative (258). Similar reaction after methylation at (2-16 (259) gave the product (260), which was hydrolysed and cyclized (KOH-MeOH) to give the Dhomo- 17-en-16-one (261).247 OH

(256) R = H (259) R = M e OMe

(257) R = H (260) R = Me

6 Molecular Rearrangements

Backbone Rearrangements.-Full details of the behaviour of oestr-4-ene-3,17dione in the hyperacidic medium HF-SbF5 show that this system contrasts markedly with conventional acids in not promoting enolization, presumably because of the absence of an effective basic species. Instead both carbonyl oxygen atoms are protonated, forming a hydroxyallyl cation in ring A. At O'C, C-4 is additionally protonated, promoting migration of a cationic centre between C-5 and C-14 along the steroid backbone. Added cyclohexane or methylcyclopentane, or a perdeuteriated hydrocarbon, traps the migrating carbocation by a hydride (or deuteride) transfer mainly to the 8p-position, along with some attack at 9a or 7p, to give Similar hydride transfer from monodeuterio- 14p -0estrane-3,17-diones.~~~ hydrocarbons in HF-SbF5 reduced oestrone and oestra-4,9-diene-3,17-dioneto give 14p-oestrane-3,17-dione; these reactions involve stepwise transfer of two hydrogen or deuterium atoms to sites in ring B.249Oestrone and various oestrene derivatives in SbF,-HF are reduced by gaseous hydrogen to give the 14panthrasteroid (262), through a mechanism involving protonation, carbocationic rearrangement, and a final reductive 247 248 249

250

B. M. Trost and K. Hiroi, J. Amer. Chem. SOC.,1975,97,6911. J.-C. Jacquesy, R. Jacquesy, and G. Joly, Bull. SOC.chim. France, 1975, 2281. J.-C. Jacquesy, R. Jacquesy, and G. Joly, Bull. SOC.chim. France, 1975, 2289. J.-C. Jacquesy, R. Jacquesy, and G. Joly, Tetrahedron, 1975,31, 2237.

Terpenoids and Steroids

274

(262)

In a most remarkable variant of rearrangements of ‘backbone’ type, androst-4ene-3,17-dione was transformed in HF-SbF, into 7p-methyl-14P-oestr-4-ene3,17-dione (263).*’l The detailed mechanism remains in doubt. Inversion of

(263)

configuration at C-14 is a well known feature (see above), proceeding normally through a series of 1,2-hydride shifts along the steroid backbone. The transient appearance of a carbocation at C-7 has also been demonstrated in related and presumably provides the activation required for migration of the C-19 methyl group to C-7, but the steps involved in the transposition of the methyl group from the lop-position are not clear, and present a challenge for the future. Androsta-4,6diene-3,17-dione (264) appears to be triply protonated by HF-SbF5 to give the trication (265), which undergoes a partial ‘backbone’ type rearrangement to afford the 14P-isomer (266), and a 1 0 6 -+9 P methyl shift to give 9-methyl-8a,9&14Poestrone (267).252

(264) 1 4 ~ ~ - H (266) 14P-H

The backbone isomerizations of cholest-5-ene to give a A’”17)-01efin, and of androst-5-ene and D-homoandrost-5-ene to give mixtures of isomeric AgC9)~ l e f i n s , ~are ’ ~now reported in Trifluoroacetic acid effects these rearrange251

252 257

254

J.-C. Jacquesy, R. Jacquesy, and C. Narbonne, Bull. SOC.chim. France, 1976, 1240. R. Jacquesy and H. L. Ung, Tetrahedron, 1976, 32, 1375. ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1972, Vol. 2, p. 304. D. N. Kirk and P. M. Shaw, J.C.S. Perkin I, 1975, 2284.

Steroid Properties, Reactions, and Partial Synthesis

275

ments rapidly at room temperature, in contrast to the prolonged heating required in acidified acetic acid. Androst-5 -en- 17-one (268) rearranges less rapidly in trifluoroacetic acid, giving 5-methyl-SP-oestr-9(11)-en- 17-one (269); further reaction in sulphuric acid-methanol affords 5-methyl-5& 14P-oestr-8-en- 17-one (270) and its 5a,lOar-isomer (271). The factors influencing product stabilities in these olefin equilibrations are

Backbone-rearranged hydrocarbons of the 5P, 14P-dimethyl- 18,19-dinor8a,9~,10a,-cholest13(17)-ene type have been identified as components of a bituminous shale excavated from the Paris Basin. It is suggested that these compounds had their origin in natural sterols, since they are not known to occur in living organisms. This hypothesis is supported by the demonstrated formation of the rearranged olefins when 5a -cholestan-3P-ol was heated with the acidic mineral clay m o n t r n ~ r i l l o n i t e .The ~ ~ ~first stage in the Kober colour reaction of oestrogen 3-methyl ethers in sulphuric acid is a backbone-type rearrangement which begins with the 13P-methyl group migrating to a cationic centre at C-17; the charge finally appears at C-9, in conjugation with the phenolic ring, The solution accordingly develops an absorption maximum at 372 nm. Quenching of such a solution from the 17ar-methyl-17~-hydroxy-compound(272) into water is now shown to give a A8-unsaturated derivative (273) in high yield.256 The configurations at C- 13 and C-14 are as yet unknown, so it is not possible to judge whether rearrangement is likely to proceed through a series of concerted hydride migration steps.

Aromatization of Rings.-A full account of the acid-catalysed aromatization (in ring A!) of 5,6-epoxyandrostan-7-0ls~~’ includes an additional example in the formation of a 1,4-dimethyloestra-l,3,5(lO)-triene (275) from a 3a-methyl-5,6P-epoxy-5Pandrostan-7P -01 (274). This reaction clearly involves a skeletal rearrangement 255 256

257

I. Rubinstein, 0. Sieskind, and P. Albrecht, J.C.S. Perkin I, 1975, 1833. M. Kimura and T. Miura, Chem. and Pharm. Bull. (Japan), 1976,24, 181. Ref. 36, p. 269.

Terpenoids and Steroids

276

rather than merely a methyl migration. A detailed mechanism is proposed for the transfer of unsaturation into ring A.258 A 1,4,1l-trien-3-one (276) aromatizes with unusual facility under acidic conditions to give the B-seco-compound (277) as the major product. The A’’-bond participates in 9,lO-bond cleavage, probably giving an allylic cation (279) as the intermediate. A minor product (278), with the 9P-configuration, could result from intramolecular alkylation at C-4 in the aromatic ring A by the allylic cation (279).259 1 7 a -Methyltestosterone (280) was dehydrogenated and aromatized in ring c by heating with trichloroacetic acid in aqueous ethanol in the presence of air, to give the ‘phenyl-dienone’ (28 1). Other acids were ineff ective.260 AcO

(279)

Miscellaneous Rearrangements.-A new preparation of compounds of the 19(10P -B 9P)-abeo series empIoys the 9-hydroxy-5a-lanostan- 11-one derivative (282) as the source of a C-9 carbocation.261 Dehydration under ‘Westphalen’ conditions (H2S0,-HOAc-Ac20) was accompanied by methyl migration to give the 9~-methyl-19-norlanost-l(lO)-ene (283) and -5(10)-ene (284). Further acid treatment of the 5(10)-ene (284) afforded the aromatized 9(10)-seco-compound (285). Another rearrangement product, obtained from the ketol (282) by heating with toluene-p-sulphonic acid in benzene, was assigned the C-nor-D-homo structure (286).261A preliminary shift of the cationic centre from C-9 to C-12 seems necessary to provide a pathway for this contraction of ring C . 258

259

261

D. Baldwin and J. R. Hanson, J.C.S. Perkin I, 1975, 1941. K. Takeda, H. Tanida, and K. Horiki, Chern. and Pharrn. Bull. (Japan), 1975, 23, 2711. A. Britten and E. Njau, J.C.S. Perkiti I, 1976, 158. 0. E. Edwards and Z. Paryzek, Canad. J. Chem., 197S153, 3498.

277

Steroid Properties, Reactions, and Partial Synthesis

J$p C8H 17

AcO

5

(283) A1(l0), 5a-H (284)

The A-nor-3(5),8(14)-diene (287), obtained in several stages from ergosterol, i s rearranged by HBr to give both the 17a- and the 17P-A14-isomers(288) and (289), according to reaction conditions.262The epimerization at C-17 is thought to proceed through a C-14 spiranic intermediate (cf. ref. 263).

&& I

I

(288) 17a (289) 17p

An unusual D-homoannulation has been during a sequence of reactions intended to degrade withanolide E (290) to a 17P-hydroxy-17a-pregnan-20one derivative (29 1). Very weakly acidic conditions promoted a rearrangement to the D-homoandrostan- 17a-one (293). Intramolecular hemiacetal formation involving the 14a-hydroxy-group appears to be an essential feature, the preferred configuration (292) of the hemiacetal enforcing migration of the anti-periplanar 16,17-bond in the manner illustrated. The basic nature of methylenetriphenylphosphorane caused D-homoannulation of 17a -acetyloestr-4-en-l7P-ol (294) before effecting a Wittig condensation; the mixed 17-methylene-D-homoandrostanes (295) were formed. When the 17P-OH group was protected by acetylation, an intramolecular Claisen condensation occurred in polar solvents under Wittig conditions, giving the spiro-lactone (296) and a 262

263 264

E.-J. Brunke, R.B o h m , and H.Wolf, Tetrahedron Letters, 1976, 3137. Ref. 70, p. 267. D. Rabinovich,Z. Shakked,I.Kirson,G. Giinzberg,andE. Glotter, J.C.S. Chem. Comm., 1976,461.

Terpenoids and Steroids

278

(294)

(295)

(296)

compound which may be the spiro-ether (297); non-polar media, in contrast, favoured formation of the D-homo- €7,€7a-dione, isolated in enolic form (298).265

(297)

(298)

The 22,23-epoxystigmastane side-chain (299) rearranges with boron trifluoride to form 22,25-epoxy-derivatives [tetrahydrofurans; (300)l; two €,2-hydride shifts or a single 1,3-hydride shift are required to activate C-25 for attack by the oxygen atom.2663-Methoxyoestra-2,5( €0)-dienes isomerize during g.1.c. to the 3-methoxy3,5-diene~.*~~ 2hS

766 267

H. A. C. M. Keuss and J . Lakeman, Tetrahedron, 1976.32, 1541. G. Berti, S. Catalano, A. Marsili, I. Morelli, and V. Scartoni, Tetrahedron Letters, 1976, 401. S. Gorog and A. Lauko, J. Chromatog., 1976, 118, 41 1.

279

Steroid Properties, Reactions, and Partial Synthesis

7 Functionalization of Non- activated Positions Ingenious application of ‘remote oxidation’ has opened the way to a novel and potentially useful degradation of 5a -cholestan-3a -01 to 3a-hydroxy-5a -androstan17-one (‘androsterone’).268 The ‘radical relay’ process, whereby photolysis of an iodoaryl ester with iodobenzene dichloride introduces a chlorine atom or unsaturation into the steroid nucleus, has been adapted by use of the 3a-(4’-iodobiphenyl-3carboxylate) (301). The size of this ester grouping allows the iodine atom to come

close to 17a-H. The photolysis product, after processing in the usual way, gave 3 a acetoxy-5a-cholest-16-ene (302) in up to 56% yield. Transfer of unsaturation to the position (304) was achieved by forming the ene adduct (303) with 4-phenyl1,2,4-triazoline-3,5 -dione, followed by reduction (Li-EtNH2). Ozonolysis completed the degradation to give the 17-ketone (305). A 7a-(3-iodobenzoate) was

H

(305) -0

IN

(303) R = * . * - N .

I

),...-NPh

0 (304) R = H 268

B. B. Snider, R.J. Corcoran, and R.Breslow, J. Amer. Chem. Soc., 1975,97,6580.

Terpenoids and Steroids

280

similarly effective in introducing unsaturation at the A16-position. The aroyl esters of a -configuration required for this work were prepared in a convenient single step from the corresponding p -alcohols by inversion-esterification with triphenylphosphine, diethyl azodicarboxylate, and the appropriate carboxylic acid.268 Electrolytic oxidation of 5a -cholestan-3a-y1 rn -iodobenzoate, under prescribed conditions including the presence of chloride ion, leads to an efficient templatedirected chlorination at the 9a -position. Arguments are offered for an initial oxidation at iodine to a radical-cation; hydrogen abstraction from C-9 is thought to be followed by chlorination involving electrochemically generated C12.269Irradiation of a mixture of the ester (306) with sulphuryl chloride and azobis-isobutyronitrile, in

anhydrous CC14,led to highly effective chlorination at C-14, in a novel version of the radical-relay process: dehydrochlorination gave the cholest- 14-ene derivative in an isolated yield of 64’?/0.*~’This should be compared with 18% yield when the 3 a -( p-iodopheny1)acetate was used to transfer chlorine from PhIC12 to the Several new products [e.g. the lactone (307)] were obtained as by-products from remote oxidation of steroids by photochemically excited benzophenone substituents. The benzhydrol asymmetric centre is generated with slight stereoselectivity. Deuterium labelling (at 15a) confirmed that the main product of reaction, the 14-ene (308), results from hydrogen abstraction from C-14 followed by transfer of the 15a-hydrogen to the benzhydryl

(307) 269 270 271 272

(308)

R. Breslow and R. Goodwin, Tetrahedron Letters, 1976, 2675. R. Breslow, R. L. Wife, and D. Prezant, Tetrahedron Letters, 1976, 1925. Ref. 70, p. 268. R. L. Wife, D. Prezant, and R. Breslow, Tetrahedron Letters, 1976, 517.

Steroid Properties, Reactions, and Partial Synthesis

281

The first applications of ‘remote oxidation’ in the 5 P -series include the introduction of A14-unsaturation by irradiation of 5p -cholestan-3a -yl m -iodophenylacetate with iodobenzene dichloride in CC14, followed by dehydrochlorination, and the formation of 3P-acetoxy-5P-pregn-14-en-20-one from the saturated analogue by irradiation in the presence of iodobenzene d i ~ h l o r i d e . ~ ~ ~ Free-radical attack on tertiary C-H bonds has been used for the direct hydroxylation of but with almost random attack at the available tertiary centres. In a novel regio- and stereo-specific version of this procedure, the solid inclusion complex of deoxycholic acid and di-t-butyl diperoxycarbonate (4 : 1) gave the 5phydroxy-derivative of deoxycholic acid as the only hydroxylated product, on heating at 90 “C or by photolysis. An X-ray study of the inclusion complex showed a normal arrangement of deoxycholic acid molecu!es to form a channel, but the guest peroxy-compound is apparently disordered within the channel, as it could not be located. 275 Electrophilic fluorination by substitution of hydrogen at unactivated tertiary carbon has been achieved by use of either CF,OF or elementary fluorine (diluted with N2). Electron-attracting substituents direct the reaction to remote C-H bonds, suggesting that the reaction has electrophilic rather than free-radical character. Examples include the 9a -fluorination of 5a -androstane-3& 17p-diol esters (309), 14a -fluorination of various 5a,6~-dichloro-3,17-disubstituted steroids of type (310),and 17a-fluorination of 5a -cholestan-3P-yl esters or their Sa,bP-dichloroHypobromite and other hypohalite reactions for the functionalization of unactivated carbon atoms are ~eviewed.”~

(309) R = Ac or CF3C0

(310) R = Oor/?-COMe,a-H

8 Photochemical Reactions New products from long-term irradiation of compounds in the vitamin D series have been reviewed.278The allenes (31 l),previously isolated from among the irradiation products of cholecalciferol, equilibrate to a 1: 1 mixture of isomers on further i~radiation.~~’ Toxisterols2-D and -E, which are among the products of irradiation of 273 274 275 276

277 278 279

R. J. Corcoran, Tetrahedron Letters, 1976, 317. Ref. 36, p. 276. N. Friedman, M. Lahav, L. Leiserowitz, R. Popovitz-Biro, C.-P. Tang, and V. I. Zaretzkii, J.C.S. Chem. Comm., 1975,864. D. H. R. Barton, R. H. Hesse, R. E. Markwell, M. M. Pechet, and S. Rozen, J. Amer. Chem. SOC.,1976, 98, 3036. P. Brun and B. Waegell, Tetrahedron, 1976,32, 517. E. Havinga, Chimia (Switz.), 1976, 30, 27. J. A. van Koeveringe and J. Lugtenburg, Rec. Trau. chim., 1976,95, 80.

282

Terpenoids and Steroids

(311)

ergosterol, have the structures of 3,lO-ethers (312) and (313), determined by an X-ray analysis of the 7a,8a -epoxy-derivative of toxistero12-D.280

(312) (D)

(313) (E)

Optimum conditions have been determined for the continuous-flow production of ergocalciferol by irradiation of Although 19-acetoxy-7-dehydrocholesterolphotolyses in the usual manner for 5,7-dienes7the 19-hydroxy anologue (3 14) fragments under irradiation to give the 19-nor-5(10),6-diene (11). Intramolecular hydrogen transfer was established by use of the 0-deuterio-deri~ative.~~

(3 14)

Cholesta-3,5 -diene and similar transoid dienes undergo a variety of complex photochemically induced reactions, which differ for singlet- and triplet-excited states. Singlet products are derived in part from the very strained 3,5:4,6-bis-cyclo ('bicyclobutane') intermediates of the type (315), which open by solvent attack to give such products as (316). The singlet-excited diene may alternatively react via 280

281

A. G. M. Barrett, D. H. R. Barton, R. A. Russell, P. F. Lindley, and M. M. Mahmoud, J.C.S. Chem. Comm., 1976,659. M. E. Meller, L. G . Selezneo, F. I. Luknitsky, A. B. Aksenovich, Z. Z. Drok, andMs. A. Veksler, Khim. Farm. Zhur., 1975,9,41.

283

Steroid Properties, Reactions, and Partial Synthesis

protonation, leading to products of solvent addition. The triplet state reacts only by a Steroidal 3,5-dienes and bimolecular process to give adducts with the 4,6-dienes have singlet-excited energies of ca. 90 kcal mol-’ and triplet energies of about half this value.283 Stereoelectronic control has been demonstrated in the p -scission of 3a75-cyclo5a -cholestan-6-y1 and 3p,5-cyclo-5p -cholestan-6-y1 radicals, generated by irradiation of the corresponding 6/3 -chloro-derivatives in the presence of Ph3SnH and azobisisobutyronitrile. 284 The Type I1 photoreactions of 2a-propyl-3-oxo-5a -steroids (3 17) give cyclobutanols (3 18) in higher proportion, relative to the alternative fragmentation products (319), than would be expected by analogy with comparable reactions of

(317) R = H or Me

(318)

(3 19)

open-chain ketones. Conformational features unfavourable to orbital overlap are thought to retard fragmentati~n.~” (320) gave the 5P-adduct (321) Photocyclization of 4-phenoxycholest-4-en-3-one with high stereo~electivity.~~~

(320)

(321)

Triplet-excited double bonds of cholest-4-en-3/3-01~and cholest-5-en-3P-ols, including 4-methyl and other derivatives, may be deactivated by protonation, leading to intramolecular addition to the C-5 carbocation to give oxetans of the type (322). Other reactions of these systems include fragmentation, which is followed by 282 283

284 285 286

J. Pusset and R. Beugelmans, Tetrahedron, 1976,32,797. J. Pusset and R. Beugelmans, Tetrahedron, 1976,32, 791. A. L. J. Beckwith and G. Phillipou, Austral. J. Chem., 1976, 29, 123. I. Fleming, A. V.Kemp-Jones, W. E. Long, and E. J. Thomas, J.C.S. Perkin II, 1976, 7. A. G. Schultz and W. Y. Fu, J. Org. Chem., 1976,41, 1483.

Terpenoids and Steroids

284

photocycloaddition to give the oxetans (323), and a simple A4$ A5 interconversion. The reactions are interpreted in terms of conformational changes available to the n-,7 ~ *triplet .287

(322)

(323)

U.V. irradiation of the unsaturated A-seco-5-ketone (324) gave none of the expected oxetan (325), but instead produced the cyclobutanols (327) as major products, along with a little of the B-Seco decarbonylation product (328). Cyclobutanol formation proceeds through hydrogen transfer from C-2 to the carbonyl oxygen, which is followed by cyclization of the 2,5-biradical(326). Similar reactions occur with the alkynyl-ketone (329) and with the saturated analogue (330).288

ftLY

R

RJ2?

(324) R = CH=CH2 (329)-R = C=CH (330) R = Et

+]&R[

OH

(326)

(327)

The primary product of photolysis of 4,4-dimethylcholesta- 1,5-dien-3-one (33 1) was the spiro-compound (332), which isomerized further under prolonged irradiation or was cleaved to the cyclopentenone (333) by acetic

@ @ $ 2\

0 0

(331) 287

288 289

0

(332)

D. Gutnard and R. Beugelmans, Tetrahedron, 1976,32, 781. D. Gutnard and R. Beugelmans, Bull. SOC.chim. France, 1975, 2202. L. J. Dolby and M. Tuttle, J. Org. Chem., 1975, 40, 3786.

(333)

285

Steroid Properties, Reactions, and Partial Synthesis

The structures proposed for the isomeric 5-vinyl-A-norcholestan-3-ones(335) from the photoisomerization of the ~-homo-4a(S)-en-3-one(334) have been confirmed by synthesis and an X-ray analysis of the minor ( 5 a )product. C.d. data for the 5-vinyl and 5-ethyl A-nor-ketones are discussed anew.29o A review of the photochemistry and spectroscopy of py -unsaturated carbonyl compounds includes examples drawn from steroid

(334)

(335)

In an interesting experiment directed towards the use of solar energy, the ruthenium(I1) complex (336) was coated as a monolayer on glass slides, which were

\

/ (Sa-cholestan-3P-yl)

(Sa-cholestan-3P-yl) (336)

immersed in water. The complex was rendered insoluble by the choice of 5acholestan-3P-01 as the esterifying alcohol. Irradiation through Pyrex led to energy absorption, with displacement of an electron to give the ruthenium(II1) species which is believed to oxidize hydroxide ion to generate 02.Slow evolution of a mixture of HZand O2was Irradiation of the enamide (337) in benzene led to products of substitution (338) or addition [(339) and (340)] to the olefinic bond: the hydroxy-groups were apparently derived from traces of water in the solvent. Oxygenation during irradiation gave as additional products the dioxetan (341) and the ketol (342).293 The morpholine enamines (343) and (344) in the etiojervane series were degraded by photo-oxygenation to give the corresponding ketones (345) and (346), 290 291

292

293

T. Akiyama, D. Pedder, J. V. Silverton, J. I. Seeman, and H. Ziffer, J. Org. Chem., 1975,40, 3675. K. N. Houk, Chem. Rev., 1976, 76, 1. G. Sprintschnik, H. W. Sprintschnik, P. P. Kirsch, and D. G. Whitten, J. Amer. Chem. Soc., 1976,98, 2337. J. Boix, J. Gbmez, and J.-J. Bonet, Helv. Chim. Acta, 1975, 58, 2545; F. Abello, J. Boix, J . Gbmez, J . Morel], and J.-J. Bonet, ibid., p. 2549.

286

Terpenoids and Steroids

respectively, the latter being accompanied by the abnormal ring-contracted product (347).294

(337) R = H (338) R = P h

(343) R = C H N

/-7

LJo

(345) R = O

(339) R = H 2 (340) R = @-OH,H (342) R = O

(344) R = C H N

n

(34 1)

(347)

\/"

(346) R = O

The photolysis of esters in HMPA to give hydrocarbons is promoted by the presence of water (5 YO). Likely mechanisms are

9 Miscellaneous With the manufacture and use of steroids in pharmaceutical and contraceptive preparations increasing steadily, the quantities appearing in rivers and other natural waters are beginning to be a cause for concern. A report has now appeared on the identification and estimation of steroids in water.296 With 500 references, it is a useful source of information on analytical methods. The extent of interference by various cholestane derivatives in cholesterol determinations has been evaluated. Of five methods examined, none is wholly specific to Poor reproducibility in steroid solubility determinations can result from adsorption by filter papers.298 The g.1.c. retention times of an extensive series of sterols have been measured on four different stationary phases, in order to devise methods for the separation of particular mixtures. Some mixtures of saturated compounds with the corresponding unsaturated A4-, A5-,Ah-, A'-, or A s ( 1 4 ) - ~ t e could r ~ 1 ~ not be separated, but A7-,A*'-, and some dienic derivatives are easily separable from their isomers. The results were The applied in the examination of sterols in sunflower and other plant 294 2q5

29h

29' 298

299

A. Murai, C. Sato, H. Sasamori, and T. Masamune, Bull. Chem. SOC. Japan, 1976,49,499.

H. Deshayes, J. P. Pkte, and C. Portella, Tetrahedron Letters, 1976, 2019. I. Wilson, 'Steroids as Water Pollutants', Technical Memorandum TM 115, Water Research Centre, Stevenage, U.K.., 1976. D. J. Munster, M. Lever, and R. W. Carrell, Clin. Chim. Acta, 1976, 68, 167. W. L. Chiou, Canad. J. Pharm. Sci., 1975, 10, 112. A. Seher and H. Vogel, Fette, Sejfen, Anstrichm., 1976, 7 8 , 106, 301.

Steroid Properties, Reactions, and Partial Synthesis

287

distinctive gas-chromatographic characteristics of sterols, 4-methylsterols, and 4,4dimethylsterols and their respective acetates, reflect the degree of m e t h y l a t i ~ n . ~ ~ ~ Some epimeric steroid alcohols and their TMS derivatives are separable on the nematic liquid-crystalline phase of NN'-bis-( p-methoxybenzy1idene)-a,a '-bi-ptol~idine.~?Electron-capture detection is reviewed, with reference to steroid derivatives of halogeno-ester and halogeno-ether type.302 Novel heptafluorobutanoyl derivatives [e.g. (348)], prepared from hydroxy-steroids, have excel0

lent g.1.c. characteristics and permit electron-capture The 14a hydroxy-7-en-6-one system of ecdysones also confers high sensitivity to electron Steroids were among a variety of organic compounds used in a study of programming techniques in high-pressure liquid c h r ~ r n a t o g r a p h y . ~ ~ ~ Dicholesteryl esters of straight-chain dicarboxylic acids from C4 to Clo exhibit liquid-crystal behaviour over various temperature ranges.3o6 Cholesteryl para -substituted benzoates give mesophases with transition temperatures and thermodynamic parameters which depend upon the para - s ~ b s t i t u e n t . ~ ~ ~ Crystal and mesophase structures of cholesteryl myristate appear to show some similarities in molecular packing.308 X-Ray studies show that cholesteryl 17bromoheptadecanoate crystals contain alternating regions with cholesterol and hydrocarbon-chain packing.309 Polymerization of cis- or trans-pentadienes as inclusion compounds with deoxycholic acid, by y -irradiation, gave optically active The electrochemical determination of vitamin D in the presence of vitamin A has been explored.311 Substantial losses of corticosterone and its 11-deoxy-derivative occurred when methanolic solutions were evaporated in soda-lime test tubes, although borosilicate tubes were The fire and explosion hazards have been assessed for a variety of commercial steroids in aerosol form.313 A review of 300

301 302 303 304

305 306

307 308 309 310 311

312 313

T. Itoh, T. Tamura, T. Iida, and T. Matsurnoto, Steroids, 1975,26, 93. W. L. Zielinski, jun., K. Johnston, and G. M. Muschik, Analyr. Chem., 1976,48, 907. C. F. Poole, Chem. and Ind., 1976, 479. L. Dehennin and R. Scholler, J. Chromatog., 1975, 111, 238. C. F. Poole and E. D . Morgan, J. Chromatog., 1975,115, 587. H. Engelhardt, Z. anafyt. Chem., 1975, 277, 267. J. Rault, L. Litbert, and L. Strzelecki, Bull. Soc. chim. France, 1975, 1175. M. J. S. Dewar and A . C. Griffin, J.C.S. Perkin II, 1976, 713. B. M. Craven and G. T. DeTitta, J.C.S. Perkin ZI, 1976, 814. S. Abrahamsson and B. DahlCn, J.C.S. Chem. Comm., 1976, 117. G. Audisio and A . Silvani, J.C.S. Chem. Comm., 1976, 481. S. S. Atuma, K. Lundstrom, and J. Lindquist, Analyst, 1975,100, 827. S. Burstein, Steroids, 1976,27, 493. A. Y. Korolchenko, A . V. Ivanov, and E. M. Aristova, Khim. Farm. Zhur., 1975, 9, 31.

288

Terpenoids and Steroids

carboxylic acids found in petroleum deposits includes a variety of steroidal bile acids and related Alkyl-cholestanes have been found in a bituminous shale from the Paris Basin.315 Reaction studies are reported for epoxy-derivatives of and unsaturated compounds [e.g. (349)] in the 9(10 + 19)-abeo-5cu-pregnane series (derivatives of the alkaloid N-isobutyrylbuxaline F),316and for ‘nicandrenone’ (Nic- 1),317 a naturally occurring steroid (3.50) with an aromatic ring D.

I

Section B: Partial Synthesis of Steroids 10 Cholestane Derivatives and Analogues 14P-Cholest-5-en-3P-01 (35 1) has been prepared from cholesta-5,7-dien-3P-y1 tosylate by the route outlined (Scheme 10); the known deconjugation procedure

liii

HO

&c8:

\

(351)

dl ( 3 5 5 ’ .____.

&

OH

------ .

/

OSiMe,

Reagents: i, Buffered hydrolysis; ii, Cr03-py; iii, NaH; Me3SiCLEt3N; iv, NaBH4; v, B,H,; hydrolysis.

Scheme 10 314

3ls 3Ih

31’

W. K. Seifert, Fortschr. Chem. org. Naturstoffe, 1975, 32, 1.

I. Rubinstein and P. Albrecht, J.C.S. Chem. Comm., 1975, 957. M. Btntchie and F. Khuong-Huu, Tetrahedion, 1976, 32,701. E.Glotter, P. Krinsky, and I. Kirson, J.C.S. Perkin I, 1976, 669.

EtCO2H;

289

Steroid Properties, Reactions, and Partial Synthesis

involving formation and reduction of a dienyl trimethylsilyl ether was applied in a novel situation. The scheme led to a mixture of cholesterol and its 14P-isomer (351), but the cholesterol was easily removed by virtue of its lower s ~ l u b i l i t y . ~ ' ~ Following a possible biosynthetic pathway to 3p, 14-dihydroxycholest-7-en-6-one (355), a precursor of ecdysones, 3P -acetoxycholesta-5,7-diene(352) was isomerized to the 6,8(14)-diene (353); epoxidation and acidic hydrolysis then gave the mixed 6,14a-diols (354), which were oxidized by M n 0 2 to give the required 14a-hydroxy7-en-6-one system (355).319 Several cholest-7-en-6-one derivatives related to ecdysones, but lacking side-chain hydroxylation, have been prepared from cholesterol by efficient routes based largely on known individual 22,23-Dihydroergosterol has been prepared from 5a-ergost-7-en-3-one and the derived 4,7-dien-3-one via the 3,5,7-trien-3-yl acetate (356), which was reduced with NaBH4 to generate the required 5,7-dien-3@-01(357).321

(352) R = A c (357) R = H

(353)

(356)

(354)R = a- or @-OH (355) R = =O

The 22-aldehyde (358) is a useful precursor of various side-chains. 20Methylcholesterol was obtained by methylation of the aldehyde at C-20 via its carbanion, followed by a conventional Wittig reaction, hydrogenation, and solvolysis of the 3,5-cyclo-~ystem.~~~ The aldehyde (358) also provided the starting material for Wittig synthesis of a series of cis- and trans-A22-sterolswith modified side-chains, ranging from the Cz3 to the C27 series, and including various patterns of chainbranching. The cis- and trans-isomers were distinguishable by their n.m.r. Cholesterol analogues (359) with novel side-chains have also been 318

319 32O 321 322 323

M. Aaastasia, A . Scala, and G. Galli, J. Org. Chem., 1976, 41, 1064. K. Wada, Agric. and Biol. Chem. (Japan), 1975,39, 1679. K. T. Alston, P. M. Bebbington, S. E. Green, E. D. Morgan, and C. F. Poole, Steroids, 1976, 27, 609. J. Brynjolffssen, D . Hands, J. M. Midgley, and W. B. Whalley, J.C.S. Perkin I, 1976, 826. Y. Letourneux, G. Bujuktur, M. T. Ryzlak, A . K. Banerjee, and M. Gut, J. Org. Chem., 1976,41,2288. Y. M. Sheikh and C. Djerassi, Steroids, 1975, 26, 129.

290

Terpenoids and Steroids

obtained from the 24-tosyloxycholane (360) by reaction with Li2CuC1, and the appropriate Grignard reagent. 324

(358)

(359) R = Bun, Pri, cyclohexyl, or Ph (360) R=OTs

Cholic acid has been converted into 5P-cholestane-3a,7a,l2a,25-tetrol and the 3a,7a, 12a,24,25-pentols. Extension of the side-chain involved conversion of the acid via the diazo-ketone (361) into a homocholanic ester derivative (362). Grignard reaction then gave the 25-hydroxy-cholestane (363). Dehydration followed by hydroxylation (OsO,) afforded the 24,25-diols with a little of the 25,26-di01.~” 0

(361)

(362)

(363)

The 22-isomeric 5~-cholestane-3cr,7a,l2a,22,25-pentols (365) have been synthesized from cholic acid after a preliminary oxidative degradation to the dinor-22aldehyde (364), which was followed by a Grignard step with 3-methyl-3(tetrahydropyran-2’-yloxyl)-butynylmagnesiumbromide, and h~drogenation.~’~ OH AcO

HO

Diosgenin has been converted into a-ecdysone by a multistage sequence which made use of the stereochemical features of the spiro-acetal system to attain the required configurations at C-20 and C-22 in the product. Most of the steps were already known in principle, but the reduction of the 16,22-epoxy-7,14-dien-6-one 324 325 326

J. E. Herz and E. Vazquez, Steroids, 1976, 27, 133. B. Dayal, S. Shefer, G. S. Tint, G. Salen, and E. H. Mosbach, J. Lipid Res., 1976, 17,74. K.Kihira, T. Kuramoto, and T. Hoshita, Steroids, 1976, 27,383.

Steroid Properties, Reactions, and Partial Synthesis

291

(366) with zinc-acetic acid to give the (22R)-acetoxy-8(14),15-dien-6-one (367) is of particular interest; cleavage of the tetrahydrofuran ring was accompanied by acetyl group migration from the 25- to the 22-hydroxy-gro~p.~~’

AcO AcO&

AcO OAc

AcO

4 a -Methyl and 46-methyl derivatives of (24R)-24-ethyl-5a -cholestan-36-01 and (24S)-24-ethylcholesta-5,22-dien-3P-olwere obtained by conventional methods from (24S)-24-ethylcholesta-4,22-dien-3-0ne.~~*

11 Vitamin D and its Metabolites The photolytic preparation of previtamin D2 (368) from ergosterol is normally a low-yield process because of the formation of the 6,7-truns-isomer (tachy~terol~) as a

(368)

major product. A second irradiation of the reaction mixture, with added fluorenone as a triplet sensitizer, is found to produce a very marked increase in the proportion of previtamin D2.329 Cholesta-5,7-dien-3a -01 was easily prepared from its 36-isomer by forming the 4-phenyl-1,2,4-triazoline-3,5-dione adduct, oxidizing this to the 3-ketone, and reducing the ketone with borohydride. Hindrance by the heterocycle bonded to the a -face controlled the stereochemistry of reduction. The 5,7-diene 327 328

329

E. Lee, Y.-T. Liu, P. H. Solomon, and K. Nakanishi, J. Amer. Chem. SOC.,1976,98, 1634. F. F. Knapp, jun., and G. J. Schoepfer, jun., Steroids, 1975,26, 339. S. C. Eyley and D. H. Williams, J.C.S. Chem. Comm., 1975, 858.

292

Terpenoids and Steroids

was regenerated by reduction with LiAlH,. Photolysis and thermal isomerization then gave 3-epi-cholecalcifero1(369) and its 5,6-trans-isomer (370).330A review of thermal sigmatropic rearrangements includes the interconversion of precalcif erol and vitamin D.331 1’

The tricarbonyliron adduct (371) of a 5,7-diene is easily formed and can be cleaved by iron(rI1) chloride in ethanol to regenerate the diene. It survives oxidation ( N chlorosuccinimide-Me2S) and reduction (LiA1H4)of oxygen substituents at C-3. The a-and P-adducts (372) from calciferol have similar properties, offering a simple way of protecting the very sensitive t ~ i e n e In . ~an~ attempt ~ at devising another reversible protection of the triene system, vitamin D3 was treated with 4-phenyl- 1,2,4triazoline-3,5-dione to give the 6,19-adduct [(373); 95% a-face addition]. Unlike other adducts with this dienophile, however, the complex could not be cleaved by

H0 *-

(372) 33* 331 332

- Fe(CO),

(373)

D. J. Aberhart, J. Y.-R. Chu, and A. C.-T. Hsu, J. Org. Chern., 1976, 41, 1067. C. W. Spangler, Chem. Rev., 1976,76, 187. D. H. R. Barton and H. Patin, J.C.S. Perkin I, 1976, 829.

293

Steroid Properties, Reactions, and Partial Synthesis

reduction, and vigorous alkaline hydrolysis unfortunately led to the 5,6-truns -isomer of vitamin D3.333 Buffered methanolysis of cholecalciferyl 3-tosylate (374) leads to the 3,5-cyclo methyl ethers (375), and a little cholecalciferyl methyl ether. The 3,5-cyclocompounds were found to revert largely to cholecalciferol on acidic hydrolysis, raising hopes that they would prove suitable as a means for protecting the sensitive However, the methyl ethers (375) proved to be rather triene Oxidation (Mn02) of the (6R)-6-hydroxy-3,5-cyclo-compound(376) gave the ketone (377), which could be reduced to a mixture of the (6R)and (6s)-alcohols. Reduction of the derived epoxy-ketone (378) with di-isobutylaluminium hydride gave the C-8 spiro-derivative (379) as a result of attack of the exocyclic methylene group on C-8. Acid-catalysed rearrangement of compound (379) with dehydration gave the dihydronaphthalene (380).335 Support for the intermediacy of a homoallylic cholecalciferyl cation (38 1) in the formation of the 3,5-cyclo-products (375) and (376) came from the solvolysis of cholecalciferyl tosylate (374) under a variety of conditions. Depending upon the solvent, and any nucleophiles supplied, products showed compositions varying from total retention of configuration to 89% inversion, interpreted as evidence of competing pathways through either the homoallylic cation (38 1)or an SN2substitution, respectively.336 The syntheses and biological activities of hydroxylated derivatives of vitamins D2 and D3 have been reviewed (to 1974).337 A new of la -hydroxycholecalciferol ( l a -hydroxy-vitamin D3)from cholesterol employs transformations in rings A and B which differ only in detail from an earlier sequence for introduction of the la - h y d r o ~ y - g r o u pthe ; ~ ~la,2a-epoxy~ 3@,6@ -diol derivative (382) was the key intermediate, allowing regeneration of

--+

HO. HO.

TsO.'

(374)

333

334 335 336

337

338

339

(375) R = &OMe (376) R = (6R)-OH (377) R = =O

(378)

(379)

D. J. Aberhart and A. C.-T. Hsu, J. Org. Chem., 1976, 41, 2098. M. Sheves and Y. Mazur, J. Amer. Chem. SOC.,1975,97, 6249. M. Sheves and Y. Mazur, Tetrahedron Letters, 1976, 2987. M. Sheves and Y . Mazur, Tetrahedron Letters, 1976, 1913. H. K. Schnoes and H. F. DeLuca, Vitamins and Hormones, 1974, 32, 385. M. Morisaki, A. Saika, K. Bannai, M. Sawamura, J. R. Lightbourn, and N. Ikekawa, Chem. and Pharm. Bull, (Japan), 1975,23, 3272. T. A. Narwid, J. F. Blount, J. A. Iacobelli, and M. R. UskokoviC, Helu. Chim. Acta, 1974,57, 781.

Terpenoids and Steroids

294

A5-unsaturation (by P o c l , ) and reduction of the epoxide (LiAlH,) to establish the 1a -hydroxy-group. Cholest-5-ene-la,3a -diol has been obtained via the inversion-esterification process (Ph3P-EtO2CN=NCO2Et-HCO2H) and hydrolysis from 1a -hydroxycholesterol, illustrating the selectivity of this reagent system for an unhindered alcohol. Conventional transformations converted the l a , 3 a -diol into l a -hydroxy3-epi-vitamin D3,which exists predominantly (70%) in the conformation with axial hydroxy-groups, on n.m.r. evidence.,,' Another application of inversionesterification is described on p. 280. 2P-Hydroxy-vitamin D, was obtained by the normal route from chole~ta-5,7-diene-2p,3p-diol,~~~ and 3P-fluorocholest-5-ene was transformed via the 5,7-diene into the 3-fluOrO analogue of vitamin D3,which exhibits antirachitic activity comparable with that of vitamin D3 itself.342 Ozone on silica gel introduces a 25-hydroxy-substituent into suitable compounds with a cholestane side-chain. By using the l a , 3 p -diacetoxy-G&7a -dibromoderivative (383), prepared from the known 6-ene, the 25-hydroxylated compound was obtained as the only product (11% conversion). Trifluoroacetylation followed by dehydrobromination afforded the 5,7-diene (385), which was transformed into la,25-dihydroxy-vitamin D, by the usual method.343

Br

(383) R = H (384) R = O H

(385)

The 25-hydroxycholestane side-chain has been built on to an androstane by the route outlined in Scheme 11. Alkylation of the pregnan-21-oic ester at C-20 proceeded as required to give the ( 2 0 R ) - e ~ i m e r .Despite ~ ~ ~ the large number of 340 34*

342

343 344

W. H. Okamura and M. R. Pirio, Tetrahedron Letters, 1975, 4317. C. Kaneko, S. Yamada, A. Sugimoto, and M. Ishikawa, Chem. andPharm. Bull. (Japan), 1975,23,1616. R. I. Yakhimovich, V. M. Klimashevsky, and G. M. Segal, Khim. Farm. Zhur., 1976, 10, 58. Z. Cohen, E. Keinan, Y. Mazur, and A. Ulman, J. Org. Chem., 1976,41, 2651. J. Wicha and K. Bal, J.C.S. Chem. Comm., 1975, 968.

295

Steroid Properties, Reactions, and Partial Synthesis

Reagents: i, BrCH2C02Et-Zn; -H20; ii, selective hydrogenation; iii, LiNPrI2; Br(CH&CMe; iv, four steps; v, MeMgI.

0’ ‘0

Scheme 11

W

steps, the overall yield of 42% offers an attractive alternative to older and generally inefficient procedures for generation of the 25-0x0-27-nor-intermediate. Another synthesis of side-chain-hydroxylated cholesta-5,7-dien-3P-o1 derivatives uses the aldehyde (386), prepared by ozonolysis of the adduct of ergosteryl acetate with 4-phenyl- 1,2,4-triazoline-3,5-dione.An aldol condensation between the aldehyde (386) and the pre-formed enolate of 3-methyl-3-tetrahydropyranyloxybutan-2-one (387) led to the enone (388), after acidic work-up. Reduc-

. tion with sodium borohydride in pyridine saturated the A22-olefinicbond to give the 245;25-diols; removal of the protecting heterocycle with LiAlH, then gave cholesta5,7-diene-3&24(,25-triols. A different sequence of reactions, using a Grignard reagent, converted the aldehyde (386) into chole~ta-5,7-diene-3p,25&26-triols.~~~ A stereochemically controlled synthesis of 24(R),25-dihydroxycholesterol has been achieved (Scheme 12). The key step was the stereoselective epoxidation of a Zcholest-23-en-25-01 (389) with t-butyl hydroperoxide catalysed by vanadyl acetoacetate, at low temperature; epoxidation with a peroxy-acid was non-selective. The E - A 2 3 - i ~ ~ m(390) er could also be epoxidized selectively, but reduction of the resulting (23R,24S)-epoxide (391) gave a mixture of 23(R),25- and 345

S. C. Eyley and D. H . Williams, J.C.S. Perkin I, 1976, 7 2 7 .

Terpenoids and Steroids

296

(389)

(23R, 24R) liii

C

O

H

(391) (23R,24S)

(24R)

Reagents: i, Hz-Lindlar catalyst; ii, Bu'OlH-vanadyl acetoacetate; iii, LiAIH4.

Scheme 12

2 4 ( S ) , 2 5 - d i o l ~ The . ~ ~ ~24(R),25- and 24(S),25-dihydroxy-derivatives of vitamin D3are separable by h.p.1.c. of their tris-trimethylsilyl ethers. The naturally occurring and biologically active isomer has the (24R Syntheses are also reported for the (24R)- and (24S)-isomers of 1a,24,25trihydroxy-vitamin D3,348and for a number of hydroxylated vitamin D analogues with shortened side-chains, including 24-nor-25-hydroxy-D3, which was synthesized uia the reaction of methyl-lithium with a methyl cholan-24-oate derivative and shows some anti-vitamin The 27-nor-25-hydroxy- and 26,27-dinor-25hydroxy-derivatives of vitamin D3 have also been examined.350Biological activities decrease rapidly with diminished length of side-chain, almost vanishing in pregnane analogue^.^"^^^^ The l a -hydroxy and 2P-hydroxy analogues of vitamin D without any C- 17 side-chain (androstane series) showed only feeble calcium-transport

12 Pregnanes Miscellaneous Pregnanes.-A novel synthesis of progesterone from the tetrahydropyranyl ether of 3P-hydroxyandrost-5-en-17-one uses a reaction sequence com346 347

348

349

350

351 352

J. J . Partridge, V. Toome, and M. R. UskokoviC, J. Amer. Chem. SOC.,1976, 98, 3739. Y. Tanaka, H. F. DeLuca, N. Ikekawa, M. Morisaki, and N. Koizumi, Arch. Biochem. Biophys., 1975, 170, 620. N. Ikekawa, M. Morisaki, Y. Koizumi, Y. Kato, and T. Takeshita, Chem. and Pharm. Bull. (Japan), 1975, 23, 695. R. L. Johnson, W. H. Okamura, and A. W. Norman, Biochem. Biophys. Res. Comm., 1975,67,797; Clin. Res., 1976,24, 132A. M. F. Holick, M. Garabedian, H. K. Schnoes, and H. F. DeLuca, J. Biol. Chem., 1975, 250, 226. H.-Y. Lam, H. K. Schnoes, H. F. DeLuca, and L. Reeve, Steroids, 1975,26,422. H. Sakamoto, A. Sugimoto, C. Karreko, T. Suda, and S . Sasaki, Chem. and Pharm. Bull (Japan), 1975, 23, 1733.

297

Steroid Properties, Reactions, and Partial Synthesis

patible with the presence of As-unsaturation in the starting material. The side-chain (392) was introduced by treating the 17-ketone with the carbanion derived from 2-(diethy1phosphono)propionitrile. The mixed 20-cyanopregn-l7(20)-enes (392) were reduced selectively (Mg-MeOH) at A17(20), and the cyano-group was removed (‘oxidative decyanation’) to give the 2 0 - k e t 0 n e . ~ A ~ ~new route from 17-0x0steroids to 21-acetoxypregn-16-en-20-ones(395) proceeds by known methods through the 17a-ethynyl-17P-alcohol to the 17P-acetoxy-17a -dibromoacetyl derivative (393). Treatment with trimethyl phosphite gave the monobromo-ketone (394), which with potassium acetate afforded the 2 l-acetoxypregn-16-en-20-one (395) in a single Me

(392)

(393) R = Br (394) R = H

(395)

New routes to 2 1-fluoropregnan-20-one derivatives include the reactions either of the 21-diazo-ketone with HF or of the 21-mesyloxy-20-0x0-compoundwith the radical-anion derived from lithium and biphenyl, followed by treatment with perchloryl 3a,6a -Dihydroxy-5fl-pregn-16-en-20-one, available from hyodeoxycholic acid, has been used as the starting point for a new synthesis of 16a,17a-epoxy-16/3-methylprogesterone,using known 1 6 4 17pMethyleneprogesterone was prepared from the same source, by methylene addition (dimethylsulphoxonium methylide) on to the 16-enc, and modification of the A / B ring system. The 16a,17a -methylenepregnan-20-one system (396) reacts with HCl to give a 16a -chloromethylpregnan-2O-one (397).356

(396)

(397)

A series of pregnane- 17-thiol derivatives (e.g. 16a -OH-17a -SH, 166-OH- 17a SH, and 16P-OH-17P-SH derivatives of progesterone, and some of their esters) has been prepared for biological 3a,ba-Dihydroxy-Sa-pregn-9( 11)en-20-one, isolated from starfish, has been synthesized from 1la-hydroxy5-Bromo-6P -fluoro-3p, 16a,17a -trihydroxy-5a -pregnan-20-one and derived 16.17-acetonides and D-homo-compounds (rearrangement 353 354

355 356

357 358

M.L. Raggio and D. S. Watt, J. Org. Chem., 1976, 41, 1873. H.-G. Lehmann, Tetrahedron Letters, 1976, 987. P. Wieland, Helv. Chim. Acta, 1976, 59, 1027. U. Eberhardt, Pharmazie, 1975,30, 22. H. Hofmeister, G. A. Hoyer, G. Cleve, H. Laurent, and R. Wiechert, Chem. Ber., 1976,109, 185. D. S. H. Smith and A. B. Turner, J.C.S. Perkin I, 1975, 1751.

Terpenoids and Steroids

298

on A1203) were prepared from the corresponding 1 6 - e n - 2 0 - 0 n e . ~50-Bromo~~ 6P-fluoro-substituents are introduced by reaction of A5-unsaturated compounds with aqueous 70% HF and 1,3-dibrom0-5,5-dirnethylhydantoin.~~~ la-Hydroxycorticosterone. found in the skate, has been synthesized from the corresponding l a , 2 a -epoxy-4,6-dien-3-one by selective hydrogenation of both the epoxide and A6-unsaturation in pyridine over palladium-calcium DHomo-Sa, 14P-pregnan-20-ones have been prepared by the route outlined in Scheme 13.362 0

fi

iii

,

COMe

Reagents: i, NBS; ii, CaC03; iii, HZ-Pd; iv, HCrCMgBr; v, Hg2+.

Scheme 13

Pregnanes Substituted at C-18.-18,21-Dihydroxypregn-4-ene-3,20-dione (‘18hydroxy-DOC’) as the (18 -+20)-hemiacetal (398) has been by treating 18-hydroxypregn-4-ene-3,20-dione (399) with lead tetra-acetate to give the 2 1 -acetate (400), and subsequent alkaline hydrolysis. The acetoxylation is believed to proceed through the 18,20-epoxypregn-20-ene (401), which has since been

(398) R = OH (399) R = H (400) R = O A c 359

360

361 362 363

T. I. Gusarova, G. S. Grinenko, 0.S. Anisimova, and L. M. Alekseeva, Khim. Farm. Zhur., 1976,10,27; T. I. Gusarova, G. S. Grinenko, A. I. Terekhina, I. V. Ganina, and G. I. Gritsina, ibid., p. 34. N. V. Samsonova, G. S. Grinenko, L. M. Alekseeva, and Y. N. Sheinker, Khim. Farm. Zhur., 1976,10, 106. D. E. Kime, J.C.S. Perkin I, 1975, 2371. T. Nambara, S. Iwamura, and K. Shimada, Chem. and Pharm. Bull. (Japan), 1975,23, 1834. D. N. Kirk and M. S. Rajagopalan, J.C.S. Perkin I, 1975, 1860.

299

Steroid Properties, Reactions, and Partial Synthesis

by heating the parent compound (399) with aluminium isopropoxide in refluxing toluene. The vinyl ether (401) reacted as expected with lead tetra-acetate to give the 21-acetate (400). The vinyl ether (401) has also been obtained from the hemiacetal (399) by dehydration (POC1,-Et,N-py) under carefully defined conditions; hydroxylation with osmium tetroxide then gave 18-hydroxydeoxyc o r t i c ~ s t e r o n e . Irradiation ~~ of the 21-acetoxypregnan-20-one(402) in ethanol, followed by careful hydrolysis with dilute acetic acid, gave 18-hydroxyprogesterone [as the hemiacetal (399)] in 15-24% yield. The 18,20-cyclo-derivative (403) was also formed.37 An improved synthesis of '18-hydroxyprogesterone' (399) relies on direct crystallization of the intermediate acetal (404),365 avoiding the tedious chromatographic purification of the free hemiacetal (405) used earlier. CH,OAc

0&--OH

(403)

(404)R = M e (405) R = H

Another synthesis of 18-hydroxy-DOC (398) employs photolysis of the nitrite (406)of a 20P-alcohol in presence of oxygen, leading directly to the 18-nitrate (407), H

AcO

(406) R' = ON, R2 = H (407) R1 = H, R2 = O2NO-

which serves as a convenient protection for the 18-hydroxy function. Oxidative steps to generate 20-oxo- and A4-3-oxo-groups, and reduction of the 18-nitrate with zinc, 364

365

M. Biolaz, J. Kalvoda, and J. Schmidlin, Helv. Chim. Acta, 1975, 58, 1425. D. N. Kirk and M. S. Rajagopalan, Steroids, 1976, 27, 269.

300

Terpenoidsand Steroids

gave 18-hydroxyprogesterone (399).366Acetoxylation at C-2 1 employed lead tetraacetate, as above. Photolysis in oxygen of the 11-nitrite (408) derived from 1,2-didehydrocorticosterone21 -acetate gave the 18-nitrate (409), which afforded

(408) R' = ON, R2= H (409) R'.= H, R2= 0 2 N 0

1,2-didehydro- 18-hydroxycorticosterone 21-acetate (4 10) on reduction with zinc. Selective hydrogenation with a soluble catalyst gave 18-hydroxycorticosterone 21-acetate (41 l), offering a convenient route to the tritium-labelled Another synthesis of 18-hydroxycorticosterone started from 3P-acetoxypregn-5ene-ll,20-dione (412), which was converted into 1lP,18-dihydroxyprogesterone using known reactions (413).367 Lead tetra-acetate then introduced a 21-acetoxysubstituent (41 1) as above. 18-Hydroxycorticosterone (414) shows strange

(410) (41 1) (413) (414)

R = OAc, A' R = OAc, 1,2-dihydro R = H, 1,2-dihydro R = OH,1,2-dihydro

behaviour in solution, giving a mixture of two interconvertible forms which differ in polarity.368 The less polar form is converted more readily into aldosterone in uiuo, and appears from recent chromatographic evidence to be of higher molecular weight than the more polar form. The possibility that the less-polar form may be a reversibly formed dimer invites study, now that 18-hydroxycorticosterone is available in reasonable quantity by synthesis. An improved route to a l d o ~ t e r o n makes e ~ ~ ~ use of the 1I@-nitriteof a 1,4-dien-3one derivative (415), where C-19 is tilted away from the 11P-oxygen atom, to achieve attack (Barton reaction) only at C-18. The subsequent steps include some unusual heterocyclic chemistry. The 18-oxime (4 16) cyclized on heating to give the nitrone (417), thereby affording the necessary activation for acetoxylation at C-21. 366

367 368

369

D . H. R. Barton, M. J. Day, R. H. Hesse, and M. M. Pechet, J.C.S. Perkin I, 1975, 2252. D. N. Kirk and M. S. Rajagopalan, J.C.S. Chem. Comm., 1976, 77. M. C. Damasco and C. P. Lantos, J. Steroid Siochem., 1975,6, 69. D. H. R. Barton, N. K. Basu, M. J. Day, R. H. Hesse, M. M. Pechet, and A. N. Starratt, J.C.S. Perkin I, 1975, 2243.

Steroid Properties, Reactions, and Partial Synthesis

301

This step proceeds through the hydroxy-N-acetate (4 IS), which undergoes rearrangement in acetic anhydride-sodium acetate to give the N-acetyl-acetate (419). Further simple steps afforded 1,2-didehydroaldosterone 18,21-diacetate (420), permitting tritiation to produce radioactive-labelled aldosterone. Several oxidations of the nitrone (417) are also described;369Jones chromic acid in aqueous acetone

Ac

OAc

OAc I

(419)

gave 1,2-didehydro-2 1-deoxyaldosterone (42 1). Similar reactions are described in the 1,4,6-trien-3-one series.

The reduced metabolites of 18-hydroxydeoxycorticosterone (3a - and 3P-OH, 5a- and 5P-H; four 'tetrahydro' isomers) have been identified in rat liver and adrenals, and have been obtained on a semi-micro scale by conventional chemical reductions of the parent compound. Their separation has been achieved by g.1.c. and t . l . ~ . ~The ~ ' 5a - and SP-dihydro-derivatives of aldosterone have been obtained by hydrogenation of aldosterone 18,21-diacetate (422) and hydrolysis; the C-5 isomers were separable as their 18,21-diacetates, although no comparable separation has been achieved with either aldosterone itself or its 2 1-acetate. Further hydrogenation of the Sp-dihydro-derivative (423), and hydrolysis, gave the 3p- and 3a-hydroxy370

P. Bournot, M. Prost, and B. F. Maume, J. Chromatog., 1975, 112,617

302

Terpenoidsand Steroids

derivatives in a 4 : 1 mixture which was separable with difficulty, providing the first chemical synthesis of 3a,SP-tetrahydroaldosterone (424), a natural metabolite of aldo~terone.~~~

(422) R1= 0, R2 = Ac; A4 (423) R' = 0, R2 = Ac; 5P-H (424) R' = H,a-OH, R2 = H; 5P-H1

13 Lactones and Cardenolides Lactones (428) fused to ring A have been synthesized as potential antiandrogenic cytotoxic agents by opening the 2a,3a -epoxide (425) with allylmagnesium bromide, oxidizing the 2P-ally1 derivative (426) to give the androstan-2P-ylacetic acid (427), and cyclization with perchloric Another synthesis of y-lactones employs ethoxyethynyldiethylalane, generated from lithium ethoxyacetylide and chlorodiethylalane, to open an epoxide as the first step. Applied to 2a,3a-epoxy-5acholestane, the reaction gave the diaxial product (429), which was converted by methanolic HCl into the methyl ester (430) before cyclization to give the lactone (428) in good yield.373

()::.a I - "a 1 -Ro2cHm j 1 H

(425)

HO'

H

(426) R = CHz=CH-CH* (429) R = EtOCGC

H

__*

o

m H

(427) R = H (430) R = M e

Steroids substituted by spiro-a -methylene-7-lactones [e.g. (43 l)] have been synthesized as possible antitumour agents by Reformatsky reactions between ethyl a -(bromomethyl)acrylate and suitable steroid ketones.374

372

373 374

M. Harnik, Y. Lederman, R. Szpigielman, and J. Herling, Tetrahedron, 1976, 32, 1001. G. C. Wolf and R. T. Blickenstaff, J. Org. Chem., 1976, 41, 1254. S. Danishefsky, T. Kitahara, M. Tsai, and J. Dynak, J. Org. Chem., 1976, 41, 1669. K.-H. Lee, T. Ibuka, S.-H. Kim, B. R. Vestal, I. H. Hall, and E.-S. Huang, J. Medicin. Chem., 1975,18, 812.

Steroid Properties, Reactions, and Partial Synthesis

303

Butenolides [e.g. (43S)I have been synthesized from P-keto-sulphoxides by alkylation with methyl bromoacetate, followed by reduction and lactonization (Scheme 14). The required @ -keto-sulphoxide (432) was prepared by reaction between the methyl etienate and ‘dimsyl’ potassium (MeSOCH2K+).375 MeSO

MeSO

I

I

‘

CH-CH,

CH,

I

‘C02Me

\ (432)

(435)

(434)

Reagents: i, BrCH2C02Me-base; ii, NaBH4.

Scheme 14

Syntheses of the cardenolides digitoxigenin (436) and xysmalogenin (437) used the alternative routes outlined in Scheme 15 to produce the unsaturated lactone ring.376 Normal methods have been used for the preparation of 3-deoxy-cardenolides and -cardanolide~~ and ~ ’ for the 3P -thiocyanato analogue of digit~xigenin.~~’ Variously substituted (at C-3) cardenolide derivatives have been prepared from digitoxigenone by reaction with organolithium and other reagents.379 3p, 14-Dihydroxy-14/3-carda-4,20(22)-dienolide (canarigenin; 439) and its 5adihydro-derivative (uzarigenin; 440) have been prepared by conventional steps (Scheme 16) from digitoxigenin (436).380 The intermediate 4-en-3-one (canarigenone; 438) was transformed via its 4P75P-epoxy-derivative into the 375 376

377

378 379 380

P. A. Bartlett, J. Amer. Chem. SOC.,1976, 98, 3305. E. Yoshii, T. Koizumi, H. Ikeshima, K. Ozaki, and I. Hayashi, Chem. and Pharm. Bull. (Japan), 1975, 23, 2496. T. R. Witty, W. A. Remers, and H. R. Besch jun., J. Pharm. Sci., 1975,64, 1248. H. N. Abramson, C. L. Huang, T. F. Wu, and T. Tobin, J. Pharm. Sci.,1976,65, 765. H. P. Albrecht and B. Kunz, Annalen, 1975, 2216. Y. Kamano, G.R. Pettit, and M. Tozawa, J.C.S. Perkin I, 1975, 1972.

Terpenoidsand Steroids

304

3

CH,OAc

I

(436) 5p-H (437) A' Reagents: i, BrCHzCO2Me-Zn; ii, M e 3 0 BF4, NaOH; iii, A1203.

Scheme 15

(436)

* 0

HO

(440)

(441)

Reagents: i, Bu'OCl; ii, LEI-DMF; iii, LiAlH(OBu')3; iv, LiBH4-py; v, m-ClC6H4CO3H; vi, Cr(0Ac)z; vii, Ni.

Scheme 16

305

Steroid Properties, Reactions, and Partial Synthesis

3P,SP-diol (periplogenin; 44 1).38121-Hydroxypregn-4-ene-3,20-dione has been converted into 6a -methyldigitoxigenin 3-acetate by adaptation of conventional

14 Heterocyclic Steroids Curtius reaction conditions converted the A-seco-keto-acid (442) into A-nor-3azacholest-3(5)-ene (443), which was reduced (HCl-NaBH4) to the pyrrolidine analogue (444).383 The keto-acid (442) reacts with hydrazine or substituted hydrazines to give 4-amino-4-aza-steroids (445)-(449). The phenylhydrazine derivatives (446) could be cyclized to the indole (450).384

(443)

(444)

(445)R' = R2= H (446)R' = H,R2 = Ph (447) R' = H,R2= Ac (448)R' = H,R2= Pr' (449)R' + R2 = (CH2)5

Other steroidal indoles [e.g.(45l)]have been synthesized by Fischer cyclization of phenylhydrazones of 3-0x0- and 1 7 - 0 x o - ~ t e r o i d ~ . ~ ~ ~

3s1

382 383

384 385

Y. Kamano, G. R. Pettit, and M. Tozawa, J.C.S. Perkin I, 1975, 1976. U. Valcavi, B. Corsi, R. Caponi, S. Innocenti, and P. Martelli, J. Medicin. Chem., 1975, 18, 1258. V. A. Ruiin, V. F. Shner, L. I. Lisitsa, A. I. Terekhina, andN. N. Suvorov, Zhur. org. Khim., 1975,11, 1763. R. Franzmair, Monatsh., 1976,107, 511. P. Catsoulacos and B. Papadopoulos, J. Heterocyclic Chem., 1976,13, 159.

306

Terpenoids and Steroids

Diosgenin has been converted into [3,2-c]pyrazole and [2,3-d]isoxazole derivatives of types (452) and (453).386Pyrazolines (454),prepared from the corresponding 2-benzylidine-3-0x0-steroid and phenylhydrazine, were dehydrogenated to give the substituted pyrazole (455).387

(452) X = N H , N M e , etc. (453) 0

x=

Ph *h-N p

Ph-E(fy H

H

(455)

(454)

A 3P-hydroxy-5-aza-steroid (460) has been obtained from the B-nor-4-en-3-one (456) through a Beckmann rearrangement of the derived 4,5-seco-5-oximino-ester (457). The amide (458) was cyclized to the imide (459); reduction with LiAlH4 then afforded the desired 5-aza-steroid (460).3x8

/

0

I

OH

Ph,CH (457)

(456)

(460)

(459)

(458)

The reaction of ketones with hydrazoic acid-boron trifluoride has been used to synthesize a further series of tetrazoles fused to ring B of the cholestane nuc386

w7

388

M. P. Irismetov, M. I. Goraev, and G. Y. Tsvetkova, Zhur. obshchei Khim., 1976,46, 1407. J.-B. Cazaux, R . Jacquier, and G. Maury, Bull. SOC.chim. France, 1976, 2 5 5 . W. J. Rodewald and J. R. Jaszczynski, Tetrahedron Letters, 1976, 2977.

307

Steroid Properties, Reactions, and Partial Synthesis

leus.389,390 Oestrogen derivatives (462) with a [ 16,15-c]pyrazole system were system (461) with obtained by treating the 15-hydroxymethylene-17-OTHP-16-oxo hydrazine. 391

&: CHOH

RO

\

NH

‘

(46 1)

(462)

Cyanamide in methanolic ammonia converts 2 1-hydroxypregnan-20-ones (463) into 17p-(2-amino-oxazol-4-yl)androstanes(464). The reaction proceeds equally well in the presence of a 17a-hydroxy-gro~p.~’~

(463)

(464)

Known reaction steps were used for the preparation of 17a-acetoxy-11oxaprogesterone (465) from h e ~ o g e n i n and , ~ ~ of ~ the 11-oxa analogue (466) of ‘Reichstein’s Compound S’ from 1l-o~a-5a-pregnane-3,20-dione.~~~ The A-nor-3-thia-Sp-pregnanederivative (468) was obtained from the corresponding 4-en-3-one via the 3,4-seco-dicarboxylic acid; Hunsdiecker reaction afforded the dibromo-compounds (467)’ which reacted with sodium sulphide to close the tetrahydrothiophen ring.395 A 2 1-tosyloxypregnan-20-one reacted with alkaline CH,R I

(465) R = H (466) R = OH 389

390 391

392

393 394

395

M. S. Ahmad, Z. H. Chaudry, and P. N. Khan, Austral. J. Chem., 1976, 29, 447. H. Singh, K. K. Bhutani, and L. R. Gupta, J.C.S. Perkin I, 1976, 1210. P. de Ruggieri, M. Fazio, G. Montoro, and 0. Sighinolfi, Farmaco, Ed. x i . , 1975, 30, 547. G. Rapi, M. Ginanneschi, and M. Chelli, J.C.S. Perkin I, 1975, 1999. Ch. R. Engel, S. Salvi, and M. N. R. Chowdhury, Steroids, 1975, 25, 781. V. S. Salvi, D. Mukherjee, M. N. R. Chowdhury, and Ch. R. Engel, Steroids, 1976, 27, 717. C. M. Cimarusti, F. F. Giarrusso, P. Grabowich, and S. D. Levine, Steroids, 1975, 26, 359.

Terpenoids and Steroids

308

2-hydroxyethanethiol to give the 2 1-hydroxyethylthio-derivative (469) which cyclized under conditions intended to form the 2 1-chloroethylthio-derivative, giving instead the heterocycle (470).396

(469)

(470)

Steroid hormone analogues [e.g. (47 l)]carrying the ‘cyclophosphamide’ system have been synthesized as potential anti-tumour

(471)

Novel compounds of alkaloid type with a heterocycle in the steroid side-chain have been synthesized by reaction between the acid chlorides (472) and pyrrolemagnesium iodide. Reduction followed by selective dehydrogenation converted the acylpyrrole (473) successively into the pyrrolidine (474) and 23 (N)-unsaturated (475) derivative^.^"

(474) 396

397

398

B. R. Samant and F. Sweet, J. Org. Chem., 1976,41, 2292. E. L. Foster and R . T. Blickenstaff, Steroids, 1976, 27, 3 5 3 . G. Piancatelli and A. Scettri, Tetrahedron,1976, 32, 1745.

Steroid Properties, Reactions, and Partial Synthesis

309

The 16@,23:16a,24-diepoxy-system (477), found in the unusual steroidal genin cimigenol (478), has been elaborated by a thirteen-stage synthesis from 3@,16adiacetoxy-5a -pregnan-20-one (476). The route is indicated, in outline only, in Scheme 17.399

&

CO,Et

- - OAC

Me

AcO

several steps

several, steps

SC

/

li

H (476)

(477)

Reagents: i, Wittig; ii, 0~0,; iii, H+.

Scheme 17

15 Steroid Radioimmunoassay and Labelled Steroids Radioimmunoassay (RIA) of steroid hormones, a rapidly maturing branch of biochemistry, forms the subject of a mon~graph.~"The method depends upon the ability of certain proteins to bind steroids selectively and reversibly: [St] + [Prot] $ [St Prot]

By choosing suitable reaction conditions, it is possible to use the system as a very sensitive assay technique. In the presence of a fixed amount of binding protein, the amount of steroid will determine the ratio of unbound steroid to steroid-protein complex at equilibrium. By adding a tracer amount of labelled steroid to the system, a simple means of determining this ratio is available, and hence, by reference to a standard curve, the amount of steroid can be found. In practice, this usually requires separation of the unbounded [St] and bound [St * Prot] fractions, and then isotope counting of one or other fraction. Separation of unbound and bound steroid may be 399

G. Piancatelli and A. Scettri, Guzzetta, 1975, 105,473.

400

D.Gupta 'Radioimmunoassay of Steroid Hormones', Verlag Chemie, Weinheim, 1975.

Terpenoids and Steroids

3 10

achieved either by collecting the unbound steroid on prepared charcoal, or by precipitating the protein with a suitable agent, such as ammonium sulphate or polyethylene glycol. The requirements are therefore for a labelled steroid to act as tracer, and a specific binding protein. This latter may be derived from tissues or from plasma, but most commonly nowadays by raising a specific antibody protein against the particular steroid involved. A derivative of the steroid to be assayed, designed to permit covalent bonding to a protein, is commonly linked to bovine serum albumin (BSA). The BSA-steroid conjugate is injected into a sheep or rabbit where it acts as an antigen, causing the formation of antibodies which ideally have the capacity to bind the steroid hormone with high affinity and specificity. Steroid chemistry is involved at two points: (i) the preparation of a steroid derivative (‘hapten’; e.g. a carboxymethyloxime or a hydrogen succinate ester) suitable for chemical combination with free amino-groups in BSA (see below) and (ii) the synthesis of labelled steroids of high specific radioactivity for use as tracers. Haptens.-Haptens have been prepared from steroid hormones by reactions at C-3 or C-17, or in the pregnane side-chain. Antibody specificity is often improved, however, by anchoring the steroid through a middle-ring site to the protein, so that both ‘ends’ of the steroid component of the complex are exposed for recognition in the antibody-forming process. Carboxymethyloxime formation is reported for a variety of 3-0x0- and 7-0x0steroids, suitably protected at other 0x0-groups (C- 17 or C-20) where necessary. Syn - and anti-forms of carboxymethyloximes were separated by repeated t.l.~.~’l The 6-carboxymethyloximino-derivative(479) of ‘oestetrol’ was used as hapten in the production of a highly specific antiserum for oestetr01.~~’~ The synthesis of 6-0x0-oestetrol proceeded through known steps. RIA of 18-hydroxydeoxycorticosterone (480)403has been based upon the 3-carboxymethyloxime of the intact steroid, but 18-hydroxycorticosterone (481) was degraded by periodic acid to the y-lactone (482) before formation of its 3-carboxymethyloxime.404 The antiserum to this y-lactone responds equally to the y-lactone derived from 18hydroxydeoxycorticosterone, but other corticosteroids did not interfere. OH

‘OC H (479) 4n1

402

403

404

co H (480) R = H (481) R = OH

E. Mappus, C. Grenot, M. Forest, and C. Y. Cuilleron, Compt. rend., 1975, 281, C, 247. N. Kundu and M. Grant, Steroids, 1976, 27, 785. U. Schrnied, W. Vetter, J. Nussberger, and W. Siegenthaler, Steroids, 1975,26, 478; D. W. Chandler, M. Tuck, and D. M. Mayes, ibid., 1976,27, 2 3 5 . V. I. Martin,C. R. W. Edwards,E. G. Biglieri, G. P. Vinson,andF. C. Bartter, Steroids, 1975,26,591.

Steroid Properties, Reactions, and Partial Synthesis

31 1

(482)

The 7-carboxymethyloxime (483) of 3a,20a-dihydroxy-5P-pregnan-7-one, derived in several steps from 3a,7a -dihydroxy-SP-cholan-24-oic acid

(483)

(chenodeoxycholic acid), has been used as hapten in RIA of 5P-pregnane-3a,20a di01.~” Michael addition of a malonic ester on to 1-en-3-ones or 15-en-17-ones was used to introduce la - or 15a-carboxymethyl groups, respectively (Scheme 18), for

H 0 , C C H,

HO,CCH,

0

HO Me

HO,CCH,

Reagents: i, Michael addition: CH2(C02Et),, hydrolysis, -C02; ii, KBH4.

Scheme 18 405

I. Yoshizawa and M. Kimura, J. Pharm. SOC.Japan, 1975,95, 843.

312

Terpenoids and Steroids

linkage to BSA. A point of interest is the separation of the la-carboxymethyl5a-androstane-3~~,17/3and -3&17P-diols by making use of the favourable conformation of the formcr isomer for l a c t o n i ~ a t i o n . ~Some ~ ~ further 7(carboxymethy1oximino)-steroids are also d e ~ c r i b e d . ~ " ~ Recent examples of the preparation of hydrogen succinates and their use as haptens for RIA include the C-17 derivative of o e ~ t r a d i o l and ~ " ~the C-6 derivatives of 6 a - and 60 -hydroxytestoster~nes.~~~ The 21 -(hydrogen succinate) of 'betamethasone 17-benzoate' (484) illustrates an application of RIA to a synthetic steroid analogue which is found in appreciable concentrations in plasma after topical a p p l i ~ a t i o n . ~An " ~ antiserum against 3p,16a -dihydroxyandrost-5-en-l7-onewas obtained by using the BSA conjugate of the 3-(hydrogen succinate) (485) obtained

9 CH,OH I OPh

0

'

.oH

co I

C H ?C'H ?CO, H

(484)

(485)

by microbiological 16a -hydroxylation of the 3-(hydrogen succinate) of 3phydroxyandrost-5-en-17-0nes.~~~ The 15P-(carboxyethylthio) derivatives of 3phydroxyandrost-5-en- 17-one (486) and testosterone (487) were obtained via a

C'H2C0,H

HO'

(486)

CH,C'O,H

(487)

conjugate addition of potassium 3-mercaptopropionate on to a 15-en-17-one. After coupling to BSA through the carboxy-group, these compounds were used to raise antisera with high affinity and specificity for the respective Labelling with Isotopic Hydrogen.-Various oestrogenic steroids with high specific radioactivity were obtained by reduction of their 2'4-dibromo- or 2,4-iododerivatives with tritium gas over 5 % Pd-AI2O3, to give 2,4-ditritiated Betamethasone 17-benzoate (484) was labelled [ 1,2-3H2]by selective reduction of 406 407 408

409

410

411

4L2

R. Condom, Compt. rend., 1975, 281, C , 139. D. Exley and B. Woodhams, Steroids, 1976, 27, 813. H. Sone, H. Yoshimasu, and M. Kojima, J. Pharm. SOC.Japan, 1976,96, 199. A, Mizuchi, N. Okada, Z. Henmi, and Y. Miyachi, Steroids, 1975, 26, 635. K. Furuya, T. Yoshida, S. Takagi, A. Kanbegawa, H. Yamashita, Y. Kurosawa, and A. Naito, Steroids, 1976,27, 797. P. N. Rao and P. H. Moore, jun., Steroids, 1976, 28, 101, 110. A. D. Fraser, S . J. Clark, and H. H. Wotiz, J. Labelled Compounds, 1976, 12,213.

313

Steroid Properties, Reactions, and Partial Synthesis

the A'-bond with tritium, catalysed by the soluble complex [(Ph,P),RhCl], followed by restoration of A'-unsaturation by dehydrogenation with DDQ.,I3 Hydroboration (488) can be controlled to give of 17a -acetoxy-3,3-ethylenedioxpregn-5-en-20-one the 6P -hydroxy-SP-pregnane derivative (489), without attack on the side-chain or acetoxy-group. Dehydration (POC1,-py), followed by reduction (LiAlH,), removal of the acetal, and reduction of the 3-oxo-group, gave 5P-pregn-6-ene-3a, 17a,20atrio1 (490) and the 20P-isomer, suitable for tritiation at the 6,7-positions to give the corresponding [6,7-3Hz]-labelled 5P -pregnane-3a, 17a,2O-triol~.~'~

n

A

(488)

(489)

(490)

7 a -Tritio-steroids have been prepared by selective catalytic tritiation (6a,7a) of 4,6-dien-3-ones, and removal of 6a-,H by proton exchange. Steroids with a 6-[,H3]methyl substituent (492) were prepared by catalytic tritiation of a 6dibromomethylene-4-en-3-one (491).,15

CT3

CBr,

(49 1)

(492)

Oestrogens with high specific activity have been prepared by tritiation of a A9(")-derivative. The compounds have the naturaI 9a -configuration, but the 1l-,H configuration is not e ~ t a b l i s h e d . ~ ' 3/3-Hydroxy-5a,25(R)-spirostan-12-one ~ ('hecogenin') labelled with deuterium at C-11 has been used as a source of sulphates of labelled 3P-hydroxy-Sa -pregnan-20-one and 5a -pregnane-3@,2Oa-di01.~'~ Lithocholic and chenodeoxycholic acids with 11,12-[2H2]-and -[3Hz]-labellinghave been prepared from the corresponding 11-enes.,18 Oestrone and oestradiol with specific 2H labels at the 14a-, 15a-, 15P-, and 16a-positions were obtained by reactions including those illustrated in Scheme 19.,19 Reduction of 3a-hydroxy- and 3P-hydroxy-Sa-pregn-16-en-2O-oneswith LiA1D4, followed by hydrogenation of the AI6-bond, gave samples of 5a-[20P'H]pregnane-3a,20a - and -3P,20a -dials. The 16-en-20-ones were chosen in order 413

414

415 416 417 418

419

T. Kobari, S. Watanabe, and S. Ikegarni, J. Labelled Compounds, 1975, 11,591. G. Cooley and A. E. Kellie, J.C.S. Perkin I, 1976, 452. R. C. Thomas, G. J. Ikeda, J. A. Campbell, and H. Harpootlian, J. Labelled Compounds, 1975,11,99. K. Ponsold, J. Rorner, and H. Wagner, J. Labelled Compounds, 1974,10, 533. T. A. Baillie, J. Sjovall, and J. E. Herz, Steroids, 1975, 26, 438. A. F. Hofmann, J. Lipid Res., 1976, 17, 231. H . Hosoda, K. Yamashita, and T. Nambara, Chem. and Pharm. Bull. (Japan),1976, 24, 380.

Terpenoids and Steroids

3 14 OSiMe,Bu' OTs

i,

OSiMe,Bu'

I:iii

ii

OAc

G

H

O

H

D

Rcagents: i, LiAID4; ii, HCI-acetone; iii, B2D6, then 02H-; iv, TsC1-py; v, LiAlH4; vi, py,HCl.

Scheme 19

to optimize the yields of 20a-alcohols in the reductive The fungal sex hormone antheridiol(493) has been prepared in [22,23-3H2]-labelledform; the key step for introduction of tritium was the reduction of a 22-0x0 analogue with NaB3H4 in d i ~ x a n - ' H ~ O . ~ ~ *

(493)

Non-specific deuteriation of many steroids has been achieved by exchange with D,O in the presence of activated platinum or palladium or under homogeneous conditions by the action of Na2PtC14 or Na2PdC1, in deuterioacetic acid (CH3C02D). Mechanisms are suggested for exchange at saturated and unsaturated carbon and in aromatic rings. Selectivity is somewhat greater with homogeneous catalysis.422 450 421 422

T. A. Baillie, J. E. Herz, and J. SjGvall, J. Labelled Compounds, 1974, 10, 549. T. C. McMorris and T. Arunachalam, J. Labelled Compounds, 1975, 11, 577. J . L. Garnett and J. H. O'Keefe, J. Labelled Compounds, 1975, 11,177, 201.

315

Steroid Properties, Reactions, and Partial Synthesis

Other Isotopes.--17a -Hydroxy-6a -methylpregn-4-ene-3,2O-dionehas been converted into doubly labelled 'medroxyprogesterone acetate' (494). The 17a hydroxy-group was first acetylated with [ l-'4C]acetic anhydride. Dehydrogenation (DDQ) to the 1,4,6-trien-3-one was followed by selective tritiation of the A'-bond to give the I4C- and 3H-labelled product (494).423The reaction of [''C]diazomethane with the acid chloride (495) has been employed in a convenient route to the anaesthetic [21-14C]pregnanederivatives (496) and (497).424

T@coMe

eC

-- 014COMe

0

R'O"

H

(495) R' = 0 2 N , R2 = C1 (496) R' = H, R2 = I4CH3 (497) R' = H, R2 = 14CH20H

(494)

Partial rearrangement to 6P-iodomethyl- 19-norcholest-5(10)-en-3~-ol(25), which is liable to occur in the preparation of 19-iodocholesterol (24), (p. 236) was avoided by a modified reaction sequence, used for the synthesis of [1311]-19iodocholesterol.425 The [1311]-6P-iodomethyl derivative (25) is described as a new adrenal cortex imaging agent.426 Iodine-labelled tracers available for RIA427now include iodinated (1251) derivatives prepared from the condensation products of testosterone 3-carboxymethyloxime with either tyrosine methyl ester (498) or tyramine (499).428 75Se-Labelled 6-benzyiseleno-19-norcholest-5-en-3~-ol has been prepared.429 OH

OCH,CONH

I

RCHCH2CJ140H-p (498) R = C02Me (499) R = H 423 424 425 426

427 428

4*9

S. Runic, M. Miljkovic, R. J. Bogumil, D. Nahrwold, and C. W. Bardin, Endocrinology, 1976,99,108. B. E. Ayres, C. E. Newall, axd G . H. Phillipps, Steroids, 1975, 26, 219. M. W. Couch, K. N. Scott, and C. M. Williams, Steroids, 1976,27, 451. G. P. Basmadjian, K. R. Hetzel, R. D. Ice, and W. H. Beierwaltes, J. Labelled Compounds, 1975,11,427. Ref. 400, p. 185. A. R. Soto, 0.del Valle, M. Brotherton, M. E. Castellanos, and K. W. Chambliss, Clin. Chem., 1976,22, 1182. G . P. Basmadjian, K. R. Hetzel, and R. D. Ice, Infernat.J. A p p l . Radiation Isotopes, 1975, 26, 695.

3 16

Terpenoidsand Steroids 16 Miscellaneous Syntheses

The 2-methoxy-4a-methyl-5a -androst-2-en-l-one system (500),corresponding to the ring A substitution pattern of quassin, has been elaborated from a 5a-androst- 1en-3-one by application of a sequence of familiar transformation^.^^^ 5,6P -Epoxy4~-hydroxy-5~-cholest-2-en-l-one (501) has been synthesized as a model for rings A and B of withaferin A (502). The synthesis involved multiple steps from cholesta2,5-dien-l-one; related compounds were synthesized from the 2,4-dien-l-0ne.~~'

'0

Cholestane, pregnan-20-one, and androstan- 17-one derivatives with the 5,lOseco-19-nor-5-yne-3,10-dionestructure (506) have been prepared uia cleavage (tosylhydrazide) of the 5P, 10P-epoxy-6-ketones (505). The required 5(10)-en-6ones (504) were obtained in one step by oxidation of the respective 19-hydroxy-Asderivatives (503) with chromium tri~xide-pyridine.~~~

(503)

Androgenic and anabolic characteristics are reported for a series of novel oestra4,9,11-trien-3-ones, including 2-oxa-, and 7 a -, 17a -, and 18-methylated deriva430 431

412

H. J. Koch, H. Pfenninger, and W. Graf, Helu. Chim. Actu, 1975, 58, 1727. M. Ishiguro, A. Kajikawa, T. Haruyama, Y .Ogura, M. Okubayashi, M. Morisaki, and N. Ikekawa, J.C.S. Perkin I, 1975, 2295. F. H. Batzold and C. H. Robinson, J. Org. Chem., 1976, 41, 313.

Steroid Properties, Reactions, and Partial Synthesis

317

t i v e ~ The . ~ ~7 a~-substituted spirolactones (507), prepared from the 4,6-dien-3-one, have anti-aldosterone Chromic acid oxidation of oestradiol 3-methyl ether 17-acetate was used to open ring C, giving the keto-acid (508); reductive steps then gave 9,ll-seco-oestradiol (509).435Hecogenin has been converted into a series of 12-oxygenated conanine

16P-Ethyl-l9-nortestosterone, an anti-androgen, has been synthesized by a route which includes C-acetylation of oestrone methyl ether (EtOAc-NaOMe) to give the 16-acetyl derivative (510), conversion into a mixture of enol acetates (51 1) and (512), and hydrogenation over Raney nickel, which gave the 16P-ethyl derivative (5 13) as the main

New derivatives of steroidal hormones, prepared- for biological evaluation, include 17-dialkylaminoalkanoates and other novel esters of 17a -hydroxypr~gesterone,~~' trimethylsilyl ethers of 17a - h y d r o x y p r ~ g e s t e r o n e , ~ ~ ~ testosterone, 19-nortestosterone, 17a-methyltestosterone, and other androstane 433

434 435 436

437

45g 439

G. Azadian-Boulanger, R. Bucourt, L. Nedelec, and G. Nomine, European J. Med. Chem., 1975, 10, 353. R. M. Weier and L. M. Hofmann, J. Medicin. Chem., 1975, 18, 817. P. Kole, S. Ray, V. P. Kamboj, and N. Anand, J. Medicin. Chem., 1975, 18, 765. G. van de Woude and L. van Hove, Bull. SOC.chim. belges, 1975, 84, 91 1. K. Yoshioka, G. Goto, H. Mabuchi, K. Hiraga, and T. Miki, Chem. and Pharm. Bull. (Japan), 1975,23, 3203. B. Beyer, L. Terenius, R. W. Brueggemeier, V. V. Ranade, and R. E. Counsell, Steroids, 1976,27,123. L. E. Golubovskaya and K. K. Pivnitsky, Khim.-Farm. Zhur., 1976,10, 5 2 .

Terpenoids and Steroids

318

derivative^,^^' the triethylsilyl ethers of some androgenic and the 3-(3isopropylamino-2-hydroxypropyl)ether of o e s t r ~ n e Some . ~ ~ ~di-steroid esters of succinic acid have been prepared, with 17p -hydroxyandrost-4-en-3p-yl and 3oxoandrost-4-en- 17p -yl and similar steroidal esterifying groups as long-acting androgens.443 The 3- [NN-bis-p- (2-chloroet hy 1)aminophen ylace tates] (5 14) of 170x0- 17a-oxa-5a -androstan-3c-u- and -3p -01s were prepared for anti-tumour studies but proved to be less effective than the corresponding lactam derivative (515).444

(514) X = 0, 3a or 3p (515) X = N H , 3p

The three isomeric monosulphates of cholic acid are Syntheses of the were four monoglucuronides of oestra-l,3,5(10)-triene-3,15a,l6a,l7~-tetrol achieved by carefully chosen routes via suitably protected intermediate^.^^^ The 2- and 3-monomethyl ethers of 2,16p-dihydroxy-oestroneand -0estradiol have been prepared from 2-hydroxyoestrone, protected at the phenolic hydroxy-groups by forming the 3-benzyloxy-2-methoxy- and 2-benzyloxy-3-methoxy-derivatives, respectively. Acetoxylation at the 166-position used the reaction between lead tetra-acetate and the AI6-eno1 acetates (516) and (517); the benzyl group was removed reductively as the final step, leading to the monomethyl ethers (518) and (5 19).447

(516) (5 17) (518) (519)

440

441

4d2 443 444

445

446 447

R1 = Me, R2 = PhCH2 R' = PhCH2, R2 = Me R'=Me, R 2 = H R'=H,R2=Me

A. A. Shishkina, T. I. Ivanenko, L. E. Golubovskaya, V. I. Melnikova, L. G. Sheimina, and K . K. Pivnitsky, Khim. Farm. Zhur., 1976,10, 53. 0. N. Minailova, T. I. Ivanenko, V. M. Rzheznikov, and K. K. Pivnitsky, Khim. Farm. Zhur., 1976,10, 37. P. Da Re, P. Valenti, P. C. Braga, and S. Ferri, Arch. Pharm., 1975, 308, 981. H. Kuhl and H.-D. Taubert, Steroids, 1976, 28, 89. P. Catsoulacos, L. Boutis, and K . Dimitropoulos, European J. Med. Chem., 1976, 11,189. G. Parmentier and H. Eyssen, Steroids, 1975, 26,721. T. Nambara, K. Sudo, and M. Sudo, Steroids, 1976, 27, 11 1. T. Nambara and Y. Kawarada, Chem. and Pharm. Bull. (Japan), 1975,23, 1613.

Steroid Properties, Reactions, a n d Partial Synthc sis

319

also 12a-hydroxypregna- 1,4-dien-3-one-20-carboxylic Compounds with some structural similarity to a prostaglandin enantiomer have been obtained from 4-propyltestosterone and from 6a -pentylandrost-4-ene-3,17-dione.Ring A was opened by oxidation, which was followed by manipulations of functional groups to give the enantio-tetrahydro-PGA analogues (520) and (521) and related compound~.~~~

(520)

(521)

The annelation reactions which have found numerous applications in steroid synthesis, including the construction of ‘fifth’ rings, have been reviewed.45o

448 449

4s0

P. J. Barnes, J. D. Baty, R. F. Bilton, and A. N. Mason, Tetrahedron, 1975, 32, 89. M. Baumgarth and K.Irmscher, Tetrahedron, 1975, 31, 3109, 3119. M. E. Jung, Tetrahedron,1975, 32, 3.

Steroid Total Synthesis BY J. S. WHITEHURST

The cyclization of (1) (chiral centre at C-11) can conceptually give rise to the diastereoisomers (2) (R equatorial) and/or (3) (R axial). Compound (1; R = Me) has

(1)

been synthesized as outlined in the Scheme.’ On reaction with trifluoroacetic acid in trifluoroethanol it gave (2; R = Me) (66%) as a 91 : 9 mixture of 17p- and 17aepimers. This in turn was converted into (&)- 1la-methylprogesterone (4) (obtained pure) and (*)-1 la-methyl-17-isoprogesterone (5) (ratio 82 : 18). No 11pmethylprogesterone was formed. This work has been extended to the synthesis and cyclization2 of (1; R = OH) and, as already r e p ~ r t e d ,it~ yields (*)-llahydroxyprogesterone (6). The known vinyl ketone (11)has been prepared4by the route (7) + (8) + (9). The last compound on heating gave (11). Whereas the reaction between (9) and 2methylcyclopentane-1,3-dione gave (12), the corresponding reaction with (10) gave (13), evidently owing to the benzenesulphenic acid produced in the reaction. Asymmetrically synthesized C/D intermediates with the natural configuration continue to provide intermediates for steroid synthesis. Thus the alkylation of (+)-(18) with rn-methoxyphenacyl bromide (19)gave (14) in high yield5 in contrast to the low yields in this type of alkylation6 obtained with (20). The action of trimethyl orthoformate on (14) gave the extremely sensitive compound (15) which cyclized with toluene-p-sulphonic acid in benzene to yield (22). High-pressure hydrogenation W. S. Johnson and G. E. DuBois, J. Amer. Chem. SOC.,1976, 98, 1038. W. S. Johnson, S. Escher, and B. W. Metcalf, J. Amer. Chem. SOC.,1976,98,1039; W. S. Johnson, Bioorg. Chem., 1975,4, 342. ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 6, p. 279. Y. Oikawa, T. Kurosawa, and 0. Yonemitsu, Chem. and Pharm. Bull. (Japan), 1975,23, 2466. U. Eder, H. Gibian, G. Haffer, G. Neef, G. Sauer, and R. Wiechert, Chem. Ber., 1976,109, 2948. G. H. Douglas, J. M. H. Graves, D. Hartley, G. A. Hughes, B. J. McLoughlin, J. Siddal, and R.Smith, J. Chem. Soc., 1963,5072;D. J. Crispin,A. E.Vanstone,andJ. S.Whitehurst, J. Chem. SOC.( C ) ,1970,lO.

320

321

Steroid Total Synthesis

r l

x:jl

HO

\ u

0 O D 6 : h 3

om(1; R = M e ) 0

0

(2; R = M e )

(4)R = Me, X = @-COMe,a-H ( 5 ) R = Me, X = P-H,a-COMe (6) R = OH, X = P-COMe,a-H Scheme

of this furnished (23) and thence, by oxidation, (24). With sodium methoxide in methanol compound (24) was quantitatively epimerized to (25),from which known paths lead to oestradiol and oestrone. R

Me0 (7) R = OMe (8) R = MeSOCH2 (9) R = MeSOCHMe (10) R = PhSOCHMe (11) R=CH=CH;!

R'

(13) R' = 0, R2 = H2 (14)R' = P-oBu',~-H, R~ = o (15) R' = P-OBu',a-H, R2 = (OMe)* (16) R 1 = O , R2=CH2

(17) R 1 = O (18) R' = P-OBu',a-H

Terpenoids and Steroids

322

OBu' Me0

R2 (19) R 2 = 0 , X = B r (20) R2= H2, X = Br or OTs (21) R2=CH2,X = B r

MeO'

(23) R = P-OH,(Y-H (24) R = O (25) C* epimer of (24)

The morpholine and piperidine dienamines corresponding to formula (26) [from optically active (17)] react with allylic halides to form N-allylated salts which then undergo [3,3] sigmatropic change to C-products containing rearranged ally1 groups.' However, the pyrrolidine enamine corresponding to (26) reacted with the bromide (21) in acetonitrile to form the C-alkyl product directly which by hydrolysis then gave (16). Sodium borohydride reduction, acetylation, and acid-catalysed cyclization then yielded (27). In previous work3 compound (28) was produced ultimately from (+)-(17) by a single annelation employing 1,3-dichlorobut-2-ene. The possibility of bisannelation using a C,reagent has now been realized.' The nitrile (29) was converted successively into (30), (31), (32), (33), and (34). Alkylation of (+)-(18) with (34) in

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

X=CN X = CHO X=CHOHCH=CH2 X = COCH=CH2 X = COCHzCHzCl

U. K. Pandit and H. Bieraugel, Rec. Truu. chim., 1976,95, 2 2 3 . U. Eder, G. Sauer, G. Haffer, J. Ruppert, R. Wiechert, A. Fiirst, and W. Meier, Helv. Chim. A m , 1976, 59, 999.

Steroid Total Synthesis

323

1,2-dimethoxyethanol containing sodium hydride gave (35) (68%), which reacted with trimethyl orthoformate to produce (36). Cyclization to (37) with malonic acid in hot benzene was followed by catalytic addition of one molecule of hydrogen. Hydrolysis and subsequent cyclization afforded (38) [85% from (37)]. Reaction of the sodium enolate of (38) with methyl iodide at -70 "C then produced (39) (73%) from which androsta-4,9(1l)-diene-3,17-dione (40) was readily obtained. Catalytic hydrogenation of (38) followed by ring closure produced 19-

(35) R = O (36) R = (OMe),?

The dione (4 l), obtained from 2-methylcyclopentane- 1,3-dione, undergoes asymmetric cyclization to yield (42) (82% yield, 86% optical purity) with L-phenylalanine in acetonitrile.' Reduction with sodium borohydride to (43) followed by catalytic reduction gave (45) (major product), (46), and, unexpectedly, compound (44) S. Danishefsky and P. Cain, J. Amer. Chem. SOC.,1975,97, 5 2 8 2 .

324

Terpenoidsand Steroids

(21%). The transformations (47) + (48) -P (49) + (50) were carried through by Birch reduction, hydrolysis, and cyclization with mild alkali. Oxidation and acidcatalysed cyclization then furnished the complete steroid (5 1)which was converted into oestrone. 0 RZ

(45)R1 = 0, R = a-H (43) R' = 0, R2 = B-OH,a-H (46) R ' = O , R = & H (44)R' = H2, R2 = P-OH,a-H (47) R' = OCH2CH20, R = a-H

(42) R ' = R ~ = o

__ (48) R'

= OCH2CH20.

The isothiouronium salt ( 5 2 )reacts with 2-methylcyclopentane-1,3-dioneto form (53) in low yield: moreover, attempted cyclization of (53) gave only cleavage products. However, the lithium compound (55), obtained from (54) by halogen exchange with butyl-lithium, when treated with 6-methoxy- 1-tetralone formed (56) from which the quaternary compounds (57) and (58) were obtained. The sodium derivative of 2-methylcyclopentane-1,3-dionereacted with (58) in xylene containing hexamethylphosphoramide to form (59). Cyciization with toluene-p-sulphonic acid in cold benzene yielded the unstable ketone (60) which was reduced to (61). Catalytic reduction of this over a palladium on alumina catalyst in benzene gave (62). Further reduction, by sodium in ammonia, then produced the corresponding 1lpmethyloestrone compound.10 Interestingly, hydrogenation of (6 1)with palladium on calcium carbonate in benzene yielded, by a 1,6-addition to the unsaturated system, compound (63). lo

R. B. Garland, J. R. Palmer, and R. Pappo, J. Org. Chem., 1976, 41, 531.

325

Steroid Total Synthesis

RL (54) N RM= Ber ,

(55) R = L i

fjJjH # ' '

Me0 (56) R=NMc2 (57) R = NMe3+I(58) R = NMe3+0H-

Me0

(59)

(60) R = 0 (61) R = P-OH,a-H

Toluene-psulphonylmethyl isocyanide is a useful reagent for the conversion -CO- -+ -CHCN-. In an attempt to transform compound (64) into (65) by the sequence (64) -+ (66) -+ (67) -+ (68) -+ (69) -+ (70) -+ (65) the surprising observation was made" that compound (70) changes to (65) only on keeping; efforts made to hasten the process by the usual hydrolytic methods brought about extensive decomposition. The compound was synthesized from (71) by addition of lithium dimethylcuprate [to (72)] followed by the sequence (72) -+ (73) -+(74) + (75). Hydrolysis of the acetal protecting group in (75) and ring closure then gave (65).

(64) R' = &OH,a-H (65) R' = &COMe,a-H

I'

(66) R' =p-OH,a-H, R 2 = OCH2CHzO (67) R1 = 0,R2= OCH2CH20 (68) R1= @-CN,a-H,R2 = OCH2CH20 (69) R' = @-COMe,a-H,R2= OCH2CHz0 (70) R' = @-COMe,a-H,R = 0

J. R. Bull, J. Floor, and A. Tuinman, Tetrahedron, 1975, 31, 3157; J. R. Bull and A. Tuinman, ibid., p. 2151.

326

Terpenoids and Steroids

(72) (73) (74) (75)

R' = @-OH,&-H,R2 = OCH2CH20 R' = 0, R2 = OCH2CH20 R1 = P-CN,a-H, R2 = OCH2CH2O R' = @-COMe,a-H, R2 = OCH2CH20

Compound (go), prepared from 2-methylcyclopentane-1,3-dione and methyl 2-chloroacrylate followed by the sequence (76) -+ (77) -+ (78) -+ (79) (resolved) + (go), combined with (7 1) (prepared from rn-methoxyphenylstyrene and diborane) to form the seco-steroid (82).12 Acetic anhydride-toluene-psulphonic acid then cyclized this stereoselectively to furnish the triacetate (83) which on saponification gave the trio1 (84). Interestingly, this compound reacted with toluene-p-sulphonic acid in alcohol to produce, by dehydration and change of configuration at C-14, the compound (85), which served as a source of various 8a-oestrone compounds. Compound (84) on treatment with boron trifluoride etherate underwent pinacol transformation in preference to dehydration to yield the ketone (86); this ketone was correlated with the known compound (87). 0

(76) (77) (78) (79) (80)

R' = OMe, R2 = C1 R' = OH, R2= C1 R1 = OH, R2 = O H R1=OH, R 2 = O A c R' = CHN2, R2 = OAc

(83) R = OAc (84) R = OH

a 0

I

l2

ri

0

A.l

A. R. Daniewski, J. Org. Chem., 1975, 40, 3124, 3127, 3135; A. R. Daniewski, M. Guzewska, and M. Kocor, J . Org. Chem., 1975,40, 3131.

Steroid Total Synthesis

327

A novel synthesis13 of D-homo-oestrone (101) begins with the aldehyde (88). Conversion into (89)followed by sodamide-ammonia cyclization yielded (90),which was then transformed into (91). The second component required for the synthesis, (94), was prepared by addition of 2-methyclyclohex-2-en- 1-one to vinylmagnesium bromide, the product (92) being converted by way of (93) into (94). The reaction between the compounds (91) and (94) in t-butyl alcohol containing potassium

Me0

Me0

(88) X=CHO (89) x = CHzCHzCN

(90) X = C N (91) X = CH2CH21

t-butoxide led to (95) and thence by hydrolysis to (96). This compound was heated for 4 h in o-dichlorobenzene and gave selectively the methyl ether of D-homooestrone (100). The four-membered ring in (96) opens preferentially to form the sterically favoured E-oriented o-quinodimethene (97) which was not isolated. The cycloaddition of (97) proceeds regiospecifically through the transition state (98) rather than through (99) in which the juxtaposition of the aromatic and cyclohexane rings is unfavourable.

(95) R = CHSBu" (96) R = H z

(97)

(99)

(100) R = OMe (101) R = O H

The ylide from methoxymethyltriphenylphosphonium chloride reacts with the ketone (102) to give (103). Treatment of (103) with trifluoroacetic acid or toluenep-sulphonic acid gave the cyclized product (104). Sodium-ammonia reduction of this was completely stereoselective, leading to the 9aH-compound (105); the homoB-ring adopts a chair conformation.14 l3 l4

T. Kametani, H. Nemoto, H. Ishikawa, K. Shiroyama, and K. Fukumoto, J. Amer. Chem. SOC.,1976, 98,3378. E. Abushanab, D.-Y. Lee, W. A. Meresak, and W. L. Duax, J. Qrg. Chern., 1976, 41, 1601; C . M. Weeks, D . C . Rohrer, and W. L. Duax, Steroids, 1976,27,261.

328

Terpenoids and Steroids OBu'

Me0 (102) R = 0 (103) R = CHOMe

OMe

(104)

OH

Erratum Vol. 6 1976 Page 188, line 12. The statement following the semicolon should read: ‘ent-7-oxokaurenoic acid appeared not to be a precursor of gibberellin A1, aldehyde.. .’

Author Index Aasen, A,. 49 Aasen, A. J., 108, 121 Aaskamp, E., 234 Abaeva, N. Kh., 44 Abdusarnatov, A., 45 Abello, F., 285 Aberhart, D. J., 292, 293 Abernethy, D., 202 Abraharnson, E. W., 172 Abraharnsson, S., 287 Abrarnson, H. N., 303 Abushanab, E., 327 Achari, B., 141, 153 Achini, R., 67 Achiwa, K., 16, 61, 130, 222 Aclinou, P.-, 257 Adam, G., 107, 120, 121 Adarns, D. R., 10,45, 59, 169 Adarns, R. P., 223 Adesina, S. K., 1 11 Adesogan, E. K., 117 Adinolfi, M., 237, 244, 245 Adler, G., 214 Adler, J. H., 205 Ageta, M., 152 Agosta, W. C., 41 Aguiar, J. M., 70 Aguilar-Martinez, M., 223 Agurell, S., S O , 5 1 Ahrnad, M. S., 234, 307 Ahond, A., 11 1 Ahrens, E. H., 203 Aikawa, Y., 46 Aithie, G. C. M., 10 Aitzetrnuller, K., 157 Akashi, K., 6 Akasu. M.. 9 Akeson, A., 125, 181 Akirnoto, A,, 253 Akita, H., 115 Akita, K., 24 Akiyarna, T., 152, 285 Aksenovich, A. B., 282 Akutagawa, S., 11, 12, 31, 52 Alais, J., 208 Alarn, S. S., 220 Al-Badr, A. A,, 38 Albers, F., 140 Albert, O., 262 Albrecht, H. P., 248, 303 Albrecht, P., 134, 151, 275, 288 Alder, A. P.. 170 Alekseeva, L. M., 243,298 Aleshina, V. A., 44 Alewood, P. F., 132, 271 Alexakis, A., 14, 15

Alexander, K., 185 Ah, E., 81 Ali, S. S., 2 12 Allen, K. G., 9, 184 Allinger, N. L., 227 Alrnquist, S. O., 107 Al’perovich, M. A., 172 Alston, K. T., 289 Arnagaya, S., 144 Amarc), J. M., 103 Ambles, A,, 237 Arnice, P., 8 Amico, V., 107, 123 Anand, N., 317 Anand, R. C., 30 Anastasia, M., 254, 289 Anderson, A. B., 11 1 Anderson, R. L., 235 Anderson, W. G., 230 Anding, C., 130, 131, 182, 214 Andre, C., 171 Andrewes, A. G., 155, 159, 161, 163, 166,218,219 Andrews, D. A., 17 Angew, W., 181 Anigk, H. H., 220 Anisimova, 0. S., 256, 298 Ansari, G. A. S., 234 Ansari, H. R., 31 Antkowiak, R., 39 Antkowiak, W. Z., 39 Aoki, T., 146 Aota, K., 27, 89, 198 ApSirnon, J. W., 115 Arai, Y., 152 Aragon, C. M. G., 2 17 Arase, A., 33 Arata, K., 31 Aratani, T., 88 Arbuzov, B. A,, 44 Arendsen, D., 50 Argon, R., 114 Arias, I., 202 Arigoni, D., 73, 76, 181, 187, 22 1 Aringer, L., 212 Aristova, E.-M., 287 Arnone, A,, 49, 50 Arora, S. K., 114, 122 Arpiani, M. P., 246 Arpin. N., 157, 158, 160 Artarnonov, A. F., 42 Arteaga, J. M., 97 Arthur, J. R., 21 1 Arunachalarn, T., 314 Asahara, T., 17 Asakawa, Y., 87

330

Asano, S., 179 Asif, M., 234 Assmann, G., 178 Astin, K. B., 17 Astruc, M., 182 Atabekyan, V. G., 248 Atkin, S. D., 202 Atkinson, R., 6 Aturna, S. S., 287 Atwood, J. L., 27, 186 Audisio, G., 287 Aufrere, M. B., 208 Aul’chenko, I. S., 17 Aurniller, J. C., 173 Avazkhodzhaev, M. K., 71 Avruch, L., 207 Awata, N., 206, 240 Ayanoglu, E., 144 Ayengar, K. N. N., 135, 147 Ayer, W. A., 95 Ayyar, K. S., 169 Ayres, B. E., 3 15 Azzaro, M., 3 Azadian-Boulagner, G., 317 Azarnoff, D. L., 202 Azzaro, M., 33, 111 Baba, H., 173 Baba, N., 4 Babler, J. H., 21 Baeckstrom, P., 22 Baert, F., 29 Baggaley, K. H., 202 Bagnell, L., 249 Baigent, D. R., 145 Bailey, D., 223 Bailey, G. F., 41 Bailey, R. B., 207 Baillie, T. A., 313 Baillie, T. A., 314 Baines, D. A., 45 Baird, M. L., 217 Baisted, D. J., 214 Baker, F. C., 100, 196 Baker, J. T., 124 Baker, P. M., 138 Baker, R., 11 Bal, K., 294 Balashova, E. G., 243 Balasubramaniarn, S., 179,211 Baldwin, D., 276 Baldwin, J. E., 259 Baldwin, S. W., 96 Bally, R., 11 1 Balquist, J. M., 41 Balzano, P., 5

178,

Author Index Bamboria, B. K., 9 Banerjee, A. K., 126, 289 Banerjee, S. K., 143 Banks, C. M., 97 Bannai, K., 293 Bannon, C. D., 146 Banthorpe, D. V., 9, 184, 185, 186 Baran, J. S., 14 Baranyai, M., 159 Bardin, C. W., 315 Bardyshev, I. I., 31, 35, 39, 44 Barendse, G. W. M., 201 Barlow, L., 13, 159 Barnes, P. J., 3 19 Barnett, R. E., 235 Barnier, J.-P., 255 Baron, J., 21 1 Barone, G., 237,244 Barras, S. J., 9 Barrett, A. G. M., 282 Barriero, E. J. L., 138 Barrow, K. D., 200 Barrueco, J. F. S., 42 Barth61Cmy, M., 41 Bartlett, L., 172 Bartlett, P. A., 303 Barton, D. H. R., 7, 134, 241, 242, 246, 252, 253, 267, 269,272,281,282,292,300 Bartter, F. C., 211, 310 Barua, A. K., 143, 145, 153 Basak, A., 143, 145, 153 Bascoul, J., 182 Baskevitch-Varon, Z., 138 Basmadjian, G. P., 3 15 Bass, R. T., 222 Basu, N. K., 300 Basu, K., 143 Bates, G. S., 270 Bates, M. L., 208, 252 Bates, R. B., 114, 122 Battalova, S., 42 Baty, J. D., 319 Batzold, F. H., 316 Baulieu, E. E., 222 Bauman, A. J., 224 Baumgarth, M., 319 Baxter, R. L., 90 Bazyl’chick, V. V., 32 Bearder, J. R., 120, 201 Beasley, G. H., 128 Beavers, W. A.. 122 Bebbington, P. M., 289 Beckett, A. H., 38 Beckwith, A. L. J., 31, 33, 283 Bedoukian, R. H., 17, 18 Beedle, A. S., 221 Beeley, L. J., 120. Begley, M. J., 48, 49, 229 Behere, A. G., 219 Beierbeck, H., 115, 230 Beierwaltes, W. H., 315 Beirne, 0. R., 178

33 1 Bell, A. A., 71 Bell, J. J., 178 Bell, R. A., 109 Bellesia, F., 87 Bellido, I. S., 32, 42,43 Belobaba, D. T. E., 222 Beloeil, J.-C., 251 Ben-Aziz, A., 155,217 BCnCchie, M., 136, 288 BeneS, J., 149 Benn, M. H., 121, 132,271 Bensasson, R., 172 Benson, H., 208 Benson, H. D., 250 Bentley, R., 174, 220 Benveniste, P., 130, 135, 182, 204 Ben-Zvi, Z., 50 Beppu, K., 3 Beratis, N. E., 178 Berchfold, J. P., 222 Berg, A., 2 11 Bergmann, E. D., 146, 261 Bermejo, J., 103 Bernard, D., 15 Bernard;, F., 237 Bernardi, R., 49 Bernasconi, P.,76, 187 Bernassau, J.-M., 132 Bernhard, K., 160 Bernstein, H. J., 172 Berti, G., 278 Bertrand, C., 33 Bertrand, J. A,, 62 Bertrand, M., 82 Besch, H. R., jun., 303 Bessiere, Y., 35, 41 Bessikre-Chretien. Y., 43 Betz, G., 21 1 Beugelmans, R., 283, 284 Beyer, B., 317 Beytia, E. D., 216 Bhacca, N. S.,229 Bhadane, N. R., 103 Bhalerao, U. T., 61 Bhatnagar, S. P., 10, 45, 59, 169 Bhatt, M. V., 267 Bhattacharya, P. K., 4 Bhattacharyya, J., 27, 186 Bhavani, B. R., 222 Bhutan;, K. K., 307 Bickel, H., 216 Bidan, G., 16 Biemann, K., 150 Bieraugel, H., 322 Bigham, D. A., 243 Biglieri, E. G., 310 Biguet, J., 97 Bikbulatova, G. Sh., 44 Bilbao, J. L. G., 23 Billet, D., 11 1 Billets, S., 50, 51, 117 Bilton, R. F., 319

Binder, M., 50, 51 Binkley, R. W., 6 Biolaz, M., 299 Birch, A. J., 14, 46, 176 Birge, R. R., 173 Birmingham, M. K., 233 Birnbaum, G. I., 94, 197 Bisset, N. G., 23, 28 Bissett, F. H., 230 Bjeldanes, L. F., 9 Bjorkheim, I., 211, 212 Bjornland, T., 223 Black, D. R., 9 Blackman, A. J., 107, 158 Blair, H. A. F., 21 1 Blake, J. A., 171 Blanco, L., 8 Blankenhorn, D. H., 178 Blattna, J., 171 Blatz, P. E., 173 Bleile, D. M., 243 Blickenstaff, R. T., 302, 308 Blount, J. F., 114, 124, 293 Blunt, J. W., 115,230 Boar, R. B., 134, 176, 231, 267,272 Bock, M. G., 8 Bodor, N., 241 Bohm, R., 277 Boelens, H., 33, 36 Boeren, E. G., 49 Boger, D. L., 232 Bogucka-Ledbchowska, M., 8 1 Bogumil, R. J., 3 15 Boguslawski, W., 209 Boguth, W., 165 Bohlmann, F., 3, 29, 35, 52, 72, 75, 97, 108, 112, 113, 117 Boid, R., 205, 213 Boinon, B., 41, 43 Boix, J., 285 Bokadia, M. M., 9 Boll, P. M., 46 Bollenbacher, W. E., 212 Boiler, A., 267 Bombardelli, E., 134 Bonati, A., 134 Bond, F. T., 264 Bondavalli, F., 34 Bonet, J.-J., 285 Boon, A., 49 Booth, R., 179 Borch, G., 156, 158, 160, 163 Borch, R. F., 74 Borchers, F., 3 BorEit, S.,238 Bordwell, F. G., 42 Borer, R., 168 Bormann, S., 11 Borowski, E., 81 Bory, S., 110 Bose, A. K., 29 Boucugnani, A. A., 93

Author Index

332 Boumann, T. D., 231 Bouquant, J . , 231 Bournot, P. 301 Boutis, L., 318 Bowd, A., 51 Bowers, W. S., 10, 224 Boyd, G. S., 115,211 Boyd, J., 21 Bracke, J . W., 9 Bradbeer, J. W., 202 Brady, D. R., 222 Braekrnan, J. C., 81 Braga, P. C., 3 18 Brand, J. M., 9 Bratoeff, E. A., 83 Brauman, J . I., 7 Breen, D. L., 174 Breitholle, E. G., 6 5 Brennan, T. F., 124 Breslow, J . L., 178 Breslow, R., 279, 280 Breton, J. L., 97 Briant, R. H., 5 0 Bricout, J., 9, 222 Briedis, A..V., 182 Brieskorn, C. H., 43,255 Brisou, J., 174 Britten, A., 276 Britton, G., 155, 217, 216 Britton, L. N., 9 Broadhurst, M. D., 128 Brodie, H. J., 210 Broekhof, N. L. J. M., 243 Broess, A. I. A., 261 Bronstein, A. C., 3, 6 2 Brooks, C. J. W., 100, 196, 234, 241 Brossas, J., 11 Brotherton, M., 3 15 Brouard, J. P., 111 Brown, A. W., 201 Brown, D. J., 216 Brown, F. C., 38 Brown, H. C., 7, 8 , 31, 37, 59 Brown, K. S., I14 Brown, M. S., 179 Brown, R. G., 178 Brown, R. S., 30 Brown, R. T., 3, 27 Brown, W. V., 5 Bruckmann, P., 173 Brueggemeier, R. W., 3 17 Brun, P., 281 Brunke, E.-J., 277 Bryan, R. F., 122 Brynjolffssen, J., 289 Bryson, T. A,, 27, 93, 186 Buchbauer, G., 38 Buchecker, R., 156, 157, 160, 163 Bucholtz, M. L., 182 Buck, H. M., 131 Bucknall, G. A., 9, 18.5 Buckwater, B. L., 107

Bucourt, R., 317 Buddhsukh, D., 9 5 BudCSinsky, M., 146,237 Budowski, P., 216 Budzikiewicz, H., 171, 234 Bujuktur, G., 289 Buffet, H., 248 Buhrley, L. E., 209 Buinova, E. F., 3 1 , 4 4 Bull, D. L., 3 6 Bull, J. R.,263, 325 Bullivant, M. J., 22 Bu’Lock, J . D., 204 Burack, K., 42 Burfitt, I. R., 107, 113 Burger, B. V., 3 I Burger, U., 4 0 Burgers, P. C., 49 Burgstahler, A. W., 23 1, 232 Burke, S. D., 97 Burman, M. J. F., 254 Burnett, J . H., 155 Burnner, B., 264 Burnstein, S., 4 9 Burreson, B. J., 19, 71, 1Q7, 121, 186 Burrows, E. P., 4 , 2 3 2 Bursey, J. T., 234 Bursey, M. M., 234 Burstein, S., 209, 287 Butler, A. R., 230 Byon, C. Y., 2 0 9 , 2 3 0 Byrd, J . E., 30 Byme, B., 4 1 Byrne, K., 12 Cachia, P., 37 Cahiez, G., 15 Cain, B. F., 123 Cain, P., 323 Caine, D., 95, 100 Cairns, J., 264 Cais, M., 8 9 Calas, R., 2 1 Callender, R. H., 173 Callipolitis, A.. 16 Calo, V., 264 Camain, R., 3 Cambie, R. C., 113, 118, 246 Cameron, A. F., 20, 139 Campbell, J . A., 313 Cane, D. E., 62, 82, 196 Capellini, C., 54 Caple, R., 34 Caponi, R., 305 Capparelli, A. L., 173 C a r d e d , E., 9, 176, 186 Cardillo, G., 6, 1 4 Carey, F. A., 245 Carey, P. R., 172 Carlson, R. M., 3 4 Carlstrom, K., 21 1 Carman, R. M., 8 , 34 Carrascal, I., 118

Carrell, R. W., 286 Carrella, M., 177. Carrier, D. J . R., 205 Carrol, P. J., 6 5 Casares, A., 67, 101 Cashmore, A. R., 123 Casida, J . E., 1 0 Caspi, E., 204, 205, 249 Cassan, J., 3, 111 Castellanos, M. E., 315 Castillo, R., 130, 182 Catalan, C. A. N., 37, 4 3 Cataland, S., 278 Catsoulacos, P., 267, 305, 318 Cattel, L., 130, 135, 182, 204 Cavagnat, R., 173 Cazaux, J.-B., 306 Cella, J. A., 6 Centini, F., 10 Cerda-Olmedo, E., 2 17 Cerfontain, H., 170 Cha, D. Y., 248 Chabudzinski, Z., 4 2 Chakrabarti, P., 143, 152, 53 Chadha, M. S., 208 Chae, Q., 173 Chakravarti, S., 126, 143, 45, 153 Chan, W., 168 Chambaz, E. M., 248 Chambers, L., 167 Chambliss, K. W., 3 15 Chan, K. K., 12 Chaq, T. H., 233 Chandler, D. W., 310 Chandra, G., 34 Chang, S. Y., 121 Chao, S. T., 9 5 Chapelle, J.-P., 23, 27 Chapman, D. J., 217 Chapple, C. L., 27 Chardon-Loriaux, I., 223 Chari, V. M., 25 Charlwood, B. V., 9, 184 Chatterjee, A., 118 Chaturvedi, H. C., 222 Chatzopoulos, M., 41, 4 3 Chaudhry, Z. H., 307 Chavdarian, C. G., 97 Chavez, P. I., 224 Chayet, L., 176 Chee, T. L., 58 Chelli, M., 307 Chen, C. H., 2 3 8 , 2 5 3 Chen, F.-M., 4, 232 Chen, S. L., 233 Chen, S. M. L., 206, 240 Cheng, C. S., 6 5 Cheng, Y. S., 31 Cheo, K. L., 2 10 Cherel, J. M., 174 Chern, C.-I., 6 Chernyshev, V. O., 11 Cheung, H.-C., 5 , 1 6 8 , 2 4 3

Author Index Cheyallier, F., 203 Chichester, C. O., 155, 165, 216, 218 Chiou, W. L., 286 Chojnacki, T., 173, 174 Chong, A. O., 248 Chou, P.-C. C., 114 Chou, S., 132 Choudhury, A. K., 28 Choudhury, M. K., 143, 152, 153 Chow, Y. L., 40 Cbowdhury, M. N. R., 307 Christophersen, C., 70, 107 Chu, J. Y.-R., 292 Chugh, 0. P., 48 Chuihe, J., 231 Chujo, R., 172 Churnan, T., 121 Cirnarusti, C. M., 307 Cirnino, G., 57 Cisneros, C., 108 Ciuffarin, E., 4 Clapp, L. B., 34 Clardy, J., 18, 58, 97, 124 Clardy, J. C., 19 Clark, R. D., 35,97 Clark, S. J., 3 12 Claude-Lafontaine, A,, 111 Clayton, R. B., 204 Cleere, J. S., 224 Clernans, G. B., 126 Cleve, G., 297 Clifford, K. H., 203 Clinkenbeard, K. D., 177 Closs, L. E., 4 Clouet, F., 11 Clower, M. G., 62 Clowes, A. W., 178 Coates, R. M., 125, 181 Cocker, W., 12,45 Cohen, B. I., 211 Cohen, G. M., 97 Cohen, K. F., 132 Cohen, Z., 294 Cole, J. R., 122 Collins, D. J., 255 Collins, D. W., 173 Collrnan, J. P., 7 Colvin, J. R., 150 Colwell, W. T., 8 Cornan, R. E., 164 Cornissarenko, N. F., 23 Cornmerqon, A., 14 Condom, R., 312 Conia, J. M., 8, 255 Connin, R. V., M Connell, C. M., 203 Connolly, G. E., 9 Conradi, R. A,, 125, 181 Contreras, M. D. C., 9, 186 Cook, A. H., 11 Cook, I. F., 118, 207 Cookingharn, R. E., 173

333 Cookson, R. C., 10,55,59, 169 Coolbaugh, R. C., 200,201 Cooley, G., 313 Cooper, R. D. G., 164 Corbella, A., 54 Corbett, R. D., 58, 153, 154 Corcoran, R. J., 279, 281 Cordell, G. A., 52, 187 Corey, E. J., 4, 6, 8, 30, 61, 131, 181,235,240,244,262 Cori, O., 176 Cornelis, A., 23 Corsano, S., 135 Corsi, B., 305 Coscia, C. J., 5, 186, 219 Cote, P., 199 Couch, M. W., 315 Counsell, R. E., 317 Covey, D. F., 38 Cowen, A. E., 222 Cowherd, C. M., 83 Cox, P. J., 243 Cradwick, P. D., 243 Cragg, G. M., 104 Craig, J. C., 117 Crastes de Paulet, A., 182 Crawford, M., 149 Craven, B. M., 287 Crews, P., 19 Crirnrnin, M. J., 11 Crispin, D. J., 320 Croft, J. A., 133 Crornbie, L., 20, 48, 49, 90, 128,229 Croteau, R., 183 Crouch, R. K., 168, 173 Crouse, J. R., 203 Crowe, D. F., 264 Crowley, K. J., 12 Crozier, A., 119, 201 Cruege, F., 173 Crurnrine, A. L., 14 Cuilleron, C. Y., 310 Cullen, D. L., 97 Cunningharn, I. M., 255 Cutler, R. S., 122 Cuvigny, T., 15, 17, 30 Daemen, F. J. M., 173 Dahlen, B., 287 Dahrn, K. H., 54 Dahrnen, J., 51 Daley, J. D., 242 Dalle, J. P., 47 Daloze, D., 8 1 Dalzell, H. C., 50 Darnasco, M. C., 300 Darnodaran, N. P., 13, 76 d’Angelo, J., 21, 26 Danieli, B., 40, 134 Danielsson, H., 212 Daniewski, A. R., 326 Daniewski, W., 81 Daniewski, W. M., 173

Danishefsky, S., 97, 302, 323 Danks, L. J., 246 Darby, N., 37 DaRe, P., 318 Darias, J., 69, 198 Das, B. C., 138 Datta, S., 7, 258 Dawson, J. B., 95 Dauben, W. G., 34, 128,269 Dauphin, G., 37 Dauter, Z., 81 Davies, B. H., 155, 158, 215, 216 Davies, J. E. D., 234 Davis, B. R., 260 Davis, D. L., 170 Davis, J. B., 17, 164 Davis, R. A,, 176, 222 Davis, R. E., 18 Dawe, E. A., 172 Dawson, R. M., 200 Day, M. J., 269,300 Day, R. A., 17 Dayal, B., 290 De, A. U., 42 Dean, P. D. G., 182 Debacq, J. J., 174 Debal, E., 17 Decamp, W. H., 121 Decouzon, M., 33 Defaye, G., 248 de Freitas Leitao Filho, H., 108 Degenhardt, C. R., 235 DeGraw, J. I., 8 de Haan, J. W., 131 Dehennin, L., 287 Dehrnlow, E. V., 250 Dehn, R. L., 8 Dekkers, H. P. J. M., 4 de Klerk, G. J. M., 201 de la Guardia, M. D., 217 de la Mare, P. B. D., 245 Dellacherie, E., 222 de Luca, C., 24 DeLuca, H. F., 208, 293, 296 de Lue, N. R., 8 del Valle, O., 315 de Mayo, P., 40, 47 Dernole, C., 37, 121 Demole, E., 37, 121 de Nicola, A. F., 209 Denis, F. A., 174 Dennis, D. T., 200 de P. Carnpello, J., 108, 113, 149 de P. Teresa, J., 32,42,43 De Oliveira, A. B., 96 De Oliveira, G. G., 96 Derkach, A. I . , 23 de Ruggieri, P., 307 De Rosa, M., 207 Descomps, B., 182 Descotes, G., 32 Deshayes, H., 286

Author Index Deshmane, S. S., 238 Deshits, G. V., 44 Desmukh, S. K., 119 De Silva, J. A. F., 171 DeStefano, S., 57 De Titta, G. T., 287 Detraz, P., 38 Dev,S., 13, 30, 76, 121, 176 Devaprabhakara, D., 82 Deves, R., 176 Devreux, M., 121 de Waard, E. R., 10 Dewar, M. J. S., 287 Dhar, M. M., 108 Diakur, J., 270 Dialameh, G. H., 174 Diaz, A., 69, 198 Diaz, E., 83 Di Blasio, B., 71 Dietrich, C. O., 8 Dietrich-Buchecker, C., 271 Dietrych-Szostak, D., 214 Dietschy, J. M., 177, 203 Dijkstra, G., 49 Dike, S. Y., 48 Dillon, J., 233 Dimitropoulos, K., 3 18 Dimitrov, D. N., 25 Dinizo, S. E., 270 Djarrnati, Z., 107, 121, 231 Djerassi, C., 81, 229, 230, 233, 234, 269,289 Dodd, J. R., 244 Dodge, P., 50 Do Khac Manh, D., 110 Dolby, L. J., 284 Dollery, C. T., 50 Dominguez, B., 103 Dominguez, X. A., 108, 114 Donkin, P., 217 Donnahey, P. L., 174 Doonan, H. J., 9, 185 Doonan, S., 9, 185 Dopper, J. H., 4 Dorn, F., 73, 76, 187 Dos Santos Filho, D., 114 Douglas, G. H., 320 Doukas, A., 173 D’Oultremont, P. A., 174 Drake, A. F., 143, 231 Dren, A., 50 Dreyer, D. L., 108 Drok, Z. Z . , 282 Duax, W. L., 228, 229, 245, 327 DuBois, G. E., 320 Dukhovlinova, L. I., 35 Dulova, V. G., 17 Duncan, G. R., 244 Duncanson, F. D., 139 Dunnigan, D., 50 Dunogueks, J., 21 Duprey, R. J. H., 9 Durgeat, M., 11 1

Durley, R. C., 120, 201 Durodola, J. I., 117 Dutcher, J. S., 147 Dutky, S. R., 212 Dutta, P. C., 126 Dutta, S., 142 Dwivedy, A. K., 205 D’yakonova, R. R., 44 Dyborg, E., 21 1 Dynak, J., 302 Dyrszka, H., 202 Dzhemilev, U. M., 12, 13 Eade, R. A., 146 Eakin, M. A., 104 Eberhardt, U., 297 Ebrey, T., 173 Ebrey, T. G., 168, 173 Eck, C. R.,37 Eder, U., 320, 322 Edlund, U., 230 Edmond, J., 179 Edmonds, A. C. F., 272 Edmonds, C. G., 234 Edwards, C. R. W., 310 Edwards, 0 . E., 136, 276 Edwards, P. A,, 177, 178 Eggert, H., 81, 229, 230 Ehrenberg, B., 4 Eidem, A., 163 Eignerova, L., 241 Eilati, S. K., 216 Eisenbraun, E. J., 26 Eisenstein, O., 258 Ekong, D. E. U., 138, 139 Ekundayo, O., 9, 184 Elden, T. C., 206 Eletti-Bianchi, G., 10 El-Feraly, F. S., 49, 50, 117 Ellames, G., 119 Elliott, D. R., 254 Elliott, M., 10 Elliott, W. H., 212 Ellis, J. E., 147 Ellis, L. C., 209 Ellison, R. A., 67 Ellison, R. H., 104 El-Emary, A. A., 117 El’yanov, B. S., 252 Eman, A., 34 Eneroth, P., 212 Engel, Ch. R., 307 Engel, L. L., 210 Engelhardt, H., 287 Enger, A., 237 Enggist, P., 37 Englert, G., 171 English, P. DJ 202 Enomoto, S., 19 Ensley, H. E., 4, 30 Enzell, C. R., 107, 108, 121 Enzmann, F., 9 Epe, B., 140 Epiotis, N. D., 237

Epstein, W., 21, 185 Epstein, W. W., 20, 185 Erickson, K. L., 54, 69 Erker, G., 8, 268 Erm, A. Y., 11, 12 Erman, M. B., 17 Erman, M. G., 245 Ermer, O., 228 Ernster, L., 2 11 Eschenmoser, W., 161, 167 Escher, S., 320 Esposito, P., 24 Etheridge, S. J., 97 Etman-Gervais, C., 174 Eugster, C. H., 113, 117, 157, 161, 167 Evans, A. J., 74 Evans, D. A,, 9, 174, 262 Evans, F. J., 123 Evans, R., 58,67, 193, 194 Evans, S. M., 42 Evstatieva, L. N., 25 Exley, D., 3 12 Eyley, S. C., 291, 295 Eyssen, H., 318 Ezimora, G. C., 250 FajkoS, J., 251, 253 Fallis, A. G., 43, 65 Fang, J. M., 3 1 Fang, T. Y., 214 Fascio, M., 114 Fatiadi, A. J., 5, 241 Fattorusso, E., 71, 107, 123, 223 Faulkner, J. D., 17, 18, 19, 20, 58,69, 124 Faust, J. R., 179 Favier, J. S., 261 Fayos, J., 18, 118 Fazio, M., 307 Fears, R., 203 Fedorov, P. I., 32 Fedorova, 0. I., 256 Fedorowski, T., 202 Feliziani, F., 249 Fenical, W., 54, 69, 124, 198 Ferguson, G., 20, 28, 119 Ferrara, G., 219 Ferrero, L., 33 Ferri, S., 318 Ferro, M. P., 167 Fessler, D. C., 104 Fetizon, M., 109, 110, 132 Fetterman, P. S., 50 Feutrill, 0. I., 128 Fiasson, J.-L., 158 Ficini, J., 21, 26, 34 Fido, P. E., 31 Fiecchi, A., 254 Finer, J., 19, 58, 124 Finke, R. G., 7 Finner, E., 25 Fisher, J., 222

335

Author Index Fisher, M. M., 2 11 Fischer, N. H., 84 Fischli, A., 161, 167 Fitzell, D. L., 221 Flamm, B. L., 97 Fleming, I., 283 Fleming, M. P., 24 1 Flippen, J., 232 Floor, J., 325 Floyd, D. M., 260 Fogelman, A. M., 178, 179 Fonseca, S. F., 113 Forbes, C. P., 241 Ford, M. E., 260 Forest, M., 3 10 Forrester, J., 77 Forsen, K., 223 Forster, H. J., 150 Fortunato, J. M., 7 Foster, E. L., 308 Foucher, J. P., 28 Fouret, R., 29 Fourneron, J. D., 69, 198 Fournier, C., 36 Fraga, B. M., 108, 119, 135 Franck-Neumann, M., 27 1 Francis, M. J., 111 Francisco, C. G., 107, 109, 266 Franco, J. M., 29 Fransen, M. R., 173 Franzmair, R., 305 Fraser, A. D., 312 Friiter, G., 21 Frei, B., 36 Friedman, N., 281 Freire, R., 107, 109, 266 Fringuelli, F., 44 Froyen, P., 15 Fryberg, M., 207 Frydman, V. M., 120,201 Fu, W. Y., 283 Fiirst, A,, 267, 322 Fugate, R. D., 173 Fuji, K., 107 Fujihara, Y., 43 Fujimori, T., 121, 158 Fujimoto, K., 10 Fujimoto, Y., 87, 206, 242, 257 Fujisawa, T., 24 Fujita, E., 107, 118, 119 Fujita, M., 173 Fujita, S.-I., 9 Fujita, Y., 9 Fukazawa, S., 9 Fukui, K., 126 Fukumoto, K., 327 Fukuzumi, T., 121 Fullerton, D. S., 253 Funamizu, M., 97 Furuhata, K., 232 Furukawa, J., 80 Furukawa, N., 4 Furusaki, A., 78

Furuya, K., 312 Furuya, T., 208 Gabinskaya, K. N., 243 Gabetta, B., 134, 219 Gaffney, J . S., 6 Gailyunas, I., 31 Galasko, G., 172 Galbraith, M:N., 114, 212 Gal’chenko, G. L., 44 GalIi, G., 289 Games, D. E., 171 Gammill, R. B., 93 Ganem, B., 7,47, 241 Ganguly, A. K., 246 Ganguly, M., 210 Ganina, I. V., 298 Garabedian, M., 296 Garanti, L., 23 Garber, E. D., 217 Garbers,C. F., 15, 21, 31, 61 Garcia-Blanco, S., 29 Garcia-Peregrin, E., 223 Gariboldi, P., 54 Garland, R. B., 324 Garnett, J. L., 314 Garver, L., 30 Gasa, S., 121, 128 GaSiC, M,J., 230 Gaskin, P., 117, 120, 201 Gastambide, B., 257 Gaudemer, A., 97 Gaughan, L. C., 10 Gausser, C., 169 Gawley, R. E., 96 Gawrbnski, J. K., 23 1 Gaylor, J. L., 222 Geenevasen, J. A. J., 170 Geissmann, T. A., 24 Genard, P., 227 George, R., 178 Georgian, V., 234 Geraghty, M. B., 73 Geribaldi, S., 33 Ghatak, U. R., 126 Ghilezau, I., 265 Ghisalberti, E. L., 65 Ghosal, P. K., 126 Ghosh, A., 153 Ghosh, S., 126 Ghosh, V. J., 173 Ghosh-Dastidar, P. P., 7, 142, 258 Ghosh-Datta, S., 258 Ghozland, F., 34 Giacobbe, T. J., 104 Gianfermi, A., 41 Giarrusso, F. F., 307 Gibbons, G. F., 203, 204 Gibian, H., 320 Gifkins, K. B., 124 Gilbert, B., 83, 114, 138 Gilbert, L. I., 200, 212 Gilchrist, B. M., 217

Giles, H. G., 40 Gill, S. S., 200 Gillette, J. R., 21 1 Gilmore, C. J., 122, 125 Ginanneschi, M., 307 Ginsburg, D., 89 Girault, Y., 33 Glass, R. W., 155 Gleason, W. B., 235 Gleizes, M., 9, 176 Glotter, E., 228, 239,277, 288 Go, K. T., 29 Goddard, R., 125 Godfrey, J. E., 114 Goh, E. H., 177 Gokhale, P. D., 13, 76 Goldfarb, S., 202 Goldsmith, D. J . , 90 Goldstein, J. L., 179 Golgolab, H., 269 Golob, N. F., 22 Golubovskaya, L. E., 317, 318 Gomez, J., 285 Gonzales, H., 114 Gonziilez, A. G., 54, 60, 69, 70, 97, 103, 107, 108, 109, 119, 135, 198,266 GonzBlez, A. S., 43 GonzBlez, P., 135 Goodfellow, D., 160 Goodfellow, R.J., 20 Goodman, W., 2 12 Goodwin, C. D., 222 Goodwin, R., 280 Goodwin, T. E., 113 Goodwin, T. W., 3, 155, 202, 205, 207, 212, 213, 216, 217,221 Goraev, M. I., 306 Gordon, K. M., 5 Gordon, M. H., 254 Gore, J., 236 Gorog, S., 278 Goryaev, M. I., 42 Goto, G., 317 Gottlieb, H. E., 44 Gottlieb, 0. R., 96 Govindjee, R., 168 Grabowich, P., 307 Graf, W., 316 Graham, S. L., 100 Graham, W. D., 40 Grandi, R., 7, 87, 268 Grandolfo, M. C., 157 Granger, P., 159 Granger, R., 10 Granqvist, L., 12 Grant, M., 310 Grant, P. K., 111 Granzow, C., 203 Gras, J.-L., 8, 82, 244 Gray, J. R., 71 Grayson, D. H., 45 Graves, J. M. H., 320

Author Index

336 Gravestock, M. B., 109 Green, J., 202 Green, M. J., 261 Green, S. E., 289 Greenberg, A. D., 173 Greijdanus, B., 4 Greiner, A. C., 151 Greiner, G., 255 Grenot, C., 310 Grenz, M., 35 Greico, P. A., 62, 90, 97, 105 Griffin, A. C., 287 Griffi.., J. F., 245 Grimm, K. G., 262 Grinenko, G. S., 256, 298 Grishina, G. V., 33 Grison, C., 43 Gritsina, G. I., 298 Groman, E. V., 210 Gross, P. M., 229 Grumbach, K. H., 220 Grund, N., 9 Grunwald, C., 12 1 Grunwell, J. F., 250 Grutzner, J. B., 8 Guajardo, E., 107 GuCnard, D., 284 Giinzberg, G., 277 Guerrero, C., 83 Guerriero, A., 57 Guiso, M., 24 Guiterrez, M., 114 Gunatilaka, A. A. L., 253 Gupta, D., 309. 315 Gupta, K. C., 48 Gupta, L. R., 307 Gurria, G. M., 33, 238 Gusarova, T. I., 298 Gustafsson, J. A,, 209, 211, 212 Gut, M., 209, 230, 289 Guzewska, M., 326 Hachey, D. L., 222 Haffer, G., 320, 322 Hagaman, E. W., 44 Hager, A., 156 Hager, L. P., 198 Hagerman, A., 223 Hagitani, A., 263 Hagiwara, H., 73 Haigh, W. G., 150 Hajek, M., 43 Hajos, Z. G., 244 Hall, E. A. H., 164 Hall, 1. H., 302 Hall, S. S., 59 Hallas, R., 50 Hallcher, R. C., 34 Halsall, T. G., 139 Ham, P. J., 229 Hamanaka, N., 121, 128 Hamilton, R., 201 Hammerum, S., 233, 234

Hammock, B. D., 199,200 Hampel, A., 8 1 Hampp, R., 179 Hana, G. W., 38 Hanack, M., 37 Handa, G., 146 Handjieva, N. V., 25 Handrick, G. R., 50 Hands, D., 289 Hannaway, C., 20 Hanson, J. R., 58, 67, 76, 82, 105, 107, 109, 119, 176, 192, 193, 194, 195,230,276 Hanson, R. F., 2 11, 222 Hanson, S. W., 149 Harada, J., 125, 181 Harada, N., 233 Harashima, K., 157 Harbone, J. B., 111 Harigaya, Y., 115 Harnik, M., 302 Harper, S. H., 3 Harpootlian, H., 313 Harrison, C. R., 248 Harrison, M. A., 199 Hart, N. K., 142 Hartley, D., 320 Hartshorn, M. P., 115 Haruyama, T., 3 16 Harvey, D. J., 49 Harvey, W. E., 120 Hasegawa, T., 9 Hashimoto, K., 11, 23 Hashimoto, S., 17 Haslanger, M. F., 240 Haslinger, E., 43 Hassan, M., 9 Hassner, A., 5, 267 Hata, G., 11, 12 Hatam, L., 178 Hatanaka, A., 9, 186 Hatton, I. K., 120, 125 Havinga, E., 281 Hawes, G. B., 125 Hawkins, D. W., 134, 272 Haxo, F. T., 157 Hayakawa, Y., 38 Hayashi, I., 303 Hayashi, K., 47 Hayashi, S., 75, 112 Hayashi, T., 9 Hayman, E. P., 216 Haynes, R. K., 7,252 Hayward, R. C., 118, 246 Heald, J . K., 120, 202 Heathcock, C. H., 35, 97, 147 Heather, J. B., 169,270 Heble, M. R., 208 Hecker, E., 122, 123 Hedgecock, H. C., 8 Heerma. W., 49 Hefendehl, F. W., 224 Heimberg, M., 177 Heitz, S., 111

Heller, R. A,, 177 Hemada, A,, 243 Hemmer, E., 43 Hemming, F. W., 174 Hendrickson, J. B., 38 Hendriks, H., 9,223 Henmi, Z., 3 12 Hensch, M., 113 Hensens, 0. D., 145 Henson, R. D., 36 Herald, C. L., 124 Herber, R., 159 Herkstroeter, W. G., 172 Herling, J., 302 Hernindez, M. G., 108, 119 Hernandez, R., 107, 109, 266 Herscovics, A., 173 Herz, J. E., 290, 313, 314 Herz, W., 83, 84, 85, 104, 117 Hesse, R. H., 246, 269, 281, 300 Hethelyi, E., 10 Hetzel, K. R., 3 15 Hewett, C. L., 264 Hewett, W. A., 42 Higginbotham, J. D., 111 Higgs, M. D., 9 Highet, R. L., 108 Hignite, C., 202 Higo, A., 85 Higuchi, R., 144, 146 Hikino, H., 82, 99, 140, 197, 198,206,2 13 Hilgard, S., 146 Hilscher, J. C., 256 Hiltunen, R., 223, 224 Himmelle, W., 43 Hindley, N. C., 17 Hindley, R. M.,202 Hiraga, K., 120, 317 Hirai, H., 22 Hirai, M., 23 Hirano, J., 49 Hirao, N., 3 Hirata, Y., 8, 131, 132 Hiratuka, K., 179 Hirayanagi, S., 11 Hiroi, K., 64, 273 Hiroi, M., 12 Hirose, Y., 19, 197 Hirota, H., 102 Hirotani, M., 208 Hirotsu, K., 139 Hirschmann, H., 238 Hitchcock, P. B., 58 Hiyama, T., 61 Hlubucek, J. R., 108, 121 Ho, P. T., 128 Hobbs, D. T., 50, 222 Hobbs, P. D.. 22 Hobrock, B. W., 234 Hodge, P., 234, 248 Hodgson, G. L., 62 Hogberg, H.-E., 48

337

Author Index Holzl, J., 25 Hoffmann, J. A., 212 Hoffman, J. M., 174 Hoffmann, W., 35,43 Hofmann, A. F., 222, 313 Hofmann, L. M., 250, 317 Hofrneister, H., 297 Hogg, J. W., 3, 62 HolasovA, M., 171 Holick, M. F., 296 Holman, R. J., 33 Holmes, A. W., 115 Holmstead, R. L., 10 Holtz, J., 221 Holy, N., 64 Honda, T., 144 Honig, B., 168, 173 Honma, K., 243 Hoornaert, G., 127 HoiejSi, M., 146 Horgan, R., 120, 202 Hori, H., 119 Hori, T., 8 Horiki, K., 276 Horiuchi, C. A., 263 Horn, D. H. S., 212 Hornig, D., 21 1 Horton, B. J., 202 Hoshita, T., 290 Hosoda, H., 243,249, 313 Hosoyama, K., 242 Hossain, A. M. M., 242 Hotchandani, S., 173 Houk, K. N., 5,285 Houminer, Y., 239, 271 House, H. O., 127 Howard, B. M., 54, 69, 124, 198 Howard, J. A. K., 125 Hoyer, G. A., 297 Hoz, T., 241 Hrycay, E. G., 2 11 Hsieh, D. P. H., 221 Hsieh, S. H., 65 Hsiung, H. M., 204 HSU,A. C.-T., 292,293 Hsu, S. S., 31 Hsu, W. J., 216 Huang, C. L., 303 Huang, E.-S., 302 Huang, P.-K. C., 124 Huang, T.-J., 34 Huang, W. Y., 202 Huber, C. P., 94, 197 Hubert, P., 222 Huckel, W., 39 Huet, J., 258 Huffman, J. C., 112 Hug, W., 41 Hughes, G. A., 320 Hughes, J. M., 20 Hughes, P. R., 9, 41, 187 Hui, W.-H., 142, 144, 147, 149, 152

Huisman, H. O., 10 Hull, P., 17 Hullot, P., 30 Hulshof, L. A., 40 Huneck, S., 138 Hung, Ph. D., 107 Hungund, B. L., 205 Husson, A., 28 Husson, H.-P., 28 Hutchins, R.-O., 258 Hutchinson, S. A., 100 Hwang, K., 50 Hylands, P. J., 137 Iacobelli, J. A,, 293 Ibuka, T., 302 Ice, R. D., 3 15 Ichikawa, N., 19 Ichino, T., 253 Ichinose, I., 8, 54 Iernura, S., 17 Iguchi, M., 85 Iida, T., 287 Iitaka, Y., 144 Ikawa, S., 212 Ikeda, G. J., 313 Ikeda, R.,121 Ikeda, S., 46 Ikegami, S., 313 Ikegawa, S., 267 Ikekawa, N., 206, 223, 240, 242,247,257,293,296,316 Ikenishi, Y., 145 Ikeshima, H., 303 Im, K. S., 145, 146 Imai, K., 9, 41 Imaizumi, F., 11 Imaizumi, S., 29 Imakura, Y., 104 Imarnura, K., 29 Imamura, T., 33 Impellizzeri, G., 223 Inada, A., 146 Inagaki, F., 172 Ingelman-Sundberg, M., 21 1 Ingwalson, P. F., 95 Innocenti, S.. 305 Inoue, K., 26 Inoue, S., 30 Inouye, H., 23, 24, 26, 28, 29, 186 Inouye, Y., 4, 46, 101, 169, 172 Ireland, C., 69, 124 Ireland, R.E., 147 Irikawa, H., 131 Irismetov, M. P., 306 Irmscher, K., 319 Irvin, R. L., 26 Isaeva, Z. G., 44 Isenring, H.-P., 73 Ishida, A., 168 Ishige, M., 259 Ishiguro, M., 247, 316

Ishii, K., 67 Ishikawa, H., 46, 327 Ishikawa, M., 294 Isihara, M., 169 Ismailov, A. I., 71 Isola, M., 4 Istomina, Z. I., 240 Itaya, N., 10 Ito, M., 163 Ito, O., 8 Ito, S., 87 Ito, T., 236 Itoh, T., 287 Itoi, K., 10, 15 Itokawa, H., 9 Ivanenko, T. I., 249,3 18 Ivanov, A. V., 287 Ivanov, G. E., 12, 13 Ivie, G. W., 10, 36 Iwamura, J., 3 Iwamura, S., 298 Iwata, T., 268 Izawa, K., 133 Izumi, G., 33 Jabalquinto, A., 176 Jackson, W., 167 Jackson, W. R., 255 Jacquesy, J.-C., 39, 273, 274 Jacquesy, R., 39,237,273,274 Jacquier, R., 306 Jaggy, H., 23 Jain, K. M., 172 Jain, T. C., 85, 97 James, M. J., 202 Jarnmaer, G., 127 Janes, N. F., 9, 10 Janiszowska, W., 221 Jankowski, W., 174 Jansen, P. A. A., 173 Jaszczynski, J. R., 306 Jeanloz, R. W., 173 Jefferies, P. R., 200 Jeffery, J., 209 Jefford, C. W., 40,42 Jeger, O., 110, 170 Jen, J. J., 216 Jenkins, R. W., 222 Jennings, R. C., 54 Jetuah, F. K., 267 Jimknez, L., 83 Jin, H., 213 Johansen, J. E., 160 Johnson, C. R., 4 Johnson, D. B., 222,235 Johnson, E. A., 21 1 Johnson, K. K., 12 Johnson, P., 207, 213 Johnson, R. A., 6 Johnson, €2. L., 296 Johnson, W. S., 130, 320 Johnston, J. C., 17 Johnston, J. O N . , 250 Johnston, K., 287

338 Joland, S. D., 142 Joly, G., 273 Jommi, G., 54 Jones,A. J., 121, 132, 271,272 Jones, Sir, E. R. H., 265 Jones, H. A., 230 Jones, R. B., 200 Joshi, A. P., 13, 76 Joska, J., 253 Joulain, D., 9 Juchau, M. R., 21 1 Judy, K. J., 54 Julia, M., 16, 38, 167 Jung, M. E., 319 Junghans, K., 253 Jurd, L., 48, 170 Jurzysta, M., 214 Juvonen, S., 223,224 Kaal, T., 11 Kabalka, G. W., 5, 8 Kagi, D. A,, 169 Kahn, S., 204 Kaisin, M., 8 1 Kaiser, R., 9, 23 Kajii, K., 152 Kajikawa, A., 3 16 Kajiwara, T., 9, 186 Kajtar-Peredy, M., 135 Kakisawa, H., 46, 101, 169 Kalapurackal, M., 2 10 Kaljurand, M., 12 Kallner, A., 2 11 Kalra, V. K., 178 Kalvoda, J., 228, 25 1, 299 Kalyanaraman, P. S., 84 Kalyani, K., 121 Kamaev, F. G., 71 Kamano, Y., 3 0 3 , 3 0 5 Kamata, S., 270 Kamboj, V. P., 317 Kamernitsky, A. V., 240, 252 Kametani, T., 327 Kamienska, A,, 120 Kamikawa, T., 67 Karninski, J. J., 241 Kamiyama, Y., 11 Kamoshida, A., 54 Kanazawa, A., 207 Kanazawa, R., 128 Kanbegawa, A., 3 12 Kandasamy, D., 258 Kaneko, C., 294,296 Kaneko, H., 121, 158 Kaneiwa, Y., 146 Kang, S. S., 144 Kaniwa, M., 26 Kao, S. T., 65 Kapke, G., 21 1 Kaplanis, J. N., 2 12 Kaposi, P., 10 Karasawa, I., 216 Karimian, K., 8 4 Karindzhovaev, A. K., 71

Author Index Karlsen, S., 15 Kartha, G., 29 Kasai, R., 112, 117, 138 Kasal, A., 237, 241 Kasarna, T., 152 Kasano, M., 35 Kasper, B., 42 Kasprzyk, Z., 214, 221 Kasuga, R., 121, 158 Katagiri, T., 11 Katayama, M., 131 Katayama, T., 165, 218 Katiyar, S. S., 182 Kato, G., 157 Kato, K., 8, 9 7 Kato, M., 261 Kato, T., 8, 54, 128 Kato, Y., 296 Katz, J.-J., 59, 157 Katzenellenbogen, J. A., 14 Kaufmann, H., 25 1 Kawarada, Y., 243, 318 Kawasaki, T., 144, 146 Kawazoe. Y., 41 Kayden, H. J., 178 Kayser, H., 157, 166 Keenan, R. W., 174 Keiderling, T. A., 4 Keinan, E., 7, 294 Keller, R., 212 Kelley, J. A., 6 Kellie, A. E., 313 Kelly, R. C., 248 Kelsey, R. G., 223 Kemp-Jones, A. V., 283 Kendall, J., 234 Kendall, M. C. R., 239 Kenehan, E. F., 6 Kergornard, A., 37 Kern, F., 176, 222 Kerr, V. N., 221 Kessler, B., 202 Kesterke, H., J. 234 Keuss, H. A. C. M., 278 Kevill, D. N., 235 Khakhar, A. Q., 38 Khan, M. N., 234 Khan, N., 159 Khan, P. N., 307 Khan, R., 223 Kharitov, Kh. Sh., 11 1 Khastgir, H. N., 141 Kheifits, L. A., 17, 32 Khong, P. W., 145 Kho-Wiseman, E., 19 Khukhryansky, V. G., 266 Khuong-Huu, F., 136, 259, 288 Khusnutdinov, R. I., 13 Kienzle, F., 164 Kigasawa, K., 268 Kihira, K., 290 Kim, B., 34, 269 Kime, D. E., 298

Kim, J. H., 126 Kim, S.-H., 302 Kimball, H. L., 209 Kimura, M., 2 7 5 , 3 1 1 Kimura, T., 8 3 King, R. W., 48, 158 King, T. J., 4 8 Kingston, D. G. I., 97, 234 Kinoshita, M., 4 Kinsman, L. T., 222 Kint, S., 4 1 Kinuyama, Y., 249 Kirk, D. M., 231, 242, 264, 274,298,299,300 Kirsch, P. P., 285 Kirson, I., 277, 288 Kirtany, J. K., 50 Kise, H., 17 Kitagawa, I., 24, 136, 145, 146, 152 Kitagawa, N., 3 9 Kitagawa, Y., 17 Kitaguchi, T., 123 Kitahara, T., 97, 302 Kitahara, Y., 8, 54, 97, 128 Kitamura, J., 179 Kitamura, S., 10 Kitatani, K., 61 Kiyooka, S.-I., 4 KjBsen, H., 157, 160, 163 Klambt, D., 221 Klein, E., 3, 102 Klein, K. P., 41 Klein, P. D., 211, 222 Kleinig, H., 217 Kleudgen, H. K., 220 Kliger, D. S., 173 Klimashevsky, V. M., 294 Klimek, J., 209 Klinot, J., 146 KlinotovB, E., 142, 149 Klyne, W., 172, 231 Knaak, W. F., 24 Knapp, F. F., jun., 291 Kneen, G., 128 Knight, D. W., 219 Knight, J. O., 24 Knoche, H. W., 205 Knoll, K. H., 112 Knoll, W., 67 Knox, J. R., 118,200 Knox, R. S., 173 Knox, S. D., 272 Kobari, T., 313 Kobayashi, A., 10 Kobayashi, M., 207 Kobayashi, T., 128 Kober, W., 4 1 Kobori, T., 24 Kobrina, N. S., 120 Koch, H., 38 Koch, H. J., 316 Kocbr, M., 81, 248,326 Kodama, M., 87

339

Author Index Koel, M. N., 11 Konsty, W. M. B., 33 Kogarni, K., 47 Kogure, T., 170 Kohda, H., 117 Kohler, B. E., 173 Kohout, L., 25 1 Koizurni, N., 296 Koizurni, T., 303 Kojirna, M., 236, 312 Koker, M. E. S., 149 Kokpol, U., 27, 186 Kole, P., 317 Kologrivova, N. E., 32 Kornatsu, A., 12 Kornatsu, H., 236 Kondo, K., 46, 53 Kondo, N., 138, 146 Kondo, Y., 242 Kone, N., 110 Konitz, A., 81 Kooiman, P., 23, 223 Kopperman, H. L., 34 Koreeda, M., 249 Koritz, S. B., 209 Korolchenko, A. Y., 287 Korte, F., 50 Kosnikova, L. V., 39 Kossanyi, J., 16 Kosugi, H., 22 Kotsonis, F. N., 67 Kotsuki, H., 128, 139 Kozhin, S. A., 32 Kozina, b4. P., 44 Kraatz, U., 50 Krarner, H. F., 49 Kravchenko, L. V., 12 Kreiser, W., 132 Kretchmer, R. A., 104 Krezo, L. M., 39 Krinsky, P., 239, 288 Krishnamurthy, S., 7 Kroon, J., 29 Kropf, A., 171 Kropf, H., 42 Kruczek, M., 174 Krull, I. S., 41, 187 Kruse, C. G., 243 Kubota, T., 25 Kuczynski, H., 32 Kiinstler, K., 23 Kuhl, H., 318 Kuksis, A., 210 Kulig, M. J., 235, 252 Kulkarni, A. B., 6 Kulshreshtha, D. K., 75, 133 Kurnar, A., 82 Kurnar, S. D., 12 Kurnrnerow, F. A., 202 Kundu, N., 310 Kunieda, N., 4 Kunirnatsu, M., 9 Kunz, B., 303 Kuo, T. H., 65

Kuo, Y. K., 25 Kupchan, S. M., 104, 122 Kuramoto, T., 2 1 1, 290 Kurasawa, Y., 254 Kurata, S., 46, 169 Kurijama, K., 136 Kurosawa, E., 67 Kurosawa, T., 320 Kurosawa, Y., 312 Kurth, H.-J., 50 Kusano, G., 117, 135 Kusumi, T., 46, 169 Kutschabsky, L., 120 Kuyama, M., 47 Kyncl, J., 50 Kyong-Hwi Park, 108 Labinger, J. A., 5 Lablache-Cornbier, A., 97, 208 Lack, L., 222, 235 Lacoste, L., 208 Ladd, M. F. C., 134, 272 Lafferty, J., 172 Lahav, M., 281 LajSiC, S., 121 Lakeman, J., 278 Lala, A. K., 6 Lalezari, I., 269 LaLonde, R. T., 26 Lam, H.-Y., 296 Lamarre, C., 42 Lamaty, G., 239 Lambert, J. L., 38 Larnberton, J. A., 131, 142 Larnmertsma, K., 40 Lamparsky, D., 9, 23 Larny, J., 10 Land, E. J., 172, 173 Lander, N., 3 4 , 5 0 Lane, C. F., 5 Lane, L., 173 Lane, M. D., 177 Lang, S., 230 Langenheim, J. H., 9, 87, 223, 224 Langworthy, T. A., 151 Lantos, C. P., 300 Laonigro, G., 237,244 Larcheveque, M., 15, 17, 30 Largueux, B., 212 Larruga, F., 108, 119 Larsson, A., 209 Lauer, R. F., 5, 90 Lauko, A., 278 Laurent, H., 297 Laval-Martin, D., 216 Lawler, R. G., 34 Lawrence, B. M., 3 , 6 2 Lawson, J. A., 8 Leander, K., 51 Leblanc, R. M., 173 LeBorgne, J. F., 15 Leclerc, G., 7, 252 Lederman, Y., 302

Ledouble, G., 262 Lee, D.-Y., 327 Lee, E., 291 Lee, K.-H., 83, 104, 302 Lee, M. H., 260 Lee, Q. P., 21 1 Lee, S.-C., 125, 181 Lee, S. F., 128 Lee, S.-L., 28 Lee, T.-C., 155, 165, 216 Lee, T. H., 216 Lee, W. L., 217 Lee, Y.-H., 50 Leets, K. B., 11 Lefebvre, Y., 257 Lefingwell, J. C., 31 Leftwick, A. P., 164 Lehrnann, H., 169,297 Leiserowitz, L., 281 LeQuesne, P. W., 124 Letourneux, Y., 289 Leuenberger, U., 158, 165, 166 Le Van Ngo, 113 Lever, M., 286 Lever, 0. W., jun., 259 Levin, R. H., 62 Levery, S. B., 124 Levina, I. S., 252 Levine, S. D., 307 Levsen, K., 3 Levy, D. A., 125 Levy, G. C., 230 Lewbart, M. L., 263 Lewis, A., 173 Lewis, A. J., 244 Lewis, K. G., 145 Ley, D. A., 181 Li, M.-M., 142, 144, 147, 149, 152 Li, M. P., 233 Liaaen-Jensen, 156, 157, 158, 160, 163 Liberalli, C. T. M., 96 Lichtenthaler, H. K., 216, 220 Liebrnan, P. A., 173 LiCbert, L., 287 Lightbourn, J. R., 293 Lightner, D. A,, 231 Likerova, A. A., 42 Lin, H. K., 205 Lin, H.-N., 84 Lin, T. D., 138 Lin, Y. T., 65 Lincoln, D. E,, 9, 223 Lindduer, R. F., 85 Lindgren, J.-A,, 51 Lindley, P. F., 282 Lindquist, J., 287 Liotta, D. C., 13 L id , E., 142 Lischewski, M., 120 Lisitsa, L. I., 240, 305 Liu, G. C. K., 203

Author Index

340 Liu, I. Y., 173 Liu, R. S. H., 168, 170 Liu, Y.-T.,291 Lockley, W. J. S., 205 Loeber, D. E., 159 Loewenthal, H. J. E., 127 Logan, R. T., 264 Loika, Zh. F., 31 Lomas, M. M., 23 Lombardi, P., 55, 169 tompa-Krzymien, L., 210 Long, D. J., 183 Long, W. E., 283 Longobardi, M., 34 Loomis, W. D., 183 Lopez, L., 264 Lorenc, L., 228 Lorenz, I., 37 Lorenzi, R., 120, 202 Lothrop, D. A., 178 Low, K. S., 11 1 Lugtenburg. J., 173, 281 Luis, J. G., 108, 119 Lukefahr, M. J., 71 Luknitsky, F. I., 282 Lund, E. D., 5 Lundberg, R. D., 236, 245 Lundin, R., 170 Lundstrom, K., 287 Lusinchi, X., 271 Luyten, W. C. M. M., 173 Lyle, M. A., 51 Lyons, C. W., 138 Mabry, T. J., 71, 85, 103, 224 Mabuchi, H., 317 McAlees, A. J., 118, 119 McCallum, N. K., 49 McCandlish, L. E., 153 McCloskey, J. E., 85, 97 McCombie, S. W., 242 McCormick, 1. R., 123 McCrindle, R., 11 1, 118, 119 McDermott, J. X., 253 Macdonald, T. L., 260 McEnrose, F. J., 59 McFarlane, J., 219 McGarry, G., 264 McGee, L. R., 20 McGhie, J. F., 134, 267, 272 McGrath, J. P., 6 McGurk, D. J., 26 Machida, Y., 6, 235 McInnes, A. C., 222 Mack, H., 123 McLaughlin, P., 203 McLean, S., 26 McLoughlin, B. J., 320 McMillan, C., 224 MacMillan, J., 117, 120, 125, 20 1 MacMillan, J. G., 147 McMorris, T. C., 3 14 McMurry, J. E., 241

McNamara, D. J., 203 McPhail, A. T., 89, 104, 229. 26 1 McQuillin, F. J., 13, 14 MacSweeney, D. F., 6 2 Madrigal, R. V., 108 Madyastha, K. M., 186, 219 Maeda, M., 236 Maeda, S., 9 7 Maestas, P. D., 5 Magalhaes, M. T., 96 Maggiora, G . M., 173 Magide, A. A., 178 Magno, S., 71, 107, 123, 223 Magnus, P. D., 7, 22, 95, 252 Mahajan, J. R., 114 Mahalanabis, K. K., 64 Mahendran, M., 19 Mahley, R. W., 178 Mahmoud, M. M., 282 Maignan, C., 30 Maione, A. M., 270 Maiti, B., 3 6 Malanina, G. G., 267 Maldonado, L. A,, 67, 101 Malek, J., 4 3 Malinow, M. R., 203 Mallaby, R., 169 Mallams, A. K., 172 Mallik, B., 172 Malmberg, C. E., 243 Maloq, R., 239 Manchand, P. S., 109, 114, 124, 167 Mandal, K., 172 Mandelbaum, A., 89 Mandell, L., 17 Mangiafico, S., 223 Mangoni, L., 237, 244, 245 Mani, J. C., 4 7 Mankowski, T., 173, 174 Man-moon Li, 122 Mann, J., 9, 184 Manning, R. A., 126 Mansuy, D., 38 Manukov, E. N., 3 5 Mappus, E., 310 Marchesini, A., 7, 87, 268 Marcus, M. A., 173 Marekov, N. L., 25, 27 Margolis, S., 222 Marin, M. G., 37 Marino, J. P., 260 Marinovic, N., 97 Markovetz, A. J., 9 Markowicz, S. W., 4 3 Markwell, R. E., 281 Maroni, P., 34 Maroni-Barnaud, Y., 34, 258 Marquez, C., 118 Marrs, B., 217 Marsaioli, A. J., 108, 149 Marsella, P. A., 224 Marsh, L. L., 20

Marsh, W. C., 28, 119 Marshall, J. A., 97, 104 Marshall, J. G., 208 Marsili, A., 278 Marson, S. A,, 125 Martelli, P., 305 Marten, T., 67, 82, 192, 193 Martens, H., 127 Martin, B., 50, 51 Martin, J. D., 54, 60, 69, 70, 198 Martin, K. O., 210 Martin, S.S., 87, 224 Martin, V. I., 310 Martinelli, E. M., 134 Martinez, A. G., 3 7 Martinez-Carrera, S., 29 Marty, R. A., 40 Marumo, S., 9, 131 Masada, Y., 23 Masaki, Y., 97 Masamune, S., 270 Masamune, T., 286 Maslen, E. N., 122, 124 Mason, A. N., 319 Mason, J. I., 211 Massanet, G. M., 103 Massey, E. H., 4 Massinova, 0. V., 243 Masuda, Y., 33 Mateescu, G. D., 172 Mathe, D., 203 Mathew, C. P., 30 Mathies, R., 173 Matlock, P. L., 7 Matsubara, Y., 3 5 , 4 3 Matsuguchi, H., 218 Matsui, M., 6, 22, 127, 249 Matsuki, Y., 8 7 Matsumoto, M., 46,53 Matsumoto, T., 78, 79, 121, 126, 128,287 Matsunaga, S., 128 Matsuo, A,, 75, 112 Matsuo, T., 10, 22 Matsushita, H., 121 Matthews, R. S., 26 Mattingly, T. W., 222 Mattox, V. R., 244 Matz, M. J., 122 Maudinas, B., 159, 172, 182 Maujean, A., 231 Maume, B. F., 301 Maumy, M., 252 Maury, G., 306 Maxa, E., 43 Maxwell, J. R., 171 Mayberry, W. R., 151 Mayer, H., 161, 167 Mayer, H. J., 55, 169 Mayes, D. M., 310 Maynez, S. R., 8, 268 Mayol, L., 71, 123 Mazur, Y.,7 , 2 9 3 , 2 9 4

Author Index Meakins, G. D., 265 Mechoulam, R., 34,49, 50 Meehan, T. D., 186 Mehta, G., 94, 102 Meier, W., 322 Meisters, A., 249 Melihn, M. A., 60 Melitskii, L. R., 7 1 Meller, M. E., 282 Melnikova, V. I., 3 18 Melvin, L. S., jun., 240 Menard, R. H., 2 11 Mendelsohn, R., 172 Menezes, F. A., 149 Menger, E. L., 173 Menzies, I. D., 7, 252 Mercer, E. I., 205 Merchant, J. R., 48 Merep, D. J., 39, 4 3 Meresak, W. A,, 327 Merlini, L., 49, 50 Metcalf, B. W., 320 Metge, C., 33 Meyer, W. L., 126 Meyers, A. I., 5, 243, 260 Mez, H.-C., 228 Michaelis, G., 244 Michalski, W., 221 Michel, C., 124 Middleditch, B. S., 209 Middleton, E. J., 212 Midgley, J. M., 289 Miersch, O., 169 Mihailovic, M. Lj., 228 Miki, T., 317. Mikolajczak, K. L., 108 Milani, A., 203 Milborrow, B. V., 58, 169, 199 Miles, D. H., 27, 186 Miljkovic, M., 315 Miller, C. H., 105 Miller, J. A., 10 Miller, L., 207 Miller, R. W., 89, 229, 261 Milliet, A., 259, 271 Minailova, 0. N., 3 18 Minale, L., 57, 124, 207 Minato, H., 146 Mincione, E., 249 Minder, R. E., 164 Miners, J. O., 265 Mirrington, R. N., 128 Mishaw, C. O., 203 Misra, D. R., 141 Misra, S. C., 34, 134, 272 Misra, T. N., 172 Missakian, M. G., 121 Misumi, S., 78 Mitchell, J. R., 21 1 Mitra, G., 242 Mitropoulos, K. A., 178, 203, 204,211 Mitschelen, J. J., 177 Mitsuhashi, H., 27, 117, 207

34 1 Mittal, R. S. D., 169, 270 Miura, K., 33 Miura, T., 275 Miyachi, Y., 312 Miyahara, M., 8 Miyase, T., 82, 197 Miyashita, M., 73, 9 0 Miyazawa, T., 172 Miyoshi, Y., 100, 172 Miziorko, H. M., 177 Mizoguchi, T., 44 Mizuchi, A,, 312 Mizutani, T., 10 Mochida, I., 11 Modawi, B. M., 9 Mody, N. V., 36, 121 Moinova, K., 224 Moir, M., 7 7 Mole, M. L., 117 Mole, T., 249 Mornpon, B., 8 9 Mon, T. R., 9 Monder, C., 210, 234,268 Mondon, A., 140 Moneger, R., 216 Money, T., 3 7 , 6 2 Monselise, S. P., 216 Monteiro, M. B., 114 Montero, J.-L., 50 Monterosso, V., 5 Montheard, J.-P., 41,43 Montoro, G., 307 Moolenaar, M. J., 10 Moore, B. P., 5, 128 Moore, P. H., jun., 312 Moore, R. E., 19, 186 Moore, T. C., 200 Morales, A., 103 Moran, J. J., 171 Morand, P., 210 Morat, C., 29 Morgan, B., 202, 203 Morgan, E. D., 243,287, 289 Morgan, J., 3 8 Morgan, K. D., 168, 256 Moreau, S., 9 7 Morell, J., 285 Morelli, I., 278 Mori, F., 10, 15 Mori, H., 100, 253 Mori, K., 11, 15, 22, 41, 127, 270 Moriarty, R. M., 232 Moriguchi, M., 29 Morikawa, A., 6 Morikawa, K., 197 Morin, L., 40 Morisaki, M., 206, 223, 240, 247,257,293,296,316 Moriya, T., 12 Moriyama, M., 4 Moriyama, Y., 141 Morizur, J. P., 16 Morris, D. G., 38

Morrow, C. J., 5 Mors, W. B., 114 Mortikova, E. I., 252 Morton, J. B., 271 Mosbach, E. H., 202,211,222, 290 Mose, W. P., 172 Moss,G.P., 155, 159, 160, 164 Moss, R. A., 251 Mousseron-Canet, M., 4 7 Moustafa, A. M., 209 Mrozinska, D., 32 Muller, D. M., 37 Muller, N., 35 Mukaiyama, T., 6, 46, 168 Mukhamedova, R. A., 71 Mukherjee, D., 126, 307 Mukherjee, P. R., 7, 142, 258 Mukhina, M. V., 248 Mukitanova, T. R., 42 Muller, B., 67, 128 Munakata, K., 224 Munro, M. H. G., 115 Munster, D. J., 286 Murae, T., 140, 144 Murai, A., 286 Murakarni, K., 117 Murakami, Y., 135 Murillo, F. J., 217 Murofushi, N., 120 Murphy, R., 7, 18 Murphy, S. T., 118, 119 Murphy, W. S., 132 Murray, A. M., 38 Murray, M. J., 224 Murrill, P. A., 179 Muschik, G. M., 287 Muscio, 0.J., 2 0 Mushfiq, M., 234 Musuoka, N., 67 Mustich, G., 134 Myant, N. B., 178 Mynderse, J. S., 1 9 Nachbar, R. B., 82, 196 Naf, F., 107 Nafie, L. A., 4 Nagahama, Y., 102 Nagai, K., 17 Nagai, M., 133 Nagai, Y., 170 Nagakura, I., 97 Nagao, Y., 107 Nagasawa, T., 9 Nagase, H., 8 Nagel, A. A., 107 Nagumo, S., 133 Nahrwold, D., 315 Naik, N. C., 232 Naik, V. G., 13, 7 6 Nair, M. S. R., 146, 183 Nair, P. M., 219 Naito, A., 312 Nakadaira, Y., 11

342 Nakahara, J.-I., 157 Nakamura, E., 11 1, 206 Nakanishi, K., 168, 173, 206, 233,240,249,29 1 Nakanishi, M., 100 Nakanishi, T., 152 Nakane, M., 247 Nakata, T., 116 Nakayama, M., 75, 112 Nakazima, K., 243 Nambara, T., 243, 249, 268, 298,313, 318 Nambudiri, A. M. B., 220 Naoki, H., 102 Narasaka, K., 4 6 Narayanaswamy, S., 208 Narbonne, C., 274 Narwid, T. A., 293 Nash, L. J., 201 Nasipuri, D., 4, 7, 142, 258 Naves, Y. R., 29 Naya, K., 100 Naya, Y., 19, 102 Nayak, U. R., 1 3 , 7 6 Nedelec, L., 317 Nederlof, P. J., 10 Neef, G., 320 Neel, J., 222 Negishi, E., 59 Neher, R., 203 Nelson, A. N., 244 Nelson, J. A,, 132, 204 Nelson, S. D., 21 1 Nernoto, H., 327 Nervi, F. O., 177 Nes, W. R., 259 Neubert, L. A., 112 Newall, C. E., 315 Newell, G. C., 222 Ngan, N. L., 181 Nguyen Trong Anh, 258 Nickon, A,, 38 Nicolaou, K. C., 6 Nicolas, A,, 182 Nicolaou, K. C., 235 Nicolau, G., 222 Nicoletti, M., 24 Nidy, E. G., 6 Nigg, N. N., 212 Nikonov, G. K., 3 5 Nilles, G. P., 10 Nishi, K., 117 Nishida, T., 10, 15, 107, 121 Nishimura, H., 24 Nishimura, S . , 253 Nishioka, I., 9, 26, 49, 219 Nishitani, K., 90, 9 2 Nishiyama, A., 8 5 Nishiyama, K., 4 Nishizawa, M., 92, 97 Nitta, K., 236 Niwa, M., 8 5 Nixon, P. E., 123 Niyogi, S. K., 81

Author Index Njau, E., 276 Noble, T., 185 Node, M., 107, 119 Noguchi, M., 121. 158 Noguez, J . A., 9 7 Nojima, M., 3 9 Nomine, G., 3 17 Nomoto, K., 117 Nooijen, P. J. F., 8 4 Nooijen, W. J., 8 4 Nordqvist, M., 50, 5 1 Nordstrom, J. L., 177 Nordstrom, L., 212 Norgird, S., 157, 158 Norman, A. W., 230, 296 Norrnant, H., 15, 30 Normant, J. F., 14, 15 Novrkov, Yu. N., 17 Nowacki, E., 2 14 Noyori, R., 38 Nozaki, H., 6, 17, 6 1 Nozoe, S., 80, 197, 198 Nurrenbach, A., 5 Numata, T., 4 Nussberger, J., 310 Nyfeler, R., 58, 76, 82, 105, 192, 194, 195 Oae, S., 4 Oba, K., 221 Oberhansli, W. E., 125 Ochi, M., 139 Ochiai, M., 118 Ockels, W., 234 Oda, J., 4 Oda, M., 49 Ode, R. H., 104, 109. 124 O’Donovon, D., 183 Oehlschlager, A. C., 207 Ogawa, H., 236 Ogawa, M., 163 Ogawa, T., 6 Ogawa, Y., 120 Ogihara, Y., 144 Ognyanova, A., 224 Ogura. H., 232 Ogura, K., 9, 180, 219 Ogura, Y., 316 Oguri, T., 4 Oh, S.-W., 268 Ohara, S., 116 Ohashi, M., 3 0 Ohfune, Y., 78, 79 Oh-hashi, N., 16, 130, 222 Ohizumi, Y., 206, 213 Ohloff, G., 5 , 17, 110 Ohno, N., 10 Ohta, H., 24 Ohta, T., 140, 224 Ohtaki, T., 9 Ohtsuka, Y., 116 Oikawa, Y., 320 Ojirna, I., 170 Ojima, N., 219

Okada, N., 312 Okamoto, M., 8 3 Okamoto, T., 7 3 Okamura, W. H., 230, 294, 296 O’Keefe, J. H., 314 Okogun, J. I., 138, 139 Okomura, Y., 131 Okubayashi, M., 316 Okuno, T., 128 Okuno, Y., 10 Oliver, J. E., 38 Olson, G. L., 5, 168, 243, 256 Omura, Y., 10 Onan, K. D., 104 Onda, M., 115 Onions, A,, 11 Oonk, H. A., J., 29 Opdyke, D. L. J., 8 Oppolzer, W., 64 Orena, M., 6, 14 Orgiyan, T. M., 11 1 Oriente, G., 107, 123 Oritani, T., 168 Orr, J. C., 210 Ortar, G., 246, 266 Ortiz de Montellano, P. R., 130, 182 Osagie, A. U., 204 Osawa, Y., 228 Osdene, T. S., 222 Oshima, K., 6, 248 Otsuka, S., 11, 52 Ott, D. G., 221 Ottersen, T., 4 9 Ottery, F. D., 202 Ouar, F., 3 5 Oudman, D., 4 Ourisson, G., 88, 131, 150, 151,214 Overman, L. E., 5 Overton, K. H., 62, 195, 255 Owen, J. D., 10 Oxenrider, B. C., 41 Ozainne, M., 8 9 Ozaki, K., 303 Ozari, Y., 228 Paaren, H., 232 Packer, R. A., 134 Pagnoni, U. M., 7, 23, 87, 268 Paice, M. G., 9 5 Pakaln, D. A., 2 3 Paknikar, S. K., 5 0 Pakrashi,S. C.,7, 81, 141, 142, 153,258 Pal, A., 153 Pal, R., 133, 146 Pallos, F. M., 10 Palmer, J. R., 324 Palmisano, G., 4 0 Pandit, U. K., 322 Panizo, F. M., 118 Papadopoulos, B., 305

Author Index Papageorgios, V. P., 43 Papastephanou, C., 182 Pappo, R., 324 Paquer, D., 36,40 Paquette, L. A., 13 Paradisi, M. P., 242 Parish, E. J., 203 Parker, D. G., 13 Parker, W., 77 Parkes, J. H., 173 Parks, L. W., 207 Parmentier, G., 3 18 Parrilli, M., 237, 244 Parsons, R. F., 224 Partridge, J. J., 26, 296 Paryzek, Z., 136, 276 Pascard-Billy, C., 25 1 Pascual, C., 107 Passet, J., 10 Patel, D. J., 168 Patin, H., 253, 292 Patoiseau, J.-F., 39 Patrick, D. W., 5 Pattenden, G., 13, 20, 22, 128, 159,219 Patterson, G. W., 204, 205 Pauling, H., 17, 38 Paupardin, C., 9, 222 Paust, J., 43 Paxson, J. R., 51 Pearce, G. T., 12 Pearson, A. J., 14 Pechet, M. M., 246, 269, 281, 300 Peck, R. G.,.254 Pedder, D., 285 Pedersen, R., 160 Pedone, C., 71 Pek, G. Y., 35 Pelavin, L., 8, 268 Pelletier, S. W., 36, 107, 121, 230 Pemberton, P. W., 200 Pentegova, V. A., 108 Peppard, D. J., 128 Perdue, R. E., 109 Perel’son, M. E., 35 Pkrez, C., 54, 69, 198 Perez-Ossorio, R., 37 Perron, J. M., 212 Perry, D. L., 84 Persoons, C. J.. 84 Pertsovskii, A. L., 39 Pesce, G., 264 Pesnelle, P., 128 Petcher, T. J., 113 Pkte, J. P., 237, 286 Petelina, L. P., 42 Peter, M. G., 54 Peters, R. H., 8 Petterson, R. C., 97 Peterson, K., 51 Petrow, V., 250

343 Pettit, G. R., 104, 109, 124, 303,305 Pettus, J. A,, 97 Pfaffenberger, C. D., 31 Pfander, H., 158, 166 Pfenninger, H., 316 Pfohl, S., 43 Phaff, H. J., 155,218,219 Pham Van Huong, 173 Pharis, R. P., 120, 201 Philips, G. T., 203 Phillipou, G., 31, 33, 243, 283 Phillipps, G. H., 227, 315 Phillips, L., 200 Phinney, B. O., 120, 201 Piancatelli, G., 308, 309 Piatelli, M., 107, 123, 223 Piatkowski, K., 32 Picken, D. J., 62, 195 Picot, A., 271 Piers, E., 73 Pillot, J. P., 21 Pimenov, M. G., 35 Pinetti, A., 23 Pinfield, N. J., 222 Pinhey, J. T., 132 Piozzi, F., 107, 109 Pirio, M. R., 230, 294 Pistor, H., 24 Pitt, C. G., 50, 222 Pitts, J. N., 6 Pitzele, B. S., 14 Pivnitsky, K. K., 249, 257, 317, 318 Place, P., 236 Plattner, J. J., 61 Ploner, K. J., 12 Plotnikoff, N., 50 Plummer, E. L., 12 Pohjola, J., 224 Poling, S. M., 216 Pollock, E., 168 Polonski, T., 4 Polonsky, J., 138 Pommer, H., 5 Pons, J., 107 Ponsold, K., 231, 240, 313 Poole, C. F., 243, 287,289 Popa, D. P., 111, 112 Popjak, G., 178, 179, 181 Popov, S. S., 25, 27 Popova, L. A., 31 Popova, N. I., 43 Popova, N. V., 266 Popovitz-Biro, R., 281 Popplestone, R. J., 11 Poppleton, B. J., 114 Portella, C., 286 Porter, J. W., 182, 216 Posner, G. H., 7, 33, 238 Post, M. L., 94, 197 Potapov, V. M., 33 Poulter, C. D., 9, 20, 179, 180 Pouzar, V., 142

Povey, D. C., 134,272 Powell, J. W., 111 Powell, R. A., 223 Pradhan, S. K., 256 Prager, R. H., 7, 18 Prajer, K., 4 Prange, T., 251 Prasad, R. S., 30, 121 Pratt, G. E., 200 Press, C. M., 178 Prezant, D., 280 Price, C., 164 Prost, M., 301 Protiva, J., 142 Puglisi, C. V., 171 Pulman, D. A., 10 Purdy, J., 26 Purushothaman, K. K., 121 Purvin, V., 173 Pushpangadam, P., 223 Pusset, J., 283 Quackenbush, F. W., 156 Quennemet, J., 216 Quinney, J. C., 252 Quon, H. H., 40 Rabanal, R. M., 107 Rabinovich, D., 277 Rabinsohn, Y., 228 Radeglia, R., 107 Radhakrishnan, T. V., 256 Radin, L., 135, 159 Rae, D. R., 261 Raffauf, R. F., 124 Ragault, M., 9 Raggio, M. L., 297 Rahier, A., 135, 204 Railton, I. D., 201 Rajagopalan, M. S., 264, 298, 299,300 Rajan, S. J., 17, 222 Ralph, D. E., 65 Ramachandran, C. K., 179 Ramamurthy, V., 168, 170 Ramasarma, T., 178 Ramaswamy, N. K., 2 19 Ramirez, M. A,, 54 Ramstad, E., 111 Ranade, V. V., 3 17 Rang, K. A., 11 Rangaswami, S., 135, 147 Rao, C. G., 267 Rao, J. M., 48 Rao, K. V. J., 48 Rao, M. M., 97 Rao, P. N., 312 Rao, R. B.. 121 Rapi, G., 307 Rapoport, H., 61, 157 Rasmussen, J. K., 5 Rassat, A., 29 Rastogi, R. P., 75, 133

344 Ratner, V. V., 44 Raulston, D. L., 203 Rault, J., 287 Ray, S., 3 17 Ray, T. K., 141 Raymundo, L. C., 216 Ravelo, A. G., 135 Razdan, R. K., 50 Re, L., 10 Read, W. L., 177 Reap, J. J., 62 Reck, G., 120 Reddy, G. C. S., 147 Reece, C. A., 221 Reed, B. C., 180 Reed, W. D., 177 Rees, H. H., 202, 205, 207, 212, 213 Reeve, D. R., 119,201 Reeve, L., 296 Reeves, B. E. A., 204 Reffstrup, T., 46 Regan, J. W., 9 Regen, S. L., 6 Rego, A.. 230 Reich, H. J., 90 Reich, 1. L., 90 Reichling, P., 248 Reid, W. W., 208, 252 Reinbol’d, A. M.. 112 Reingold, 1. D., 239 Rejto, M., 239 Remers, W. A., 303 Rendle, D. F., 37, 227 Renga, J. M., 90 Rengaraju, S., 267 Renwick, J. A. A., 9, 41, 187 Retamar, J . A., 37, 39, 43 Revesz, C., 257 Rey, P., 29 Rhoades, D. G., 9,223 Riccio, R., 124 Rice, K. C., 36 Richer, J. C., 42 Richter, H., 234 Ridgway, R. L., 36 Riehl, A., 34 Rigassi, N., 55, 169 Rigaudy, J., 252 Righetti, M., 179 Rik,G. R., 12 Rilling, H. C., 9, 179, 180 Rimpler, H., 24 Ripperberger, H., 137 Rist, G., 228 Ritchie, E., 133 Ritter, F. J., 84 Rivers, G. T., 34, 269 Rivett, D. E. A,, 109 Robbins, W. E., 212, 206 Roberts, J. S., 77 Robertson, L. W., 5 1 Robinson, C. H., 316 Robinson, J. R.. 94, 197

Author Index Robinson, M. J. T., 254 Robinson, M. S., 267 Robinson, T., 3 Rockey, J. H., 173 Rodewald, W. J., 306 Roddick, J. G., 219 Rodriguez, B., 23, 107, 118, 155, 165,216 Rodriguez, M. L., 70 Rodwell, V. W., 177 Romer, J., 3 13 Rogers, D., 29 Rogers, H. R., 253 Rogit, M. M., 41 Rohmer, M., 131, 150, 151, 214 Rohrer, D. C., 228, 229, 327 Romanikhin, A. M., 43 Romeo, A., 246,266 Komo de Vivar, A., 83 Ronchetti, F., 219 Rosenberg, H., 202 Rosenberger, M., 167 Rosenfeld, J. M., 242 Rossiter, M., 171 Rosskopf, F., 25 Rothschild, M. A., 21 1 Rotmans, J. P., 171 Rouessac, F., 30 Rouillard, M., 33, 111 Roumestant, M.-L., 236 Rousseau, J., 209 Roussel, A., 42 Rowan, M. G., 9, 185 Rowland, A. T., 243, 245 Royals, E. E., 31 Rozen, S., 146, 281 Rozynov, B. V., 120 Rubinstein, I., 134, 275, 288 Rudney, H., 220 Ruedi, P., 113, 117 Rulin, V. A., 305 Rumpf, P., 169 Runic, S., 3 15 Runquist, A. W., 7 Ruokonen, A., 234 Ruppert, J. F., 21, 322 Rupprecht, R., 11 Russell, R. A., 282 Russo, G., 219 Rutledge, P. S., 118,246 Ruzo, L. O., 10 Rykowski, Z., 42 Ryzlak, M. T., 289 Rzheznikov, V. N., 257, 318 Sabadie, J., 32 Sabanski, M., 59 Sabine, J. R., 202 Sadet, J., 169 Sadykov, A. S., 71 Safe, L. M., 133 Sagae, H., 243 Safe, S., 133

Sagramora, L., 4 Sahni, R., 13, 76 Saigo, K., 6 Saika, A., 293 Saiki, K., 163 Saito, A., 9, 180 Saito, T., 206 Sakai, H., 29 Sakamoto, H., 261, 296 Sakano, I., 90 Sakina, K., 27 Sakuda, Y., 31 Sakurai, H., 11 Sakurai, N., 135 Salama, A. M., 137 Salares, V. R., 172 Salazar, J. A., 107, 109, 266 Salem, L., 173 Salemink, C. A., 49 Salen, G., 202, 290 Salvi, S., 307 Salzmann, T. N., 90 Samaan, H. J., 146 Samant, B. R., 308 Samatov, A., 45 Samsonova, N. V., 298 Samuel, P., 203 Sanchez, W. E., 114 Sandri, S., 6, 14 San Filippo, J., 6 Sankawa, U., 80 Santacroce, C., 71, 107, 123, 223 Sanyal, B., 126 Saraswathi, G. N., 34 Sargeant, T. E., 178 Sarma, A. S., 126 Sarti, S. J., 83 Sasak, W., 173, 174 Sasaki, S., 296 Sasame, H. A., 21 1 Sasamori, H., 286 Sassa, T., 123 Sathe, G. M., 128 Sathe, R. M., 36 Sato, C., 286 Sato, I., 12 Sato, K., 30 Sato, T., 8, 17, 33 Sato, Y., 4 Satoh, J. Y., 263, 264 Sattar, A., 77 Satterwhite, D. M., 9, 180 Saucy, G., 12, 167, 168,256 Sauer, G., 320,322 Saunders, J. K., 115,230 Savona, G., 107, 109 Sawamura, N., 29,293 Scala, A., 254, 289 Scallen, T. J., 177 Scarset, A., 37 Scartoni, V., 278 Scettri, A,, 308, 309 Schade, K., 202

Author Index Schatzmiller, S., 127 Schenone, P., 34 Scherer, J. R., 41 Scheuer, P. J., 71, 107, 121, 134 Schild-Knecht, H., 9, 224 Schilling, G., 23 Schindler, E., 126 Schlude, H., 269 Schmidlin, J., 299 Schmidt, E. N., 108 Schmidt, R. J., 123 Schmied, U., 3 10 Schneider, H. .I., 39 Schneider-Bernahr, H., 39 Schnoes, H. K., 293,296 Schonecker, B., 231 Schoepfer, G. J., jun., 291 Scholl, T., 22 1 Schoiler, R., 287 Schooley, D. A., 54 Schran, H., 50 Schreibman, P. H., 203 Schroeder, R. S., 126 Schroeder, W. A., 155 Schroepfer, G. J., 207, 204 Schubert, G., 240 Schubert, K., 202 Schuda, P. F., 97 Schudel, P., 9 Schiitte, H. R., 169 Schuetz, R. D., 10 Schulz, G., 43 Schultz, A. G., 283 Schultz, G., 216 Schultz, R. M., 210 Schultz, T. H., 9 Schwartz, J., 5 Schwartzman, S., 5, 243 Schwarz, H., 3 Schweiter, U., 55, 169 Sciuto, S., 223 Scopes, P. M., 172, 233 Scott, A. I., 28, 40 Scott, C. G., 12 Scott, F., 15 Scott, K. N., 315 Seamark, R. F., 243 Sedzik-Hibner, D., 32 Seelye, R. N., 123 Seeman, J. I., 285 Segal, G. M., 294 Seher, A,, 286 Seiber, J. N., 221 Seifert, W. K., 288 Seiyama, T., 11 Sekiguchi, S., 22 Sekita, R., 22 Sekiya, J., 9, 186 Selezneo, L. G., 282 Seligmann, O., 25 Selve, C., 239 Semmelhack, M. F., 105 Sen, M., 81

345 Senda, Y., 29 Sengupta, P., 81 Seno, M., 17 Seo, S., 146, 150, 214 Serebryakov, E. P., 120 Servi, S., 49, 50 Sestak, Z . , 171 Seto, S., 9, 180, 219 Sevenet, Th., 28 Seyden-Penne, J., 258 Shafizadeh, F., 103,223 Shah, S. N., 179 Shahak, I., 146 Shaikhutdinov, V. A., 44 Shakked, Z., 277 Shapiro, M. I., 222 Sharma, M. L., 30, 234 Sharma, R. P., 83, 84, 85, 104, 117 Sharma, S. C., 108 Sharma, S. D., 30 Sharp, H. L., 222 Sharpless, K. B., 5, 6, 8, 90, 204,248 Shashkina, M. Y., 3 1 Shaw, I. M., 8 Shaw, J., 185 Shaw, M. A,, 209 Shaw, P. E., 5 , 3 2 Shaw, P. M., 274 Shechter, I., 200 Shefer, S., 202, 222, 290 Sheikh, Y. M., 81, 289 Sheimina, L. G., 318 Sheinker, Y. N., 35, 298 Sheppard, P. N., 124 Sheremet, I. P., 23 Shergina, G. P., 31 Sherman, C. A., 21 1 Sheves, M., 293 Shew, D. C., 126 Shibasaki, M., 6, 35, 169, 235 Shibata, K., 228 Shibata, S., 80, 146 Shichi, H., 173 Shiga, M., 9 Shima, M., 179 Shima, S., 29 Shimada, K., 298 Shimagaki, M., 116 Shirnaoka, A., 146 Shimizu, T., 87 Shimizu, Y., 206, 240 Shindo, T., 123 Shiner, C. S., 6, 235 Shinzo, K., 138 Shioiri, T., 4 Shiojirna, K., 152 Shiota, M., 259 Shir, I., 202 Shirahama, H., 78, 79 Shiroyama, K., 327 Shishibori, T., 29, 131, 213 Shishkina, A. A., 249, 318

Shiue, C.-Y., 34 Shner, V. F., 243, 305 Shoji, J., 138, 146 Shono, T., 30 Shoppee, C. W., 236, 245 Shortie, D., 177 Showalter, J. P., 176, 222 Shoyama, Y., 9,49, 219 Shrewsbury, M. A., 177 Shriver, J., 172 Shue, H.-J., 59, 261 Shumskaya, I. V., 32 Sica, D., 71, 107, 123, 223 Siddall, J., 320 Siddiqi, M., 179 Siefermann, D., 217 Siegel, H., 43 Siegelman, H. W., 156 Siemieniuk, A., 32 Siegenthaler, W., 3 10 Sieskind, O., 275 Sigel, C. W., 122 Sighinolfi, O., 307 Sih, C. J., 169, 270 Silvani, A., 287 Silverstein, R. M., 12 Silverton, J. V., 152, 285 Sim, G. A., 243 Simchen, G., 41 Simcox, P. D., 200 Simes, J. J. H., 146 Simmonds, D. J., 20, 90 Simmons, D., 224 Simon, W., 167 Simpson, K. L., 155, 165, 216, 218 Simpson, T. J., 222 Sims, D., 104 Sims, J. J., 97 Singaram, B., 30, 33 Singer, S. P., 5 Singh, A., 82 Singh, B. P., 94, 102 Singh, H., 307 Singh, R. K., 155, 217 Singy, G., 81 Sioumis, A. A., 142 Siperstein, M. D., 179, 202 Sitton, D., 200 Sivade, A,, 239 Sivapalan, A., 19 Siverns, M., 107, 109, 230 Siwatibau, S., 223 Sjovall, J., 313, 314 Skattebol, L., 15, 34 Skeean, R. W., 125 Skett, P., 209 Sklyar, Y. E., 35 Slack, D. A., 48 Sliwowski, J. K., 204 Slobbe, J., 46 Smalley, H. E., 10 Smallidge, R. L., 156 Smillie, R. D., 73

346 Smith, A. G., 241 Smith, C. A., 8 Smith, C. R., 108 Smith, D. S. H., 297 Smith, H., 320 Smith, H. E., 4, 232 Smith, L. L., 210, 235, 252 Smith, M. G. J., 62 Smith, P.'F., 151 Smith, R. M., 89, 223 Smith, T. N., 11 Smith-Palmer, T., 118, 246 Smudin, D. J., 251 Snider, B. B., 279 Soai, K., 4 6 Sobti, S. N., 223 Sockolov, B. B., 264 Sodano, G., 207 Solomon, P. H., 291 Solomonovici, A,, 261 Somehara, T., 4 9 Sometani, T., 12 Sondengam, B. L., 139 Sone, H., 312 Song, P.-S., 173 Sopova, A. S., 248 Sorarrain, 0. M., 173 Sorensen, T. S., 37 Sorenson, D. K., 209 Sorochinskaya, E. I., 32 Soto, A. R., 3 15 Sotskova, I. V., 240 Souchi, T., 38 Soucy, M., 7 3 Souzu, I., 27 Spangler, C. W., 292 Spaulding, D. R., 178 Spencer, T. A., 132, 204. 239 Spies, H. S. C., 3 I Spiff, A. I., 138 Spike, T. E., 204 Spirikhin, L, V., 31 Spiteller, G., 234 Spittler, T. D., 97 Sprintschnik, G., 285 Sprintschnik, H. W., 285 Springer, J. P., 97 Spyckerelle, C., 15 1 Snajberk, K., 222, 223 Srikantaiah, M. V., 177 Srivastava, S. N., 222 Srivastava, S. P., 42 Staba, E. J., 208 Stallard, M. O., 18, 6 9 Stamoudis, V., 200 Standoli, L., 135 Stanton, J. L., 5 Starr,M.P., 155, 1 5 9 , 2 1 8 , 2 1 9 Starratt, A. N., 300 Steelink, C., 142 Steenkamp, J. A., 21, 61 Steinberg, I. Z . , 4 Steinman, D. H., 14 Stemke, J. E., 264

Author Index Stenberg, A., 209 Stephens, P. J., 4 Stevens, C. S., 8 4 Stevens, K. L., 48, 170 Stevenson, D. F. M., 264 Stewart, I., 158 Stewart, T. E., 12 Sticher, O., 23 Still, W. C., 260 Stipanovic, R. D., 7 1 Stobart, B. K., 222 Stoessl, A,, 52, 94, 187, 197 Stoffel, W., 244 Stohs, S. J., 202, 208 Stoller, H.-J., 167 Stone, K. E., 27, 186 Stothers, J. B., 47, 52, 94, 187, 197 Stout, G. H., 153 Strack, E., 37 Strain, H. H., 157 Straka, H., 140 Stransky, H., 156 Strickland, R. C., 127 Strickler, H., 17 Stromquist, P., 5 Struckmeyer, H. F., 243 Stryer, L., 173 Strzelecki, L., 287 Studinger, G., 212 Suares, H., 142 Suarez, E., 107, 109, 266 Subba Rao, G., 178 Subbiah, M. T. R., 210 Subramanian, R., 256 Subrahmanyam, K., 48 Suckling, K. E., 21 1 Suda, T., 296 Sudjic, M. M., 179 Sudo, K., 318 Sudo, M., 3 18 Suga, T., 29, 131, 146, 213 Sugawara, T., 136 Suggs, J. W., 30, 262 Sugie, A., 140 Sugihara, Y., 270 Sugimoto, A., 294, 296 Sugiyama, T., 10 Suleeva, R., 42 Sullivan, M. J., 173 Sumita, T., 117 Sun, H. H., 54 Sunder, R., 135 Sung, T. V., 12 1 Sunko, D. E., 238 Suter, C., 128 Suvorov, N. N., 305 Suvorov, N. P., 243 Suwita, A., 72, 97 Suzuki, A., 33 Suzuki, H., 1 5 2 , 2 2 1 Suzuki, K., 4 Suzuki, K. T., 6 2 Suzuki, M., 6 7

Suzuki, T., 6 7 Svec, W. A., 157 Svoboda, J. A., 212 Swann, A,, 202 Swann, D. A,, 5 1 Sweet, F., 308 Sweetser, P. B., 171 Swoboda, J. A., 206 sy, w. w., 128 Sych, F. J., 120 Sydnes, L., 34 Syrova, G. P., 35 Sazbolcs, J., 159, 160, 172 Szczepanik, P. A., 21 1 Szpigielman, R., 302 Tabacik, C., 182 Tachibana, K., 141 Tada, A., 146 Tada, M., 33 Tadasa, K., 9 Taguchi, T., 41 Taguchi, V. Y., 109 Tahara, A., 115, 116 Tahara, T., 3 1 Taira, Z., 1 14 Takabe, K., 11 Takada, A., 254 Takada, S., 116 Takagi, S., 3 12 Takagi, Y., 3 0 , 4 7 Takahama, A., 123 Takahashi, C., 267 Takahashi, I., 219 Takahashi, N., 120 Takahashi, S., 46, 5 3 Takahashi, T., 102, 140, 144 Takahashi, T . T., 264 Takai, K., 100 Takai, M., 144 Takamura, N., 44 Takaoka, D., 12 Takata, R. H., 134 Takayanagi, H., 232 Takeda, K., 276 Takeda, N., 128 Takeda, Y., 2 3 , 2 4 , 2 8 , 186 Takemoto, I., 127 Takemoto, T., 82, 117, 135, 140, 197,206, 213,242 Takeshima, K., 4 Takeshita, T., 296 Taketomi, T., 52 Takeya, K., 9 Takken, H. J., 3 6 Talebarovskaya, I. K., 33 Talman, E., 84 Tamm, C., 67, 1 3 2 , 2 6 7 Tammar, A. R., 212 Tamura, T., 287 Tan, L., 209 Tanabe, K., 31 Tanabe, M., 8 , 6 2 , 2 6 4 Tanahashi, T., 26

347

Author Index Tanahashi, Y., 102, 141 Tanaka, J., 11 Tanaka, K., 4 Tanaka; M., 12 Tanaka, O., 112, 117, 138 Tanaka, T., 116 Tanaka, Y., 165,218,296 Tandon, J. S., 108 Tang, C.-P., 281 Tani, T., 24 Tanida, H., 276 Tanio, Y., 146 Tarle, M., 238 Tarzia, G., 246 Taskinen, J., 73 Tasumi, M., 172 Tatematsu, H., 221 Taticchi, A., 44 Tatsuno, T., 87 Tattric, N. H., 150 Taubert, H.-D., 318 Taylor, D. R., 3, 138 Taylor, E. J., 269 Taylor, R. F., 158, 215 Taylor, W. C., 133 Templeton, J. F., 239 Teng, J. I., 210, 235 Teranishi, Y., 90 Terashima, S., 35, 169 Terekhina, A. I., 240, 298, 305 Terenius, L., 3 17 Terhune, S. J., 3, 62 Terlouw, J. K., 49 Terui, Y., 230 Teshima, S. I., 207 Tetenyi, P., 10, 224 Thal, C., 28 Thies, P. W., 25 Thomel, F., 102 Thomas, A. F., 89 Thomas, A. M., 104 Thomas, E. J., 283 Thomas, G., 220 Thomas, J. W., 223 Thomas, M. T., 43 Thomas, P. J., 222 Thomas, R. C., 313 Thomas, R. L., 216 Thompson, J. A., 212 Thompson, M. J., 206, 212 Thompson, R. H., 48 Thompson, W. J., 104 Threlfall, D. R., 220 Tialowska, B., 209 Tibbetts, M. S., 29 Tietze, L.-F., 29 Tigerstedt, P. M. A., 223, 224 Timmerman, B. N., 103 Timms, R. N., 255 Tint, G. S., 290 Tobin, T., 303 Tobita, S., 29 Toda, M., 132 Toemanen, C. D., 177

Togashi, M., 123 Toia, R. F., 122 Tokes, L., 222 Tokito, Y., 172 Tokoroyama, T., 128, 139 Tokura, N., 39 Tolstikov, E. E., 31 Tolstikov, G. A., 12, 13 Tominaga, T., 90 Tomita, Y., 150, 214 Tomofuji, I., 163 Toome, V., 296 Tori, K., 150, 214, 230 Torii, S., 47,56,73, 169 Torrance, S. J., 122 Torrini, I., 270 Tortorello, A. J., 21 Tbth, G., 159, 160, 172 Toth, K., 12 Toube, T. P., 159 Toubiana, R., 89 Touzin, A. M., 34 Townsend, C. A., 221 Townsend, J. M., 239 Tozawa, M., 303,305 Traas, P. C., 36 Trammell, G. L., 125 Trave, R., 7, 23,87, 268 Traynor, S. G., 12 Tresselt, D., 23 1 Trevillone, E., 57 Tribble, M. T., 227 Tringali, C., 107, 123 Troke, J. A., 139 Trost, B. M., 5, 64, 90, 105, 273 Trotter, J., 37, 227 Truesdale, L. K., 8, 262 Truscott, T. G., 172 Tsai, A. I.-M., 26 Tsai, L. B., 204, 205 Tsai, M., 302 Tsai, M. D., 31 Tsai, P., 2 11 Tseng, C. K., 10 Tsuboi, S., 5 Tsuji, N., 230 Tsukida, K., 163 Tsuneda, K., 253 Tsuneya, T., 9 Tsuyuki, T., 140, 141, 144 Tsvetkova, G. Y., 306 Tuck, M., 310 Tuddenham, R. M., 10,59 Tuinman, A., 263, 325 Turley, S. D., 202 Turnbull, J. H., 51 Turner, A. B., 297 Turner, C. E., 49,50 Turro, N. J., 173 Tursch, B., 81 Turuta, A. M., 240 Tuttle, M., 284 Twine, C. E., 50, 222

Tyor, M. P., 222 Tyson, B. J., 5 Tzikas, A., 267 Tzodikov, N. R., 259 Uchida, I., 118 Uchida, M., 135 Uchida, Y., 101 Uchio, Y., 75 Uda, H., 22, 73 Udarov, B. G., 31 Ueda, K., 12,22 Ueda, S., 23 Ueda, T., 254 Uematsu, T., 243 Ueno, J., 117 Ueno, M., 97 Uguen, D., 16, 167 Uhubelen, A,, 144 Uliss, D. B., 50 Ullman, A., 294 Ulrich, A., 120 Ulrich, P., 8, 244 Ulrich, W., 132 Umemoto, K., 9 Unai, T., 10 Uneyama, K., 47,56, 169 Ung, H. L., 274 Unrau, A. M., 207 Uobe, K., 23 Upadhyay, R. R., 12- 123 Uritani, I., 221 UskokoviC, M. R., 26,293,296 Usui, S., 126 Utley, J. H. P., 33, 164 Uto, s., 112 Uzarewicz, A,, 40 Uzarewicz, I., 40 Valcavi, U., 5, 305 Valenti, P., 318 Valentine, D., jun., 12 Valentine, J. S., 6 Valkanas, G. N., 42 Valverde, S., 23, 107, 118 Van Antwerp, C. L., 229 van Breugel, P. J. G. M., 173 van der Gen, A., 243 Van Derveer, D., 62 van de Woude, G., 317 van Dommelen, M. E., 131 van Eikeren, P., 30 van Hove, L., 3 17 van Koeveringe, J. A,, 281 Van Os, F. H. L., 9, 223 van Rheenan, J. W. A., 207 Van Rheenen, V., 248 Vanstone, A. E., 320 van Tamelen, E. E., 125 van Thuijl, J., 173 van Tongerloo, A., 210 van Vliet, N. P., 261 van Wageningen, A., 170 Varkey, T. E., 259

348 Varma, R. K., 249 Varshney, I. P., 146 Vatvars, A., 171 Vazeux, M., 36 Vkzquez, E., 290 Vecchio, G., 219 Vedeckis, W. V., 2 12 Veech, J. A,, 71 Veenstra, G. E., 41 Veerman, A., 160 Veksler, M. A., 282 Vercruysse, A., 171 Verghese, J., 29, 30, 33, 34 Verwiel, P. E. J., 84 Vestal, B. R., 302 Vetter, W., 310 Vial, Ch., 110 Vichnewski, W., 83, 114 Vicuna, R., 176 Vidal, G., 208 Vidal, J.-P., 28 Vig, A. K., 12, 48 Vig, 0. P., 12, 30, 48 Villarreal, R., 108 Villieras, J., 14, 15 Villoutreix, J., 159 Vinson, G. P., 3 10 Vinson, W., 130, 182 Visagie, H. E., 2 1, 3 1, 6 1 Vogeli, U., 167 Vogel, H., 286 Voigt, B., 121 Volante, R. P., 131, 181 Volovelsky, L. N., 266 Vol’pin, M. E., 17 von Carstenn-Lichterfelde, C., 107 Von Dreele, R. B., 104, 109, 124 von Fraunberg, K., 17, 43 von Rudloff, E., 222, 223 von Schantz, M., 12 von Wartburg, B. R., 170 Voogt, P. A,, 207 Vul’fson, N. S., 35 VystrEil, A., 142, 146, 149 Wada, K., 289 Waddell, W. H., 173 Wade, J. J., 74 Waegell, B., 281 Wagner, H., 3 13 Wahlberg, I., 84, 107 Wahren, R., 7 Wai-Haan Hui, 122 Waisser, K., 146 Walba, D. M., 147 Walker, E. R. H., 5,258 Wall, M. E., 49 Wallach, O., 37 Walling, C. T., 30 Walton, D. C., 199 Walton, M. J., 221 Wample, R. L., 201

Author Index Waraszkiewicz, S. M., 54, 69 Ward, E. W. B., 52, 94, 187, 197 Warrell, D. C., 261 Warren, C. D., 173 Watanabe, S., 313 Waters, J. M., 114 Waters, T. N., 123 Watson, J. A., 178 Watson, T. J., 223 Watson, W. H., 114 Watt, D. S., 245, 270, 297 Watt, G. W., 5 1 Watts, C. D., 171 Weakley, R., 21 1 Weavers, R. T., 111 Weber, H. P., 55, 113 Weber, J., 203 Weedon, B. C. L., 55, 155, 159, 160, 164, 169, 172 Weeks, C. M., 228, 229, 327 Weeks, 0. B., 161 Wegfahrt, P., 157 Wehrli, F. W., 107 Wehrli, P. A., 167 Wei, J. S., 130, 182 Weier, R. M., 250, 317 Weigel, L. O., 231 Weimann, L. J., 173 Weinges, K., 23 Weis, H. J., 203 Weiser, H., 21 1 Weisflog, A., 23 Weisleder, D., 108 Weissenberg, M., 239 Welankiwar, S. S., 132 Welch, S. C., 126 Wellburn, A. R., 179 Wells, R. J., 107, 125, 158 Wels, C. M., 120, 201 Wemple, J., 17, 222 Wenkert, E., 44, 107, 113 Werner, D., 203 West, C. A., 125, 181, 200 West, C. E., 202 Westphal, D., 246, 247 Weyler, W., 264 Whalley, W. B., 289 White, A. H., 122, 124 White, E. M., 17 White, J. D., 21, 109, 125, 208, 252 White, R. H., 198 Whitehurst, J. S., 134, 320 Whitesell, J. K., 26 Whitesides, G. M., 253 Whiting, D. A,, 48, 49, 90, 229 Whiting, M. C., 17 Whitten, D. G., 285 Whittingham, C. P., 155 Wicha, J., 248, 294 Wiczewski, M.,262 Widdowson, D. A., 176,253 Widen, K.-G., 12

Widman, M., 50, 51 Widmer, E., 165 Wie, C. W., 239 Wiechert, R., 297, 320, 322 Wiedhopf, R. M., 122 Wieland, P., 297 Wiesner, K., 128 Wife, R. L., 280 Wigfield, D. C., 259 Wikwall, K., 212 Wiley, M. H., 179, 202 Wiley, R. A., 84 Wilkie, J. S., 212 Wilkins, A. L., 153, 154 Wilcott, M. R., 18 Williams, C. M., 315 Williams, D. H., 291, 295 Williams, D. L., 50, 222 Williams, G. C., 2 11, 222 Williams, P. M., 202 Willig, A., 2 12 Willis, A. C., 122, 124 Willis, C. R., 30 Wilson, A. R. N., 131 Wilson, B. J., 11 1 Wilson, C., 27, 186 Wilson, C. A,, 41 Wilson, C. W., 32 Wilson, H. W., 41 Wilson, I., 286 Wilson, R. D., 245 Wilson, R. S., 36 Wilson, S. R., 112 Wilton, D. C., 210 Wilz, I., 9 Wing, R. M., 230 Winn, M., 50 Winter, R. E. K., 85 Winterfeldt, E., 5 Winternitz, F., 50 Wiss, O., 203 Witteveen, J. G., 33 Wittwer, F., 158 Witty, T. R., 303 Wolf, G. C., 302 Wolf, H., 277 Wolf, H. R., 36, 110, 170 Wolinsky, J., 17, 18 Wolinsky, L. E., 20, 58, 69 Wolloch, A., 271 Wong, C., 26 Wong, H., 167 Wong, J., 132, 271 Wong, K.-M., 147 woo, s. L., 97 Woo, W. S., 144 Wood, M., 14 Woodgate, P. D., 118, 246, 260 Woodhams, B., 3 12 Woods, G. F., 264 Woods, R. A., 203 Woolard, F. X., 19, 186 Worth, B. R., 253

349

Author Index Wotiz, H. H., 312 Wovkulich, P. M., 44 Wray, V., 230 Wright, J. E., 10 Wright, J. J., 271 Wright, J. L. C., 222 Wrixon, A. D., 4 0 wu, E. s. c.,105 Wu, T. F., 303 Wuilmet, M., 23 1 Wylde, J., 239 Wynberg, H., 4 , 4 0 Yagen, B., 249 Yakhimovich, R. I., 294 Yagi, M., 9, 1 2 , 2 1 9 Yakovleva, M. Y., 266 Yamada, K., 8 Yamada, S., 16, 130, 141, 222, 294 Yamada, S.-I., 4, 35,44, 169 Yamaguchi, I., 120 Yamakawa, K., 9 0 , 9 2 Yamamoto, A., 9 2 Yamamoto, H., 4 , 6 , 17 Yamamoto, H. Y., 217 Yamamoto, K., 12 Yamamura, S., 85, 131, 132 Yamanaka, H., 152 Yamanaka, T., 3 0 Yamane, H., 120 Yamasaki, K., 112, 117 Yamashita, H., 312 Yamashita, K., 10, 168, 221, 243,249,313 Yamauchi, T., 9, 219 Yang, 1. C., 6 5

Yang, J., 34, 269 Yang, N. C., 34 Yasuda, A., 6 Yates, P., 37 Yates, R. L., 237 Yatin, Y., 200 Yen, H., 217 Yip, R. W., 4 7 Yokota, T., 120 Yokoyama, H., 2 1 6 , 2 2 4 Yonemitsu, O., 320 Yoon, N. M., 7 Yoshida, T., 3 12 Yoshii, E., 303 Yoshikawa, M., 145 Yoshikoshi, A., 73 Yoshimasu, H., 312 Yoshioka, H., 10, 8 5 Yoshioka, K., 317 Yoshioka, Y., 103 Yoshizawa, I., 3 11 Yosioka, I., 24, 136, 145, 146, 152 Young, M. W., 5 Young, N. C., 269 Young, N. L., 212 Young, P., 50 Younglai, E. V., 242 Yousef, I. M., 21 1 Yousufzai, S. Y. K., 179 Yuasa, S., 11 Yudd, A. P., 168 Yugai, V. A., 42 Yuh, Y., 227 Yumoto, O., 253 Yunusov, S. Yu., 4 5 Yur’ev, V. P., 31

Zabik, M.J., 10 Zachariah, P. K., 2 11 Zafra, M., 223 Zaikin, V. G., 3 5 Zaiko, E. J., 127 Zalkow, L. H., 62 Zamudio, A., 108 Zanoni, T. A., 223 Zarecki, A., 248 Zaretskii, V. I., 35, 281 Zaugg, H., 50 Zavarin, E., 87, 222,223,224 Zawisza, T., 170 Zbiral, E., 43, 246, 247, 271 Zdero, C., 29, 52, 72, 75, 97, 108, 117 Zkches, M., 262 Zechmeister, L., 155 Zeevaart, J. A. D., 199 Zehavi, U., 236 Zeisberg, R., 3 Zelenova, L. M., 1 3 Zelewski, L., 209 Zell, R., 165 Zen’ko,R. I., 35 Zhang, S.-R., 34 Ziegler, M., 9 Ziegler, R.,132 Zielinski, W. L.. jun., 287 Ziffer, H., 285 Zil’berman, I. I., 172 Zimmerman, W. T., 34,269 Zinkel, D. F., 108 Zontova, V. N., 257 Zutshi, S . K., 9 Zwanenberg, B., 41