Terpenoids and Steroids: Volume 8 (Terpenoids & Steroids)

A Specialist Periodical Report

Terpenoids and Steroids Volume 8

A Review of the Literature Published between September 1976 and August 1977

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

G. Britton, University of Liverpool J. D. Connolly, University of Glasgow D.N. Kirk, Westfield College, London B. A. Marples, University of Technology, Loughborough T. Money, University of British Columbia, Vancouver, Canada R. B. b a t s , Bishop's University, Lennoxville, Quebec, Canada

The Chemical Society Burlington House, London, WIV OBN

ISBN 0-85186-326-4 ISSN 0300-5922 Library of Congress Catalog Card No. 74-615720

Copyright @ 1978 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 uction During the year under review the number of known terpenoids has increased significantly, particularly amongst the sesqui- and di-terpenoids where a number of novel skeleta have been described. In a number of instances the novel diterpenoid skeleta are reminiscent of sesquiterpenoids. Marine organisms have provided the source of many new halogenated terpenoids. It is interesting to speculate o n the role of the halogen, particularly bromine, in the biosynthesis of these compounds. The sites of halogenation are in a number of instances those which would be expected if the halogen were playing a role in the cyclization of acyclic prenyl precursors. The format of these Reports has remained relatively constant from year t o year t o facilitate the location of subject matter. However, this year two changes have occurred. Firstly, as an experiment, the information on biosynthesis is contained within the chapters dealing with the individual group of terpenoids rather than as a separate chapter. Secondly, the steroid section has been recast t o minimize overlap. A report of the application of physical methods t o steroids forms o n e chapter whilst steroid reactions and partial syntheses are reported in the second. Total synthesis will be reviewed biennially.

J. R. HANSON

Contents Part I Terpenoids 3

Chapter 1 Monoterpenoids By R. 8.Yeats 1 Physical Measurements: Spectra etc.; Chirality

4

2 General Synthetic Reactions

9

3 Biogenesis, Occurrence, and Biological Activity

13

4 Acyclic Monoterpenoids 20 Terpenoid Synthesis from Isoprene 20 2,6-Dimethyloctanes 22 Halogenated Monoterpenoids 30 Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives 32 5 Monocyclic Monoterpenoids Cyclobutane Cyclopentanes, Iridoids p-Menthanes o-Menthanes m-Menthanes Tetramethy lcyclohexanes Dimethyleth ylcyclohexanes Cycloheptanes

35 35 35 39 46 46

6 Bicyclic Monoterpenoids Bicyclo[3,l,0]hexanes Bicyclo[2,2,l]heptanes Bicyclo[3,l ,l]heptanes Bicyclo[4,1,O]heptanes

48

7 Furanoid and Pyranoid Monoterpenoids

58

8 Cannabinoids and other Phenolic Monoterpenoids

61

46

47 48

48 49

53 56

V

Contents

vi

Chapter 2 Sesquiterpenoids By T. Money

64

1 Farnesane

64

2 Mono- and Bi-cyclofarnesane

66

3 Bisabolane

67

4 Sesquipinane, Sesquicamphane, Sesquifenchane

71

5 Cuparane, Trichothecane, Laurane

73

6 Acorane, Cedrane, Carotane

76

7 Chamigrane, Widdrane, Thujopsane

79

8 Cadinane, Amorphane, Copacamphane, etc

80

9 Himachalane, Longipinane, Longicamphane, etc.

86

10 Humulane, Caryophyllrrne

89

11 Germacrane

94

12 Eudesmane

99

13 Vetispirane, Elemane

106

14 Eremophilane, Bakkane (Fukinane), Ishwarane

111

15 Guaiane, Pseudoguaiane

118

16 Miscellaneous

121

Chapter 3 Diterpenoids By J. R. Hanson

123

1 Introduction

123

2 Bicyclic Diterpenoids Labdanes Clerodanes

123 123 127

3 Tricyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tricyclic Diterpenoids

129 129 132

4 Tetracyclic Diterpenoids Naturally Occurring Substances Chemistry of the Tetracyclic Diterpenoids Gibberellins Grayanotoxins Diterpenoid Alkaloids

133 133 136 137 139 139

5 Macrocyclic Diterpenoids and their Cycliation Products

141

vii

Contents 6 Miscellaneous Diterpenoids

144

7 Diterpenoid Total Synthesis

147

Chapter 4 Triterpenoids By J. D. Connolly

150

1 Squalene Group

150

2 Fusidane-Lanostane Group

152

3 Dammarane-Euphane Group Tetranortriterpenoids Pentanortriterpenoids Quassinoids

160 163 165 167

4 Shionaae-Baccharane Group

168

5 Lupane Group

169

6 Oleanane Group

172

7 UFsaneGroup

178

0 Hopane Group

179

9 Stictane-Flavicane Group

180

Chapter 5 Carotenoids and Polyterpenoids By G. Britton

181

1 Introduction

181

2 Carotenoids New Structures Acyclic Carotenoids Monocyclic Carotenoids Bicyclic Carotenoids Apocarotenoids Carotenoid Glycosides Carotenoproteins Degraded Carotenoids Stereochemistry Synthesis and Reactions Carotenoids Retinol Derivatives Other Degraded Carotenoids Physical Methods and Physical Chemistry Separation and Assay Methods 13 C N.M.R. Spectroscopy Circular Dichroism

181 181 182 182 182 185 185 185 187 188 189 189 193 196 198 198 198 198

...

Contents

Vlll

Electronic Absorption Spectroscopy Resonance Raman Spectroscopy X-Ray Crystallography Miscellaneous Physical Chemistry Spectroscopy and Physical Chemistry of Retinal and Visual Pigments Biosynthesis and Metabolism Pathways and Reactions Enzyme Systems Regulation Carotenoid Metabolism and Metabolites

198 199 199 199 200 201 201 203 204 205

3 Polyprenols

206

4 Isoprenylated Quinones Chemistry Biosy nthesis Ubiquinone Menaquinone Other Quinones

206 207 208 208 208 208

Part lI Steroids Chapter 1 Physical Methods By 0.N. Kirk

211

1 Structure and Conformation

211

2 N.M.R. Spectroscopy 'H Spectra 3H Spectra 13 C Spectra

213 213 2 14 215

3 Chiroptical Phenomena

218

4 Mass Spectrometry

22 1

5 Miscellaneous Physical Properties

223

6 Analytical Methods Radioimmunoassay of Steroids Chromatography

224 224 225

Chapter 2 Steroid Reactions and Partial Syntheses By 8. A. Marples

227

Section A ; Steroid Reactions 1 Alcohols and their Derivatives, Halides, and Epoxides Substitution Oxidation and Reduction

227 227 229

ix

Contents

Epoxide formation and Ring-opening Ethers, Esters, and Related Derivatives of Alcohols 2 Unsaturated Compounds Electrophilic Addition Other Addition Reactions Other Reactions of Olefinic Steroids Aromatic Compounds

3 Carbonyl Compounds Reduction of Carbonyl Compounds and @-Unsaturated Carbonyl Compounds Nucleophilic Addition to Carbonyl Compounds and C Y-Unsaturated ~ Carbonyl Compounds Reaction involving Enols or Enolic Derivatives Oximes, Hydrazones, and Semicarbazones

23 1 233 234 234 236 237 238

239 241 243 244

4 Compounds of Nitrogen, Sulphur, and Selenium

245

5 Molecular Rearrangements Backbone Rearrangements Miscellaneous Rearrangements

247 247 249

6 Functionalization of Non-activated Positions

252

7 Photochemical Reactions

255

8 Miscellaneous

260

Section B : Partial Syntheses 9 Cholestane Derivatives and Analogues

260

10 Vitamin D and its Metabolites

266

11 Pregnanes

270

12 Androstanes

27 1

13.Cardenolides

272

14 Seco-steroids and Cyclo-steroids

274

15 Heterocyclic Steroids

275

16 Microbiological Oxidations and Reductions

279

17 Miscellaneous Syntheses

280

Errata

282

Author Index

283

Part I TERPENOIDS

1 Mon oterpeno ids BY R. B. YEATS

The format established in previous volumes is maintained, except that a consolidation this year brings all monoterpenoid biosynthetic work into this chapter; in keeping with previous practice, metabolic functionalization of monoterpenoids is reported in the relevant structural sections and not under Biogenesis. The number of monoterpenoid papers published this year appears to have increased,’ although a decline is noted for papers on essential o i k 2 Keeping abreast of this burgeoning literature, especially by means of alerting services and computer data bases, could be made easier if all authors and editors selected titles more judiciously and insisted upon the inclusion of keywords. For example, it is noted that, to the uninitiated, the title of Trost’s full paper3 on grandisol and fragranol synthesis (c$ Vol. 6, p. 21) gives too little clue of its content; the same is true of McMurry’s perillene ~ y n t h e s i sand , ~ even the author’s own abstract provides no clue of the inclusion of a yomogi alcohol synthesis in the paper by Wada et aL5 Such inadequacies result in an unnecessary shortfall in the number of monoterpenoid-related papers retrievable by the use of anticipatable keywords in alerting services such as Current Contents, Science Citation Index, and Index to Scientific Reviews when compared with this Reporter’s literature search.’ The inability to retrieve references to previous Reports o n monoterpenoids in this series by the use of Index to Scientific Reviews6 is, fortunately, not repeated in Lewis’s valuable index.’ The use of Chemical Abstracts as an alerting service again reveals some apparently inconsistent abstracting and misplaced abstracts. Examples include the unnecessary separation of abstracts referring to Volume 6,’ the classification of a

*

7

Approximately 1995 monoterpenoid-related papers were retrieved from the page-by-page search of 135 titles published since compiling the previous Report (Vol. 7, p. 3) to August 1977 and available to early November 1977; additional papers were retrieved via Current Abstracts of Chemistry and index Chemicus, and relevant sections of Current Contents, Physical and Chemical Sciences, and Chemical Abstracts. 1210 of these papers provided the core upon which this Report is based. Based upon computer-retrieved papers from the Essential Oils Section of Chemical Abstracts; September 1975 to August 1976,223 papers; September 1976 to August 1977, 144 papers. B. M. Trost, D. E. Keeley, H. C. Arndt, and M. J. Bogdanowicz, J. Amer. Chem. SOC.,1977,99,3088. J. E. McMurry and S. F. Donovan, Tetrahedron Letters, 1977, 2869. M. Wada, A. Fukui, H. Nakamura, and H. Takei, Chem. Letters, 1977, 557. Index to Scientific Reviews, Institute for Scientific Information, Philadelphia, 1975, 1976, and 1977 Semiannual. ‘ Index of Reviews in Organic Chemistry, Second Cumulative Volume 1976’. compiled by D. A. Lewis and P. Charnock, The Chemical Society, London, 1977. For example, see Chem. Abs., 1977,86, 72 919 for reference to the entire volume, Chem. Abs., 1976, 85, 192 902 for Monoterpenoids, and Chem. Abs., 1977,86,43 821 for Diterpenoids.

3

4

Terpenoids and Steroids

paper on cis-3,4-A1-THC under alkaloids,' and the inclusion of the non-terpenoid C1 compound pestalotin under Terpenoids," especially when neither Cavill's

characterization of the cyclopentane monoterpenoid dolichodial and related compounds'' nor the identification of new limonene metabolites12 is even crossreferenced. Papers on the characterization of iridoids are rarely found under T e r p e n ~ i d s , 'and ~ cross-referencing to and between carbohydrate^'^ and Plant Biochemistry," where papers seem to be located at random, is poor. It would also be helpful to translate more than a title for abstracts based upon Referativnyi Zhurnal, Khimiya.16 The prompt compilation of future Reports will be helped substantially if monoterpenoid chemists would be willing automatically to send reprints of papers, particularly of articles published in less accessible journals, directly to this Reporter. 1 Physical Measurements: Spectra etc.; Chirality A review of 'H n.m.r. spectra of cyclic alkenes points out the need to re-examine car-2-ene and car-3-ene conformations (cf. Vol. 5, p. 41).17Further 'H n.m.r. data on methyl-substituted norborneols in the presence of [Eu(dpm),] shift reagent have been reported." Attempts to correlate calculated and experimental lanthanideinduced shift data could not distinguish between diastereomeric esters of transmyrtanoic acid," gave poor results with the 4-arninoborneols,'' and, although readily distinguishing between cis- and trans -pinocarveol, could not distinguish between proposed conformations with certainty.20 The use of [Eu(fod),] with Mosher's reagent esters of diastereomeric secondary alcohols (e.g. borneol/isoborneol, cis-carveolltrans-carveol, isopinocampheol/neoisopinocampheol) allows configurational assignments at the carbinol centre by observing the magnitude of methoxy lanthanide-induced shifts and should be valuable in assigning stereochemistry in diastereoselective reductions of ketones.21 The absolute configuration of chiral thiols can be determined from the 'H n.m.r. spectra of the diastereomeric hydratropic thioesters.22 The observation that the well known iridoid aucubin is R. M. Smith and K. D. Kempfert, Phytochernistry, 1977,16, 1088 (Chem.Abs., 1977,87,98 815). Chem. Abs., 1977,86,90 039. G. W. K. Cavill, E. Houghton, F. J. McDonald, and P. J. Williams, Insect Biochem., 1976, 6, 483 (Chem.Abs., 1977,86,1399). I' R. Kodama, T. Yano, K. Furukawa, K. Noda, and H. Ide, Xenobiotica, 1976,6,377. l3 For xylomollin (145) see I. Kubo, I. Miura, and K. Nakanishi, J. Amer. Chem. SOC.,1976, 98, 6704 (Chem. Abs., 1977,86, 16 795). l4 For bartsioside (121; X = H , R=@-Glu) see A. Bianco, M. Guiso, C. Iavarone, and C. Trogolo, Gazzetta, 1976,106, 725 (Chem.Abs., 1977, 86, 106 984). " For example, vogeloside (Vol. 7, p. 27, ref. 265) is abstracted under Plant Biochemistry (Chem. Abs., 1976, 85, 74 898) and is not cross-referenced from Carbohydrates or Terpenoids, whereas the related centapicrin (Vol. 7, p. 27, ref. 266) is similarly located (Chem. Abs., 1976, 85, 74968) but is cross-referenced from Carbohydrates. l6 For example, see 'Stereochemistry of some new rearrangements of bicyclic terpenes', T. F. Gavrilova, I. S. Aul'chenko, and L.A. Kheifits, Voprosy StereokhirniiResp. Mezhved. Nauch. Sb., 1976,77 (Chem. Abs., 1977,86, 121 534). " H. Giinther and G. Jikeli, Chem. Rev., 1977, 7 7 , 599. " K.-T. Liu,J. Chinese Chem. SOC.(Taiwan), 1976,23, 1; cf. Vol. 4, p. 3. '9 G. R. Sullivan, J. Amer. Chem. Sac., 1976,98, 7162. 2o C. C. Hinckley and W. C. Brumley, J. Magn. Resonance, 1976, 24, 239. S. Yamaguchi and F. Yasuhara, Tetrahedron Letters, 1977, 89. " G. Helmchen and R. Schmierer, Angew. Chem. Znternar. Edn., 1976,15,703. 'O

Monoterpenoids

5

readily identified in an intact seed of Aucuba japonica may signal a useful monitoring role of I3cn.m.r. spectroscopy in plants.23 The bathochromic-hypochromic shift in the U.V. spectra of umbellulone and verbenone has been interpreted as being due to extension of the ap-unsaturated carbonyl c h r ~ m o p h o r e .U.V. ~ ~ and c.d. data into the vacuum region have been recorded in the vapour phase and in solution for a- and p-pinene, camphene, bornene, fenchylidenefenchane, and bornylidenebornane; the major c.d. bands were assigned." Whilst calculated rotatory strengths of cisoid dienes of fixed conformation are in good agreement with experimental results, calculations on the conformationally flexible a -phellandrene fail to give good agreement.2hThe value and limitations of using n-propylammonium (+)-camphor-10-sulphonate as a standard for c.d. and 0.r.d. calibration have been discussed f ~ r t h e r . ~Variations ' in the rotivities of (-)-a-pinene and (+)-limonene with temperature and solvent are reported.** The discussion of a series displacement index for classifying mass spectra and for correlation with structural stability includes some monoterpenoids (e.g. myrcene limonene, ~ a n t e n e ) . ~ ~ Rate constants are reported for the reactions of a - and 0-pinene and of (+)limonene with OH radicals so that comparison is now possible with those from reaction with O ( 3 P )(see Vol. 7, p. 6) and with ozone (see Vol. 6, p. 8); results are consistent with those calculated from the data of Grimsrud et aE. (Vol. 6, p. 8) from which further rate constants for the reaction of nine other monoterpenoid hydrocarbons with OH radicals have been ~ a l c u l a t e d . ~In ' the oxidation of sterically unhindered alcohols (e.g. borneol, the pinocampheols, the nopinols), the reaction rate correlates with the strain difference between the alcohols and the derived ketones, suggesting that the properties of the carbonyl group are reflected in the oxidation transition state.31 A second paper reports Sicher correlations for the chromic acid oxidation of epimeric alcohols (e.g. the i s o ~ e r b a n o l s ) .Attempts ~~ have been made to calculate the proportions of epimeric alcohols formed on complex metal hydride reduction of cyclic ketones by considering steric congestion and torsional effects, interpreting the results in favour of a mechanism involving initial complexation between the ketone and the reagent followed by rate-determining nucleophile transfer. Camphor and isopinocamphone calculations bear out known epimeric alcohol proportions but agreement for the hindered fenchone and for chrysanthenone is not good. In chrysanthenone reduction the major predicted product is not in keeping with that which is observed;33the authors suggest that the 23 24

z5

26 27

29

30

31

32 33

M. Kainosho, Tetrahedron Letters, 1976, 4279. A. Y. Meyer, R. Pasternak, J. Sterling, N. Lander, and R. Mechoulam, Tetrahedron, 1976,32, 2805. A. F. Drake and S. F. Mason, Tetrahedron, 1977, 33, 937. J. S. Rosenfield and E. Charney, J. Amer. Chem. Soc., 1977, 99, 3209. Y. Nakagawa, M. F. Gillen, and R. E. Williams, Cunad. J. Chem., 1976,54, 3200; see M. F. Gillen and R. E. Williams, ibid., 1975, 53, 2351 for the earlier unreported c.d. calibration. R. Lauricella, J. Kechayan, and H. Bodot, J. Phys. Chem., 1977,81, 542. R. G . Dromey, Analyt. Chem., 1976.48, 1464. A. M. Winer, A. C. Lloyd, K. R. Darnall, and J. N. Pitts, J. Phys. Chem., 1976,80, 1635. P. Miiller and J.-C. Perlberger, J. Amer. Chem. SOE.,1976,98,8407; see also P. Miiller, Chimia (Swirz.), 1977.31, 209. P. Miiller and J.-C. Perlberger, Helv. Chim. Acta, 1976.59, 2335. W. T. Wipke and P. Gund, J. Amer. Chem. Soc., 1976,98, 8107.

6

Terpenoids and Steroids

original assignment of product stereochemistry may be in error,34without reference to recent Another approach for substituted cyclohexanone reduction by NaBH, in propan-2-01, which is based upon free-energy increments for non-polar substituent groups, gives good agreement between theory and experiment for menth~ne.~~ The adsorption of (+)-camphor-10-sulphonate ions on a mercury electrode is a two-dimensional associative adsorption of ions as micelles in equilibrium with free adsorbed ions (cf. camphor and borneol, Vol. 5, p. 4).37 The factors affecting asymmetric electrochemical reduction of (-)-menthy1 phenylglyoxylate have been examined.38 Asymmetric homogeneous catalytic hydrogenation of substituted cinnamic acids (in up to 70% enantiomeric excess) with [Rh(~od)C1]~-(-)-menthylmethylphenylphosphine catalyst is probably more influenced by the chirality at phosphorus than that at carbon, with results similar to those obtained with a (-)-neomenthyldiphenylphosphine ligand39 which is also reported to yield 95% of (3R)-(+)-dihydrogeranic acid from geranic acid ( E : Z/9: l).40Much useful asymmetric synthetic work has centred on boron reagents. Lithium B-isopinocampheyl-9-borabicyclo[3,3,l]nonylhydride reduces ketones to R-alcohols in up to 37% enantiomeric excess;41 the reagent is readily available from B-isopinocampheyl-9-borabicyclo[3,3,l]nonane, the product of oxidation of hydroboration of (+)-a-pinene with 9-borabicyc10[3,3,1]nonane;~~~~ B-isopinocampheyl-9-borabicyclo[3,3,l]nonane yields isopinocampheol(1; 99.9% optical and it can also be used for the highly enantioselective reduction of

(1)

aldehydes (e.g. [c~-~H]benzaldehyde to the corresponding S-alcohol in 90% enantiomeric excess; a modification yields the R-alcohol) with the promise of chemoselectivity Monoisopin~campheylborane,~~ which is readily available from the corresponding triethylamine c o r n p l e ~hydroborates ~~ trisubstituted alkenes leading to alcohols of S-configuration in up to 72% enantiomeric excess;44 useful asymmetric reductions of ketones with di-isopinocampheylborane of high 34

35 36

37

38 39 40 41

42 43

44

"

J. J. Hurst and G. H. Whitham, J. Chep. SOC.,1960, 2864. See Vol. 6, p. 42, refs. 312, 313, and Vol. 7, p. 43, ref. 430. D. C. Wigfield, Canad. J. Chem., 1977, 55, 646. A. C. Ramamurthy and S . Sathyanarayana, J. Electroanalyt. Chem. Interfacial Electrochem., 1976, 73, 253. M. Jubault, E. Raoult, and D. Peltier, Electrochim. Acta, 1977, 22, 67. C. Fisher and H. S . Mosher, Tetrahedron Letters, 1977, 2487. F. Hoffmann-La Roche und Co., Dutch P. 12 729/1975 (Chem. Abs., 1977,86,55 597). S. Krishnamurthy, F. Vogel, and H. C. Brown, J. Org. Chem., 1977, 42, 2534; 173rd A.C.S. Meeting, New Orleans, March 1977, Abstracts ORGN, No. 17. H. C. Brown, R. Liotta, and L. Brener, J. Amer. Chem. SOC.,1977,99, 3427; see also ref. 47. M. M. Midland, A. Tramontano, and S. A. Zderic, J. Amer. Chem. SOC.,1977,99,5211; 174th A.C.k. Meeting, Chicago, August 1977, Abstracts ORGN, No. 28. H. C. Brown and N. M. Yoon, J. Amer. Chem. SOC.,1977,99,5514. H. C. Brown, N. M. Yoon, and A. K. Mandal, J. Organometallic Chem., 1977, 135,C10.

Monoterpenoids

7

optical purity,46 two syntheses of which have been r e ~ o r t e d , ~as ~ ,well ~ ' as nearly complete asymmetric induction in the hydroboration-oxidation of c i s - b ~ t - 2 - e n e ~ ~ have been discussed. The full paper on the asymmetric reduction of acetophenone with monoterpenoid glycol-lithium aluminium hydride complexes (Vol. 7, p. 5 ; cf. Vol. 4, p. S)49 has been published as well as further synthetic work on S-(+)-2,2,2trifluoro-l-phenylethanol (Vol. 7, p. 4)50and on its resolution as (-)-o-camphanic acid esters;51 the latterS1 is one of a number of examples in which resolution via (-)-w-camphanic esters is monitored by 'H n.m.r. in the presence of [ E u ( f ~ d ) ~ ] ~ l , ~ ~ or [ E ~ ( d p m )[see ~ ] ~Vol. ~ 4, p. 4; formula (4) should have the alkoxycarbonyl group attached to the bridgehead position]. In an extension of previous work (Vol. 6, p. 6), the asymmetric reduction of ethyl benzoylformate with the NAD(P)H model system (2kmagnesium perchlorate is best when X=NH;54 the inability of horse liver alcohol dehydrogenase to reduce fenchone and camphor is consistent with the diamond lattice section model of the active and accounts for the HLADHcatalysed oxidation of (f)-(3) to the 'unnatural' (-)-cis-tetrahydroactinidiolide

(258) (p. 60) in 14% optical purity.56 Such reactions must be interpreted with care in view of the observation that N-benzyl-1,4-dihydronicotinamideacts as an electron donor in the reduction of 2-exo-brom0-2-endo-nitrobornane.~~ The synthesis and use of peroxycamphoric acid as an asymmetric oxidizing agent has been r e - e ~ a l u a t e d . ~ ~ Other interesting examples of asymmetric syntheses involving chiral monoterpenoids include the Claisen reaction between (-)-menthy1 phenylacetate and benzaldehyde (optical purity is confirmed by micr~calorimetry),~~ a highly enanand the crossed aldol tioselective carbenoid cyclopropanation catalysed by (4),60 H. C. Brown and A. K. Mandal, J. Org. Chem., 1977,42, 2996. H. C. Brown and N. M. Yoon, Israel J. Chem., 1976/1977,15, 12. H. C. Brown, A. K. Mandal, and S. U. Kulkarni, J. Org. Chem., 1977.42, 1392. 49 E. D. Lund and P. E. Shaw, J. Org. Chem., 1977,42,2073. 5 0 D. Nasipuri and P. K. Bhattacharya, J.C.S. Perkin I, 1977,576. 5 1 J. Jurczak, A. Konowal, and Z. Krawczyk, Synthesis, 1977, 258. '' A. Konowal, J. Jurczak, and A. Zamojski, Tetrahedron, 1976, 32, 2957 [formula (7) lacks a carbonyl group]; C. Belzecki and I. Panfil, J.C.S. Chern. Comrn., 1977,303 [in Table 2 footnote e, [o]$:g should be -236" and not -23.6", ref. 4 should be to Synthesis 1975 and not 1976, and in Current Abstracts of Chemistry, Abstract Number 258 347 [formula (X) is completely incorrect]. 53 W. L. F. Armarego, B. A. Milloy, and W. Pendergast, J.C.S. Perkin I, 1976,2229; E. Caspi and C. R. Eck, J. Org. Chem., 1977, 42, 767. s4 A. Ohno, H. Yamamoto, T. Kimura, S. Oka, and Y. Ohnishi, Tetrahedron Letters, 1976, 4585. 5 5 A. J. Irwin and J. B. Jones, J. Amer. Chem. SOC.,1976,98, 8476. 56 J. B. Jones and H. B. Goodbrand, Canad. J. Chem., 1977,55,2685. " R. J. Kill and D. A. Widdowson, J.C.S. Chem. Comrn., 1976, 755. 5 8 W. H. Pirkle and P. L. Rinaldi, J. Org. Chem., 1977, 42, 2080. 59 N. A. Kirtchev, N. D. Berova, C. G. Kratchanov, and B. J. Kurtev, Compt. rend. Acad. bulg. Sci.,1976, 29, 849. 60 A. Nakamura, A. Konishi, R. Tsujitani, and S. Otsuka, 172nd A.C.S. Meeting, San Francisco, August-September 1976, Abstracts ORGN, No. 144. 46

47

48

8

Terpenoids and Steroids

addition of silyl enol ethers6' as well as the addition of allyltrimethylsilane62 to (-)-menthy1 keto-esters; in the latter case the product stereochemistry was tentatively assigned according to the Prelog g e n e r a l i ~ a t i o nwhich , ~ ~ is not applicable to ~~ Reformatsky reactions of (-)-menthy1 and (+)-bornyl p y r ~ v a t e s .Applications involving chiral centres other than carbon include organosilane synthesis,65 the reaction of (-)-menthy1 (-)-(S)-toluene-p-sulphinate with Grignard66.67 and organocopper-lithium and selenonium ylide formation.68 Asymmetric hydrolysis of (*)-menthy1 acetate by Rhodotorula rnuciluginosa is reported.69 A method for determining optical purities of less than one percent for secondary alcohols has been p ~ b l i s h e d , ~and ' Mislow has observed a partial resolution which may serve to distinguish between a rneso and a racemic host product when a derived inclusion compound is recrystallized from an enantiomerically enriched guest solvent . 7 1 G.1.c. papers of interest include the classification of 22 acyclic monoterpenoid alcohols according to retention indexes,72 resolution of cyclic ketones [e.g. (+)menthone, (&)-isomenthone] as diethyl (+)-tartrate a ~ e t a l s ,and ~ ~ the use of lanthanide shift reagents to resolve non-terpenoid racemic e p o x i d e ~ .The ~ ~ occurrence and prevention of monoterpenoid hydrocarbon isomerization during silica gel chromatography has been examined75 and the separation of monoterpenoids and sesquiterpenoids by gel permeation chromatography is reported.76 Monoterpenoid hydrocarbons have been selectively extracted from essential oils using dirnethyl~ilicone.~~

61

" 63 64 65

67

69

70 71 72

73 74 75

76 77

I. Ojima, K. Yoshida, and S.-I. Inaba, Chem. Letters, 1977, 429. I. Ojima, Y. Miyazawa, and M. Kumagai, J.C.S. Chem. Comm., 1976,927. V. Prelog, Helv. Chim. Acta, 1953, 36, 308; Bull. SOC.chim. France, 1956, 987. S. Brandange, S. Josephson, and S . VallCn, Acta Chem. Scand., 1977, B31, 179. R. J. P. Corriu and J. J. E. Moreau, Nouv. J. Chim., 1977, 1, 71; J. Organometallic Chem., 1976, 120, 337. M. Cinquini, S . Colonna, F. Cozzi, and C. J. M. Stirling, J.C.S. Perkin I, 1976, 2061. D. N. Harpp, S. M. Vines, J. P. Montillier, and T. H. Chan, J. Org. Chem., 1976,41, 3987. K. Sakaki and S . Oae, Tetrahedron Letters, 1976, 3703. Y. Yamaguchi, A. Komatsu, and T. Moroe, Nippon Nogei Kagaku Kaishi, 1977,51,411. A. Schoofs and A. Horeau, Tetrahedron, 1977, 33, 245. K. S. Hayes, W. D. Hounshell, P. Finocchiaro, and K. Mislow, J. Amer. Chem. SOC., 1977,99,4152. R. ter Heide, J. Chromatog., 1976, 129, 143. J. Irurre-Perez and M. Sanz-Burata, Anales de Quim., 1977,73, 254. B. T. Golding, P. J. Sellars, and A. K. Wong, J.C.S. Chem. Comm., 1977, 570. J. J. C. Scheffer, A. Koedam, and A. Baerheim Svendsen, Chromarographia, 1976,9,425. N. Hayashi, Y. Yamamura, and H. Komae, Chem. and Znd., 1977, 34. M, Yoshikura, H. Kobayashi, and Y. Nakayama, Jap. P. 29 500/1975 (Chem. Abs., 1976,85,99 028).

Monoterpenoids

9

2 General Synthetic Reactions Some useful reviews which discuss applications from, or are of value to, monoterpenoid chemistry include applications of diborane reduction^,^^^^' transition metals in organic synthesis," 0-silylated enolates,'l the Barbier reaction," selenium dioxide ~ x i d a t i o n , 'Birch ~ reduction of a@-unsaturatedcarbonyl compounds,84and homogeneous hydrogenation catalyst^.'^ A broad overview of organoboranes has been published.86 Kagan has reviewed the use of graphite insertion corn pound^.^^ Less substituted @-unsaturated cycloalkenones rearrange by double-bond migration around the ring to the more substituted @-unsaturated cycloalkenones in high yield, catalysed by RhC1,,3H2O; non-conjugated double bonds also migrate into the ring system to become conjugated; e.g., dihydrocarvone rearranges efficiently to [ ( 5 ) :(6)/7 : 11." The thermodynamically favoured isomerization of

(5)

(6)

alkenes (e.g. P-pinene to a-pinene) in sulphur dioxide has been interpreted as a reversible ene reaction;" an earlier Report (Vol. 1, p. 43) erroneously alludes to the reaction of P-pinene with sulphur dioxide to form the corresponding cyclic sulphite. Relatively rapid racemization of p-menth- 1-ene is also observed in sulphur d i o ~ i d e . ' ~The rearrangement of a-ethylenic and a-acetylenic alcohols (e.g. 1,2-dehydrolinalool to citral, cf. Vol. 7, p. 17) via vanadate esters has been discussed.90 Methods for oxidative transformations continue to receive attention. Nickel peroxide on graphite oxidizes geraniol to citral in 89% yield." Three groups r e p ~ r t ~the * - oxidative ~~ rearrangement of tertiary vinyl carbinols. Linalool is conC. F. Lane, Chem. Rev., 1976, 76, 773; Aldrichimica Acta, 1977, 10,41. A. Pelter, Chem. and Ind., 1976, 888. A. P. Kozikowski and H. F. Wetter, Synthesis, 1976, 561. 8 1 J. K. Rasmussen, Synthesis, 1977, 91. 82 C. Blomberg and F. A. Hartog, Synthesis, 1977, 18. 83 N. Rabjohn, Org. Reactions, 1976, 24, 261. 84 D. Caine, Org. Reactions, 1976, 23, 1. 85 A. J. Birch and D. H. Williamson, Org. Reactions, 1976, 24, 1. 86 H. C. Brown, Pure Appl. Chern., 1976,47,49. '' (a)H. B. Kagan, Pure Appl. Chem., 1976,46, 177; ( b ) Chem. TechnoL, 1976,6,510. 88 P. A. Grieco, M. Nishizawa, N. Marinovic, and W. J. Ehmann, J. Amer. Chem. SOC.,1976,98,7102. M. M. RogiC and D. Masilamani, J. Amer. Chem. SOC.,1977, 99, 5219; the entry in Table I under 2,4,4-trimethyl-2-pentene is in error. 90 P. Chabardes, E. Kuntz, and J. Varagnat, Tetrahedron, 1977,33, 1775; see also T. Hosogai, T. Nishida, and K. Itoi, Jap. P. 48 608/1976 (Chem. A h . , 1976,85, 142 638). Last year's Report questioned that only E-citral was formed (Vol. 7, p. 17, ref. 190); the English translation of the full paper clarifies that E :2 ratios vary during the course of the reaction. y1 J. D. Surmatis, U.S.P. 4 005 031 (Chem. Abs., 1977.86, 140 297). See Vol. 4,p. 6 for chromic oxide on graphite oxidations. 92 J. H. Babler and M. J. Coghlan, Synrh. Comm., 1976,6, 469. 93 W. G. Dauben and D. M. Michno, J. Org. Chem., 1977,42,682. 94 P.Sundararaman and W. Herz, J. Org. Chem., 1977,42,813; formula (13)should have a hydrogen atom and not a methyl group at C-2 and the formula for linalool has a misplaced double bond. 78

79

10

Terpenoids and Steroids

verted smoothly into a 1 : 1 mixture of E - and 2-citral using pyridinium chlorochromate (cf.Vol. 6 , p. 8; Vol. 7, p. 30); oxidation of linalool with Collins reagent yields only 10% of E- and 2-citral with the epoxides (7) pred~minating.’~By analogy with nerolidol, chromous chloride would be expected to convert (7) into Eand Z - ~ i t r a l . ’Alkylative ~ enone transposition is achieved by the l ,4-addition of trialkylstannyl-lithium-THFto ap-unsaturated ketones (in contrast the reagent gives 1,2-addition in ether as solvent) followed by alkylation, oxidative destannylation with Collins reagent, and dehydration; (*)-piperitone (8; X = H)is readily synthesized from 4-isopropylcyclohex-2-enone.95Applications of polymeric oxidizing agents include the efficient oxidation of alcohols ( e.g. geraniol, menth01)’~ and allylic halides (e.g. geranyl b r ~ m i d e ) ~to’ aldehydes and ketones with chromic acid on anion-exchange resin, and sensitized oxidation of the enamino-ketone (9)

(7)

(81

(9)

in the presence of polymer-bound Rose Bengal yields buchucamphor (8; X = OH) in 81% overall yield from menthone.” Selenium dioxide allylic oxidation may be effected much more cleanly than with selenium dioxide alone by using t-butyl hydroperoxide in the presence of a catalytic amount of selenium dioxide; e.g., geranyl acetate is oxidized to (E,E)-8-acetoxy-2,6-dimethylocta-2,6-dien-1-01 (48%) and the corresponding aldehyde (7’/0).~’Some further details of the photochemical cleavage of pyruvate esters (Vol. 7, p. 6 ) have been published;’00when so much of these two papers-results, references, and actual paragraphs-are virtually identical, there seems little need for separate publication. An improved method (high to quantitative yields) for oxidizing alcohols, uia dimethylalkoxysulphonium salt, using DMSO-TFAA followed by base at very low temperatures, works well with sterically hindered alcohols; isoborneol yields camphor at low temperature (>go%) but camphene (>85%), by rearrangement-elimination, when the base treatment is at room temperature.”’ Other oxidation papers of interest include alkali hypochlorite oxidation catalysed by RuOz (chrysanthemyl alcohol to chrysanthemaldehyde),lo2 the full paper which extends earlier observations (Vol. 4, p. 6 ) on the oxidation of saturated secondary alcohols with 2,3-dichloro-5,6-dicyano95 96

97

98 99

lo’

W. C. Still, J. Amer. Chem. SOC.,1977,99, 4836. G. Cainelli, G. Cardillo, M. Orena, and S. Sandri, J. Amer. Chem. SOC.,1976,98,6737. For a review of polymers as chemical reagents see ‘Encyclopaedia of Polymer Science and Technology’, Supplement Vol. 1, ed. H. F. Mark and N. B. Bikales, Wiley-Interscience, New York, 1976, p. 468. G. Cardillo, M. Orena, and S. Sandri, Tetrahedron Letters, 1976, 3985; cf Vol. 7, p. 6, ref. 53. H. H. Wasserman and J. L. Ives, J. Amer. Chem. SOC., 1976,98, 7868. M. A. Umbreit and K. B. Sharpless, J. Amer. Chem. Soc., 1977,99,5526. R. W. Binkley, J. Org. Chem., 1976, 41, 3030. S. L. Huang, K. Omura, and D. Swern, J. Org. Chem., 1976.41, 3329. For earlier applications of this reagent see K. Omura, A. K. Sharma, and D. Swern, ibid., 1976, 41,957. A. I. Dalton, H. J. Doran, and R. D. H. Murray, Ger. Offen. 2 642 671 (Chem. Abs., 1977,87,6228).

Monoterpenoids

11

1 , 4 - b e n ~ o q u i n o n e , 'halothiation ~~ as a method for oxidizing primary halides and terminal alkenes (e.g. 0-pinene; low yield) to aldehydes,lo4 and the oxidation of secondary alcohols by trichloroacetaldehyde on alumina (e.g. menthol to menthone, plus some i~omenthone);'~'homogeneous catalytic oxidation of secondary alcohols with 0,-PdC1,-NaOAc fails in the presence of alkenes (e.g. p-menth8-en-3-01). lo6 Benzeneseleninic acid and hydrogen peroxide epoxidizes alkenes [e.g. citronel101, (-)-isopdlegol (10; R = H), E-3,7-dimethyloct-5-en-l-ol and the corresponding acetate]; (11; X=O) and (12; X = 0)are obtained from geraniol (the structure is incorrect in the paper) and linalool respectively by predominant epoxidation distant from the hydroxy-group,Io7 in contrast to epoxidation with t-butyl hydroperoxide-vanadium or -molybdenum complexes (Vol. 5 , p. 6). In the presence of the chiral acetylacetonato-[(-)-N-alkylephedrinato]dioxomolybdenum(~~), cumene hydroperoxide converts nerol into (13) in 33% enantiomeric excess.Io8 Sharpless finds t-butyl hydroperoxide more efficient than cumene hydroperoxide in asymmetric epoxidation in the presence of N-phenylcampholylhydroxamic acid: VO(acac),/S : 1;lo9geraniol yields a 30% enantiomeric excess of (14),'09 the enantiomer of that produced from geraniol by the Japanese group.lo8

Selective catalytic hydrogenation with chromium-promoted Raney nickel is reported (e.g. citral and citronella1 to citronellol);l10 NaHCr2(CO)lo and KHFe(CO), reduction of ap-unsaturated ketones (e.g. citral to citronellal) has been described (cf. Vol. 7, p. 7).l11 The full paper on selective carbonyl reductions on alumina (Vol. 7, p. 7) has been published.'12 Dehydrogenation of monoterpenoid alcohols over liquid-metal catalysts gives aldehydes and ketones in useful ~ i e 1 d s . l ' ~ Sensitized photo-oxidation of substituted cyclohexanone silyl enol ethers yields substituted ~ y c l o h e x - 2 - e n o n e s .For ~ ~ ~example, menthone may yield (8; X = H ) or (15)'14 depending upon the direction of enoli~ation;"~ the corresponding hydroxyJ.-I. Iwamura, Nippon Kagaku Kaishi, 1977, 10U3. L. A. Paquette, W. D. Klobucar, and R. A. Snow, Synth. Comm., 1976,6,575. G. H. Posner, R. B. Perfetti, and A. W. Runquist, Tetrahedron Letters, 1976, 3499. T. F. Blackburn and J. Schwartz, J.C.S. Chem. Comm., 1977, 157. 107 P. A. Grieco, Y. Yokoyama, S. Gilman, and M. Nishizawa, J. Org. Chem., 1977, 42, 2034. lo* S.-I. Yamada, T. Mashiko, and S . Terashima, J. Amer. Chem. SOC.,1977,99, 1988. R. C . Michaelson, R. E. Palermo, and K. B. Sharpless, J. Amer. Chem. SOC.,1977,99, 1990. P. S. Gradeff and G . Formica, Tetrahedron Letters, 1976, 4681; cf. Vol. 4, p. 17. G. P. Boldrini, A. Umani-Ronchi, and M. Panunzio, Synthesis, 1976, 596. G. H. Posner, A. W. Runquist, and M. J. Chapdelaine, J. Org. Chem., 1977,42, 1202. Y. Saito and Y. Ogino, Nippon Kagaku Kaishi, 1976, 1018. E. Friedrich and W. Lutz, Angew. Chem. Internat. Edn., 1977,16,413. "'For a recent discussion of regiospecific synthesis of trimethylsilyl enol ethers see G . M. Rubottorn, R. C. Mott, and D. S . Krueger, Synth. Comm., 1977,7, 327. lo3

Terpenoids and Steroids

12

ketones (16) and (17; major product) are also reported (with no supporting data) from respective competing ene reacti~ns.''~a-Nitro-ketones (e.g. 3-nitrocamphor) are formed by treating trimethylsilyl enol ethers with nitronium tetrafluoroborate.ll6 a-Epoxysilanes are readily formed by what is essentially reductive nucleophilic acylation of a carbonyl group from a-chloro-a-trimethylsilyl carbanion; nopinone yields (18),'17 from which one should obtain myrtanal in good yield.

Q

o (15)

Q: 90 (16)

(17)

(18)

Azides [e.g. (+)-neomenthyl azide; no physical data reported] are formed efficiently''' by inversion, from the corresponding alcohols and diphenylphosphoryl azide, in the presence of triphenylphosphine and diethyl azodicarboxylate [which has also been used for esterification with inversion (Vol. 5 , p. 334); for a related esterification of (-)-menthol see ref. 1191; a conceptually similar synthesis also yields (+)-neomenthyl azide.'" Cyanoselenenylation of a1dehydesl2l and of alcohols122has been reported; thus treatment of geraniol with o-nitrophenyl selenocyanide-Bun3P-THF yields the selenide (19) which can be converted into the

(19)

known (Vol. 4, p. 6, ref. 27) linalool epoxide (12; X=O) with 30% hydrogen peroxide-pyridine-CH2Clz.'22 Further papers of interest report regeneration of ketones from oximes using NOCl,123 synthesis of acetamides from alcohols with SOzC12,124alkylation of

'19

'" 12'

I. Sh. Shvarts, V. N. Yarovenko, M. M. Krayushkin, S. S. Novikov, and V. V. Sevost'yanova, Bull. Acad. Sci.,U.S.S.R.,Div. Chem. Sci., 1976, 25, 1589. C. Burford, F. Cooke, E. Ehlinger, and P. Magnus, J. Amer. Chem. Soc., 1977,99,4536. B. Lal, B. N. Pramanik, M. S. Manhas, and A. K. Bose, Tehahedron Letters, 1977, 1977; the presumed (+)-neomenthyl azide is named (+)-menthy1 azide in this paper. 0. Achmatowicz and G. Grynkiewicz, Tetrahedron Letters, 1977, 3179. Y. Chapleur, B. Castro, and B. Gross, Synth. Comm., 1977, 7, 143; the azide is poorly named and based upon an incorrect structure for (-)-menthol. P. A. Grieco and Y. Yokoyama, J. Amer. Chem. SOC.,1977,99,5210. T. Kametani, H. Nemoto, and K. Fukumoto, Heterocycles, 1977, 6 , 1365; see also P. A. Grieco, S. Gilman, and M. Nishizawa, J. Org. Chem., 1976,41, 1485. C. R. Narayanan, P. S. Ramaswamy, and M. S. Wadia, Chem. and Znd., 1977,454. K. Takeuchi, M. Nojima, and N. Tokura, J.C.S. Perkin Z, 1976, 2205.

Monoterpenoids

13

ketones with a dianion of ethyl a - m e r c a p t ~ a c e t a t e , 'the ~ ~ addition of l-lithiocyclopropyl phenyl sulphide to saturated and @-unsaturated ketones,'26 thio-. cyanate and selenocyanate formation,127and the formation of a-chloro-ketones via dichloromet hyl -lit hium. '28

3 Biogenesis, Occurrence, and Biological Activity Last year's Report propagated an error in Chemical abstract^;"^ Opdyke has published further monographs on fragrance raw materials, including data on legal status and toxi~ology.'~"Two useful books on perfume technology have a ~ p e a r e d ' ~ ~and . ' ~ 'the industrial importance of monoterpenoids and essential oils has been reviewed.'33 The biennial review of essential oils by Guenther et and a collection of 6 4 essential oil analyses (emphasizing g.c. and m.s. data, with references to 1974 in some cases)13s have been published. The well known problems of essential oil composition studies have been reviewed. 13' The biosynthesis of monoterpenoids is included in a book devoted largely to unfortunately some formulae have been drawn carelessly [e.g. menthol (p. 282)' loganin (p. 284), presqualene pyrophosphate (p. 209)]. Other reviews in this section cover monoterpenoid and sesquiterpenoid b i o s y n t h e s i ~biogenetic-type ,~~~ rearrangements of monoterpenoids and related model the biosynthesis of loganin-derived alkaloids,'40 and monoterpenoid alkaloid chemistry.14' Microbial transformations of monoterpenoids have been reviewed with a literature coverage to 1973/74.14'" 125 K. Tanaka, N. Yamagishi, R. Tanikaga, and A. Kaji, Chem. Leffers,1977, 471. B. M. Trost, D. E. Keeley, H. C. Arndt, J. H. Rigby, and M. J. Bogdanowicz, J. Amer. Chem. SOC., 1977, 99, 3080; see also ref. 3. lZ7 A. Arase and Y. Masuda, Chem. Letters, 1976, 1115. 128 H. Taguchi, H.Yamamoto, and H. Nozaki, Bull. Chem. SOC. Japan, 1977, 50, 1592. Ref. 84 in Vol. 7, p. 8 should read D. L. J. Opdyke, Food and Cosmetics Toxicol., 1975, 13 suppl., 681 (Special Issue 11; Monographs on Fragrance Raw Materials); for the first special issue in this series, see D. L. J. Opdyke, ibid., 1974, 12 suppl., 807. 13* D. L. J. Opdyke, Food and Cosmefics Toxicol., 1976, 1 4 suppl., 659 (Special Issue 111; Monographs on Fragrance Raw Materials); additional monographs have been published periodical!y by D. L. J. Opdyke, beginning ibid., 1973, 11, 95. For recent monographs see D. L. J. Opdyke, ibid., 1976, 14, 197, 307,443,601. 131 M. Billot and F. V. Wells, 'Perfumery Technology. Art: Science: Industry', Ellis Horwood, Chichester, England, 1975. 13* R. W. James, 'Fragrance Technology. Synthetic and Natural Perfumes', Noyes Data Corporation, Park Ridge, New Jersey, 1975; this useful review covers the US. Patent literature from January 1964 (U.S. P. 3 117 982) until mid-1974 (U.S. P. 3 819 737). 133 R. E. Erickson, Lloydia, 1976, 39, 8. For an earlier review of industrial syntheses which was inadvertently omitted from these Reports, see W. Hoffmann, Seifen-Ole Ferte- Wachse, 1975, 101, 89. 134 E. Guenther, G. Gilbertson, and R. T. Koenig, Analyt. Chem., 1977, 49, 83R; these biennial reviews (see also Vol. 6, p. 10, ref. 70) are particularly important since the limited space available for these Reports allows little detailed coverage of this field. 135 Y. Masada, 'Analysis of Essential Oils by Gas Chromatography and Mass Spectrometry', Wiley, 1976. 136 J. Garnero, Parfums, Cosmet., Aromes, 1977, 14, 31. 137 W. R. Nes and M. L. McKean, 'Biochemistry of Steroids and other Isopentenoids', University Park Press, Baltimore, 1977, pp. 271-284. 13' M. Gleizes, Annie BioL, 1976,15, 101. 139 R. M. Coates, Fortschr. Chem. org. Naturstoffe, 1976, 33, 73. D. S . Bhakuni, J. Sci. Ind. Res., India, 1976, 35, 449; see also A. I. Scott, Recent A d v . Phytochem., 1975, 9, 189. 141 V. Snieckus, in 'Alkaloids', ed. K. Wiesner, MTP International Review of Science, Organic Chemistry, Series Two, Vol. 9, Butterworth, London, 1976; Chapter 7, pp. 191-263. 1410 K. Kieslich, 'Microbial Transformations of Non-Steroid Cyclic Compounds', Wiley, New York, 1976; pp. 56-70. lZ6

'''

14

Terpenoids and Steroids

The number of computer-generated monoterpenoid carbon skeletons exceeds those which are presently HLADH oxidation of 3-methylpentane-1,3,S-triolyields, after silver oxide oxidation, (3s)-(+)-mevalonolactone of 14% optical p ~ r i t y . ’ ~ ’The synthesis of [4,5-13C2]MVA using known procedures was omitted from last year’s Report,144 and another synthesis of (*)-mevalonolactone has been rep~rted.’~’ There have been significant advances in our knowledge of monoterpenoid biosynthesis this year, particularly with the painstaking work of Banthorpe’s group in examining partially purified enzyme systems and stereochemical implications; 146-150 further papers from Poulter’s group on biosynthetic model s t ~ d i e s , ’ ~which ~ - ’ ~ may ~ be usefully read in conjunction with some of Banthorpe’s work on the irregular m ~ n ~ t e t - p e n ~ iare d ~reviewed , ~ ~ ~ ”in~the ~ ~Artemisyl, ~ ~ ~ Santolinyl, Lavandulyl, Chrysanthemyl section. In one of them,’51Poulter proposes a simple numerical method for describing the various linkings of isoprene units and suggests that it will overcome the confusion caused by some workers (including Poulter) who describe ‘the tail of isoprene as its head’.lS4 Monoterpenoid biosynthesis in excised epidermis of Majorana hortensis has been examined’55 and Banthorpe has made the interesting observation that the highest rates of incorporation of biosynthetic precursors with Tanacetum vulgare occur in uivo during the plant’s dormant phase (75-fold increase over the growing phase).I4’ The incorporation of [2-14C]MVA into monoterpenoids (e.g. geraniol) in a microbial system (Ceratocystismoniliformis)results in a symmetrical distribution between the IPP- and DMAPP-derived moieties of the monoterpenoid ske1et0n.l~~ Feeding experiments with [2-’4C,S-3H2]MVA and Citrus natsudaidai, Perilla frutescens, and Cinnamomum camphora have shown that (+)-limonene, (-)-perillaldehyde, and (+)-camphor respectively are biosynthesized with retention of all four tritium atoms, indicating symmetrical distribution between IPP and DMAPP derivation; the results are also consistent with a biosynthetic pathway involving geranyl pyrophosphate (GPP) neryl pyrophosphate (NPP) isomerization via a non-oxidative pathway.ls7 An alternative suggestion, which has

+

143

D. H. Smith and R.’ E. Carhart, Tetrahedron, 1976,32,2513. A. J. Irwin and J. B. Jones, J. Amer. Chem. SOC.,1977,99, 556.

144

J. R. Hanson and R. Nyfeler, J.C.S. Chem. Comm., 1976, 72; see Vol. 6, p. 10, ref. 73.

14*

145 146

14’

H. Omichi, H. Machida, T. Miyakoshi, and S. Saito, Nippon Kugaku Kaishi, 1977, 1021. K. G. Allen, D. V. Banthorpe, B. V. Charlwood, and C. M. Voller, Phytochemistry, 1977,16,79; tho numbering of formulae (1)and (3) in this paper should be reversed. D. V. Banthorpe, S. Doonan, and J. A. Gutowski, Phytochemistry, 1977, 16, 8 5 ; the reference to

3,3-dimenthylallyl alcohol in the Experimental is obviously a typographical error and formula (2) in figure 3 should be formula (12). 14’ D. V. Banthorpe, G. A. Bucknall, J. A. Gutowski, and M. G. Rowan, Phytochemistry, 1977,16, 355. 149 D. V. Banthorpe, J. Mann, and I. Poots, Phytochemistry, 1977,16, 547. 150 D. V. Banthorpe, B. V. Charlwood, G. M. Greaves, and C. M. Voller, Phyrochemistry, 1977,16, 1387. 15’ C. D. Poulter, L. L. Marsh, J. M. Hughes, J. C. Argyle, D. M. Satterwhite, R. J. Goodfellow, and S. G. Moesinger. J. Amer. Chem. SOC., 1977,99, 3816. lS2 C. D. Poulter and J. M. Hughes, J. Amer. Chem. SOC.,1977, 99, 3824. lS3 C. D. Poulter and J. M. Hughes, J. Amer. Chem. SOC.,1977,99,3830; corrigendum, ibid., p. 7400. lS4 See, for example, I. L. Finar, ‘Organic Chemistry’, Vol. 2, 5th Edn., Longman, London, 1975, p. 3551 155 R. Croteau, PluntPhysiol., 1977, 59, 519. E. Lanza and J. K. Palmer, Phytochemistry, 1977, 16, 1555; for a review of some earlier work on volatile odorous materials (including monoterpenoids) produced by micro-organisms see R. P. Collins, Lloydia, 1976, 39, 20. T. Suga, T. Shishibori, and T. Hirata, Chem. Letters, 1977, 937. For previous discussion of these two pathways see Vol. 4, p. 255 and VoI. 7, pp. 181, 186.

Monoterpenoids

15

been made to account for results with soluble enzymes from Citrus limonum where a substrate isomerization is not observed,lT8is that both GPP and NPP produce enzyme-bound carbocations, whose conformations on species-specific cyclases determine their direct incorporation into monoterpenoids; the low in vitro incorporation of substrates into limonene with these soluble enzymes1ss may be consistent with Banthorpe's similar o b s e r v a t i ~ n with ' ~ ~ cell-free extracts of Tuna cetum vulgare, Artemisia annua, and Santolina chamaecyparissus, which is attributed to seasonally dependent enzymes converting IPP, DMAPP, GPP, and NPP into water-soluble products, possibly as a salvage system regulating the nonphysiological levels of monoterpenoid precursors. For example, the epoxide (1 1; X = 0)and the corresponding trans,trans-3,7-dimethylocta-2,5-diene-l,7-diol are major products from GPP substrate, with minor products involving C-2-C-3 epoxidation; it is suggested that the decomposition of such salvage products may account for difficulties encountered in the purification of monoterpenoids biosynthesized from radioactive exogenous The full paper on Banthorpe's previously reported (Vol. 2, pp. 13, 202) work on the biosynthesis of artemisia ketone (20; X=O) in Artemisia annua and Santolina chamaecyparissus includes some new findings, namely the non-incorporation of dimethylvinylcarbinol (DMVC) and the cis- and trans -chrysanthemic acids and alcohols in uivo, and the asymmetry of labelling of artemisia ketone (20; X=O) derived from IPP and DMAPP in S. chamaecyparissus via the 'two pool hypothesis' (see Vol. 7, p. 184). (+)-trans-Chrysanthemyl alcohol (21) is also reported to serve as an excellent precursor of the pyrethrins in Chrysanthemum cinerariaefolium (see Vol. 6 , p. 1l).146To overcome difficulties of substrate incorporation due to possible compartmentation, a second paper'47 reports biosynthesis using cell-free extracts in vitro. IPP, DMAPP, and particularly DMVC (cf.Vol. 7 , p. 185; difficulties encountered in purifying DMVC pyrophosphate did not allow its comparison with IPP and DMAPP) were effective precursors of artemisia alcohol (20; X = H,OH), artemisia ketone (20; X = 0),trans-chrysanthemyl alcohol (21) (whose interconversions were also catalysed), and lavandulol (22); interestingly, neither (21) nor (22) has been detected in the essential oils of A. annua or S. chamaecyparissus. Whereas cis-chrysanthemyl alcohol and its pyrophosphate are effectively converted into (20; X=O) and (20; X=H,OH) also, little effective incorporation of GPP, NPP, and linaloyl pyrophosphate was observed. Artemisia ketone (20; X = 0)and trans-chrysanthemyl alcohol (21) were effectively formed from [Me-14C]DMVC pyrophosphate with the now well established asymmetry of labelling (cf. Vol. 7, p. 184), raising the question of an obligatory role of DMVC in monoterpenoid biosynthesis and its relation to a metabolic pool of protein-bound DMAPP. Other important observations from this most important paper are the involvement of sulphydryl groups in the metabolic pathway and of a dehydrogenase system in the formation of artemisia ketone (20; X=O) rather than a mixedfunction oxidase system dependent upon cytochrome P450. A tentative biosynthetic scheme has been proposed (Scheme 1; alcohol intermediates are shown for clarity) to accommodate these observations in which artemisyl and chrysanthemyl compounds are now suggested to be on divergent pathways (for earlier obserL. Chayet, C. Rojas, E. Cardemil, A. M. Jabalquinto, R. Vicuna, and 0. Cori, Arch. Biochem. Biophys., 1977,180, 318; for earlier work see Vol. 4, p. 255.

16

Terpenoids and Steroids

Scheme 1

vations see Vol. 2, p. 13; Vol. 7, p. 185) beginning with the ylide form of the protein-bound pool of DMAPP [e.g. (23)]. The paper also reports reliable methods A comparison for the purification of pyrophosphate esters of substrate of the incorporation of [2-14C]- and [4-I4C]-geraniol and -nerol into the cooccurring regular (borneol, trans-thujan-3-one, and pinocamphone) and irregular [artemisia ketone (20; X=O)] monoterpenoids in A. annua is consistent with intact incorporation of Clo precursors into the regular monoterpenoids, but extensive degradation must occur in artemisia ketone (20; X = 0)biosynthesis to account for the extensive scrambling of the label from [2-I4C]geraniol over all ten carbon atoms.1s0 Oxidative degradation, via the epoxide (11; X=O),14' to yield a C s fragment which is incorporated intact into artemisia ketone (20; X = 0),along with a second Cs moiety which may arise from simpler precursors, provides a plausible explanation of these result^.'^' It is not possible to evaluate the significance of thiamine in artemisyl biosynthesis at present.159 Some progress has been made towards understanding the conversion of MVA, via 1 0-hydroxygeraniol (24),I6O into iridoids and secoiridoids; the suggestion that two distinct biosynthetic pathways may exist, depending upon whether iridoid glucosides, containing a highly oxidized cyclopentane ring, or secoiridoids (and indole alkaloids) are being formed (Vol. 7, p. 22, ref. 230), has received additional support. Whereas the secoiridoid and indole alkaloid pathway usually involves the If('

160

G. E. Risinger, K. Karimian, S. Jungk, and R. L. Bell, 174th A.C.S. Meeting, Chicago, August 1977, Abstracts ORGN, No. 140. The paper by K. M. Madyastha, T. D. Meehan, and C. J. Coscia, Biochemistry, 1976, 15, 1097, which was inadvertently omitted from last year's Report, discusses a cytochrome P450-dependent hydroxylase involved in biosynthesis of (24).

Monoterpenoids

17

equal labelling o f C-3 and C-11 from [2-I4C]MVA (see Vol. 1, p. 229*), similar feeding experiments with [2-l4C]MVA and Lamium amplexicaule, Deutzia crenata, and Galium spurium have established that the radioactive label essentially resides only at C-3 (as well as C-7) for deutzioside (25; X = H), scabroside (25; X = OH), lamioside (26), asperuloside (27), lamiide (28; X = OH, R = H), and ipolamiide (28; R=X=H).16' In these cases, this result may be interpreted in terms of cyclization of a precursor such as 10-hydroxygeraniol (24) to a methylcyclopentane intermediate without eqivalence of the carbon atoms which give rise to C-3 and C-11 [this is not so with verbenalin (Vol. 1, p. 231)'62" and plumieride;16*' with the latter randomization has been observed]. Formation of the C-11 oxygenated iridoids (27), (28; R = X = H), and (28; X = OH, R = H) seems to involve the sequence CH3 -+ C H 2 0 H + CO,R after the initial cyclization (see also on deutzioside [whose stereochemistry is Vol. 3, p. 254). In a second pape? now confirmed as (25; X = H)] biosynthesis in Deutzia crenata, Inouye et al. provide evidence in favour of the biosynthetic sequence 10-hydroxygeraniol (24) -+ iridodial (29; R = H) -+ iridodialglucoside (29; R = P-Glu) -+ deutzioside (25; X=H). It is suggested that this pathway may also apply to the biosynthesis of lamioside (26), ipolamiide (28; R = X = H ) , lamiide (28; X = O H , R = H ) , and

' ~ ~ cell-free asperuloside (27)163as discussed in the earlier paper. 16' C r ~ t e a u ,using preparations from Salvia officinalis, has shown that NPP independently forms a-terpineol, limonene, and 1 , 8 - ~ i n e o l e , with ' ~ ~ no evidence for any free inter16' 16'

163 164

16'

H.Inouye, S. Ueda, and s. Uesato, Tetrahedron Letters, 1977, 709. ( a )J. E.S. Hueni, H. Hiltebrand, H. Schmid, D. Groeger, S. Johne, and K. Mothes, Experientia, 1966, 22,656; ( b ) D. A. Yeowell and H. Schmid, ibid., 1964.20, 250. H . Inouye, S. Ueda, and S. Uesato, Tetrahedron Letters, 1977, 713. R. Croteau and W. D. Loomis, Znternat. Flavours Food Additives, 1975,6,292; this excellent review of monoterpenoids was omitted from Vol. 7. R. Croteau and F. Karp, Arch. Biochem. Biophys., 1976, 176, 734; this is another example of a monoterpenoid paper which is not recorded in the Terpenoids section of Chemical Abstracts (see also refs. 164, 166, 167).

* The numbering system used for the iridoids in this Report conforms to that used in earlier recent Monoterpenoid Reports; in the Vol. 1 references, however, a different numbering system was used.

Terpenoids a n d Steroids

18

mediates between NPP and 1 , 8 - ~ i n e o l e ; the ' ~ ~ cyclase activity may involve enzyme thiol-bound intermediates.'66 An enzyme preparation, containing both cyclase and dehydrogenase, also converts NPP into borneol and camphor.167 The recent observation (Vol. 7, p. 18.5) that a-terpineol is a more effective precursor of (+)-thuj-3-one (30) (see Vol. 6, p. 11) than p-menth-l-en-4-01 in cell-free extracts of Tanacetum vulgare is now supported by in uivo feeding experiments with (3RS)-[2-'4CC,2-3Hz]MVA,(3RS,2R)-[2-'4C,2-3Hl]MVA, (3RS,2S)-[2-'4C,2-3Hl]MVA, and [9-'4C,4-3H1,10-3H,]-a-terpineol and considered to be consistent with the biosynthetic mechanism (Scheme 2) which involves the stereospecific migration of the pro-(2S) hydrogen of MVA in one of the two 1,2-shifts proposed in forming (+)-thuj-3-one (30) via the corresponding neothujan-3-01 (31).14'

Scheme 2

Cantharidin (Vol. 1, p. 228; Vol. 5, p. 42) is biosynthesized from farnesol by degradation but not from geraniol.16' Attempts to investigate boll weevil (Anthonornus grandis) pheromone biosynthesis have identified isomerization, dehydration, and oxidation of the pheromone alcohols, and anticipated allylic oxidation of myrcene and limonene, but no evidence for the cyclization of acyclic precursors. 16' The aggregation pheromones of bark beetles have been r e ~ i e w e d . ' ~Ips ' calligraphus responds to ipsdienol only in the presence of the cis-verbenol (32); large additional concentrations of the enantiomer (lR,4R,jR)-(32) reduce beetle r e ~ p 0 n s e . lS-(-)-Ipsenol, ~~ the pheromone of Ips grandicollis, increases the response of I. avulsus to its own pheromone ip~dienol.'~' I

(32) 166

167

170

17'

17'

R, Croteau and F. Karp, Arch. Biochem. Biophys., 1977, 179, 257; for an earlier uncited paper on 1,8-cineole biosynthesis in Rosmarinus officinalis, see B. Achiiladelis and J. R. Hanson, Phytochemistry, 1968,7, 1317. R. Croteau and F. Karp, Biochem. Biophys. Res. Comm.,1976,72.440. M. G . Peter, W.-D. Woggon, C. Schlatter, and H. Schmid, Helu. Chim. Acta, 1977,60, 844, 1262. P. A. Hedin, J. Chem. Ecol., 1917, 3 , 279. J. P. VitC and W. Francke, Naturwiss., 1976,63, 550; the absolute configuration of (+)-trans-verbenol in figure 5 is incorrect (see Vol. 7, p. 41). J. P. VitB, D. Klirnetzek, G. Loskant, R. Heddon, and K. Mori, Naturwiss., 1976,63,582; see ref. 485 for the synthesis of these enantiomers. R. Heddon, J. P. VitC, and K. Mori, Nature, 1976, 261, 696.

Monoterpenoids

19

The limited space available for this Report allows for little discussion of essential papers of chemotaxonomic importance from this year's literature will be discussed in next year's Report (i.e. biennially). Apparatus for isolating trace volatile component^'^^ and also for undergraduate laboratory essential oils extract i ~ n has ' ~ been ~ described. Methods of analysis of 1,8-cineole in essential oils have been ~ u b 1 i s h e d . lEssential ~~ oil composition studies of interest are of Tagetes lunulafa (tagetone, dehydrotagetone, and d i h y d r ~ t a g e t o n e ) , 'Eucalyptus ~~ species (cis-piperitol, cis-p-menth-2-en-1-01, and frans-p-menth-Z-en-l-~I),'~~ Chaerophyllum hursutum (fenchyl acetate),'78 Piper nigrum (further oxygenated menthadienol~),"~Hyssopus officinalis [no reference is made to the earlier communication by the same author (Vol. 7, p. 9); myrtenol methyl ether is an additional component],180Arfemisia pontica (artemisia ketone and not isoartemisia ketone as stated),'" and Sanfolina virens and S. chamaecyparissus.18*The surprising feature of the last paper is the claim to have isolated a-santolinenone,lR2which is generally believed not to exist;lR3incredibly the claim is not substantiated by spectral data and recent analytical work on these species is not cited. The bacteriostatic behaviour of six chemotypes of Thymus vulgaris has been examined.lR4 Papers from the symposium on the chemistry, biochemistry, and insecticidal action of natural and synthetic pyrethroids (Helsinki 1974, Third I.U.P.A.C. International Congress on Pesticide Chemistry)'8' and the proceedings of a symposium on synthetic pyrethroids held at the 172nd A.C.S. Meeting (San Francisco, 1976)186 have been published. Other pyrethroid papers of interest include 13Cn.m.r. spectra of synthetic pyrethroids (cf. Vol. 7, p. 20),lE7g.1.c. analysis of permethrin"* and b i ~ r e s m e t h r i nfurther , ~ ~ ~ work (Vol. 7, p. 10) on permethrin metabolism in rats'" R. A. Flath and R. R. Forrey, J. Agric. Food Chem., 1977, 25, 103; T. H. Schultz, R. A. Flath, T. R. Mon, S.B. Eggling, and R. Teranishi, ibid., 1977, 25, 446; S. S. Chang, F. M. Vallese, L. S. Hwang, 0. A. L. Hsieh, and D. B. S. Min, ibid., 1977, 25, 450. 174 A. A. Craveiro, F. J. A. Matos, and J. W. de Alencar, J. Chem. Educ., 1976,53, 652. ''' ( a ) A. M. Humphrey, J. H. Greaves, B. E. Kent, W. S. Matthews, D. A. Moyler, R. G. Perry, J. Ridlington, R. A. Stocks, and G. Watson, Analyst, 1977,102,607; C. L. Goodwin and A. E. Squillace, Phytochemistry, 1976,15,1771; (b)C. H. Brieskorn and W. Schlicht, Pharm. Actu Helu., 1976,51,133. 176 J. Calderon, J. L. Munoz, L. Quijano, and T. Rios, Rev. Latinoamer. Quim., 1976,7, 114 (Chem. Abs., 1977,86,47 204). 177 E. V. Lassak, 10th I.U.P.A.C. International Symposium on the Chemistry of Natural Products, Dunedin, New Zealand, 1976, Abstract D27. 17' F. W. Kudrzycka-Bieloszabska and K. Glowniak, Actu Polon. Pharm., 1976, 33, 395. 17' J. Debrauwere and M. Verzele, J. Sci. Food Agric., 1975, 26, 1887; cf. Vol. 6, p. 13. D. Joulain, Riuista Ital. Essenze-Profumi, Piante Ofic., Aromi, Suponi, Cosmet., Aerosol., 1976, 58, 479. M. Hurabielle, F. Tillequin, and M. Paris, P l u m Med., 1977, 31, 97. 182 V. A. Ushakov, D. A. Murav'eva, and L. A. Bakina, Chem. Natural Compounds, 1976,12,597. 183 L. H. Zalkow, D. R. Brannon, and J. W. Uecke, J. Org. Chem., 1964.29,2786; A. F. Thomas and B. Willhalm, Tetrahedron Letters, 1964, 3775. 184 M. S. de Bouchberg, J. Allegrini, C. Bessiere, M. Attisso, J. Passet, and R. Granger, Riuistu Ital. Essenze-Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1976, 58, 527. lS5 Pesticide Science, 1976,7, issue 3. la6 'Synthetic Pyrethroids', ed. M. Elliot, ACS Symposium Series, Volume 42, Washington, American Chemical Society, 1977. N. F. Janes, J.C.S. Perkin I, 1977, 1878. M. Horiba, A. Kobayashi, and A. Murano, Agric. and Biol. Chem. (Japan), 1977, 41, 581. I. Camoni, E. Chiacchierini, A. di Domenico, R. Iachetta, and A. L. Magri, Ann. Chim. (Italy), 1976, 66,439. 190 L. C. Gaughan, T. Unai, and J. E. Casida, J. Agric. Food Chem., 1977, 25, 9. 170

20

Terpenoids and Steroids

and lactating goats,”’ the asymmetric synthesis of R-(-)-allethr~lone,”~and the synthesis and insecticidal properties of some [2-(5-aryl)furyl]methyl chrysanthernate~.’~~ Many papers from the patent literature on pyrethroids and juvenile hormones cannot be included in this Report. Papers have reported the synthesis and activity of monoterpenoid juvenoids, including geranyl pyridyl ether^''^ and geranyl alkyl ethers and amines and their e p o ~ i d e s . ~ ~ Further ’ , ~ ’ ~ papers in this section include a report of the potent lung toxicity of perillaket~ne,”~ the observation that the malodorous water contaminant 2-methylisoborneol has the 1-R -ex0 configuration,19*and that fenchyl methyl L-aspartylaminomalonate is 2 X lo4 times sweeter than sucrose.199 4 Acyclic Monoterpenoids

Terpenoid Synthesis from Isoprene.-Syntheses of the useful synthons (33) and (34) have been reported.”’ The vinyl-oxygen bond of diketen is selectively cleaved by Me,SiCH,MgCl-NiCl, to yield the synthon (35)”* which is readily converted into the dicopper dienolate (Vol. 7, p. 14) and prenylated to yield (36; X = CO,H) after hydrolytic work-up and desilylation; (36; X = C 0 2 H ) yields

(33)

(34)

(35)

(36)

geranic acid (E:Z/91: 9) on treatment with strong base (see Vol. 5 , p. 12).202 Prenylation of a previously reported phenylsulphoxide synthon [Vol. 7, p. 10, formula (9)] yields, after desulphurization, linalool in 78% yield.“, Much of the telomerization work this year is either closely related or similar to work reported previously. This includes tail-to-tail isoprene dimerization [Pd(PEt),-CO,] to (37) which is extensively isomerized on prolonged reaction,204 191 192

19‘ 195

‘91

19’ 19* 199

’On 201

2n2

203 204

L. M. Hunt and B. N. Gilbert, J. Agric. Food Chem., 1977,25,673. M. Kitamoto, K. Kameo, S. Terashima, and S.-I. Yamada, Chem. and Pharm. Bull. (Japan), 1977,25, 1273. Y. P. Volkov, I. I. Zavedeeva, P. I. Zimov, G. M. Zubova, and A. F. Oleinik, Khim. Farm. Zhur., 1976, 10, 26. H. Solli, H. B. Madsen, P. L. Holst, and P. D. Klemmensen, Pesticide Science, 1976, 7 , 503. R. S. Deshpande, H. P. Tipnis, and V. M. Kulkarni, Indian J. G e m . , 1976,14B, 979. J. W. Patterson and M. Schwarz, J. Insect. Physiol., 1977, 23, 121. B. J. Wilson, J. E. Garst, R. D. Linnabary, and R. B. Channell, Science, 1977, 197, 573. N. F. Wood and V. L. Snoeyink, J. Chromatog., 1977, 132, 405. M. Fujino, M. Wakimasu, M. Mano, K. Tanaka, N. Nakajima, and H. Aoki, Chem. and Pharm. Bull. (Japan), 1976,24,2112. J. Paust, W. Reif, and H. Schumacher, Annalen, 1976, 2194, K. Itoh, T. Yogo, and Y. Ishii, Chem. Letters, 1977, 103. K. Itoh, M. Fukui, and Y.Kurachi, J.C.S. Chem. Comm., 1977, 500; reference 3 of this paper should refer to p. 4925 and not p. 492. P. J. R. Nederlof, M. J. Moolenaar, E. R. de Waard, and H. 0. Huisman, Tetrahedron, 1977, 33, 579. A. Musco, J. Mol. Catalysis, 1975/1976,1, 443.

Monoterpenoids

21

dimerization .to (37) in up to 90% yield and/or to 2,7-dimethylo.cta-2,7-dien-l-ol and 2,7-dimethylocta-l,7-dien-3-ol, or to various acetates depending upon the palladium catalyst/water/acetic acid/C02 . ratio,205 dimerization to (37)

exclusively or with accompanying 8-alkoxy-2,7-dimethylocta- 1,6-diene and 3alkoxy-2,7-dimethylocta- 1,7-diene (palladium catalysts-alcohols) (cf. Vol. 6, p. 15, ref. 115),206and considerable product variation is reported (palladium catalystsalcohols) in another paper (cf. Vol. 6, p. 15, ref. 116);207thus the head-to-tail and E-8-methoxy-3,7-dimethylocta1,6dimers E-2,6-dimethylocta-l,3,7-triene diene and the tail-to-tail dimer 2,7-dimethylocta- 1,7-diene may each be formed in high yield.207 Further reports of myrcene formation by telomerization of isoprene using sodium and amines (cf. Vol. 6, p. 15)'08 or using palladium catalystsalkoxides or -phenoxides, with accompanying ocimene formation (see Vol. 7, p. 12),209have been published. The catalytic activity of [Ni(PPh3)2C12]-NaBH4-amine in isoprene dimerization is enhanced to a maximum by water with little effect on product distribution (see Vol. 7, p. 11).210 The influence of triorganophosphine-palladium salts on the reductive dimerization of isoprene in the presence of formic acid and triethylamine has been investigated mechanistically and synthetically; the head-to-tail dimers 2,6-dimethylocta-1,7-dieneand 3,7-dimethylocta-1,6-diene,the former usually predominating, may be formed in up to 79% yield; preferential hydrochlorination allowed separation from tail-to-tail dimers and elaboration into citronellol and its double-bond isomer and into linalool.*" Another synthesis of citronellol (50% overall yield) involves dimerization of isoprene [(Et0)4Zr-Et2A1C1-Ph3P] to 3E,6Z-2,6-dimethylocta-1,3,6-triene,selective 1,4hydrogenation [Cr(CO),PhC02Me-H2], hydrozirconation, and oxidation.212 Sodamide in ethylenediamine isomerizes the well known telomer N-(3,7-dimethylocta-2,6-dienyl)dialkylamineto N-(3,7-dimethylocta-1,3-dienyl)dialkylamine,which is hydrolysed to dihydrocitral in good yield,213in contrast to elimination in the absence of solvent (Vol. 7, p. 12), where metallation occurs at the &position. Further syntheses with isoprene units are discussed in the next section. 205

206

207 208

209 210

L. I. Zakharkin, S. A. Babich, and I. V. Pisareva, Bull. Acad. Sci., U.S.S.R., Div. Chem. Sci., 1976,25, 1531. L. I. Zakharkin and S. A. Babich, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1976, 25, 1967. H. Yagi, E. Tanaka, H. Ishiwatari, M. Hidai, and Y. Uchida, Synthesis, 1977,334. K. Takabe, A. Agata, T. Katagiri, and J. Tanaka, Synthesis, 1977, 307; A. Murata, S. Tsuchiya, A. Konno, J. Tanaka, and K. Takabe, Ger. Offen. 2 542 798 (Chem. A h . , 1976,85,94 544). S . Akutagawa, Jap. P. 70 70511976 (Chem. Abs., 1976,85, 143 332). I. Mochida, K. Kitagawa, H. Fujitsu, and K. Takeshita, Chem. Letters, 1977,417. J. P. Neilan, R. M. Laine, N. Cortese, and R. F. Heck, J. Org. Chem., 1976, 41,3455. H. Yagi, M. Shirado, M. Hidai, and Y. Uchida, Yukagaku, 1977, 26, 232. M. Tanaka and G. Hata, Chem. and Ind., 1977,202.

'"

22

Terpenoids and Steroids

2,6-Dimethyloctanes.-McQuillin has reviewed the functionalization of alkenes and alkanes using homogeneous catalysis, emphasizing his own work with acyclic m o n o t e r p e n ~ i d s . ' ~Linalool ~ P-~-O-glucoside-3,4-diangelicate has been isolated from Syneilesis a~onitifolia,~'~ and the dehydronerol esters (38; R = Ac) and (38; R = COHCMe2) from Schkuhria senecioides; (38; R = COCHMe2) is also present in S. pinnata.216The essential oil of Artemisia absinthium is reported to contain up to 57% of the epoxides (39),217and further analysis (cf.Vol. 4, p. 12)of lavender oil has revealed the presence of (40) and (41))in addition to related oxidation and reduction uroducts.218

OAC

(38) (39) (40) (41) C N.m.r. relaxation of linalool has been analy~ed.''~The use of myrcene as an indicating quencher to distinguish between singlet and triplet excited-state photodecarboxylation of phenylacetic acid has been reported.'" R -(+)-a-Methyl-pnitrobenzylamide derivatives of chiral dihydro- and tetrahydro-geranic acids have been used for liquid chromatographic and the g.c. analysis of geraniol oxidation products using a graphite porous-layer open-tubular column has been reported twice.222 There has been considerable activity in this area of monoterpenoid synthesis. Syntheses of [7-'4C]-,223[7',8-14C]-, and [7',8-3H]-geraniol have been reported.'68 The ocimene (42; X=H) has been synthesized again by Vig et al., this time from trans-6,6-ethylenedioxy-2-methylhept-2-en-1-01via Wittig reactions.224 Both (4E)- and (42)-(6S)-2,6-dirnethyloct-4-ene have been synthesized by known The addition of organohomocuprates (e.g. routes from S-3-methylpent-l-yne.225 13

F. J. McQhillin, Chem. andInd., 1976, 941. F. Bohlmann and M. Grenz, Phytochemistry, 1977, 16,1057; formulae (3) and (9) erroneously depict B-L-glucoside derivatives. 2*6 F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16,780; the keyword index refers in addition to a new dehydrocinnarnyl alcohol derivative. It should refer to a dihydrocinnamyl alcohol derivative: 21' F. Chialva, G. Doglia, G. Gabri, S. Aime, and L. Milone, Riuisfa Ztal., Essenze-Profirmi, Pianre W c . , Aromi, Saponi,Cosmet., Aerosol, 1976, 58, 522. 218 R. Kaiser and D. Lamparsky, Tetrahedron Letters, 1977, 665; formula (3) should have a 3,4-double bond. 'I9 A. Olivson and E. Lippmaa, in 'Magnetic Resonance and Related Phenomena, Proceedings of the 19th Ampere Congress', ed. H. Brunner, K. H. Hawser, and D. Schweitzer, Group Ampere, Heidelberg, 1976; p, 325 (Chem. Abs., 1977,87,23524). 220 G. A. Epling and A. Lopes, J. Amer. Chem. Soc., 1977,99, 2700. zzl c . G. Scott, M. J. Petrin, and T. McCorkle, J. Chromatog., 1976, 125, 157; see refs. 248-250 for related synthetic work. This method was previously applied to citronellic acid, see Vol. 7, p. 12, ref. 154. 222 C. Vidal-Madjar, S. BtkBssy, M. F. Gonnord, P. Arpino, and G. Guiochon, Analyt. Chem., 1977, 49, 768; P. Arpino, C. Vidal-Madjar, G. Guiochon, and S . BBkLssy, J. Chromatog., 1977, 138,173. 223 An earlier synthesis, H. D. Durst and E. Leete, J. Labelled Compounds, 1971,7, 52, was omitted from these Reports. 224 0. P. Vig, S. D. Sharma, M. L. Sharma, and K. C. Gupta, Indian J. Chem., 1977, 15B,25. '" A. M. Caporusso, G. Giacomelli, and L. Lardicci, Gazzetta, 1976, 106,879.

'I4

215

23

Monoterpenoids

R2CuMgCl) to the triple bond of conjugated enynes to yield vinylic cuprates has been used in a one-step synthesis of myrcene (43; X=H, 96% pure in 90% yield).226 Reaction of myrcene (43; X = H ) with magnesium in THF yields an enediyl metal species which may be hydrolysed to a mixture of (36; X = Me, 87%) and 3,7-dimethylocta- 1,6-diene (13%), or treated with acetone to yield 3-methyl(36; X = CMe20H),227an isomer of which is reported by the same author via the telomerization of isoprene in the presence of acetone and nickel-ligand catalyst.229 Cuprous iodide-catalysed a-coupling of prenylmagnesium chloride with E-4chloro-3-methylbut-2-en-1-01 yields pure gerani01.’’~ Syntheses of geraniol isomers have been reported. y-Geraniol [(36; X = CH20H); it is named isogeraniol in the paper] is obtained in 72% yield (see Vol. 6, p. 33, ref. 252 for earlier syntheses) from myrcene (43; X = H) via BF3,Et20-peroxide treatment of the derived enediyl species,227and Vig et al. report a straightforward second synthesis.231Borohydride reduction of citral enol acetate yields the E-A’-isomer of geraniol (Vol. 7, p. 16; line 4 should refer to this same A3-isomer and not to a A2-isomer); methylation yields the corresponding methyl ether which is one of four products (44) obtained after

(42)

(43)

(44)

dehydrochlorination of the products of the two-step TiC14-catalysed addition of methoxymethyl chloride to isoprene followed by product addition to 2-methylpropene (cf. Vol. 7, p. 17, which should have referred to a-isogeranyl methyl ether).’’’ Geranyl esters can be prepared from myrcene (43; X = H ) via NNdiethylgeranylamine.233 2-Fluorogeraniol and its 2-isomer are obtained via the corresponding aldehydes which result from the easy solvolytic cleavage of the chlorofluoromethoxycyclopropane obtained by addition of chlorofluorocarbene to l-methoxy-2,6-dimethylhepta-1,5-diene; l-methoxy-2,6-dimethylhept-l-ene correspondingly produces the dihydro-2-fluorogeraniols in better yield, as expected 226 227

”*229

230 231 232

233

H. Westmijze, H. Kleijn, J. Meijer, and P. Vermeer, Tetrahedron Letters, 1977, 869. S. Akutagawa and S. Otsuka, J. Amer. Chem. SOC.,1976,98, 7420; the formula for isogeraniol lacks the 6,7-double bond and the diene minor product is named incorrectly. No experimental details are given for the hydrolysis of this myrcene-magnesium complex but the results contradict those reported by Cookson et al. who have extensively investigated its reactions with carbonyl compounds, epoxides, carbon dioxide, and acetonitrile.228 R. Baker, R. C. Cookson, and A. D. Saunders, J.C.S. Perkin I, 1976, 1809, 1815. S. Akutagawa, Bull. Chem. SOC.Japan, 1976, 49 3646; formula ( 1 ) of this paper has a double bond omitted. Earlier uncited reports of this work22i*229 have appeared in the patent literature; e.g. T. Moroe, A. Komatsu, S. Akutagawa, T. Sakaguchi, and H. Matsuyama, Jap. P. 3770/1971 (Chem. Abs., 1971, 75, 20 583); T. Sakaguchi, S. Akutagma, and A. Komasu (sic), Jap. P. 15 941/1972 (Chem. Abs., 1972,77, 48 616). F. Derguini-Boumechal, R. Lorne, and G. Linstrumelle, Tetrahedron Letters, 1977, 1181. 0. P. Vig, S. D. Sharma, S. S. Bari, and S. D. Kumar, Indian J. Chem., 1977, 15B,93. B. V. Burger, C. F. Garbers, and F. Scott, J. S. African Chem. Inst., 1976, 29, 143; the preliminary communication (Vol. 6, p. 14, ref. 111) was only available as the Chemical Abstract, which gives no information on the work reported here, nor is any of the work in the abstract reported in this paper. K. Suga, T. Fujita, S. Watanabe, and R. Takiguchi, Yukagaku, 1976,25, 494.

Terpenoids and Steroids

24

when there is only one site of chlorofluorocarbene addition. Similarly, isopropenyl methyl ether readily yields 3-fluorobut-3-en-2-01 which undergoes Grignard addition to yield 2-fluorolinaloo1.234Poulter et al. have also synthesized 2-fluorogeraniol, which is readily separable from accompanying 2-fluoronerol, using the known addition of 1,2,2-trifluoroethenyl-lithium to ketones as the key step; using 2fluorogeranyl pyrophosphate, further evidence is provided for prenyltransferasecatalysed head-to-tail coupling in terpenoid biosynthesis occurring tiia an ionization-condensation-elimination mechanism (see Vol. 7, p. 1 The full paper (cfi Vol. 7, p. 15) on the synthesis of E-3,7-dimethyloct-2-ene-1,8-diol from the The chiral ipsdienols, RMonarch butterfly by Kossanyi et al. has been and S-(43; X = OH) have been synthesized elegantly. NaH-THF deconjugation of the (+)-enone (45) to (46) and reduction yields the (+)-alcohol (47) which is pyrolysed to R-(-)-ipsdienol (43; X = R-OH, 90% optical purity); (-)-verbenone [(45); enantiomer] similarly yields S-(+)-ipsdienol (43; X = S-OH) via the corresponding alcohol [(47); enantiomer] which is also obtained by LiAlH, reduction of the enol acetate (48) of (-)-verbenone. Lithium-ammonia reduction of the ketone (46) and its enantiomer yields inter alia th_ecorresponding trans-alcohols [e.g.(49)]; (49) is also pyrolysed to R-(-)-ipsdienol (43; X = R-OH) as expected.237 These

OH (45)

(46)

(47)

OH

OAc

(48)

(49)

results suggest an optical purity of 75% for the natural S-(+)-ipsdienol (43; X = S-OH), which would mean that Mori's syntheticsample of R-(-)-ipsdienol (Vol. 7, p. 15) had an optical purity of 38% and not 50% as claimed.237 Reaction of 2-buta-1,3-dienylmagnesium chloride with 4-methyl- lY2-epoxypentane yields ipsenol [2,3-dihydro-(43; X = OH)] and with 4-methylpent-4-ena1, (50) is 3-Methylpentadienyl-lithium reacts with methacrolein to yield (42; X = OH), a component of Ledum palustre essential oil (Vol. 4, p. 12), together with a minor amount of the exclusively E-lY4-adduct(51; R = vinyl); in the presence of cuprous iodide the yield of (5 1;R = vinyl) increases to 30% and a similar amount of the 1,2-adduct (52; R=vinyI) at the C-3 position of 3-methylpentadiene is formed!239 The lithium salt of (52; R = vinyl) readily undergoes exclusive [3;3] sigmatropic rearrangement to (51 ; R = vinyl) rather than the [1,3] sigmatropic rearrangement required for (42; X = OH) formation.240 Hotrienol (53) has been synthesized in one step from 2-methylpentadienyl-lithium and methyl vinyl ketone,239and also uia a straightforward Grignard-Wittig reaction sequence from 234

235

236

237 238 239 240

Y. Bessitre, D. N.-H. Savary, and M. Schlosser, Helu. Chim.Acta, 1977, 60, 1739. C. D. Poulter, J. C. Argyle, and E. A . Mash, J. Amer. Chem. Soc., 1977,99, 957. G. Bidan, J. Kossanyi, V. Meyer, and J.-P. Morizur, Tetrahedron, 1977, 33, 2193; formulae (2) and (7A) on p. 2194 both lack a methyl group. G. Ohloff and W. Giersch, Helv. Chim.Acra, 1977,60, 1496. K. Kondo, S. Dobashi, and M. Matsumoto, Chem. Letters, 1976, 1077. S. R. Wilson, K. M. Jernberg, and D . T. Mao, J. Urg. Chem., 1976,41, 3209. S. R. Wilson, D. T. Mao, K. M. Jernberg, and S. T. Ezmirly, Tetrahedron Letters, 1977, 2559. In contrast (52; R = ethynyl) undergoes [3,3] sigmatropic rearrangement in refluxing diglyme to a 45 : 55 mixture of (51; R=ethynyl) and the corresponding Z-isomer; M. L. Roumestant, P. Place, and J. Gore, Tetrahedron, 1977, 33, 1283.

Monoterpenoids

25

4,4-dirnethoxybutan-2-0ne.~~’ Citral has been synthesized by [3,3] sigmatropic rearrangement of a linalool thionocarbamate (cf. Vol. 4, p. 17, and Trost’s [2,3] sigmatropic rearrangement of allylic sulphoxides-Vol. 7, p. 5),242and by pyrolysis (cf.Vol. 7, p. 15).243The of prenol and 3-methyl-l-trimethylsilyloxybuta-1,3-diene favoured terminal Vilsmeier formylation of 2,6-dimethylhepta-l,3,5-triene (presumably a mixture of E- and 2-isomers) yields the four dehydrocitrals [ratio ~ ~ ~hydrounspecified; ambrosial (Vol. 6, p. 15) was not ~ h a r a c t e r i z e d ]and formylation has been used in a straightforward synthesis of h y d r o ~ y c i t r o n e l l a l . ~ ~ ~ Pyrolysis of the di-isoamyl acetal of 3-methylbut-3-enal is reported to yield 3,7d i m e t h y l o ~ t - 2 - e n a l .The ~ ~ ~ocimenones (54; E: Z/4:1) have been prepared from the kinetic enolate of mesityl oxide and methyl vinyl ketone; similar aldol condensation using the kinetic enolate from methyl isobutyl ketone yields tagetonol which is

(50)

(52)

(51)

(53)

(54)

likewise dehydrated to the tagetones [2,3-dihydro-(54; E: 2 / 7 :3)].247 Tagetonol has also been synthesized from 4,4-dimethoxybutan-2-oneby Grignard reaction^.^^' In attempted syntheses of chiral a-tocopherol a number of chiral monoterpenoid acids and other derivatives have been ~ y n t h e s i z e d ~ ~and ~ - ~shownzz1 ” to have high optical purity. Addition of propynylmagnesium bromide to isovaleraldehyde gave, after resolution, two acetylenic carbinols one of which was reduced to (55) and the other to (56); both (55) and (56), as vinyl ethers or other derivatives, undergo [3,3] sigmatropic rearrangement with almost 100°/~chiral transmission to yield, after work-up, S-(+)-E-3,7-dimethyloct-4-enoicacid which is reduced without racemization, using Raney nickel, to R-(+)-3,7-dimethyloctanoicacid (57; X = C02H, 90.8% optical Another approach to (+)-(57; X = C02H) and (+)-(57; X = CHzOH)of almost 100% optical purity uses the bacterial oxidation product S-(+)-3hydroxy-2-methylpropanoic acid to yield (57; X = Bu‘O) by treating the derived

w a xu \

(55) 241 242

243 244

24s

246 247 248 249 250

(56)

(57)

0.P. Vig, S. D. Sharma, S. S. Rana, and S. S. Bari, Indian J. Chem., 1976, 14B, 562. T. Nakai, T. Mimura, and A. Ari-Izumi, Tetrahedron Letters, 1977, 2425. P. Chabardes, Ger. Offen. 2 632 220 (Chem. Abs., 1977,87,38 877). P. C. Traas, H. J. Takken, and H. Boelens, Tetrahedron Letters, 1977, 2129. R. Van Helden and A. J. De Jong, Ger. Offen. 2 652 202 (Chem. Abs., 1977,87,67 845; the abstract has an obvious formula misprint). Y. Ichikawa, M. Yamamoto, and T. Yamaji, Jap. P. 75 015/1976 (Chem. Abs., 1976,85, 177 693). 0. S. Park, Y. Grillasca, G. A. Garcia, and L. A. Maldonado, Synrh. Cumm., 1977,7, 345. K.-K.Chan, N. Cohen, J. P. DeNoble, A. C. Specian, jun., and G . Saucy,J. Org. Chem., 1976,41,3497. N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom, and G. Saucy, J. Org. Chem., 1976,41,3505. N. Cohen, W. F. Eichel, R. J. Lopresti, C. Neukom, and G. Saucy, J. Org. Chem., 1976,41, 3512.

26

Terpenoids and Steroids

3-t-butoxy-2-methylpropan-1-01 tosylate with 3-methyl-1-butylmagnesium bromide in the presence of dilithium tetrachlorocuprate; further elaboration is s t r a i g h t f o r ~ a r dA . ~combination ~~ of these two appro ache^^^^.^^' has been used to synthesize ethyl (3R,7R)-(E)-8-t-butoxy-3,7-dimethyloct-4-enoate having an 8789% ( 3 R ) and >99% ( 7 R ) enantiomeric composition.250 R-(+)-Citronello1 (98% optical purity) is prepared by reduction of the chiral citronellal obtained via the 1,4-Grignard addition to the aldimine formed from (2E)-butenal and D-t-leucine t-butyl ester of high optical (+)-Methyl citronellate upon epoxidation, rearrangement, and hydrolysis, yields the (+)-enantiomer of (-)-(5 8), a new constituent of Pelargonium graveolens essential Other synthetic work of interest is an improved synthesis of geranyl chloride (cf. Vol. 6,p. 15)2’3 and syntheses of 2,7-diamino-2,7-dimethyloct-4-ene1,8-dioic acid254and its y - m o n ~ l a c t o n e ~and ~’ of ethyl 4-thiage~anate.~’~ The 1-pro-R-hydrogen is lost on oxidizing geraniol with a cell-free extract from Cannabis sativa (Vol. 7, p. 9, ref. 96), asymmetric microbial reduction of (*)citronellal to (-)-citronello1 is reported,257and callus cultures of Nicotiana tabacum selectively hydroxylate linalool, dihydrolinalool, and the derived acetates at the trans-methyl group [e.g. to give (59)].258 0H

/‘CH,OH

2,4,4,6-Tetrabromocyclohexa-2,5-dienone in methylene chloride promotes the biomimetic cyclization of linalool and dehydrolinalool to (60;R=vinyl or ethynyl) as the major product with minor amounts of (61; X = Br, R =vinyl or ethynyl) in contrast to brominative cyclization with N-bromosuccinimide when (61 ; X = Br,

25’ 252

253 254

255

256 257 258

S . 4 . Hashimoto, S . 4 . Yamada, and K. Koga, J. Amer. Chem. SOC.,1976,98,7450. E.Klein and W. Rojahn, Dragoco Ber., 1977,24,55. J. H.Chan and H. M. Pitt, U.S. P. 4 006 196 (Chem. A h . , 1977,86,171 655). A . A . Akhnazaryan, M. A . Manukyan, and M. T. Dangyan, J. Org. Chem. (U.S.S.R.),1976,12,1854. M. A. Manukyan, A. A. Akhnazaryan, S. M. Asikyan, and M. T. Dangyan, Khim. gererotsikl. Soedinenii, 1977,453. K.-C. Liu and L.-C. Lee, Arch. Pharm., 1976,309,1019. Y . Yamaguchi, M. Aso, A . Komatsu, and T. Moroe, Nippon Nogei Kagaku Kaishi, 1976,50,443. T.Suga, T. Hirata, Y. Hirano, and T. Ito, Chem. Letters, 1976,1245.

Monoterpenoids

27

R=vinyl or ethynyl) predominates (cf. Vol. 1, p. 36; Vol. 2, p. 35).259 Base treatment of a 2-alkoxypyridinium tosylate of nerol gives expected (e.g. limonene 82%) cyclic hydrocarbons whereas the corresponding geraniol salt yields similar amounts of cyclic and acyclic hydrocarbons.260 SnC14-catalysed cyclization of the N-benzylimine derived from R-(+)-citronella1 yields the expected menthylamines after catalytic hydrogenation.261 The well known Diels-Alder cycloaddition of myrcene (43; X=H) and isoprene has been re-investigated thoroughly (cf Vol. 1, p. 10; Vol. 7, p. 13).262 Further papers which report Diels-Alder cycloaddition reactions involving geranic acid and ~ y c l o p e n t a d i e n e (37) , ~ ~ ~and methyl vinyl ketone,264citral enamines and methyl vinyl ketone or a ~ r y l o n i t r i l e and , ~ ~ ~(43; X = H ) and carbonyl compounds266provide expected results. Photocyclization of citronellyl iodide may be a free-radical process (cf Vol. 7, p. 13).267Manganese(II1) acetate oxidation of linalyl acetate under thermodynamic control results in expected free-radical 1,2-addition followed by 2,6-cyclization (Vol. 7, p. 14).268Allylic oxidation [i.e. to (62)] is now reported to predominate on treating (63; X = H ) with manganese(II1) acetate and only one mole of acetone or dimethyl malonate in contrast to previous results with excess addend (Vol. 7, p. 14); oxidation in acetic acid in the presence of bromide ion exhibits a different selectivity in forming (63; X = OAc), along with some allylic isomer, presumably via intervention of bromine free radical, allylic hydrogen abstraction, oxidation, and nucleophilic addition. Similar reaction with (64; X = H) yields (65; R = Me).268 Thiyl radical addition to geranyl acetate yields expected cyclic and acyclic adducts in proportions ranging

between 5 : 1 and 1: 17 depending upon photolysis conditions; Raney nickel desulphurization yields dihydrocyclogeranyl acetate and tetrahydrogeranyl acetate.269 T . Kato, I. Ichinose, T . Hosogai, and Y. Kitahara, Chem. Letters, 1976,1187; refs. 8 and 9 of this paper should be to p. 456 (not 465) and p. 1845 (not 1945) respectively. S. Kobayashi, M. Tsutsui, and T. Mukaiyama, Chem. Letters, 1976, 1137. 261 G . Demailly and G . SolladiC, Tetrahedron Letters, 1977, 1885. 262 W. Eisfelder and P. Weyerstahl, Annulen, 1977, 988. 263 H. Duttmann and P. Weyerstahl, Annalen, 1976, 1753. 264 S. Wgtanabe, K. Suga, H. Tsuruta, and T. Sato, J. Appl. Chem. Biotechnol., 1977, 27, 423. 265 S. H. Mashraqui and G. K. Trivedi, Indian J. Chem., 1977, 15B,305. 266 J. B. Hall, US.P. 3 981 924 (Chern. A h . , 1977,86,55 071); US.P. 3 965 186 (Chem. Ah., 1977,86, 29 435). 267 J. L. Charlton and G. J. Williams, Tetrahedron Letters, 1977, 1473. '" F. J. McQuillin and M. Wood, J. Chem. Res. (M), 1977, 752; the minor allylic component corresponding to (63) is incorrectly named in the experimental section. 269 M. E. Kuehllz and R. E. Damon, J. Org. Chem., 1977; 42, 1825. 259

260

28

Terpenoids and Steroids

The solvolysis of linalyl p-nitrobenzoate to (+)-a-terpineol has been shown, by deuterium and 13Clabelling experiments, to be consistent with the anti process [e.g. (66) -+ (67) + (68)], rather than by the syn process proposed by Winstein (Vol. 3, OR

(66)

(67)

(68)

p. 15).270 A new type of cyclization of geraniol, using thallium(II1) perchlorate, yields predominantly five-membered carbocycles (69), together with (70), a result

Ho&o

H

@

OH

(69)

(70)

which may have synthetic and biogenetic implications in the iridoid field.271 Superacid cyclization of citronellol (cf. Vol. 5, p. 20) yields inter alia (71) and (72), which results from the loss of a C-7 methyl Similar cyclization of citral yields (73) and (74), in contrast to the Wagner-Meerwein shifts and ring contrac-

(72)

(73)

(74)

tions observed with geraniol (Vol. 5, p. 20), presumably via protonation of the oxygen of the +-unsaturated aldehyde to an initial stable delocalized cation, rearrangement to further cations, some of which are spectroscopically detectabte, and rapid quenching.272A study of the mechanism of cyclization of citral at pH 2.5 has shown that major products are dehydrocineol (Vol. 5, p. 23) and the two diols (75) which may dehydrate to two other major products, uiz. the dienes (76); p-cymen-8-01 results from the air oxidation of (76).273Acid-catalysed cyclization of tricarbonylmyrceneiron followed by protonation with HBF,-CO yields (77; X = Z Me) after borohydride reduction.274Further chloroacetic acid hydration papers (cf. Vol. 6, p. 29) include hydration of 2,6-dimethylocta-2,6-dieneand of 2,6-dimethylocta- 1,6-diene2” and hydrative cyclization of the dihydromyrcene (63; X = H), O ’

271 272

273 274 275

S. Godtfredsen, J. P. Obrecht, and D. Arigoni, Chiiniu (Switz.), 1977, 31, 62. Y. Yamada, H. Sanjoh, and K. Iguchi, J.C.S. Chem. Comm., 1976,997. D. V. Banthorpe and P. A. Boullier, J.C.S. Perkin I, 1977, 114. B. C. Clark, jun., C. C. Powell, and T.Radford, Tetrahedron, 1977, 33, 2187. A. J. Pearson, Austral. J. Chem., 1976,29, 1841. K. Tanaka and Y. Matsubara, Nippon Kugaku Kuishi, 1977,514.

Monoterpenoids

29

predominantly to (78) (2,6,6-trimethylcycloheptanolis a minor cationic resin-catalysed condensation of limonene (via a -terpinene-see Vol. 6, p. 29) with the cresols has been reported.277 The reaction of citral, dihydrocitral, or 3-methylbut-2-enal with strong base to yield aldol-type dimers (79) has been thoroughly re-investigated; (79) may iso-

merize to a 1,4-diene, aromatize, or be partially reduced by serving as a hydrogen acceptor during a r o m a t i z a t i ~ n .Stereoselective ~~~ C- 1 methylation of geraniol and nerol is accomplished without change in olefin geometry, by treating the lithium alkoxymethylcuprates with NN-methylphenylaminotriphenylphosphonium iodide279 or the corresponding acetates with lithium dimethylcuprate;280 stereoselective C-3 methylation with lithium methylcyanocuprate probably results from alkyl-group transfer involving copper.”’ Similar C-1 stereoselectivity is observed with geranyl acetate-dimethyl malonate-[ (Ph3P)4Pd,Ph3P,THF],although with neryl acetate, alkylation at C-3 is preferred using dimethyl malonate compared with high regioselectivity at C-1 using methyl phenylsulphonylacetate.281 Whereas fluorochlorocarbene addition to geranyl methyl ether is not regioselecregioselectivity of addition is observed with dichlorocarbene and linalool [to yield (12; X=CCI2)] and is suggested for geraniol [to yield (11; X = CC12)]which is considerably less reactive;282similar regioselectivity is observed for citral diethyl acetal although dicyclopropanation predominate^."^ Dichlorocarbene addition to myrcene using tributylamine catalyst is regiospecific at the non-conjugated double bond (cf Vol. 6, p. 16).284 Uncatalysed cleavage of epoxides has been reported [e.g. tetrahydro(39) + dihydro-(64; X = OH)],285and oxidation of tetrahydrogeranyl acetate with ozone on silica gel yields dihydro-(65; R = H) predominantly with some 8-acetoxy6-methyloctan-2-one (cf. Vol. 7, p. 7).286 276 277

278 279

282

283 284

285

286

K. Tanaka and Y. Matsubara, Nippon Kagaku Kaishi, 1977,922; (63; X = H) is named incorrectly. E. Pottier and L. Savidan, Bull. SOC.chim. France, 1977, 557. A. F. Thomas and R. Guntz-Dubini, Helv. Chim. Acta, 1976, 59, 2261. Y. Tanigawa, H. Kanamaru, A. Sonoda, and S.-I. Murahashi, J. Amer. Chem. Soc., 1977, 99, 2361. J. Levisalles, M. Rudler-Chauvin, and H. Rudler, J. Organometallic Chem., 1977,136, 103. B. M. Trost and T. R. Verhoeven, J. Org. Chem., 1976,41,3215; formula (7) in this paper should have an ethenyl group at C-3 and not at C-4. K. Kleveland, L. Skattebol, and L. K. Sydnes, Acta Chem. Scand., 1977, B31,463. G. V. Kryshtal, A. Kh. Khusid, V. F. Kucherov, and L. A. Yanovskaya, Izoest. Akad. Nauk S.S.S.R., Ser. khim., 1977,709. Y. Kimura, K. Isagawa, and Y. Otsuji, Chem. ktters, 1977, 951. S. N. Merchant, S. C. Sethi, and H. R. Sonawane, Indian J. Chem., 1976,14B, 460. A. L. J. Beckwith, C. L. Bodkin, and T. Duong, Chem. Letters, 1977, 425.

30

Terpenoids and Steroids

Other papers of interest in this section report the sequential homogeneous hydrogenation of geraniol to citronellol and tetrahydr~geraniol,~~’ the reduction of citral to citronella1,288 electrolytic reduction of chiral 6-chlor0-2,6-dimethylreduction of 2-geranic acid using a chiral rhodium catalyst preferably to (3S)-(-)-3,7-dimethyloct-6-enoicacid,”* largely unsuccessful attempts at isoprenoid homologation using ~ - m e t h y l c y c l ~ b u t e n e - ~ ~ ~ ~ Prins - ~ n Mformale~,~~~ dehyde reaction on allo-ocimene (cf. Vol. 6 , p. 16),2y2phenylation-reduction of ~ i t r a l , *and ~ j reaction of dehydrolinalool with NN-dimethylformamide acetals to yield djenamines and enamine orthoformate (cf.Vol. 6, p. 6).2y4

Halogenated Monoterpenoids.-A reviewzy5and a brief discussion2y6have been published. Crews has reviewed his work with Plocamium and Microcladia ~pecies,~”including some results published s u b s e q ~ e n t l y . ~P.~ sandvicense ~-~~~ is r e p ~ r t e d ~ ~ to ’ . ~yield ~ ’ the two diastereomeric pentachloro-octatrienes previously reported by Faulkner (Vol. 6, p. 20) from P. cartilagineurn, whereas P. oregonurn yields oregonene A (80; X = C1) and the tentatively assigned (80; X = H) together with the isomer (81) already isolated from Aplysia californica (Vol. 7 , p. 18) and

CI

CI

(80)

(81)

the corresponding dehydrochlorinated molecules as previously reported in P. cartilagineurn (VoI. 6 , p. 20) by Faulkner; I3C n.m.r. data are included.zy8 The chirality at C-7 reported for (80; X = H) last year by analogy with the corresponding tribromo-compound reported earlier [Vol. 7, p. 18, formula (61)] has not been verified. From P. violaceurn, the preplocamenes are assigned structures (82; X = Br, Y = S-Br), (82; X=C1, Y =R-Cl), and (82; X=Cl, Y = S-Cl) by analogy with

”’ Y.Takagi, S . Teratani, S. Takahashi, and K. Tanaka, J. Mol. Catalysis, 1977, 2 , 321. 288

289 290

291

292 293 294

295

296

297

298

D. V. Sokol’skii, A. M. Pak, M. A. Ginzburg, and A. M. Khisametdinov, J. Appl. Chem. (U.SB.R.), 1976, 49, 2095; the identical results are also reported D. V. Sokol’skii, A. M. Pak, and M. A. Ginzburg, Maslo-Zhir. Prom., 1976, No. 7, p. 20. T. Nonaka, T. Ota, and K. Odo, Bull. Chem. SOC.Japan, 1977, 50,419; formula (11) is misprinted. D. H. Valentine, jun., Ger. Offen. 2 548 884 (Chem. Abs., 1976, 85, 94 550); see also refs. 221 and 248-250. S. R. Wilson and D. E. Schalk, J. Org. Chem., 1976, 41, 3928. K. Takabe, N. Ike, T. Katagiri, and J. Tanaka, Nippon Kagaku Kaishi, 1977, 1253. F. J. McEnroe, C.-K. Sha, and S. S . Hall, J. Org. Chem., 1976,41,3465. K. A. Parker, R. W. Kosley, jun., S. L. Buchwald, and J. J. Petraitis, J. Amer. Chem. SOC.,1976, 98, 7104. D. J. Faulkner, Tetrahedron, 1977,33, 1421; formula (88) in this paper is incorrect [see Vol. 7, p. 20, formula (77)]. R. E. Moore, Accounts Chem. Res., 1977,10,40. P. Crews in ‘Marine Natural Products Chemistry’, ed. D. J. Faulkner and W. H. Fenical, NATO Conference Series: IV, Marine Sciences, Vol. 1, Plenum Press, New York, 1977 (Proceedings of a conference on Marine Natural Products, Jersey, Channel Islands, October 1976), p. 21 1. Formulae (8) and (13) in this paper are identical, which may suggest an error. P. Crews, J. Org. Chem., 1977,42, 2634.

Monoterpenoids

31

Faulkner's violacene 2 (Vol. 7, p. 19),2')9and P. cosratum has yielded costatol (83),301the related costatone (S4),301.302and costatolide (85),302all confirmed by X-ray diffraction; spontaneous dehydration of the hemiacetal (84)to the expected

~~'~ trienones is ~ b s e r v e d . ~ " Various plocamenes from M i c r ~ c l a d i a ~ ~ 'and Plocamium 297*299 species have been discussed by Crews; plocamene A (violacene) and plocamene B (Vol. 6, p. 33) seem to be firmly established but the structure of plocamene C, claimed3" as an epimer of Faulkner's violacene 2, is still not adequately d i s c ~ s s e d ; ~comparison ~ ~ ~ ~ ~ ' of later data3" on M. coulteri analysis might suggest that Crews now regards plocamene C (Vol. 7, p. 19) as (86),297but structural proof has not been published. Plocamene D (87) is reported in various

CI

/ Cl

cldcl

papers297.299.300 with no reported comparison with. the compound of identical structure prepared by Faulkner on treating violacene with chromous ~ u l p h a t e ; ~no '~ details of its characterization have been published. Other potentially interesting halogenated dimethylethylcyclohexanes have been indicated297but reports of their characterization are needed; this also applies to the five new compounds (88), (89), (90), (91), and the biochemically significant (92) discussed by F a ~ l k n e r . ~ ~ '

(88) 299

300 301

302 303

(89)

(90)

P. Crews and E. Kho-Wiseman, J. Org. Chem., 1 9 7 7 , 4 2 , 2 8 1 2 ;formula (20)of this paper should have a chlorovinyl group instead of a 2-chloroethyl group. Plocamene B and plocamene D are reported here without comment, with absolute stereochemistry the same as violacene 2 (cf. refs. 297, 300). P. Crews, P. Ng, E. Kho-Wiseman, and C. Pace, Phyrochemisrry, 1976,15, 1707. R. Kazlauskas, P. T. Murphy, R.J. Quinn, and R. J. Wells, Tetrahedron Lerrers, 1976,4451. D. B. Stierle, R. M. Wing, and J. J. Sims, Tetrahedron Letters, 1976, 4455. J. S . Mynderse and D. J. Faulkner, J. Amer. Chem. Soc., 1 9 7 4 , 9 6 , 6 7 7 1 .

Terpenoids and Steroids

32

(91)

(92)

Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-The presence of (41) in lavender oil has been reported earlier.'18 Poulter has published the full details of his work (Vol. 5 , p. 14) on synthetic151and s t e r e ~ c h e m i c a l 'aspects ~~ of chrysanthemyl ester and alkoxypyridinium salt solvolyses (Vol. 3, pp. 20-22) and discussed its biosynthetic implications. Over 98% of the solvolysis products are now reported to be artemisyl derivatives which are formed from the primary cyclopropylcarbinyl ion (93) which results from predominant (86%) ionization of the antiperiplanar conformation of (21)-N-methyl-4-pyridinium iodide; the tail-totail product (96; 0.01%) may then result from the suprafacial migration of the cyclopropane ring bond as shown stereochemically in Scheme 3. This is consistent with earlier work (Vol. 7, p. 20, ref. 214) reporting the efficient rearrangement of the cyclobutyl cation (94) to (96) and its allylic isomer, uia the tertiary cyclopropylcarbinyl cation (95).ls3

The full paper on Julia's artemisia ketone (20; X = 0) synthesis (Vol. 5, p. 14) has. been a minor product in this synthesis is (97) which is also produced in good yield uia an alkylation-sulphoxide elimination sequence subsequent to [2,3] sigmatropic rearrangement reported by Julia earlier;305hydrolysis of (97) yields artemisia ketone (20; X = 0).304,305 The Cr"-catalysed attachment of the more substituted y-carbon of an ally1 group to a carbonyl carbon, even with a@-unsaturated aldehydes, has been used in an efficient synthesis of artemisyl alcohol (20; X=H,OH) from prenyl bromide and 3 - m e t h y I b ~ t - 2 - e n a l .Similar ~~~ reaction with the acetal(98) yields (99), which is readily hydrolysed and methylated to yomogi alcohol another synthesis of (100) involves a [2,3] sigmatropic rearrangemen? analogous to that reported by Julia.305 Thus the allylic ether (101) rearranges to the allylic alcohol (102) on treating with n-butyl-lithium; hydrolysis to the a@-unsaturated aldehyde and alkylation steps readily yield yomogi alcohol '04 305

3w

D. Michelot, G . Linstrumelle,and S. Julia, Synfh. Comm., 1977,7, 95. C. Huynh and S. Julia, Synrh. Comm., 1977, 7, 103; for the earlier work, see references therein Y. Okude, S. Hirano, T. Hiyama, and H. Nozaki, J. Amer. Chem. Soc., 1 9 7 7 , 9 9 , 3179.

Monoterpenoids

33

An elegant two-step synthesis of lavandulol (22) consists of the 1,4-addition of lithium dimethylcuprate to the allenic ester (103) followed by prenylation and reduction of the intermediate which is formed.307 Much effort this year has been expended on chrysanthemic acid syntheses. Aratani et al. have extended earlier work on asymmetric synthesis (Vol. 6, p. 21) by decomposing various alkyl diazoacetates in 2,5-dimethylhexa-2,4-dienein the presence of chiral copper complexes to yield up to 92% of trans-chrysanthemic acid in 88% dextrorotatory enantiomeric excess.3o8Mitra has used ozonolysis of (+)-a pinene to obtain, stereospecifically, the bromo-ketone (104) which undergoes Favorskii rearrangement to yield the anticipated ester (105) from which (+)-transchrysanthemic acid is readily obtained;309a second paper reports another route from (+)-car-3-ene initially to methyl (-)-cis-chrysanthemate or to (-)-dihydrochrysanthemolactone (106), both of which are convertible into (+)-trans-chrysan-

themic acid by known means, e.g. by the Matsui synthesis or the Sukh Dev modification (see Vol. 5 , p. 15, ref. 101).310An elegant one-step stereospecific synthesis of methyl (*)-trans-chrysanthemate in over 60% yield consists of mixing T H F solutions of methyl trans-4-oxobutenoate and isopropylidenetriphenylphosphorane (2.4 equivalents); the reaction probably proceeds via initial betaine formation at the aldehydic carbonyl group. A useful modification provides the synthetically useful trans-(107; R = CHO).311A second paper reports the first one-pot stereospecific synthesis of (*)-cis-chrysanthemic esters by reaction of a-butenolide (108) 307 308

309

310 311

M. Bertrand, G. Gil, and J. Viala, Tefruhedron Letters, 1977, 1785. T. Aratani, Y. Yoneyoshi, and T. Nagase, Tefruhedron Letters, 1977, 2599; T. Aratani, Y. Yoneyoshi, F. Fujita, and T. Nagase, Get. Offen. 2 634 663 (Chem. A h . , 1977.87, 68 506). For related work see also T. Nagase, T. Aratani, and M. Hazarna, Japan P. 137 955/1975 (Chem. A h . , 1976,85, 94 542). R. B. Mitra and A. S. Khanra, Synth. Comm., 1977,7, 245. A. S. Khanra and R. B. Mitra, Indian J. Chem., 1976,14B, 716. M. J. Devos, L. Hevesi, P. Bayet, and A. Krief, Tetrahedron Letters, 1976, 3911; A. Krief and L. Hevesi, Belg. P. 827 651 (Chem. Abs., 1976.85, 177 686); Ger. Offen. 2 615 159 (Chem. A h . , 1977, 86,72 921.

Terpenoids and Steroids

34

with the sulphur ylide (109) to yield (110) which is readily converted into cis-(107; R = CH,OH); another route to cis-(107; R=CH,OH) or the lactone (110) involves stereospecific addition of (109) to (1 1l).312 From methyl E-4,4-dimethoxybut-2-

+-/

PhzS-C

Me

THPOCH2 \

C02Me

c=c/

\Me

H

'

\H

enoate and (109), trans-[107; R=CH(OMe)*] is readily formed in 82% yield; elaboration of (107; R = CHO) to the individual pure racemic chrysanthemic esters is then ~traightforward.~~' Another synthesis313 of (*)-trans-chrysanthemic acid involves the known3I4alkylation of eucarvone (1 12) to (1 13) whose separation from 2,6,6,7-tetramethylcyclohepta-2,4-dienone is dependent upon the ease of oxidation of the latter by sodium chlorate and a catalytic amount of 0 ~ 0 ,ozonolysis ; of (1 13) and appropriate modification in a single synthetic stage yields (114) which is 0

(1 12)

(113)

..

(114)

epimerized and readily elaborated into methyl (*)-rrans-~hrysanthemate.~'~ Two further papers describe the synthesis of [ 1-3H]-(1R,3R)-(+)-trans-chrysanthemic acid315and a synthetic route to (*)-chrysanthemate analogues.316 Pyrocin (1 15) has been synthesized by Michael addition of 2-methylprop- 1-enylmagnesium bromide to the known butenolide (116) using (-)-sparteine-CuC1; base-catalysed debenzoylation yields (115) with a 2% optical yield; the conversion of (115) into ethyl (*)-trans-chrysanthemate was also investigated.317 The degradation of artemisia alcohol (20; X = H,OH) by retro-ene cleavage and by the novel [1,3] sigmatropic rearrangement (20; X = H,OH] --+(1 17) has been de~cribed.'~' Wittig rearrangement of allylic ethers of chrysanthemyl alcohol by competing [1,2], [ 1,4], homo-[2,5], and homo-[4,5] sigmatropic rearrangements is 312 313

314

'I5 'I6 317

M. Sevrin, L. Hevesi, and A. Krief, Tetrahedron Letters, 1976, 3915. S. C. Welch and T. A. Valdes, J. Org. Chem., 1977, 42, 2108. Ref. 5 in this paper should be to J.C.S. Perkin ZZ;see ref. 314. A. J. Bellamy and W. Krilly, J.C.S. Perkin ZI, 1972, 395. G.Pattenden and R. Storer, J. Labelled Compounds, 1976.12, 551. K.Kondo, K. Matsui, and Y. Takahatake, Tetrahedron Letters, 1976, 4359. A. Takeda, T. Sakai, S. Shinohara, and S.Tsuboi, Bull. Chem. SOC.Japan, 1977,50, 1133.

Monoterpenoids

35

c,; 0

0 T

QCOPh 0 (1 16)

(115)

(1 17)

reported3" and it has been shown that thermal acid-catalysed rearrangement products from trans-chrysanthemic acid result from cleavage of all three cyclopropane ring 5 Monocyclic Monoterpenoids

Cyc1obutane.-Grandisol syntheses have been r e v i e ~ e d , ~ ~and * * ~Trost's ~' full paper on grandisol and fragranol synthesis (Vol. 6, pp. 21, 22)3 has been published. Cyclopentanes, 1ridoids.-Two doidS.322.323

papers report the analysis and separation of iri-

The characterization of trans,trans-dolichodial (118) from Iridomyrmex humilis has been reported (cf. Vol. 6, p. 25)," and chrysomelidial (119) and plagiolactone (120; the assigned absolute stereochemistry is tentative) are present in the defensive secretion of Plagiodera v e r s i c ~ l o r a . ~ ~ ~

ACHO (118)

(119)

(120)

New CISiridoid glucosides, occurring as minor components, are bartsioside, or ~ or 106-deoxyaucubin (121; X = H, R = p-Glu), from Bartsia t r i x a g ~ , 'linaride, deoxyaucubin (122), from Linaria r n u r ~ l i s , and ~ * ~a third picroside, 6'-(4-hydroxy-

(121)

(122)

L. Crombie, G. Darnbrough, and G. Pattenden, J.C.S. Chem. Comm., 1976, 684. 319 D. A. Otieno, G. Pattenden, and C. R. Popplestone, J.C.S. Perkin I, 1977, 196. 320 J. A. Katzenellenbogen, Science, 1976,194, 139. 321 C. A. Hendrick, Tetrahedron, 1977, 33, 1845. 322 B. Meier and 0. Sticher, J. Chromatog., 1977,138,453. 323 0 .Sticher, Pharm. Acta Helv., 1977, 52, 20. 324 J. Meinwald, T. H. Jones, T. Eisner, and K. Hicks, Proc. Nut. Acad. Sci. U.S.A., 1977, 74, 2189; independent and unpublished work on these compounds by M. S. Blum, H. M. Fales, J. E. Wheeler, and G. W. K. Cavil1 is awaited. 325 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Gazzetta, 1977,107,83. 318

Terpenoids and Steroids

36

3-methoxycinnamoyl)catalpol (cf. Vol. 3, p. 27; Vol. 6, p. 23), from Picrorhiza k~rrooa.~~~ The full paper on the synthesis of onikulactone and mitsugashiwalactone (Vol. 7, p. 24) has been p ~ b l i s h e d . ~ ”Whitesell reports two further useful sequences (cf. Vol. 7, p. 26) from accessible bicyclo[3,3,0]octanes which may lead to iridoids; (123; X=H2, Y = H) may be converted into (124) via (123; X = H2, Y = C02Me), the product of ester enolate Claisen rearrangement of the derived allylic alcohol and oxidative d e c a r b o ~ y l a t i o n ,whereas ~~~ (123; X = 0, Y = H) readily leads to (125), a known derivative of antirride (126) via an alkylation-dehydration-epoxidation-rearrangement sequence.329 Aucubigenin (121; X = OH, R = H), which is stable at -20°C and readily obtained by enzymic hydrolysis of aucubin (121; X = OH, R = P-Glu), is converted by mild acid into (127)330with no dialdehyde detected;331sodium borohydride reduction of aucubigenin yields the non-naturally occurring isoeucommiol (128; X=H,OH) probably uia the aldehyde (128; X =

01.~~’

eoMe

q$

phco**oMe

X H

OMe

(123)

(126)

OMe

(124)

(125)

(127)

(128)

New CI6 iridoid glucosides include mussaenoside (129; X = H , R = M e ) and shanzhiside methyl ester (129; X = OH, R = Me) from Mussaenda paruifEoru and M. ~ h i k o k i a n aipolamiidoside ,~~~ (28; X = H, R = Ac), the acetate of ipolamiide (28; X = R = H), whose stereochemistry is now assigned (cf.’Vol. 6 , p. 24), from Lamium a r n p l e s s i c a ~ l eand , ~ ~another ~ component from Phlomis fruticosa (cf. vol. K. Weinges and K.Kiinstler, Annalen, 1977, 1053. H. Ohta, T. Kobori, and T. Fujisawa, J. Org. Chem., 1977,42, 1231; some details are also published in T. Fujisawa, T. Kobori, and H. Ota (sic),Jap. P. 39 668/1976 (Chem. Abs., 1976.85, 108 823). 328 J. K. Whitesell and A. M. Helbling, J.C.S. Chem. Comm., 1977, 594; an intermediate is obviously lacking a double bond. 329 J. K. Whitesell, R. S . Matthews, and P. K. S. Wang, Synth. Comm., 1977, 7 , 355; compound (8) lacks an exocyclic methylene group. 330 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Tetrahedron, 1977, 33, 847. 331 A. Bianco, M. Guiso, C. Iavarone, P. Passacantilli, and C. Trogolo, Tetrahedron, 1977, 33, 851; see Vol. 6, p. 24 for eucommiol. 332 Y. Takeda, H. Nishimura, and H. Inouye, Phytochemistry, 1977, 16, 1401. An earlier paper, H. Inouye, Y.Takeda, S. Saito, H. Nishimura, and R. Sakuragi, Yukuguku Zusshi, 1974, 94, 577, on gardenoside, shanzhiside (129; X = OH, R = H), and methyl deacetylasperulosidate from Gardenia jusminoides grundiflora was inadvertently omitted from earlier Reports; however, see Vol. 1, p. 20. 333 A. Bianco, M. Guiso, C. Iavarone, R. Marini-Bettolo, and C. Trogolo, Guzzenu, 1976, 106, 947; see, however, Vol. 7, p. 27, ref. 267 for an earlier report of the correct stereochemistry for ipolamiide. 326

327

37

Monoterpenoids

6, p. 24), the closely related lamiidoside (28; X = 4-hydroxycinnamoyloxy, R = H), a derivative of lamiide (28; X = O H , R=H).334 Previous reports (Vol. 5 , p. 17; Vol. 7, p. 24) did not recognize the identity of lamiide (28; X = OH, R = H) and durantoside. The 10-acetyl derivative of geniposide (Vol. 1, p. 20) is another component from Gardenia jasminoides grandiflora 335 and the structures of some iridoids present in Fouquieria species, including adoxoside (130), which is unknown to this Reporter, are only tentative at present.336 The structure of a compound previously named feretoside (Vol. 6, p. 24; Vol. 7, p. 24) by the authors has been revised to (131), which is methyl scandoside; it is disturbing that the revised structure (131) is assigned to a compound with different physical data, except for R f C0,Me

1

HO",

O-B-Glu

I

0-P-Glu

HO'

(129)

0,Me

Po O-fi-Glu

OH

(130)

(131)

value, from those recorded previously (Vol. 6, p. 24)and from a new source of Feretia apodanthera ; it is difficult to see why a relationship to gardenoside (Vol. 1,p. 20) was suggested (Vol. 6, p. 24).337 13C N.m.r. data are also recorded for some related known iridoids and monoterpenoid alkaloids.337 Papers reporting known valepotriates using the incorrect stereochemistry at C-7 and/or C-8 have been published (see Vol. 7, p. 25).338Four new valepotriates are kanokoside A (132; R =p-Glu), kanokoside B (133), kanokoside C (132; R = pgentiobiose), and kanokoside D (134; R = p - g e n t i ~ b i o s e ) . ~ ~ ~

; *o

HO

Hoq

H;@oo-P-G1u

',

H

H,COH 0 , C B u '

(132)

HO

CH,OR

02CBU'

(133)

HO'

0,CBu'

(1 34)

A significant synthetic achievement this year is Fleming's conversion (Scheme 4) of trimethylsilylcyclopentadiene (135) into the racemic aglucone acetate (136) which has already been converted into loganin (Vol. 1, pp. 20, 21; Vol. 4, p. 26). Cycloaddition of (135) to dichloroketen yields the adduct (137),340"whose conversion into the acetate (138) is straightforward; the key steps are the clean 334

335

A . Bianco, C. Bonini, M. Guiso, C. Iavarone, and C. Trogolo, Gazzena, 1977,107,67. Y. Takeda, H. Nishimura, 0. Kadota, and H. Inouye, Chem. andPharm. Bull. (Japan), 1976,24,2644.

m6 R. Dahlgren, S. R. Jensen, and B. J. Nielsen, Boran. Noriser, 1976, 129, 207. 337 F. Bailleul, P. Delaveau, A . Rabaron, M. Plat, and M. Koch, Phytochemistry, 1977, 16, 723. 338 N. Marekov, N. Handjieva, S. Popov, and I. Yankulov, Izuesr. Khim. (Bulgaria), 1975, 8, 672; M. Di Gusto and E. Mandrile, Reo. Farmaceur., 1976,118,77;H. Becker, R. Schrall, and W. Hartmann, Arch. 339 340

Pham., 1977,310,481. T. Endo and H . Taguchi, Chem. and Pharm. Bull. (Japan), 1977,25,2140. B.-W. Au-Yeung and I. Flemming, J.C.S. Chem. Comm., ( a ) 1977,79 [formula (1)obviously lacks two methyl groups]; ( b ) 1977, 81.

Terpenoids and Steroids

38

FI

Sih

SiMe, [iv, v

(139)

(140)

(136)

Reagents: i, CI,CHCOCI-Et3N; ii, Zn-AcOH-HzO; iii, MeCHNz-EtzO-MeOH; iv, excess Zn-AcOHHz0; v, NaOMe-MeOH; vi, NaBH4-MeOH; vii, MeSOzC1-py; viii, Et4N+AcO--MezCO; ix, CISO.LNCO-CCI~;x, NaN02-AcZO-AcOH; xi, NaOAc-HzO; xii, CHzN2; xiii, 03; xiv, MezS

Scheme 4

reaction of (138) with chlorosulphonyl isocyanate to give (139), which is best hydrolysed by sodium nitrite-acetic acid and aqueous sodium acetate to give (140), after esterification. Conversion into the loganin derivative (136) is then straightand, despite the fourteen steps, the overall yield compares very favourably with that reported earlier by Buchi. The previous report of a cyclopentene ester from Turkish tobacco (Vol. 6, p. 27) did not acknowledge the almost identical synthesis of the corresponding aldehyde R -( 141) by van T a m e l e r ~ ; ~ ~ ~ S-(141) is now reported.342 The name fulvoiridoid is used to describe pseudo-azulenic compounds with the highly conjugated cyclopenta[c]pyran structure, e.g. (142), the red-orange product from heating the aglycone of ipolamiide (28; X = R = H ) at pH 5.2; perchloric acid-acetic acid treatment of (28; X = R = H ) gives the two blue pyrilium salts (143), suggesting that the characteristic blue colour reactions of iridoids may be due to conversion of fulvoiridoids into the corresponding pyrilium 341

342

343

E. E. van Tamelen, G. M. Milne, M. I. Suffness, M. C. Rudler-Chauvin, R. J. Anderson, and R. S . Achini, J. Amer. Chem. Soc., 1970, 92,7202. J. F. Ruppert, M. A. Avery, and J. D. White, J.C.S. Chem. Comm., 1976, 978. A. Bianco, M. Guiso, C. Iavarone, R. Marini-Bettolo, and C. Trogolo, Guzzettu, 1976,106, 733.

Monoterpenoids

39

A secoiridoid, secogalioside (144), has been isolated from Galium album (the paper includes 13C n.m.r. data for a number of secoiridoids and derived and xylomollin (145) has been obtained from Xylocarpus molluscen sis l 3 to add to a number of biogenetically anticipatable secologanin-related compounds, e.g. morroniside and kingoside (Vol. 1, p. 19), and sarracenin (Vol. 7, p. 27). The full paper of Tietze’s biogenetic-type synthesis of secologanin aglucone methyl ether and sweroside aglucone methyl ether has been published (Vol. 5, p. and a second paper independently reports in full the rapid enzymic cleavage of secologanin t o the bicyclic hemiacetal previously described by R. T. Brown (Vol. 7, p. 27); longer reaction times result in the formation of (146).346 CHO C 0 , M e

(144)

(145)

(146)

Mass spectral data of some known monoterpenoid alkaloids have been analy~ed.~~~

p-Menthanes.-A number of species have yielded new thymol derivatives348and Syneilesis aconitifolia has also yielded D-a-terpineol-/3-D-glucopyranoside-3,4diangelicate.’’’ The diol (147) has been isolated349from Mentha gentilis in addition t o (148; R = Ac), which has been reported three times350without comparison with the known keto-alcohol (148; R = H);3s1the trio1 (149) has been isolated from Zanthoxylum b u d r ~ n g a . ~ ~ ~ 344

34s 346

347 348

349 350

3s1

3s2

K. Bock, S. R. Jensen, and B. J. Nielsen, Acta. Chem. Scand., 1976, B30, 743. G. Kinast and L.-F. Tietze, Chem. Ber., 1976, 109, 3626. G. Kinast and L.-F. Tietze, Chem. Ber., 1976, 109, 3640. W. Berg, D. Gross, H. R. Schiitte, and M. Herrmann, Pharmazie, 1977, 32,41. S. K. Zutshi and M. M. Bokadia, Indian J. Chem., 1976,14B, 711; F. Bohlmann, J. Jakupovic, and M. Lonitz, Chem. Ber., 1977,110,301;F. Bohlmann and C. Zdero, Phytochemistry, 1977.16, 1243; W. L. Lasswell, jun. and C. D. Hufford, ibid.,p. 1439. K. Umemoto and T. Nagasawa, Nippon Nogei Kagaku Kaishi, 1977,51, 245. T. Nagasawa, K. Umemoto, T. Tsuneya, and M. Shiga, Agric. and Biol. Chem. (Japan),1975,39,2083 (inadvertently omitted from last year’s Report); K. Umemoto and T. Nagasawa, Nagoya Gakuin University Review, 1976, 12, 117; T. Nagasawa, K. Umemoto, and N. Hirao, Nippon Nogei Kagaku Kaishi, 1977, 51, 81. J. Wiemann and Y. Dubois, Bull. Soc. chim. France, 1962, 1813. R. K. Thappa, K. L. Dhar, and C. K. Atal, Phytochemistry, 1976.15, 1568.

Terpenoids and Steroids

40

A (147)

A (148)

(149)

The most stable rotamer of menthone has been identified by combining selective excitation and gated decoupling of the Fourier-transform 13C n.m.r. ~pectrum.”~ The effect of glucosylation on the shielding of a - and P-carbon atoms in (+)- and (-)-menthol has been examined; the dependence of such shielding on alcohol chirality may be valuable in determining absolute configuration^.^^^ The chiral shift reagent tris[(hydroxymethylene)menthanato]europium has been reported.”’ N.m.r., i.r., and m.s. data have been reported for fourteen p-menth-8-enediols resulting from ,various selenium dioxide oxidations (e.g. see Vol. 6 , p. 30).3561.r. and Raman spectra of limonene, p-menth-1-ene, trans-isolimonene, p-menth-3ene, and trans-p-menth-2-ene have been a n a l y ~ e d . ~C.d. ’~ on 2-hydroxymethylenementhone (for which further synthetic data are and the corresponding chloromethylene derivatives have established the existence of a cisltruns enolic equilibrium, which is also reported for the corresponding carvone and camphor derivative^.^'^" Calorimetric data for carvoxime have been and kinetic data reported for the addition of trifluoroacetic acid to R-(+)-limonene in weakly polar solvents (cf.Vol. 6 , p. 29).360 In contrast to base-catalysed eliminations (e.g. Vol. 7, p. 33), cis-p-menth-2-ene is the exclusive product from reaction of truns-6-isopropylcyclohex-2-enolmesitoate or trans -4-isopropylcyclohex-2-en01 mesitoate with lithium dimethylcuprate; the corresponding cis-mesitoates yield the same mixture of trans-p-mentb-2-ene Two papers report related syntheses of the known and tr~ns-o-rnenth-2-ene.~~~ ’ R’ = R2 = 02CPri),363 thymol derivatives (150; R’=02CPri, R2= O A C ) , ~ ~(150; (15 1; R’ = R2= 02CPri),363and (15 1; R’ = OMe, R2 = H)363without novelty; the thermal rearrangement of (150; R’=OAc, R2=H), which has been obtained in improved yield in three steps from 4,7-dimethylcoumarin, to (152) may have applications in further thymol syntheses.364 Another application of polymer-bound Rose Bengalg8involves allylic photo-oxygenation of R -(+)-pulegone as a first step 353 354 355

356

357 358

359

360

362 363 364

R. Freeman, G. A. Morris, and M. J. T. Robinson, J.C.S. Chem. Comm., 1976, 754. R. Kasai, M. Suzuo, J.-I. Asakawa, and 0. Tanaka, Teirahedron Leiiers, 1977, 175. V. M. Potapov, V. G . Bakhmutskaya, 1. G. Il’ina, G. I. Vinnik, and E. G. Rukhadze, J. Gen. Chem. (U.S.S.R.), 1975, 45,2071. T. Tahara and Y . Sakuda, Kochi Joshi Daigaku Kiyo, Shizen Kagaku Hen, 1976, 24, 1 (Chem. Abs., 1977,86, 72 891). F. E. Fernandes Gomes, 0. D. Ul’yanova, and Y . A. Pentin, Russ. J. Phys. Chem., 1976,50, 1310. V. M. Potapov, G. V. Grishina, and I. K. Talebarovskaya, J. Org. Chem. (U.S.S.R.),( a ) 1976, 12, 2193; ( 6 ) 1976,12, 1399. H. A. J. Oonk, K. H. Tjoa, F. E. Brants, and J. Kroon, Thermochim.Acra, 1977,19,161; E. L. Meijer, J. G. Blok, J. Kroon, and H. A. J. Oonk, ibid., 1977, 20, 325. R. M. G. Roberts, J.C.S. Perkin ZZ, 1976, 1374. A. Kreft, Tetrahedron Leiiers, 1977, 1035. F. Bohlmann and J. Kocur, Chem. Ber., 1976, 109,2969. K. J. Divakar, B. D. Kulkarni, and A. S . Rao, Indian J. Chem., 1977,15B, 322. K. J. Divakar and A. S . Rao, Synih. Comm., 1976,6, 423.

Monoterpenoids

41

in the 1,3-carbonyl transposition sequence to produce S-(-)-pulegone; the reaction sequence is very similar to the unacknowledged scheme previously reported for (15) (Vol. 5 , p. 25).365 Anodic oxidation of 4-methylcyclohexanone enol acetate in the presence of absolute methanol-tetraethylammonium toluene-p-sulphonate yields the n-methoxy-ketone which, after Grignard reaction and hydrolysis, produces menthol viu a 1,2-carbonyl t r a n ~ p o s i t i o n .Complete ~~~ transfer of chirality, via a double suprafacial transition state, has been observed in the [3,3] sigmatropic rearrangement of the trichloroacetimidate [ 153; R = C(NH)CCl,] to the trichloroacetamide (154; R = C0CCl3), which is reminiscent of the [3,3] sigmatropic rearrangement reported earlier by Thomas and Ohloff (Vol. 1, p. 33); an elimination by-product is the corresponding mentha-1,5,8-triene (Vol. 1, p. 24).367Dehydrohalogenation of the endo- and exo-6-bromo-1,3,3-trimethyl-2-oxabicyclo[2,2,2]octane (80 :20) with potassium t-butoxide-DMSO yields dehydrocineol (Vol. 5 , p. 23) with minor amounts of (+)-pin01 (155) and (-)-isopinol(l56) to add to the small number of examples of cineol -+ pinol rearrangements (e.g. see Vol. 6, p. 31); using 1,5-diazabicyclo[5,4,0]undec-5-ene, the major product is (155; 85%) together with (156; 9%). Attempted dehydration of the corresponding alcohols yields (157).368Photo-oxygenation of p-mentha-3,8-diene, from isopulegol thio-

benzoate photolysis or isopulegol S-methylxanthate pyrolysis, followed by lithium di-isopropylamide cleavage of the derived endo-peroxide gave p - m e n t h ~ f u r a na, ~ ~ ~ further synthesis of which involves thermal decomposition of dimethyl diazomalonate in l-methoxy-5-methylcyclohexeneover trimethoxyphosphinecopper(1) iodide to yield (158) followed by reduction of the sodio-enolate and

'" H. E. 366

367

368

369

Ensley and R. V. C. Carr, Tetrahedron Letters, 1977, 513; Current Abstracts of Chemistry, Abstract 255 431 incorrectly identifies the product as S-(-)-pulegone. T. Shono, I. Nishiguchi, and M. Nitta, Chem. Letters, 1976, 1319. Y. Yamamoto, H. Shimoda, J.-I. Oda, and Y . Inouye, Bull, Chem. SOC.Japan, 1976,49,3247; for an earlier application of this method, see Vol. 7, p. 5. F. Bondzvalli, P. Schenone, S. Lanteri, and A. Ranise, J.C.S. Perkin I, 1977, 430; see also ref. 391. B. Harirchian and P. D. Magnus, Synrh. Comm., 1977, 7 , 119. For other syntheses of p-mentha-3,8diene, see R. G. Buttery and L. C. Ling, J. Agric. Food Chem., 1977,25, 291, and ref. 379.

Terpenoids and Steroids

42

a~idification;~~’ benzophenone-sensitized photolysis of methyl a-diazopropionate in l-methoxy-5-methylcyclohexeneto yield (159) also results in p-menthofuran after reduction, Fetizon oxidation, and acid treatment.370 Other papers of synthetic interest are the full paper on uroterpenol synthesis (Vol. 6, p. 27),371straightforward syntheses of 2-methyl-5-isopropenylanisole372and of a- and P-phellandrene,373and the preparation of 7,7,7-trifluoro-p-menthan-3-01~.~~~ Further work on p-menthane hydroxylation using Pseudomonas mendocina-SF (Vol. 6, p. 12) has resulted in isolating the metabolites (160; R = C H 2 0 H ) and (160;

(158)

(159)

(160)

R = C02H),375and more urinary metabolites formed from (+)-limonene (Vol. 7, p. 9) are reported in a species-comparative study (earlier papers in this series were inadvertently omitted from Vol. 6).” Microbial conversion of (-)-menthone, using a Pseudomonas putida strain, yields (+)-isomenthone, (10; R = H), (61; X = H, R = CH2C02H), and (58; stereochemistry unspecified) and the corresponding hydroxy-a~id.~~~ The Diels-Alder reaction of a -phellandrene with acrylic acid derivatives has been examined, apparently superficially377in contrast to the re-investigation of the reaction with benzalbisurethane, catalysed by B F , , E ~ , O - C U B ~The . ~ ~1,4-adducts ~ (161; endo: exo/37 : 63) may result effecJively fr6m the concerted [4, +2,] addition involving the immonium ion (PhCH=NHC02Et); however, with the corresponding unsubstituted immonium ion, formal 1,3-addition to a -phellandrene occurs essentially via the isomerized a -terpinene and isoterpinolene to yield [(162): (163)/84: 16].378 K0Bu‘-DMF is the preferred reagent in tosylate elimination reactions with no accompanying substitution reactions [(-)-menthy1 tosylate, (-)-bornyl tosylate, (+)-carvomenthyl tosylate]; the tosylate of (+)-dihydrocarveol (164) gives a good yield (85%) of (-)-p-mentha-3,8-diene and (-)-p-mentha-2,4(8)-diene as sole products, presumably via base-catalysed rearrangement of i~olirnonene.~’~ 370

37’ 372

373 374

375 376

377

378

379

E. Wenkert, M. E. Alonso, B. L. Buckwalter, and K. J. Chou, J. Amer. Chem. Soc., 1977, 99, 4778. A. Kergomard and H. Veschambre, Tetrahedron, 1977, 33, 2215. T. K. John and G. S. K. Rao, Indian J. Chem., 1976,14B, 805. B. Singaram and J. Verghese, Indian J. Chem., 1976, 14B, 1003. A. N. Blakitnyi, E. V. Konovalov, R. K. Orlova, A. P. Sevast’yan, Y. A. Failkov, and L. M. Yagupol’skii, U.S.S.R. P. 520 343 (Chem. Abs., 1976,85, 160 356). Y. Tsukamoto, S. Nonomura, and H. Sakai, Agric. and Biol. Chem. (Japan), 1977, 41, 435. 0. Nakajima, R. Iriye, and T. Hayashi, Nippon Nogei Kaguku Kaishi, 1976, 50,403. E. Patyk, H. Sadowska, and J. Wilczynska, Zeszyty Nuuk. Politech. kodz., Chem. Spozyw., 1976,28,79 (Chem. Abs., 1977,86,121544). G. R. Krow, K. M. Damodaran, D. M. Fan, R. Rodebaugh, A. Gaspari, and U. K. Nadir, J. Org. Chem., 1971,42,2486. Z. Rykowski and H. Orszanska, Roczniki Chem., 1976, 50, 1901; this paper implies but does not specify that (-)-p-mentha-3,8-diene is the minor product (40:60). Chem. Abs., 1977, 86, 121 536 states the opposite!

Monoterpenoids

43

/

Ph

Base-aprotic solvent elimination has also been reported for 1-hydroxyneodihydrocarveyl tosylate and for 1-hydroxyneocarvomenthyl tosylate (epoxide and allylic alcohol Manganese(II1) acetate oxidation of (+)-p-menth-1-ene yields the two lactones (165; X=O, Y = CH2)and (165; X = CH2, Y = 0)as major products together with anticipated acetates;381similar oxidation of (+)-pulegone yields the C-2 acetates in low yield3" and oxidation of isomenthone in the presence of isopropenyl acetate results in acetonylation at C-2 and C-4.383 Further examples of the rearrangement of epoxides with K0Bu'-aprotic solvents (pyridine is favoured) have been reported (cf. Vol. 6, p. 44), e.g. (166) to (167), although with the corresponding 1,2-epoxy-

(165)

(166)

(167)

trans-p-menth-8-ene the expected aromatization is observed.384It is not clear why tosylate elimination from 1-hydroxyneocarvomenthyl t o ~ y l a t e ~ yields ~ ' (166; 98%) with little observed (167; 2%) under essentially identical conditions.384 Further papers from Arata's group on the rearrangement of limonene-1,2-epoxides over solid catalysts have been published (cf. Vol. 7, p. 31).385 Herz has carried out a thorough investigation of the ferrous ion-promoted decomposition of a-phellandrene epidioxides (168) and the corresponding epoxides [e.g. (169)].386 Products, formed by Fe"-Fe"' redox system-induced rearrangement, include inter alia (170)(173) and some derived epoxides, with no intramolecular 1,5-hydrogen abstraction The epoxide (169) decomposed rapidly on silica gel to the mixture [epoxy-(17l)+epoxy-(172); 1,4-trans-dialkyl]; all reported examples of such easy and unexplained rearrangements require hydrogen a to an epidioxide which must 380

381

382 383 384

"' 386

Z. Rykowski, K. Burak, and Z. Chabudzinski, Roczniki Chem., 1976,50,2107. K. Witkiewicz and Z. Chabudzinski, Roczniki Chem., 1976,50,1545;formulae (11) and (13) both lack a double bond. G . J. Williams and N. R. Hunter, Canad. J. Chem., 1976, 54, 3830. M. Chatzopoulos and J.-P. Montheard, Compt. rend., 1977,284, C,133. Z. Rykowski and K. Burak, Roczniki Chem., 1976, 50, 1709. K. Tanabe and K. Arata, Jap. P. 16 641/1976 (Chem. Abs., 1976,85,94 545); K. Arata, H . Takahashi, and K. Tanabe, Rocrniki Chem., 1976, 50, 2101; T. Yamada, K. Arata, M. Itoh, H. Hattori, and K. Tanabe, Bull. Chem. SOC.Japan, 1976,49,2946. J. A . Turner and W. Herz, J. Org. Chem., ( a ) 1977,42, 1895; ( b ) 1977,42,2006.

Terpenoids and Steroids

44

be cis to an adjacent e p o x y - g r o ~ p The . ~ ~ferrous ~~ ion-promoted rearrangement of ascaridole (174), via isoascaridole (175), to ascaridole glycol (176) has also been clarified. 386n

A (173)

A further paper on the reduction (lithium-ethylenediamine) of p-cymene has been The stereoselectivity of reduction of menthone and isomenthone to the corresponding menthols using dissolving metals and catalytic hydrogenation has been examined under a variety of conditions; for example Li-NH3 at -78 "C results in stereospecific reduction to menthol and isomenthol, respectively, in contrast to catalytic hydrogenation where high selectivity for menthol formation was not observed although good selectivity was observed for the other menthol isomers (e.g. neomenthol; 82%) with interesting selectivity shifts according to reaction temperature.388 A synthetic and mechanistic study of 13cineole hydrogenolysis reports cis - and trans -p-menthanes exclusively.389 pMentha-l$-diene can be synthesized efficiently by reductive cleavage of (153; R = H or Ac) or the C-2 epimeric carve01.~~'Another cineole + pinol rearrangement (see ref. 368) is observed in the lithium aluminium hydride reduction of the cineol chlorohydrin (177) which has been investigated mechanistically; excess hydride yields (178; X = H , endo-OH; 50%), (179; 32%), and (180; X=H; 11Y0) whereas one equivalent of hydride yields (177), (180; X = Cl), and (178; X = 0) and an epoxy precursor of (179).391 Thermal isomerization of (177) gave a mixture [(177): (180; X = C1)/20: 801 and data for the corresponding endo-dihalides have been reported.391bAlkene formation in the Ti" reductive coupling of menthone with itself392and the dehydrogenation of s o b r e r 0 1 ~have ~ ~ been described. 387 388 389 390 391

392

393

V. V. Bazyl'chik and P. I. Fedorov, Zhur. org. Khim., 1977,13, 1012; cf. Vol. 7, p. 32. J. Solodar, J. Org. Chem., 1976, 41, 3461. H. M. Hiigel, W. R. Jackson, C. D. Kachel, and I. D. Rae, Austral. J. Chem., 1977,30, 1287. I. Elphimoff-Felkin and P. Sarda, Org. Synth., 1977.56, 101. ( a ) J. Wolinsky, J. H. Thorstenson, and M. K. Vogel, J. Org. Chem., 1977, 42, 253; ( b ) M. K. Vogel, Diss. Abs. Internat. ( B ) , 1977, 37, 3969. D. Lenoir, Synthesis, 1977,553; for a related coupling between pulegone and acetone, see J. E. McMurry and L. R. Krepski, J. Org. Chem., 1976,41, 3929. S. S. Poddubnaya, Z. A. Surnina, V. G . Cherkaev, N. D. Antonova, and A . A . Skorubskii, Zhur. Vsesoyuz. Khim. obshch. im. D. I. Mendeleeva, 1976,21,455.

45

Monoterpenoids

OH

CI

Acylation of limonene at the disubstituted double bond is favoured by a factor of 2.3 over reaction at the trisubstituted double bond using acetyl hexachloroant i m ~ n a t e Mixed . ~ ~ ~ alkylcuprate alkylation of tricarbonylcyclohexadienyliron salts has been used to synthesize the a -phellandrene tricarbonyliron complex.395 Dichlorocarbene addition to limonene in the presence of 1,4-diazabicyclo[2,2,2]octane is almost 100% stereoselective at the trisubstituted double bond (no yield given) (cf. Vol. 6, p. 31);284in contrast to dibromocarbene addition to carvone (Vol. 7, p. 34), dichlorocarbene addition to the carveols is not regiospecific.**’ In an enamine alkylation study, piperitone (8; X = H) gave, in addition to the expected dienamines, two rearranged dienamines via ring opening and reclosure; hydrolysis yielded the o-menthenones (181).396Dauben’s full paper (Vol. 7, p. 34)on

pulegone and isopulegone tosylhydrazone decomposition397has been published. Other papers related to p-menthanes concern nitrosyl chloride addition to (*)-aterpineyl acetate,398 the stereochemistry and conformations of amino-oximes derived from limonene and p-menth-1-ene nitro so chloride^,"^ phenylationreduction of (+)-pulegone, piperitone (8; X = H), and ( - ) - ~ a r v o n e , ’ ~reactions ~ of a-terpinene in the presence of salicylic acid,400stereochemical assignment of cisand truns-1,S-terpin (!)401 and reaction of the cis-isomer with azide conversion of tetrahydrocarvone into an enol phosphate and reduction to p-menth-lene,403the non-photochemical reaction of (+)-pulegone with 4-phenyl- 1,2,4-tri394 395

396

397 398

399 400

401 402

403

H. M. R. Hoffmann and T. Tsushima, J. Amer. Chem. Soc., 1977,99,6008. A . J. Pearson, Austral. J. Chem., 1977,30, 345. Y. Bessiire and F. Derguini-BoumCchal, J. Chem. Res. ( M ) , 1977, 2301. W. G. Dauben, G. T. Rivers, and W. T. Zimmerman, J. Amer. Chem. Soc., 1977, 99, 3414. B. Singaram and J. Verghese, Indian J. Chem., 1977,153, 217. R. M. Carman, P. C. Mathew, G. N. Saraswathi, B. Singaram, and J. Verghese, Austral. J. Chem., 1977,30, 1323; see also ref. 413. I. I. Bardyshev, L. A . Popova, and E. F. Buinova, Vestsi Akad. Navuk belarusk, S.S.R., Ser. khim. Navuk, 1976, 112 (Chem. Abs., 1976,85, 177 634). B. Singaram, P. M. Abraham, G. N. Saraswathi, and J. Verghese, Indian J. Chem., 1976,14B, 934. A. Pancrazi, I. KaborC, and Q. Khuong-Huu, Bull. SOC.chim. France, 1977, 162. R. P. Gregson and R. N. Mirrington, Austral. J. Chem., 1976, 29, 2037.

46

Terpenoids and Steroids

a~oline-3,5-dione,~'~ isocarvoxime ~ y n t h e s i s , ~and ' ~ the constitution of the 1,scineol-ferric thiocyanate406and cymene-vanillin-sulphuric acid complexes.407 o-Menthanes.-Two earlier papers report syntheses of molecules with the omenthane carbon ~ k e l e t o n . ~ "Other . ~ ~ ~ papers of interest concern g.1.c. separation of 0- and p-menthenes and men thane^,^"* lithium-ethylenediamine reduction of o-cymene to o-menthadiene~,~'~ and neo-o-menthan-2-01 synthesis from ocreso~.~" rn-Menthanes.-The m-thymol derivative (182) has been isolated from Macowania h ~ r n a t u . ~ 1.r. ' ~ and Raman spectra of sylvestrene have been a n a l y ~ e d .A~ ~ ~ synthesis of the sesquiterpenoid frullanolide includes the formation of the mmenthane (183) via a modified ester enolate Claisen The stereochemistry and conformations of amino-oximes (184) derived from sylvestrene nitrosochloride by treatment with amines have been d i s c ~ s s e d ; last ~ ' ~ year's Report (Vol. 7, p. 30) omitted reference to AgN0,-DMSO dehydrohalogenation of sylvestrene n i t r o s ~ c h l o r i d e . ~ ~ ~

l_i_

OH (182)

HoNQ

C0,Me

(183)

(184)

Tetramethylcyc1ohexanes.-The structure of picrocrocinic acid from Gardenia jasminoides grundifloru has been established as (185) by relating it to picrocrocin (Vol. 4,p. 37).335

(185)

The formation of dihydrocyclogeranyl acetate via thiyl radical addition to geranyl and aldol-type condensations of citral, of dihydrocitral, anh of 3 - m e t h y l b ~ t - 2 - e n a l ~have ~ ~ been discussed already. a -Cyclocitral behaves 404 405

406 407 408 409

410

411 412 413

414

J. D. Shiloff and N. R. Hunter, Tetrahedron Letters, 1976, 3773. B. Singaram and J. Verghese, Current Sci., 1977, 46, 259. C. H. Brieskorn and W. Schlicht, Arch. Phurm., 1977,310,305; see also ref. 1756. H. Auterhoff and C. Baur, Arch. Pharm., 1977,310,518. V. V. Bazyl'chik, B. G . Udarov, and N. P. Polyakova, J. Anafyt. Chem. (U.S.S.R.),1976,31, 507. V. V. Bazyl'chik, I. I. Bardyshev, P. I. Fedorov, E. D. Skakovskii, and N. M. Ryabushkina, Vesrsi Akad. Navuk belarusk. S.S.R.,Ser. khim. Navuk, 1976,75 (Chem. Abs., 1976,85,94 497). V. V. Bazyl'chik, E. A. Ionova, and I. I. Bardyshev, Vestsi Akad. Nuvuk belarusk. S.S.R., Ser. khim. Nuvuk, 1976, 112 (Chem. Abs., 1977,86,140262). F. Bohlmann and C. Zdero, Phyrochemistry, 1977,16, 1583. W. C. Still and M. J. Schneider, J. Amer. Chem. Soc., 1977,99,948. D. J. Brecknell, R. M. Carman, B. Singaram, and J. Verghese, Austral. J. Chem., 1977, 30, 195; for related work see refs. 398, 399, and Vol. 5, p. 24. B. Singaram and J. Verghese, Indian J. Chem., 1976, 14B, 479; Chem. Abs., 1976, 85, 177633 incorrectly refers to NaN03-Me2SO dehydrochlorination.

47

Monoterpenoids

similarly to citral on treatment with fluorosulphonic a~id;’~’however, (74), from which a-cyclocitral and a-cyclogeranyl acetate are readily available, is now formed in fair yield (53%). In contrast, P-cyclocitral is less reactive, because of delocalized cation formation, being recovered largely unchanged (73%) along with methyl P-cyclogeranate (2370).272 The brominative cyclization of geranyl cyanide using 2,4,4,6-tetrabromocyclohexa-2,5-dienone-Lewis acid (15% yield) was omitted from earlier report^.^" Cyclization of (E+Z)-geranic acid using graphite bisulphate favours the formation of (186) over the conjugated cyclogeranic acid by 9 to l.416Deoxygenation of (187), which is readily available from 3-methylcyclohex-2-enone, with TiC1,LiAlH, reagent leads to y-cyclocitral (188) in good yield.417 Vilsmeier formylation of dihydroisophorone yields (189; X=Br or CI), which may be reduced selectively to (189; X = H ) using an improved catalyst (cf. ref. 420).,*’

CHO

(186)

(187)

(188)

(189)

Dimethylethylcyc1ohexanes.-Halogenated members of this class,29s~297~299~300~303 the formation of (77; X = Z - M e ) from m y r ~ e n e , ’and ~ ~ hydrative cyclization of dihydromyrcene to (78)276have already been reported. Extending their earlier work on Vilsmeier formylation (cf. Vol. 7, p. 36), Traas et al. have formylated the @unsaturated ketone isophorone almost exclusively at the more favoured exocyclic position to yield (190),419which may be selectively

090)

reduced without isomerization to the boll weevil pheromones (77; X=CHO, E :2 / 2 : 1) in high overall yield; an alternative route from isophorone involves reduction with sodium dihydrobismethoxyethoxyaluminateand dehydration prior to formylation and selective reduction.420 Alkylation of 3,3-dimethylcyclohexanone with O-ethyl S-ethoxycarbonylmethyl dithiocarbonate yields the boll weevil pheromone intermediate (77; X=E-C02Et) stereo~electively,~~~ although no 415

416

417 41R 419

420 421

T. Kato, I. Ichinose, S. Kurnazawa, and Y. Kitahara, Bioorg. Chem., 1975, 4, 188. J. P. Alazard, R. Setton, and H. B. Kagan, unpublished data reported in ref. 87; the name8’“ and are misprinted in these papers. T. Mukaiyama, K. Saigo, and 0.Takazawa, Chem. Letters, 1976, 1033. P. C. Traas, H. J. Takken, and H. Boelens, Tetrahedron Letters, 1977,2027. P. C. Traas, H. Boelens, and H. J. Takken, Rev. Trav. chim., 1976, 95, 308; W. Hoffmann and E. Mueller, Ger. Offen. 2 152 193 (Chem. Abs., 1973, 79, 18 212) have described an almost identical synthesis in slightly lower yield. P. C. Traas, H. Boelens, and H. J. Takken, Synth. Comm., 1976,6,489. K. Tanaka, R. Tanikaga, and A . Kaji, Chem. Letters, 1976, 917.

48

Terpenoids and Steroids

stereoselectivity is observed in the pyridinium chlorochromate (cf. Vol. 7, p. 30) oxidative rearrangement of 3,3-dimethyl-l-vinylcyclohexanol to (77; X=CHO).92 An alternative non-stereoselective route from 3,3-dimethyl-l-vinylcyclohexanol involves the previously reported242[3,3] sigmatropic rearrangement of a derived thionocarbamate as the key step. A routine synthesis of 1,4-dimethylcyclohex-3enyl methyl ketone does not refer to Thomas's improved synthesis (Vol. 5, p. 29).422 Cyc1oheptanes.-The C-1 -C-2 bond in y-thujaplicin is essentially single,423Co"P-thujaplicin-amine complexes have been and thermodynamic data on the U"'-P-thujaplicin complex have been calculated.425 The biomimetic cyclization of the silyl enol ether (191) to karahanaenone (192), using methylaluminium bis(trifluor0acetate) is almost q ~ a n t i t a t i v e ; ~(192) ' ~ is also synthesized by thermolysis followed by desilylation of the silyl enol ether (193) which is readily available from l-bromo-2-methyl-2-vinylcyclopropane and i ~ o b u t y r a l d e h y d e . ~ ~ ~ Dehalogenation of 3-bromo-1 -iodo-3-methylbutan-2-one with Zn-Cu couple on alumina in the presence of isoprene yields (192) and minor amounts of the isomers (194) and (195); however, dehalogenation with Fe2(C0)9 favours ( 195).428 Acetolysis of karahanaenol tosylate yields anticipated p-menthane derivatives and no f i ~ i f o ~ e n e . ~ ~ ~

6 Bicyclic Monoterpenoids

Bicyclo[3,1,0]hexanes.-Hach has concluded his efforts to provide preparativescale syntheses of pure (+)-thuj-3-one (30), and (-)-isothuj-3-one, and the four derived thujanols, uiz. (+)-thujan-3-01, (-)-isothujan-3-01, (+)-neothujan-3-01 (31), and (-)-neoisothujan-3-01 (for earlier related work see Vol. 2, pp. 30, 37, 38; Vol. 4, p. 42; Vol. 7, p. 36)."' A conformational study on these four thujanols indicates that they have a slightly developed boat-like conformation, whereas the five-membered ring in (+)-thuj-3-one (30) and (-)-isothuj-3-one is flat, according 422

423

424

425 426

427 428 429 430

0. P. Vig, S. D. Sharma, S . S. Bari, and M. Lal, Indian J. Chem., 1976, 14B,932. J.-E. Berg, B. Karlsson, A.-M. Pilotti, and A.-C. Wiehager, Actu Cryst., 1976, B32, 3121; for b-thujaplicin see Vol. 3, p. 55. B. Maiti and R. M. Sathe, J. Inorg. Nuclear Chem., 1977,39, 1244; cf. the Ni" complex (Vol. 7, p. 36). T.-M. Hseu, C. Chang, and K.-L. Hsu, J. Chinese Chem. Soc. (Taiwan), 1977,24,11. S . Hashimoto, A. Itoh, Y. Kitagawa, H. Yamamoto, and H. Nozaki, J. Amer. Chem. Soc., 1977, 99, 4192; see Vol. 7, p. 17 for a related organoaluminium-promoted cyclization. P. A. Wender and M. P. Filosa, J. Org. Chem., 1976, 41, 3490. R. Chidgey and H. M. R. Hoffmann, Tetrahedron Letters, 1977, 2633. C. Capellini, A. Corbella, P. Gariboldi, and G. Jommi, Guzzettu, 1977,107, 171. V. Hach, J. Org. Chem., 1977, 42, 1616. The nomenclature used by Whittaker (Vol. 5, p. 30) has already been noted; in addition, the formula given for (-)-thujan-3-01 is actually that of (+)-thujan-301. Further confusion in this field results from Banthorpe using149 the name (+)-isothujanol for the (+)-neoisothujanol structure; Banthorpe uses the same nomenclature as Whittaker.

Monoterpenoids

49

to evidence, from lanthanide-induced shifts in the ‘H n.m.r. spectrum, from rates of chromium trioxide oxidation, and from rates of a~etylation;~” this confirms earlier work (Vol. 5 , p. 30) on (-)-thujan-3-01 and (+)-neothujan-3-01 (31). The full paper by Whittaker concerning the carbonium ion derived from neothujan-3-01 (31) (cf. Vol. 5 , p. 30; Vol. 6, p. 35; Vol. 7, p. 36) has been p ~ b l i s h e d ; ~the ~’ products derived from solvolysis of thujan-3-01 (called isothujol) and neothujan-301 (31) (called neoisothujol) esters are compared with those from earlier work on the hydration of sabinene and a-thujene (Vol. 4, pp. 42, 43) as well as Norin’s tosylate a c e t o l y ~ e sand ~ ~interpreted ~ in terms of the ions (196) and (197); Whittaker interprets the formation of cyclopentenes from thujan-3-01 and neothujan-301 (31) in strong acid as proceeding uia ion (197), which predictably rearranges to the more stable (198), despite Sorensen’s view (Vol. 7, p. 36) that the first formed ion must be (199).431The products of reduction of umbellulone (200) (cf. Vol. 1, p. 39; Vol. 3, p. 57) and dihydroumbellulone (201; R’,R2=0),* using different reducing agents, have been interpreted based upon their respective conformations; complete assignment of ‘H and 13Cn.m.r. spectra indicated that dihydroumbellulone (201; R1,R2= 0)has a flattened boat conformation and that each of the ~’ derived alcohols (201; R’,R2 = H,OH) also exists in a boat c ~ n f o r m a t i o n . ~Both thermal and photochemical elimination of cyclohexyl isocyanide by a,a-carboncarbon bond cleavage fails with N-cyclohexylthujan-3-imine.434

Bicyclo[2,2,1]heptanes.-Vulgarole (202; R = Ac) has been isolated from Artemisia v u l g a r i ~and ~ ~ Ferula ~ dshizakensis has yielded a new borneol ester, isotschimgin (cfiVol. 3, p. 58).436 X-Ray diffraction studies of (~t)-carbocamphenilone,~~~ of (-)-camphene-8carboxylic and of a number of Money’s brominated camphor derivatives (Vol. 6 , p. 39; Vol. 7, p. 40) have been published; they include 8-bromo1,7-dibromo-4camphor,439 1,7-dibromo-3,3,4-trimethylnorbornan-2-one,440 431

432 433

434 435

436

437 438 439 440

C. M. Holden and D. Whittaker, J.C.S.Perkin ZI, 1976, 1345. T. Norin, Tetrahedron Letters, 1964, 37. C. M. Holden, J. C. Rees, S. P. Scott, and D. Whittaker, J.C.S. Perkin 11, 1976, 1342; on page 1344 line 14 ‘the 0-01’ should read ‘the p-01’. J. H. Boyer and K. G. Srinivasan, J.C.S. Perkin I, 1976, 1583. G. M. Nano, C. Bicchi, C. Frattini, and M. Gallino, PZuntu Med., 1976, 30, 211; see also ref. 459. V. N. Borisov, A. I. Ban’kovskii, V. I. Sheichenko, V. S. Kabanov, and M. G. Pimenov, Chern. Natural Compounds, 1976,12,598. J. P. Seymour, B. Lee, and A. W. Burgstahler, Acta Cryst., 1977, B33, 2667. P. C. Moews, J. R. Knox, and W. R. Vaughan, Tetrahedron Letters, 1977, 359. C. A. Bear and J. Trotter, Actu Cryst., 1975, B31, 903. C. A. Bear and J. Trotter, Actu Cryst.,1975, B31, 904.

* Named isodihydroumbellulone by the authors; see the footnote, Vol. 2, p. 37

50

Terpenoids and Steroids

dibromomethyl-3,3-dimethylnorbornan-2-one,441 and endo-3,9,9-tribromocamphor.442 ‘HN.m.r. signals of the C-8 and C-9 methyl groups of a series of bornane derivatives have been assigned.443 Further papers on 13C n.m.r. include chemical shifts of 1-substituted camphenilones, their derived N-nitro-imines, fenchone oxime, and fenchone N - n i t ~ o - i m i n eand ~ ~ ~of 4-substituted camphors, N-nitrocamphorimines, and d i a z o ~ a m p h o r s . ~ Raman ~~ c.i.d. spectral data have been extended to additional bicyclo[2,2, llheptane monoterpenoids (cf.Vol. 6, p. 36).446 C.d. data for (1R)-[2-’s0]- and (1R)-[1-2H]-a-fenchocamphoronequinone(cf. Vol. 4, p. 50) and rotational strengths for (1R)-camphorquinone and (19-1bromo-a-fenchocamphoronequinone have been ~ a l c u l a t e d . ~ ~ Further ’ fluorescence data for camphorquinone in the solid and gas phases have been reported (cf. Vol. 6, p. 35)448and a photoluminescence study includes data on camphor and fenchone fluorescence and p h o s p h o r e ~ c e n c e .The ~ ~ ~kinetics of mutarotation of (+)-3-bromocamphor and (+)-3-bromo-3-deuteriocamphor and of bromination of (+)-3-nitrocamphor and (+)-3-deuterio-3-nitrocamphor have been in~estigated,~” and the standard enthalpy of formation of camphor has been measured.451 The synthesis of camphor (80% optical purity) by heating optically pure dihydrocarvone at 400 “C for 20 h is reminiscent of Money’s racemic camphor synthesis (Vol. 1, p. 39) in that both correspond to a biogenetic-type synthesis via enol formation.452Further synthetic work on deuteriated camphors (see references therein and Vol. 3, p. 67; Vol. 4, p. 48; Vol. 7, p. 38 for earlier work) includes syntheses of optically pure [tb2H1]-,[8-2H2]-, and [8-2H3]-(-)-camphor (204) by modification of known reactions (Scheme 5)453 and the use of an improved Zn-Cu

(202)

(203)

(204)

Reagents: i, H’; ii, LiAID4; iii, PhCOCI; iv, Cr03; v, OH-; vi, PBr3; vii, Bu3SnD Scheme 5 441

442

443 444

44s 446 447

448 449 4s0

451 4s2 453

S. E. V. Phillips and J. Trotter, Acfa Cryst., 1976, B32, 1423. S.E. V. Phillips and J. Trotter, Acfa Crysr., 1977, B33, 200; last year’s Report erroneously reports the is the major X-ray crystal structure of this compound. Although endo-3,9,9-tribromocamphor component of the by-product in preparing 3,9-dibromocamphor, the X-ray structure reported last year (Vol. 7, p. 37, ref. 372) was of the minor by-product, the corresponding exo-isomer. L. Lacombe and L. Mamlok, J. Chem. Rex (M), 1977, 1401. F. C. Brown and D. G. Morris, J.C.S.Perkin Il, 1977, 125. D. G. Morris and A. M. Murray, J.C.S.Perkin 11,1976, 1579. L. D. Barron, J.C.S. Perkin Il, 1977. 1074. R. F. R. Dezentje and H. P. J. M. Dekkers, Chem. Phys., 1976.18, 189. P. Avouris, W. D. Hopewell, and M. A. El-Sayed, J. Chem. Phys., 1977,66, 1376. W. H. Waddell, N. J. Turro, and G. Farrington, Mol. Photochern., 1976, 7, 475. R. P. Bell and S. Grainger, J.C.S. Perkin II, 1976, 1606. W. V. Steele, J. Chem. Thermodynamics, 1977,9, 311. G. L. Lange and J. M. Conia, Nouveau J. Chim., 1977, 1,189. W. L. Meyer, C. E. Capshew, J. H.Johnson, A. R. Klusener, A. P. Lobo, and R. N. McCarty, J. Org. Chem., 1977,42,527.

Mono terpenoids

51

couple to prepare exo-[3-’Hl]-(+)-camphor (cf. Vol. 2, p. 39; Vol. 5 , p. 33) from 3 - b r o m o ~ a m p h o r . ~ ’Other ~ syntheses of interest include the syntheses of camphorquinone by Pummerer-type reaction during the oxidation of 3-phenylselenocamphor with thallium(II1) nitrate,455[8-14C]camphene,456the first example of a tetracyclic monoterpenoid (205),457 and an improved synthesis of ~amphenilone.~’~ Money et al. have accomplished the chemical functionalization of (-)-bornyl acetate, to yield (206) as the major product with smaller amounts of the 3-keto- and 6-keto-isomers of (206) and exo-(207; R = Ac), as well as microbiological hydroxylation using Helminthosporium sativum, to yield endo- and exo-(207; R=H) : 6exo-hydroxyborneol: (208; R=H)/5 : 1 : 2.459

(205)

(206)

(207)

(208)

The long-known rearrangement of a -bromocamphoric anhydride (209; X=Me) to (210; X = Me) has been shown to proceed via at least two competitive pathways to account for the observation, using (209; X = CD,), that the C-9 methyl group is the precursor of X [no (210; X = CD,) is obtained] but that the C-8 methyl group is the precursor of both the C-1 methyl group (71%) and the C-3 methyl group (29%) in (210; X = CH,). This paper also confirms the unequivocal methyl resonance

+-.{ x o

H F

...-.--

(209)

(2 10)

assignments in the ‘H n.m.r. of camphor and that the rearrangement (202) + (203) proceeds with no rearrangements resulting in r a ~ e m i z a t i o n . ~ In ’ ~ contrast, the acid-catalysed rearrangement of camphene into isobornyl acetate (Vol. 5 , p. 31) in the presence of CuC12 does not involve Nametkin rearrangement, thus allowing exclusive deuterium labelling of the C- 10 methyl group; P-pinene behaved similarly.460 Camphene reacts with chloroacetic acid-KBr to form the expected lactones without rearrangement.461 The rearrangement of fenchenes formed during the titanic acid-catalysed isomerization of a -pinene gives the expected results 454

45s

4s6 4s7 4SR 459 460 46‘

L. M. Stephenson, R. V. Gemmer, and S. P. Current, J. Org. Chem., 1977, 42, 212; Registry Numbers have been assigned incorrectly to these compounds, Y, Nago, M. Ochiai, K. Kaneko, A . Maeda, K. Watanabe, and E. Fujita, Tetrahedron Letters, 1977, 1345. J. E. Oliver, J. Labelled Compounds, 1977.13, 349. D . Heissler, F. Jung, J. P. Vevert, and J. J. Riehl, Tetrahedron Letters, 1976,4879. J. San Filippo, jun. and J. W. Nicoletti, J. Org. Chem., 1977, 42, 1940. M. S. Allen, N. Darby, P. Salisbury, and T. Money, J.C.S. Chem. Comm., 1977, 358. A. Heumann and B. Waegell, Nouoeau J. Chim., 1977,1,275. T. Kishimoto, H. Ishihara, and Y. Matsubara, Bull. Chem. SOC.Japan, 1977.50, 1897.

52

Terpenoids and Steroids

(see Vol. 3, pp. 59, 60; Vol. 4, p. 44).462 A thermodynamic and kinetic study, via acetoxylation-deacetoxylation,complements an earlier camphene study (Vol. 5, p. 31) and confirms the relative stability of a- and P-fenchenes as well as cyclof e n ~ h e n e .Synthetic ~~~ details have been published for the trifluoromethanesulphonates (211; X=H, Y = OSO2CF3; 35%) and (211; X = OS02CF3,Y = H; 65%) reported last year (Vol. 7, p. 37);464a second preliminary paper reports the same reaction-camphor treated with (CF3S02)20-CH2C12-Na2C03-but with different The authors describe (211; X = OS02CF3, Y = H) as the only bicyclic triflate together with carvenone (5) and carvacryl triflate; however, the authors’ limited spectral data46’ correspond most closely to those reported far (2 11; X = H, Y = OS02CF3).464 Similar reaction of fenchone (212; X = 0) yielded (213) and (214), and isofenchone (215; X = Me, Y = 0)yielded (215; X = OS02CF3,Y = CH2) and (216), as expected from carbonium ion rearrangement^.^^^ The addition of chlorine in carbon tetrachloride to camphene alcohol (2 17) yielded (218) quant i t a t i ~ e l y .Ring ~ ~ ~expansion of camphene to (219; X = 0,Y = H2)and (219; X = H2, Y = 0)occurs with PdC12-CuC12-02-H20.467

p by

& && Y (21 1)

(212)

(213)

(2 14)

(215)

OHC

\

OTf

Y (216)

(217)

(218)

(219)

Full details of Barton’s selenofenchone (212; X = Se) and fenchylidenefenchane and (212; X = 2-fenchylidene) synthesis (Vol. 6, p. 40) have been Wynberg has discussed the antipodal interaction effect in the reductive dimertzation of (+)- and (*)-camphor to bornylidenebornanes (Vol. 7, p. 41),469sensitized photo-oxidation of which has also been r e p ~ r t e d . ~ ”The CuC12-promoted dimerization of camphor-lithium enolate yields the expected mixture of dia462

463 464

465 466

467 468 469 470

G. A. Rudakov, T. N. Pisareva, and N. F. Ovsyukova, J. Org. Chem. (U.S.S.R.),1977, 13, 298; the formula given for cyclofenchene is actually that of tricyclene. Y. Castanet, F. Petit, and M. Evrard, Bull. Soc. chim. France, 1976, 1583. H. Bentz, L. R. Subramanian, M. Hanack, A. G. Martinez, M. G. Marin, and R. Perez-Ossorio, Tetrahedron Letters, 1977, 9. W. Kraus and G. Zartner, TetrahedronLetters, 1977, 13. J. S. Yadav, H. P. S. Chawla, and S. Dev, TetrahedronLetters, 1977, 201. P. Boontanonda and R. Grigg, J.C.S. Chem. Comm., 1977, 583. T. G. Back, D. H. R. Barton, M. R. Britten-Kelly, and F. S. Guziec, jun., J.C.S. Perkin I, 1976, 2079. H. Wynberg and B. Feringa, Tetrahedron, 1976, 32, 2831. H. Takeshita, T. Hatsui, and 0. Jinnai, Chem. Letters, 1976, 1059; for a related paper see F. McCapra and I. Beheshti, J.C.S. Chem. Comm., 1977,517.

Monoterpenoids

53

stereo isomer^,^^^ which also results from treating 3-bromocamphor with CO~(CO)~NaOH-PhCHZ~Et3C1--C~H6.472 A revised structure for the dicamphene selenide produced by selenium dioxide oxidation of camphene has been Camphor is one of the ketones investigated in a comparative stereochemical reduction study using both simple and complex main-group metal h y d r i d e ~ . ~ ~ ~ Base-promoted tosylate elimination from (-)-bornyl tosylate is reported to yield bornene as the only hydrocarbon using potassium t-butoxide in DMF,379 in DMS0,379and in benzene-(1 8 - ~ r o w n - 6 ) although ,~~~ a second report of reaction in DMSO detects some ~ a m p h e n e . ~ ~ ’ Beckmann rearrangement of 6-endo -chlorocamphor oxime (Vol. 7, p. 43) yields (220) and the cis- and trans-ring-fused (221),476and camphor oxime rearranges with hydrazoic acid in polyphosphoric acid to yield (222).477

Other papers of interest in this section report transamination of camphor-3carbothioamides with secondary cyclic a m i n e ~reaction , ~ ~ ~ of camphorquinone with dimethyl P - k e t o g l ~ t a r a t ethe , ~ ~use ~ of fenchone (212; X=O) in alkene formation from Grignard reagents,480 bromination of 2-endo-6-endo-dibromobornaneto yield 2,3,6-endo-tribromob0rn-2-ene,~~~ and camphor-en01 trimethylsilyl ether formation by quenching the reaction mixture of butyl-lithium and camphor tosylhydrazone with trimethylsilyl ~ h l o r i d e . ~ ”

Bicyclo[3,l,l]heptanes.-Spin-lattice relaxation time measurements have facilitated the 13C n.m.r. spectral assignments of paeoniflorin and albiflorin (Vol. 3, p. 71).483 trans-Pinocarveol (223) has been synthesized from P-pinene in t-butyl alcohol with hydrogen peroxide in the presence of a catalytic amount of selenium 471 472 473

474

475 476

477

478

479

480

481 482 483

Y. Ito, T. Konoike, T. Harada, and T. Saegusa, J. Amer. Chem. SOC., 1977, 99, 1487. H. Alper, K. D. Logbo, and H. des Abbayes, Tetrahedron Letters, 1977,2861. G . Mehta and U. R. Nayak, Indian J. Chem., 1977,15B, 419; for the earlier work see W. Zacharewicz, Roczniki Chem., 1936.16, 290. E. C. Ashby and J. R. Boone, J. Org. Chem., 1976,41,2890. R. A. Bartsch, J. R. Allaway, and J. G. Lee, Tetrahedron Letters, 1977, 779. C. H. Brieskorn and E. Hemmer, Arch. Pharm., 1977,310.65. T. Duong, R. H. Prager, J. M. Tippett, A. D. Ward, and D. I. B. Kerr, Austral. J. Chem., 1976, 29, 2667. A.-M. Lamazoutre and J. Sotiropoulos, Bull. SOC.chim. France, 1976, 1851. S. Yang-Lan, M. Mueller-Johnson, J. Oehldrich, D. Wichman, and J. M. Cook, J. Org. Chem., 1976, 41, 4053. M. T. Reetz and C. Weis, Synthesis, 1977, 135. R. M. Carman and G. J. Walker, Austral. J. Chem., 1977, 30, 1393. R. T. Taylor, C. R. Degenhardt, W. P. Melega, and L. A. Paquette, Tetrahedron Letters, 1977, 159. K. Yamasaki, M. Kaneda, and 0.Tanaka, Tetrahedron Letters, 1976,3965; the structure of albiflorin is incorrect in Chem. Abs., 1977, 86, 121 691.

Terpenoids and Steroids

54

The conversion of (+)-a -pinene into methyl (+)-truns-chrysanthemate was reported earlier."' Mori et al. have now synthesized the cis-verbenols [(32) and its enantiomer] in optically pure state using essentially the same route as used for trans-verbenol (Vol. 7, p. 41); in connection with optical purity and stereochemical comparisons based upon optical rotations, it is of interest to note that optically pure (32) has [a]::= -9.8" in chloroform and [a]: = +11.4" in methanol and +6.2" in acetone, emphasizing the value of using chiral designation^.^^' a-Pinene is metabolized in the rabbit to verbenol (32; unspecified stereochemistry) and traces of myrtenol (224; R=CH,OH); (-)-0-pinene similarly yields trans-pinocarveol (223; enantiomer), trans-myrtanol, a-terpineol, and p-menthl-ene-7,8-di01.~'~ The ene reactions between 0-pinene and ethyl propiolate (AlCl, catalyst),487 but-3-yn-2-one (ZnX,! catalyst^),^'' chloral (various Lewis acid catalysts),489and methyl cyanodithi~formate~~' have been described; using chloral, asymmetric induction is observed at the newly generated chiral centre depending upon the catalyst, varying between R : S/83 : 17 for the non-catalysed reaction and R :S/O : 100 for the TiC1,-catalysed reaction (cf. Vol. 5 , p. 39).-489[2,3] Sigmatropic rearrangement of the methyl cyanodithioformate-0-pinene adduct provides a useful functionalization at C-3.49' Reports of a-pinene rearrangement49' and the conversion of a-pinene into P - ~ i n e n e ~contribute '~ further papers to the literature. Manganese(II1) acetate oxidation of a-pinene yields two lactones analogous to those reported earlier381with (+)-p-menth- l-ene; however, the major product consists of derived acetates [of a-terpineol, cis-pin-3-en-2-01, and myrtenol (224;

(223)

(224)

R = CH,OH)] which suggests both carbonium-ion and free-radical mechanisms;493 oxidation of cis-verbanone (225; R=H) in the presence of isopropenyl acetate 484

485

486 487 488

489 490 491

492

4y3

J. M. Coxon, E. Dansted, and M. P. Hartshorn, O r g . Synth., 1976, 56, 25; an earlier synthesis, J. K. Crandall and L. C. Crawley, Org. Synth., 1973, 53, 17, was omitted from these Reports, cf. ref.'99. K. Mori, N. Mizumachi, and M. Matsui, Agric. and Biol. Chem. (Japan), 1976, 40, 1611; see also ref. 237 for optical rotations and related synthetic work. T. Ishida, Y. Asakawa, M. Okano, and T. Aratani, Tetrahedron Letters, 1977, 2437. B. B. Snider, J. Org. Chem., 1976,41, 3061. B. B. Snider, L. A. Brown, R. S. E. Conn, and T. A. Killinger, Tetrahedron Letters, 1977, 2831. G . B. Gill and B . Wallace, J.C.S. Chem. Comm., ( a ) 1977,380; ( b ) 1977, 382. B. B. Snider, N. J. Hrib, and L. Fuzesi, J. Amer. Chem. Soc., 1976, 98, 71 15. L. P. Petelina, M. I. Goryaev, G . N. Tupoleva, R. Suleeva, and V. A . Yagai, Izvest. Akad. Nauk karakh. S.S.R., Ser. khim., ( a ) 1976, 26(5), 81( Chem. Abs., 1977, 86, 72 900); ( b ) 1976, 26(6), 40 (Chem. Abs., 1977, 86, 121 538); ( c ) V.V. Bazyl'chik, N. P. Polyakova, V. S. Shavyrin, and N. I. Skrebkova, Izvest. Vyssh. Uchebn. Zaued., Khim. khim. Tekhnoi., 1976, 19, 234 (Chem. Abs., 1976, 85, 177 619); ( d ) Sh. B. Battalova, N. D. Pak, and T. R. Mukitanova, Vestnik Akad. Nauk kazakh. S.S.R., 1977, 33 (Chem. Abs., 1977,87, 23 516). G. L. Kaiser, ( a ) U.S. P. 4 000 207 (Chem. Abs., 1977, 86, 121 565); ( 6 ) U.S. P. 4 000 208 (Chem Abs., 1977,86, 121 564); ( c ) P. M. Koppel and W. I. Taylor, US.P. 3 987 121 (Chem. A h . , 1977,86, 55 599). K. Witkiewicz and Z. Chabudzinski, Roczniki Chem., 1977, 51, 475.

Monoterpenoids

55

gives (225; R = CH2COMe).383 Cobalt acetate-catalysed air oxidation of apinene in the presence of benzaldehyde yields less verbenone (45 ; unspecified stereochemistry) and verbenol but more a-pinene epoxide (-40%) than the cobalt abietate-catalysed oxidation (Vol. 3, p. 73).494The reaction of diphenyl diselenide with (+)-2a,3a -epoxypinane failed to give significant amounts of (226), as might have been anticipated although the corresponding cis-(226) should result cleanly from the 2@,3@-epoxypinane(Vol. 3, p. 72).49s Catalytic hydrogenation of apinene in the presence of Pd-exchange resin favours the formation of cis-pinane more so than with Pd-C catalyst; the stereoselectivity change in myrtenal (224; R = CHO) reduction is i n ~ i g n i f i c a n t .Hydroboration-oxidation ~~~ of myrtenyl acetate (224; R=CH,OAc), myrtenic acid (224; R=CO,H), and a series of myrtenic acid esters has been investigated; the formation of pinane-3,lO-diol is preferred for (224; R = C H 2 0 A c or R = CO,H) whereas the esters (224; R = C 0 ,alkyl) yield myrtanol [dihydro-(224; R = CH20H)] predominantly with no pinane3,lO-diol formation.497 Acetylation of @ -pinene with acetyl hexachloroantimonate proceeds in low yield.394 cis-8-Pinene (227) is formed (63% yield) in the K0Bu'-DMF elimination from the tosylate ester of isopinocampheol (l), along with a-pinene (15%) formed by syn -elimination;498 under the same conditions detosylation of 2a-hydroxy-3atosyloxypinane yields pinocamphone (228; S-Me) and isopinocamphone (228;

(225)

(226)

(227)

(228)

R-Me) with none of the well known ring-contracted ketone which is observed in protic solvents (Vol. 2, p. 54; Vol. 4, p. 63; Vol. 5 , p. 41).499Similar reaction of the isomeric 2a-hydroxy-3@-tosyloxypinane yields trans-pinocarveol (223 ; 74%) presumably via 2a,3a-epoxypinane (Vol. 6, p. 44).380 Further details of the photoaddition of N-nitrosopiperidine to a-pinene have been p~blished.~''The claim of a-fenchen-6-one oxime formation (Vol. 7, p. 43) has been retracted; the product is optically active carvone oxime.sol The stereochemistry and conformations of amino-oximes derived from a-pinene nitrosochloride have been examined.399 Wolinsky's re-examination of the reaction of a-pinene with hypochlorous acid has shown that the major product is (229; 90?!0);~~~this paper should be read in 494

495 496 497 498

499

500

A . M. Romanikhin, N. I. Popova, and E. K. Prudnichenko, Izvest. Vyssh. Uchebn. Zaved., Khim. khim. Tekhnol., 1977,20, 177 (Chem. Abs., 1 9 7 7 , 8 7 , 23 520). A. Uzarewicz and E. Zientek, Roczniki Chem., 1 9 7 7 , 5 1 , 181. C. Allandrieu, G. Descotes, J. P. Praly, and J. Sabadie, Bull. SOC.chim. France, 1977, 519. L. Borowiecki and E. Reca, Roczniki Chem., 1976, 50, 1689. Z. Rykowski, H. Orszanska, and Z. Chabudzinski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1976, 24, 681. Z. Rykowski, K. Burak, and Z. Chabudzinski, Bull. Acad. polon. Sci., Sir. Sci. chim., 1976, 24, 771; Vol. 5, p. 41, ref. 303 should be to p. 2305 and not p. 2505. Y. L. Chow, S. K. Pillay, and H. H. Quon, J.C.S. Perkin ZZ, 1977, 1255; for earlier work see Vol. 7, p. 43. S. W. Markowicz, Roczniki Chem., 1 9 7 6 , 5 0 , 1641. J. Wolinsky and M. K. Vogel, J. Org. Chem., 1977, 42, 249.

56

Terpenoids and Steroids

conjunction with those reported earlier on cineol+ pinol rearrangement^.^" The nature of the products derived from (229) by treatment with base varies with reaction conditions. One product is (230) which undergoes a quasi-benzylic acid rearrangement and elimination to yield (23 1);502(230) is also readily converted into (+)-(232)502 from which (179)391" is readily obtained. The (-)-enantiomer of (232), which is available from (229) along with traces of (230) when the base treatment is refluxing aqueous potassium h y d r o ~ i d e , ~is' the ~ precursor of (177).391 COMe 0

OH

(229)

(230)

(231)

(232)

Further papers in this section include the hydrosilylation of a-pinene503 and of p-pinene,'" thiocyanation and selenocyanation of ~x-pinene,~'~ cationic poly'~ of (*)-cis -pinonic acid merization of a- and p -pinene e p ~ x i d e s , ~bromination with dioxan dibr~mide,~"and straightforward myrtenol (224; R=CH20H)50Eand tetrahydroperillyl alcoho1509syntheses from p -pinene epoxide.

Bicycl0[4,1,O]heptanes.--'~C N.m.r. and 'H n.m.r. data suggest that 3a,4a - and 3P,4p-thioepoxycarane exist mainly in the inverted boat onf formation.^'' No allylic oxidation is observed in the metabolism of (+)-car-3-ene in the rabbit, which yields small amounts of (233) and (234), together with trace amounts of m-cymen-8-01.~~~ Microbial reduction of car-3-ene-2,5-dione (235; X=Y = 0) using Rhodotorula mucilaginosa yields (235; X = S-H,OH, Y =O), dihydro-(235; X = O , Y=S-H,OH), and small amounts of (235; X=O, Y=S-H,OH) and dihydro-(235; X = Y = O).511

V. P. Yur'ev, I. M. Salimgareeva, and V. V. Kaverin, Zhur. obshchei Khim., 1977,47,592. V. P. Yur'ev, I. M. Salimgareeva, V. V. Kaverin, and G. A. Tolstikov, Zhur. obshchei Khim., 1977,47, 355. 505 A. Arase and Y. Masuda, Chem. Letters, 1976, 1115. E. R. Ruckel, R. T. Wojcik, and H.G. Arlt, jun., J. Macromol. Sci.-Chem., 1976, A10, 1371. '"'F. Avotins and E. Liepins, Law. P.S.R. Zinatnu Akad. Vestis, Kim. Ser., 1976,220 (Chem. Abs., 1976, 85, 177 621). A. Kergomard and J. Guyot, Fr. P. 2 267 296 (Chem. Abs., 1976,85,78 230). ' 0 9 A. F. Thomas and G. Ohloff, Swiss P. 581 592 (Chem. Abs., 1977,86,72 923). 'lo Y. Y. Samitov, 0. N. Nuretdinova, S. G . Vul'fson, A. P. Timosheva, and B. A. Arbuzov, Bull. Acad. Sci., U.S.S.R.,Div. Chem. Sci., 1976, 25, 2509. A. Siewinski, W. Peczynska-Czoch, A. Zabza, and A. Szewczuk, Tetrahedron, 1977.33, 1139. 504

Monoterpenoids

57

Isomerization of car-3-ene, predominantly to car-2- ene, over magnesium and calcium oxides has been examined mechanistically (cf, Vol. 6, p. 45)512and dehydrogenation of car-3-ene over chromia and chromia-alumina catalysts has been Sensitized photo-oxygenation of car-2-enesL4(named car-4-ene by the authors) has been re-examined more thoroughly and the absence of dioxetan formation reported. Manganese(Ir1) acetate oxidation has been extended to car-3ene; there is no excuse for not numbering formulae in this paper which is further complicated when it is stated that the lactone ring in the product is ‘cis’ to the cyclopropane ring. It would appear that the product is (236).5’5 Rearrangement of 3,4-epoxycarane (unspecified stereochemistry) over solid acids and bases may yield predominantly carbonyl compounds [e.g. (237)] or allylic alcohols [(238) or the exocyclic isomer] in contrast to 2,3-epoxycarane in which ring opening always occurs, with up to 100% stereoselectivity in favour of (lR,4R)-mentha-2,8-dien-l01 (cf. Vol. 6, p. 46).516 Isomerization of 3a,4a-epoxycarane with K0Bu’-pyridine yields (238) exclusively, presumably via the exocyclic isomer.384 3p,40 -Epoxy-

carane reacts rapidly with diphenyl diselenide to yield (3R)-(239) exclusively, but reaction with 3a,4a-epoxycarane was expectedly poorer and yielded (3S)-(239) (the authors number the carane skeleton incorre~tly).~’~ Hydroboration-oxidation of (3R)-(239) yields predominantly (240) along with (3R)-(241; R = Me) whereas (3S)-(239) yields (242) which is the major product using di-isoamylborane but the minor product using diborane [when the elimination-derived (3R)-(241; R = Me) predominate^.^" The same reaction has been reported again for the two 3,4e p o x y c a r a n e ~ ; ~3a,4cu-epoxycarane ’~ yields (3R)-(241; R = CH,OH) and (3s)(241; R = CH20H) along with some (3R)-(241; R = Me) whereas 3&4P-epoxycarane yields (243) predominantly, using diborane-oxidation, and exclusively, The expected lithium aluminium hydride using di-isoamylborane-oxidati~n.~~~ reduction of (244) has been reported.”’ Other papers in this section report catalytic hydrogenolysis of cis- and transcaranes to m- and p-rnenthane~,~~’ the stereochemistry of amines derived from ”* K. Shimazu, H. Hattori, and K. Tanabe, J. Catalysis, 1977,48, 302. V. Krishnasamy and L. M. Yeddanapalli, Canad. J. Chem., 1976,54,3458; ibid., 1977,55,3046. H. Takeshita and I. Kuono, Reports Res. Insr. Ind. Sci., Kyushu Univ., 1977, 65, 13. ’15 -K. Witkiewicz and Z. Chabudzinski, Rocrniki Chem., 1977,51,825; cf refs. 381,493. 516 K. Arata, J. 0. Bledsoe, and K. Tanabe, Tetrahedron Letters, 1976, 3861. 517 I. Uzarewicz, E. Zientek, and A. Uzarewicz, Rocrniki Chem., 1976, 50, 1515. 518 A. Uzarewicz, E. Zientek, and I. Uzarewicz, Rocrniki Chem., 1977, 51,723; this paper provides full details of and extends earlier (uncited) work (Vol. 3, p. 81, ref. 365). *19 B. A. Arbuzov, A . N. Karaseva, Z. G . Isaeva, and I. P. Povodyreva, Doklady Akad. NaukS.S.S.R.,1977, 233,366 (Chem. Abs., 1977,87, 102 438). 520 I. I. Bardyshev, G . V. Deshchits, and B. G . Udarov, Vestsi Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1976,67 (Chem.Abs., 1977,86, 16 793). 513 ’14

Terpenoids and Steroids

58

(242)

(243)

(244)

reduction (Vol. 6, p. 46) of the lactams formed by Beckmann rearrangement (Vol. 4, p. 65)of caranone ~ x i m e sand , ~ the ~ ~cyclic sulphites derived from carane-3a,4a-diol and carane-3P,4a-di01.~~~ 7 Furanoid and Pyranoid Monoterpenoids Pyranoid monoterpenoid alkaloids have been reviewed,141 and halogenated members of this class, (84) and (85), have already been discussed in the halogenated monoterpenoids The monoterpenoid ether (245) is reported from Artemisia trident at^;^^^ from reported mass spectral data it may well be identical with the previously reported (and uncited) arthole (Vol. 7, p. 20), the characterization of which is still not published. Loliolide (246) is claimed to be an in uiuo carotenoid degradation product in Cunscoru decussatu ; additional spectral data have been

(245)

(246)

Treatment of the selenide (19) with unbuffered 30% hydrogen peroxide-THF yields the cis- and truns-linalyl oxides (247) via [2,3] sigmatropic rearrangement.12* Kossanyi et al. have improved upon the efficiency of Vig's synthesis of the four lilac alcohols (248).236 The synthesis of the furanoid (249), formed during sulphuric The known halfacid-catalysed dimerization of isoprene, is ~traightforward.~~' 521 522

523

524 525

C. Wawrzenczyk and A. Zabza, Bull. Acad. polon. Sci., Sir. Sci. chim., 1976, 24, 939, 951. B. A. Arbuzov, I. S. Andreeva, and Z. G. Isaeva, Bull. Acad. Sci. U.S.S.R., 1976, 25, 1584; Chem. Abs., 1977, 85, 143 311 has the structures of these cyclic sulphites hopelessly in error, presumably because conformations and structural formulae have been confused from poor representations in the paper. H. Buttkus and R. J. Bose, J. Amer. Oil Chemists' Soc., 1977, 54, 212; for the essential oil analysis see H. A. Buttkus, R. J. Bose, and D. A. Shearer, J. Agric. Food Chem., 1977.25, 288. S . Ghosal, A. K. Singh, and R. K. Chaudhuri, J. Pharm. Sci., 1976,65, 1549. 0 .P. Vig and M. S. Bhatia, Reichstofe, Aromen, Korperpflegemirtel, 1976, 26, 78.

Monoterpenoids

59

HO (247)

ester acid (250) has been converted into perillene (25 1) under mild conditions (Scheme 6)4 and another useful synthesis of 3-substituted furans based upon the

Reagents: i, MezC=CHCH2CHO; ii, NaAIEtZHz; iii, p-TsOH; iv, A ~ z O ~ - C ~v,HB~u ;' AIH, ~ -40 "C

Scheme 6

alkylation of (252) could be used to synthesize perillene (251);526 Kondo has extended his sensitized photo-oxygenation of dienes (cf. Vol. 7, p. 46) to syntheses of the related perillaketone (253) and a-clausenane (254)"' New syntheses of

rosefuran (255) involve prenylation of 3-methyl-2-furylmagnesium or of 3-bromo-2-furyl-lithium followed by m e t h y l a t i ~ n and , ~ ~ a~ synthesis of elsholtzia ketone (256) has the [2,3] sigmatropic rearrangement of the lithio cyanhydrin ether (257) as the key step.530Further experimental details of Boll and Reffstrup's

An improved nectriapyrone synthesis (Vol. 7, p. 46) have been synthesis of dihydroactinidiolide is reported from 2,2,6-trimethylcyclohexanqne via aeginetolide (Vol. 6, p. 47), and the corresponding cis-tetrahydroactinidiolide (258) has been synthesized stereospecifically from the same starting material by 526

s27

529

s3'

H. Kotake, K. Inomata, S.-I. Aoyama, and H. Kinoshita, Chem. Lerrers, 1977, 73. K. Kondo and M. Matsumoto, Tetrahedron Letters, 1976, 4363; see ref. 533 for an alternative 3,6-dihydro-1,2-dioxin + furan conversion. A. Takeda, K. Shinhama, and S. Tsuboi, Bull. Chem. Soc. Japan, 1977, 50, 1903. N. D. Ly and M. SchlGsser, Helu. Chim.Acta, 1977,60, 2085. B. Cazes and S. Julia, Synrh. Comm., 1977, 7, 113. T. Reffstrup and P. M. Boll, Acta Chem. Scand., 1976, B30,613.

60

Terpenoids and Steroids

formic acid dehydration of the Reformatsky product (259).532An asymmetric synthesis of (258) has already been r e p ~ r t e d . ’ The ~ formation of 3-substituted furans in excellent yield in one step by treating 3,6-dihydro-l,2-dioxins with ferrous ion has obvious biosynthetic and synthetic implications, limited only by the accessibility of the appropriate d i e n e ~ . ~ ~ ~

8 Cannabinoids and other Phenolic Monoterpenoids The structures of six new geranyl-hydroquinone-derived compounds, from Cordia alliodora, provide additional support for proposed biogenesis in Cordia species (see Vol. 4,p. 69).534The isolation of ethuliacoumarin (260) and cycloethuliacoumarin (261) from Ethulia conyzoides suggests an ocimenone (54)biogenetic origin.535

(260)

(261)

Xanthochymol (262) from Garcinia xanthochymus, whose structure has now been determined by X-ray diffraction,536 is another compound of biogenetic interest. Cymopol (Vol. 7,p. 48)and its monomethyl ether have been ~ynthesized.’~’Other

Ho\

\

‘

532

B. Goyau and F. Rouessac, Compt. rend., 1976,283, C, 597.

533

J. A.Turner and W. Herz, J. Org. Chem., 1977,42,1900;for such diene syntheses see ref. 238.

534

535

537

G. D. Manners and L. Jurd, J.C.S. Perkin I, 1977,405. J. H.Tatum and R. E. Berry, Phytochernistry, 1977,16,1091. J. F. Blount and T. H. Williams, Tetrahedron Letters, 1976,2921. P. W. Raynolds, M. J. Manning, and J. S.Swenton, J.C.S. Chem. Comm., 1977,499.

Monoterpenoids

61

synthetic work of little novelty includes syntheses of m a h a r ~ i m b i n e , ~curry~~" anine,538band ~ u r r y a n g i n e(see ~ ~ Vol. ~ ~ 5 , p. 45) and the extension by Dike and Merchant of previous work to include other components of Flerningia wallichin, vir. the trimethyl ether of flemiwallichin B (cf. Vol. 7, p. 48)539and the dimethyl ether of flemichin A.540 An annotated bibliography (3045 references; 1964-1974) of marihuana has been p ~ b l i s h e d ~and ~ ' the pharmacology of m a r i h ~ a n a , ~the ~* and biochemical aspectss436of Cannabis, and the chemistry of ~ a n n a b i n o i d s ~have ~~" been reviewed. The analysis of THC and metabolites in physiological fluids has been A1-3,4-cis-THC has now been found in Cannabis safiva (Phenotype III);9 other papers reporting the characterization of compounds from Cannabis safiva concern conclusive identification and synthesis of ~ a n n a b i n o d i o lwhich , ~ ~ ~ is known to result from the photochemical irradiation of cannabinol (Vol. 7, p. 51), and the identification of A6-tetrahydrocannabinolic acid5j6 and (+)-cannabitriol (263);547 (263) and the corresponding C-2 ethyl ether may be e p ~ x i d e - d e r i v e d . ~ ~ '

Further 13C n.m.r. data on A'-THC, A6-THC, A1-3,4-cis-THC, and related substances have been reported (cf Vol. 3, p. 90).548Harvey has examined the use s38

( a ) N. S . Narasimhan, M. V. Paradkar, and A. M. Gokhale, Indian J. Chem., 1976,14B. 329; ( b )N. S.

539

Narasimhan and S.L. Kelkar, ibid., p. 430. S. Y. Dike, M. S. Kamath, and J. R. Merchant, Indian J. Chem., 1976,14B, 461.

540 541

s42

543

544

545

546 547

548

S. Y. Dike and J. R. Merchant, Chem. and Ind., 1976, 996. C. W. Waller, J. J. Johnson, J. Buelke, and C. E. Turner, 'Marihuana: An Annotated Bibliography', MacMillan Information, New York, 1976. W. D. M. Paton, 'Annual Review of Pharmacology', Vol. 15, ed. H. W. Elliott et al., Annual Reviews Inc., Palo Alto, 1975, p. 191. 'Cannabis and Health', ed. J. D. P. Graham, Academic Press, New York, 1976; ( a ) W. M. L. Crombie, p. 21; ( b ) L. J. King, J. D. Teale, and V. Marks, p. 77; ( c ) L. Crombie and W. M. L. Crombie, p. 43. 173rd A.C.S. Meeting, New Orleans, March 1977, Abstracts ANAL, Nos. 68-73, 89-94, and 110115. Some of this work has been published: ( a ) M. E. Wall, T. M. Harvey, J. T. Bursey, D. R. Brine, and D. Rosenthal, Research Monograph Series-National Institute of Drug Abuse (U.S.), 1976.7, 107; ( b ) D. E. Green, ibid., p. 70; ( c ) E. R. Garrett and C. A. Hunt, ibid., p. 33; J. Pharm. Sci., 1977,66, 20; (d) J. A. Vinson, D. D. Patel, and A. H. Patel, Analyt. Chem., 1977, 49, 163. R. J. J. C. Lousberg, C. A. L. Bercht, R. van Ooyen, and H. J. W. Spronck, Phytochemistry, 1977.16, 595; Chem. Abs., 1977,87, 102 442 has the structure of cannabinodid incorrect. For related work see Vol. 6, p. 48, ref. 356. L. Hanus and'Z. Krejci, Acta Univ. Palacki Olomuc., Fac. Med., 1975,74, 161 (Chem. Abs., 1976,85, 177 622). M. A. Elsohly, F. S. El-Feraly, and C. E. Turner, Lloydia, 1977, 40, 275. An earlier report of (-)-(263) was omitted from last year's Report; see W. R. Chan, K. E. Magnus, and H. A. Watson, Experientia, 1976, 32, 283. R. A. Archer, D. W. Johnson, E. W. Hagaman, L. N. Moreno, and E. Wenkert, J. Org. Chem., 1977, 42,490.

62

Terpenoids and Steroids

of new silyl ethers for g.c.-m.s. of ~ a n n a b i n o i d and s ~ ~of ~ cyclic alkylboronates for g.c.-m.s. of cannabinolic acids,ss0 and mass spectral data for C-6 and C-7 oxygenated A’-THC and A6-THC derivatives have been reported.5s1 The fragmentation of cannabinoid metastable ions has been Further syntheses of [4”,5”-2H2]-and [4”,5”-3H2]-A’-THC and -A6-THC have been described (cf. Vol. 7, p. 50),553and Crombie et al. have extended miniaturized synthesis and chromatographic analysis (cf. Vol. 6, p. 49) to cannabinoid large-scale syntheses of which using acid-catalysed terpenylation of methyl olivetolate have also been ester cleavage, using lithium npropylmercaptide, is accomplished without d e c a r b ~ x y l a t i o n .The ~ ~ ~full paper on the synthesis of A’- and A6-3,4-cis-THC has been published556 together with syntheses of A’- and A6-3,4-cis-cannabidio1557 and their anticipated acid-catalysed cyclization which is dependent upon acid c ~ n c e n t r a t i o n . ~Other ~ ’ papers of synthetic interest concern cannabinoid glucuronides,5sRside-chain thio-analogues of A6-THC from (+)-(lR,4R)-mentha-2,8-dien- 1-01and phloroglucinol thio-ether~,~” 2’-thiocannabinoids via 0-aryl thiocarbamate-S-aryl thiocarbamate rearrangement,560 which has also been used in 2’-thi0-8~*~-THC synthesis,s61and side-chain nitrogen analogues of A6-THC.562 Last year’s Report numbered some hydroxylated cannabinoid metabolites inconsistently. The numbering system used in these Reports (see Vol. 2, p. 61) requires that the pentyl side-chain be numbered C-1” -+ C-5”; references to microbiological hydroxylation last year (Vol. 7, pp. 5 0 , 5 1)designated as occurring at C-l’, C-2’, C-3’, C-4’, and C-5‘ referred to side-chain-hydroxylated metabolites which should have been numbered C- I”, C-2”, C-3”, C-4”, and C-5” respectively. The metabolic functionalization of cannabinoids is of continuing interest (cf. Vol. 4, p. 71; Vol. 7, p. 50). A3-THC may be hydroxylated at C-4 using Mycobacterium rhodochrous (together with aromatization) or at C-4” of the side-chain with Bacillus cereus or may be oxygenated at C-5 with Streptomyces species.563 A6-THC has been hydroxylated in both the ring system and the side-chain with Pellicularia filamentosa and Streptomyces l a ~ e n d u l a e and , ~ ~ further ~ evidence in favour of in uivo epoxy metabolites and derivatives in the mouse has been presented (cf, Vol. 4, 549

550 551

552

553

554

s55 s56

557

s58 559

56”

562

s63

564

D. J. Harvey, Biomed. Mass Specfrometry, 1977,4,265; Org. Mass Spectrometry, 1977, 12,473;see also E.E. Knaus, R. T. Coutts, and C. W. Kazakoff, J. Chromatog. Sci., 1976,14,525. D. J. Harvey, Biomed. Mass Spectrometry, 1977,4,88. S. Inayama, A. Sawa, and E. Hosoya, Chem. and Pharm. Bull. (Japan), 1976,24,2209. P. C. Burgers, G. Dijkstra, W. Heerma, J. K. Terlouw, A. Boon, H. F. Kramer, F. J. E. M. Kuppers, R. J. J. C. Lousberg, and C. A . Salemink, Adv. Mass Spectrometry Biochem. Med., 1976.1,391. H. Hoellinger, N.-H. Nam, J.-F. Decauchereux, and L. Pichat, J. Labelled Compounds, 1977,13,401. L. Crombie and W. M. L. Crombie, Phytochemistry, 1977,16,1413. L.Crombie, W. M. L. Crombie, R. Forbes, and A. Whittaker, J. Chem. Res. ( M ) , 1977,1301. D.B. Uliss, R. K. Razdan, H. C. Dalzell, and G. R. Handrick, Tetrahedron, 1977,33,2055; see Vol. 7, p. 50 for the preliminary report. G. R. Handrick, R. K. Razdan, D. B. Uliss, H C. Dalzell, and E. Boger, J. Org. Chem., 1977,42,2563. M.A. Lyle, S. Pallante, K. Head, and C. Fenseiau, Biomed. Mass Spectrometry, 1977,4,190. U.Kraatz, H. Wolfers, A. Kraatz, and F Korte, Chem. Ber., 1977,110,1776;the authors use the name (+)-frans-p-2,8-menthadien-l-ol for this menthadienol. H.-J. Kurth, U. Kraatz, and F.Korte, Annalen, 1976, 1313. K. Matsumoto, P. Stark, and R. G. Meister, J. Medicin. Chem., 1977,20, 17. F. Lotz, U . Kraatz, and F. Korte, Annalen, 1977,1132. B. J. Abbott, D. S. Fukuda, and R. A. Archer, Experientia, 1977,33, 718;formula I on p. 718 is incorrect. H.-J. Vidic, G.-A. Hoyer, K. Kieslich, and D. Rosenberg, Chem. Ber., 1976,109,3606.

Monoterpenoids

63

p. 71).M5 A'-THC is also converted into di- and tri-hydroxy metabolites in the mouse (cf. Vol. 7, p. 51 for similar cannabidiol metabolites).566 Further papers concerning anticipated cannabinoid functionalization' include in vitro rat liver dihydroxylation of c a n n a b i n 0 1 ~as~ ~well as predominant in oivo monohydroxyla t i ~ nthe , ~formation ~ ~ of hexahydrocannabinol-7-oicacids and some hydroxylated derivatives from A'-THC and A6-THC in mice,569 and the identification of a species-dependent series of homologous side-chain acids from A'-THC in the guinea pig, mouse, and rabbit.570 Intramolecular cyclization of cannabielsoin in benzene-toluene-p -sulphonic acid to the 1,s-cineol (264) is quantitative.571 The previously reported rearrangement

HO (264)

of la,2a-epoxyhexahydrocannabinolacetate using boron trifluoride etherate (Vol. 4, p. 72, ref. 338) has been re-investigated and the fluoro-acetate which accompanies ketone formation has now been shown to be (265) rather than the isomeric acetate.572 Further analysis of cannabidiol pyrolysis (see Vol. 6, p. 50) has identified (266),573and h.p.1.c. analysis is preferred over g.1.c. analysis for examin-

(265)

(266)

ing the decomposition patterns of acidic and neutral cannabinoids in cannabis resin.574

"' D . J. Harvey and W. D . M. Paton, J. Pharm. Pharmacol., 1977,29,498. D . J. Harvey, B. R. Martin, and W. D . M. Paton, J. Pharm. Pharmacol., 1977, 29,482. K. Fonseka and M. Widman, J. Pharm. Pharmacol., 1977,29, 12. ''' W.-A. Yisak, M. Widman, J.-E. Lindgren, and S. Agurell, J. Pharm. Pharmacol., 1977,29,487. s69 D. J. Harvey, B. R. Martin, and W. D . M. Paton, J. Pharm. Pharmacol., 1977,29,495. "O B. R. Martin, D . J. Harvey, and W. D . M. Paton, J. Pharm. Pharmacol., 1976,28,773. D . B. Uliss, G. R. Handrick, H. C. Dalzell, and R. K. Razdan, Experientia, 1977,33, 577. s72 T. Petrzilka, K. K. Prasad, and G. Schrnid, Helu. Chim. Acta, 1976, 59, 1963. 573 H. J. W. Spronck and R. J. J. C. Lousberg, Experientia, 1977,33,705. 574 R. N. Smith and C. G. Vaughan, J. Pharm. Pharmacol., 1977,29,286. s66

s67

2 Sesqu iterpenoids BY T. MONEY

1 Famesane Further investigations on the terpenoid constituents of various species of Euparorium have revealed the presence of two new acyclic sesquiterpenoids, (1) and ( 2)'

OH

OH (1)

R = C(Me)=CHMe

( 21

The same research group has also accomplished the synthesis of 5,7-dehydro-4oxonerolidol(3) by the route outlined in Scheme 1.' A new furanosesquiterpenoid

R = ...

Q

Reagents: i, C r ( 0 H k ; ii, Cr03-py; iii, CH,=CHMgBr; iv, MnO,;

Scheme 1

' F. Bohlmann and M. Grenz, Chem. Ber., 1977,110, 1321.

*

F. Bohlmann and R. Kramer, Chem. Ber., 1976,109,3362.

64

t, Ag,O;

vi, Me'C=CHLi

65

Sesquiterpenoids

( 5 ) has been added to the list of compounds isolated from soft coral3 (cf. Vol. 5, p. 70). 6-Hydroxymyoporone (6)4 and 6-hydroxy-2-dehydromy~porone~ have been

identified as two of several stress metabolites @hytoalexins*) produced by sweet potato which has been infected by fungi. Ipomeamorone (8) and its C-9 epimer have previously been reported as phytoalexins from diseased sweet potato and an alternative synthesis of these compounds has been accomplished by a synthetic route (Scheme 2 ) in which the furan ring system is constructed by photo-oxygenation of a 1,3-diene intermediate (716 (cf.Vol. 7, p. 53).

OH

OH

ivI

fi

v.

n

0

d %

I \

Reagents: i, lo2; is, Me,CO-; iii, HzSO,; iv, NIS-NaHCO,; v, BuLivii, AgN03-NCS-MeCN

Scheme 2

’

:I

(

;vi, BuLi-Me2CHCHzC1;

J. C. Coll, S . J. Mitchell, and G . J . Stokie, TetrahedronLerrers, 1977, 1539. L. T. Burka, L. Kuhnert, and B. J. Wilson, TetrahedronLerrers, 1974, 4017. H. lnoue, N. Kato, and 1. Uritani, PhyrochemisQ, 1977,16, 1063. K. Kondo and M. Matsumoto, TetrahedronLerrers, 1976, 4363.

* Phytoalexins are metabolites produced by damaged plants or plants infected with fungi, bacteria, or viruses.

66

Terpenoids and Steroids

A new synthesis of nerolidol(10) from geranyl bromide has been achieved by the use of the hydroxy-sulphoxide (9),'" a new prenylating agent (Scheme 3).7b

Reagents: i, PhSH-0,; ii, BuLi; iii, geranyl bromide; iv, Li-EtNH,

Scheme 3

2 Mono- and Bi-cyclofarnesane A recent investigation of marine red algae has shown that the major lipid-soluble metabolite of Laurencia obtusa, collected in the English Channel, is 3P-bromo-8epicaparrapi oxide (11)' (cf. isolation of a- and P-snyderol (12) from L. obtusa collected in Spain; Vol. 7, p. 54).

Br

m (1 1)

Br

(12)

The structure of aplysistatin (13), a potential anticancer agent isolated from Australian sea hare (Aplysia angasi) has been determined by X-ray crystallographic analysis.' Examination of the bark extracts of East African Warburgia plants has revealed the presence of warbuganal (14) and the known bicyclofarnesanes polygodial (15) and ugandensidial (16)." These compounds exhibit strong antifeedant activity in African army worms (Spodoptera species).

H

3r

/

O

' P. J. R. Nederlof, M. J. Moolenar, E. R. de Waard, and H. 0. Huisman,

lo

(a) Tetrahedron Letters, 1976, 3175; (b) Tetrahedron 1977,33,579. D. J. Faulkner, Phyrochemisrry, 1976, 15,1993. G. R. Pettit, C. L. Herald, M. S. Allen, R. B. Van Dreele, L. D. Vanell, J. P. Y. Kao, and W. Blake, J. Amer. Chem. Soc., 1977,99,263. I. Kubo, Y.-W. Lee, M. Pettei, F. Pilkiewicz, and K. Nakanishi, J.C.S. Chem. Comm., 1976, 1013.

67

Sesquiterpenoids

The structure of polyalthenol (17), a metabolite of the African plant Pofyafthia ofiueri, has been determined by analysis of its n.m.r. spectra." It has been suggested that the rearranged bicyclofarnesane structure of this compound is produced by 1,2-methyl shift of a drimane-type intermediate. A detailed account of the chemical and spectroscopic evidence for the structures of cochlioquinone-A (18a) and -B (18b) has been published.'* These compounds are metabolites of Cochliobofusmiyabeanus, a parasitic mould which grows on rice, and their unusual cyclofarnesane structure is probably derived in nature by introduction of a farnesyl unit into an aromatic precursor followed by cyclization of an intermediate bis-epoxide.

0

(18) a; R' = OH, R2 = H, R3= OAc b; R' = H, R2R3= 0

3 Bisabolane Full details of the chemical and spectroscopic evidence used to establish the structure of deodarone (19) have been published13 (cf.Vol. 4,p. 88; Vol. 6, p. 58). Further research on terpenoid insect hormones present in various species of fir has resulted in the isolation of juvabione (20), juvabiol (21), and epijuvabiol (22) from 0

'I

l3

M. Leboeuf, M. Hamonnikre, A. Cave, H. E. Gottlieb, N. Kunesch, and E. Wenkert, Tetrahedron Letters, 1976, 3559. L. Canonica, C. G . Casinovi, A. Fiecchi, C. Galeffi, G . B. Marini-Bettolo, A. Scala, and A. M. W. Torracca, Gazrenu, 1976, 106, 147; cf. L. Canonica, B. M. Ranzi, B. Rindone, A. Scala, and G . Scolastico, J.C.S. Chem. Comm., 1973, 213. S. Shankaranarayan,S. Krishnappa, S. C. Bisarya, and S. Dev, Tetrahedron, 1977,33, 1201.

68

Terpenoids and Steroids

Alpine fir (Abies l~siocarpa).'~Since the corresponding compounds present in Balsam fir have the R configuration at C-1' and both R and S configuration at C-3' it has been suggested that different biosynthetic pathways to juvabione-type compounds are operating in different species of fir.14 Chemical and spectroscopic evidence has been used to establish the structures of the new bisabolane-type compounds (23)-(25) isolated from Stevia species and Elephantopus rn011is.'~~ The structure of phyllanthocin (26a), the aglycone of the antileukaemic compound phyllanthoside (26b), has been established by X-ray crystallographic analysis.I6

COCH=CHPh

(25) R = Me,C=CH

(26) a; R = Me b; R = C16H2501o

The conditions used" to convert geranic acid (27) into filifolone (28) (cf. Vol. 1, p. 45; Vol. 2, p. 55) and piperitenone (29) have been applied to cis,trans- and trans,

trans-farnesic acids (30), and the expected formation of compounds (3 l t ( 3 3 ) has been confirled." When a mixture of cis,cis- and trans,cis-farnesic acid (34) was treated in a similar fashion the reaction product was a mixture of (32), (33), and the C-2 epimer of (31)." l4

Is '6

l7

J. F. Manville and C. D. Kriz, Canad. J. Chem., 1 9 7 7 , 5 5 2 5 4 7 . ( a ) F. Bohlmann, C. Zdero, and S. Schonewei, Chem. Ber., 1976,109, 3366; ( b ) F. Bohlmann and C. Zdero, ibid., 1976, 109, 3956. S. M. Kupchan, E. J . LaVoie, A. R. Branfman, B. Y. Fei, W. M. Bright, and R. F. Bryan, J. Amer. Chem. SOC.,1977,99,3199. q.J. J. Beereboom, J. Org. Chem., 1965, 30, 4230. A. Corbella, P. Gariboldi, M. Gil-Quintero, G. Jommi, and J. St. Pyrek, Experientia, 1977,33, 703.

69

Sesquiterpenoids

(32) R' = H, R2 = Me2C=CHCH2 (33) R' = Me2C=CHCH2, R2= H

(31)

AQONaOAcb

(31) (C-2 epimer)+(32)+(33)

Simple synthetic routes to bisabolol-3-one (35) (cu-bisabololone) (cf. Vol. 6, p. 5 8 ) and ar-turmerone (36) have been achieved by condensing the kinetic enolate

t vii, viii

GOH (37)

Reagents: i, LiNPri2-THF-MezC=CHCOMe; ii, TsOH-C6H6, A; iii, Me2CuLi; iv, LiNPr12-THF; v, H,O+; vi, LiAIH4; vii, HI04; viii, 90% HOAc

Scheme 4

70

Terpenoids and Steroids

derived from mesityl oxide with 4-acetyl- 1-methylcyclohexene and p-tolualdehyde respe~tively.'~"The same research group has also published an alternative synthesis of (Y -atlantone (37) (Scheme 4).19' Diastereomeric epoxides (39) and (40) derived from (-)-limonene (38) have been used to synthesize the diastereorneric a -bisabolones (41) and (42)2" (Scheme 5).

i-iv

(40)

(42)

Reagents: i, KCN-EtOH; ii, CH2=C(Me)CHzMgCI; iii, H,O+; iv, KOH-MeOH

Scheme 5

Previous studies2'" on the cyclization of geranyl diphenyl phosphate have been extended to the corresponding derivatives (43) of &,trans- and trans,transfarneso1.2'b The main reaction product was a mixture of isomeric bisabolenes (44), bisabolol ( 4 9 , and a mixture of isomeric farnesenes (46)."* It has been suggested

(43)

l9

2o 21

(46) (a) 0.S. Park, Y. Grillasca, G . A. Garcia, and L. A. Maldonado, Synrh. Comm., 1977,7,345;( b )F. L. Malanco and L. A. Maldonado, ibid., 1976.6, 515. A. Kergomard and H. Veschambre, Tetrahedron Letters, 1976, 4069. ( a ) R. C. Haley, J. A. Miller, and H. C. S. Wood, J. Chem. SOC.(C), 1969, 264; ( b )J. P. Larkin, D. C. Nonhebel, and H. C. S. Wood, J.C.S. Perkin I, 1976, 2524.

Sesquiterpenoids

71

that (48)220and jungianol (50),22bmetabolites of the plants Coreposus paruiuolia and Jungia maluaefolia, are biosynthesized by cyclization of bisabolane intermediates (47) and (49).”

+m“ \

/

(47)

+ql

RO

OH (49)

Norbisabolide (52), a C,, norsesquiterpenoid isolated from the root bark of Atlantia rn~nophylla,’~has been synthesizedz4 from (+ )-limonene monoepoxide (51)25by the reaction sequence shown in Scheme 6. Norbisabolide (52) co-occurs

..

Ill-v

M.

Q

OH

(51) Reagents; i, 0 3 ; ii, NaOAc-HOAc-NaI-Zn; vi, Cr03-MezCO-H30+

iii,

‘i, (52)

CH2CH2MgBr; iv, AczO; v, NaOH-MeOH;

Scheme 6

with (+)-a-bisabolene (53) and bisabolene oxide (54) and is probably biosynthesized by oxidative cleavage of (54) or a related compound.z4

4 Sesquipinane, Sesquicamphane, Sesquifenchane The recent isolation of P-trans-bergamotene ( 5 5 ) from the mycelium of A. fumigatusZ6and P. oualisZ7has provided indirect support for the proposed intermediacy F. Bohlmann and C. Zdero, ( a ) Chem. Ber., 1977, 110,468; ( b ) Phytochemistry, 1977,16, 239. J. D. Shringapure and B. K. Sabata, Indian J. Chem., 1976, 13, 24. 24 G. Feldstein and P. J. Kocienski, Synrh. Comm., 1977, 7 , 27. 25 q. W. Knoll and C. Tamm, Helu. Chim. Acta. 1975.58, 1162. 26 S. Nozoe, H. Kobayashi, and N. Morisaki, Teiruhedron Letters, 1976, 4625. ” D. E. Cane and G. G. S. King, Tetrahedron Letters, 1976, 4737. 22

23

Terpenoids and Steroids

72

of this compound in the biosynthesis of furnagillin (56) and ovalicin (57)(cfi Vol. 6, p. 181; Vol. 7 , pp. 62, 196).

OCOR

(56) R = (CH=CH)dCO2H

Further studies on the biosynthesis of ovalicin (57)have demonstrated the use of deuterium magnetic resonance in biosynthetic studies.” Compounds (59)--(62), structurally related to (-)-a-santalene (58), have been isolated from the essential oil of Lavandula oficinalis and L. hybrids." An alternative synthesis of a-santalol OH

’* 29

D. E. Cane and S. L. Buchwald, J. Amer. Chem. Soc., 1977, 99, 6132. R. Kaiser and D. Lamparsky, Tetrahedron Letters, 1977, 665.

73

Sesquiterpenoids

(66) has been accomplished3’ by adaptation of the previously published route to cw-~antalene.~~

(63)

(64) R=CH2Ph i, HMPA

5 Cuparane, Trichothecane, Laurane Proton and carbon- 13 n.m.r. spectral data have been used to establish the structure of satratoxin H (67), a metabolite of Stachybotrys Satratoxin H (67) and the other macrocyclic dilactone derivatives of trichotheca-9,12-diene-4,15-diol(68) produced by S. atra are responsible for the disease (Stachybotryotoxicosis) which affects livestock and humans after ingestion of food contaminated with this fungus. The structure of baccharin (69), a potent antileukaernic compound isolated from a Brazilian shrub (Baccharis megapotarnica), has been established by X-ray crystallographic analy~is.’~ Verrucarin K (70), another trichothecane derivative produced by a strain of Myrothecium uerrucaria, is of biosynthetic interest since it is the first member of the series which does not possess a 12,13-epoxide

0

OH OH (67) 30

31 32

” 34

K. Sato, S. Inoue, Y. Takagi, and S. Morii, Bull. Chem. SOC.Japan, 1976.49, 3351. E. J. Corey and M. F. Sernrnelhack, J. Amer. Chem. Soc., 1967,89, 2755. R. M. Eppley, E. P. Mazzola, R. J. Highet, and W. J. Bailey, J. Org. Chem., 1977, 42, 240. S. M. Kupchan, B. B. Jarvis, R. G. Dailey, W. Bright, R. F. Bryan, and Y. Shizuri, J . Amer. Chem. Soc., 1976,98,7092. W. Breitenstein and C. Tamm, Helu. Chim. Acta, 1977,60, 1522.

74

Terpenoids and Steroids

(69)

(70)

Trichodiene (72), the bicyclic hydrocarbon intermediate in trichothecane biosynthesis (cf. Vol. 7, p. 192; Vol. 6, p. 64; Vol. 4, p. 90) has been s ~ n t h e s i z e d ~ ~ (in tacemic form) from the known lactone (71) by the two stereoselective routes outlined in Scheme 7.

mo&m0 Po H

H

4

(711

H

'

,

/*

X I I I , XIV. VII

"./"'O ' THP

b-.,

(72) Reagents: i, LiNPr',-DME; ii, MeI; iii, Br(CH2),0THP-HMPA; iv p-TsOH-MeOH; v, Ca-NH3-THFHMPA; vi, Cr03-H30+-Me2CO; vii, CH2N2; viii, NaN(SiMe3h-DME; ix, HCI, 0 "C; x, DBU-xylene, A; xi, silica gel-15%AgN03; xii, CH2=PPh3-DMSO; xiii, MeOH-H+; xiv, HCI gas-CHZCI2; xv, collidine, A; xvi, LiAIH4; xvii, 10% NaOH; xviii, Li-NH3-EtOH

Scheme 7 35

( a ) S. C. Welch, A. S. C. P. Rao, and C. G. Gibbs, Synrh. Comm., 1976,6,485; ( b )S. C. Welch, A. S. C. P. Rao, and R. Y . Wong, ibid., p. 443.

75

Sesquiterpenoids

Re-examination of the chemistry and spectroscopic properties of bazzanene [formerly (73): cf. Vol. 1p. 76; Vol. 3, p. 841 has resulted in a revised structure (74) for this compound.36 (+)-Bazzanene (74) is therefore a diastereomer of (+)-

(73)

(74)

trichodiene (72) and it is interesting to note that a simple double-bond shift formally interconverts these compounds. The co-occurrence of bazzanene (74) with a- and P-pompene (75) (syn. (Y- and P-barbatene, syn. isogymno- and gymnomitrene; cf. Vol. 6, p. 63; Vol. 5, p. 53) in the liverwort Bazzania pompeana may indicate that the latter compounds are formed in nature by cyclization of bazzanene or a closely related compound. In this connection it is interesting to note that acid-catalysed cyclization of (+ jbazzanene (74) produces (f)-cyclobazzanene (76), a compound whose structure has been established by X-ray analysis.”

(75)

(76)

The ability of marine organisms to synthesize halogenated sesquiterpenoids (cf. ref. 105 and pp. 66, 79, 101) is further illustrated by the isolation of the lauranetype compounds (77)-(79)38 from red seaweed (Laurencia g l a n d ~ l i f e r a ) .The ~~ absolute configuration of aplysinol (80), a metabolite of various species of Lauren-

(77) R = H (78) R = B r

cia (red algae), has been established by X-ray analysis39and a new stereoselective synthesis of (*)-debromoaplysin (81) and (*)-aplysin (82) has been achieved by the route outlined in Scheme 8.4” 36

A. Matsuo and S. Hayashi, J.C.S. Chem. Comm., 1977,566.

37

A. Matsuo, H. Nozaki, T. Maeda, M. Nakayama, Y. Kushni, and S. Hayashi, J.C.S. Chem. Comm.,

38

M. Suzuki and E. Kurosawa, Tetrahedron Letters, 1976,4817. J. A. McMillan and I. C. Paul, Tetrahedron Letters., 1976, 4219; the compound numbers in this paper are erroneous. R. C. Ronald, Tetrahedron Letters., 1976, 4413.

1977,568. 39

40

Terpenoids and Steroids

76

(82)

(81)

Reagents: i, KOH-MeOH; ii, PBr3; iii, MeMgBr; iv, PPh3-(PPh3),RhCI; v, H,-PtO,-EtOH; Na2C03-Br2-C6H 14

vi,

Scheme 8

6 Acorane, Cedrane, Carotane An elegant, general synthetic route to spirocarbocyclic systems (cf. Vol. 5, p. 55) involving regiospecific ring cleavage of appropriate tricyclic ketones [cf.(83)+ (84)]

(83)

(84)

has been used in a recent alternative synthesis (Scheme 9) of (-)-acorenone B (85)4' (cf. Vol. 6, p. 62; Vol. 7, pp. 63, 64 for previous syntheses). Acorenone B (85) has recently been converted into its allylic isomer, acorenone (87), by rearrangement of the corresponding epoxy-ketone (86)42 (Scheme 10). An alternative synthesis of (*)-acorone (88) and (*)-isoacorone (89) (cf.Vol. 6, p. 61) has been achieved by a route (Scheme 11) in which the spiro[4,5]decane system is constructed by intramolecular aldol condensation of a 1,4-diketone inter~nediate.~, Further studies on the remote biological hydroxylation of sesquiterpenoids by mammalian systems (cf. Vol. 6, p. 62) have shown that dogs can hydroxylate 41

42 43

( a ) J. F. Ruppert, M. A. Avery, and J. D. White, J.C.S. Chem. Comm., 1976,978; ( b ) cf. J. F. Ruppert and J. D. White, ibid., p. 976. W. Rascher and H. Wolf, Tetrahedron, 1 9 7 7 , 3 3 , 5 7 5 . D. A. McCrae and L. Dolby, J. Org. Chem., 1977,42, 1607.

77

Sesquiterpenoids

(+)-cedrol (90) at the C-3, C-4,C-12, and C-15 positions.44 In a related investigation by the same research group it was shown that dry zonation*^ of cedryl acetate (9 1 ) results in stereoselective and regiospecific hydroxylation at C-2.46 The retention of configuration at C-2 in the product (92) is consistent with previous CCOR

R = OH, C1, or CHN2

I

iv

(R = CHN2)

(85) Reagents: i, CH,=C(CH,Br)CO,Et-Zn;

ii, H2-Pt02; iii, H2-Pd/CaC0,; iv, Cu; v, HCI; vi, H,-Rh/C

Scheme 9

Reagents: i, DIBAH; ii, m-C1C6H4C03H; iii, Cr03-Me2CO-H30+; iv, NH2NH2-MeOH-HOAc

Scheme 10 44 45

46

E. Trifilieff, Luu Bang, and G. Ourisson, Tetrahedron Lerrers, 1975, 4307. 0 . 2 . Cohen, E. Keinan, Y. Mazur, and T. H. Varkony, J. O g . Chem., 1975, 40,2141 and references cited; T. M. Hellman and G. A. Hamilton, J. Amer. Chem. SOC.,1974,96, 1530. E. Trifilieff, Luu Bang, and G. Ourisson, Tetrahedron Letters, 1977, 2991.

78

Terpenoids and Steroids

-

w Pxi-xiii

0

A

A

(88)

(89)

Reagents: i, Bu'NH~; ii, BuLi; iii, BrCH2CECSiMe3; iv, HCI-H2O; v, HgSO.,-H,S04-H20-THF; vi, NaOEt-EtOH; vii, NaOMe-HCOzEt; viii, AczO; ix, MezCuLi; x, H30+; xi, BH3,DMS; xii, H202-OH-; xiii, CrO3-Me2CO-H3O*

Scheme 11

HoflAc H (90) R = H (91) R = A c

conclusions concerning the stereochemistry of the dry ozonation procedure.45 The cyclic ether (94)47derived by oxidation cyclization of neoisocedranol (93).,*has been used in a recent synthesis (Scheme 12) of a-biotol (95)* (4-P-hydroxy-acedrene), a co-metabolite of a-cedrol in the essential oil of Biota o r i e n t ~ l i s . ~ ~ A new carotane sesquiterpenoid, linkiol, has been isolated from the plant Ferula linkii and assigned structure (96) on the basis of its chemical and spectroscopic pr~perties.~' 47

48 49

P. Brun and B. Waegell, Tetrahedron, 1976, 32, 1137. CJ P. Teisseire, M. Plattier, W. Wojnarowski, and G. Ourisson, Bull. SOC.chim. France, 1966, 2749. P. Brun, Tetrahedron Letters, 1977. 2269. A. G. Gonzalez, B. M. Fraga, M. G. Hernandez, J. G. Luis, R. Estevez, J. L. Biez, and M. Rivero, Phytochemistry, 1977,16,265.

* a-Biotol (95) has also been produced by selective dehydration by mammalian hydroxylation of a-cedrol (90); cf. ref. 44.

of the 4-hydroxy-derivative produced

79

Sesquiterpenoids

(93)

(94) OAc

(95) (+4-epimer) Reagents:

I,

P b ( 0 A c k ; ii, CSHsNHCI-Ac20; iii, p-N02C6H4C0,H; iv, BF,, Et20-C6H,; v, LiAlH,

Scheme 12

OCOC(Me)=CHMe

7 Chamigrane, Widdrane, Thujopsane A recent X-ray crystallographic study has resulted in a revised structure (98) for nidifocene, a minor metabolite of the Hawaiian marine alga Laurencia n i d i f i ~ a . In ~’ the previous structure (Vol. 7, p. 69) the positions of chlorine and bromine were reversed. An extension of previous work on the non-enzymic biogenetic cyclization of geranyl and farnesyl diphenylphosphatess2 has shown that (Z)-monocyclofarnesyl diethylphosphate (99) can be converted into (*)-a-chamigrene (100) in

(99)

’*S. M. Waraszkiewicz and K. L. Erickson, Tetrahedron Lefrers, 1977, 231 1.

(1 00)

’’ q.ref. 21; cf. T. Money, ‘Progress in Organic Chemistry’, Vol. 8, 1973, p. 29 and references cited; cf. Vol. 7, pp. 54, 69.

80

Terpenoids and Steroids

high yield (72%) by treatment with tetraisobutylaluminoxan (TIBA0).53 (*)-aChamigrene has also been synthesized by thermal cyclization of the isomeric tetraenes (102) derived from cis- and trans-p-ionol (101)54 (cf. synthesis of

bromochamigrene, Vol. 7, p. 69). Treatment of American cedarwood oil with acetic anhydride-polyphosphoric acid produces a tricyclic ketone (106) which has commercial value in the perfume industry. It has been suggested (cf. Vol. 3, pp. 116, 117) that this compound (106) is derived from (-)-thujopsene (103) (a principal component of cedarwood oil) by a reaction sequence which involves the intermediacy of p-chamigrene (104) and the tricyclic alkene (105). This proposal is supported by the fact that the sequence (103)+(105)+(106) can be accom-

plished in the laboratory. Recent independent studies in this area have culminated in the development of synthetic routes to the tricyclic alkene (105) (Scheme 13)and ketone (106) (Scheme 14).56

8 Cadinane, Amorphane, Copacamphane, etc. Chromolaenin (108) and 1-acetoxydihydroisochromolaenin(109) are new sesquiterpenoids which co-occur with eupatene (110) in several Chromolaena specie^.^' Experimental details have been provided5' for the stereospecific total synthesis of (+)-E-cadinene (1 12) and (-)-7,-cadinene (113) from the known enol ether (111) 53

54 55 56 57

Y.Kitagawa, S. Hashimoto, S. Iemura, H. Yamamoto, and H. Nozaki, J. Amer. Chem. SOC.1976, 98, 5030. F. Frater, Helv. Chim. Acta, 1977,60, 515. E.L. McDonald and J. S. Roberts, Tetrahedron Letters, 1976,4521. R. F. Tavares and E. Katten, Tetrahedron Letters, 1977, 1713. F. Bohlmann and C. Zdero, Chem. Ber., 1977,110,487. L. A. Burk and M. D. Soffer, Tetrahedron, 1976.32, 2083.

81

Sesquiterpenoids

Reagents: i, LCNH3-ROH; ii, Bu'O--DMSO; iii, maleic anhydride; iv, CF3C02H; v, Pb(OAc),+; vi, H2-Pd/C

Scheme 13

(106) Reagents: i, Li-NH3; ii, EtOH-THF; iii, KOBU'; iv, CH,=CHLi; v, A; vi, H,-Pd/C; vii, HCrCLi; viii, H20-HCOzH

Scheme 14

Terpenoids and Steroids

82

(Scheme 15) (cf. Vol. 1, p. 63). A further illustration of the use of known photochemical reactions in natural product synthesis is provided by the recent synthesis59

\i,

Reagents: CH,=PPh,-DMSO;

iv

ii, HCI-EtOH; iii, MeLi; iv, S0CI2-py

Scheme 15

of (*)-3-oxo-a-cadinol (116) and (*)-a-cadinol (117) from the dienone (114)* (Scheme 16). A complete account of the previously reported synthesis of (*)amorphene (120) has been published6' (cf.Vol. 5 , p. 60). An interesting feature of the synthetic route is the stereospecific construction of the amorphane skeletone by * [3,3] sigmatropic rearrangement (oxy-Cope) of the bicyclic alcohol (118). The structure of simularene (123), a new structurally interesting sesquiterpenoid isolated from soft coral (Sirnularia mayi), has been established by X-ray analysis.61 It has been suggested6' that the cyclosesquifenchene skeleton of simdarene (123) is derived by rearrangement of the intermediate (122) proposed in the biosynthesis of a-and P-copaene (124). An alternative synthesis of (*)-sativene (128) and (*)-copacamphene (129) (cf. Vol. 1, p. 66; Vol. 2, p. 77, Vol. 3, p. 108; Vol. 4, p. 106; Vol. 5 , pp. 60,63; Vol. 7,

'' D. Caine and A. S. Frobese, Tetrahedron Letters, 1977, 3107 6o "

R. P. Gregson and R. N. Mirrington, Austral. J. Chern., 1976, 29, 2037, C. M. Beechan, C. Djerassi, J. S. Finer, and J. Clardy, TehuhedronLetters, 1977, 2395.

* A synthesis of (*)-oplopanone from dienone (1 15) (Scheme 16) has previously been reported; see Vol. 3, p. 60; Vol. 5 , p. 114.

Sesquiterpenoids

83

(114) R = H (115) R = O M e

IX,

x

OCH

\

(117)

(1 16)

Reagents: i, hv-HOAc; ii, LiAIH4; iii, Cr03-Me2CO-H30+; iv, Li-NH3; v, LiNPr' PhzS2; vi, EtLi; vii, Pb(0Ac)z-HOAc; viii, KOH-MeOH; ix, NHzNH2-py-EtOH; x, KOBJItoluene

Scheme 16

-

I.B~'K-(E~O)~P~CI II.

OH

Farnesyl pyrophosphate - - - -+

L~-NH~-BU'OH

H

H

$p-JJ&J H

,:at& (121)

(122)

/

p. 7 3 ) has recently been achieved by a route (Scheme 17) in which the tricyclic framework of these compounds is produced by free-radical cyciization of a bromoalkene intermediate (127).'j2 A complete account of the previously reported synthesis of (+)-cis-sativenediol (135) (Vol. 6, p. 67) and (+)-trans-sativenediol 62

P. Bakuzis, 0. 0. S. Campos, and M. L. F. Bakuzis, J. Org. Chem., 1976, 41, 3261.

84

Terpenoids and Steroids

% -& & 0

0

0

(128)

( 1 29)

Reagents: i, LiNPrI2-DME; ii, MeI; iii, BuMgBr-HMPA; iv, CH2=CHCH2Br; v, PhSH-AIBN; vi, NCS; vii, CuO-CuCIz; viii, Me2C=PPh3-DMS0, -65 O C ; * ix, Bu3SnH; x, MeLi; xi, SOC12-py, 0 ° C

Scheme 17

(136) has been published63 (cf. Vol. 7, p. 73). The synthetic route (outlined in Scheme 18) involves an intermediate bicyclic enol (130) which was used by the same group in a previous synthesis of (+)-sativene and (+)-cyclosativene (cf. Vol. 5, p.bO; Vol. 7, p. 73). It has been ~ u g g e s t e dthat ~ ~ the oxidative cyclization of enol (130) to enone (133) (Scheme 18) involves internal Prins reaction of the corresponding aldehyde (131 j followed by oxidation of the derived alcohol (133). Since (- j-cis-sativenediol (137) has been chemically correlated with co-metabolites, prehelminthosporal (138), prehelminthosporol (139), isosativenediol (140), and victoxinine (141j, the synthetic route outlined in Scheme 18 also constitutes a formal total synthesis of the enantioners of these biologically interesting sesquiterpenoids. An alternative synthesis (Scheme 19) of (*)-sativenediol, (136)+ (137), and its congeners (138)-(141) has been accomplished by simple modification of a previous route to (*)-sativene (128).64 The modified route to the norsativane 64

E. Piers and H.-P. Isenring, Cunud. J. Chem., 1977, 55, 1039. J. E. McMurry and M. G. Silvestri, J. Org. Chem., 1976, 41, 3953.

* At 60 "C this reaction leads to the bromo-ketone (126)!

Sesquiterpenoids

HO

F AF O H

L

Y

Y

Y

OH (136)

(135)

(134)

Reagents: i, Cr03-py-CF3C02H; ii, LiNPr12; iii, Moo5-HMPA-py; iv, LiAIHl

Scheme 18

85

86

Terpenoids and Steroids

framework, cf (145), involves intramolecular alkylation of the enone tosylate (143) and it is interesting that the undesired product (144) of this reaction underwent subsequent vinylcyclopropane-cyclopentane rearrangement to provide the required tricyclic enone (145).

&

+-++@ A

0

:

H

OTs

(142)

(136)+(137)

(143)

@

/

\

(144)

&-4

Xo

2

0

H (146)

(145)

Reagents: i, MeSOCH2--DMSO; ii, 450 "C; iii, MeLi; iv, SOC12-py; v, HCI, 20°C. 3 days

Scheme 19

Aduncin, a picrotoxane sesquiterpenoid isolated from Dendrobium aduncum, has been assigned structure (147) on the basis of its spectroscopic properties and their similarity to those of a- and p-dihydropicrotoxinin (148).65 A full paper dealing with the previously reported synthesis of 4-epidendrobine (149)* has been published66(cf. Vol. 7, p. 74).

9 Himachalane, Longipinane, Longicamphane, etc. The stereochemistry of p-himachalene epoxide (15 l), onq of two diastereomeric epoxides [(151), (152)] previously isolated from Cedrus atlantica (Vol. 7, p. 60), '* 66

L. Gawell and K. Leander, Phyrochemistry, 1976,15, 1991. R. F. Borch, A. J. Evans, and J. J. Wade, J. Amer. Chem. SOC.,1977, 99, 1612.

* In ref. 66 and previous reports (Vol. 7, p. 74) this compound is described as 8-epidendrobine. In this report we have adopted the generally accepted numbering system for the picrotoxane framework. It should also be noted that 4-epidendrobine does not occur in nature.

Sesquiterpenoids

87

has been deter’mined by its conversion into himachalol (lSS).67 Isohimachalone (154)68and oxidohimachalene (153)6y have been isolated from the essential oil of Cedrus deodora and assigned structures (154) and (153) on the basis of their chemical relationship with p -himachalene (1 SO).

( I SO)

(151)

(153)

(154)

\

(152)

(155)

Chemical and spectroscopic evidence has been provided for the structure of the longipinane sesquiterpenoid vulgarone B (1S6), a co-metabolite of vulgarone A (157)” in the essential oil of Chrysanthemum ~lulgure.’~Vulgarone B (156) can be

(157)

(156)

photochemically isomerized to the vulgarone A (157) [cf. known conversion of verbenone (158) into chrysanthenone (159)] and it is possible that a similar rearrangement could occur in nature.

(159)

(158)

It has been suggested that the biosynthesis of (+)-secolongifolenediol (163) involves ring cleavage of an epoxy-alcohol (161) related to (- )-longifolene (160).” This proposal is supported by the co-occurrence of (160) and (163) in Helmin”

A. P. S. Narula and S. Dev, Tefruhedron, 1977, 33, 813.

‘* R. Shankaranarayan, S. Krishnappa, and S. Dev, Tetrahedron, 1977, 33, 885. 69 70

”

R. Shankaranarayan, S. C. Bisarya, and S. Dev, Tenuhedron, 1977,33, 1207. Y . Uchio, A. Matsuo, S. Eguchi, M. Nakayama, and S. Hayashi, Tetrahedron Letters, 1977, 1191. F. Dorn and D . Arigoni Experientiu, 1974,30, 851.

* This compound was previously named vulgarone; cf.

Vol. 7, p. 75.

88

Terpenoids and Steroids

thosporium sativum and H. victoriae” and laboratory analogy for the ring-cleavage process has been provided in a recent report”” describing the acid-catalysed rearrangement of the epoxy-alcohol (164) to the aldehyde (165). A related reac-

(166)

(167)

tion involving ring cleavage of homoallylic alcohols [e.g. (166) -+ (167)72”]has been used in a recent synthesis of (-)-secolongifolenediol (175) from (+)-longicyclene (168)726(Scheme 20).

(175)

(172)

(174)

(173)

Reagents: i, NBS; ii, Li2C03-dioxan-H20; iii, HC1044ioxan-H20; iv, C12-LizC0,; v, NaBH4

Scheme 20

’’ ( a )J. S. Yadav, H. P. S. Chawla, and S. Dev, Tetrahedron Letters, 1977, 201; ( b ) ibid., p. 1749.

Sesquiterpenoids

89

10-Ketolongibornane (176) has been produced by treatment of (+)-longicyclene (168) with lead t e t r a - a ~ e t a t e .The ~ ~ claim that this compound is ‘the truealongicamphor’ seems unjustified since (-)-longicamphor (177) and its enantiomer, as described in the literature, are derived by oxidation of the natural products (-)longiborneol (178) and its enantiomer. In addition longicamphor (177) belongs to a group of ‘sesquicamphors’ [campherenone (179), copacamphor (180), ylangocamphor (181), and longicamphor (177)) whose common structural feature is the attachment of an isoprenoid C, unit at the C-8 and, in some cases, the C-3 position of the basic camphor framework [cf. (182)].

(179)

(180)

‘

(181)

‘

Oxidative cyclization of longifolol (183)74 has been used to provide intermediates, (184)and (189, in a recent synthesis (Scheme 2 1) of loqgifol-7( 15)-en56-01 (186) and its co-metabolite longifolan-3a,7a-oxide ( 1 8 7 p (cf. Vol. 3, p. 131). A full paper on the biosynthesis of culmorin (188)76has appeared (cf. Vol. 7, pp. 76, 192).

10 Homulane, Caryophyllane A new elegant stereoselective synthesis of humulene (192) has been achieved by a route (Scheme 22) in which the 11-membered-ring framework [cf. (191)] is produced by cyclization of the 11-allylpalladium complex derived from intermediate (190).77 Buddledin-A (193), -B (194), and -C (195) are new piscicidal sesquiterpenoids which have recently been isolated from the root bark of Buddleju d a ~ i d i i . ~ ~ The caryophyllane framework of these compounds has been established by spectroscopic data and X-ray analysis of the mono-bromohydrin (196) derived from buddledin A (193).78 An extension of previous on the cyclization of the epoxy-ketone (197) derived from caryophyllene has shown that the base-cataiysed cyclization of the isomeric epoxy-ketones (198) and (199) provides compounds S. N. Suryawanshi and U. R. Nayak, Tetrahedron Letters, 1977, 2619. Cf.J. Lhomme and G. Ourisson, Tetrahedron, 1968, 24, 3177. P. K. Jadhav and U. R. Nayak, Tetrahedron Lerrers, 1976,4858. 76 J. R. Hanson and R. Nyfeler, J.C.S. Perkin I, 1976, 2471. ” Y. Kitagawa, A. Itoh, S. Hashimoto, H. Yamamoto, and H. Nozaki, J. Amer. Chem. SOC.,1977.99, 3864. 78 Y. Yoshida, J. Nobuhara, M. Uchida, and T. Okuda, Tetrahedron Lerters, 1976, 3717. 79 D. H. R. Barton and A. S. Lindsey, J. Chem. Soc., 1951,2988. ” 74

’’

Terpenoids and Steroids

90

@

+

6::""

OH

v, v i j

vii, v i j

(186)

(187)

Reagents: i, Pb(0Ach-12; ii, CrO3-HOAc; iii, LiAIH4; iv, NBS-Bu'OH-py; v, KHS04, A; vi, Na-PrOH; vii, Ac2O-py, A; viii, H+

Scheme 21

OH (188)

(201)-(203) as major products.80 The formation of these compounds can be explained by considering the steric accessibility of the epoxide group to the derived enolate ions. The first total synthesis of (*)-marasmic acid (212) (cf. synthesis of isomarasmic acid, Voi. 1. p. 81) has been accomplished by the reaction sequence shown in E. W. Warnhoff and V. Srinivasan, Cunud. J. Chem., 1977,55, 1629.

91

Sesquiterpenoids

OTs

(1921

Reagents: i, CH2COE(Me)CO2Me; ii, AczO-py, A; iii, NaH-THF; iv, (Ph3P)4Pd-Ph2PCH2CHzPPh2HMPA-THF; v, LiAIH4; vi, TsCI; vii, KOBu'-THF, 0°C; viii, Et2AINMePh; ix, NCS-Me2S; x, Et,N; xi, NHzNHTs

Scheme 22

(193) R = O A c (194) R = O H (195) R = H

0&

____* KOH-MeOH

0

)I

OH

0

KOH-B"'OH

H' 0

@

H20

+

92

Terpenoids and Steroids

H 0 ( 1 99)

Hfy H

HO" (203)

Scheme 23." A schematic representation of the postulated involvement of a protoilludane intermediate (2 13) in the biosynthesis of various sesquiterpenoid

e

a. (205)

(204)

CO,R

H

o

z

X

CO,R

VI

t

\

\

\

H

H (20to

(210)

&*

CO,R

H (207) R = But, X = CHzBr

(211)

(2 12)

Reagents: i, CHz=CHOEt-ZnCIz; ii, HOAc-NaOAc; iii, DIBAH; iv, (2-bromoethyl)maleicanhydride; v, Me2=CHz-H+; vi, KOBU'-HOBU'-C~H~; vii, DIBAH-toluene, -78 "C; viii, NaBH,; ix, COC12-quinoline; x, DMSO-NEt,; xi, CF3COZH

Scheme 23

''

W. J. Greenlee and R. B. Woodward, J. Amer. Chem. SOC.,1976,98, 6075.

93

Sesquiterpenoids

structures is outlined in Scheme 24 and the results of various biosynthetic investigations using 14C- or I3C-labelled acetate and mevalonate are consistent with this general scheme (cf. Vol. 4., p. 112; Vol. 5, pp. 69, 180; Vol. 7, pp. 82, 197).

Illudane

seco-Illudane

t

Illudalane (seco-protoilludane)

(21 3) Protoiliudane

Fornannosane (seco-protoilludane)

1

Marasrnane

1

Hirsutane

Vellerane

Lactarane (seco-vellerane)

Scheme 24

Further indirect support for this proposal has been provided by the recent demonstration that A6-protoilludene (214) and compounds (2 15)-(220), belonging to some of the structural classes shown in Scheme 24, co-occur in the fungus Fomitopsis insuluria.82 Blennin A (221) and blennin B (222) have been identified as new metabolites of the inedible mushroom Lactarius blennius and a revised structure has been propojed for the co-metabolite, blennin C (223).83 An attempt to synthesize velleral (224) has provided a compound (225) which would seem to be 82

83

S. Nozoe, H. Kobayashi, S. Urano, and J. Furukawa, Tetruhedron Lerrers, 1977, 1381 and references cited. G. Vidari, M. De Bernardi, P. Vita-Finzi, and G. Fronza, Phyfochemistry, 1976, 15, 1953.

94

Terpenoids and Steroids

P”

R

(224) R = C H O (225) R = C0,Me

(223)

one or two steps removed from the natural Unfortunately attempts to complete the final stages of the velleral synthesis are not described in this paper.84

11 Germacrane The diverse biological activity (allergenic, antitumour, fungitoxic, phytotoxic, cytotoxic, etc.) of germacranolides (226a and b) and other sesquiterpenoids containing aP-unsaturated y-butyrolactone units has been reviewed.85 During the period of

Q wo (226a)

84

”

0

(226b)

T. Fex, J. Froborg, G. Magnusson, and S. Thoren, J . Org. Chern., 1976, 41, 3518. E. Rodriguez, G . H. N. Towers, and J. C. Mitchell, Phytochemistry, 1976,15, 1573; cf. Vol. 4, pp. 116, 133; Vol. 5, pp. 75, 87; Vol. 6, pp. 76, 78; Vol. 7, pp. 83, 88, 96, 103, 104.

Sesquiterpenoids

95

coverage structures or revised structures have been proposed for the Eollowing germacranolides: pectorolide (227), vernopectolide-A (228), and vernopectolide-B (229) ( Vernonia pectoralis);86 nobilin (230), 3-epinobilin, l,lO-epoxynobilin, 3dehydronobilin, eucannabinolide (23 l), and hydroxyisonobilin (232) (Anthemis n~bilis),'~*~'15-deoxygoyazensolide (233) ( Vanillosmopsis e r y t h r o p a p p ~ ) ; ~ ~ (Me)=CH,

R ' o q R 2

/ R

'OCOC(Me)=CHMe 0

HO

0

0 0

(227) R = CHzOH (228) R = CHzOAc (229) R = C H O

(230) R' (231) R'

= R2= H = Ac, RZ= OCOC(CH20H)=CHCH20H

0

0

co I

C (Me)=C H

desacetyleupaserrin (234) (Helianthus p u m i l i ~ )herbolides ;~~ A (235), B (236), and C (237) (Arternisia herba ~ l b a ) ; eupaformosanin ~' (238),92" eupatolide (240)92b and eupaformonin (239)92' (Eupatorium formosanum); euperfolitin (241) and , ~ -acetoxyzacatechinolide ~ (243) and euperfolin (242) (Eupatorium p e r f ~ l i a t u m )la 1-oxozacatechinolide (244) (Calea z a ~ a t e c h i c h i ) , ~ lactone ~" (245) (Chrysan~' themum poteriifolium),946lactone (246) (Inula b r i t t ~ n i c a ) ; ~peroxycostunolide (247) and peroxyparthenolide (248) (Magnolia grandijlora),95 verlotorin (syn. peroxycostunolide), and artemorin (249).95 B. Mompon and R. Toubiana, Tetrahedron, 1976,32, 2545. M. Holub and Z. Samek, Coil. Czech. Chem. Comm., 1977,42, 1053. Z. Samek, M. Holub, H. Grabarczyk, B. Drozdz, and V. Herout, Coil. Czech. Chem. Comm., 1977,42, 1065. 89 W. Vichnewski, J. N. C. Lopes, D. D. S. Filho, and W. Herz, Phytochemistry, 1976,15, 1775. 90 W. Herz and R. DeCroote, Phytochemistry, 1977,16, 1307. 9 ' R. Segal, S. Sokoloff, B. Haran, D. V. Zaitschek, and D. Lichtenberg, Phytochemistry, 1977,16, 1237. 92 (a) K.-H. Lee, T. Kimura, M. Haruna, A. T. McPhail, K. D. Onan, and H.-C. Huang, Phytochemistry, 1977, 16, 1068; (b) A. T. McPhail and K. D. Onan, J.C.S. Perkin XI, 1975, 1798; (c) ibid., 1976, 578. 93 W. Herz, P. S. Kalyanaraman, G. Rankikrishnan, and J. F. Blount, J. Org. Chem., 1977,42, 2264. y4 (a) F. Bohlmann and C. Zdero, Phytochemistry, 1977, 16, 1065; ( b ) F. bohlmann and D. Ehlers, ibid., p. 137; ( c )F. Bohlmann and C. Zdero, ibid., p. 1243. '' F. S. El-Feraly, Y.-M. Chan, E. H. Fairchild, and R. W. Doskotch, TetrahedronLetters, 1977,23, 1973. 86

Terpenoids and Steroids

96

HO..R

(CH,OH)=CHMe

0

0 (234)

(235) (236) 1,2-epoxide (237) 5,6-epoxide

R1oQoR* 0

0 (238) R' = Ac, R2 = COC(CH,OH)= CHCHPOH (239) R' = Ac, R2 = H

R

-

q

,

:

C

(Me)=C H M e

HO

0 (241) R = O H (242) R = H

(245)

0 (243) R = H,OAc (244) R = O

(247) R = O O H (248) R = OOH, 4,s-epoxide (249) R = O H

Spectroscopic evidence has been provided for the structure of the germacrane derivatives (250)-(253), isolated from several Ligularia species96(cf. p. 53). Two research groups have published synthetic routes to germacradiene systems based on the well known Cope rearrangement which interconverts germacradienes [cf: (254)] and elemenes (1,2-divinylcyclohexane derivatives) [cf.(255)]. In one report the total synthesis of (+)-costunolide (258) has been achieved by Cope rearrangement of (+)-dehydrosaussurea lactone (257) derived from santonin (256) 96

F. Bohlmann, D. Ehlers, C. Zdero, and M. Grenz, Chem. Ber., 1977, 110,2640.

97

Sesquiterpenoids

~

4

RO

0

(253) R = COC(Me)=Me

(250) R' = R2 = H, R3= R4= COC(Me)=CHMe (251) R' = H, R2 = R3 = R4= COC(Me)=CHMe (252) R2 = H, R' = R2 = R4= CO(Me)=CHMe

(255)

(254)

(Scheme 25)'7 (cf. Vol. 7, p. 99 and references cited). In a related study the synthesis of isoacoragermacrone (26 1) is accomplished by oxy-Cope rearrangement of compound (260) derived from isopiperitenone (259).98 Subsequent isomerization of (261) produced (*)-acoragermacrone (262) and (*)-preisocalamenediol (263)98 (Scheme 26) (cf. Vol. 4, p. 119; Vol. 5 , p. 71; Vol. 7, p. 85). Further studies on the acid-catalysed cyclization of germacradienes (cf. Vol. 7,

n,. - oq,. q,.

0

0

0

'

O

0

0-

'

0

1

(256)

(257)

(258)

Reagents: i, TsNHNH2; ii, LiNPr',-THF; iii, 03-CH2C12-MeOH; iv, NaBH4; v, ArSeCN-PBu3-THFpy; vi, H202-THF; vii, LiNPr',-PhS&ePh-HMPA-THF; viii, A, 200 "C, g.1.c.

Scheme 25 97 98

P. A. Grieco and M. Nishizawa, J. Org. Chem., 1977, 42, 1717 W. C. Still, J. Amer. Chem. Soc., 1977,99,4186.

98

Terpeno ids and Steroids

Reagents: i, Me2CHC(Li)=CH2; ii, KH-THF-18-crown-6; Me,SnLi; v, Me,SiCI; vi, MnOz

iii, LiNPr',-THF-HMPA-HOAc;

iv,

Scheme 26

p. 85) have shown that isoacoragermacrone (261) and acoragermacrone (262) can be cyclized to cadinane- (264) and (266), eudesmane- (267)-(269), and guaiane-

H 1 .OR 80% HOAc -

A

ether

(264) a ; R = H

HOAc -PhSH

(265)

+ HO,C**

H

Sesquiterpenoids

99

type (265) corn pound^.^^" Experimental details of previous studies on the cyclization of epoxygermacrone (270)* (Vol. 7, p. 85) as well as related results on the cyclization of the isomeric epoxide (271) and epoxy-acetate (275) have also been described in a recent paper.99b

(275)

(276)

A new approach to the cyclodeca-l,5-diene systems [cf. (281) and (282)] characteristic of germacranolides involves a photochemical-cycloaddition and thermalcycloreversion sequence shown in Scheme 27."' 12 Eudesmane

An extension of previous investigations on the sesquiterpenoid constituents of Ambrosia species has resulted in the isolation and structural elucidation of granilin (283) and ivasperin (284)."' A similar compound (285) has been identified as a co-metabolite of germacranolide (246) (cf. p. 96) in h u l a britt~nica.~~' Several independent investigations have shown that many of the sesquiterpenoid constituents of liverworts are enantiomeric to the same compounds isolated from vascular plants (Vol. 6, pp. 63, 89). A recent investigation has shown that essential oils of two liverworts of the genus Diplophyllum (albicans and taxifolium)contain ent-aselinene (286), ent-selina-4,ll-diene (287), and diplophyllin (288).'02 The latter 99 loo

'O'

lo*

M. Niva. M. Iguchi, and S. Yamamura, ( a )Bull. Chem. Soc. Jupan. 1976, 49,3148; ( b ) ibid., p. 3137. G. L. Lange, M.-A. Huggins, and E. Neidert, TefruhedronLetfers, 1976, 4409. W. Vichnewski, 1. K. Shuhama, R. C. Rosanske, and W. Herz, Phytochemisfry, 1976.15, 1531. Y. Ohta, N. H. Andersen, and C.-B. Liu, Tetrahedron, 1977, 33, 617.

* This compound was incorrectly named isoacoragermacrone epoxide in Vol. 7, p. 85.

Terpenoids and Steroids

100

mo""... Ram

Reagents: i, h v ; ii, NaBH,; iii, A

Scheme 27

HO

HO

(285) R = COCH=CMe2

(284)

(283)

(286)

0

(288)

(287)

compound shows significantly greater antitumour activity than its enantiomer and this represents the first demonstration of chiral selectivity in the cytotoxicity ofsesquiterpenoid a-methylene-y-butyrolactones. Albicanol (289), another constituent of D. a6bicans, has been chemically correlated with (-)-drimenol (290), a (OH

(289)

(OH (290)

constituent of the liverworr Bazzania trilobata, and it has been noted that, in general, the stereochemistry of drimanes found in liverworts is the same as that found in vascular p1ants.l''

101

Sesquiterpenoids

mm

Cinnamate esters of rupestrinol (292) and p-chaenocephalol (293) have been identified as co-metabolites of rupestrol cinnamate (291) in the shrub Verbesina rupestris'03(cf.Vol. 2, p. 146). HO

H8

HO PhCH=CHCO'

I1

0

I

OH

COCH=CHPh

0 (291) R = O H (292) R = H

(293)

An investigation of the constituents of Mexican species of the genus Eupatorium has resulted in the isolation of sesquiterpenoids belonging to the eudesmane (294a and b), eudesmanolide (295a and b), cadinane (296), and guanolide (297)

'"4

(294) a; R = 0 b; R = H,OH

(29% and b)

20H)=CHCH20H

0 0 (296)

(297)

There has been much interest recently in terpenoid metabolites of marine organisms1os and two recent reports in this area describe the independent identification of the bromoeudesmane (298) as a constituent of red seaweed ?r

(298) '03 '04

Io5

V. G. S. Box, V. Bardouille, and W. R. Chan, Phytochemistry, 1977,16,987. F. Bohlmann, J. Jakupovic, and M. Lonitz, Chem. Ber., 1977,110, 301. (a) q.Vol. 1 , p. 74; Vol. 2, p. 84; Vol. 4, pp. 96, 142; Vol. 5, pp. 48,55, 70, 77, 78, 84; Vol. 6, pp. 64, 65, 87-89, 91-93; Vol. 7, pp. 18-20, 5 4 - 6 0 , 65-71, 123; ( b ) 'Marine Natural Products Chemistry', ed. D. J. Faulkner and W. H. Fenical, Plenum, New York, 1977.

102

Terpenoids and Steroids

(Laurencia) collected in Australia'"6 and Calif~rnia.'"~ This compound represents the first naturally occurring brominated sesquiterpenoid belonging to the eudesmane (selinane) group. 4,ll-Epoxy-cis-eudesmane (300), the defence pheromone of the West African termite, has been synthesized from 10-epi-y-eudesmol (299) by means of an i,Hg(OAc)z-THF-H20,

+

11.2 NaBH4-HO-

OH

,'

H 0

H'

0

internal oxymercuration reaction.lo8 Simple functional group transformations also form the basis of a reported synthetic route from the known dienone (302) to intermedeol (307) via the naturally occurring diene (304)109a*b (Scheme 28).

(302)

iiil

(305) Reagents: i, NH2NH2-KOH-(CH20H)2; ii, m-CIC6H4C03H; iii, LiAIH4

Scheme 28

Chemical and spectroscopic evidence has been provided for the structure of 30-epijunenol (308), a new member of the rare cis-eudesmane group of sesquiterpenoids."' Rosifoliol, a component of the leaf oil of Australian native raspberry (Rubus rosifolius) has been assigned structure (309) on the basis of its spectroscopic lo6 lo'

lo' lo9

'lo

A . F. Rose and J. J. Sims, Tetrahedron Letters, 1977, 2935. 6. M. Howard and W. Fenical, J. Org. Chem., 1977, 42, 2518. R. Baker, D . A . Evans, and P. G. McDowell, J.C.S. Chem. Comm., 1977, 11 1. ( a )L. H. Zalkow, M. Smith, G. L. Chetty, A . W. Shaligram, and P. Ingwalson, J. Org. Chem., 1976,41, 3710; ( b ) cf. J. W. Huffman, C. A . Miller, and A . R. Pinder, ibid., p. 3705. A . F. Thomas, M. Ozainne, R. Decorzant, F. Naf, and G. Lukacs, Tetrahdron, 1976, 32, 2261.

-

Sesquiterpenoids

103

(310)

(309)

(308)

properties and chemical correlation with (- )-8-selinene ( 3 1(I)."' Other components of the leaf oil are bicyclogermacradienes (31 l), 10-epi-y-eudesmol (299), and the trisnor-sesquiterpenoid pregeijerene ( 3 12).'" The key feature of a

( 3 12)

(31 1 )

new synthetic route to (*)-occidentalol (314) (cf. Vol. 3 , p. 150; Vol. 4, p. 119) is the cyclization of a suitably substituted cyclohexadiene aldehyde (3 13) derived from m-toluic acid"' (Scheme 29). It seems reasonable to assume that

CO, Me C0,Me x, ii. x i 1

t

t-

CHO OAc

(3 14)

(313)

Reagents: i , Li-NH3-Br(CH2)40CH2Ph; i i , L I A I H ~ iii, ; TsCI-py; iv, LiBHEt,-HMPA; v. Na-NHxBuOH; vi, NCS-MezS-toluene; vii, AgzO; viii, MeOH-HC; ix, CIC02Et-

X,

NaH;

XI,

M n 0 2 ; xi], Ac20-HCI0,; xiii, Ag20-NaOH;

XIV,

I?!;

CH2N,; xv, MeLi

Scheme 29

modification of this approach would be of value in the synthesis of eudesmanolides and germacranolides. An interesting new approach to a-substituted acrylic esters 'I1 'I2

1. A . Southwell, Tetruhedron Letters, 1977, 873. J . A . Marshall and P. G. M. Wuts, J . Org. Chem., 1977. 42, 1794

104

Terpenoids and Steroids

[cf. (316)+ (317)] has been successfully incorporated into the first total synthesis of the allergenic sesquiterpenoid frullanolide (318)11-’(Scheme 30) (cf. Vol. 4, p.

(3 17)

q& O

o

&Q (3 18) *

o

Reagents: i, H,02-OH-; ii, NH2NH2,H20-MeOH; i i i , LiNPri2; iv, CH,=CHCOCI; v, pyrrolidinc; vi, Et,SiCI; vii, toluene, A; viii, Me2S04-K2C0,-MeOH; ix, KOH-MeOH; x, K13-NaHC03H 2 0 ; xi, DBu-THF. A

Scheme 30

124; Vol. 5 , p. 76). Related studies have shown that the butenolide derivative (319) can be used as an annulating agent in the construction of linear tricyclic y-lactones [cf. (322) and (323)] and it is expected that this methodology may be applied to the synthesis of naturally occurring eude~manolides.”~ Acetyl, benzoyl, cinnamoyl, and nicotinyl esters of polyols based on the dihydroagarofuran framework [cf. (324) etc.] have been established as constituents of ‘I3

’I4

W. C. Still and M. J . Schneider, J . Amer. Chem. SOC.,1977.99.948. A . G . Schultz and J . D. Godfrey. J . Org. Chem., 1976, 41, 3494.

Sesquiterpenoids

105

mO \

'

-..

ii.i.:2O,-MeS03H K2CO3-MeOH

COzMe

(323)

0 CO,Me

OH

(322)

various genera of Celastraceae (Celastrus, Euonymus, Muytenus, and Cuthu) (cf. Vol. 4, p. 125; Vol. 6, pp. 77,78; Vol. 7, p. 90). Further investigations in this area have resulted in the isolation of various esters of celorbicol (324) and isocelorbicol (325) from the seeds of Celustrus orbicufatus,115 maytoline (326), maytine (327), and maytolidine (328) from Muytenus serratu,"6 euonymine (329) and neoeuonyand cassinin (33 1) from Cussine mine (330) from Euonymus sieb~fdiunu,"~ mutubelicu (Celastraceae). ' l R

"C3;-ii

AcO

OAc OAc

/

R 2

(324) R' = H, R2 = OH (325) R' =OH, R2 = H

(326) R' =OH, R2 = Ac (327) R' = H, R2 = Ac (328) R' = OAc,R2= COPh

(329) R' = Ac, R2 = OH (330) R' = H, R2 =OH (33 1) R' = COPh, R2= H

Re-examination of spectroscopic and chemical evidence has led to a revised structure for mortonin (334).lI9 The proposed biosynthesis of mortonin (334) involves ring cleavage of a dihydroagarofuran derivative (333) and this proposal is indirectly supported by the co-occurrence of mortonin (334) and dihydroagarofuran derivatives [cf. (326)-(33 l)] in the same family of plants (Celastraceae). 'I5 'I6

'I7 'Is

'''

C. R. Smith, R. W. Miller, D . Weisleder, and W. K. Rohwedder, J. Org. Chem., 1976, 41, 3264. S. M. Kupchan and R. M. Smith, J. Org. Chem., 1977,42, 115. K. Yamada, K. Sugiura, Y. Shizuri, H. Wada, and Y. Hirata, Tetrahedron, 1977, 33, 1725. H. Wagner, R. Bruning, H. Lotter, and A. Jones, Tetrahedron Letters, 1977, 125. L. Rodriguez-Hahn, M. Jiminez, E. Diaz, C. Guerrero, A. Ortega, A. Romo de Vivar, Tetrahedron, 1977, 33, 657.

106

Terpenoids and Steroids

@

HO

H + H o @ H +COH H o p j

(332)

(333)

(334) R=COPh

13 Vetispirane, Elemane The recent upsurge of interest in phytoalexins has been maintained during the past year.”” Particular attention has been given to phytoalexins produced by potato tubers which have been infected with fungi (Phytophthora infestans, Fusarium avenaceum, Phoma exigua var. foveata) or bacteria (Erwiniu carotovora var. atrosepticu), and sesquiterpenoids previously identified from this source include lubimin (3354, 9-hydroxylubimin* (336), solavetivone (337), anhydro-P-rotunol (338), phytuberin (339), rishitin (341), and rishitinol (340) (cf. Vol. 4, p. 125; Vol. 5, p. 80; Vol. 6, p. 80; Vol. 7, p. 94). Full papers on the structural elucidation of lubimin (335),’” 9-hydroxylubimin” (336),”’ rishitin (341),lZZaand phytuberin (339),1’3,’’4 and a detailed account ”” of the synthesis of rishitin (341) from (-)-a-santonin (256) have been published. In addition 9-hydroxylubimin (336), whose relative configuration was previously established by X-ray analysis (Vol. 7, 94), has been assigned the absolute configuration shown, on the basis of n.m.r.

For previous references to phytoalexins see Vol. 4, p. 125; Vol. 5, p. 80; Vol. 6, p. 80; Vol. 7, pp. 52, 94. N. Katsui, A. Matsunaga, H. Kitahara, F. Yagihashi, A. Murai, T. Masamune, and N. Sato, Bull. Chem. SOC.Japan, 1977, 50, 1217. ( a ) T. Masamune, A. Murai, M. Takasugi, A. Matsunaga, N. Katsui, N. Sato, and K. Tomiyama, Bull. Chem. SOC.Japan, 1977,50, 1201; (b) A. Murai, K. Nishizakura, N. Katsui, and T. Masamune, ibid., p. 1206. D. T. Coxon, K. R. Price, B. Howard, and R. F. Curtis, J.C.S. Perkin I, 1977, 53. D. L. Hughes, J.C.S. Perkin I, 1976, 1338.

*Two numbering systems, (A) and (B), for tRe parent vetispirane structure are being used in the literature. In this and previous Reports we have adopted the IUPAC (A) rather than the biogenetic numbering (B).

107

Sesquiterpenoids

(338)

(339)

(34 1)

(340)

(342)

and c.d. spectral data.'25 A new phytoalexin isolated from potatoes infected with Phytophthora infestuns, has been identified as 6-epilubimin (342).lz6 The structure and absolute configuration of the aglycones, (343)-(346), of vetispirane

R3

(343) R' = R3= H, R2 = O H (344) R' = R2= H, R3 = OH (345) R' =OH, R2,R3= H

(346)

glucosides isolated from flue-cured Virginia tobacco have been deduced from X-ray analysis and chemical correlation with (- )-solavetivone" (337).lZ7O Further investigations on the biosynthesis of phytoalexins (cf. Vol. 7, p. 94) have established labelling patterns in lubimin (335), 9-hydroxylubimin (336), solavetivone (337), phytuberin (339), and rishitin (341) derived from [ 1,2-13C]acetate which are consistent with their proposed derivation from a eudesmane precursor.128 The spiroketone (347), previously used as an intermediate in the synthesis of several vetispirane sesquiterpenoids (cf. Vol. 5 , p. 79) has been converted into (f)-solavetivone (337) by the sequence of reactions shown in Scheme 31.129 '21 la'

'21

12' 129

N. Katsui, H. Kitahara, F. Yagihashi, A . Matsunaga, and T. Masamune, Chem. Leriers, 1976, 861. N. Katsui, F. Yagihashi, A. Matsunaga, K. Orito, A. Murai, and T. Masamune, Chem. Leiters, 1977, 723. (a) R. C. Anderson, D. M. Gunn, J. Murray-Rust, P. Murray-Rust, and J. S. Roberts, J.C.S. Chem. Comm., 1977,27; ( b )T. Fujimori, R. Kasuga, H. Kaneko, and M. Noguchi, Phytochemistry, 1977,16, 392. A. Stoessl and E. W. B. Ward, Tetrahedron Letters, 1976, 3271. K. Yamada, S. Goto, H. Nagase, and A. T. Christensen, Tefrahedron Leiiers, 1977, 554.

* This compound has also been isolated from tobacco

Terpenoids and Steroids

108

. -

H

(347)

...a%

4-=-

k0

I' 0%

b

O OH H OH

QH

OH

OH

Reaction: i, LiNPr',-PhSeSePh; ii, m-CIC,H4C03H; iii, NaHC03-toluene; iv, CHz=C(Me)MgBr-CuITHF; v, NH2NH2-KOH-(CHzOH)2; vi, Os04-THF-py; vii, (CO,Hh-MeOH-H,O; viii, (PhO)$Me I--BF3, Et20-MeCN; ix, Zn-NH4C1; x,

Scheme 31

Two additional synthetic routes to (*)-p-vetivone (350) have been d e ~ e l o p e d . ' ~In~ one " ~ ~of these a suitably substituted spirocyclic system [cf. (349)] is constructed by addition of Me,CuLi to the fulvene derivative (348).130 Subsequent functional group modification (cf. Scheme 32) provides (*)-p-vetivone (350). In the other total ~ynthesis'~' the well-known intramolecular alkylation of para-substituted phenols has been used to produce a spirocyclic intermediate (353) which can be converted into (*)-p-vetivone (350) (cf. Scheme 33). Sesquiterpenoids based on the axane skeleton (354) have been reported previously as metabolites of marine sponges or algae (cf. Vol. 5, p. 77; Vol. 6, p. 89). Further investigations in this area have revealed the presence of axisonitrile-4 (355), axisothiocyanate (356), and axamide-4 (357) in the sponge Axinella cannabina. 1 3 2 ~ 1 3 3 These compounds are A'O"'-derivatives of known metabolites (axisonitrile-1 erc.) of this sponge and are included in this section because their biosynthesis may involve rearrangement of a eudesmane precursor. P-Elemenone (359), a compound which co-occurs with germacrone (358) in Bulgarian zdravetz oil and which can be formed from germacrone (358) by thermal rearrangement, has recently been synthesized by a route (Scheme 34) in which the 13' 13'

133

G. Biichi, D. Berthet, R. Decorzant, S. Grieder, and A. Hauser, J. Org. Chem., 1976,41, 3208. K. Uneyama, K. Okamoto, and S. Torii, Chem. Letters, 1977,493. A. Iengo, L. Mayol, and C. Santacroce, Expn'entia, 1977,33, 1 1 . M. Adinolfi, L. De Napoli, B. D. Blasio, A. Iengo, C. Pedone, and C. Santacroce, Tetrahedron Letters, 1977.2815.

Sesquiterpenoids

3

%

---.

109

iv-vii

~

---. 0

(348)

(349)

O

q

-

viiil

9

L

-

q

CN OH

(3.50) Reagents: i, Me2CuLi; ii, MeCOCI-PhNMe2; iii, NH=NH; iv, NaOH-EtOH; v, MeC0,H; vi, BuLi; vii, TSOH-C,&; viii, MeC6H4NC; ix, MeMgBr; x, MeLi; xi, CrO,-py; xii, TSOH-C6H6, A

Scheme 32

+ 1-1V H O W ; ,

Hoy+/,JCo2Me

(35 1 )

(352)

oq I.

(350)+c-10 epimer

-

.

(353) Reagents: i, LiNPr',-Me,CO;

ii, SOCl2-py; iii, LiAIH4; iv, TsC1-py; v, KOBU'; vi, Me2CuLi; vii, RhCI3

Scheme 33

(354)

(355) R = N C (356) R=NCS (357) R = NHCHO

110

Terpenoids and Steroids

(359)

(358)

1, 2-divinylcyclohexane system [cf. (362)] is produced from the diselenide intermediate (361).13, (Other studies on the use of elemane derivatives as intermediates in the synthesis of germacranolides etc. are described on p. 97).

(362) Reagents: i, Li-NH3-Bu'OH-THF;

(359) ii, LiNPr'2-(EtO)2POCI; iii, Li-EtNH,;

vi, o-N02C6H4SeCN-Bu3P; vii, H,02-THF; x, MeI; x i , MezCuLi

iv, 03-MeOH; v, NaBH,;

viii, HCI-THF; ix, CS2-Li+

Scheme 34

Complete details of the previously reported total synthesis of the antiturnour elemanolides vernolepin (363) and vernomenin (364) (Vol. 7, p. 97) have been Other research groups have reported the synthesis of compounds (365)-(367) which could be of considerable value as intermediates in alternative synthetic routes to vernolepin and v e ~ n o m e n i n . ' ~ ' - * ~The ~ antitumour activity of 134 135

G. Majetich, P. A . Grieco, and M. Nishizawa, J. Org. Chem., 1977, 42, 2327. P. A. Grieco, M. Nishizawa, T. Oguri, S. D. Burke, and N. Marinovic, J. Amer. Chem. Sac., 1977.99, 5773.

"'S. Danishefsky, P. F. Schuder, T. Kitahara, and S. J. Etheridge, J. Amer. Chem. Soc., 1977,99,6066. 137 13" 139

P. M. Wege, R. D. Clark, and C. H. Heathcock, J. Org. Chem., 1Y76,41, 3144. M. Isobe, H. Iio, T. Kawai, and T. Goto, Tetrahedron Letters, 1977, 703. S. Torii, T. Okarnoto, and S. Kadono. Chem. Lefters, 1977, 495.

Sesquiterpenoids

111

" F '

0

I'

OH (364)

(363)

&---o 0

H

(365)

C0,Me

: H C0,Me

(366)

(367)

vernoiepin (364) has also stimulated research on the synthesis of compounds of similar type and recent investigations have shown that ( f )-deoxyvernolepin (369), synthesized by the route outlined in Scheme 35, is more potent than vernolepin as an antitumour agent.I4" The structural elucidation of micordilin (370), a complex elemanolide produced by a medicinal plant (Mikania cordifofia),has been determined by X-ray crystallographic a n a 1 y ~ i s . l ~Germazone ~ (371), a component of the essential oil of Geranium mucrorrhizum (zdravetz oil), is the first example of a new structural type of sesquiterpenoid and it has been suggested that the biosynthesis of this compound involves cyclization of the co-metabolite, germacrone (358).14' In previous i n v e s t i g a t i o n ~ 'it~ ~was noted that an unidentified product from the reaction of patchoulol (patchouli alcohol) (372) with Pb(OAc), (cf. Vol. 7, p. 112) was transformed to an unsaturated alcohol after g . 1 A~ recent ~ ~ analysis ~ of the spectroscopic data for these compounds has led to the proposal that the initial reaction product is the bicyclic enone (374) which undergoes internal Prins reaction o n the g.1.c. column to furnish the unsaturated alcohol (375)144(cf. cedrane framework p. 78). Cybullol (377), previously reported as a metabolite of Bird's Nest fungi (cf. Vol. 7, p. 95), and geosmin (379), a degradation product of cybullol and the fungal metabolite responsible for the 'earthy' aroma of freshly ploughed soil, have been synthesized by the routes outlined in Schemes 36 and 37.145

14 Eremophlane, Bakkane (Fukinane), Ishwarane Acid-catalysed rearrangement of 11,12-dihydroparadisiol (382) to 11,12-dihydrovalencene (383) has provided further support for the 1,2-methyl shift postu14" I4l 142 143

'44 145

P. A. Grieco, J. A. Noguez, and Y. Masaki, J. Org. Chem., 1977, 42, 495. W. Herz, P. S. Subramaniam, R. Murari, N. Dennis, and J. F. Blount, J. Org. Chem., 1977, 42, 1720. E. Tsankova and I. Ognyanov, Tetrahedron Letters, 1976, 3 8 3 3 . B. A. Gubler, Promotionsarbeit, E. T. H., Zurich, 1965; cf. G. Mehta and B. P. Singh, Tetrahedron Letters, 1975, 4495. A. F. Thomas and M. Ozainne, J.C.S. Chetn. Comm., 1977, 120. W. A. Ayer, L. M. Browne. and S. Fung, Canad. J. Chem., 1976, 54,3276.

112

Terpenoids and Steroids

MHe 0 , CO

J H

J.

h

xi-xiii.

viii

OAc C0,Me

OAc C 0 , M e

XV

-

xviii,xix,

0 OAc C0,Me

oq H

OAc C0,Me

O

'0

OH

0

HO (369) Reagents: i, NaH-MeI-THF; ii, BH3-THF-HO- iii, Cr03,2py-CHzC12; iv, NaH-(MeO)zC04ioxan; v, NaH-BrCH2COZMe;vi, Ba(0Hh-A; vii, Na-Pr'OH; viii, CH2Nz; ix, Ac20-py; x, HCI-THF; xi, CHz=C(OAc)Me-TsOH; xii, 03-MeOH-CH2Cl2; xiii, NaBH4-HO-; xiv, MsC1-py, 0 "C; XV, BBr3-CHzC12,-78 "C; xvi, O-NO&H~S~CN-BH~--DMF; xvii, HzOz-THF; xviii, KzC03-MeOH; xix, TSOH-C6H6; xx, LiNPr'Z-CHzO-HMPA; xxi, MsCI-py, b

Scheme 35

0

(370)

Sesquiterpenoids

(374)

(375)

lated in the biosynthesis of eremophilane sesquiterpenoids from eudesmane prec u r s o r ~(cf. ~ Vol. ~ ~ 4,p. 131; Vol. 6, p. 184; Vol. 7, p. 100). Although it has also been shown that addition of [3-14C]paradisiol (381) to grapefruit results in the formation of radioactive valencene (382) the significance of this observation will

“O.-rn OHj

(377) Reagents: i, LiAIH4; ii, A; iii, hv-O2CH2CI2, -78 “C, Rose Bengal; iv, Al-Hg-ether; v, H2-Pt0,, 40 psi

Scheme 36

(378)

(379)

Reagents: i, H202-NaOH-MeOH; ii, Li-NH,; iii, (CH2SH)2-BF3-HOAc; iv, Raney Ni(W-2kEtOH

Scheme 37 146

C. A. Miller and A. R. Pinder, J.C.S. Chem. Comm., 1977, 230

114

Terpenoids and Steroids

ultimately depend on whether or not the radioactivity is specifically located at C-3 in ~ a 1 e n c e n e . lThe ~ ~ alternative structure (385) proposed for nardostachone has been invalidated by the recent demonstration that synthetic (385), derived from ( f )-7-epinootkatone (384), has spectroscopic properties which differ from those of

(384)

(385)

the natural A further investigation of the South American plant Tessaria absynthioides has revealed the presence of eremophilane derivatives (386) and (387) as co-metabolites of the known compounds tessaric acid (388) and carrissone (389).14' A new sesquiterpenoid, eremofortin C (390), has been isolated from cultures of Penicillium roquefortii and its structure determined by chemical correlation and spectral comparison with known metabolites [eremofortin A (391), PR toxin (392)] of this organism'49 (cf. Vol. 6, p. 84; Vol. 7, p. 97).

(386) R' (387) R' (388) R'

(390)

14'

(389)

= H2, R2 = C 0 2 H = 0,R2 = C 0 2 H

OH

AcO

'41

= H2, R2 = CH,OAc

CHO

AcO

AcO

(391)

W. D. Saunders and A. R. Pinder, Tetrahedron Letters, 1977, 1687. F. Bohlmann, C. Zdero. and M. Silva, Phyfochemistry, 1977, 16, 1302. S. Moreau, M . Cacan. and A. Lablache-Combier, J. Org. Chem., 1977, 42. 2632

(392)

Sesquiterpenoids

115

Alternative synthetic routes to (*)-eremophilone (395) have been achieved by two research group^^^^.'^^ (cf.Vol. 5, p. 82; Vol. 6, p. 84 for previous syntheses). In one of the routes15" (Scheme 38) the required stereochemistry at C-7 is achieved at

)

xv. xvi, xif

HO

(395) Reagents: i, (CH2=CH)zCuLi-Bu3P; ii, LiAIH4-EtzO; iii, m-CIC6H4CO3H; iv, CrO3-3,S-dimethylpyrazole-CHzClz; v, KOBu'-HOBu'; vi, MnOz; viii, Ph3P=CHC02Me-CH2C12; viii, (CH,OH),-H+; ix, [CH2=C(Me)]2CuLi; x, HCI-H20-THF; xi, Li-NH,; xii, Cr03-pyCH2C12; xiii, NaOH-MeOH; xiv, 250 "C; xv, H202-NaOH-MeOH; xvi, NH2NH2,HzO-I If

Scheme 38

an intermediate stage by 1,4-addition of an isopropenyl group to a syn-cyclopropyl acrylic ester (394). In the other total synthesis1'' (Scheme 39) the required stereochemistry is produced by l,4-addition of Grignard reagent (397) to the enone (396). The isolation of eremophilane derivatives (398)-(402) from several Ligularia species96.152*153 and (403a-c) from Gynoxys and Pseudogynoxys 150

15'

I"

F J F Y

E Ziegler, G R Re~d,W L Studt, and P A Wender, I Org Chem, 1977, 42, 1991 Ficini and A M Touzin, Tetrahedron Lefters, 1977. 1081 Bohlmann dnd A Suwita, Chem Ber, 1977, 110, 1759 Moriyama and T Takahashi, Bull Chem Soc Japan, 1976.49, 3196

Terpenoids and Steroids

116

.

..

MgBr

(397)

9"

YR

0 ii

iii -vJ

0

fi

vi,vii,iv

Reagents: i, CuI-THF; ii, HCI-H20; iii, Ac20; iv, CHZ=CHOEt-H+; v, OH--H20; vi, Cr03-pyCH2C12; vii, NaOMe-MeOH; viii, NaBH4-MeOH, 0 "C; ix, Li-EtNHz; x, Cr03-MezCOH2S04; xi, alumina, 280 "C; xii, H202-OH-; xiii, CrClz

Scheme 39

(398) R' = H, R2 = COC(Me)=CHCH,OH (399aand b) R' = COC(Me)=CH2, R2= Ac or H (400aand b) R' = COC(Me)=CHMe, R2 = Ac or H

(402) R = COC(Me)=CHMe

(401) a; R = OH b;R=H

= RZ= COC(Me)=CHMe b; R' = COCH=CMe2, R2 = COC(Me)=CHMe c; R' = H, R2 = COC(Me)=CHMe

(403) a; R'

117

Sesquiterpenoids

species154has been reported. An extension of previous studies (cf Vol. 6, p. 85) on the hepatotoxic constituents of the plant Tetrudymu glubrutu resulted in the isolation of tetradymodiol (404) and the determination of its Structure by X-ray An alternative synthesis of (*)-cacalol (405) and confirmation for the ".~ Vol. 7, structure of the co-metabolite cacalone (406) have been p ~ b l i s h e d ' ~ ~(cf. pp. 100-102). Compounds (407) and (408a-c) related to cacalol (405) have been isolated rccently from various Senecio ~pecies"~ where they co-occur with a variety of eremophilane derivatives. The co-occurrence of cacalane and eremophilane compounds provides indirect support for the proposed biosynthetic relationship (1,2 methyl shift) between these sesquiterpenoid groups.

(407)

(408)a; R' =Me, R2= CHO b; R' = R2= CHO c; R' = CHO, R2 = CH20Ac

Experimental details for the previously reported synthesis of ( f)-bakkenolide-A (41 1) (syn. fukinanolide) have been provided in a recent paper which also describes the potential of [2,3]sigmatropic rearrangement in natural product In the particular case of bakkenolide-A the correct configuration at C-7 is achieved by [2,3]sigmatropic rearrangement of the intermediate (409) (cf. Vol. 5, p. 8 5 ) . A NNHTs

I54 15s

156

15' 15'

F. Bohlmann, M. Grenz, and A . Suwita, Phyrochemistry, 1977, 16, 774. P. W. Jennings, J. C. Hurley, S. K. Reeder, A . Holian, P. Lee. C. N. Caughlan, and R. D. Larsen, J. Org. Chem., 1976, 41, 4078. ( a )F.Yuste and F. Walls, Austral. J. Chem., 1976,29,2333;( b )F. Yuste, E. Diaz, and F. Walls, J. Org. Chem., 1976,41,4103. F. Bohlmann, C. Zdero, and M. Grenz, Chem. Ber., 1977, 110,474. F. Bohlmann, K.-H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A. Suwita, D. Ehlers, N. LeVan, W.-R. Abraham, and A . A. Natu, Phytochernisfry, 1977,16, 965. D. A . Evans, C. L. Sims, and G. C. Andrew?, J. Amer. Chem. SOC..1977,99,5453.

Terpenoids and Steroids

118

recent report describes the distribution of bakkenolide-A (4 11) in Petasites species and also makes the interesting observation that the cytoxicity of bakkenolide-A compares favourably with that of several sesquiterpenoids containing a-methylene-y-lactone rings160(cf.pp. 94, 112). An extension of previous studies on the synthesis of ishwarane (413) (cf. Vol. 4, p. 132) and the diterpenoid trachylobane (414) has provided an improved procedure for the conversion of the previously reported intermediate (412) into ishwarane (413).161

=**OH

i, M\CI-py, O T , 11,

.

L1AlH4-Et20 ,

I

I

15 Guaiane, Pseudoguaiane A general investigation of acid-catalysed rearrangement of unsaturated sesquiterpenoids has shown that a-bulnesene (415), a-guaiene (416), guaiol (417), or cy -gurjunene (4 18) provides ent- 10-epizonarene (4 19), bicyclohumulene (420) is converted into 6-selinene (421), and (-)-y-muurolene (422) rearranges to (-)zonarene (423).16' The structural elucidation of several new guaiane derivatives found in plants has been reported during the past year. These include (424)-(426)

,

n2s04,

A (419)

-

Q O H

(420) I6O

'" I62

(421)

G. R. Jamieson, E. H. Reid, B. P. Turner, and A. T. Jamieson, Phytochemistry, 1976, 15, 1713. R. B. Kelly and S. J. Alward, Canad. J. Chem., 1977, 55, 1786. G. Mehta and B. P. Singh, J. Org. Chem.. 1977. 42, 632.

Sesquiterpenoids

119

QOH

(424)

(425)

(426)

from the Chilean plant Pleocarphus revolutus,lh3 arctolide (427) from Arctotis g r a n d i ~ , 'eufoliatin ~~ (428) from Eupatorium perf~liaturn,~~ (429h(432) from Poduchaenium eminens,lhsu(433) and (434) from various Arctotis and (435) from Liabum species.16" The structure and relative configuration of the first furanoguaiane derivative, gnididione (436), has been recorded16' and X-ray analysis has resulted in a revised structure (437) for chrysartemin B, a metabolite of Chrysanthemum morifolium.168

(428)R = COC(Me)=CHMe

(431) (432) 11,13-dihydro

(433) (434) 11,13-dihydro

(429)R = H (430)R = O A c

(435)R = COC(Me)=CHMe

M. Silva, A. Wiesenfeld, P. G. Sammes, and T. W. Tyler, Phylochemisrry, 1977, 16. 379. 2. Samek, M. Holub, B. Druzdz, and H. Grabarczyk, Coil. Czech. Chem. Comm., 1977.42, 2217 ( a ) F. Rohlmann and N. Le Van, Phyruchemistry, 1977. 16, 1304; ( b ) ibid., p. 487. F. Bohlmann, M. Grenz, and C. Zdero, Phyrochemisrry, 1977, 16, 285. "' S. M. Kupchan, Y. Shizuri, R. L. Baxter. and H. R. Haynes, J. Org. Chem., 1977,42,348. 16* T. Osawa. D. Taylor, A. Sumki, and S. TamUrd, Tefrahedron Letters, 1977. 1169. lb3

L64 165

Terpenoids and Steroids

120

(436)

(437)

0

Interest in the antitumour properties of pseudoguanianolides has led to the discovery of several new biologically active members of this structural group. A comprehensive survey of the cytoxic constituents of Sendai Helenium autumnale plants has resulted in the isolation of 2-methoxydihydrohelenalin (438),169npicrohelenin (439),169bhalshalin (440),169cakihalin (44 and a novel sulphonyl

(438) R1 =Me, R2 = 0 (439) R’ = Ac, R2= H,OH

pseudoguaianolide, sulferalin (442).169cFurther examination of the biologically active extract of Helenium microcephalum has revealed the presence of new antitumour constituents, microhelenin-A (443),l7O” -B (444),170b and -C (445),”Ob as well as the previously known norguaianolide mexicanin-E (446). Other papers in this area report the isolation of carpesiolin (447) from Carpesium abrotanoide~,’~’

(444) R = COC(Me)CH,Me (445) R = COC(Me)=CHMe

(446) 169

170

171

(447)

F. Yoshizaki, Hererocycles, 1976, 5, 373; (b) Y. Kondo, T. Tomimori, N. Hiraga, and T. Takemoto, ibid., 1977, 6, 19; (c) Y. Kondo, F. Yoshizaki, F. Hamada, J. Imai, and G. Kusano, Tetrahedron Letters, 1977, 2 155. ( u ) K. H. Lee, Y. Imakura, and D. Sims, J. Pharm. Sci., 1976,65, 1410; (b) K. H. Lee, Y. Imakura, D. Sims, A. T. McPhail, and K. D. Onan, Phytochemistry, 1977, 16, 393. ( a ) Y. Kondo, F. Hamada, and

M. Maruyama and S. Omura, Phytochemistry, 1977, 16. 7 8 2 .

Sesquiterpenoids

121

2,3-epoxyambrosin (448) from the aerial parts of Ambrosia ~ u m a n e n s i s , 'and ~~ isoguaiene (449) and 11-hydroxyisoguaiene (450) from the roots of Purthenium hysterophorus.17'

0

(449) R = H (450) R = O H

(448)

16 Miscellaneous Norbotryal acetate (451) has been identified as a co-metabolite of botrydial (452) in cultures of the plant pathogen Botrytis cine re^'^^ (cf. Vol. 6, p. 95; Vol. 7, pp. 105, 195). Further examination of the metabolites of Porella species has revealed the presence of the pinguisane derivative (453).'74 It has been that

(452)

(453)

(453) may be a biosynthetic precursor of other pinguisane-type compounds, (454)-(457), produced by this plant. The novel structure of isocomene (458), a

(454) R = M e (455) R = C02Me

(456) R = M e (457) R = C 0 2 M e

(458)

new metabolite of the toxic plant rayless goldenrod (Isocoma Wrightii), has been established by X-ray analysis. 175 The structure (460) previously proposed for albene (cf. Vol. 5, p. 59) has been assigned to a compound whose spectroscopic properties differ from those of authentic albene.'76 Since compound (460) is derived from a thio-ether (459) 17* 173

'71

F. Bohlmann, C. Zdero, and M . Lonitz, Phyfochemisfry, 1977, 16, 575. 0. Cuevas and J . R. Hanson, Phytochemistry. 1977, 16, 1061. Y. Asakawa, M. Toyota, and T. Ahatani, Tetrahedron Letters, 1976, 3619. L.H. Zalkow, R. N. Harris, D. Van Derveer, and J. A. Bertrand, J . C S . Chem. Comm., 1977,456. W. Kreiser, L. Janitschke, and W. S. Sheldrick, J.C.S. Chem. Comm., 1977, 269.

122

Terpenoids and Steroids

whose structure has been confirmed by X-ray analysis, a revised structure has been proposed for albene. Unfortunately this structure and the new evidence in its favour are not provided in this paper.176

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 1977. The value of the I3C n.m.r. correlations recorded in previous years has been demonstrated by the ease with which a number of new structures have been elucidated. The resolving power of high-field (220 and 270 MHz) proton n.m.r. has also been put to good use in some recent structural studies. Marine organisms have continued to afford novel diterpenoids. Progress in this area has been reviewed.’ Some of the new skeleta which have been described are reminiscent of sesquiterpenoids. An interesting review’ describes the detection of diterpenoids in resins used in works of art and in archaeological specimens. A series of phytanylglyceryl ethers has been obtained3 from the lipids of thermoacidophilic bacteria, and geranylgeranylglycerol was detected4 in the brown alga Dilophus fasciola. 2 Bicyclic Diterpenoids

Labdanes.-The configuration at C-13 of the bicyclic diterpenoids has been a problem that has extended over many years. A method of differentiating between manool and 13-epimanool using n.m.r. chiral shift reagents has been d e ~ c r i b e d . ~ Tetrahydroabienol has been shown6 to be a mixture of C-13 epimers. Oxygenation at C-12 is found in some tobacco diterpenoids. The per-acid oxidation of (122)abienol has been used7 in the synthesis of (12R,13R)- and (12S,13S~-8,12epoxylabda- 14-en- 13-01 together with some 8,13-ethers. The cationic cyclization of labda-8(17),12- and labda-8(17),13(16)-dien-14-01~ has been examined* in

’

‘International Symposium o n Marine Natural Products’, Aberdeen, September, 1975, Pure Appl. Chem., 1976,48, 1-44; D. J . Faulkner, Tetrahedron, 1977,33, 1421. J. S. Mills and R. White, Studies in Consemation, 1977, 22, 12. M. de Rosa, S. de Rosa, A . Gambacorta, and J. D. B u ’ h c k , Phyfochemistry, 1976,15, 1995. V. Amico, G . Oriente, M . Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Experientia, 1977, 33, 989. A . H. Connor and J. W..Rowe, Phyfochemistry, 1976,159, 1949. R. M. Carman and G . W. Zerner, Austral. J. Chem., 1976,29,2091. I. Wahlberg, K. Karlsson, T. Nishida, K. P. Cheng, C. R. Enzell, J. E. Berg, and A . M. Pilotti, Acra Chem. Scand., 1977, B31,453. P. Sundararaman and W. Herz, J. Org. Chem., 1977,42,806.

123

124

Terpenoids and Steroids

attempts to synthesize the tricyclic strobane skeleton. However, the A"-isomer (1) gave the tricyclic diterpenoid (2) whereas the products from the A'3"6'-isomer (3) were the compounds (4) and (5). It is interesting that these represent two different modes of cyclization.

Jungermanool (6) is a new labdadienediol which has been isolated' from Jungermania terticalyx. 4-Epi-isocommunic acid [labda-8( 17),13(16),14-trien-18oic acid] has been isolated'' from Callitris rhomboidea (Cupressaceae). A number of Stevia (Compositae) species have been examined" for terpenoids, and cativic acid has been isolated from S. jaliscensis. 6P-Acetoxylabda-8( 17)-en- 15-oic acid has been isolated from Cistus, hirsutus and its structure established" by interrelationship with 6-oxocativic acid. Extraction of the resin of Aruucaria bidwillii has affordedI3 a number of neutral diterpenoids including ent-labda-8,13E-dien15-01 and its 15-acetate, ent-8~,15-dihydroxylabda-13-ene, and both 8a and 8P epimers of methyl ent-8-hydroxylabda- 13-en- 15-oate. Communic acid and 3acetoxylabda-8( 17),13-dien-15-oic acid have been isolated14 from Metasequoia glyptostroboides. The angelate ester (7) of dendroidinic acid has been obtained"

' A. Matsuo, T. Nakamoto, M. Nakayama, and S. Hayashi, Expen'entia, 1976,32,966. lo

l3 l4

J. S. Prasad and H. G. Krishnamurty, Phytochernisfry, 1977,16,801. F. Bohlmann, C. Zdero, and S. Schoneweiss, Chern. Ber., 1976, 109, 3366. J. de Pascual Teresa, J. G. Urones, and A. Montes Sanchez, Anales de Quim, 1976,72,713. R. Caputo, L. Mangoni, P. Monaco, L. Pdosi, and L. Previtera, Phytochemistry, 1976.15, 1401. S. Braun and H. Breitenbach, Tetrahedron, 1977,33, 145.

Diferpenoids

125

from Agerafina dendroides. The unusual seco-9,lO-structure (8) was also proposed for hebeclinolide, a furanoid diterpenoid obtained from another Eupatorium (Compositae) species, Hebeclinium macrophyllum. The 7-galacto-pyranoside of a new diterpenoid triol, acanthospermol (9), has been isolated16 from Acanfhospermum hispidum (Compositae).

d o ,;isI..OH / i O

0.

HO'

'OH

Sideritis (Labiatae) have been a rich source of novel bi- and tetra-cyclic diterpenoids." Andalusol (lo), which has been isolated18 from S. arborescens, was assigned the enf-labdane configuration. Its structure was deduced by a combination of spectroscopic'measurements and an X-ray analysis of the degradation product (11).

Some new diterpenoid oxides have been obtained'' from Eupatorium jhanii. They are jhanol (12) and its 18-acetate together with jhanidiol (13) and its 18monoacetate and diacetate. Their structures were established by correlation with manoyl oxide and by an examination of their 13C n.m.r. spectra. llp-Hydroxymanoyl oxide (14) has been isolated from Juniperus oxycedrus.20 A group of new 11 -oxomanoyl oxide derivatives (1 5 a - e ) has been obtainedz1 from Coleus forskohlii (Labiatae). Their oxygenation pattern is reminiscent of that of the tricyclic diterpenoids which have beecobtained from other Coleus species. Is l6

Is

l9

*"

F. Bohlmann and M. Grenz, Chem. Ber., 1977, 110, 1321. A. G . R. Nair, S. S. Subramanian, F. Bohlmann, S. Schoneweiss, and T. J. Mabry, Phylochemistry, 1976,15, 1776. 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 6, p. 106 and previous volumes. M. Mpez, C. von Carstenn-Lichterfelde, B. Rodriguez, J. Fayos, and M. Martinez-Ripolli, J. Org. Chem., 1977,42,2517. A. G. Gonzalez, J. M. Arteaga, J. L. Breton, and B . M. Fraga, Phytochemistry, 1977, 16, 107. J. de Pascual Teresa, A. San Feliciano, and M. J. Miguel del Corral, Farm. Nueua, 1976, 41, 343 (Chem. Abs., 1977,86,29 949). S. V. Bhat, B. S. Bajwa, H. Dornauer, N. J. de Souza, and H. W. Fehlhaber, Tetrahedron Letters, 1977, 1669.

Terpenoids and Steroids

126

H

(12) R - H (13) R = O H .,,\

(15) a; R' = H, RZ= 0-OH, R3= P-OAc, R4 = H

3$

R?

b; R ' = H , R 2 = R 3 = P - O H , R 4 = H c; R' = a-OH, Rz= P-OH, R3= 0-OAc, R4= OH d; R' = a-OH, Rz= R3 = 0-OH, R4 = OH e ; R' = a-OH, Rz = 0-OAc, R3 = P-OH, R4 = O H

Vitexilactone, obtained from Vitex cannabifolia (Verbenaceae), has been shownz2 to have the structure (16). It has been correlated with rotundifuran. An interesting iron(ir)-catalysed decomposition of unsaturated cyclic peroxides derived from butadienes leadsz3to 3-alkylfurans. This procedure has been used to convert the peroxide (17) from cis-biformene into the furan (18). Some diterpenoid furans arez4 amongst the constituents of Austroeupatorium inulaefolium (Compositae). These include the diketone austrofoiin (19), the corresponding 12-alcohol, and the 15-alcohol (20). A triol, austroinulin (21), was also identified.

a: do

fl H

H

H OAC

(16)

p / O

*' 23

*'

H. Taguchi, Chern. and Pharrn. Bull. (Japan), 1976,24, 1668. J. A. Turner and W. Herz, J. Org, Chem., 1977,42, 1900. F. Bohlmann, C. Zdero, and M. Grenz, Chern. Ber., 1977, 110, 1034.

/I

Y

Diterpenoids

127

The 15,16: 3,18-di-isopropylidene, 15,16-diacetyl, and 16-mono-O-acetyl-3,18isopropylidene derivatives of lagochilin have been isolated2' from Lagochilus pubescens. A number of new diterpenoids have been obtained from Baffota (Labiatae) species. These include ballonigrin (22; R = Hz) and ballonigrinone (22; R = 0) from B. rupestris.26 7a-Acetoxymarrubiin (23) and ballotenol (24) were isolated2' from B. nigra. Their structures were established by examination of their 'H and 13C n.m.r. spectra.

A group of new tetranorditerpenoids (25)-(27) has been isolatedz8 from the metabolites of Acrostafagmus species. They are clearly related to the antifungal antibiotic LL-Z1271a (see p. 147) which has previously been isolated from this fungus. 0

c,.Ilr. CO,H

Clerodanes.-In a study of South African Mucowania species, a cis-clerodane acid (28) and labdanolic acid were obtainedz9from M. glandulosa. Deoxymarrubialactone (29) has been isolated3' from Chaiturus marrubiastrum. Linarienone (30) is another cis-fused clerodane which has been obtained3' from the roots of Linaria japonica (Scrophulariaceae) and correlated with linaridial. The bacchotricuneatins A (31) and B (32) are two new diterpenoid lactones which were isolated3' from Baccharis trkuneata (Astereae) and whose structures were determined by a combination of spectra and X-ray analysis. 25

Z . I. Mavlyankulova, U. N. Zamutdinov, and Kh. A . Aslanov, Khim. prirod. Soedinenii, 1977,46.

'' G . Savona, F. Piozzi, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1977, 322. 27 28

29 30

31

32

G . Savona, F. Piozzi, J. R. Hanson, and M. Siverns, J.C.S. Perkin I, 1977, 497. M. Sat0 and H. Kakisawa, J.C.S. Perkin I, 1976, 2407. F. Bohlmann and C. Zdero, Phytochernistry, 1977,16, 1583. D. P. Popa and L. A. Salei, Khirn. prirod. Soedinenii, 1976,399 (Chem. Abs., 1976,88, 124 188). I. Kitagawa, M. Yoshihara, and T. Kamigauchi, Tetrahedron Letters, 1977, 1221; I. Kitagawa, M. Yoshrhara, T. Tani, and I. Yosioka, Chem. and Phurm. Bull. (Japan), 1976,24,294. H. Wagner, R. Seitz, V. M. Chari, H. Lotter, and W. Herz, Tetrahedron Letters, 1977,3039.

Terpenoids and Steroids

128

AcO

I 0

II

/

/

\

CH,OC C=C Me

Me

H

I

(30)

The ajugarins are a group of trans-clerodanes [I ( 3 3 ) ; I1 ( 3 3 ; 6a-OH);I11 ( 3 3 ; 4a-OH,4/3-CH20H)] which were as insect antifeedants from the leaves of Ajuga remota (Labiatae). Their structures were established by a combination of 'H and I3C n.m.r. studies. Corylifuran, which is a clerodane isolated from Croton corylifolius (Euphorbiaceae), has been assigned34the structure (34) on the basis of an X-ray analysis and a circular dichroism study. Examination of Mallotus repandus (Euphorbiaceae) has afforded35 mallotucin A which is identical with teucrin and the dimethyl ester, mallotucin B ( 3 5 ) . Some further aspects of the chemistry of teucrin A have been described.36 Acid-catalysed cyclization of the pentaol (36), obtained by the reduction of teucrin A with lithium aluminium hydride, affords the cther (37). Teucrin PI, isolated from Teucrium polium (Labiatae), has an interesting structure ( 3 8 ) which is related to this.

: C0,Me

Me0,C

Me0,C

C0,Me

OAc

OAc (33)

(34)

(35)

I. Kubo, Y . W. Lee, V. Balogh-Nair, K. Nakanishi, and A. Chapya, J.CS. Chem. Comm., 1976,949. 34 B. A. Burke, W. R. Chan, E. C. Prince, P. S. Manchand, N. Eickman, and J. Clardy, Tetruhedron, 1976, 32,1881. 35 T. Kawashima, T. Nakatsu, Y. Fukazawa, and S. Ito, Heterocycles, 1976,5, 227. '' A. M. Reinbol'd and D. P. Popa, Khim. prirod. Soedinenii, 1976,752; D. P. Popa, Phan Thug Anh, and L. A. Salei, ibid., 1977, 49. 33

Diterpenoids

129

P O H

'OH

OH

3 Tricyclic Diterpenoids

Naturally Occurring Substances.-Pimara-8(9),15-diene (39) has been detected37 as a metabolite of the fungus Trichothecium roseum. However, it is not an intermediate in the biosynthesis of rosenonolactone. The dihydroxyabietene (40) and its 7a-hydro~y-A~"~'-isomer have been obtained3' from Nepeta granatensis (Labiatae). lsoaplysin-20 (4 l ) is a bromine-containing diterpenoid which has been isofrom the sea-hare, Aplysia kurudai. The location and stereochemistry of the bromine atom suggest that it may play a role in the cyclization stages of the biosynthesis.

& & ,& H I

H

(39)

, H CH20H (40)

H

OH

'CH20H

Br' (41)

A further paper has appeared4' describing salvin and salvin monomethyl ether (42) as antimicrobial substances from Salvia officinalis.Arucatriol(43) and galdosol (44) are related phenolic diterpenoids from Salvia canariensis (Labiatae).41

37 3R

39 40

41

B. Dockerill and J. R. Hanson, J.C.S. Perkin I, 1977, 324. A. G. GonzBlez, J. L. Breton, C. R. Fagundo, and J. M. Trujillo, Anales de Quim., 1976,72,65. S . Yamamura and Y. Terada, Tetrahedron Letters, 1977,2171. V. D. Dobrynin, M. N. Kolosov, B. K. Chernov, and N. A. Derbentseva, Khim. prirod. Soedinenii, 1976,686. A. G. Gonzilez, B. M. Fraga, J. G. Luis, and A. G. Ravelo, Anales de Quim., 1975,71,701.

130

Terpenoids and Steroids

Horminone and the 14-methoxytaxodione (45) have been obtained4' from another Labiate, Hyptis fruticosa. Some more highly oxygenated abietanes have been isolated from Coleus species. Coleon L is a labile diosphenol(46) from Coleus sornaliensis. It rapidly tautomerizes to afford the 6,7-diketone, coleon K. This has led to a revision of the structures of coleons H, I, and 1'. Coleon H is the 15-alcohol corresponding to coleon L whilst coleon I bears the same relationship to coleon K. Coleon I' is the 3-formate. Coleon S (47) and the corresponding diketone, coleon T, have been obtained from Plectrunthus caninus (Labiatae).44 A further paper has appeared45on the diterpenoid quinones of Salvia ballotaeflora, conacytone, icetexone (48), and its ortho-quinone tautomer, romulogarzone. The full paperj6 on the X-ray analysis of icetexone has been published, as has that on the tumour-inhibitory diterpenoids barbatusin and cyclob~tatusin.~~ The unusual C- 1-C- 1 1 four-membered ring of cyclobutatusin can be generated photochemically. Thus irradiation of barbatusin (49) gives48dehydrocyclobutatusin (50).

(46) R' = R2= OAc, R3 = OH (47) R' =OH, R2= R3 = H

The structure ( 51) of a tumour-inhibitory diepoxide, jolkinolide B, isolated from Euphorbia jolkinii, has been established49by X-ray analysis. Three further polar cytotoxic dilactones (52)-(54) have been isolated5' from Podocarpus nagi. Their 42

44

45

46 47

48

49

''

F. Marletti, F. Delle Monache, G. B. Marino-Bettolo, M. do Carmo, M. de Araujo, M. de Salete Barros Cavalcanti, I. L. D'Albuquerque, and 0. GonGalves de Lima, Guzzerra, 1976,106, 119. P. Ruedi and C. H.Eugster, Helv. Chim. Acta, 1977.60, 1233. S . Arihara, P. Ruedi, and C. H. Eugster, Helv. Chim. Acta, 1977,60, 1443. X. A. Dorninguez, F. H. Gonzalez, R. Aragon, M. Gutierrez, J. S. Marroquin, and W. Watson, Plunfa Med., 1976,30,231 (Chem. Abs., 1977,86,21658). Z. Taira, W. H. Watson, and X. A. Dorninguez, J.C.S. Perkin 11, 1976, 1728. R. Zelnik, D. Lavie, E. C. Levy, A. H. J. Wang, and I. C. Paul, Tetrahedron, 1977,33, 1457. R. Zelnik, I. A. McMillan, I. C. Paul, D. Lavia, V.G. Toscano, and R. R. DaSilva, J. Org. Chem., 1977, 42,923. D. Uemura, C. Katayama, and Y. Hirata, Tetrahedron Letters, 1977,283. Y. Hayashi, Y. Yuki, T. Matsurnoto, and T. Sakan, Tetrahedron Letters, 1977,2953.

Diterpenoids

131

structures were established by a careful analysis of their ‘H n.m.r. spectra. An X-ray analysis has been published5’ of a related dilactone, inumakilactone D (55).

OH

co-0

co-0 0

OH

co-0

co-0 (55)

(54)

The momilactones are a group of growth inhibitors which have been isolated from rice husks. X-Ray analysis of momilactone C (56)” and of annonalide (57) ~~ the unusual 9-PH stereochemistry. (from Annona c o r i ~ c e a ) established Annonalide has been converted into momilactone B (58). Momilactone A has the

(56)

(57)

(58)

stereochemistry (59). A number of chemical transformations of the momilactones have been de~cribed,’~ including the retro-aldol cleavage of ring A of momilactone B to afford compounds such as (60). Ineketone (61) is another growth and germination inhibitor of rice. It has been assigned” the unusual rearranged structure with a A*(14)-do~ble bond. The metabolites of Acrernoniurn luzulue (Oosporu uirescens), virescenosides D and H,

** 53 54

55

M.Kodarna, C. Kabuto, M. Sunagawa, and S. Ito, TetrahedronLetters, 1977, 2909. M. Tsunakawa, A . Ohba, N. Sasaki, C. Kabuto, T. Kato, Y. Kitahara, and N. Takahashi, Chem. Letters, 1976, 1157. F. Orsini, F. Pellizoni, A. T. McPhail, K. D. Onan, and E. Wenkert, TetrahedronLetters, 1977, 1085. T. Kato, H. Aizawa, M. Tsunakawa, N. Sasaki, Y. Kitahara, and N. Takahashi, J.C.S. Perkin I, 1977, 250. T. Kato, M. Tsunakawa, N. Sasaki, H. Aizawa, K. Fujita, Y. Kitahara, and N. Takahashi, Phytochemistry, 1977,16,45.

132

fl

HO'. ,..

co-0

Terpenoids and Steroids

o

.


o

(59)

p

o

(60)

$ OH

(61)

are56 the 4-deoxy-P-~-threohex-4-enodialdopyranosideand 4-deoxy-P-~threohex-4-enopyranoside respectively of virescenol B. Virescenols E and L are similar and possess virescenol A as the aglycone. Chemistry of the Tricyclic Diterpenoids.-The acid-catalysed rearrangements of the tricyclic diterpenoids have continued to attract attention. Treatment of abietic acid with fluorosulphonic acid at -40 "C afford?' the C , , trienes (62) and (63). In an extension of some previous work, the rearrangement of some 8cr,9a-epoxypodocarpanoic acid derivatives to rosanes has been examined.58 An unusual remote oxidation has been observed5' in the iron(n)-catalysed decomposition of a ring c epidioxide. The epidioxide (64), obtained from methyl levopimarate, gave inter alia the transannular ether (65) and the olefin (66). These epoxy-epidioxides undergo6' easy decomposition on silica to the y-hydroxy-a#-epoxy-ketones [e.g.

(6711.

I

I

(6.9

(66)

(67)

Ozonolysis of dehydroabietic acid has been used6' to give keto-esters such as (68) which have been converted into sesquiterpenoid drimane derivatives. An 56

57 58 5y

61

N. Cagnoli-Bellavita, P. Ceccherelli, M. Ribaldi, J. Polonsky, Z . Baskevitch-Varon, and J. Varenne, J.C.S. Perkin I, 1977, 351; Garzetta, 1977, 107,51. D. G. Farnum and R. A. Mader, J. Org. Chem., 1977,42, 214. W. S. Hancock, L. N. Mander, and R. A. Massey-Westropp, Austraf. J. Chem., 1977,30, 1093. W. Herz, R. C. Ligon, J . A . Turner, and J. F. Blount, J. Org. Chem., 1977, 42, 1885. J. A. Turner and W. Herz, J. Org. Chem., 1977,42, 2006. H. Akita, K. Mori, and A . Tahara, Chem. and Pharm. Buff.(Japan), 1977, 25, 974.

Diterpenoids

133

interesting approach62 towards the synthesis of 11,14-dimethoxypodocarpicacid derivatives from podocarpic acid itself utilizes the cleavage of ring B. BaeyerVilliger oxidation of 7-ketones (69), hydrolysis to (70), and cyclization afford the methyl ester of 11,14-dimethoxypodocarpicacid (7 1). This relationship between the ring c oxygen atoms is found in many of the more highly oxygenated diterpenoids.

C0,Me

OMe

(701

Various tricyclic diterpenoids have been terolemic action in test animals.

(71)

to possess a hypocholes-

4 Tetracyclic Diterpenoids

Naturally Occurring Substances.-Beyeria (Euphorbiaceae) species have been the source of a number of tetracyclic diterpenoids. Some of these were new or poorly defined species and their classification has now been clarified.64 The presence of ent-kaurenal has again been recorded in Fusarium rn~noliforme,~~ whilst ent-kaur16-en- 19-oic acid (72) has been isolated66 from Mikania hirsutissima (Compositae). Microbiological hydroxylation of ent-kaur-16-en-19-oic acid by Cunninghamella blakesleana affords6' the 7P-hydroxy-, 16a-hydroxy-, 16,17dihydroxy-, and 7P, 16a-dihydroxy-derivatives. The angelic acid ester of ent-15Phydroxykaur-16-en- 19-oic acid (73) and its 16,17-epoxide (perymenic acid) have been obtained6' from Perymenium ecuadoricum (Compositae). A group of

64 65

66

67 68

S. W. Pelletier and Y. Ohtsuka, Tetrahedron, 1977,33, 1021. H. Enomoto, Y. Yoshikuni, Y. Yasutomi, K. Ohata, K. Sempuku, K. Kitaguchi, Y. Fujita, and T. Mori, Chem. and Pharm. Bull. (Japan), 1977,25,507. S. G. Errington, E. L. Ghisalberti, and P. R. Jefferies, Austral. J. Chem., 1976,29, 1809. V. A. Rdldugin and V. A. Pentegova, Khim. prirod. Soedinenii, 1976, 821. J. Muradian, M. Motidome, P. C. Ferreira, and R. Braz Filho, Reu. Lafinoamer. Quim., 1977, 88 (Chem. Abs., 1977,86, 156 028). N. A. El-Emary, G. Kusano, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1976,24, 1664. F. Bohlmann and C. Zdero, Phyrochemistry, 1977,16, 786.

134

Terpenoids a n d Steroids

kaurene acids has been detectedh9in Wedelia (Compositae) species. These include the angelate, tiglate, cinnamate, and senecioate esters of ent-3a-hydroxykaur- 16-en- 19-oic acid (74), the 15-cinnamate, tiglate, senecioate, and epoxyangelate esters of ent- 15P-hydroxykaur- 16-en- 19-oic acid (73), and the unusual 9p-hydroxy-acid (75).

CO,H (72) R' = R*= H

CO,H (75)

(73) R ' = H, R2 = OH (74) R' = O H , R' = H

A number of kauranoid diterpenoids have been isolated from the liverworts. (16R)-ent-Kauran-15-0ne, ent-1 Sa-hydroxykaur- 16-ene, and the corresponding 15-ketone have been isolated'' from the liverwort Jungermannia infusca and (16R)-ent-18-hydroxykauran-15-one,ent-kaur-16-en-18-oic acid, and ent-1 l a hydroxykaur- 16-en- 15-one have been found7' in another species, Porella densifolia. The full paper on the crystal structure of ent-1 la,l5a-dihydroxykaur-16ene, which has been obtained from Jungermannia sphaerocarpa and Solenostoma trista, has appeared.72 The South American shrub Sfevia rebaudiana (Compositae) has received considerable attention as a new source of natural sweetening agents. Two further groups of glycoside, the d u l ~ o s i d e sand ~ ~ r e b a u d i ~ s i d e s ,have ~ ~ been isolated. In each case steviol is the aglycone. Microlepin and 16-epimicrolepin, from Microlepia marginata, are75 ent- 16a,17,19-trihydroxykauran- 19-p-(4-O-methyl-glucoside) and its 16-epimer. Cofaryloside (76) is a 9P-hydroxykauran- 19-oic acid derivative which has been obtained76 from green coffee beans. Coffee 'atractyloside' is the 2-O-(3-O-~-~-glucopyranosyl-2-O-isovaleryl-~-~-glucopyranoside) of actractyligenin (77).77 Atracyloside itself has been detected78as the toxic principle in Callilepsis laureola (Compositae), which has occasionally been used as an (unsuccessful) herbal medicine. Epoxyisofoliol (78) has been obtained79 from Sideritis paulii and its 3-acetate, epoxyisosidol, is one of a series of acetates of enf-36,7a, 18-trihydroxykaur- 15- and 6y

70 71

72

73

74

75

76

77 78 7y

F. Bohlmann and Ngo Le Van, Phytochemisfiy, 1977,16,579. A. Matsuo, J. Kodoma, M. Nakayama, and S. Hayoshi, Phytochemistry, 1977,16,489. A. Matsuo, S. Uto, M. Nakayama, and S. Hayashi, Chem. Letters, 1977, 327. M. Przybylska and F. R. Ahmed, Acta Cryst., 1977, B33, 366. M. Kobayashi, S. Horikawa, I. H. Degrandi, J. Ueno, and H. Mitsuhashi, Phytochemistry, 1977, 16, 1405. I. Sakamoto, K. Yamasaki, and 0. Tanaka, Chem. and Pharm. BUN.(Japan), 1977,25,844. N . Tanaka, M. Hasegawa, T. Murakami, Y. Saiki, and C. M. Chen, Chem. and Pharm. Bull. (Japan), 1976,24,2891. H. Richter, H . Obermann, and G . Spiteller, Chem. Ber., 1977,110, 1963. H. Obermann and G. Spiteller, Chem. Ber., 1976, 109, 3450. H. A. Candy, K. H. Pegel, B. Brookes, and M. Rodwell, Phytochemistry, 1977,16, 1308. B. Rodriguez and S. Valverde, Anales de Quim., 1976,72, 189,

Diterpenoids

135

-16-enes which have been isolated" from S. biflora. The Greek Sideritis species S. euboea, S. roeseri, S. distans, and S. syriaca contain" the knowns2 Sideritis diterpenoids siderol, epoxysiderol, isolinearol, sideridiol, epoxyisolinearol, and sideroxol. The diterpenoids of Isodon (Labiatae) species have been re~iewed.'~The presence of an a-methylenecyclopentanone moiety in these diterpenoids is important for their anti-tumour and anti-bacterial a~tivity.'~Inflexin (79) is a cytotoxin and insect antifeedant which has been isolated" from Isodon infiexus. Isodomedin (80) is another member of this series, isolateds6 from I. shikokianus, which shows this type of biological activity. Its structure was assigned on the basis of its 'H and 13C n.m.r. spectra and on an interrelationship with kamebanin (81), isolateds3 from I. kameba.

(79)

(80) R = O A c (81) R = H

ent-Beyeren-19-oic acid, its ent-3P-tiglate, and the corresponding A9(l')unsaturated acid have been obtained8' from Dimorphotheca aurantiaca (Compositae). The 19-aldehyde and alcohol were obtained from another species, D. pseudoaurantiaca. Viguera stenoloba contains ent-kaur-16-en-19-oic acid and its 15aangelate, tiglate, senecioate, and isovalerate. Maritimol (82) and stemodinol (83) are two unusual tetracyclic diterpenoids which have been isolated8' from Stemodia maritima. 80 81

82 83 84

85 86

87 88

M. Garcia-Alvarez and B. Rodriguez, Phytochemistry, 1976,15, 1994. A. Bellino and P. Venturella, Fitoterapia, 1977,48, 3. P. Venturella, A. Bellino, and F. Piozzi, Phytochemistry, 1975, 14, 1451. E. Fujita, Y. Nagao, and M. Node, HeteroLycles, 1976,5, 793. E. Fujita, Y. Nagao, K . Kaneko, S. Nakazawa, and H. Kuroda, Chem. andPhorm. Bull., (Japan), 1976, 24, 2118. I. Kubo, K. Nakanishi, T. Kamikawa, T. Isobe, and T. Kubota, Chem. Letters, 1977, 99. I. Kubo, I. Miura, K Nakanishi, T. Kamikawa, T. Isobe, and T. Kubota, J.C.S. Chem. Comm., 1977, 555. F. Bohlmann, C. Zdero, and P. Mahanta, Phytochemistry, 1977,16, 1073. C. D. Hufford, 0. R. Guerrero, and N. J. Doorenbos, J. Pharm. Sci., 1976,65,778.

Terpenoids and Steroids

136 OH

R’=OH, R2 = H ( 8 3 ) R’ = H, R2 =OH

(82)

Chemistry of the Tetracyclic Diterpenoids-The transannular hypoiodite reactions of 6-hydroxy- 17-norkauranes have been studieds9 with the object of functionalizing the methyl groups of ring A. Whereas the 6a-alcohols afford the 6-20 ethers, the 6P-alcohols produce substitution at C-19. A further detailed study of the ring contraction of kauranolides to form gibberellanes has been made.90The results were rationalized in terms of the shape of ring B and the need for the C-5-C-6 bond and the C-7-0 bond to adopt an antiperiplanar conformation. A full paper describing the detailed chemistry involved in the conversion of enmein into gibberellins AI5and A3, has appeared.” Since an intermediate in this partial synthesis has been the subject of a total synthesis, this work constitutes a formal total synthesis of these gibberellins. The functionalization of C-1 1 through transannular C-1 1--C-17 ether formation involving the oxidation of a 17-alcohol with lead tetra-acetate has been described.92 The oxidative rearrangement of en?-17-norkauran-16-one (84)with thallium(rI1) nitrate leads to compounds possessing the en?-9(8- 15aH)-abeokaurane skeleton [e.g. (85>].93

I3C N.m.r. spectroscopy has played a major role in structural determination in the diterpenoid series. Some further compounds in the beyerene (stachene) series have been examined94and the substituent effects have been rati~nalized.’~ 89 90 91

92

93

94

95

M. Node, H. Hori, and E. Fujita, Chem. and Pharm. Bull. (Japan),1976,24,2149. M . Node, H. Hori, and E. Fujita, J.C.S. Perkin I, 1976, 2144. E. Fujita, M. Node, and H. Hori, J.C.S. Perkin f, 1977, 611. N. Fukuzawa, N. Funamizu, Y . Kitahara, and T. Kato, Chem. Letters, 1976, 1253. E. Fujita and M. Ochiai, J.C.S. Perkin I, 1977, 1182: T. Taga, T. Higashi, H. Iizuka, K. Osaki, M. Ochiai, and E. Fujita, ACIUCrysr., 1977, B33, 298. A. A. Chalmers, C. P. Gorst-Allman, and L. P. L. Piacenza, Tetrahedron Letters, 1977, 1665. C. von Carstenn-Lichterfelde, C. Pascaul, R. M. Habanal, B. Rodriguez, and S. Valverde, Tefiahedron, 1977,33, 1989.

137

Diterpenoids

Gibberellins.-A collection of reviews, mainly of a biological character, concerning the gibberellins has appeared.96 The A15(16)-isomerof gibberellin A, has been detected,' in Picea sitchensis. Gibberellin A,, (86) is formed,' from gibberellin A, in Gibberella fujikuroi. Gibberellins A,, (87), A,, (88), and A4, (89) and a new kaurenolide, 7p,12a-hydroxykaurenolide (90), have been isolated99 from Cucurbita pep0 and their structures proven. Gibberellins A1,, AZ5,and A45 have been identified'"" by g.c.-m.s. in Pyrus communis (pear) seed. 16,17-Dihydroxygibberellin A, is formed'"' from gibberellin A, in chloroplast sonicates of Pisum sativum.

HO CO,H

co-0 (88) R=P-OH,(Y-H (89) R = (Y-OH,P-H

(90)

A number of [2+ 21 adducts across the A''2'-double bond of gibberellic acid have been briefly described. The full paper on their X-ray structure has now appeared. Gibberethione, which has been regarded as a possible gibberellin deactivation product, has been preparedlo3from gibberellic acid by the addition of thiopyruvic acid to the AI-3-ketone. Papers have appeared describing the prepand of gibberellin A,.1o5A aration of trititiated gibberellins AZ0,A5, and number of gibberellin glucosides have been isolated and now the partial synthesis of 3 - 0 - and 13-0-glucosyl derivatives of gibberellic acid has been described. lo6 96

97 98

99

loo lo' lo*

Io3 Io4 Io5

'06

'Gibberellins and Plant Growth', ed. H. N. Krishnamoorthy, Wiley-Eastern, Delhi, 1975. R. Lorenzi, P.F. Saunders, J. K. Heald, and R. Horgan, Plant Sci. Letters, 1977,8, 179. A. G. McInnes, D. G. Smith, R. C. Durley, R. P. Pharis, G. P. Arsenault, J. MacMillan, P. Gaskin, and L. C. Vining, Canad. J. Biochem., 1977,55, 728. H. Fukui, K. Koshimizu, S. Usuda, and Y. Yamazaki, Agric. and Biol. Chern. ( J a p a n ) , 1977,41, 175; H. Fukui, R. Nemori, K. Koshimizu, and Y. Yamazaki, Agric. andBioZ. Chem. ( J a p a n ) , 1977,41, 181. G. C. Martin, F. G. Dennis, P. Gaskin, and J. MacMillan, Phytochemistry, 1977,16, 605. I. D. Railton, 2. Ppanzenphysiol., 1977, 81, 323. L. Kutschabsky, G. Reck, B. Voigt, and G. Adam, Tetrahedron, 1976, 32,2021. T. Yokota, H. Yamane, and N. Takahashi, Agric. and Biol. Chem. ( J a p a n ) , 1976, 40, 2507. N. Murofushi, R. C. Durley, and R. P. Pharis, Agric. and Biol. Chem. ( J a p a n ) , 1977,41, 1075. T. Yokota, D. R. Reeve, and A. Crozier, Agric. and Biol. Chem. ( J a p a n ) , 1976,40,2091. G. Schneider, G. Sembdner, and K. Schreiber, Tetrahedron,1977,33, 1391.

138

Terpenoids and Steroids

The preparation of a number of gibberellic acid amino-acid conjugates has also been described.lo7 Another chemical conversion of gibberellin A,, into gibberellin A, through the oxidative decarboxylation of the C-20 carboxy-group with lead tetra-acetate has been reported.'" Photolysis of the methyl ester of the isogibberellin (91) (gibberellin C) p r o c e e d ~ " ~through a Norrish Type I cleavage to afford a secoaldehyde which then undergoes an intramolecular [2 + 21 cycloaddition to give the oxetan (92).

HO CO,Me

C0,Me

In continuation of previous work, the reactions of gibberellin A, and A, with neutral manganese dioxide have been examined.'" The products include those of decarboxylation and of lactonization on to C-15. The full paper describing the interesting bridgehead C- 13 fluorination of gibberellins with fluoramine has appeared."' A number of papers on the biological activity of gibberellins and their derivatives have appeared."' The stimulation of plant mRNA synthesis by gibberellic acid has been noted.'I3 A review of some aspects of gibberellin biosynthesis has been p~b1ished.l'~ The origin of both the oxygen atoms of the lactone ring of the C,, gibberellins lies in the C-19 carboxy-group of the Cz0 precursor^.^'^ There was no loss in " 0 content when gibberellin A,, alcohol (93), labelled in the 19-carboxy-group, was fed to Gibberellafujikurui, and the C,, gibberellins, such as gibberellic acid, were isolated. The metabolism of a number of gibberellins by higher plants has been studied. The content of endogenous gibberellins in higher plants changes during seed development, maturation, and germination.l16 Gibberellins A,, A,, A5, and A,, were fed to immature bean seeds for 3 and 10 day periods. Gibberellin A, (94) was converted by hydroxylation at C-13 into gibberellin A, (95) and thence by hy-. droxylation at C-2 into gibberellin A, (96) whilst gibberellin A,, (97) was con'07

'08

'09

'lo 'I'

'''

'I6

M. Lischewski and A . Guenter, 2. Chem., 1976,16,357; G. Adam, M. Mischewski, F. J. Sych, and A. Ulrich, Tefruhedron, 1977, 33, 95. N. Murofushi, I. Yamaguchi, H. Ishigooka, and N. Takahashi, Agric. and Biol. Chem. ( J u p n ) , 1976, 40,247 1 . G. Adam and T. V. Sung, Tetrahedron Leffers,1976,3989. E. P. Serebryakov and V. F. Kucherov, Tetrahedron, 1976,32, 2599. R. E. Banks and B. E. Cross, J.C.S. Perkin I, 1977, 512. G. V. Hoad, R. P. Pharis, I. D . Railton, and R. C. Durley, PZuntu, 1976,130, 113; S. Okuda, S. Sanai, Y. Kimura, S. Tamura, and A. Tahara, Agric. and Biol. G e m . (Japan), 1976, 40, 1327; T. W. A . Jones, PhyfochemDtry, 1976,15, 1825. L. D . Wasilewska and K. Kleczkowska, European J. Biochem., 1976,66,405. J. R. Bearder and V. M. Sponsel, Biochem. SOC.Trans., 1977,5,569. J. R. Bearder, J. MacMillan, and B. 0. Phinney, J.C.S. Chem. Comm., 1976, 834. H. Yamane, N. Murofushi, H. Osada, and N. Takahashi, Phytachemistry, 1977,16,831; I. Yamaguchi and N. Takahashi, Plunf Cell Physiol., 1976,17,611.

Diterpenoids

139

verted into gibberellins A, (95), A, (96), and A,, (98). Gibberellin was only converted into the glucosyl ester as the seed matured. Gibberellin A, (94) was also converted"' into gibberellins A, (95) and A34(99) by the germinating pollen of Pinus attenuata.

(93)

(94) R'

= R3= H, R2 = OH K' = H, R2 = R3 = OH (96) R' = R2= R3= OH (97) R' = R2 = H, R3= OH (98) R' = OH, R2 = H, R3=OH (99) R' = R2 = OH, R3 = H

(95)

Grayanotoxim-Pieris japonica (Ericaceae) contains a number of diterpenoid toxins. An X-ray analysis of pieristoxin G (100) has been published'18 and the structures (101)-(103) have been assigned''' to asebotoxins VI, VIII, and IX respectively.

HO OH

Diterpenoid Alkaloids.-The structure and synthesis of the diterpenoid alkaloids have been reviewed.I2' The subject is also covered in detaiI in the Specialist Periodical Report o n the Alkaloids. A number of new alkaloids with the entkaurene skeleton have been isolated from Anopterus glandulosus and A. macleayanus. The structure of the major alkaloid anopterine (104) was assigned121 A. Kamienska, R. C. Durley, and R. P. Pharis, Plant Physiol., 1976, 58, 68. H. Fukuyama, T. Tsukihara, Y. Katsube, M. Katai, and H. Meguri, Chem. and Pharm. Bull. (Japan), 1976,24277'5.

I2O

12'

H. Hikino, M. Ogura, S. Fushiya, C. Konno, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1977, 25, 523. S. W. Pelletier and S. W. Page, in 'Alkaloids', ed. K. Wiesner, MTP International Review of Science, Organic Chemistry Series Two, Vol. 9 , Butterworths, London, p. 53. N. K. Hart, S. R. Johns, J. A. Lamberton, H . Suarcs, and R. I. Willing, Austral. J. Chem., 1976, 29, 1295.

Terpenoids and Steroids

140

on the basis of chemical and spectral studies and an X-ray analysis of the methiodide of anopteryl alcohol tetra-acetate. Minor alkaloids include"' anopterimine (1 OS), its N-oxide, and some alkaloids with additional hydroxy-groups at C-1 or C-3. 0

II

0-c-c=c

OR

/

H

Me

\

( 104) R = C-C=C

II

0

/Me 'H

The isomerization of atisine to isoatisine and the conformational analysis of rings E and F of atisine, veatchine, and related alkaloids have been by 13C n.m.r. spectroscopy. 12-0-Acetylnapelline is a new alkaloid which has been isolatedIz5from Aconitum karakolicum. The alkaloids of Delphinium staphisagria have been reviewed.'26 Delphidine has been shown to possess the structure ( 106)127whilst delphirine (107) possesses the unusual C- 1 hydroxy-group."* Staphigine and staphirine are bisditerpenoid alkaloids which have been ~ b t a i n e d "from ~ D . staphisagria. Examination of D. tricorne a f f ~ r d e d ' ~a" new alkaloid tricornine (108) which was shown to be 18-acetyl-

R2

(106) R' = a-OH, R' = OMe, R3 = H, R4 = OAc, R5=OH (107) R' = p-OH, R2 = OMe, R3 = H, R4= OH, R5 = OH (108) R' = H, R2= OAc, R3 = R4= OH, R5= OMe (109) R' = p-OMe, R2 = o-02CC6H4NHAc,R3 = R4 = R5= OH

lZ3 124

12'

'26

'21

'"

N. K. Hart, S. R. Johns, J. A. Lamberton, H. Suares, and R. A. Willing, Austral. J. Chem., 1976,29, 1319. S. W. Pelletier and N. V. Mody, Tetrahedron Letters, 1977, 1477. S. W. Pelletier and N. V. Mody, J. Amer. Chem. SOC.,1977,99, 284. M. N. Sultankhodzhaev, L. V. Beshitaishvili, M. S. Yunusov, and S . Yu. Yunusov,. Khim prirod. Soedinenii, 1976, 681. S. W. Pelletier and N. V. Mody, Heterocycles, 1976,5, 771. S. W. Pellktier, J. K. Thakkar, N. V. Mody, Z . Djarmati, and J. Bhattacharyya, Phytochemistry, 1977, 16, 404. S. W. Pelletier and J. Bhattacharyya, Tetrahedron Leners, 1976, 4679. S. W. Pelletier, N. V. Mody, Z. Djarmati, and S. D. La@, J. Org. Chem., 1976, 41, 3042. S. W. Pelletier and J . Bhattacharyya, Phytochemistry, 1977,16, 1464.

Diterpenoids

141

lycoctonine. A 'T n.m.r. study of delsemine, previously isolated from D. semibar' it was a mixture of bases arising from batum and D. tricorne, ~ h o w e d ' ~that methyl-lycaconitine during work-up. An alkaloid isolated'32from D. dictyocarpum is N-acetyldelectine (109). Veratroylpseudoaconine, pseudoaconitine, and indaconitine have been from Aconiturn falconeri. Bishaconitine, previously isolated from this source, is probably a mixture. Two novel alkaloids, falaconitine (110) and mithaconitine (1 1 l), are the first naturally occurring members of this series with an 8(15)-double Umbrosine, from A. unbrosurn, has been assigned135the structure (1 12).

& ---.-.

,OMe

Me

-------

L- -N HO-'

H a OMe OMe (110) R = veratroyl (111) R = benzoyl

OMe (112)

5 Macrocyclic Diterpenoids and their Cyclization Products Incensole (113) and isoincensole oxide (114) have been ~ y n t h e s i z e dfrom ' ~ ~ mukulo1 by methods which allow the determination of their stereochemistry. The X-ray analysis of a thunbergadienediol (115), obtained from Greek tobacco, has been described.13'

A large number of cembrane diterpenoids have been obtained from marine organisms, particularly soft corals. 2-Hydroxynephthenol (116) was isolated138 from Litophyton uiridis. A dehydro-derivative (117) of epoxynephthenol was S. W. Pelletier and J. Bhattacharyya, Tefmhedron Letters, 1977, 2735. B. T. Salimov, M. S. Yunusov, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1977, 128. 133 S. W. Pelletier, N. V. Mody, and H. S. Puri, Phytochernistry, 1977,16, 623. 134 S. W. Pelletier, N. V. Mody, and H. S. Puri, J.C.S. Chern. Comm., 1977, 12. 135 V. A. Tel'nov, N. M. Colubev, and M. S. Yunusov, Khim. prirod. Soedinenii, 1976, 675. 136 T. Kato, C. C. Yen, T. Uyehara, and Y. Kitahara, Chem. Letters, 1977, 565. 13' A. J. Aasen, A. Pilotti, C. Enzell, J. E. Berg, and A. M. Pilotti, Actu Chem. Scund., 1976, B30,999. 13' B. Tursch, J. C. Braekman, and D. Daloze, Bull. Soc. chim. belges, 1975,84, 767. 13' 13'

Terpenoids and Steroids

142

isolated'39 from a Surcophyton species and its structure established by X-ray crystallography. Lobolide (118) was obtained14' from a Lobophytum species. The full paper o n the X-ray analysis of lobophytolide (119) has appeared.14' The structure and absolute configuration of sinulariolide (120) have been dete~mined.'~' 6-Hydroxysinulariolide (1 12) and 11-dehydrosinulariolide (122) are minor diterpenoids of the soft coral S i n u l a r i ~ ~ e x i b i l i sAsperdiol(l23) .'~~ is a marine anticancer agent which has been isolated'44 from the gorgonians Euniceu asperulu and E. toumeforti. Its structure was established through an X-ray analysis.

@

R2 (120) R' =@-OH,R2 = H (121) R' = R2 =,f-OH (122) R ' = O , R = H

mm

The oxidation of various cembrane diterpenoids by chromium trioxide has been noted.145 The full paper on the X-ray analysis of ovatodiolide and ovatodiolic acid has appeared.'46 Detailed n.m.r. studies have led147to the structures (124)-(127) K'0 0

OH

-'.O

(124) R' =cinnamate;'R2 = CH20H (125) R' = cinnamate, R2 = Me '31

14' '41 143 144

145 146

'41

R2 (126) R' (127) R'

= H,

RZ= 0 R2= H,OH

= Ac,

J. C. Coll, G. B. Hawes, N. Liyanage, W. Oberhansli, and R. J. Wells, Austral. J. Chem., 1977, 30, 1305. Y. Kashman and A. Groweiss, Tetrahedron Letters, 1977, 1159. R. Karlsson, Acta Cryst., 1977, B33, 2032. R. Karlsson, Actu Cryst., 1977, B33, 2027. M. Herin and B. Tursch, Bull. SOC.chim. belges, 1976,85, 707. A. J. Weinheimer, J. A. Matson, D. van der Helm, and M. Poling, Tetruhedron Letters, 1977, 1295. V. A. Raldugin, V. K. Fedorov, and V. A. Pentegova, Khim. prirod. Soedinenii, 1976, 313. R. Toubiana, M. J. Toubiana, A. T. McPhail, R. W. Miller, and K. Tori, J.C.S. Perkin II, 1976, 1881. D. Uemura, K. Nobuhara, Y. Nakayama, Y. Shizuri, and Y. Hirata, Tetrahedron Letters, 1976 4591

Diterpenoids

143

respectively for a group of new lathyrane diterpenoids, jolkinols A, B, C, and D, which were isolated from Euphorbia jolkini. The toxic and irritant diterpenoid constituents of the Euphorbiaceae have continued to attract attention.'48 A combined t.1.c.-m.s. technique for the identification of these inflammatory toxins has been described.'49 Ingenol has been detected'" in the latex of Euphorbia seguieriana. The 12-0-isobutyl-13-acetoxy20-angelate (128) of phorbol has been i ~ o l a t e d ' ~from ' the latex of E. frankiana and E. coerulescens and some aromatic esters of 12-deoxyphorbol (129) and proresiniferatoxin (130)were found'52 in E. poisonii. The same latex afforded'" the candletoxins A and B which are esters of 12-deoxy-16-hydroxyphorbol.The former is the 13-phenylacetatc-16-a-methylbutyrate-20-acetate(131) and the a latter is the C-20 desacetyl derivative. The latex of E. tirucalli ~ontains"~.'~' series (132)-(140) of highly unsaturated esters of phorbol and 4-deoxyphorbol together with some 3-0-acylingenol derivatives esterified with the same unsaturated fatty acids.

8' "OCAr 0 CH ,OC Ar

I1

CH,0R4

0

20

( 1 30)

(128) (129) (13 1) (132) (133) (134) (135) (1 36) (137) (138) (139) (140)

R' = 02CCH2Pri,R2 = OAc, R3 = H, R4 = OAng, R5= O H R' = H, R2 = OzCAr, R3= R4= H, R5 = OH R' = H, Rz= 02CAr, R3= 02CBu",R4 = Ac, R5 = OH R' = O,C(CH=CH),CH,CH,Me, R2 = OAc, R3 = R4 = R5 = H R' = OAc, R2 = O2C(CH=CH),CHZCHzMe,R3= R4= R5= H R' = OAc, R2 = 02C(CH=CH)5CH2CH2Me,R3 = R4 = R5= H R' = OAc, R2 = 02C(CH=CH)4(CHz)4Me,R3= R4= R5= H R' = 02C(CH=CH)ZCH2CH2Me, R2 = OAc, R3 = R4 = H, R' = OH R' = 02C(CH=CH)3CH2CH2Me, R2= OAc, R3= R4 = H, R5 = OH R' = OZC(CH=CH),CH2CH2Me,R2 = OAc, R3= R4 = H, R5 = OH R' = OzC(CH=CH),(CH2),Me, R2 = OAc, R3 = R4 = H, R5= OH R' = OAc, R2 = 02C(CH=CH)5CH2CH2Me,R3 = R4 = H, K' = OH

Odoracin (141) is an insecticidal constituent of Daphne odora which contains an unusual deca-2,j-dienoate ortho-ester function. ' 5 6 Gnidilatidin (142) and gnidi14R 149

Y. Hirata, Pur Appl. Chem., 1975, 14, 175. F. J. Evans, R. J. Schmidt, and A. D. Kinghorn, Biomed. Mass Specfromefry, 1975,2,126 (Chem. A h . ,

1976,85, 143 324). R. R. Upadhyay, M. H. Zarintan, and M. Ansarin, PIunru Med., 1976,30, 196 (Chem. A h . , 1976,85, 139 787). Is' F. J. Evans, Phyfochemistry, 1977,16, 395. Is* R. J. Schmidt and F. J. Evans, Phytochemistry, 1976,15, 1778. 1 5 3 R. J. Schmidt and F. J. Evans, Experienfiu, 1977, 33, 1197. G. Furstenberger and E. Hecker, Tetrahedron Leffers, 1977,925, "'G. Furstenberger and E. Hecker, Exprienfia, 1977, 33, 986. S. Kogiso, K. Wada, and K. Munakata, Agric. and Bid. Chem. ( J u p n ) , 1976,40, 21 19. ''O

Terpenoids and Steroids

144

glaucin (143) are antileukaemic diterpenoid esters which have been obtained'" from Gnidia lutifolia and G. glaucus (Thymelaceae). Gnidimacrin (144) and its C-20 palmitate are related macrocyclic esters which were isolated from G. subcorduta. Their structures were established'" by X-ray analysis. A novel diterpenoid hydrocarbon, flexibilene (1 45), possessing a 15-membered ring has been from the soft coral Sinuluriu flexibilis.

Me

(141) R' = (CH=CH),(CH,),Me, R2 = 02CPh, R3 = H (142) R' = (CH2),Me, R2 = 02CPh, R3= 02C(CH ) Me (143) R' = (CH=CH),(CH,),Me, R2= O,CPh, R3b402C(CH2)14Me

6 Miscellaneous Diterpenoids Investigations into marine organisms have led to the isolation of a number of new skeletal types of diterpenoid. Some of these are prenylated relatives of sesquiterpenoid skeleta. Thus dilophol (146), obtainedI6' from the brown alga Dilophus ligulatus, has a ten-membered ring which is reminiscent of a germacrene. The unusual structures of dictyoxepin (147) and dictyolene (148) from Dicfyotu ucutibola were detennined161by X-ray analysis. lS7

lSR

lS9

'"

S. M. Kupchan, Y. Shizuri, W. C. Sumner, H. R. Haynes, A. P. Leighton, and B. R. Sickles, J. Org. Chem., 1976,41,3850. S. M. Kupchan, Y. Shizuri, T. Murae, J. G. Sweeny, H. R. Haynes, M. S. Shen, J. C. Barrick, R. F. Bryan, D. van der Helm, and K. K. Wu, J. Amer. Chem. Suc., 1976,98,5719. M. Herin, M. Colin, and B. Tursch, Bull. SUC.chim. beiges, 1976,85,801. V. Amico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, J.C.S. Chem. Cumm., 1976, 1024. H. H. Sun, S. M. Waraszkiewicz, K. L. Erickson, J. Finer, and J. Clardy, J. Amer. Chem. SUC.,1977,99, 3516.

Diterpenoids

145

(148)

A group of guaiane diterpenoids including dictyol B acetate (149) and dictyotadiol (150) has been obtained162from the brown seaweed Dictyotu dichotomu. Dictyol C (151) from Aplysiu depiluns, dictyol D (152) from Dictyotu dichotomu, and dictyol E (153) from Dilophus 1igulul;Usare further examples of this structural type.'63 The em-epoxide of pachydictyol A (154) was from Dictyotu flabellutu.

(149) (151) (152) (153)

R' = H, R2 = OAc, R3 = H R'=R2=R3=H R'=OH, R Z = R 3 = H R'=R'=H, R ~ = O H H 0-

I

I

( 154)

Sacculatal (155) and its C-9 epimer, isosacculatal, are165two diterpenoid dialdehydes which contribute to the pungent odour of the liverwort, Trichocoleopsis succulutu. Their structures bear a resemblance to the sesquiterpenoid drimanes. A diterpenoid analogue of the cadinene group is found'66 in the structure of dihydroxyserrulatic acid (156),from Eremophilu serrulutu (Myoporaceae). Ptilosarcone (157) is a toxin which was i~olated'~'from the sea pen, Ptilosurcus gurneyi. Its structure was assigned by comparison of its n.m.r. spectrum with that of 163

'"

D. J. Faulkner, B. N. Ravi, J. Finer, and J. Clardy, Phytochemisiry, 1977,16, 991. B. Danise, L. Minale, R. Riccio, V. Arnico, G. Oriente, M. Piattelli, C. Tringali, E. Fattorusso, S. Magno, and L. Mayol, Experientia, 1977,33,413. K. J. Robertson and W. Fenical, PhytochemisQ, 1977, 16, 1071. Y.Asakawa, T. Takemoto, M. Toyota, and T. Aretani, Tetrahedron Letters, 1977, 1407. K. D . Croft, E. L. Ghisalberti, P. R. Jefferies, C. L. Raston, A. H. White, and S. R. Hall, Tenahedron, 1977,33,1475. S. J. Wratten, W. Fenical, D . J. Faulkner, and J. C. Wekell, Tetrahedron Letters, 1977, 1559.

Terpenoids and Steroids

146

briarein A (158), a constituent of Briareum asbestinum, whose structure had been determined by X-ray analysis.16* Stylatulide (159) is another sea pen toxin whose structure was also determined’”’ by X-ray analysis. Xenicin (160) is a diterpenoid possessing an unusual nine-membered ring. It was i ~ o l a t e d ”from ~ the soft coral Xenia elongatu and its structure was proven by an X-ray analysis.

OAc

0

AcO--

,OAc

.

-CI

0

(1 59)

Bromosphaerol (161) is a dibromo-diterpenoid from the red alga Sphaerococcus coronopifolius. Its structure was determined”’ through a combination of n.m.r. spectroscopy and X-ray analysis of a degradation product. A group of novel diterpenoids has been isolated from the sticky secretions of the frontal glands of nasute termite soldiers. The structure of trinervi-2P,3a,9a-triol J. E. Burks, D. van der Helm, C. Y. Chang, and L. S. Ciereszko, Acfu Cryst., 1977, B33,704. S. J. Wratten, D. J. Faulkner, K. Hirotsu, and J. Clardy, J. Amer. Chem. Soc., 1977,99, 2824. D. J. Vanderah, P. A. Steudler, L. S. Ciereszko, F. J. Schmitz, J. D. Ekstrand, and D. van der Helm, J. Amer. Chem. Soc., 1977,99, 5780. E. Fattorusso, S. Magno, C. Santacroce, D. Sica, B. di Blasio, C. Pedone, G. Impellizzeri, S. Mangiafico, G. Oriente, M. Piattelli, and S. Sciuto, Guzzeftu, 1976, 106, 779.

lbY ”O

147

Diterpertoids

9-0-acetate (162), 'which possesses a bridgehead double bond, was e~tablished'~' by X-ray analysis. The structures of the congeners were then related to this by a series of spectral correlation^.^'^ Cinnzeylanine (163) and its desacetoxy alcohol, cinnzeylanol, are insecticidal polyhydroxylated pentacyclic diterpenoids, which were isolated from Cinnamonum zeylunicum. Their structure, which is similar to that of ryanodine, was established by X-ray

Br

HO

OH (161)

( 162)

(163)

7 Diterpenoid Total Synthesis Synthetic endeavours have continued in the diterpenoid series. The cyclization of geranylgeranic acid chloride to derivatives of cembrene, and their conversion into cembrene itself, have been d e ~ c r i b e d . " ~Some further extensions of the route to macrocyclic diterpenoids based on the intramolecular cyclization of epoxysulphides and the subsequent modification of the macrocylic product have been described. 176 A stereoselective total synthesis of the antifungal mould metabolite (*)-LLZ1271a (165) from the readily available Wieland-Miescher diketone, tliu the keto-lactone (164), has been d e ~ c r i b e d . 'A~ ~synthesis of grindelic acid (167) from the unsaturated 7-toluene-psulphonate (166) utilized'78 an intramolecular solvolysis of the toluene-psulphonate to construct the 9-1 3 ether bridge. A n alternative synthesis of the tricyclic intermediate (168), together with the elaboration of C-4 with the configuration of both podocarpic and dehydroabietic acids, has been r e ~ 0 r t e d . IIn~ ~a stereoselective total Synthesis''' of (*)-callitrisic acid and (*)-podocarpic acid, the C-4 stereochemistry was established by reductive methylation of the enol-ether (169). In an A + B --+ C approach to diterpenoid total synthesis, the Michael addition of t-butyl P-keto-esters to the unsaturated aldehyde (170) formed"' a key step. 172

173

174

179

'"

G. D. Prestwich, S . P. Tanis, J. P. Springer, and J. Clardy, J. Amer. Chem. SOC., 1976,98,6061. G. D. Prestwich, S. P. Tanis, F. G. Pilkiewicz, I. Miura, and K. Nakanishi, J. Amer. Chem. SOC.,1976, 98.6062. A.'Isogai, A. Suzuki, S. Tamura, S. Murakoshi, Y. Ohashi, and Y. Susuda, Agric. und Biol. Chem. (Jupan), 1976,40,2305. T. Kato, T. Kobayashi, T. Kumagai, and Y. Kitahara, Synrh. Comm., 1976,6, 365. M. Kodama, K. Shimada, and S. Ito, Tetrahedron Lerrers, 1977, 2763. S. C. Welch, C. P. Hagan, D. H. White, W. P. Fleming, and J. W. Trotter, J. Amer. Chem. Soc., 1977, 99,549. M. Adinolfi, G. Laonigro, M. Parrilli, and L. Mangoni, Gazzefru,1976, 106, 625. J. W. Huffman and P. G. Harris, J. Org. Chem., 1977,42, 2357. S. C. Welch, C. P. Hagan, J. H. Kim, and P. S. Chu, J. Org. Chem., 1977,42,2879. W. L. Meyer, R. A. Manning, P. G. Schroeder, and D. C. Shew, J. Org. Chem., 1977,42,2754.

Terpenoids and Steroids

148

The subsequent cyclization of the adduct (171) afforded tricylic compounds such as (172). The stereochemistry of these products has been the subject of detailed study. This approach has been used'" in a total synthesis of methyl (*)-dehydroabietate. The synthesis of bicyclic compounds such as (173) with angular C-10 functionality has also been r e p ~ r t e d . " ~ A convenient synthesis of (*)-taxodione, (*)-ferruginol, and (*)-sugiol the addition of a substituted benzyl chloride moiety to the aldehyde group of cyclocitral and subsequent oxidation. Cyclization of the product (174) afforded the tricyclic system (175) which was then elaborated further. This 0

M 2& e:

(168)

0

(po

@

H

0

Et0,C (173)

0

(174)

"'W. L. Meyer and C. W. Sigel, J. Org. Chem., 1977,42,

0 (175)

2769. W. L. Meyer, T. E. Goudwin, R. J. Hoff, and C. W. Sigel, J. Org. Chem., 1977.42, 2761. T.Matsumoto, S. Usui, and T. Morimoto, Bull. Chem. SOC.(Jupun),1977,50, 1575.

Diterpenoids

149

approach has been utilized'85 in a synthesis of (*)-maytenoquinone and (*)-dispermol. The of ferruginol and methyl 12-hydroxydehydroabietate at C-11 with benzoyl peroxide to afford the 1l-phenols has provided a route for the synthesis of taxoquinone, royleanone, and horminone from ferruginol. Some studies directed at the total synthesis of the triepoxide triptolide have been reported.'** The synthesis of the furan (176)lS9and its conversion into the triester ( I 77) as an intermediate in the synthesis of fujenoic acid have been described."" The metalammonia reduction of some polyfunctional tetrahydrofluorenes with the object of preparing intermediates for gibberellin synthesis has been noted.'"

(176)

(177)

The full paper has appeared on a synthesis of steviol.1'2 The route was based on the stereocontrolled photoaddition of allene to the cyclopentene- l-aldehyde (178), reduction of the aldehyde, and then solvolysis of the methanesulphonate (179). Papers on the synthesis of the aromatic ether (180)193 and o n the constructiqn of the C/D ring system of the alkaloid ~ h a s m a n i n ehave ' ~ ~ been published.

T. Matsumoto and T. Ohmura, Chem. Lefters, 1977,335. T. Matsumoto and S. Harada, Chem. Letfers, 1976, 13 11. T. Matsumoto, Y. Ohsuga, S. Harada, and K. Fukui, Bull. Chem. Soc. (Japan), 1977,50,266. "'F. T. Sher and G. A. Berchtold, J. Org. Chem., 1977,42,2569. T. Kato, T. Suzuki, N . Ototani, H. Maeda, K. Yamada, and Y. Kitahara, J.C.S. Perkin I, 1977,206. I9O T. Kato, T. Suzuki, N. Ototani, and Y. Kitahara, Chem. Letters, 1976, 887. 19' Y. Yamada and H. Nagaoka, Synthesis, 1977, 577. IYzF. E. Ziegler and J . A. Kloek, Tetrahedron, 1977,33, 373. 193 T. Kametani, Y. Kato, T. Honda, and K. Fukumoto, J. Amer. Chem. Soc. 1976,98,8185. 194 K. Wiesner, 1. H. Sanchez, K. S. Atwal, and S. F. Lee, Cnnad. J. Chem., 1977,55, 1091.

4 Triterpenoids BY J. D. CONNOLLY

1 Squalene Group The biogenetic-type rearrangement of terpenoids has been reviewed.' The latest results from van Tamelen's laboratory concerning terpenoid terminal epoxide polycyclizations indicate that ring A is formed with a high degree of neighbouring n-bond participation during epoxide opening and suggest that the overall process is not fully concerted but involves a series of conformationally rigid cyclic carbonium ion intermediates.' Further detailed study of the substrate specificity of yeast squalene synthetase has been reported' (see Vol. 7, p. 130). The enzyme is very sensitive to changes in substrate. For example, 10,ll-dihydrofarnesyl pyrophosphate was converted into 2,3,22,23-tetrahydrosqualene with only 60% of the efficiency of farnesyl pyrophosphate whereas 6,7-dihydro- and 6,7,10,11 -tetrahydro-farnesyl pyrophosphates were not metabolized. The first of the two binding sites has a greater preference for farnesyl pyrophosphate and this accounts for the formation of the unsymmetrical squalene product when mixtures of farnesyl pyrophosphate and a modified substrate are used. The importance of the methyl groups, especially that at C-3, for binding is emphasized by the low efficiency of conversion of 3-desmethylfarnesyl, E,E-3-methylundeca-2,6-dien1-yl (l), and E,E-7desmethylfarnesyl pyrophosphates. The prenylated cyclobutanones (2) and (3) Y

O

P

do

P

R' (2) R' = geranyl, R' = H (3) R' = geranyl, R' = tetrahydrogeranyl

~ compounds have weak activity as inhibitors of yeast squalene ~ y n t h e t a s e .The were prepared by polar cycloaddition of the ketene-immonium cations (4) and (5) to the tetraene (6). The synthesis failed when the intermediate (7), with a geranyl substituent, was used. The full details of the resolution of 2,3-dihydrosqualene-2,3-

*

R. M. Coates, Fortschr. Chem. org. Nuhustoffe, i 9 7 6 , 33, 73. E. E. van Tamelen and D. R. James, .I. Amer. Chem. SOC., 1 9 7 7 , 9 9 , 9 5 0 .

' W. N. Washburn and R. Kow, Tetrahedron Letters, 1977, 1555.

P. R. Ortiz de Montellano and R. Castillo, Tefruhedron Letters, 1976, 41 15.

150

151

Triterpenoids

(6) R = geranyl

(4) R = H (5) R = tetrahydrogeranyl (7) R = geranyl

diol and the synthesis of (3R)- and (3S)-2,3-epoxy-2,3-dihydrosqualene have appeared.' The biosynthetic implications for the cyclization of squalene of the fact that natural sterols have the same configuration at C-20 have been discussed6 and are illustrated in Scheme 1.

Scheme 1

Squalene 2,3-oxide is converted into a-amyrin by microsomes of bramble cell suspension culture^.^ This system is particularly useful for studying a-amyrin since it constitutes more than 70% of the pentacyclic triterpenoid fraction. Squalene is one of the major products when [2-'4C]mevalonate is fed to a cell-free system of retarded young iris leaf (Iris hollaidica).8 Investigation of the biosynthesis of sitosterol in the pea from (3RS,2R)- and (3RS,2S)-[2-'4C,2-3H]mevalonate suggests that the pattern of transformation of the tetracyclic moieties is the same in the pea and in rat liver tissues regardless of whether cycloartenol or lanosterol is the p r e c u r ~ o r An . ~ independent I3C n.m.r. study of the spin-lattice relaxation times of squalene supports the conclusion reported last year (see Vol. 7, p. 131) that the conformation of the molecule does not alter greatly on increasing the aqueous content of the medium." These results render unlikely t h e suggested 'coiling' explanation for the selective terminal oxidation of squalene with N-bromosuccinimide. The biosynthesis of triterpenoids in the latex of Hoya australis, H. carnosa, Euphorbia pulcherrima, and related species has received detailed attention."*" R. B. Boar and K. Damps, J.C.S. Perkin I, 1977,709. W. R. Nes, J. E. Varkey, and K. Krevitz, J. Amer. Chem. SOC.,1977,99, 260. ' J. W. Elder, P. Benveniste, and P. Fonteneau, Phyfochemistry,1977,16,490. ' N. Ceccarelli, A. Alpi, R. Lorenzi, and M. Benetti, PIanf Sci. Letters, 1977,8, 257. J. K. Sliwowski and E. Caspi, J. Amer. Chem. Soc., 1977, 99, 4479. '" J. M. Brown and D . R. M. Martens, Tetrahedron,1977, 33,931. I ' H. W. Groeneveld and J. Koning, Actu Botun. Neerl., 1976, 25, 227. *'H. W. Groeneveld, Acta Botan. Neerl., 1976, 25, 459.

Terpenoids and Steroids

152

The timing of triterpenoid biosynthesis in developing Sorghum bicolor grains and in Pinus pinea has been i n ~ e s t i g a t e d . ’ ~ ” ~ The detailed structure of caldariellaquinone (12), a unique benzo[b]thiophen~ experi4,7-quinone from Caldariella acidophila, has been e 1 ~ c i d a t e d . lFeeding ments with I3C-labelled acetate helped to define the nature and biosynthetic origin of the C,’ isoprenoid chain.

The chemistry of the Daphniphyllum alkaloids has been reviewed. “J’ Terpenoid alkaloids are also reviewed in the Specialist Periodical Report ‘The Alkaloids’. Two new alkaloids, deoxyyuzurimine (13) and isodaphnilactone B (14), have been isolated from the leaves of Daphniphyllum gracile.’”

2 Fusidane-Lanostane Group The enedione (15), a tetracyclic intermediate o n a synthetic route to fusidic has been synthesized from the a-methylene-ketone (16) (Scheme 2). The first step, involving a Diels-Alder reaction with a substituted acrylate (17), provides a new versatile annelation procedure. Further modification of (15) by a route worked out on model systems (see Vol. 4, p. 318) afforded the tetracyclic enone (24) with the desired trans-syn-trans geometry (Scheme 3 ) . This compound (24) has also been prepared by degradation of fusidic acid.*’ Attempts to introduce the C- 11 oxygen function necessary for the synthesis of fusidic acid have not been very 13

14 19

16

17

in IY

20

M. A. Palmer and B. N. Bowden, Phyfochemisfry, 1977,16,459. M. L. McKean and W. R. Nes, Lipids, 1977, 12, 382. M. De Rosa, S. De Rosa, A. Gambacorta, L. Minale, R. H. Thomson, and R. D. Worthington, J.C.S. Perkin I, 1977,653. S . Yamamura and Y. Hirata, ‘The Alkaloids’, Vol. XV, ed. R. H. K. Manske, Academic Press, New York, 1975, p. 41. S. Yamamura and Y. Hirata, in ‘Alkaloids’, ed. K. Wiesner, M.T.P. International Review of Science, Organic Chemistry Series Two, Volume 9, Butterworths, London, 1976, p. 161. S. Yamamura and Y. Terada, Chem. Letters, 1976, 1381. R. E. Ireland, P. Beslin, R. Giger, U. Hengartner, H. A. Kirst, and H. Maag, J. Org. Chem., 1977,42, 1267. R. E. Ireland, R. Giger, and S. Kumata, J. Org. Chem., 1977,42, 1276.

Triterpenoids

153

(15) Reagents: i, A, 180"C; ii, LiAIH4-Et20; BuLi-THF-TMEDA-CIPO(NMe2)z;iii, Li-Ph2-THF, MeI; iv, O-,-MeOH, Me2S; v, 0. 18M-KOH-H20-MeOH; vi, Li-NH3-THF-H20, MeI, H 3 0 +

Scheme 2

i, vi-viii,

H

@oTB:-x,,

0

:

t

S

0

H

O H

iiiJ

T

B

S

H

(23)

(24)

Reagents: i, Li(OBut)3AIH-THF; ii, (CH2oH)2-Hf-C6H6; iii, ButMe2SiCI-imidazole-DMF; iv, MCPBA-CH,CI,; v, BF3-CH&; vi, LDA-THF, CIPO(NMe2)2-THF-HMPA; vii, Lix, DDQ-C&; xi, (Ph3P)3RhCIBu'OH-THF-EtNH2; viii, H30+; ix, NaH-HC02Et-C,&; C6H6; xii, LDA-THF, Me1

Scheme 3

154

Terpenoids and Steroids

successful. A method has been devised” for the introduction of the characteristic 17(20)-Z-iso-octenoic acid side-chain of fusidic acid and related compounds to a tetracyclic intermediate (25) with a 17-ketone (Scheme 4). Separation of the (20R)- and (20S)-isomers of (26) followed by acetylation and dehydration gave methyl diacetoxyfusidate (27) and methyl diacetoxylumifusidate (28) respectively.

I:...

0

(26) 111, IV

(28)

1

@OR)

(27)

Reagents: i, BuLi-Pr\NHd-methyIhept-5-enoic acid; ii, CH2N2; iii, Ac20-py; iv, POC13-py

Scheme 4

In an approach to the stereocontrolled creation of the acyclic side-chain of tetracyclic triterpenoids and other natural products, Trost and his colleagues have converted the acyclic starting compound (29) into the cyclopropanoid intermediate (31) via the diazo-ketone (30).22 The key step in the scheme is the cleavage of the cyclopropane with lithium dimethylcuprate to give (32). The stereochemistry at C-7 is determined by the configuration of the double bond in (29). The c.d. and U.V. spectra of a series of triterpenoid olefins have been mea~ured.’~ The Scott-Wrixon rules can be used to correlate the sign of the c.d. curves with molecular structure. A 21

22 23

M. Tanabe, D. M. Yasuda, and R. H. Peters, TetrahedronLetters, 1977, 1481. B. M. Trost, D. F. Taber, and J . B. Alper, Tetrahedron Letters, 1976, 3857. A. F. Drake, P. Salvadori, A. Marsili, and I. Morelli, Tefmhedron, 1977, 33, 199.

Triterpenoids

155

(29) R = H,H

(30) R = N ,

paper o n the semiempirical derivation of "C n.m.r. shifts includes some triterpenoid~.'~ Photolysis of the imidazolide (33) of 3/3-acetoxy-25,26,27-trisnorlanost-8-en24-oic acid to give (34) has the advantages of simpler experimentation and higher

(34)

yields over other photochemical methods for degradation of the lanosteror sidechain.25 The full paper on the functionalization of the 4a-methyl group of lanosterol by thermolysis of the azidoformate has appeared." Another group has reported similar results by thermolysis or photolysis of the corresponding azidocarbonate." Nitrite photolysis has been used as a conformational probe in a series of 6a- and 6P-nitrites of 4,4-dimethylandro~tanes.~~ Kadsuric acid ( 3 3 , a new A-secolanostane, has been isolated from the stems of Kadsura japonica.2y Several lanostanes with methylated side-chains have been reported. These include 24,25-dimethyl-lanosta-9( 1 1),23-dien-3P-d (36) and the corresponding acetate (37) and ketone ( 3 8 ) from Quercus myrsinaefolia,3" 24,24dimethyl-lanosta-9(11),25-dien-3P-y1 acetate (39) from the leaves of Q. gilz~a,~' and O-methylclausenol (40) from the aerial parts of Clausena pentaphylla.32 The structure (41) has been proposed for citrullonol from the neutral portion of the oil of Cifrullus c o l o ~ y n t h i s The . ~ ~ configuration of the methyl group at C-4 of citrostadienol (42) from Calendula officinalis has been revised to a.34 24-Methylenelanost-8-en-3/3-01 has been detected for the first time in higher plants, in the H. Beierbeck, J . K. Saunders, and J. W. ApSimon, Canad. J. Chem., 1977,55,2813. S . Iwasaki, Helv. Chim. Acta, 1976, 59, 2753. P. F. Alewood, M. Benn, J. Wong, and A . J. Jones, Canad. J. Chem., 1977,55,2510. '' J . J . Wright and J. B. Morton, J.C.S. Chem. Comm., 1976, 668. 2R J . M. Midgley, J. E. Parkin, and W. B. Whalley, J.C.S. Perkin i, 1977, 834. 29 Y. Yamada, C.-S. Hsu, K. Iguchi, S. Suzuki, H.-Y. Hsu, and Y.-P. Chen, Chem. Letters, 1976, 1307. 3" W.-H. Hui and M.-M. Li, J.CS. Perkin I, 1977, 897. 3 1 Y. Tachi, Y. Kamano, J . Sawada, I . Tanaka, and H. Itokawa, Yakugaku Zasshi, 1976,96, 1213. 32 M. D. Manandhar, A . Shoeb, R. S. Kapil, and S. P. Popli, Experientia, 1977,33, 153. 33 L. Yankov and S. Khusein, Doklady bolgarsk. Akad. Nauk, 1975,28, 1641. 34 J . St. Pyrek and A. Schmidt-Szalowska, Roczniki Chem., 1977,51, 951. 24

2s

26

156

H

2

Terpenoids and Steroids

HO,C:

(35)

(36) R = H,P-OH (37) R = H,P-OAc (38) R = O

pi

(39) R = H H,POAc, ,B-OMeo R' = H

\

HO

HO

I

(4 1)

(42)

seeds of Brassica n a p ~ s The . ~ ~methyl ethers of cycloartenol and parkeol are new natural products from Chionochloa species.36a Polycarpol, from the bark of Polyalthia oliveri, is 15a-hydroxyagnosterol.366 Crystal structure analysis of the major isomer (43) formed on autoxidation of 3a-hydroxy-4,4,14a-trimethyl-l9-nor1Oa-pregna-5,16-diene-ll,20-dione (44) followed by reduction of the intermediate hydroperoxide has confirmed the 17a configuration which had been assigned to the hydroxy-group.37 The conformation of the 17-acetyl group in both isomers has been studied in different solvents. A second compound, formed in addition to (45)in the rearrangement of

vo HO"

&EH

(43) 35 36

37

@ CH,OH

\

(44)

(45)

T. Itoh, T. Tamura, and T. Matsumoto, Phyfochemistry, 1976.15, 1781. (a)G . B. Russel, H. E. Connor, and A. W. Purdie, Phyfochemistry, 1976,15, 1933; ( b )M. Hamonnikre, A. Fournet, M. Leboeuf, A. Bouquet, and A. Cave, Compt. rend., 1976,282, C, 1045. P. R. Ensiin, J. Coetzer, and G . J. Kruger, J.C.S.Perkin II, 1977, 402.

Triterpenoids

157

(46) with boron trichloride, has been shown by X-ray analysis to have the structure (47).38Presumably it arises by the trapping of an intermediate cationic species by chloride ion. The full details of the preparation of the stable dithiet derivative (48) have appeared39 (see Vol. 7, p. 134). Irradiation of the lanostadiene (49) yielded the photoproduct (50) whose structure has been confirmed by X-ray analysis.

& -0

(49)

CI

AcO

(50)

Hydrolysis of thelothurins A and B, the defensive saponins of the Indo-Pacific sea cucumber Thelonota ananas, with aqueous acetic acid yields the genuine aglycones (51) and (52) whose structures were proved chemically by interrelation

(51)

(52)

with seychellogenin acetate.40 Hydrolysis of the saponin mixture with stronger acid led to the formation of the artifacts (53)-(58) with a 9( 11)-double bond.41 Feeding experiments with labelled acetate have resulted in only low incorporation into the sap on in^.^^^^ However, an impressive incorporation (18%) of [3-3H]lanosterol into holotoxinogenin (59) by the sea cucumber Stichopus californicus has been reported.43 Oxidation of (59) resulted in loss of tritium. An X-ray structural 3x

39 40

41 42 43

T. Prange, C. Pascard, G. Sozzi, and M. Fetizon, TetrahedronLetters, 1977,245. R. B. Boar, D. W. Hawkins, J. F. McGhie, and D. H. R. Barton, J.C.S. Perkin I, 1977, 515. A. Kelecorn, D . Daloze, and B. Tursch, Tefruhedron, 1976,32, 2313. A. Kelecom, D. Daloze, and B. Tursch, Tetruhedron, 1976,32, 2353. G. B. Elyakov, V. A. Stonik, E. V. Livina, and V. S. Levin, Comp. Biochem. PhysioL, 1975,52B, 321. Y. M. Sheikh and C. Djerassi, J.C.S. Chem. Comm., 1976, 1057.

Terpenoids and Steroids

158

(53) R' (54) R'

= H.

RZ= Ac

= R2 = Ac

(57) R * = R ' = H (58) R' = H, R2 = AC

(55) R' (56) R'

=R ~ H = = H, R2 = Ac

(59) R ' = H

analysis of 17-deoxy-22,25-epoxyholothurinogeninacetate (60) has been publi~hed.~~

Acetylshengmanol (6 I), an unstable sapogenin from Cimifuga japor~ica:~is a likely precursor of cimigenol (62)and cimigol (63). It occurs as a xyloside. The parent xyloside was converted into cimigenol on acid hydrolysis and to cimigol xyloside on treatment with alkali. The details of the crystal structure of passifloric acid methyl ester (64), from PassifIora edulis, have appeared.46 Mollic acid 3p-Dglucoside (65)is a structurally related saponin from the leaves of Combretum

P" -

... ...

44

45 46

S. G. Il'in, B. L. Tarnopol'skii, Z . 1. Safina, A. N. Sobolev, A. K . Dzizenko, and G. B. Elyakov, Doklady Akad. Nauk S.S.S.R., 1976,230, 860. N. Sakurai, T. Inoue, and M. Nagai, Chem. and Pharm. Bull. (Japan), 1976,24, 3220. G. D. Andreetti, G. Bocelli, and P. Sgarabotto, J.CS. Perkin II, 1977, 605.

Triterpenoids

159

H .......

0

OH

* (64) R 1= H, R2 = M e

As (64)

!F AcO

(65) R'

= P-D-GIu, R2 = H

%I

CO,H

(66)

rn~ffe.~ On ' treatment with acid it undergoes the same cyclopropane transposition [to (66)] as (64) (see Vol. 7, p. 134). Partial syntheses of mangiferolic acid (67),48 buxandonine (68)49 and cycloprotobuxines A (69) and F (70)4' from cycloartenol, and ambolic acid (71)48from cyclolaudenol have been reported. Papers on the Buxus alkaloids include contri-

(68) R' = 0,R2= NMe, (69) R' = H,a-NMe,, R2 = NMe, (70) R' = H,a-NHZ, R2 = NMe, 47

4x 4y

(7 1) R' = H,p-OH

K. H.Pegel and C. B. Rogers, Tetrahedron Letters, 1976,4299. C . Singh and S. Dev, Tetrahedron, 1977, 33, 817. C.Singh and S.Dev, Tetrahedron, 1977, 33, 1053.

Terpenoids and Steroids

160

butions to the stereochemistry of cyclobuxaminesOand L-cycloprotobuxine C5’ and a tentative structure for cyclobuxargentine G.” The full details of the conversion of cycloeucalenol into [ 19-2H]obtusifoliol by the microsomes of Zea mays in D,O have appeareds3 (see Vol. 7, p. 135). The formation of a A’(11) intermediate in the enzymatic cleavage of the cyclopropane ring is excluded by the incorporation of only one deuterium atom. Both cyclox ~ ~ artenol and lanosterol are converted into normal sterols by Saprolegnia f e r ~ and Chlorella e l l i p ~ o i d e a . ~ ~ The transformation of the lanostane keto-epoxide (72) into the cucurbitacin derivative (73) has been achieved with boron trifluoride in acetic anhydride.56 The presence of the acetic anhydride appears to favour the backbone rearrangement. The structure of (73) was confirmed by correlation with the oxidation product (74) of deoxybryogenin acetate. Two new cucurbitacin glycosides, arvenins I (75) and I1 (76) from Anagallis arvensis, have been reported.57

(73) R = H,POAc (74) R = O

(75) (76) 23,24-dihydro

3 Dammarane-Euphane Group Several interesting dammaranes have been isolated from the male flowers of Alnus serrulatoides.s840 Alnuserol (77)” and alnuselide (78)s9 have the uncommon

’(’ Z. Voticky and V. Paulik, Coll. Czech. Chem. Comm., 1977, 42, 541. B. U. Khodzhaev, R. Shakirov, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1976, 554. K. I. Kuchkova, Z. Voticky, and V. Paulik, Chem. Zuesti, 1976,30, 174. A. Rahier, L. Cattel, and P. Benveniste, Phytochemistry, 1977, 16, 1187. J. D. Bu’Lock and A. U. Osagie, Phytochemistry, 1976,15, 1249. 5 5 L. B. Tsai and G. W. Patterson, Phytochemistry, 1976, 15, 1131. 56 Z. Paryzek, Tetrahedron Letters, 1976,4761. 57 Y. Yamada, H. Hagiwara, and K. Iguchi, Tetrahedron Letters, 1977, 2099. ” T. Hirata, K. Murai, T. Suga, and A. Christensen, Chem. Letters, 1977, 95. ’9 T. Hirata, R. Ideo, and T. Suga, Chem. Letters, 1977, 711. T. Hirata, R. Ideo, and T. Suga, Chem. Letters, 1977,283.

’*

53

‘’

161

Triterpenoids

feature of oxygenation at C-11. The structure of the former was confirmed by X-ray analysis. Alnuserol (77) was converted into alnuselide (78) by abnormal Beckmann rearrangement of the corresponding oxime followed by hydrolysis. Alnuseric acid (79) was synthesized from alcincanone (go), with which it

(78)

(79)

(80)

co-occurs, by a similar route.60 Dammar-24-ene-3a, 17a,20-triol (81) and betulafolienetetraol oxide (82) have been obtained from the leaves of Betufu

4

HO-’

OH

HO” (8 1)

(82)

costatu.61The latter was formed together with its 24-epimer on treatment of betulafolienetetraol (83) with perbenzoic acid. Other new compounds include betulafolienepentaol(84) from the leaves of B . plutyphylla6’ and bacogenin A3 (85), a new sapogenin from Bacopa r n ~ n n i e r a . ~ ~ The full details of the determination of the configuration of the trisubstituted epoxide of aglaiol (86) have appeared.64 During the course of this work three new compounds, the ketone (87), the keto-diol(88), and the trio1 (89), have been found 61

N. I. Uvarova, G. V. Malinovskaya, and G. B. Elyakov, Tetrahedron Lerters, 1976, 4617

63

R. S. Chandel, D. K. Kulshreshtha, and R. P. Rastogi, Fhyrochemistry, 1977,16, 141.

64

R. B. Boar and K. Damps, J.CS. Perkin I, 1977, 510.

’’ B. H. Han and B. J. Song, Fhyiochernistry, 1977,16, 1075.

Terpenoids and Steroids

162

in Agluiu odoruta. It is interesting that the configuration at C-24 in (88) and (89) (24R) is the opposite to that in (86) and (87).

(86) R=H,F-OH (87) R = O

(88) R = O (89) R = H,P-OH

The I3C n.m.r. resonances of a series of 20-hydroxy-dammarane derivatives related to the ginseng sapogenins have been assigned." The chemical shifts of C-17, C-21, and C-22 are characteristic of the C-20 configuration especially in the presence of a 12P-hydroxy-group. New saponins from Punax ginseng have been ~ e p o r t e d . ~ "The ' ~ ~structures of chikusetsusaponins L,, L9,, and L,, have been elucidated.6* Chikusetsusaponin L,, (90) is the first 12-0-glucoside in this series. Photosensitized oxidation of (90) followed by reduction afforded chikusetsusaponin L a (91)Tirucalla-7,24-dienol (92) from tea seed oil6' and the aldehyde (93), corare responding to methyl isomasticadienoate, from the berries of Schinus rn~lle,~' new natural products. Sapelins A and B, from Burseru klugii, have cytotoxic activity7' (see Vol. 1 , p. 172). J. Asakawa, R. Kasai, K. Yamasaki, and 0. Tanaka, Tetrahedron, 1977,33, 1935. S. Yahara, 0. Tanaka, and T. Komori, Chem. and Pharm Bull. (Japan), 1976,24, 2204. S. Yahara, K. Matsuura, R. Kasai, and 0.Tanaka, Chem. and Pharm. Bull. (Japan), 1976,24, 3212. '' S. Yahara, R.Kasai, and 0. Tanaka, Chem. andfharm. Bull. (Japan),1977,25, 2041. T. Itoh, T. Tamura, and T. Matsumoto, Lipids, 1976, 11, 434. 7u T . Pozzo-Balbi, L. Nobile, G. Scapini, and M. Cini, Gazzerra, 1976,106, 7x5. 71 S. D. Jolad, R. M. Wiedhopf, and J. R. Cole, J. Pharm. Sci., 1977, 66, 889.

65

66

67

163

Triterpenuids

(92)

(93)

Tetranortriterpen0ids.-The I3C n.m.r. assignments for a large group of limonoids have been r e p ~ r t e d . ~The ' chemistry of azadirachtin has been reviewed73(see Vol. 6, p. 162). Anthothecol (94) and hirtin (95) have been interrelated uiu the trione (96).74 Dysobinin (97) is a new tetranortriterpenoid from Dysuxylum binect~riferum.~' An intermediate in a projected limonoid synthesis has been shown to have structure (98) by X-ray analysis.76 An unusual feature of harrisonin (99), a compound with insect antifeeding, cytotoxic, and antibacterial properties from Hurrisonii u b y s ~ i n i c u is ,~~ the stable hemiacetal function. The novel structure (100) has been reported for cyclo~~ epiatalantin, an interesting new limonoid from Atuluntiu m u n ~ p h y l l u . Base cleavage of (1 00) followed by methylation gave epiatalantin (101). Chemical and spectroscopic evidence has been for the revised structures (102) and (103) of atalantin and atalantolide. 2-(4-Ethylphenoxy)triethylamine and 2-(3,4-dimethoxyphenoxy)triethylamine markedly reduce the biosynthesis of limonoids in citrus leaves, presumably by inhibition of cyclase activity." Radio-tracer studies have revealed that limonoids are synthesized in the leaves of citrus and transported to the fruit.'l The fruit tissue does not appear to be capable of the de nuuo synthesis of limonoids from acetate or mevalonate. 72

73 74

75

l6 77

78 79

Hn

D . A. H . Taylor, J. Chem. Res. ( S ) , 1977, 2. K. Nakanishi, Recent Adv. Phytochem., 1975,9,283. B. A. Burke, W. R. Chan, J. R. Rawle, and D. R. Taylor, Experientiu, 1977,33,578. S . Singh, H. S. Garg, and N . M. Khanna, Phytochemzslry, 1976,15, 2001. K. Neupart-Laves and M. Dobler, Cryst. Structure Comm., 1977,6, 183. I. Kubo, S. P. Tanis, Y.-W. Lee, I. Miura, K. Nakanishi, and A. Chapya, Heterocycles, 1976, 5 , 4 8 5 . D . L. Dreyer, R. D . Bennett, and S. C. Basa, Tefruhedron, 1976,32, 2367. B. Sabata, J. D . Connolly, C. Labbe, and D . S. Rycroft, J.C.S. Perkin I, 1977, 1875. S. Hasegawa, H. Yokoyama, and J. E. Hoagland, Phyrochemisfry, 1977,16, 1083. S. Hasegawa and J. E. Hoagland, Phytochemzsfry, 1977, 16, 469.

*

Terpenoids and Steroids

164

0

OH

Me0,C

(94)

OH (95)

fl

0

'OAc

Me0 CN

AcO (97)

0 'OH

Triterpenoids

165

The structures of two complex highly oxygenated tetranortriterpenoids related to prieurianin (see Vol. 6, p. 126) have been elucidated." Dregeanin (104) from Trichilia dregeana and rohitukin (105) from the seeds of Aphnamixis polystacha both exist as a mixture of conformers in solution at room temperature. Xyloccensins A (106), B (107), D (log), and F (109) are new bicyclononanolides from the seed of Xylocarpus m o l u ~ c e n s i s .The ~ ~ 1,8-hemiacetal function is a new feature in this series. Selenium dioxide oxidation of carapin afforded a product which has been assigned structure (110) with a 3,g-hemiacetal bridge. This compound (110) occurs naturally in Cedrela glaziovii.

I

v I

Y Ok oco 0

CH2 Q

oco

0

0

AcOH,C

1

HO

(106) R' = COPr' or COBu', R2= H (107) dihydro-( 106) (108) R' = COPr'or COBu', R2= OH (109) dihydro-( 108)

Pentanortriterpen0ids.-A clearer picture of the structural and stereochemical relationships among the cneorins and tricoccins, pentanortriterpenoids from Cneorum tricoccon and Neochamaelea pulverulenta, is beginning to emerge. The stereoisomeric forms of the olefin (111) and the alcohol (112) are summarized in Tables 1 and 2. Tricoccin R, (113) has a methoxy-group attached to C-30 but undergoes easy loss of methanol to give cneorin B1.84The structure of tricoccin S, (1 14) has been confirmed by X-ray analy~is.~'The corresponding methyl acetal, 82

83 84

85

J. D . Connolly, D . A. Okorie, D . L. D e Wit, and D . A. H. Taylor, J.CS. Chern. Comm., 1976,909. J. D . Connolly, M. A. MacLellan, D . A. Okorie, and D . A. H. Taylor, J.C.S. Perkin I, 1976, 1993. A. Mondon, D. Trautmann, B. Epe, and U. Oelbermann, Tetrnhedron Lerrers, 1976:3291. A. Mondon, D. Trautmann, B. Epe, and U. Oelbermann, TerruhedronL.efrers,1976,3295.

Terpenoids and Steroids

166

tricoccin S,, (115), also occurs naturally. Tricoccins S, (116) and S, (117) are stereoisomers of (114).

(114) R = H (115) R = M e

(116)

Table 1 Stereoisomers of the olefin (1 1 1) Configuration at C-7 C-9 C-37 R S S S S S R S R R S S S (Ri*, R R (S) R

Cneorin C Cneorin C, Cneorin B Cneorin B, Tricoccin R, Tricoccin R,

* Uncertain assignment,

Table 2 Stereoisomers of the alcohol (1 12)

Cneorin D Cneorin H Cneorin N Cneorin 0 Tricoccin &

C-7 S R S R S

Configuration at C-8 C-9 S S S S S S S S R S

C-17 S S R R R

Triterpenoids

167

Quassinoids.-The antileukaemic activity of some quassinoids ha5 revived interest in this group. Three new biologically active compounds have been isolated.86-8* Quassimarin (1 18) occurs in Quassia amara with the inactive simalikalactone D (119).86Bruceoside A, from Brucea javanica, is the glucoside (120).87The third

(118) R=OAc (119) R = H

compound, samaderine E (121) from Samadera indica, is accompanied by a novel quassinoid, samaderine A (122), whose structure has been established by X-ray analysis.'* Bruceine Q (123) is a new bitter principle from Brucea sumafrana.8y

?"

'

OH (123)

In approaches to a synthesis of quassinoids, the ketone (124), derived from cholic acid, has been converted into the lactone (125), with the C-7 stereochemistry of quas~inoids.~~~~' 86 R7

90

9'

S. M. Kupchan and D. R. Streelman, J. Org. Chem., 1976,41,3481. K.-H. Lee, Y. Imakura, and H.-C. Huang, J.C.S. Chem. Comm., 1977,69. M. C. Wani, H . L. Taylor, M. E. Wall, A. T. McPhail, and K. D . Onan, J.C.S. Chem. Comm., 1977, 295. H.-C. Chiang, Proc. Nat. Sci. Council Purr 1 (Taiwan), 1975, 8, 139. J. R. Dias and R. Ramachandra, Tetrahedron Letfers, 1976,3685. J. R. Dias and R. Ramachandra, J. Org. Chem., 1977, 42, 1613.

Terpenoids and Steroids

168

4 Shionane-Baccharane Group Methyl trisnorshionanoate (126) has been synthesizedY2 from friedelan-19a-01 (127) uia the ring-contracted intermediate ( 1 28) and the trisnor-ketone (129). Irradiation of (129) in methanol afforded the desired ester (126). An investigation of the effect of solvent on the backbone rearrangement of 3p,4@-epoxyshionane (130) by boron trifluoride etherate has shownY3that nucleophilic solvents tend to interrupt the rearrangement at an early stage (see Vol. 6, p. 130).

The baccharane derivative (13 1) is formed by Lewis acid-catalysed rearrangement of both the a- and @-epoxides (132) and (133) of the A18-isomer of betulin d i a ~ e t a t e The . ~ ~ rearranged product has been synthesized by an independent (131) route. The stereochemistry of the @-epoxide(133) has been confirmed by X-ray analysis.

’)’Y. Yokoyama, T. Hirao, T. Tsuyuki, Y. Moriyama, T. Murae, and T. Takahashi,

Tetrahedron Lerrers,

1977,273. 93 y4

M. Tori, K. Tachibana, Y. Moriyama, T. Tsuyuki, and T. Takahashi, Chern. Letters, 1976, 1359. (a) E. Suokas and T. Hase, Actu Chern. Scund., 1977, B31, 23 1; ( b ) ibid., p. 182.

169

Triterpenoids

&

H,OAc

AcO (13 1)

(132) ( 133) P-epoxide

5 Lupane Group

The structure of benulin (134), a lupene hemiacetal from Bursera arida, has been confirmed by X-ray analy~is.’~An investigation of several Senecio species has resulted in the isolation of a series of lupane derivatives which include the acids (135), (137), and (139), the corresponding aldehydes (136), (138), and (140), the ketone (141), and betulonic acid.” Three more triterpenoids (142)-( 144) have

-f

-4

HO” (135) Alycz1),R = C 0 2 H (136) A ’ Y ( 2 1 ) , R = C H 0 (137) AI2, R = C 0 2 H (138) A12, R = CHO (139) A’‘’ I ) , R = C 0 2 H (140) Arc’’), R = C H O (141) A”(z’), R = M e

(142) R ’ = 0 , R 2 = M e , R 3 = O H (143) R’ = H,D-OAc, R2 = CHO. R3 = H (144) R’ = H$-OH, R2 = CH,OH, R3 = H ”

F. Ionescu, S. D. Jolad, J. R. Cole, S. K. Arora, and R. B. Bates, .I. Org. Chem., 1977,42, 1627. K. H. Knoll, C. Zdero, P. K. Mahanta, M. Grenz, A. Suwita, D. Ehlers, N. Le Van, W.-R. Abraham, and A. A. Natu, Phyrochemistry, 1977,16,965.

’‘ F. Bohlmann,

Terpenoids and Steroids

170

been obtained from the stems of Lithocarpus polystachya" (see Vol. 6, p. 122). Other new natural products include 3~-acetoxy-30-norlupan-20-one(145) from Claoxylon polot,'s 3P-hydroxylup-20(29)-en-30-ol(146) and lupane-3@,30-diol (147) from Quercus ~ h a m p i o n i ilup-20(29)-ene-2a,2@-diol ,~~ (148) from the bark of Pterocarpus santalinus," and betulic acid 3-O-P-~-glucoside(149) from the leaves of Eryngium bromeliifolium. '('O

04.

HOH,C-J

Q

HOH,CG(

n2

9

\

\

\

(145) R ' = H,P-OAc

(148) R' (149) R'

(146) R' = H,P-OH

(147) R' = H,P-OH

= H, R ' = OH, R3 = M e = B-D-G~u,R2 = H, R3= C 0 2 H

The confusion surrounding the structure of thurberine (calenduladiol) has been resolved'0'.'02 (see Vol. 7, p. 142). It is identical with beyeriadiol, 3p,l6p-dihydroxylup-20(29)-ene (150), from Beyeria laschenaulrii."' Authentic lupane-3,12dione (15 l), prepared from 3P,28-diacetoxylup- 12-ene, is not identical with the corresponding thurberine derivative."' A necessary consequence of this work is the revision of the structure of resinone, from Fluoresia resinosa, to 3-0x0-16phydroxylup-20(29)-ene ( 1 52)?

0

(150) R = H,P-OH (152) R = O 97 98 9y

100 101

(151)

W.-H. Hui and M.-M. Li, Phytochemistry, 1977, 16, 1 1 1 . W.-H. Hui, M.-M. Li, and Y.-C.Lee, Phytochemistry, 1977,16,607. N. Kumar and T. R. Seshadri, Phytochemistry, 1976,15, 1417. K. Hiller, K. Q. Nguyen, P. Franke, and R. Hintsche, Pharmnzie, 1976, 31,891. J . St. Pyrek and E. Baranowska, Roczniki Chem., 1977,51, 1141.

Triterpenoids

171

Acid-catalysed isomerization of the olefins (153)-(155), obtained on decarboxylation of lupan-28-oic acid, resulted in the formation of the lup-17-ene derivative (156) with inversion at C-19 and not 28-norlup-l3(18)-ene (157) as previously ~uggested.'"~ Further studies have been reported on a series of lupan12-one104 and 29-hydroxy-30-norlupan-20-one (1 S8)'" derivatives. The nitrone (159) and the N-hydroxy-lactam (160) were produced on irradiation of 3pacetoxy-28-nitrosyloxylupane(161).Io6

(153) R = H

(154) R = H

(155) R = H

o=/CHzoH

(156) R = H

1

(157) R = H

-/

CH,OAc

(158) R = O A c

(159) R = O A c

(160) R = O A c

(161) R = O A c 102

I03

I 04

I05 1W

J. Protiva, F. Turecek, and A. Vystrkil, Coll. Czech. Chem. Comm., 1977,42, 140. G . V. Baddeley, C. J. R. Fookes, and S. K. Nigam, Austral. J. Chem., 1976,29, 2707. V. Pouzar and A. Vystrtil, Coll. Czech. Chem. Comm., 1976,41,3452. V . Pouzar and A. VystrEil, Coll. Czech. Chem. Comm., 1977,42,2224. J. Protiva, M. BudkSinsky, and A. Vystrtil, CON. Czech. Chem. Comm., 1977.42, 1220.

Terpenoids and Steroids

172

Dehydrogenation of lupenone pnitrophenylhydrazone with iodine and t-butoxide followed by treatment with aqueous TiCl, gave the AI-3-ketone glochidone in 50% yield.Io7 The trihydroxylupane (162) is formed on hydroboration of betulin. lo*

(162) R = O H

6 Oleanane Group Arjunglucosides I (163) and I1 (164) from Terminalia arjuna are the glucose esters of arjungenin and arjunolic acid r e s p e c t i ~ e l y . 'The ~ ~ full details of the structure elucidation of arjungenin are included in this paper. Three lyxosides (165)-(167) have been obtained, together with 16cu,21P,22a,28-tetrahydroxyolean-12-en-3-

HO..

"R HO CH,OH

(163) R = O H (164) R = H

(165) R = O H (166) R = O A c (167) R = H

one (168), from the bark extract of Planchonia careya following mild acid hydrolysis.l'o Another ketotetrol, harpullone (169), occurs in the bark of Harpullia pendula."' Barrigenic acid (170) is a sapogenin from the fruits of Barringtonia acutangula"' while acutangulic acid (171) is found in the 1 e a ~ e s . l Olean-13(18)'~ ene-2P,3P-diol (172) and olean-12-ene-3@,28,29-triol(173) have been isolated from Salvia h~rrninurn"~ and the stems of Hedyotis a~utangula''~ respectively. Other new oleanane natural products include the three lactones (174)-(176) from Rhodomyrtus tornentosa,"6 olean- 12-ene-3,16-dione from Quercus lo' I"'

'09 'lo

'I1 'I2

'I4

A. Chatterjee and A. Banerjee, Indian J. Chem., 1977, B15,87. L. G. Matyukhina and I. A. Sdtykova, ZhuL obshchei Khim., 1976,46, 2759. T. Honda, T. Murae, T. Tsuyuki, T. Takahashi, and M. Sawai, Bull. Chem. SOC.Japan, 1976,49,3213. P. W. Khong and K. G. Lewis, Ausfrul. J. Chem., 1977,30, 1311. R. F. Cherry, P. W. Khong, and K. G. Lewis, Ausfral. J. Chem., 1977,30, 1397. A. K. Barua, P. Chakrabarti, A. S. D. Gupta, S. K. Pal, A. Basak, S. K. Banerjee, and K. Basu, Phytochemistry, 1976,15, 1780. K. G . A. S. S. Narayan, L. R. Row,and C. S. Sastry, Cunenr Sci., 1976,45,518. A. Ulubelen, C. H. Brieskorn, and N. Oezdemir, Phytochemistry, 1977,16, 790. W.-H. Hui and M.-M. Li, Phytochemistry, 1977, 16, 1309. W.-H. Hui and M.-M. Li, Phyfochernisfry, 1976,15, 1741.

Triterpenoids

173

fl

'0H E H

R' HO (168) R ' = H , R 2 = O H (169) R' = OH, R2 = H

(170) R=CO,H

(171) R = M e

X20H R HO (172) R = O H

(173) R = H

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

174

Terpenoids and Steroids

p-peltoboykinolic acid acetate from Astilbe rivularis”7 (see barnbusaef~lia,~~ Vol. 1, p. 190), and assorted triterpenoid esters from Mimusups litturalis1‘8and Saussurea lappa.”’ Daturanolone, from Datura fastuosa, has been shown to be identical with daturaolone (177) from D. innoxia.”’

(177)

Full papers _ _ on the crystal structures of echinocystic acid diacetate bromolactone121 and papyrogenin A’22 have appeared. The structure of 3p,16/3dimethoxyoIean-12-en-28,21/3-olide (178) has been confirmed by X-ray analy-

(178)

s ~ s . ”Another ~ crystal structure of campanulin (dendropanoxide) (196) (p. 178) has been published’24 (see Vol. 3, p. 214). A short stereoselective synthesis of the pentacyclic key intermediate (179) in Ireland’s syntheses of friedelin and alnusenone (see Vol. 7, p. 149) is outlined in Scheme 5.Iz5 Forced Wolff-Kishner reduction of the ketone ( I 85) from arjunic acid and. subsequent methylation and acetylation afforded the 13aH derivative (186).”‘ Conversion of acacic acid lactone (187) into dihydrosapogenin B (1 88) establishes the l8PH configuration of (187).’*’ Phosphorus oxychloride converts (187) into ‘I7

120 lZ1

124

IZ5

127

B. S. Sastry and E. V. Rao, Indian J. Chem., 1977,15B, 494. R. Banerji, G. Misra, and S. K. Nigam, Fitoterapia, 1977,48, 68. P. P. Pai and G. H. Kulkarni, Current Sci., 1977, 46, 261. M. Ahmad, M. A. Hai, A. Khaleque, and M. A. W. Miah, Indian J. Chem., 1976,14B, 1007. C. H. Carlisle, P. F. Lindley, and A. Perales, Acta Cryst., 1976, B32, 3053. S. Amagaya, M. Takai, Y. Ogihara, and Y. Iitaka, Acta Cryst., 1977, B33, 261. R. Roques, L. Comeau, R. Fourme, R. Kahn, and D. Andre, Acta Cryst., 1977, B33, 1682. F. Mo, Acta Cryst., 1977, B33, 641. T. Kametani, Y. Hirai, F. Satoh, and K. Fukumoto, J.C.S. Chern. Comm., 1977, 16. T. Honda, T. Murae, T. Tsuyuki, and T. Takahashi, Chem. Letters, 1977, 271. A. S. R. Anjaneyulu, M. Bapuji, M. G. Rao, L. R. Row, P. C. S. A. Sastry, and C. Subrahmanyam, Indian J. Chem., 1977, 15B, 1.

Triterpenoids

175

SO '\

Me0

CN

(179) Reagents: i, isoprene, A; ii, NaNH,-liq. NH,; iii, A; iv, BuiAiH-C6H6; v, NH'NHz-KOH

Scheme 5

the triene (189).'28 Attention has been given to the preparation of the isomeric 2,3-di01s,'*'-'~' 2,3-ket01s,'~'-'~~ and ring A lac tarn^'^^ of several pentacyclic triterpenoids.

A. S. R. Anjaneyulu, M. Bapuji, and L. R. Row, Indian J. Chem., 1977, 15B, 7. D. R. Misra, H. N. Khastgir, M. Sung, and L. J. Durham, Indian J. Chem., 1976, 14B, 41 1 . K. Chattopadhyay, D. R. Misra, and H. N. Khastgir, Indian J. Chem., 1977,15B, 21. G. R. Mallavarapu, T. S. Rarnaiah, and V. V. Bai, Current Sci., 1977,46, 252. '31 K. Chattopadhyay, D. R. Misra, and H. N. Khastgir, Indian J. Chem., 1976,14B, 839. 133 D. R. Misra, H. N . Khastgir, M. Sung, and L. J. Durham, Indian J. Chem., 1976, 14B, 407. 134 T. S. Ramaiah, S. K. Ramraj, K. L. Rao, and V. V. Bai, J. Indian Chem. SOC., 1916, 53, 664. '21

129

176

Terpenoids and Steroids

Several papers dealing with the reactions of glycyrrhetic acid derivative^'^^-'^^ have been published. The distribution and structural elucidation of saponins have been re~iewed.'~' Glucuronides with a free carboxy-group and carbohydrate residues at C-2' and C-4' are readily cleaved with acetic anhydride in refluxing pyridine to give the genuine a g l y ~ o n e '(see ~ ~ Vol. 7, p. 145). Details of the mass spectra of a series of permethylated oleanane saponins have been discussed. 140 The increasing use of 13C n.m.r. spectroscopy in the structural investigation of saponins is reflected in the number of papers which have appeared in this area. The 13C resonances of ~ a i k o g e n i n sand ~ ~ ' ~aikosaponins~~' from Burpleum falcatum and of other acylated sap on in^'^^ have been assigned and the data applied in the structure elucidation of minor sap on in^^^^ from the same source. Glycosidation shifts and their stereochemical dependence have been discussed for a wide range of glycosides and a g l y ~ o n e s . ' ~ ~ ~ ' ~ ~ Publications have appeared on the following saponins: sakurasosaponin from the root of Primula ~ i e b o l d i , 'saponin ~~ A from the stem bark of Anthocephalus 136 13'

S. Rozen, I. Shahak, and E. D. Bergmann, Israel J. G e m . , 1975, 13, 234. R. K. Gayanov, H.-0. Kim, M. P. Irismetov, and M. I. Goryaev, Zhur. org. Khim., 1977.13, 895. R. K. Gayanov, H.-0. Kim, M. I. Goryaev, and M. P. Irismetov, Zhur. obshchei Khim.,1976,46,2375. K. Hiller and G. Voigt, Phnrmazie, 1977, 32, 365. I. Kitagawa, Y. Ikenishi, M. Yoshikawa, and K. S. Im, Chem. and Pham. Bull. (Japan), 1977, 25, 1408.

141 142

143

144

'41 146

'41

R. Higuchi, T. Komori, and T. Kawasaki, G e m . andPharm. Bull. (Japan), 1976,24,2610. K. Tori, Y. Yoshimura, S. Seo, K. Sakurawi, Y. Tomita, and 5.Ishii, Tetrahedron Lefters, 19764fii3. K. Tori, S. Seo, Y. Yoshimura, M. Nakamura, Y. Tomita, and H. Ishii, Tetrahedron Letfers, 1976,4167. K. Yamasaki, R. Kasai, Y. Masaki, M. Okihara, H. Oshio, S. Takagi, M. Yamaki, K. Masuda, G. Nonaka, M. Tsuboi, and I. Nishioka, Tefiahedron Letters, 1977, 1231. H. Ishii, S. Seo, K. Tori, T. Tozyo, and Y. Yoshimura, Tefrahedron Letters, 1977, 1227. K. Tori, S. Seo, Y. Yoshimura, H.Arita, and Y. Tomita, Tetrahedron Letters, 1977, 179. R. Kasai, M. Suzuo, J. Asakawa, and 0. Tanaka, Tetrahedron Letters, 1977, 175. I. Kitagawa, Y. Ikenishi, M. Yoshikawa, and I. Yosioka, Chem. and Pharm. Bull. (Japan), 1976, 24, 2470.

Triterpenoids

177

~adarnba,'~' songorosides C , G , I, M, and 0 from Scabiosa s o o n g o r i ~ a , ' ~ ~ ~ ~ ~ ~ caulosides C-G from Caulophyllum r o b u s t ~ m , 'and ~ ~ ,lebbekanin ~~~ E from Albizzia lebbek.153 Two new taraxeranes (190) and (191) have been isolated from Quercus barnb~saefolia.~~ Isomultiflorenone (192) and isomultiflorenol acetate (193) are new natural products from Cucurbita lundelliana and Vernonia fasciculata155 respectively. Studies on the allylic oxidation and bromination of taraxeryl acetate (194)156and on the Lewis acid-catalysed rearrangement of (1 94) and friedelan01'~~ have been reported.

(190)R' = 0,R' = H (191)R' = H,P-OH, R2= OH; 1,2-dihydro (194)R' = H,P-OAc,R2= H; 1,2-dihydro

(192)R = O (193)R = H,/3-OAc

Full papers have appeared on the friedelanes from Hydnocarpus octandra"' and Trichadenia ~eylanica,~'~ the mechanism of the photochemical reaction of friedelin with acetone,'6o and the rearrangement of 3p74P-epoxyfriedelane (195) to

149

''I

'53

'" '51

160

N. Banerji and N. L. Dutta, Indian J. Chem., 1976,14B, 614. A. Akimaliev, P. K. Alimbaeva, L. G. Mzhel'skaya, and N. K. Abubakirov, Khim. prirod. Soedinenii, 1976,472. A. Akimaliev, P. K. Alimbaeva, L. G. Mzhel'skaya, and N. K. Abubakirov, Khim. prirod. Soedinenii, 1976,476. N. S. Chetyrina, L. I. Strigina, Y. N. El'kin, and V. V. Isakov, Tezisy Doklady Vses. Simp. Bioorg. Khim., 1975. 13. L. I. Strigina, N. S. Chetyrina, and V. V. Isakov, Khim. prirod. Soedinenii, 1976,619. 1. P. Varshney, R. Pal, and P. Vyas, J. Indian Chem. Suc., 1976,53, 859. K. Seifert, H. Budzikiewin, and K. Schreiber, Pharmazie, 1976, 31, 816. N. K. Narain, Canad. J. Pharm Sci., 1977,12, 18. K. Chattopadhyay, D. R. Misra, and H. N. Khastgir, IndianJ. Chem., 1976, 14B,403. A. Chatterjee, S. Mukhopadhyay, and K. Chattopadhyay, Tetrahedron, 1976,32, 3051. S. P. Gunasekera and M. U. S. Sultanbawa, J.C.S. Perkin I, 1977, 418. S. P. Gunasekera and M. U. S. Sultanbawa, J.CS. Perkin I, 1977,483. H. Shirasaki, T. Tsuyuki, T. Takahashi, and R. Stevenson, Bull. Chem. SOC.Japan, 1977,50,921.

Terpenoids and Steroids

178

dendropanoxide (campanulin) ( 1 96).16' Trichadenal (197) and acetyltrichadenal (198) are new friedelanes from T. ~ e y l a n i c a . 'Reaction ~~ of 3@,4P-epoxyfriedelane (195) with boron trifluoride ctherate in benzene, instead of ether, afforded germanicol (199)16' in addition to the known rearrangement products (see Vol. 6, p. 137).

(197) R = H (198) R = A c

7 Ursane Group

Jacoumaric acid (200) and jacarandic acid (201) have been isolated from Jacaranda c a ~ c a n a . ' ~Three ~ ' ' ~ new ~ 13aH-ursane lactones (202)-(204) have been reported ~ ~ new compounds include barbinervic acid (205) from Mallotus r e p a n d ~ s . 'Other from the leaves of Ckthra barbinervis'66and the bauerene derivative myrtifolic acid (206) from the bark of Mesua myrtifolia. 16' The methyl resonances in the proton spectra of a series of ursenes have been assigned.'68

HO..

Rl&02H

Ho--

,

R2

(201) R' =OH, R2= Me (205) R' = H, R2 = CH20H

161

M. Tori, T. Torii, K. Tachibana, S. Yamada, T. Tsuyuki, and T. Takahashi, Bull. Chem. SOC.Japan, 1977, 50, 469. M. Tori, T. Tsuyuki, and T. Takahashi, Chem. Lerters, 1977,699. 163 M. Ogura, G. A . Cordell, and N . R. Farnsworth, Phytochemistry, 1977,16,286. 164 M. Ogura, G. A . Cordell, and N. R. Farnsworth, Lloydia, 1977,40, 157. 165 W.-H. Hui and M.-M. t i , Phyrochernistry, 1977,16, 113. M. Takani, K . Kubota, M. Nozawa, T. Ushiki, and K. Takahashi, Chem. and Pharm. Bull. (Japan), 1977, 25, 981. 16' S. P.Gunasekera and M. U. S. Sultanbawa, J.C.S. Perkin I, 1977, 6. 16* G. Romeo, P. Giannetto, and M. C. Aversa, Org. Magn. Resonance, 1977,9,29. '62

Triterpenoids

179

(202) R = H,P-OH (203) R = H,POBz (204) R=H,(u-OH

8 Hopane Group 21 aH-Hop-22(29)-ene-3&3O-diol (207) and the corresponding aldehyde (208) have been isolated from Rhodomyrtus tomentosa."5 Other new hopane natural products include 6&22-dihydroxyhopane (209) from the fern Cheilanthes marantae'" and 2 1aH-hopane-3P,22-diol and hop- 17(2l)-en-3-one from Quercus ~hampionii.~'

OH (207) R = CH20H (208) R = C H O

The main triterpanes in Russian petroleum are C,,-,, 1 7 a H - h o p a n e ~ . ~ ~ ~ * ~ ' ~ A crystal structure analysis of tetrahymanol (210) has a p p e a ~ e d . ' ~The ' methyl resonances in the proton spectra of tetrahymanol and tetrahymanone have been assigned.173

(210) I70

I72 173

A. G. Gonzalez, C. Betancor, R. Hernindez, and J. A. Salazar, Phytochemisny, 1976,15, 1996. S. D. Pustil'nikova, N. N. Abryutina, G. R. Kagramanova, and A. A. Petrov, Geokhimiya, 1976, 460. A. A. Petrov, S. D. Pustil'nikova, N. N. Abryutina, and G . R. Kagramanova, Neftekhimiya, 1976, 16, 41 1 D. A. L a n g , W. L. Duax, H. L. Carrell, M. Berman, and E. Caspi, J. Org. Chem., 1977,42,2134. T. A. Wittsruck and E. Caspi, J. Chem. Res. ( S ) , 1977, 180.

Terpenoids and Steroids

180 9 Stictane-Flavicane Group

The structure of retigeradiol, from the lichen Lobaria retigeru, has been revised to stictane-3&22a-diol (2 1 l)."' It was originally thought to be taraxerane-3/3,19Pdiol. The ketol previously isolated from Centrariu niuuli~''~is probably 22ahydroxystictan-3-one (212).'"

(211) R=H,P-OH (212) R = O

'71 '71 176

R. E. Corbett, C. K. Heng, and A. L. Wilkins, Austral. J. Chem., 1976,29, 2567. T. Bruun, Acra Chem. Scand., 1969, 23, 3038. A. L. Wilkins, Phyrochemistry,1977,16,608.

5 Carotenoids and Polyterpenoids BY

G. BRllTON

1 Introduction The main lectures from the 4th International Symposium on Carotenoids, held at Bern, Switzerland, in 1975 have been published in a book' that is intended to serve as a supplement to the 1971 Isler monograph.2 The first part, dealing with carotenoid chemistry, consists of chapters on the 13Cn.m.r. spectra of carotenoids,'" carotenoid-protein complexes,'b carotenoid glycosides," new structures,ld carotenoid stereochemistry," the synthesis of carotenoids and related polyenes," the enol-ether synthesis of polyenes,18 and the commercial synthesis of carotenoids."' Biologically important 'degraded carotenoids' are dealt with in papers on the apocarotenoid system of sex hormones and prohormones in Mucorales" and on xanthoxin and abscisic acid,'' and three contributions discuss the early steps,lk later reactions," and photoregulation of carotenoid biosynthesis.'" Another book, a 'Key to Car~tenoids',~ extends the list of natural carotenoids in the 1971 monograph.4 Reviews published include a summary5 of progress in the chemistry and biology of fat-soluble vitamins and carotenoids over the past 10 years, chapters on carotenoids6 and hormones' in filamentous fungi, and a survey of ionones, irones, and their derivatives in Nature.8

2 Carotenoids New Structures.-The 'Key to Carotenoid~'~ lists all carotenoids found in Nature up to the middle of 1975, and gives extensive references to occurrence and physical, chemical, and spectroscopic properties. An outline of work on the eluci-

'

Pure Appl. Chem., 1976,47, pp. 97-243, also published as 'Carotenoids-4 (Berne, 1975'). ed. B. C. L. Weedon, Pergamon Press, Oxford, 1977; (a) G. P. Moss, p. 97; (6) P. F. Zagalsky, p. 103; ( c ) H. Pfander,p. 121; ( d ) S. Liaaen-Jensen, p. 129; (e) J. Szabolcs, p. 147; V, B. C. L. Weedon, p. 161; ( g ) S. M. Makin, p. 173; (h) F. Kienzle, p. 183; (i) J. D. Bu'Lock, B. E. Jones, and N. Winskill, p. 191; 0') R. S. Burden and H. F. Taylor, p. 203; ( k ) B. H. Davies and R. F. Taylor, p. 21 1; (1) G. Britton, p. 223; ( m ) W. Rau, p. 237. 'Carotenoids',ed. 0. Isler, Birkhauser, Basel, 1971. 0. Straub, 'Key to Carotenoids-Lists of Natural Carotenoids', Birkhauser,Basel, 1976. 0. Straub, in ref. 2, p. 771. ' 0. Isler, Experienfia, 1977,33,555. T. W. Goodwin, Filamentous Fungi, 1976,2,423. ' J. D. Bu'Lock, Filamentous Fungi, 1976, 2, 345. Y . R. Naves, Rivista Ital. Essenze, Profumi, Piante Ofic., Aromi, Saponi, Cosmet., Aerosol., 1976, 58, 505.

181

Terpenoids and Steroids

182

dation of new carotenoid structures over the period 1970-1975 lished.Id

has been pub-

Acyclic Carotenoids. Two pigments from Rhodopseudomonas sphaeroides have been identifiedg as methoxyspheroidene [ l,l'-dimethoxy-3,4-didehydro1,2,1',2',7',8'-hexahydro-+,+-carotene (l)] and methoxyspheroidenone [ 1,l'dimethoxy-3,4-didehydro-1,2,1',2',7',8'-hexahydro-$,+-caroten-2-one (2)]. Ano-

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

ther Rhodopseudornonas species, Rps. viridis, contains small amounts of crossconjugated carotenoid aldehydes including 13-cis-$,$-caroten-2O-al (3) and a novel 1,2-dihydro-derivative." The methods used could not distinguish between the alternative structures 3,4-dide hydro- 1,2-dihydro- +-caroten-20-al (4) and 3',4'-didehydro- 1 ',2'-dihydro- +-caroten-2O-al (5).

+,

3 +,

R' -

RZ

L

L ...

...

b

a

(3) R ' = R ~ = ~ (4) R' = b, R2= a (5) R ' = a , R 2 = b

Monocyclic Carotenoids. Eighteen carotenoid hydrocarbons have been isolated from the ladybird beet,le Coccinella septempunctata." Amongst the minor' components were detected small amounts of the new y-ring derivatives 3',4'didehydro-y,$-carotene (6), 7',Sf-dihydro-y,$-carotene (7), and 7',8',1 1',12'tetrahydro- y, $-carotene (8). Bicyclic Carotenoids. A major pigment of the bacterium Rhizobium lupini, 2,3,2',3'-di-trans-tetrahydroxy-P,P-caroten-4-one (9), is the first natural carotenoid to be described with oxygen substituents at positions 2, 3, and 4 of the ring.I2 Also present were 2,3,2'(or 3')-trihydroxy-@,@-caroten-4-one, (10) or (1 l),

lo

"

'*

G. Britton, H. C. Malhotra, R. K. Singh, S. Taylor, T. W. Goodwin, and A. Ben-Aziz, Phytochemtstry, 1976,15, 1971. G. Britton, H. C. Malhotra, R. K. Singh, T. W. Goodwin, and A. Ben-Aziz, Phytochemistry, 1976,15, 1749. G. Britton, W. J. S. Lockley, G. A. Harriman, and T. W. Goodwin, Nature, 1977, 266,49. H. Kleinig, W. Heumann, W. Meister, and G. Englert, Helv. Chim. Acfu, 1977,60, 254.

183

Carotenoids and Polyterpenoids

and carotenoids that appear to be identical to the recently characterizedI3 caloxanthin [P,P-carotene-2,3,3’-triol (1 2)] and nostoxanthin [P$-carotene-2,3,2’,3’tetrol (1 3)].

(9) X ’ = X 2 = y 1 = Y 2 = O H , R = O (10) X’ = x2= Y’ =OH, y2= H, R = o ( I 1) X’ = Y ’ = y2= OH, x2= H, R = o (12) X I = Y ’ = Y’ = OH, x2= H, R = H,H (13) X ’ = X Z = Y ’ = Y 2 = O H , R = H , H

A minor carotenoid of the alga Coccolithus huxleyi has been identifiedz4 as 3’-desacetyl- 19’-n-hexanoyloxyfucoxanthin [5,6-epoxy- 19’-n-hexanoyloxy-3,3’,5’trihydroxy-6‘,7’-didehydro-5,6,7,8,5’,6‘-hexahydro-~,~-~aroten-8-one (14)]. Two

CO

I

(CH,),Me (1.1)

C-5 epimers of 6,7-didehydro-5,6,5’,6‘-tetrahydro-P,P-carotene-3,5,3’,5‘,6’pent01 (15), isolated as minor constituents of a sample of neoxanthin [5’,6‘-epoxy6,7-didehydro-5,6,5’,6’-tetrahydro-P,P-carotene-3,5,3’-triol (16)] from Trollius europaeus, may be artefacts.I5 In Sarcina lutea, sarcinaxanthin [2,2’-bis-(4i3 i4

*5

R. Buchecker, S. Liaaen-Jensen, G. Borch, and H. W. Siegelman, Phyrochemzsrry, 1976, 15,1015. S. Hertzberg, T. Mortensen, G. Borch, H. W. Siegelman, and S. Liaaen-Jensen, Phytochernistry, 1977, 16, 587. R. Buchecker and S. Liaaen-Jensen, Phytochemishy, 1977, 16, 729.

184

Terpenoids and Steroids

HO

,,go”

(16) R = O

hydroxy-3-methylbut-2-enyl)-y,y-carotene (17)] occurs at least partly esterified with a C9H,,C0,H acid.16

(17) R =

Animal tissues have yielded several carotenoids of previously unknown structure. Chiriquixanthins A and B from a yellow frog, Ate6opus chiriquiensis,, have been found” to be epimeric ~,~-carotene-3,3’-diols (18) and (19) differing

(18) X = H , Y = O H (19) X = O H , Y = H

only in their stereochemistry at C-3. Major carotenoids of the stick insect Curuusius morosus are esters of P,P-caroten-2-01 (20) and P,P-carotene-2,2’-diol (21).18Also present” are six 2-oxo-derivatives, 3,4,3’,4’-tetradehydro-fi,fi-carotene-2,2’-dione (22), 3,4-didehydro-p,p-carotene-2,2’-dione (23), 2’-hydroxy-3,4didehydro-P,P-caroten-2-one (24), 2‘-hydroxy-P,P-caroten-2-one (25), P,Pcaroten-2-one (26), and P,P-carotene-2,2’-dione (27). Parasiloxanthin [7,8-dihydro-P,P-carotene-3,3‘-diol (28)] and 7,8-dihydroparasiloxanthin [7,8,7‘,8’-tetrahydro-p,P-carotene-3,3’-diol (29)] have been isolated from a Japanese fish, Parasilurus asotus.“ The presence of the 7,8-dihydro structure was deduced from the ‘H n.m.r. spectrum.

’‘ ” ”

’’

S. Hertzberg and S. Liaaen-Jensen, Actu Chem. Scund., 1977, B31, 215. A. Bingham, H. S. Mosher, and A. G. Andrewes, J.C.S. G e m . Comm., 1977,96. H. Kayser, Z. Narurforsch., 1976, 31c, 646. H. Kayser, Z. Nuhrrforsch., 1977,32c, 327. T. Matsuno, S. Nagata, and K. Kitamura, Tetrahedron Letters, 1977,4601.

Carotenoids and Polyterpenoids

185

b

a

(20) R’ = a (X = H,OH), R’ = a (X = H,H) (21) R’ = R’ = a = H,OH) (22) R 1 = R 2 = b

(x

( 2 3 ) R’ = b, R 2 = a ( X = 0)

(24) R’= b, R2 = a (X = H,OH) (25) R’ = a (X = 0),R’ = a (X = H,OH) (26) R’ = a ( X = 0),R’= a (X = H,H) (27) R’= R2 = a (X = 0)

Two aryl carotenoids from marine sponges, clathriaxanthin” and tedaniaxanthin,” have been assigned the structures 3-hydroxy-P,~-caroten-4-one (30) and 2,3-didehydro-P,x-caroten-3-01(3 1). Clathriaxanthin, normally present as an ester, is readily autoxidized to form the corresponding diosphenol clathricine [3-hydroxy-2,3-didehydro-P,X-caroten-4-one (32)]. The trivial nomenclature is very confusing since this structure was previously assigned to another sponge carotenoid, tedanin.23

Apocarotenoids. The natural occurrence of neurosporaxanthin methyl ester [methyl 4‘-apo-P-caroten-4‘-oate (33)] in the fungus Verticillium agaricinum has been reported.24 Carotenoid Glycosides. The chemistry and distribution of carotenoid glycosides have been reviewed.’“ A dihexoside (presumed diglucoside) of sarcinaxanthin has been detected in Sarcina lutea.‘6 The gliding bacterium Herpetosiphon giganteus contains a series of esterified glycosides, the 1’-X-0-acylglucosyloxy-, 1’-X- 0acyldiglucosyloxy-, and 1’-diglucosyloxy-derivativesof 3’,4‘-didehydro-l’,2’-dihydro-P,+-caroten-4-one (34), which were identified from their m.s. and ‘H n.m.r. spectra.” Carotenoproteins. These complexes are arousing increasing interest as the form in which many carotenoids probably exist in vivo. The carotenoprotein field has been reviewed.” Two reports have described new blue carotenoproteins, a canthaxanthin (35)-lipovitellin of crustacean origin26and, from a marine chondrophore, an astaxanthin (36) complex which dissociates into different pigment forms at different ionic strength^.^' Further details have been obtained concerning the quaternary structure of the lnbster exoskeleton astaxanthin complex, crustacyanin.28 Algal sources have also yielded carotenoid-protein complexes. A water-soluble

*’ Y. Tanaka and T. Katayama, Bull. Jup. SOC.Sci. Fisheries, 1976,42, 801. 22

23 24

” 26 27

Y. Tanaka, Y. Fujita, and T. Katayarna, Bull. Jup. Soc. Sci. Fisheries, 1977,43, 761. N. Okukado, B U N Chem. Soc. Jupun, 1975,48, 1061. L. R. G. Valadon and R. S. Mummery, Phytochemishy, 1977,16,613. H. Kleinig and H. Reichenbach, Arch. Microbiol., 1977,112, 307. P. Z. Zagalsky and B. M. Gilchrist, Comp. Biochem. Physiol., 1976,55B, 195. P. F. Zagalsky and P. J . Herring, Phil. Trans. Roy. Soc. London, Ser. B., 1977, 279, 289. R. Quarmby, D. A. Norden, P. F. Zagalsky, H. J . Ceccaldi, and R. Daumas, Comp. Biochem. Physiol., 1977,56B, 5 5 .

Terpenoids and Steroids

186

chromoprotein from the green alga Scenedesmus obliquus has violaxanthin [5,6,S',6'-diepoxy-5,6,S',6'-tetrahydro-/3,/3-carotene-3,3'-diol (37)] together with

H

0 a

b

d

e

C

0 f

h

(28) R' = a , R2 = b (X = OH) (29) R ' = R ~ = ~ (30) R' = c (Y =OH), R2 = d (31) R ' = e , R 2 = d (32) R'==f, R 2 = d

(33) R' = b (X = H), R2 = CH=CH-CH=C(Me)CO,Me (34) R * = c (Y = H), R2 = g (35) R' = R2 = C (Y = H) (36) R ' = R ~ = c ( Y = o H ) (37) R' = R 2 = h

some neoxanthin (16) as its carotenoid components,29 and the photosynthetic light-harvesting complex from several marine dinoflagellates has been identified as a peridinin [5',6'-epoxy-3,5,3'-trihydroxy-6,7-didehydro-S,6,5',6'-tetrahydro10,11,2O-trinor-/3,~-caroten-19',1 l'-olide-3-acetate (38)]-chlorophyll-a prot ein . ' 3073

I

Lnu

'' R. Powls and G. Britton, Biochirn. Biophys. Acta, 19'76, 453, 270.

'"B. B. Prtzelin and F. T. Haxo, Plantu (Berlin),1976, 128, 133. 3'

P.-S.Song, P. Koka, B. B. PrCzelin, and F. T. Haxo, Biochemisiry, 1976, 15, 4422

187

Carotenoids and Polyterpenoids

Degraded Carotenoids. Several compounds have been described and characterized which are related structurally to carotenoids and may be biodegradation products of carotenoids. The structure of the vitamin A dimer kitol has been determined as (39).32Three metabolic products of retinoic acid (40) have been isolated from rat urine and characterized as (44), ( 4 3 , and (46).33Rat faeces yielded three further products (41), (42),and (43).34 YH,OH

X (40) X = H,H, R = Me (41) X = O , R = M e

(42) X = H,H, K = C H 2 0 H (43) X = H,H, R = CHIOH, 9,10-&

CO,H

0

"

O0

H

2

W

(44) R = M e (45) R=CH,OH

Examination3' of the flavour constituents of the passion fruit Pussiflora edulis has yielded the novel ionone derivatives (47) and (48). Edulans I and 11, (49) and (50),36and dihydroedulans 1 and 11, (51) and (S2)," from the same source have been characterized fully. Two bicyclodamascenones, (53) and (54),have been identified as components of the flavour of Virginia t o b a c ~ o , ~and ' several ionone, damascone, and cyclocitral derivatives are present amongst the many volatile compounds produced during flue-curing of this t o b a c ~ o . ~ ' T. Yano, Kyushu Daigaku Nogakuba Gakugei Zasshi, 1976,31,41 (Chem. Abs., 1977,86, 90 087). R. Hanni, F. Bigler, W. Meister, and G. Englert, Helv. Chim. Acfa, 1976, 59, 2221. R. Hanni and F. Bigler, Helu. Chim. Acfa, 1977,60, 881. 35 F. Naf, R. Dkorzant, B. Willhalm, A . Velluz, and M. Winter, Tefrahedron Lefrers, 1977, 1413. 36 F. B. Whitfield and G. Stanley, Austral. J. Chem., 1977, 30, 1073. 37 G. D. Prestwich, F. B. Whitfield, and G. Stanley, Tetrahedron, 1976, 32, 2945. '' E. Demole and P. Enggist, Helu. Chim. Acra, 1976, 59, 1938. 39 1. Wahlberg, K. Karlsson, D. J. Austin, N. Junker, J . Roeraade. C. R. Enzell, and W. H. Johnson, Phytochemisfry, 1977, 16, 1217.

32

33

34

Terpenoids and Steroids

188

(47) X = H,OH (48) x - 0

(49) R’ = Me, R2 = H (SO) R’ = H, R2=Me

(51) R ’ = M e , R 2 = H (52) R’ = H, R2 = Me

Stere0chemistry.-Various aspects of carotenoid stereochemistry are dealt with extensively in two reviews.’d‘ The (6’s) configuration has been assigned to natural P,y-carotene (55) from Culoscyphu fulgens by c.d. correlation with P,y-carotene samples enriched in the (6’R) and (6’s) enantiomers synthesized from partly resolved y-ionone (64).40 The same configuration was established for C-6 and C-6‘ of the Cs0carotenoid sarcinaxanthin.16 The substituents at C-2 and C-6 are in a cis relationship and the double bond of the C, substituent is E (56). Bacterial zeaxanthin [&/3-carotene-3,3’-diol (57)] rhamnoside has the (3R,3’R) configuration and an a-L-rhamnopyranosyl glycosidic link.41C.d correlation has shown that the end groups in ‘asterinic acid’ [7&didehydroastaxanthin (58) + 7,8,7’,8’-tetradehydroastaxanthin (59)] have the same (3s) chirality as lobster astaxanthin [3,3’dihydroxy-/3,/3-carotene-4,4’-dione (60)].42 The ~,~-carotene-3,3’-diols chiriquixanthins A and B represent the first examples of two carotenoid epimers being present in the same source. Their chirality was established as (3R,6R,3’$6’R) (18) and (3S,6R,3’S,6’R) (19) respectively, the 3,6-cis or trans stereochemistry following from ‘H n.m.r. considerations and the (6R,6’R) chirality being assigned from the c.d. curves. Chiriquixanthin A is the first example of a carotenoid in which the two end-groups are constitutionally identical but stereochemically different.” The trans arrangement of 2- and 3-hydroxy-groups in 2,3,2’,3‘-tetrahydroxy@,P-caroten-4-one (9) and related compounds was deduced from the ‘H n.m.i. spectra of the tetra-acetates,12 although it is not yet established whether the absolute configurations at C-2 and C-3 are the same as in caloxanthin (12) and nostoxanthin (13). The absolute configurations of heteroxanthin [(3S,5S,6S,3’R)-7’,8’-didehydro5,6-dihydro-P,P-carotene-3,5,6,3‘-tetrol (61)] and diadinoxanthin [(3S,5R,6S, 3’R)-5,6-epoxy-7’,8’-didehydro-5,6-dihydro-~,~-carotene-3,3’-diol (62)] from Euglena grucilis have been established” by chemical reactions, hydrogenbonding studies (Lr.), ‘Hn.m.r., and c.d. 19’-Hexanoyloxyfucoxanthin (65) has been shown14 to have the same stereochemistry (3S,.5R,6S,3’S,SfR,6’S)as fuco40 41

42

M. Hallenstvet, R. Buchecker, G. Borch, and S. Liaaen-Jensen, Phytochemtsm, 1977,16, 583 S. Hertzberg, G. Borch, and S. Liaaen-Jensen, Arch. MicrobioL, 1976,110,95. R. Berger, G. Borch, and S. Liaaen-Jensen, Acta Chem. Scad., 1977, B31, 243.

Carotenoids and Pofyterpenoids

189

xanthin [5,6-epoxy-3,3',5'-trihydroxy-6',7'-didehydro-5,6,7,8,5',6'-hexahydroP,P-caroten-S-one 3'-acetate (66)]. ,

a+e.: e.. c"

0

___

HO

HO

HO

OH

0 d

f

e

HO

HO h

g

(55) (56) (57) (58) (59)

R'=a(X=H),R2=b R' = R~ = c R'=R2=a(X=OH) R' = d, R2 = e R' = R2 = d

(60) (61) (62) (63)

R'=R2=e R'=f,R2=g R'=h,R2=g R' = R2 = a (X = H)

(65) R = CH20CO(CH2),Me (66) R = M e

Synthesis and Reactions.-Curotenoids. Several review^'^^^"''^ survey recent progress in the synthesis and chemistry of carotenoids and related polyenes. Two other

190

Terpenoids and Steroids

reviews on recent developments in sulphone chemistry4' and the Wittig reaction in industrial practice4, include work on syntheses in the carotenoid and vitamin A series. The preparation of p-carotene [@$-carotene (63)] in 50% yield by reductive coupling of retinaldehyde (67) with TiC1,-LiAIH, has been described. Similarly p-ionone (68) gives the symmetrical olefin (69).45 The enolic p-diketone caro-

(69)

tenoids mytiloxanthin C3,3',8'-trihydroxy-7,8-didehydr~-p,~-caroten-6'-one (70)] (71)] have been and trikentriorhodin [3,8-dihydroxy-~,~-caroten-6-one ~ y n t h e s i z e d .The ~ ~ intermediate protected methyl ketone (77), prepared from (+)-camphor, underwent Claisen-type condensation with the ester (72) obtained from the dial (73) by successive Wittig reactions. The product (74) on acid treatment gave (7 1). 9-cis-Mytiloxanthin was prepared by Claisen condensation of the protected ester (75) with (77), followed by acid cleavage of the protecting acetal group and Wittig reaction on the resulting apoaldehyde (76). All attempts to prepare all-trans-(70) failed. In a synthesis o f optically active (2S)-P,P-caroten-201 (78) the key chiral intermediate (2S)-2-hydroxy-P-ionone (79) was prepared by fermentative reduction of 2-oxo-p-ionone (80) by baker's yeast.47 An improved route to (80) is described. The intermediate 8,8'-diapo-20-acetoxycarotene-8,8'-dial(81)48 has been used4' to synthesize the cross-conjugated carotenoid aldehydes X,X-caroten-20-al (82), (2R,2'R)-2,2'-bis-(3-methylbutyl)-3,4,3',4'-~~trahydr~-~,~-caroten-20-a1 (83), and (2R,6R,2'K,6'R)-2,2'-dimethyldecapreno-~,~-caroten-25-al (84). Wittig condensation of (81) with the appropriate phosphonium salts in the presence of butylene- 1,2-oxide to avoid excess base prevented formation of undesired condensation products due to oxidation of the acetoxy-group of (81) to the corresponding aldehyde. The synthesis of one such product ( 8 5 ) is reported.49 The model compounds (2R,6S,2'R,6'S)-2,2'-dimethyly, y-carotene (87) and (2R,2'R,6'S)-2,2'-dimethyLP,y-~arotene (88) have been prepared5' by standard methods from natural (+)-(2S,6R)-cis-y-irone (86). Similarly, optically active 43 44

45 46

47 48 49

P. D. Magnus, Tetrahedron, 1977,33, 2019. H. Pommer, Angew. Chem. Znfernar. Edn., 1977, 16. 423. A. Ishida and T. Mukaiyama, Chem. Letters, 1976, 1127. A. K. C h o p , G. P. Moss, and B. C. L. Weedon, J.C.S. Chem. Comm., IY77,467. M. Ito, R. Masahara, and K. Tsukida, TefruhedronLetfers, 1977, 2767. J. E. Johansen and S . Liaaen-Jensen, Acru Chem. Scand., 1975, B29, 315. J. E. Johansen and S. Liaaen-Jensen, Tetrahedron, 1977,33, 381. A. G. Andrewes, G . Borch, and S . Liaaen-Jensen, Acfu Chem. Scund., 1977, B31,212.

Carotenoids and Polyterpenoids

191

OX a

.*,

\

d

(70) R' = a ( X = H), R'= b (71) R1 = a (X = H), R2 = c (72) R ' = c , R ' = d (73) R' = R' = CHO

"H

O

W

(79)

o

e

(74) R' = B (X = Me$&), RZ= c

(75) R ' = d . R ' = e (76) R' = a (x= H), R'

= CHO

192

Terpenoids and Steroids CHO

a

b

C

(82) R = a

(83) R = b

(84) R = c

(86)

samples of y-ionone (64), partly resolved as the menthydrazones, were used for the synthesis of P,y-carotene (55) samples enriched in the (6’R) and (6’s)enantiomer~.~’ The Cs0 carotenoid decaprenoxanthin [2,2’-bis-(4-hydroxy-3-methylbut-ienyl)-&,e-carotene (89)] has been prepared from the functionalized a-irone derivative ( 9 9 , the synthesis of which is outlined in Scheme l.51 In the mixture of (89) isomers formed, those with 2,6-trans end-groups predominated. O n treatment with MnO, in acetone, carotenoid diosphenols are converted into 2-nor-analogues which possess a cyclopentenedione end-group.s2 Thus astacene [3,3’-dihydroxy-2,3,2’,3’-tetradehydro-~,/3-carotene-4,4’-dione (90)] yields the blue pigment violerythrin [2,2’-dinor-/3$-carotene-3,4,3’,4’-tetraone (91)]. Cathodic cleavage of acetate from retinyl acetate (96) and crustaxanthin tetraacetate (92) gives novel and convenient routes to, respectively, axerophtene (97) 51

A. K. Chopra, B. P. S. Khambay, H. Madden, G . P. Moss, and B. C. L. Weedon, J . C S . Chem. Comm.,

52

1977,357. R. Coman, A. P. Leftwick, and B. C. L. Weedon, J . C S . Perkin I. 1976, 2140.

193

Carotenoids and Polyterpenoids

and 3,4,3',4'-tetradehydro-@,p-~arotene(93), hydrocarbons that otherwise are difficult to prepare.53 Treatment of diadinoxanthin (62) bistrimethylsilyl ether with lithium aluminium hydride affords the bistrimethylsilyl ether of diatoxanthin (94), although similar

a

b

C

e

d

f

h

g

(87) R 1 = R 2 = a (88) R' = b, R2 = a (89) R' = R~= c (90) R' = R 2 = d

1

(91) (92) (93) (94)

R'=R2=e R' = R2 = f R'=R2=g R' = h, R2 = i

conversion of free (62) does not occur. With aqueous acid, (62) yields heteroxanthin (61).15 In acid solution, p,p-carotene-2,2'-diol (2 1) is specifically dehydrogenated and rearranged to ketones with retro structures, behaviour analogous to that of P,P-caroten-2-01 (2O).', The final product from the diol is 4,5-dihydro-4,5'reti-o-P,P-carotene-2,2'-dione ( 101).I8 Hydrogenation of the 3,4-double bond is observed as a side-reaction during NaBH, reduction of 3,4,3',4'-tetradehydro-P,Pcarotene-2,2'-dione (22).' Retinol Derivatives. Aryl sulphones have been used in two new syntheses in the vitamin A series. Reaction of P-cyclocitryl phenyl sulphone (102) with the bromocompound (103) gives the intermediate sulphone (104), which on base-catalysed elimination affords methyl retinoate (98)." Alternatively retinol (99) has been prepared in high yield by condensation of the CIS bromide (105) with the Cs hydroxy-sulphone (106),followed by elimination of sulphinic The syntheses

'' J. C. Gourcy, M. Hodler, B. Terem, and J. H. P. Utley, J.C.S. Chem. Comm., 1976, 779. 54 55 56

H. Kayser, Tetrahedron Letters, 1975, 3743. K. Uneyama and S . Toni, Chem. Letters, 1977, 39. G. L. Olson, H.-C. Cheung, K. D. Morgan, C. Neukom, and G. Saucy, J. Org. Chem., 1976,41,3287.

Terpenoids and Steroids

194

( 8 ~ ) )viii,iii

MeOzC

wpp '

(95) Reagents: i, (CH20H)2; ii, N,CH,CO,Et; iii, LiAIH4; iv, BF3-AcOH-H3PO4; v, THP; vi, Wittig reaction; vii, PPh3-HCI-MeOH; v k , C14dial

Scheme 1

(96) R=CH,OAc (97) R - M e (98) R = C 0 2 M e

(99) R=CI-120H ( 1 00) R = COOP(OH)20

0

0

(101)

BrH2C&m2m

~ H z (102) s O z p h

(103)

Carotenoids and Polyterpenoids

195 S0,Ph

S0,Ph

Pco of ring and four side-chain dihydroretinoic acids and their esters and of several vitamin A analogues with a substituted aromatic ring have been de~cribed.’~ Standard methods, especially Horner reactions, were used. The Wittig reaction was used in the synthesis of the vitamin A furanone derivates (107) and (108).5R High specific activity [ 1l-3H]-all-rruns-a-retinyl acetate (109) has been ~ r e p a r e d . ~The ’ chemical synthesis of all-trans-retinoyl phosphate (100) in 1015% yield from retinoic acid has been reported.“

Conditions have been for catalytic hydrogenation of the acetylene group of the vitamin A synthesis intermediate (110). Several chemical reactions of geometrical isomers of the product (11 1) and its acetate and of (110) have been described .63,64

’’ B. A. Pawson, H.-C. Cheung, R.-J. L. Han, P. W. Trown, M. Buck, R. Hansen, W. Bollag, U. Ineichen, 5R 59

6o

62

63 64

H. Pleil, R. Riiegg, N. M. Dunlop, D. L. Newton, and M. B. Sporn, J. Medicin. Chem., 1977,20, 918. J. F. Blount, R.-.I. L. Han, B. A. Pawson, R. G. Pitcher, and T. H. Williams, J. Org. Chem., 1976,41, 4108. R. L. Hale, W. Burger, C. W. Perry, and A. A. Liebman, J. Labelled Compounds Radiopharmaceuticals, 1977,13, 1 2 3 . J. P. Frot-Coutaz and L. M. DeLuca, Biochem. J., 1976, 159,799. M. A. Veksler, G. P. Chernysh, E. A. Oger, E. G. Koreshkova, and G. I. Samokhvalov, Khim.-Farm. Zhur., 1976, 10, 92. E. A. Ozer, T. M. Beloslyudova, G. P. Chernysh, and G. I. Samokhvalov, Khim.-Farm. Zhur., 1976, 10, I l l . G. P. Chernysh, V. M. Kozhukhovskaya, L. V. Yanchuk, N. M. Savel’eva, and G. I. Samokhvalov, Zhur. org. Khim., 1976, 12, 2624. G. P. Chernysh, V. M. Kozhukhovskaya, T. M. Filippova, A. R. Becker, N. M. Savel’eva, L. V. Yanchuk, T. A. Gritsenko, Zh. K. Torosyan, and G. I. Samokhvalov, Zhur. org. Khim., 1977,13,53.

Terpenoids and Steroids

196

( 1 10)

(111)

Some conversion into the anhydrovitamin (1 12) occurs during silica gel t.1.c. of retinyl palmitate in non-polar Some new colour reactions of vitamin A are reported to be better than the Carr-Price reaction.66 The kinetics and mechanism of acid-catalysed isomerization of retinyl acetate into the trans-retroderivative (113) have been s t ~ d i e d . ~Oppenauer ' oxidation of kitol (39) results in specific cyclopentanol-cyclopentanone oxidation.6H

(112)

(113)

Other Degraded Carotenoids. A new synthesis6' of the fungal sex hormone (*)(7E,9E)-trisporic acid B methyl ester (114) utilized as the key step a Michael-aldol sequence on the p-keto-ester (1 15) to yield the highly functionalized cyclohexenone ( 1 16). The latter underwent Wittig reaction with the phosphonium salt (117) to give (1 14). After basic alumina-catalysed hydrogen exchange in tritiated

C02Me

@"'OMe)* 0 (116)

water, 1-hydroxy-4-keto-a-ionone(118) was used in a Wittig reaction to give tritiated (RS)-abscisic acid (1 19) of high specific a~tivity.~'Reformatsky or Wittig reactions have been used in the synthesis of 36 different 3-methyl-5-aryl penta-2,4dienoic acids and esters, analogues of abscisic acid.7' The 2,3,4,6-tetra-O-acetylR. Dobrucki, Acra Polon. Pharm., 1976, 33, 131. E. F. Lang and H. S. Lang, Deut. Lebensm.-Rundsch., 1977,73, 5. G . P. Chernysh, V. M. Kozhukhovskaya, N . M. Savel'eva, T. M. Filippova, A. R. Becker, and G . I. Samokhvalov, Khim.-Farm. Zhur., 1976,10, 101. " T. Yano, Kyushu Daigaku Nogakubu Gakugei Zasshi, 1976,31,49 (Chem. Abs., 1977,87,52 840). " J. A. Secrist, C. J. Hickey, and R. E. Norris, J. Org. Chem., 1977, 42, 525. 'O D. Walton, R. Wellner, and R. Horgan, Phytochernisfry, 1977,16, 1059. " S. Bittner, M. Gorodetsky, I. Har-Paz, Y . Mizrahi, and A. E. Richmond, Phytochemistry, 1977, 16, 1143.

66

67

Carotenoids and Polyterpenoids

197

p-D-glucopyranosyl esters of abscisic acid and p-ionylideneacetic acid (120) have been prepared by treatment of the acid with a-acetobromoglucose in the presence of trieth~lamine.~'Two paper^^^.^^ describe a new synthesis of y-ionone (64) in which the key intermediate (121) is prepared from y-cyclocitral (122) and acetone in the presence of Bu2BS03CH2CF3.

(118) x = o (119) X = CHC02Me

(121)

(122)

Syntheses have been reported for several other natural products related structurally to carotenoids, viz. dihydroactinidiolide (123) and tetrahydroactinidiolide (124),75,76trans- and cis-a-damascone (125),77dihydroedulans I and 11, (51) and (52),37 bicyclodamascenones A and B, (53) and (54),3' the diastereoisomeric caparrapi oxides (126),78 (*)-a-chamigrene (1 27),79 and the novel passion-fruit ionone derivatives (47) and (48).35

Photochemical isomerization of trans-p-ionol (128) in benzene gave the 7-cisisomer in high yield.'" The photochemical behaviour of y,6- and &&-unsaturated carbonyl compounds of the dihydroionone series has been studied in detail, and H. Lehmann and H. R. Schette, J. prakt. Chem., 1977, 319, 117. T. Mukaiyama, K. Saigo, and 0.Takazawa, Chem. Letters, 1976, 1033. K. Hermann, Nachr. Chem., Tech. Lab., 1977,25, 120. 7 5 S. Torii, K. Uneyama, and M. Kuyama, Tefruhedron Letters, 1976, 1513. '' B. Goyau and F. Rouessac, Compt. rend., 1976,283, C, 597. 7 7 H. J. Liu, H. K. Hung, and G. L. Mhehe, Tetrahedron Letters, 1976,4129. 78 P. Lombardi, R. C. Cookson, H. P. Weber, W. Renold, A. Hauser, K. H. Schulte-Elk, B. Willhalm, W. Thommen, and G. Ohloff, Helv. Chim Acta, 1976,59, 1158. 79 G. Frater, Helv. Chim. Acta, 1977,60, 515. *O V. Ramamurthy and R. S. H. Liu, Org. Phofochem. Synth., 1976,2,70. 72

73 74

198

Terpenoids and Steroids

many products of U.V.irradiation have been characterized.81 In a surveyx2of the selective reduction of @-unsaturated carbonyl compounds with alkali-metal carbonyl chromates [M+HCr,(CO),, -1 or carbonyl ferrates [M+HFe(CO), -1 it was found that a - and p-ionones, (129) and (68), give the corresponding 7,8-dihydroionones in 50-5S% yield.

( 1 28)

(129)

Physical Methods and Physical Chemistry.-Separation and Assay Methods. A procedure for h.p.1.c. of plant pigments has been used to separate the carotenoids of spinach and of a diatom.83 H.p.1.c. separations of citrus carotenoids,8-6 and of retinal (67) isomer^^^.^^ have also been reported. Carotenoid mixtures have also been separated efficiently and rapidly by centrifugal c h r ~ m a t o g r a p h y . ~ ~ 13 C N.M.R. Spectroscopy. This powerful technique is not yet being used routinely in carotenoid analysis, but the review by Mossla discusses methods and applications and tabulates chemical shift data obtained for a range of carotenoids. Elsewhere” the 13C n.m.r. spectra of (3S,3’S)-astaxanthin (60), its IS-cis-isomer, its diacetate, and its IS,lS’-didehydro analogue are presented and assigned, along with ‘H n.m.r., u.v., and c.d. data.

Circular Dichroism. Several papers’4-‘774G42,59.90 report the use of c.d. correlations in establishing the absolute configurations of carotenoids. One report” sounds a cautionary note since the signs of all maxima in the c.d. spectrum of 15-cis-(3S,3’S)-astaxanthin are opposite to those of the all-trans-isomer. Electronic Absorption Spectroscopy. Absorption spectra have been obtained for radical cations and anions generated from a number of carotenoids [phytoene (7,8,11,12,7’,8’,11’,12’-octahydro-~,I,!J-carotene) (135) and canthaxanthin (p,pcarotene-4,4’-dione) (130)] and related polyenes [7,7‘-dihydro-P-carotene (1 3 l), 0

’’

**

M. P. Zink, H. R. Wolf, E. P. Miiller, W. B. Schweitzer, and 0.Jeger, Helv. Chim. Acta, 1976,59, 32. G. P. Boldrini, A. Umani-Ronchi, and M. Panunzio, Synthesis, 1976, 596.

’’ K. Eskins, C. R. Scholfield, and H. J. Dutton, J. Chromatog., 1977, 135, 217.

I . Stewart and U. Leuenberger, Alimenta, 1976, 15, 33. U . Leuenberger, Chimia (Switz.), 1976, 30,496. I. Stewart, J. Assoc. Ofic. Analyt. Chemists, 1977,60, 132. *’ K. Tsukida, A. Kodama, and M. Ito, J. Chromatog., 1977, 134, 331. ’’ F. G. Pilkiewicz, M. J. Pettei, A. P. Yudd, and K. Nakanishi, Exp. Eye Res., 1977, 24, 421. ” H. Pfander, F. Haller, F. J. Leuenberger, and H. Thommen, Chromafographia, 1976, 9. 630. 9” G. Englert, F. Kienzle, and K. Noack, Helv. Chim. A c f a , 1977, 60, 1209. x4

” Rb

Carotenoids and Polyterpenoids

199

heptapreno-@-carotene (132),decapreno-@-carotene(133), and dodecapreno-Pcarotene (134)]. Broad absorption maxima were observed at much longer wavelengths than those of the parent molecule. Theoretical calculations are in broad agreement with the experimental findings.”’

(132) x = 2 , y = 1 (133) x = y = 3 (134) x = y = 4

Resonance Raman Spectroscopy. A review” of the interpretation of resonance Raman spectra of biological molecules includes a consideration of carotenoids and retinal derivatives. Another review93 of resonance Raman studies of visual pigments deals extensively with retinals. Excitation profiles of the coherent antiStokes resonance Raman spectrum of 0-carotene have been p r e ~ e n t e d . ~ ~ Resonance Raman spectroscopic methods have been used for the detection of very low concentrations of carotenoids in blood plasmag5and for the determination of carotenoid concentrations in marine phytoplankton, either in situ or in acetone extracts.’6 X-Ray Crystallography. The crystal and molecular structure of dl-2-cis-4-transabscisic acid (7-trans-9-cis, carotenoid numbering) has been determined by the X-ray method.”’ X-Ray crystallographic data are presented for the retinal derivative (107)? Miscellaneous Physical Chemistry. A review of the year’s literature (mid- 1975mid- 1976) on excited states of biomolecules including carotenoids and related polyenes has been published.”’ Various aspects of the physical chemistry of carotenoids have been reported, including electron donor-acceptor proper tie^,^^"^" 9’ y2

93 Y4 y5

” yx yy

loo

J . Lafferty, A. C. Roach, K. S. Sinclair,T. G . Truscott, and E. J. Land, J.C.S. Faradayl, 1977,73,416. A. Warshel, Ann. Rev. Biophys. Bioeng., 1977, 6 , 273. R. Callender and B. Honig, Ann. Rev. Biophys. Bioeng., 1977,6, 33. L. A. Carreira, T. C. Maguire, and T. B. Malloy, jun., J. Chem. Phys., 1977, 66, 2621. A. J . Rein, D. D. Saperstein, S. H. Pines, and P. C. Kadlick, Experientia, 1976,32, 1352. L. C. Hoskins and V. Alexander, Analyf.Chem., 1977,49, 695. H. Ueda and J. Tanaka, Bull. Chem. SOC.Japan, 1977,50, 1506. R. D. Fugate and P.-S. Song, Phorochem. and Photohiol., 1976,24, 629. V. Mairanovskii, A. A. Engovatov, N. T. Ioffe, and G . 1. Samokhvalov, Khim.-Farm. Zhur., 1976, 10, 105. N. T. Ioffe, A. A. Engovatov, and V. Mairanovskii, Zhur. ohshchei Khim., 1 9 7 6 , 4 6 1 6 3 8 .

200

Terpenoids and Steroids

eiectrochromism,’O1and electrical conduction studies.lo* Several papers103-”3 discuss spectroscopic and physicochemical properties of carotenoids in vivo, e.g. in chloroplast membranes, chromatophores, and photosynthetic reaction centres.

Spectroscopy and Physical Chemistry of Retinal and Visual Pigments. Several reviews and symposium proceedings discuss the spectroscopic, photochemical, or physicochemical properties of retinal and related compounds, and of natural and model visual pigments derived from them.92’93”8”14-’’* In addition, many papers have been published dealing with specific aspects of the spectroscopy (u.v., n.m.r., resonance Raman) of retinals and rhodopsins”y-128 or with aspects of the photochemistry and physical chemistry of retinal derivatives which may be relevant to the functioning of rhodopsin and other visual pigment^.'*^-'^^ The bacterial purple

lo’

’05

lo‘

lb7

Io9

I” I13

’”

‘I9 IZo

IZ1

’’’ Iz3

IZ5

IZ8

13” 131

13’

13’

R. Reich and K.-U. Sewe, Photochem. and Photobiof., 1977, 26, 11. T. J. Lewis and R. Pethig, in ‘Excited States of Biological Molecules, Proceedings of the International Conference, 1974’, ed. J. B. Birks, Wiley, Chichester, 1976, p. 342; D. K. Das Gupta and M. K. Barbarez, ibid., p. 353. M. C. Kung and D. DeVault, Photochem. and Phofobiof.,1976,24, 87. C. E. Swenberg, R. Dominijanni, and N. E. Geacintov, Phofochem.and PhofobioL, 1976.24.601, H. Conjeaud, M. Michel-Villaz, A. Vermeglio, and P. Mathis, F.E.B.S.Leners, 1976, 71,138. K. Matsuura and M. Nishimura, Biochim. Biophys. Acfa, 1977,459,483. G. S. Beddard, R. S. Davidson, and K. R. Trethewey, Nature, 1977, 267, 373. K.-U. Sewe and R. Reich, 2. Nahtrforsch., 1977, 32e, 161. G. P. Borisevich, A. A. Kononenko, and A. B. Rubin, Phofosynfhetica,1977, 11,81. A. Kageyama, Y. Yokohama, S. Shimura, and T. Ikawa, Plunt Cell Physiol., 1977, 18,477. K.-U. Sewe and R. Reich, F.E.B.S. Leners, 1977,80, 30. R. J. Cogdell, S. Celis, H. Celis, and A. R. Crofts, F.E.B.S. Lefters, 1977, 80, 190. S. S. Brody and M. Brody, Photochem. and Phofobiol., 1977, 26, 57. ‘Excited States of Biological Molecules, Proceedings of the International Conference, 1974’, ed. J. B. Birks, Wiley, Chichester, 1976: B. Rosenberg, p. 509; R. Azerad, R. Bensasson, M. B. Cooper, E. A. Dawe, and E. J. Land, p. 531; T. Rosenfeld, A. Alchalel, and M. Ottolenghi, p. 540; S. J. Formosinho, p. 555. W. L. Stone and E. A. Dratz, Photochem. and Photobiol., 1’177, 26, 79. S . E. Ostroy, Biochim. Biophys. Acta, 1977, 463, 91. T. Kakitani and H. Kakitani, Kagaku No Ryoiki, 1976, 30, 870 (Chem. Abs., 1977, 86, 1137). ‘Biophysics of Structure and Mechanism’, 1977, Vol. 3: W. Sperling, P. Carl, C. N. Rafferty, and N. A. Dencher, p. 79; T. G. Ebrey, p. 95; A. Lewis, p. 97; B. E. Kohler, p. 101; F. J. M. Daemen and S. L. Bonting, p. 117; R. Henderson and P. N. T. Unwin, p. 121; C. N. Rafferty, p. 123; J. Wyman, N. A. Dencher, and K. Hamacher, p. 127; K. Kirschfeld and N. Franceschini, p. 191. M. Sulkes, A. Lewis, A. T. Lemley, and R. Cookingham, Proc. Nuf. Acad. Sci. U.S.A., 1976,73,4266. R. S. Becker, G. Hug, P. K. Das, A. M. Schaffer, T. Takemura, N. Yamamoto, and W. Waddell, J. Phys. Chem., 1976, 80,2265: T. Takemura, P. K. Das, G. Hug, and R. S. Becker, J. Amer. Chem. SOC.,1976,98, 7099. B. Honig, A. D. Greenberg, U. Dinur, and T. G. Ebrey, Biochemisfzy, 1’176, 15,4593. R. Mathies, A. R. Oseroff, T. B. Freedman, and L. Stryer, in ‘Tunable Lasers, Applications, Proceeding of the Loen Conference‘, Springer Series Optical Science, 1976, p. 294. D. S. Kliger, S. J. Milder, and E. A. Dratz, Photochem. and Phofobiol., 1977, 25, 277. S. J. Milder and D. S. Kliger, Photochem. and Phofobiol., 1977, 25, 287. R. Mathies, T. B. Freedman, and L. Stryer, J. Mol. Biof., 1977, 109, 367. Y. Inoue, Y. Tokito, R. Chujo, and Y. Miyoshi, J. Amer. Chem. SOC.,1’177,99, 5592. S. Hotchandani, P. Paquin, and R. M. Leblanc, Photochern. and Photobiof., 1977, 26, 167. G. Hug and R. S. Becker, J. Chem. Phys., 1976,65,55. J. W. Laing, M. G. Sceats, S. A. Rice, and R. M. Gavin, Chem. Phys. Leners, 1976, 41,419. R. M. Hochstrasser, D. L. Narva, and A. C. Nelson, Chem. Phys. Letters, 1976,43, 15. D. Huppert, P. M. Rentzepis, and D. S. Kliger, Phofochem. and Photobiof., 1977, 25, 193. A. tfarriman and R. S. H. Liu, Photochem. and Phofobiol., 1977,26, 29. T. Rosenfeld, 0. Kalisky, and M. Ottolenghi, J. Phys. Chem., 1977, 81, 1496. H. Kakitani, T. Kakitani, and S. Yomosa, J. Phys. SOC.Japan, 1977,42, 996

Carotenoids and Polyterpenoids

201

membrane retinal-protein complex bacteriorhodopsin has also received considerable a t t e n t i ~ n . ' ~ ~ ' ' ~ ~ - ' ~ ' Biosynthesis and Metabolism.-Path ways and Reactions. Two reviews of carotenoid biosynthesis discuss, respectively, the early stepslk and the later reactions." The former paperlk deals with the mechanism of formation of phytoene and the series of desaturation reactions by which phytoene is converted into lycopene, and carotenoids. The second also describes in detail the biosynthesis of bacterial paper'' presents details of the mechanism and stereochemistry of cyclization and the other reactions that involve the carotenoid C-1 -C-2 double bond and the later modifications, especially the introduction of oxygen functions. Kinetic studies of the incorporation of the I4C-labelled precursors mevalonic acid, isopentenyl pyrophosphate, and phytoene into C40 carotenes by Halobacterium cutirubrum cell-free preparation^'^' produced results consistent with the pathways outlined in Schemes 2 and 3 . Only the trans-isomers seemed to be involved. A mutant strain,14' PG1, of the green alga Scenedesmus obliquus accumulates phytoene (135), phytofluene (136), and &-carotene (137) in place of the

(135)

normal cyclic carotenoids when grown in the dark. On illumination, these acyclic precursors are converted into p-carotene and xanthophylls. Kinetic studies'" support the operation of the pathway outlined in Schemes 2 and 3, but in this case the 15-cis-isomers of phytoene, phytofluene, and perhaps &-carotene seem to be i m p ~ r t a n t . ' ~Direct ' demonstration of the incorporation of the accumulated acyclic precursors into cyclic carotenoids was achieved by illuminating dark-grown cells after resuspension in deuterium oxide. Under these conditions, deuterium was incorporated specifically at C-2 of the ring of carotenoid molecules formed by cyclization in D,O of accumulated acyclic precursors (Scheme 4).15*A similar procedure has been used with a Flavobacterium species.'53 Cells grown in the presence of nicotine accumulated lycopene (139) which was converted into R. Henderson, Ann. Rev. Biophys. Bioeng., 1977, 6, 87. R. H. Lozier and W. Niederberger, Fed. Proc., 1977, 36, 1805. T. Schreckenbach and D . Oesterhelt, Fed. Proc., 1977,36, 1810. 13' W. V. Sherman and S. R. Caplan, Nature, 1977,265, 273. '41 J. J. Englander and S. W. Englander, Nature, 1977, 265, 657. 14' A . Campion, J. Tzrner, and M. A. El-Sayed, Nature, 1977,265,659. '41 M. A . Marcus and A . Lewis, Science, 1977,195, 1328. M. J. Pettei, A. P. Yudd, K. Nakanishi, R. Henselman, and W. Stoeckenius, Biochemistry, 1977, 16, 1955. 144 B. Aton, A . G . Doukas, R. H. Callender, B . Becher, and T. G. Ebrey, Biochemistry, 1977,16,2995. 145 M. M. Long, D . W. Urry, and W. Stoeckenius, Biochem. Biophys. Res. Comm., 1977,75,725. '41 T. Schreckenbach, B. Walckhoff, and D. Oesterhelt, European J. Biochem., 1977,76,499. '41 F. Tokunaga, R. Govindjee, T. G. Ebrey, and R. Crouch, Biophys. J., 1977, 19, 191. 14R S. C. Kushwaha, M. Kates, and J. W. Porter, Canad. J. Biochem., 1976, 54, 816. IJ9 R. Powls and G. Britton, Arch. Microbial., 1977, 113, 275. G . Britton, R. Powls, and R. M. Schulze, Arch. MicrobioL, 1977, 113, 281. Is' G . Britton and R. Powls, Phytochemistry, 1977, 16, 1253. 15* G. Britton, W. J. S. Lockley, R. Powls, T. W. Goodwin, and L. M. Heyes, Nature, 1977, 268, 81. Is3 G . Britton, W. J . S. Lockley. N. J . Patel, and 1 '.W. Goodwin, F.E.B.S. Letters, 1977, 79, 281. 13'

13'

13*

Terpenoids and Steroids

202

.c

(139)

Scheme 2

Carotenoids and Polyterpenoids

203

Scheme 4

zeaxanthin (57) on removal of the inhibitor; zeaxanthin produced by cyclization in D 2 0 contained deuterium substituents at C-2and C-2’. The incorporation of ‘“C-labelled neurosporene (138), lycopene, and y-carotene (141) into p-carotene by cell extracts of Phycomyces blakesleeanus mutants has been demonstrated.’’“ Addition of unlabelled lycopene or p-zeacarotene (140) caused approximately equal reduction of the incorpsration of [‘“C]neurosporene into p-carotene, indicating that the alternative routes of Scheme 3 are of equivalent importance. The absolute configuration of C-6‘ of natural @,?-carotene ( 5 5 ) is opposite to that of all C,, carotenoids with an &-ring e n d - g r ~ u p . ~ ’Opposite foldings of the aliphatic precursor are therefore required for cyclization to produce the y- and &-end-groups. Inhibitors have been used to investigate the biosynthesis of 1,2-dihydroneurosporene [ 1,2,7,8-tetrahydro-$,$-carotene (143)] and related 1,2-dihydrocarotenoids in Rhodopseudomonas viridis, and possible alternative sequences are presented.”’ The C-1,2hydrogenation reaction is inhibited by CPTA [2-(4chloropheny1thio)triethylammonium chloride], a compound known to inhibit cyclization and C- 1,2-hydration in other systems, thus indicating possible similarity of the reactions involved. The cyclization inhibitor nicotine prevents formation of the Cso carotenoid bacterioruberin [2,2‘-bis-(3-hydroxy-3-methylbutyl)-3,4,3’,4‘-tetradehydro1,2,1’,2’-tetrahydro-$,$-carotene-l,l’-diol (144)], which is normally the main pigment of Halobacterium cutirubrum, and lycopene then accumulates.156 The identification of other compounds that appear in smaller amounts, notably bisanhydrohacterioruberin ~2,2’-bis-(3-methylbut-2-enyl)-3,4,3’,4’-tetradehydro1,2,1’,2’-tetrahydro-$,$-carotene-l,l’-diol (145)], suggests that nicotine inhibits hydration of the double bond of the added C, side-chain more readily than addition of the Csside-chain and C-1 hydroxy-group. Pathways for the biosynthesis of the cyclopentane carotenoids capsanthin [3,3’dihydroxy-p,~-caroten-6’-one ( 146)] and capsorubin [3,3’-dihydroxy- K , K -carotene-6,6’-dione (147)]have been proposed from consideration of the carotenoids identified in extracts of lilies and red peppers.157

Enzyme Systems. Carotenoid biosynthesis by crude cell-free preparations from Halobacterium cutirubrum (p-car~tene),’“~ Phycomyces blakesleeanus mutants (pcarotene),’ 54,’ ’’ and a Neurospora crussu mutant (phytoene) has been dernon~trated.’‘~Detailed studies of carotenogenic enzymes from tomato fruit P. M. Bramley, Aung Than. and B. H. Davies, Phyfochemistry, 1977, 16,235. G. Britton, R. K. Singh, H. C. Malhotra, T. W. Goodwin, and A. Ben-Aziz, Phyfochemistry, 1977.16, 1561. S. C. Kushwaha and M. Kates, Canad. J. Biochern., 1976, 54, 824. Is’ L. R. G. Valadon and R. S . Mummery, Z. Pflantenphysiol., 1977,82,407. P. M. Bramley and B. H. Ihvies, Phyfochernisiry, 1976, 15, 1913. ”’ G. S . Bobowski, W. G. Barker, and R . E. Subden, Canad. J . Bot., 1977,55, 2137. Is’

Terpenoids and Steroids

204

a

b

OH

d

C

HO

OH e

f

HOh

(143) (144) (145) (146)

R1=a,R2=b R1=R2=c R'=R2=d R1=e,R2=f

(147) (148) (149) (150)

R'=R2=f R'=R2=g R1=g,R2=b R'=e,R2=h

plastids have been continued by Porter and co-workers, who have achieved partial purification of the phytoene-synthesizing enzyme system'60 and dissociation of a prelycopersene pyrophosphate [ = prephytoene pyrophosphate ( 1 5 l)] synthetase, mol. wt. 40 000, from the phytoene synthetase complex (mol. wt. 200 OOO).'61 CH,OPP

(151)

Regulation. Inhibition continues to be useful for the elucidation of some details of carotenoid biosynthesis; some examples have been reported above. 153-155~1564-[P"O

"'

B. Maudinas, M. L. Bucholtz, C. Papastephanou, S. S. Katiyar, A. V. Briedis, and J. W. Porter, Arch. Biochem. Biophys., 1977,180,354. M. A. Islam, S. .4.Lyrene, E. M. Milier, jun., and J . W. Porter, J. Biol. Chem., 1977,252, 1523.

Carotenoids and Polyterpenoids

205

(Diethylamino)ethoxy]benzophenone,a known cyclization inhibitor, blocks spirilloxanthin [l,l'-dimethoxy-3,4,3',4'-tetradehydro-l,2,1',2'-tetrahydro-~,~-carotene (148)] biosynthesis in Rhodospirillum rubrum and causes the accumulation of lycopene and anhydrorhodovibrin [l-methoxy-3,4-didehydro-1,2-dihydro-~,~carotene (149)].'62 The inhibitory effect of nicotine on the biosynthesis of cyclic carotenoid in a Flavobacterium 163 and in banana leavesLh4has been described. Pyridazinone herbicides prevent the formation of coloured carotenoids in algae165 and plant'66 systems, and similar effects have been observed with the fungus Verticillium agaricinum in the presence of various nitrogenous heterocyclic corn pound^.'^^ Very large increases in the carotene content of citrus fruit have been achieved by treatment with series of synthetic amines and esters.168"6y Regulatory effects of p - i ~ n o n e , ' ~trisporic " a ~ i d , ' ~ " retin01,'~~ ,'~~ and p e n i ~ i l l i n ' ~ ~ on carotene production by Blakeslea trispora have been described. Light is a major regulatory influence on carotenoid synthesis in many plant and microbial systems. A review of this photoregulation has been published.'" Other papers report the photoinduction of the biosynthesis of phytoene and other carotenoids in strains of Neurospora crassa.'74,'7s Further genetic studies have provided additional information about the regulat ion of car0tenoge nesis in Phycomyces blakesleeanus. 76 Carotenoid Metabolism and Metabolites. A scheme has been proposed for the metabolism of @-carotene by the stick insect Carausius morosus to give p,@caroten-2-01 (20) and p,p-carotene-2,2'-diol (2 1) via intermediate 2-0x0compounds such as (27)."," Feeding experiments have shown that in the goldfish lutein [P,~-carotene-3,3'-diol(1 50)] and zeaxanthin are converted into astaxanthin (60) whereas @-carotene and canthaxanthin (130) are not.177 Further suggest that marine red fish such as sea bream cannot oxidize the 3- and 4-positions of the p-ring. In the intestine of a freshwater fish, Sacchobranchus fossilis, p-carotene was converted into retinoic acid (40) whereas 3,4-didehydroretinol (152) and 3-hydroxyretinol (153) were obtained from l ~ t e i n . " ~The breakdown of E. P. Hayman and H. Yokoyama, J. Bacrerioi., 1976, 127, 1030. G. Britton, D. J. Brown, T. W. Goodwin, F. J. Leuenberger, and A. J. Schocher, Arch. Microbioi., 1977,113,33. l h 4 J. Gross and C. Costes, Physiol. vigitale, 1976,14, 427. lh5 D. Urbach, M. Suchanka, and W. Urbach, Z. Naturforsch., 1976,31c, 652. l h 6 H. K. Lichtenthaler and H. K. Kleudgen, 2. Nahtrforsch., 1977, 32c, 236. lh7 L. R. G . Valadon and R. S . Mummery, Microbios., 1976, 15, 203. S. M. Poling, W.-J. Hsu, and H. Yokoyama, Phytochemisrry, 1976,15, 1685. l h 9 S. M. Poling, W.-J. Hsu, F. J. Koehm, and H. Yokoyama, Phytochemistry, 1977,16, 551. '71 E. P. Feofilova, T. V. Fateeva, and V. A. Arbuzov, Mikrobiologiya. 1976, 45, 169. 17' S. Rao and V. V. Modi, Experientia, 1977.33, 31. 172 E. P. Feofilova and M. N. Bekhtereva, Mikrobiologiya, 1976, 45, 557. 173 H. G. Desai and V. V. Modi, Phytochemispy, 1977, 16, 1373. I74 J. C. Lansbergen, R. L. Renaud, and R. E. Subden, Canad. J. Bot., 1976, 54, 2445. '71 U. Mitzka and W. Rau, Arch. Microbioi., 1977, 111, 261. 176 F. J . Murillo and E. Cerdi-Olmedo, Mol. Gen. Genet., 1976, 148, 19. 177 Y. Tanaka, T. Katayama, K. L. Simpson, and C. 0. Chichcster, Bull. Jap. SOC.Sci. Fisheries, 1976,42, 885. '71 Y. Tanaka, T. Katayama, K. L. Simpson, and C. 0.Chichcster, Bull. Jap. Soc. Sci. Fisheries, 1976,42. 11 77. 179 A. B. Barua and U. C. Goswami, Biochem. J., 1977,166, 133. lh2

lh3

Terpenoids a n d Steroids

206

HO

( 153)

@-carotene to retinal and apocarotenals and the conversion of the latter into apocarotenoic acids in chicken and rat intestine have been described.'" The mechanism of formation of vitamin A from carotene is discussed in a review.181 When retinoic acid is fed to rats, several new metabolites (41)-(46) can be isolated from the and

3 Polyprenols The CSs polyprenol (154) obtained from leaves of Magnolia campbellii has been shown to be a mixture of cis- and trans-isomers.'8z The preparation of dolichyl phosphate (155) by a pea cell-free extract has been d e ~ c r ib e d . ' * Evidence ~ has been obtained that a lipid, containing N-acetylglucosamine, which was obtained from Phaseolus vulgaris hypocotyls, consists of a mixture of the dolichol (156) derivatives dolichyl pyrophosphate N-acetylglucosamine and dolichyl pyrophosphate di-N-acetyl~hitobiose.'~~

(154)

(155) X = OP03HZ (156) X = O H

4 Isoprenylated Quinones The best known isoprenylated quinones are the benzoquinone ubiquinone (157) and the naphthoquinone menaquinone (158), which normally occur in natural tissues as a mixture of homologues (isoprenylogues) with different chain lengths. ~ ~ menaquinone'86 isoprenylogues Analysis of the mixtures of u b i q u i n ~ n e 'or present in various species has been used in the chemotaxonomic characterization of bacteria. R. V. Sharma, S. N. Mathur, A. A. Drnitrovskii, R. C. Das, and J. Ganguly, Biochim. Biophys. Actu, 1977,486, 183. N. Babushkina, Suvrem. Med., 1977, 28,46 (Chem. Abs. 1977,87, 51 919). Is' W. Sasak, T. Mankowski, and T. Chojnacki, Chem. and Phys. Lipids, 1977, 18, 199. l X 3 G . R. Daleo and R. Pont Lezica, F.E.B.S. Letters, 1977, 74, 244. I X 4L. Lehle, F. Fartaczek, W. Tanner, and H. Kauss, Arch. Biochem. Biophys., 1976, 175,419. Ix5Y. Yarnada, E. Nakazawa, A. Nozaki, and K. Kondo, J. Gen. Appl. Microbiof., 1976,22, 285. lX6 M. D. Collins, T. Pirouz, M. Goodfellow, and D. E. Minnikin, J. Gen. Microbiol., 1977, 100,221. " I

207

Carotenoids and Polyterpenoids M e o * M H

0

M eO 0 ri

(158) R = M e

(157)

Chemistry.-The chemical structures of several bacterial menaquinones (MKs) with partly saturated isoprenoid side-chains have been studied. Spectroscopic (u.v., ix., m.s., and 'H n.m.r.) and chromatographic data have been recorded for the tetrahydro-MK8 and -MK9 mixture of some nocardioform and coryneform bacteria.lS7 The main component tetrahydro-MK9 has the second and third isoprene residues from the quinone ring saturated,'88 i.e. has structure (159), 20

(1 59)

[ = menaquinone-9 methyl-3-II,1II-tetrahydromul tipreny1"- 1,4-napthoquinone (IIJII-HJ]. Acfinomyces ofiuaceus contains a variety of hydrogenated menaquinones,''' the main components being MK-9 (II-H2), MK-9(I17111-H4), MK-9(I17111,1X-H6), MK-9(II,III,VIII,I~-H~),MK-tS(TI-H,), MK-8(I17111-H4), M K - 8 ( ~ ~ , ~ ~ ~ , vand ~ ~MK-8(II,III,VII,VIII-H,). ~-H6), The separation of plant isoprenoid lipids, including ubiquinone, phylloquinone [- MK-4(1I,III,IV-H6], and plastoquinone (160) by h.p.1.c. has been de~cribed.'~' Caldariellaquinone, from an extremely thermophilic and acidophilic bacterium Caldariella acidophila, is a unique sulphur-containing benzoquinone with structure (16I), 6-(3,7,11,15,19,23-hexamethyitetracosyl)-5-methylthiobenzo[~]thiophen4,7-quinone. The structure was deduced from spectroscopic data (including 'H and 13Cn.m.r.) and chemical degradation.'" 0

0

( 160) I8n

'91

19'

(161)

Y. Yamada, G. Inouye. Y. Tahara,.and K. Kondo, Biochirn. Biophys. Acra, 1977,486, 195. G . Inouye, Y. Yarnada, Y. Tahara, and K. Kondo, Agric. and Biol. Chem. (Japan), 1977,41,917. S. G. Batrakov, A, G. Panosyan, B. V. Rosynov, I. V. Kohova, and L. D. Bergel'son, Bioorg. Khim., 1976, 2, 1538. H. K. Lichtenthaler and U. Prenzel, J. Chromatogr., 1977, 135,493. M. DeRosa, S. DeRosa, A. Garnbacorta, L. Minale, K. H. Thomson, and R. D. Worthington, J.C.S. Perkin I, 1977, 653.

208

Terpenoids and Steroids

Bi0synthesis.-Ubiquinone. The identification"' of 3,4-dihydroxyhexaprenylbenzoate (162) in a Saccharomyces cerevisiae mutant strain that cannot synthesize ubiquinone suggests that ( 1 62) may be an intermediate in ubiquinone-6 biosynthesis in eukaryotes, in contrast to the pathway via 2-polyprenylphenol which operates in prokaryotes. In mammalian systems alternative routes have been discussed for ubiquinone biosynthesis in rats.lY3Some properties of mitochondria1 4-hydroxybenzoate-polyprenoltransferase have been described. Menaquinone. The incorporation of [2-14C]mevalonateand [2-'4C]-2-methyl- 1,4naphthoquinone into MK-4, normally considered a bacterial quinone, has been demonstrated in marine invertebrates such as crabs and tarf fish."^ Incorporation into 2,3-epoxy-MK-4 (163) was also observed. Cell-free extracts have been prepared from Escherichia coli which catalyse the conversion of o-succinylbenzoic acid (164) into 1,4-dihydroxy-2-naphthoicacid (165) and menaquinones.'y6 In the presence of farnesyl pyrophosphate the major menaquinone produced was MK-3. Genetic studies with mutants of E. coli K12 that require (164) offer support for the generally accepted pathway for MK biosynthesis via (164) and (165).'y7 The enzyme system that catalyses the attachment of the polyprenyl side-chain to 1,4-dihydroxy-2-naphthoicacid to form demethylmenaquinone-9 (166) has been isolated from E. coli."'

(163)

(162)

(164)

(165)

( 166)

Other Quinones. The isoprenoid nature of the C,, side-chain of caldariellaquinone (161) has been established by incorporation studies with [13C]acetate.191

'9j '9j

194

195

'91

198

R. R. Goewert, C. J . Sippel, and R. E. Olson, Biochem. Biophys. Res. Comm., 1977,77,599. A . M. D. Nambudiri, D. Brockman, S. S. Alam, and H. Rudney, Biochem. Biophys. Res. Comm., 1977, 76, 282. T. Nishino and H. Rudney, Biochemistry, 1977.16, 605. V. T. Burt, E. Bee, and J. F. Pennock, Biochem. J., 1977,162,297. R. W. Bryant, jun. and R. Bentley, Biochemistry, 1976,15,4792. J . R. Guest, J. Bacteriol., 1977, 130, 1038. B . Shineberg and I. G . Young, Biochemistry, 1976,15, 2754.

Part I1 STER 0I DS

1 Physica I Methods BY D. N. KIRK

This chapter reviews the year's published work on physical and analytical aspects of steroid chemistry. N o attempt has been made to survey the enormous number of routine applications of spectroscopic methods to structure determination. Attention has been concentrated mainly upon those developments of a fundamental nature which increase our understanding of the physical techniques and the phenomena which they explore. The major advances reported this year in the area of spectroscopy lie in the interpretation and applications o f "C n.m.r.; tritium n.m.r. has made its appearance as a method for the analysis of labelled steroids. The short sections on analytical mcthods give the Reviewer's selection of significant advances in radioimmunoassay and chromatographic methods of interest to chemists.

1 Structure and Conformation The 'deformed-chair' conformation of ring A in a 4,4-dimethyl-3-oxo-Sa -steroid has been confirmed by an X-ray study of a 17P-benzoyloxyandrostane derivative.' The results agree with those of an earlier study of the 17-i0doacetate,~and with the geometry indicated by force-field calculations. Dipole moments calculated by the application of 'molecular mechanics' to 5a-androstane-3,17-dioneand its distorted 4,4-dimethyl derivative are larger than those observed:' the reasons for these deviations are not yet clear. 11-0x0-9a- and 11-0x0-9P-derivatives (1) of oestradiol 3-benzyl ether equilibrate in favour of the 9p-isomer (90°h).3 The free-energy difference (1.47 kcal mol-') could not be reproduced by molecular mechanics calculations,

PhCH,O

'

pH '

N. L. Allinger, U. Burkert, and W. H. Decamp, Tetrahedron, 1977, 33, 1891. G. Ferguson, E. W. Macaulay, J. M. Midgley, .I. M. Robertson, and W. B. Whalley, J.C.S. Chem. Comm., 1970,954. C. D. b a n g . J. S. Baran. N. L. Allinger, and Y. Yuh, Tetrahedron, 1976, 32. 2067.

21 1

Terpenoids and Steroids

212

although the 9p-isomer was predicted to be the more stable by a small margin. The ketones were obtained from the 9( 11)-ene via epoxidation followed by treatment with alkali.3 Steroidal 8-en-1 1-ones (2) prefer the cis (14p) rather than the trans (14a) configuration at the C/D ring junction, irrespective of substitution at C-17.4 This experimental finding, which confirms conclusions based upon force-field calculations, contrasts with the configurational preferences of 15-0x0-steroids at C-14, which vary according to the nature of alkyl substituents at C-17. The variation in relative stabilities of cis- and trans-hexahydroindanones according to substitution patterns is further illustrated by an extensive collection of data for compounds of type (3) in the etiojervane series, which have been equilibrated at the

(3) 5 a - H or A5

(2)

ring-junction position designated by the authors at C-12 (C-13 according to the preferred IUPAC system, unless ‘abeo’ nomenclature is used). Analyses were based primarily o n ‘H n.m.r. data.5 The reported (in 1969)6 isolation of two stable ‘rotamers’ of 20-methyl-20-(2hydroxyethoxy)pregn-5-ene-3/3,17a-diol (4)is contradicted by X-ray analysis of the diacetate of the major ‘rotamer’, which shows it to be the D-homoandrostane derivative (5).’ Me

(4)

(5)

N.m.r. evidence has indicated that vitamin D3 exists in solution as a mixture of the alternative chair conformers in ring A . X-Ray ~ data now show that the same is true of the crystalline vitamin, which comprises an equimolar ratio of the conformers with 3-OH equatorial and axial, respectively.’ Strong hydrogen-bonding between hydroxy-groups results in an extended helix of molecules about an axis D . G. Patterson, C. Djerassi, Y. Yuh, and N. L. Allinger, J. Org. Chem., 1977,42, 2365. and T. Masamune, Bull. Chem. SOC.Japan, 1976, 49, 1602, 1612; T. Masamune, A. Murai, K. Nishizakura, T. Orito, S. Numata, and H. Sasamori, ibid., p. 1622. ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1971, Vol. 1, p. 265. ’ C. M. Weeks, G. J. Kruger, W. L. Duax, T. Makino, and Y. Osawa, Steroids, 1977,29, 261. ’ Ref. 6, 1977, Vol. 7, p. 230. Trinh-Toan, H. F. DeLuca, and L. F. Dahl, J. Org. Chem., 1976, 41, 3476.

’ A . Murai, T. Nishimura,

Physical Methods

213

defined by the associated hydroxy-groups, the two conformers occupying alternate positions. X-Ray crystallography confirms the structure of the anthrasteroid (6), derived from cholesta-5,7-dien-3@01 by rearrangement of the 4-phenyl- 1,2,4triazoline-3,5-dione adduct (7) with boron trifluoride."

RO' (6)

(7)

The 1,ll-etheno-derivative (8) of oestrone methyl ether has an unusually flat structure, as a consequence of the presence of the extra aromatic ring." X-Ray analysis has established the geometry of 3a,17a-dihydroxy-4,4,14a-trimethyl19-nor-l0a-pregn-5-ene-l1,20-dione (9)12 and the configuration of the S=O bond in 2a,3a-epithio-5a-androstan-l7fl-ol ( R ) S-oxide (lO).I3

2 N.M.R. Spectroscopy 'H Spectra.-Assignments of 'H signals to 4-methyl substituents in 4-methylated cholesterols and related compounds are aided by their large downfield shifts (0.2-0.3 p.p.m.) in pyridine compared with spectra in c h l o r ~ f o r m .Spectra '~ of the lo

I'

N. Bosworth, A. Emke, J. M. Midgley, C. J. Moore, W. B. Whailey, G. Ferguson, and W. C. Marsh, J.C.S. Perkin I, 1977,805. C. G. Pitt, D. H. Rector, D. H. White, M. C. Wani, A. T. McPhail, and K. D. Onan, J.C.S. Perkin I, 1977, 131.

*'P. R. Enslin, J. Coetzer, and G. J. Kruger, J.C.S. Perkin 11, 1977,402. l3 l4

H. Koyama and H. Nakai, J.C.S. Perkin il, 1977, 741. T. Iida, T. Tamura, N. Miura, and T. Matsumoto, Steroids, 1977, 29, 453.

Terpenoids and Steroids

214

4-methylated 3-0x0-derivatives show appreciable downfield shifts only for the equatorial 4a-methyl proton signals.“ The ‘H signals due to side-chain methyl groups have been assigned for a series of compounds of the ergostane and stigmastane series.‘s The C-25 methyl groups give coincident or overlapping signals at 100 MHz for cholestanes and ergostanes (24-Me), but are just resolved into two doublets for stigmastanes (24-Et). Examination of ‘H spectra over the temperature range -50 to +60°C has allowed the assignment of preferred side-chain conformations to a series of 22-substitued and 22,23-disubstituted sterols:16 The 20,22-bond in particular avoids those conformations which would compress the C-22 substituent against C-16. Solutions of pregnane-3,20-diols, -3,16a,20-triols, and -3,17a,20-triols in CDCl’ and [2H,]pyridine show ‘H spectral solvent shifts which depend upon configurations at C-2O.I7 The C-18 protons in particular show solvent shifts which are larger for 20p- than for 20a-ols, allowing assignments of configuration. The observed effects are rationalized in terms of the magnetic anisotropies of pyridine molecules associated with hydroxy-groups in their preferred conformations.” A simple quantitative analysis of a mixture of diastereosiomeric secondary carbinols ( e . g steroidal 3a- and 3,C?-alcohols) can be achieved by measuring the lanthanide-induced shifts and integrals of ‘H methoxy signals for the mixture of esters formed with ( R ) - (+ )-a-methoxy-a-trifluoromethylphenylacetic acid (Mosher’s reagent). In 14 pairs of alcohols studied, the (R)-isomer invariably showed the larger lanthanide-induced shift of the methoxy signal, caused apparently by preferential complexing when the methoxy-group lies on the same side of the ester framework (11) as the ‘smaller’ component (R,) rather than the larger (RJ of the carbinol structure.’*

RL (1 I ) ( R )configuration

3H Spectra.-Pulsed Fourier-transform 3H n.m.r. spectroscopy of labelled steroids, with noise-modulated proton decoupling, is an effective method for the location and quantitative determination of tritium. Testosterone, progesterone, oestrone, and related compounds were labelled by a variety of methods including catalytic tritiation of unsaturated bonds and exchange via enolization.” The 3H n.m.r. method of analysis is unique in revealing the quantitative distribution of tritium atoms. The first paper to appear on this topic” indicates that nuclear Overhauser enhancement (NOE) is not a problem in making ’H measurements, but a more recent paper’” states firmly that suppression of NOE is essential. Examples of studies with NOE suppression include a demonstration that a sample supposed to I’ l6

”)

2”

T. A. Wittstruck, J . K. Sliwowski, and E. Caspi, J.C.S. Perkin I , 1977, 1403. M. Nakane and N. Ikekawa, J.C.S. Perkin I, 1977, 1426. G. Cooky, D. N. Kirk, R. E. Morgan, and M. L. SB e Melo, J.C.S. Perkin I, 1977. 1390. S. Yamaguchi and F. Yasuhara, Tetrahedron Lerters, 1977, 89. J . M. A. A1 Rawi, J . P. Bloxsidge, J. A. Elvidge, and J . R. Jones, Steroids, 1976, 28, 359 L. J . Altman and N . Silberman, Steroids, 1977, 29, 557.

Physical Methods

215

be [ 1~,2P-3H(N)]testosteronecontained at least four distinct molecular species ([lp,2P-3H,], [1p-3H], [2p-3H], and [la,2a-3Hz]). 13 C Spectra.-A new extensive semi-empirical analysis of 13C chemical shift data for saturated hydrocarbons, alcohols, amines, ketones, and olefins has led to a set of parameters which allows the calculation of carbon resonances for a wide variety of carbocyclic structures, including steroids, as well as for N-heterocycles.” The compounds all have essentially rigid six-membered rings in the chair conformation. The basis of the calculation is the initial selection of the parameter appropriate to the pattern of a-substitution on the carbon atom in question (primary, secondary, tertiary, or quaternary; C-0, C-N, etc.). This is followed by the addition of increments to allow for the presence of more remote structural features, particularly for the number of H-H interactions of 1,3-diaxial type, any exocyclic C-C gauche interactions, and syn-axial interactions with &carbon atoms (or the corresponding geometrical dispositions involving heteroatoms). Calculated I3C chemical shifts rarely deviate by more than f 3 p.p.m. from observed values.” Non-bonded interactions with y-hydrogen atoms are now considered unsatisfactory as an explanation of the upfield shifts commonly associated with gauche y-substitution. It is argued” that the apparent y-effect could equally well result from the absence of that p-hydrogen atom which the y-substituent replaces [cf. (12)+(13)]. On the basis of 13Cdata for a large number of pairs of compounds, the

H

P

@

H Ry;1, (shielding)

(12)

[@D]

Ayrn,

H;c~

-“r;r’. H

(NoeffLt)

(13)

authors’’ demonstrate that an interaction of ‘1,3-(syn)diaxial’ type between a hydrogen atom on the carbon under observation and a hydrogen atom on the P-carbon produces a deshielding which amounts on average to some 5 p.p.m. Removal of the P-hydrogen atom, either by alkyl substitution (C,) or by the introduction of unsaturation of C,, results in the loss of the deshielding due to the @-hydrogen atom which has previously been interpreted as a y-substituent effect. The magnitudes of the observed shifts depend mainly on the number of 1,3(syn)diaxial-type H-H interactions which are removed by the structural change. Discussion” covers compounds with heteroatom substituents as well as those with essentially hydrocarbon structures. Chemical shifts for monohydroxy-steroids may be used additively to predict those for diols, except in cases where the two functional groups are in a 1,2relationship or in certain 1,3-relation~hips.~~ Steric ioteractions of hydroxy-groups in 1,2-gauche or 1,3-diaxial relationships are thought to explain some of the observed deviations from additivity, which closely resemble those asociated with 22

23

H. Beierbeck, J. K . Saunders, and J. W. ApSirnon, Cunad. J. Chern., 1977,55,2813. H. Beierbeck and J . K. Saunders, Cunud. J. Chem., 1976,54,2985. C. L. VanAntwerp, H. Eggert, G. D. Meakins, J . 0,Miners, and C. Djerassi, J. Org. Chern., 1977,42, 789.

216

Terpenoids and Steroids

analogous OH-C o r C-C interactions. Deviations found for 1,2-diaxial (antiperiplanar) and 1,3-axial-equatorial diols probably result from electronic perturbations which are not yet fully understood. Sa-Substitution (14), whether by methyl or by polar groups, causes a marked downfield shift (2-8 p.p.m.) of the 10P-methyl I3C resonance.24 This is another example of mutual interactions of anti-periplanar groups. Such groups are linked by a periplanar zig-zag of cr-bonds, suggesting that the n.m.r. effects may be related to phenomena observed in other fields (e.g. c.d.), where delocalized MOs have recently been invoked as a basis for interpreting through-bond effectsz5 Methyl substitution into ring A adjacent to an epoxide may cause an anomalous upfield shift of the C, signal [e.g. of C-1 in a fcu-methyl-2,3-epoxide (15) or (16)].

(16)

(15)

(14)

The effect is discussed in terms of distortions of the normal half-chair conformation of the epoxycyclohexane ring, although the precise cause of the anomaly is not yet clear.26 The data serve as a warning for chemists using 13Cspectra for structural analysis of compounds with non-rigid conformations. Cholesterol samples biosynthesized from [5-I3C]- and from [3',4-I3C2]mevalonate, respectively, showed I3C distributions in accordance with the accepted biosynthetic sequence (Scheme 1). 13C N.m.r. spectra of the I3C-enriched products not only revealed the positions of the labels, but also showed the expected I3C-l3C

0

Me OH H02$&FH,0H 2 0

4

[5-13~]meva~onate

o [3',4- '3~2]meva~onate

HO

+$-I3 23

pro-(R) 25

27CH3

pr0-W

13

C distribution in cholesterol from labelled mevalonate, and stereochemistry at C-25 Scheme 1

24

25

26

W. A. Ayer, L. M. Browne, S. Fung, and J. B. Stothers, Canad. J. Chem., 1976.54, 3272. See, for example ( a ) T. D. Bouman and D. A. Lightner, J. Amer. Chem. Soc., 1976,98,3145, ( b ) D. N. Kirk and W. Klyne, J.C.S. Perkin I, 1974, 1076; see also refs. 36 and 37. M. Sangart, B. Septe, G. Btrenger, G. Lukacs, K. Tori, and T. Komeno, TetrahedronLetters, 1977,699.

Physical Methods

217

spin couplings over one bond (11-12) and over three bonds (12-16)). The resonances due to the non-equivalent C-26 and C-27 were separately assigned, and it is proposed for purposes of nomenclature that C-26 should be designated the pro-(R)-methyl group, which originates from C-2 of mevalonate, and C-27 the pro-(S)-methyl group, from C-3' of mevalonate. The configuration at C-25 is decided by the stereochemistry of reduction of the A24-bondof lanosterol, which is indicated in Scheme 1 by circled H atoms.27 Erroneous earlier assignments of C-15 and C-16 resonances in some pregnan20-ones have been corrected.'" The new conclusions have allowed evaluation of substituent effects due to 17a-OH and 17a-Br groups. 13C N.m.r. spectroscopy has been applied in a study of the steroidal trisaccharides thevetin A and B, particularly the manner of linkage of the sugar units, leading to structures (17) and (18) re~pectively.'~

OH

HO

Me0 (17) R = C H O (18) R = M e

13

C Spectra are also reported for some glucoside and mannoside derivatives of alcohols of a sterol type,30 and for a series of steroidal Sofanum alkaloids with various E/F-ring ~ t r u c t u r e s . ~ ~ A report3* o n the preparation of 6~-[1311]iodomethyl-19-norcholest-5( 10)-en30-01 of high purity points out the possible dangers in relying too heavily upon 'H n.m.r. spectra in identifying new steroids and estimating their purity. The 13C spectrum is better able to reveal impurities, because of its resolution of peaks due to individual carbon atoms. 13CN.m.r. data can be used to assign configurations to tosylhydrazones, oximes, and other imine derivative^.^^ l3C-l9F Couplings have been observed for 17a-fluoro-oestr-4-ene and some 3-fluoro-~teroids.~~ 27

29

30

31 32 33

34

G. Popjik, J. Edmond, F. A . L. Anet, and N. R. Easton, jun., J. Amer. Chem. Soc., 1977,99, 931. D. J. Kim, L. D. Colebrook, and'T. J. Adley, Canad. J. Chem., 1976.54, 3766. K. Tori, T. T. "hang, M. Sangark, and G. Lukacs, Tetrahedron Lerrers, 1977, 717. R. Kasai, M. Suzuo, J. Asakawa, and 0.Tanaka, Tetrahedron Lerrers, 1977, 175; K. Tori, S. Seo, Y . Yoshimura, H. Arita, and Y. Tomita, ibid., p. 179. R. Radeglia, G. Adam, and H. Ripperger, Tetruhedron Lerrers, 1977,903. K. N. Scott, M. W. Couch, T. H. Mareci, and C. M. Williams, Steroids, 1976, 28, 295. J. Casanova and J.-P. Zahra, Tetrahedron Letters, 1977, 1773; C. A. Bunnell and P. L. Fuchs, J. Org. Chem., 1977,42,2614. H.-J. Schneider, W. Gschwendtner, D. Heiske, V. Hoppen, and F. Thomas, Terrahedron, 1977, 33, 1769.

218

Terpenoids and Steroids

3 Chiroptical Phenomena The dependence of ketone c.d. on coupling paths between the carbonyl group and perturbing substituents3’ has how been correlated with the calculated (CND0/2) degrees of twist of the no- and .rr*-orbitals, resulting from the chiral pattern of s u b s t i t ~ t i o n .A~ ~series of steroidal and other ketones, with F, CI, and other heteroatoms (X) separated from the carbonyl group by between one and five C-C bonds, provided the examples (Scheme 2). Coupling paths associated with strongly consignate effects of substituents ideally lie along periplanar zig-zags of C-C bonds, although the non-planar five-bond zig-zag in compounds of type (23) also appears to be permissible. Other bond-paths are generally ‘non-coupling’, and often produce weakly dissignate substituent effects.

Me

ii’ 0

,!

(22)

(23)

(24)

Examples of zig-zag coupling paths: Substituent X is separated from the carbonyl groups by 1, 2, 3, 4 , and 5 C-C bonds, respectively, in structures (19)-(23). Structure (24) illustrates a coupling path which extends into a ‘front octant’ region Scheme 2

An extension of the CND0/2 calculations to ‘front octant’ regions3’ suggests that the ‘front octant’ sign reversals which have been established empirically may be best interpreted on the basis of a quadrant rule, supplemented by a rule for the recognition of ‘coupling’ and ‘non-coupling’ bond paths between the ‘front octant’ substituent and the carbonyl group. A ‘coupling path’ extending into a ‘front octant’ region is illustrated in (24). The effect of the ‘coupled’ interaction again emerges as a twisting of the no-orbital, which is known to be highly delocalized through the hydrocarbon framework. An empirical analysis of c.d. data38 for compounds containing a chiral cyclopentanone ring (e.g. ring D in steroids) has led to the proposal that the observed 35 36

37 38

Ref, 6, 1971, Vol. 1, p. 273; 1972, Vol. 2, p. 235. M. R. Giddings, E. E. Ernstbrunner, and J. Hudec, J.C.S. Chem. Comm. 1976,954. M. R. Giddings, E. E. Ernstbrunner, and J. Hudec, J.C.S. Chem. Comm., 1976,956. D. N. Kirk, J.CS. Perkin I, 1976, 2171.

219

Physical Methods

Cotton effects (n47r*) arise primarily from dissignate (‘anti-octant’) effects of C,-H bonds (Figure l a ) rather than from the ‘octant’ dispositions of the carbon atoms (or bonds) of the ring itself, as has been implied by conventional octant projections lacking the ‘a’-hydrogen atoms (Figure lb).3YThe concept of dissignate C,-H effects, of magnitude proportional to sin’ o (Figure l c ) has been extended to some compounds with twisted cyclohexanone rings.38

(4

09

(4

Figure 1 (a) a t a n t projection of twisted cyclopentanone with a-hydrogen atoms. (b) Octant projection without a-hydrogen atoms. ( c ) Newman projection of O=C-C,-H to show torsion angle o

0.r.d. data for a highly purified sample of 17P-hydroxy-4,4-dimethyl-5aoestran-3-one4’ differ only slightly from a previous report. A new empirical analysis of c.d. data for 228 chiral olefinic c ~ m p o u n d s , mostly ~’ of steroid or terpenoid types, has substantially confirmed the earlier proposal of ‘reverse-octant’ (dissignate) effects of saturated non-polar substituents. The wide scope of this study, however, has revealed numerous regularities which include some instances of consignate behaviour. Olefinic compounds. were classified according to their ‘ethylene’ substitution type (i.e. as 1,l-di-, 1,2-di-, tri-, or tetra-substituted ‘ethylenes’). Each class gives c.d. maxima (generally two o r three) at characteristic wavelengths. The lowest-energy c.d. band for compounds of the 1,l-disubstituted type, with an exocyclic methylene group, generally exhibits carbonyl-like consignate effects of substituents, but the reverse is true for the other three classes of olefin. Apparent anomalies in previously reported data for olefins of the tetrasubstituted class are shown to arise from lack of differentiation between two distinct low-energy c.d. bands, which can appear in the ranges 215-225 nm and 195-210 nm, respectively. One or other of these bands is often very weak or unobservable. It is now clear that they arise from distinct electronic transitions [Probably 7r-b3s (Rydberg) and v-m*, respectively]; each shows its own pattern of sensitivity to substituent effects.41 Numerical ‘group increments’ which have been derived from experimental data may be used to ‘predict’ values of A& for new chiral olefins, although their reliability is markedly less than that achieved by an earlier similar analysis of c.d. data for ketone^.^' Although the acetyl side-chain in 3a,17a-dihydroxy-4,4-14a-trimethyl-l9-nor1Oa -pregn-5-ene-l1,20-dione(9) has the normal conformational preference in the crystal, the carbonyl oxygen atom almost eclipsing C-16, c.d. and other 39 4u

41 42

W. Klyne, Bull. SOC.chim. France, 1960, 1396; Tetrahedron, 1961, 13, 29. J. M. Midgiey, W. B. Whalley, P. A. Dodson, G . F. Katekar, and B. A. Lodge, J.C.5. Perkin I, 1977, 602. J. Hudec and D. N. Kirk, Tefrahedron, 1976,32,2475. See Ref. 256.

220

Terpenoids and Steroids

spectroscopic studies suggest that a second conformer is stabilized by intramolecular hydrogen-bonding in solutions in non-polar solvents. The C- 17 isomeric ketol (25), however, exists only as a single conformer, without intramolecular hydrogenbonding. Molecular models show that the 14a-methyl group imposes a conformational restraint on the l7a-acetyl side-chain. M e ?H

The c.d. spectra of cholest-5-ene and some of its simple derivatives have been examined in detail as part of a study of olefins of diverse Evidence provided by blue-shifts of the lowest-energy c.d. maximum (ca.210-200 nm) in solvents of high internal pressure, particularly at low temperatures, indicates that the ~ + 3 s(Rydberg) assignment favoured by some earlier workers is correct. The stronger c.d. band centred near 185 nm is considered to arise from the valence-shell .rr,+n-z transition. Many olefins, however, show a distinct couplet of oppositely signed c.d. bands assigned to mixing of ?r,+n-,* and mx--+n-; transitions. This paper is valuable in containing discussion and diagrams of the Rydberg 3s and the n-: -orbital, and transitions involving these orbitals, which have only recently become of interest to organic chemists. The possible roles of olefin torsion and of static and dynamic coupling mechanisms are also Another paper44 dealing with c.d. data for methylated cholest-5-enes and cholest-6-enes, and for ‘overcrowded’ t-butyl derivatives, bases discussion on the postulate of a n--bu* c.d. band, considered to lie between the Rydberg n-+3s and n-+n-* bands. It is suggested that olefin torsion becomes important in certain highly substituted derivatives, where the sign of the c.d. curve is reversed in the long-wavelength region. U.V. and c.d. data for 18 highly substituted steroid and triterpenoid olefins include some additional examples which for the most part follow the ‘dissignate’ sector rule with respect to the lowest-energy transition and a ‘consignate’ rule for the next transition of higher energy.45 Calculations of oscillator and rotatory strengths for skewed dienes have been refined by the inclusion of allylic substituents, rather than concentrating only on the skew angle of the butadiene component as in the past. The CNDO/S method has given results quite close to those observed experimentally, and reported last year, for steroidal 1,3-dienes (26); the apparent anomaly of a sign reversal depending upon the number of allylic methyl groups is excellently reproduced by the calculations, showing that the perturbation of the diene n--orbitals by mixing with a-type molecular orbitals is a major contributing factor. The CND0/2 method of calculation is far less satisfactory than CNDO/S in this instance.46 The 0.r.d. curve 43

44

45 46

A. F. Drake and S. F. Mason, Tetruhedron,1977,33,937. J . K. Gawronski, Tetruhedron,1977,33, 1235. A. F. Drake, P. Salvaldori, A. Marsili, and I. Morelli, Tetrahedron, 1977, 33, 199. J . S. Rosenfield and E. Charney, J. Amer. Chem. Soc., 1977, 99, 3209.

22 1

Physical Methods

R2

(26) R' and R2 = H or Me

of cholesta- 1,3,7-triene differs only slightly from that of the 1,3-diene, implying similar chirality of their cisoid conjugated diene component^.^^ Amino-steroids of various types form c.d.-active complexes with copper(I1) succinimidate, by amine exchange in a solution of [CuSu2 'Pr2] (Su = succinimidate, 'Pr = i~opropylamine).~" Cotton effects associated with d-d transitions appear in the regions of 700 and 600nm, although quantitative measurement of rotatory strengths is not possible under the conditions used. A tentative 'torsion angle rule' relates the signs of the c.d. bands to the predicted conformation of the complex about its N-Cu bond. C.d. data are reported for some steroidal alkaloids which have a nitrogen atom in 'side-chain' positions.49 An analysis of c.d. data for the 260 nm n - m transition of episulphides, including some steroidal derivatives, provides support for a rather complicated symmetry rule, which divides space around the chromophore into a total of 16 regions. A dynamic coupling mechanism is pr~posed.~'

4 Mass Spectrometry

The mass-spectral fragmentations of cholesterol and its analogues with varied side-chains display well-known ( M -85)' and ( M - 111)' ions; several fragmentation pathways proposed by earlier workers are now shown to be incorrect, since they fail to explain new data obtained with the aid of eleven deuteriumlabelled derivatives. The A5-olefinic bond triggers fragmentations through complex multi-stage processes, which involve hydrogen-transfer steps. The proposed mechanisms, which are compatible with the observed fate of deuterium labels, are illustrated in Scheme 3.'' Fragmentations of A'-enes include the. retro-Diels-Alder (RDA) cleavage of ring B (Scheme 4).52 New data show a marked dependence o n stereochemistry at the A ~ ring B junction: R D A cleavage is most strongly favoured in compounds of the 5/3 (cis) configuration, as would be required for a concerted process controlled by orbital symmetry. Although other instances of R D A cleavage (e.g. of a A2-5asteroid) appear to be non-concerted, it is proposed that a 'quasi-thermal' symmetry-controlled R D A reaction is energetically favourable for those compounds of the 5P-series where initial allylic cleavage of the strained 13,14-bond can readily afford a 13,14-seco radical cation of type (27). M. H. Barnes and W. B. Whalley, J.C.S. Perkin I, 1977,828. F. Kerek, G. Snatzke, K. Ponsold, and B. Schonecker, Tetruhedron, 1977, 33,2013. G. P. Moiseeva, R. Shakirov, M. R. Yagudaev, and S. Yu. Yunusov, Khim. prirod. Soedinenii, 1976, 623; G . P. Moiseeva, R. Shakirov, and S. Yu. Yunusov, ibid, p. 650. " G . Gottarelli, B. Samori, I. Moretti, and G . Torre, J.CS. Perkin ZZ, 1977, 1105. " S. G. Wyllie, B. A. Amos, and L. TokCs, J. Org. Chem., 1977,42, 725. 5 2 J. S. Dixon, 1. Midgley, and C. Djerassi, J . Amer. Chem. Soc., 1977,99, 3432. 47 4R

49

Terpenoids and Steroids

222

1

gt

t.

R

R

R

1

H.9 ( M - 85)'

R

( M - 1 1 I)+ R

Mass-spectral fragmentation of cholesterol and its analogues with As-unsaturation: pathways to account for ( M - 85)+ and ( M - 111) ions

Scheme 3

18-Norpregnanes give mass spectra which closely resemble those of the corresponding compounds possessing the methyl group (C-18). Extensive hydrogen migration is indicated by the mass spectra of 20-hydroxy-l S-nor-Sa-pregnan- 12ones, labelled with deuterium.53 Some peculiarities of the mass spectra of vitamin D3 and related molecules have been Metastable ion studies in a doublefocusing mass spectrometer have been used for the analyses of mixtures of steranes and related corn pound^.^^ 53

Y . Shimizu, Steroids, 1976, 28, 159.

55

E. J. Gallegos, Analyt. Chem., 1976,48, 1348.

'' W. H. Okamura, M. L. Hammond, H. J. C. Jacobs, and J. van Thuijl, Tetrahedron Letters, 1976,4807.

223

Physical Methods

e, R&

H

R

Mass-spectral fragmentation of Sp -steroidal 7-enes, including a ‘quasi-thermal’ retro-DielsAlder cleavage Scheme 4

5 Miscellaneous Physical Properties The vibrational structure and polarization properties of the phosphorescence spectra of testosterone and two other 4-en-3-ones indicate that excitation to the lowest ~~ to earlier triplet state ’( r,.rr*)causes little change in g e ~ m e t r y ,contrary conclusions. A sharply contrasting phosphorescence spectrum from 3P-acetoxycholest-5-en-7-one indicates that emission in this compound is from the 3(n,7r*) rather than the 3(7r,7r*) state. Studies of electron-spin exchange in rigid nitroxyl Biradicals of types such as (28) reveal variations with structure and with solvent polarity, but only a small temperature coefficient.”

56

57

C. R. Jones and D. R. Kearns, J. Amer. Chem. SOC.,1977,99, 344. E. K. Metzner, L. J. Libertini, and M. Calvin, J. Amer. Chem SOC.,1977,99,4500.

Terpenoids and Steroids

224

The phase transitions of cholesteryl nonanoate have been studied with a new apparatus for thermal analytical microscopy.'* The enantiomer ratio of some chiral sulphoxides can be changed from racemic to a modest preference for one enantiomeric form by dissolution in a cholesteryl ester in its liquid-crystalline ('cholesteric') ~ t a t e . ' ~5,6-Epoxycholestan-3-yl p-nitrobenzoates exhibit liquid-crystal properties, but 5,6-diols and dibromides are inactive.60 Differential pulse polarography has been used for the estimation of progesterone, testosterone, and related 4-en-3-ones in some parenteral formulations (in oil or aqueous suspensions).6'

6 Analytical Methods Radioimmunoassay of Steroids.62-6~-Hydroxycortisol 21-acetate (29) reacted selectively in cold pyridine with carboxymethoxylamine, giving the 3-(O-carboxymethy1)oxime: the 2 1-acetoxy-group seemingly slows competing reaction with the 20-ketone. The BSA conjugate was used to raise an antibody for the RIA of 6P -.hydroxyc~rtisol.~~ A novel anchorage of 3P-hydroxyandrost-5-en- 17-one (DHA) to BSA was achieved via C-19, by forming the 0-(carboxymethyl) oxime (30) of the 19CH,OAc

(29)

CH,CO,H

(30)

aldehyde.64 To this end it was necessary to protect the 17-0x0-group of 19hydroxy-DHA as its ethylene acetal before oxidizing at C- 19 (with Cr0,-pyridine) to the 19-aldehyde; the free 3P-hydroxy-group survived the brief reaction which was sufficient to oxidize the primary 19-hydroxy-group. Other steroidal 0-(carboxymethy1)oximes which have been prepared for linkage to BSA include those of 30,16cu -dihydroxypregn-5-ene-7,20-dione6'(at C-7), 3-

hydroxyoestra-1,3,5(10),7-tetraen-l7-0ne,~~ 3a-hydroxy-5~-androstan-17-one ('etiocholanolone'),67 and 17P-hydroxyandrost-4-ene-3,ll-dione(at C-3).68 0K. S. Kunihisa and S. Hagiwara, Bull. Chem. SOC.Jupun, 1976, 49, 2658. W. H. Pirkle and P. L. Rinaldi, J. Amer. Chem. Soc., 1977, 99, 3510. V. G. Atabekyan, and A. S. Sopova, Zhur. org. Khim., 1976,12,2263. 6 1 L. G. Chatten, R. N. Yadav, and D. K. Madan, Phurm. Aclu Hefu., 1976,51,381. 62 Ref. 6, Vol. 7, 1977, p. 309. 6 3 B. K. Park, P. H. Rowe, M. Osborne, and P. D. G. Dean, F.E.B.S. Letters, 1976,68,237. 64 T. A. Rance, B. K. Park, P. H. Rowe, and P. D. G. Dean, J. Steroid Biochem., 1976,7, 677. B. K. Park and P. D. G. Dean, J. Steroid Biochem., 1976,7,697. 66 B. K. Park, T. A. Rance, and P. D. G. Dean, F.E.B.S. Letters, 1976,71, 18. " K. Sat0 and N. Ohsawa, Steroids, 1977, 29, 295. " T. H. Simpson and R. S. Wright, Steroids, 1977, 29, 383. 58

59

6o M. V. Mukhina,

Physical Methods

225

(Carboxymethy1)-oximes are normally prepared in a single step from ketones, but the 11-0x0-group in 17/3-hydroxy-5a-androstane-3,ll-dione was too hindered to react with 0-carboxymethy!hydroxylamine. Instead the 11-oxime, obtained by selective cleavage of the 3,1l-dioxirne, was treated with alkaline sodium chloroacetate to prepare the hapten (31) for linking to BSA via C-11.69 HO,CCH,O

Compounds described as the 15.$-carboxymethyl derivatives (32) of oestrone and oestradiol have been described as haptens, without any evidence as to their configurations at C-15, or their homogeneity.” The method of synthesis (via Michael addition of malonic ester to the 15-en-17-one) normally gives 15psubstituted Some 15/3-carboxyethylmercaptoandrostane derivatives (33), obtained by addition of methyl 3-mercaptopropionate to androst-15-enOH

CH2C0,H

<

OH

(32) R = = O o r

(33)

’H

17-ones, have also been used in RIA.” 3-0-Carboxymethyl ethers of oestrogens have been used as their BSA conjugates to produce antisera with high specificity for ring D substitution type [17-oxo, 17P-OH, or 1 6 ~ x , 1 7 P - ( O H ) ~7-Carboxy].~~ methyl-androstanes and -pregnanes, prepared from 7-OX0 via 7-cyanomethyl derivatives, have also proved useful as hap ten^.^^

Chromatography.-A computer programme has been developed for prediction of the optimum compositions of binary stationary phases for the g.1.c. separation of mixtures of Problems in the gas chromatography of 3H- and ’‘C-labelled by

70

71

’’

’’

74

75

T. S. Baker and D. Exley, Steroids, 1977,29,429. M. Linder, B. Desfosses, and R. Emiliozzi, Steroids, 1977, 29, 161. D. N. Kirk and M. P. Hartshorn, ‘Steroid Reaction Mechanisms’, Elsevier, Amsterdam, 1968, p. 194. P. N. Rao, A. H. Khan, and P. H. Moore, jun., Steroids, 1977, 29, 171. P. N. Rao and P. H. Moore, jun., Steroids, 1977,29, 461. D. Duval, M. Azzaro, and R. Emiliozzi, Compf. rend., 1977, 284, C, 77. R. J. Laub, J. H. Purnell, and P. S. Williams, J. Chromafog., 1977, 134, 249,

226

Terpenoids and Steroids

steroids and other compounds have been reviewed.76 Bile acid esters are separated efficiently by g.1.c. on a cyanopropylphenylsiloxane liquid phase (0V-225).77 A new spray reagent (SnC1,-CHC1,-ClCH,CO,H) is claimed to detect many steroids in quantities down to 0.5 ,!~g.~* Komarowsky’s reagent (methanolic phydroxybenzaldehyde containing H2S04)is a useful spray reagent for t.1.c. of bile acids, giving a wide range of characteristic c010urs.’~ The conversion of steroids and other compounds into derivatives suitable for h.p.1.c. has been reviewed.”

76 77

79

M. Matucha and E. Smolkova, J. Chromatog., 1976, 127, 163. I. M. Yousef, M. M. Fisher, J. J. Myher, and A . Kuksis, Analyf. Biochem., 1976,75, 538. J. C. Kohli and A. K . Arora, Ann. Chim. (France), 1977,2,67. I. A . MacDonald, J. Chromatog., 1977, 136, 348. M. S. F. Ross, J. Chromatog., 1977, 141, 107.

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

Section A: Steroid Reactions 1 Alcohols and their Derivatives, Halides, and Epoxides Substitution.-Diphenylphosphorylazide’ or N3H2., in the presence of triphenylphosphine and diethyl azodicarboxylate smoothly converts alcohols into azides in high yield. Notably, cholesterol is smoothly converted into 3a-azidocholest-5-ene, and 1la-hydroxy-steroids give the 110-azido-compounds. The reactions reported for cholesterol contrast with its reactions with carboxylic acids in the presence of triphenylphosphine and diethyl azodicarboxylate when a number of products are formed as a result of participation of the 5,6-double bond.4 The range of nucleophiles used in these triphenylphosphine-diethyl azodicarboxylate-mediated reactions has been extended.*” Reaction of some 19-hydroxy-steroids with Ph3P-Br2, Ph3P-CCl,, or (PhO),P-MeI-DMF failed to give the 19-halogeno-compounds.S However, one interesting reaction was the conversion of the 19-hydroxycompound (1) into the A-homo-derivative (2) in the presence of (PhO),P-MeIDMF. The physical data reported here for compound (2) differ from those reported

H

(1)

(2)

Interest continues in the preparation and characterization of the 6p-bromomethyl- and 6p-iodomethyl-cholest-5(lO)-en-3~-ols (4) and (5) respectively owing to the potential use of their radiohalogenated derivatives as adrenal scanning agents.&’ The 6p -bromomethyl compound (4) is conveniently prepared by B. Lal, B. N. Pramanik, M. S. Manhas, and A. K. Bose, Tetrahedron Letters, 1977, 1977. H. Loibner and E. Zbiral, Helu. Chim. Act4 1977, 60,416. H. Loibner and E. Zbiral, Helu. Chim. Actu, 1976, 59, 2100. See ‘Terpenoids and Steroids’, ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1976, Vol. 6, p. 226. E. Santaniello, E. Caspi, W. L. Duax, and C. M. Weeks, J. Org. Chem., 1977, 42,482. K. N. Scott, M. W. Couch, T. H. Mareci, and C. N. Williams, Steroids, 1976,28, 295. H. Komatsu, M. Maeda, and M. Kojima, Synthesis, 1977, 36. M. Kojima, M. Maeda, H. Komatsu, H. Shimoirisa, H. Ogawa, K. Nitta, and T. Iko, Steroids,1977,29, 443.

227

Terpenoids and Steroids

228

treatment with LiBr of the tosylate (3), available from the rearrangement of the 19-tosylate (6), or by treatment of (6) with NH,Br or NaBr in acetonitrile.* The reactions between LiCuMe, and certain homoallylic and cyclopropylcarbinyl substrates have been reported in full and are exemplified by the conversion of cholesteryl tosylate into the methyl-substituted compounds (7) and (8).9 The same mixture of products is obtained from the reaction with 6p-chloro-3a,5a-cyclocholestane.

HO (3) R=OTs (4) R = B r (5) R = I

02 .......

I

Me

(7)

(8)

A study of the solvolysis of tertiary trifluoroacetates indicates that nucleophilic substitution occurs with a significant amount of elimination." The reaction of steroidal halides, containing a suitable functional group which may act as an internal nucleophile, with iodine tris(trifluoroacetate) results in nucleophilic substitution with retention of configuration." Thus, the 2-azido-3-iodo-compound (9) was converted into the 2p-azido-3cu-trifluoroacetate (12). In the absence of neighbouring-group participation, the reaction takes a different course and the 3a-iodo-compound (10) and the 3p-epimer (11) were oxidized to the iodotrifluoroacetate (13)." The epimerization of compound (11) is interesting and is assumed to occur though the ylide (14). A number of 16a-hetero-substituted

I

R@'7

H

:;Yx? H

(9) R = N 3 , 3 a (10) R = H , 3 a (11) R=H,3/3

CF 3COz'

(12) R' = N,, R2 = CF3C02 (13) R1=CF3C02,R = I

lo

G. H. Posner, J.4. Ting, and C. M. Lentz, Tetrahedron, 1976, 32, 2281. G . Ortar and A. Romeo, J. Org. Chern., 1976,41,4036.

'*

M. Linskeseder and E. Zbiral, Annnlen, 1977, 1039.

'' F. Czech, M. Linskeseder, and E. Zbiral, Monarsh., 1976,107, 1429.

H (14)

Steroid Reactions and Partial Syntheses

229

oestradiol 3-methyl ether derivatives have been prepared by reaction of the 16pbromo- 17/3-hydroxy-compound with various nu~leophiles.'~ Oxidation and Reduction.-A number of selective oxidation procedures have been reported. Trichloroacetaldehyde on dehydrated chromatographic alumina converts the diol (15) into the 36-hydroxy-17-ketone (68%).14 Primary alcohols are reported to be less readily oxidized than secondary alcohols by this reagent. Similarly, bromine or chlorine with HMPA oxidizes secondary alcohols more readily than primary alcohols. Thus the diol (16) was converted into the ketol (17)

(16) R = P - O H , H (17) R = O

in 60% ~ i e 1 d . ISuccessive ~ treatment of the diketone (18) and the keto-ester (19) with AlBu',H and Pr'OH-acetone gave testosterone and the ketol (20) respectively. The process involved selective oxidation of the intermediate aluminium

(18)

(19)

(20)

alkoxide.l6 Conversion of primary, secondary diols into their bistrityl ethers f followed by hydride ion abstraction with Ph3CBF4 and hydrolysis allows selective oxidation of the secondary alcohol^.'^ Thus, the bistrityl ether (21) was converted 'into the ketol (22). The authors suggest that this particular example may not be a fair test of the method, but other non-steroidal examples are reported. However, in

&

*&

Ph,CO (21) l3 l4

l5

''

(22)

K. Ponsold and G. Schonecker, J. prakt. Chem., 1976,318,483. G. H. Posner, R. B. Perfetti, and A. W. Runquist, Tetrahedron Letters, 1976, 3499. M. A1 Neirabeyeh, J.-C. Ziegler, B. Gross, and P. Canbbre, Synthesis, 1976, 811. U. Eder, Chem. Ber., 1976,109,2954. M. E. Jung and L. M. Speltz, J. Amer. Chem. SOC.,1976,98, 7882.

Terpenoids and Steroids

230

the Reporter's experience, selective oxidation of similar diol systems is not readily achieved with CrV1.Cholesterol is best oxidized to cholest-5-en-3-one with a ten-fold excess of CrV' oxide monopyridine complex in dichloromethane at 0 "C under an atmosphere of nitrogen." A one-pot procedure for the preparation of epoxy-ketones from olefinic alcohols involves successive treatment with m-chloroperbenzoic acid and rn-chloroperbenzoic acid with 2,2,6,6-tetramethylpiperidine hydrochloride." Applied to cholesterol the reaction gave the 3,6-dione (23) and the A4-6a -01-3-one (24) which are rearrangement products of the expected 3-0x0-

5,6-epoxide(s). Allylic alcohols may be isomerized by use of this oxidation procedure followed by reduction with hydrazine (Wharton). Accordingly, the A4-3p-01 (25) was converted via (26) into the isomeric A3-5-01 (27).

Reduction of the 19-tosylates (28) and (30) with lithium aluminium hydride gave the 5,10-methano-compound (29) and the alcohol (31) respectively.*' Vicinal dibromo-steroids are converted readily into olefins when treated with silver salts in the presence of amines." Diaxial bromohydrins are converted into the epoxides under these conditions.

&

Ho&

HO (28)

'* 2o 21

(29)

E. Piers and P. M. Worster, Canad. J. Chem., 1977,55, 733. J. A. Cella, J. P. McGrath, J. A. Kelley, 0. El Soukkary, and L. Hilpert, J. Urg. Chem., 1977, 42, 2077. E. Santaniello and E. Caspi, J. Steroid Biochem., 1976, 7 , 223. A. Kasal, Coll. Czech. Chem. Comm., 1976,41, 2040.

Steroid Reactions and Partial Syntheses

(30)

23 1

(31)

Epoxide Formation and Ring-opening.-Treatment of A 1 ’ 4 ’ 6 - 3 - ~ ~ ~ - ~with ter~id~ hexachloromelamine-lN-H2S04 followed by methanolic sodium hydroxide gave the 6P,7P-epoxides whereas peracids gave the corresponding a-epoxides.22 The synthesis of the oxetanones (32) by treatment of the corresponding 7 p -bromo-Sahydroxy-6-ketones with base has been reported.23 This work follows the earlier Treatment of 5,6aanalogous synthesis of the 5~,7~-epoxy-6-oxo-compounds. epoxy-5a-cholestan-3~-01 with benzonitrile and perchloric acid in dichloromethane gave compound (33) and exemplifies the use of the Ritter reaction in the preparation of vicinal diaxial acylamino- or aroylamino-hydroxycorn pound^.^^ The reaction between 15~,16~-epoxy-17-oxo-steroids and hydroxylamine hydrochloride is sensitive to reaction condition^.^^ Brief treatment in KOAc-EtOH at 20 “C resulted in simple oxime formation whereas prolonged treatment (24 h) gave the dioloxime (34). In the absence of KOAc, the chlorhydrin

R 0 (33)

(34) R = OH (35) R = C I

oxime (35) was rapidly produced. Cleavage of the 4P-acetoxy-Sa,6a-epoxide(36) with BF, led to the acetoxy-diols (38) and (39) (overall diequatorial opening) owing to neighbouring-group participation.26 The intermediate acetoxonium ion (37) was trapped through its sodium borohydride reduction product (40). The acetoxyepoxy-ketone (4 1) was converted with acidic alumina into the A-ring aromatic steroid (42).27 The 8a,9a-epoxy-7-oxo-compound (43) reacted with acetic acid to give the dienone (44) whereas its 8a,l4a-isomer (45) gave the epimeric 14acetoxy-compounds (46) and the 6a-acetoxy-compound (47) which arises from the carbocation (48).28 2z

23 24 25 26

” z8

M. Kocbr, A . Kurek, and M. Maczka, Roctniki Chem., 1976,50,97. A . T. Rowland, R. S. Drawbaugh, and J. R. Dalton, J. Org. Chem., 1977, 42, 487. C. R. Narayanan, A. K. Kulkarni, A. B. Landge, and M. S. Wadia, Synthesis, 1977.35. K. Ponsold, G. Schubert, and W. Ihn, Pharmazie, 1976,31, 14. T. H. Carnpion, G. A . Morrison, and J. B. Wilkinson, J.C.S. Perkin I, 1976, 2509. M. Lj. Mihailovit, J. ForSek, and Lj. Lorenc, Tetrahedron, 1977, 33, 235. M. Anastasia, G. Cighetti, and A . M. Soave, J.C.S. Perkin I, 1977,427.

Terpenoids and Steroids

232 C8Hl7

Me0

@(36)

(3")

1

(38) R' (39) R'

= H, R2= Ac = Ac, R2 = H

OAc

Aco9 H HO

'o

d

0

AcO

(43)

AcO

(44)

AcO (45)

c

233

Steroid Reactions and Partial Syntheses

OAc (47)

Ethers, Esters, and Related Derivatives of Alcohols.-Demethylation of methyl ethers with retention of configuration occurs on treatment with a thiol and BF3.” Oestradiol dimethyl ether has been selectively demethylated to give the 3monomethyl ether, and 3p-methoxy-5a-cholestanegave 5a-cholestan-3p-01. Oestrone dimethyl ally1 ether was rearranged to the normal Claisen rearrangement product (49) in acceptable yields by heating in acetic anhydride with either sodium acetate or potassium acetate.30 Rearrangement in butyric anhydride-dimethylaniline, a previously recommended reaction medium, gave the analogous butyrate in much reduced yield. Condensation of the appropriate aglycone with Lrhamnopyranose orthoacetate led to a partial synthesis of convallatoxin, evomonoside, and peripl~rrhamnoside.~’

(49)

(50) X = Br or c1

Medroxyprogesterone can be converted into the biologically interesting bromoor chloro-acetates (50) by treatment with (CF,CO),O and either BrCH,CO,H or ClCH,CO,H followed by hydrolysis with HBr-EtOH or HC1-EtOH.22*33 The e!ectron-withdrawing halogen atom directs the mixed anhydride reaction. Hydrolysis of the initial reaction mixture derived from (CF,CO),O-BrCH,CO,H with HCl-EtOH gave the l7a-chloroacetate. Selective hydrolysis of the 3a -acetoxy-group of fully acetylated cholic acid derivatives has been achieved with methanolic HCl. The hydrolysis occurs more rapidly than the methylation of the side-chain carboxylic The 3-monosulphates of cholic, chenodeoxycholic, and deoxycholic acids have been prepared using this selective hydrolysis on the fully acetylated methyl esters. The resultant 3a -hydroxy-compounds were then treated with chlorosulphonic acid and the 29 30 31

32 33 34

M. Node, H. Hori, and E. Fujita, J.C.S. Perkin I, 1976, 2237. D. S. Karanewsky and Y. Kishi, J. Org. Chem., 1976,41, 3026. N. Sh. Pal’yants, A. F. Bochkov, and N. K. Abubakirov, Khim. prirod. Soedinenii, 1976, 58. B. R. Samant and F. Sweet, J. Org. Chem., 1977,42, 1981. B. R. Samant and F. Sweet, J. Medicin. Chem., 1977, 20, 833. J. R. Dias and R. Ramachandra, Synth. Comm., 1977,7, 293.

234

Terpenoids and Steroids

carboxylic ester groups finally hydrolysed with aqueous NaOH.35 Optimal conditions have been reported for the preparation of a number of sterol heptafluorobutanoic 2 Unsaturated Compounds

Electrophilic Addition.-The application of the Prkvost reaction to steroidal olefins has been re~iewed,~’ and a detailed analysis of the reaction with 5a-androst-2-ene showed that the products are analogous to those obtained with 5a-cholest-2-ene, viz. the 2p,3a-diol dibenzoate, the 2a,3p-diol dibenzoate, and the la-iodo2p,3p-diol dibenzoate (5 l).38Two regioisomqric vic-iodobenzoates were shown to be the intermediates leading to the trans -diol dibenzoates. Thallium(II1) acetate provides an alternative reagent for cis-hydroxylation and A2-compounds have been converted into the 2p,3p-diol~.~’A 5a-hydroxy-group assists this reaction. Iodine oxide, generated from ozone and iodine in acetic anhydride, reacted with 5a -androst-2-ene to give mainly the 2p -hydroxy-3a -iodo-compound (52).40 Although cyclohexene reacts with iodine and water in tetramethylenesulphone-CHCI, to give the trans-iodohydrin, 5a-androst-2-ene failed to react:’

(51)

(52)

The recently reported reaction between alkenes and ICNS42has been ,improved.43 The reaction between 5a -androst-2-ene in chloroform-water with a phase-transfer catalyst or in chloroform with 18-crown-6 proceeded smoothly to give the vicinal iodothiocyanates and iodoisothiocyanates. An extension of the procedure to 12-NaN3, leading to the vicinal iodoazides, has also been reported. Hydroxymercuration-demercuration of Sa-cholest-2-ene has been reported to give ~holestan-3p-ol.~~ Transannular participation of the 5a-hydroxy-group occurs in the reactions of 5-hydroxy-5a-cholest-2-eneswith HOBr (from NBA)45and with I,-AgOAc (Woodward condition^).^^ Accordingly, compounds (53) were converted in the former reaction into the 2a,5a-epoxides (54) and in the latter into the 2qSa-epoxides (55). Whereas in both reactions some of the expected vicinal E. S. Haslewood, Biochem. J., 1976, 155, 401. L. Dehennin and J. Levisalle, Bull. SOC.chim. belges, 1976, 85, 333. Y. Kamano and M. Tozawa, Yuki Gosei Kagaku Kyokai Shi, 1976,34, 118. 38 R. C. Cambie, G . J. Potter, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1977, 530. 39 E. Glotter and A. Schwartz, J.C.S. Perkin I, 1976, 1660. 40 R. C. Cambie, R. C. Hayward, B. G. Lindsay, A. I. T. Phan, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1976, 1961. 41 R. C. Cambie, W. I. Noall, G. J. Potter, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1977,226. 42 P. D . Woodgate, H. 0. H. Lee, and P. S. Rutledge, Tetrahedron Letters, 1976, 1531. 43 P. D . Woodgate, H. 0. H. Lee, P. S. Rutledge, and R. C. Cambie, Synrhesis, 1977,462. 44 W. Holtmeier, K. Hcbert, and P. Welzel, Tetrahedron Letters, 1976,4709. 45 P. Kobvsky and V. Cerny, Coll. Czech. Chem. Comm., 1977,42,353. “ P. KobvskL and V. CernL. Coll. Czech. Chem. Comm., 1977,42, 163. 3s 36

37

235

Steroid Reactions and Partial Syntheses

(53)

(55)

(54)

bromohydrins and diols respectively were isolated, an additional 2au,5a-epoxide (57) was isolated from the former. The authors suggest that this epimer arises from the acetamido-bromo-compound(56) which is derived from the 2a,3a-bromonium ion. The absence of the 2a,3a-diacetates in the Woodward reaction suggests that the rate of reaction of the intermediate 2@,3@-iodoniumion with the Sa-hydroxygroup is much greater than that with acetate ion.

MecoNHm \

Br’

\

Br.

HO

R

(56)

(57)

A detailed examination of OsO, reactions with A4-steroids has been r e p ~ r t e d . ~ ’ The A-ring conformation of the reactant or derived complex is important in determining the stereoselectivity of these reactions, and the major role of the proximate substituents is to anchor the appropriate conformation favouring a - or @-attack. Studies on the stereochemistry of electrophilic attack on cholest-5-en-3one c ~ n t i n u e . ~As ’ with bromine appreciable @ -attack occurs and the 5@,6@-epoxidewas isolated along with the previously reported 5a,6a-epoxide and the Baeyer-Villiger product, the A-homo-enol lactone (58). Base-catalysed

(58)

rearrangement of the 5@,6P-epoxide to the 6@-hydroxy-3-0x0-A4-compound is thought to involve the unusual removal of the anti (4a)-proton. Peracid oxidation of the D-homo-oestrone derivative (59) gave the c-ring aromatic compound (60).” Mono- or tri-formylation with DMF-POCI, of 17methylene-steroids led to the unsaturated aldehydes (61) or the dimethylaminobisaldehydes (62) which were readily converted with NH,-EtOH into the heterocycles (63).51 14-Azidopregnanes are available from the reactions of A14” 48 49

J. R. Bull and J. Floor, J.C.S. Perkin I , 1977, 724. P. B. D. de la Mare and R. D. Wilson, J.C.S. Perkin II, 1977, 975. See ‘Terpenoids and Steroids’, ed. J. R. Hanson (Specialist Periodical Reports), The Chemical Society, London, 1977, Vol. 7, p. 245. S. V. Sunthankar and S. D. Mehendale, Indian J. Chem., 1976, 14B,91. G . Dauphin and D . Planat, Tetrahedron Letters, 1976,4065.

236

Terpenoids and Steroids

compounds with N,H-BF3,Et20.s2 Isomerization of the double bond to give the A87'4-compound also occurs. Chromous chloride-promoted reaction of N-halogeno-amides with pregnenolone acetate gave the mixed adducts (64).53

(62)

(63)

(64) R = Et or CHzPh

Other Addition Reactions.-At variance with previous reports, the palladiumcatalysed reduction of 9cu-fluoro- 1 1P-hydro~y-A'-and-A'~~-corticosteroids proceeded stereospecifically to give the 5 P - i ~ o m e r s .The ~ ~ 9 a -fluorine atom appears to be responsible for an increased folding of ring A towards the a-face, thus exposing the p-face to the catalyst. Reaction of dimethyl acetylenedicarboxylate with A z ' 4 - ~ ~ m p in ~ ~boiling nd~ xylene gave the unstable Diels-Alder adducts (65) which rearranged by a retroDiels-Alder reaction to the aromatic seco-compound (67).5' Using dicyanoacetylene at lower temperature, the adducts (66) have been isolated and these were converted, in boiling xylene, into the analogous aromatic seco-compound (68). No

R I

R (65) R=CO,Me (66) R = C N " 53 54

"

(67) R=CO,Me (68) R = CN

A. Astier, A. Pancrazi, and Q. Khuong-Huu, Bull. SOC.chim. France, 1976, 1581. H. Driguez, J. M. Paton, and J. Lessard, Canad. J. Chern., 1977, 55, 700. E. L. Shapiro, M. J. Gentles, A. T. McPhail, and K. D. Onan, J . C S . Chem. Comrn., 1976, 961. P. Yates and F. M. Walliser, Canad. J. Chern., 1976, 54, 3508.

Steroid Reactions and Partial Syntheses

237

ene reaction products were detected, as is the case with A5.'-steroids. Reaction of cholesteryl acetate with trithiazyl trichloride (S,N,Cl,) in pyridine gave the isothiazole (69), whereas reaction of cholesteryl benzoate (70) with the monomeric species (NSC1) gave the 7a-chloro-derivative (72).56 The latter product, which was hydrolysed during work-up, was formed by two ene reactions and involves the intermediate (71). The reaction of NSCl with cholesteryl acetate is similar but rather more complex.

AcO'

GT7 S-N

(70)

(71)

(72)

Other Reactions of Olefinic Steroids.-Reaction of cholest-5-en-3-one with air and acetic acid shows that isomerization to the A4-3-0x0-compound is accompanied and the 3,6by autoxidation to the 6a- and 6~-hydroxy-3-oxo-A4-compounds dio~o-A~-~ompo~ The n doxidation .~~ appears to be controlled by heterolysis of the 4p-proton and formation of the intermediate ion pair (73). Sitosterol was autoxidized at C-7 to give the 7-0x0- and the epimeric 7-hydro~y-derivatives.~'Oxidation of a 17-methylene steroid with Pb'", Tf",and Hg" acetates in methanol gave a wide variety of The reaction with Pb(OAc), gave the rearranged products (74), (75), and (76) whereas the T l l I r and Hg" products retained the

(73)

(74)

(75)

(76)

original carbon skeleton. Reaction of Na,Fe(CO)., with the two olefinic carbonates (77) and (78) gave the tricarbonyliron complexes (79) and (230) which show no tendency to racemize.60 The reactions are stereospecific but the absolute configurations of the products are not known. D. H. R. Barton and W. A. Bubb, J.C.S. Perkin I, 1977,916. P. B. D. de la Mare and R. D. Wilson, J.C.S. Perkin ZI, 1977, 157. li8 A. Dinner and K. Z . Farid, Lfoydia, 1976,39, 144. liYG. Ortar and I. Torrini, Tetrahedron, 1977, 33, 859. 60 F. I. Carroll, H. H. Seltzman, and F. M. Hauser, Tetrahedron Letters, 1976,4237. 56 57

238

Terpenoids and Steroids

Aromatic Compounds.-A number of 2,3-dihydroxyoestra- 1,3,5(10)-trienes have been prepared from the corresponding 2-amino-3-hydroxy-compoundsusing a novel inverse oxidation procedure followed by reduction with KL6' Addition of the substrate to sodium metaperiodate in high dilution ensures no coupling with the intermediate quinonimines. 2-Bromo-oestradiol was readily 'converted into 2methoxyoestradiol by treatment with NaOMe-MeOH-DMF-CuI.62 Novel preparations of the biologically interesting 1lp-methyl- and 1lp-ethyl-oestradiol have been reported in full."3 The key intermediates were the 1 1-0x0-oestradiol 3-benzyl ether (82) and its 9p-epimer (83).64 The latter was derived from the 9,11-epoxides (81) by treatment with KOH followed by benzylation. The thermodynamically unstable 9a-epimer (82) was prepared from the 9p-epimer (83) by

(82) 9a (83) 9P

deprotonation with NaH followed by kinetic protonation with acetic acid. Chloranil dehydrogenates the gona- 1,3,5(lO),S-tetraene (84) to give the c-ring aromatic compound (85).65 The major product of T l I X 1 perchlorate oxidation of oestrone is the 11-oxoquinol (86).66 This contrasts with an earlier observation that nrI1

'*

G. Stubenrauch and R. Knuppen, Steroids, 1976,28, 733. P. N. Rao and J. E. Burdett, jun., Synthesis, 1977, 168.

66

Y . Yamada, K. Hosaka, T. Sawahata, Y. Watanabe, and K. Iguchi, Tetrahedron Leners, 1977, 2675.

61

'' J. S. Baran, D. D. Langford, I. Laos, and C. D. Liang, Tetrahedron, 1977,33,609. C. D. Liang, J. S. Baran, N. L. Allinger, and Y. Yuh, Tetrahedron, 1976, 32, 2067. '' L. J. Chinn and K. W. Salamon, J. Medicin. Chem., 1977, 20, 229.

Steroid Reactions and Partial Syntheses

239

trifluoroacetate gave the quinol (87), a minor product in the 3"'perchlorate reaction. The reaction pathways appear to be quite distinct and it is suggested that (86) is derived from the quinone methide (88). Reaction of the ll-ethynyloestratriene (89)with tris(triphenylsily1) vanadate, or rather less efficiently with acid, gave the 1,ll-etheno-steroid (90).67

(84)

(86) R = O (87) R = H 2

3 Carbonyl Compounds Reduction of Carbonyl Compounds and (YP-Unsaturated Carbonyl Compounds.-A detailed study of the NaBH., reduction of a series of l-oxocholestanes has confirmed the stereospecific production of la -hydroxycholestanes from 5a- and 50-cholestan- 1-0ne.~* In addition the 10-hydroxy-compounds are obtained stereospecifically from the 40,SP-epoxy- and the 5@,6@-epoxy-l-oxocholestanes. 1,2-Attack occurs with l-oxo-5a-cholest-2-ene to give the epimeric 1-hydroxy-compounds ( a :0 , 1: 1) whereas 1,4-attack is reported for 1-0x0-50cholest-2-ene. An approach vector analysis of a number of steroidal enones allows the stereochemical outcome of hydride reductions to be predicted.69 In particular, reduction of 1-0xo-5a-cholest-2-ene would be expected to be particularly influenced by substituents at C-5 and C-10 and to lead predominantly to the 10-hydroxy-compound. This prediction is in accord with earlier reported work but the agreement is less good with the latest results,68although the anticipated trend is observed. The Reporter suggests that the 1,4-attack observed for 1-0x0-50cholest-2-ene may be rationalized by application of this analysis. Both a- and p-attack at C-1 would be expected to be precluded, the former owing to the folding-down of ring A associated with the 50-configuration and the latter owing to the 10p-methyl group. Improved selectivity has been reported for the metal-ammonia reductions of androstan-11-one and -17-one by the incorporation of ethanol in the reaction C. G. Pitt, D. H. Rector, D. H. White, M. C. Wani, A. T. McPhail, and K. D. Onan, J.C.S. Perkin I, 1977,1144. M. Weissenberg and E. Glotter, J.C.S. Perkin I, 1977, 988. '' J. E. Baldwin, J.C.S. Chem. Comm., 1976, 738. "

Terpenoids and Steroids

240

m e d i ~ r n . ~Selective " reduction of the 3-0x0-group of progesterone and androst-4ene-3,17-dione was achieved with poly-(N-isopropyliminoalane).71These reductions contrast nicely with those using sodium borohydride. The authors suggest that the reactions are controlled by steric hindrance owing to the absence of electrophilic catalysis. Selective reduction of 3,6-, 3,17-, and 3,20-diketones at position 3 was achieved using dehydrated alumina impregnated with propan-2-01.~' In addition, the keto-aldehyde (91) is reduced selectively at the aldehyde group. The

YCHO

(91)

selective formation of enolate anions provides protection for carbonyl groups against reduction with LiA1H,.73 This is exemplified by conversion of the 3,lldi~xo-A'~~-cornpound (92) into the lithium enolate (93) by titration with Ph,CLi, followed by reduction and hydrolysis, giving the 1lP-hydroxy-3-0xo-A'*~compound (94). Gaseous NH, is the reagent of choice for the destruction of excess

&

$1)

LiO

0

(92)

(93)

\ &o (94)

LiAlH, as this avoids protonation of the enolate and the production of any over-reduction products. Cholest-4-en-3-one may be reduced to cholestanone (5a :5/3, 1: 19) with alkali-metal carbonyl c h r o r n a t e ~ .The ~ ~ studies on intramolecular hydride shifts on hydroxy-ketones and -aldehydes75 have been extended.76 The hydride shifts were examined in a number of y- and 6-hydroxy-carbonyl compounds by heating the substrates with alkaline alumina containing DzO. Exchange of protons on the carbon a to both oxygen functions signals the intramolecular hydride shift: typically, the hemiacetals (95) and (96) each incorporate up to six deuterium atoms. The general conclusion, in common with literature precedent, is that, whereas 1,5-shifts are common, 1,4-shifts are rare. 70 71 72

73 74

7J 76

A. M. Giroud and A. Rassat, BUN.Soc. chim. France, 1976, 1881. M. P. Paradisi, G. P. Zecchini, and A. Romeo, Tetrahedron Letters, 1977, 2369. G. H. Posner, A. W. Runquist, and M. J. Chapdelaine, J. Org. Chem., 1977,42, 1202. D. H. R. Barton, R. H. Hesse, C. Wilshire, and M. M. Pechet, J.C.S. Perkin I, 1977, 1075. G. P. Boldrini and A. Umani-Ronchi, Synthesis, 1976, 596. See ref. 49, p. 24 1. A. Kasal and A. Trka, Coll. Czech. Chem. Comm., 1977,42, 1389.

Steroid Reactions and Partial Syntheses

24 1

H

H

(96)

(95)

Nucleop ilic Addition to Carbonj Compounds and @-Unsaturatec Carbonyl Compounds.-Although the reactions of 17-0x0-steroids with various carbanion reagents are reported to have varying success,77the use of alcohols or DMF as solvents appears to facilitate the Wittig-Horner ~eaction.~’For example, the ketone (97) was converted with (EtO),POCHCO,Et into the E-ethyl ester (98) in

(97)

(98)

89% yield. Interestingly, the use of (Me0),POCHCO2Me gave a mixture of the Z(21%) and the E-(47%)methyl esters. Attempted additions of the lithium enolate of methyl dimethoxyacetate to 17-0x0-steroids failed.79 Reformatsky reaction of the aldehyde (99) led uiu the hydroxy-ester (100) to the ester diene (101).**

#+{yJ

CH(OH)CH,CO,Et

+

AcO

(99)

(100)

{a

CH=CHCO,Et

(101)

Dehydration of the derived acetoxy-compound (102) led to the diene (103), the dihydropyran (104), and surprisingly the oxetan (105). A Wittig reaction of the 17-oxo-7(8-lla)-abeo-compound(106) led to the A 1 7 ( 2 0 ) - ~ ~ m p(107)? ~ ~ n d Homologation of carbonyl compounds to carboxylic ”

See ref. 49, p. 259. J. Wicha, K. Bal, and S. Piekut, Synth. Comm., 1977,7, 215.

’’ G. Neef and U. Eder, Teiruhedron Letters, 1977, 2825.

A . H. Akhrem, A . V. Kamernitskii, R. P. Litvinovskaya, and I. G. Reshetova, Zzuest. Akud. Nuuk S.S.S.R., &r. khim., 1976, 161. M. C. Wani, D. H. Rector, D. H. White, C. G. Pitt, and G. L. Kimmel, J. Medicin. Chem., 1977, 20, 547.

242

Terpenoids and Steroids

(106)

(1071

acids, esters, and amides employs (EtO)zPOC(CN)OBu' (Scheme 1). Cholest-4en-3-one was thus converted into the mixed acids (108) but 5a-androstane-3,17-

boi+

R'

R2

R)=( ' CN

R2

&

R

OBu'

g

N

R2

OAc

ji+

R'

COZ

X R2 H

z = OH, OR^, or NR: Reagents: i, (EtOhPOc(CN)oBu'; ii, ZnC12-Ac20; iii, -OH, -OR3, or NHR;

Scheme 1 6

dione reacted only at position 3.'' A further homologation employs Me,SiCHCl, which added to 5a -cholestan-3-one to give the epimeric epoxysilanes (109) which on hydrolysis yielded the epimeric aldehydes (1

Me,Si (108) A3+A4

(109)

The reaction of 3P-acetoxy-5a-cholest-8(14)-en-7-one with EtzAICN was the key reaction in a synthesis of cholestanes containing an oxygenated 14a-substit ~ e n t . ' ~Cholest-4-en-3-one reacted smoothly with KCN-acetone cyanohydrin in benzene or acetonitrile containing 18-crown-6 to give the epimeric 5-cyanocholestan-3-0nes.~~An 11P-hydroxy-group increased the proportion of a-epoxide produced in the reaction of 3-0x0-A4-steroids with H202-OH-. A 9a-fluorine substituent also influenced the stereochemistry of the reaction products and a

*'

S. E. Dinizo, R. W. Freerksen, W. E. Pabst, and D. S. Watt, J. Amer. Chem. Soc., 1977,99, 182. C. Burford, F. Cooke, E. Ehlinger, and P. Magnus, J. Amer. Chem. Soc.,1977,99,4537. 84 M. Anastasia, A. Fiecchi, G. Cighetti, and G. Galli, J.C.S. Perkin I, 1977, 700. " C. L. Liotta, A. M. Dabdoub, and L. H. Zalkow, Tetrahedron Letters, 1977, 1117.

63

Steroid Reactions and Partial Syntheses

243

9a-fluoro- 11p-hydroxy-3-oxo-A4-steroid gave only the p-epoxide in a relatively slow reaction.86 This is attributed t o steric and field effects and incidentally is comparable with the recent hydrogenation reactions reported above.54 Whereas Knoevenagel condensation of 17-oxo-steroids occurs readily, 16a substituted-16-methylene- 17-oxo-Steroids are unreactive. The enamine (1 1l), however, reacted with CH(CN), to g i v e mainly the aromatic compounds (112) by the mechanism outlined in Scheme 2.87

1

Scheme 2

Reactions involving Enols or Enolic Derivatives.-Monoand di-bromination of lcr-methyl- and la-phenyl-3-oxo-5cy - and -5p-steroids proceeds as in the unsubstituted 3-0xo-steroids.~~ S e l e c t i v e free-radical a-bromination of diketones is achieved by irradiating a carbon tetrachloride solution containing the substrate, bromine, and an added epoxide which a c t s as a scavenger of HBr, thus preventing acid-catalysed enolization. 3,20-DiOxo-steroids may be selectively brominated at position 17 using this technique.89 A n u m b e r of polybrominated derivatives of 5a-androstan-3-one and 5a-oestran.-3-one have been reported. Successive treatment Of 2,4-dibromo-5a-oestran- 3 -one with NaBH, and Zn-Cu couple gave a 2P,4p-~yclo-steroid.~~ Cholest-5-en-3 -one was smoothly converted into cholest4-en-3-one with phosphorus o x y a c i d ~ . ~ ' Base-catalysed autoxidation of e i t h e r 3a,5-cyc]o-5a-cho]estan-6-one or 3 4 cyclo-5cy -cholestan-7-one gave the s a m e products, which included the oxetanone (113).92 Similar oxidations of 2-0xo-steroids were reported, and of particular interest is the formation of the dioxide (115) from the 2,11-dioxo-5P-compound 86

89 90

9i 92

H. L. Chang, C. M. Cimarusti, P. A. Diassi, a m d P. Grabowich, J. Org. Chem., 1977,42,358. B. Green, I. S. Khaiden, R. I. Crane, and s. s - N e w = , Tetrahedron, 1976, 32, 2997. T. T. Takahashi and J. Y. Satoh, Bull. Chem. SOCjapan 1976,49, 1089. V. Calo, L. Lopez, and G. Pesce, J.C.S. Perkim r, ;977, J. F. Templeton, C. W. Wie, and F.E.Hruska, canad. J. them., 1976,54, 2865. A. Kergomard, Li5 Q. Xing, and M.F. Renard, Tenahedron, 1976,32, 1989. V. &rnq, A. Trka, J. Kohoutovl, J. Smolikova, and M. BudBSinskjr, Coll. Czech. Chem. Comm., 1976, 41, 2788.

244

Terpenoids and Steroids

(114). In the absence of the ll-oxo-group the main product is the 2,3-dioxoThe structure of the major product arising from autoxidation and (EtOXP reduction of the enol (116) has been confirmed as the l7a-hydroxycompound (117) by an X-ray analysis, and the minor product of this reaction sequence was thereby shown to be the 1 7 - e ~ i r n e r . ~ ~

(1 17)

(1 16)

The full account of the use of sulphenylation-dehydrosulphenylation for the introduction of a@-unsaturation into carbonyl compounds includes some steroidal example^.^' The similar selenylation-dehydroselenylation of 17-oxo-steroids resulted96 in the formation of the unsaturated lactones (1 18) owing to BaeyerVilliger oxidation during the H 2 0 2oxidation of the LY -phenyI selenyl intermediate (see also ref. 2 10).

(1 18)

Oximes, Hydrazones, and Semicarbazones.-Hydrazones and semicarbazones of 3-0x0-A”~-and -A’*4*6-steroids may be smoothly converted into the parent ketones by treatment with benzene seleninic anhydride.97 Beckmann fragmentation of the hydroxy-oxime (1 19) gave the 16,17-secocompound (120) which can be converted, by NaBH, reduction and acid hydrolysis, into the lactone (121). The lactone (121) may also be‘ obtained directly upon acidification of the reaction mixture from heating the hydroxy-oxime (1 19) with S. Nakajima, R. Konaka, and K. Takeda, Yukuguku Zusshi, 1976,96,764. P. R. Enslin, J. Coetzer, and G. J. Kruger, J.C.S. Perkin 11, 1977,402. 95 B. M. Trost, T. N. Salemann, and K. Hiroi, J. Amer. Chem. Soc., 1976,98,4887. % J. R. Williams and J. D. Leber, Synthesis, 1977, 427. ” D. H. R. Barton, D. J. Lester, and S. V. Ley, J.C.S. Chem. Cornrn., 1977,445. 93

94

245

Steroid Reactions and Partial Syntheses

'

M e 0@ N 0 H + / C - / y J 0

(1 19)

(120)

(121)

KOH-ethylene This latter reaction apparently involves an unusual basecatalysed Beckmann fragmentation and reduction of the resultant aldehyde by KOH-ethylene glycol. 4 Compounds of Nitrogen, Sulphur, and Selenium

y-Hydroxy-NN-dimethylcarboxamides,which are prepared by the addition of Me2NCOCH,Li to epoxides, are converted into y-lactones by thermolysis or hydrolysis with an acidic ion-exchange resin in acetone.99 Thus, the 17,20-epoxide (122) is converted uia the hydroxy-amide (123) into the lactone (124). Addition of

(122)

(123)

(124)

MezNCOCHzLi to steroidal ketones provides the P-hydroxy-NN-dimethylcarboxamides and analogous reactions of Me2NS02CH2Liwith steroidal epoxides and ketones provide the y-hydroxy- and p -hydroxy-sulphonamides.'OO Both the (20s)- and, in contrast to earlier work, the (20R)-amino-2l-hydroxypregn-5-enes (125) can be diazotized with nitrous acid to give acceptable yields CH,OH

dNH

co

(125)

(50%)of the 20,21-diols with retention of configuration.'" The 1,3-dipolar addition of diphenyl phosphorazidate [N,PO(OPhk] to enamines of cyclic ketones D. Miljkovik and J. Petrovik, J. Org. Chem, 1977,42, 2101.

* U. Klein and W. Sucrow, Chem. Ber., 1977,110,994. loo lo'

U. Klein and W. Sucrow, Chem. Ber., 1977,110, 1611. F. Lobt-Tobo and F. Khuong-Huu, Bull. SOC.chim. France, 1976, 1835.

Terpenoids and Steroids

246

provides a means of ring contraction. Thus, the enamine (126) reacted by way of the unstable adduct (127) to give the ring-contracted product (128) which may be hydrolysed to give the A-nor-acid (129).'02 Reaction of the 2-bromo-3-0x0-

(127)

(126)

1

H

- c.3"d: H

NPO(OPh)* (129)

(128)

A 1 ~ 4 - ~ ~ m (130) p ~ ~ with n d ~CH,NO, leads to the nitrocyclopropanes (13 1) by Michael addition and elimination of HBr.lo3 Various transformations of the lanitromethyl-3-0x0-compounds (132) include its conversion into the la-formyl-30x0-compound (133), which on hydride reduction was converted into the tetrahydrofuran (134).Io4

(132)

(133)

(134)

Oxidation of the 7/3-phenylselenyl-A5-steroids (135) with H,O, gave the two configurationally stable R - and S-selenoxides (136) and (137) respectively which react by independent pathways.Io5 The R-isomer (136) underwent the familiar 2,3-sigmatropic shift leading, after solvolysis, to the allylic alcohol (138) whereas the S-isomer (137) gave the A5*'-diene owing to pronounced steric hindrance to the Io2 lo3 '04

'ol

S. Yamada, Y. Hamada, K. Ninomiya, and T. Shioiri, Tehuhedron Letters, 1976, 4749. M. K o d r and W. Krosznynski, Synthesis, 1976, 813. T. Cynkowski and M. K o d r , Roczniki Chem., 1976,50,257. W. G. Salmond, M. A. Barta, A. M. Cain, and M. C. Sobala, Tetrahedron Letters, 1977, 1683.

Steroid Reactions and Partial Synrheses

247

2,3-sigmatropic shift. The base-catalysed rearrangement of the a-chlorosulphone (139) to the pentaene (140) is a key step fn a synthetic approach to steroids.106

(139)

(140)

5 Molecular Rearrangements of 1-methyl-6-dehydro-oestrone in Backbone Rearrangements.-Rearrangement HF-SbF, at -50°C gave five isomeric phenols of which (141)-(144) have the original carbon skeleton and the fifth has the rearranged 1-hydroxy-3-methyl structure (145).'07 Compounds (141) and (142) are thought to derive from equilibrating carbocations [C-6-C-7-C-S-C-9] whereas compounds (143) and (144), possessing the c i s - C / ~ring junction, are formed through Ascr4)-olefinicintermediates. The skeletal rearrangement leading to compound (145) is assumed to be in hyperacid analogous to that reported for 6- or 9-dehydro-3-oxo-A1~4-compounds media,"* which contrasts with the conventional acid-catalysed dienone-phenol rearrangement of these compounds. The backbone rearrangement of the epoxide (146) in the presence of chloride ion, which is more nucleophilic than anions customarily present, allows the intermediate cations (147) to be trapped as the chloro-hydroxy-compound (148).lo9 Rearrangement of the octacyclic diol (149) with BF, gave the compound (151), whereas rearrangement of the octacyclic diketone (150) with H,S04-MeOH gave the compound (152).'" The movement '06

lo'

log

J. Kattenberg, E. R. de Waard, and H. 0.Huisman, Tetrahedron Letters, 1977, 1173. R. Jacquesy and H. L. Ung, Bull. SOC.chrm. France, 1976, 1889. See 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London. 1915, Vol. 5, p. 26g. T. Prange, C. Pascard, G. Sozzi, and M. Fetlzon, Tetrahedron Lerrers, 1977, 245. C. Chavis, J. Bascoul, and A. Crastes de Paulet, Tetrahedron, 1977, 33, 11 19.

Terpenoids and Steroids

248

(141) 14a (142) 14p

(143)

R (149) R=OH,H

(150) R = O

0

H

249

Steroid Reactions and Partial Syntheses

of the double bond towards the five-membered ring is attributed to intracyclic strain in the hydrindane moiety. Miscellaneous Rearrangements-Ergosteryl acetate reacted with nitrosocarbonyl benzene (PhCONO) to give the two adducts (153) and (154), of which the latter readily underwent a novel 3,3-sigmatropic rearrangement to give the dioxazine (155)."' The full account of the BF,-catalysed anthrasteroid rearrangement of the adduct (156) to the compound (157) includes confirmatory X-ray structure data."*

Ph

(156) R = H , A c , o r k

(157)

The 3-oxo-l,5-cyclocholestane(158) rearranges with BF, and with HCOzH to give the enone (159): electrophilic attack at the carbonyl oxygen is followed by cleavage of the 1,5-bond to produce an intermediate C-5 carbocation. A minor product (160) in the BF,-catalysed reaction is derived from cleavage of the 1,lObond.113 Addition of methanol or ethanol across the 1,5-bond is catalysed by FeC13,6Hz0.

(158)

(159)

( 160)

Chlorination of the 17a-hydroxy-16-methylenepregnan-20-one(161) gave a small amount of the unusual oxetan (162) in addition to the expected 16a,17a'I' 112

'I3

G. W. Kirby and J. W. M. Mackinnon, J.C.S. Chem. Comm., 1977,23. N. Bosworth, A. Emke, J. M. Midgley, C. J. Moore, W. B. Whalley, G. Ferguson, and W. C. Marsh, J.C.S. Perkin I, 1977,805. G. Habermehl and W. Walz, 2.Naturforsch., 1976,Jlb, 983.

Terpenoids and Steroids

250

T

CH,CI

0

li

CI

(161)

@ + CH,CI

H HO

goci

C1

q
CHzCl

Reagent: i, C12-pyridine

Scheme 3

epoxide (Scheme 3). In the presence of base, the oxetan (162) rearranged to the enol ether (163), which on acid hydrolysis gave the 16-dichloromethyl-17-acetyl derivative (164).'14 The reaction of the 20-ethylenedioxy- 17a-hydroxypregn-5C1

0

ene (165) with MeMgBr has now been shown, by an X-ray structure analysis, to give the D-homo-compound (166) in addition to the 17a-hydroxy-20-methyl20-(2-hydroxyethoxy lpregn-5 -ene (167). 115*116 Earlier reports had suggested that C-17-C-20 rotamers of the latter were formed. The Reporter suggests that the most likely mechanism for the D-homoannulation would involve MgBr2-catalysed cleavage of the C-20-oxygen bond and migration of the 13,17-bond. Reaction of 'I4

liS 116

E. L. Shapiro, L. Weber, S. Polovsky, J. Morton, A. T. McPhail, K. D . Onan, and D . H. R. Barton, J. Org. Chem., 1976,41, 3940. Y. Osawa, T. Makino, and C. M. Weeks, J.C.S. Chem. Comm., 1976,990. C . M. Weeks, G. J. Kruger, W. L. Duax, T. Makino, and Y . Osawa, Steroids, 1977,29, 261.

25 1

Steroid Reactions and Partial Syntheses

MeMgBr with the resultant 17-0x0-group would occur in the usual way. Although BF,-catalysed D-homoannulation of 17a-hydroxy-20-oxopregnanes usually occurs with migration of the 16,17-bond, this result is perhaps not too surprising since steric and conformational effects have been shown to be very important from a study of model Treatment of the 1a,2a -epoxy-3-0x0-A4-compound (168) with formic acid at 100 "C caused ring contraction and decarbonylation to the A-nor-3-0x0-A4-compound (169) in high yield.' l8 Reductive rearrangement of the

(168)

(169)

14a,l5a-epoxycholest-7-ene(170) occurred with LiAlH, or LiEt3BH to give the 15cu-hydroxycholest-8(14)-ene (171); attack of hydride ion at C-7 is established by

(170)

(171)

&

'the use of LiA1D,.ll9 Thermolysis of the 17,20-epoxide (172) has been reported to give the rearranged structures (173)--(175).'20 Perchloric acid-catalysed

Me0 I"

'" 12"

'

(172)

(173)

/fi2*H

l f i O

(174)

(175)

D. N. Kirk and C. R. McHugh, J.C.S. Perkin I, 1977, 893. A. M. Maione, I . Torrini, and A. Romeo, J.C.S. Perkin I, 1976, 2363. E. J. Parish and G. J. Schroepfer, jun., Tetrahedron Lerrers, 1976, 3775. U. Klein and W. Sucrow, Chem. Ber., 1977, 110,2400.

Terpenoids and Steroids

252

rearrangement of the epoxide (176) gave the cyclobutanones (177) and (178) which may be converted into the y-lactones (179) and (180) by Baeyer-Villiger oxidation.'" Analogous y-lactones fused across positions 3 and 4 may be prepared by a similar route. Studies have been reported on the BF,-catalysed cleavage of a series of 17a-acetyl- 12a,13a-epoxyetiojervanes (18 l t ( l 8 4 ) with varying substituents at C-11.lZ2 As expected, the major product from the 1la-acetoxy-derivative (182) was the fluorohydrin (185), and in general C-12-0 cleavage is inhibited by the more electronegative substituents. The 11-deoxy-compound (184) rather surprisingly led to the aromatic compound (186) as the major product. Treatment of the

n

(181) (182) (183) (184)

R=a-OH,H R = CX-OAC,H R=O R = H2

fluorohydrin (185) or its 1la-hydroxy-analogue with base resulted in rearrangement to the hemiacetal (187) (Scheme 4).

6 Functionalhation of Non-activated Positions Reactions of 5a- and 5p-androstane-3,17-dioneswith ozone in HF-SbF, gave directly the 6-0x0- and 7-0x0-compounds. Some epimerization of the 5p-6-0x0I22

R. Drammann, M. Braun, and D. Seebach, Helu. Chim. Acra, 1976,59,2821. A. Murai, H. Sasamori, and T.Masamune, Bull. Chem. Soc. Japan, 1977,50,437.

Steroid Reactions and Partial Syntheses OH?

H (185) --+

253

How T H

1

(187)

Scheme 4

compounds to the Sa-0x0-compounds was observed. The reaction is analogous to similar oxidations of alkanes and probably involves the C-6 and C-7 carbocations.'23 The full account has appeared of the use of attached and unattached aryl iodine dichlorides in selective chlorination of unactivated tertiary positions in the steroid nucleus.'24 Satisfactory reactions with unattached aryl iodine dichlorides are achieved with aromatic solvents and it is believed that the reactive species is a complex between the chlorine radical and the solvent. Conversely, and consistent with this view, the most efficient reactions are observed for the attached aryl iodine dichlorides when non-aromatic solvents are employed, as intermolecular side, reactions are reduced and intramolecular chlorination occurs through the Ar-I-Cl template. Template-directed remote epoxidation is exemplified by the conversion of the unsaturated ester (188) into the epoxide (190) with Bu'OOH and a catalytic quantity of Mo(CO)~.'~'These reagents are particularly effective for epoxidation of hydroxy-olefins and the failure of the ester (189)

(188) n = 1 (189) n = 2 J.-C. Jacquesy and I.-F. Patoiseau, TetruahedronLetters, 1977, 1499. R. Breslow, R. J. Corcoran, B. B. Snider, R. J. Doll, P. L. Khanna, and R. Kaleya, J. Amer. Chem. Soc., 1977,99,905. R. Breslow and L. M. Maresca, Tetrahedron Letters, 1977, 623.

254

Terpenoids and Steroids

to react demonstrates that the hydroxy-group of the template complexes with the catalyst and further that, as expected, the geometrical requirements of the template are strict. 18-Cyano-20-oxo-steroids (193) are available by photolysis of the a-peracetoxynitriles (192).’26 Yields are comparable to those obtained by Kalvoda from the reactions of 20-cyano-20-hydroxy-steroidswith Pb(OAc),-I,. The preparation of the a-peracetoxy-nitriles (192) is outlined in Scheme 5 ; and attention is drawn to the conversion of the 17-oxo-steroids into the ap-unsaturated nitrile (191) in a

iiii, iv

(193)

(192)

Reagents: i, (Et0)2POC(Me)CN; ii, Mg-MeOH; iii, LiNPjz-02; iv, MeCOCI; v, hv

Scheme 5

Wittig-Horner reaction (see p. 241). Photolysis of the nitrite of the 21-chloro-20hydroxy-compound (194) gave the 18-oximino-compound (195) which on Jones oxidation was converted into the chlorolactone (196).12’ Hypoiodite reaction of the 2 1-chloro-2O-hydroxy-compound (194) also gives the chloro-lactone (196) which with modification gives 18-hydroxy-11-deoxycorticosterone (see also ref. 198). CI

c1

(194)

(195)

( 196)

Functionalization of the methyl groups in the photolysis of the nitrites of 6hydroxy-4,4-dimethyl steroids is used as a probe for conformational analysis. It is confirmed that in the 4,4-dimethyl- 19-nor-series ring A has the normal chair 126

12’

R. W. Freerksen, W. E. Pabst, M. L. Raggio, S. A. Sherman, R. R. Wroble, and D. S. Watt, J. Amer. Chem. SOC.,1977,99, 1536. G . R.Lenz,J. Org. Chem., 1976,41, 3532.

Steroid Reactions and Partial Syntheses

255

conformation whereas in the 4,4-dimethyl series ring A has a flattened chair conformation.128The functionalization of the 4a-methyl group of lanostanes and similar systems resulting from the thermolysis of 3a -azido-formates has been reported in fu11.'29,130 7 Photochemical Reactions Studies on the identification of toxister01~~'~' and t 0 ~ i ~ t e r o 1over-irradias~,~~~~~~~ tion products derived from alcoholic or ethereal solutions of ergosterol and 7dehydrocholesterol respectively, have been reported in full. Although there are differences in nomenclature used by the two groups (London and Leiden) there are two common structural types: ( a ) the C-8-spiran structures (197), reported as -A3, and toxisterols,-A, -B, and -C by the London g r ~ u p ' ~and ~ , toxisterols,-A,, '~~ -AZrespectively by the Leiden and (6) the alcohol adduct (198), called t o x i ~ t e r o l ~ - For ' ~ ~t o x i ~ t e r o l ~ - B ~ . 'Other ~ ~ . ' ~ structures, ~ such as the 3,10ether^'^"'^^ and the des-AB-ergo~tenes,'~~""~ have no equivalent in the work reported by the Leiden group1323133 in which the major product is the 6,lO-cyclocompound (199) which is called toxistero13-C1. These and other differences in the product distribution may be due to somewhat different experimental conditions.

HOP (197)

(198) R' = M e or Et

( 199)

Photoisomerization of the unsaturated lactone (200) to the 1,5-cyclo-lactone (201) provides the first example of a Type A rearrangement in an ap-unsaturated lactone. '31 An X-ray structure analysis has confirmed the photoisomerization of the py-unsaturated ketone (202) to the cyclopentanone (203) by a 1,3-acyl shift.'37 A similar rearrangement of the 3-0xo-A~('~)'~(' "-compound (204) to the cyclobutanone (205) is in contrast with earlier reports of the oxo-di-.rr-methane rearrangement of 3-oxo-A5"0'-compounds on direct irradiation.I3* BenzophenoneJ. M. Midgley, J. E. Parkin, and W. B. Whalley, J.C.S. Perkin I, 1977, 834. P. F. Alewood, M. Benn, J. Wong, and A. J. Jones, Cunud. J. Chem., 1977,552510. See ref. 49, p. 271. 13' A. G. M. Barrett, D. H. R. Barton, R. A. Russell, and D. A. Widdowson, J.C.S. Perkin I, 1977,631. F. Boomsma, H. J. C. Jacobs, E. Havinga, and A. van der Gen, Rec. Trav. chim., 1977,96, 104. 133 H. J. C. Jacobs, F. Boomsma, E. Havinga, and A. van der Gen, Rec. Truv. chim., 1977,96, 113. 134 See ref. 4, p. 269. ' 3 See ref. 49, p. 282. i36 V. Ferrer, J. Gbmez, and J.-J. Bonet, Helv. Chim. Acta, 1977,60, 1357. 13' C. M. Weeks, W. L. Duax, J. R. Williams, and G. M. Sarkisian, Steroids, 1976, 28, 377. 13' J. R. Williams, H. Salama, and J. D. Leber, J. Org. Chem., 1977, 42, 102. IZ9

130

Terpenoids and Steroids

256

sensitized photoaddition of acetaldehyde to 5a-cholest-1-en-3-one gave laacetyl-5a-cholestan-3-one whereas under similar conditions cholest-4-en-3-onefailed to Photochemical Diels-Alder additions (r45+ r2a) have been reported between 3-o~o-A~~~-steroids and a variety of dienes to give products of the type (2O6).l4O Photolysis of 4-methoxycholest-4-en-3-one(207) proceeds by H

(206)

transfer to the allylic radical (208) and then to the oxetanols (209) and the oxetanone (2 lo). 14' Analysis of the polarized phosphorescence emission spectra of various ap-unsaturated ketones indicates that a 7-oxocholest-5-ene has an n,m* lowest-energy triplet state, in contrast to those of 3-oxoandrost-4-enes which are T,T*.This could be a significant factor in determining photochemical reactivity. 142 In contrast to earlier literature reports, photo-oxygenation of 17p-hydroxyoestr5(10)-en-3-one has been shown not to be stereospecific, since a mixture of 1 O a - and 10~-hydroperoxy-3-oxo-A4-compounds was obtained.'43 Thermal rearrangement of these products gave the 10a- and lop-hydroxy-3-oxo- A' 4compounds. Photo-oxygenation of Sa-cholesta- 1,3-diene led only to cholesta-1,4139

I4O

14'

143

D. R. Hicks and R. C. Anderson, Synrh. Comm., 1976,6,417. G. R. Lenz, Tetrahedron Letrers, 1977, 2483. A. Feigenbaum and J.-P. Pkte, Bull. Soc. chim. France, 1977, 351. C. R. Jones and D. R. Keams, J. Amer. Chern. Soc., 1977,99,344. M. Maumy and J. Rigaudy, Bull. Soc. chim. France, 1976,2021.

Steroid Reactions and Partial Syntheses

257

0

OMe

,o

(210)

dien-3-one through an ene reaction;144the trans A/B ring junction precludes the formation of a 1,4-endoperoxide. Photolysis of acetone solutions of 4~1,S-epoxy5a-cholest-2-ene and 4~,5-epoxy-S~-cholest-2-ene gave the A-nor-B-cholestenones (211) and (212) The p-diketone (214) is the primary

(211) 5P (212) 5a

product derived from the photolysis of each of the four isomeric a,B-epoxyketones (213). The reaction involves cleavage of the C - 3 - 0 bond followed by a 1,2-H shift and epimerization at C-3 where required to give the thermodynamically stable 3a-configuration. Further photolysis of the P-diketone (214) gave a number of secondary products, including the Sa-benzoyl compound (2 15) and the hemiacetal (216), which are formed as indicated in Scheme 6.146 *Photoexcited nitrobenzene may be used for benzylic hydroxylation (at C-9)of 17~-acetoxy-3-methoxyoestra1,3,5(10)-triene.14' The photochemistry of the 17p-nitro-steroid (217) is markedly solvent dependent, the major products being in ether the 17-desnitro-compound (218), in propan-2-01 the hydroxylamine (219), and in EtOH-NaOEt the hydroxamic 'acid (220) and the cyclopropane (22 l)."' The hydroxamic acid (220) is probably formed through the oxaziridine (Scheme 7). Although there are analogies to this in the photochemistry of nitrones and oximes, the photoreduction of a nitroalkane in propan-2-01 to an alkyl-hydroxylamine appears to have no precedent. Further studies of photochemistry of conjugated

'41 14*

J. W. Huffman, J. Org. Chem., 1976, 41, 3847. J. M. Coxon and G. S. C. Hii, Ausrrul. J. Chem., 1976, 29, 1143. J. Muzart and J.-P. Pkte, BuU. Soc. chim. France, 1976, 1953. J. Libman and E. Berman, Tetrahedron Letters, 1977, 2191. S. H. Imam and B. A. Marples, Tetrahedron Lerters, 1977, 2613.

Terpenoids and Steroids

258

\

\

0 Ph A OH

HO

Ph

Ph (216)

Scheme 6

AcO

OH

I

Steroid Reactions and Partial Syntheses

259

Scheme 7

nitroalkenes include a number of steroidal examples and confirm that the major process is deconjugation where y-hydrogen atoms are available for intramolecular a b s t r a ~ t i o n . ' ~A~ detailed study has been reported on the mechanism of the photoconversion of the veratr-13(17)-en-l lp-yl nitrite (222) into the nitrone (223).1s0,1s1Further photolysis of the nitrone (223) gave the oxaziridine (224) which reverted to the original nitrone (223) thermally at room t e m p e r a t ~ r e . ' ~ ~ Conversion of the carboxylic acid (225) into the N-acylimidazole (226) followed by photolysis gave the olefin (227); this demonstrates a novel degradative procedure. The photolysis involves 1,2-acyl migration followed by Norrish Type I1 elimination. l S 3 ONO,,

'&

Ac

...( N,

0

149 150 151

"* '53

J. S. Cridland, P. J. Moles, S. T. Reid, and K. T. Taylor, Tetrahedron Letfers, 1976, 4497. H. Suginome, T. Mizuguchi, S. Honda, and T. Masamune, J.C.S. Perkin I, 1977,927. H. Suginome, T. Mizuguchi, and T. Masamune, J.C.S. Perkin I, 1976, 2365. H. Suginome, T. Mizuguchi, and T. Masamune, Bull. Chem. SOC.Jupun, 1977,50,987. S . Iwasaki, Helu. Chim. Acra, 1976, 59, 2753.

Terpenoidsand Steroids

260 8 Miscellaneous

A review of neighbouring-group effects in natural products includes steroidal example^."^ The 19-acetoxy-5a-bromo-6-oxo-steroids (228) fragment with base to give the ~ - o x o - A ~ ( ~ ~ ) - c(229) o ~ ~ which o u ~ ~are s regarded as potentially useful intermediates in prostanoid ~ y n t h e s i s . ’ The ~ ~ preparation and properties of the 6-spirocyclopropane (230) have been reported. Attempts to cleave the cyclopropane symmetrically were unsuccessful although other cleavages are discussed.lS6

Section B: Partial Syntheses 9 Cholestane Derivatives and Analogues 2-17(20)-Dehydrocholesterol(23 1) has been prepared from pregnenolone by two independent routes. Dehydration of a mixture of 20a- and 20P-hydroxycholesterol gave the required compound (23 1) along with the previously prepared

E- 17(20)-dehydro-20-cyanopregnene,which may be isomerized in base to the 2-isomer. Elaboration of the side-chain by successive Grignard reaction, reduction, and removal of the 22-hydroxy-group followed.157 Key steps in two stereoswere pecific syntheses of Z-20(22)-dehydrocholesterol(234) from pregneno10ne~~~ (a)stereospecific removal of the 20- and 22-oxygen atoms of (20R,22S)-20,22dihydroxycholesterol by conversion into the thiocarbonate (232) and treatment with triethyl phosphite and (b) selective epoxidation of E-20(22)-dehydrocholesteryl benzoate to the epoxides (233), which were allowed to react with hexamethyldisilane-KOMe in HMPA (see also ref. 179). Syntheses of the 24-

lS6

Is’

A. Ichihara, Yuki Gosei Kagaku Kyokai Shi, 1976, 34, 378. S . V. Sunthankar and V. V. Vakatkar, J.C.S. Chem. Comm., 1976,913. A. F. A. Wallis and W. B. Whalley, J.C.S. Perkin I, 1977, 832. W. R.Nes, T. E. Varkey, D. R. Crump, and M. Gut, J. Org. Chem., 1976,41, 3429. M. Koreeda, N. Koizumi, and B. A. Teicher, J.CS. Chem. Comm., 1976, 1035.

26 1

Steroid Reactions and Partial Syntheses

alkylidene-steroids (235),159 (236),'59 (237),l6' citrostadienol (238),161 and methylenelophenol (239)I6l employed the Wittig reaction on the appropriate 240x0-derivative which in each case may be prepared from ergosterol. Lophenol (240) was prepared by Wolff-Kishner reduction of the corresponding 24-0x0-

R2

(235) (236) (237) (238) (239) (240)

R'

= H, R2= CH2 R' = H, R2= 2-MeCH R' = H, R2 = 2-MeCH, A7,9(111 R' =Me, R2 = Z-MeCH, A' R' = Me, R2 = CH2, A7 R' =Me, R2 = H,, A7

derivative.16' Ergosta-5,7,22,24(28)-tetraen-3p-yl acetate (242) was obtained directly by heating the 22,23-dibromo-N-phenyltriazolinedione adduct (241) with DBN, and confirmation that cholesta-5,7,22-trien-3P-ol is a metabolite of Tetrahymena pyriformis was obtained by its partial synthesis from stigmasterol.'62 Degradation of stigmasterol led to the 3,5-cyclo-22-tosyloxy-compound(243), W. Sucrow and W. Littmann, Chem. Ber., 1976, 109, 2884. W. Littmann and W. Sucrow, Chem. Eer., 1977, 110, 1607, W. Sucrow, W. Littmann, and B. Raduchel, Chem. Ber., 1977,110, 1523. A. B. Carry, J. M. Midgley, W. B. Whalley, and B. J. Wilkins, J.C.S. Perkin I, 1977, 809.

262

Terpenoids and Steroids

which on reaction with LiC=C-CHMe, sterols (244) and (245) re~pectively.'~'

AcO

or LiCECMe gave the newly isolated

MM .

'~.N /, N

AcO

\

'x.

kNkO

O

(242)

I

Ph (241)

(243)

(244) R = Pr' (245) R = M e

Cholic acid may be converted in several steps into the 3,9-epoxy-carboxylic acid ~ ~ synthesis of 24-nor(246) which has the ABC ring system of b a t r a c h ~ t o x i n . ' The Sa -cholic acid from methyl cholate involved the Barbier-Wieland degradation of the side-chain and treatment of the resultant 24-nor-5p-cholic acid with Raney nickel. A major product of this reaction was the Sa-3-0x0-compound (247) which

(246)

(247)

on reduction with Pt-H, gave the epimeric 3-hydroxy-compounds.'6s Deuteriated and tritiated chenodeoxycholic acid and lithocholic acid have been prepared by 163

164

E. Steiner, C. Djerassi, E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, and D . Sica, Helv. Chim. Act, 1977,60, 475. J. F. W. Keana and R. R. Schumaker, J. Org. Chem., 1976,41, 3840. Y. Shalon and W. H. Elliott, Steroids, 1976, 28, 655.

Steroid Reactions and Partial Syntheses

263

catalytic reduction of the A”-derivatives.’66 A partial synthesis of fusidic acid from the degradation product (248) employed the previously reported reactions of 17-0x0-steroids with lithium dianions of carboxylic acids. The key steps are outlined in Scheme 8.16’

OAc

% 2

AcO-’

(248)

R = H o r Ac

Reagents: i, Me2C=CHCH2CH2CHC02Li; ii, MeI-NaHCOs-MeCONMez; iii, AczO-py; iv, POC13-py

Scheme 8

An alternative synthesis of 22,23-dihydroergosteryl acetate involved hydrogenation of the epidioxide (249) to the saturated Sa,7a-dihydroxy-derivative (250). This was followed by an improved carefully controlled dehydration with I

(249) 166

A. E. Cowan, A. F. Hoffmann, D. L. Hachey, P. J. Thomas, D. T. Belobaba, P. D. Klein, and L. Tokes, J. Lipid Res., 1976,17, 231. M. Tanabe, D. M. Yasuda, and R. H. Peters, Tetrahedron Letters, 1977, 1481.

264

Terpenoids and Steroids

methanolic HCl to afford the 5a-hydroxy-A7-compound (25 1) (40-50°/0) and then by further dehydration with SOCl,.'h8 A key step in the synthesis of 4a-methyl5a-cholest-8(9)-en-3/3-01 is the monoalkylation at C-4 of the 2,2-trimethylenedithian-3-oxo-derivatives.'hg The synthesis confirmed the occurrence of this sterol in certain mouse transplantable preputial gland tumours. A series of 3-oxygenated 4,4-dimethyl-4-homocholestenes,170 5a-hydroxycholestenes,~7' and 5p -methyl- 19 - n o r c h o l e s t - 9 - e n e ~has ~ ~ ~been synthesized. The first synthesis of 15-oxygenated-14P-A7-steroids employed the BF,catalysed rearrangement of a 14a,15a-epoxy-A'-compound (252) to the 15-0x014p-A7-compound (253) which on hydride reduction gave the epimeric 15-

BzO

BzO (252)

(253)

hydroxy-compounds.173 Stereocontrolled syntheses of (22R)-22,25-dihydroxycholesterol and the (22s)-isomer have been r e ~ 0 r t e d . lThe ~ ~ intermediate (256) was common to all the syntheses and was prepared by reduction of (255) which is available from the reaction of the allylic acetoxy-compound (254) with (Ph,P),Pd and PhSO,CH(Na)CO,Me. One synthesis of the (22R)-isomer is outlined in Scheme 9. An interesting feature is the isolation of a single carboxylic acid (258) after hydrolysis of the epimetic 22-carboxylic esters (257). It is believed that lactone formation between the 22-carboxy-group and the 25-hydroxy-group allows epimerization to the preferred configuration. 2-Deoxyecdysones have been synthesized from 3a,7a-dihydroxy-5~-~holestanes.'~~ Inversion and protection of the 3-hydroxy-group as the formate were achieved using formic acid, triphenylphosphine, and diethyl a~odicarboxylate.'~~ The full account has been given of model syntheses of withanolides leading to a series of 4-hydroxy-1-oxocholest16R 169

170 17' 172

173

'74

'71

176

D. J. Curry, J. M. Midgley, S. L. Leung, R. Watt, and W. B. Whalley, J . C S . Perkin 1, 1977, 822. P. J. Hylands, J. M. Midgley, C. Smith, A. F. A. Wallis, and W. B. Whalley, J.C.S. Perkin l, 1977, 817. H. Velgova and V. cerny, Coll. Czech. Chem. Comm., 1976,41, 3131. P. KoEovsky and V. b n y , Coll. Czech. Chem. Comm., 1977,42, 155. P. KoEovsky and V. tern?, Coll. Czech. Chem. Comm., 1976,41,2620. F. J. Parish, M. E. Newcomer, G. L. Gilliland, F. A. Quiocho, and G. J. Schroepfer, jun., Terrahedron Letters, 1976,4401. B. M. Trost and Y . Matsumura, J. Org. Chem., 1977,42,2036. J. F. Kinnear, M. D. Martin, D. H. S. Horn, E. J. Middleton, J . S. Wilkie, M. N. Galbraith, and R. I. Willing, Austral. J. Chem., 1976, 29, 1815. R. Hanna and B. Muckensturm, Bull. SOC.chim. France, 1976, 1865.

Steroid Reactions and Partial Syntheses

FO,Me

265

C02Me

COMe

OAc

Reagents: i, H2-Pd-BaC03; ii, NaH-MezC=CHCH,Br; iii, Na-Hg-MeOH-Na2HP04; iv, Hg(0Ack; v, NaOH-MeOH; vi, MeLi; vii, MezNPh-AczO-CHC1,; viii, m-CIC6H4C03H; ix, LiAIH4, x, TsOH-H~O

Scheme 9

2-enes.I7’ The Paterno-Buchi reaction, which ?4lows the preparation of the la,5aepoxycholestane (260) from the photolysis of the 5,10-~ecocholestene(259), is the first step in a convenient synthesis of l a - and lp-hydroxycholesterol. Cleavage of the 1,5-epoxycholestane (260) with HI-MeC0,H afforded 1 a-hydroxycholesteryl M. Weissenberg, D. Lavie, and E. Glotter, J.C.S. Perkin I, 1977, 795.

Terpenoids and Steroids

266

acetate, which by successive oxidation and reduction led to lp-hydroxycholesterol. 17' A full account of the syntheses of the four isomeric 20,22-epoxycholesterols179 is accompanied by two similar reports. 180*181 Pregnenolone has been converted by two independent routes into 25-0x0-27-norcholesteryl Both routes employed the highly stereoselective platinium-catalysed hydrogenation of the 20,22-double bond which in one case183was shown to have the E-configuration. Three additional syntheses of 25-hydroxycholesterol have been reported. 1 8 ~ 1 8 6 The 6~-methoxy-3a,5a-cyclo-20-carboxaldehyde (261), derived from stigmasterol, was converted into the diene (262)lS4or the dichloro-olefin (263)lS5and thence into 25-hydroxycholesterol as indicated in Scheme 10. Alternatively the side-chain of the bromo-derivative (264) was extended as indicated in Scheme 11.IS6

10 Vitamin D and its Metabolites The chemistry of vitamins D and hydroxylated derivatives has been reviewed.lS7 A new route to la-hydroxycholecalciferol is provided by a synthesis of cholesta-5,7diene- la,3P-diol from Scy-cholest-7-en-3~-0ne.~~~ Selective 2,4-dibromination and dehydrobromination gave the 3-0xo-A~*~*~-triene (265) which was efficiently converted into the 3p-hydro~y-A'~~~'-triene (266) by enol acetylation and Ca(BH4k reduction. The 5,7-diene system of (266) was protected by formation of the adduct (267), which on silylation, epoxidation, desilylation, and LiAIH, reduction gave cholesta-5,7-diene-la,3p-diol. The enol acetylation-CaBH, reduction procedure provides an interesting alternative for 3-0xo-A~~~-deconjugation. Further studies have been reported on the effect of variation of the wavelength of U.V. irradiation on the conversion of provitamins into vitamins D.lS9 In ethanol, U.V. light of wavelength 295 nm provided maximum yields. Irradiation of 170-acetoxy-4,4dimethylandrost-5,7-dien-3P-o1gave only a low yield of the vitamin D analogue, the major product being the 5,8,10(19)-triene (268).l9' 17' 179

M. Lj. Mihailovif, Lj. Lorenc, V. PavloviC, and J. Kalvoda, Tefruhedron, 1977,33,441. C.-Y. Byon and M. Gut, J. Org. Chem., 1976,41,3716.

"'K. Bannai, M. Morisaki, and N. Ikekawa, J.C.S. Perkin I, 1976, 2116.

M. Koreeda, N. Koizumi, and B. A. Teicher, Tetrahedron Letters, 1976,4565. B. Tschesche, B. Goossens, G . Piestert, and A. Topfer, Tefiuhedron, 1977,33, 735. T. C. McMorris and S. R. Schow, J. Org. Chem., 1976, 41, 3759. Is4 W. G . Salmond and M. C. Sobala, Tefruhedron Letters, 1977, 1695. W. G. Salmond, M. C. Sobala, and K. D. Maisto, Tetrahedron Letzers, 1977, 1237. W. G. Salmond and K. D. Maisto, Tefruhedron Letters, 1977, 987. I*' P. E. Georghiou, Chem. Soc. Reo., 1977,6,83. '*' A. Emke, D. Hands, J. M. Midgley, W. B . Whalley, and R. Ahmad, J.C.S. Perkin I, 1977, 820. T. Kobayashi, M. Hirooka, and M. Yasamura, Vitamins, 1976,50, 185. "'J. Brynjolffsen, J. M. Midgley, and W. B. Whalley, J.C.S. PerkinI, 1977, 812. Is*

Steroid Reactions and Partial Syntheses

267

liii

:262)

Reagents: i, Me2C=CHCH=PPh3; ii, MeC03H; iii, HZ-Pt/C; iv, BrCC13-(Me2N)3P; V,2 equiv. Bu"Li; vi, HMPA-

)LI

; vii, H2-Pt0,;

viii, TsOH-H20

Scheme 10

Y

OMe

Ir."'/?""

, l ___l i

Reagents: i,

c)

Li; ii, Bu"Li,

S

;iii, LiAIH4-TiC13

Scheme 11

Terpenoids and Steroids

268

0

HO

I

Ph (267)

The syntheses have been reported of 1c~,3/3-dihydroxy-4,4-dimethylcholesta5,7-diene (269) and its 3a-epimer, along with the ergostane a n a l o g ~ e s . ~ As ’~ reported in the preliminary account, 4,4-dimethylcholesta-5,7-dien-3-one underwent the ene reaction with 4-phenyl- 1,2,4-triazoline-3,5-dione to give (270) rather than the normal Diels-Alder adduct.’’* Treatment of (270) with acid gave the trienone (27 1). Treatment of cholecalciferyl tosylate with aq. KHC03-

acetone gave the 3,5-cyclo-derivative (272) which could be oxidized with MnO, to the 6-oxo-3,5-cycIocholecalciferol(273). Reaction of (273) with MeLi and dehydration of the resultant alcohols gave 6-methylcholecalciferol (274) and 6methyl-trans-cholecalciferol (275). The former compound underwent a thermal 1,7-H shift to give 6-methylprecholecalciferol (276), the equilibrium of this reaction being very much in favour of (276) owing to the steric interaction between the 6-methyl group and the 9-hydrogen atoms in 6-methylcholecalciferol (274).’” Similar steric interactions significantly influence the iodine-induced equilibria between 6-methylcholecalciferol (274) and 6-methyl-trans-cholecalciferol(275) (15 : 85) and between 6-methylprecholecalciferol (276) and 6-methyltachysterol, 19’ 19’

M. Sheves and Y . Mazur, Tetrahedron Leiters, 1976, 2987. M. Sheves and Y. Mazur, J.C.S. Chem. Comm., 1977,21.

269

Steroid Reactions and Partial Syntheses

(277) (50: 50). In addition, differences between the U.V. spectra of the 6-methyl isomers and the non-methylated analogues were attributed to these steric interactions. Catalytic hydrogenation of trans-cholecalciferol gave mainly the previously unknown (lOR)-epimer of dihydrotachysterol, (278) whereas hydroboration-acetic acid treatment gave a 1 : l mixture of (278) and the (10s)17

C*H 1 -

C,Hl?

i-" ci'

0

HO'

(276)

(277)

(278)

e ~ i m e r . 'Syntheses ~~ of 2 5 - f l ~ o r o - , ' ~ 25-aza-,19' ~:'~~ 24-dehydro,lY5and 25-dehydro-cholecalciferol'y5 have been reportsd in addition to the syntheses of a homologous series of side-chain analogues of 25-hydroxycholecalciferol.lg6 In the latter series all are biologically inactive apart from the homo-derivative (279) which has similar activity to 25-hydroxycholecalciferol in mobilization of bone calcium and half its activity in stimulation of intestinal calcium transport.

IFH (279)

193

194

'91

W. H. Okamura, M. L. Hammond, A. Rego, A. W. Norman, and R. M. Wing, J. Urg. Chem., 1977,42, 2284. S . S. Yang, C. P. Dorn, and H. Jones, Tetrahedron Letters, 1977, 2315. B. L. Onisko, H. K. Schnoes, and H. F. DeLuca, Tetrahedron Letters, 1977, 1107. R. L. Johnson, S. C. Carey, A. W. Norman, and W. H. Okamura, J. Medicin. Chem., 1977, 20, 5 .

Terpenoids and Steroids

270

11 Pregnanes 18-Methylideneprogesterone has been synthesized from the readily available 3pacetoxy- 18-cyanopregn-5-en-2O-one which may be transformed into the amine oxide (280). Cope degradation of this intermediate gave the 18-methylidene derivative (28 l),'" which was readily converted into 18-methylideneprogesterone. Alternative syntheses employ the lactone (282) which in one instance was trans-

(280)

(281)

(282)

formed into the epimeric tosylates (283) which fragmented with KOBu' to give the 18-methylidene derivatives (284) which are epimeric at C-17. An alternative

(283)

(284)

~ynthesis'~'of 18-hydroxy-11-deoxycorticosterone employs dehydration of 18hydroxyprogesterone and OsO, hydroxylation of the resultant 20721-double bond (see ref. 127). The propensity has been noted of 18-hydroxy-1 l-deoxycorticosterone to form acetals with reagent-grade methanol or ethanol containing traces of acid. 199 Reaction of variously isotopically labelled MeMgBr with 3p -acetoxy- 17ahydroxypregn-5-en-20-one and 3p -acetoxy- 16a,17a -epoxypregn-5-en-20-one followed by LiAIH, reduction gave respectively (20s)- and (20R)-[20-'3CH,]-, [20-C3H,]-, and [20-C2H,]-20-methylpregn-5-ene-3p, 17a,20-triol owing to conformational localization of the 20-carbonyl group by neighbouring substitution.'" A synthesis of the B-ring aromatic corticosteroid (286), the analogue of cortexolone, started with the previously reported B-ring aromatic norpregnane (285). Development of the corticosteroid side-chain employed bromination of the 17a-hydroxy-20-0x0-derivative with trimethylphenylammonium bromide perbromide.'" Reaction of perchloryl fluoride with the mixed enol ethers (287) and (288) provided, after hydrolysis, the 17a-fluoro-20-0x0-compound (290) and the 21-fluoro-20-0x0-compound (291). In contrast, the enamine (289) led only to the 17a,21-difluoro-20-oxo-compound.zoz A series of 17a-acyloxy-21-deoxyJ. Kalvoda, J. Grob, and G . Anner, Helv. Chim. Acta, 1977,60, 1579. M. P. Li, M. K. Birmingham, and T. H. Chan, J. Org. Chem., 1976,41,2552. A. K. Roy, L. C. Ramirez, and S. Ulick, J. Steroid Biochem., 1976, 7 , 81. Y.Osawa, T. Makino, K. Shibata, C. M. Weeks, and W. L. Duax, J . C S . Chem. Comrn., 1976,991 P. Kokovsk9 and 2. Prochazka, Coll. Czech. Chem. Comm., 1977,42,553. J. Pataki and E. V. Jensen, Steroids, 1976, 28, 437.

IY8

'" 2oo

201 202

27 1

Steroid Reactions and Partial Syntheses

HO

(290) R' = F, R2= H (291) R * = H , R ~ = F

(288) R' = OMe, R2 = Ac Et (289) R' = N

/ \

,R~=H CHZPh

corticoids has been prepared from the corresponding 17-acyloxy-21-tosylates by in situ reduction through the corresponding 17-acyloxy-2 1-iodo-compounds.203 Syntheses of 6~-fluoro-corticoidsemploy the normal reactions of HF with 5a,6aepoxides. The usual epimerization of the 6p-fluorine atom in 3 - 0 x 0 4 ~ compounds was avoided by first brominating at C-2: for example, the 2a-bromo5a-hydroxy-6p-fluoro-compound (292) gave the 6 ~ - f l ~ 0 r o - A " ~ ~ ~ ( " ) - 3 - o x o compound (293) on treatment with LiBr-Li,CO, in DMF.'04 CH,OAc

I

F

12 Androstanes The synthesis of 4,4-dimethyl-5a-androstan-l7p-ol-3-one and its 19-noranalogue employed methylation of the 2,2-trimethylenedithian derivatives and subsequent desulphurization. It was confirmed that catalytic hydrogenation of '03

204

R. Vitali, S. Gladiali, G. Falconi, G. Celasco, and R. Gardi, J. Medicin. Chew., 1977, 20, 853. L. Toscano, G. Grisanti, G. Fioriello, L. Barlotti, A. Bianchetti, and M. Riva, J. Medicin. Chem., 1977, 20. 213.

Terpenoids and Steroids

272

4,4-dimethylandrost-5-en-l7p-ol-3-onegave the 5a-dihydro-compound but, contrary to earlier reports, similar hydrogenation of 4,4-dimethyl- 19-norandrost5-en-17p-ol-3-one gave a mixture of the 5a- and 5P-dihydro-compounds rather than simply the 5a-i~orner.’~~ Syntheses of 5P-androst-7-ene and 5P-pregn-7-ene have been reported as part of a study of electron-impact-induced retro-DielsAlder reactions.2M Standard procedures starting from 7-dehydrodiosgenin were employed. The synthesis of the little-studied androsta-2,5-dien-4-onesfrom androstenolone has been reported. Allylic bromination of androstenolone followed by AgOAc-pyridine treatment gave 4P-acetoxyandrostenolone which after selective tosylation of the 3P-hydroxy-group and reduction with NaH-THF gave androst-5-ene-4,17-dione.Dehydrogenation with DDQ gave androsta-2,sdiene-4,1 7-dione.’07 A series of D-homo-5cu -androstanediones has been synthesized and, interestingly, prolonged reaction time in the dehydrobromination of the 17,17-dibromo-~-homoandrostan-17~ -one (294) led to the dienone (295).’OS An improved synthesis has been reported for 3p, 16p-dihydroxyandrost5-en-17-0ne.’~ 0

13 Cardenolides Two syntheses have been reported for 14p-hydroxyandrostan-17-ones which are useful intermediates in cardenolide synthesis. Photo-oxygenation of Sa-androsta14,16-diene gave the epidioxide (296) which was transformed with base into

H (296)

140-hydroxy-5a-androst- 15-en-17-one which was in turn hydrogenated to give 14p-hydroxy-5a-androstan-17-one.Testosterone may be converted into 3phydroxy-56-androstan- 17-one which was transformed into 3p,14p-dihydroxy-5p’05

*07

’08

’09

J. M. Midgley, W. B. Whalley, P. A. Dodson, G . F. Katekar, and B. A. Lodge, J.CS. Perkin I, 1977, 823. J. S. Dixon, I. Midgley, and C. Djerassi, J. Amer. Chem. Soc., 1977, 99, 3432. J. R. Hanson, D. Raines, and H. Wadsworth, J.C.S. Perkin I, 1977,499. D. de Marcano, J. M. Evans, L. Kohout, I. Ludovic, M. Narvaez, 0. Salas, and C. Vallejos, J. Org. Chem., 1977,42, 1221. F. A. Kincl, J. Steroid Biochem., 1976,7,419.

273

Steroid Reactions and Partial Syntheses

androstan-17-one (297) by the reaction sequence shown in Scheme 12.210 The unsaturated aldehyde (301), a cardenolide analogue with lower biological activity 0

rY-5 Reagents: i, TsNHNH2; ii, MeLi; iii, m-CIC&4CO& viii, Hz-Pd

4vii, viii

iv, PhSeSePh-NaBH4; v, H202;vi, Cr03-py; vii, 0 2 ;

Scheme 12

than digitoxigenin, was prepared from the tetrol (298) which is obtained by degradation of digitoxin.211 Periodate oxidation of the tetrol (298) gave the aldehyde (299) which was allowed to react with (EtO),P(O)CH-CH=NC,H,, to give the azadiene (300). Oxalic acid hydrolysis of (300) gave the required aldehyde (301). Digitoxigenin was transformed into the 20-epimeric 22-methylene-14-

("

so16 dHO OH

(298)

(299)

OH

(300)

OH

(301)

enolides (302).'12 The butenolide ring was modified by successive hydrogenation, enolate carboxylation, and reaction with CH20-Et2NH. The 17p-homocardenolide (304) was synthesized from the 17-carboxylic acid (303).'13 210

212

213

V. Balogh, J.-C. Beloeil, and M. Fetizon, Terruhedron, 1977,33, 1321. D. S. Fullerton, M. C. Pankaskie, K.Ahmed, and A. H. L. From, J. Medicin. Chem., 1976,19, 1330. D. S. Fullerton, T. M. Gilman, M. C. Pankaskie, K. Ahmed, A. H. L. From, W. L. Duax, and D. C. Rohrer, J. Medicin. Chem., 1977, 20, 841. T. W. Giintert, H. H. A. Linde, M. S. Ragab, and S. Spengel, Helo. Chim. Actu, 1976,59, 2125.

274

Terpenoids and Steroids

14 Seco-steroids and Cyclo-steroids 0-Keto-sulphides, which are available by sulphenylation of the enolate of the ketone, may be cleaved directly with alkaline hydrogen peroxide to the dicarboxylic acids or converted with Pb(OAc), into the P-keto-acetoxysulphides which are also cleaved with alkaline hydrogen peroxide. This novel procedure has been applied to a number of steroidal ketones.’14 High yields of 16,17-seco-dicarboxylicacids have been obtained from the reaction of the en01 acetates of 17-0x0-steroids with KMnO, in benzene containing 18-cr0wn-6.’~~Degradation of cholic acid to 3a,7a, I2a-triacetoxy-5p-pregn- 16-en-20-one followed by ozonolysis gave the 16,17-seco-dicarboxylic acid which is a useful intermediate for the synthesis of q ~ a s s i n o i d s . ’ ~ ~ The * ’ ~ ~5,10-seco-allenes (306) and (307) were obtained by basecatalysed isomerization of the 5,lO-seco-acetylenes (305) which were previously

*I5 216

B. M. Trost and G. S . Massiot, J. Amer. Chem. SOC., 1977, 99, 4405. J. R. Dias and R. M. Fregoso, Rev. Lafinoamer. Quim., 1976,7, 29. J. R. Dias and R. Ramachandra, Terruhedron Letters, 1976, 3685. J. R. Dias and R. Ramachandra, J. Org. Chem., 1977,42, 1613.

Steroid Reactions and Partial Syntheses

275

reported to be inhibitors of a bacterial 3-oxo-A5-steroid isomerase.218 It was confirmed that the allenes are produced from the acetylenes by the enzyme system. The large-scale preparation of the 3,5-seco-4-nor-carboxylicacid (308) employs NaI0,-KMnO, oxidation of testosterone- 17p-yl a ~ e t a t e . ”Oxidation ~ of the 3,scyclo-&ketone (309) with potassium hypobromite gave the 6,7-seco-carboxylic acid (310) which was transformed into further derivatives.’*” A number of 2-

and 4,S-cyclo-A-homo-Boxygenated 4,5-cyclo-A-homo-B-norcholestanes’2~ norandrostanesZz2have been synthesized. The key step in these syntheses is the Simmons-Smith methylenation of ~-nor-A~-compounds.

15 Heterocyclic Steroids The chemistry of oxa-steroids has been r e ~ i e w e d . ” ~The 17P-pyrrolinone ( 3 14) was synthesized from 3P-acetoxypregn-5-en-2 I-01-20-one which was first converted into the 2 1-azido-compound ( 3 11) with NH,-Ph3P-EtO,CN=NCO,Et. Catalytic reduction of the 21 -azido-compound (311) gave the amide (312) which with ZnBr,-K-THF underwent the Reformatsky reaction to give the hydroxypyrrolidinone (3 13) which in turn was dehydrated with thionyl chloride, giving the 17P-pyrrolinone (3 14).’24 A similar synthesis of the homologous 17p-pyrrolinone (3 17) started from the azido-compound (316) which is available from the diazoketone (315).225 Catalytic hydrogenation of the azide (316) gave the dimeric

(311) ’I8

’I9 z20

”’ 223 224 225

(3 12)

(313)

D. F. Covey and C. H. Robinson, J. Amer. Chem. Soc., 1976,98, 5038. L. Milewich and L. R. Axelrod, Or5 Synrh., 1976,55, 67. H. Velgovi and V. CernL, Coll. Czech. Chem. Comm., 1976,41, 2630. J. Joska and J. FajkoS, Coll. Czech. Chem. Comm., 1977,42, 1035. J. Joska and J. FajkoS, CON.Czech. Chem. Comm., 1977, 42, 1044. S. R. Ramdas and A. P. Chaudhuri, J. Sci. Ind. Res. India, 1975,34, 563. T. W. Guntert, H. H. A. Linde, M. S. Ragab, and S. Spengel, Helv. Chim. Acra, 1977,60, 334. T. W. Guntert, H. H. A. Linde, M. S. Ragab, and S. Spengel, Helv. Chim. Acfu, 1976, 59, 2138.

276

Terpenoids and Steroids

H

pyrazine (318). The aldehyde (319) reacted with 2-furyl-lithium to give the adduct (320) which underwent rearrangement to the hydroxycyclopentenone (32 1) with sulphuric acid in aqueous acetone or cleavage to the oxomethoxyacetal (322) with methanolic sulphuric acid. The mechanisms of these transformations are being investigated.*" Beckmann rearrangement of the seco-B-noroxime (323) afforded the lactam (324) which with DCC and subsequent LiAIH, reduction gave the 5-aza-androstane (325).227 A detailed account of the syntheses of 2-azaoestratrienes [e.g. (33O)J has been reported. Base-catalysed oxygenation of the 6p, 19-epoxy-3-ketone (326) provided the diosphenol (327) which on ozonolysis

AcO' 226 227

G. Piancatelli and A. Scettri, Tefruhedron, 1977, 33, 69. W,J. Rodewaid and J. R. Jaszczyriski, Tetrahedron Letters, 1976, 2977.

277

Steroid Reactions and Partial Syntheses

gave the 2-oxa-3-oxo~A4-compound(328) with loss of CO,. Reaction of (328) with NH.,HCO,-HC0,H provided the unsaturated lactam (329) which was transformed into 17~-acetoxy-3-methoxy-2-azaoestra-1,3,5( 10)-triene (330).228 The 4-aza-

(319)

I HO,C

HO,C

OH

0

(329)

HO

(330)

oestratriene (33 l), which was prepared from nortestosterone according to Scheme 13, was transformed into the ylide (332) by reaction successively with mesitylsulphonylhydroxylamine and ethyl chloroformate-K,CO,. Photolysis of (332) 228

R.J. Chorvak and R.Pappo, 1.Org. Chem., 1976,41,2864,

Terpenoids and Steroids

278

&

e

\N

o

H

c

(331) Reagents: i,

0 3 ; ii,

NaOAc-AczO; iii, BuhAIH; iv, NH20H

Scheme 13

gave the diazepine (333) which on prolonged irradiation gave the [2+2] cycloadduct (334).229 Halogenation of the conanine (335) led to the mono-, di-, and tri-chlorinated or di- and tri-brominated derivatives (336)-(340) along with, in certain instances, the oxaziridine (34 1)?'' The 17-phospha-steroid (344) was

& ' CS) ,N-N

-I

N

\

EtZ%' 02C

CO2Et

C0,Et

(332)

(335) (336) (337) (338) (339) (340)

'*' 23"

(333)

R' = R 2 = R' = H R' = C1, R2 = R3= H R' = R2 = CI, R' = H R' = R2= R' = C1 R' = R2 = Br, R' = H R' = R2 = R' = Br

A. Frankowski and J. Streith, Tetrahedron, 1977, 33, 427., A. Picot, M. Dendane, and X. Lusinchi, Tefrahedron, 1976,32,2899.

(334)

(342)

!

279

Steroid Reactions and Partial Syntheses

(344)

(343)

prepared by hydrolysis of the phosphonium salts (343) which in turn are prepared by addition of MePCl, to the diene (342).231The equivalent 15-phospha-steroid was prepared by an analogous route. The C-23 spirosolane alkaloid (347) was A key step involved the prepared from 3p, 1 6 a -diacetoxy-5c~-pregn-20-one.~~~ addition of pyrrolylmagnesium iodide to the acid chloride (345) to give the 2acylpyrrole derivative (346).

0

HO

16 Microbiological Oxidations and Reductions Microbial and enzymic transformations of steroids have been reviewed.233 5aPregnane-7,20-dione gave a reasonable yield of the l a , 12p-dihydroxy-derivative on incubation with Calonectria d e c ~ r a . ~High ' ~ yields of lop-hydroxy- 19-nortestosterone were obtained by incubation of 19-nortestosterone with Rhizopus arrhizus (Fischer Oxidation of canrenone" with a Penicillium species provided the 15a-hydroxy-derivative (348) which is a product of human metabolism of spironolactone.2'" 16p-Hydroxylation of androstenolone, androst-4-ene-3,17-

(348) 231

232 233 234

235 23G

C. Symmes, jun., J. Morris, and L. D. Quin, Tefruhedron Letters, 1977, 335. G. Piancatelli and A. Scettri, Guzzettu, 1976, 106, 167. H. C. Murray, Ind. Microbial., 1976, 79. E. R. H. Jones, G. D. Meakins, J. 0. Miners, R. N. Mirrington, and A. L. Wilkins, J.C.S. Perkin I, 1976, 1842. J. Favero, J. Marchand, and F. Winternitz, Bull. SOC.chim. France, 1977, 310. L. J. Chinn, E. A. Brown, S. S. Mizuba, and A. Karim, J. Medicin. Chem., 1977, 20, 352.

* 3-(3-0xo-17~-hydroxyandrosta-4,6-dien-l7~-yl~ropionic acid lactone.

280

Terpenoids and Steroids

dione, and testosterone has been reported with Aspergillus niger237and 16p,18dihydroxylation of 3,6-dioxygenated Sa-androstanes with Leptoporus f i ~ s i l i s . ~ ~ ’ Hydroxylation of a series of 14a-cardenolides with Curvularia lunata, Cunninghamella blakesleeana, and Aspergillus ochraceus occurred preferentially with a-attack at C-11, C-14, and C-17.239 Several species of Arthrobacter, Mycobacterium, and Nocardia immobilized in a polyacrylamide gel transformed 3 p acetoxy- and 3p-hydroxy-AS-steroids and 3-0x0-A4-steroids into 3-0x0-A”~Stereospecific reduction of 20-0x0-steroids may be achieved with Bacillus megaterium in certain instances: I 7a-hydroxyprogesterone gave 17a,2Oa-dihydroxypregn-4-en-3-one whereas cortexolone gave 17a,2Op,2 1 -trihydroxypregn-4-en-3-0ne.~~’ Cultures of Nocardia opaca transformed 4-chlorotestosterone and related molecules into 9,lO-seco-derivatives by a 9a-hydroxylation and a l-dehydr~genation.~~’

17 Miscellaneous Syntheses A review of the syntheses of carbocyclic spiro-compounds contains several steroidal examples.243A series of 17-oxygenated 12,13-epoxyetiojervanes has been prepared from the trienone (349) which is available by degradation of j e r ~ i n e . ’ ~ ~ Hydride reduction of (349) to the epimeric alcohols (350) followed by Os04Na1O4 oxidation gave the 17-0x0-derivative (35 1). Birch reduction removed the 12-hydroxy-group and subsequent reduction of the 17-0x0-group with BH, gave the 17a-hydroxy-derivative (352) whereas reduction with AlH3 gave the 17phydroxy-derivative (353). Epoxidation of (352) and (353) gave the 12,13-epoxy17-hydroxyetiojervanes (354). The equivalent 12,13-epoxy- 17-oxoetiojervanes were also described. The syntheses from jervine of etiojervane analogues of 5aandrostan-3p-01~~~ and 5a-pregnan-3&01,~~~ namely (355) and (356) respectively, have been described and a study of the relative stabilities of the cis- and trans-C/D

(349) 237

238

239 240

24’ 242

243 244

245 246

(350)

H. Yarnashita, K. Shibata, N. Yarnakoshi, Y. Kurosawa, and H. Mori, Agric. andBiol. Chem. (Jupan), 1976,40, 505. W. A. Denny, R. M. Fredericks, I. Ghilezan, E. R. H. Jones, G. D. Meakins, and J. 0. Miners, J.C.S. Chem. Comm., 1976,900. F. Wagner and S. Lang, Chem. Ber., 1976,109,3304. N. E. Voishvillo, N. E. Karnernitskii, A. Y. Khaikova, I. G. Leontev, V. N. Paukov, and L. A. Nakhapetyan, Izvest. Akud. Nauk S.S.S.R., Ser khim., 1976, 1357. H. Yamashita, N. Yamakoshi, and Y. Kurosawa, Nippon Nogei Kugaku Kuishi, 1976, 50, 119. C. Hoerhold, G. Rose, E. Hueller, and K. Schubert, J. Sreroid Biochem., 1976, 7 , 199. A. P. Krapcho, Synthesis, 1976, 425. A. Murai, N. Iwasa, M. Takeda, H. Sasarnori, and T. Masamune, Bull. Chem. SOC.Japan, 1977, 50, 429. A. Murai, T. Nishirnura, and T. Masarnune, Bull. Chem. SOC.Japun, 1976,49, 1612. A. Murai, T. Nishirnura, and T. Masarnune, Bull. Chem. SOC.Japan, 1976, 49, 1602.

Steroid Reactions and Partial Syntheses

(351)

281

(352) a-OH (353) @-OH

(355) R = H (356) R = E t

ring junctions suggested a dependence on the configuration and bulkiness of the C- 17 substit~ent.’~’ A series of disteroidal enol ethers [e.g. (357)], which have, in some cases, long-lasting uterotrophic activity, has been prepared by acid-catalysed exchange

etherification between a 17-hydroxyoestra-l,3,5(10)-triene and a 3-ethoxy-A3*’steroid.248A series of androsta-3,5-dienes7 oestra-3,5-dienes, and gona-3,5-dienes has been prepared and evaluated as claudogenic agents. 7-Methyloestra-3,5-dien17/3-01 is one example of a potent compound in this class.249A number of steroidal nitroxide ~ a d i c a l s ~and ~ ~b*i ~r a~d’i c a l ~have ~ ~ ~been reported. 247

248

249

”*

T. Masamune, A. Murai, K. Nishizakura, T. Orito, S. Numata, and H. Sasamori, Bull. Chem. Soc. Japars 1976,49,1622. R. Vitali, S. Gladiali, G. Falconi, G. Celasco, M. A. Saccani, and R. Gardi, J. Medicin. Chem., 1977, 20, 359. P. M. Weintraub, P. L. Tiernan, H. D. Benson, J. F. Grunwell, J. 0”. Johnston, and V. Petrow, J. Medicin. Chem., 1976, 19, 1395. G. Sosnovsky and M. Konienny, ‘synthesis, 1976, 537. M. Adackaparyil and J. H. Smith, J. Org. Chem., 1977,42, 1655. E. K. Metzner, L. J. Libertini, and M. Calvin, J. Amer. Chem. SOC.,1977, 99, 4500.

Errata Vol. 6 1976 p. 10, ref. 73. For ‘J. Sih’ read ‘C. J . Sih’. p. 22, Scheme 8. Include xii over the arrow between (79) and (73). ~ ~ ’ . ‘6P,7-dihydroxy-A6p. 50, line 10. For ‘ 6 P , 7 - d i h y d r o ~ y - A ~ - T H C ~Read THC370’. VoI. 7 1977 p. 5 , ref. 34. For ‘J. J. Fatiadi, Synthesis, 1976, 65, 133’ read ‘J. J. Fatiadi, Synthesis, 1976, 65, 133’. p. 9, last line of text. For ‘p-menthen-4-01’ read ‘p-menth-l-en-4-01’, p. 26, eighth line from bottom of the text. For ‘acetoxyleuropein’ read ‘acetoxyoleuropein’ . p. 31, references. For ‘331’ read ‘311’. p. 33, line 10. For ‘methyl tosylate’ read ‘menthyl tosylate’. p. 5 1, line 7. For ‘dihydrocannabidiols’ read ‘dihydroxycannabidiols.’ p. 5 1 line 9. For ‘7-hydroxycannabionol’ read ‘7-hydroxycannabinol’.

Author Index Aasen, A. J., 141 Abbott, B. J., 62 Abraham, P. M., 45 Abraham, W.-R., 117, 169 Abryutina, N. N., 179 Abubakirov, N. K., 177,233 Achini, R. S., 38 Achmatowicz, O., 12 Adackaparayil, M., 281 Adam, G., 137,138, 217 Adinolfi, M., 108, 147 Adley, T. J., 217 Agata, A., 21 Agurell, S., 63 . Ahatanl. T., 121 Ahmad, M., 174 Ahmad, R., 266 Ahmed, F. R., 134 Ahmed, K., 273 Aime, S., 22 Aizawa, H., 131 Akhnazaryan, A. A., 26 Akhrem, A. H., 241 Akimaliev, A,, 177 Akita, H., 132 Akutagawa, S., 21, 23 Alam, S. S., 208 Alazard, J. P., 47 Alchalel, A,, 200 Alewood, P. F., 155, 255 Alexander, V., 199 Alimbaeva, P. K., 177 Allandrieu, C., 55 Allaway, J. R., 53 Allegrini, J., 19 Allen, K. G., 14 Allen, M. S., 51, 66 Allinger, N. L., 211, 212, 238 AI Neirabeyeh, M., 229 Alonso, M. E., 42 Alper, H., 53 Alper, J. B., 154 Alpi, A,, 151 Al Rawi, J. M. A,, 214 Altman, L. J., 214 Alward, S. J., 118 Amagaya, S., 174 Amico, V., 123, 144, 145 Amos, B. A,, 221 Anastasia, M., 231, 242 Anderson, N. H., 99 Anderson, R. C., 107,256 Anderson, R. J., 38 Andre. D., 174

Andreetti, G. D.. 158 Andreeva, I. S., 58 Andrewes, A. G., 184, 190 Andrews, G. C., 117 Anet, F. A. L., 217 Anjaneyulu, A. S. R., 174, 175 Anner, G., 270 Ansarin, M., 143 Antonova, N. D., 44 Aoki, H., 20 Aoyama, %-I., 59 ApSimon, J. W., 155. 215 Aragon, R., 130 Arase, A., 13, 56 Arata, K., 43, 57 Aratani, T., 33, 45, 54 Arbuzov, B. A,, 56,57,58,205 Archer, R. A,. 61, 62 Argyle, J. C., 14, 24 Arigoni, D., 28, 87 Ari-Izumi, A,, 25 Arimara, S., 130 Arita, H., 176, 217 Ark, H. G., jun. 56 Armarego, W. L. F., 7 Arndt, H. C., 3, 13 Arora, A. K., 226 Arora, S. K., 169 Arpino, P., 22 Arsenault, G. P., 137 Arteaga, J. M., 125 Asakawa, J.-I., 40, 217 Asakawa, Y., 54,121,145,162, 176 Ashby, E. C., 53 Asikyan, S . M., 26 Aslanov, Kh. A,, 127 Aso, M., 26 Astier, A,, 236 Atabekyan, V. G., 224 Atal, C. K., 39 Aton, B., 201 Attisso, M., 19 Atwal, K. S., 149 Aul’chenko, I. S., 4 Aung Than, 203 Austin, D. J., 187 Auterhoff, H., 46 Au-Yeung, B.-W., 37 Aversa, M. C., 178 Avery, M. A,, 38, 76 Avotins, F., 56 Avouris, P., 50 Axelrod, L. R., 275

283

Ayer, W. A., 11 1,216 Azerad, R., 200 Azzaro, M., 225 Babich, S. A,, 21 Babler, J. H., 9 Babushkina, N., 206 Rack, T. G., 52 Baddeley, G. V., 171 Baerheim Svendscn, A,, 8 Baez, J. L., 78 Bai, V. V., 175 Bailey, W. J.. 73 Bailleul, F., 37 Bajwa, B. S., 125 Baker, R., 102 Baker, T. S., 225 Bakhmutskaya, V G., 40 Bakina, L. A,, 19 Rakuzis, M. L. F., 83 Bakuzis, P., 83 Bal, K., 241 Baldwin, J. E., 239 Balogh-Nair, V., 128, 273 Banerjee, A,, 172 Banerjee, S. K., 172 Banerji, N., 177 Banerji, R., 174 Ban’kovskii, A. I., 49 Banks, R. E., 138 Bannai, K., 266 Banthorpe, D. V..14, 28 Bapuji, M., 174, 175 Baran, J. S., 211, 238 Baranowska, E., 170 Barbarez, M. K., 200 Bardouille, V., 101 Bardyshev, I. I., 45, 46, 57 Bari, S. S., 23, 25, 48 Barker, W. G., 203 Barlotti, L., 271 Barnes, M. H., 221 Barrett, A. G. M., 255 Barrick, J. C., 144 Barron, L. D., 50 Barta, M. A,, 246 Barton, D. H. R., 52, 89, 157, 237,240,244, 250,255 Bartsch, R. A,, 53 Barua, A. B., 205 Barua, A. K., 172 Basa, S. C., 163 Basak. A,. 172

Author Index

284 Bascoul, J., 247 Baskevitch-Varon, Z., 132 Basu, K., 172 Bates, R. B., 169 Batrakov, S. G., 207 Battalova, Sh. B., 54 Baur, C., 46 Baxter, R. L., 119 Bazyl'chik, V. V.. 44, 46, 54 Bayet, P., 33 Bear, C. A,, 49 Bearder, J. R., 138 Becher, B., 201 Becker, A. R., 195, 196 Becker, H., 37 Becker, R. S., 200 Beckwith, A. L. J., 29 Beddard, G. S., 200 Bee, E., 208 Beechan, C. M., 82 Beereboom, J. J., 68 Beierbeck, H., 155, 215 BCkissy, S., 22 Bekhtereva, M. N., 205 Bell, R. L., 16 Bell, R. P., 50 Bellamy, A. J., 34 Bellino, A., 135 Belobaba, D. T., 263 Beloeil, J.-C., 273 Be1oslyudoua:'T. M., 195 Belzecki, C., 7 Ben-Aziz, A,, 182, 203 Benetti, M., 151 Benn, M., 155,255 Bennet, R. D., 163 Bensasson, R., 200 Benson, H. D., 281 Bentley, ,R..208 Bentz, H., 52 Benveniste, P., 151, 160 Bercht, C. A. L., 61 Berchtold, G. A., 149 BBrenger, G., 216 Berg, J.-E., 48, 123, 141 Berg, W., 39 Bergel'son, L. D., 207 Berger, R., 188 Bergmann, E. D., 176 Berman, E., 256 Berrnan, M., 179 Berova, N. D., 7 Berry, R. E., 60 Berthet, D., 108 Bertrand, J. A,, 121 Bertrand, M., 33 Beshitaishvili, L. V., 140 Beslin, P., 152 Bessiere, C., 19 Bessiere, Y., 24,45 Betmcor, C., 179 Bhakuni, D. S., 13 Bhat, S. V., 125 Bhatia, M. S., 58

Bhattacharya, P. K., 7 Bhattacharyya, J., 140, 141 Bianchetti, A,, 271 Bianco, A., 4, 35, 36,37, 38 Bicchi, C., 49 Bidan, G., 24 Bigler, F., 187 Billot, M., 1 3 Bingham, A,, 184 Binkley, R. W., 10 Birch, A. J., 9 Birmingham, M. K., 270 Bisarya, S. C., 67, 87 Bittner, S., 196 Blackburn, T. F., 11 Blake, W., 66 Blakitnyi, A. N., 42 Blasjo, B. D., 108 Bledsoe, J. 0..57 Blok, J. G., 40 Blomberg, C., 9 Blount, J. F., 60, 95, 111, 132, 195 Bloxsidge, J. P., 214 Blum, M. S., 35, Boar, R. B., 151, 157, 161 Bobowski, G. S., 203 Bocelli, G., 158 Bochkov, A. F., 233 Bock, K., 39 Bodkin, C. L., 29 Bodot, H., 5 Boelens, H., 25, 47 Bogdanowicz, M. J., 3, 13 Boger, E., 62 Bohlmann, F., 22, 39, 40, 46, 64, 68, 71, 80, 95, 96, 101, 114,115, 117,119,121, 124, 125,126, 127, 133, 134, 135, 169 Bokadia, M. M., 39 Boldrini, G. P., 11, 198, 240 Boll, P. M., 59 Bollag, W., 195 Bondavalli, F., 41 Bonet, J.-J., 255 Bonini, C., 37 Bonting, S. L., 200 Boomsma, F., 255 Boon, A,, 62 Boone, J. R., 53 Boontanonda, P., 52 Borch, G., 183, 188, 190 Borch, R. F., 86 Borisevich, G. P., 200 Borisov, V. N., 49 Borowiecki, L., 55 Bose, A. K., 12, 227 Bose, R. J., 58 Bosworth, N., 213, 249 Boullier, P. A., 28 Bouman, T. D., 216 Bouquet, A., 156 Bowden, B. N., 152

Box, V. G. S., 101 Boyer, J. H., 49 Braekman, J. C., 141 Brarnley, P. M., 203 Brandange, S., 8 Branfrnan, A. R., 68 Brannon, D. R., 19 Brants, F. E., 40 Braun, M., 252 Braun, S., 124 Braz, Filho, R., 133 Brecknell, D. J., 46 Breitenbach, H., 124 Breitenstein, W., 73 Brener, L., 6 Breslow, R., 253 Breton, J. L., 125, 129 Briedis, A. V., 204 Brieskorn, C. H., 19, 46, 53, 172 Bright, W. M., 68,73 Brine, D. R., 61 Britten-Kelly, M. R., 52 Britton,G., 181, 182, 186,201, 203,205 Brockman, D., 208 Brody, M., 200 Brody, S. S., 200 Brookes, B., 134 Brown, D. J., 205 Brown, E. A., 279 Brown, F. C., 50 Brown, H. C., 6, 7, 9 Brown, J. M., 151 Brown, L. A,, 54 Browne, L. M., 111, 216 Brumley, W. C., 4 Brun, P., 78 Bruning, R., 105 Bruun, T., 180 Bryan, R. F., 68, 73, 144 Bryant, R. N., jun., 208 Brynjolffsen, J., 266 Bubb, W. A,, 237 Buchecker, R., 183, 188 Bucholtz, M. L., 204 Buchwald, S. L., 30 Buck, M., 195 Bucknall, C. A., 14 Buchwald, S. L., 72 Buckwalter, B. L., 42 BudtSinskL, M., 171,243 Budzikiewicz, H., 177 Biichi, G., 108 Buelke, J., 61 Buinova, E. F., 45 Bull, J. R., 235 Bu'Lock, J. D., 123, 160, 181 Bunnell, C. A,, 217 Burak, K., 43, 55 Burden, R. S., 181 Burdett, J. E., 238 Burford, C., 12,242 Burger, B. V., 23

Author Index Burger, W., 195 Burgers, P. C., 62 Burgstahler, A, W., 49 Burk, L. A., 80 Burka, L. T., 65 Burke, B. A,, 128, 163 Burke, S. D., 110 Burkert, U., 211 Burks, J. E., 146 Bursey, J. T., 61 Burt, V. T., 208 Buttery, R. G., 41 Buttkus, H. A., 58 Byon, C.-Y., 266

Cacan, M., 114 Cagnoii-Bellavita, N., 132 Cain, A. M., 246 Caine, D., 9, 82 Cainelli, G., 10 Calderon, J., 19 Callender, R., 199, 201 Calb, V., 243 Calvin, M., 223, 281 Cambacorta, A,, 123 Cambie, R. C., 234 Camoni, I., 19 Campion, A., 201 Campion, T. H., 231 Campos, 0. 0. S., 83 Canbere, P., 229 Candy, H. A,, 134 Cane, D. E., 71, 72 Canonica, L., 67 C a p e h i , C., 48 Caplan, S. R., 201 Caporusso, A. M., 22 Capshew, C. E., 50 Caputo, R., 124 Cardemil, 15 Cardillo, G., 10 Carey, S. C., 269 Carhart, R. E., 114 Carl, P., 200 Carlisle, C. H., 174 Carman, R. M., 45,46, 53, 123 Carr, R. V. C., 41 Carreira, L. A,, 199 Carrell, H. L., 179 Carroll, F. I., 237 Casanova, J., 217 Casida, J. E., 19 Casinovi, C. G., 67 Caspi, E., 151, 179, 214, 227, 230 Castanet, Y., 52 Castillo, R., 150 Castro, B., 12 Cattel, L., 160 Caughlan, C. N., 117 Cave, A., 67,156

285 Cavill, G. W. K., 4, 35 Cazes, B., 59 Ceccaldi, H. J., 185 Ceccarelli, N., 151 Ceccherelli, P., 132 Celasco, G., 271, 281 Celis, H., 200 Celis, S., 200 Cella, J. A., 230 Cerdi-Olmedo, E., 205 tern?, V., 234, 243, 264,275 Chabardes, P., 9, 25 Chabudzinski, Z., 43,54,55,57 Chakrabarti, P., 172 Chalmers, A. A,, 136 Chan, J. H., 26 Chan, K.-K., 25 Chan, T. H., 8, 270 Chan, W. R.,61, 101, 128, 163 Chan, Y.-M., 95 Chandel, R. S., 161 Chang, C., 48 Chang, C. Y., 146 Chang, H. L., 243 Chang, S. S., 19 Channell, R. B., 20 Chapdelaine, M. J., 11, 240 Chapleur, Y., 12 Chapya, A,, 128, 163 Chari, V. M., 127 Charlton, J. L., 27 Charlwood, B. V., 14 Charnock, P., 3 Charney, E., 5, 220 Chatten, L. G., 224 Chatterjee, A,, 172, 177 Chattopadhyay, K., 175, 177 Chatzopoulos, M., 43 Chaudhuri, A. P., 275 Chaudhuri, R. K., 58 Chavis. C., 247 Chawla, H. P. S., 52, 88 Chayet, L., 15 Chen, C. M., 134 Chen, Y.-P., 155 Cheng, K. P. 123 Cherkaev, V. G., 44 Chernov, B. K., 129 Chernysh, G. P., 195, 196 Cherry, R. F., 172 Chetty, G. L., 102 Chetyrina, N. S., 177 Cheung, H.-G., 193, 195 Chiacchierini, E., 19 Chialva, F., 22 Chiang, H.-C., 167 Chichester, C. O., 205 Chidgey, R., 48 Chinn, L. J., 238, 279 Chojnacki, T., 206 Chopra, A. K., 190, 192 Chorvak, R. J., 277 Chou, K. J., 42 Chow, Y. L., 55

Christensen, A. T., 107, 160 Chu, P. S., 147 Chujo, R., 200 Ciereszko, L. S., 146 Cighetti, G., 231, 242 Cimarusti, C. M., 243 Cini, M., 162 Cinquini, M., 8 Clardy, J., 82, 128, 144, 145, 146,147 Clark, B. C. jun., 28 Clark, R. D., 110 Coates, R. M., 13, 150 Codley, G., 214 Coetzer, J., 156,213,244 Cogdell, R. J., 200 Coghlan, M. J., 9 Cohen, N., 25 Cohen, Z., 17 Cole, J. R., 162, 169 Colebrook, L. D., 217 Colin, M., 144 Coll, J. C., 65, 142 Collins, M. D., 206 Colonna, S., 8 Coman, R., 192 Comeau, L., I74 Conia, J. M., 50 Conn, R. S. E., 54 Connolly, J. D., 163, 165 Connor, A. H., 123 Connor, H. E., 156 Conjeaud, H., 200 Cook, J. M., 53 Cooke, F., 12,242 Cookingham, R., 200 Cookson, R. C., 197 Cooper, M. B., 200 Corbella, A., 48, 68 Corbett, R. E., 180 Corcoran, R. J., 253 Cordell, G. A., 178 Corey, E. J., 73 Cori, O., 15 Corriu, R. J. P., 8 Cortese, N., 21 Coscia, C. J., 16 Costes, C., 205 Couch, M. W., 217,227 Coutts, R. T., 62 Covey, D. F., 275 Cowan, A. E., 263 Coxon, D. T., 106 Coxon, J. M., 54,256 Cozzi, F., 8 Crandall, J . K.,54 Crane, R. I., 243 Crastes de Paulet, A., 247 Craveiro, A. A., 19 Crawley, L. C., 54 Crews, P., 30, 31 Cridland, J. S.,259 Croft, K. D., 145 Crofts, A. R., 200

Author Index

286 Crombie:L., 35, 61, 62 Crombie, W. M. L., 61,62 Cross, B. E., 138 Croteau, R., 14, 17, 18 Crouch, R., 201 Crozier, A., 137 Crump, D. R., 260 Cuevas, O., 121 Current, S. P., 51 Curry, D. J., 264 Curtis, R. F., 106 Cynkowski, T., 246 Czech, F., 228 Dabdoub, A. M., 242 Daemen, F. J. M., 200 Dahl, L. F., 212 Dahlgren, R., 37 Dailey, R. G., 73 D’Albuqueirque, I. L., 130 Daleo, G. R., 206 Daloze, D., 141, 157 Dalton, A. I., 10 Dalton, J. R., 231 Dalzell, H. C., 62, 63 Damodaran, K. M., 42 Damon, R. E., 27 Damps, K., 151, 161 Dangyan, M. T., 26 Danise, B., 145 Danishefsky, S., 110 Dansted, E., 54 Darby, N., 51 Darnall, K. R., 5 Darnbrough, G., 35 Das, P. K., 200 Das, R. C., 206 Das Gupta, D. K., 200 Da Silva, R. R.. 130 Dauben, W. G., 9 , 4 5 Daunas, R., 185 Dauphin, G., 235 Davidson, R. S., 200 Davies, B. H., 181, 203 Dawe, E. A,, 200 de Alencar, J. W., 19 Dean, P. D. G., 224 de Araujo, M., 130 D e Bernardi, M., 93 De Bouchberg, M. S., 19 Debrauwere. J., 19 De Camp, W. H., 211 Decauchereux, J.-F., 62 Decorzant, R., 102, 108, 187 Degenhardt, C. R., 53 Degrandi, I. H., 134 De Groote, R., 95 Dehennin, L., 234 De Jong, A. J., 25 Dekkers, H. P. J. M., 50 de la Mare, P. B. D., 235, 237 Delaveav, P., 37 Delle Monache, F. D., 130

Deluca, H. F., 212, 269 Deluca, L. M., 195 Demailly, G., 27 de Marcano, D., 272 Demole, E., 187 De Napoli, L., 108 Dencher, N. A,, 200 Dendane, M., 278 Dennis, F. G., 137 Dennis, N., 111 Denny, W. A,, 280 De Noble, J. P., 25 de Pascual Teresa, J.. 124, 125 Derbentseva, N. A., 129 Derguini-Boumechal, F., 23,45 de Rosa, M., 123, 152,207 de Rosa, S., 123, 152, 207 des Abbayes, H., 53 Desai, H. G., 205 de Saiete Barros Cavalcanti, M., 130 Descotes, G., 55 Desfosses, B., 225 Deshchits, G. V., 57 Deshpande, R. S., 20 de Souza, N. J., 125 Dev, S., 52,67, 87, 88 DeVault, D., 200 Devos, M. J., 33 de Waard, E. R., 20, 66,247 De Wit, D. L., 165 Dezentje, R. F. R., 50 Dhar, K. L., 39 Dharis, R. P., 137 Dias, J. R., 167, 233, 274 Diassi, P. A,, 243 Diaz, E., 105, 117 di Blasio, B., 146 Di Domenico, A,, 19 Di Gusto, M., 37 Dijkstra, G., 62 Dike, S. Y., 61 Dinizo, S. E., 242 Dinner, A,, 237 Dinur, U., 200 Divakar, K.J , 4 0 Dixon, J. S., 221, 272 Djarmati, Z., 140 Djerassi, C., 82, 157, 212, 215, 221,262,272 Dmitrovskii, A. A,, 206 Dobashi, S., 24 Dobler, M., 163 Dobrucki, R., 196 Dobrynin, V. D., 129 do Carmo, M., 130 Dockerill, B., 129 Dodson, P. A,, 219, 272 Doglia, G., 22 Dolby, L., 76 Doll, R. J., 253 Dominijanni, R., 200 Dominguez. X. A., 130 Donovan, S. F., 3

Doonan, S., 14 Doorenbos, N. J., 135 Doran, H. J., 10 Dorn, C. P., 269 Dorn, F., 87 Dornaver, H., 125 Doskotch, R. W., 95 Doukas, A. G., 201 Drake, A. F., 5 , 154, 220 Drammann, R., 252 Dratz, E. A,, 200 Drawbaugh, R. S., 231 Dreyer, D. L., 163 Driguez, H., 236 Dromey, R. G., 5 Drozdz, B., 95, 119 Duax, W. I>,, 179, 212, 227, 250,270,273 Dubois, Y.. 39 Diittmann, H‘., 27 Dunlop, N. M., 195 Duong, T., 29,53 Durham, L. J., 175 Durley, R. C., 137, 138, 139 Durst, H. D., 22 Dutta, N. L., 177 Dutton, H. J., 198 Duval, D., 225 Dzizenko, A. K., 158 Easton. N. R., jun., 217 Ebrey, T. G., 200, 201 Eder, U., 229,241 Edmond, J., 217 Eggert, H., 215 Eggling, S. B., 19 Eguchi, S., 87 Ehlers, D., 95, 96, 117, 169 Ehlinger, E., 12, 242 Ehmann, W. J., 9 Eichel, W. F., 25 Eickman, N., 128 Eisfelder, W., 27 Eisner, T., 35 Ekstrand, J. D., 146 Elder, J. W., 151 El-Emary, N. A., 133 El-Feraly, F. S., 61, 95 El’kin, Y. N., 177 Elliottt, W. H., 262 Elphimoff-Felkin, I., 44 El-Sayed, M. A., 50,201 Elsohly, M. A,, 61 El Soukkary, O., 230 Elvidge, J. A,, 214 Elyakov, G. B., 157, 158, 161 Emiliozzi, R., 225 Emke, A,, 213,249,266 Endo, T., 37 Enggist, P., 187 Englander, J. J., 201 Englander, S. W., 201 Englert, G., 182, 187, 198

Author Index Engovatov, A. A., 199 Enomoto, H., 133 Ensley, H. E., 41 Enslin, P. R., 156,213, 244 Enzell, C. R., 123, 141, 187 Epe, B., 165 Epling, G. A,, 22 Eppley, R. M., 73 Erickson, K. L., 79, 144 Erickson, R. E., 13 Ernstbrunner, E. E., 21 8 Errington, S. G., 133 Eskins, K., 198 Estevez, R., 78 Etheridge, S. J., 110 Eugster, C. H., 130 Evans, A. J., 86 Evans, D. A., 102, 117 Evans, F. J., 143 Evans, J. M., 272 Evrard, M., 52 Exley, D., 225 Ezmirly, S. T., 24

Fagundo, C. R., 129 Failkov, Y. A,, 42 Fairchild, E. H., 95 FajkoS, J., 275 Falconi, G., 271, 281 Fales, H. M., 35 Fan, D. M., 42 Farid, K., Z., 237 Farnsworth, N. R., 178 Farnum, D. G., 132 Farrington, G., 50 Fartaczek, F., 206 Fateeva, T. V., 205 Fattorusso, E., 123, 144, 145, 146, 262 Faulkner, D. J., 30,31,66,101, 123, 145, 146 Favtro, J., 279 Fayos, J., 125 Fedorov, P. I., 44, 46 Fedorov, V. K., 142 Fehlhaber, H. W., 125 Fei, B. Y., 68 Feigenbaum, A,, 256 Feldstein, G., 71 Fenical, W., 101, 102, 145 Fenselau, C., 62 Feofilova, E. P., 205 Ferguson, G., 211, 213,249 Feringa, B., 52 Fernandes-Comes, F. E., 40 Ferreira, P. C., 133 Ferrer, V., 255 Fetizon, M., 157, 247, 273 Fex, T., 94 Ficini, J., 115 Fiecchi, A., 67, 242 Filho, D. D. S., 95

287 Filippova, T. M., 195, 196 Filosa, M. P., 48 Finar, I. L., 14 Finer, J., 82, 144, 145 Finocchiaro, P., 8 Fioriello, G., 271 Fisher, C., 6 Fisher, M. M., 226 math, R. A., 19 Fleming, W. P., 147 Flemming, I., 37 Floor, J., 235 Fonseka, K., 62 Fonteneau, P., 151 Fookes, C. J. R., 171 Forbes, R., 62 Formica, G., 11 Formosinho, S. J., 200 Forrey, R. R., 19 ForSek, J., 231 Fourme, R., 174 Fournet, A., 156 Fraga, B. M., 78, 125, 129 Franceschini, N., 200 Francke, W.. 18 Franke, P., 170 Frankowski, A., 278 Frater, G., 80, 197 Frattini, C., 49 Fredericks, R. M., 280 Freedman, T. B., 200 Freeman, R., 40 Freerksen, R. W., 242, 254 Fregoso, R. M., 274 Friedrich, E., 11 Frobese, A. S., 82 Froborg, J., 94 From, A. H. L., 273 Fronza, G., 93 Frot-Coutaz, J. P., 195 Fuchs, P. L., 217 Fugate, R. D., 199 Fujimori, T., 107 Fujino, M., 20 Fujisawa, T., 36 Fujita, E., 51, 135, 136, 233 Fujita, F., 33 Fujita, K., 131 Fujita, T., 23 Fujita, Y., 133, 185 Fujitsu, K., 21 Fukazawa, Y., 128, 136 Fukuda, D. S., 62 Fukui, A., 3 Fukui, H., 137 Fukui, K., 149 Fukui, M., 20 Fukumoto, K., 12, 149, 174 Fukuyama, H., 139 Fullerton, D. S., 273 Funamizu, N., 136 Fung, S., 111, 216 Furstenberger, G., 143 Furukawa. J.. 93

Furukawa, K., 4 Fushiya, S., 139 Fuzesi, L., 54 Gabri, G., 22 Galbraith, M. N., 264 Galeffi, C., 67 Gallegos, E. J., 222 Galli, G., 242 Gallino, M., 49 Gambacorta, A,, 152, 207 Ganguly, J., 206 Garbers, C. F., 23 Garcia, G. A,, 25, 70 Garcia-Alvarez, M., 135 Gardi, R., 271, 281 Garg, H. S., 163 Gariboldi, P., 48, 68 Garnero, J., 13 Garrett, E. R., 61 Carry, A. B., 261 Garst, J. E., 20 Gaskin, P., 137 Gaspari, A., 42 Gaughan, L. C., 19 Gavin, R. M., 200 Gavrilova, T. F., 4 Gawell, L., 86 Gawronski, J. K., 220 Gayanov, R. K., 176 Geacintov, N. E., 200 Gemmer, R. V., 51 Gentles, M. J., 236 Georghiou, P. E., 266 Ghilezan, I., 280 Ghisalberti, E. L., 133, 145 Ghosal, S., 58 Giacomelli, G., 22 Giannetto, P., 178 Gibbs, C. G., 74 Giddings, M. R., 21 8 Giersch, W., 24 Giger, R., 152 Gil, G., 33 Gilbert, B. N., 20 Gilbertson, G., 13 Gilchrist, B. M., 185 Gill, G. B., 54 Gillen, M. F., 5 Gilliland, G. L., 264 Gilman, S., 11, 12 Gilman, T. M., 273 Ginzburg, M. A,, 30 Gil-Quintero, M., 68 Giroud, A. M., 240 Gladiali, S., 271, 281 Gleizes, M., 13 Glotter, E., 234, 239, 265 Glowniak, K., 19 Godfrey, J. D., 104 Godtfredsen, S., 28 Goewert, R. R., 208 Gokhale, A. M., 61

Author Index

288 Golding, B. T., 8 Golubev, N. M., 141 Gbmez, J., 255 Consalves de Lima, 0.. 130 Gonnord, M. F., 22 Gonzilez, A,, G., 78, 125, 129, 179 Gonzilez, F. H., 130 Goodbrand, H. B., 7 Goodfellow, M., 206 Goodfellow, R.J., 14 Goodwin, C. L., 19 Goodwin, T. E., 148 Goodwin,T. W., 181,182,201, 203,205 Goossens, B., 266 Gore, J., 24 Gorodetsky, M., 196 Gorst-Allman, C. P., 136 Goryaev, M. I., 54, 176 Goswami, U. C., 205 Goto, S., 107 Goto, T., 110 Gottarelli, G., 221 Gottlieb, H. E., 67 Gourcy, J. C., 193 Govindjee, R., 201 Goyau, B., 60, 197 Grabarczyk, H., 95, 119 Grabowich, P., 243 Gradeff. P. S., 11 Grainger, S., 50 Granger, R., 19 Greaves, G. M., 14 Greaves, J. H., 19 Green, B., 243 Green, D. E., 61 Greenberg, A. D., 200 Greenlee, W. J., 92 Gregson, R. P., 45, 82 Grenz, M., 22,64,96, 117,119, 125,126,169 Grieco, P. A., 9,11,12,97,110, 111 Grieder, S., 108 Grigg, R., 52 Grillasca, Y.,25, 70 Grisanti, G., 271 Grishina, G. V., 40 Gritsenko. T. A,, 195 Grob, J., 270 Groeger, D., 17 Groeneveld, H. W., 151 Gross, B., 12, 229 Gross, D., 39 Gross, J., 205 Groweiss, A,, 142 Grunwell, J. F., 281 Grynkiewicz, G., 12 Gschwendtner, W., 217 Gubler, B. A,, 111 Guenter, A., 138 Giintert, T. W., 273, 275 Guenther, E., 13

Giinther, H., 4 Guerrero, C., 105 Guerrero, 0. R.,135 Guest, J. R., 208 Guiochon, C., 22 Guiso, M., 4, 35, 36, 37, 38 Gunasekera, S. P., 177, 178 Gund, P., 5 Gunn, D. M., 107 Guntz-Dubini, R., 29 Gupta, A. S. D., 172 Gupta, K. C., 22 Gut, 260,266 Gutierrez, M., 130 Gutowski, J. A,, 14 Guyot, J., 56 Guziec, F. S. jun., 52 Habanal, R.M., 136 Habermehl, G., 249 Hach, V., 48 Hachey, D. L., 263 Hanni, R., 187 Hagaman, E. W., 61 Hagan, C. P., 147 Hagiwara, H., 160 Hagiwara, S., 224 Hai, M. A,, 174 Hale, R. L., 195 Haley, R. C., 70 Hall, S. R., 145 Hall, J. B., 27 Hall, S. S., 30 Hallenstvet, M., 188 Haller, F., 198 Hamacher, K., 200 Hamada, F., 120 Hamada, Y.,246 Hamilton, G. A., 77 Hammond, M. L., 222,269 Hamonniire, M., 67, 156 Han, B. H., 161 Han, R.-J. L., 195 Hanack, M., 52 Hancock, W. S., 132 Handjieva, N., 37 Handrick, G. R., 62,63 Hands, D., 266 Hanna, R.,264 Hansen, R.,195 Hanson, J. R.,14, 89, 121, 127, 129, 272 Hanus, L., 61 Harada, S., 149 Harada, T., 53 Haran, B., 95 Harichian, B., 41 Har-Paz, I., 196 Harpp, D. N., 8 Harriman, A,, 200 Harriman, G. A., 182 Harris, P. G., 147 Harris, R. N., 121

Hart, N. K., 139, 140 Hartmann, W., 37 Hartog, F. A., 9 Hartshorn, M. P., 54, 225 Haruna, M., 95 Harvey, D. J., 62,63 Harvey, T. M., 61 Hase, T., 168 Hasegawa, M., 134 Hasegawa, S., 163 Hashimoto, S., 48, 80, 89 Haslewood, E. S., 234 Hata, G., 21 Hatsui, T., 52 Hattori, H., 43, 57 Hauser, A., 108, 197 Hauser, F. M., 237 Havinga, E., 255 Hawes, G. B., 142 Hawkins, D. W., 157 Haxo, F. T., 186 Hayashi, N., 8 Hayashi, S., 75, 87, 124, 134 Hayashi, T., 42 Hayashi, Y., 130 Hayes, K. S., 8 Hayman, E. P., 205 Haynes, H. R., 119,144 Hayward, R. C., 234 Hazama, M., 33 Heathcock, C. H., 110 Head, K., 62 Heald, J. K., 137 Heck, R. F., 21 Hecker, E., 143 Heddon, R.,18 Hedin, P. A., 18 Heerma, W., 62 Heiske, D., 2 17 Heissler, D., 51 Helbling, A. M., 36 Hellman, T. M., 77 Helmchen, G., 4 Hemmer, E., 53 Henderson, R.,200, 201 Hendrick, C. A., 35 Heng, C. K., 180 Hengartner, U., 152 Henselman, R., 201 Herald, C. L., 66 Herin, M., 144 Hermann, K., 197 Hernandez, M. G., 78 Herout, V., 95 Herrmann, M., 39 Herring, P. J., 185 Hernandez, R., 179 Hertzberg, S., 183, 184, 188 Herz, W., 9,43,60,95,99, 111, 123, 126, 127, 132 Hesse, R. H., 240 Heumann, A., 51 Heumann, W., 182 Hevesi, L., 33, 34

289

Author Index Heyes, L. M., 201 Hickey, C. J., 196 Hicks, D. R., 256 Hicks, K., 35 Hidai, M., 21 Higashi, T., 136 Highet, R. J., 73 Higuchi, R., 176 Hii, G. S. C., 256 Hikino, H., 139 Hiller, K., 170, 176 Hilpert, L., 230 Hiltebrand, H., 17 Hinckley, C. C., 4 Hintsche, R., 170 Hiraga, N., i20 Hirai, Y., 174 Hirano, S., 32 Hirano, Y., 26 Hirao, N., 39 Hirao, T., 168 Hirata, T., 14, 26, 160 Hirata, Y., 105, 130, 142, 143, 152 Hiroi, K.. 244 Hirooka, M., 266 Hirotsu, H., 146 Hiyama, T., 32 Hoad, G. V., 138 Hoagland, J. E., 163 Hobert, K., 234 Hochstrasser, R. M., 200 Hodler, M., 193 Hoellinger, H., 62 Hoerhold, C., 280 Hoff, R. J., 148 Hoffmann, A. F., 263 Hoffmann,H. M. R., 45,48 Hoffmann, W., 47 Hoffmann-La Roche, F., 6 Holden, C. M., 49 Holian, A ,, 117 Holst, P. L., 20 Holtmeier, W., 234 Holub, M., 95, 119 Honda, S., 259 Honda, T., 149, 172, 174 Honig, B., 199, 200 Hopewell, W. D., 50 Hoppen, V., 217 Horeau, A,, 8 Horgan, R., 137, 196 Hori, H., 136, 233 Horiba, M., 19 Horikawa, S., 134 Horn, D. H. S., 264 Hosaka, K., 238 Hoskins, L. C., 199 Hosogai, T., 9, 27 Hosoya, E., 62 Hotchandani, S., 200 Houghton, E., 4 Hounshell, W. D., 8 Howard, B., 106

Howard, B. M., 102, 106 Hoyer, G.-A,, 62 Hrib, N. J., 54 Hruska, F. E., 243 Hseu, T.-M., 48 Hsieh, 0. A. L., 19 HSU,C.-S., 155 HSU,H.-Y., 155 HSU,K.-L., 48 HSU,W.-J., 205 Huang, H.-C., 95, 167 Huang, S. L., 10 Hudec, J., 218, 219 Hiigel, H. M., 44 Hueller, E., 280 Hueni, J. E. S., 17 Huffman, J. W., 102, 147, 257 Hufford, C. D., 39, 135 Hug, G., 200 Huggins, M.-A., 99 Hughes, D. L., 106 Hughes, J. M., 14 Hui, W.-H., 155, 170, 172, 178 Huisman, H. O., 20, 66, 247 Humphrey, A. M., 19 Hung, H. K., 197 Hunt, C. A., 61 Hunt, L. M., 20 Hunter, N. R., 43, 46 Huppert, D., 200 Hurabielle, M., 19 Hurley, J. C., 117 Hurst, J. J., 6 Huynh, C., 32 Huwang, L. S., 19 Hylands, P. J., 264 Iachetta, R., 19 Iavarone, C., 4, 35, 36, 37, 38 Ichihara, A,, 260 Ichikawa, Y., 25 Ichinose, I., 27,47 Ide, H., 4 Ideo, R., 160 Iemura, S., 80 Iengo, A,, 108 Iguchi, K., 28, 155, 160, 238 Iguchi, M., 99 Ihn, W., 231 Iida, T., 213 Il’ina, I. G., 40 Iio, H., 110 Iitaka, Y., 174 Iizuka, H., 136 Ikawa, T., 200 Ike, N., 30 Ikekawa, N., 214,266 Ikenishi, Y., 176 Iko, T., 227 Im, K. S., 176 Imai, J., 120 Imakura, Y., 120, 167 Imam, S. H., 256

Impellizzeri, G., 146 Inaba, S.-I., 8 Inayama, S., 62 Ineichen, U., 195 Ingwalson, P., 102 Inomata, K., 59 Inouye, G., 207 Inouye, H., 17,36,37, 65 Inoue, S., 73 Inoue, T., 158 Inouye, Y., 41,200 Ioffe, N. T., 199 Ionescu, F., 169 Ionova, E. A,, 46 Ireland, R. E., 152 Irismetov, M. P., 176 Iriye, R., 42 Irurre-Perez, J., 8 Irwin, A. J., 7, 14 Isaeva, 2. G., 57, 58 Isagawa, K., 29 Isakov, V. V., 177 Isenring, H.-P., 84 Ishida, A,, 190 Ishida, T., 54 Ishigooka, H., 138 Ishihara, H., 51 Ishii, H., 176 Ishii, Y.,20 Ishiwatari, H., 21 Islam, M. A., 204 Isler, O., 181 Isobe, M., 110 Isobe, T., 135 Isogai, A,, 147 Ito, M., 190, 198 Ito, S., 128, 131, 147 Ito, T., 26 Ito, Y., 53 Itoh, A., 48, 89 Itoh, M., 43 Itoh, T., 156, 162 Itoi, K., 9, 20 Itokawa, H., 155 Ives, J. L., 10 Iwanura, J.-I., 11 Iwasa, N., 280 Iwasaki, S., 155, 259 Jabalquinto, A. M., 15 Jackson, W. R., 44 Jacobs, H. J. C., 222, 255 Jacquesy, J.-C., 253 Jacquesy, R., 247 Jadhav, P. K., 89 Jakuopovic, J., 39, 101 James, D. R., 150 James, R. W., 13 Jamieson, A. T., 118 Jamieson, G. R., 118 Janes, N. F., 19 Janitschke, L., 121 Jarvis, B. B., 73

Author Index

290 Jaszczykki, J. R., 276 Jefferies, P. R., 133, 145 Jeger, O., 198 Jennings, P. W., 117 Jensen, E. V., 270 Jensen, S. R., 37, 39 Jernberg, K. M., 24 Jikeli, G., 4 Jimenez, M., 105 Jinnai, 0..52 Johansen, J. E., 190 John, T. K., 42 Johne, S . , 17 Johns, S. R., 139, 140 Johnson, D. W., 61 Johnson, J. H., 50 Johnson, J. J., 61 Johnson, R. L., 269 Johnson, W. H., 187 Jolad, S. D., 162, 169 Jommi, G., 48,68 Jones, A,, 105 Jones, A. J., 155,255 Jones, B. E., 181 Jones, C. R., 223, 256 Jones, E. R. H., 279,280 Jones, H., 269 Jones, J. B., 7, 14 Jones, J. R., 214 Jones, T. H., 35 Jones, T. W. A , , 138 Josephson, S., 8 Joska, J., 275 Joulain, D., 19 Jubault, M., 6 Julia, S., 32, 59 Jung, F., 51 Jung, M. E., 229 Jungk, S., 16 Junker, N., 187 Jurczak, J., 7 jurd, L., 60 Kabanov, V. S., 49 Kabork, I., 45 Kabuto, C., 131 Kachel, C. D., 44 Kadono, S., 110 Kadota, O., 37 Kagan, H. B., 9 , 4 7 Kageyama, A,, 200 Kagramanova, G. R.. 179 Kahn, R., 174 Kainosho, M., 5 Kaiser, G. L., 54 Kaiser, R., 22, 72 Kaji, A., 13,47 Kakisang, H., 127 Kakitani, H., 200 Kakitani, T., 200 Kaleya, R., 253 Kalisky, O., 200 Kalvoda, J., 266, 270

Kalyanaraman, P. S., 95 Kamano, Y., 155,234 Kamath, M. S., 61 Kameo, K., 20 Kamernitskii, A. V., 241 Kamernki, N. E., 280 Kametani, T., 12, 149, 174 Kamienska, A,, 139 Kamigauchi, T., 127 Kamikawa, T., 135 Kanamaru, H., 29 Kanashima, T., 128 Kaneda, M., 53 Kaneko, H., 107 Kaneko, K., 51, 135 Kao, J. P. Y., 66 Kapil, R. S., 155 Karanewsky, D. S., 233 Karaseva, A. N., 57 Karim, A , , 279 Karimian, K., 16 Karlsson, B., 48 Karlsson, K., 123, 142, 187 Karp, F., 17, 18 Kasai, R., 40, 162, 176, 217 Kasal, A,, 230, 240 Kashman, Y., 142 Kasuga, R., 107 Katagiri, T., 21, 30 Katai, M., 139 Katayama, C., 130 Katayama, T., 185, 205 Katekar, G. F., 219, 272 Kates, M., 201, 203 Katiyar, S. S., 204 Kato, N., 65 Kato,T., 27,47, 131, 136, 141, 147, 149 Kato, Y., 149 Katsube, Y., 139 Katsui, N., 106, 107 Katten, E., 80 Kattenberg, J., 247 Katzenellenbogen, J. A., 35 Kauss, H., 206 Kaverin, V. V., 56 Kawai, T., 110 Kawasaki, T., 176 Kayser, H., 184, 193 Kazakoff, C. W., 62 Kazlauskas, R., 3 1 Keana, J. F. W., 262 Kearns, D. R., 223, 256 Kechayan, J., 5 Keeley, D. E., 3, 13 Keinan, E., 77 Kelecon, A,, 157 Kelkar, S. L., 61 Kelley, J. A., 230 Kelly, R. B., 118 Kempfert, K. D., 4 Kent, ByE., 19 Kerek, F., 221 Kergomard, A,. 42, 56,70,243

Kerr, D. I. B., 53 Khaiden, I. S., 243 Khaikova, A. Y., 280 Khaleque, A,, 174 Khambay, B. P. S., 192 Khan, A. H., 225 Khanna, N. M., 163 Khanna, P. L., 253 Khanra, A. S., 33 Khastgir, H. N., 175, 177 Kheifits, L. A., 4 Khisametdinov, A. M., 30 Khodzhaev, B. U., 160 Khong, P. W., 172 Kho-Wiseman, E., 31 Khuong-Huu, F., 245 Khuong-Huu, Q., 45,236 Khusein, S., 155 Khusid, A . Kh., 29 Kienzle, F., 181, 198 Kieslich, K., 13, 62 Kill, R. J., 7 Killinger, T. A,, 54 Kim, D. J., 217 Kim, H.-O., 176 Kim, J. H., 147 Kimmel, G. L., 241 Kimura, T., 7, 95 Kimura, Y . , 29, 138 Kinast, G., 39 Kincl, F. A , , 272 King, G . G. S., 71 King, L. J., 61 Kinghorn, A. D., 143 Kinnear, J. F., 264 Kinoshifa, H., 59 Kirby, G. W., 249 Kirk,D. N.,214,216,218,219, 225,251 Kirshfeld, K., 200 Kirst, H. A., 152 Kitrchev, N. A,, 7 Kishi, Y., 233 Kishimoto, T., 5 1 Kitagawa, I., 127, 176 Kitagawa, K., 21 Kitagawa, Y., 48, 80, 89 Kitaguchi, K,., 133 Kitahara, H., 106, 107 Kitahara, Y., 27, 47, 110, 131, 136,141,147,149 Kitamoto, M., 20 Kitamura, K., 184 Kleczkowska, K., 138 Kleijn, H., 23 Klein, E., 26 Klein, P. D., 263 Klein, U., 245, 251 Kleinig, H., 182, 185 Klemmensen, P. D., 20 Kleudgen, H. K., 205 Kleveland, K., 29 Kliger, D. S., 200 Klimetzek, D., 18

291

Author Index Klobucar, W. D., 11 Kloek, J. A., 149 Klusener, A. R., 50 Klyne, W., 216, 219 Knaus, E. E., 62 Knoll, K.-H., 117, 169 Knoll, W., 71 Knox, J. R., 49 Knuppen, R., 238 Kobayashi, A,, 19 Kobayashi, H., 8, 71, 93 Kobayashi, M., 134 Kobayashi, S., 27 Kobayashi, T., 147,266 Kobori, T., 36 Koch, M., 37 Kocienski, P. J., 71 Kocbr, M., 231,246 Kotovsk9, P., 234,270 Kocur, J., 40 Kodama, A . , 198 Kodama, M., 131,147 Kodoma. J., 134 Kodama, R., 4 Koedam, A , , 8 Koehrn, F. J., 205 Koenig, R. T., 13 Koga, K., 26 Kogiso, S., 143 Kohler, 8.E., 200 Kohli, J. C., 226 Kohout, L., 272 Kohoutova, J. 243 Koizumi, N., 260, 266 Kojima, M., 227 Koka, P., 186 Kolosov, M. N., 129 Komae, H., 8 Komatsu, A ,, 8, 23,26 Komatsu, H., 227 Komeno, T., 216 Komori, T., 162, 176 Konaka, R., 244 Kondo, K., 24, 34, 59,65, L!06, 207 Kocdo, Y., 120 Konieczny, M., 281 Koning, J., 151 Konishi, A., 7 Konno, A., 21 Konno, C., 139 Konoike, T., 53 Kononenko, A. A,, 200 Konova, I. V., 207 Konovalov, E. V., 42 Konowal, A., 7 Koppel, P. M., 54 Koreeda, M., 260,266 Koreshkova, E. G., 195 Korte, F., 62 Koshimizu, K., 137 Kosley, R. W. jun., 30 Kossanyi, J., 24 Kotake, H., 59

Kovovskg, P., 264 Kow, R., 150 Koyama, H., 213 Kozhukhovskaya, V. M., 195, 196 Kozikowski, A. P., 9 Kradtz, A., 62 Kraatz, U., 62 Kramer, H. F., 62 Kramer, R., 64 Krapcho, A. P., 280 Kratchanov, C. G., 7 Kraus, W., 52 Krawczyk, Z., 7 Krayushkin, M. M., 12 Kreft, A,, 40 Kreiser, W., 121 Krejci, Z., 61 Krepski, L. R., 44 Krevitz, K., 151 Krief, A. , 33, 34 Krilly, W., 34 Krishnamurty, H. G., 124 Krishnamurthy, S., 6 Krishnappa, S., 67, 87 Krishnasamy, V., 57 Kriz, C. D., 68 Kroon, J., 40 Kroszczyfiski, W., 246 Krow, G. R., 42 Krueger, D. S., 11 Kruger, G . J., 156, 212, 213, 244,250 Kryshtal, G V., 29 Kubo, I., 66, 128,135,163, 178 Kubo, K., 4 Kubota, T., 135 Kucherov, V. F., 29, 138 Kuchkova, K. I., 160 Kudrzycka-Bieloszabska, F. W., 19 Kuehne, M. E.. 27 Kunstler, K., 36 Kuhnert, L., 65 Kuksis, A., 226 Kulkarni, A. K., 231 Kulkarni, B. D., 40 Kulkarni, G . H., 174 Kulkarni, S. U., 7 Kulkarni, V. M., 20 Kulshreshtha, D. K., 161 Kumagai, M., 8 . Kumagai, T., 147 Kumar, N., 170 Kumar, S. D., 23 Kumata, S., 152 Kumazawa, S., 47 Kunesch, N., 67 Kung, M. C., 200 Kunihisa, K. S., 224 Kuntz, E., 9 Kuono, I., 57 Kupchan, S. M., 68, 73, 105, 119, 144, 167

Kuppers, F. J. E. M., 62 Kurachi, Y., 20 Kurek, A,, 231 Kuroda, H., 135 Kurosawa, E., 75 Kurosawa, Y.,280 Kurtev, B. J., 7 Kurth, H.-J., 62 Kusano, G., 120,133 Kushni, Y., 75 Kushwaha, S. C., 201,203 Kutschabsky, L., 137 Kuyama, M., 197

Labbe, C., 163 Lablache-Combier, A,, 114 Lacombe, L., 50 Lafferty, J., 199 Laine, R. M., 21 Laing, J. W., 200 LajSii, S. D., 140 Lal, B., 227 Lal, M., 48 Lamazoubre, A.-M., 53 Lamberton, J. A,, 140 Lamparsky, D., 22, 72 Land, E. J., 199,200 Lander, N., 5 Landge, A. B., 231 Lane, C. F., 9 Lang, E. F., 196 Lang, H. S., 196 Lang, S., 280 Lange, G. L., 50, 99 Langford, D. D., 238 Langs, D. A., 179 Lansbergen, J. C., 205 Lanteri, S., 41 Lanza, E., 14 Laonigro, G . , 147 Laos, I., 238 Lardicci, L., 22 Larkin, J. P., 70 Larsen, R. D., 117 Lassak, E. V., 19 Lasswell, W. L. jun., 39 Laub, R. J., 225 Lauricella, R., 5 Lavie, D., 130, 265 Lavoie, E. J., 68 Leander, K., 86 Leber, J. D., 244,255 Leblanc, R. M., 200 Leboeuf, M., 67, 156 Lee, B., 49 Lee, H. 0. H., 234 Lee, J. G., 53 Lee, K.-H., 95, 120, 167 Lee, L.-C., 26 Lee, P., 117 Lee, S. F., 149 Lee, Y.-C., 170 Lee, Y.-W., 66, 128, 163

292 Leete, E., 22 Leftwick, A. P., 192 Lehle, L., 206 Lehmann, H., 197 Leighton, A. P., 144 Lemberton, J. A., 139 Lernley, A. T.,200 Lenoir, D., 44 Lentz, C. M., 228 Lenz, G. R., 254,256 Leontiv, I. G., 280 Lessard, J., 236 Lester, D. J., 244 Leuenberger, F. J., 198, 205 Leuenberger, U., 198 Leung, S. L., 264 Levan, N., 117, 119, 169 Levin, V. S., 157 Levisalles, J., 29, 234 Levy, E. C., 130 Lewis, A., 200, 201 Lewis, D. A., 3 Lewis, K. G., 172 Lewis, T. J., 200 Ley, S. V., 244 Lhomrne, J., 89 Li, M.-M., 155, 170, 172, 188 Li, M. P., 270 Liaaen-Jensen, S., 181, 183, 184, 188,190 Liang, C. D., 211, 238 Libertini, L. J., 223, 281 Libman, J., 256 Lichtenberg, D., 95 Lichtenthaler, H. K., 205. 207 Liebman, A. A., 195 Liepins, E., 56 Lightner, D. A,, 216 Ligon, R. C., 132 Linde, H. H. A,, 273, 275 Linder, M., 225 Lindgren, J.-E., 63 Lindley, P. F., 174 Lindsay, B.G., 234 Lindsey, A. S., 89 Ling, L.-C., 41 Linnabary, R. D., 20 Linskeseder. M., 228 Linstrumelle, G., 23, 132 Liotta, C. L., 242 Liotta, R., 6 Lischewski, M., 138 Littmann, W., 261 Litvinovskaya, R. P., 241 Liu, C.-B., 99 Liu, H. J., 197 Liu, K.-C., 26 Liu, K.-T., 4 Liu, R. S. H., 197, 200 Livina, E. V., 157 Liyanage, N., 142 Ll’in, S. G., 158 Lloyd, A. C., 5 Lob&-TObo,F., 245

Author Index Lobo, A. P., 50 Lockley, W. J., S., 182, 201 Lodge, B. A., 219,272 Logbo, K. D., 53 Loibner, H., 227 Lombardi, P., 197 Long, M.M., 201 Lonitz, M., 39, 101, 121 Loomis, W. D., 17 Lopes, A., 22 Lopes, J. N. C., 95 Lopez, L., 243 Lopez, M., 125 Lorne, R., 23 Lopresti, R. J., 25 Lorenc, L. J., 231, 266 Lorenzi, R., 137, 151 Loskant, G., 18 Lotter, H., 105, 127 Lotz, F., 62 Lousberg, R. J. J. C., 61,62,63 Lozier, R. H., 201 Ludovic, I., 272 Luis, J. G., 78, 129 Lukacs, G., 102,216,217 Lund, E. D., 7 Lusinchi, X., 278 Lutz, w., 11 Luu Bang, 77 Ly, N. D., 59 Lyle, M. A,, 62 Lyrene, S. A,, 204 Maag, H., 152 Mabry, T. J., 125 McCarty, R. N., 50 Macaulay, E. W., 211 McCrae, D. A., 76 McDonald, E. L., 80 McDonald, F. J., 4 Macdonald, I. A., 226 McDowell, P. G., 102 McEnroe, F. J., 30 McGhie, J. F., 157 McGrath, J. P., 230 Machida, H., 14 McHugh, C. R., 25 1 McInnes, A. B., 137 McKean, M. L., 13, 152 Mackinnon, J. W. M., 249 Maclellan, M. A,, 165 Macmillan, J., 137, 138 McMillan, J. A., 75, 130 McMorris, T. C.. 266 McMurry, J. E., 3,44, 84 McCorkle, T., 22 McPhail, A. T., 95, 120, 131, 142,167,213,236,239,250 McQuillin, F. J., 22, 27 Maczka, M., 231 Madan, D. K., 224 Madden, H., 192 Mader, R. A., 132 Madsen, H. B., 20

Madyastha, K. M., 16 Maeda, A., 51 Maeda, H., 149 Maeda, M., 227 Maeda, T., 75 Magno, S., 123, 144, 145, 146, 262 Magnus, K. E., 61 Magnus, P., 12,41, 190, 242 Magnusson, G., 94 Magri, A. L., 19 Maguire, T. C., 199 Mahanta, P. K., 117, 135, 169 Maione, A. M., 251 Mairanovskii, V., 199 Maisto, K. D., 266 Maiti, B., 48 Majetich, G., 110 Makin, S. M., 181 Makino, T., 212, 250, 270 Malango, F. L., 70 Maldonado, L. A., 25,70 Malhotra, H. C., 182, 203 Malinovskaya, G. V., 161 Mallavarapu, G. R., 175 Malloy, T. B., 199 Mamlok, L., 50 Manandhar, M. D., 155 Manchand, P. S,, 128 Mandal, A. K., 6, 7 Mander, L. N., 132 Mandrile, E., 37 Mangiafico, S., 146 Mangoni, L. 124, 147 Manhas, M. S., 227 Mankowski, T., 206 Mann, J., 14 Manners, G. D., 60 Manning, M. J., 60 Manning, R. A., 147 Mano, M., 20 Manukyan, M. A., 26 Manville, J. F., 68 Mao, D. T., 24 Marchand, J., 279 Marcus, M. A,, 201 Mareci, T. H., 217, 227 Marekov, N., 37 hlaresca, L. M., 253 Marin, M. G., 52 Marini-Bettolo, G. B., 67, 130 Marini-Bettolo, R., 36, 38 Marinovic, N., 9, 110 Markowicz, S. W., 55 Marks, V., 61 Marletti, F., 130 Marples, B. A,, 256 Marroquin, J. S., 130 Marsh, L. L., 14 Marsh, W. C., 213, 249 Marshall, J. A,, 103 Marsili, A,, 154, 220 Martens, D. R. M., 151 Martin, B. R., 62, 63

A uthar Index Martin, G. C., 137 Martin, M. D., 264 Martinez, A. G., 52 Martinez-Ripolli, M., 125 Maruyama, M., 120 Masada, Y., 13, 56 Masahara, R., 190 Masaki, Y., 111, 176 Masarnune, T., 106, 107, 212, 252,259,280,281 Mash, E. A,, 24 Mashiko, T., 11 Mashraqui, S. H., 27 Masilamani, D., 9 Mason, S. F., 5, 220 Massey-Westropp, R. A,, 132 Massiot, G. S., 274 Masuda, K., 176 Mathew, P. C . , 45 Mathies, R., 200 Mathis, P., 200 Mathur, S. N., 206 Matos, F. J. A,, 19 Matson, J. A,, 142 Matsubara, Y.,28, 29, 51 Matsui, K., 34 Matsui, M., 54 Matsumoto, K., 62 Matsumoto, M., 24, 59.65 Matsumoto, T., 130, 148, 149, 156,162,213 Matsumura, Y., 264 Matsunaga, A,, 106, 107 Matsuno, T., 184 Matsuo, A., 75, 87, 124, 134 Matsuura, K., 162, 200 Matsuyama, H., 23 Matthews, R. S., 36 Matthews, W. S., 19 Matucha, M., 226 Matyukhina, L. G., 172 Maudinas, B., 204 Maumy, M., 256 Mavlyankulova, Z. I., 127 Mayol, L., 108, 123, 144, 145, 262 Mazur, Y., 77, 268 Mazzola, E. P.. 73 Meakins, G. D., 215, 279, 280 Mechoulam, R., 5 Meehan, T. D., 16 Meguri, H., 139 Mehendale, S. D., 235 Mehta, G . , 53, 111, 118 Meier, B., 35 Meijer, E. L., 40 Meijer, J., 23 Meinwald, J., 35 Meister, R. G., 62 Meister, W., 187 Melega, W. P., 53 Merchant, J. R., 61 Merchant, S. N., 29 Metzner, E. K., 223,281

293 Meyer, A. Y., 5 Meyer, V., 24 Meyer, W. L., 50, 147, 148 Mhehe, G. L., 197 Miah, M. A. W., 174 Michaelson, R. C., 11 Michelot, D., 32 Michel-Villaz, M., 200 Michno, D. M., 9 Middleton, E. J., 264 Midgley, I., 221 Midgley, J. M., 155, 211, 213, 219,249,255,261, 264,266, 272 Midland, M. M., 6 Miguel del Corral, M. J., 125 Mihailovii, M., Lj., 231, 266 Milder, S. J., 200 Milewich, L., 275 Miljkovii, D., 245 Miller. C. A., 102, 113 Miller, E. M. jun., 204 Miller, J. A,, 70 Miller, R. W., 105, 142 Milloy, B. A,, 7 Mills, J. S., 123 Milne, G. M., 38 Milone, L., 22 Mimura, T., 25 Min, D. B. S., 19 Minale, L., 145, 152, 207 Miners, J. O . , 215, 279, 280 Minnikin, D. E., 206 Mirrington, R. N., 45, 82, 279 Mischewski, M., 138 Mislow, K., 8 Misra, D. R., 175, 177 Misra, G., 174 Mitchell, J . C., 94 Mitchell, S. J., 65 Mitra, R. B., 33 Mitsuhashi, H., 134 Mitzka, U., 205 Miura, I., 135, 147, 163 .Miura, N., 213 Miyakoshi, T., 14 Miyazawa, Y., 8 Miyoshi, Y., 200 Mizrahi, Y ., 196 Mizuba, S. S., 279 Mizuguchi, T., 259 Mizurnachi, N., 54 Mo, F., 174 Mochida, I., 21 Modi, V. V., 205 Mody, N. V., 140, 141 Moesinger, S. G., 14 Moews, P. C., 49 Moiseeva, G. P., 221 Moles, P. J., 259 Mompon, B., 95 Mon, T. R., 19 Monaco, P., 124 Mondon, A . , 165

Money, T., 51, 79 Montes Sanchez, A,. 124 Montheard, J.-P., 43 Montillier, J. P., 8 Moolenaar, M. J., 20, 66 Moore, C. J., 213,249 Moore, P. H., 225 Moore, R. E., 30 Moreau, J. J. E., 8 Moreau, S., 114 Morelli, I . , 154, 220, 221 Moreno, L. N., 61 Morgan, K. D., 193 Morgan, R. E., 214 Mori, H., 280 Mori, K., 18, 54, 132 Mori, T., 133 Morii, S., 73 Morimoto, T., 148 Morisaki, M., 266 Morisaki, N., 71 Moriyama, Y., 115, 168 Morizur, J.-P., 24 Moroe, T., 8 , 2 3 , 2 6 Morris, D. G., 50 Morris, G. A., 40 Morris, J., 279 Morrison, G . A., 231 Mortensen, T., 183 Morton, J., 250 Morton, J. B., 155 Mosher, H. S., 6, 184 Moss, G . P., 181, 190, 192 Mothes, K., 17 Motidome, M., 133 Mott, R. C., 11 Moyler, D. A., 19 Muckensturm, B., 264 Mueller, E., 47 Miiller, E. P., 198 Miiller, P., 5 Mueller-Johnson, M., 53 Mukaiyama, T., 27, 47, 190, 197 Mukhina, M. V., 224 Mukhopadhyay, S., 177 Mukitanova, T. R., 54 Mummery, R. S., 185,203,205 Munakata, K., 143 Munoz, J. L., 19 Muradian, J., 133 Murae, T., 144, 168, 172, 174 Murahashi. S.-I., 29 Murai, A,, 106, 107, 212, 252, 280,281 Murai, K., 160 Murakami, T., 134 Murakoshi, S., 147 Murano, A., 19 Murari, R., 11I Murata, A., 21 Murav’eva, D. A,, 19 Murillo, F. J., 205 Murofushi, N., 137. 138

294 Murphy, P. T., 31 Murray, A. M., 5 0 Murray, H . C., 279 Murray, R. D. H., 1 0 Murray-Rust,, J.. 107 Murray-Rust. P., 107 M u s w , A., 2 0 Muzart, J., 256 Myher, J. J., 226 Mynderse, J. S., 3 1 Mzhel’skaya, L. G., 177 Nadir, U. K., 42 Naf, F., 102, 187 Nagai, M., 158 Nagao, Y., 135 Nagaoka, H., 149 Nagasawa, T., 39 Nagase, H., 107 Nagase, T., 3 3 Nagata, S., 184 Nago, Y ”, 5 1 Nair, A. G. R., 125 Nakagawa, Y . , 5 Nakai, H., 213 Nakai, T., 25 Nakajima, N., 20 Nakajima, O., 42 Nakajima, S . , 244 Nakamoto, T., 124 Nakamura, A,. 7 Nakamura, H., 3 Nakamura, M., 176 Nakane, M., 214 Nakanishi, K., 66, 128, 135, 147, 163, 198, 201 Nakatsu, T., 128 Nakayama, M., 7 5 , 8 7 , 1 2 4 , 1 3 4 Nakayarna, Y., 8, 142 Nakazawa, E., 206 Nakazawa, S., 135 Nakhapetyan, L. A,, 280 Nam, N.-H., 62 Narnbudiri, A. M. D., 208 Nano, G. M., 4 9 Narain, N. K., 177 Narasirnhan, N. S., 6 1 Narayan, K. G. A. S. S., 172 Narayanan, C. R., 12, 231 Narula, A. P. S., 87 Narva, D. L., 200 Narvaez, M., 272 Nasipuri, D . , 7 Natu, A. A,, 117, 169 Naves, Y. R., 181 Nayak, U. R., 53, 8 9 Nederlof, P. J. R., 20, 6 6 Neef, G., 241 Neidert, E., 9 9 Neilan, J. P., 21 Nelson, A . C., 200 Nemori, R., 137 Nemoto, H., 12

Author Index Nes, W. R., 13, 151, 152, 260 Neukorn, C.. 2 5 , 1 9 3 Neupart-Laves, K., 163 Newaz, S. S., 243 Newcomer, M. E., 264 Newton, D . L., 195 Ng, P. 3 1 Ngo-Le Van, 134 Nguyen, K. Q., 170 Nicoletti, J. W., 51 Niederberger, W., 201 Nielsen, B. J., 37, 3 9 Nigam, S. K., 171, 174 Ninorniya, K., 246 Nishida, T., 9, 123 Nishiguchi, I., 4 1 Nishimura, H., 36, 37 Nishimura, M., 200 Nishimura, T., 212, 280 Nishino, T., 208 Nishioka, I., 176 Nishizawa, M., 9, 11, 12, 97, 110 Nishizakura, K., 106, 212, 281 Nitta, K., 227 Nitta, M., 4 1 Niwa, M., 99 Noack, K., 198 Noall, W. I . , 234 Nobile, L., 162 Nobuhara, J., 8 9 Nobuhara, K., 142 Noda, K., 4 Node, M., 135, 136, 233 Noguchi, M., 107 Noguez, J. A., 111 Nojima, M., 12 Nonaka, G., 176 Nonaka, T., 30 Nonhebel, D. C., 70 Nonomura, S., 42 Norden, D . A , , 185 Norin, T., 4 9 Norman, A. W., 269 Norris, R. E., 196 Novikov, S. S., 12 Nozaki, A,, 206 Nozaki, H., 13, 32, 48, 75, 80, 89 Nozawa, M., 178 Nozoe, S., 71, 9 3 Numata, S., 212, 281 Nuretdinova, 0. N., 5 6 Nyfeler, R., 14, 89 Oae, S., 8 Oberhansli, W., 142 Obermann, H., 134 Obrecht, J. P., 28 Ochiai, M., 51, 136 Oda, J.-I., 41 Odo, K., 3 0 Oehldrich, J.. 5 3

Oelbermann, U., 165 Oesterhelt, D . , 201 Oezdernir, N., 172 Ogawa, H., 227 Oger, E. A,, 195 Ogihara, Y., 174 Ogino, Y., 11 Ognyanov, I., 111 Ogura, M., 139, 178 Oguri, T., 110 Ohashi, Y.,147 Ohata, K., 133 Ohba, A,, 131 Ohloff, G., 24, 56, 197 Ohmura, T., 149 Ohnishi, Y., 7 Ohno, A., 7 Ohsawa, N., 224 Ohsuga, Y., 149 Ohta, H., 3 6 Ohta, Y . ,99 Ohtsuka, Y., 133 Ojima, I., 8 Oka, S., 7 Okarnoto, K., 108 Okamoto, T., 110 Okamura, W. H., 222, 269 Okano, M., 54 Okihara, M., 176 Okorie, D . A,, 165 Okuda, S., 138 Okuda, T., 8 9 Okude, Y . , 32 Okukado, N., 185 Oleinik, A. F., 2 0 Oliver, J. E., 5 1 Olson, G . L., 193 Olson, R. E., 208 Omichi, H., 1 4 Omura, K., 1 0 Ornura, S . , 120 Onan, K. D . , 9 5 , 1 2 0 , 1 3 1 , 1 6 7 , 2 1 3 , 2 3 6 , 2 3 9 , 250 Onisko, B. L., 269 0”. Johnson, J., 281 Oonk, H . A . J., 40 Opdyke, D . L. J., 1 3 Orena, M., 10 Oriente, G., 123, 144, 145, 146 Orito, K., 107 Orito, T., 212, 281 Orlova, R. K., 42 Orsini, F., 131 Orszanska, H., 42, 55 Ortar, G., 228, 237 Ortega, A,, 105 Ortiz de Montellano, P. R., 150 Osada, H., 138 Osagie, A. U., 160 Osaki, K., 136 Osawa, T., 119 Osawa, Y., 2 1 2 , 2 5 0 , 2 7 0 Osborne, M., 224 Oseroff, A. R., 200

295

Author Index Oshio, H., 176 Ostroy, S. E., 200 Ota, H., 36 Ota, T., 30 Otieno, D. A,, 35 Ototani, N., 149 Otsuji, Y., 29 Otsuka, S., 7, 23 Ottolenghi, M., 200 Ourisson, G., 77, 78, 89 Ovsyukova, N. F., 52 Ozainne, M., 102, 111 Ozer, E. A,, 195 Pabst, W. E., 242, 254 Pace, C., 31 Page, S . W., 139 Pai, P. P., 174 Pak, A. M., 30 Pak, N. D., 54 Pal, R., 177 Pal, S. K., 172 Palermo, R. F., 11 Pallante, S., 62 Palmer, J. K., 14 Palmer, M. A,, 152 Pal’yants, N. Sh., 233 Pancrazi, a,, 45, 236 Panfil, I., 7 Pankaskie, M. C., 273 Panosyan, A. G., 207 Panunzio, M., 11, 198 Papastephanou, C., 204 Pappo, R., 277 Paquette, L. A., 11, 53 Paquin, P., 200 Paradisi, M. P., 240 Paradkar, M. V., 61 Paris, M., 19 Parish, E. J., 251 Parish, F. J., 264 Park, B. K.,, 224 Park, 0. S., 25, 70 Parker, K. A,, 30 Parkin, J. E., 155, 255 Parrilli, M., 147 Paryzek, Z., 160 Pascard, C., 157, 247 Pascaul, C., 136 Passacantilli, P., 35, 36 Passet, J., 19 Pasternak, R., 5 Pataki, J., 270 Patel, A. H., 61 Patel, D. D., 61 Patel, N. J., 201 Patoiseau, J.-F., 253 Paton, J. M., 236 Paton, W. D. M., 61, 62, 63 Pattenden, G., 34, 35 Patterson, D. G., 212 Patterson, G. W., 160 Patterson, J. W., 20

Patyk, E., 42 Paukov, V. N., 280 Paul, I. C., 75, 130 Paulik, V., 160 Paust, J., 20 Pavlovic, V., 266 Pawson, B. A,, 195 Pearson, A. J., 28, 45 Pechet, M. M., 240 Peczynska-Czoch, W., 56 Pedone, C., 108, 146 Pegel, K. H., 134, 159 Pelletier, S. W., 133, 139, 140, 141 Pellizoni, F., 131 Pelosi, L., 124 Pelter, A,, 9 Peltier, D., 6 Pendergast, W., 7 Pennock, J. F., 208 Pentegova, V. A., 133, 142 Pentin, Y. A., 40 Perales, A,, 174 Perez-Ossorio, R., 52 Perfetti, R. B., 11, 229 Perlberger, J.-C., 5 Perry, C. W., 195 Perry, R. G., 19 Pesce, G., 243 Pkte, J.-P., 256 Petelina, L. P., 54 Peter, M. G., 18 Peters, R. H., 154, 263 Pethig, R., 200 Petit, F., 52 Petraitis, J. J., 30 Petrin, M. J., 22 Petrov, A. A,, 179 PetroviC, J., 245 Petrow, V., 281 Petrzilka, T., 63 Pettei, M., 66 Pettei, M. J., 198, 201 Pettit, G. R., 66 Pfander, H., 181, 198 Phan, A. I. T., 234 Phan Thug Anh, 128 Pharis, R. P., 137, 138, 139 Phillips, S. E. V., 50 Phinney, B. O., 138 Piacenza, L. P. L., 136 Piancatelli, G., 276, 279 Piattelli, M., 123, 144,145,146 Pichat, L., 62 Picot, A,, 278 Piekut, S., 241 Piers, E., 84, 230 Piestert, G., 266 Pilkiewicz, F. G., 66, 147, 198 Pillay, S. K., 55 Pilotti, A. M., 48, 123, 141 Pimenov, M. G., 49 Pinder, A. R., 102, 113, 114 Pines, S . H., 199

Piozzi, F., 127, 135 Pirkle, W. H., 7, 224 Pirouz, T., 206 Pisareva, I. V., 21 Pisareva, T. N., 52 Pitcher, R. G., 195 Pitt, C. G., 213, 239, 241 Pitt, H. M., 26 Pitts, J. N., 5 Place, P., 24 Planat, D., 235 Plat, M., 37 Plattier, M., 78 Pleil, H., 195 Poddubnaya, S. S., 44 Poling, M., 142 Poling, S . M., 205 Polonsky, J., 132 Polovsky, S., 250 Polyakova, N. P., 46, 54 Pommer, H., 190 Ponsold, K., 221, 229, 231 Pont Lezica, R., 206 Poots, I., 14 Popa, D. P., 127, 128 Popli, S. P., 155 Popov, s.,37 Popova, L. A,, 45 Popova, N. I., 55 Popplestone, C. R., 35 Popjik, G., 217 Porter, J. W., 201, 204 Posner, G. H., 1 1 , 228, 229, 240 Potapov, V. M., 40 Potter, G. J., 234 Pottier, E., 29 Poulter, C. D., 14, 24 Pouzar, V., 171 Povodyreva, I. P., 57 Powell, C. C., 28 Powls, R., 186,201 Pozzo-Balbi, T., 162 Prager, R. H., 53 Praly, J. P., 55 Prarnanik, B. N., 227 Prange, T., 157, 247 Prasad, J. S., 124 Prasad, K. K., 63 Prelog, V., 8 Prenzel, U., 207 Prestwich, G. D., 147, 187 Previtera, L., 124 Prkzelin, B. B., 186 Price, K. R., 106 Prince, E. C;, 128 Prochizka, Z., 270 Protiva, J., 171 Prudnichenko, E. K., 55 Przybylska, M., 134 Purdie, A. W., 156 Puri, H. S., 141 Purnell, J. H., 225 Pustil’nikova, S. D., 179

296 Quarmby, R., 185 Quijano, L., 19 Quin, L. D., 279 Quinn, R. J., 31 Quiocho, F. A., 264 Quon, H. H., 55 Rabaron, A,, 37 Rabjohn, N., 9 Radeglia, R., 217 Radford, T., 28 Radlick, P. C., 199 Raduchel, B., 261 Rae, I. D., 44 Rafferty, C. N., 200 Ragab, M. S., 273,275 Raggio, M. L., 254 Rahier, A., 160 Railton, I. D., 137, 138 Raines, D., 272 Raldugin, V. A., 133, 142 Ramachandra, R., 167, 233, 274 Ramaiah, T. S., 175 Ramakrishnan, G., 95 Ramamurthy, A. C., 6 Ramamurthy, V., 197 Ramaswamy, P. S., 12 Ramdas, S. R., 275 Ramirez, L. C., 270 Ramraj, S. K., 175 Rana, S. S., 25 Rance, T. A., 224 Ranise, A., 41 Ranzi, B. M., 67 Rao, A. S., 40, 74 Rao, E. V., 174 Rao, G. S. K., 42 Rao, K. L., 175 Rao, M. G., 174 Rao, P. N., 225, 238 Rao, S., 205 Raoult, E., 6 Rascher, W., 76 Rasmussen, J. K., 9 Rassat, A., 240 Rastogi, R. P., 161 Raston, C. L., 145 Rau, W., 181,205 Ravelo, A. G., 129 Ravi, B. N., 145 Rawle, J. R., 163 Raynolds, P. W., 60 Razdan, R. K., 62,63 Reca, E., 55 Reck, G., 137 Rector, D. H., 213,239, 241 Reeder, S. K., 117 Rees, J. C., 49 Reetz, M. T., 53 Reeve, D. R., 137 Reffstrup, T., 59 Rego, A., 269

Author Index Reich, R., 200 Reichenbach, H., 185 Reid, E. H., 118 Reid, G. R., 115 Reid, S. T., 259 Reif, W., 20 Rein, A. J., 199 Reinbol’d, A. M., 128 Renard, M. F., 243 Renaud, R. L., 205 Renold, W., 197 Rentzepis, P.M., 200 Reshetova, I. G., 241 Ribaldi, M., 132 Riccio, R., 145 Rice, S. A,, 200 Richmond, A. E., 196 Richter, H., 134 Ridlington, J., 19 Riehl, J. J., 51 Rigaudy, J., 256 Rigby, J. H., 13 Rinaldi, P. L., 7, 224 Rindone, B., 67 Rios, T., 19 Ripperger, H., 217 Risinger, G. E., 16 Riva, M., 271 Rivero, M., 78 Rivers, G. T., 45 Roach, A. C., 199 Roberts, J. S., 80, 107 Roberts, R. M. G., 40 Robertson, J. M., 211 Robertson, K. J., 145 Robinson, C. H., 275 Robinson, M. J. T., 40 Rodebaugh, R., 42 Rodewald, W. J., 276 Rodriguez, B., 125, 134, 135, 136 Rodriguez, E., 94 Rodriguez-Hahn, L., 105 Rodwell, M., 134 Roeraade, J., 187 Rogers, C. B., 159 RogiE, M. M., 9 Rohrer, D. C., 273 Rohwedder, W.K., 105 Rojahn, W., 26 Rojas, C., 15 Romanikhin, A. M., 55 Romeo, A., 228,240,251 Romeo, G., 178 Romo de Vivar, A., 105 Ronald, R. C., 75 Roques, R., 174 Rosanske, R. C., 99 Rose, A. F., 102 Rose, G., 280 Rosenberg, B., 200 Rosenberg, D., 62 Rosenfeld, T., 200 Rosenfield, J. S.. 5, 220

Rosenthal, D., 61 Ross, M. S. F., 226 Rosynov, B. V., 207 Rouessac, F., fi0, 197 Roumestant, M. L., 24 Row, L. R., 172, 174,175 Rowan, M. G., 14 Rowe, J. N., 123 Rowe, P. H., 224 Rowland, A. T., 231 Roy, A. K., 270 Rozen, S., 176 Rubin, A. B., 200 Rubottom, G. M.. 11 Ruckel, E. R., 56 Rudakov, G. A,, 52 Rudler, H., 29 Rudler-Chauvin, M., 29, 38 Rudney, H., 208 Ruedi, P., 130 Ruegg, R., 195 Rukhadze, E. G., 40 Runquist, A. W., 11, 229, 240 Ruppert, J. F., 38, 76 Russel, G. B., 156 Russell, R. A., 255 Rutledge, P. S., 234 Ryabushkina, N. M., 46 Rycroft, D. S., 163 Rykowski, Z., 42,43, 55 Sabadie, J., 55 Sabata, B. K., 71, 163 Saccani, M. A., 281 Sadowska, H., 42 Saegusa, T., 53 Sa’e Melo, M. L., 214 Safina, Z. I., 158 Saigo, K., 47, 197 Saiki, Y., 134 St.-Pyrek, J., 68, 155, 170 Saito, S., 14, 36 Saito, .Y., 11 Sakaguchi, T., 23 Sakai, H., 42 Sakai, T., 34 Sakaki, K., 8 Sakamoto, I., 134 Sakan, T., 130 Sakuda, Y.,40 Sakuragi, R., 36 Sakurai, N., 158 Sakurawi, K., 176 Salama, H., 255 Salamon, K. W., 238 Salas, O., 272 Salazar, J. A., 179 Salei, L. A., 127, 128 Salemann, T. N., 244 Salemink, C. A., 62 Salimgareeva, I. M., 56 Salimov, B. T., 141 Salisbury, P., 5 1

,

Author Index Salmond, W. G., 246,266 Saltykova, I. A., 172 Salvadori, P.. 154, 220 Samant, B. R., 233 Samek, Z., 95, 1.19 Samitov, Y. Y.,56 Sammes, P. G., 119 Samokhvalov, G. I., 195, 196, 199 Samori, B., 221 Sanai, S., 138 Sanchez, I. H., 149 Sandgi, S., 10 San Feliciano, A,, 125 San Filippo, J. jun., 5 1 Sangar’e, M., 216, 217 Sanjoh, H., 28 Santacroce, C., 108, 146, 262 Santaniello, E., 227, 230 Sanz-Burata, M., 8 Saperstein, D. D., 199 Saraswathi, G. N., 45 Sarda, P., 44 Sarkisian, G. M., 255 Sasak, W., 206 Sasaki, N., 131 Sasamori, H., 212, 252, 280, 281 Sastry, B. S., 174 Sastry, C. S., 172 Sastry, P. C. S. A., 174 Sathe, R. M., 48 Sathyanarayana, S., 6 Sato, K., 73, 224 Sato, M., 127 Sato, N., 106 Sato, T., 27 Satoh, F., 174 Satoh, J. Y., 243 Satterwhite, D. M., 14 Saucy, G., 25, 193 Saunders, J. K., 155, 215 Saunders, P. F., 137 Saunders, W. D., 114 Savary, D. N.-H., 24 Savel’eva, N. M., 195, 196 Savidan, L., 29 -Savona, G., 127 Sawa, A,, 62 Sawada, J., 155 Sawahata, T., 238 Sawai, M., 172 Scala, A,, 67 Scapini, G., 162 Sceats, M. G., 200 Scettri, A., 276, 279 Schaffer, A. M., 200 Schalk, D. E., 30 Scheffer, J. J. C., 8 Schenone, P., 41 Schette, H. R., 197 Schlatter, C., 18 Schlicht, W., 19, 46 Schlosser, M., 24, 59

297 Schmid, G., 63 Schmid, H., 17, 18 Schmidt, R. J., 143 Schmidt-Szalowska, A., 155 Schmierer, R., 4 Schmitz, F. J., 146 Schneider, G., 137 Schneider, H.-J., 217 Schneider, M. J., 46, 104 Schnoes, H. K., 269 Schocher, A. J., 205 Schonecker, B., 221,229 Scholfield, C. R., 198 Schoneweiss, S., 68, 124, 125 Schoofs, A,, 8 Schow, S. R., 266 Schrall, R., 37 Schreckenbach, T., 201 Schreiber, K., 137, 177 Schroeder, P. G., 147 Schroepfer, G. J. jun., 251,264 Schubert, G., 231 Schubert, K., 280 Schuder, P. F., 110 Schutte, H. R., 39 Schulte-Elte, K. H., 197 Schultz, A. G., 104 Schultz, T. H., 19 Schulze, R. M., 201 Schumacher, H., 20 Schumaker, R. R., 262 Schwartz, A,, 234 Schwartz, J., 11 Schwarz, M., 20 Schweitzer, W. B., 198 Sciuto, S., 146 Scolastico, G., 67 Scott, C. G., 22 Scott, F., 23 Scott, E.N., 217. 227 Scott, s. P., 49 Secrist, J. A,, 196 Seebach, D., 252 Segal, R., 95 Seifert, K., 177 Seitz, R., 127 Sellars, P. J., 8 Seltzman, H. H., 237 Sembdner, G., 137 Semmelhack, M. F., 73 Seo, S., 176, 217 Sempuku, K., 133 Septe, B., 216 Serebryakov, E. P., 138 Seshadri, T. R., 170 Sethi, S. C., 29 Setton, R., 47 Sevast’yan, A. P., 42 Sevost’yanova, V. V., ,12 Sevrin, M., 34 Sewe, K.-U., 200 Seymour, J. P., 49 Sgarabotto, P., 158 Sha, C.-K., 30

Shahak, I., 176 Shakirov, R., 160, 221 Shaligram, A. W., I02 Shalon, Y., 262 Shankaranarayan, R., 67, 87 Shapiro, E. L., 236, 250 Sharma, A. K., 10 Sharma, M. L., 22 Sharma, R. V., 206 Sharma, S. D., 22, 23, 25, 48 Sharpless, K. B., 10, 11 Shavyrin, V. S., 54 Shaw, P. E., 7 Shearer, D. A., 58 Sheichenko, V. I., 49 Sheikh, Y. M., 157 Sheldrick, W. S., 121 Shen, M. S., 144 Sher, F. T., 149 Sherman, S. A., 254 Sherman, W. V., 201 Sheves, M., 268 Shew, D. C., 147 Shibata, K., 270, 280 Shiga, M., 39 Shiloff, J. D., 46 Shimada, K., 147 Shimazu, K., 57 Shimizu, Y.,222 Shimoda, H., 41 Shimoirisa, H., 227 Shimura, S., 200 Shineberg, B., 208 Shinhama, K., 59 Shinohara, S., 34 Shioiri, T., 246 Shirado, M., 2 1 Shirasaki, H., 177 Shishibori, T., 14 Shizuri, Y.,73, 105, 119, 142, 144 Shoeb, A., 155 Shono, T., 41 Shringapure, J. D., 71 Shuhama, I. K., 99 Shvarts, Sh. I., 12 Sica, D., 146, 262 Sickles, B. R., 144 Siegelman, H. W., 183 Siewinski, A., 56 Sigel, C. W., 148 Silbernan, N., 214 Silva, M., 114, 119 Silvestri, M. G., 84 Simpson, K. L., 205 Simpson, T. H., 224 Sims, C. L., 117 Sims, D., 120 Sims, J. J., 31, 102 Sinclair, R. S., 199 Singaram, B., 42, 45,46 Singh, A. K., 58 Singh, B. P., 111, 118 Singh, C., 159

298 Singh, R. K., 182, 203 Singh, S., 163 Sippel, C. J., 208 Siverns, M., 127 Skattebol, L., 29 Skakovskii, E. D., 46 Skorubskii, A. A,, 44 Skrebkova, N. I., 54 Sliwowski, J. K., 151, 214 Smith, C., 264 Smith, C. R., 105 Smith, D. G., 137 Smith, D. H., 14 Smith, J. H., 281 Smith, M., 102 Smith, R. M., 4, 105 Smith, R. N., 63 Smolikovi, J., 243 Smolkova, E., 226 Snatzke, G., 221 Snider, B. B., 54, 253 Snieckus, V., 13 Snoeyink, V. L., 20 Snow, R. A,, 11 Soave, A. M., 231 Sobola, M. C., 246, 266 Sobolev, A. N., 158 Soffer, M. D., 80 Sokoloff, S., 95 Sokol’skii, D. V., 30 Solladie, G., 27 Solli, H., 20 Solodar, J., 44 Sonawane, H. R., 29 Song, B. J., 161 Song, P.-S., 186, 199 Sonoda, A,, 29 Sopova, A. S., 224 Sosnovsky, G., 281 Sotiropoulos, J., 53 Southwell, I. A,, 103 Sozzi, G., 157, 247 Specian, A. C. jun., 25 Speltz, L. M., 229 Spengel, S., 273, 275 Sperling, W., 200 Spiteller, G., 134 Sponsel, V. M., 138 Sporn, M. B., 195 Springer, J. P., 147 Spronck, H. J. W., 61, 63 Squillace, A. E., 19 Srinivasan, V., 90 Srinivasan, K. G., 49 Stanley, G., 187 Stark, P., 62 Steele, W. V., 50 Steiner, E., 262 Stephenson, L. M., 51 Sterling, J., 5 Steudler, P. A,, 146 Stevenson, R., 177 Stewart, I., 198 StierIe, D. B., 31

Author Index Still, W. C., 10, 46, 97, 154 Stirling, C. J. M., 8 Stitcher, O., 35 Stocks, R. A,, 19 Stoekenius, W., 201 Stoessl, A,, 107 Stokie, G. J., 65 Stone, W. L., 200 Stonik, V. A,, 157 Storer, R., 34 Stothers, J. B., 216 Straub, O., 181 Streelman, D. R., 167 Streith, J., 278 Strigina, L. I., 177 Stryer, L., 200 Stubenrauch, G., 238 Studt, W. L., 115 Suares, H., 139, 140 Subden, R. E., 203,205 Subrahmanyam, C., 174 Subramaniam, P. S., 111 Subramanian, L. R., 52 Subramanian, S. S., 125 Suchanka, M., 205 Sucrow, W., 245,251,261 Suffness, M. I., 38 Suga, K., 23, 27 Suga, T., 14,26,160 Suginome, H., 259 Sugiura, K., 105 Sukh Dev, 159 Suleeva, R., 54 Sulkes, M., 200 Sullivan, G. R., 4 Sultanbana, M. U. S., 177, 178 Sultankhodzhaev, M. N., 140 Sumner, W. C., 144 Sun, H. H., 144 Sunagawa, M., 131 Sundararaman, P. 9, 123 Sung, M., 175 Sung, T. V., 138 Sunthankar, S. V., 235, 260 Suokas, E., 168 Surmatis, J. D., 9 Surnina, Z. A,, 44 Suryawanshi, S. N., 89 Susuda, Y., 147 Suwita, A,, 115, 117, 169 Suzuki, A., 119, 147 Suzuki, M., 75 Suzuki, S., 155 Suzuki, T., 149 Suzuo, M., 4& 176,217 Sweet, F., 233 Swenberg, C. E., 200 Swenton, J. S., 60 Swern, D., 10 Sych, F. J., 138 Sydnes, L. K., 29 Symmes, C. jun., 279 Szabolcs, J., 181 Szewczuk, A,, 56

Taber, D. F., 154 Tachi, Y., 155 Tachibana, K., 168, 178 Taga, T., 136 Taguchi, H., 13, 37, 126 Tahara, A., 132, 138 Tahara, T., 40 Tahara, Y., 207 Taira, Z., 130 Takabe, K., 21,30 Takagi, S., 176 Takagi, Y., 30, 73 Takahashi, H., 43 Takahashi, K., 178 Takahashi, N., 131, 137, 138 Takahashi, S., 30 Takahashi, T., 115, 168, 172, 174, 177,178,243 Takahatake, Y., 34 Takai, M., 174 Takani, M., 178 Takasugi, M., 106 Takazawa, O., 47, 197 Takeda, A., 34, 59 Takeda, K., 244 Takeda, M., 280 Takeda, Y., 36, 37 Takei, H., 3 Takemoto, T., 120, 133, 139, 145 Takemura, T., 200 Takeshita, H., 52, 57 Takeshita, K., 21 Takeuchi, K., 12 Takken, H. J., 25,47 Takiguchi, R., 23 Talebarovskaya, I. K., 40 Tamm, C., 73 Tamura, S., 119, 138, 147 Tamura, T., 156, 162, 213 Tanabe, K., 43,57 Tanabe, M., 154,263 Tanaka, E., 21 Tanaka, I., 155 Tanaka, J., 21, 30, 199 Tanaka, K., 13, 20, 28, 29, 30, 47 Tanaka, M., 21 Tanaka, N., 134 Tanaka, O., 40, 53, 134, 162, 176,217 Tanaka, Y., 185,205 Tani, T., 127 Tanigawa, Y., 29 Tanikaga, R., 13,47 Tanis, S. P., 147, 163 Tanner, W., 206 Tarnopol’skii, B. L., 158 Tatum, J. H., 60 Tavares, R. F., 80 Taylor, D., 119 Taylor, D. A. H., 163, 165 Taylor, D. R., 163 Taylor, H. F., 181

Author Index Taylor, H. L., 167 Taylor, K. T., 259 Taylor, R. F., 181 Taylor, R. T., 53 Taylor, S., 182 Taylor, W. I., 54 Teale, J. D., 61 Teicher, B. A,, 260, 266 Teisseire, P., 78 Tel’nov, V. A,, 141 Templeton, J. F., 243 Terada, Y . , 129, 152 Teranishi, R., 19 Terashima, S., 11, 20 Teratani, S., 30 Terem, B., 193 Ter Heide, R., 8 Terlouw, J. K., 62 Terner, J., 201 Thakkar, J. K., 140 Thang, T. T., 217 Thappa, R. K., 39 Thomas, A. F., 19,29,56, 102, 111 Thomas, F., 217 Thomas, P. J., 263 Thommen, H., 198 Thornmen, W., 197 Thomson, R. H., 152,207 Thoren, S., 94 Thorstenson, J. H., 44 Tiernan, P. L., 281 Tietze, L.-F., 39 Tillequin, F., 19 Timosheva, A. P., 56 Ting, J.-S., 228 Tipnis, H. P., 20 Tippett, J. M., 53 Tjoa, K. H., 40 TokBs, L., 221 Topfer, A., 266 Tokes, L., 263 Tokito, Y . ,200 Tokunaga, F., 201 Tokura, N., 12 Tolstikov, G. A,, 56 Tomimori, T., 120 Tohita, Y., 176, 217 Tomiyama, K., 106 Toni, S., 193 Tori, K., 142, 176, 216, 217 Tori, M., 168, 178 Torii, S., 108, 110, 197 Torii, T., 178 Torosyan, Zh. K., 195 Torracca, A. M. W., 67 Torre, G., 221 Torrini, I., 237, 251 Toscano, L., 271 Toscano, V. G., 130 Toubiana, M. J., 142 Toubiana, R., 95, 142 Touzin, A. M., 115 Towers, G. H. N., 94

Toyota, M., 121, 145 Tozawa, M., 234 Tozyo, T., 176 Traas, P. C., 25,47 Tramontano, A,, 6 Trautmann, D., 165 Trethewey, K. R., 200 Trifilieff, E., 77 Tringali, C., 123, 144, 145 Trinh-Toan, 212 Trivedi, G. K., 27 Trka, A., 240, 243 Trogolo, C., 4, 35,36, 37, 38 Trost, B. M., 3, 13, 29, 1.54, 244, 261,274 Trotter, J., 49, SO, 147 Trown, P. W., 195 Trujillo, J. M., 129 Truscott, T. G . , 199 Tsai, L. B., 160 Tsankova, E., 111 Tschesche, B., 266 Tsuboi, M., 176 Tsuboi, S., 34, 59 Tsuchiya, S., 21 Tsujitani, R., 7 Tsukamoto, Y . ,42 Tsukida, K., 190, 198 Tsukihara, T., 139 Tsunakawa, M., 131 Tsuneya, T., 39 Tsuruta, H., 27 Tsushima, T., 45 Tsutsui, M., 27 Tsuyuki,T., 168, 172,174,177, 178 Tupoleva, G. N., 54 Turecek, F., 171 Turner, B. P., 118 Turner, C. E., 61 Turner, J. A,, 43, 60, 126, 132 Turro, N. J., S O Tursch, B., 141, 142, 144, 157 Tyler, T. W., 119 Uchida, M., 89 Uchida, Y., 21 Uchio, Y., 87 Udarov, B. G . , 46, 57 Uecke, J. W., 19 Ueda, H., 199 Ueda, S., 17 Uemura, D., 142 Uesato, S., 17 Ulick, S., 270 Uliss, D. B., 62, 63 Ulrich, A., 138 Ulubelen, A,, 172 Ul’yanova, 0.D., 40 Umani-Ronchi, A., 11, 198, 240 Umbreit, M. A,, 10 Umemoto, K., 39

Unai, T., 19 Uneyama, K., 108, 193, 197 Ung, H. L., 247 Unwin, P. N. T., 200 Upadhyay, R. R., 143 Urano, S., 93 Urbach, D., 205 Urbach, W., 205 Uritani, I., 65 Urones, J. G., 124 Urry, D. W., 201 Ushakov, V. A,, 19 Ushiki, T., 178 Usuda, S., 137 Usui, S., 148 Utley, J. H. P., 193 Uto, S., 134 Uvarova, N. I., 161 Uyehara, T., 141 Uzarewicz, A,, 55, 57 Uzarewicz, I., 57 I

Vakatkar, V. V., 260 Valadon, L. R. G., 185, 203, 205 Valdes, T. A,, 34 Valentine, D. H. jun., 30 Vallejos, C., 272 Vall’en, S., 8 Vallese, F. M., 19 Valverde, S., 134, 136 Vanantwerp, C. L., 215 Vanderah, D. J., 146 Van der Gen, A,, 255 Van der Helm, D., 142, 144, 146 Van Derveer, D., 121 Van Dreele, R. B., 66 Vanell, L. D., 66 Van Heldern, R., 25 Van Ooyen, R., 61 Van Tamelen, E. E., 38, 150 Van Thuijl, J., 222 Varagnat, J., 9 Varenne, J., 132 Varkey, T. E., 260 Varkony, T. H., 77 Varshney, I. P., 177 Vaughan, C . G., 63 Vaughan, W. R., 49 Veksler, M. A,, 195 Velgova, H., 264, 275 Velluz, A., 187 Vemura, D., 130 Veno, J., 134 Venturella, P.; 135 Verghese, J., 42, 45, 46 Verhoeven, T. R., 29 Vermeer, P., 23 Vermeglio, A,, 200 Verzele, M., 19 Veschambre, H., 42, 70 Vevert, J. P., 51

300 Viala, J., 33 Vichnewski, W., 95,99 Vicuna, R., 15 Vidal-Madjar, C., 22 Vidari, G., 93 Vidic, H.-J., 62 Vig, 0.P.,22, 23, 25,48, 58 Vines, S. M., 8 Vining, L. C., 137 Vinnik, G. I., 40 Vinson, J. A., 61 Vita-Finzi, P., 93 Vitali, R., 2713281 VitB, J. P., 18 Vogel, F., 6 Vogel, M. K., 44, 55 Voigt, B., 137 Voigt, G., 176 Voller, C. M., 14 Volkov, Y. P., 20 Von Carstenn-Lichterfelde, C., 125,136 Vop, N. E., 280 Voticky, Z., 160 Vul’fson, S . G., 56 Vyas, P., 177 Vystrcil, A,, 171 Wada, H., 105 Wada, K., 143 Wada, M., 3 Waddell, W., 200 Waddell, W. H., 50 Wade, J. J., 86 Wadia, M. S., 12, 231 Wadsworth, H., 272 Waegell, B., 51, 78 Wagner, F., 280 Wagner, H., 105, 127 Wahiberg, I., 123, 187 Wakimasu, M., 20 Walckhoff, B., 201 Walker, G. J., 53 Wall, M. E., 61, 167 Wallace, B., 54 Waller, C. W., 61 Wallis, A. F. A., 260, 264 Walliser, F. M., 236 Walls, F., 117 Walton, D., 196 Walz, W., 249 Wang, A. H. J., 130 Wang, P. K. S., 36 Wani,M.C., 167,213,239,241 Waraszkiewicz, S. M., 79, 144 Ward, A. D., 53 Ward, E. W. B., 107 Warnhoff, E. W., 90 Warshel, A,, 199 Washburn, W. N., 150 Wasilewska, L. D., 138 Wasserman, H. H., 10 Watanabe, K., 51

Author Index Watanabe, S., 23, 27 Watanabe, Y., 238 Watson, G., 19 Watson, H. A., 61 Watson, W. H., 130 Watt, D. S., 242. 254 Watt, R., 264 Wawrzenczyk, C., 58 Weber, H. P., 197 Weber, L., 250 Weedon, B. C. L., 181, 190, 192 Weeks, C. M., 212, 227, 250, 270 Wege, P. M., 110 Weinges, K., 36 Weinheimer, A. J., 142 Weintraub, P. M., 281 Weis, C., 53 Weisleder, D., 105 Weissenberg, M., 239, 265 Wekell, J. C., 145 Welch, S. C., 34, 74, 147 Wellner, R., 196 Wells, F. V., 13 Wells, R. J., 31, 142 Welzel, P., 234 Wender, P. A., 48, 115 Wenkert, E., 42,61, 67, 131 Westmijze, H., 23 Wetter, H. F., 9 Weyerstahl, P., 27 Whalley, W. B., 155, 211, 213, 219,221,249,255,260,261, 264, 266-, 272 Wheeler, J. E., 35 White, A. H., 145 White, D. H., 147, 213, 239, 24 1 White, J. D., 38, 76 White, R., 123 Whitesell, J. K., 36 Whitfield, F. B., 187 Whitham, G. H., 6 Whittaker, A., 62 Whittaker, D., 49 Wicha, J., 241 Wichman, D., 53 Widdowson, D. A., 7, 255 Widman, M., 62, 63 Wie, C. W., 243 Wiedhopf, R. M., 162 Wiehager, A.-C., 48 Wiemann, J., 39 Wiesenfeld, A., 119 Wiesner, K., 149 Wigfield, D. C., 6 Wilczynska, J., 42 Wilkie, J. S., 264 Wilkins, A. L., 180, 279 Wilkins, B. J., 261 Wilkinson, J. B., 231 Willhalm, B., 19, 187, 197 Williams, C. M., 217, 227

Williams, G. J., 27, 43 Williams, J. R., 244 Williams, P. J., 4 Williams, P. S., 225 Williams, R. E., 5 Williams, T. H., 60, 195 Williamson, D. H., 9 Willing, R. I., 139, 140, 264 Wilshire, C., 240 Wilson , B. J., 20, 65 Wilson, R. D., 235, 237 Wilson, S. R., 24, 30 Winer, A. M., 5 Wing, R. M., 31, 269 Winskill, N., 181 Winter, M., 187 Winternitz, F., 279 Wipke, W. T., 5 Witkiewicz, K., 43, 54, 57 Wittsruck, T. A,, 179, 214 Woggon, W.-D., 18 Wojcik, R. T., 56 Wojnarowski, W., 78 Wolf, H., 76, 198 Wolfers, H., 62 Wolinsky, J., 44, 55 Wong, A. K., 8 Wong, J., 155, 255 Wong, R. Y., 74 Wood, H. C. S., 70 Wood, M., 27 Wood, N. F., 20 Woodgate, P. D., 234 Woodward, R. B., 92 Worster, P. M., 230 Worthington, R. D., 152, 207 Wratten, S. J., 145, 146 Wright, J. J., 155 Wroble, R. R., 254 Wright, R. S., 224 Wu, K. K., 144 Wuts, P. G. M., 103 Wyllie, S. G., 221 Wyman, J., 200 Wynberg, H., 52 Xing, L&Q., 243 Yadav, J. S., 52,88 Yadav, R. N., 224 Yagai, V. A., 54 Yagi, H., 21 Yagihashi, F., 106, 107 Yagudaev, M. R., 221 Yagupol’skii, L. M., 42 Yahara, S., 162 Yamada, K., 105, 107,149 Yamada, S.-I., 11, 20, 26, 178, 246 Yamada, T., 43 Yamada, Y., 28, 149,155,160, 206,207,238 Yamagishi, N., 13

Author Index Yamaguchi, I., 138 Yamaguchi, S., 4, 214 Yamaguchi, Y., 8, 26 Yamaji, T., 25 Yamaki, M., 176 Yamakoshi, N., 280 Yamamoto, H., 7,13,48,80,89 Yamamoto, M., 25 Yamamoto, N.. 200 Ydmamoto, Y.,41 Yamamura, S., 99, 129, 152 Yamamura, Y., 8 Yamane, H., 137, 138 Yamasaki, K., 53, 134, 162, 176 Yamashita, H., 280 Yamazaki, Y., 137 Yanchuk, L. V., 195 Yang, S. S., 269 Yang-Lan, S., 53 Yankov, L., 155 Yankulov, I., 37 Yano, T.. 4, 187, 196 Yanovskaya, L. A,, 29 Yarovenko, V. N., 12 Yasamura, M., 266 Yasuda, D. M., 154,263 Yasuhara, F., 4, 214 Yasutomi, Y., 133 Yates, P., 236

301 Yeddanapalli, L. M., 57 Yen, C. C., 141 Yeowell, D. A., 17 Yisak, W.-A,, 63 Yogo, T., 20 Yokota, T., 137 Yokoyama, H., 163,205 Yokoyama, Y., 11,12,168,200 Yomosa, S., 200 Yoneyoshi, Y., 33 Yoon, N. M., 6 , 7 Yoshida, K., 8 Yoshida, Y., 89 Yoshihara, M., 127 Yoshikawa, M., 176 Yoshikuni, Y., 133 Yoshikura, M., 8 Yoshimura, Y., 176, 217 Yoshizaki, F., 120 Yosioka, I., 127, 176 Young, I. G., 208 Yousef, I. M., 226 Yudd, A. P., 198,201 Yuh, Y., 211,212,238 Yuki, Y., 130 Yunusov, M. S., 140, 141 Yunus0v.S. Yu., 140, 141, 160, 22 1 Yur'ev, V. P., 56 Yuste, F., 117

Zabza, A,, 56, 58 Zagalsky, P. F., 181, 185 Zahra, J.-P., 217 Zaitscher, D. V., 95 Zakharkin, L. I., 21 Zalkow, L. H., 19, 102, 121, 242 Zamojski, A,, 7 Zamutdinov, U. N., 127 Zarintan, M., H., 143 Zartner, G., 52 Zavedeeva, I. I., 20 Zbiral, E., 227, 228 Zderic, S. A., 6 Zdero, C., 22, 39, 46, 68, 71, 80, 95, 96, 114, 117, 119, 121, 124, 126, 127, 133, 135, 169 Zecchini, G. P., 240 Zelnik, R., 130 Zerner, G. W., 123 Ziegler, F. E., 115, 149 Ziegler, J.-C., 229 Zientek, E., 55, 57 Zimmerman, W. T., 45 Zimov, P. I., 20 Zink, M. P., 198 Zubova, G. M., 20 Zurich, E. T. H., 11 1 Zutshi, S. K., 39