Terpenoids and Steroids: Volume 3 (Specialist Periodical Reports)

A Specialist Periodical Report

Terpenoids and Steroids Volume 3

A Review of the Literature Published between September 1971 and August 1972

Senior Reporter

K. H. Overton, Department of Chemistry, University of Glasgow Reporters J. D. Connolly, University of Glasgow

P. Crabbe, National University of Mexico J. R . Hanson, University of Sussex

D. N. Kirk, Westfield College, University of London

G . P. Moss, Queen Mary College, University of London J. S . Roberts, University of Stirling A. F. Thomas, Firmenich et Cie., Geneva, Switzerland

0 Copyright 1973

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

ISBN: 0 85186 276 4 Libraw of Congress Catalog Card No. 74-615720

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

Made in Great Britain

General Introduction

The period covered by this Report is September 1971 to August 1972. The aims and presentation follow those of Volumes 1 and 2. J.D.C. P.C. J.R.H. D.N.K.

G.P.M. K.H.O. J.S.R. A.F.T.

Contents Part I Terpenoids Introduction Chapter 1 Monoterpenoids By A. F. Thomas

1 Analytical Methods and General Chemistry

5

2 Biogenesis, Occurrence, and Biological Activity

7

3 Acyclic Monoterpenoids Terpene Synthesis from Isoprene 2,6-Dimeth y loctanes Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives

11 11 12 20

4 Monocyclic Monoterpenoids Cyclobu tane Cyclopentanes, including Iridoids p-Menthanes General Chemistry and Hydrocarbons Oxygenated p-Menthanes rn-Menthanes Tetrameth ylcyclohexanes 1,4-Dirnethyl-1-ethylcyclohexanes Cycloheptanes

24 24 26 31 31 31 51

5 Bicyclic Monoterpenoids Bicyclo[2, I, Ilhexane Bicyclo[3,1,O]hexanes Bicyclo[2,2, I] heptanes Bicycle[3,1,1] heptanes Bicyclo[4,1,O]heptanes

56 56 57 58 71 80

6 Furanoid and Pyranoid Monoterpenoids

84

7 Cannabboids and other Phenolic Monoterpenoids

86

51 53 53

Chapter 2 Sesquiterpenoids By J . S. Roberts 1 Farnesane

92

vi

Terpenoids and Steroids

2 Mono- and Bi-cyclofanresanes

101

3 Bisabolme, Bergamotane, Campberane, Santalane, and Related Tricyclic Sesquiterpewids

104

4 C a k e , Copaane, Ylangane, and Cubebane

111

5 Cuparaw, ThuppSane, Chamigrane, Acoraw, Alaskane, Cedrane, Zizaane, and Trichothecane

115

6 Daucane

127

7 Longifoiane and Longipinane

130

8 Caryophyllane, Humulane, and Related Tricyclic Sesquiterpenoids

132

9 Germacrane

137

10 Elemane

144

11 Eudesmane

145

12 Eremophilane, Valencane, and Valerane

152

13 Guaiane

154

14 Maaliane and Aromadendrane

160

15 General

161

Chapter 3 Diterpenoids By J. R . Hanson I Introduction

163

2 Bicyclic Diterpenoids The Labdane Series T h e Clerodane Series

163 163 166

3 Tricyclic Diterpenoids The Pimarane Series Abietanes Cassane and Miscellaneous Tricyclic Diterpenoids The Chemistry of Ring A The Chemistry of Ring B The Chemistry of Ring c

168 168 169 171 172 173 173

4 Tetracyclic Diterpenoids The Kaurane Series Trachylobane Series Gibberellins

175 175 180 180

vii

Contents

Grayanotoxins

183

5 Diterpene Alkaloids

184

6 Macrocyclic Diterpenoids and their Cyclization Products Taxanes

185 186

7 Miscellaneous Diterpenoids

186

8 Diterpenoid Synthesis

187

Chapter 4 Sesterterpenoids By J. D. Connolly

193

Chapter 5 Triterpenoids By J. D . Connolly 1 Reviews

196

2 Squalene Group

196

3 Fusidan+Lanostane Group

198

4 Dammarane-Euphane Group Tetranortriterpenoids Quassinoids

206

5 Baccharis Oxide

21 1

6 Lupane Group

212

7 Oleanane Group

216

8 UrsaneGroup

225

9 HopaneGroup

227

10 Serratane Group

228

20 5 210

Chapter 6 Carotenoids and Polyterpenoids By G.P. Moss 1 Introduction

230

2 Physical Methods

230

...

Terpenoids and Steroids

Vlll

3 Carotenoids Acyclic Carotenoids Monocyclic Carotenoids Bicyclic Carotenoids Acetylenic and Allenic Carotenoids Isoprenylated Carotenoids Carotenoid Chemistry

234 234 235 236 238 239 239

4 Degraded Carotenoids

240

5 Polyterpenoids

244

Chapter 7 Biosynthesis of Terpenoids and Steroids By G. P. Moss 1 Introduction

245

2 Acyclic Precursors

246

3 Hemiterpenoids

25 1

4 Monoterpenoids Cyclopentanoid Monoterpenoids

252 254

5 Sesquiterpenoids

255

6 Diterpenoids

258

7 Sesterterpenoids

260

8 Steroidal Triterpenoids

260 26 1 262 263 264 264 265 26 5

Squalene Cyclization Loss of the 4,4-Dimethyl Groups Loss of the 14~-MethylGroup Formation of the A5-Double Bond Reduction of the A2'-Double Bond Formation of the AZ2-DoubleBond Sidechain Alkylation

9 Cholesterol Metabolism Spirostanols and Related Compounds Side-chain Cleavage Modification of Ring A

266 267 268 269

10 Triterpenoids

270

11 Carotenoids Degraded Carotenoids

270 272

12 Polyterpenoids

27 3

13 Taxonomy

273

ix

Contents

Part I/ Steroids Introduction

275

Chapter 1 Steroid Properties and Reactions By D . N. Kirk 1 Structure, Stereochemistry, and Conformational Analysis Spectroscopic Methods 1.r. spectra U.V.Spectra and Chiroptical Properties (O.R.D. and C.D.) N. M. R. Spectroscopy Mass Spectrometry

279 284 284

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

300 300 303 309 314

3 Unsaturated Compounds Addition Reactions Reduction of Unsaturated Steroids Oxidation and Dehydrogenation Alkynes and Allenes Miscellaneous

315 315 327 328 332 335

4 Carbonyl Compounds Reduction of Ketones Other Reactions at the Carbonyl Carbon Atom Reactions Involving Enols or Enolate Anions Reactions of Enol Esters, Ethers, and Enamines Reactions of Oximes, Hydrazones, and Related Derivatives Reactions of Carboxylic Acids and their Derivatives

336 336 338 342 352

5 Compounds of Nitrogen and Sulphur Amines and their Derivatives Miscellaneous Nitrogen Compounds Sulphur Compounds

365 365 368 37 1

6 Molecular Rearrangements Contraction and Expansion of Steroid Rings ‘Backbone’ and Related Rearrangements Epoxide Rearrangements Miscellaneous Rearrangements

373 373 378 387 39 1

285 295 298

356 36 1

Terpenoids and Steroids

X

7 Functionalization of Non-activated Positions

393

8 Photochemical Reactions Unsaturated Steroids Carbonyl Compounds Esters Miscellaneous

397 397 40 1 404 405

9 Miscellaneous Properties and Reactions

407

Chapter 2 Steroid Synthesis By P . Crabbe in collaboration with G. A. Garcia, A. Guzrnan, L. A. Maldonado, G. Perez, C. Rius, and E. Santos I Introduction

409

2 Total Synthesis

409

3 Halogeno-steroids

41 7

4 Oestranes

419

5 Androstanes

432

6 Pregnanes and Corticoids

445

7 Seco-steroids

463

8 Cholestane and Analogues

467

9 Steroidal Insect and Plant Hormones

487

10 Steroidal Alkaloids

490

11 Sapogenins

502

12 Bufadienolides

504

13 Cardenolides

506

Errata

5 10

Author Index

51 1

Part 1 TERPENOIDS

Int roduc t ion *

The interesting formal parallel that exists between the rearrangements of the chrysanthemyl cation and the conversion of presqualene alcohol into squalene (and now of prephytoene alcohol into phytoene) has been further explored. S o l v ~ l y s e sof' ~the ~ cyclopropyl(65) and cyclobutyl(63) esters both afford headto-head coupled C,, chains analogous to squalene. A versatile new method provides access to 9-substituted p-menthanes. This starts with natural limonene and proceeds via the anion (135) which retains chirality and leads to chiral products (see below). Skeletal rearrangements in the bicycloheptane series, an historic field in the study of organic reaction mechanisms, has received a fresh impetus from the extended work of Kirmse and his colleagues,26s~266 which is of preparative and mechanistic significance. Excellence and diversity in the synthetic field again characterize the year's work on sesquiterpenoids, with some notable examples of sophisticated methodology on the industrial scale. The production of C,, and C18juvenile hormones' ' * 1 2 and the conversion of the C,, into the C,, hormone are cases in point. The metallation of limonene referred to above has been turned to good account2, in stereospecific routes to bisabolane sesquiterpenoids. The unique antibiotic fumagillin has been ~ y n t h e s i z e dby ~ ~an imaginative route. Two notable syntheses of zizaene' have been reported. Wiesner's approach utilized a synthetic route to bicyclo[3,2,l]octanes developed in the course of an approach to diterpene alkaloids. The labile trans,trans-1,5-cyclodecadiene system of hedycaryol has been successfully generated by Marshall fragmentation of the appropriate cyclo-octyl tosylate.' O 8 Ourisson has described' 53 a simple two-stage procedure whereby the a-methylene-y-butyrolactonefunction so widespread among natural sesquiterpenoids can be obtained from the more readily available a-methyl-y-lactones. The method succeeds only with cis-fused lactones. The in vitro interconversion of acyclic, mono-, bi-, and tri-cyclic sesquiterpenes and their potential relevance to biosynthesis continue to attract widespread experimental attention7'-"and the complex acid-catalysed rearrangements of thujopsene have been subjected to penetrating s t ~ d y . ~An ~-~~ attempt' l6 to systematize the nomenclature of germacranolides should be noted by workers in the field. Much effort in the diterpenoid field is concentrated on substances having biological activity. Thus the c o l e o n ~ ,inumakila~tones,~~ ~~~~~ and * Reference and structure numbers are those of the appropriate chapter. 'pB2

5 2 9 1

3

4

Terpenoids and Steroids

p o d o l a ~ t o n e *scontrol ~ ~ ~ ~ the expansion and division of cells. Combined g.1.c. and mass spectrometry has played an important part in the detection and characterization of new gibberellinsg9-' O 1 and there have been important advances in gibberellin synthesis. ' 3 4 , 1 3 5 * 1 4 0 * 1 4 1 The antheridium-inducing factor of ferns' O6 has a gibberellin-like structure. Cyathin A,, isolated from the 'bird's nest' fungus, represents a novel mode of cyclization of geranylgeraniol. Notable synthetic successes in the diterpene alkaloid field have come from Wiesner's laboratory in the total ~ y n t h e s i s ' of ~ ~the delphinine degradation product (158) and the intermediate ( 159)'45 for a synthesis of songorine. Cheilanthatriol' represents a new type of sesterterpenoid whose carbon skeleton resembles that of triterpenoids. The structure of Baccharis oxide has been revised ;66 biosynthetically this is close to the previous structure (Vol. 2, p. 168) and therefore of comparable interest. The total laboratory synthesis of lupeoI6' is a notable further achievement in the synthesis of unsymmetrical triterpenoids. Cornforth and his colleagues have investigated2, the stereochemistry of isomerization of isopentenyl to dimethylallyl pyrophosphate in isoprenoid biosynthesis. They find that the prototropic change involved is stereochemically different from the superficially analogous association of C, units. Bisabolene appears to be excluded as an intermediate in the biosynthesis of helicobasidin and trichothecin by recent labelling studie~~'-'~(see also Vol. 1, p. 232, ref. 81) and a 1,4-hydride shift in the initially formed intermediate is indicated. The loss of the C-14 methyl group in cholesterol biosynthesis differs" from loss of the C-4 methyl groups. The 32-carbon atom is released at the aldehyde oxidation level as formic acid. In the carotenoid and polyterpenoid field a number of important stereochemical studies have appeared. These include assignments of the complete stereochemistry of phytoene' and lutein4' and the absolute configurations of absicic a ~ i d ~ ' - ~and * the natural irones."

1 Monoterpenoids BY A. F. THOMAS

The volume of work published on monoterpenoids is increasing, not only in the absolute sense, but relative to that on other natural products (including other terpenoids). There are at least three possible causes : many monoterpenoids are plentiful, further exploitation is desired, and recent refinements of analytical techniques have made possible the examination of reaction detail that was previously inaccessible. Monoterpenoids lend themselves especially well to such studies because of their suitability for gas chromatography, and also provide examples of a wide variety of structural types. Chemotaxonomy is also increasingly moving toward the use of monoterpenes because of the simplicity of analysis. Duplication of previously published work (see Vol. 2, p. 5 ) is reaching new levels. It is incomprehensible that reputable journals (in some cases) with a good refereeing policy still do not detect earlier work-even when it has appeared in this and other reviews-and this year an attempt has been made to quote the earlier reference (this is rarely done by the later authors) in order to highlight the problem. 1 Analytical Methods and General Chemistry

The first of two books with monoterpenoid sections is of the ‘dictionary’ type.’ It would be useful were it not for the incredible number of errors. Space will not permit a full criticism, but they include incorrect formulae (carquejyl acetate, artemisia and isoartemisia ketones, linalool, linalool oxide, lippione), double bonds of incorrect geometry (yomogi alcohol, cosmene), the inclusion of many discredited or doubtful compounds (santolinenones, osmane, hymentherene, etc.), and a very unusual biogenetic scheme. The other book purports to give a brief introduction to the chemistry, but terpenoids related to chrysanthemic acid, iridoids, ortho-menthanes, and heterocyclic terpenoids are omitted, and there are only 236 references, eight of which are post-1969 and twenty post-196fL2 Omission of recent literature also spoils a review of photochemistry in the field of monoterpenes : 3 although this has a large literature collection, it is mostly only up to 1969.

*

T. K. Devon and A. I. Scott, ‘Handbook of Naturally Occurring Compounds, Vol. 2, Terpenes’, Academic Press, New York, 197 1 . D . Whittaker, in ‘Chemistry ofTerpenes and Terpenoids’, ed. A . A. Newman, Academic Press, London, 1972, p, 1 1 . M. Pfau, Flavour Ind., 1972, 3, 89. The Specialist Periodical Reports are not quoted among the several reviews listed here.

5

Terpenoids and Steroids

6

A method for purifying saturated monoterpenoid hydrocarbons by multistage ex tractive crystallization with thiourea has been used for menthane, pinane, carane. and 1.1.4-trimethylcycloheptanepurification." The results are analogous to distillation or liquid-liquid extraction with greatly increased volatility between components in the two phases in the adduct-formation process. A more specific crystallization process concerns the isolation of 98 pure ( - )-menthol by crystallizing the mixture with wintergreen oil or limonene at 5 '(2.5 Monoterpenes are also used in a discussion about physical (especially crystallographic) properties of racemates susceptible to spontaneous or induced resolution by crystallization,6 and a later paper from the same laboratory gives details of the carvoximes and camphoroximes.- Gas chromatography of monoterpenoids is included in a paper concerned with an improved calculation of Kovats indices in gas chromatography' and the use of various columns is discussed.' Retention index data of various substituted cyclohexanes have been used to establish the stereochemistry of various p-menthanediols." A microtechnique for the analysis of monoterpenoids consists of hydrogenolysis in the inlet port of a gas chromatograph and analysis of the saturated hydrocarbons. Certain ring cleavages occur, and p-alcohols lose their CH,OH group. The products obtained are identified by mass and i.r. spectrometry.' The mass spectrometry of some monoterpenoid semicarbazones is reported ; many mechanisms are described. but without labelling evidence.' l a Terpenoids are frequently used to introduce asymmetry into molecules (a classic example is isopinocamphenylborane), and the use of camphor to introduce chirality into lanthanide shift reagents is now established' (see also the section on bicyclo[2,2,llheptanes below). The difference in geminal nonequivalence of methylene hydrogens of diastereomeric ( - )-menthoxyacetamides has been used as a monitor for the optical resolution of amines,13 this being a development of earlier work using menthoxyacetates for diastereomeric alcohols. The optical purity of chiral amines can also be checked from the n.m.r. spectrum of acid.14 Use of a the amides obtained with (+)-( lR.4R)-camphor-lO-sulphonic menthol ester to separate pseudoasymmetric ferrocenes has been described.' (-)-Menthy1 glyoxylate has been used in an attempt to induce asymmetry during a Diels-Alder reaction between the aldehyde group of the glyoxylate and a

'

F. P. McCandless, Ind. arid Eng. Chem., Product Rrs. and Dewlopment, 1971, 10, 406.

' Y . Matsubara, H . Hashimoto, J . Katsuhara. and H . Watanabe, Jap. P., 26 93311971 (Chenz. A h . , 1971, 75, 141 018). A . Collet, M.-J. Brienne, and J . Jacques, BrrN. Soc. chim. France, 1972, 127.

- J . Jacques and J . Gabard, Bull. Soc. chim. France, 1972, 342. ' R . U. Luisetti and R . A . Yunes, J . Chronratog. Sci., 1971, 9, 624. l o

I I

' la 1

I

l5

1. I . Bardyshev and V . I . Kulikov, Zhur. analir. Khim., 1971, 26, 1857 (Chem. Abs., 1971, 75, 15 192); T. J . Betts, Australas. J . Pharni., 1971, 52, S57. C . Paris and P. Alexandre, J . Chromatog. Sci., 1972, 10, 402. R . E. Kepner and H . Maarse, J . Chromatog., 1972,66, 229. J . Cassan, M.Azarro, and R . I . Reed, Org. Mass Spectrometry, 1972,6, 1023. G . M . Whitesides and D. W . Lewis. J . Amer. Chern. Soc., 1 9 7 ~ 9 35914; , H . L. Goering, J . N. Eikenberry. and G. S. Koermer. ibid., p. 591 3. T. Ci. Cochrane and A. C. Huitric. J . Org. Chem., 1971,36, 3046. G.-A. Hoyer, D. Rosenberg, C. Rufer, and A . Seeger, Tetrahedron Letters, 1972, 985. S. I . Goldberg and W . D. Bailey, Tetrahedron Letrers, 1971, 4087.

Monoterpenoids

7

1-alkoxybutadiene. In the simple case the optical yield was very I o w , ' ~ but it rose to 25% when the reaction was effected in the presence of Lewis acids at low temperatures.' ' Another attempt at inducing asymmetry in a Diels-Alder reaction used (-)-dimenthy1 fumarate and isoprene. The optical yield rose from 0 % at atmospheric pressure to 4.7 % at 5000 atmospheres.' The preferred rotational conformations of acetyl and formyl groups can be predicted by temperature-dependent c.d. measurements, and the technique has been applied to some monoterpene aldehydes." The sign of the Cotton effect has been related to the chirality of a series of n-molecular complexes of monoterpene (and other) hydrocarbons with tetracyanoethylene. Inconclusive results found with (+)-sabinene were ascribed to complexation with the cyclopropane ring2'

2 Biogenesis, Occurrence, and Biological Activity An excellent review, particularly where it concerns his own work, has been published by Banthorpe2' which covers the whole field of monoterpene biogenesis. The same author has examined the biosynthesis of (+)-pulegone in Mentha pulegium, in which [2-'4C]mevalonic acid gave unequal labelling, almost all the tracer being associated with the isopentenyl pyrophosphate part of the molecule, in agreement with earlier work (Vol. 2, p. 6). 3,3-Dimethy1[1-14C]acrylicacid, on the other hand, appeared to be incorporatedafter degradation toacetate units.22 The conversion of monoterpenes into carotenoids in Tunacetum vulgare and Artemisiu annua has been found to occur in whole plants either as undegraded C,, units or as 3,3-dimethylallyl pyrophosphate equivalent^.^^ Some studies on in vitro tissue cultures of 7:uulgare were also made.24 In this plant the petals contain p-D-glucosides of isothujol, neoisothujol, and other compounds, and it is observed that [2-'4C]mevalonate incorporation into the glucose portion is ten times more than into the terpenoid portion.25 Results not in agreement with Banthorpe's unequal labelling have been obtained by Suga et a/., who fed [2-'4C]mevalonic acid to twigs of Cinnamomum camphora Sieb. oar. linalool$erum and found the linalool to be equally labelled.26 When [2-'4C]mevalonate is fed through cut stems of Mentha piperita in the presence of sucrose, the incorporation into the monoterpenes is markedly increased. This was interpreted as support for the compartmentation of sites of monoterpene J. Jurczak and A. Zamojski, Tetrahedron, 1972, 28, 1505. 0. Achamatowicz, jun. and B. Szechner, J . Org. Chem., 1972,37, 964. ' * B. S. El'yanov, E. I . Klabunovskii, M . G . Gronikberg, G. M. Parfenova, and L. F. Godunova, Izvest. Akad. Nauk S . S . S . R . , Ser. khim., 1971, 1658. T. Suga, K. Imamura, and T. Shishibori, Bull. Chem. SOC.Japan, 1972,45, 545. '' A. I. Scott and A. D. Wrixton, Tetrahedron, 1972, 28, 933. " D. V. Banthorpe, B. V . Charlwood, and M. J . 0. Francis, Chem. Rev., 1972, 72, 101. The carquejol formula is incorrect in this review (see Vol. 1, p. 35 of these Reports). " D. V . Banthorpe, B. V . Charlwood, and M . R. Young, J.C.S. Perkin I , 1972, 1532. 2 3 D. V. Banthorpe, H . J. Doonan, and A. Wirz-Justice, J.C.S. Perkin I , 1972, 1764. 2 4 D. V. Banthorpe and A. Wirz-Justice, J.C.S. Perkin I , 1972, 1769. 2 5 D. V. Banthorpe and J. Mann, Phytochemistry, 1972, 11, 2589. 2 6 T. Suga, T. Shishibori, and M . Bukeo, Phytochemistry, 1971, 10, 2725. l6

"

8

Terpenoids and Steroids

biosynthesis, these sites being deficient in energy, which can be supplied by sucrose.*’ The same group has suggested that since labelled mevalonate is readily incorporated into sesquiterpenoids but poorly into monoterpenoids in this plant, the two types of terpenoids are produced at different sites.28 They concur with Banthorpe’s unsymmetrical labelling results, finding that 14C02is incorporated into pulegone to at least 90% in the seven-carbon-ring part, with no label in the isopropyl group, which suggests that endogenous dimethylallyl pyrophosphate participate^.^^ The stereochemistry of protonation of isopentenyl pyrophosphate in its conversion into dimethylallyl pyrophosphate by isopentenyl pyrophosphate isomerase has been elucidated by Cornforth et Acetate is found to be a poor precursor of alkaloids in Rauwolja serpentina and Ccphaelis acurninata, and since it is a specific precursor of sitosterol in these plants it is suggested that monoterpene units in the alkaloids and the steroids must be formed by different pathway^.^' Geraniol is suspected as a natural isoprenoid inhibitor in apples; thisand other known inhibitors increase the breakdown ofthe tissue below 5 0C.32 Aspects of chrysanthemate-related and iridoid biogenesis are discussed in the appropriate sections (below). Analytical work on the natural occurrence of monoterpenoids takes three forms. Chemotaxonomy requires a study of proportions of compounds occurring in similar species in different geographical locations. Thus Zavarin’s work on Abies balsarnea and A . fraseri shows that A . frasvri evolved from eastern A . balsamea by gene-loss during the xerothermic period, by following the content of the pinenes, carene, limonene, and ~hellandrene.~This continues from earlier work on the statistical relationships of monoterpenoids (see Vol. 1, p. 7, and ref. 34). In this context the monoterpenoid composition of the cortical oleoresin of red spruce (Picea rubens) in different populations has been examined.35 A second type of analysis is undertaken to ascertain the effect of some extraneous factor on a plant. Examples are the studies made on the effect of various metabolites or inhibitors that might change the monoterpenoid production of a commercial crop such as roses.36 Effect of seasonal change on the composition of monoterpenoids from Rosmarinus officinalis, particularly in the spring, has been examined.j’ The fact that the bark beetles Dendroctonus breuicomis and D. ponderosae preferentially attack Pinus ponderosa trees that have been injured by photochemical air pollution suggested study of the monoterpenoid composition

‘’ R . Croteau, A. J . Burbott, and W. D. Loomis, Phyrochemistry, 1972, 1 1 , 2937. R. Croteau, A . J . Burbott, and W . D. Loomis, Phytochemistry, 1972, 1 1 , 1055. ’’ R. Croteau, A. J . Burbott, and W. D. Loomis, Phytochemistry, 1972, 1 1 , 2459. ’’ K. Clifford, J . W . Cornforth, R . Mallaby, and G . T. Phillips, Chem. C o m m . , 1971, 1599. ’‘ A . K . Gary and J . R. Gear, Phytochemistry, 1972, 1 1 , 689. ’’ R . B. H . Wills and B. D. Patterson, Phytochemistry, 1971, 10, 2983. ’3 34

”

” ”

E. Zavarin and K . Snajberk, Phyiochemisiry, 1972, 11, 1407. E. Zavarin, W. B. Critchfield, and K . Snajberk, Phytochemisrry, 1971, 10, 3229. R . C. Wilkinson and J. W . Hanover, Phytochemisrry, 1972, 11,2007. D. A. Voloshina, A. A. Bakhtenov, and M . Zhurakova, Byul. Nikit. Bot. Sada, 1970,51 (Chem. Abs., 1972,76,6620). K . E. Rasmussen, S. Rasmussen, and A . Bzerheim Svendsen, Pharm. Weekblad, 1972, 107, 309.

Monoterpenoids

9

of the two trees (in this case there was no differen~e).~'A possible connection with the pheromones of the male boll weevil, Anthonomus grandis, led to an ~~ examination of the volatile alcohols of cotton oil (Gossypiurn h i r s ~ t u m ) .Plant breeding experiments may also lead to improved commercial crops; one hybrid from Mentha sachalinensia, a valuable source of ( - )-menthol, inherited chemical characteristics of only the female plant,40 and in Mentha aquatica change in one gene altered the whole monoterpenoid compo~ition.~'Analysis of the monoterpenoids in some Canadian Mentha hybrids has shown some interesting variation~.~~ The third and most common type of chemical plant analysis sets out to find what is present. Much of this work is of poor quality, sometimes because insufficient care was given to extraction conditions but mostly because results are too meagre to warrant publication (description of only four or five compounds of the many hundreds in the essential oil of a plant is only interesting if a new substance is included). In this Report, such trivial analyses will not be included.* The following analyses of monoterpenoids in plants are somewhat more useful : Amornum cardamomum and A. globosum (containing respectively 1,8-cineol and camphor as the main components among a large number various analyses of plants producing non-head-to-tail linked monoterpenoids like Ar~emisia,4~ Chry~anthemurn,~~ and T ~ g e t e sspecies, ~~ and many commercially interesting lavender and plants and oils, such as Geranium bourb~n,~'tangerine e~sence,~' l a ~ a n d i nand , ~ ~majoram Majorana hortensis and Origanum uulgare, where the thymol, carvacrol, and eucalypt01 contents were used to distinguish between 38 39

4o

F. W. Cobb, jun., E. Zavarin, and J. Bergot, Phytochemistry, 1972, 11, 1815. P. A . Hedin, A. C. Thompson, R. C. Gueldner, and J. P. Minyard, Phytochemistry, 1971, 10, 3316. This work also led to a comparison of the rnonoterpenes of cotton leaf oils from different geographic locations, c j : P. A. Hedin, A. C. Thompson, R. C. Gueldner, A. M. Rizk, and H. S. Salama, Phytochemistry, 1972, 11, 2356, and refs. therein. A. G. Nikolaev and V. B. Yakubovich, Trudy Khim. prir. Soedinenii, 1969, no. 8, 114 (Chem. Abs., 1971,75,91 232); V . B. Yakubovich, A. G. Nikolaev, G . V. Lauzr'evskii, and 0. A. Belinskaya, Aktual. Probl. Izuch. Efirnomaslich. Rast. Efirn. Masel, 1970, 149

(Chem. Abs., 1972,76, 89 944). F. W. Hefendehl and M. J. Murray, Phytochemistry, 1972, 11, 189, 2469. 4 2 B. M . Lawrence, J . W. Hogg, S. J . Terhune, J. K. Morton, and L. S. Gill, Phytochemistry, 1972, 11, 2638. 4 3 B. M. Lawrence, J . W. Hogg, S. J. Terhune, and N . Pichitakul, Phytochemistry, 1972, 11, 1534. " T. P. Berezovskaya, V. V. Dudko, R. V. Usynina, R. P. Uralova, and E. A. Serykh, Aktuul. Probl. Izuch. Efrnomaslich. Rast. Efrn. Masel, 1970, 137 (Chem. Abs., 1972, 76, 89 939). 4 5 K. Forsen and M. von Schautz, Arch. Pharm., 1971,304, 944. 4 h N. A. Kekelidze, V. G . Pruidze, and A. D. Dernbitskii, Aktual. Probf. izuch. Efirnomaslich. Rast. Efirn. Masel, 1970, 135 (Chem. Abs., 1972,76, 89 943). 4 7 R.Timmer, R. Heide, P. J. De Valois, and H. J. Wobben, J . Agric. Food Chem., 1971, 19, 1066. 4 8 M . G . Moshonas and P. E. Shaw, J. Agric. Food Chem., 1972,20,70. 4 y L. Peyron, Compt. rend. Seances Acad. Agric. France, 1971, 57, 1368; Plant. Med. Phytother., 1972, 6 , 7. 4'

* Where a new terpenoid has been reported during the investigation of plant material, it has been included, as usual, in the section concerning the new structure. Some of these papers are also examples of excellent analyses (e.g. ref. 77).

10

Terpenoids and Steroids

similar plants.” A good analysis of parsley aroma also includes some cogent remarks on the presence of ‘suspect’ constituent^.'^ The enzymic reduction of geraniol and nerol to citronellol was mentioned in Vol. 1, p. 8 ; Dunphy and Allcock have now isolated a solubilized enzyme reductase from rose petals that is specific for the reduction of primary terpene alcohols with either a cis- or a trans-allylic double bond.s2 A pseudomonade has been found that converts linalool in to camphor and 2,6-dimethyl-6-hydroxyocta-2,7dienoic acid.’ More epoxides (1) with juvenile hormone activity (Vol. 2, p. 7) have been made by epoxidizing the Wittig products of citronella1(2),and some of these substances also increase silk produ~tion.’~Reduction of the double bond sometimes increases the activity against Oncopeltus fasciatus.” Insecticidal activity is also reported for certain terpenoid cyclopropanes [e.g. (3), made from limonene and ethyl dia~oacetate]’~ and for isobornyl thiocyanoethyl ether (made from camphene and ethylene chlorohydrin followed by treatment with potassium thiocyanate).” The insect-repelling activity shown by thujic acid amides (4)is

A

50

5 1

52

53

54

55

56

5 7

J. Jolivet, P. Rey, and M . F. Boussarie, Plant. Med. Phytorher., 1971,5, 199; this paper employs the older nomenclature ‘Origanum majorana’ for M . hortensis. Another analysis of M. horrensis seeds lists only four rnonoterpenoids and two other compounds (B. Dayal and R . M. Purohit, Flarour f n d . , 1971, 2 , 477). R . Kasting, J . Anderson, and E. von Sydow, Phytochernistry, 1972, 11, 2277; see also Vol. 1 , p. 23 of these Reports. P. J. Dunphy and C . Allcock, Phj.tochemisrry, 1972, 1 1 , 1887. S. Mitzutani, T. Hayashi, H. Ueda, and C. Tatsumi, Nippon NGgeikagaku Kaishi, 1971, 45, 368. S. Murakoshi, C.-F. Chang, and S. Tarnura, Agrir. and Biol. Chern. (Japan), 1972, 36, 695. M. Schwarz, R. E. Redfern. R. M. Waters, N. Wakabayashi, and P. E. Sonnet, Life Sci., 1971, 10, 1125. M . Nakaishi, S. Inamasu, and S. Sakuragi, Jap. P. 27 18611971 ( C h e m . A h . , 1971, 75, 110 465). T. Waida, S. Asada, and M. Kodama, Jap. P. 34 4201 I97 1 (Chrm. Abs., l972,76,4032).

11

Monoterpenoids

interesting in view of the relationship with thujic acid, a component of the bark of Thuja plicata (Western red cedar), well-known to be resistant to insect attack.5s Homopinane ethanolamines are said to be anticholinergic and spas moly ti^.^^ More work on terpenoid quaternary salts as growth-retarding substances (Vol. 2, p. 7) has appeared.60 Reports concerning the metabolism and analysis (in the blood) of the hypoglycaemic agent 'Glibornuride' ( 5 ) are appearing.6 Bactericidal activity is claimed for another bornylamine derivative (6),62and the ethylenethiol derivatives [7; X = SO,H, H, PO,H,, or C(NH,)=NH] offer protection against irradiati~n.~, Other biologically active compounds are mentioned in the appropriate sections.

6"" NHCONHSOZ (6) R (5)

=

7 fJJ

c1

0 (7) R = CH,CH,SX

3 Acyclic Monoterpenoids

Terpene Synthesis from Isoprene.-A frankly advertising review of the subject has been given.64 The telomerization of a mixture of isoprene and prenyl acetate in ethyl acetate, catalysed by boron trifluoride, gives the usual complex mixture of acetates; this includes geranyl and a-terpinyl acetates.65 Isoprene dimerizes in the presence of certain titanium or zirconium catalysts, e.g. ZrBu,Cl + AlClEt, + Ph,P, giving 70% of the hydrocarbon (S), 8 % of (9), and 22'1/,, of trimers.66 Heggie and 58

59 ' O

" b2

63

64

65

66

V. Hach and E. C . McDonald, Science, 1971, 174, 144. R. Baronnet, Ger. Offen. 2 137 988. H . Haruta, H. Yagi, T. Iwata, and S. Tamura, Agric. and Biol. Chem. (Jupun), 1972,36, 881. J. A. F. de Silva and M . R. Hackman, Analyt. Chem., 1972, 44, 1145, list the leading references. K. Bernauer, J. Borgulya, and E. Boehni, Ger. Offen. 2 135 712. R. D. Elliott, J . R. Piper, C. R. Stringfellow, and T . P. Johnston, J. M e d . Chem., 1972, 15, 595. W. C . Meuly, Riechstofle, Aromen, Korperpflegem., 1972, 22, 191. K . Takabe, T . Katagiri, and J. Tanaka, Kogyo Kuguku Zasshi, 1971, 74, 1162 (Chem. Abs., 1971, 75, 129 947). H. Morikawa. Ger. Offen. 2 061 352; 2 063 038.

12

Terpenoids and Steroids

Sutheriand have confirmed6’ an earlier report68 about the dimerization of isoprene over a nickel-based catalyst, and have additionally shown that the proportions of the products [(lo), (1l), and (12)] are 78 : 8 : 14, the cyclo-octadiene (10) being more than 98% head-to-tail linked. Some interesting reactions of the cyclo-octadiene (10)are described. Dimerization of isoprene with nickel-ligand

(8)

(91

(10)

(12)

catalysts involves several steps, and with cyclododecatrienetriphenylphosphinenickel [(cdt)Ni(PPh,)]the intermediate (13)is obtained, which can be converted into dipentene (12) with carbon monoxide, into the 2,6-dimethyl-cis,trans-cyclodeca-1,5-diene with ethylene, or back into isoprene with triphenylph~sphine.~~ Reactions of isoprene in the presence of lithium naphthalene in tetrahydrofuran with camphor [yielding (14) as the main product in 30% yield], fenchone, and menthone have been examined. With propylene oxide, the alcohols (15a) and (15b) are produced in 10% and 1 5 % yields.” A synthesis employing prenyl bromide (i.e. effectively using isoprene) to form the geranyl skeleton, is described below.

2,6-Dimethyloctanes.-Work on the base-catalysed rearrangement of cis- and trans-p-ocimene (Voi. 2, p. 8) has been repeated,’l and so has the even better known Wolff-Kishner reduction of citronellal, leading to displacement of the ailylic double bond.72 ‘ 7

” 69

’’ ? ’

’‘

W . Heggie and J . K . Sutherland, J . C . S . Chem. Comm.. 1972, 957. L . I . Zakharin and G . G. Zhigareva, Izcest. Akad. Nauk S . S . S . R . , Ser. khim., 1968, 168. B. Barnett, B. Bussemeier, P. Heimbach, P. W. Jolly, C. Kruger, I . Tkatchenko, and G . Wilke, Tetrahedron Letters, 1972, 1457. S. Watanabe, K. Suga, and T. Fujita, Chem. andlnd., 1971, 1234. D. McHale, Terrahedron, 1971,27,4843; the original work is T. Sasaki, S. Eguchi, and H . Yamada, Tetrahedron Letters, 1971, 99. W. Daniewski and A . Dgmbska, Roczniki Chem., 1971, 45, 923; the original work is R . Fischer, G . Lardelli, and 0. Jeger. Hrlr. Chim. Acra, 1951,34. 1577.

Monoterpenoids

13

Sasaki et a!. have continued their work on 1,4-cycloadditions to monoterpenoids with a study of the reaction between propiolonitrile and allo-~cimene.’~ In the presence of aluminium chloride, Diels-Alder addition of maleic anhydride to ocimene involves a second ring-closure, leading to the indane (16).74 Direct

ccH20

addition of acetic acid to myrcene (17) in the presence of palladium chloride and triphenylphosphine gives only a 15 yield of a mixture of linalyl acetate (18), neryl and geranyl acetates (19),and the acetates (20) and (21).75

-1

--3

+

The trans-isomer of the recently described ocimene e p o x i d e ~has ~ ~been isolated frgm Ocirnurn ba~ificurn.~~ ” 74

75

76

’’

T. Sasaki, S. Eguchi, and H . Yamada, Tetrahedron, 1971, 27, 451 1. J. Alexander and G . S. K . Rao, Indian J . Chem., 1972, 10, 244. S. Watanabe, K . Suga, and K. Hijikata, Israel J . Chem., 1971, 9, 273; K. Suga, S. Watanabe, T. Fujita, and K. Hijikata, Yukagaku, 1972, 21, 322, appears not to add anything to the earlier reference. G. H. Buchi, H . Wuest, H. Strickler, and G . Ohloff, Swiss P., 501 609 (Chem. A h . , 1971, 75, 88 792). B. M . Lawrence, J. W . Hogg, S. J . Terhune, and N . Pichitakul, Flavour Ind., 1972, 3, 47.

14

Terpenoids und Steroids

A review exists (in Japanese) of various polyprenyl alcohol syntheses.'* Muntyan et al. have prepared 2-methylhept- 1-en-6-one (22) (Scheme l), and thence r-linalool (23). The alternative pathway cia the ketal (24) was unsatisfactory because of the difficulty experienced in hydrolysing the ketal group and subsequent purification of the methylheptenone ( B ) . ' ~This work makes other

(231

(22)

Reagents: i, H , O * ; ii, LiAIH,: i i i , A c , O ; iv. H,SO,; v, P h , P = C H , ; viii, HOCH,CH , O H - H * .

vi, N a O H ; vii, CrO,;

Scheme 1

-'K. S a t 0 a n d S. inoue,

Y'iiki Gosri Kagakir Kyokai Shi, 1971, 29, 237. G . E. M u n t y a n , V. A. Smit, A . V. Semenovskii, a n d V. F. Kucherov, Izrest. Akad. .Vnuk S.S.S.R.. Ser. khim.. 1972. 909.

Mono terpenoids

15

substances of the a-series available. Granger et al. report the presence of ‘cismyrcen-8-01’ (25) and its acetate in Thymus vulgaris;*’ although this type of trivial nomenclature in the case of (25) shows immediately the relation of the substance to myrcene, ‘myrcenol’ should not be used for the substance (26), made conventionally from the aldehydo-ester (27).*

A total synthesis of ethyl geranate (28) makes use of the addition of ethyl 4-bromo-3-methylbut-2-enoate (29) to the nickel carbonyl complex (30) of prenyl bromide. Geranyl acetate and the ethyl ether were made in a similar way.82

The kinetics of the solvolysis of linalyl p-nitrobenzoate were published in note form 18 years ago, but a full discussion of the reaction, including the mechanism for retention of optical activity in the cyclized products, has now been published as one of the Winstein memorial papers.83 Another paper on the reaction of linalool with phosphorus pentachloride reports 88 % yield of a ca. 3 : 1 mixture of geranyl and linalyl chlorides (after 4 h at - 10 0C).84Acetylation of linalool is notoriously fickle on account of ready rearrangements ; now a method using t-butyl acetate and sodium methoxide is said to give a 90% yield of the unrearranged a ~ e t a t e . ’The ~ rearrangements involved in the acid decomposition of the

*’ 82

*3

84

85

R . Granger, J . Passet, and J. P. Girard, Phytochemistry, 1972, 1 1 , 2301. 0.P. Vig, A . S. Dhindsa, A . K . Vig, and 0. P. Chugh, J. Indian Chem. Soc., 1972,49, 163. K . Sato, S. Inoue, S. Ota, and Y . Fujita, J. Org. Chem., 1972,37,462. S. Winstein, G . Valkanas, and C. F. Wilcox, jun,, J. Amer. Chem. Snc., 1972,94, 2286; see also S. Winstein, Experientia, 1955, suppl. No. 2, 137. S. Teng and K. Laats, Eesti N.S.V. Teaduste Akad. Toimetised, Keem., Geol., 1971,20, 318. H . Pasedach, G . P. I 768 980 ( C h e m . Abs., 1971, 75, 110 464).

Terpenoids and Steroids

16

diazo-compound formed from geranylamine (31), and which give nerol, aterpineol, and linalool, have been discussed.86 Mild acid treatment (oxalic acid, 1 for 2 h) of geraniol leads to a mixture in which 27 substances were identified, most of which are at the same oxidation level as geraniol and are formed by hydration and proton-transfer reactions, although hydride transfer does take place, as illustrated by the 16.301; of citronellol ~ b t a i n e d . ~ ’

When geraniol reacts with phenols in the presence of acid, the common products are usually cyclized: the use of 1 ’/:, oxalic acid has now been found to minimize cyclization in the reaction between orcinol and geranioL8’ Nerol has been labelled with deuterium in various positions [a, b, c, and d in (32)] and then converted into the chloride (33). Kinetic isotope effects on hydrolysis of (33) were measured, and n-participation in the cationic intermediate (34) leading to the cyclized terpinyl derivatives is discussed.89 Schwartz and Dunn proposed to use the complex ( 3 3 , from geranyl methyl ether, as a model for a farnesol cyclization. They were not able to isolate this complex (although there was some evidence for its formation), the main complex ( 3 6 ” / )being a dimeric o-complex (36), together with 39”/, of the ketone (37), but no cyclized material.” The cyclization of the acid chloride (38) to menthone and the C, hydrocarbon (39) with tributyltin hydride.” and also the optimum conditions for the cyclization of ( +)-citronella1

R

C OMe 1 2 (35)

’’ Y . Butsugan, Y . Kuroda, M . Muto, and T. Bito, Nagoya Kogyo Daigaku Cakuho, 1970, *’ KK

89

9o 9’

22, 4 4 3 (Chem. A h . , 1972,76, 14 723).

K . L. Stevens, L. Jurd, and G . Manners, Tetrahedron, 1972.28, 1939. G . Manners, L . Jurd, and K . L. Stevens, Tetrahedron, 1972, 28, 2949. C. A. Bunton, J. P. Leresche, and D. Hachey, Tetrahedron Letters, 1972, 2431. M . A. Schwartz and T. J . Dunn, J . Amer. Chem. SOC., 1972,94,4205. Z . Cekovic, Tetrahedron Letters, 1972, 749.

17

Mono terpeno ids

to ( - ) - i s o p ~ l e g o lhave ~ ~ been reported. Citral is cyclized with chloranil to a mixture of p-cymene and methyl-4-isopropenylbenzene. Further cyclizations are mentioned in the section on tetramethylcyclohexane monoterpenoids. Several diols have been prepared from geranyl acetate. The photo-oxidation leads to two hydroperoxides that can be converted into the diol acetates (40)and (41) and thence to the corresponding di01.s.~~

In order to obtain the diol (42), occurring on the hairpencils of the butterfly Danaus chrysippus (African monarch), Meinwald et al. reduced in two stages the aldehyde (43),which arises from the selenium oxide oxidation of geranyl acetate ; the overall yield was, however, only 16%. They also made the cis-isomer corresponding to (42).” When Katzenellenbogen and Corey expected to obtain the tetrahydropyranyl ether (44) of this diol by reaction of the iodide (45) with dimethylcopper lithium, they observed only 30 % yield, the remainder consisting of a cyclized compound (46) and two compounds (47) and (48),where addition had occurred to the normally unreactive pyranyl ether.96 Further examples of

(431

(42) R = H

(44) R =

0

’’ J . Kulesza, J . Gora, K . Kowalska, Z. Dogielska, and M. Druri, Przem. Chem., 1971, 50, 571 (Chem. Abs., 1972,76, 14722).

93

S . Fujita, Y . Kimura, R . Suemitsu, and Y . Fujita, Nippon Kuguku Zasshi, 1971, 92, 175.

94

95

P. J . Dunphy, Chem. and Ind., 1972, 731. J . Meinwald, W . R. Thompson;T. Eisner, and D . F. Owen, Tetrahedron Letters, 1971, 3485.

96

J . A . Katzenellenbogen and E. J . Corey, J . O r g . Chem., 1972, 37, 1441.

Terpenoids and Steroids

18

the use in synthesis of the ozonolysis product from geranyl acetate, including its decarbonylation [to (49; R = Me)] have been given,97and it has been suggested that a better method for preparing this compound (49; R = CH,CHO) is to treat geranyl acetate with an equimolecular amount of periodic acid in aqueous butanol with a catalytic amount of potassium ~ e r m a n g a n a t e . ~ ~

A~OCH,

R

(49)

1

M e Cu L i

The addition of two carbon atoms to geraniol via the dihydro-oxazine (50) does not work well at the hydrolysis stage; the aldehyde (51) is unstable except when cold and in an inert atmosphere. and cyclization is a side reaction.99 The allylic cross-coupling between geranyl bromide (or neryl bromide) and geranyl, allyl, or crotyl mesitoates using lithium in tetrahydrofuran can lead to two isomers, joined either tail-to-tail (52) or in the 'artemisia' fashion (53). Whereas geranyl-geranyl, neryl-neryl, or crotyl-geranyl coupling gives both isomers (90", in the case of the monoterpenes but only 19"; in the crotyl-geranyl case), coupling between allyl and geranyl gives only the tail-to-tail product (52).'0°

'-P. A . Gritco. J . C . S . Cheni. Conirii., 1972, 486.

'' loo

L. Canonica, B. Rindone, E. Santaniello, and C. Scoiastico, Tetrahedron, 1972, 28, 4395. This paper also describes some of the compounds related to geranyl acetate 6,7-epoxide. T. Kato, H . Maeda, M. Tsunakawa, and Y . Kitahara, Bull. Cliem. Soc. Japan, 1971,44, 3437. J . A . Katzenellenbogen and R . S . Lenox. Tetrahedron Letters, 1972, 1471.

Monoterpenoids

19

+

-b

R3 R4

R' geranyl; R' = R3 = Me R2 = R4 = CH2CH2CH=CMe2

R2

(53)

Reduced 2,6-dimethyloctane terpenoids are often made by reduction of the terpenoids just discussed, but catalytic reduction of citral to citronella1 (2) does not normally give high yields because of interfering 1,Qreduction. Now Easter et al. have found that the addition of a few per cent of water and base prevents carbonyl reduction during palladium~harcoalhydrogenation of citral.' Tetrahydrocitral has been made by the reductive carbonylation of either of the two hydrocarbons (54) and (55) (or a mixture of both) in the presence of certain cobalt catalysts.'02 The Carrol reaction has been used in the preparation of

(54) Ioi '02

(55)

W . M . Easter, jun., J . R. Dorsky, and R. F. Tavares, Ger. Offen. 2 114 21 1 . M . Tanomura, T. Nishida, T. Kawaguchi, K . Nakao, H . Nomori, T. Takagi, and K . Itoi, Ger. Offen. 2 138 833.

Terpenoids and Steroids

20

dihydrotagetone (56),allylic rearrangement of the ally1 alcohol during the transesterification step leading to the impurity (57) (see Scheme 2).'03

r + C0,Et

'+dH20H

c

0

Scheme 2

Artemisyl, Santolinyl, Lavandulyl, and Chrysanthemyl Derivatives.-Interest in the biogenetic relationships of this group continues because of their use as models for squalene biogenesis (Vol. 2, p. 13). Particularly active is the group from the University of Utah, who showed that the N-methyl-4-pyridinium salt (58) of chrysanthemyl alcohol solvolyses under mild conditions to give a 93 % yield of alcohols with the artemisyl skeleton [yomogi (59) and artemisia (60) alcohols in approximately their equilibrium amounts'04] and some chrysanthemyl alcohol (61), together with 0.5 % santolina alcohol (62).*'05 Then, by specifically labelling the starting material (58) in the a-methylene group (marked Ha in the formula), they demonstrated that the solvolysis occurs stereoselectively (Scheme 3), which they ascribe to electronic control by the vinyl substituent at C-3."' One of the problems associated with the chrysanthemyl model for squalene biogenesis was that reactions of chrysanthemyl derivatives in solution lead principally to ring-cleavage products. Now Coates and Robinson"' and the Utah group'09 lo'

B. A . McAndrew and G . Riezebos, J.C.S. Perkin I , 1972, 367. A . F. Thomas and W. Pawlak, Helv. Chim. Acta, 1971,W. 1822. ' 0 5 C. D. Poulter, S. G . Moesinger, and W . W. Epstein, Tetrahedron Letters, 1972, 67. l o b T. Sasaki and M . Ohno, Chem. Letters, 1972,503 (Chem. A h . , 1972,77.62 148). lo' C. D. Poulter, J . Amer. Chem. Soc., 1972,94, 5515. R . M. Coates and W. H. Robinson, J . Amer. Chem. SOC.,1972,94, 5920. I o 9 C. D. Poulter, 0. J . Muscio, C. J. Spillner, and R. G . Goodfellow, J . Amer. Chem. SOC., 1972,94, 592 1 . * Somewhat similar work (solvolysis of chrysanthemyl 3,s-dinitrobenzoate) has been reported by Sasaki and Ohno. I o 6

21

Monoterpenoids

MeN'

&O

J Hb I

H'

1 OH

(62) 0.5%

(59) 80%

Scheme 3 have examined the solvolysis of the cyclobutyl toluene-p-sulphonate (63), a corresponding cyclobutyl carbonium ion having been postulated as an enzymatic intermediate in the squalene route. The products from these solvolyses were mainly head-to-head linked terpenoids [(64) and its allyl-rearranged isomer] implying that the function of the enzyme may be chiefly to avoid the thermodynamically favoured ring-opening reaction. Poulter is of the opinion'09 that headto-head linked monoterpenes are the ultimate thermodynamic products of the rearrangement sequence, although none has yet been found in nature. The cyclopropylcarbinyl cation from the solvolysis of (65), the monoterpenoid model for another intermediate in the squalene biogenesis,also leads to head-to-head linked monoterpenoids.' O 9 Trost has shown that such skeletal rearrangements from chrysanthemyl to the squalene-type (head-to-head) monterpenoids are possible under normal solvolytic conditions using the artemisia model (66). Although solvolysis in aqueous acetone leads only to yomogi alcohol (59), alcoholic

Tvrpenoids and Steroids

22

p-NB = p-nitrobenzoyl

(65) solvolysis gives compounds (59--62), with, in addition, the head-to-head linked type (64)' l o Crombie's group has also discussed the biogenesis of these monoterpenoids, giving examples of the various possibilities of the scission of the chrysanthemyl skeleton to the other skeletons. including the synthesis of the dehydrolavandulol (67) from a cis-chrysanthemic diol (68). They report some feeding experiments with ''C-labelled chrysanthemate, but incorporation into artemisia ketone was very low.' ' The synthesis of a cyclopropyl terpenoid once discussed by Robinson as a possible biogenetic intermediate to artemisia ketone has been accomplished from nerol oxide; it is discussed in the section on pyranoid monoterpenoids (below).

'

&SMe2 (66)

Poulter et al. have shown that the absolute configuration of natural santolinyl alcohol (62) is S, the same as that of natural methyl chrysanthemate ( R , because of the change in priorities), by ring-opening dihydrochrysanthemyl alcohol (69) I In ' I 1

B. M . Trost, P. Conway, and J . Stanton, Chern. Comm., 1971, 1639. L. Cromb'e, P. A. Firth, R . P. Houghton, D. A . Whiting, and D. K . Woods, J . C . S . Perkin I , 1972, 642.

Monoterpenoids

23

with perchloric acid in aqueous dioxan, giving a dihydrosantolinyl alcohol, which was then converted into the fully hydrogenated alcohol (70), identical with that obtained from natural santolinyl alcohol (62).' l 2 A novel synthesis of the lavandulyl skeleton depends on the hydrolysis of the spiro-compound (71), obtainable by a carbene addition on the allene (72). The resulting alcohol is converted into the bromide (73) from which isolavandulyl acetate (74) can be obtained.Il3 Ally1 rearrangement of the bromide (73) during acetolysis and subsequent formation of the hydrocarbon (75), also mentioned in this paper, has been previously observed (cf. ref. 114). Photochemical sensitized oxygenation of lavandulyl acetate (76)is described ;it yields the expected products (77) and (78).'15

w+L+ +-A..-&

CH2Br

CH,OAc

(75)

(74)

(731

+

( )-Car-4-ene derivatives (79) are readily available from car-3-ene, and their ozonolysis leads to ( + )-cis-homocaronic acid dimethyl ester (80), easily convertible into (+)-trans-chrysanthemic acid.' l 6 Purification of mixtures of cis- and trans-chrysanthemic acid by lactonization of the cis-acid with a Lewis acid is reported,' l 7 as is an improved method for resolving the ( f)-trans-acid using L-lysine.' A reinvestigation of the synthesis of pyrethric acid isomers has been carried out.'" Two studies of the metabolism of the insecticidal esters of ' I 2

'I3 'I4

'

l6

I'

l9

C. D. Poulter, R . J . Goodfellow, and W. W. Epstein, Tetrahedron Letters, 1972, 71. R. Maurin and M. Bertrand, Bull. SOC.rhim. France, 1972, 2356. K . Takabe, T. Katagiri, and J . Tanaka, Nippon Kagaku Zasshi, 1969, 90, 943. J . C. Belsten, A . F. Bramwell, J . W. Burrell, and D. M . Michalkiewicz, Tetrahedron, 1972, 28, 3439. W. Cocker, H. St.J. Lauder, and P. V. R. Shannon, J.C.S., Chem. Comm., 1972,684. M . Matsui and K . Ueda, Ger. Offen. 2 013 222 (Chem. Abs., 1971,75, I18 029). M. Matsui and F. Horiuchi, Agric. and Biof. Chem. (Japan), 1971, 35, 1984. T . Sugiyama, A. Kobayashi, and K . Yamashita, Agric. and Biol. Chem. (Japan), 1972, 36, 565.

24

Terpenoids und Steroids

(79) R

=

CH20Ac or COMe

1

( + )-trans-chrysanthemic acid

chrysanthemic acid [ e g . pyrethrin I (82) and allethrin (82)]have shown that both in rats' 2o and in houseflies"' one route involves oxidation at the terminal carbon atom of the isopropylidenegroup. In one case' ? ' the metabolites were synthesized and found to be less toxic to houseflies, supporting this as a detoxication process. The other paper mentions a hydrolytic pathway for metabolism, and also describes a convenient method for preparing tritium-labelled ( + )-pyrethrolone and ( +)-allethrolone.' ** A problem in the commercial use of pyrethrins is their

(82) R =

Ht.$.4 0

rapid decomposition, one route being photochemical, and further studies on the photochemistry of chrysanthemic acid and its esters are reported.' 2 2 This instability of pyrethroids in air and U.V.light of wavelength 290-320 nm can be avoided for at least 4 h by combining an antioxidant and a U.V. screening agent in the insecticide f o r r n u l a t i ~ n . ' ~ ~ 4 Monocyclic Monoterpenoids

Cyciobutanes.-Two syntheses of grandisol (83) have been published. In the first of these124the cyclobutane ring is formed by a photochemical reaction beM . Elliott and J . E. Casida, J . Agric. Food Chem., 1972. 20, 295; J . E. Casida, E. C. Kimmel, M . Elliott, and N. F. Janes, Pyrethrum Post, 1971, 11, 58. A . Kobayashi, K. Yamashita, K . Ohshima, and I . Yamamoto, Agric. and Biol. Chem. (Japan), 1971,35, 1961. M . J . Bullivant and G . Pattenden, P.vrethrum Post, 1971, 11, 7 2 ; see also Vol. 1 , p. 14, Vol. 2, p. 15 of these Reports. R . P. Miskus and T. L. Andrews, J . Agric. Food Chem., 1972, 20, 313. J . H. Tumlinson, R . C. Gueldner, D. D. Hardee, A. C. Thompson, P. A. Hedin, and J . P. Minyard, J . Or g . Chem., 1971, 36, 2616.

lZ0

12'

I*'

25

Monoterpenoids

tween isoprene and but- 1-en-3-one (Scheme 4), followed by conventional reactions with the isomer mixture, and separation at the end. The second synthesis has appeared both as a paper'25 and, with a different author, as a patent;'26 the cyclobutane is formed by irradiation of a benzene solution of the dihydropyrone (84)in the presence of ethylene, leading to only the cis-ring-fused lactone (85), so that the diol (86) in this case is also mostly cis (actually it contained 12-15% trans). The remainder of the synthesis is shown in Scheme 4.

I

0

4H::;H20Ac

1

+

T H 2 0 A C

@

2:l (from cis-isomer)

4:::;";"" H (83) Reagents: i, hv; ii, MeMgI; iii, B,H,, then H,O,; iv, MeLi; v, Ac,O; vi, POC1,-pyridine.

Scheme 4

'

l5

12'

R. C. Gueldner, A. C. Thompson, and P. A. Hedin, J . Org. Chem., 1972,37, 1854. J . B . Siddall, Ger. Offen. 2 05641 1 (Chern. Abs., 1971, 75, 328).

Terpenoids and Steroids

26 Cyclopentanes, including 1ridoids.-The

long-known campholenyl skeleton (87) (a non ’head-to-tail’ isoprenoid) has been identified in the oil of Juniperus comm ~ n i s . ’ ~ ’ Whereas the nitrile of cr-campholenic acid (87a; R = CN) reacts normally with Grignard reagents, P-campholenonitrile (87b ; R = CN) dimerizes, and the P-campholenones (87b; R = CO-alkyl) must be made by heating the r-series (87a; R = CO-afkyl) in hydrochloric acid.’28

eH2R &CH2.

(87a) R

=

CHO, CH,OH, CH20Ac,or CO,H

(87b)

In a discussion of botanical distribution, Bate-Smith suggests that the name ‘iridoid’ is unfortunate (which it possibly is from a botanical point of view) and suggests, following Hegnauer, the name ‘aucubinoid’ (which would mean little to an organic chemist, who might even question whether ‘asperuloside and aucubin are the best known members‘!).’29 ‘Aucubinartig’is, in fact, used by Hegnauer not as a general term for iridoids, but for the sub-group of iridoids comprising only g l u c ~ s i d e s . ’Hegnauer ~~ has shown admirably how these fit into the taxonomic pattern of plants,130 but uses a deplorable numbering system from Sevenet et a/.‘ 3 1 The odoriferous glands of the beetle Sraphylinus oleus (Coleoptera : staphywith which linidae) produce iridodial (88),but without 6-methylhept-5-en-2-one, it is associated in ants. 1 3 2 5,9-Dehydronepetalactone (89) has been identified in Nepeta cataria.’ 33 Newly reported iridoids include the first chlorine-containing iridoid, linarioside (90),isolated from Linaria japonica.’34 In addition to the usual spectral methods of identification, it was converted’ 34 into antirrhinoAntirrhinoside (91) is converted by side (91), a constituent of Linaria ~ulgaris.’~~

’” I”

”” I ”

13? ‘.I3

’

A . F. Thomas, H e l t . Chini. .4ctu. 1972. 55, 815. G . Pirisino and F. Sparatore, Ann. Chim.(ff&), 1972, 62, 113. E. C. Bate-Smith, Nature, 1972, 236, 353. R . Hegnauer, Naturwiss., 1971, 58, 585. T. Sevenet, C . Thal, and P. Potier, Teirahedron, 1971, 27, 663. This paper was inadvertently omitted from Vol. 2. S. A. Abou-Donia, L. J . Fish, and G . Pattenden, Tetrahedron Letters, 1971, 4037. S. D. Sastry, W . R . Springstube, and G . R . Waller, Phyrochemistry, 1972, 1 1 , 453. I . Kitigawa, T. Tani, K . Akita, and I . Yosioka, Tetrahedron Letters, 1972,419. 0. Sticher, Phyrmhemistrj~,197 1 . 10. 1974.

27

Monoterpenoids

HO

eo

H 0-GI11

Glu = fl-glucoside

OHOH

(90)

OHOH

HO--&o

H

HO

'

H Q-Glu

0-Glu

qo oHOH

H

0-Glu

alkaline hydrolysis into hydroxyharpagide (92), which is not identical, as previously believed, with procumbide (93), isolated from Harpagophytum procurnbens. 3 6 A new glucoside, kutkoside (94),is reported in Picrorhiza kurrooa, which yields 'kutkin', a stable mixed crystal of kutkoside and the known picroside-1 ( 9 9 , both components of which are derived from catapol (96).13' The double iridoid cantleyoside (97) has been isolated from Canrleya corniculata (IcaciTwo monoterpenoids are reported from Nauclea diderriclzii, and naceae).

'

''

e0

R'OH,C

HO

H CozMe

0

OH

(94) R' = vanilloyl, R2 = H ( 9 5 ) R ' = H, R 2 = cinnamoyl

(96) R' = R2 = H

'" 13'

A . Bianco, P. Esposito, M . Guiso, and M . L. Scarpati, Gazzefta, 1971, 101, 764. B . Singh and R . P. Rastog, lndiun J . Chem., 1972, 10, 29.

28

Terpenoids and Steroids

0-g1u

named naucleol and naucledal. The structures [(98)and (99)]are tentative, and as (39) was impure this work must be regarded as speculative.'38 The year has seen a strengthening of the biogenetic links between the regular iridoids and the seco-compounds. Feeding experiments on Gentiana asclepiuda have shown that the new iridoid gentioside (100) is a precursor of gentiopicroside ( 101).139 Inouye's group have shown that tritium-labelled loganin (102; R' = 3H, R 2 = O H ) is transformed by Genfiuna tliumbergii into morronoside (103; R' = 3H) and that secologanin (104; R' = H) labelled with I4C is converted by Cornus o$cinalis also into morronoside (103; R' = H) with retention of the ~~ label.140 Jasminin (105), the bitter principle of Jasminium p r i r n u l i n ~ m 'was shown to be formed from deoxyloganic acid (102; R' = R2 = H ; acid) via secologanin (104; R' = H), oleuropein (106) following a similar biogenesis (Scheme 5). The seco-iridoid kingiside (107) can also be incorporated by the same plant into this ~equence.'~'From the Chinese drug 'nuzhenide' (Ligustrum Iucidunz and L. japonicurn) a bitter glucoside ester of secologanoside (i.e. containing two glucose units) has been isolated, together with oleuropein (106);'43 this new ester will clearly fit into the same biogenetic scheme (Scheme 5). The postulated intermediate in these (and similar) routes to the seco-compounds is secologanin, and this has now been isolated as secologanic acid (108) from Vinca rosea, which contains another acid, secologanoside ( 109).'44

'" 14' I" 142 14' 144

S. McLean and D. G . Murray, Cunud. J . Chem., 1972,50, 1496. S. Popov and N . Marekov, Phytochemistry, 1971, 10, 3077. H . Inouye, S. Ueda, and Y . Takeda, Tetrahedron Letters, 1971, 4069. T. Kamikawa, K. Inoue, T. Kubota, and M. C. Woods, Tetruhedron, 1970,26,4561 H . Inouye, S. Ueda, K . Inoue, and Y . Takeda, Tetrahedron Letters, 1971, 4073. H . Inouye and T. Nishioka, Tetrahedron, 1972,28, 4231. R . Guranaccia and C. J . Coscia, J . Amer. Chem. SOC.,1971,93, 6320.

29

Monotcrpenoids

R:qo 0-GI u

0-Glu

Scheme 5 HO..

0yyyoMe 0-Glu

;E0 Hoz; 0

0

0-Glu

0-g1u

Using a simplified version of his original method, Horeau has shown how the absolute configuration of a genipin derivative can be measured.'45 Chemical approaches to the iridane skeleton are illustrated by the total synthesis of the trio1 (110), obtained by mild alkaline hydrolysis of jasminin 14'

A . Horeau and A . Nouaille, Tetrahedron Letters, 1971, 1939.

30

Terpenoidsand Steroids

(105). The route is shown in Scheme 6 , in which the stereochemistry of the acid ( I 11) was carefully checked. 14'

+

Ho f '"

2 0,''0

+

J

I. B , H , HIO,

11.

-

(105)

A 23 %

Scheme 6 One of the plinols is a starting point in a synthesis of the five-membered-ring sesquiterpene cyclonerolidol 1 4 7 and the dehydroplinol obtained from thermal cyclization of dehydrolinalool is the starting point for another, acorane (Chapter 2, p. 118)."* The action of lead tetra-acetate on the stereoisomers of ioganin-0-methyl ether [(112), four isomers] has been found in every case to yield the same two cyclic acetals, (113) and (114), the former ~ r e d 0 m i n a t i n g . l ~ ~

E?,

H O *o

H ( 1 12) lih

OMe

Go+qo H C0,Me

C0,Me

OMe ( 1 13)

C0,Me

OMe (1 14)

Y . Asaka. T. Kamikawa, and T. Kubota, Tetrahedron Lctters, 1972, 1597. '" S. Nozoe, M . Goi, and N . Morisaki, Tetrahedron Letters, 1971, 3701. I J R P. Naegeli and R . Kaiser, Tetrahedron Letters, 1972, 2013. 1 4 9 J . J . Partridge, N. K . Chadha, S. Faber, and M . R . Uskokovic, Synrh. Cotnm., 1971, 1, 233.

Monoterpenoids

31

A classification of indole alkaloids has been made, based on the number of bonds between the tryptamine and secologanin parts of the skeleton.' 50 Another version (in Japanese) has been published'51 of the synthesis ofan actinidine isomer from citronellonitrile (Vol. 2, p. 20). A section on monoterpenoid piperidine alkaloids (iridoids) occurs in a review on natural piperidines.' 52

p-Menthanes.-General Chemistry and Hydrocarbons. A review on a-terpinene containing 123 references, only 18 of which are post-1960 (the latest 1968!) has appeared. ' The preparation of mentha-l(7),2,4(8)-triene (115) in 28 % yield by MeerweinPonndorf-Verlay reduction of piperitenone (116) is claimed,'54 but the experimental evidence is thin, and at least one fact is incorrect in this paper [the mass spectrum of isopiperitenol, the alcohol corresponding to (116)]. An earlier report of the triene (115) was equally lacking in experimental evidence for the structure.' 55' A surprising report is that catalytic hydrogenation of isolimonene [trans-mentha-2,8-diene (11711 gives mainly trans-menth-2-ene (together with a little menth-4(8)-eneand trans-p-menthane. ' The zinc-acetic acid reduction of optically active carveol (118) or its acetate leads to racemic dipentene (12), showing that the reaction passes through a symmetrical intermediate.' s 7 With

'

(115)

(116)

(117)

(118)

chloranil at 130-170 "C,limonene [optically active (12)] undergoes a complex reaction. Within an hour, the starting material has racemized, and terpinolene (119) has begun to form. In two hours, disproportionation to the menthenes and aromatic compounds has taken place, besides isomerization to the menthadienes and dimerization [mostly to the indane (12011 (Scheme 7).'58 Irradiation of limonene with a continuous-wave CO, laser gives isoprene as the main product, showing that the same symmetry rules are followed as in the thermal reaction.' 59 A note on the polymerization of vinyl-p-cymeneshas appeared.' 59a I5l

15* 153

lS4 155 156

15*

Is9

I . Kompis, M. Hesse, and H. Schmid, Lfoydia, 1971, 34, 269. Y. Butsugan, S. Yoshida, M. Muto, T. Bito, T. Matsuura, and R . Nakashima, Nippon Kagaku Zasshi, 1971, 92, 548. D. Gross, Fortschr. Chem. org. Naturstofe, 1971, 29, 1 . J . Verghese, Flavour Ind., 1972,3, 252. R. A . Jones and T. C. Webb, Tetrahedron, 1972,28,2877. R. L. Kenny and G . S. Fisher, J . Gas Chromatog., 1963, 1 , 19. I . I . Bardyshev and V. I . Lysenkov, Zhur. org. Khim., 1972, 8, 279. I . Elphimoff-Felkin and P. Sarda, Tetrahedron Letters, 1972, 725. S. Fujita, Y. Kimura, R. Suemitsu, and Y. Fujita, BuU. Chem. SOC.Japan, 1971, 44, 2841. A. Yogev, R. M. J . Loewenstein, and D. Amar, J . Amer. Chem. SOC.,1972,94, 1091. R. Lalande, J.-P. Pillion, F. Flies, and J . Roux, Compt. rend., 1972, 274, C , 2060.

Terpenoids and Steroids

32

" 1

A

(excess)

A.

+

Scheme 7 Carbene additions (of :CH,, :CCl,, and :CBr,) to various menthenes have been reported. In every case the (predictable) result follows the epoxidationtype stereochemistry. l6' Carman and Venzke have continued their examination of the action of halogens on monoterpenoids (Vol. 2, p. 23) by showing that bromine gives an unstable tetrabromide (121) with terpinolene (119), which rearranges to a more stable tetrabromide (122) in boiling ethanol. The latter does not rearrange with HBr, but reacts with sodium iodide to yield a terpinolene dibromide (123) that can be hydrobrominated (Scheme 8).161 A repetition of the known epoxidation of limonene with peroxybenzimidic acid has been published'" (see Vol. 1, p. 26). Gollnick et al. have used r-terpinene (124) to study the reaction of singlet oxygen with olefins in the presence of azide ion. The products of the photooxygenation of r-terpinene are (125), (126), and (127) in the presence of azide, and the same products are formed by electrolysis of r-terpinene (124)in methanol containing azide ion. and saturated with rriplet oxygen. Singlet oxygen is known to give ascaridole (128)with x-terpinene, and this does not react with azide, but the

'''('

C. Filliatre and A . Bonakdar, Compr. rend., 1971, 273, C,1 0 0 1 . Chem., 1971,24, 1905. R . G . Carlson, N. S . Behn, and C. Cowles, J . Org. Chem., 1971, 36, 3872; the original work is by G . Farges and A . Kergomard, Bull. Soc. chim. France, 1969,4476.

' R . M . Carman and B. N. Venzke, Austral. J .

Ih'

33

Monoterpenoids Br (119)

EtOH. boil

3 Br

Br

Br -

(121)

W

B

r

z

e

(122)

&Br/

~

Br ( 123)

Scheme 8 ethers obtained from the reaction of ascaridole (128) with triphenylphosphine" give the same products (125),(126),and (127)with azide as were obtained directly from cr-terpinene. The conclusion is that in the presence of azide ion and singlet oxygen, azide radicals are formed that can produce azide hydroperoxides which, in turn, yield the products observed with olefins (Scheme 9).163 Oxidation of

X C i i

=

OH; Y

=

N,, or vice-versa c

\

Y

tv

( 128) Reagents: i, hv-0,-sens.-NaN,; v, NaN,.

(1 28a) ii, electrolyse-0,-NaN,;

iii, hv-0,-sens.;

iv. Ph,P;

Scheme 9 K. Gollnick, D. Haisch, and G . Schade, J . Amer. Chem. Soc., 1972,94, 1747. G . 0. Pierson and 0. A. Runquist, J . Org. Chem., 1969, 34, 3654. * Gollnick et af. claim163to have spectral data in support of structure (128a). It is a pity they did not quote them since doubt as to the existence of this oxide (128a) has been expressed. 1 6 3 a lh3

34

Terpenoids and Steroids

limonene with t-butyl peroxide has been examined by reducing the products catalytical14 and analysing the menthols produced. The hydroxy-group was found only in the cyolohexane ring, lo", at C-1, 60°, at C-2, and 30°/, at C-3, with only a trace at C-4. The peroxidation of the cis- and trans-menth-7-enes was examined in the same way ;various amounts ofmenth-4-01and menth-9-01were identified.164 The oxidation of limonene with manganese(II1)acetate gives 387; of the acid (129), menth-1-ene yielding 6O*, of the acid (130) under the same conditions. No rotations were r e ~ 0 r t e d . lUnlike ~~ most oxidations of p-cymene (131), in which the isopropyl group rather than the methyl group is attacked, oxygen in acetic acid, catalysed by Co"', results in 90 O , p-isopropylbenzoic acid (132), the other 10O,, being mostly p-acetylbenzoic acid ( I 33). Prolonged oxidation in these conditions leads to p-acetoxybenzoic acid ( 134).'66

9 90 CO,H

\

/

C02H

-t

/

COMe (131)

(132)

A

+

A c 0 0 C 0 2 H ( 134)

(133)

One of the most interesting facets of a new approach to making limonene derivatives substituted in the isopropenyl group is the fact that when the anion (135) formed in the first stage of the reaction is quenched with water, optically active limonene is recovered. The reagent is the complex from butyl-lithium and tetramethylethylenediamine. The anion (135) can be converted inter alia into alkyl-substituted limonenes (with alkyl halides), the acid (136; R = C0,H) with carbon dioxide, and mentha-1,8-dien-lO-o1 (136; R = OH) with oxygen followed by r e d ~ c t i 0 n . l ~The ' reaction has already found use in the addition of ethylene oxide to the anion prepared from a (protected)dihydrocarvone.' 6 8

'"

C. Fitliatre, F. Pisciotti, and R . Lalande, Bull. Soc. chim. France, 197 I , 3961. M . Okano, Chetn. andInd.. 1972, 423. Ibh A . Onopchenko, J . G . D. Schulz, and R . Seekircher, J . O r g . Chem., 1972,37, 1414. ib' R . J . Crawford, W . F . Erman, and C. D. Broaddus, J . Amer. Chem. Soc., 1972, 94, 4298 ; W . F. Erman and C. D. Broaddus, U.S. P. 3 658 925. I h s G . L. Hodgson, D . F. MacSweeney, and T. Money, Trtruhedron Letters, 1972, 3683.

Mono twpeno ids

35 \ /

Li+

(136) ( 1 37) (135) Oxymercuration [Hg(OAc), in aqueous tetrahydrofuran] and demercuration (NaBH,) of limonene give 70 "/, wterpineol(l37). 69 The cyclic hydroboration of ( +)-limonene with 1,1,2-trimethylpropylboranegives the cyclic boranes (1 38a) and (138b). Oxidation of the reaction mixture gives a mixture of the cis- and trans-diols (139a) and (1 39b), but oxidation of the distilled product yields only the cis-diol ( 1 39a).' 7 0 The stereochemistry at C-8 was not mentioned in this paper, nor in the accompanying one' 7 1 concerning hydroboration with diborane, but it seems unlikely that it would be as specific at this carbon atom as is implied ( ~ f . ref. 172). Using the same cyclic boranes (138a) and (138b), Pelter et al. made the bicyclo[3,3,l]nonanones (140a) and (140b), but here the isomerism referred to concerned only the other methyl group (Scheme lo).' 7 3

10

c

( 1 38a)

/

+

[OH2C

(1 38b)

Ho.Q

M : h M e 'H

+ r

e

h

M -l-

HOH,C ( 1 40a)

(139a)

( 140b)

( 1 39b)

Reagents: i, HzO,; ii, NaCN, then (CF,CO),O, then oxidize.

Scheme 10 IhY

H . C. Brown, P. J. Geoghegan, jun., G. J . Lynch, and J . T. Kurek. J . Org. C h t n . , 1972,37, 1941.

I 7 O

173

H . C. Brown, E. Negishi, and P. L. Burke, J . Atner. Chetn. Soc., 1972,94, 3561. H. C. Brown, E. Negishi, and P. L. Burke, J . Attier. Chern. Soc., 1972, 94, 3 5 6 1 . G. Ohloff, W. Giersch, K. H . Schulte-Elte, and E. sz. Kovats, Helc. Chirn. 1969, 52, 153 1 ; see also Vol. 1, p. 29 of these Reports. A . Pelter, M . G . Hutchings, and K. Smith, Chem. Catnm., 1971, 1048.

Acfa,

36

Terpenoids and Steroids

The Diels-Alder reactions of r-terpinene with acrolein' 7 4 and with methyl acrylate' ' 5 have been examined ; the presence of aluminium chloride in the latter case alters the stereochemistry of the products considerably. Of the four products formed ( 1 4 1 a 4 ) ,the endo (141c 141d) : e m (141a 141b) ratio is 71 : 29 for the thermal reaction, but 96 : 4 for the catalysed r e a c t i ~ n . ' ' ~

+

+

&O ; 2Me

(141a)

&H

(141b)

C02Me

&H C0,Me

(14lc)

(I4ld)

Iodine azide adds to the double bonds of menth-1-sne and limonene. Reduction of the menth-1-ene adduct leads to the aziridine (142) from which the aminated menth-2-ene (143)is accessible by acylation. An alternative substitution (144) NHCOMe LiAIH,

Ac,O

kH:CO

*,NHCOMe

A '-' I-'

A

Y . Matsubara. T. Kishimoto, and W . Minematsu, Nippon Kagaku Zasshi, 1971, 92, 874. Y . Matsubara, W . Minematsu, and T. Kishimoto, Nippon Kagaku Zasshi, 1971, 92, 437. 2097.

Monoterpenoids

37

is achieved by pyrolysis of the acylaziridine. 7 6 The oxymercuration of transmenth-2-ene (145)occurs in both directions, but stereospecifically,so that borohydride reduction of the mercury compounds leads to neocarvomenthoI(l46) and neomenthol (147).'77

Oxygenated p-Menthanes. The conformations of dihydrocarvone (148), the diastereoisomeric pairs of the corresponding I-hydroxy-compound, and some related substances have been studied by temperature-dependent c.d.' 7 8 The conformations of the various stereoisomers (149) of the reduction products of carvotanacetone epoxide, as well as some of the corresponding alcohols from carvone epoxide (150) have been examined through their 'H n.m.r. spectra.' 7 9

A rapid method for resolving ( f)-carvone through the derivative (151) has been described.'*' Reaction of carvone with ally1 Grignard reagents leads to the expected products (152), and these can be aromatized with toluene-p-sulphonic acid to (153) and (154).'" An improved method for the preparation of carvone 1,3,8-tribromide [(155); see Vol. 1, p. 311 consists in treating the dibromide (156), obtained by Wallach from dihydrocarvone (148),with phenyltrimethylammonium tribromide in tetrahydrofuran. l S 2 17'

'" '78 '19

Is"

IS2

B. Bochwic, J . KapuScinski, and B. Olejniczak, Rocznikz Chem., 1971, 45, 869. I. I. Bardyshev and V. I . Lysenkov, Vestsi Akad. Nacuk Belarus. S . S . R . , Ser. khim. Navuk, 1972, 8 2 (Chem. A h . , 1972, 77, 34 713). T . Suga and S . Watanabe, Bull. Chem. SOC.Japan, 1972,45, 570. V . R. Tadwalkar, M. Narayanaswamy, and A . S . Rao, Indian J . Chem., 1971,9, 1223. H. Kaehler, F. Nerdel, G . Engemann, and K. Schwerin, Annalen, 1972, 757, 15. N . Boccara and P. Maitte, Bull. SOC.chim. France, 1972, 1463. A . Collet, M.-J. Brienne, and J . Jacques, Bull. SOC.chim. France, 1972, 336.

38

Terpenoids and Steroids

TsOH

+

___)

\ /

/

( 152)

(153) R = H : 55"10 R = Me; 8 5 " ,

(148)

_*

( 1 54)

35 (;< 15 0,;

0 3" +

Br

+

The previously unknown ( )-( lS,2S,4R)-isodihydrocarveol (157) has been made from ( + )-limonene epoxide (158) as a component of a mixture of isomers, ~ ~with the stoicheiometric amount of either with lithium in e t h ~ l a m i n e 'or lithium aluminium hydride.I8" Dihydrocarveol ( 159) has been synthesized from 4-acetyl- 1-methylcyclohexene by conventional means."' A method that is said to convert allyl alcohols into the corresponding chlorides without allyl rearrangement has been applied to carveol. The chloride was indeed obtained, but since the rotations of the compounds were not recorded it is unfortunately impossible to draw any conclusions about rearrangement.' 3 6 An ingenious synthesis of pure stereoisomers of carvomenthone-9-carboxylic acids involves a [2 23type cycloaddition of an ynamine to 2-methylcyclohex-5-enone(160). This leads

+

In'

'" In'

Z. Chabudzinski, D . qdzik-Hibner, and U . Lipnicka, Roczniki Chem., 1971,45, 1783. J . Kuduk-Jaworska, Diss. Pharnz. Pharniacol., 1972, 24, 51. 0. P. Vig, A . K . Sharma, J . Chander, and B . Ram, J . fndian Chem. Soc., 1972,49, 159. E. W . Collington and A . 1. Meyers, J . Org. Chcm., 1971, 36, 3044.

Monoterpeno ids

39

to the cis-substituted bicyclo[4,2,0]octenone(161),which is converted in neutral or basic solution into the isomer (162).'" These substances (161)and (162)when treated with 10% hydrochloric acid for one hour yield the pure isomer (163a). Two isomers (163a) and (163b) are formed with 60% acetic acid, whereas dry hydrogen chloride followed by concentrated sodium carbonate solution and then acetic acid yields the other two isomers (163c)and (163d), 10 % hydrochloric acid converting (163c)completely into (163d).lsg This simple route (Scheme 11)makes many 9-substituted menthanes available in principle, but they will be racemates, unlike the compounds available through Erman's route (above).16'

I ' o

0

H

1'

( 163a)

H (163b) Reagents: i, HOAc; ii, HCl-H,O; i i i , dry HCl, then Na,CO,

Scheme 11 The full paper about the cycloaddition of olefins to carvenone (164) has appeared. Although these additions always occur predominantly in a cis manner, '13'

J . Ficini and A . M . Touzin, Tetrahedron Letters, 1972, 2093. J . Ficini and A . M . Touzin, Tetrahedron Letters, 1972, 2097.

40

Terpenoids and Steroids

ethyl vinyl ether and 1,l-dimethoxyethylene give some trans-isomer [e.g. (165)], into which the cis-isomer is converted by passage over a 1 ~ r n i n a . lThe ~ ~ stereochemistry of the Diels-Alder reaction between (+ )- and ( - )-carvone enol acetate and maleic anhydride has been discussed.’ 89a

P

<

OEt (165)

7:l

Menthylethylamine, prepared by the reaction of menthone with cyanoacetic ester followed by reduction of the nitrile obtained by hydrolysis and decarboxylation, is reported to have anti-inflammatory activity.’ 90 A study of the conditions required for formation of the various isomers of (166),obtained by chlorination of menthone with chlorine or sulphuryl chloride, has been published. (Bromine gives only the trans-2,4-dibrornide.” ’) Hydroboration of the pyrrolidine enamines of isomenthone (167),followed by pyrolysis of the corresponding N-oxide, yields a mixture of trans-carvenol (168) and isocarvomenthone (169)from one of the enamines, and menth-2-ene from the other (Scheme 12).19’ The use of hydroxymethylene menthone (170) was mentioned earlier (cf. Voi. 2, p. 28), and part of the work described has been repeated.’93 This compound (170) and the Mannich base derived from menthone (171) have been used to prepare some heterocyclic compounds related to menthone (Scheme 12)’ 94 Somewhat similar is the reaction of piperitenone (172) with ammonia, leading

’” I800

’”’ ‘‘I

Iy2

’”

P. Singh. J . Org. Chenr., 1971,36, 3334. S. Geribaldi, G . Torri, and M. Azzaro, Cotnpt. rend., 1972, 274, C. 2121. P. Schenone, E. Mariani, and G . Bignardi, Farmaco, Edn. sci., 1972, 27, 322. F. Yasuhara, M. Arai, and M . Yamaguchi, Nippon Kagaku Zasshi, 1971,92, 1189. J.-J. Barieux and J . Gore, Bull. SOC.chim. France, 1971, 3978. Y. Tanaka, R . Tanaka, H . Uda, and A. Yoshikoshi, J . C . S . Pvrkin I , 1972, 1721. It is not suggested that the whole o f this paper is duplication: see, for example, under caranone (below). K . H . Spohn and E. Breitmaier, Chitilia ( S w i f z . ) , 1971, 25, 365.

Monoterpeno ids

41

Scheme 12 directly to the isoquinuclidine system (173) in one step. 19' Hydroxymethylene derivatives can be used to prepare higher terpenoids, and pulegone (174) was thus converted into the octalin (175),which lacks only one carbon atom of the cadinene ske1et0n.I~~ The Mannich reaction with piperitone (176) occurs with substitution ' is not in agreement with an earlier report of at the C-7 methyl g r o ~ p ; ' ~this substitution at C-4.'98 The full paper about the reaction of benzoyl chloride and sodium amylate with pulegone (174) (cf. Vol. 2, p. 30) has appeared.'99 A . Rassat and P. Rey, Tetrahedron, 1972, 28, 741. T. Matsuura and A. Horinaka, Nippon Kagaku Zasshi, 1971,92, 1199. l Y 7H. J . Roth and K. Thassler, Arch. Pharm., 1971,304, 816. 1 9 8 R. Jacquier, M. Mousseron, and S. Boyer, Bull. SOC.chirn. France, 1956, 1653. "' P. Crabbe, E. Diaz, J. Haro, G. Perez, D . Salgado, and E. Santos, J.C.S. Perkin I, lY5

1972, 46.

42

c

Terprnoids and Steroids

CHOH

0

+ RNHNH,

-+

$I?-. A

+ R1CH2COR2-+

+

HCONH,

-+

pR p

Scheme 13

Both ( +)-cis- and ( - )-rrans-pulegone epoxides (177) (readily separable by spinning band distillation200)undergo ring-expansion to the eucarvone system (178) with zinc bromide, optical activity being retained.201Epoxypulegone (177) is a case where the cis-configuration of the corresponding tosylazo-system is fixed and a normal fragmentation reaction is impossible. A suggested explanation for the recovery of pulegone in high yield when the epoxide is treated with tosylhydrazine in methylene chloride and acetic acid is shown in Scheme 14.,02 2''"

I"'

:'I2

G . L . Lange and M . Bosch, Canad. J . Chrrn., 1971,49, 3381. H . Watanabe, J . Katsuhara, and N . Yamamoto, Bull. Chem. SOC.Japan, 1971, 44, 1328. D . Felix, J . Schreiber, G . OhlofT, and A . Eschenmoser, H r l c . Chim. Actu, 1971, 54, 2896.

43

Mono t erpeno ids

1

N (174)

HN-Ts

1

Scheme 14

+ N, + TsOH

Terpenoids and Steroids

44

(174)

*

+ 0

HO'

(

-

)-s ( 186b)

( 186a)

Reagents: i,

ii. Ph,P; iii, H , O , - O H - ; iv, N , H , ; v, M n O , ; vi, T s N H N H , ; vii, H ' ;

lo2;

viii,

OH

A

H2.

Scheme 15

45

Mono terpeno ids

An unexpected difference in the product distribution after sensitized photooxygenation of pulegone (174)and cis-pulegol" (179)results from the fact that the singlet oxygen attacks preferentially at C-8 in the former case, leading to the alcoholds (180), (181),and (182) (after reduction of the hydroperoxides), 80",: of the mixture being (180). The mixture of diols [(183),(184),and (185)l obtained in the same way from cis-pulegol contains only 21 % of (183), corresponding to attack at C-8.204 Using one of the ketols (180)from the pulegone photo-oxygenation, Skorianetz et al. prepared both optical isomers of hydroxycitronellal (186a) and (186b) in order to examine the differences in odour (see Scheme 15).205 Elimination reactions of menthyl and carvomenthyl tosylates have been studied in different contexts. In aprotic polar solvents, the E l mechanism has been examined by Nojima et a/., together with the inversion (at 75 "C in dimethylformamide) of menthyl (187) to neomenthyl (147) tosylate.206 Inversion to the extent of 3-8 "/, (to neomenthol) also accompanies the elimination of menthyl tosylate on alumina, and the basicity of the alumina has a marked effect on the direction of elimination (as shown under the formulae of the products).207

Neutral Acid Basic

1.5 2 4

: : :

1 1 1

In sodium ethoxide+thanol solution, reaction of isocarvomenthol (188) and neodihydrocarveol (189) tosylates (i.e. having axial leaving groups) proceeds primarily by the E2 mechanism, and a discussion of the reaction, which is accompanied by a small amount of S,2 reaction (leadingto ethers),has been given.208 Using the separated pulegone epoxide (177) isomers, Lange and Bosch have prepared the mesylates (190),(191),and (192),to show that the group that is antiperiplanar to the leaving mesyloxy-group is always involved, dilute base yielding primarily the products (193), (194),and (195), with no 1,3-diol monosulphonate reactions because the bulky group can never be V. R. Tadwalkar and A. S. Rao, Indian J . Chem., 1971,9, 1416. K. H . Schulte-Elte, M . Gadola, and B. L. Muller, H e f v . Chim. Acta, 1971,54, 1870. 2 0 5 W. Skorianetz, H . Giger, and G . Ohloff, Helv. Chim. Acta, 1971, 54, 1797. Z n b M. Nojima, M . Yoshimura, and N. Tokura, Bull. Chem. SOC.Japan, 1972,45,285. 2 0 7 G . H . Posner, R . J . Johnson, and M. J. Whelan, J.C.S. Chem. Comm., 1972, 281. 2 0 8 J. Kuduk-Jaworska, Diss. Pharm. Pharmacol., 1971,23,495; see also 2. Chabudzinski and J. Kuduk, Roczniki Chem., 1965,39, 1037. * In this connection, it is interesting that cis-pulegol is reported to exist predominantly in the conformation with both methyl and hydroxy-groups *03 204

Terpenoids and Steroids

46

1

0 (193)

1

1

/t\ OH

OH

The evodone synthesis reported in Vol. 2, p. 33, has been published again.2o9 Menthenolides have been synthesized by Tadwalkar and Rao. cis-Isopulegol acetate gives the lactone (196),and by the same route cis-pulegol (179) was converted into ( 197).203 Menthyl and thymol esters of some simple amino-acids have been made.210 Bohlmann and Zdero have reported yet more naturally occurring thymol esters, this time from Arnica amplexicaulis.2' The photo-Fries reaction of the nicotinic ester of thymol(198)gives two rearranged products (199)and (200), together with recovered thymol, but only one(201)is obtained from carvacryl nicotinate (202).2l 2 By oxymercuration of isocryptone (203) (with the carbonyl group ketalized), followed by a Wittig reaction on the resulting ketol, Vig et a / . have made menth.""

'I

'

' l 2

A . Moiseenkov, F. A . Lakhvich, and A . A . Akhrern, Akrual. Probl. Izuch. EfirnomasIrch. Rast. Efirn. Adasel, 1970, 159 ( C h e m . A b s . , 1972,76, 99 847). E. G . Titkova and S. A. Kozhin, Zhur. obshchei Khim., 1972, 42, 1175. F. Bohlmann and C. Zdero, Tetrahedron Letters, 1972, 2827. M . T. Le Goff and R. Beugelmans, Bull. SOC.chim. France, 1972, 1 1 15.

Mono terpenoids

47

0

ACHO

ACO,H

1(7)-en-4-01(204), a known, but not naturally occurring s ~ b s t a n c e . ~ 'Microbiological conversion (using Pseudornonas pseudornallei) of a-terpineol (205) into 8,9-epoxy-p-menthan-l-o1 (206) is r e p ~ r t e dl4. ~

nic = -CO

213 214

a

0. P. Vig, M . S. Bhatia, 0. P. Chugh, and K. L. Matta, Indian J . Chem., 1971, 9, 899. T. Hayashi, S. Uedono, and C. Tatsumi, Agric. and Biol. Chem. (Japan), 1972,36,690.

48

Terpenoids and Steroids

It was known that ( - )-P-pinene reacts with iodine to give aromatic products, but now Barton’s group has found that in controlled conditions (e.g.benzene at room temperature for five minutes), an unstable di-iodide (207) is formed, which liberates iodine on standing but which can be converted into a number of other monoterpenoids, e.g. limonene (with lithium aluminium hydride) or a mixture of ( - )-perilla aldehyde (208) and its isomer (209) (with sodium hydrogen carbonate in dimethyl sulphoxide). In ether or glyme the monoiodide (210) predominates in the mixture, and in ethylene oxide the compound (21 1) is formed. This compound (21 l)can,ofcourse, also be converted into an aldehyde using the Kornblum conditions as in the preparation of (208).”’” Ring-opening of a suitable pinene

8

s?

CHO

CHO

NaHCO, DMSO

H‘

I

(207)

alcohol with zinc-copper couple at 20@“C has also been used to prepare homoperilla alcohol (212) and the corresponding aldehyde and esters.Z1b Further examples of pinene ring-opening reactions are discussed in the section on bicyclo[3,1,l]heptanes. li5 lh

D. H . R . Barton, I. A. Blair, and P. D. Magnus, J.C.S. P e r k i n l , 1972, 614. Y . Matsubara, W. Minematsu, and S. Ikeda, Yuki Gosei Kagaku Kyokai Shi,1971, 29, 877 (Chem. Ahs , 1972,76,388).

49

Monoterpenoids

The preparation of a menthene-substituted butenolide (213) via a Wittig reaction of menth-l-en-9-a1(214) with a phosphorane (215)is described briefly.217

s

+

A new synthesis of racemic oleuropeic acid (216)starts with the known DielsAlder reaction between methyl vinyl ketone and chloroprene, yielding the chloroketone (217). The acid function is introduced by exchanging the chlorine atom for lithium, followed by conversion into the aldehyde with dimethylformamide, and the additional methyl group is put in with a Grignard reaction (Scheme 16).2'8

c1

CHO

OH

OH (2 16)

Reagents: i, HOCH,CH,OH-H'; vii, Ag,O.

ii, Li; iii, DMF; iv, H , O + ; v, HC(OEt),; vi, MeMgI;

Scheme 16 For the first time from a plant source, the cis-diol (218)has been isolated from the aerial parts of Eupatoriurn rnacrocephalurn. The structure was confirmed by A series of comparison of the n.m.r. spectrum with all the known

A (218) 217 218

219

J. E. T. Corrie, TefruhedronLerfers, 1971, 4873. A. A . Drabkina, 0. V . Efimova, and Yu. S. Tsizin, Zhur. obshchei Khim., 1972, 42, 1139. A . G . Gontalez, J . Bermejo Barrera, J . L. Bermejo Barrera., and G. M . Massanet, A n d e s de Quirn., 1972,68, 319.

50

Terpenoids and Steroids

menthane polyols has been made by Cocker et a1.,220starting from sobrerol(219) (for which analeptic and expectorant properties have recently been claimed22') and pinol(220). This work should be read in conjunction with a paper222quoted last year. Some of the key steps are shown in Scheme 17.

0.

OH

A

+

OH

OH

OH

1"

1"

unstable

HO. . q o H O H

H 0'

A Br

i l

Reagents: i , peroxysuccinic acid: ii, H , O ; iii, perbenzoic acid; iv, H , O ; v. HBr-HOAc; vi, base.

Scheme 17

':') W . Cocker, K . J . Crowley, and K . Srinivasan, J.C.S. Perkin I , 1972, 1971. I

_"_ '_

C. Corvi-Mora, Ger. Offen. 2 I 14 I38 J . Wolinsky, R . 0. Hutchins, and J . H . Thorstenson, Terruhedron, 1971. 27, 753.

Mono terpenoids

51

rn-Menthanes.-These substances are generally made, both by accident and design, from the caranes, hydrohalogenation of carane itself yielding a mixture of rn- and p-menthane halides, the dehydrohalogenation ofwhich has been The corresponding well-known transformation of car-3-ene into sylvestrene dihydrochloride leads to various rn-rnenthadienes including ‘sylveterpinolene’ (221) and its isomer (222).224 Some reactions of these compounds (DielsAlder,224bromination, catalytic reduction,225and isomerization in the presence of N-lithioethy1enediaminezz6)have been described. Spectral data for Wallach’s (+)-sylveterpineol (223) have been givenz2’ (although the structure was in no doubt).

(221)

(222)

(223)

Tetramethylcyc1ohexanes.-The derivatives of I , 1,2,3-tetramethylcyclohexane are associated with saffron (the dried stigmas of Crocus sativa),and a new investigation has revealed two new members of the series, some with one carbon atom less. Of those shown below, the first four were synthesized from isophorone (224), which was also found in saffron.228 Saffron is somewhat similar to Tournefortia sibirica, a perennial of the boraginaceae, which also contains safranol (225).229

OH

”’ I. I . Bardyshev, E. F. Buinova, and I . V. Prostashchik, Zhur. org. Khim., 1971,7,2307. 224 225

N.V. Muraleedharan and J. Verghese, J . Indian Chem. SOC.,1972,49,289. N.N.Balashov and I . I. Bardyshev, Ref. Zhur. Khim., Abstract No. llZh525 (Chem. A h . , 1972,77,5617).

226

227 228 229

I . I . Bardyshev, Zh. F. Loiko, R. I . Zen’ko, L. A. Popova, and B. G . Udarov, Zhur. org. Khim., 1971,7,2519. G . K. Kaimal and J. Verghese, J . Indian Chem. Soc., 1971,48,759. N.S. Zarghami and D. E.Heinz, Phytochemistry, 1971, 10,2755. Z. I. Abasova, Aktual. Probl. Izuch. EJrnomaslich. Rast. Efirn. Masel, 1970, 131 (Chem. Abs., 1972,76,158210).

Terpenoids and Steroids

52

Safranal [the aldehyde corresponding to (225)]is also found in Greek and other A related acid has been reported in celery seed oil (Apium graueolens), but this paper is pointless since the structure was not determined.231 The application of a new general synthesis of unsaturated aldehydes to ycyclocitral and thence to P-cyclocitral(226)(Scheme 18) is disappointing from the point of view of these monoterpenoids, for which a good synthesis is indeed desired. The yields on the last two steps of the route were not given, nor were the conditions of the hydrolysis of the dithian (227).232Access to the series is usually

(226) Reagents: i, 1.3-dithian; i i , BuLi.

Scheme 18

by cyclization of a geraniol derivative-geranyl acetate and benzoyl peroxide in the presence of copper salts (cf. Vol. 1, p. 36) being one method. Beckwith et a!. have suggested an alternative explanation for this cyclization, which they consider surprising, closely related species leading rather to five-membered rings.23 3 One of the problems associated with the acid cyclization of methyl geranate (228), which depends on the rate of protonation, is the number of by-products. Using liquid sulphur dioxide at - 70 "C, Kurbanov et al. have obtained the ester (229) exclusively.234The same group has shown that methyl geranate (228) can also be cyclized (like many other isoprenoids) with mercuric trifluoroacetate in nitromethane, although several isomers are formed.23

'

2Jo

2"

"' "'

B. Kimland, R. A . Appleton, A. J . Aasen, J . Roeraade, and C. R. Enzell, Phytochernisfry, 1972, 11, 309. Many related substances are in Burley tobacco ( E . Demole, personal communication). M . M . Ahujaand S. S. Nigam, Riechsrofle, Aromen, Korperppegem., 1971,21,281,284. E. Hunt and B. Lythgoe, J . C . S . Chem. Comm., 1972, 757. A. J . L. Beckwith, G. E. Gream, and D . L. Struble, Austral. J . Chem., 1972,25, 1081. M. Kurbanov, A. V . Semenovskii, V. A . Smit, and V. F. Kucherov, Kzcest. Akad. Nauk S . S . S . R . , Ser. khim., 197 I , 245 1 . M . Kurbanov, A. V . Semenovskii. W. A . Smit. L. V. Shmelov. and V. F. Kucherov, Terrahedron Lettcrs. 1972, 2 175.

Monoterpenoids

53

c.!co2Me a C02Me

1,4-Dirnethyl-l-ethylcyclohexanes.-These compounds have not yet been reported in nature, although they are known, and are even isoprenoid (although not head-to-tail coupled). The conformational analysis of one representative (230) has been discussed.236 Cycloheptanes4ne synthesis of karahanaenone (231) depends upon thermal and the conditions for rearrangement of a 2-methylene-5-vinyltetrahydrofuran, this type of reaction have been examined on a simpler model (232), which arises from the dihydrofuran (233)at 1 4 G 2 0 0 "C. The reaction to the cycloheptenone (234)occurs rapidly at active sites on a glass surface, but is arrested in tubes coated with sodium hydroxide. Higher temperatures and lower pressures give two other compounds (235) and (236). All these reactions involve the biradical (237), as does the conversion of the cyclopropane (238) into the cycloheptenone (234).237 Karahanaenone (231)has also been made by isomerization of terpinolene epoxide (239)with boron trifluoride etherate.238Eucarvone (240; R = H)should not be

R

0 II

\

1

23h 23'

238

(231) R = Me (234) R = H

(237)

T

T. Suga and S. Watanabe, Bull. Chem. Soc. Japan, 1972,45, 240. S. J. Rhoads and C. F. Brandenburg, J . Amer. Chem. SOC.,1971,93,5805; S . J. Rhoads and J . M . Watson, ibid., p. 5815. E. Klein and W. Rojahn, Dragoco Rept., 1971, 18, 159, 239.

Terpenoids and Steroids

54

regarded as a universal model for the photoisomerization of conjugated cycloh e p t a d i e n ~ n e s .Thus ~ ~ ~ the eucarvone isomer (241) is converted into the cyclopentenone (242) in trifluoroethanol ( n-+ n*). No analogous product is formed from eucarvone, but even 7-methyleucarvone (240;R = Me) leads in part to a cyclopentenone analogous to (242).

( 240 1

(241)

(242)

(243)

Reduction of eucarvone with lithium in ethylamine is said to give a mixture of the fully saturated ketone 2,6,6-trimethylcycloheptanoneand 7-dihydroeucarvone (243),but this and other described reductions are unsupported by n.m.r. data.240 Reduction of eucarvone ap-epoxide is described, with its conversion by conventional means into 1,4,4-trimethyl~ycloheptanol.~~' Eucarvone is readily enolized in trifluoroacetic acid, and reaction of the enol with tetracyanoethylene leads to the product (244); the postulated mechanism uses as its driving force the stabilization of the negative charge by the cyano-groups (Scheme 19).242

WCN

H 0

OI 2

G:

NC *cN NC

NC NC

NC'

'H CLH' CN

0

P NC

CN

( 244 1

Scheme 19

""

"'

2i2

H . Hart and A . F . Naples, J . ,4nier. Chrm. Soc., 1972,94, 3256; see also K . E. Hine and R. F . Childs. J.C.S. Cheni. Comm., 1972, 145. A . Hendrich and H . Kuczynski, Rociniki Chem., 1971, 45, 1275. Z . Chabudzinski and M . Skwarek, Roczniki Chem., 1971,45, 1907. M . Acar, A . Cornelis, and P. Laszlo. Tetrahedron Lrttrrs, 1972, 3625.

55

Monoterpenoids

An X-ray structure determination of p-thujaplicin (245) has shown that the C-1-C-2 bond is essentially single.243 Two new thujaplicin syntheses have appeared. The first (Scheme 20) depends on the presence of trimethylchlorosilane in the acyloin ring-closure in order to avoid Dieckmann condensation to the five-membered ring, and gives pure products. The scheme shows the j-thujaplicin synthesis,but choice of the appropriate ~ of p- (245) isopropylcyclohexanone leads to c(- or y - t h ~ j a p l i c i n s .A~ ~mixture

4-

&C02Et

+

Et

/

NaOH-McOH

1 1

Scheme 20 and y-thujaplicin (246) is obtained by transformation of the bicyclo[3,2,0]heptanes (247) resulting from the cycloaddition of dichioroketen to isopropylcyclopentadienes (Scheme 21).245 243 244 245

J . E. Derry and T. A. Hamor, J . C . S . Perkin I I , 1972, 694. H . D. Durst and L. Liebeskind, reported in Chem. andEng. News, 1972, April 17,25. K . Tanaka and A. Yoshikoshi, Tetrahedron, 1971, 27,4889.

56

Terpenoids and Steroids

1 H

+ c1O

+ i\c1

m C1 H

I

(247)

Scheme 21

5 Bicyclic Monoterpenoids

Bicycl~2,l,l]hexane.-This interesting terpenoid (248) has been isolated from 'Scotch spearmint' (Menthp x cardiacu), and one wonders whether it has been missed on earlier occasions in view of its isomerization to myrcene (17) and the cyclopentane (249) at temperatures above 170 "C. The authors of this work discuss the possibility of its being an artefact from myrcene (known to form it by

Monoterpenoidrs

57

irradiation), which they dismiss, but unfortunately they do not give an optical rotation, which might have settled the matter.246

U.V.

Bicycl@3,1,O]hexanes.-A good review of the literature up to August 1971 has appeared (115 reference^).^^' The acid-catalysed hydration of ( + )-sabinene (250) leads to stereospecific formation of (+ )-menth-1-en-4-01(25l), a fact used to argue against the involvement of a classical carbonium ion such as (252). Since (-)-or-thujene (253) yields the same products in different proportions, the ion (254) is also excluded.248

The reaction of sabinene with carbenes and halogenocarbenes has been described, together with the conversion of the dihalogenocyclopropane adducts to the corresponding allene and acetylene. (The reaction of camphene and P-pinene is also included in these papers.249) 1-Isopropyl-4-methylenebicyclo[3,1,O]hex-2-ene (255)can be made by dehydration of the umbellulols (256); with acid it yields p- and m-cymene, and, under solvolytic conditions, acetates of (256). The dehydration of umbellulol(256) is easier (it occurs in dimethyl sulphoxide) than that of sabinol(257) because removal of an allyiic rather than a methylene proton is involved.2s0 This paper also offers confirmation of the previous configurations assigned to the umbellulols.255'These are based on the attack of carbene in the Simmons-Smith reaction from the same side of the molecule as the hydroxygroup [to (258)l. Oxidation then gave two ketones (259a and b), one of which (259b)was already known.2s0 This confirmation is doubly interesting in that it has been contested simultaneously, primarily on the grounds of n.m.r. analysis of 15 bicyclo[3,l,0]hex-3-en-2-olsin eight pairs of isomers, and the authors suggest that lithium aluminium hydride reduction of umbellulone (260) is more likely to lead to exo-umbellulo12s2(the opposite from that proposed earlier25'). Details 246

247

248 249

250

251 25

J. W. Hogg and B. M. Lawrence, Flavour Inn., 1972, 3, 321. D. Whittaker and D. V. Banthorpe, Chem. Rev.. 1972, 7 2 , 305. This review unfortunately uses 'iso' to mean trans methyl and isopropyl groups (see Vol. 2, p. 37 of these Reports). T. Norin and L.-i(. Smedman, A c f a Chem. Scand., 1971, 25, 2010. J. Graefe, L. Quang Thanh, and M. Muhlstadt, Z . Chem., 1971,11,304; M. Muhlstadt, L. Quang Thanh, and J. Graefe, Tetrahedron, 1972, 28, 4389. R. H. Chung, G. J . Lin, J . M. Nicholson, A. Tseng, 0. Tucker, and J. W. Wheeler, J . Amer. Chem. SOC., 1972,94, 21 83. J. W. Wheeler and R. H. Chung, J. Org. Chem., 1969,34, 1149. G. Cueille and R. Fraisse-Jullien, Tetrahedron, 1972, 28. 1331 .

58

Terpenoids and Steroids

of the preparation of l-isopropyl-3-methylbicyclo[3,3,l]hexan-4-one(VoJ. 2, p. 36) have appeared.253

A

a

1

6

or

or

_*

OH

0

‘OH

A

A 1258)

A. (259a)

A (259b)

Bicycl42,2,l]heptanes.-A C compound (monoterpenoid?) ‘albene’ (26 1 ) has been isolated from plants of the genera Petasites and Adenostyles and directly correlated with ( + )-camphene (262).254 The esters tschimganin (263)and tschimgin (264), isolated from Ferula tchimganica, are those of b o r n e 0 1 . ~ ~ ~

(263) R

=

-CO -OH

(264) R = - C O O O H

”’ 2f.4

’”

A . van der Gen, L. M . van der Linde, J. G. Witteveen, and H. Boelens, Rec. Trar). chin?.,1971, 90,1045. K . Vokac, Z. Samek, V. Herout. and F. Sorm, Tetrahedron Letters, 1972, 1665. A . Sh. Kadyrov and G. K. Nikonov, Khim. prir. Soedinenii, 1972, 8, 59.

Monoterpenoids

59

The I3C n.m.r. chemical shifts for several bicyclo[2,2,l]heptanes, including camphene, fenchol, fenchone, and other oxygenated compounds, have been listed.256 An interpretation of the pseudocontact model for n.m.r. shift reagents has been carried out using borneol and isoborne01.~~'Various nitrogen-containing derivatives of camphor and epicamphor have been examined mass spe~trometrically,~~~ and loss of keten from bornyl acetate and related substances in the mass spectrometer has been shown to occur by a four-centre mechanism.259 Mass-spectrometric loss of water from borneol and isoborneol appears to occur by the same two-step mechanism, involving formation of an intermediate camphene or bornene ion.260The enthalpies for various conformations of borneols, fenchols, and isofenchols have been calculated ; for these sterically hindered molecules, the results fitted experimental values reasonably well, but the fit was not as good for less methylated homologues.26' The products of carbene addition to camphene are described.249 Rearrangements of carbonium ions derived from bicyclo[2,2,l]heptanes are still under intensive investigation. Two cations (265a and b) are obtained from either a-fenchene (266), P-fenchene (267), or cyclofenchene (268) (but not afenchol) and S0,ClF-FS03H at - 130 "C. On warming to -92 "C another change gives what the authors describe as an equilibrating pair of ions (269), which at - 15 "C rearrange to the ultimate ion of the series (270), although at 25 "C a ring-opened ion (271) is formed. Quenching experiments lead to the various fenchenesshown in Scheme 22.262 Ions of this kind are certainly involved in the complex rearrangements that the fenchenes undergo over a silica-phosphorus pentoxide catalyst, but in this case other rearrangements are involved, since, in addition to the other fenchenes, bicyclo[3,2,lloctenes, bicyclo[3,3,0]octenes, aromatic compounds, and methylhexahydroindenes are formed.263 Sorensen and Ranganayakulu have also presented 'unequivocal physical evidence' for equilibrating structures in the methylated fenchyl cations (272a and b), based on the fact that these structures are non-degenerate and are not isoenergetic, so that the averaged a and b peaks from the n.m.r. spectrum of the two have different chemical shifts, and the latter are temperature dependent.264 One might question the statement that 'addition of two further geminal methyl groups is extremely unlikely to change the basic cation' (referring to a dimethylnorbornyl 2sh

257 258

2s9 2bo 2b

*

262

263 2b4

E. Lippmaa, T. Pehk, J . Paasivirta, N. Belikova, and A . Plate, Org. Magn. Resonance, 1970,2,581; N . H . Werstiuk, R. Taillefer, R . A . Bell, and B. G. Sayer, Canad. J . Chem., 1972,50,2146. R . E. Davis and M. R. Willcott, tert., J . Amer. Chem. Soc., 1972, 94, 1744. A . Daniel and A. A. Pavia, Org. Mass Spectrometry, 1971, 5 , 1237, 1257. J . Kossanyi, B. Furth, and J . P. Morizur, Org. Mass Spectrometry, 1972,6,593. D . R. Dimmel and J . M . Seipenbusch, J . Amer. Chem. Soc., 1972,94,6211. C. Coulombeau and A. Rassat, Tetrahedron, 1972,28,2299. These authors have calculated energies of other bicyclo[2,2, llheptane alcohols and ketols by a semi-empirical method; see Tetrahedron, 1972,28, 4559. E. Huang, K. Ranganayakulu, andT. S. Sorensen, J . Amer. Chem. SOC.,1972,94,1779. Methylnorbornyl cations are treated in J . Amer. Chem. Soc., 1972,94, 1780, by the same authors. F. Petit, M . Blanchard, and J . Verguin, Bull. Soc. chim. France, 1972, 61 1 . T. S. Sorensen and K . Ranganayakulu, Tetrahedron Letters, 1972, 2447.

60

Terpenoids and Steroids

(270)

new fenchenes

Scheme 22

cation), in view of Kirmse’s work. Kirmse has found that by introducing a suitable leaving group at C-10 (+)-camphor (273) can be converted, uia the diazonium zwitterion (274), to a 3 : l mixture of camphene (262) and (+)-P-pinene (275)(Scheme 23).265In other papers266he shows that the yield of bicyclo[3,1,1]heptane rearranged material depends not only on the substituent [it reaches 91 % 265 lb6

W . Kirmse and W . Gruber, Chem. Ber., 1972,105, 2764. W . Kirmse and G. Arend, Chem. Ber., 1972, 105, 2738, 2746; W. Kirmse and R . Siegfried, ibid., p. 2754.

61

Monoterpenoids

(272a)

(272b)

of (276) from the amino-compound (277), falling to less than 6% when the substituent is acetoxy (278)],but also on the number of methyl groups attached to the norbornane skeleton. Kirmse’s work is important not only from a theoretical point of view, but also because it represents a total synthesis of the pinane skeleton, which has not many precedents. Furthermore, in the first paper,265the P-pinene

h0--

CH2 0 i ,

(273)

\ S02CI

I

SO2-NH

6

I?:::. C H 2 SO 2-

hNAhN CH,SO,I

liii

+ CH2SO,-

CH,SO,(274)

(262)

(275)

Reagents: i, N,H,; ii, h v ; iii, MeOH.

Scheme 23 (simplified) obtained is apparently optically pure, which is rarely the case with naturally occurring B-pinene! The ions discussed by Kirmse have been more frequently approached from the pinene side; a recent example is discussed in the bicyclo[3,l,l]heptane section. Carbonium ions of this nature have also been used by

62

Terprnoids and Steroids

x

+&+&-A

N2 (277) X = NH, (278) X = OAc

H,N

NH2

N;

0

(276)

Blattel and Yates’” to explain the reaction of the diazoisofenchone (279) with sulphuric acid (Scheme 24). The effect of added acetic acid was also investigated ; it yields acetates.268 The reaction of the corresponding diazocamphor (280) (the crystal structure of which has been determined269)is also shown in Scheme

-73,268

(279)

I

1T

0

+ H Scheme 24 2b7

‘“

268

R. A. Blattel and P. Yates, Tetrahedron Lerters, 1972, 1073. R. A . Blattel and P . Yates, Tetrahedron Letters, 1972, 1069. A. F . Cameron. N. J. Hair, and D. G. Morris, J.C.S. Perkin If, 1972, 1331

Monoterpmo ids

63

Reaction of several bicyclo[2,2,l]heptenes with phenyl(trichloromethy1)mercury reveals the fact that born-2-ene (281) (the synthesis of which has just appeared in Organic Syntheses2”) is completely unreactive to this substance, because steric hindrance prevents the exo-attack required by torsional train.^ The labelled bornyl--isobornyl Grignard mixture (282) undergoes cis-exo eliminative transfer to phenyl isopropyl ketone, although to a lesser extent than in the norbornyl system, this probably being a reflection of the fact that the gem-dimethyl group reduces the energy difference between exo- and endo-tran~fer.~~’

’’

MgCl 50 : 50 (282)

75 : 25 (281

The reactions of phenyliodoso dichloride and phenyliodoso chloride azide with a series of olefins including camphene (262) have been described. They react in the same way with camphene [yielding (283)],and differently from chlorine azide, which gives the isobornyl azide substituted on C-10 (284).273In connection

AN3 x

b N 3 CH2C1

+‘IN3 +‘IN3

(262)-

A PhIClX

&cH2x CI (283) X = C1 or N,

with the synthesis of zizaene sesquiterpenes (p. 124), Kido et al. have described a number of reactions with C-1-substituted camphenes. One route involved ring expansion to bicyclo[3,2,l]octane systems (Scheme 25), but this gave very poor yields of pure products. Preparation of the aldehyde (285)was achieved by oxidation of the corresponding alcohol with dicyclohexylcarbodi-imideand phosphoric acid in dimethyl ~ u l p h o x i d e . ’ ~ ~ Bornyl esters of amino-acids have been made.2l o The rate of acid-catalysed heterolysis of the carbon-oxygen bond in borneol isomers has been measured by following the oxygen exchange. Whereas camphene and J. H. Duncan, Org. Synrh., 1971,51, 66. ”’ CR.. WH .. Shapiro Jefford, D. T. Hill, J. Gore, and B . Waegell, Hefv. Chim.Acta, 1972,55, 790. ’’’ J. D . Morrison and G. Lambert,J. Org. Chem., 1972,37, 1034. 270

273 274

E. Zbiral and J. Ehrenfreund, Tetrahedron, 1971, 27, 4125. F. Kido, H . Uda, and A . Yoshikoshi, J . C . S . Perkin I , 1972, 1755.

Terpenoidsand Steroids

64

(285) R = CHO or C0,Me

Br

1 l e 0 ,&oBul C Scheme 25

hydrate (286) exchanges 38 times faster than it racemizes, methyicamphenilol (287) heterolysis occurs 1.3 x lo3 times slower. Isoborneol racemizes and The exchanges at the same rate, which is 2.3 times faster than that for borne01.~’~ full paper on the novel synthesis of substituted fenchanes (Vol. 2, p. 42) has appeared. A minor criticism must be levelled at the claim that the fenchol obtained in the course of this work had the highest recorded rotation ; its magnitude was not actually recorded, and only an impure specimen was described, together with its p-nitrobenzoate. This does not impugn the substance of the discussion; on the contrary, the concerted mechanism proposed is very reasonable. In this work it is reported that the acetoxyfenchyl toluene-p-sulphonate (288a) is formed in the reaction of the ether (289) with acetyl toluene-p-sulphonate;276it was suggested that the position of the substituents should be reversed (288b), but this

(286)

(287)

(288a) R’ = OTs,R2 = OAC

(289)

(288b) R’ = OAc,R2 = OTS

-.- C . A . Bunton, K . Khaleeluddin, and D. Whittaker, J.C.S. Perkin 11, 1972, 1154. 27b

N . Bosworth and P. D. Magnus, J.C.S. Perkin I . 1972, 943.

Mono terpeno ids

65

appears in the briefest of notes, in which the method was used for synthesis of a fenchene-like sesquiterpene, and the subject is still under Diels-Alder reaction of l,l-dimethylcyclopenta-2,4-diene and 2-acetoxyacrylic acid ester gives two esters (290),which can be converted by conventional reductive steps into the two a-fenchene hydrates (291) and (292).278Cyclopentadiene and ethyl but-2-ynoate also undergo a Diels-Alder reaction, this time to a norbornadiene ester (293), which was the start of a synthesis of a C,, aldehyde (294)found in East Indian sandalwood

An informative and amusing background to that unique material, camphor, has appeared.280 Its preparation by Oppenauer oxidation of the epimeric borneols occurs without epimerization.28 Epimerization does not occur in the presence of potassium t-butoxide in t-butyl alcohol, but it does with potassium isopropoxide in propan-2-01.'~~The reaction of camphor with phosphoric acid yields a complex mixture of m- and p-cymenes, 3,4-dimethylethylbenzene, 1,2,3,4and 1,2,3,5tetramethylbenzene,fenchone, carvenone, and c a r v a c r 0 1 . ~A~ ~very detailed examination of the metal-ammonia reduction has revealed an intermediate camphor analogue of pinacol formed by association of a camphor anion radical with the metal cation. This intermediate was isolated and characterized. Other effects are discussed, such as that of adding a large excess of metal salt (LiBr, KBr, or NH,C1).284 Benzylidene-epicamphor, according to its n.m.r. spectrum exists in the form (295),rather than the geometrical isomer.285 Catalytic reduction of benzylidenecamphor* (296) leads to the two possible benzylcamphors (297) and (298). Reduction of these with sodium borohydride leads to epimerization before reduction unless 2 % of water is added to the diglyme used as solvent.287 Y. Bessiere-Chretien and C. Grison, Compt. rend., 1972, 275, C , 503; Y. BessiereChretien and P. D. Magnus, personal communications. L. Pirila, Ann. Acad. Sci. Fennicae, Ser. A 2 , 1971, No. 157, 52. 2 7 9 T. Gibson and Z . J. Barneis, Tetrahedron Letters, 1972, 2207. 2 8 0 N. E. Bean, Chem. in Britain, 1972, 8, 386. 2 8 1 M. Sakashita, T. Takeshita, and R. Ohnishi, Nippon Kagaku Zasshi, 1971, 92, 1173. 2 8 2 M. Sakashita, T. Takeshita, and R. Ohnishi, Nippon Kagaku Zasshi, 1971,92, 1212. 2 8 3 Y. Fujita, S. Fujita, and H . Yoshikawa, Nippon Kagaku Zasshi, 1971,92, 1220. 2 8 4 W. S. Murphy and D. F . Sullivan, J . C . S . , Perkin I , 1972, 999. 2 n 5 F. Labruyere and C. Bertrand, Compt. rend., 1971, 273, C , 664. 2 8 6 R. Welters and H . Russmann, Ger. Offen. 2051 824. 2 8 ' J.-C. Richer and A. Rossi, Canad. J . Chem., 1972, 50, 1376. * Some derivatives of this arylidene kind are claimed to be sunburn-preventing (they absorb light in the range 285-315 277

Terpenoids and Steroids

66

I

Ph

(296)

(297)’ -+

NaHH,

(298)

Re-examination of some very old work on the chlorination of 3-benzoylcamphor (299) with phosphorus pentachloride has revealed that after loss of chlorine (boiling in ethanol),the product is (300),rather than a chlorobenzylidenecamphor.’H8 The enols of aroylcamphors [corresponding to (299),with R = Ph, C,H,.hal. or o-MeO-C,H,] have been prepared. and their conversion into the diketones with formic acid has been examined. The copper chelates here also

(299) R = Ph (301) R = CF3

(300)

made.2H9 A good way of making 3-trifluoroacetyl-camphorato-complexes (especially the n.m.r. shift reagents) is by exchange of the metal nitrates with the barium salt of ( + )-3-trifluoroacetylcamphor (301).290 The reaction of 3,3dibromocamphor with silver nitrate in boiling acetic acid leads to various acid products (Vol. 2, p 47) and some neutral bromides, one of which (302) was characterized by reduction to a mixture of the e m - and endo-epitricyclenols (303).”’ An isomeric tricyclenol (304) was made by a Bayer-Villiger-type route from the knohn acid (305). The esters of this alcohol (304) were required to establish whether the cyclopropane ring had any effect when it was constrained

(302)

(303)

J . Sotiropoulos, Cotizpt. rend., 1972. 273, c‘. 197. A . P. Terent’ev. G . V . Panova, N . B . Kupietskaya. and V . P. Shevchenko, Zhirr. ohshchei Khim., 1972. 42. 1 I 43. I I 50, 1 158. V . Schurig, Inorg. Cherri., 1972, 1 1 , 736; Tetrahedron Letters, 1972, 3297. A . J . M . Reuvers. A . Sinnema, and H . van Bekkurn. Terrahedron, 1972, 28. 4353.

Mono t erpcnoids

67

to lie directly above a carbonium ion; it was concluded that no stability was conferred on the ion.292 The structure of the cis-lactone formed by nitric acid ring-opening of 3,ndibromocamphor (Vol. 2, p. 44),has been confirmed by X-ray diffra~tion.'~~ The equilibrium mixture of 1-hydroxycamphenilone (306) and l-hydroxyapocamphor (307)(Vol.2, p. 42), when acetylat?d with diketen, yields acetates of both substances, but acetic anhydride gives only the acetate (308) of l-hydroxycam~henilone.~~~

(306)

(307)

(308)

The preparation of further specifically deuteriated camphors is described (see Vol. 2, p. 39); the key step is specific reduction of the chlorosulphoxide (309), giving a methyl group (310)with Raney nickel and hydrogen, or a thiol(311) with aluminium amalgam. Sulphonation of the bromide (312) is more effective than sulphonation of camphor for introducing deuterium into the methyl groups on the bridgehead, because an optically active sulphonic acid (313) is obtained. The bromine atom can be removed in the reduction step.295

i. SOCi, ii. TsOH

Br (312) R = Me (313) R = CH2S0,H 202

293 294

295

S. A. Sherrod, R . G . Bergman, G . J. Gleicher, and D. G . Morris, J . Amer. Chem. SOC., I972,94, 461 5 . D. W . Hudson and 0. S. Mills, J.C.S. Chem. Comm., 1972, 647. J . V. Paukstelis and D. N . Stephens, Terrahedron Letters, 1971, 3549. G . C. Joshi and E. W. Warnhoff, J. Org. Chem., 1972,37,2383.

68

Terpenoids and Steroids

It has been suggested on the basis of calculation, that (+)-camphorquinone (314) and isofenchoquinone (315) have small but detectable right-handed dione but this has been contested.297 Thermodynamic parameters have been quoted for the two ketols in each sense (2-hydroxy-3-0x0- and 3-hydroxy-20x0-) derived from camphorquinone (314), and it was shown that the more stable conformation possesses intramolecular hydrogen-bonding.29* A brief report about the reaction of aldehydes with camphorquinone in the presence of irradiation of wavelength > 390 nm records that acetaldehyde gives 50”1~of a mixture of (316) + (317) and (318) + (319). propionaldehyde gives only a trace of (318) + (319), and higher aldehydes give only (316) + (317).299 Re-examination of the irradiation of camphorquinone in benzene solution revealed biphenyl among the

( 3 14)

(315)

R

=

R

Me or Et

=

&:

OCOR

Me or Et

(317)

(316)

&OH

0

R > Et

R > Et

(318)

1319)

(320)

OTs (321)

products, showing that benzene is not necessarily an inert ofv vent.^"^ Monotosylates of camphorquinone glycols give with potassium t-butoxide the corresponding epoxide in the case of the cis-glycol tosylates, but the trans-isomers also give a ketone, 269, camphor in the case of the 2-em-hydroxy-3-endo-tosylate (320). and 29 O U epicamphor in the case of the 3-exo-hydroxy-2-endo-tosylate (321)(the name of the latter is misprinted as ‘endo-hydroxy’ in the experimental section of the paper).301 Another diol tosylate (322) undergoes some interesting

”‘ W . H ug and G . Wagniere, H r l r . Chim. Acru, 1971, 54, 633. -- ., - A . W. Burgstahler and N . C . Naik, Helr. Chitn. Acra, 1971,54, 2920. ’‘)’ C . Coulombeau and A. Rassat. Tetrahedron. 1972. 28, 7 5 1 . ’99

’””

M . 9. Rubin, J . M . Ben-Bassdt, B. Oppenheim, and W . Weiner, IUPAC Symposium on Photochemistry, Baden-Baden, July. 1972. Contributed paper no. 5 I . M . B. Rubin and Z . Neuwirth-Weiss. J . Anrrr. Chem. Sot.., 1972, 94, 6048. R . F. Cole. J . M . Coxon, and M . P. Hartshorn. Aiisfral. J . Chrrn., 1972,25, 361.

Monorerpenoids

69

reactions ; with sodium bicarbonate in dimethyl sulphoxide the cyclic carbonate (323) is formed (Scheme 26), whereas the oxetan (324) results on reaction with potassium t-butoxide. 3 0 2

@-oco2H CH, -pOTs

(322)

\

KOBu'

Scheme 26 Some details about the reduction of hydroximinocamphor (325) and its conversion into the pyrazine (326)have been published.303 In addition to its preparation with 2-octyl nitrite on camphor,303this compound (325) is also one of the

23 "/o

'"

8%

N. Bosworth and P. D. Magnus, J.C.S. Chem. Comm., 1972, 257. A . A . Hicks, J . Org. Chem., 1971, 36, 3659. Most of the monoterpenoids described here are known from R. C . Cookson, J. Hudec, A . Szabo, and G . E. Usher, Tt>irahedron,1968, 24, 4353.

'"'H . E. Smith and

Terpcnoids und Steroids

70

products formed when 3-nitrobornan-2-one is irradiated in ethanol or acetonitrile, the others being the ring-opened compounds (327)and (328).3"4 The stereochemistry of epiborneol and epi-isoborneol has been established chemically. The two were prepared by reduction of the thioketal of each of the two acetoxycamphors (329a and b). The latter were then converted into the corresponding 4-hydroxy-cis-camphoric acids (330), only one of which had an intramolecular hydrogen bond and formed a lactone, and must therefore correspond to epiborneol (331), having an e ~ d o - h y d r o x y - g r o u p . ~ ~ ~

&

Aco&o

OAc (329a)

:'...

HOP

H& HO

(329b) (331)

CO,H

(330)

The bornane furoxan (332)exists as a 1 : 1 mixture of the isomers shown. With trimethyl phosphite in benzene, the cyclopentane (333) is obtained with no intermediate furazan. The corresponding furoxan derived from the pinane system gives first the furazan (334) and then the cyclobutane (335),showing that although the total strain of the system is greater in the pinanes, that applied to the atoms of the furoxan ring is relieved.306

0-

0-

J

V

1

J

MeCHCN

(333) (334)

CN (335)

"lJ

''J5

"''

S. T . Reid and J . N . Tucker, C'hetn. Cotnt?~., 1971, 1609. E. Hainanen, S~oriietiK e m . , ( B ) . 1971,44, 375, 379 (Chem. A h . , 1972, 76, 34406). J . Ackrell, M . Altaf-ur-Rahrnan, A. J . Boulton. and R . C. Brown, J.C.S. Perkin I , 1972. 1587.

Mono terpenoids

71

Bornanes substituted at C-10 can be made by rearrangement of myrtenol(336) esters ; this results in a fairly rapid synthesis of apocamphanecarboxylic acid (337). O '

(337)

(336)

Bicyclo[3,l,l]heptanes.--The structure of paeoniflorin (338), a monoterpenoid glucoside that is the major principle from Chinese paeony root (Paeonia albiJora), has been confirmed by X-ray analysis of a b r o m o - d e r i ~ a t i v e It . ~is~ accompanied ~ in the plant by albiflorin (339).309The crystal structure of bis-(71-pineny1)nickel has been given as an example of the use of automated X-ray structural determination as an analytical method.310 The conversion of the pinenes into other monoterpenoid hydrocarbons continues to produce many publications ;e.g. conversion 0

R'OCH,

HO

OH OH (338) R' = PhC0,R2 = H

Y

(339)

'

into ocimene, allo-ocimene, or myrcene either pyr~lytically~'or by U.V.irradiaconversion into ~ a m p h e n e , ~etc.* The vapour-phase catalytic t i ~ nl 2, catalytic ~ transformations of a-pinene are very complex ;on alumina there are two paths, one leading to bi- and tri-cyclic compounds and the other to menthanes. More acid catalysts favour the formation of monocyclic products, the addition of sodium increasing the primary products, camphene and dipentene, at the expense of aand y - t e r ~ i n e n e . ~Acidity '~ is also important in the case of chromia gel and '07

309

31" 31'

312 313

'I4

315

Y . Matsubara, T. Yamaga, H. Yamamoto, and Y . Morichika, Yuki Gosei Kugaku Kyokai Shi, 1971, 29, 883. M. Kaneda and Y. Itaka, Acta Cryst., 1972, B28, 141 1 . M. Kaneda, Y . Itaka, and S. Shibata, Tetrahedron, 1972, 28, 4309. C . Kriiger, Angew. Chem. Internut. Edn., 1972, 11, 387. S. A . Voitkevich, V. V. Kashnikov, 0.N . Zhuchkova, T. P. Bogacheva, and N. N. Zelenetskii, Maslo-Zhir. Prom., 1971, 37, 24. P. J . K r o p p a n d W. F. Erman, U.S. P., 3616372. M . Dul and M. Bukala. Chem. Stosow., 1971, 15, 75, 317, 341. I . 1. Bardyshev and G . V. Deshchits, Vestsi Akad. Nuvuk Belarus. S . S . R . , Ser. khim. Nutwk, 1972, 112. A . Stanislaus and L. M . Yeddanapalli, Canad. J . Chem., 1972, 50, 6 1 .

* Here 'etc.' includes such trivia as change of the acid (e.g. to isomerization.

used for the

Terpenoids and Steroids

72

chromia-alumina catalysts, over which more aromatic hydrocarbons (p-cymene, rn-cymene, and tri- and tetra-methylbenzenes) are ~ b t a i n e d . ~ The third recorded production of bicyclo[4,1,l]octanes from the reaction of carbenes with x-pinene has appeared (see VoI. 2, p. 50), but this is clearly independent work, since it is nearly contemporary (202a).3” There is a fourth note describing carbene additions to pinenes. but this time including verbenene (340) (which reacts first on the exocyclic double bond and then on the other) and some oxygenated compound^.^ I *

’

1343)

I. 111.

TsCI-py KOH- EtOH

(342) Cocker et af. have said that ‘the configuration of ( +)-2a,3a-epoxypinene (341) is generally, although not universally, accepted’.220 i t will now have to be universally accepted since Chabudzinski er a/. have prepared the 2/3,3/3-epoxide (342) from the ketol acetate (343), by first making a mixture of glycols with a Grignard reagent and then solvolysing the 2B,3~-tosylatewith potassium hydroxide. The B-epoxide (342) is less stable than the better known isomer (341). Some problems about acetylation of ketols, described below, were avoided in this work because the acetate (343) was obtained from ozonolysis of 3a-acetoxypin2(10)-ene.319 In an examination of the epoxidation of various olefins in the bicyclo[3,3,l]heptane series using p-nitroperbenzoic acid, and of various ketones using dimethylsulphonium methylide, kssiere-Chretien’s group found that ’orthodene’ (344) gives some cis-epoxide, the amount increasing when methyl groups are adjacent to the methylene In the hydroboration of the olefins these methyl groups provide hindrance to trans attack. This increases from 40 yo cis attack in the case of (344) to virtually 1 0 0 ~ cis o in the case of its 2,4-dirnethyi h o m ~ l o g u e . ~ ”It is thus not surprising that the corresponding methylated 316 i17

3 18 319

.I 2 0

32 I

A . Stanislaus and L . M. Yeddanapalli. Cnnnd. J . Chem.. 1972, 50, 113. J . Grafe, L. Quang Thanh, and M. Muhlstadt, Z.Chem.. 1971, 11, 252. C . Filliatre and C. Guerand. Compr. rend.. 1971, 273, C. 1186. Z. Chabudzinski, Z. Rykowski. U. Lipnicka, and D. Scdzik-Hibner, Roczniki Chem., 1972.46. 1443. Y . Bessiere-Chretien, M . M . El Gaied. and B. IMeklati, Bull. Soc. chim. Frunce, 1972, 1000. Y . Bessiere-Chretien and B . Meklati. Bull. Soc. chim. France, 1972. 2933.

Mono terpenoids

73

ketone (345) is reduced with lithium aluminium hydride to give 70% of the cisalcohol (346), although it is odd that diborane in ether leads to 75% transisomer!322This group has also examined the factors that cause ally1 alcohols or pyrazoles to result from the action of hydrazine hydrate on up-epoxy-ketones in the pinene series.323.

(344)

(345)

(347)

Cobalt abietate-catalysed air oxidation of u-pinene yields 32 % verbenone (347) and 40% verbenol, with traces of the epoxide and myrtenol (336).324 The preferred conformation of the formyl group in myrtenal(348)has been discussed in the light of temperature-dependent c.d. As expected, hydroboration of myrtenyl halides leads to predominately truns introduction of the h y d r o ~ y - g r o u p .Some ~ ~ ~ myrtenylacetaldehydes have been de~cribed.~ 27 The reduction of myrtenol epoxide (the oxiran ring is trans to the bridge) with metal hydride and diborane has been compared with that of epoxyisomyrtenol (349).328 Differences in reaction between these ‘ortho’ isomers and the normal pinanes are well-known (cf. Vol. 1, p. 44),and it has now been shown how the monotosylate of the glycol (350)derived from (349) undergoes ring expansion (a pinacol rearrangement) with calcium carbonate and lithium perchlorate (catalyst), in contrast to the corresponding pinane glycol m o n ~ t o s y l a t e .Solvolysis ~~~ of myrtanyl cis- (351) and truns- (352) tosylates leads to the same carbonium ions as were obtained by Kirmse from camphor derivatives. Whittaker’s group have continued their studies of piny1 carbonium ions by following ester solvolyses in

(349) 322

” 324

325

’” ’’’ 328

329

(350)

yH,OTs

CH,OTs

(351)

(352)

Y . Bessiere-Chretien, G . Boussac, and M . Barthilemy, B u f f .SOC.chim. France, 1972, 1419. A review of metal hydride reduction includes some bicyclic monoterpenoid ketones: K . Milek and M . Cerny, Sjinthesis, 1972, 217. B. Meklati and Y . Bessiere-Chretien, Bull. SOC.chim. France, 1972, 3 133. E. Tsankova, J . Kulesza, and J . Gora, Riechstoffe, Aromen, Korperpjlegem., 1971, 21, 412, 414, 416. T. Suga, K . Imamura, and T. Shishibori, Bull. Chem. SOC.Japan, 1972,45,545. 1. Uzarewicz, E. Zientek, and A. Uzarewicz, Roczniki Chem., 1972,46, 1069. J. B. Ball, Ger. Offen. 2054257. Y . Bessiere-Chretien, C. Grison, J.-P. Montheard, F. Ouar, and M . Chatzopoulos, Bull. SOC.chim. France, 197 1, 439 I . W. Tubiana and B. Waegell, A n g e w . Chem. Internat. Edn., 1972, 1 1 , 640.

Terpenoids and Steroids

74

alkaiine methanol330and the nitrous acid deamination of ~is-myrtanylamine.~~' The solvolyses are partly unimolecular [leading to the ions (353a and b) and thence to the products shown in Scheme 271 and partly bimolecular, leading to methyl ethers without skeletal change. From the trans-tosylate (352), up to 99%

I

(353a)

1

x-pinene P-pinene fenchenes a-fenchyl methyl ether trans-pin-2-yl methyl ether

cis-myrtanyl ether 0-P'tnene

(353b)

.t

1

pinenes camphene bornyl methyl ether cis-pin-2-yl methyl ether limonene terpinolene 8-terpinyl methyl ether

trans-m yr tan y 1 ether

Scheme 27

of the methyl ether can be obtained.330 Myrtanyiamine deamination leads to some ring-expanded products, but these are not the major compounds.331 The reaction of the acid corresponding to myrtenal (348) with N-bromosuccinimide is described, together with various other reactions of the system, and the preparation of ~ i n a n - 4 , l O - d i o l . ~ ~ ~ The synthesis and deamination of the 3-aminopinanes, including the unknown 3%-amino-trans-pinane (354) is described. The latter was made by oxidation of rrans-pinocamphone oxime (355) to the nitro-compound, which was catalytically reduced, direct catalytic reduction of the oxime giving the 3/l-amino-isomer (356).j3' The various conformations ascribed to the four possible amines were 330 'j'

133

P. I. Meikle, J . R . Salmon, and D. Whittaker, J. C. S . Perkin I I , 1972, 23. P. I. Meikle and D. Whittaker, J.C.S. Chern. Conim., 1972, 789. L. Borowiecki and E. Reca, Roczniki Chem., 1971,45,493, 573. D. G . Cooper and R . A . Jones, J . Chern. Soc. (0,1971, 3920.

75

Monoterpenoids

confirmed by n.m.r. spectrometry using a shift reagent.334 Conversion of transpinocamphone into trans-verbanone (357) via the benzylidene derivative (358) requires a longer route (Scheme 28) than reduction with lithium aluminium hydride in the presence of aluminium chloride, but the latter method leads to a very complex

1

(354)

(355)

CHPh

(354)

0

CHPh

Reagents: i, oxidize; ii, H,-cat.; iii, Pt-H,; iv, NaBH,; v, AcO-py; vi, 0,; vii, Zn-HOAc.

Scheme 28 The conformations of the verbanols have been discussed in relation to their n.m.r. The photochemical conversion of verbenone (347) into chrysanthenone (359) is discussed again,337 and it has been shown that the same reaction occurs with y-radiation. I n the latter case the conversion is small, verbenone being surprisingly stable towards y-radiation. In t k s e conditions, rrans-verbenol is also stable, but cis-verbenol is converted into a mixture of the trans-isomer and ~ e r b e n o n e . ~The ~ ’ known apoverbenone (360) has been made by a much improved route.338 The first stage, N-bromosuccinimide bromination of nopinone (361) leads initially to the a-bromoketone (362) (this is the kinetic

(359) J34

335 336

(361)

(362)

(360)

E. C. Sen and R. A. Jones, Tetrahedron, 1972, 28, 2871. R. A. Jones and T. C. Webb, J . Chem. SOC.( C ) , 1971, 3926. C. W . Jefford, S. M . Evans, U . Burger, and W. Wojnarowski, Chimia (Switz.), 1971,25, 413.

337 33*

E. Tsankova, J. Kulesza, and J. Gora, Roczniki Chem., 1971,45, 1791. J. Grimshaw, J. T. Grimshaw, and H. R. Juneja, J.C.S. Perkin I , 1972, 50.

Terpenoids and Steroids

76

product ; the p-bromoketone is the thermodynamic and this bromoketone (362) is almost quantitatively converted into apoverbenone (360) using lithium carbonate and lithium bromide in dimethyl sulphoxide, by which chirality is retained.338 Hinckley et al. have used verbanols and verbenols deuteriated on the carbinol carbon atom [C-41 to demonstrate a deuterium isotope effect using lanthanide shift reagents in the n.m.r. spectra. They discuss this in terms of the stereochemistry of the verbenol and verbanol complexes, but it could be due to an increase in the basic strength of the alcohol group on deuterium Substitution of nopinone (361) can be carried out uia the @-keto-ester,made by the action of dimethyl oxalate, but annelation of a third ring [e.g.from (363)] does not occur as easily as in other systems.34* Nopinol can be used to introduce a function on C-9; when the cis-isomer (364) is treated with nitrosyl chloride in pyridine, and the product irradiated and pyrolysed, an oxime is obtained, the acid hydrolysis of which yields (365).342The most effective way of functionalizing the C-9 methyl group in pinane is by treatment of the ether (289) with acetic anhydride in the presence of pyridine hydrochloride, when 9-acetoxypin-2-ene (366) is obtained in 70"
OH

OH CH,OAc

1

(364)

(365)

k

Irradiation of nopinone (361) in methanol opens the cyclohexane ring, in the same way as in the case of verbanone, and leads to the cyclobutane (367), further irradiation in t-butyl alcohol giving an open-chain aldehyde ( 368).343

H (367) The remainder of this section concerns reactions of the pinane system resulting in ring-opening. Hirata and Suga have examined the acid-catalysed rearrangement of 2x-bromo-cis-pinocamphone (369), the major product of bromination of the "" 140

"' 34'

J . Roux and R. Lalande, Compt. rend., 1971, 273. C , 997. G . V. Smith, W . A. Boyd, and C. C . Hinckley, J . Anier. Chem. Soc., 1971. 93, 6319; C . C . Hinckley, W . A . Boyd, and G . V. Smith, Tetrahedron Letters, 1972, 879. E. Brown. J Touet. and M . Ragault, Bid/. Sor. chirn. France, 1972,212. T. Gibson, U S . P. 3 636 069. G . W. Shaffer, A . B. Doerr. and K . L. Purzycki, J . Org. Chem.. 1972, 37. 25.

Monoterpenoids

77

enol acetate of pinocamphone. In addition to various menthane derivatives, 6-endo-bromocamphor (370) is obtained; this is also a minor product of the bromination reaction used to prepare (369).344The full paper about the reaction of ( +)-2cr-hydroxypinan-3-one (371)with anhydrous oxalic acid (Vol. 2, p. 54) has been published, but one wonders what the significance of a product (372) found in 0.05 yield is, when the purity of the starting material was not ascertained.345 Acetic anhydride and the ketol (371) yield not only the acetate, but some rearranged products (373) (reminiscent of Warnhoff s ketol acetate rearrangem e n t ~and ~ ~~~a )r v o n e A . ~reinvestigation ~~ of the pyrolysis of the pinan-2-01s

Ac,O

O (371) G H AcO (373)

(372)

(374) has shown that in addition to linalool and various isomers of plinol (373, a methyl ketone (376; R = Me) is formed,348analogous to the aldehyde (376; R = H) formed on pyrolysis of nopinol (364),the full paper of which (correcting some points in the preliminary communication) has appeared.349 The pyrolysis of (+ )-isopinocampheol (377) leads to somewhat similar products, but the reaction can be made selective. The primary product (378), formed at 330°C, is converted into the cyclopentanols (379)on longer treatment at that temperature, '44 34s 34h

347 '48

J49

T. Hirata and T. Suga, Bull. Chem. SOC.Japan, 1971, 44,2833. T. Suga, T. Hirata, and T. Matsuura, J . C . S . Perkin I , 1972, 258. I . S.-Y. Wang and E. W . Warnhoff, Chem. Comm., 1969, 1158. T. Hirata, Bull. Chem. SOC.Japan, 1972,45, 599. J . M. Coxon, R . P. Garland, and M . P. Hartshorn, Ausrral. J . Chem., 1972,25,353. J . M. Coxon, R. P. Garland, and M . P. Hartshorn, Airsrral. J . Chem., 1972, 25. 947.

Twpenoids and Steroids

78

6" (373)

M

e

c

R

(376)

(375)

whereas at over 400 "C in the case of (378),or at over 500 "C in the case of (379), these molecules break up further. A by-product is dihydroisocarveol ( 157).350 cis-Verbanone (380)is surprisingly stable but at 580 "C products derived from two different biradicals (381) and (382) are obtained (Scheme 30) although even then 17 of starting material is recovered.35 "()

( 157)

(378)

J 1

CHO

(379)

The classical permanganate oxidation of a-pinene yields cis-phonic acid (383). Now, using dicyclohexyl-18-crown4 ether in benzene, the yield has been raised to 90°,.352in the conventional oxidation, the yield of the acid (383) is very low, but in the neutral part the interesting ether (384)has been found. This is quantitatively dehydrated by thionyl chloride to (385),"' which has led to the synthesis of ( - )-7-epichrysanthenol(386), the structure of which was linked to chrysanthenone by oxidation.354 I t has been noted that with iodosobenzene diacetate and K . H . Schulte-Eke, M . Gadola, and G . Ohloff, Helr. Chin?.Acta, 1971, 54, 1813. J . M . Coxon. R . P . Garland, and M . P. Hartshorn. C'hem. Comm., 1971, 1131. J . Sam and H . E. Simmons, J . Artier. Chem. SOL-.,1972,94,4024. ' ' D. D. Joulain and F. Rouessac, Bull. Soc. chirn. France, 197 1, 3359. I T ' D. Joulain and F. Rouessac. J.C.S. Chem. Comni., 1972, 314.

'")

"'

79

Monoterpenoids

is formed

0

Scheme 30 trimethylsilyl azide, a-pinene yields the nitrile of the acid (383), whereas with lead tetra-acetate and trimethylsilyl azide, an a-azidopinene is formed, but details are not yet available.355

35s

J. Ehrenfreund and E. Zbiral, Terrahedron, 1972, 28, 1697.

80

Terpenoids and Steroids

Ring-opening of P-pinene with iodine,’ * and of a-pinene with a zinc-copper couple216 have been mentioned ; addition of acrolein and methyl acrylate to /?-pinenemay also result in some ring-opened products,356and so do the reactions with iodine a ~ i d e , ~ ’aldehydes ’ in the presence of light,358and ketones in the presence of t-butyl peroxide.359 Of particular interest in this respect is a paper by Julia rr a/., who describe the production of cis- and trans-carveols ( 1 18) from apinene, and perilla alcohol (388) from P-pinene with retention of configuration, using benzoyl peroxide in the presence of cupric salts.360

CH,OH

0 h (388) Bicyclo[4,1,O]heptanes.-As usual. most research on carane derivatives stems from Poland and Russia, on account of the extensive plantations of Pinus sylcesrris, of which it is the main monoterpenoid. The reaction of carbenes with car-3-ene (Vol. 1, p. 48) was simultaneously reported by Volkov, but the paper was not available earlier in the West.36’ Chlorination of car-3-ene (389)yields two dichlorocarenes (390)and (391),which are converted into a mixture of monochlorides with potassium t-butoxide [(390)slower than (39111. The reaction of this mixture with silver acetate in acetic acid gives a variety of acetates which, unlike the monochlorides, were identified.362 It is difficult today to accept the excuse of product complexity in a one-step

3S6

JST

358 359

3h0 361

36 2

Y . Matsubara, T. Kishimoto, H . Yamamoto, and W . Minematsu, Nippon Kngaku Kaishi, 1972, 669. B . Bochwic. J . Kapuscinski, and B. Olejniczak, Roczniki Chem., 1971,45, 707. R . Lalande and M.-J. Bourgeois. Cornpi. retid., I97 I , 273, C , 1546. M . Cazaux and R. Lalande, Bull. SOC.chim. France, 1972, 18b7, 1894, 1897. M . Julia, D. Mansuy. and J.-Y. Lallemand, Bull. SOC.chim. France, 1972, 2695. Y u . P. Volkov, Trudy tseni. nauch.-issled. dezinfek. I n s t . , 1969, No. 20, 387 (Cliem.Abs., 1972,76. 14 725). B. A. Arburov, Z . G. Isaeva, and G . Sh. Bikbulatova, I x e s t . Akad. Nauk S . S . S . R . ,Ser. khim., 1972, 388.

81

Monoterpenoids

chemical reaction for failure to identify them ! More reactions of carene bromohydrin (VoI. 1, p. 47; Vol. 2, p. 56) have been published, including the interesting conversion with lithium aluminium hydride into 4f?-caranol,3P,4f?-epoxycarane, and the ring-contracted product (392)in the proportion 2 :2 : l.363In a discussion on conformational preferences of six-membered rings, the carene epoxides are mentioned (they are, of course, boats).364 The various glycols accessible from hydroboration of carene epoxides have been described.365 The conversion of car-4-ene a-epoxide into isomeric ally1 alcohols gave products that were too unstable for purification by gas chromatography; the alcohols (393) and (394) were identified as esters.366 Work on 3P-acetylcar-3-eneepoxide (395) includes

(393)

(395)

(394)

(396)

its reduction (lithium aluminium hydride) to various diols, converted into car-3ones (396) with periodic and its isomerization to the ketol (397) with lithium dieth~lamide.’~~ Similar reactions have been carried out on 3a-acetylcar4-ene epoxide (398).369Conversion of 3-substituted car-4-enesinto chrysanthemic acid has already been mentioned. An examination of the effect of catalysts on the Prins reaction of car-3-ene shows that in acetic acid, using phosphoric or formic acids, the yield of (399)can rise to 61 %.370 363

364 365 366

367

368

3 69 370

B. A . Arbuzov, Z. G. Isaeva, I. B. Nemirovskaya, and V . A. Naumov, Doklady Akad. Nauk S . S . S . R . , 1971, 197, 1322. V. A. Naumov, Izvest. Aknd. Nauk S.S.S.R., Ser. khim., 1971, 2425. I. Uzarewicz, A . Uzarewicz, and E. Zientek, Roczniki Chem., 1972,46, 1189. B. A. Arbuzov, Z. G . Isaeva, A. R . Vil’chinskaya, and M . G. Belyaeva, Doklady Akad. Nauk S . S . S . R . , 1971,199, 1304. B. A. Arbuzov, Z . G. Isaeva, N . D. Ibragimova, and N. Kh. Abaeva, Doklady Akad. Nauk S . S . S . R . , 1972, 203, 817. B. A. Arbuzov, Z. G . Isaeva, and N . D. Ibragimova, Izoest. Akad. Noirk S . S . S . R . , Ser. khim., 1971,2084. B. A. Arbuzov, Z. G. Isaeva, N . D. Ibragimova, S. G . Vulf son, and A. N. Vereshchagin, Doklady Akad. Nauk S.S.S.R., 1972,203, 58 1. J . Chlebicki and B. Burczyk, Chem. Stosow., 1971, 15, 357; Rocznikz Chem., 1971,45, 1225, 1231.

Terpenoidsand Steroids

82

(397)

(399)

(400)

(401)

The carane ring is cleaved by different reagents in different ways, and many examples appear annually (cf. Vol. 1, p. 47; Vol. 2, p. 56). The reaction with t-butyl chromate leads to fairly indiscriminate opening; it has been re-investigated, and whereas in benzene the main products are the carenone (400) and the dione (401),more than half the products in acetic acid are rn-cymenes, although eucarvone isomers are always Formation of rn-menthanes (and some pmenthanes) occurs with hydrochloric acid and carane (the carene reaction is wellalthough mercuric acetate, followed by sodium borohydride, gives only p-men thanes (mostly r-terpineol) besides the principal product, fl-caran-4-01 (402),373the conformation of which is discussed in the light of its i.r. spectrum.374 Car-4-ene yields only ring-opened acetates (403a and b) with mercuric acetate,375 somewhat similar results [the formation of (403b) and other p-menthanes] being obtained with lead tetra-a~etate.~”’ From cis-caran-3-one [cis-(396)], the

(402)

(403a)

(403b)

T. Suga, T. Shishibori, and T. Matsuura, Bull. Chem. Sor. Japan, 1972,45, 1873. 5 7 2 I . I . Bardyshev, E. F. Buinova, and 1. V . Protashchik, Z h u r . org. Khim., 1971,7, 2307. 3 ’ 3 B. A . Arbuzov, V . V . Ratner, Z . G . Isaeva, and E. Kh. Kazakova, Imest. Akad. Nauk S . S . S . R . , Ser, khim., 1972, 3 8 5 . ”’ R . R . Shagidullin, Z. G . Isaeva, I . P. Povodyreva, and R . R . D’yakonova, Doklady Akad. Nauk S . S . S . R . , 1972, 202, 1349. ‘ 7 5 B. A. ArbuLov, V . V . Ratner, Z . G . Isaeva, E. Kh. Kazakova, and M . G. Belyaeva, Izuest. Akad. Nauk S . S . S . R . , Ser. khini 1972. 2752. 1750 9. A . Arbuzov, V . V. Ratnet, Z. G . Isaeva, and M . G. Belyaeva, Doklady Akad. Nauk S . S . S . R . , 1972, 204. 1115. ’’I

.

83

Mono terpeno ids

(404)

(405)

lactone (404) was prepared by standard means and then opened to a pmentha2,8-diene on heating in pyridine,* treatment with diazomethane giving the ester (405)in 70% yield.’93

(406)

(408)

In an examination of the photochemical transformation of 3-methylcar-4-en-2one (406; R = Me) [to (407)], Bellamy and Crilly showed that the earlier belief that alkylation of the eucarvone enolate ion (408)occurs from the same side as the cyclopropane ring is incorrect. Using R = benzyl, which gives an n.m.r. spectrum that is easier to interpret, they showed that the alkylation product was (406; R = benzyl). (401 )

I. 11.

acid

methylate

M M o)eee 0

-

(409a)

OMe

OMe Me

\

Me

OMe

(409b) 3’h

W. Cocker, D. P. Hanna, and P. V . R . Shannon, J . Chem. SOC.(0, 1968,489. A. J . Bellamy and W. Crilly, J . C . S . Perkin If, 1972, 395. * This is based on earlier ring-opening of caran-2-01.~’~

377

Terpenoids and Steroids

84

The diketone (401) undergoes rearrangement and dimerization in the presence of acid. Methylation of the mixture enabled a variety of isomers of the flavone (409a), (409b), etc. to be identified.378

6 Furanoid and Pyranoid Monoterpenoids A ketol ether (410)which, so far as the Reporter knows, is a new natural product,

has been isolated from Perillafrutescens var. U C U ~ U . ~All ’ ~ four of the lilac alcohol (411) isomers are present in the oil from flowers of lilac, a complete analysis of which has been published.380 Further work on the irradiation of fi-carotene [yielding loliolide (412),Vol. 1, p. 501 has revealed the presence of further products; the same reaction with zeaxanthin (413) yields the same substances, with, in addition, 3-hydroxy-p-cyclocitral (414).381

0

OMe

+CH20H

(410)

(411)

1

Two further syntheses of rose oxide (415) are described. The first is a modification of the route from citronellol (416),anodic oxidation of which (in acetonitrile with tetraethylammonium tosylate as supporting electrolyte) leads to a 71 : 29 mixture of cis : t r a n ~ - ( 4 1 5 ) . ~The ~ * other route is of the dihydropyran type;

’”

I. W. J . Still and D. J . Snodln, Cunud. J. Chern., 1972. 50, 1276. K . Ina and I. Suzuki, Nippon Nogei Kugaku Kaishi, 1971,45, I13 (Chern. A h . , 1971,75, 91 228). ”’ S. Wakayama. S . Namba, and M. Ohno, Nippon Kagaku Zasshi, 1971,92,256 (Chern. A h . , 1972, 76. 37 341). The lilac alcohols are now patented: Jap P., 16 300/1972 (Chern. A h . , 1972,77,61 793). S . Isoe, S. B. Hyeon. S. Katsumura, and T. Sakan, Tetrahedron Letters, 1972, 2517. ”’ T. Shono, A. Ikeda, and Y. Kimura. Tetrahedron Lerrers, 1971, 3599.

’7q

85

Mono terpeno ids

hydrogen chloride at - 10 "C gives the chloride (417),which, with isobutylene in the presence of a Lewis acid gives a substance that can be dehydrochlorinated to a mixture of the two rose oxides (415)(65 % trans) and cis- and trans-iso-rose oxide (418).38

When nerol oxide (419) is metallated with butyl-lithium, a sigmatropic rearrangement of the anion to (420)occurs. The two isomers of (420)can be trapped in acetic anhydride as the enol acetates (421),hydrolysis of the latter yielding the aldehydes (422).384 Additional interest is given to this reaction because the

0

383 384

Li'

M . Muhlstadt and C. Duschek, Z . Chem., 1971, 11,459. V . Rautenstrauch, Helv. Chim. Acta, 1972,55, 594.

Li+

86

Terpenoids and Steroids

aldehyde (422)possesses the skeleton that Robinson once discussed as a possible intermediate in the artemisia ketone bi~genesis.~'' Thermolysis of the acetates (421) leads to the cycloheptadiene (423).384

7 Cannabinoids and other Phenolic Monoterpenoids Another review386 and a meeting (largely concerning pharmacology)387 have been devoted to Cannabis. The propyl cannabinoids corresponding to A '-tetrahydrocannabinol [(424) = A'-THC],388cannabichromene (425),389cannabidiol (426),390and cannabivarin (427; R = Pr)391have been found, particularly in Asian Cannabis, and methods for their detection, identification, and evaluation have been

R

=

(427)

CSH (regular series) or Pr (propyl series)

R' (428) R ' = O H , R 2 = H (429) R 1 = H , R 2 = OH

3x

3Hh

"'ItH

38y

3y"

3v'

'"

R. Robinson. 'Structural Relations of Natural Products', Oxford University Press, 1955, p. 14. H. G. Parsand R. K. Razdan. A m . N e w York AM^. Sci.,1971, 191, 1 5 . Swedish Academy of Pharmaceutical Sciences, Stockholm, October 1971 ; Nature, 1971, 234, 14. E. W. Gill, J . C/teni. S o < .( C ) , 197 I , 579. R . A. de Zeeuw, J. Wijsbeek, D. D. Breimer, T. B. Vree, C. A . M. van Ginneken, and J . M .van Rossum, Science, 1972, 175,778. L. Vollner, D. Bienek, and F. Korte, Tetraltedroti Lerrers, 1969, 145. F. W. H. M. Merkus, Pharm. Weekblad, 1971, 106, 69. F. W. H . M . Merkus, Narrtrr, 1971, 232, 579.

87

Mono terpeno ids

The metabolism of A’-THC and A6-THC is very i m ~ o r t a n t , and ~ ” ~two more metabolites from the latter have been isolated394and synthesized.395 The synthesis involves reaction of a suitably functionalized resorcinol (430) with a cismenthadienol (431)(Scheme 31) for one of the metabolites (428); the other (429)

Scheme 31 was made analogously, although removing the thioketal protecting group was more Metabolism of both THC’s involves oxidation of C-7, and 7-hydroxy-A6-THC(432; R = H, R2 = 0 H ) h a s been synthesizedfrom A’(7’THC (433) (Scheme 32).396 The conversion of (-)-A6-THC into (-)-A’-THC with of hydrogen chloride followed by dehydrochlorination always gives 3-5 A1(7’-THCtoo; this is easily isolated by chromatography on silver nitrateimpregnated silica This work also contains studies on the oxidation of 39 3

394

395

3’46 397

Leading references in R. L. Flotz, A . F. Fentiman, jun., E. G . Leighty, J. L. Walter, H . R. Drewes, W. E. Schwartz, T. F. Page, jun., and E. B. Truitt, jun., Science, 1970, 168, 844; H . D. Christensen, R . I . Freudenthal, J . T. Gidley, R. Rosenfeld, G . Boegli, L. Testino, D . R . Brine, C. G . Pitt, and M. E. Wall, Science, 1971, 172, 165; see also ref. 379. A characteristic of much work on cannabinoids is the vast number of authors apparently necessary to d o one reaction and test pharmacologically one substance ! (see also ref. 404). D. E. Maynard, 0. Gurny, R. G . Pitcher, and R. W. Kierstead, Experientia, 1971,27, 1154. K . E. Fahrenhotz, J . O r g . Chrrn., 1972, 37, 2204. K. K. Weinhardt, R. K . Razdan, and H. Weinhardt, Tetrahedron Letters, 1971,4827. R. K. Razdan, A . J . Puttick, B. A, Zitko, and G. R. Handrick, Experientia, 1972, 15, 121.

88

Terpenoids and Steroids

A'-THC, which is slowly converted into cannabinol (427; R = C , H l l ) in air.398 The oxidation occurs via dienes, the existence of which was demonstrated by trapping with a d i e n ~ p h i l e . ~ ~ '

4(433: R'

= Ac) +

/

(432) R'

(433:R' = H)

= ~

(432:R' = H , R 2 = OH)

Ac, R2 = Br 1

"

(432;R' = Ac,R2 = OAc)

Reagents: i. Ac,O; ii, NBS; i i i , AgOAc-HOAc; iv, O H - .

Scheme 32

For these metabolic studies, it is desirable to have readily available labelled cannabinoids. ' 4C-Labelled A'-THC, with the label in the pentyl side-chain has been prepared by following the synthetic route of Scheme 31, but using the brominated resorcinol(434; R = CH2Br)with the menthadienol(431), leading to the bromocannabinoid (424; R = CH2Br). The bromine atom can then be replaced using labelled lithium butyl copper.399 Another synthesis uses the same reaction between (431) and, this time, an olivetol (435)having the label already incorporated by condensing labelled diethyl malonate (436)with non-3-en-2-one (437).400 Tritium-labelled THC's have also been made by using pre-labelled olivetol in a standard synthesis.400" An improvement in the route involving citric acid at room temperature for phenol alkylation is to use as the catalyst 5 :(,

HO (434) (435) R = C,H,

"'

OH

', I4C at C-4 and C-6

(438)

R . F . Turk, J . E. Manno, N. C. Jain, and R . B. Forney, J . Pharm. Pharrnarol., 1971, 23, 190. '*' W . Gau, D. Bieniek, and F. Korte, Terrahedron Letters, 1972, 2507. 4 0 0 A. A . Liebman, D . H . Malarek, A. M . Dorsky, and H. H. Kaegi, J . Labelled Compounds, 1971, 7, 241. 4 0 0 0 E. W. Gill and G . Jones, J . Labelled Compounds, 1972, 8, 237.

Monoterpenoids

89

CO2Et

I

*CH,

I

+ C,H,,CH=CHCOMe

C02Et

--+

(435)

(437)

(436) five days, a much milder procedure than usual. Reaction of piperitol* (438)with olivetol, for example, yields a variety of cannabinoids (Scheme 33). In the same way, the authors were able to prepare cannabidiol and its isomers from isopiperitenol(439), as well as other analogues from pulegol and menth-4-en-3-01. In (435)

(438)

A

OH R

=

Me or C5H11

Scheme 33 certain cases, yields are low and separations difficult.401 When attempting to make a glucoside from A6-THC and a- or P-glucose penta-acetate, Bailey and Verner observed the unexpected formation of a C-glucoside,although the phenolic group was unprotected.402

(439)

(440)

Besides the analogues mentioned in the work quoted above, some aza-cannabinols (corresponding to THC in the same way as alkaloids do to terpenes) 401

B. Cardillo, L. Merlini, and S. Servi, Tetrahedron Letters, 1972, 945. K. Bailey and D. Verner, J.C.S. Chem. Comm., 1972, 89. * The piperitol was made by reduction of piperitone (176) with sodium borohydride. Borohydride is a poor reducing agent in this case, giving a large amount of hydrocarbon; it would have been better to use lithium aluminium hydride in ether.

402

90

Terpenoids and Steroids

have been made,403and Zitko er al. have shown that solubilizing THC by esterification of the phenol (using dicyclohexylcarbodi-imide)with a water-soluble amino-acid [(e.g.to (410)ltakes place with no loss of bioIogical activity.404 A full analysis of the I3C n.m.r. spectrum of A'-THC and related substances has been published,405and the n.m.r. spectrum of the synthetic analogue from phloroglucinol dimethyl ether and citral is discussed.406 Kane and Grayeck have extended Crombie's work on the condensation of citral with the phloroglucinol(441) (Vol. 2, p. 62). With two equivalents of citral,

OH

I

COMe

(442) R = Me (443) R = PhCH=CH

+ OH

OH

OH

OH

qecofJo HO

(445) ""

'Oh

(446) R' = Ac;R2 = H o r R ' = H ; R 2 = AC

W . Greb, D. Bieniek, and F. Korte, Tetrahedron Letters, 1972, 545. B . A. Zitko, J . F . Howes, R . K . Razdan, B . C. Dalzell, H . C. Dalzell, J . C. Sheehan, H . G . Pars, W . L . Dewey, and L. S. Harris, Science, 1972, 177,442; H . G . Pars, R . K . Razdan, and K . K . Weinhardt, Ger. Offen. 2 106705. E. Wenkert, D. W . Cochran, F. M . Schell, R . A. Archer, and K. Matsumoto, Experientia, 1972, 28, 250. V . V . Kane, Tetrahedron Letters, 1971,4104.

Mono t erpenoids

91

two products are formed, one of which (442)can be converted directly into rubramine (443).407 From the 1 : 1 condensation product (W),Combes et al. have made the c y c k product (445) with camphorsulphonic acid, and the acetylcannabicyclol (446) by U.V. p h o t ~ l y s i s . ~A" ~very full paper409 on the synthesis of A'-THC and A6-THC has been published by Mechoulam et af. They give a historical survey first and then reinvestigate the Taylor synthesis (citral and olivetol), in which, by using a lower concentration of boron trifluoride, they achieve 20% of (+)-A'-THC, and 5 % of A'-cis-THC, probably the best method for making the racemate published so far. In order to make optically active THC, they used optically active verbenol(447) with olivetol(435) in the presence of toluene-psulphonic acid, when the major product (448)can be converted into A6-THC with boron trifluoride etherate, and A'-THC is obtained by the known route (Scheme 34). A6-THC can be obtained in one step in 44%yield with boron t r i f l ~ o r i d e . ~ ' ~ The (+)-isomers (non-natural) accessible by this route are not active biologic a l ] ~ O. ~

'

+ J OH

(447)

15%

(435)

Reagents: i, p-TsOH; ii, BF,--Et,O; iii, ZnC1,-dry HCI; iv, K t-amylate.

Scheme 34 407 408 409

V. V. Kane and T. L. Grayeck, Tetrahedron Letters, 197 1 , 399 1. G . Combes, J. Moutero, and F. Winternitz, Compt. rend., 1972, 274, C , 13 13. R. Mechoulam, P. Braun, and Y . Gaoni, J. Amet-. Chem. SOC.,1972,94,6159. H , Edery, Y . Grunfeld, Z. Ben-Zvi, and R. Mechoulam, Ann. N e w Yurk Acad. Sci., 1971, 191,40.

Sesquiterpenoids BY J. S. ROBERTS

1 Farnesane

Fungal metabolism of ( f )-lO,l 1-epoxyfarnesol by Hrlminthosporium satiuum occurs preferentially with the dextrorotatory enantiomer, producing ( - )-10,11dihydroxyfarnesol (1 ; R = CH,OH), (-)-10,ll-dihydroxyfarnesic acid (1 ; R = C0,H). and (-)-9,lO-dihydroxygeranylacetone (2).' By chemical transformations,' (1 ; R = CH,OH) has been converted into R-( )-10,l l-epoxyfarnesol (3) and S-( -)-10,ll-epoxyfarnesol (4),both of which may be useful in sesquiterpenoid biosynthetic studies. In an attempt to induce terminal cyclization of a farnesyl derivative, thus generating a member of the germacrene series, Schwartz and Dunn3 have investigated the co-ordination of farnesyl methyl ether with potassium tetrachloroplatinate(~r). Although a number of o-complexes were formed, none of these underwent acid-catalysed cyclization. . ~presented a second, independent proof of the absolute Nakanishi et ~ 1 have stereochemistry of the ( +)-C, Cecropici juvenile hormone (5).This determination

+

OH

OH

0

'

'

(4) Y . Suzuki and S. Marumo, Trtruhedron Letters, 1972, 1887. Y . Susuki and S. Marumo, Chem. Comm., 1971, 1199. M . A. Schwartz and T. J . Dunn, J . Amer. Chem. Soc., 1972,94,4205. K . Nakanishi, D. A . Schooley, M . Koreeda, and J . Dillon, Chem. Comm., 1971, 1235; K . Nakanishi, XXlIIrd I.U.P.A.C. Special Lectures, Boston, U.S.A.. Butterworths, London, 1971, Vol. 3, p. 27.

92

Sesquiterpenoids

93

(5) R = Et (6) R = Me

was achieved by application of a new c.d. method suitable for acyclic and cyclic 1,2-diols using tris(dipivaloy1methanato)praseodymium. For the past five years the syntheses of the C and C , juvenile hormones have attracted a great deal of attention in various research laboratories throughout the world and this year has been no exception. The emphasis this year has been on larger-scale syntheses while still retaining high stereoselectivity. Recognizing the synthetic potentialities of both neryl (7) and geranyl (8) acetates in the con~ ~accomplished the struction of the CI7 juvenile hormone (6), G r i e ~ ohas sequence outlined in Scheme 1. The overall strategy of this synthesis is similar to

A

CHO

I

(PPh,),RhCI

OAc

I

I,

11.

(7)

111.

I\,

(8) iii. PBr,

(9)

Scheme 1 's

p. A . Grieco, J . C . S . Chem. Cornm., 1972,486

1

MeOH-K,CO, MeLi rsct PhS

94

Terpenoids and Steroids

that reported earlier by van Tamelen er a / . s bAlkylation of (9) using the anion derived from (10)yielded the thioether ( I 1) which has previously been elaborated to (6). One of the merits of this route, as originally demonstrated by Stork et a[.,' is that by retaining the requisite trisubstituted double bonds in the precursors ( 7 ) and (8) the problems associated with the stereospecific introduction of trisubstituted double bonds have been eliminated. This has always been a key factor in juvenile hormone syntheses. Cochrane and Hanson7' have reported two syntheses of the C I Shormone, the The latter first of which followed along the lines first described by Braun er stages of the second synthesis (Scheme 2) utilized a number of steps which have

-

+

I.T\CI py

'\\\

11.

111.

Nal

PPh,

1-

Scheme 2

already been described in this field.8 The syntheses of a number of key intermediates for the construction of the juvenile hormones have also been described . ~ include the two alcohols (12) and (14)and the ketone (15). by Mori et ~ 1 These The stereospecific synthesis of (13)was achieved independently along the same lines as those described by Corey er a/..'' but in view of the iow overall yield a stereoselective synthesis of this compound was also performed as shown. A similar process was used for the stereoselective synthesis of (141, which involved ' b

' '

' ' Ir'

E. E. van Tamelen. P. McCurry. and U . Huber. Prnc. A'at. Acad. Sci. U . S . A . , 1971, 68, 1294. G . Stork. M . Gregson. and P. Grieco, Tetrahedron Letrers, 1969, 1391, 1393. ( a ) J . S. Cochrane and J . R. Hanson, J . C . S . Prrkin I , 1972, 361 ; ( b )B. H . Braun, M. Jacobsen, M . Schwarz, P. E. Sonnet, N . Wakabayashi, and R. M . Waters, J. Eeon. Entomal., 1968, 61, 866. E. J . Corey, J . A . Katzenellenbogen. W . H. Gilman, S. A . Roman, and B. W . Erickson. J . Amer. Chenz. Soc., 1968, 90, 5618. K. Mori, M . Ohki, A . Sato. and M . Matsui, Tetrahedron, 1972,28,3739; K. Mori, ibid., p. 3747. E. J . Corey, J . A . Katzenellenbogen, S. A . Roman, and N . W . Gilman, Tetrahedron Letter.$. 197 1 . 182 I .

95

Sesquiterpenoids

III

111 &OH%

L

O

H

+ trans-isomer (15%)

(13)

(14)

the di-imide reduction of the known alcohol (1 3). The bromo-derivative of (12) was utilized ‘in the synthesis of the well-known ketone (15) as outlined in Scheme 3. The major problem with the above sequences is the over-reduction of the conjugated ene-yne system with di-imide. from the Zoecon Corporation describe the stereoTwo recent papers’ selective syntheses of both C , , and C18hormones which are suitable for relatively 0

Br

C02Et

I

i. Ba(OHl,-heat NaC-CH

11.

rB-

I

“ OH I I,

11.

111.

NaCN HN=NH MeMgl

(15) Scheme 3

’

C. A . Henrick, F. Schaub, and J. B. Siddall, J . Amer. Chrm. SOC.,1972,94, 5374. R . J . Anderson, C. A . Henrick, J . B. Siddall, and R. Zurfliih, J . Amer. Chem. Soc., 1972,94, 5379.

Terpenoids and Steroids

96

large-scale production of pure material. These syntheses, starting from known synthetic intermediates, are summarized in Schemes 4 and 5.

OH

CO,Me

Me0,C

I

I.

11.

I I I.

LIAIH, IC,H5N)2Cr0, E t C(0Me)=PP h,

(16) NCS

--

1

aq acetone

<

c02 Me

c1

+ ca. 187; erythro-isomer

H (5) Scheme 4a

97

Sesquiterpenoids

1

i, '0,ii, HMPA

L

C

l

+

OH

\

MeC(OEt),-H+

7

i, NaAIH,(OCH,CH,OMe),

ii' (C5H5N)2Cr03

l i i i . (CH,OH),-H+

I

i. Li ii, Cul iii, M e C E C C 0 , M e iv, H , O +

OHC

W

c

o

m

1

EtC(OMe)= PPh,

Scheme 4b The second paperI2 also describes the first reported conversion of the C17 hormone into the homologated CI8hormone. This was accomplished by singlet oxygen addition to the C17 compound and in situ reduction of the resultant hydroperoxides with hexamethylphosphoramide. This yielded as the major

98

Terpenoids and Steroids

1

NBS aq.THF

Br

1

NCS aq acetone

0x' ( d A / J b C 0 2 M e

\

+ ca. 18 7; erpthro-isomer

H 16) Scheme 5

99

Sesquiterpeno ids

product the allylic alcohol (17), the acetate or 3,5-dinitrobenzoate of which was treated with lithium dimethylcuprate. The C,, hormone ( 5 ) was obtained from the reaction mixture together with its A'-cis-isomer. The very attractive possibility of direct conversion of (1S), derived from ethyl trans,trans-farnesoa te, into the bis-homologated ester was not so successful in the sense that only a small amount of the desired truY1s,truns,ciS-isomer was obtained.

CO,Et OAc

OAc

(18)

A second synthesis of the biologically active imino-analogue of the C, hormone (19) has been r e p ~ r t e d 'together ~ with the trans-isomer (20).

A component of the defensive secretion of gyrinid beetles has been identified14"9'46 as the nor-sesquiterpenoid aldehyde gyrinidal (21). The odour associated with the essential oil of Artemisia pallens Wall. has been ascribed to three stereoisomers of davana ether (22) which have been synthesized by epoxidation of the enone double bond of the co-occurring ketone, davanone (23),followed by treatment with acidic ion-exchange resin.'

'

l3

l4

Is

R. J . Anderson, C. A. Henrick, and J. B. Siddall. J . Urg. Chem., 1972, 37, 1266; J . B . Siddall, R. J. Anderson, and C. A. Henrick, XXlIIrd I.U.P.A.C. Special Lectures, Boston, U.S.A., Butterworths, London, 1971, Vol. 3 , p. 17. ( a ) J . Meinwald, K . Opheim, and T. Eisner, Proc. Nut. Acad. Sci. U.S.A., (6) H . Schildknecht, H . Neumaier, and B. Tauscher, Annalen, 1972, 756, 155. A . F. Thomas and G . Pitton, Helt.. Chim. Acta, 1971, 54. 1890.

Terpenoids and Steroids

100

A large number of new furanosesquiterpenoids of chemotaxonomic interest have been isolated and identified; these include lasiospermane (24) and its two dehydro-derivatives (25) and (26),16 phymaspermane (27)" and its dihydroderivatives (28) and (29),dehydro-ngaione (30),(31),athanasin (32), cis- and trunsdehydrongaional (33) and (34), ( 3 3 , (36),and (37).'* Two further examples are sesquirose furan (38)and longifolin (39).

'

1 / 0\

(30)

'Is l9

H. Bornowski, Terrahedron, 1971, 27, 4101. F. Bohlmann and C. Zdero, Terrahedron Letters, 1972, 851. F. Bohlmann and N . Rao, Tetrahedron Letters, 1972, 1039. N . Hayashi, H. Komae, S. Eguchi, M. Nakayama, S. Hayashi, and T. Sakao, Chem. ond Ind.. 1972, 572.

Sesqu iterpeno ids

101

(34)

(35)

, , , h 2 Mono- and Bi-cyclofarnesanes On the basis of photo-oxygenation studies of certain carotenoids2' and the synthesis of optically active ethyl abscisate,21 the absolute configuration of (+)-abscisicacid has been revised* to S and is therefore defined by structure (40). Radioactive derivatives of abscisic acid have been prepared for biological studies. These include samples with 14C labelling at C-1022and 3H labelling at C-2, C-4, and the methyl group on C-5.23 2o

22

23

S . Isoe, S.-B. Hyeon, S. Katsumura, and T. Sakan, Tetrahedron Letters, 1972, 2517. T. Oritani and K. Yamashita, Tetrahedron Letters, 1972, 2521. J.-C. Bonnafous and M. Mousseron-Canet, Bull. SOC.chim. France, 1971, 4551. J.-C. Bonnafous, L. Fonzes, and M. Mousseron-Canet, Bull. SOC.chim. France, 1971, 4552.

* See G. Ryback, J.C.S. Chem. Comm., 1972, 1 190.

Terpenoids and Steroids

102

Two new compounds. blumenol B (41 ;R = OH) and C (41; R = H), have been isolated” from the leaves of Potlocurpus bluniei Endl. These co-occur with !.omifolio1 (42: R = O H ) and on the basis of 0.r.d. data they have been shown to have the same absolute stereochemistry at the ring chiral centre as abscisic acid in the revised form (40). The dehydro-derivative (42; R = H) of blumenol C has been identified as a constituent of Greek t o b a ~ c o . ~ ’ have now Following their recent isolation of cyclonerodiol(43), Nozoe et completed its synthesis. which in turn established the relative stereochemistry at three of the four contiguous chiral centres. Thus, pyrolysis of linalool (44) afforded plinol-C (45)as a major ’ene’ product, which, on ozonolysis, epimerization. and reaction with 4-methylpent-3-enylmagnesiumbromide yielded cyclonerodiol (probably as a diastereoisomeric mixture!. Complete details of the X-ray structural analysis of isocollybolide (46) have been published.”

’‘ ‘j

”

‘-

(46) M . N . Galbraith and D. H . S. Horn, J . C . S . Chem. Comm ., 1972, 113. A . J . Aasen, B . Kimland, and C. R . Enzell, Acta Chem. Scand., 1971, 25, 1481 S. Nozoe, M . Goi, and N . Morisaki, Tetrahedron Letters, 1971, 3701. C . Pascard-Billy. Acta Cryst.. 1972, B28. 331.

103

Sesquit erpeno ids ( - )-limonene

HO

p (49) + E-isomer

( + )-limonene

Scheme 6

Terpenoids and Steroids

104

3 Bisabolane, Bergamotane, Campherane, Santalane, and Related Tricyclic Sesquiterpenoids With few exceptions the syntheses of bisabolane sesquiterpenoids have been accomplished by non-stereospecific, multi-stage routes. A significant break. , ~ ~ have found that through in this field has been reported by Crawford et L Z ~ who limonene can be selectively metalated at C-10 with the n-butyl-lithium-NNN’N’tetramethylethylenediamine complex. The resultant ally1 carbanion, e.g.(47), can then be converted into a number of derivatives suitable for further elaboration to bisabolane-type sesquiterpenoids, as outlined in Scheme 6. This versatile sequence has been cogently illustrated by the short syntheses of ( - )-fl-bisabolene (48), ( - )-lance01 (49), ( & )-dihydro-ur-turmerone (50), (+)-ar-turmerone (51), ( + )-/?-atlantone (52), and ( + )-r-atlantone (53). An additional bonus of this sequence is the fact that the metalation-derivatization of optically active limonene occurs without racemization at the chiral centre at C-4. Two further points of interest emerge from this work, ciz. the structure of naturally occurring lanceol is considered to be (49) rather than the previously suggested E-isomer and r-atlantone, as isolated from Nature, is practically racemic.

HO

PP (56)

(57)

Further non-stereospecific syntheses of isobisabolene (54) and P-bisabolene (48) have been reported by Vig and c o - ~ o r k e r s The . ~ ~ structural and stereochemical assignments of delobanone (55 ; R = H) and its acetoxy-derivative (55 ; R = OAc) have been carried out and, furthermore, this study has demonstrated that cryptomerion has the absolute stereochemistry depicted by ( 56).30 Two recent additions

’’ R . J. Crawford, W . F. Erman, and C. D. Broaddus, .I. Arner. 2q

.’(I

Chem. SOC.,1972, 94, 4298. 0. P. Vig, S. D. Sharma, K. L. Matta, and J . M . Sehgal, J. Indian Chem. Soc., 1971,48, 993. K. Takeda, K. Sakurawi, and H. Ishii. Tefruhedron, 1971, 27, 6049.

105

Sesquiterpenoids

to this group of sesquiterpenoids are a-bisabololone (57)31 and bisabolene oxide (58),32 both of whose structural assignments rest primarily on spectroscopic evidence.

A (59)

Rogers and Manville3j have isolated the acid (59) from the British Columbia Interior variety of Douglas fir. This compound is closely related to juvabione but one interesting feature is that they differ in absolute stereochemistry at the exocyclic chiral centre. The exact formulation of the naturally occurring bergamotenes has posed a difficult problem. Ultimate solution lay in total synthesis,an approach which was initiated by Gibson and E r m a r ~ whose , ~ ~ work, although clarifying part of the problem, still left certain questions unanswered.* Corey et have now provided another part of the jigsaw in the successful syntheses of racemic or-transbergamotene (63) and P-trans-bergamotene (64). Comparison of these with the naturally occurring bergamotenes shows that (63) is identical with a natural isomer and (64) may be identical with a minor constituent of opopanax oil. These results, taken in conjunction with Gibson and Erman’s studies, clearly demonstrate that Bhattacharyya’s ‘bergamotene’ from Indian Valerian root oil must, in fact, have a different carbocyclic structure. The Harvard syntheses of the two bergamotenes are outlined in Scheme 7. The crucial steps in this sequence are the construction and subsequent photo-cyclization of the appropriately functionalized triene (60)and the ring-expansion of the bicyclo[2,1,1]-derivative (61) to the requisite bicyclo[3,l,l]heptanone (62). Although the structure of the antibiotic fumagillin (65) has been known for over ten years, a total synthesis of this unique sesquiterpenoid has eluded synthetic endeavour. Corey and Snider36 have now successfully taken up this challenge,culminating in the ingenious and successful route described in Scheme 8. The complete details of the synthesis of racemic dihydro-P-santalol (66) have been p~blished.~’ A new three-step synthesis of p-santalene (71) has been ”

F. Bohlmann and N. Rao, Tetrahedron Letters, 1972, 1295.

’’ P. A. Hedin, A . C . Thompson, R . C. Gueldner, and J. M . Ruth, Phytochemistry, 1972, 11, 2118. I . H . Rogers and J . F. Manville, Cunad. J . Chem., 1972, 50, 2380. 3 4 T. W . Gibson and W . F. Erman, J . Amer. Chem. Soc., 1969,91,4771. ” E. J . Corey, D. E. Cane, and L. Libit, J . Amer. Chem. Soc., 1971,93, 7016. ’’ E. J . Corey and B. B. Snider, J . Amer. Chem. SOC.,1972, 94, 2549. 3 7 W . I. Fanta and W . F. Erman, J . Org. Chem., 1972,37, 1624. * Another synthesis of a-cis-bergamotene has been reported; see K . Narasaka, M . Hayashi, and T. Mukaiyama, Chem. Letters, 1972, 259. 33

Terpenoids and Steroids

104 1. 11.

OAc

0, ICH20H12-H'

III.

K,CO,-MeOH

I\,

PBr,-CaH,

0

0

mo ,

111. 11. I, ICF,COJ,O KHCO, H202

0

U

I,

1

I.

11.

1

NaBH, H,O-

F1.

11,

CHO

H,O'

I,

11.

11;.

IV,

NaBH, py-SO,-LiAIH,'

NaBH, PBr, Na*NHNHTC HOAC-OAC

(631

11,

(Me),C=PPh,

Sesquiterpenoids

107

0 &CO,Me

LB~+ L c 0 , M

e

11. I , OH-

6 C0,Me


OHC Br p

c

o

2

M

e

~

>C02Me

I

i, NaBH, ii. Me,SiCI-Et,N iii. m-CIC,H,CO,H

Br

Me,SiOH,C

C0,Me CO, Me

> i Bu N ' F -

/

1

I,

11.

P

H

1.

11,

OaO, NdOArn' hlcl

CO,h,le

MeLi

Ac2O-p~

'OMe

'OMe

OH

OAc

1

i, MsCI-Et,N ii, Bu,N'Br-

1,

KZCO,

MeLiCIOC(C&CH),COCI

b

11,

'OMe

I

OAc

0,

c-

4

(CH+CH),CO,H

0

(65) Scheme 8

108

Terpenoids and Steroids

reported.38 This involved alkylation of the lithio-salt of camphene sultone (67) with 1-bromo-3-methyl-2-butene to give a 1 : 1 mixture of the products (68) and (69), which, on aluminium hydride reduction followed by dehydration of the resultant alcohol (70),gave /?-santalene in 56 % overall yield from (67).

The full paper on the total synthesis of copacamphene (72) and its acidcatalysed interconversion with sativene (73) has been published by M ~ M u r r y . ~ ~ Last year Money et ~ 1 . ~reported ' an efficient route for the conversion of dihydrocarvone into campherenone (74) and epi-campherenone (75). Not only has the efficiency of this synthesis been improved but recently Money et uL4' have demonstrated that these two bicyclic ketones are at the epicentre of a very kersatile synthetic sequence (Scheme 9). The full development of this scheme has still to be realized since copacamphor (76) is a potential precursor of copaborneol (78), copacamphene (72), and cyclocopacamphene (79) in the same sense as ylangocamphor (77) is related to epi-copaborneol (80), sativene (73), and cyclosativene (81). As suggested by these authors,suitableelaboration ofcampherenone could also permit entry into the longi- series as exemplified by longicamphor (82). 38

'' 40 4'

J . Wolinsky, R . L. Marhenke, and R . Lau, Synthetic Cornrn., 1972, 2 , 165. J . E. McMurry, J . Org. Chem., 1971, 36, 2826. G. L. Hodgson, D. F. MacSweeney, and T. Money, Chem. Cornrn., 1971, 766. G . L. Hodgson, D. F. MacSweeney, and T. Money, Tetrahedron Letters, 1972, 3683.

109

Sesquiterpenoids

+\

a-santalene

1

ii, TsCI-py

m-CIC,H,CO,H

Scheme 9

epi -1-san talene

I10

Terpenoids and Steroids

It is interesting to note that the enol-acetate of(74)didnot undergo the anticipated acid-catalysed ring-closure to give either (76) or (77). In the course of preparing a labelled sample of copacamphor (76) for bio' that, in contrast to the relative synthetic studies (cide infra),Arigoni et ~ 1 . ~found ease of incorporation of up to three deuterium atoms into longicamphor (82) under homoenolization conditions (Bu'OK in Bu'OD; sealed tube; 48 h ; 185 "C), copacamphor (76)could only be induced to exchange its bridgehead proton under the same conditions. These results reflect the subtle effect of a four-carbon bridge verbus a three-carbon bridge joined to C-2and C-7 of a bicyclo[2,2,l]heptan-3-one nucleus in the honioenolization process. Earlier biosynthetic studies had strongly implicated copaborneol (78) in the biosynthesis of certain members of the picrotosane group of sesquiterpenoids. This suggestion has now been verified by the

unambiguous demonstration of the in v i m conversion of tritium-labelled copaborneol [starred position in (78)] into tutin (83).43 In a further probe of the have shown that tutin derived from biosynthesis of tutin (83), Jommi ef (4R)-[4-3H]mevalonicacid retains one tritium atom at C-4. This result therefore excludes the possibility of a double 1,z-hydride shift in the hypothetical germacradiene cation (84)which has been suggested as one possible starting point for the subsequent cyclization steps to a tricyclic derivative such as copaborneol. A compound, previously known as pseudotutin, has been shown to be a 1 : 1 nnolecular complex of tutin (83) and corianin (85).45 Two synthetic approaches

'' ''

+

K . W . Turnbull, S. J . Gould, and D. Arigoni, J.C.S. Chem. Comm., 1972,597. K . W. Turnbull, W . Acklin, D. Arigoni, A. Corbella, P. Gariboldi, and G . Jommi, J.C.S. Chrm. Cotnm., 1972. 598. A . Corbella, P. Gariboldi, and G. J o m m i . J.C.S. C ' l w t r i . Co m m ., 1972, 600. T. Okuda and T. Yoshida. Trrruhedron Lrrrers. 1971, 4499. Compounds with this absolute stereochemistry are not yet known

111

Sesguiterpenoids

to this group of sesquiterpenoids have been announced. These include the formation of the diketo-acid (86)46and the keto-acid (87).47 Two new members of this group include 4-hydroxydendroxine (88)and nobilomethylene (89).48

HQ,C

0 'H

'H

CQ,H

H

@

0

'H

4 Cadinane, Copaane, Ylangane, and Cubebane Lin et have re-opened the controversy concerning the structure of ( - ) torreyol [( -)-6-cadinol]. They suggest that it should be the amorphane derivative (90) but their evidence for this assignment still does not exclude Westfelt's J6

K. Yamamoto, T. Sohda, I . Kawasaki, and T. Kaneko, Bull. Chem. SOC.Japan, 1971,

44,2197. 47

48

49

Y . Hayakawa, H . Nakamura, K . Aoki, M . Suzuki, K. Yamada, and Y . Hirata, Tefrahrdron, 1971, 27, 5157. T. Okamoto, M . Natsume, T. Onaka, F. Uchimaru, and M . Shimizu, Chem. andPharm. Bull. (Japan), 1972, 20, 418. Y . T. Lin, Y . S . Cheng, and Y. H . Kuo. Tetrahedron. 1971. 21. 5 3 3 7 .

112

Terpenoids and Steroids

structure (91).” In fact, the Chinese authors admit that (-)-torreyo1 gives rise to pmuurolene (92), a-muurolene (93), and 6-cadinene (94) on dehydration, a finding which is difficult to reconcile with the amorphane stereochemistry. Zonarene (95) is reported to be the major hydrocarbon component of the brown seaweed, Dictyopteris zonaroiodes.

(931

(94)

(95)

It is now well recognized that the various varieties of vetiver oil provide a prodigious hunting-ground for sesquiterpenes of different structural types. In this respect the vetiver plant could be a very fruitful test-bed for biogenetic proposals. Recently, Raj et aLS2 have isolated (+)-khusitene (96) from two varieties of North Indian vetiver oil and it would appear that this compound is antipodally related to similar nor-sesquiterpenoids such as khusitone (97). In another study of North Indian vetiver oil ( Vetiueria zizanioides Linn), Trivedi et aLS3 have isolated the new sesquiterpene, (-)-y-cadinene (98), together with

50

51

52

53

L. Westfelt, Acra Chem. Scand., 1970. 24, 1618. W. Fenical, J . J . Sims, R. M . Wing, and P. C. Radlick, Phyfochemistry, 1972, 11, 1161. B . Raj, J . C . Kohli, M . S. Wadia, and P. S. Kalsi, Indian J . Chem., 1971, 9, 1047. G. K . Trivedi, K . K . Chakravarti, and S. C . Bhattacharyya, Indian J . Chem., 1971, 9, 1049.

113

Sesquiterpenoids

H i

A

HO

&

(99)

the known compounds, (- )-y,-cadinene (99), (- )-&cadino1 (91), and ( + )khusimol (100). Burk and Soffers4 have now synthesized (-)-7,-cadinene (99) from a precursor previously used in the synthesis of (+)-~-cadinene(101). In connection with the potential syntheses of this group of sesquiterpenes, the are of interest. They have found that the Birch reduction results of Piers et of 4-alkyl-A'(9'-2-octalonesis highly sensitive to the configuration of the 4-alkyl group, as is demonstrated by the fact that (102)and (104) gave stereoselectively the ketones (103) and (105) respectively.

54

55

L. A. Burk and M . D. Soffer, Tetrahedron Letters, 1971, 4367. E. Piers, W . M . Phillips-Johnson, and C. Berger, Tetrahedron Letters, 1972, 2915.

114

Terpenoids and Steroids

A useful method of effecting aromatization of certain sesquiterpenes has been reported.56Thus, treatment of a selection of cadinane-type sesquiterpenes in an n-decane solution with excess trifluoroacetic acid at room temperature resulted in rapid conversion into calamenene (106). A careful study using n.m.r. and c.d. techniques has permitted the assignment of the absolute stereochemistry of the naturally occurring ~ a l a m e n e n e s .The ~ ~ major laevorotatory isomer from the leaf oil of Alaska cedar is (107) with a lesser amount of (-)-( 108). In contrast, the major calamenene from Cade and Cupressus oils is (108), together with the enantiomer of (107)as a minor component. I

Complete details of the structural and stereochemical assignment of chiloscyphone (109) have now been p~blished.’~ Another interesting source of antipodal sesquiterpenes is the Muhuhu tree (Brachylaena hutchinsii Hutch.). From this source Klein and Schmidts9 have isolated (-)-or-ylangene, (+)-or-copaene, ( + )-;,-amorphene, ( - )-6-cadinene, ( + )-x-amorphene, ( - )-or-calacorene,and the unusual tetrahydrofuran derivative, brachyl oxide ( 110). The ring-contracted cadinane sesquiterpenoid, oplopanone (11I) has now been synthesized in racemic form using a key photochemical step to construct the requisite perhydroindane skeleton.‘’ The synthetic sequence is outlined in Scheme 10. Yoshikoshi et ~ 1 1 . ~have ‘ published the complete details of their syntheses of the cubebenes and cubebol.

’’ ” 58

59 ‘()

N . H . Andersen, D . D. Syrdal. and C. Graham, Tetrahedron Letters, 1972, 903. N . H . Andersen, D. D. Syrdal, and C. Graham, Tetrahedron Letters, 1972,905. A . Matsuo, Tetrahedron, 1972, 28, 1203. E. Klein and W . Schmidt, J . Agric. Food Chem., 1971, 19, 1 1 15. D. Caine and F. N. Tuller, J . Amer. Chem. Soc., 1971, 93, 631 1 . A . Tanaka, R . Tanaka, H . Uda. and A . Yoshikoshi, J . C . S . P c r k i n I , 1972, 1721

Sesquiterpenoids

115

OMe

I

OMe

1

I. NaBH,

11.

Ac,O-py

i Ca-NH

L3 ii, CrO,

AcO

0@H

5 Cuparane, Thujopsane, Chamigrane, Acorane, , Jaskane, Cec rane, Zizaane, and Trichothecane Yamada et ~ 1 have . reported ~ ~ the synthesis of (112), which is a potential precursor of such sesquiterpenoids as aplysin (1 13).

'' K . Yamada, H . Yazawa, and Y . Hirata, Bull. Chem. SOC.Japan, 1972, 45, 587.

Terpenoids and Steroids

116

Br

( 1 13)

(112)

An interesting series of has served to unfold the complex story of the acid-catalysed rearrangements of thujopsene (1 14). In essence this story highlights an area of chemistry which is poorly understood at the present time,

T

Scheme 11 b3

64

65

66

H . U.Daeniker, A . R . Hochstetler, K. Kaiser, and G. C. Kitchens, J . Org. Chem., 1972, 37, I . W. G . Dauben, L. E. Friedrich, P. Oberhansli, and E. I. Aoyagi, J . Org. Chem., 1972, 37, 9. W. G. Dauben and L. E. Friedrich, J . Org. Chem., 1972,37, 241. W . G. Dauben and E. I . Aoyagi, J . Org. Chem., 1972,37, 251.

Sesquiterpenoids

117

namely the way in which the subtle interplay of thermodynamic stabilities and cation solvation in different acidic media can influence quite dramatically the reaction pathway(s). A combination of all the reports connected with the primary and sequential rearrangements of thujopsene is summarized in Scheme 11. A number of the compounds in this scheme had already been isolated by Japanese workers but the evidence for their structures was based largely on spectroscopic and mechanistic interpretations. It is also interesting to note that Daeniker et aL6’ have shown that the major product of acetylation of American cedarwood oil, which contains predominantly a-cedrene and thujopsene, is, in fact, the acetyl derivative (116) of the tricyclic hydrocarbon (1 15).

A further communication6* from the Givaudan group reports that hydroboration of dihydrothujopsene (117) follows an abnormal course from two standpoints. In the first place the major product is the tertiary alcohol (1 18), formed as a result of an atypical Markovnikoff hydration process, and secondly the minor product is the diol(l19), which presumably arises by the facile formation of an intramolecular dialkylborane intermediate.

have isolated another dibromo-sesquiterpenoid, johnstonol(120), Sims et from a species of seaweed of the genus Laurencia. This compound co-occurs with the closely related pacifenol in at least two species of this genus. Undoubtedly one of the major highlights in the sesquiterpenoid field this year has been the very interesting results concerning the co-occurrence patterns and in vitro conversions of sesquiterpenes within the farnesane,bisabolane, curcumane, acorane, alaskane, cedrane, and zizaane groups. For instance, Kaiser and 67

6* 69

H. U . Daeniker, A . R . Hochstetler, K . Kaiser, and G . C . Kitchens, J . Org. Chem., 1972, 37, 6. A . R . Hochstetler, J . Org. Chem., 1972, 37, 1883. J . J . Sims, W. Fenical, R . M . Wing, and P. Radlick, Terrahedrori Lerrers, 1972, 195.

Terpenoids and Steroids

I18

( 120)

Naegeli,-* in a detailed investigation of the essential oil of Vetiueria zizanoides (Stapf), have isolated a large number of new compounds (121)- (126). At the present time the absolute configurations of some of these, viz. (122)-125), have not been rigorously established and are based on the grounds of their co-occurrence and possible biogeneses (ride itfro). Of particular interest is the first recorded isolation of (+)-r-cedrene (126; R = Me). Furthermore, the same authors" have provided additional proof for the structures of two of these new compounds, (122) and (125; R = Me), by the synthetic sequence outlined in Scheme 12. Hydrogenation of ( 1 25 ; R = Me) gave the C-8 epimer of (128).

ROH (121)

R -

H R

=

Me, CH,OH, CHO, or C0,H (125)

-'R. Kaiser and P. Naegeli, "

i

pvR H

R = Me, CH,OH, or CHO (126)

Teirahedron Letters. 1972, 2009. P. Naegeli and R . Kaiser, Tetrahedron Letrers. 1972, 2013.

Sesquiterpeno ids

119

heat --+

a=( 133)

H

-

=(136)

H

Scheme 12

1

SnCI,

I20

Terpenoids and Steroids

The above results are very interesting in the light of some recent work by Demole et al.72 Previously these workers had studied the reaction of N-bromosuccinimide with ( +_ )-nerolidol and had shown that the intermediate bromofuran "C to derivative (129) could be dehydrobrominated with collidine at 11@-120 give (131), which arises by a [3,3] sigmatropic rearrangement of the initially formed triene (130). The cycloheptenone ( 1 3 l), on treatment with stannic chloride, cyclizes in 58 ol0 yield to the oxetan (132), which can be reductively

y

A

o

rearranged with a mixture of lithium aluminium hydride and aluminium chloride in 700, yield to afford the triene (127), which appears to be identical with that obtained by Kaiser and Naegeli." Demole and co-workers also found that (127) can be cyclized to 2,8-cedradiene (133) in 35"/, yield with boron trifluoride etherate. Furthermore, selective hydroboration and oxidation of (133) gave the ketone (134) which, on Wolff-Kishner reduction, yielded a mixture of a-cedrene (1 35) and 2-epi-r-cedrene ( 136). the latter of which could also be obtained from ( 133) by partial reduction.

H (133)

H (135)

H (136)

-'E. Demole, P. Enggist, and C. Borer, Helc. Chim.Acfa, 1971, 54, 1845.

Sesquiterpenoids

121

It is clear from these and previous results obtained over the past two or three years that the spiro-sesquiterpenes provide an important link between certain monocyclic and tricyclic sesquiterpenes. This is further exemplified by the recent l ~ ~have now reappraised the absolute stereowork of Andersen and S ~ r d a who chemistries of (-)-a- (137) and (-)-B-alaskene (138). It now appears that 6acoradiene, isolated by Hirose et al.,74is, in fact, (+)-8-alaskene. Andersen and Syrdal also made the interesting observation that phthalic anhydride dehydration of the diols derived from iso-acorone (1 39) gave rise to small amounts of ( + )-acedrene (126 ; R = Me) and ( - )-Zepi-a-cedrene (136). Subsequently these found that (+)-nerolidol(140)and a number of its derivatives undergo acid-catalysed cyclization to a mixture of c1- and /?-bisabolenes(141), of which the

latter is the major isomer and is predominantly laevorotatory. Of particular interest is the relatively high degree of optical purity (- 37 %) of the (-)-/?bisabolene obtained from the reaction of the lithio-salt of (+)-nerolidol with chlorosulphonyl isocyanate. To explain this high degree of asymmetric induction l 3 74

75

N . H. Andersen and D. D. Syrdal, Tetrahedron Letters, 1972, 899. B. Tomita, T. Isono, and Y . Hirose, Tetrahedron Letters, 1970, 1371. N. H . Andersen and D. D. Syrdal, Tetrahedron Letters, 1972, 2455.

122

Terpenoids and Steroids

a concerted elimination-cyclization pathway has been proposed. Further treatment of 8-bisabolene with tritluoroacetic acid gave a mixture of a-curcumene ( 142), x-cedrene ( 139, and 2-epi-a-cedrene (136) as racemates. This, therefore, constitutes the second report of the conversion of nerolidol into a-cedrene and must surely approximate to the actual biosynthetic pathway. In contrast to the acid-catalysed cyclization of nerolidol, treatment of farnesol with boron trifluoride etherate generates a rather more complex set of monocyclic, bicyclic, and tricyclic hydrocarbons. 7 6 These include a-, p-, and y-bisabolene, a-curcumene, r-cedrene, 2-epi-x-cedrene, 6-selinene ( 143), and the muuroladienes (144H147) [both epimers of (147),cf: zonarene (95)]. The formation of 6-selinene is interesting since it might imply that farnesol can undergo terminal cyclization to form a germacradiene cation which czn then ring-close (see, however, ref. 143).

(143)

A combination of the in citro results and co-occurrence patterns suggests a biogenetic map such as that outlined in Scheme 13. It should be noted, however, that alternative routes are available, e.g. Andersen and S ~ r d a have I ~ ~suggested a pathway leading from ( - )-nerolidyl pyrophosphate through to ( - )-a-cedrene ria ( - )-;*-curcumene. "'I

Y.Ohta and Y . Hirose,

Chem. Letters, 1972, 263.

Sesquiterpeno ids

123

I

+

T

v

T

I

“I I

‘

1

+

v

t

Terpenoids and Steroids

124

Joseph-Nathan et uL7’ have isolated three new cedrane-type sesquiterpenoids from Perezia heheclada, ri;. 3- (148; R = H), p- (149),and y- (148; R = angeloyl) perezols.

’ reported an attempted synthesis of acorone (150)using as Pinder et ~ 1 . ’ ~ have the key step to the spiro-system the intramolecular Michael reaction of the diketo-ester ( 151). An almost identical sequence, however, was reported eight years ago by Mellor and M ~ n a v a l l i ’in~ the ~ form of a personal communication! All attempts by Pinder and co-workers to effect isopropylation of the resultant spiro diketo-ester ( 1 52) met with failure.*

The synthesis of racemic ethyl acorate (153)has been reported by Birch et This task was achieved with some difficulty since initial attempts involving conjugate additions to appropriately substituted cyclohexenones were unsuccessful. Ultimately a viable route was devised as shown in Scheme 14. Yoshikoshi et aLEOhave published the complete details of the synthesis of epi-zizanoic acid (154). Having developed an efficient route for the construction

-’ P. Joseph-Nathan,

Ma. P. Gonziilez, and V. M . Rodriguez, Phyiochemislry, 1972, 11, 1803. (a) A. R. Pinder, S. J. Price, and R . M . Rice, J . Org. Chrm., 1972, 37, 2202; ( b ) J. M. Mellor and S. Munavalli, Quart. Rer., 1964, 18, 293. -’A . J. Birch, J. E. T. Corrie, P. L. Macdonald, and G. Subba Rao, J.C.S. Perkin I, 1972,

’’

1186.

F. Kido, H. Uda, and A. Yoshikoshi, J.C.S. Perkin I, 1972. 1755.

* Although preliminary results seemed to indicate some measure of success at this same penultimate step, thus justifying the personal communication to Mellor and Munavalli by Parker, Ramage, and Raphael, subsequent experimentation proved that isopropylation had not occurred (personal communication from Professor W. Parker).

125

Sesquiterpenoids

($

I,

THPO CN IMe),CIOH)CN H Z C 0 ,

I.

II,DHP-H'

111.

IMe),CHMGgBr Ac,O-p-TsOH

I. 111.

1.1 N H MeCH=CHCN

i. H , O , - O H 11,

iii.

Et,O'BF, H,O+

0

Scheme 14 of a suitably substituted bicyclo[3,2,l]octyl derivative in the course of alkaloid synthesis, Wiesner et ~ 1 . have ~ ' now utilized this key reaction in the first synthesis of zizaene (155). The synthetic sequence is described in Scheme 15 and this route also permitted the production of the two epi-zizaenes (156) and (157).

A . Deljac, W. D. MacKay, C. S. J. Pan, K. J. Wiesner, a n d K. Wiesner, Canad. J . Chern., 1972. 50, 726.

Terpenoids and Steroids

I26

1

I.

11.

LI \ H , - B u ' O H lCOzt1l:

0

+ epimer at C-2 0

HO

0

I

I

11.

111.

I\.

H

4c,0 py H L PJ c' (CHIOH), H ' KOH McOH

0 7

HO

#

III.KOH MeOH

I

I,

11,

CH,=PPh, Zn C u CH,I,

1 1 i . H ~PtO,

Scheme 15 continued on nest page

127

Sesquiterpeno ids

H

I

I.

oso,

ii.

NalO,

NaOMr

I. 11.

MeLi Ac,O -py heat

Scheme 15 A second and completely different approach to the synthesis of zizaene (155) has also been reported recently by Coates and S ~ w e r b y ” ,starting ~~ from norcamphor as illustrated in Scheme 16. An excellent review of the trichothecane sesquiterpenoids has been p~blished.’~ The major research activity this year with this group of fungal metabolites has been of a biosynthetic nature and will be discussed in the relevant chapter.

6 Daucane Within the context of the acoranexedrane type compounds it was noted that Demole er ~ 1 . ’had ~ identified the unusual oxetan compound (132) in the stannic chloride-promoted cyclization of (131). This compound appears to be an obvious candidate for conversion into carotol (165). However, it would appear that efforts to effect this conversion have not yet met with success. Naegeli and Kaiser7 also made the interesting observation that acid-catalysed cyclization of the diene-ol ( 1 58) (see Scheme 12) yielded, as the major product, a hydrocarbon whose spectral properties were identical with those of ( f)-daucene (160and 164). The above result was almost simultaneously communicated by Yamasaki,” who

’’ R . M . Coates and R . L. Sowerby, J . A m r r . Chem. Soc., 1972,94, 5386. ’’ R . L. Sowerby and R . M . Coates, J . Atner. Chem. S O C . ,1972,94,4758. 85

J . R . Bamburg and F. M. Strong, in ‘Microbial Toxins’, ed. S. Kadis, A . Ciegler, and S. J . Ail, Academic Press, New York, 1971, vol. VII, p. 207. M . Yamasaki, J.C.S. Chem. Cnm m . , 1972, 606.

Terpenoidsand Steroids

128

1 I.

11.

as-

1

i. N 2 0 J ii. N a O M e

Bun

I.

1

I.

11.

SaH- tiC0,Et

t

L I UH,-Bu'OH tiel

SPh

I. 11.

PhSCH,Li Bu"LI-PhCOCI

p&oph

Scheme 16

NBS CaCO,

Sesquiterpenoids

129

prepared the precursor (1 58) in optically active form from ( + )-limonene (1 59), as described in Scheme 17. The derived (-)-daucene (160) is the enantiomer of the naturally occurring compound and is about 50 % optically pure.

c

i. P h C 0 , H

i i , ~ , ~ + iii, NalO,

Q

’

HOAc

H ,

d-

CHO

A

A

I

i, acetone-OHii, Ph,Sn H-Ph Me- heat

(159)

i, H,-Pd-C ii, NaCGCH iii, Lindlar

A

A

1

HC0,H

Scheme 17

published the syntheses of (+)Shortly after this report Levisalles et daucene (164), (+)-carotol (165), and (-)-daucol (166) as shown in Scheme 18. The ketol (163) had been obtained previously from (+)-carvone (161) uia epi-acyperone (162). H. De Broissia, J . Levisalles, and H.Rudler, J.C.S. Chem. Comm., 1972, 8 5 5 .

130

Terpenoidsand Steroids

p

-

p

o

@

H

o

~

o

+ C-7 keto-isomer

1

I.

11.

MeMgl SOCl:-p).

H 0 P Scheme 18 7 Longifolane and Longipinane Ourisson et aL8' have shown that the alkylborane derived from hydroboration of longifolene (167)is auto-oxidized in the presence of oxygen to give the expected product (168) in about 33", yield and significant amounts of the two epimeric

'' Y. Tanahashi, J. Lhomme, and G. Ourisson,

Tetrahedron, 1972, 28, 2655.

Sesquiterpenoids

131

alcohols (169),both of which are derived by a transannular hydrogen-atom shift. In another paper the same authors" have described the results of solvolyses of the two tosylates corresponding to (169). Both tosylates give the olefins (170) which are derived by a ring-contraction mechanism.

Two new longifolane derivatives (171) and (172) have been isolated from Juniperus conferta Although both of these compounds have been converted into longifolene, no specific rotation was given and hence the absolute stereochemistry has still to be announced. This is relatively important since a number of antipodally related sesquiterpenoids are known, e.g. culmorin. An interesting rearrangement and fragmentation in the longifolane field has been reported." Treatment of o-bromolongifolene (173)with trifluoroacetic acid and subsequent hydrolysis gave the bromo-alcohol (174) in 30 % yield which, on oxidation and reaction with dimsyl sodium, yielded a mixture of the two ketones (175) in 80% yield by a fragmentation pathway. Both these compounds are potential synthetic precursors of such compounds as P-himachalene (176) and cr-longipinene (177).

Y , Tanahashi, J . Lhomme, and G. Ourisson, Tetrahedron, 1972, 28, 2663. K . Doi, T. Shibuya, T. Matsuo, and S. Miki, Tetrahedron Letters, 197 1, 4003. G. Mehta and S. K. Kapoor, Tetrahedron Letters, 1972, 715.

132

Terpenoids and Steroids

As another route to the longipinane skeleton, Miyashita and Yoshikoshi'l have described the synthetic sequence summarized in Scheme 19. The ketone (178) did not undergo a photochemical ring-closure to give (179) directly.

+ isomeric epoxide OH

1

I.

11.

111.

DHP-H' LIAIH, MsC1-p~

OMS 1

I, LIAIH, II.Ac,O py iii,

H,O'

=OH i, CH,=PPh,

ii,

HIO,

o *

P ( 179)

Scheme 19

8 Caryopbyllane, Humulane, and Related Tricyclic Sesquiterpenoids Some time ago it was claimed that caryophyllene (180)* is not a naturally occurring sesquiterpene and that it was an artefact of the steam-distillation process used in the extraction of clove buds. However, careful room-temperature 9'

*

M. Miyashita and A. Yoshikoshi, Chem. Cumm., 1911, 1091. The results of a biosynthetic study of caryophyllene are described in Chapter 7.

133

Sesquiterpenoids

extractim of clove buds with organic solvents has now shown that this is not the case and that caryophyllene is present in the intact Epoxidation of zerumbone (181) with hydrogen peroxide-sodium hydroxide gives the diepoxide (182), whereas substituting pyridine as the base produces the monoepoxide ( 183).93

The structure (184)of the second pseudoclovene (-B), obtained by dehydration of caryolan-1-01 (185), has now been determined by X-ray crystallographic means.94 Mechanistically this structure can be accommodated in the scheme

*oH

M

OH (186)

HO

OMe e

o

p

0 (187)

92 93 94

R. H . Walter, Phytochemistry, 1972, 11, 405. M. T. Saindane, P. S. Kalsi, and M . S. Wadia, Chem. and Ind., 1972, 77. R . I . Crane, C . Eck, W. Parker, A. B. Penrose, T. F. W . McKillop, D. M . Hawley, and J . M . Robertson, J.C.S. C h r m . Comm., 1972, 3 8 5 .

134

Terpenoids und Steroids

previously preposed to account for the formation of isoclovene and pseudoclovene-A. Two neN sesquiterpenoid metabolites, dihydroilludin M ( 186)95and illudacetalic acid ( 187),96 have been isolated from Clitocjbe illudens. Treatment of illudin S (188) with 40",, sulphuric acid at 0 "C gives the dimeric product (189) which is believed to arise by a retro-Prins reaction to generate formaldehyde and the acyl fulvene ( 190)followed by electrophilic recombination of the liberated formaldehyde and two molecules of the fulvene.97

0 0

0

Recently. Japanese workers reported the synthesis of the tricyclic compound (191)as a potential precursor of illudol (192). These authors98 have now completed the total synthesis in the manner shown in Scheme 20. Matsumoto er have published three papers describing the syntheses of a number of key intermediates used in the successful syntheses of illudin M and s.

"' P. Singh.

M . S. R . Nair. T. C. McMorris, and M. Anchel, Phytochemistry, 1971, 10, 2229. '' M . S. R . Nair and M. Anchel. Tetruhdron Lvtters, 1972, 2753. '' S. M. Weinreb. T. C. McMorris, and M. Anchel. Tetralredruon Letters, 1971, 3489. Q y T. Matsumoto. K . Miyano. S. Kagawa, S. Yii. J. Ogawa, a n d A. Ichihara, Tetrahedron Letters, 1971, 3521. 99 T. Matsumoto, H . Shirahama, A. Ichihara, H. Shin, S. Kagawa, T. Hisamitsu, T. Kamada, and F. Sakan, BIIII. Cllem. Suc. Japan, 1972, 45, 1136; T. Matsumoto, H . Shirahama, A. Ichihara, H . Shin, S. Kagawa, F. Sakan, S. Nishida, S. Matsumoto, K. Saito, and H . Hashimoto, ibid.,p. 1 1 4 0 ; T. Matsumoto, H. Shirahama, A . Ichihara, H. Shin, and S. Kagawa. ihid., p. 1144.

Sesquit erpenoids

135

,CHO HO MgBr

I, 11,

P

0,

H EtO

OEt

EtO

4, MsCl NaAIH,(OCH,CH,OMe), py 11,

& EtO

OEt

OEt

Me: EtO

OEt

i

(Mc),C=O H

Ho HO I H

0

NaAIH,(OCH,CH,OMe),

*

0 Scheme 20 A new sesquiterpenoid skeleton has been discovered in the form of lactarorufin A (193) isolated from Lactarius ~ t @ s . At~ the ~ ~ present time only the relative stereochemistry of the four asymmetric centres is known and it has been suggested that its biogenesis can be considered in terms of opening of the cyclopropylcarbinyl cation (194) which has previously been proposed in the marasmic acid biogenesis. In another study of Lactarius species, Magnusson et af."' have isolated the dialdehyde (195) which is closely related to marasmic acid. loo

lo'

W. M . Daniewski and M . Kocor, Bull. Acad. polon. Sci., Ser. Sci. chim., 1971, 19, 5 5 3 ; W. M . Daniewski, A. Ejchart, J. Jurczak, L. Kozerski, and J . S. Pyrek, ibid., 1972, 20, 13 I . G . Magnusson, S. Thoren, and B . Wickberg, Tetrahedron Letters, 1972. 1105.

136

Terpenoids and Steroids

Last year Lansbury and co-workers reported the first synthetic approaches to the fungal metabolite hirsutic acid C (196). They have now taken one of their previous intermediates (197)through to isohirsutic acid (201),which is a rearrangement product of hirsutic acid C . l o 2 Thus, Claisen alkylation of (197) with the alcohol (198) gave (199) together with the epimer at C-7. Treatment of (199) with 90°, sulphuric acid effected a number of transformations : (i) vinyl chloride hydrolysis, (ii) p-thiol elimination, and (iii) ester hydrolysis to generate (200),

H

H

v

H

H

( 200) (201) which underwent aldolization and esterification to give (201). Another approach to the hirsutane skeleton has been devised by Sakan et u1.'03 as outlined in Scheme 21. '03

P. T. Lansbury, N . Y . Wang, and J. E. Rhodes, Tetrahedron Letters, 1972, 2053. F. Sakan, H . Hashimoto, A. Ichihara, H . Shirahama, and T. Matsumoto, Tetrahedron Letters, 197 1 , 3703.

Sesquiterpeno ids

a)r-cr3<")

137

H

H

d MeOCH:

H

OMe

+ epinier

0

A

i. H ' CrO,

ii.

iii. CH,N,

I,

HC0,Et

MeO,C H

H

CH,OH

H

H Scheme 21

9 Germacrane A review of the germacrane sesquiterpenoids has been presented by 50rrn.l'~ Continuing their work on germacrene (202), Sam and Sutherland l o 5 have found that addition of photochemically generated singlet oxygen to this triene gives rise to the two compounds (203) and (204). This result is in contrast to the epoxidation of germacrene in which it has been shown that both endocyclic double bonds are considerably more reactive than the exocyclic double bond. On

I"'

F. Sorm, J . Agric. Food Chem., 1971, 19, 1081. T. W . Sam a n d J. K . Sutherland, J . C . S . Chrm. Cowirn.. 1972. 424.

Terpenoids and Steroids

0 (206)

(207)

(208)

the other hand, reaction of germacrene with another singlet oxygen source, namely the triphenyl phosphite-ozone complex. at -45 "C gives (205) as the major product. Overall. these results are in accord with the 'ene' mechanism for singlet oxygen addition. In another study of the cyclization of the germacrane skeleton. Iguchi et ~ 1 . ' ' ~have treated the epoxygermacrone (206) with 809; formic acid. A major product of this reaction is the bicyclic hydroxy-ketone (207) which, on acetylation and isomerization, yields (208), a compound which can also be obtained from ( 2 0 6 ) by reaction with potassium t-butoxide followed by acetylation. This is the first report of the formation of a cis-eudesmane product from a ten-membered-ring precursor. Three years ago Corey and Broger'"' attempted the synthesis of hedycaryol (210) but found that a Cope rearrangement of one of the intermediates could not be prevented under the experimental conditions and thus they achieved a synthesis of elemol. Wharton er a1.,lo8 using a different approach to generate the labile 1,5-dimethyl-trans,rrans1,5-~yclodecadienesystem, namely a Marshal1 fragmentation, have been more successful. Their synthetic methodology is shown in Scheme 22. Wolff-Kishner reduction of the ketone (209) gave a mixture of ( & )-7-eudesmol(2 1 1) and ( & )-epi-;b-eudesmol (2 12). The complete details of the isolation, structural elucidation, and syntheses of a number of closely related sesquiterpenoids from Acorus calainus L. have been published. 09. ' ' M . Iguchi. M. Niwa. a n d S. Y a m a m u r a , J . C . S . Chetn. Cotiitn., 1972, 689. E. J . Corey a n d E. A . Broger. Tetrnhedrari Le"crY. 1969. 1779. P. S . Wharton. C. E . Sundin. D . W. Johnson. a n d H. C. Kluender, J . O r g . C'hrnr.,1972, 37, 34. S. Yamamura. M . Iguchi, A . Nishiyama, M . Niwa, H . Koyama, a n d Y . Hirata, Tefruh d r o t i . 197 I , 27, 54 19. K . Kato. Y. Hirata. and S. Y a m a m u r a . Terruiietirotr, 1971, 27. 5987.

Sesquiterpenoids

139 i, H,-RuO,-IOO"C

Me0,C

C0,Me

\

260 "C

Me0,C

I , NalO,

0

C0,Me

I.

OH

ii.

Q I 11,

MeLi Me,SO-l3OoC

J

NaH-Me1

I

ii, TsCI-py

i, LiAlH,

OH

+moH

I 40

Terpenoids and Steroids

Watanabe and Yoshikoshi' l 1 have converted dihydro-u-santonin (213) into dihydronovanin (216; R = a-Me), the reduction product of novanin (216; R = =CH,), by a route which is not dissimilar to that used by Corey and Hortmann in the synthesis of dihydrocostunolide. Enol acetylation of (213) with isopropenyl acetate gave the diene (214) which, on photolysis and treatment with potassium hydroxide, yielded the dienone (215). Reduction of (215)with sodium borohydride and subsequent acetylation afforded (216; R = r-Me).

The new germacrane trio], agaratriol (217), has been isolated from Achillea ageratum L.,' and dehydrocurdione (218) from Curcurnu zedoaria.' l 3 Matsueda' l 4 has reported that hydrogenation of parthenolide (219) on 10% palladium-charcoal does not yield the simple 1 1,13-dihydro-derivative as ~ that the product is, in fact, the dihydroindicated by Govindachari et ~ 1 . ' ' but guaianolide (220). It should be noted, however, that Govindachari et al. have

OH

I

'

'I2

' I 3

Q

M . Watanabe and A . Yoshikoshi, J . C . S . Chern. Comm., 1972, 698. L. Garanti, A. Marchesini, U . M . Pagnoni, and R . Trave, Tetrahedron Letters, 1972, 1397. H. Hikino, C. Konno, and T. Takemoto. Chem. and Pharm. Bull. (Japan), 1972, 20, 981.

'I4

'I5

S. Matsueda, Sci. Reports Hirosaki Unir., 1971, 18, 8 . T. R.Govindachari, B. S. Joshi, and V. N . Karnat, Terrahedrun, 1965, 21, 1509.

14I

Sesquiterpenoids

(219)

(220)

already shown that acid treatment or photolysis of genuine 11,13-dihydroparthenolide yields (220). Since 1957, when the first structural elucidation of a germacrane sesquiterpenoid was performed, a relatively large number of these compounds have been isolated from various natural sources (especially in Compositae). The majority of these have a fused a-methylene-y-lactone moiety and variegated oxygencontaining groups. To depict such an array of functionality attached to an inherently symmetric carbon skeleton in a reasonable stereo projection has resulted in a number of ambiguities. Rogers et a/.' l 6 have analysed these problems and in an effort to ameliorate the situation have proposed a number of rules including nomenclature, numbering system, and assignment of a and p configuration. The reader is recommended to consult the actual reference for complete details. The revised structure [221; R = CO.C(CH,OH)=CHCH,OHj for eupatoriopicrin, first suggested by Doskotch and El-Feraly,' l 7 has been accepted by Sorm et a1.'I8 as a result of extensive n.m.r. studies and it has been shown to co-occur with eupatolide (221; R = H). A number of new germacranolides have been isolated and identified. These include badgerin (222),'19 melampodin (223),'20,'21 woodhousin (224),122

(221) l6 l7 118

'

l9

lZo

' 2 2

D. Rogers, G . P. Moss, and S. Neidle, J.C.S. Chem. Comm., 1972, 142. R. W. Doskotch and F. El-Feraly, J. Org. Chem,, 1970,35, 1928. B. Drozdz, H. Grabarczyk, Z. Samek, M . Holub, V. Herout, and F. Sorm, Coll. Czech. Chem. Comm., 1972,37, 1546. F. Shafizadeh and N . R. Bhadane, J. Org. Chem., 1972,37, 274. N . H . Fischer, R. Wiley, and J . L). Wander, J.C.S. Chem. Comm., 1972, 137. S. Neidle and D . Rogers, J.C.S. Chem. Comm., 1972, 140. W . Herz and S. V. Bhat, J. Org. Chem., 1972, 37, 906.

Terptwoids and Steroids

I42

frutewn (725),”’ tluctuanln (226. R = angelyl),”4 and fluctuadin [226, R = CO-C(Me)=CH2] The l d 4 t t u o compounds co-occur with enhydrin (uiedaliii epoxide) uhich. i n lieu of i t \ i e r j similar n.m r spectrum with respect to meldinpodin acetate. may perhaps be represented as (397) Kupchan and co-v,orLt.rs.‘” in a continuing search for tumour inhibitors from plant sources, hd\e isolated d number of nokel gerrnacranolides, I : eupacunln (228 ; 0 / \ R = angel~l).eupacunoxin (178. R = CO-C-CHMe), eupatocunin (229),

I Me ki

0 (322)

0 (223)

(225)

0

(226)

”’ ’”

W . Herz. S. V. Bhat, and V . Sudarsanam, Phytochetnistry, 1972, 1 1 , 1829. E. Ah, P. P. Ghosh Dastidar. S C . Pakrashi. L. J . Durham, and A . M. Duffield, Tt~truhedroti,1972. 28, 2985.

S. M . Kupchan, M . Maruyama, R . J . Hemingway, J . C. Hemingway. S. Shibuya, T. Fujita. P. D. Cradwick, A . D . U . Hardy, and G. A . Sim, J . Anirr. Chem. Sot.., 1971, 93. 4914.

Sesquiterpenoids

143

and liatrin (230).' 26 Both eupacunin and ljatrin have significant antileukemic properties. Further work has been carried out on confertolide with the result that structure (231) is favoured although its absolute and relative stereochemistry has yet to be ascertained.I2'

AcO h O

/

A

c

\

HO

(230) The structural elucidation of laurenobiolide (232) has been carried out' and, like a number of other germacranolides, this compound exhibits conformational isomerism with a free energy difference of 0.72 kcal mol-I between the two conformer^.'^^ In another study of this kind sericenine (233) has been shown to exist in a conformational equilibrium. 3 0 Glechomafuran (234)and glechomanolide (235) have been isolated from the ground ivy, Glechoriia hederaceu L. 1 3 '

0 (232) 126

127

I28 129

I30 131

S. M . Kupchan, V. H . Davies, T. Fujita, M . R . Cox, and R. F. Bryan, J . Arner. C h e m . Soc., 1971, 93, 4916. R. Toubiana, M.-J. Toubiana, and B. C . Das, Tetrahedron Letters, 1972, 207. H . Tada and K. Takeda, Chem. Comm., 1971, 1391. K. Tori, I . Horibe, K. Kuriyama, PI. Tada, and K. Takeda, Chrm. Cornm., 1971, 1393. K . Tori, I . Horibe, H . Minato, and K. Takeda, Tetrahedron Letters, 1971,4355. E. Stahl and S . N . Datta. Annulen, 1972, 757, 23.

144

Terpenoids and Steroids

(234)

(235)

10 Elemane Kato and Hirata' 3 2 have described the synthesis of the desisopropyl sesquiterpene geijerene (237), starting from the iodo-acetate (236) [derived from ( - )-santonin and previously used in the synthesis of shyobunone] as outlined in Scheme 23.

(236) ii.

iii,

NaOBr HgO-Mrz

iv, Zn- HOAc

I

I.

LIA!H,

ii. MsCI- p>

iii,

Nal

(237) Scheme 23 I)'

K . Kato and Y . Hirata, Tetrahedron Letrers, 1971, 3513.

145

Sesquiterpenoids

Co-occurring with laserolide, a germacranolide, is the Cope-related compound, isolaserolide (238).'3 3

(238) 11 Eudesmane

New eudesmane sesquiterpenoids include (239) (unassigned stereochemistry),' 3 4 (240),'35 and the dimeric compound carindone (241).'36 The structure of the latter compound may be in doubt since it is reported that dehydrogenation gives a product whose structure is assigned as (240). There are many discrepancies between the physical and spectral properties of the two samples.

HO

13'

'34 135

13'

M. Holub, Z. Samek, and V. Herout, Phytochemistry, 1972, 11, 3 0 5 3 . N. N. Gerber, Phytochemistry, 1972,11, 385. D. L. Roberts, Phyrochemistry, 1972, 1 1 , 2077. B. Singh and R . P. Rastogi, Phyrochemistry, 1972, 1 1 , 1797.

Terpenoids and Steroids

I46

A closer examination of grapefruit oil [from which nootkatone (242) has already been isolated] has resulted in the isolation and structural elucidation of paradisiol (243).”- The interesting feature of this compound is that it embodies the precise stereochemical requirements for rearrangement to the valencane-type sesquiterpenoids of which nootkatone (242) is a member*

(242)

(243)

OH

HO

(I’ H O \

OH

% Ph

Ph

(234)

(245)

(236)

Box et u1.l 3 p have isolated a new eudesmane sesquiterpenoid, rupestrol, which occurs naturally as its orthocinnamate (244) and cinnamate esters (245). The absolute configuration is based on the c.d. spectrum of the derivative (246) but this does not rule out unambiguously a structure with an r-isopropyl group and, furthermore. certain {j-acetoxy-ketones are known to exhibit anti-octant behaviour. Recently a number of eudesmane-based alkaloids have been isolated 13-

’”

H . Sulser. J . R . Scherer, a n d K . L. Stevens. J . Org. C/zem., 1971, 36, 2422. V . G . S. Box, W. R . C h a n . a n d D . R . Taylor, Terrrtherlron Letters, 1971, 4371.

* Recently. paradisiol has been identified with intermedeol, which re-defines i t s structure a s the C-4 epimer of (243): see J . W. H o E m a n n a n d L. H . Zalkow, Tetrahedron Letters, 1973. 751.

Sesquiterpenoids

147

which include evonine (247; R' = R3 = Ac, R' = =O), neo-evonine (247; R' = Ac, R' = H, R3 = =O), euonymine (247; R' = R3 = Ac, R' = 1)-OAc), neo-euonymine (247; R' = H, R2 = P-OAc, R3 = A c ) , ' ~and ~ evozine (247; R' = R 3 = H, R2 = =O).I4O As with maytoline (248)141 the absolute stereochemistry of these highly oxygenated sesquiterpenoids has still to be determined.

0

(247) Huffman and have published full details of their synthetic approach to the basic eudesmane skeleton. In the past the synthetic strategy for the construction of this bicyclic ring system has been largely restricted to standard reaction sequences involving at some stage a Robinson annelation procedure. Schwartz et ~ 1 .have l ~ now ~ developed a new approach to this problem, culminating in the synthesis of (+)-junenol (251) as outlined in Scheme 24. From the 11.

/'

C02Me

111.

ZnCI,-H,O ZnCI, C,H,

C0,Me 1

1

i, LiAIH, (C,H,N),CrO,

ii.

(249) Scheme 24 139

140 141 142

143

H . Wada, Y . Shizuri, K . Sugiura, K. Yamada, and Y. Hirata, Tetrahedron Letters, I97 1, 3 13 1 and references cited therein. A. Klasek, Z . Samek, and F. Santavy, Tetrahedron Letters, 1972, 941. R. F. Bryan and R . M. Smith, J . Chem. Soc. ( B ) , 1971,2159. J . W . Huffman and M. L. Mole, J . Org. Chem., 1972, 37, 13. M . A. Schwartz, J . D. Crowell, and J . H . Musser, J . Atner. Chem. Sac., 1972, 94, 4361.

Terpenoids and Steroids

148

OH

OH

mixture of alcohols (249) the isomer (250)could be isolated which, on selective reduction with tris(tripheny1phosphine)rhodium chloride and photoisomerization, afforded (+)-junenol (251). As can be appreciated this route suggests an alternative biogenetic pathway to the eudesmane sesquiterpenoids, although at present the weight of evidence, largely from in uitro studies, seems to favour the cyclization of a 1,5-~yclodecadieneprecursor. Another approach to the eudesmane skeleton has recently been described by Carlson and Zey144 which also does not depend upon a Robinson annelation reaction (Scheme 25). By this sequence the keto-ester (252) was obtained as the predominant isomer. Previously this compound has been converted into P-eudesmol (cf ref. 142).

C02H I

I.

PPA

' II.H,O' CO,M~ 111.

CH2N,

0 1. 11.

LIbk,CU NaOMe-MeOH

Scheme 25 14*

R . G . Carlson and E. G . Zey, J . O r g . Chern., 1972,37, 2468.

C0,Me

149

Sesquiterpenoids

Y 4,

0

-80

L

E

M

+

---

v

u X 0 X

o

I50

Trrpenoids and Steroids

Two groups145.146 have independently reported the synthesis of ( +)-Occident-

alol(254)starting from the same intermediate (253)which, in turn, can be obtained from (+)-dihydrocarvone. The two routes are depicted in Scheme 26. Cooccurring with occidentalol in T h j d oc*cirlmtalisL. is the related alcohol, occidol (255).Ho14- has now reported a third synthesis of this compound starting from 3.6-dimethylphthalic anhydride, which, on reduction to the diol and bromination, gave the dibromide (256). Dehydrobromination of (256) with zinc dust in the presence of methyl acrylate yielded the ester (258) cia the intermediate o-quinodimethane (257). Subsequent reaction of (258) with methyl-lithium afforded racemic occidol (255).

+

(255)

(257)

(256)

p

COzMe

(258)

The 13C n.m.r. spectra of santonin (259) and some of its derivatives indicate that the data obtained can be used to determine the stereochemistry of the lactone fusion and the configuration of the methyl group at C-1l.14* Further work on the chemistry of santonin, santonene, and related compounds has been r e p ~ r t e d ' ~ ' and pyrosantonin has been shown to have structure (260).l5O Pyrolysis of santonin also produces a smaller amount of I-nordesmotroposantonin (261). Reaction of santonin (259)with nonacarbonyldi-iron at 40 "C produces the two

(259)

'" I"'

*" lay

""

(260)

M . Sergent. M. Mongrain. and P. Deslongchamps, Canad. J . Chetn., 1972,50, 336. Y . Amano and C . H . Heathcock. Caticrd. J . Chtjni.. 1972. 50. 340. T.-L. Ho, C u r ~ dJ. . Cht'ttl.. 1972, 50, 1098. P. S. Pregnsin. E. W . Randall. and T. B . H. M c M u r r y . J . C . S . Perkin I , 1972,299. T. B. H . McMurry and D. F. Rane, J . C I i m . Soc. ( C ) , 1971, 3851. T. B. H . McMLrry a n d D . F. Rane. J . CIZPIII. Soc. (C), 1971. 1389.

151

Sesquiterpenoids

'

tricarbonyliron complexes (262; R = OH) and (262; R = =O) in low yield.' The ligand of the latter compound is the monomer portion of the dimeric compound derived from solid-state photolysis of santonin. The major compound (262; R = OH) appears to be the result of an unusual reduction by nonacarbonyldi-iron. The a-methylene-7-butyrolactone grouping is incorporated in a large number of sesquiterpenoids, many of which have significant biological activity. A number of routes have been devised for the synthesis of this moiety but recently an important contribution from Ourisson's laboratory has demonstrated that the more accessible a-methyl-7;-lactonescan be converted in two steps into the a-methylene analogues.'52 This is achieved by reaction of the lactone (263; R = H) with triphenylmethyl-lithium and quenching the resultant enolate with 1,2-dibromoethane. Dehydrobromination of the derived bromide (263; R = Br) with diazabicyclononene gives exclusively the exocyclic methylene lactone (264). This method is only suitable for cis-y-lactones since the trans-lactone yields exclusively the endocyclic isomer. To illustrate this method Ourisson et al. have converted dihydro-6-epi-santonin (265) into ( - )-frullanolide (266). More recently the same a ~ t h o r s ' ' have ~ developed a method which is applicable to

mo mo R

Is'

Is'

'*'

H . Alper a n d E. C.-H. Keung. J . Amer. Cfiem. Soc., 1972, 94, 2144. A . E. Greene. J.-C. Muller, a n d G . Ourisson, Tetmhedron Letters, 1972. 2489. A . E. Greene, J.-C. Muller. a n d G. Ourisson, Tetroliedron Letters, 1972, 3375.

Terpenoids and Steroids

152

trans-;4actones. Thus treatment of the enolate derived from (267 ; R = H) with dibenzoyl peroxide gave the lactone-benzoate (267; R = 0,CPh) which, on pyrolysis, yielded predominantly the lactone (268). Application of this method to the lactone (269),derived from ( - )-santonin, gave ( + )-arbusculin (270).

(269)

(270)

New eudesmanolides include ludalbin (271)ls4 and virginin (272).’55 MCyclocostunolide (273) and dihydro-/?-cyclocostunolide (274) have been isolated from Moquinea uelutina.’ 5 6

HO

(272)

(273)

(274)

12 Erernopbilane, Valencane, and Valerane Pinder and Torrence’” have published the full details of their synthesis of fukiilone (275). This paper also describes the synthesis of (+)-hydroxyeremophilone (276). A number of new eremophilane sesquiterpenoids have been

’” ‘ 5 5

’”

T. A. Geissman and T. Saitoh. Phyrcichetnisrry, 1972, 11, 1157. J . J . Sims and K. A. Berryman, Phytochenristry, 1972, 11, 444. T. C. B. Tomassini and B. Gilbert, Phyrochrmistry, 1972, 11, 1177. A. R.Pinder and A . K. Torrence, J . Chem. Soc. (0,1971, 3410.

153

Sesquiterpenoids

isolated and characterized ; these include petasitolone (277),lS8(278),lS9(279 ; R = H), (279; R = Me), [279; R = CO*CH(Me)Et],'60 istanbulin (280),16' (281),'62 and the trisnor-compound narchinol A (282).163It is not absolutely clear whether the latter compound belongs to the eremophilane group or the valencane group (probably the latter).

OR (279) AngO..

(280) From a further study of compounds related to valeranone, Rao' 64 has provided additional evidence in favour of the preferred conformation (283) which had been suggested previously on the basis of 0.r.d. studies.

15'

IhV

16'

164

K . Naya, F. Yoshimura, and I. Takagi, Bull. Chem. SOC.Japan, 1971, 44, 3165. W. Schild, Tetrahedron, 1971, 27, 5735. M. Tada, Y . Moriyama, Y . Tanahashi, T. Takahashi, M . Fukuyama, and K . Sato, Tetrahedron Letters, 1971, 4007. A . Ulubelen, S. oksuz, Z . Samek. and M. Holub, Tetrahedron Letters, 1971, 4455. L. Novotny, K . Kotva, J . Toman, and V. Herout, Phytochemistry, 1972, 11, 2795. H . Hikino, Y . Hikino, S. Koakutsu, and T . Takemoto, Phytochemisfry, 1972, 1 1 , 2097. P. N . Rao, J . Org. Chcm.. 1971,36, 2426.

154

Terpenoids and Steroids

In connection with potential routes to sesquiterpenoids of the eremophilane and valencane classes, Marshall and Ruden' 6 5 have found that acid-catalysed cleavage of the cyclopropyl ketone (284) gives exclusively the enone (285). This is in contrast to the epimeric ketone (286) which yields predominantly (287). Leitereg'" has found that Robinson annelation of ( + )-dihydrocarvone with rrans-3-penten-2-one gives as a major compound the bicyclic enone (288) which is isomeric with (+)-nootkatone(242). The full paper on the structures of cy- (289) and /l-rotunol (290) has been published. * 6 -

(286)

13 Guaiane

The synthesis of appropriately functionalized bicyclo[4.3.0]decane derivatives continues to be a topic of current research. In this area, Heathcock et ul.' 68 have published complete details of the syntheses and solvolyses of various 9-methyl- 1decalyl tosylates, a study which ultimately led to the obtention of bulnesol (291) and x-buinesene (292). Similarly, Marshall and Greene16' have given a full account of their syntheses of guaiol (293) and 7-epi-guaiol. Marshall et ul."* Ih5

'

"" lb7

'61

lb9

I-"

J . A. Marshall and R . A . Ruden, Synthetic Cornin., 1971, 1,227; J . O r g . Chem., 1972,

37, 659. T. J . Leitereg, Tetrahedron Letters, 1972, 261 7. H . Hikino, K . Aota, D. Kuwano. and T. Takemoto, Tetrahedron, 1971, 27,4831. C. H . Heathcock, R . Ratcliffe, and J . Van. J . O r g . Chmm., 1972, 37, 1796. J . A . Marshall and R . A . Ruden. J . 0,x. C h e m . , 1971, 36, 2569; J . A. Marshall and A. E. Greene, ihid., 1972, 37, 982. J . A . Marshall, W . F. Huffman, and J . A . Ruth, J . A i w r . Chem. Soc., 1972,94,4691 ;see also P . S . Wharton and M . D . Baird. J . O r g . Chctri.. 1971. 36. 2932.

Sesquiterpenoids

155

have also carried out further work on the transannular cyclization of cyclodecadienol derivatives. As reported two years ago, solvolysis of the p-nitrobenzoates of (294; R = H) proceeds with high stereoselectivity and regioselectivity to give the hydroazulenol(295 ;R = H). In an extension of this general method Marshall and co-workers have shown that the methyl homologue (294; R = Me) also gives (295; R = Me) in approximately 60% yield. Alternatively the isomeric p-nitrobenzoate of (296; R = H ) undergoes cyclization to give (295; R = H) in over 40 % yield. As a potential entry into the pseudo-guaiane skeleton the acetolysis of the tertiary alcohol (296 ; R = Me) was carried out which led to the formation of the acetate (297) in high yield. l ' l

Another route to the hydroazulene ring system has been investigated by Kretchmer and F r a ~ e e , who ' ~ ~ have shown that pyrolysis of the epoxide (298) gives the ketone (299) in 75 y/o yield. On the other hand, pyrolysis of the epimeric epoxide (300) gives the bicyclo[4,3,l]ketone (301) as the principal product. "I l2

J . A . Marshall and W . F. Huffman, Syniheiic Comm., 1971, 1, 221 R. A . Kretchmer and W . J. Frazee, J . O r g . Chem., 1971, 36, 2 8 5 5 .

156

Terpenoids and Steroids

Further work has been carried out on the microbial transformations of certain sesquiterpenoids. Thus oxidation of guaioxide (302) by Streptomyces purpurescens produces various derivatives with hydroxy-groups at C - ~ X C-3q , C-4a, C-8q C-8/l, and C-9c.t and as a result of this study the structure of bulnesoxide is shown to be (303).1'3

(302)

(303)

Ourisson t'r ale1 have shown that P-patchoulene epoxide (304) undergoes a number of rearrangements according to the nature and solvent of the acid medium as summarized in Scheme 27. 7J

+

0

(305) Scheme 27

"' H . Ishii, T. Tozyo, and M . Nakarnura, Tetrahedron, 1971, 27, 4263; see also H . Ishii, T. Tozyo, M . Nakamura, and E. Funke, Chem. and Pharm. Bull. (Japan), 1972, 20, 203. "'L. Bang, I . G . Guest, and G . Ourissor?. Terrahedron Lerrers, 1972, 2089.

Sesqu i t erpenoids

157

Piers et uf.175have published the complete details of their elegant synthesis of seychellene (306). A third approach to this sesquiterpene has been described by Yoshikoshi et a/. 7 6 which involved an intramolecular Diels-Alder reaction for

'

the construction of the tricyclic skeleton (307) as shown in Scheme 28. Hydrogenation of (307) afforded norseychelianones, which had previously been converted into seychellene.

0

0

Br

I. 11. 111.

p-TsOH Me,NH HZO,

V

430 "C

w

N

0

M

e

2

0

(307) Scheme 28

The absolute stereochemistry of artabsin (308) has been established,' 7 7 and the complete stereochemical assignment of hydroxyachillin (309) has been reported by two groups.178,'7 9 Further work on four related guaianolides has 17h 177

E. Piers, W. de Waal, and R . W . Britton, J . Am er . Chem. Sor., 1971. 93. 5 1 1 3 . N . Fukamiya, M . Kato, and .4. Yoshikoshi, Chem. Comm., 1971, 1120. K . VokaE, Z . Samek, V . Herout, and F. Sorm, Coll. Czech. Chem. Comm., 1972. 37. 1346.

17R

H . Kaneko, S. Naruto, and S. Takahashi. Phyrochernisrry, 1971, 10, 3 3 0 5 . F. W . Bachelor. A . B. Paraiikar. and S. It6, Canad. J . Chem., 1972. 50, 3 3 3 .

158

Terpenoids and Steroids

established the structures of cynaropicrin (310: R = OH), dehydrocynaropicrin (310; R = =O), grosheimin (311 : R = =CH,), and isoamberboin (31 1; R = x-Me).!80.1*1

(-4 0

0 (309)

(308)

R

0

(310) Harley-Mason et d.'szhave reported the isolation and X-ray structural determination ofcentaurepensin ( 3 12) (from Centatrrea repens L.).This compound is not only interesting from the point of view of the two chlorine atoms but also represents the first example of a guaianolide with this absolute stereochemistry (in particular with the C-7 H in a configuration). Shortly after this communication, Gonzilez er a/.183announced the structural determination of chlorohyssopifolin A and B (desacyl derivative) isolated from C. hyssopijolia Vahl. Chlorohyssopifolin A appears to differ from centaurepensin only in the position of the secondary hydroxy-group, i.e. at C-2 rather than C-3. although its absolute stereochemistry has not yet been determined.* lxO

li

Is'

Z. Samek, M . Holub, B. Droidz, C. Jommi, A . Corbella, and P. Gariboldi, Tetruhedron Letters, 1971. 4775. A . Corbella, P. Gariboldi. G . Jommi, Z. Samek. M. Holub, B. Drozdz, and E. Bloszyk, J.C.S. Chem. Comm., 1972, 386. J. Harley-Mason. A . T. Hewson, 0.Kennard, and R. D. Pettersen, J.C.S. Chem. Comm., 1972, 460. A . G . Gonzalez, J . Bermejo, J. L. Breton, and J . Triana, Tetrahedron Letters, 1972, 2017.

* Despite the fact that centaurepensin and chlorohyssopifolin A have very similar m.p.'s and [a],'s they are not identical (personal communication from Dr. J. Harley-Mason).

Sesquiterpenoids

159

New guaianolides are listed in the Table. Table

New guaianolides 15

0 Name

Position(s) of double bond(s)

Bahifolin Isomontanolide”

3,4; 11,13 3,4

Acetylisomon tanolide” Ludartinb

394

Dehydroleukodin Iso-epoxyestafiatin eremanthine

3,4; 1,lO; 11,13

1,lO; 11,13

I1,13 4,14; 11,13; 9,lO

Unassigned lactone stereochemistry. C-11 Me stereochemistry.

Acyl groups

0thc.r fiatures

Ref.

8&(3-furoyl)

5a-H ; 10,15-epoxy 10-OH

I84 185

8-angeloyl ; 1 1-OAc 8-angeloy 1; 10-OAc ; 1 1- 0 A c

I85 3a,4a-epoxy ; 4P-Me ; 5a-H 2-keto ; 5a-H 3,4-epoxy ; 1,lO-epoxy ; 5a-H

186

5a-H

188

187 I87

Also 1 1,13-dihydro-compound of unassigned

By the synthesis of dihydroarbiglovin (313; R = r-Me) starting from 2santonin, Marx and McGaughey 8 9 have determined the complete stereochemistry of arbiglovin (313 ; R = =CH,). i n 4

I 85

186 187 188

I

nu

W. Herz, S. V. Bhat, H. Crawford, H. Wagner, G. Maurer, and L. Farkas, Phytochemistry, 1972, 11, 371. M. Holub, 0. Motl, Z. Samek, and V. Herout, Coil. Czech. Chem. Cornm., 1972, 37, 1186. T. A. Geissman and T. S. Griffin, Phytochemistry, 1972, 11, 833. F. Bohlmann and C. Zdero, Tetrahedron Letters, 1972, 621. W. Vichnewski and B. Gilbert, Phytochemistry, 1972, 11, 2563. J . N .Marx and S. M. McGaughey, Tetrahedron, 1972, 28, 3583.

Terpenoids and Steroids

160

QR

I

0 0

Go OH (314)

Q OR

0

(315)

(313)

Kew pseudo-guaianolides include amblyodin ( 314)190 and arnicolide A (315 ; R = Ac), B (315; R = C0.CH2CHMe2),C (315; R = CO-CHMe,), and D (315; R = CO-CMe=CH,)."' Geissrnan et U I . ~ ' ' have shown that red and blue colorations are produced when certain sesquiterpenoid lactones (0.5-1 .0 mg) are treated with an ethanolic solution of concentrated hydrochloric acid. As a result of submitting a broad spectrum of structural types to this medium these authors have put forward some empirical rules which may be of diagnostic value with respect to new lactones.

14 Maaliane and Aromadendrane Making use of their recently developed photochemical decarboxylation of cisfused y-lactones (diffuse Strasbourg sunlight), Ourisson ei have converted the keto-lactone (316), derived from dihydro-6-epi-santonin, into-epi-maalienone (317). Further irradiation of (317) resulted in the formation of x-cyperene (318) and b-cyperene (319).

oQ-

(318)

'')" I"

'')3

(31 %

W . Herz and A. Srinivasan. Phj-tochrrnistry, 1972, 11, 2093.

J . Popldwski, M . Holub, Z. Samek, and V. Herout, Cull. Czech. Chrm. Comm., 1971, 36, 2189. T. A . Geissman and T. S. Griffin, Phytochemistry, 1971, 10, 2475; T. S. Griffin, T. A . Geissman, and T. E. Winters, ibid., p . 2487. A . E. Greene, J.-C. Muller. and G. Ourisson. Trtruhrdron LPrrrrs, 1971, 4147.

Sesquiterpenoids

161

It6 et have studied the sensitized photo-oxidation of a-gurjunene (320). In the first paper they described the isolation of four major products, uiz. ( 3 2 1 b (324). In view of the structural similarity between (323) and (324) and the unusual sesquiterpenoid zierone (325), It6 at ~ 1 . ” ~repeated the photo-oxidation, and borohydride reduction of the reaction mixture yielded (326) as the major compound. Acid treatment of (326) and lithium aluminium hydride reduction of the resultant acetate gave the alcohol (327), which, on Collins oxidation, yielded the C- 10 epimer of zierone.

Batey et ~ 1 . ’ ~have ‘ isolated and identified the new sesquiterpenoid squarnulosone (328). 15 General A tabulation of sesquiterpenoids is included in a recent handbook by Devon

and ‘94

lg5 lY6 19’

This volume lists all the known sesquiterpenoids in the literature

S. It6, H . Takeshita, M . Hirama, and Y . Fukazawa, Tetrahedrorz Letters, 1972. 9. H.Takeshita, M . Hirama, and S. It6, Tetrahedron Letters, 1972, 1775. I . L . Batey, R . 0. Hellyer, and J . T. Pinhey, Austral. J . Chem., 1971, 24. 2173. T. K . Devon and A. I . Scott, ‘Handbook of Naturally Occurring Compounds, Vol. 11, Terpenes’, Academic Press, New York, 1972.

I62

Terpenoids and Steroids

up to the early part of 1971 (approximately 1000). However. unlike Ourisson's treatise, the information associated with each compound is much more limited. A number of papers of chemotaxonomic interest have been published this year. These include a survey of the sesquiterpenoids in elm species,19* the genus Vernoniu,' 99 the genus Amhrosia,200 and the genus Artemisia.201

"" ''Iy

'"('

"'

J . W. Rowe, M. K . Seikel. D. N . Roy, and E. Jorgensen, Phprochemisrry, 1972, 11, 2513. Z. H. Abdel-Baset, L. Southwick, W . G . Padolina, H. Yoshioka, T. J . Mabry, a n d S. B. Jones, jun., Ph?,rochemisrr:, 197 1 , 10, 2201. A . Higo, Z. H am m a m, B. N . Timmermann. H . Yoshioka, J . Lee, T. J . Mabry, and W. W . Payne, Phgtochernistrj3, I 97 1 , 10, 224 I . F. Shafizadeh, N. R. Bhadane, M . S. Morris, R. G. Kelsey, a n d S. N. Khanna, Phytochenzrsrry, 197 1 , 10, 2754.

3 Diterpenoids BY J.

R. HANSON

1 Introduction

This chapter follows the layout of the previous Report with sections based on the major skeletal types of diterpenoid. A number of reviews have covered aspects of diterpenoid chemistry.’ A review of the chemistry of the order Pinales has been published,2 including information on the occurrence of diterpenoids in these conifers. 2 Bicyclic Diterpenoids

The Labdane Series-The conifers are an important source of diterpenoids. Araucaria excelsa has been examined3 and manool, torulosol, abietinol, torulosal, and abietinal have been detected in the neutral fraction of the oleoresin. This fraction also contained the epimeric 18- and 19-nor-labdane-4,13-diols(l), which may arise by autoxidation of torulosal. Chromatography of this aldehyde on alumina or silica led4 to up to 14%of the epimeric C-4 hydroperoxides. Consequently, whenever these nor-diterpenoids are detected, the possibility that they are artefacts has to be borne in mind. Oxidative decarboxylation of acetylcupressic acid by lead tetra-acetate affords a synthetic entry to this series of compounds. The chemistry of manool (2) has been examined. The study of the cationic rearrangements and cyclizations of diterpenoid substances as biogenetic models

I

T. K . Devon and A . I . Scott, ‘Handbook of Naturally Occurring Compounds’, Academic Press, New York, 1972, Vol. 2 ; J . R . Hanson, in ‘Chemistry of Terpenes and Terpenoids’, ed. A . A . Newman, Academic Press, New York, 1972, p. 155. T. Norin, Phytochemistry, 1972, 11, 123 1. R . Caputo, L. Mangoni, and P. Monaco, Phytochemistry, 1972, 1 1 , 839. R . Caputo, L. Mangoni, L. Previtera, and R . Iaccarino, Tetrahedron Letters, 1971, 373 1 .

163

164

Terpenoids and Steroids

has been pursued in several laboratories. A full paper has appeared5 describing the cyclization of maiiool in acetic acid. In addition to the pimaradienes and rosadienes described, obtained previously with formic acid, small amounts of a compound, the 8,13-burnadiene (3), possessing a new ring system have been described. This is of particular interest in terms of the cyclization pathway to the 14-hibyl esters (cide iyfi-a). Taondiol is a diterpenoid chromene which was recently isolatedb from a marine alga, Tuoniu atomaria. The preparation of desoxytaondiol methyl ether ( 5 ) by aikylation of toluquinol 4-methyl ether (4) with manool (2), followed by an acid-catalysed cyclization, formed' a biogenetically patterned synthesis of this compound.

(5) The oxidation of manooi has been re-examined' with the aim of producing ambergris-ty pe perfumes. Oxidation with potassium permanganate afforded the known9 methyl ketone (6).the diether (7).and at 40 "C the lactone (8). Sodium dichromate gave the aldehyde (9) as a mixture of E- and 2-isomers. Further oxidation of the methyl ketone with hypobromite gave an a-hydroxy-acid (10) arid an ether (1 1) which was also obtained from manoyl oxide. Oxidation of the ketone with per-acid gave an acetoxy-epoxide which on reduction with lithium aluminium hydride afforded a diol. This was converted into an odoriferous ether (12). The ready formation of 5- and 6-membered-ring ethers of this type is a characteristic feature of this area of diterpenoid chemistry. 7r-Hydroxymanool has been recorded as a constituent of Dacrydium kirkii. Bromination of dihydromanool with N-broniosuccinimide followed by hydrolysis

' S. F. Hall and A. C

''

Oehlschlager. Tcrruhedron, 1972, 28, 3155.

A . C . Gonzalez, J. Darias. and J . D . Martin, Tetrahedron Letters, 1971, 2729. A . G . Conzalez and J . D. Martin, Tetrahedron Letters, 1972. 2259. R . C. Cambie, K . N . Joblin, and A . F. Preston, Austral. J. Chem., 1971, 24, 2365. ' H . R . Schenk, H . Gutmann, 0.Jeger. and L. Ruzicka. Hell.. Chin].Acra, 1952,35,817.

'

165

Diterpenoids

OH

R

(11) R = CO,H

(12) R = H afforded" the 7a-hydroxy-derivative and the 9,13-epoxide. Hydrogenation gave labdane-7a,13-diol identical with material from the natural product. Reduction of the corresponding 7-ketone afforded a 7fl-alcohol. 8,13-Epoxylabd-14-en-12-one and 8,13P-epoxylabd-14-en-12-one have been isolated' as minor constituents of Turkish tobacco. Their structures were assigned by mass spectrometry and by correlation with manoyl oxide and 13epimanoyl oxide respectively. Anticopalic acid has been found' in the needles and wood of Pinus strobus and in the wood of Pinus rnonticoh. The diterpenoid constituents of Juniperus phoenica includeI3 manoyl oxide, eperuene diol, labd-8-ene-12-hydroxy-19-oic acid (13), sandaracopimaric acid, and 6a-hydroxysandaracopimaric acid. Imbricatalic acid (14) has been i ~ o l a t e das ' ~ its methyl ester from Pinus effiottii.

OH

HO

(13)

'*

(14)

P . K . Grant, C. Huntrakul, and R. T. Weavers, Austral. J . Cliern., 1972, 25, 365. ' I A . J . Aasen, B. Kimland, S. Alrnquist, and C. R . Enzell, A c t a Chem. Scand., 1972,26, 832. l z D. F . Zinkel and B. P. Spalding, Phytachernistry, 1972, 11,425. l 3 C. Tabacik and Y. Laporthe, Phytochernistry, 1971, 10, 2147. ' 4 D . P. Spalding, D. F. Zinkel, and D. R . Roberts, Phyrochernisrry, 1971,10, 3289.

166

Terpenoids and Steroids

The dehydrogenation of agathic acid by selenium has been studied15 under various conditions. The results have been rationalized in terms of the formation, on the one hand, of tricyclic compounds such as 1,6-dimethylphenanthreneand, on the other hand, of bicyclic compounds such as 1,2,5-trimethylnaphthalene. The full paper describing the structure and stereochemistry of neoandrographolide-a (15) has appeared.16 The n.m.r. and U.V. spectra established the presence of an $-unsaturated butenolide, an exocyclic methylene, and an axial hydroxymethyl group at C-4. Cleavage of the exocyclic methylene gave a cyclohexanone which possessed a positive Cotton effect in the c.d. superimposable on that of the corresponding andrographolide derivative. Interrelationship with a degradation product of andrographolide served to confirm structure ( I 5). Pinusolid (16) is a related lactone which has been isolated from Pirzus sibiricu."

0

II

The Clerodane Series.-Some further contributions have been made to the chemotaxonomy of Cistus species.18. Whereas C. labdanijerus contains mainly labdanes such as labdane-8r,l5,19-triol, C. monspeliensis contains a group of clerodane diterpenoids whose structures are summarized in (171, together with 1abdan olic acid and labdane-8r,l5-diol.

R'

R' R' R' R'

R2 = C 0 2 H R2 = C H 2 0 H = CO,H; R2 = C H 2 0 H = C H 2 0 H ; R 2 = CO,H = =

A new diterpenoid (18), related to hardwickiic acid, has been isolated" from Annona coriacea. The furan (19) was also isolated from this source. A further

''

'* "

'' Iq 20

R . M . Carrnan and W . J . Craig, Aicsrra/. J . Chetn,, 1971, 24, 2379. W. R . Chan, D. R. Taylor, C. R . Willis, R . L. Bodden, and H . W. Fehlhaber, Tetrah d r o n , 197 I , 27, 508 I . V . A . Raldugen. A . I . Lisina, N . K . Kashtanova, and V. A. Pentegova, Khim. prirod. Soedinenii. 1970, 6, 54 1 . G . Berti, 0. Livi, and D. Segnini, Tetrohrdrun Lrlters, 1971, 1401. C . Tabacik and M . Bard, Phytochentistry, 1971, 10, 3093. M . Ferrari, F. Pelizzonii, and G . Ferrari, Phyrochemisrrv, 1971, 10, 3267.

Diterpeno ids

167

paper2' describing the isolation and structure of maingayic acid, a piscicidal constituent of Callicarpa maingayi, has appeared. 11-Dehydro-(- )-hardwickiic acid has been isolated22from Croton oblongifolius. Hautriwaic acid (20), isolated from Dodonuea viscosa, has been related23 to a degradation product of an acetoxy-hydroxy-acid which had been isolatedt4 earlier from Dodonaea attenuata. An unusual chloro-diterpenoid lactone, gutierolide (21), has been isolated2' from the herb Gutierrezia dracunculoides and its structure established by an X-ray analysis.

OH

'' 22

23 24

25

C. Nishino, K. Kawazu, and T. Mitsui, Agric. and Biol. Chem. (Japan), 1971,35, 1921. V. N . Aiyer and T. R . Seshadri, Phytochemistry, 1972, 11, 1473. H . Y . Hsu, V. P. Chen, and H . Kakisawa, Phytochernistry, 1971,10, 2813. P. R . Jefferies and T. G . Payne, Tetrahedron Letters, 1967, 4777. W. B. T. Crase, M . N . G . James, A . A. AIShamma, J . K . Beal, and R . W. Doskotch, Chem. Comm., 1971, 1278.

168

Terpenoids and Steroids

Clerodendrin A, which was isolated as a bitter principle from Clerodendron tricotomunz, has been assigned26 the structure (22) on the basis of an X-ray analysis of the p-bromobenzoate-chlorohydrin. The full paper describing additional work on the structure of olearin (23) has a ~ p e a r e d . ~The ' stereochemistry at all but one centre has been determined and olearin has been interrelated with a diterpenoid of known structure from a Dodonaea species.

3 Tricyclic Diterpenoids

The Pimarane Series. -1 8-Norpimara-8( 14).15-dien-4-01(24)has been isolated28 from lodgepole pine bark. Pinirs contorts. Its structure was proven by correlation with the lead tetra-acetate decarboxylation product of dihydropimaric acid. 3/?-Hydroxysandaracopimaric acid (25)has been isolated from Juniperus rigid^.^^ Its structure was proven by reduction of the acetoxymethyl ester to a diol which had been obtained earlier from X y f i a dolahrafornzis. Sandaracopimaric acid, abietic acid. levopimaric acid. palustric acid. dehydroabietic acid, neoabietic acid. abieta-8,ll. 13-trien-7-one. and 13-epimanool have all been detected3' in Cedrits urlunticu. With the exception of isopimaric acid and 13-epimanool, the same diterpenoids were present in C. lihnni.

OH

'' N . Kato. S. Shibayama, K . Munakata, and C. Katayama, Chem. Camm., 1971, 1632. '-J. T. Pinhey, R.F. Simpson, and I. L. Batey, Austral. J. Chem., 1971, 24,2621. J . W . Rowe, R. C. Ronald, and B. A. Nagasampagi, Phytochemistry, 1972, 11, 365. '' K . Doi and T. Kawamura, Phyrochemisiry, 1972, 11, 841. .'" T. Norin and B. Winell, Phxrochentistry, 1971. 10. 2818.

169

Diterpenoids

Virescenoside C is the P-D-altropyranoside of virescenol C (26), a metabolite of Oospora ~irescens.~'The carbon-13 n.m.r. spectra of a group of pimaradienes have been recorded and the resonances assigned.32 These results have been applied33to the study of the biosynthesis of the virescenosides ( q . ~ . ) Abietanes.-A number of more highly oxygenated abietanes related to the royleanones have been described recently. A new quinone, nemorone (27), has been isolated34from the roots of Saluia nemorosa. Coleon C (28)and its tautomer coleon D, which possesses a trans A/B ring junction and a 6,7-diketone in place of the diosphenol on ring B, have been i ~ o l a t e dfrom ~ ~ Coleus , ~ ~ aquaticus. These compounds have a very characteristic U.V. spectrum. Lycoxanthol is an ether (29) which has been isolated3' from Lycopodium lucidulum and which possesses a very similar structure.

@ OAc

@OH

OH

In the continuing search for irritant substances from Euphorbia species, two unusual epoxides, jolkinolides A and B [(30) and (31) respectively], have been isolated38 from Euphorbia jolkini. Hydrogenation of jolkinolide B gave a diol (32) which was converted via the phenolic acid (33) into ferruginol.

-'' ' 2

33

34

35 3h 37 38

N . Cagnoli-Bellavita, P. Ceccherelli, R . Mariani, J . Polonsky, and Z. Baskervitch, European J. Biochem., 1970, 15, 356. E. Wenkert and B. L. Buckwalter, J. Amer. Chem. SOC., 1972, 94, 4367. J . Polonsky, Z . Baskevitch, N . Cagnoli-Bellavita, P. Ceccherelli, B. L. Buckwalter, and E. Wenkert, J. Amer. Chem. Soc., 1972, 94, 4369. A. S. Romanova, G . F. Pribylova, P. I . Zakharov, V . I . Sheichenko, and A . I. Ban'lovskii, Khim. prirod. Soedinenii, I97 1,7, 199. M . P. Ruedi and C. H . Eugster, Hell;. Chirn. Acta, 1971, 54, 1606. M . P. Ruedi and C . H . Eugster, Helv. Chim. Acta, 1972, 55, 1736. R . H . Burnell, L. Mo, and M . Moinas, Phytochemistry, 1972, 11, 2815. D . Uemura and Y . Hirata, Tetrahedron Lerters, 1972, 1387.

170

Terpenoids and Steroids

0-c=o

0-c=o

A further group of ring c nor-diterpenoid substances have been isolated from Podocarpus species. Inumakilactone A (34)glucoside, which is a potent inhibitor of the expansion and division of plant cells, has been isolated39 along with inumakilactone E (35) from Podocarpus macrophyllus. N.m.r. spectroscopy has played an important part in the structural assignments in this series. A podolactone (36)has been isolated4' from Pudocarpus saligna, and sellowin A (37) and sellowin B (38)have been isolated4' from P. sellowii. Totarol, 3-oxototaroi, A1-3-oxototarol, 1,3-dioxototarol, xanthoperol, sugiol, sandaracopimaric acid, and isopimaric acid have been isolated from Juniperus con$ert a.

'

0

OGlu

co-0 (341 '9

4o

'I

"

co-0 (35)

T. Hayashi, H . Kakisawa, S. Ito, Y . P. Chen, and H . Y . Hsu, Tetrahedron Letters, 1972, 3385. M . Silva, M . Hoeneisen, and P. G . Sammes, Phyrochemistry, 1972, 1 1 , 4 3 3 . L. Sanchez, E. Wolfango, V. S. Brown, T. Nishida, L. J . Durham, and A. M . Duffield, .4nais Acad. brasil. Cienc., 1970. 42, 77 ( C h e m . Abs., 1971, 75, 72 460). K . Do1 and T. Shibuya, Phyrorhrrnistry, 1971. I I , 1175.

Diterpenoids

171

0

0

Me

O d R

co-0 (37) R = CH(Me)C02Me

(38) R

=

CH:CH2

Cassane and Miscellaneous Tricyclic Diterpenoids.-A group of furanoid diterpenoids, related to the caesalpins, has been isolated from Pterodon ernarginaUS^^^ and P . p ~ b e s c e n s .They ~ ~ ~ include compounds ( 3 9 4 2 ) . Some further diterpene alkaloids of the cassaic acid class have been isolated44 from Erythrophleum ivorense. A full paper on the structure of rosein 111 has appeared.45

OAc

OAc

( a ) J . R. Mahajan a n d M. B. Monteiro, Anais Acad. b r a d . Cienc., 1970,42, 103 (Chem. A h . , 1971, 75, 85 140); (b) M. Fascio, B. Gilbert, W. B. Mors, a n d T. Nishida, Anais Acad. hrasil. Cietic., 1970, 42, 97 (Chem. A h . , 1971, 75, 72461). A . Cronlund a n d F. Sandberg, Acta Pharm. Suecica, 1971,8,351 (Chem. Abs., 1972,76, 1 1 995). N. Kiriyama. Y . Y a m a m o t o , a n d Y . Tsuda, Yakirgaku Zasshi, 1971, 91, 1078.

I72

Terpmoids and Steroids

The Chemistry of Ring A .-The thermal behaviour of methyl dehydroabietate at 6-800 "C has been The products include a large number of naphthalenes, which arise by cleavage of ring A of the parent molecule, presumably facilitated by thermal decarboxylation. The conversion of podocarpic acid methyl ether into (43) by oxidative decarboxylation, epoxidation. and isomerization has been e ~ t e n d e d . ~Methylation ' of the corresponding ap-unsaturated ketone afforded a 4,4-dimethyl ketone (44). The 0.r.d. of this ketone suggested that ring A exists in a boat conformation. Although hydrogenation of C-5 unsaturated diterpenoids ncrmally gives the rrans A/B ring junction, in this case 25 0; of a product containing a cis A/B ring junction was obtained. The sequence series to provide of reactions was extended to the 12-methoxyabieta-8,11,13-triene a synthesis of hinokione methyl ether. OMe

d

0 (43)

(44)

The mixture of olefins obtained by lead tetra-acetate decarboxylation of 4-epidehydroabietic acid is very nearly the same as from dehydroabietic Isomerization of these 19-nor-tetra-enes led to some products with a cis A/B ring

(45)

@ \

OMe

/

R. F. Severson, W. H. Schuller, and R . V . Lawrence. Canad. J . Chem., 1971,49, 4027. R. C. Cambie and T. J . Fullerton, Austral. J . Chem., 1971, 24, 261 1 . *' J . W . Huffman. J . Org. Chern., 1972, 37. 17. 46

47

173

Diterpenoids

OMe

junction. Decarbonylation of podocarpic acid methyl ether with phosphoryl chloride led49 to products exemplified by (45--47), the formation of which may involve the intervention of a spirocyclic cation such as (48).

The Chemistry of Ring R.--The conformation of ring B of some aromatic diterpenoids has been ~tudied.~'The C-6-C-7 proton coupling constants for a series of acetoxy-alcohols have been determined. These led to the conclusion that ring B exists in a half-boat conformation (49). The 6,7-diketone-benzilic acid ring-contraction sequence has been applied51 to some ring c bromoderivatives of abietic acid. The Chemistry of Ringc.-The modfication of ring c has centred on making available relays that are suitable for elaboration into more complex diterpenoids, the diterpenoid alkaloids, and triterpenoids. The unsaturated ketone (53) has proved to be a valuable relay for synthesis. It had been prepared previously from neoabietic acid, which is difficult to obtain pure. It has now been obtained52from the levopimaric acid-formaldehyde adduct (50). Oxidation of the adduct with potassium permanganate not only formed the glycol but in an unusual step converted the cyclic ether into the h-lactone (51). Dehydration, ozonolysis of the newly formed double bond, and then treatment of the keto-acetate (52) with chromous chloride afforded the ap-unsaturated ketone (53). The last step involved hydrogenolysis, j-elimination, and decarboxylation. The oxidation of levopimaric acid by potassium permanganate and with osmium tetroxide has been clarified.53 The structure (54) of the main oxidation

"OH

CO,H (50) O9

s 1

52

''

B. C. Baguley, R . C. Cambie, W . R . Dive, and R . N . Seelye, Austral. J . Chem., 1972, 25, 1271. R . C. Cambie, W . A . Denny, and J . A, Lloyd, Austral. J . Chem., 1972.25, 375. M . I . Goryaev, F. S. Sharispova, L. K . Tikhonova. L. A . El'chibekova, and E. B. Popova, Izcest. A k a d . N a u k Kaz. S . S . R . , 1971, 21, 49 (Chem. Abs., 1971, 75, 88 789). W. Herz and V. Baburao, J . Org. Chem., 1971, 36, 3271. W. Herz and R . C. Ligon, J . O r g . Chem., 1972,37, 1400.

Terpenoids and Steroids

174

0 -

product with potassium permanganate has been confirmed. Osmylation gave the diols ( 5 5 )and ( 5 6 ) together with the corresponding tetra-01. As with epoxidation, reaction proceeded from the r-face of the molecule.

CO,H (54)

.d'

\

(55)

Birch reduction of 12-methoxypodocarpa-8,11,13-trien-19-ol has been investigatedS4and methods have been developed for converting the C-12 ketones into C-13 ketones. An alternative approach55has been used to transpose the aromatic oxygen function from C-12to C-13.The best route involved mononitration of methyl podocarpate (57), reduction of the nitrophenol toluene-psulphonate (58) to an amine (59) with stannous chloride and then Raney nickel, and finally diazotization with isopentenyl nitrite in cold acidic methanol to afford the phenol ether.

'' 5J

R . C. Cambie and A . W . Missen, Austral. J . C h e m . , 1972, 25, 973. R . C. Cambie, K . P. Mathai, and A . W. Missen, Aitstral. J . Chem.. 1972, 25, 1253.

D it erpeno ids

175

During attempts to alkylate methyl podocarpate with substrates such as methoxyacetyl chloride, some dimeric products linked by a methylene bridge were ~ b t a i n e d . ' ~ N.m.r. studies on the epimeric 12-hydroxypodocarp-8-eneshave showns7that ring c exists in a half-chair conformation in which the C-1-C-11 interactions are relieved. O.r.d., n.m.r., and surface-film measurements on levopimaric acid have shown that rings B and c possess a folded conformation. X-Ray analysis has confirmed5' the conformation (60)in which interactions between the C-10 methyl and the C - l l p hydrogen atom and between the C-1-C-10 bond and the C - 1 1 ~ hydrogen atom are relieved.

t

The kinetically controlled enol-acetylation of methyl 12-oxopodocarp-l3-en19-oate affordeds9 the A' ' * l 3-isomer whereas thermodynamic conditions gave a 3 : 5 mixture of the A' ' * I 3 - and A'2*14-isomers.0.r.d. measurements suggested that the latter adopt the same folded conformation as levopimaric acid. A number of derivatives of methyl 12-acetyldehydroabietate have been prepared.60 Some 12-bromo- and 12-sulphonicacid derivatives of dehydroabietanitrile and dehydroabietylamine have been recorded.60 4 Tetracyclic Diterpenoids

The Kaurane Series.-An interesting feature of the oxygenation pattern of the tetracyclic diterpenoids is the high proportion that bear oxygen substituents at sites that are important in gibberellin biosynthesis. (- )-Kaur-16-en-19-oicacid and ( - )-kaur-15-en-19-oic acid have been found6' in Espeletia jloccosa, E. jgueirasii, and E. moritziana. Further evidence has been presented62 for the structure of grandiflorenic acid, (-)-kaur-9( 11),16-dien-19-oic acid, including the " 5'

58

59

'' 61

'*

R.C. Cambie, W. A. Denny, and K . P. Mathai, Austral. J . Chem., 1972, 25, 1363. S. G. Levine, I . Y . Chen, A. T. McPhail, and P. Coggon, Tetrahedron Letters, 1971, 3459. U. Weiss, W. B. Whalley, and I . L. Karle,J.C.S. Chem. Comm., 1972, 16. R. A . Bell and M . B. Gravestock, J . Org. Chem., 1972,37, 1065. ( a ) P. Catsoulacos, Chim. Ther., 1971, 6, 449 (Chem. Abs., 1972, 76, 127 182); ( b ) 1. I. Bardyshev and V . Paderin, Doklady Akad. Nauk Beloruss. S . S . R . , 1971,15,823 (Chem. Abs., 1972, 76, 4027). A. Usubillaga and A. Morales, Phytochemistry, 1972, 11, 1856. F. Piozzi, S. Passannanti, M . L. Marino, and V. Sprio, Canad. J . Chem., 1972,50, 109.

176

Terpmoids and Steroids

formation of the C-11 alcohols and ketone. ( - )-Kauran-16cr-ol,(-)-kaur-l&en19-oic acid, ( - )-kauran-19-al-17-oic acid. and ( - )-kauran-l7,1Poic acid have been isolated63 from A niiotia senegalemis. ( - )- 19-Norkauran-4cr-ol-17-oicacid, which was also found, may be an artefact arising during the isolation. An 11oxokaurane diol, calliterpenone (61), and its 17-acetate have been isolated64 from Callicarpa mucrophyllu. The major evidence for the structure came from the conversion into ( - )-17-norkaurane and from an examination of the n.m.r. spectrum of its derivatives. Six new kauranoid diterpenesE(62H64) and their A' 5-isomers] have been isolatedb5from Sideritis leucanthu ;three ( 6 2 4 4 )of them also occur in S . Iinearifolio. Foliol (62), sidol (63), and linearol (64)gave the same triacetate, which was isomerized with iodine to the triacetate obtained from isofoliol, isosidol, and isolinearol. These contain the C-15(16) double bond. Foliol was oxidized with chromium trioxide in pyridine to a diketo-aldehyde which was reduced to ( - )-kaurene. The location of the oxygen functions at C - ~ CC-7p, Y , and C-18 were inferred from the n.m.r. spectrum and from the formation of a 3~,18-acetonide.

H

(611

(62) R ' = R2 = H (63) R ' = Ac:R2 = H

(64) R ' = H : R2 = AC

![j.7P-Dihydroxykaurenolide

( 6 5 ) has been i ~ o l a t e d ~ ' from , ~ ~ Gihherclla

fiijihroi, It was converted rio the C-2 olefin into dihydro-7-hydroxykaurenolide, and the ready decarboxylation of the diketone formed on oxidation located the

additional oxygen function at C-3. The ring-contraction of the corresponding 7r-toluene-p-sulphonate has been e ~ a m i n e d "as ~ a route to gibberellin A,, aldehyde (66). 17-Hydroxy-(- )-kaur-15-en-19-oic acid has been isolated68 from Enhydra jirctuaris. Details of the conversion of enmein into (-)-kaurene have been d e ~ c r i b e d . ~ ~ The hemi-acetal(67),produced by an acyloin condensation of enmein derivatives, I . T. U . Eshie!. A . Akisanya. and D. A . 11. Taylor. Phyrochemistry, 1971. 10, 3294.

'' A . Chatterjee, S. K . Drsmuki, and S. Chandrasekharan, Terrahedron, 1972,28,4319. 6 5

T. G . de Quesada. B. Rodriguez, S. Valverde, and S . Huneck, Tetrahedron Letters, 1972,2187.

'' J . H . Bateson and B. E. Cross, TrrrahccfronLetters, 1117.

1971, 3407; J . C . S . Perkin I , 1972,

P. Hedden and J . MacMillan. Trrrahc~dronLetters. 1971. 4939. "'E. Ali, P. P. Dastidar, and S. C . Pakrashi, Indian J . Chem., 1971,9, 1166. 6 q E . Fujita, T. Fujita, and Y . Nagao. Tetrahedron, 1972, 28, 5 5 5 .

('-

Dilerpenoids

177

HO

.

OH

co-0

HO$

. . *

CHO

was reduced to the 6,20 diol and thence to (-)-kaurene and its isomer uia the keto-aldehyde. Treatment of the hemi-acetal (67) with zinc and acetic acid containing hydrochloric acid gave a compound (68) with the beyerane skeleton. The stereoelectronic requirements for epimerization of C-15 alcohols [(69) -+ (70)] in the enmein series have been discussed.70

OH (67)

Confirmatory evidence for the location of the secondary hydroxy-group of sideridiol at C-7 has been p r e ~ e n t e d . ~ Bromination ~ of methyl ~-oxo-( -)kauran-18-oate gave the 6P-bromo-derivative. Hydroboronation, epoxidation, and osmylation of (-)-kaur-6(7)-enes has been to occur from the p-face of the molecule and to afford a route to the functionalization of the kauranoid 6p position. N.m.r. solvent-shift studies indicated73that the h-lactones obtained by opening ring D of phyllocladene exist in the chair form. Phyllocladene is an abundant E. Fujita and Y . Nagao, J . Chern. Soc. (C), 1971,2902. F . Piozzi, P. Venturella, A . Bellino, M. L. Marino, and P. Salvadori, J.C.S. Perkin I , 1972, 759. l 2 l 3

J . R . Hanson and J. Hawker, Tetrahedron, 1972, 28, 2521. R . C. Cambie and R . C. Hayward, Ausrral. J . C h ~ r n .1972, , 25, 1135.

178

Terpenoids and Steroids

constituent of Araucuria excelsa. The conversion of isophyllocladene by ozonolysis, Baeyer-Villiger oxidation, hydrolysis, and oxidation into ( + )-podocarp8(14)-en-13-one has been de~cribed.’~ The enolization of the C-15 ketones in the kaurane and phyllocladane (138kaiirane) series has been studied.75 At temperatures below 100°C the rates of enolization of the 16R-epimers are much greater than those of the 16s-epimers and the products of ketonization are the 16R-epimers. This has been attributed to access to the C-16 proton and to torsional strain between the methyl group and the C-13 hydrogen. This dihedral angle is increased on ketonization of the enol from the r-face of ring D. The chemistry of some ring D derivatives of phyllocladene ( 13g-kaurene)have been described and some differences from the kaurene series due to interactions between the ring 1)and the C-10 angular methyl group have been noted.76 The C-15W2-16proton coupling constants for the isomers of kauran-15-01s and phyllocladan-15-01s indicate7’ that ring D exists in a twistenvelope conformation. Treatment of the ( - )-kauran-15cr,t6cx-epoxide(71) with boron trifluoride led to the atisan-15-one (72). In the phyllocladene series both the phyllocladan-15-one (73)and the neoatiseran-15-one (74) were f ~ r m e d . ~ ~ . ~ ~ H

During a study of the biosynthesis of the diterpenes in Beyeria feschenaultii, beyeren-19-01 was isolated.80 3r-Hydroxy-( - )-beyer-l5(16)-ene-2,12-dione(75) has been isolated” from Anclrostachys johnsorrii. The presence of a C-12 oxygen function permits a number of interesting skeletal rearrangements. Solvolysis of the 122-methane sulphonate (76) brought about contraction of ring c to (77). A related rearrangement has been observed” in the case of the C-12 ketone (78) to afford (79). The modification of isosteviol leading to the introduction of substituents at C- 12 and C- 14 has been described.83 The products from the carbonium ions (80) R . C . Cambie and R . C. Hayward, Artstrul. J . Chenr., 1972, 25, 959.

’’ J . MacMillan and E. R . H . Walker. J . C . S . Prrkin I, 1972, 986. ’’ J.

MacMillan and E. R . H . Walker, J.C.S. Perkin I , 1972, 981. J. MacMillan and E. R . H . Walker. J . C . S . Prrkin I , 1972, 1272. T 8 J . MacMillan and E. R. H . Walker, J . C . S . Perkin I , 1972, 1274. -’K . M . Baker, L. H . Briggs, J . G . St. C . Buchanan, R . C. Cambie, B. R. Davis, R. C. Hayward, G . A . S. Long, and P. S. Rutledge, J.C.S. Perkin I, 1972, 190. ‘I’ H . J . Bakker, E. L. Ghisalberti, and P. R . Jefferies, Phytocheniisrry, 1972,11,2221. K . H. Pegel, L. P. L . Piacenza, L. Phillips, and E. S . Waight, Chem. Cornm., 1971, 1346. ”

’’ M . Laing, P. Sommerville, D . Hanouskova. K . H . Pegel, L. P. L. Piacenza, L. Phillips,

’.’

and E. S. Waight, J . C . S . Chem. Cotritri., 1972. 196. R . M . Coatesand E. F. Bertram, J . O r g . Chrnz.. 1971. 36, 2625.

179

Diterpenoids

0

H O -’

and (8 1) are of interest in diterpene biogenesis. When the carbonium ion (80) was formed,84by deamination of the amine (82),by solvolysis of the related toluene-psulphonate, or by decomposition of the toluene-p-sulphonhydrazone, the products had the kauranoid skeleton and under protic conditions the toluene-p-sulphonhydrazone also gave the trachylobane skeleton. Solvolysis of the C-12fi-toluenep-sulphonate (83) afforded the isoatiserene (84) skeleton. Brief acetolysis of the C-16 toluene-p-sulphonate in trifluoroacetic acid and more prolonged treatment

(82)

(83)

R.M . Coates and E. F. Bertram, J . O r g . Chem., 1971,36, 3722.

Terpenoids and Steroids

180

of the C- 12 toluene-p-sulphonate gave cross-over products between the two cations. The cyclization of manool to 14a-hibyl formate has been shown to proceed through a cyclo-octenyl cation (85) and thence to a tetracyclic intermediate (86) which would ultimately give the hibyl ester (87). The corresponding tetracyclic alcohols have been synthesizeds5 and shown to be converted into the 16hibyl acetate.

The Trachylobane Series.--Ciliaric acid has been isolated86 from Helianthus ciliuris and shown to be 7~-hydroxytrachyloban-19-oic acid.

Gibberellins.4ibberellins A,, (88) and gibberellin A.34(89)have been isolated" from the immature seeds of Culonycrion aculeatum. Gibberellin A,, (90)and its glucoside were foundg8in the immature seeds of Cytisus scoparius. Gibberellin A,, (91), which exists in the lactol form, has been isolateds9 from Gibberella fujikuroi. Its structure was confirmed by reduction to the 6-lactone gibberellin A,- (92), which has been isolatedg0from Pliaseolus culguris. Gibberellin A,, (93) was isolated as its glucosyl ester from the same source. The partial synthesis of gibberellin A,, has been achieved"' by the selective reduction of the hindered

.G,:':" .....,

0

CO,H (88) n5

.. .. "

HO

.

a

CO,H (89)

Do Khac Manh Duc, M . Fetizon, and I . P. Flament, J.C.S. Chem. Comm., 1972, 886. L. F. Bjeldanes and T. A. Geissman. Phytochemisrry, 1972, 11, 327. N. Murofushi, Y . Takao. and N.Takahashi, Agric. and Biol. Chem. ( J a p a n ) , 1971,35,

'' 441. '* H . Yamane, I . Yamaguchi, N . Murofushi. and N . Takahashi, Agric. and Biol. Chem. 9o 9'

(Japan), 1971, 35, 1144. J . MacMillan and J . R . Bearder, Agrrc. undBiol. Chem. ( J u p a n ) , 1972,36, 342. K . Hiraga, T . Yokota, N . Murofushi. and N . Takahashi, Agric. and Biol. Chem. (Japan), 1972, 36, 347. D. H. Bowen, D . M. Harrison, and J . MacMillan, J . C . S . Chem. Comm., 1972, 808.

Qa

QA

Diterpenoids

. .

HO

* *

181

CO,H (90)

.

HO

.. ,-

HO

C0,H (91)

., *

. . .

HO

C0,H

*

OH

C0,H

(92)

(93)

co . ,

HOJ’C c o 2 H (94)

. .

HO’.

*

COzH (95)

angular carboxy-group of gibberellin A 1 3 . Reduction of the lactone (94)obtained from gibberellin A, 3 , gave the h-lactone (95). A group of gibbane metabolites (e.g. 96) have been i s ~ l a t e d , ~from . ~ ~ the incubation of ( - )-kaur-2,16-dien-19-01with Gibberella Jujikuroi. The minor metabolites were isolated by methylation. These compounds were shown to be microbiological transformation products by labelling the substrate with tritium. Their structures were proven by correlation with gibberellin A,, . Fluorogibberellic acid and fluorogibberellin A, have been produced by a fermentation of Gibberella fujikuroi to which a fluorinated substrate had been added.94 The biological activity of the fluorogibberellins has been de~cribed.~’4bj?,7-Dihydroxy-l -methyJ-8-methyIenegibba-l,3,4a( lOa)-trien-lO-one (97) has been found” in Gibberella fujikuroi, presumably as a degradation product of gibberellic acid. Partition procedures are often used in the initial extraction and purification of gibberellins. A detailed report has appeared9’ on the partition coefficients of

’’ I . F. C o o k , P. R . Jefferies, and J . R . Knox, 93 94

95 96 q7

Tetrahedron Letters, 1971, 2157.

H . J . Bakker, P. R . Jefferies, and J . R . Knox, Tetrahedron Letters, 1972, 2723. J . H . Bateson and B. E. Cross, J.C.S. Chem. Comm., 1972, 649. J. L. Stoddart, Planfa, 1972, 107, 81. B. E. Cross and R . E. Markwell, J. Chem. Soc. ( C ) , 1971, 2980. R. C. Durley and R . P. Pharis. Phytochemistrv, 1972, 11, 317.

182

Terpenoids and Steroids

0-c=o

gibberellins between phosphate buffer and the commonly used organic solvents. An insoluble form of poly-N-vinylpyrrolidone has been reported98 to be effective in the purification of gibberellin-like substances from plant extracts. There have been a number of reports of known gibberellins from different plants. The detection of gibberellins by g.1.c.-mass spectrometry, particularly of their trimethylsilyl derivatives, has played an important role. Thus the extension of earlier work on Phuseolus coccineus seed to young seedlings has been reported" and gibberellins A,, A,, A ; , A,, and A, have been detected'" in the tomato, Lycopersicon esculentum, and gibberellins A and A 2 3 I o 1 in ihe immature seed of Wistaria ,fioribundu. On irradiation in the solid state, ketogibberellic acid underwent"' a photoaromatization reaction to afford the phenol (98). The corresponding ester was formed by irradiation l o 3 of methyl ketogibberellate in solution in t-butyl alcohol. In benzyl alcohol this was accompanied by a ring-opened product whereas in ethanol the aromatization reaction was accompanied l o 4 by photoreduction and the addition of solvent. Gibbanes in which ring A is aromatic react with DDQ to afford l o 5 rearrangement products. When the substrate contains a C-7 hydroxygroup the 7,8-bond migrates to C-6 to give a C-7 ketone (99), whereas in the 7-deoxygibbanes the 9,9a-bond migrates to position 4b to give a 9a,lO-olefin (100). H

'*

'03

J . L . Glenn. C. C. K u o . R . C. Durley, and R . P. Pharis. Ph?~tochcmisrr.v,1972, 11, 345. A . Crozier, D. H . Bowen. J . MacMillan, D. M. Reid, and B. H . Most, Plunta, 1971, 97, 142. A . J . Perez and W. H . Lachman, Phytochrmisrrj,, I97 1 10, 2799. K . Koshirnizu, H . Ishii, H . Fukui, and T. Mitsui, Phyrorhemistry, 1972, 11, 2 3 5 5 . G. Adam and B. Voigt, Terrahedron Lctrrrs, 1971, 4601. I . A . Gurvich, N . S. Kobrina, E. P. Serebryakov, and V. F. Kucherov, Terrahedron,

Io4

E. P. Serebryakov. N . S . Kobrina, V . F. Kucherov, G . Adam. and K. Schreiber,

ILiS

Tetruhrdron, 1972, 28, 3819. B. E. Cross and R . E. Markwell, J . C . S . Chrtn. Comm.. 1972, 447.

'')

I ""

"'I ")'

1971,27, 5901.

Diterpenoids

183

( 100)

(101)

The antheridium-inducing factor of the fern Anemia phyllitidis has been shown"' to have a gibberellin-like structure (101), reminiscent of the rearrangement products of gibberellic acid in concentrated sulphuric acid. l o 7 Grayanotoxim-A number of new grayanotoxins have been isolated from Leucothoe grayana. As with other closely related groups of diterpenoids, their structures rest on spectral evidence (mainly n.m.r.) and simple correlations. Recent addition^'^^^'^^ are G VIII (102), G IX (103),G X (104), G XI (105), G XI1 (106), and G XI11 (107). Rhododendron japonicum also contains these skeletal types. Rhodojaponin V was assigned' l o the structure (108)on the basis

HO

HO

OAc

OR

OH

OH (102) R

=

H

(103)

(104) R = AC

dOH OH

HO

OH

OR

HO

\ 'OH OH

OH (105) R

=

H

(107) R = AC I Oh

107 I08

I09

I 1 0

K . Nakanishi, M. Endo, U . Naf, and L. F. Johnson, J . Amer. Chem. Soc., 1971, 93, 5579. R . N . Speake. J . Chem. S o c . , 1963. 7. H . Hikino, T. Ohta, S. Koriyama, Y . Hikino, and T. Takemoto, Chem. and Pharm. Bull. (Japan), I97 1,19, 1289. H . Hikino, S. Koriyama, T. Ohta, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1972, 20, 422. R . Iriye and I . Tomida, Tetrahedron Letters. 1972, 1381.

Terpenoids and Steroids

184

OH

\,

OH

OH

(108)

( 109)

of its hydrolysis to the known rhodojaponin Ill and its n.m.r. spectrum whereas spectral evidence (on the triacetate) was used to deduce the structure of rhodojaponin VI (109). A full paper on the structure of lyoniol A has appeared." 5 Diterpene Alkaloids

Vakognavine (1 10) is' an unusual diterpene alkaloid bearing a C-4 aldehyde group and lacking part of the N-bridge. The base exists as the free aldehyde and the salt as the hemi-acetal. Stephisine (111) is''3 a novel diterpene alkaloid dimer, one component of which possesses a rearranged atisine skeleton. A model for the atisane-aconane conversion has been studied.' l 4 However, soivolysis of both C-15 epimeric ketol toluene-p-sulphonates ( 1 12) afforded the rearrangement product ( 1 13). On the other hand, pyrolysis of one epimer gave a compound ( I 14) possessing the aconane skeleton.

.1

Me -

"*

' '' 'I'

'

(1 11) K . Takeshi, J . Sakakibara, and M . Yasue, Yukugaku Zasshi, 1971, 91, 1194. S . W. Pelletier, K . N . lyer, L. H . Wright, M . G. Newton, and N . Singh, J . Amer. Chem. SOC.,197 1, 93, 5942. S . W . Pelletier, A. H . Kapadi, L. H . Wright, S. W . Page, and M . G . Newton, J . Amer. Chem. SOC.,1972,94, 1754. J . P. Johnston and K . H . Overton, J . C . S . Prrkrn I , 1972, 1490.

D iterpeno ids

185

Lapaconidine, which was isolated from Aconitum leucostomurn, has been shown' to possess the structure (1 15), whereas indaconitine has been isolated' l 6 from Aconitum uiolaceum and identified by hydrolysis to pseudoaconine.

''

6 Macrocyclic Diterpenoids and their Cyclization Products A small amount of isoincensole oxide (1 16) has been isolated' from frankincense, the resin of Boswellia carteri. It is also a minor product of the epoxidation of incensole. The epoxide ring is very inert in this compound. Some further diterpenoid esters related to lathyrol have been isolated"8 from the irritant, co-carcinogenic seed oil of the caper spurge, Euphorbia krthyris.

Y

I" ' I *

V . A . Tel'nov, M . S. Yunusov, Y. V. Rashkes, and S. Y. Yunusov, Khim. prirod. Soedinenii, 1971, 5. 622. G. A. Miana, M. Ikram, M. I. Khan, and F. Sultana, Phytochemisrry, 1971, 10, 3320. M.L. G. Forcellese, R. Nicoletti, and U. Petrossi, Tetrahedron, 1972, 28, 325. W. Adolf and E. Hecker, Expcrientia, 1971, 27, 1393.

I86

Terpenoids and Steroids

12-Hydroxydaphnetoxin has been isolated' l 9 as a toxic constituent of Lasiosiphon burchellii. A full paper has appeared12' on the structure of huratoxin. Taxanes--The cage-like structure ( 117) of the taxinines possessing an 1 1-en-13one system allows the formation ofa transannular C-3-C-11 bond on irradiation. However, the C-13 carbonyl is held away from C-3 so that the oxygen atom cannot participate in an intramolecular hydrogen-abstraction process. Thus irradiation of the diacetate (1 18)afforded12' ( 1 19), which was related by acetylation to taxinine L. a minor constituent of T. cuspidata. When the C-9 and C-10 hydroxy-groups were converted into their isopropylidene derivative, the central ring was sufficiently deformed to increase the separation between C-3 and C-11. A different photochemical reaction then occurred and a cyclopropyl ketone (120) was obtained.

OAc

H

0 'OAc OAc ( 1 1%

7 Miscellaneous Diterpenoids

An unusual diterpenoid, cyathin A, (121). has been isolated from the 'bird's nest' fungus, Cq'arlzus helenae. Its structure, which followed' 2 2 from a careful examination of the n.m.r. spectrum supported by an X-ray analysis, represents a unique cyclization and rearrangement of geranylgeranyl pyrophosphate ( I 22). J . Coetzer and M . J . Pieterse, J . S . African Cherii. l n s r . , 1971, 24, 241 (Chem. Abs., 1972, 7 6 , 23016); Acra Cryst., 1972, B28. 620. '"' K . Sakata. K . Kazuyoshi, and T. Mitsui, Agric. ariclBiol. Chem. ( J a p a n ) , 1971,35,2113. T. Kobayashi, M . Kurono, H . Sato, and K . Nakanishi, J . Amer. Chem. SOC.,1972,94, 'I9

I Z L

2863. W. A . Ayer and H . Taube. Tetruhertroti Lt.ttcrs. 1972. 1917.

Diterpenoids

187

(121)

( 122)

A group of possibly diterpenoid substances, anastreptin, orcadensin (both C,OH24O,), barbilophozin (C22H3205),floerkein A and B (both C&3,03), barbylicopodin (C20H3002), gymnocolin (C2,H2*06),and scapanin (C2oH3oO4), have been isolated 2 3 from various mosses.

8 Diterpenoid Synthesis A full paper on the biogenetically patterned syntheses of the levantenolides outlined earlier has appeared. '2 4 A simple route to 4,4-disubstituted cis-decalins has been reported'25 involving the use of the dimethanesulphonate (123) to alkylate diethyl malonate. In the product (1 24) the ester groups may be selectively hydrolysed. A full paper describing the synthesis of marrubiin has appeared'" and the approach has been extended12' to the synthesis of the terpenoid antibiotic LL-Z 1271. The lactone (125)was converted into the ester (126),which was oxidized with selenium dioxide to form the lactol (127).

0

@-" co-0

( 1 25)

124

' 2 5

'2h ' j 7

S. Huneck and K . H . Overton, Phytochemistry, 1971, 10, 3279. T . Kato, M . Tanemura, S. Kanno, T . Suzuki, a n d Y . Kitahara, Bio-organic Chemistry, 1971, 1, 84. A . Kroniger and D. M . S . Wheeler, Tetrahedron, 1972, 28, 255. L. Mangoni, M. Adinolfi, G. Laonigro, and R. Caputo, Tetrahedron, 1972, 28, 61 1. M . Adinolfi, L. Mangoni, G. Barone, and G . Laonigro. Tetrahedron Letters, 1972,695.

188

Terpmoids and Steroids

A synthesis of methyl vinhaticoate and methyl vouacapenate has been described. 28 The key steps involved the conjugate addition of dimethylcopper lithium to (128), prepared from podocarpic acid, the transformation of the product (129) into the methoxymethylene ketone (130),and the formation of the furan ring (131) by the copper-catalysed addition of ethoxycarbonylcarbene.

0

( 128)

(1291

(131)

( 130)

This synthesis established the configuration of the C-14 methyl group. The transformation of the 'normal' diterpene A,B ring junction to the antipodal system involved 2 9 the aluminium trichloride-catalysed de-isopropylation of dehydroabietanitrile to afford a product possessing the cis ring-junction. This was then isomerized over 10°z,palladized charcoal in refluxing triglyme to give the antipodal A/B fusion. Full details of an interesting total synthesis of steviol have appeared.13' The key stage involved the Clemmensen reduction of the diketone ( 1 32) to form the

C0,Me

+\

\

( 1 34)

( 132) I Z B T. A . SDencer, R . A . J . Smith. D. L. Storm. and R. M Villirica, J . Amer. Chem. Soc., 197 I , 93,4856. '"' 2 9 S. W . Pelletier, Y . Ichinohe, and D. L. Herald, Terrahedron Lerrers, 1971,4179. K . Mori. Y . Nakahara, and M. Matsui, Tetrahedron, 1972, 28, 3217.

D iterpenoids

189

epimeric ketols (133) and (134). Steviol was converted into erythroxydiol A. Alternative synthetic routes to these compounds have also been described.' 3 1 A total synthesis of epiallogibberic acid utilized'32 a similar reduction of a diketone to form a ketol possessing a bridgehead hydroxy-group. The full paper describing the notable synthesis of gibberellin A,, has appeared. 1 3 3 The sensitive polyfunctionality of ring A of gibberellic acid renders it a challenging synthetic task. As a preliminary partial synthesis of methyl gibberellate, the diene (135) was prepared as a relay.'34 On selective reaction with rn-chloroperbenzoic acid, this was converted into (136). After saponification of the lactone this was converted into the iodohydrin (137)and thence to methyl gibberellate (1 38). The stereoselective introduction of an angular vinyl grouping by the conjugate addition of divinylcopper lithium to unsaturated ketones such as (139) and the subsequent conversion of the product (140), via the pinacolic cyclization of the keto-aldehyde (141) into the diol (142), has been studied13' as a model for the synthesis of the B,C,D ring system of gibberellic acid.

I n

C0,Me

H

C0,Me

H

(139)

13' 132

13'

'35

Y . Nakahara, K . Mori, and M. Masanao, Agric. and Biol.Chem. (Japan), 1971,35918. K. Mori, Tetrahedron, 1971, 27, 4907. W. Nagata, T. Wakabayashi, N . Masayuki, Y . Hayase, and S. Kamata, J . Amer. Chem. Soc., 1971, 93, 5750. E. J . Corey, T. M . Brennan, and R . L. Carney, J . Amer. Chem. SOC.,1971,93,7317. E. J . Corey and R . L. Carney. J . Amer. Chetn. Soc., 1971, 93, 7318.

Terpenoids and Steroids

190

Further studies have a ~ p e a r e d ' ~ ~on . ' ~the ' benzilic acid rearrangement of 6,7-dioxopodocarpanes and of the stereochemistry of the products. Some assignments of the C-9 stereochemistry of synthetic gibbanes have been made'38 on the basis of the n.m.r. spectrum. Terracinoic acid (143),a readily available degradation product of terramycin, has been converted 39 via the tricyclic @-unsaturated ketone (144) into the diketone (145). Selective reduction of the cyciopentanone afforded a ketol. The unsaturated ketone was then hydrogenated to form, after further elaboration, (146). The synthesis of a gibberellin intermediate (147; R = H or Me) by two independent routes has been d e s ~ r i b e d . ' ~ ~ . ' ~ ~

Me

C0,H

Me

(144)

(133)

.. ,, 0

Me

Me

(146)

(145)

Me0

0 (147)

"'38

'39 14'

A . Tahara and Y . Ohtsuka, J . C . S . Perkin I , 1972, 320. A . Tahara, T. Nakata. Y . Ohtsuka, and S. Takada, Chem. and Pharm. Bull. (Japan),

1971, 19, 2653. A . J . Baker, A. G . Goudie, U . R . Ghatak, and R. Dasgupta, Tetrahedrun Lerfers, 1972, 1103. A . J . Baker, 1. Brown, and R. A . Raphael, J . C . S . Perkin I , 1972, 1216. A . J . Baker and A. G. Goudie, J . C . S . Chem. Cumm., 1972,951. H . J . E. Loewenthal and S. Schatzmiller, Terrahedron Lerters, 1972, 31 IS.

Diterpenoids

191

The grayanotoxins are characterized by an A-nor-B-homokaurane skeleton. In an interesting photochemical ~ y n t h e s i s of ' ~ ~this ring system, the tetracyclic derivative (148) was photolysed to give (149). A partial synthesis of grayano~~ toxin G I1 (150) from a possible tricyclic relay (151) has been r e ~ 0 r d e d . IThe C-13 position was protected and the product was alkylated with allyl bromide. After removal of the protecting group, the allyl double bond was cleaved to form an aldehyde which underwent base-catalysed condensation at C- 13 to form a tetracyclic intermediate which was then converted into G 11.

The stereoselective total synthesis of the delphinine degradation product (158) has been d e ~ c r i b e d . 'The ~ ~ key stages involved the conversion of the tetralone (152) into the aldehyde (153) and its ring-closure to (154). This product was then converted into the compound (155), which underwent cyclization to form the lactam ( 1 56) in the presence of potassium cyanide. On acid hydrolysis, this was converted into the lactam (157), which was in turn transformed into (158), the

14'

143 144

M . Shiozaki, K . Mori, M . Matsui, and T. Hiraoka, Tetrahedron Letters, 1972, 657.

N. Hamanaka and T. Matsumoto, Tetrahedron Letters, 1972, 3087.

K . W'iesner, E. W. K . Jay, T. Y . R . Tsai, C. Demerson, L. Jay, T. Kanno, J . Krepinsky, A. Vilim, and C. S. Wu, Canad. J . Chern., 1972,50, 1925.

Terpenoids and Steroids

192

Ac

OMe

OMe

@: - cA

OH

MeOCH,

0'

I

H

OMe (157)

( 1 56)

OMe

MeOzC

@ 0

\

/

PhS0,NH

OAc OMe

1159)

( 158)

structure of which was confirmed by X-ray analysis. A new synthesis of an important intermediate (159) for the possible synthesis of songorine has been described. '

lJ5

Pak-Tsun Ho, S. Oida, and K. Wiesner, J.C.S. Chem. Comm., 1972, 883.

4 Sesterterpenoids BY J. 0.CONNOLLY

Cheilanthatriol (l),a new fundamental type of sesterterpenoid, has been isolated' from the fern Cheifunthesfurinosu. The carbon skeleton can be formally derived by cyclization of geranylfarnesol (2), initiated at the isopropylidene end.

Three linear sesterterpenoids have been obtained from species of marine sponge. These are ircinin-1 (3)and ircinin-2 (4) from lrcinia oros' and fasciculatin (5) from Irciniaf~sciculatu.~ The C-21 compounds nitenin (6) and dihydronitenin Me

I

CH2CH2CH=C---€H2CH2CHtCH--CH

I

Me

(3)

0

'

H . Khan, A. Zaman, G . L. Chetty, A. S. Gupta, and Sukh Dev, Tetrahedron Letters,

'

G . Cimino, S. De Stefano, L. Minale, and E. Fattorusso, Tetrahedron, 1972, 28, 3 3 3 . F. Cafieri, E. Fattorusso, C. Santacroce, and L. Minale, Tetrahedron. 1972, 28, 1579.

1971,4443.

193

Terpenoids and Steroids

194

Me

I

JCH2CH2CH2 - C=CH

C=C

/

\

H

( 7 ) , from Spongia nirens? and furospongin-1 (8) and several related derivatives from Spongia oficinalis and Hippospongia c ~ r n r n u n i s are ~ * ~probably degraded sesterterpenoids.

0 7CH2

ClCH /c=: -

\ -

H

0

H

H2C

\

/

Me

(4) (7) 7,8-dihydro

' E. Fattorusso, L. Minale, G . Sodano, and E. Trivellone, Tetrahedron, 1971, 27, 3909.

' G . Cimino, S. De Stefano, L. Minale, and E. Fattorusso, Tetrahedron, 1971, 27,4673. G . Cimino, S. De Stefano, L. Minale, and E. Fattorusso, Tetrahedron, 1972, 28, 267.

I95

Sesterterpenoids

The full details of the structural elucidation of fusicoccin (9) have been published.7-9

' K . D. Barrow, D. H . R . Barton, E. Chain, C. Conlay, T. C . Smale, R. Thomas, and E.

*

-

Waight, J . Chem. SOC.(0,1971, 1259. K . D. Barrow, D. H. R. Barton, E. Chain, U . F. W. Ohnsorge, and R. Thomas, J . Chem. SOC.(0,1971, 1265. M . Brufani, S. Cerrini, W . Fedeli, and A. Vaciago, J . Chem. SOC. ( B ) , 1971,2021.

5 Triterpenoids BY J. D. CONNOLLY

1 Reviews The 'Handbook of Naturally Occurring Compounds, Vol. 11, Terpenoids' contains a comprehensive survey of natural triterpenoids classified according to structural type and includes references up to 1970. A brief general review of triterpenoids, listing compound names and sources, has been published.' Other topics which have been reviewed include the cuc~rbitacins,~ the holothurinogenins,'-6 geochemistry,' and the triterpanes from petroleum distillates8

2 Squalene Group A new alkylation reaction' which involves 2-alkenylthiothiazoline lithium derivatives has been applied to the synthesis of squalene. 2-Farnesylthiothiazoline (1) was converted into its lithium salt (2) and alkylated with farnesyl bromide to form the squalene derivative (3). Desulphurization with Raney Nickel afforded squalene in 80 " yield.

' '

T. K . Devon a n d A . I . Scott, ' H a n d b o o k of Naturally Occurring C o m p o u n d s . Vol. 11, Terpenoids Academic Press, New York. 1972. M .J. Kulshreshtha. D. K . Kulshreshtha. a n d R . P. Rastogi, Phytochemistr-v, 1972, 11,

'.

2369.

D. Lavie a n d E. Glotter,

Fartsc-hr. C h c m . arg. h'utrrrstoff,

J . Scheuer. NuIurwiss., 1971. 58, 549. ' P. E. Premuzic, ForIJchr. C h r n i . org. ,Vuntrsroflt,,

1971, 29, 307.

1971, 29, 417.

J. S. Grossert, Cht,m. Sac. R r r . , 1972, 1, 1 . J. R . Maxwell, C. T. Pillinger. a n d G . Eglinton. Qtrort. R u . , 1971,25, 571. E. V. Whitehead, Cheni. and I d . . 1971, 1 1 16. K . Hirae. H. Matsuda, a n d Y. Kishida. Trtruhrdron L r t t w s , 1971, 4359.

196

197

Triterpenoids

A second new synthesis of squalene utilizes the observation that selenium dioxide oxidation of gern-dimethyl olefins or cis- and trans-allylic alcohols yields stereospecifically trans-ap-unsaturated aldehydes. The olefin (4)or a mixture of cis- and trans-diols (5) were transformed by use of selenium dioxide, followed by reduction, into the trans-allylic diol (6). The corresponding bromide (7) was used to alkylate two moles of the ylide from trans-geranyltributylphosphonium bromide leading eventually to all-trans-squalene in 46 % yield [from the diol(6)l. Protection of one of the p-alcohol groups of (6)as the tetrahydropyranyl ether opens the possibilities of unsymmetrical coupling and the introduction of specifically labelled fragments. The full details of the synthesis of squalene by Biellmann and Ducep" have appeared (see Vol. 1, p. 161). This synthesis can be readily adapted for the introduction of tritium by quenching the ylide (8) with tritiated water before the alkylation step.

(5) R = C CH, H 2 0 H (cis and trans) (4) (6) R. = CHO (7) R = CH,Br

dPh \

(8)

The bis-homosqualenes (9) and (10) have been prepared12 by enzymic condensation of the labelled homologues (11) and (12) of farnesyl pyrophosphate. The corresponding bis-homofarnesyl pyrophosphates (R' or R2 = n-C,H,) failed to condense. Enzymic cyclization of 6-demethyl-2,3-oxidosqualene has been shown to yield both AB-cis- and ~~-trans-19-norlanosterol(l3) and (14)(see Vol. 2, p. 158). Ruthenium tetroxide oxidation of either isomer afforded the enone (15). lo

I ' I' l 3

U . T. Bhalerao and H . Rapoport, J . Amer. Chem. Soc., 1971,93, 531 I . J. F. Biellmann and J. B. Ducep, Tetrahedron, 1971, 27, 5861. K. Ogura, T. Kayama, and S. Seto, J . Amer. Chem. Soc., 1972,94, 307. E. E. van Tamelen, J . A . Smaal, and R . B. Clayton, J . Amer. Chrni. SOC., 1971, 93, 5279.

I98

fl

Terpenoids and Steroids

R.T'Rz

\

\

R' R2

R' R' (9) R' (10) R'

= =

Et: R 2 = Me Me: R2 = Et

(11) R' = E t ; R 2 = Me (12) R' = Me; R2 = Et

Crombie and his colleagues have confirmed' the stereochemical assignments of their previously obtained synthetic presqualene alcohol isomers by use of lanthanide shift reagents (see Vol. 2, p. 156).

HO

3 Fusidane-Lanostane Group Viridominic acids A (16), B ( 1 7), and C ( 1 8), three new protostane derivatives with chlorosis-inducing activity, have been isolated' 5 * 1 6 from Cladosporium species. They are closely related to cephalosporin P, (19) which co-occurs with them. The presence of the 11-oxygen function of viridominic acid C was establishedI6 by oxidative degradation to the ene-dione (20). I'

l5 Ib

L . Crombie, D. A . R . Findlay, and D. A . Whiting, Terruhedron Letters, 1972, 4027. H, Kaise, K . Munakata, and T. Sassa, Tetrahedron Lerrers, 1972, 3789. H , Kaise and K . Munakata. Trrruherlron Letrerh. 1972, 199.

199

Triterpenoids

HOP OAc

(16) R' = 0: R2 = H (17) R' = O ; R 2 = OH (18) R' = H,P-OH; R2 = H (19) R' = H , ; R2 = H Fusidic acid (21) which is normally produced by Deuteromycetes and Ascomycetes, has now been isolated17 from Isaria kogane, a species of Basidiomycetes.

(22) R = Me (24) R = H

''

H. Hikino, Y. Asada, S. Arihara, a n d T. Takemoto, Chem. and P h a r m . Bull. (Japan), 1972, 20, 1067.

200

Terpenoids and Steroids

The 9,1 la-epoxylanostane (22) undergoes' a backbone rearrangement to (23) on treatment with Lewis acids. The corresponding norlanostane epoxide (24) (see p. 203) has been transformed'' into the diene (25), possessing a fusidane skeleton.

(23) R = Me (25) R = H

OH

The structure of inotodiol (obliquol) (26) has been established" by synthesis of the related diene (27). Marker's 'a-ketodehydrolanosterylacetate' has been shown2' to be 3P-acetoxylanost-9(11I-en-7-one(28),and to undergo isomerization

0

(27)

'' l9 lo

*'

(28)

I . G. Guest and B. A. Marples, J . Chem. SOC.(0,1971, 1468. T. Kazlauskas, J. T. Pinhey, and J . J . H . Simes, J . C . S . Perkin I , 1972, 1243. F. de Reinach-Hirtzbach and G. Ourisson, Tetrahedron, 1972, 28, 2259. L. H . Briggs, J. P. Bartley, and P. S. Rutledge, J.C.S. Perkin I , 1972, 581.

20 1

Triterpenoids

in base to 3~-acetoxylanost-8-en-7-one. Eburicodiol (29) and eburical (30), two likely intermediates in the transformation of lanosterol into eburicoic acid (31), have been isolated” from the fungus Fomes oficinalis. Two other triterpenoids from the same source are 3-keto-dehydrosulphurenicacid (32) and the hexanorderivative (33)23(see Vol. 1, p. 170).

HO

AcO

OH (33)

(34)

The full paper on the synthesis of 32-functionalized lanostanes has appeared.24 The 32-norlanosterol derivative (34), prepared2’ from 3P-acetoxy-7a-hydroxylanostano-32-nitrile, was found to have the unnatural 14-P-H configuration. Dihydrolanosteryl acetate has been photo-oxygenated26 in the presence of a photosensitizer with the object of functionalizing the C-14 methyl group via the 9a-hydroperoxide (35). This compound was not isolated from the reaction mixture, which included the ”-diene, the A*-7-one, the A*-7a-hydroperoxide and the two epoxides (36) and (37). The most interesting product was which could the ether (38), 3~-acetoxy-8,9-epoxy-8,9-secolanosta-7,9(ll)-diene, arise by a Criegee rearrangement of the hypothetical 9whydroperoxide (35). 22

23 24

25

2b

C. G. Anderson and W. W. Epstein, Phytochemistry, 1971, 10, 2713. C. G . Anderson, W. W. Epstein, and G . Van Lear, Phytochemistry, 1972, 11, 2847. P. L. Batten, T. J. Bentley, R. B. Boar, R. W. Draper, J . F. McGhie, and D. H. R . Barton, J.C.S. Perkin I , 1972, 739. T. J. Bentley, R . B. Boar, R. W. Draper, J. F. McGhie, and D. H . R . Barton, J.C.S. Perkin I , 1972, 749. J . E. F o x , A . I . Scott, and D . W. Young, J . C . S . Perkin I , 1972, 799.

202

Terpenoids and Steroids

The diene system of (38) underwent some interesting reactions, including bromination to give the epoxydibromide (39) and with boron trifluoride in acetic acid to yield the enone ( 1 5).

Kinetically controlled bromination of lanosteryl acetate affords2' equal amounts of the diastereoisomeric dibromides (40)and (41),whereas equilibration results in a 5 : 1 ratio of (40) to (41). The configuration of (40)(24s)was determined by X-ray analysis,27 which also indicated a fully extended side-chain. The

''

D. H . R . Barton, H . MacGrillen, P. D . Magnus, C. H . Carlisle, and P. A. Timmins, J . C . S . Perkin I , 1912, 1584.

203

Triterpenoids

explanation for the lower stability of (41) probably lies in steric interaction between the 20-methyl group and the 24R-bromine substituent. A short, high-yield sequence for the removal of one C-4 methyl group from lanostane derivatives has been published (see Scheme 1).2 The reaction probably

(42)

(43)

& 25:\ 4dry B F loluene ,ether

N fC

0

Scheme I

proceeds via the nitrile-aldehyde (46) which could be isolated after short-term reaction. This sequence was applied in the synthesis of the norlanostane epoxide (24) (see above). The full details of other methods for removal of one or both C-4 methyl groups have a ~ p e a r e d . ~ ’ The assignment of all of the resonances in the 3C n.m.r. spectrum of lanosterol and dihydrolanosterol has been p~blished.~’

(47) R (48) R 28

= =

K . F. Cohen, R . Kazlauskas, and J . T. Pinhey, Chern. Comm., 1971, 1419.

’’ G . R . Pettit and J . R . Dias, J . Org. Chem., 1972,37,973.

30

0 H,P-OMe

G . Lukacs, F. Khuong-Huu, C . R . Bennet, B. L. Buckwalter, and E. Wenkert, Terrahedron Letters. 1972, 3 5 15.

204

Terpenoids and Steroids

Cyclobalanone (47) and 24-methylene cycloartenone have been isolated from Quercus glauca3 Cyclobalanone was converted into cycloneolitsin (48) by borohydride reduction and methylation. The stereostructure (49) has been proposed for a ~ t e i n . ~ * The structure of the cucurbitacin glycoside datiscoside (50),a new antileukemic principle from Datisca glomeratu, has been determined by X-ray analysis.33 It contains a novel sugar unit, and hydrolyses to cucurbitacin D. The X-ray analysis confirms both the (2-20 stereochemistry of the cucurbitacins and the originally assigned /?-configuration of the hydroxy-group at (2-2. The c.d. arguments for a C-2 a-hydroxy-group require reconsideration. The full paper on litsomentol (51) has appeared.j4

HO (51)

'' 32 J3

''

Y . Tachi, S. Taga, Y . Kamano, and M . Komatsu, Cheni. and Pharm. Bull. (Japan), 1971, 19, 2193. G . Piancatelli, S. Corsano, and A . Scettri, Gazzetra, 1971, 101, 797. S. M. Kupchan, C. W . Sigel, L. J . Guttman, R. J . Restivo, and R.F. Bryan, J . Amer. Chem. Soc., 1972,94, 1353. T. R. Govindachari, N . Viswanathan. and P. A . Mohamed, Tetrahedron, 1971, 27, 4991.

205

Trit erpenoids

4 Dammarane-Euphane Group Four related dammaranes have been isolated from Cabralea polytricha (Melia ~ e a e ) These . ~ ~ are cabraleadiol (52),20S,24S-epoxydammarane-3a,25-diol, the corresponding ketone cabraleone (53)(see Vol. 2, p. 164),and the two trisnor derivatives cabraleahydroxylactone (54)and cabralealactone (55). The last has been previously obtained by oxidation of dipterocarpol. It is of biogenetic interest that no limonoids were detected in this extract. Full details of the structure elucidation of diacetylpyxinol(%), from the lichen Pyxine endochrysina, have appeared.36 Among the minor constituents of this lichen were the derivatives (57j--(59).36 The full papers on the 20R configuration of panaxadiol (60)37and the acid-catalysed reactions and C-20 configuration of related dammaranes3* have been published.

(52) R (53) R

= =

H,a-OH 0

(54)R

=

H,a-OH

(55) R = 0

R' (56) R' = R 3 = OAC;R 2 = OH = R 2 = R 3 = OH = R3 = OAC;R2 = H (59) R' = OAC;R2 = R 3 = O H (57) R ' ( 5 8 ) R'

3s 3h 37

''

S. C. Cascon and K. S . Brown, jun., 7'etrahedron, 1972, 28, 315. 1. Yosioka, H. Yamauchi, and I. Kitagawa, Chern. and Pharm. Bull (Japan), 1972, 20, 502. M . Nagai, 0. Tanaka, and S . Shibata, Chern. andPharm. Bull. (Japan), 1971, 19,2349. 0. Tanaka, M . Nagai, T . Ohsawa, N . Tanaka, K. Kawai, and S . Shibata, Chern. and Pharm. Bull. (Japun), 1972, 20, 1204.

An investigation into the D + catalysed euphenol-isoeuphenol rearrangement, (61) -+ (62). has shown that up to five deuterium atoms are i n ~ o r p o r a t e d The .~~

resdts indicate a rapid A8-A' equilibration and suggest the possible intervention of cyclopropane intermediates. Gluanol acetate (63)is a new tirucallol derivative from Ficus g l o r n e r ~ t a . ~ ~

H

'retranortriterpenoids-The full structures of heudelottins C (64), E (65), and F (661, from Trichilia heidelorti;, have been ~ o l v e d . ~The ' esterifying acids include 2-hydroxy-3-methylbutanoicacid, 2-hydroxy-3-methylvaleric acid, and

'' "'

Y . Nakatani, G . Ponsinet, G . Wolff, J . L. Zundel, and G . Ourisson, Tetrahedron, 1972, 28, 4249. A . G . Sen and A . R . Chowdhury. J. Irirlian Chern. S o c . , 1971, 48,1165. D. A . Okorie and D. A . H . Taylor, J.C.S. P u k i n I , 1972, 1488.

Triterpenoids

207

A

OR2

: L o

fl

0

H ; R2 = Bu'CH(0Ac)CO; Pr'CH(0H)CO CHO ; R2 = Bu'CH(0H)CO; = Pr'CH(0H)CO = CHO ; R 2 = Bu'CCH(0Ac)CO; R 3 = Pr'CH(0H)CO

(64) R' R3 (65) R' R3 (66) R'

= = =

'OR'

2-acetox y-3-met hy lvaleric acid. 1,2-Dihydrocedrelone (67) has been isolated from Cedrela t ~ o n a . ~ ~ The isolation of obacunol (68) from Lovoa trichilioides provides43 a second example of the occurrence of a ring-A-cleaved tetranortriterpenoid in the Meliaceae (see Vol. 1, p. 176). The acid limonoids present in grapefruit seeds include44 nomilinic acid (69) and deacetylnomilinic acid (70) together with the known compounds, iso-obacunoic acid (71) and epi-iso-obacunoic acid (72). The full paper on spathelin (73) has appeared.45

@

HO,C

(69) R (70) R 42

43 44 45

= =

5

0

AC H

A . Chatterjee, T. Chakraborthy, and S. Chandrasekharan, Phyrochemisrry, 1971, 10, 2533. G . A . Adesida and D . A. H . Taylor, Phytochemistry, 1972, 1 1 , 2641. R . D . Bennett, Phytochemistry, 1971, 10, 3065. B . A . Burke, W . R . Chan, and D. R . Taylor, Tetrahedron, 1972,28,425.

Terpenoids and Steroids

208

Girarea thompsonii has been reported46 to contain 6,12a-diacetoxymethyl angolensate (74). The 12r-acetate methyl group resonance appears at 6 1.50 as a result of shielding by the furan ring.

0

C0,Me (74)

HO (75)

The structure of phragmalin (75). a complex limonoid from Entandrophragrna cat~datum,has been determined by X-ray analysis." It is closely related to utilin (see Vol. 1, p. 177)and occurs in combination with nicotinic and isobutyric acids. Calodendrolide (76), a novel degraded terpenoid, has been isolated from Calodendron capense ( R ~ t a c e a e ) It . ~was ~ readily converted into pyroangolensolide (77) by hydriodic acid. Calodendrolide co-occurs with other limonoids

47

48

J . D. Connolly, D. A. Okorie, and D. A. H . Taylor, J.C.S. Perkin I , 1972, 1145. R . R . Arndt and W. H . Baarchers. Tetrahedron, 1972, 28, 2333. J. M . Cassady and C.-S. Liu, J.C.S. Chem. Comm., 1972, 86.

Triterpeno ids

209

(81)

1

3-furyl-lithium

(82) R' (83) R'

= =

2-furyl; R2 = H H ; R2 = 2-fury1

Scheme 2

and is probably a precursor of fraxinellone (78). A total synthesis of fraxinellone (78) has been reported (see Scheme 2).49 The Diels-Alder adduct (81) of methacrolein (79) and ethyl 3-methylpenta-2,4-dienoate(80) reacted with 3-furyllithium to give the diastereoisomers (82) and (83). Treatment of this mixture with base afforded fraxinellone.

Full papers have appeared on odoratin (84),50 a partial synthesis of mexicanollide5' and the acid-catalysed rearrangement of limonoid epoxides.'* The Eu(dpm), shift reagent has been utilized for the assignment of the methyl resonances of a number of limo no id^.^^ An unexpected temperature effect has been 49

50 5 1

52

53

Y . Fukuyama, T. Tokoroyama, and T. Kubota, Tetrahedron Letters, 1972, 3401. W. R . Chan, D. R . Taylor, and R. T. Aplin, Tetrahedron, 1972, 28, 431. M. E. Obasi, J. I. Okogun, and D. E. U. Ekong, J.C.S. Perkin I , 1972, 1943. D. E. U. Ekong and M. D. Selema, J.C.S. Perkin I , 1972, 1084. D. E. U . Ekong. J. I. Okogun, and M. Shok, J.C.S. Perkin I , 1972, 653.

210

Terpenoids and Steroids

observed.54 The distribution of limonoids in the genus Khaya ( M e l i a ~ e a e ) ~ ~ ) ~ ~been reviewed. and in the sub-family Aurantioideae ( R ~ t a c e a ehas Quassinoids.-The isolation of new q uassinoids from Picrasma ailan thoides (quassioides) continues. This year has seen the appearance of nigakilactones J (picrasin C) (85),57*58 K (86),59L (87f,59 M (88),60 and N (89),60and picrasins F (90)61and G (91).62 The a-configuration of the C-13 methyl group of picrasin F (90) was deduced6 ' from a nuclear Overhauser effect between the C-13 methyl and one C-15 hydrogen. Paraine, a new quassinoid from Aeschrion creneta, has been assigned the structure (92).63 The stereochemistry of nigakilactones C (93) and E (94) and related compounds has bcen confirmed64 by the observation of several intramolecular nuclear Overhauser effects, which also indicate the

a; &; (85)

R'

0

Me0

"0 (87) R = H (90) R = OH

0 (88) R ' = OH ; R2 = H ; R 3 = H,p-OH (89) R' = Hi R 2 = OH; R 3 = H,P-OH (92) R' = R Z = H ; R ~= 0

57

R . D. Bennett and R . E. Shuster, Terrahedron Letters, 1972, 673. E. K. Adesogan, D. A . Okorie, D. A. H. Taylor, and B. T . Styles, Phytochemistry, 197 1, 10, 1845. D. L. Dreyer, M.V. Pickering, and P.Cohen, Phyrochemistry, 1972,11, 705. T . Murae, T. Tsuyuki, and T . Takahashi, Chem. and Pharm. Bull. (Japan), 1971, 19,

5y

H . Hikino, T. Ohta, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1971,19,2211. T. Murae, A . Sugie, T. Tsuyuki, and T. Takahashi, Chern. and Pharm. Bull. (Japan),

'' G . A. Adesida, 56

1747.

197 1 , 19, 2426.

'' A. Sugie, T. Murae, T. Tsuyuki, and T. Takahashi,

Chem. and Pharm. Bull. (Japan),

1970,20, 1085. "

H. Hikino, T.Ohta, and T. Takemoto, Cheni. and Pharm. Bull. (Japan),1971,19,2203.

"' H. Hikino, T. Ohta. and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1971,19,2652.

'' J . C . Vitagliano and J. Comin, Phyrochernisrry, '4

1972, 11, 807.

T. Murae, T. Ikeda, T. Tsuyuki, T. Nishihama, and T. Takahashi, Tetrahedron Letters, 1971, 3897.

Trilerpenoids

21 1

(93) R = H (94) R = OH chair conformation of ring C . The full details of the structures of nigakilactone H and nigakihemiacetals A and C have appeared.65

5 Baccharis Oxide The structure of baccharis oxide (see Vol. 2, p. 168) has been revised to (95) on the basis of a direct X-ray analysis.66 Baccharan-3-one (96) was to be identical with 18,19-secolupan-3-one,prepared via cleavage of (97), the mercuric acetate oxidation product of lupenyl acetate. This provides direct chemical proof of the configuration at C- 17 in baccharis oxide.

H

AcO (97)

'' T. Murae, T. Tsuyuki, T. Ikeda, T. Nishihama, 66 67

S. Masuda, and T. Takahashi, Terrahedron, 1971, 27, 5147. F. Mo, T. Anthonsen, a n d T . Brown, A c t a Chem. Scand., 1972,26, 1287. E. Suokas and T. Hase, A c t a Chem. Scand., 1971, 25, 2359.

212

Terpenoids and Steroids

6 Lupane Group A total synthesis of lupeol(98)from the previously described tricyclic intermediate (99) has been reported.68 A major problem was the introduction of the two adjacent trans-oriented methyl groups. This was overcome by the sequence of

reactions shown in Scheme 3 and involved an extension of the enolate trapping method to the cyclopropyl ketone (104).

I

I. ethylene

11.

111. IV.

Scheme 3

''

glycol-H'

LIAIH, H' NaBH,

continued on facing page

G . Stork, S. Uyeo, T. Wakarnatsu, P. Grieco, and J . Labovitz, J . Amer. Chem. Soc., 1971, 93.4945.

213

Triterpenoids

OH

'

i. niesyl chloride

ii. H i i i . OH +

( 104)

1

ii.

j,

L~-NH,-Bu'OH-glyiiie

hexamethyl-phosphoramide

iii, Me1

I. PhCOCl 11.

111,

disiarnylborane Jones reagent

I . enol lactonization ii, EtMgBr

I, ally1

'

11,

I

I

iii, O H

~

M c ~ H

bromide

PhCOCl

hydroboration enol lactonization 111, EtMgBr i v , O H MeOH I.

ii,

continued oilerleaf'

214

Terpenoids and Steroids

OH

1

0 (110)

I

I.

11.

111.

I.

11.

J

0, NaBH,

111,

CH,\,

IV

to\y chloride

ethylene glycol-H'

sodium hexamet hyldisiia7ane Ac,O

OAc

OTs

coiitiiiued on facing page

Triterpenoids

215

LIMe POCl, iii,~+ iv, NaBH, I,

ii,

’

Scheme 3

New compounds include 3-epibetulin (114) from Canthiurn d i ~ o c e u r nand ~~ betulin 3-acetate (115) and the taraxerene derivative acetyl aleuritolic acid from Mallotus phillipen~is.~’.~’

(114) R = Hp-OH (1 15) R = H,P-OAc

Several papers have a ~ p e a r e d ~which ~ - ~ provide ~ further evidence for the course of the mercuric acetate oxidation of lupane derivatives (see Vol. 1, p. 186). The norketolactone (116), derived from the mercuric acetate oxidation product of acetyl betulinic acid, undergoes 7 7 * 7 8 a ring E-homo rearrangement to ( 1 17) on treatment with t -butoxide. h9

” l2

” l4 l5 l6

77 ’8

S. C . Das, Chem. and Ind., 1971. 1 3 3 1 . M. Bandopadhyay, V. K. Dhingra, S. K . Mukerjee. N. P. Pardeshi, and T. R . Seshadn, Phq‘tnch~mrstry,1972, I 1 , I5 1 1 . V. N . Iyer and T. R. Seshadri, Indian J . Chem., 1971,9, 1028. A . Vystrcil and Z . Blecha, Coll. Czech. Chem. Comm., 1972, 37, 624. A . Vystrcil and Z . Blecha, Coil. Czech. Chem. Comm., 1972, 37, 610. G . V. Baddeley, J . J. H . Simes, and T. G . Watson, Austral. J . Chem., 1971, 24,2639. A. Vystrcil and Z. Blecha, Chem. und Ind., 1971, 1172. A. Vystrcil and Z . Blecha, CON.Czech. Chem. Comm., 1970, 35, 3309. H. N. Khastgir, S. N . Bose, and D . B. Naskar, Terrahedron Lrfters, 1972, 1821. A . Vystrcil and Z . Blecha, Chem. and Ind., 1971, 1018.

Terpenoiils and Steroids

216

0

Acid-catalysed peracetic acid oxidation of allobetulone ( 1 18) afford^'^ (1 19)and (120)in addition to the expected E-lactone. These results are relevant to the curre'nt interest in methods for removal of one or both C-4 methyls from triterpenoids (see p. 203 and ref. 80).

7 Oleanane Group There has been fruitful activity towards the total synthesis of unsymmetrical pent acyclic t ri terpenoids. Details of the exploratory work which led to the total syntheses of germanicol and alnusenone (see Vol. 2. p. 174) have appeared.*' The key intermediate is the 79

8o

''

T. Hase, J.C.S. Chem. Comm., 1972, 755. J. S. E. Holker, W . R. Jones, and P. J . Ramm, J. Chem. Soc. ( C ) ,1969, 357. R. E. Ireland. S. W . Baldwin, and S.C. Welch, J . A t ~ e r Chcnr. . Sac., 1972,94. 2056.

Triterpenoids

217

ol-methylene ketone (121) which was found to undergo facile conjugate addition of rn-methoxybenzylmagnesium chloride in the presence of acetic anhydride to give the enol acetate (122). Methylation followed by cyclization afforded the anti-vicinally dimethylated tetracyclic ketone (1 23). A similar reaction sequence was utilized in the successful route to germanicol.

The enol acetate (122) provided a model system for investigating some of the problems associated with the synthesis of alnusenone. Saponification and introduction of a methylene group gave the olefin (124). The latter and the two related epimeric tertiary alcohols provided useful substrates for examining the stereochemistry of the Friedel-Crafts cycloalkylation reaction. Polyphosphoric acid yielded the same mixture in each case, the major product being the compound (125) with the desired stereochernistry. The mechanistic details of this reaction are considered at length.

Approaches to dimethyl diacetoxymedicagenate (126) have resulted" in the synthesis of the AB and DE fragments (127) and (128). The compound (129) has been devised83 as a useful intermediate in a route to P-amyrin. Stereoselective 82 E3

J . D. Metzger, M . W . Baker, and R . J . Morris, J . O r g . Chem., 1972,37,789. C. H . Heathcock and J . E. Ellis. Chem, Cnmm., 1971, 1474.

218

Terpenoids and Steroids

*; AcO

C0,Me

( 1 27)

syntheses of several partially reduced chrysene derivatives, suitable as precursors for a variety of triterpenoids, have been r e p ~ r t e d . ’ ~ The technique of soil bacterial hydrolysis has been applied to a number of saponins (see also p. 226). The secondary reactions which usually occur under the normal acidic hydrolysis conditions are avoided. Thus the saponin from the seed kernel of Madhuca loiigfolia afforded8’ protobassic acid (130), suggesting that bassic acid (131) is an artefact of acid hydrolysis. Jegosaponin yieldeds6 four new acylated derivatives of barringtogenol C (132): 21-0-tigloyl-28-0-acetyl,

H

85

‘ O

J . W . ApSimon. P. Baker. J . Buccini, J . W . Hooper, and S. Macauley, Cunad. J . Cheni., 1972,50, 1944. I . Kitagawa, A . Inada, I . Yosioka, R . Somanathan, and M . U . S. Sultanbawa, C h m . rind Pharnt. Blrll. (Jripan). 1972. 20. 630. I . Yosioka, S. Saijoh, and 1. Kitagawa, Chrm. and Pharm. Bull. (Japan), 1972, 20, 564.

219

Triterpenoids

21-0-tigloyl-22-0-acety1, 28-0-acetyl, and 21 (or 22)-0-2'-cis-hexenoy1-22(or 21)0-acetyl barringtogenol C. These results support the view that the previously reported 16,21- and 13,28-ethers arise during acidic hydrolysis.

H

0 HO

Macedonic acid has now been shown to be (133);87it was converted into the known 38,21sr-diacetoxyisoglabrolide (134). New oleananes include barrinic acid (135) from Barringtonia acutangula88 and 11-0x0-B-amyrin (136) and its

HO,C

HO

*' 88

0 // ', f

.OH

-0Ac

AcO

A. D . Zorina, L. G. Matyukhina, A . G . Chavva, and L. A . Saltikova, Tetrahedron Letters, 1972, 1841. A . K . Barua, S. K . Pal, and S. P. Dutta, J . Indian Chem. S O C . ,1972,49, 518.

Terpenoids and Steroids

220

W i y

palmitate ester from Deertongue leaf.89 The full details of the structure of the prosapogenin tenuifolin ( 137) have appeared.” Acid treatment of primulagenin A (138) affords’’ three new compounds (139bj141) in addition to the two previously reported products. The mode of formation of these compounds is considered in detail. In the presence of formic acid, 3,4-seco-19P,28-epoxy-18a-olean-423)-ene (142) rearrangesQ2to (143) via ( 144).

HO

‘’ I . Wahlberg, K . Karlsson, and C. Enzell, Acfu Chew. S c a d . , 1972, 26, 1383. ‘O

q2

S. W . Pelletier, S. Nakembra. and R . Soman, Teirahedron, 1971, 27, 4417. 0. D. Hensens and K . G . Lewis, Ausrral. J . Chem., 1971, 24, 21 17. J . Klinot, M . Budesinsky. and A. Vystrcil. Coli. Czech. Chem. Conim., 1972, 37, 1356.

Trit erpenoitls

22 1

(143) (144) The full papers on the photo-oxidation process utilized in the transformation of spergulagenicacid into euptelogenin have been published (seeVol.1,p. 193)P3*94 Application of this reaction to erythrodiol (145) affordedg3 the 1la,l2a-epoxy13P,28-oxide(146)together with the rearranged 1la, 12cr-epoxy-taraxerane(147).

K OH

(145) 93 y4

(146)

I . Kitagawa, K . Kitazawa, a n d 1. Yosioka, Tetrahedron, 1972, 28, 907. I . Kitagawa, K . Kitazawa, K. Aoyama. M. Asanuma, a n d I. Yosioka, Terrahedron, 1977, 28, 923.

222

Terpenoids and Steroids

The lability of 11-hydroxyolean-12-enederivatives, observed during the course of this investigation, was employed93 in the conversion of dihydropriverogenin A (148) into the thermodynamically less stable priverogenin B (149). The triacetate of 18/?-olean-3@, 12/1,13fl,28-tetraolyielded” the 13~,28-epoxy-derivative( 150)on treat men t with toluene-p-sulphonic acid.

HO‘

( 148)

HO

AcO (149)

( 150)

Maitenin (151), an antitumour agent from _MaytenusS P . ,is~ closely ~ related to pristimerin (152). The position of one carbonyl group remains to be defined. The full paper on the X-ray analysis of pristimerol bis-p-bromobenzoate has been published.” ”

G . Snatzke and M . H . A . Elgamal. AtznulPtz, 1972, 758, 190.

”

Barros Coelho, Gazzetta, 1972, 102. 3 17. P. J. Ham and D. A . Whiting, J . C . S . Perkin I , 1972, 330.

‘’ F. Delle Monache, G . B. M . Bettolo, 0.G . dc Lima, I . L. D’Albuquerque, and J . S. de

223

Triterpenoids

1/?,22P-Dihydroxyfriedelin (153)and the related enone (154)have been isolated from Phyllanthus r n u e l l e r i ~ n u s . ~A~ new trio1 (155) has been obtained from Pachysandra t e r r n i n ~ l i s .It~ ~was readily interrelated with pachysonol(l56). The configuration of the 16-hydroxy-group was established by X-ray analysis. The structure of putranjivic acid (157) has been confirmed"' by partial synthesis from friedel-3-ene. The c.d. of the xanthate of the related putranjic (putric) acid (158) indicates"' the S configuration at C-2.

i i

Ho 0 ~

HO

y8

"

G . A. Adesida, P. Girgis, and D . A. H . Taylor, Phytochernistry, 1972, 11, 851. T. Kikuchi and M . Niwa, Tetrahedron Letters, 1971, 3807. Tetrahedron, 1972, 28, 1307.

'('" P. Sengupta and A . K . Dey,

224

Terpenoidsand Steroids

'

The saturated noraldehyde (159) is formed O 1 during irradiation of friedelin with U.V.light. It was readily identified by hydrogenation of the unsaturated aldehyde (160) previously obtained'02 by irradiation of norfriedelin (161).

Deuteriation and OI8 studies clearly demonstratelo3 that (159) arises from autoxidation of a keten intermediate. 11-0xo-x-amyrin and 11-oxo-P-amyrin derivatives undergo a characteristic fragrnentationlo4*' O 5 in the mass spectrometer giving rise to a prominent peak ""

R. Stevenson, T. Tsuyuki, R . Aoyagi, and T. Takahashi, Bull. Chrm. Sor. Jupan, 1971, 44,2567. R. Aoyagi, T. Tsuyuki, and T . Takahashi. Bull. Chem. SOC. Japan, 1970,43, 3967. R . Aoyagi, T. Tsuyuki, T. Takahashi, and R. Stevenson, Tetruhedron Lpttrrs, 1972, 3397.

I"'

""

I . Wahiberg, K . Karlsson. and C. R . Enzell, Acta Chrrn. Scand., 1971, 25, 3192. V . Askam and D. M . Bradley, J . Chrni.SOC.( C ) . 1971. 1895.

Triterpenoids

225

at m / e 135. This is due to the ion (162) which is derived from ring c. The 0.r.d. and c.d. curves of a number of pentacyclic triterpenoid mono- and di-ketones have been discussed.' O6

Full details have been published'07 of the allylic oxidation of triterpenoid olefins to Aap-ketoneswith N-bromosuccinimide in visible light.

8 Ursane Group The following new ursanes have been reported : dryobalanolide (2a,3P,23trihydroxyurs-1 l-en-13P,28-olide) (163) and methyl 11-oxoasiatate (164) from

(165) R' = 0;R2 = CHO (166) R' = H,a-OH; R2 = C H 2 0 H '06 lo7

J . Sliwowski and Z. Kasprzyk, Tetrahedron, 1972, 28, 991. B. W. Finucane and J . B. Thomson, J.C.S. Perkin I , 1972, 1856.

226

Terpenoids and Steroids

Drjobalarzops aroriiatica : l o * urs- 12-en-3-on-28-al (165) from commercial Tolu balsam ; ' 0 9 urs-12-en-3ct,28-dioi (3-epiuvaol) (166) from Diospyros rnontana." Soil bacterial hydrolysis of two glycosides from Sanguisorbae oflcinalis root has shown' l 1 that pomolic acid (1671, not tomentosolic acid (168)is the genuine aglycone. Dehydration of pomolic acid (167) affords' 19(29)-dehydro-ursolic acid (169) in addition to tomentosolic acid (168) and vanguerolic acid (170).

''

"" 109

"" I

'

' ''

H . T. Cheung and C . S. Wang, Plil.toc.lirt~iistrl.,1972. 11, 177 1 , I . Wahlberg, M.-B. Hjelte. K . Karlsson. and C . R . Enzell, Acra Chem. Scund., 1971, 25. 3285. P. K . Dutta, N . L. Dutta, and R. N . Chakravarti, Phytochemisrry, 1972, 11, 1180. I. Yosioka, T. Sugawara. A . Ohsuka, and I. Kitagawa, Chrm. arid Phurm. Bull. (Jupari), 1971, 19, 1700.

C. H . Brieskorn and H.-P. Suss. Tcrruhdroti Lrtrrrs. 1972. 1515.

Triterpeno ids

227

Leuconol, previously reported as a new triterpenoid alcohol, is now shown to be a mixture of bauerenol(171) and a- and B-amyrin.' l 3 A detailed study of the oxidation products of bauerenol (171) has appeared.' l 4 The participation of C-28 oxygen functions in bromine addition to the double ')-taraxastenes' and the isomerization of 28-benzoyloxy-20cr,2labond of epoxytaraxastanes' '' form the subjects of recent papers.

'

9 Hopane Group Two new hopanes, methyl pyxinate (172) and the corresponding acetate (173), occur36 in the lichen Pyxine endochrysina along with several dammaranes. Full papers have appeared on the structure of leucotylic acid (174)'17 and on the correlation of zeorin (175) with leucotylin (176).' l 8 On treatment with acid, methyl leucotylate (177) and leucotylin (176) afford methyl isoleucotylate (178)' l 7 and isoleucotylin (179),' * respectively.

'

(+qJ... (174) (175) (176) (177) ' I 3

Il4

'Is I" 'I'

R' R' R' R'

(172) R = H (173) R = AC

= C 0 2 H ; R2 = OH = Me; R2 = H = Me; R2 = OH = C 0 , M e ; R2 = O H

(178) R = C 0 2 M e (179) R = Me

K . Y . Sirn, R . Mukherjee, M.-J. Toubiana, and B. C. Das, Phyrochemisrry, 1971, 10, 2803. M . Fukuoka and S. Natori, Chrm. and Pharm. Bull. (Japan), 1972, 974. E. Klinotova and A. Vystrcil, Coll. Czech. Chem. Comm., 1972, 37, 1883. E. Klinotova, I . Skarkova, and A . Vystrcil, Coll. Czech. Chem. Comm., 1972,37, 1748. I . Yosioka, T. Nakanishi, M . Yarnaki, and I . Kitagawa, Chem. and Pharm. Bull. (Japan), 1972, 20, 487. I . Yosioka, T. Nakanishi, H . Yamauchi, and I . Kitagawa, Chem. and Pharm. Bull. (Japan), 1972, 20, 147.

228

Terpenoids and Steroids

Hopane and homohopane (180) have been identified in Messel oil ~ h a 1 e . l ' ~ The structure of homohopane was confirmed by a partial synthesis from diploptene [hop-20(29)-ene]. It is suggested' l 9 that homohopane arises by microbiological methyiation and that a significant proportion of the triterpanes found in sediments and oils are of bacterial origin. Tetrahymanol (181) has been isolated"' from Green River Shale. The two fern-9(11)-ene derivatives retigeric acid A (182) and retigeric acid B (183) have been reportedI2' from the lichens of the Lornbaria retigera group.

(182) R (183) R

= =

Me C02H

10 Serratane Group Several new serratane derivatives have been isolated' 2 , 1 2 3 from Lycopodium ph/egmaria. These include phlegmanols B (184),C (185), D (186), E (187), and F (188), and phlegmaric acid (189). The methyl ester of phlegmaric acid was converted 2 2 by lithium aluminium hydride reduction, followed by acetylation, A. Ensminger, P. Albrecht, G. Ourisson, B. J . Kimble, J . R. Maxwell, and G. Eglinton,

Tetrahedron Letters, 1972, 3861. W . Henderson and G. Steel, Cltrm. Comni., 197 1 , 133 1 . R . Takahashi, H.-C. Chiang, N . Aimi, 0. Tanaka, and S. Shibata, Phyrochemistry, 1972, 11, 2039. Y . Inubushi, T. Hibino, T. Harayama, T . Hasegawa, and R . Somanathan, J . Chem. Sor. ( C ) , 1971, 3109. Y . inubushi, T. Hibino, T. Hasegawa, and R. Somanathan, Chent. and Pharm. Bull. (Japan). 1971, 19, 2640.

229

Triterpenoids

into lycoclavanol triacetate (190). 21-Episerratenediol-21-methyl ether (191)has been found'24 in the bark of Pinus conform (lodgepole pine). Eu(dpm), shifts have been used to assign methyl resonances in a series of serratenediol derivatives.' 2 5

(184) R' = R6 = H ; R3 = R4 = Me; R 5 = O H ;

R 2 = OCO. CH: CH. C6H,. 3,4-(OH), (185) R' = R s = H : R 2 = O A c ; R 3 = R 4 = M e ; R 6 = O H (187) R' = R5 = H ; R2 = R6 = O H ; R 3 = Me; R4 = CH,OH (189) R ' = R 6 = O H ; R 2 = R s = H ; R 3 = C 0 2 H ; R 4 = M e (190) R' = R6 = OAc; R2 = R5 = H ; R3 = CH20Ac; R4 = Me (191) R' = R 5 = H ; R 3 = R4 = Me; R2 = OH; R6 = OMe

R' (186) R' = OAc; R2 = Me; R 3 = 0 (188) R' = O H ; R 2 = C H 2 0 H ; R 3 = H,a-OH

J. W. Rowe, R. C. Ronald, and B. A. Nagasampagi, Phytochemisrry, 1972, 11, 365. Y.Inubushi, T. Hibino, and T. Shingu, J.C.S. Perkin I, 1972, 1682.

Carotenoids and Polyterpenoids BY G. P. MOSS

1 Introduction The 1.U.P.A.C.-I.U.B. tentative nomenclature for carotenoids has been widely published.' Recent progress in carotenoid and related fields has appeared in the proceedings of the Phytochemical Society Symposium held in Liverpool in 1970.2 In particular. advances in carotenoid chemistry are surveyed by Liaaen-Jensen ; the distribution and taxonomic significance of algal carotenoids by Goodwin ; and studies on abscisic acid by Milborrow. A symposium on sporopollenin has been published3 which includes a discussion on its possible origin from carotenoids. The properties of yeast pigments are summarized in a chapter written by Chichester and co-workers.' The obituary of Professor P. Karrer5 outlines some of his many contributions to carotenoid chemistry, Advances in the biosynthesis of carotenoids and polyterpenoids are dealt with in the next chapter.

2 Physical Methods The isolation ofcarotenoids still presents many problems, due in part to the close similarity between isomers differing only in the position or stereochemistry of one double bond. Several reports claim improved methods for the thin-layer chromatographic separation' or even gas-chromatographic separation' of carotenoids. Analytical methods have been reviewed' and extensive tables for the identification of carotenoids published.' ' Biochrmistrj.. I97 1 . 10. 4827 ; Biot,hrrjr. J.. 1972, 127, 74 1 ; European J . Biochrnz., 1972. 25. 397; J . B i d . Cheni.. 1972. 247. 2633; see also 'Carotenoids', ed. 0. Isler, Birkhauser Verlag. Basel. 1971. p. 8 5 1 : I.U.P.A.C. Bull. No. 19. 8. V. Milborrow, 'Aspects of Terpenoid Chemistry and Biochemistry', ed. T. W . Goodwin, Academic Press, 1971, p . 137; S. Liaaen-Jensen, ihid.,p. 223; T. W . Goodwin, ihid., p. 3 15. ' 'Sporopollenin', ed. J . Brooks, P. R . Grant, M . D. Muir, P. van Gijzcl, a n d G. Shaw, Academic Press, London, 197 1 . K . L. Simpson, C. 0. Chichester. a n d H . J . Phaff. 'The Yeasts'. ed. A . H. Rose and J . S. Harrison, Academic Press, 1971, Vol. 2, p. 493. ' A . Wettstein. Hrlr.. Chiin. A r m . 1972, 55, 313. '' D. B. Parihar. 0. Prakash, I . Bajaj, R . P. Tripathi, and K. K. Verma, J . Chrumatog., 1971,59,457; R . E. Knowles and A. L. Livingston, ihid., 61, 133; L. K . Keefer a n d D. E. Johnson. ihid.. 1972, 69. 215; L. R . G . Valadon a n d R . S. Mummery, Phptochemistry, 1972. 11. 413. R . F. Taylor and M . Ikawa, Aiiu1j.t. Biochr~ni.,1971, 44,623. S. Liaaen-Jensen and A. Jensen, 'Methods in Enzymology', ed. A. S. Pietro, Acadcmic Vol. 23A, 1971, p . 586; B. Ke. ihid.,p . 624. ' Press, F. H. Foppen, Chromurog. R c r . . I97 I , 14, 133.

230

Cur0tenoids and Poly terpenoids

23 1

An additional technique for the characterization of polar carotenoids makes use of the europium-induced shifts in the n.m.r. spectrum." A range of hydroxy-, methoxy-, and keto-derivatives each gave significantly different relative shifts which can be used to identify the position of the polar group even with a 60 MHz instrument. A detailed second analysis of the vinyl n.m.r. signals of phytoene (1) and related model compounds ( 2 H 5 )at 220 MHz confirmed" that the natural Me

R

\ /

C=CH-CH=CH-CH=C

/Me

\

R

(1) trans,cis,trans R = C,,H27 (2) trans,cis,trans R = C3H, (3) trans,trans,trans R = C3H, (4)trans,cis,cis R = C3H7 ( 5 ) trans,trans,cis R = C3H7

compound has a cis (2)central double bond, and demonstrated for the first time that the other two double bonds of the triene were trans ( E ) . Low-temperature n.m.r. studies of cis-fi-ionol(6)showed' restricted rotation about the two halves, with separate methyl signals due to this rotation at temperatures below - 32 "C.

Some problems encountered in 13C n.m.r. are exemplified by revision of the assignment of C-6 and C-7 in a- and /3-ionones(7).13 Doubts have been cast on the However, even more drastic assignment of the sp2 signals of p-carotene @).I4 revision is required, as is shown by the spectrum of [ 15,l 5'-2H2]-fi-carotene [N.B. the G(TMS) values should be multiplied by 0.9772 for comparison with the previous data].' The c.d. spectra of the natural (+)-a-irones (13) have been correlated with a-ionone, and by chemical means with camphor.16 The second chiral centre did not substantially affect the c.d. curve. Thus the c.d. spectrum of decaprenaxanthin l o I I

I

l4

l6

H. Kjmen and S . Liaaen-Jensen, Acta Chem. Scand., 1972, 26,2185. N . Khatoon, D. E. Loeber, T. P. Toube, and B. C . L. Weedon. J.C.S. Chem. Comm., 1972, 996. V. Ramamurthy, T. T. Bopp, and R. S. H . Lin, Tetrahedron Lerrers, 1972, 3915. R. Hollenstein and W. von Philipsborn, Helu. Chim. A m , 1972, 55, 2030. D. E. Dorman, M. Jautelat, and J. D. Roberts, J . Org. Chem., 1971,36,2757. W. Vetter, G. Englert, N. Rigassi, and U . Schwieter, in 'Carotenoids', ed. 0. Isler, Birkhauser Verlag, Basel, 1971, p. 189. V . Rautenstrauch and G . Ohloff. Hell'. Chim. Acta, 1971, 54, 1776.

Terpenoids and Steroids

232

a

(8) R = a (9) R = b (10) R = c

b

OH C

e

d

(9)’-,might imply 6S,6’S stereochemistry. Furthermore, correlation of the n.m.r. spectrum of decaprenaxanthin I s with cis-a-irone16 suggests a 2R,2‘R stereochemistry. The relationship of the absolute stereochemistries of bacterioruberin (10)and its bisanhydro-analogue ( 1 1 ) was established by c.d.” Zeaxanthin (12) from blue-green algae was shown by c.d. to have the same absolute stereochemistry as higher plant samples.

’

I -

’*

G . Borch, S. N o r g i r d , and S. Liaaen-Jensen, Act a Chem. Srand., 1972, 24, 402. S. Liaaen-Jensen, S. Hertzberg, 0. B. Weeks, and U . Schwieter, Acts Chern. Srand., 1968,22, 1171. A . J . Aasen. S. Liaaen-Jensen, and G. Borch. A C I Cheni. ~ Scand., 1972.24.402.

Carotenoids and Polyterpenoids

233

(15) R = CMe=CH*CHO (16) R = C02H

(17) Full details have appeared of the X-ray study of 11-cis-retinal(14)20as well as of a new investigation of the all-trans-isomer (15).2 8-Ionylidenecrotonic acid (16) is unusual, with a small dihedral angle 1+7-8 of 10.4" in the crystalline state.22 A comparison between the various published X-ray studies ofcarotenoids

M - 92

A4

-

Scheme 1 *O

2 1

**

R. D. Gilardi, I. L. Karle, and J. Karle, Acta Cryst., 1972, B28, 2605. T. Hamanaka, T. Mitsui, T. Ashida, and M . Kakudo, Acta Cryst., 1972, B28, 214. B. Koch, Acta Cryst.. 1972, B28, 1 1 51.

106

234

Terpenoids and Steroids

and analogues has appeared.23 Crocetin dial (17) has been studied by X-ray ~rystallography.~~ A modified mechanism has been proposed for formation of the M-92 and M - 106 ions in the mass spectra of carotenoids2' (see Scheme 1). Further resonance-enhanced laser Raman spectra of retinal derivatives have been reported.26 A comparison between various semi-empirical methods for the calculation of P-carotene MO's has a ~ p e a r e d . ~A' better correlation between the U.V. spectrum and theoretical predictions is claimed by Suzuki et a1.28

3 Carotenoids Surveys have appeared of the carotenoids in many blue-green algae,29 and Compositae3O species. Acyclic Carotenoids.-Phytoene (1) has been isolated from many sources, ranging from higher plants to fungi and bacteria. Davies and co-workers3' conclude that only the cis-isomer is formed. However, Herber et aL3' have suggested that, in fungi, all-trans-phytoene is formed. Possibly the difference between these results is due to the use of inhibitors in the latter case. The stereochemistry of the central double bond was confirmed by analysis of the n.m.r. spectrum.33 The coupling constants were in close agreement with those obtained by Weedon and co-workers' who also showed, by comparison with model compounds, that the 13(14)-double bond was trans. Poly-cis-S-carotene has been isolated from The P-D-glucosidesof rhodopin (18) and rhodopinal(19) have been characterized by Liaaen-Jensen and c o - w o r k e r ~ .They ~ ~ also found that use of acetone in R2

(18) R' = 0-P-D-GIu, R 2 = Me (19) R' = O-#I-D-GIU,R2 = CHO (20) R' = H, R 2 = CH:CH*CO-Me (21) R' = OH, R2 = CH:CH.CO-Me (22) R' = O-P-D-GIU,R2 = CH: CH- CO- Me "

''

" " " "

"'

lo

" 3 2 11

'' 35

M . Sundaralingam and C. Beddell, Proc. N a r . Acad. Sci. U . S . A . , 1972,69, 1569. J . Hjortis, Acra Cr ys f. , 1972, B28, 2252. G . W. Francis, Aura Chern. Scand., 1972, 26, 1443; see also ref. 15. D . Gill, M . E. Heyde, and L. Rirnai, J . Amer. Chern. Soc., 1971,93,6288; M . E. Heyde, D. Gill, R . G . Kilponen, and L. Rimai, ibid., p. 6776. E. A . Castro and 0. M. Sorarrain, J . Chim. phys., 1972, 69, 5 1 3 . H . Suzuki, N . Takizawa, and T. Komatsu, J . Phys. SOC.Japan, 1971,31, 895. S. Hertzberg, S. Liaaen-Jensen, and H. W. Siegelman, Phyrochemistry, 1971,10, 3121. L. R. G . Valadon and R . S. Mummery, Phyrochemistry, 1971, 10, 2349. A . Than, P. M . Bramley, B. H . Davies, and A . F. Rees, Phyrochemistry, 1972,11, 3187. R. Herber, B . Maudinas, and J . Villoutreix, Conipf.rend., 1972, 274, D , 327. R . Herber, B. Maudinas, J . Villoutreix, and P. Granger, Biochim. Biophys. A c t a , 1972, 280, 194. L. C. Raymundo and K . L. Simpson, Phyrochemistry, 1972, 1 1 , 397. K . Schmidt, G . W . Francis. and S. Liaaen-Jensen, Acra Chem. Scand., 1971,25,2476.

235

Curotenoids and Polyterpenoids

the work-up resulted in the formation of three artefacts (20)-422) from aldol condensation with rhodopinal. The same group's studies36 on Thiothece carotenoids have resulted in the characterization of several minor constituents. Thiothece-OH-484 (23)is an acyclic keto-carotenoid and Thiothece-425 (24)and -460 (25) are related apo-carotenoids.

0

Monocyclic Carotenoids.-Aphanizophyll (26) is a new carotenoid glycoside, probably a rhamn~pyranoside.~~ It is thus a 4-hydroxy-derivative of myxoxanthophyll, which might be considered as an intermediate in the formation of 2'-hydroxyflexixanthin (27).38 However, the presence of flexixanthin (28) and its deoxy-derivative (29)38suggests an alternative biogenesis. R3

R4 R' (26) R ' = R4 = OH, R2 = H, OH, R 3 = OC6HllO4 (27) R' = R 3 = R4 = O H , R 2 = 0 (28) R' = R4 = OH, R2 = 0,R 3 = H (29) R' = R3 = H, R 2 = 0,R4 = OH (30) R' = R3 = H . R 2 = H , , R 4 = OGlu Analysis of the carotenoids of the gliding organism F2 suggests that it is related to the green sulphur bacteria or blue-green algae.39 The glucoside of hydroxydihydrodehydro-y-carotene(30)was present, as well as the corresponding carotenoid lacking the 3',4'-double bond and its free alcohol. Retrodehydro-ycarotene (31) was also present.

(31) Jb

37

38 3q

A. G . Andrews and S. Liaaen-Jensen, Acta Chem. Scand., 1972, 26, 2194. S. Hertzberg and S. Liaaen-Jensen, Phyrochemistry, 1971, 10, 3251. M . Aguilar-Martinez and S. Liaaen-Jensen, Acta Cheni. Scand., 1972, 26, 2528. L. N . Halfen, B . K . Pierson, and G . W. Francis. Arch. Mikrobiol., 1972, 82, 240.

2-36

Terpenoids and Steroids

The structure of Thiothece-478 has been revised36 to (32) and, owing to a change in the U.V.spectrum, its name is also revised to Thiothece-474. A more oxidized carotenoid, Thiothece-484 (33), is an ester of okenone. 0

(32) R (33) R

=a =b

R'

a

b R'. R2, R 3 = Me,, C0,Me

Bicyclic Carotenoids.-Further studies by Eugster and co-workerssO have produced more evidence that lutein (34) has the 3'R configuration. Degradation of the corresponding methyl ether gave the expected ( - )-3-methoxy-P-iononeand ( + )-rrans-3-methoxy-a-ionone. However, methylation with methanolic hydrogen chloride gave, after degradation, cis-3-methoxy-a-ionone also. The stereochemistries of these ionone derivatives were proved conclusively by the interrelationships shown in Scheme 2. 2'-Norastaxanthin diester (35) has been isolated4' from Actinia equina. Its structure was confirmed by alkaline hydrolysis and oxidation to roserythrin (36), which was also synthesized in poor yield from astacene (37). Astaxanthin (38) was the carotenoid isolated from the carotenoprotein of Labidocera a c u r i j i o n ~ . ~ ~ This blue complex had a molecular weight of about 72 OOO and could be degraded to an apoprotein of molecular weight about 26 000 which corresponded to three astaxanthin molecules. The suggested hydrated-ketone, half-ester structure for the complex seems improbable chemically. Colour bimorphism in the aphid Macrosiphum liriodendri is dues3 mainly to the presence of P,y- and 7,y-carotenes (39) in the green form and to torulene in from the pink form. Neo(cis) isomers of or- and P-carotene have been H alobacteriurii cutirubrum. 40

41

42

43

44

R . Buchecker. P. Hamm. and C. H. Eugster. Chinztu ( S w i f z . ) ,1972, 26, 134. G . W . Francis, S. Hertzberg. R . R . Upadhyay, and S. Liaaen-Jensen, AL,ta Chem. Scand., 1972.26, 1097. P. F. Zagalsky and P. J . Herring, Cornp. Biochrni. Physiol., 1972,41B, 397. A . G . Andrews, H . Kjmen, S. Liaaen-Jensen, K . H . Weisgraber, R . J . J. C. Lousberg, and U . Weiss, Acra Chem. Scand., 1971,24,3878; K . H. Weisgraber, R . J . J . C. Lousberg, and U . Weiss, Exprrirntia, 1971, 27, 1017. K . C. Kushwaha, E. L. Pugh, J . K . G . Kramer, and M . Kates, Biochim. Biophys. Acra, 1972. 260.492.

237

Curotenoids und Poiyterpenoids

.OH

HO

MeO'

HO'

.**

fico2Et MeO-

c?02Et i, iii, iv. v , vi

HO'

HO

-w

'

Me0

Bo2Et Bo2M aH O

Reagents: i, K0Bu'-Me1 o r BaO-Mel; ii, 0 , - h v or NiO,; iii, LiAlH,; iv, Cr0,-py; v , (EtO),PO-CH,CN-NaH; vi, MeMgl; vii, H,-Rh; viii, K O H ; ix, CH,N,; x, 70 X H ,SO,.

Scheme 2

238

Terpenoids und Steroids

.RC02 0

0 (35) R ' = a, R 2 = b (36) R 1 = C, R2 = d (37) R' = R2 = d (38) R' = R 2 = e (39) R' = Rz = f

HO

0

0. a

b

0

C

0

f

e

d

Acetylenic and Allenic Carotenoids.-The apo-acetylenic carotenoid hopkinsioxanthin (40),identified by McBeth"' in the Nudibranch Hopkinsia rosaceu, was also isolated from its food, the Bryozoan Eurystornella bilabiuta. Other Nudibranchs contain the related carotenoid triophaxanthin (41).46

R2

b

0 a

(40) R '

R' (42) R'

(41)

(43) R' (44) R'

= a, R 2 = Ac = b, R2 = AC = c,RZ = d = e, R2 = f = d, R 2 = e

HO OH

OH

C

d

e

f

'' J. W. McBeth, Comp. Biochrm. Physiol., 1972, 41B,69.

'' J. W . McBeth.

Cornp. Biocheni. Physioi., 1972,

41B,5 5 .

239

Curotenoids and Polyterpenoids

Mimulaxanthin from Mimulus guttatus was suggested,47 on the basis of limited spectroscopic evidence and a possible correlation with neoxanthin, to be the allenic carotenoid (42). Further attempts to isolate taraxanthin have Although many workers ( e g . ref. 30) consider it is the same as lutein epoxide (43), the original work, and a subsequent'mass spectrum49 on the original sample, confirmed a C4,$,,04 formula. Nit~che,~' like other previous workers, conhave not sidered that it was identical with neoxanthin (44), but Cholnoky et accepted this identity. Isoprenylated Carotenoids.-The bacterial C, carotenoids bacterioruberin ( 10) and anhydrobacterioruberin (1 1) have the same absolute stereochemistry.I Both mono- and di-glycosides of bacterioruberin are present5' with 80% glucose and 20% mannose attached to the additional C, unit. The stereochemistry of decaprenaxanthin (9) has been discussed above. It too occurs as mono- and di-gluc~sides.~ Carotenoid Chemistry.--Chromic oxide oxidation of carotenoids gives extensive degradation. However, subtle control factors are present. Thus oxidation of vitamin A acid (45) gave a diketone (47), whereas its ester (46) gave a rearranged product (48). Its stereochemistry was deduced by degradation to the trio1 (49) which was examined by X-ray crystallography and ~ y n t h e s i z e d . ~Milder ~

(45) R = H (46) R = Et

(47)

@ f : U c o 2 m (48)

'-H . Nitsche, Phyrochemisrry, 1972, 11, 401. '* H. Nitsche and C. Pleugel, Phytochemisrry, 49

5"

51

"

(49)

1972, 1 1 , 3383. L. Cholnoky, K . Gyorgyfy, A . Ronai, J. Szabolcs, Gy. Toth. G. Galasko, A . K . Mallams, E. S. Waight, and B. C. L. Weedon, J . Chem. Soc. ( C ) ,1969, 1256. N . Arpin, J.-L. Fiasson, and S. Liaaen-Jensen, Acta Cherii. Sumd., 1972, 26, 2526. N . Arpin, S. Liaaen-Jensen, and M . Trouilloud, Acra Chem. Scand., 1972, 26; 2524. U . Schwieter, W . Arnold, W . E. Oberhansli, N . Rigassi, and W. Vetter, Helo. Chim. Acra, I97 I , 54,2447.

Terpenoids and Steroids

240

oxidizing agents such as hydrogen peroxide-permanganate gave P-apocarotenoids.’> ;I-Irradiation of a film of /]-carotene gave, as well as apocarotenoids, epoxides and hydroxy-deri~atives.~~ Peracid oxidation of canthaxanthin (SO) gave, among other products, a 9,lO:9’.10’-diepoxide derivative.” The major product of peracid treatment of retrodehydro-P-carotene (52) was isozeaxanthin (S1).56

R (SO) R = 0 (51) R = H,OH

The hydroxy-acid (53), an intermediate in vitamin A synthesis, has been prepared in 51 O 0 yield from /I-ionone and crotonic acid using lithium naphthalenide.’ 4 Degraded Carotenoids

The absolute stereochemistry of abscisic acid (57) has at last been established. Owing to the unusual bisallylic alcohol function, the previous assignment based on Mills’ rule was incorrect and this has now been reversed so that it is consistent with violaxanthin (54). Oritani et ~ 1 . ~showed ’ that (-)-a-ionone (56) was converted inio ( - )-abscisic acid with retention of configuration (their enantiomers

’’ H . Singh. A . K . Mallia. a n d H. R. Cama. Broclwni. J., 1972. 128, 1 IP. ’‘ E. Bancher. J . Washiitti, and P. Riederer, Motiarsch., 1972, 103,464. D. Obianu, E. Nicoara, and C. Bodea, R e r . Routiiaine Chin?., 1971, 16, 925. ’’ J . Szabolcs and G y. T o t h , Acta Chini. Acad. Sci. Hitng., 1971, 70, 373. 55

5’ 58

S. Watanabe, K. Suga, T. Fujita, a n d K . Fujiyoshi, Chem. andfnd.. 1972, 80. T. Oritaniand K . Yamashita, Tetrahedron Letters, 1972,2521 ;T. Oritani, K. Yamashita, and H. Meguro, Agric. und Biol. Chrnr. (Japan). 1972, 36, 885.

Curotenoids urid Polyterpenoids

24 1

are shown in Scheme 3). R y b a ~ degraded k~~ (+)-abscisic acid to the (-)-triester (58),which he independently prepared from (S)-malicacid. Taylor and Burden6' degraded violaxanthin (54) to xanthoxin (55) which they then converted into ( + )-abscisic acid. Thus all three groups support the (S)-stereochemistry shown in Scheme 3. Contrary to their claim, Oritani et aLS8 are mistaken in their

(54)

hii. 6 i i i , ix

H0,CXC02Me

Reagents: i, Zn(MnO,),; ii, Cr0,;py; iii, Mn0,-KCN; iv, K O H ; v, SeO,; vi, Bu' chromate; vii, NaBH,; viu, CH,N,; ix, Ac,O-py; x, 0,; xi, Kolbe.

Scheme 3 application of the 1966 R-S rules. Xanthoxin (55)can also be prepared enzymically from violaxanthin (54) by soybean lipoxygenase.61 Treatment of abscisic acid with formic acid-hydrogen chloride gave a product which showed an intense violet-red colour with alkali. The product was shown to be the enol-lactone (59), and the coiour may be due to the anion (60).62 The synthesis of I4C- or 2H,-labelled abscisic acid is reported,63 as well as the synthesis of a number of related corn pound^.^^ 5y

G. Ryback, J.C.S. Chem. Comm., 1972, 1190.

'" H. F. Taylor and R. S . Burden, Proc. R o y . Soc., 1972, 180B, 317. 6 1 6 2 6.'

b4

R. D. Firn and J . Friend, Plunru. 1972, 103, 263. R . Mallaby and G . Ryback, J.C.S. Perkin I I . 1972. 919. J.-C. Bonnafous and M. Mousseron-Canet, Bull. SOC.chini. France, 1971, 4551 : J.-C. Bonnafous, L. Fonzes, and M . Mousseron-Canet, ihid., p. 4552. T. O r i t a n i and K . Yamashita, Agric.. und B i d . Chem. (Japan), 1972, 36. 362.

242

Terpenoids und Steroids

(60) The absolute stereochemistry of the natural irones ( 6 1 x 6 4 ) has been resolved by interrelationships and correlation with a-ionone and camphor.16 Blumenols A, B, and C (65)--(67) were isolated from P o d o c ~ r p u s .Subsequently ~~ the name of blumenol A was abondoned since vomifoliol has precedence.66 The absolute

(66) R = OH (67) R = H

stereochemistry of blumenol C is probably R as it has a positive 0.r.d. Cotton effect. The 0.r.d. curves of blumenols A and B cannot be directly related to abscisic acid. contrary to the authors' claim. since the chromophore is clearly that of the enone rather than a dienoic acid. Quiesone (68) is a germination inhibitor from tobacco leaves.67 A number of quaternary ammonium salt hS

'' ''

M . N . Galbraith and D . H. S. Horn, J.C.S. Chem. Comm., 1972, I 13. M . N . Galbraith and D. H . S . Horn, J . C . S . Chem. Comm., 1972, 576. R . A . Leppik. D. W. Hollomon, and W. Bottomley, Ph.vtorhem1str.v. 1972, 11. 2055.

Curotenoids and Polyterpenoids

243

derivatives of CI- and p-ionine also show marked plant-growth retarding activity.68 Buchi and W i i e d 9 have synthesized a- and P-damescenone (69) and (70) from ethyl a- or /3-safronate via reaction with allyl-lithium. The photochemistry of p-ionol, trans-(6),” and of a-ionine (56)’ has been studied.

’

(71) R = OH (72) R = H

The absolute stereochemistry of loliolide (71) and dihydroactinidiolide (72) has been determined by their synthesis from zeaxanthin (12) by photochemical oxidation.72 Dihydroactinidiolide and theaspirone (73) have been synthesized by another variation on previous routes (Scheme 4).73 In Crocus sativus a large

J

1‘ (72)

(73) Reagents: i , EtOH-H,O-H,SO,:

i i , H,-Pt; iii, NaBH,; iv, KHSO,; v, Bu‘ chromate.

Scheme 4 bX

69

70

?I 72 73

M . Nagao and S . Tamura, Agric. and B i d . Chem. (Japan), 1971, 35, 1636; H . Haruta. H. Yagi, T. lwata, and S. T a mu r a , ibid., 1972, 36, 881. G . Buchi and H . Wuest, Hrlv. Chim. Acta, 1971, 54, 1767. A . A . M . Roof, A . van Wageningen, C . Kruk, a n d H. Cerfontain, Tetrahdron Lctrrrs, 1972, 367. K. Ina and E. Et6, Agric. and Biol. Chem. (Japan), 1972,36, 1091. S . Isoe, S. B. Hyeon, S. Katsamura, and T. Sakan, Tetrahedron Lrttrrs, 1972, 2517. K. Ina, T. Takano, Y . Imai, and Y . Sakato, Agric. and Biol. Chem. (Japan), 1972, 36, 1033.

Terpenoids and Steroids

244

R2

(74) (75) (76) (77)

R ’ = H Z , R Z= H R1 = H , 0 H , R 2 = H R’ = 0 , R 2 = H R’ = 0. R2 = O H

number of even more degraded carotenoids occur.’’ For example, there are the C, compounds ( 7 4 H 7 7 )and the C , , compounds (78) and (79). Several hundred compounds from tobacco have been characteri~ed.’~ Many of these are clearly derived from cyclic or acyclic carotenoids or related compounds. Black tea is also a source of ionones.’6 Parmone from violet flowers has now been shown to be ( + )+ionone (56).” 5 Polyterpenoids An interesting new polyprenol (80) from Aspergillus niger has an extra carbon atom present as a methylene group.-8 The position of the methylene group is based on biosynthetic analogy with 24-methylene steroids. This structure is also consistent with the n.m.r. spectrum, contrary to the authors’ claim. Further studies of bacterial polyprenols and their involvement in cell-wall teichoic acid formation show that glycerol phosphate-glucose-phosphate-polyprenol is an intermediate.-’

180)

” 75

76 7’

’’ 79

N . S. Zarghami and D. E. Heinz, Phyiochemisiry. 1971. 10, 2755. W. J . Irvine, B. H . Woolen, and D. H. Jones, Phyfochemisrry, 1972,11,467; B. Kimland, R . A. Appleton. A. J. Aasen. J. Roeraade, and C . R. Enzell, ibid., p. 309; B. Kimland, A . J. Aasen, and C. R. Enzell, Acra Chetn. Srarid., 1972. 26, 2177; E. Demole and D. Berthet. Heft.. Chitn. A r i a , 1972. 55, 1866. 1898. K . Ina and H. Eto, Agric.. utid Biol. Chetn. (Japan), 1972, 36, 1027. G . Uhde and G. Ohloff, HeIr. Chitm. Acra, 1972, 55, 2621. R. M .Barr and F. W. Hemming, Biochrm. J . , 1972, 126, 1193. I. C. Hancock and J . Baddiley, Biochetn. J., 1972,127, 27; see also K. J . Stone and J. L. Strominger. J. Biol. Chem.. 1972, 247, 5107.

7 Biosynthesis of Terpenoids and Steroids BY G. P. MOSS

1 Introduction As in the previous Reports in this series the hydrogen atoms of mevalonic acid ( 1 )

are labelled as shown. Thus the [2R]hydrogen of mevalonic acid is labelled HA (similarly 2s = H,, 4R = H,, 4 s = H,, 5R = HE, and 5s = HF). The use of, for example, [2-'4C,3R,4R-3H]mevalonic acid in practice means use of a mixture of [2-I4C,3RS]-,[3R,4R-3H]-,and [3S,4S-3H]-mevalonicacids, it being assumed that only the 3R,4R-isomer will be metabolized. Interest in enzyme stereospecificity and the stereochemistry of prochiral centres, such as the methylene groups of mevalonic acid, has necessitated more precise definitions of the stereochemistry of the various molecules involved' and of the enzymological consequences.2 The use of multiply labelled mevalonic ~ acid in terpenoid and steroid biosynthesis has been reviewed by H a n ~ o n .The Proceedings of the 1970 Phytochemical Society symposium have been publi~hed.~ They include a general discussion of terpenoid pathways of biosynthesis by Clayton and specific chapters on monoterpenoids, diterpenoids, ecdysones, carotenoids, ilsoprenoid quinones, and chromanols. Other reviews concerning biosynthesis have appeared on furanocoumarins, indole alkaloids,6 monoterpenoids,' and diterpenoids8

I

'

'

H. Hirschmann and K. R. Hanson, European J . Biochem., 1971,22,301; J . Org. Chem., 1971, 36, 3293. K. R. Hanson, Ann. Rec. Piunt Physioi., 1972, 23, 335. J. R. Hanson, Adr. Steroid Biochem. and Pharmocol., 1970, 1, 51. R. B. Clayton, p. 1 ; M. J . 0. Francis, p. 29; J . MacMillan, p. 153; H. H. Rees, p . 181 ; G. Britton, p. 255; 0. B. Weeks, p. 291 ; a n d D. R . Threlfall a n d G . R. Whistance, p. 357; in 'Aspects of Terpenoid Chemistry a n d Biochemistry', ed. T. W . Goodwin, Academic Press, 197 1. H . G. Floss, Recent A&>. Phytochem., 1971, 4, 143. A. R. Battersby, Accounfs Chrrn. Res., 1972, 5 , 148; J . Staunton, 'The Alkaloids', ed. J . E. Saxton (Specialist Periodical Reports), The Chemical Society, London, 1972, vol. 2, p. 1 . D. V . Banthorpe, B. V. Charlwood, a n d M . J . 0. Francis, Chem. Retl., 1972,72, 1 1 5 . J . R. Hanson, Fortschr. Chem. org. Natirrstoffe, 1971, 29, 395.

245

Terpenoids and Steroids

246

Various aspects of steroid biosynthesis were included in a Royal Society Symposium.’-’ The published proceedings and other reviews have dealt with cyclase enzymes,l 4 water-soluble steroids and triterpenoids,’ the involvement of a 14 1 5)- or 8( 14)-double bond * and its reduction in cholesterol biosynthesis, biosynthesis of sterols, steroid metabolism in insects,” pregnane steroids, l 6 cardenolides, and bufadienolides.’ 3 *

’’

-

2 Acyclic Precursors

The incorporation of malonate into mevalonic acid’* and steroids” has been investigated further. Experiments with normal and tumorous rats have demonstrated2”the previously unsuspected fact that the S-methyl group of methionine is incorporated into cholesterol and cholest-7-en-3/?-01. Some of the enzymes involved in mevalonate synthesis have been isolated. Yeast acetoacetyl coenzyme A thiolase (EC 2.3.1.9)has a molecular weight of about 190 0oO and 3-hydroxy-3methyl glutaryl coenzyme A synthetase (EC 4.1.3.5) a molecular weight of 130 OOO.’ Rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34)used only [4R-3H]NADPH in the formation of mevalonic acid with incorporation of two tritium atoms (at H, and H,)22 (see Scheme 1). As part of the extensive studies by Cornforth and co-workers of squalene biosynthesis, the stereochemistry of the last step has now been e l ~ c i d a t e d . ~ ~ This concerns the stereochemistry of proton addition to isopentenyl pyrophosphate with formation of the new methyl group of dimethylallyl pyrophosphate under the influence of isopentenyl isomerase (EC 5.3.3.2). The investigation hinged on the generation of a chiral methyl. CHDT. [2-’4C.2R-3H,3R]- and ‘‘C,2S-3H.3R]-mevalonic acid were separately converted in the presence of C. Anding, R. D. Brandt. Ci. Ourisson, R . J . Pryce, and M. Rohmer, P r o ( , . Roy. Soc., 1972, B180, 1 1 5 . G. J . Schroepfer, jun., B. N . Lutsky, J . A . Martin, S. Huntoon, B. Fourcans, W. H . Lee, and J. Vermilion. Proc.. R o j . . Soc.. 1972, B180. 125; A . Fiecchi, M. G . Kienle, A . Scala, G . Galli. E. G . Paoletti. F. Cattabeni, and R . Paoletti, ihid., p. 147. M . Akhtar, D. C . Wilton. I . A . Watkinson. and A . D. Rahimtula, Proc. Roy. Soc., 1972, B180. 167. M. J . Thompson, J . A . Sboboda. J . N . Kaplanis, and W. E . Robbins. Pro(,. Roy. S o c . , 1972. B180, 203. R . Tschesche, P r o ( , . R o j , . S w . , 1972. B180. 1 8 7 . P. D. G . Dean. Srvroiciologiu, 1971, 2. 143. L. J. Mulheirn and P. J . Ramm, Chrnr. Soc,. Rrr., 1972. I , 259. S. Burstein and M. Gut. A&. Lipid Res.. 1971. 9, 291. R. Tschesche. Planra Mrci., 1971. Suppl. 5, 34. L . Bjork. Acra Chem. Sccind., 1971, 25. 3634. A . N . Klimov, 0. K . Dokusova. L. A . Petrova, and E . D. Polyakova, Biochern. U.S.S.R.. 1971,36, 379. J . G . Lloyd-Jones. P. Heidel, B. Yagen, P. J . Doyle, G . H . Friedell, and E. Caspi, J . Biol. Chem., 1972, 247, 6347; E. Caspi, J . G. Lloyd-Jones, P. Heidel, G. H . Friedell, A . J . Tiltman. and S. Yalciner, Chrnt. Cornni.. 1971, 1201. B. Middleton and P. K . Tubbs, Biochrnt. J., 1972. 126, 27; B. Middleton, h i d . , p. 35. A . S. Beedle, K . A . Munday, and D . C . Wilton, European J . Biochem., 1972, 28, 151. J . W. Cornforth, K. Clifford. R. Mallaby, and G. T. Phillips, Proc. R0.r.. Soc., 1972, B182,277; K . Clifford, J . W. Cornforth. R . Mallaby, and G. T. Phillips, Chrrn. Comm., 197 I . 1599.

- moH 247

Biosynthesis of Terpenoids and Steroids MeCOSCoA

EC 2.3.1.9

--+

EC41.35

MeCOCH,COSCoA

C0A.S

1“‘

2.5.1.1

OH

I

*

HA EC 4.1.32 loss H > D > T

(There are three possible isomers of malic acid with X = HA,Y = D;X = HB, Y = HA;X = D,Y = HB.)

-

HA

1

~

/o OH Scheme 1

EC 4.2.1.2

HO

/O OH

248

Terpenoids and Steroids

D 2 0 into farnesyl pyrophosphate, which was then degraded to acetic acid and enzymically converted into malic acid and fumaric acid. Using the 2R-isomer of mevalonic acid 63.4Oi, of the tritium was retained whereas with the 2s-isomer 36.5% was retained (i.e.63.502 lost). From this it can be deduced that proton addition to the double bond of isopentenyl pyrophosphate is anti to the proton eliminated from the allylic carbon atom (see Scheme 1). A problem in the use of dimethylallyl pyrophosphate (3) is its instability. In a study of this problem the half-life of this substance was examined over a range of pH values and temperature^.^^ Both cis- and trans-prenyl pyrophosphates (4; n = 0, 1, or 2) occur in Pinus radiata. Their biosynthesis from [2-’4C,3R,4R-3H]mevalonic acid proceeded with retention of tritium whereas with [2-I4C,3R,4S3H]mevalonic acid tritium was lost [except in the case of isopentenyl pyrophosphate (4: n = O)]. The authors suggest2’ that since they could not detect an isomerase, there may be a cis- and a trans-prenyl transferase both of which eliminate the label derived from [4S-3H]mevalonic acid. However, compartmentalization may have resulted in the isomerase not being available to the administered monoterpenoids, although it may act on geranyl pyrophosphate formed in situ. The absence of 6-cis-farnesol derivatives tends to support this idea. Further work on this system26again produced no evidence for isomerization or metabolism of [ l-3H]nerol pyrophosphate to 2-trans-6-cis-farnesyl pyroph osphate. The steric requirements of prenyl transferase (EC 2.5.1.1) have been further defined by the use of homologues of dimethylallyl p y r ~ p h o s p h a t eand ~ ~isopentenyl pyrophosphate.28 With the former a trisubstituted double bond was needed, so that the esters (5t(8) were utilized but (9) and (10) were not. Although the ester (12) could replace isopentenyl pyrophosphate, ( 1 3 H 1 5 ) did not react. ~~ The products obtained were used in a study of squalene ~ y n t h e t a s e .Farnesyl pyrophosphate homologues (16) and (17)were utilized but (18)and (19)were not. In a similar study using [l-3H]methylpentenyl pyrophosphate (11) and [1-14C]isopentenyl pyrophosphate (2) the squalene formed was labelled with I4C only, whereas the homologues (20) and (21) contained tritium also.30 Among the steroids formed by the same system, ‘‘C-labelled lanosterol and cholesterol and their 27-methyl homologues were present, having the same 3H : 14Cratio as (20). This shows that squalene epoxidase can epoxidize only the correct end group. Hog liver squalene synthetase has been partially p ~ r i f i e d . ~Related studies with the yeast enzyme suggested a molecular weight of 426 000.32 This enzyme

’

’‘ 25

’‘ ’’ ” ” 30

’’ 3 1

D. M . Logan, J . Lipid Res., 1972, 13, 137. E. Jedlicki. G . Jacob, F. Faini. 0. Cori. and C. A . Bunton. Arch. Biochern. Biophys., 1972, 152, 590. G . Jacob, E. Cardenil, L. Chayet, R . Tellez, R . Pont-Lezica, and 0. Cori, Phytochemistry, 1972, 11, 1683. T . Nishino, K . Ogura, and S. Seto, Biochim. Biophys. Acta, 1971, 235, 322. K. Ogura, T. Koyama, and S. Seto, J . C . S . Chem. Comm.. 1972, 881. K . Ogura, T. Koyama, and S. Seto, J . Atner. Chem. Soc., 1 9 7 2 , 9 4 , 3 0 7 . A. Polito, G . Popjak, and T. Parker, J . B i d . Chem., 1972,241, 3464; Fed. Proc., 1972, 31, 895. R . E. Dugan and J . W. Porter, Arch. Biuchem. Biophys., 1972, 152, 28. I . Shechter and K . Bloch, J . B i d . Chem., 1971, 246,7690.

Biosynthesis of Terpenoids and Steroids

249

R' 3 - P,O,.O

(5) R' (6) R' (7) R' (8) R', (9) R' (10) R' (11) R'

4

R

2

(12) R = Et (13) R = H (14) R = Pr (15) R = Bu

= Et, R2 = Pr = Pr, R 2 = Et

R Z = (CH2)4 R 2 = (CH,), = H. R 2 = BU = H, R2 = amyl = Me,R2 = Et =

(16) R' = Me, R2 = Et (17) R' = Et, R 2 = Me (18) R' = Me,R2 = Pr (19) R ' = Pr,R2 = Me

(20) R'

=

Me, R2

=

Et

(21) R'

=

R 2 = Et

was separated into two interconvertible fractions.33a The protomeric unit had a molecular weight of about 450000 and was capable of synthesizing only presqualene alcohol pyrophosphate. Full activity, with squalene synthesis, was present in the other polymeric unit. The enzyme was stimulated by sterol carrier protein, a molecule which could bind presqualene alcohol pyrophosphate but not farnesyl pyr~phosphate.~~' Popjak and c o - ~ o r k e r have s ~ ~ published their confirmation of the structure of presqualene alcohol pyrophosphate (22a) in full. They showed that synthetic (racemic) material had half the activity of the natural product. The absolute configuration of the cyclopropane ring has been revised3' to RRR and this is more consistent with the known stereochemistry of the squalene produced (Scheme 2). A . A. Qureshi, E. D. Beytia, and J . W. Porter, Biachem. Biophys. Res. Comm., 1972, 48, 1123. 3 3 b H . C. Rilling, Biochem. Biophys. Res. Comm., 1972,46,470. 3 4 J. Edmond, G. Popjak, S. M . Wong, and V. P. Williams, J . Biol. Chem., 1971, 246, 6254. 3 5 G . Popak, Lecture, Biochem. SOC.,27 March 1972; see also I . Shuji, M. Horiike, and Y . Inouye, Bitll. Chem. SOC.Japan, 1969. 42, 1393. '3a

250

Terpenoids und Steroids

R

I

a series R = CH2[CH2.CH:CMe-CH2],H b series R = CH,[CH,-CH:CMe*CH,],H Scheme 2

Prephytoene alcohol pyrophosphate (22b)has been synthesized and identified36 as an intermediate in the biosynthesis of phytoene (24b). The reaction sequence shown (Scheme 2 : b series) assumes that the absolute stereochemistry is the same as for presqualene alcohol.

’’

L . T . Altman, L . Ash, R . C. Kowerski, W . W . Epstein, B. R . Larsen, H . C. Rilling, F . Muscio.and D . E. Greg0nis.J. A m v . Clirm. Soc.. I972,94,3257;seealso L.Crombie, D. A . R . Findley. and D . A . Whiting. J . C . S . Chem. Comm., 1972, 1045; Tetrahedron Lritcrs, 1972, 4027: T. C. Lee, T. H . Lee, and C . 0. Chichester, Phy~oclzrmistry,1972, 11.681.

Biosynthesis of Terpenoids and Steroids

25 1

3 Herniterpenoids The enzyme A2-isopentenyl pyrophosphate : tRNA h2-isopentenyl transferase has been further ~haracterized.~’It has a molecular weight of about 55000, needs dimethylallyl pyrophosphate (3), and is highly stereospecific in its action. The tertiary structure of the tRNA is necessary before a reaction will occur, and the enzyme then modifies the adenosine unit adjacent to the 3’-end of the anticodon. The formation of benzofuranoid and analogous ring systems seems to follow a common pathway. In the rotenoid amorphigenin (25) the sequence38is shown in Scheme 3. Here all five carbon atoms are retained. With the furanocoumarins there is a loss of three carbon atoms but the initial stages are probably analogous. Several studies39 on these sequences are summarized in Scheme 4. A similar process occurs in the biosynthesis of furanoquinoline alkaloids4’ (see Scheme 5).

1

1

l= OH

(25)

Scheme 3

’’ J . 3M 3y

4(’

K. Bartz and D. SOII, Biochirn., 1972, 54, 3 1 ; N . Rosenbaum and M . L. Gefter, J . Biol. Chem., 1972, 247, 5675. L. Crombie, P. M . Dewick, and D. A . Whiting, Chrrn. Comm., 1971, 1182. G . Caporale, F. Dall’Acqua, A . Capozzi, S. Marciani, and R. Crocco, Z . Narurforsch., 1971, 26b, 1256; F . Dall’Acqua, A . Capozzi, S. Marciani, and G. Caporale, ibid., 1972, 27b, 813; G . Caporale, F. Dall’Acqua, and S. Marciani, ibid., p. 871. M. F. Grundon and K . J . James, Chrm. Cornm., 1971,131 1 ;J. F. Collins, W. J . Donnelly, M . F. Grundon, D. M . Harrison, and C. G . Spyropoulos, J.C.S. Chpm. Cnmrn., 1972, 1029.

252

Terpenoids and Steroids

a.

1 +Q0-

psoralen (R = H) bergapten (R = OMe)

marmesin

9tl

H+- mo OH

OMe

rutaretin

xanthot ox in Scheme 4

1 OMe W

i

O

H

-

Rm OMe

R dictamnine(R = H) skimmianine (R = OMe)

platydesmine

Scbeme 5

4 Monoterpeooids

[2-'4C]Mevalonic acid gave4' nearly equal labelling in the two isoprenoid units of linalool (26). The enzyme in rose petals which reduces geraniol [the alcohol from (4; n = l)], geranial [the aldehyde from (4; n = l)], or nerol [cis-isomer of 41

T. Suga, T. Shishibori, and M.Bukeo, Phyrochemistry, 1971,10, 2725.

253

Biosynthesis of Terpenoids and Steroids

alcohol from (4; n = l)] to citronellol (27) requires NADPH.42 The benzoquinone alkannin (28) is an interesting geraniol derivative formed from p-hydroxybenzoic This constitutes a new route to the benzoquinone skeleton. Some inconclusive results have produced44 little evidence for the suggestion that artemisia ketone (30) may be derived from chrysanthemyl pyrophosphate (29).

HO

I

0

(30) (29)

The labelling pattern of pulegone (31) ( % 14Cfrom [2-'4C]mevalonate shown) was i n t e r ~ r e t e dby ~ ~two alternative routes from terpinolene (32) involving oxidation on either side of the isopropylidene group followed by reduction of the endocyclic double bond. The lack of label in the isopropylidene group is another example of compartmentalization, or the presence of a large pool of dimethylallyl pyrophosphate. In Tanacetunz uulgare petals most of the radioactivity from [2-''C]mevalonate was incorporated into the P-D-glucosides of the monoterpenoids, such as a-terpineol (33) or isothujol (34).46 a-Terpineol was shown to be a specific precursor of isoth~jol.~'However, it is further metabolized and radioactivity from it is found in other terpenoids. Their labelling implies that dimethylallyl pyrophosphate is preferentially labelled,47 possibly via a compartmentalized degradation to acetate. 42 43 4J

45

4i

P. J . Dunphy and C. Allcock, Phyrochemistry, 1972, 1 1 , 1887. M . V . Schrnid and M . H . Zenk, Tetrahedron Letters, 1971, 4151. L. Crornbie, P. A . Firth, R . P. Houghton, D . A . Whiting, and D. K . Woods, J . C . S . Perkin I , 1972, 642. D. V. Banthorpe, B. V. Charlwood, and M. R . Young, J.C.S. Perkin I, 1972, 1532. D. V. Banthorpe and J. Mann, Phytochemi:.try, 1972, 1 1 , 2589. D. V. Banthorpe. H . J . Doonan, and A . Wirz-Justice, J . C . S . Perkin I , 1972, 1764.

Terpeizoids and Steroids

254

(32)

(31)

OH (33)

(34)

Cyclopentanoid Monoterpenoids.-The incorporation of [2- 4C,2-3H]mevalonic acid into loganin (351, loganic acid (35a). secologanin (36),and secologanic acid (37) showed" retention of one tritium atom at C-7 and about a third of an atom at presumably the enol system. Full details have appeared of the biosynthesis of asperuloside (42) and related terpenoids from intermediates such as loganin, 7-epiloganin. 7-desoxyioganic acid, 10-desoxygeniposidic acid, and geniposide (381." The latter compound seems to be a key branch point to the other terpenoids such as theviridoside (39) and scandoside (40). An interesting allylic rearrangement must occur in the conversion of scandoside into gardenoside (41).

'

H

OGlu

OGiu

HO--/

OR

0'

(36) R = Me (37) R = H

( 3 5 ) R = Me (35a)R = H

HO,

OGlu

HO

(38) R = R = H (39) R = H, R = O H (40) R = O K . R = H " '4

R Guarnaccia and C. J . Coscia. J . Atrwr. CketJr.SOC.,1971, 93, 6320. H . Inouye, S. Ueda, Y . Aoki, and Y . Takeda, Chetn. and Pharni. Bull. (Japan), 1972, 20. 1287; H . Inouye. S. Ueda. and Y . Takeda. rhrd.. p. 1305.

255

Biosynthesis of Terpenoids and Steroids

Cleavage of the cyclopentane ring seems to occur at the loganin stage. Thus morroniside (43)” and jasminin (4q5’ are formed from loganin. Oleuropein (45) and jasminin were also formed from secologanin and kingiside (44)and 8epikingiside.’ Advances in the study of indole alkaloid biosynthesis cannot be detailed here. Current mainly involves studies of alkaloid interconversions. OGlu

AcO

w

0G l 0U

R 0

0

0AO M e

(43) R = H o r O H (44) R = 0

(42)

OGlu

OGlu

0

HO \

OH

(45) 5 Sesquiterpenoids

to give only farnesol. A phosphatase enzyme from Pinus radiata was However, in the absence of the enzyme the hydrolysis was controlled by the metal 50

” j 2

’’

H . Inouye, S. Ueda, and Y . Takeda, Tetrahedron Letters, 1971, 4069. H . Inouye, S. Ueda. K . Inoue, and Y . Takeda. Trtraheclrnri Lptters. 1971. 4073. A . R. Battersby, C. R . Hutchinson, and R. A . Larson, A h . Anirr. C/iet?i.Soc. Meeting, 1972, 163, O R G N . 11; A . K. Ga r g and J . R. Gear, Phytochemistry, 1972, 11, 689; J . P. Kutney. J . F. Beck, N. J . Eggers, H. W. Hanssen, R. S. Sood, and N . D. Westcott, J . Anier. Chem. Sot.., 1971, 93, 7322; J. P. Kutney, J . F. Beck, C . Ehret, G . Poulton. R. S. Sood, and N . D. Westcott, Bio-org. Chem., 1971, 1, 194; A. I . Scott. P. B. Reichardt, M . B. Slaytor, and J . G . Sweeny, ibicl., p. 157; A . I . Scott, ‘Proceedings o f th e 23rd International Congress on Pure and Applied Chemistry’, 1971, vol. 5 , p. 21. C. George-Nascimento, R . Pont-Lezica, and 0. Cori, Biochrtn. Biop/ph~’.s.R r s . C ( i t ~ 1 t 7 . . 1971,45, 119.

256

Terpenoids und Steroids

ion present. With manganese ions only nerolidol (47) was formed whereas with n = 2)]were present. magnesium ions both nerolidol and farnesol [alcohol from (4; This type of phenomenon may explain why in tea shoots only nerolidol is labelled by [2- ''C]acetate.'" Further studies on ipomeamarone (48) biosynthesis have been reported."

(48) The origin of the additional carbon atoms of insect juvenile hormone (49) is not yet settled. Methionine seemed to be incorporated only into the ester methyl g r o ~ p . ' ~ . ' ' Mevalonate was incorporated into farnesol but not into juvenile hormone. A slight incorporation of [2-'"C]acetate into the chain was noted but not of [ l - " C ] a ~ e t a t e . ~Metabolism ~ of the ester includes hydrolysis to the corresponding acid" and possibly formation also of the corresponding diol from the epoxide group.'8

OMe

Previous results on helicobasidin (51) have suggested that y-bisabolene (54) is not a precursor. A similar conclusion has been reached for trichodermol (52) and trichothecin (53). Hanson and co-workers ~ h o w e d ~ ~that - ~ ' tritium from [2-3H.2-'4C]geranyl pyrophosphate (4:n = 1) is incorporated into all three bicyctic sesquiterpenoids. The suggested explanation is that the tritium atom is transferred by a 1,4-shift as shown in Scheme 6. The involvement of trichodiene (50)was confirmed by Machida and Nozoe.62 They also isolated deshydroxytrichodermol and trichodiol A(55), which may be a precursor of the tricyclic system (seearrows). Bisabolene derivatives, as expected, were not i n ~ o r p o r a t e d . ~ ~

''

R . Saijyo and I . Uritani, Agric. arid Biol. Chenr. (Japan), 1971, 35, 2132. I . Oguni and I . Uritani, Agric. and Biol. C h e m . ( J a p a n ) , 1971, 35, 1980; Plant Cell Physiol., 1971, 12. 507. '' M . Metzler. K . H . Dahm, D . Mcyer. and H . Roller, Z . Narurfnrsch., 1971, 26b, 1270. 5' M . Metzler, D. Meyer, K . H . Dahm, H . Roller, and J . B. Siddall, Z . Naturforsch., 1972, 27b, 321. 5 8 A. F. White, Lij2 Sci.,Part / I , 1972, I I , 201. '' P. M. Adams and J . R. Hanson. Cheni. Comm., 1971. 1414. '' B. Achilladelis, P. M . Adams, and J . R . Hanson, J . C . S . Perkin I , 1972, 1425. P. M . Adams and J. R . Hanson, J . C . S . Perkin I , 1972, 586. 6 2 Y . Machida and S. Nozoe, Tetrahrdron Lerrers, 1972, 1969. h 3 J . M . Fortester and T. Money. Cutiad. J . ChtJtii..1972. 50, 3310.

Biosynthesis of Terpenoids and Steroids

257

1

OH (52) R

=

(53) R

=0

H,

Scheme 6

In the biosynthesis of tutin (57) the involvement of copaborneol (56) has been d e m ~ n s t r a t e d .As ~ ~expected, only one tritium atom was incorporated from [2-'4C,3R,4R-3H]mevalonate.65 Unfortunately, it is still not clear whether the biosynthesis involves a cadinene system or a germacrene system. The cadinene sesquiterpene, y-muurolene (58), and caryophyllene (59) are formed in Mentha piperita.66 The labelling of the latter terpenoid ( % from [2-14C]mevalonate '* K . W. Turnbull, W. Acklin, D. Arigoni, A. Corbella, P. Gariboldi, and G. Jommi, 65

"

J.C.S. Chem. Comm., 1972, 598. A . Corbella, P. Gariboldi, and G. Jomrni, J.C.S. Chem. Comm., 1972, 600. R. Croteau and W. D. Loomis, Phytochemisrry, 1972, 1 1 , 1055; R . Croteau, A. J . Burbott, and W. D. Loomis, ibid., p. 2937.

Terprrioids mid Steroids

Fhown i n formula) shows low labelling in the gumdimethyl group. probably ow iiig to compartmentali7ation or a pool of dimethylallyl pyrophosphate. lsopetasol(60)v;as shown by Brooks and KeateP7 to be formed from presum,ibly a germacrene intermediate which on cyclization and rearrangement gives a

'non-isoprenoid' skeleton. In this process the loss of one tritium atom from j'-'JC,3R.4R-3H]me~alonate may be associated with the rearrangement or formation of the enone system. 6 Diterpenoids

The promise of '-3C-n.m.r~ spectroscopy in biosynthetic work has been demonstrated by the biosynthesis of isovirescenol A (61)and B (62) using [1-I3C]- and [2-13C]-a~etate.68 Although the results \!.ere as expected the identification of all of the labelled positions demonstrates the potential of this technique for terpenoid studies.

/\

(61) R = O H (62) R = H '

C . J . W. Brooks and R . A . B. Keates, Ph?,rctr./rrriiistr~,IY72, I I , 3235. '' J . Polonsky, Z . Baskmitch. N . Cagnoli-Bellavlta. P. Ceccherelli, B. I . . Bnckwalter, and

E . Wenkuri. J . , 4 t n ~ t C . IIP~ Sol,.. . 1971. 94. 4369.

Biosynrhesis of Tei-penoids and Steroids

259

Kaurene synthetase is an enzyme with a molecular weight of about 430 OO0.6g It cycljzes geranyl-geranyl pyrophosphate (4; n = 3 ) to copaiyl pyrophosphate (63) and further cyclizes this to kaurene (65). However, there was no resolution of these two cyclases although there was a different optimum pH for their action. The cyclization of (63) to 13-epimanoyl oxide (64) as well as kaurene has been demonstrated in Gibberell~,fujikuroi.~'A further complication in the enzymology of these terpenoids is that kaurene in peas seems to be present only as a protein complex so that the free hydrocarbon is not metab~lized.~'

(65) R' = Me, R2 = H (66) R' = CO,H, R2 = OH Another new technique for the study of biosynthesis is the use of g.c.-m.s. MacMillan and co-workers have shown72 in this way that kaurene and related products had incorporated four 14C atoms per molecule and that the specific activity was equal at a!] four positions. Full details have appeared of the concerning the ring-contraction in the formation of the gibbane skeleton. The key step seems to involve a hydride shift [see (66) -+ (67)]. A late stage in gibberellic acid (A1-68)biosynthesis might involve G A , (68). However, this compound was incorporated only into GA, (69) and its g l u c ~ s i d e . ~ ~ A BaeyerThe oxidations of beyerene (70)have been studied by Bakker et Villiger oxidation of the ketone (73) may be the origin of the seco-acid (74). The involvement of beyerenol(71)and beyerol(72) was demonstrated.

'' R . R . F a l l a n d C . A . West, J . Biol. Chew., 1971, 246, 6913. J. R. H a n s o n a n d A . F. White, Phytoclzcmistry, 1972, 11, 703. '' T. C. Moore, S. A. Barlow, a n d R . C. Coolbaugh, Phyrochemisrr.v, 7 2

73 74

75

1972, 11, 3225. D. H . Bowen, J. MacMillan, a n d J. E. Graebe, Phytochemistry, 1972, 11, 2253. J . R. Hanson, J . Hawker, a n d A . F. White, J . C . S . Perkin I , 1972, 1892; see also J. E. Graebe, D. H. Bowen, a n d J . MacMillan, Planfa, 1972, 102, 261. R. Nadeau a n d L . Rappaport. Phyrochemisrry. 1972, 11, 161 1 . H. J. Bakker. E. L . Ghisalberti, a n d P. R . Jefferies, Pli.~tocket~ii.srr~, 1972, 11. 2221.

260

Terpenoids and Steroids

(68) R = H (69) R = OH R3

R'

(70) R' (71) R' (72) R' (73) R'

(74)

H 2 , R 2 = R3 = H H2,R2= OH,R3 = H H,OH, R 2 = R 3 = OH = 0, R2 = R3 = OH

= = =

7 Sesterterpenoids A study of a range of precursors for ophiobolin B (75) suggests that compartmentalization gives better incorporation of serine and pyruvate than of acetate.76 However, degradation suggests that these precursors are degraded to acetyl coenzyme A before incorporation.

H

8 Steroidal Triterpenoids As in previous years this section will deal with the biosynthesis of cholesterol and related steroids such as ergosterol : Section 9 will consider their further

metabolism, Section 10 the remaining triterpenoid systems, and Section 13 taxonomic aspects. 76

A . K. Bose, K . S. Khanchandani, and B. L. Hungund, E.vperien/ia. 1971. 27, 1403.

Biosynthesis of Terpenoids und Steroids

26 1

Many steps in sterol biosynthesis are stimulated by a sterol carrier protein. The identity of this protein is not known but its effect seems to be widespread. A rat liver carrier protein7' also affects adrenal78 and brain79 systems. Substitution by a carrier protein from Tetrahymena pyrijbrmis gave partial stimulation with the rat liver preparation.80 The function of this molecule may be regulatory. At low levels of carrier protein, sterol biosynthesis is mainly via A24-sterols, whereas at higher levels the 24,25-dihydro-derivativesare preferred.81 Apolipoprotein I1 (and to a lesser extent I) produce a similar effect.82 Squalene Cyc1ization.-Squalene epoxidase from rats needs a supernatant protein fraction for full However, this fraction does not seem to correspond to the sterol carrier proteins mentioned above. It is a heat-labile molecule with a molecular weight of about 44OOO. A 2,3-dioxetan derivative of squalene has been suggested as an intermediate in this ~xidation.'~ One of the clear distinctions between higher animals and plants is in the products resulting from cyclization of squalene epoxide (76). Plants form cycloartenol (78) whereas animals form lanosterol (80). Moreover, animals are unable to metabolize c y ~ l o a r t e n o l .Further ~~ examples of cycloartenol formation are reported with a tissue culture of Rubus jkucticosus86 and Pinus pine^.^^ Cycloartenol and 24-methylenecycloartanol are recovered unchanged with microsomes from the Rubus tissue culture but cycloeucalenol (79) is metabolized

(76) R = Me (77) R = H 77

78

79 80

81

82

83 84

85

86 87

T. J . Scallen, M . V . Srikantaiah, H. B. Skrdlant, and E. Hansbury, Fed. Proc., 1972, 31, 429. K . W. Kan, M . C. Ritter, F. Ungar, and M. E. Dempsey, Biochem. Biophys. Res. Comm., 1972, 48, 423. S. N . Shah, F.E.B.S. Letters, 1972, 20, 75. T. Calimbas, Fed. Proc., 1972, 31, 430. M . C. Ritter, M . E. Dempsey, and I. D . Frantz, jun., Fed. Proc., 1972,31,430. M . E. Dempsey, M . C. Ritter, and S. E. Lux, Fed. Proc., 1972, 31, 430. H.-H. Tai and K . Bloch, J . Biof..Chem., 1972, 247, 3767. V . Subramanyan, A. H. Soloway, and G. R. Wellum, Abs. Amer. Chem. Soc. Meeting, 1972, 163, MEDI.42. W. R. Nes and G. F. Gibbons, Fed. Proc., 1971,30, 1105. R. Heintz and P. Beneveniste, Compt. rend.. 1972, 274, D , 947. H . C. Malhotra and W. R. Nes, J . Biol. Chem., 1972, 247, 6243.

262

Terpenoids and Steroids

to obtusifoiiol (82).88 This seems to be the stage at which the cyclopropane ring is typically opened in higher plants. Lower plants vary as to which mechanism they use. The red alga Porphyridiurn cwieiitzm forms cycloartenol and diverts a negligible amount of radioactivity

R' (78) R ' = Me. R' = CH:CMe2 (79) R ' = H. R 2 = CPri:CH2

R' (130) R ' = R 3 = Me. R' = CH:CMe, (81) R ' = Me, R' = CHZCMe,. R 3 = H (82) R ' = H, R 2 = CPr':CH,. R 3 = Me Eirgleita grucilis does fortn cycloartenol, but radiointo l a n o ~ t e r o l .However. ~~ activity is also recovered in 24-methyIenelanostan01.~~ Thus, in contrast to higher plants. the cyclopropane ring may be opened at an early stage. The enzyme 2.3-oxidosqualene cycloartenol cyclase from Ochruirionus malhur?ieizsis has been partially purified.9' Further study of the rat liver cyclase shows that 6-desmethyl-2.3-oxidosqualene (77) was cyclized to 19-nor-lanosterol (81) and also its cis-fused A B ring isomer.92

Loss of the 4,4-Dimethyl Groups-The oxidation of the 4a-methyl group of lanosterol (80) to the coi responding 4a-carboxylate requires oxygen and .i

R. Htintz. P. Beneveniste. and T. Bimpson, Biochetri. Biophys. Res. Cotwz., 1972, 46, 766; R. Heintz, T. i3impson, and P. Beneveniste. ihrd., 49, 820. "' G . H. Beastall, H. H. Rees. and 1.W. Goodwin. Terrahedron Letters, 1971.4935. Anding, R . D . Brandt, and G . Ourisson. E u r o p u t t J . Biothem., 1971, 24, 259. '" " C. G . H. Beastall. H . H . Rces. and 1'. W . Goodwin, F.E.H.S. Letters, 1971, 18, 175. "' E . E. van Tamelen. J . A . Smaal. and R.B. Clayton, J . Anier. Chem. S n r . , 1971,93, 5279.

Biosynthesis of Terpenoids and Steroids

263

NADPH,93.94whereas oxidation of the 3P-alcohol to a ketone requires NAD. In the latter case a 3a-tritium atom is lost and gives [4S-3H]NADH.93 The enzyme for this oxidation and the subsequent decarboxylation has been partially p ~ r i f i e d . ~Reduction ’ of the 4a-methyl-3-ketone produccd is less specik apd proceeds with eitner NADH or NADPH.93 These oxidation processes in rat livers (Scheme 7) are inhibited by carbon monoxide so that lanosterol or 24,25dihydrolanosterol tends to a c ~ u m u l a t e . ~ ~

a-a NAD(P)H

HO

0’

,

Scheme 7 Loss of the 14a-Methyl Group.-The apparent parallel between the loss of the 14~-methylgroup and that of the 4,4-dimethyl groups has been disproved by Akhtar, Barton, and their co-worker~.~’Whereas the 4.4-dimethyl groups are lost as carbon dioxide the 14a-methyl group is lost as formic acid. When [32-3H]lanost-7-ene-32,3b-diol was metabolized, 47 ”/, of the tritium was recovered in formic acid. The oxidation of the primary alcohol to the corresponding aldehyde requires oxygen and NADPH. These results also show that the enzyme(s) responsible for the loss of the 14a-methyl group are capable of acting on steroids which retain the 4,4-dimethyl groups and have a A7 rather than a As-double bond. All attempts to trap a A8‘14) intermediate have failed even though such a compound is metaboli~ed.~’The product from deformylation is probably cholesta-8,14-dien-3P-o1, a compound isolated from several sources.99 Further metabolism of this diene normally requires reduction of the 14(15)-double ” 94

” ” 97

q8

’’

D. P. Bloxham, D. C. Wilton, a n d M . Akhtar, Biochem. J . , 1971, 125,625. W . L. Miller, D. R. Brady, a n d J . L. Gaylor, J. Bid. Chetn., 1971, 246, 5147. A. D. Rahimtula a n d J . L. Gaylor, J. Biol. Chetn., 1972, 247, 9. G. F. Gibbons a n d K. A. Mitropoulos. Biochem. J . , 1972. 127. 315. K . Alexander, M . Akhtar, R. B. Boar, J. F. McGhie, a n d D. H. R. Barton, J.C.S. Chenr. Cotnnr., 1972, 383. K. T. W . Alexander, M . Akhtar, R . B. Boar, J . F. McGhie, a n d D. H. R . Barton, Chem. Comm.. 1971, 1479. D.C. Wilton, Biochem.J., 1971,125,1153; M . A k h t a r , C . W . Freeman,A. D. Rahimtula, a n d D. C. Wilton, ihid., 1972, 129, 225.

Terpenoids and Steroids

264

1

Scheme 8 bond,'" although reduction of the 8(9)-double bond has been reported.'" Scheme 8 summarizes the details of these processes.

Formation of the A5-Double Bond.-Possi ble hydroxylic intermediates in the conversion of a A7-steroid into the corresponding A'*7-diene are incorporated into cholesterol. lo' However, anaerobic studies showed that these 7- and/or 8-hydroxy-derivatives are first converted back into a A'-steroid. A similar explanation is likely for the observation that ergosta-7,22-diene-3&5a-diol is incorporated into ergosterol although the 3r-hydrogen atom is lost. The authorslo3 interpreted this result as involving a cyclopropanol derivative on the direct route to a A5s7-diene.However, this interpretation is inconsistent with the observation' O4 that [3r-3H]ergosta-7,22-dien-3P-ol is incorporated with retention of tritium. Thus the more probable explanation is that the diol is oxidized to a 3-ketone, which is then dehydrated to a A4-3-ketone. Reduction of this system would then regenerate ergosta-7,22-dien-3P-ol. In Tetrahymena pyriforrnis the formation of the A'-double bond involves the loss of the 6a-hydrogen atom.Io5 With [6a-3H]cholest-7-en-3P-ol a substantial isotope effect was noted with the recovered starting material. Reduction of the AZ4-DoubleBond.--An X-ray studylob of a 26-hydroxycholesterol derivative showed that the absolute stereochemistry at C-25 was the 5. N . Lutsky, J . A. Martin, and G. J . Schroepfer, jun., J. B i d . Chem., 1971, 246, 6737. I U i R. B. Ramsey, R.T. Aexel, and H. J. Nicholas, J . B i d . Chem., 1971,246,6393. I"' A . Fiecchi, M. G. Kienle. A . Scala, G. Galii, R . Paoletti, and E. G . Paoletti, J. Biol. Chern., 1972, 247, 5898. lo' R . W. Topham and J . L. Gaylor. Biochetn. Biophys. Res. Comm., 1972, 47, 180. I U J M . Akhtar and M . A. Parvez, Biochem. J., 1968, 108. 527. ' O S L. J . Mulheirn. D. J . Aberhart. and E. Caspi, J. B i d . Chenr.. 1971. 246, 6556. ' 0 6 D. J . Duchamp, C . G. Chidester, J . A . F. Wickramasinghe. E. Caspi, and B. Yagen, J. A n w r . Chem. SOC.,1971, 93. 6283.

loo

265

Biosynthesis of Terpenoids and Steroids

opposite of that previously determined. Thus the reduction of the A24-double bond in rat livers should be as shown in Scheme 9. Full details have been reportedIo7 for the origin of the two hydrogen atoms.

Scheme 9 Formation of a A22-DoubleBond.-The biosynthesis of ergosterol (A5,7,22)from episterol involves the formation of the A?- and A22-doublebonds and reduction of the A24(28)-double bond. A detailed study108of the various possible + A7,22,24(28) + A5,7*22*24(28) routes suggested that the main route was A7*24(28) + A5.7.22 However, A l . 2 4 ( 2 8 ) + A? and A 7 , 2 4 ( 2 8 ) j A 5 . 7 . 2 4 2 8 ) were minor alternative routes on this metabolic grid. Formation of the A22-doublebond by Tetrahymena pyriformis is independent of the substituent at C-24. Cholest-7-eno1, cholesta-5,24-dienol, O 5 ergosta-5,24(28)-dienol, and stigmasta-5,24(28)-dieno11O9 are all dehydrogenated to the corresponding AZ2-derivatives. (A7924(28))

'

Side-chain Alky1ation.-Full details have appeared' of the formation of stigmastanol and stigmastenol in Dictyostelium discoideum where there is a migration of a proton from C-23 to C-24 in the alkylation, as well as of the proton at C-24 of the lanosterol precursor to C-25. The latter migration also occurs in This organism is even poriferasterol formation in Ochramonas malhamensis.' able to alkylate cholesterol,' l 2 presumably via an initial dehydrogenation of the side chain. Alkylation of the side chain in Trebouxia, an algal symbiont of a lichen, using [S-C-2H,]methionine showed' l 3 that ergost-5-enol contained three deuterium atoms, whereas poriferasterol or clionasterol contained two, three, or five atoms. The increased formation of the ergosterol derivatives implies an isotope effect on alkylation. However, since cycloeucalenol (79) was incorporated only into the 24-ethyl derivatives and cyclolaudenol (83) was incorporated only into the ergosterol derivatives the isotope effect must operate at the elimination stage, which implies that the same enzyme is involved in either route (Scheme 10).

''

lo'

lo'

Io9

' l o ''I

I

'I3

I . A. Watkinson, D. C. Wilton, A. D. Rahimtula, and M . Akhtar, EuropeanJ. Biochem., 1971. 23. 1. M . Fryberg, A. C . Oehlschlager, a n d A. M . Unrau, Biochem. Biophys. Res. Comni., 1972, 48, 593. W. R. Nes, P. A. G . Malya, F. B. Mallory, K. A. Ferguson, J . R . Laudrey, and R . L. Conner, J . B i d . Chem., 197 I , 246, 561. R. Ellouz and M . Lenfant, European J . Biochem., 1971, 23, 544. A . R. H. Smith, L. J . Goad, a n d T . W. Goodwin, Phyrochemisrry, 1972,11,2775. G . H. Beastall, H. H. Rees, a n d T . W. Goodwin, Biochem. J . , 1972, 128, 179. L. J . G oad, F. F. Knapp, J . R. Lenton, and T. W. Goodwin, Biochem. J . , 1972, 129, 219.

Terpenoids clild Steroids

266

9 Cholesterol Metabolism The sterol requirements of invertebrates are frequently satisfied by modification of dietary steroids. Thus, cholesterol is formed from 24-alkylated steroids, such as ergosterol and fl-sitosterol, by Crustaceans' and insects.' The mechanism of this process seems to be the reverse of their mode of formation. The 24-ethyl group of p-sitosterol is converted into a 24-ethylidene group with fucosterol, and cholesta-5,24-dienol is formed on loss of the alkyl group.!15 Cholesterol is required in insects for metabolism to the hormone ecdysone (54). However, plants also produce ecdysone and both organisms metabolize cholesterol to ecdysone. which is then further metabolized to ecdysterone (85)' ''

''

'

(84) R = H (85) R = O H !

' I i

""

S.-I. Teshima and A . Kanarawa. C,tuip. Biochrni. Piij,siol.. !971, 38B, 603; S.-I. Teshima. ;bid., 39R, 815. J . A . S\oboda. M . J . Thompson, and W . E. Robbins, Nature ( N e w Biol.), 1971, 230, 57. M . Gersch and J . Sturzebecher, Exp(>rierr[iu, 1971, 27, 1475; K . Nakanishi, M . Morivarna. T. Okauchi. S. Fujioka, and M. Koreeda, Scii>iice, 1972. 176, 5 1 ; A. T. Sipahirnalani. A . Banerji, and M. S. Chadha, J . C . S . Cheni. Corvnr., 1972, 692; A. Willig. H. H . Rees, and T. W . Goodwin. J . /rirrc.r P h j r i o l . , 1971, 17. 2 3 1 7 .

Biosynthesis of Terpenoids arid Steroids

267

The mould Mucor rouxii oxidizes ergosterol to ergosta-5,7,9( 11),22-tetraenol. '

'

Spirostanols and Related Compounds.--Sa-Furostan-3~,26-diol(86) is incorporated into tigogenin (87) in Digitalis l ~ n a t a . " ~ Presumably a similar process occurs in the formation of diosgenin (88) and yamogenin (89).' l 9 Details of the

(86) (87) metabolism of diosgenin have been studied by Takeda et a/.'20 Their conclusions are summarized in Scheme 11. Related processes are presumably involved in the

1

1

H Scheme 11

'" ' 'I8

'*'I

H (89)

L. Atherton. J . M. Duncan, and S . Safe, J.C.S. Chem. Comm., 1972, 882. L. Canonica, F. Ronchetti, and G . Russo, Phytochemisrry, 1972, 11, 243. R . Hardman and E. A. Sofowora, Planta Med., 1971,20,193; R. Hardman a n d F. R . Y . Fazli, h i d . , 1972, 21, 188; R . Hardman and C. N . Wood, Phyrochemistry, 1972, 11. 1067; R. Hardman, C. N. Wood, and K. R. Brain. ihid., p. 2073. K. Takeda, H . Minato, A. Shimaoka, and T. Nagasaki, J.C.S. Perkin I , 1972, 957.

Terpenoids and Steroids

268

&* w

biosynthesis of tomatine (90)12' and solanidine (91).'" The latter compound may be a precursor ofjervine (92)and veratramine (93).lz2

GlyO GIyO-

H

Side-ehain Cleavage.-The formation of pregnane derivatives in plants is probably similar to that in animals : 20a-hydroxycholesterol' 2 3 and tomatine (90)12'are metabolized in this way. In mammalian systems modified steroids

'"

E. Heftmann and S. Schwimmer, Phycorhemistry, 1972, 11, 2783. K . Kanedo, M . Watanabe, S. Taira, and H . Mitsuhashi, Phyrochemisrry, 1972, 11, 3199. S. J . Stohs and M . M . El-Olemy, Phgtochentisrr~~, 1971. 10. 3053.

269

Biosyitthesis of Terpenoids and Steroids

can still be metabolized. Thus, 20R-t-butylpregn-5-ene-3/l,20-diol (94) is con~ e r t e d into ' ~ ~ the pregnane derivative (95). However, although the methyl analogue (96) is hydroxylated to the 20- or 21-hydroxy-derivatives (97) or (98), the C-20-C-21 bond is not significantly cleaved.'25 (94) (95) (96) (97) (98)

R'

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

Modification of Ring A.-Some of the modifications mentioned above (Scheme 11) are common to many organisms.'26 The complete structure of A5-3-ketosteroid isomerase (EC 5.3.3.1) has been determined.'27 It has three sub-units, each of 125 amino-acids. This enzyme transfers the 4P-hydrogen atom to the 6P-position as the A5-double bond is moved into conjugation.12* Starfish convert cholesterol into 5a-cholest-7-en01 by a similar process. The A7-double bond is introduced only after reduction of the A4-3-one.I2' Estrone formation in both human preparations' 30 and Bacillus sphaericus' 3 1 involves the loss of the 2P-hydrogen atom. This result agrees with previous studies which additionally showed that the 1P-hydrogen atom is also lost. However, in Septomyxa ufJinis oxidation to form a l(2)-double bond involves the loss of the la-hydrogen atom, although again the 2P-hydrogen atom is also lost.132 Penicillium wortmannii produces a metabolite, 11-desacetoxywortmannin (99), in which ring A is cleaved. It is formed from lanosterol, and the incorporation of

(99)

' 24 12'

Ii8

'' 'I

I

B. Luttrell, R . B. Hochberg, W . R. Dixon, P. D . McDonald, and S. Lieberman, J . Biol. Chem., 1972, 247, 1462. A. D. Tait, Biochem. J . , 1972, 128, 467, S. J . Stohs and M . M . El-Olemy, Phytochemistry, 1971, 10,2987; 1972, 1 1 , 1397. A. M. Benson, R . Jarabak, and P. Talalay, J . Biol. Chem., 1971,246,7514; F. Vincent, H. Weintraub, and A. Alfsen, F.E.B.S. Letters, 1972, 22, 319. S. Murota, C. C. Fenselau, and P. Talalay, Sreroids, 1971, 17, 2 5 . A. G . Smith, R. Goodfellow, and L. J. Goad, Biochem. J . , 1972,128, 1371. T. Nambara, T. Anjyo, and H. Hosoda, Chem. and Pharm. Bull. (Japan), 1972, 20, 853. T. Anjyo, M . Ho, H . Hosoda, and T. Nambara, Chem. and Ind., 1972, 384. Y . J . Abul-Hajj, J . Biol. Chern., 1972, 247, 686.

2 70

Trrpetzoidsund Steroids

two tritium atoms from [2R-3H,2-'4C,3R]mev210nic acid was initially used to determine the stereochemistry at C-1. However, X-ray studies showed this to be incorrect.' 3 3 A possible explanation is that a A1-2.3-seco-intermediate is involved. kvhich on formation of the lactone ring effectively inverts the stereocher~istryat C-1. 10 Triterpenoids

Time studies with Helhrhzrs u i i i i ~ sindicate the progressive oxidation of (:-amyrin (1W) to echinocystic acid (101).134The enzyme involved in the cycli7:1tion of 2,3 : 22.23-bisoxidosqualene to r-onocerin (102) has been partially 135

pur,C 1 . -

(100) R' = Me. R' = H (101) R ' = CO'H. R' = O H

I I Carotecoids Tissue-culture techniques present a number of novel problems. For example, diflerent cultures of carrot tissue gave in one case p-carotene (103) and in the ' I '

' I

''

J . MacMillan, T. J. Simpson. and S. K . Yeboah, J.C.S. Chem. Comm., 1972, 1063; see also T. J . Petcher. H.-P. Weber, and Z . Kis. h i d . , p. 1061. K . Striiby. W . Janiszowska, and Z . Kasprr>k. ~ ~ f ~ [ ( ~ ~ , / z1972, ~ ~ ~11, f / 1. 7~3 3[ ;rsee ~ . also , Z . Kasprzyk. J . Sliwowski. dnd B. Skwarko. h i d . , p . 1961. M. G . R o w a n and P. D. G. Dean. P/I?[ o d w m t s r r ~ ~1971, . I I . 31 1 1 .

Biosynthesis of Terpenoids und Steroids

27 1

other lycopene ( 104).136 [9,10-14C2]Menthenol (33) is incorporated into 0carotene and xanthophylls. Degradation of these carotenoids showed that most of the label was in the cyclohexene ring4' Clearly the monoterpenoid is degraded, presumably to acetyl coenzyme A. Possibly this intermediate is converted into dimethylallyl pyrophosphate in a compartmentalized situation and the isoprenoid chain is extended with the main (unlabelled) pool of isopentenyl pyrophosphate. The stereochemistry of the cyclization of lycopene has been discussed by Britton.I3' He concluded that, based on the absolute stereochemistry of trisporic acid and a-carotene, the cyclization involves the initial formation of a boat conformer. However, this deduction assumes that both the a-and P-ring systems are formed from the same 'carbonium ion'.

R

' d \

(103)R' (104) R' (105) R' (106) R'

=

R2

R2 = a

R2 = b C, R 2 = b R2 = d (107) R' R2 = e (108) R' = R2 = f = = = =

C

d

0 e

f

Chlorobactene (105) biosynthesis involves a methyl migration. A preliminary report suggests'38 that the migrating methyl group is not labelled by [2-14C]mevalonate. Zeaxanthin (106)biosynthesis in a Flavobacterium species involves, as expected, the loss of the two tritium atoms from [2-'"C,3R,5R-3H]mevalonic 136

-37

I JH

N . Sugano, S. Miya, and A. Nishi, Plunt Cell Physiol., 1971, 12, 525; see also D. V. Banthorpe and A . Wirz-Justice, J . C . S . Perkin I , 1972, 1769; D. L. Berry, B. Singh, and D. K . Salunkhe, Plunr Cell Physiol., 1972, 13, 157. G . Britton, in 'Aspects of Terpenoid Chemistry and Biochemistry', ed. T. W. Goodwin, Academic Press, 197 1 , p. 255. S. E. Moshier and D . J . Chapman, Plant Physiol., 1972.49, Suppl. 207.

272

Terpenoids and Steroids

acid on hydroxylation on the cyclohexene ring.'39 Thus the hydroxylation goes with retention of configuration. In the formation of the polyene system tritium is retained from [2R-3H,2-'4C,3R]mevalonate. Further oxidation of j?-carotene gives astaxanthin (107) in the goldfi~h'~'and sand crab.'41 Incorporation studies in the pumpkin support the suggestion that carotenoids are involved in the formation of sporopollenin, the very inert polymeric material surrounding pollen grains. 4 2

'

Degraded Carotenoids-The enzyme from rabbits which cleaves the central double bond of carotenoids has been partially purified.1 4 3 In the mould Blakeslea rrispora further degradation gives the hormone trisporic acid C (109). The further metabolism of the methyl ester has been and shown to be dependent on whether the ( + )- or (-)-strain was used. The latter mainly gave the free acid whereas the ( + )-strain gave various oxidized products.

The plant hormone abscisic acid (1 10) may be a degraded carotenoid or a sesquiterpenoid. Studies using [2R- H,2- 4C,3R]-, [2S- H , 2- I 4C,3RI-, and [2-'4C,3R,5S-3H]-mevalonic acid show that either route is possible.'45 Xanthoxin (111) may be involved it being formed in turn from violaxanthin (108). Two new metabolites of abscisic acid have been detected.147

'

I "

"O

''I

14'

IJ3 IJ4

IJ5

14'

T. W. Goodwin, Biochem. J . , 1972, 1 2 8 , I IP. W.-J. Hsu, D. B. Rodriguez, and C. 0. Chichester, fnrernar. J . Eiochem., 1972,3, 333. B. M. Gilchrist and W. L. Lee, Comp. Eiochem. Physiol., 1972,42B, 263. G. Shaw, in 'Sporopollenin', ed. J . Brooks, P. R . Grant, M . Muir, P. van Gijzel, and G . Shaw, Academic Press, 1971, p. 305. M . R . Lakshmanan, H . Chansang, and J . A. Olson, J . LipidRes., 1972, 13,477. J . D . Bu'Lock, D . Drake, and D. J. Winstanley, Phyrochemistry, 1972, 11, 201 1 . B. V. Milborrow, Eiochem. J . , 1972, 128, 1135. H . F. Taylor and R . S. Burden, Proc. Roy. Soc., 1972, B180, 3 1 7 ; see also D . C. Walton and E. Sondheimer, PIanr Physiol., 1972, 49, 290. D . C. Walton and E. Sondheirner, Plant Physrol., 1972, 49, 285.

Biosynthesis of Terpenoids and Steroids

273

12 Polyterpenoids

In Phytophthora cactorum the polyprenols are all trans in the ubiquinones-8 and -9 (112) whereas dolichols-13 to -16 (113) all have three double bonds trans and the rest cis. This stereochemistry was shown in the usual way by the incorporation of tritium from [2-'4C,3R,4R-3H]- and [2-'4C,3R,4S-3H]-mevalonic acid. '41 The incorporation of mevalonate into various polyprenols has been reported.' 49 Polyprenols are involved in bacterial cell-wall synthesis. Some of the enzymes involved in this process have been studied.lS0

13 Taxonomy As in previous Reports this section is particularly concerned with non-vertebrate

species and their ability to synthesize steroids from simple precursors, Further Protozoan studies have confirmed their ability to synthesize steroids.' 5 1 However, in the Porifera one species had this ability but another did not.' 5 2 Coelenterate examples' ' * - l j 3 again showed the absence of squalene or steroid biosynthesis. Previous studies on Echinodermata species suggested that they too could not synthesize steroids. However, recent results suggest that this is not 54 Further studies on Mollusca confirm the previous suggestion that the class ~

14'

149

ISD

Is' 15' 153

0

.

~

J. B. Richards and F. W. Hemming, Biochem. J., 1972, 128, 1345. R . M . Barr and F. W. Hemming, Biochem. J . , 1972, 126, 1203; I . F. Durr and M. Z. Habbal, ibid., 127, 345; T. Kurokawa, K. Ogura, and S. Seto, Biochem. Biophys. Res. Comm., 1971, 45, 251. E. Willoughby, Y . Higashi, and J . L. Strominger, J. Biol. Chem., 1972, 247, 5 1 1 3 ; R . Goldman and J . L. Strominger, ibid., p. 5116; H. Sandermann, jun. and J. L. Strominger, ibid., p. 5123. H . Dixon, C. D . Ginger, and J. Williamson, Comp. Biochem. Physiol., 1972, 418, I . M . J . Walton and J . F. Pennock, Biochem. J., 1972, 127,471. J. P. Ferezou, M . Devys, and M . Barbier, Experientiu, 1972,28, 153,407. L. J . Goad, I. Rubenstein, and A. G. Smith, Proc. Roy. Soc., 1972, B180, 223; P. A. Voogt, Comp. Biochem. Physiol., 1972, 43B. 457.

~

~

9

~

2 74

Terpenoidsand Steroids

Gastropoda can synthesize steroids'52.'55 whereas Bivalvia cannot.' 5 2 An example of Annelida was able to synthesize steroids whereas, as expected, examples of Crustacea'52.'56and Insecta'j7 could not.

'' '

j b

Is'

D. J . ban der Horst and P. A . Voogt, Cotup. Biocher?i.Physinl., I972.42B, 1 ;P. A . Voogt, ihid., 416, 831. S.-I. Teshima and A. Kanazawa, Cotnp. Biocherti. Phj-siol., 1971, 386, 597. R . D. Goodfellow and C i . C. K . Lin. J. ftisrcr Phj*siol., 1972. 18, 95.

Part 11 STEROIDS

Introduction*

Steroid Properties and Reactions-There have been notable advances in the field of semi-quantitative conformational analysis. Allinger and his colleagues, using refined force-field calculations, have obtained impressive agreement between calculated and observed strain energies and structural parameters for simple cycloalkanones, hydrindanones, and androsterone.2u*2b They believe that ‘it is now possible to understand the exact nature of the interactions which lead to the observed energy differences’and ‘-in general, within the area of applicability of the force field, (our) calculated structures are more accurate than those determined by crystallography’. Advances in spectropolarimeter design have made accessible the low-wavelength region (22&185 nm) for the first time and in consequence chiroptical studies in that region have begun to appear. Among the compounds examined are ketones (n-+ 0*),31,32alcohols,49 and ~ l e f i n s . ~ ~ The recently discovered phenomenon of linear dichroism has been used to shed unexpected light on the complex chiroptical behaviour of 01efins.~~ With the utility of lanthanide shift reagents in n.m.r. spectroscopy firmly established, recent investigations have attempted to come to grips with the problem of interpreting the observed shifts. Various procedures have been proposed but it seems that none of the currently available mathematical models has general validity. Some studies of reaction mechanisms have significance outside the steroid field. The reduction of ketones by complex hydrides still eludes satisfactory mechanistic definition. A recent investigation2’ of the reduction of a series of 5a-substituted 3-keto-steroids throws some light on this problem and implies, in the cases studied, a product-like transition state. A study of the Pummerer reaction3” with steroidal 3- and 6-sulphoxidessuggests that the reaction proceeds through a transition state with ylide character rather than by a concerted cyclic mechanism. A series of papers by Nagata and his colleagues,172-‘76concerned with the hydrocyanation of ap-unsaturated ketones extends methodology and interpretation. These workers have added two new reagents (R,AI-HCN and R,AlCN), illustrated their application to a range of conjugated ketones and enamines, and clarified the mechanism and stereochemistry of the reaction. In an interesting preparative application202 of hyperacidic reagents (HF-SbF,), oestrone has been de-aromatized to the A4.9-dien-3-onein good yield. Studies360directed towards the ‘remote oxidation’ of steroids have led to the unexpected discovery of selectivefree-radical halogenation. Irradiation of steroids

*

Reference numbers are those of the relevant chapter.

277

278

h i troduct ion

in solutions containing PhlCI effects specific !.x-halogenationat the unactivated 9- and 14-positions. The chlorosteroids are readily dehydrohalogenated, thus making available A"'' "-steroids in useful yields and providing an unexpected entry into the corticosteroid series. Interestingly, irradiation of steroids in peracetic acid also leads to hydrogen abstraction at tertiary carbon. but here the 5%- and 14~-hydroxy-compoundsare produced (see Chapter 2, ref. 164). An interesting new i n t e r p r e t a t i ~ nof~the ~ ~ photoisomerization of ergosterol follows the observation that the products are wavelength-dependent. This has led to the suggestion that products are related to specific rotameric conformations of the precalciferol first formed. Trityl tetrafluoroborate catalyses3h6 the photooxygenation ofergosteryl esters to the peroxide under exceedinglymild conditions and in excellent yield. Steroid Synthesis. -The challenge of total synthesis has produced further new solutions. A series of papers3-" reports an interesting new approach to the steroid nucleus and illustrates its versatility. An early asymmetric induction plays an important part in this route. A new bis-annelation procedure has been applied to a synthesis of D-homo-oestrone." The carbon atoms of rings A and B are supplied by 6-viny!-r-picoline which contains in a masked form the functionality necessary for annelation. Two interesting new classes of steroids have been reported in which rings A and B are modified. I n one. the terminal rings of equilenin are replaced by the I .&methano[ 101annulene system.'' In the second. a class of novel corticoids, rings A and B are replaced by the hydroazulene system of lO(5-+4)abeo-steroids, formed by photolysis of 4.5-oxido-3-ketones.l J 5 - ' The reaction of a range of fluoroxy-compounds with enol esters has been ~xarnined.~'In solution they behave as electrophilic fluorinating agents. affording a-fluoro-ketones. Bis(fluoroxy)difluoromethane is particularly promising. There has been progress in the synthesis of steroidal alkaloids. A new approach'96 to the A-ring of the samaderin type has been described and substantial effort and advances have been made'O1 - h in tackling the formidable problems posed by batrachotoxin, the steroidal alkaloid from the poison arrow frog.

1 Steroid Properties and Reactions BY D. N. KIRK

The year has seen the very welcome appearance of a two-volume work, 'Organic Reactions in Steroid Chemistry'.' Experts from several countries have contributed fifteen chapters, each reviewing in depth an important aspect of steroid chemistry.

1 Structure, Stereochemistry, and Conformational Analysis The application of force-field calculations2" to a large number of acyclic ketones and aldehydes has led to structures and energies which agree well with exyerimental data. The inclusion of cyclopentanone and a range of substituted cyclohexanones, hexahydroindanones, and decalones provides data which should be valuable to steroid chemists. Extension of the calculations to androsterone has given highly satisfactory agreement between experimental (X-ray) and calculated values for bond lengths and bond angles." Other steroids and steroid-like structures containing the hexahydroindane moiety have also yielded valuable results, particularly with regard to the relative strain energies of cis and trans ring fusions. Although equilibria generally favour a cis junction between five- and six-membered rings, the energetic preference can vary widely, depending upon subtle factors concerned with the detailed molecular structure. The calculations now reported represent a major step towards understanding these strain effects and in favourable cases begin to rival X-ray data in their reliability. The four androstanes isomeric at C-5 and C-14 have been equilibrated over palladium at elevated temperature^.^ The free energies of the isomers relative to the most stable (5a,14j3) are: 5cr,14a-, + 1.8 ; 5P,14cr-, +2.7; and 5j3,14/?-, + 1.5 kcal mol- ',Molecular force-field calculations gave somewhat lower free energy values, but placed the isomers in the correct order of stability. The major contribution to instability comes from the 14a-configuration ( c / ~ - t r a n s > as, inferred from X-ray data. Calculated torsion and bond angles agree very well with Xray data, where these are available for comparison. Aldosterone in the monohydrated crystalline form is shown by X-ray analysis to have the 18-acetal-20-hemiacetalstructure (l).4The strain imposed upon ring * 'Organic Reactions in Steroid Chemistry', ed. J. Fried and J. A. Edwards, van Nostrand 2h

Reinhold, 1972. N. L. Allinger, M . T. Tribble, and M. A. Miller, Tetrahedron, 1972,28, 1173. N. L. Allinger and M . T Tribble, Tetrahedron, 1972, 28, 1191. N. L. Allinger and F. Wu, Tetrahedron, 1971, 27, 5093. W. L. Duax, H. Hauptman, C. M. Weeks, and D. A. Norton, Chern. Comm., 1971, 1055; W. L. Duax and H. Hauptman, J. Amer. Chern. Soc., 1972,94, 5467.

279

Terpenoids and Steroids

280

c by the 18-acetal is evident in unusually large torsional angles about the C- 1 1-C- 12 and C- 12-C- 13 bonds, and a small bond angle (97 +_ 1")at C -12.

An X-ray crystallographic analysis of 17B-hydroxyoestr-5(lO)-en-3-one 17iodoacetate (2) shows ring A in the crystal to have a semiplanar conformation (3), with all carbon atoms except C-2 essentially coplanar. Recent computer treatments have suggested the half-chair conformation (4), so the new experimental finding shows the need for further study in this field (for a recent survey of conformational analysis in cyclohexenes see ref. 6).

2

(3)

2

(4)

The crystal and molecular structures of the strained steroidal bicyclobutane (5) and of a derivative of the hydrogenolysis product, the 8a-methyl steroid (6),have been determined by X-ray analysis. The shape and dimensions of the 8a-methyl compound are discussed in relation to the requirements of the receptor site for oestrogenic activity.' The crystalline 1 : 1 complex of deoxycholic acid and acetic acid comprises chains of hydrogen-bonded acetic acid molecules occupying wide tunnels between

'

R . R . Sobti, J . Bordner, and S. G . Levine, J . Amer. Chem. SOC.,1971,93, 5588. F. R. Jensen and C. H. Bushweller, J . Amer. Chem. Soc.. 1969,91, 5774. H . P. Weber and E. Galantay, Helc. Chim. Acta, 1972, 55, 544.

28 1

Steroid Properties and Reactions

pleated sheets of deoxycholic acid molecules.* X-Ray analyses of the bromobenzene-p-sulphonates of 16a- and 16~-hydroxymethyl-3-methoxy-~-noroestra1,3,5(10)-trienes(7) confirm the configurations at C-16, and show the cyclobutane rings to be considerably puckered by their trans-fusion to ring c . ~

The dangers of basing structure-function relationships upon conformational features deduced from molecular models or from solution spectra have been emphasized," only X-ray crystallographic analysis being considered to give precise and reliable information on structural detail. Caution is still necessary, however, when the molecule is considered in solution instead of in the crystal. X-Ray data have indicated that a 1,4-dien-3-one is much more 'bowed' than appears from models," and a detailed analysis of possible interactions between 17fi-hydroxyandrosta-1,4-dien-3-one and other molecules, taking account of its true shape, should be helpful in interpreting its behaviour in complex biological systems. Crystal structures and absolute configurations have been determined by X-ray methods for two marine sterols (8) and (9), related to gorgosterol, with a cyclopropane ring in the side-chain,' for 8-aza-oestradiol, '' 3P-acetoxy-17aiodoandrost-5-ene,13 and withanolide E, which is found to have the unusual 17~-configuration(lo). Structure determinations of 2P-hydroxytestosterone

'

lo l1

'' l3

l4

B. M. Craven and G. T. DeTitta, J.C.S. Chem. Comm., 1972, 530. P. Coggon, A. T. McPhail, S. G. Levine, and R . Misra, Chem. Comm., 1971, 1133. W. L. Duax, D. A. Norton, S. Pokrywiecki, and C. Eger, .Fret-oids, 1971, 18, 525. E. L. Enwall, D. van der Helm, I. Nan Hsu, T. Pattabhiraman, F. J . Schmitz, R. L. Spraggins, and A. J. Weinheimer, J.C.S. Chem. Comm., 1972, 215. J. N. Brown and L. M. Trefonas, J . Amer. Chem. Soc., 1972,94,4311. H.-C. Mez and G. Rihs, Helv. Chim. Acta, 1972, 55, 375. D. Lavie, I. Kirson, E. Glotter, D. Rabinovich, and Z . Shakked, J.C.S. Chem. Comm., 1972, 877.

Terpenoids and Steroids

282

and its 2-acetate-I 7-chloroacetate confirm the previous report of an ‘invertedchair’ conformation of ring A. X-Ray anomalous scattering can now provide the absolute configurations of compounds containing only ‘light’ atoms (C. H, and 0).Among examples listed is lOfi-rnethoxyoestra- 1.4-diene-3.17-dione ( 1 l ) . ’

’’

‘ 16

Y. Osawa and J. 0. Gardner, J. Org. Chem., 1971, 36,3246. D. W. Engel, K. Zechmeister, and W. Hoppe, Terrahedron Letters, 1972, 1323.

283

Steroid Properties and Reactions R

0

(12) 501- or 5P-H A system of tetrahedral co-ordinates has been proposed as a convenient means for handling geometrical problems concerned with systems of cyclohexane rings in the usual all-chair conformation. The idealized structures of such molecules correspond to fragments of a diamond network. Applications envisaged include descriptions of the 'fit' of substrates to enzymes and the discussion of c.d. and n.m.r. features in terms of patterns of bonding. The equilibrium between 2P,3P-disubstituted 5cc- and 5P-6-ketones (12) shows a surprising and unexplained dependence upon the nature of the C-17 substituent." The presence of an axial 2P-substituent destabilizes the 5cc-isomer, shifting the equilibrium towards the 5P-isomer where the 2/3,10p diaxial interaction is relieved. The influence of the C-17 substituent on the equilibrium varied, over a series of eight different compounds, between the extremes represented by 5P:5a ratios of 0.13 (17P-OH) and 7.06 (17P-COMe). Steric effects, conformational transmission, and inductive and electrostatic field effects are each discussed and dismissed as being incapable of providing an adequate explanation of the data. Data obtained from a systematic study of a series of a-halogenocyclohexanones show that the halogens, except fluorine, have a preference for the axial conformation." There is no correlation of conformational free energies with the 'size' of the halogens, but there is a remarkable parallel with polarizability of the C-halogen bonds, which extends also to include C-H and C-CH, bonds. By comparison with the corresponding cyclohexyl halides, the carbonyl group is shown to stabilize the axial conformation of halogens by : I, 2.23 ; Br, 1.54; C1, 1.14; and F, -0 kcal mol- '. The mechanism of interaction between an axial halogen and the carbonyl group is considered to be analogous to 'hyperconjugation' (0--7c overlap). The data and their interpretation in this paper will be valuable in the conformational analysis of steroidal halogeno-ketones, and probably also in the interpretation of their spectroscopic and chiroptical properties. The 6a- (13) and 6fi-methyloestr-4-en-3-ones (14) reach equilibrium (70 % 6a : 30 % 6p) irz acidic media, unlike their androstane analogues, where the 6P-lOP interaction results in virtually exclusive formation of the 6a-epimer. A pure 6amethyloestr-4-en-3-one can be obtained by mild alkaline hydrolysis of the enol I

Iy

D. Rogers and W. Klyne, Tetrahedron Letters, 1972, 1441. H . Velgovii, V. Cerny, and F. Sorm, Coll. Czech. Chern. Comrn., i972,37, 1015. J . Cantacuzene, R. Jantzen, and D. Riczrd, Tetrahedron, 1972, 28, 717.

Terpenoids and Steroids

284

acetate (15),when kineticaily controlled protonation of the enol occurs selectively at 6fl.20Oppenauer oxidation of the 6B-methyl-3~.5cr-diol(l6)provides the pure 6P-methyl-4-en-3-one.

&jy=o&jy

0

I

Me

Me

T

T \ * o H

AcO

Me

OH Me

0 Br (17) R = H or OAc Conformational studies of some A-homo-steroids. including the novel Ahomo-5cr-cholestan-2-one and its derivatives,2' and of 4aa-bromo-~-homo-5crcholestan-4-ones (1 7),22have been reported.

Spectroscopic Metbods.-I.r. Spectra. 1.r. spectra of progesterone and some of its 21-substituted derivatives, with added p-bromophenol as a weak acid, show that the isolated 20-0x0-group functions as a proton acceptor. Electronegative substituents at C-21 reduce the polarity of the 20-oxo-group, increasing its i.r. absorption frequency and suppressing its interaction with proton donors. From a study of 21-hydroxy-, 21-methoxy-, and other progesterone derivatives it is concluded that a 21-OH group, like a 17a-OH group, does not hydrogen-bond 2o

" 22

C . C. Bolt, A. J . Van Den Broek, G. Heijmens Visser, H. P. DeJongh, and C. M . Siegmann, Rec. Trau. chim., 1971,90, 849. M. Ephritikhine, J . Levisalles, and G . Teutsch, Bull. SOC.chirn. France, 1971,4335. H . Velgova, V. Cerny, and F. Sorm, Coil. Czech. Chern. Conirn., 1971,36,3165.

28 5

Steroid Properties and Reactions

intramolecularly with the 20-oxo-group, despite coplanarity of the C-0 bonds at C-20 and C-21. 21-Hydroxy-groups in pregnan-20-ones appear to function mainly as proton donors for intermolecular bonding, a conclusion which is discussed in the context of steroid-protein interactions in biological systems.23 1.r. spectra of cyclic a-hydroxy-ketones show 0.. .H stretching bands characteristic of the type of hydrogen-bonding p0ssible.2~Equatorial-hydroxy-substituted ketones (e.g. 18) can readily form OH***O bonds, and exhibit a single i.r. band near 3485 cm- ', whereas axial-hydroxy-substituted ketones (e.g. 19) show two bands, one near 3615-3620 cm- due to unassociated OH and the other at about 3 6 G 3 6 1 0 cm- due to an OH. **7z interaction. P-Axial hydroxy-groups can also exhibit OH. - -7z bonding. Where competition is possible between OH. and OH. - T bonding, as in 5-hydroxy-5fl-cholestane-3,6-dione (20), only the stronger OH. *Obonding is apparent from the spectrum. Carbonyl frequencies show no clear correlation with hydrogen bonding.24

'

*

a

0

*

Me H .......,

Me

R

0-H

R (20) R (18)

= =

H2 0

1.r. data for a series of carboxylic esters of androstan-17P-01 derivatives have been recorded in cyclohexane, chloroform, benzene, and carbon tetra~hloride.~ Shifts in the carbonyl stretching frequency are correlated with the length of the ester chain, and also with solvent character, on the basis of complexing with the solvent. The ester carbonyl group acts as an electron donor, apparently forming weak hydrogen bonds with chloroform. Solvent shifts, relative to cyclohexane, are in the order : CHCI, > C,H6 > Ccl,. Similar solvent shifts are reported for the 3-OX0 stretching band in testosterone esters. This band is often split into two components. separated by 2 - 4 cm- : possible explanations are discussed.

U.V. Spectra and Chiroptical Properties (O.R.D. and C.D.). Comparisons of Cotton effects for a series of 3-0x0-steroids with various configurations at C-5, C-8, C-9, C-10, C-13, and C-14 allowed discussion of conformational aspects of various 'unnatural' steroids.26 A/B-trans-Compounds (Sa,lOP or 58,98,10a) give Cotton effects (opposite signs) of nearly equal intensity, apart from a slight enhancement in 19-nor-compounds. Changes at the C/D ring junction have virtually no effect. Some of the isomers have non-chair conformations of rings B or c. which are discussed in the light of c.d. data. Contributions of 23 24 2 5

26

C. H. Eger, M. J . Greiner, and D. A. Norton, Steroids, 1971, 18, 231. T. Suga, T. Shishibori, and T. Matsuura, J.C.S. Perkin I , 1972, 171. K. C. James and P. R . Noyce, J . Chem. SOC.( B ) , 1971,2045. H . J . C. Jacobs and E. Havinga, Tetrahedron, 1972, 28, 135.

286

Terpenoids and Steroids

p-axial methyl groups in A;B-cis-compounds are ‘anti-octant’ in sign, as has been reported for the corresponding adamantanone derivatives.27 Steroids of the 5a- and 5P-3.6-dione series are best differentiated by their c.d. curves.28 The experimental curves for the two isomeric diones have been reproduced by adding the separate curves of the monoketones, each suitably weighted by a coefficient. although it is difficult to follow the reasoning behind this procedure. Interaction between the 0x0-groups is stronger in the 5p-dione. The c.d. curve for 5r-cholestane-4.7-dione (21) differs only slightly from the simple sum of curves for the monofunctional 5a-4-0x0- and 5a-7-0x0-compounds.29 The 5p-4,7-dione (22). however. exhibits a large vicinal effect which approximately doubles the A&value estimated by summing curves for the separate 5p-ketones. C.d. data are reported for the lactone (23) and lactams (24).”

(23)

(24) R

=

H or Me

Study of the c.d. of derivatives of the ~-nor-3(5 -+6) abeo steroidal ketone (25) shows that the effects of axial or equatorial substituents at C-3 parallei those of psubstituents in adamantanone : both series of compounds contain the bicyclo[3, 3,llnonane moiety. Some large changes in c.d. are reported at low temperature^.^' Many steroid ketones exhibit a strong Cotton effect in the region of 190nm, tentatively assigned to the n -+ (T* tran~ition.~The sign frequently follows that of the familiar n + n* transition (ca. 290 nm). but :here are exceptions. Contributions of both 3- and P-axial methyl (or methylene) groups appear to obey the familiar carbonyl octant rule. 2nd to be dominant in the Cotton effects of most cyclohexanone analogues. 2‘

G . Snatzke, B . Ehrig, and H . Klein, Tetrahedron, 1969, 25, 5609.

’’ G . Cleve and G.-A. Hoyer, Tetrahedron, 1972,28, 2637. 29 3u

’’

G . Snatzke and K . Kinsky, Tetrahedron, 1972. 28, 295. G . S n a t ~ k eand K . Kinsky, Tetrahedron, 1972, 28, 289. D. N. Kirk, W . Klyne, and W. P. Mose, J.C.S. Chem. Comm., 1972,35.

287

Steroid Properties and Reactions 17

(25) R

OR = H, MeCO, PhCO, or NO,

Comparison of c.d. data for the des-D-(tricyclic) and ~-homo-7-ketones(26) and (27) respectively showed that ring D makes a significant ‘front octant’ contribution to the n -+ n* transition (290 nm), the sign of its contribution reversing that of a group in the corresponding rear ~ c t a n t . ~ The , contribution of ring D

to the Cotton effect at 190 nm (n+ o*)is, however, of opposite sign to that at 290 nm, suggesting that c.d. at the short-wavelength transition follows a quadrant rather than an octant rule. The five-membered ring D in ordinary steroids makes much smaller contributions to A&values, but these obey the same rules as the six-membered ring with regard to signs. A recent proposal, based on theoretical considerations, that the longestwavelength n-+ n* transition (near 400 nm) of cisoid 1,2-diones exhibits a Cotton effect determined by the dione chirality, is now considered to be contradicted by experimental evidence.33Steroidal 11,12-diones and a variety of other cyclic a-diketones give Cotton-effect signs opposite to those predicted from the dione chirality, although it is thought possible that the second absorption band, near 300 nm, may be dominated by the chirality of the dione. It is suggested that the 400 nm band exhibits a Cotton effect dominated by the chirality contributions of adjacent axial bonds ;similar conclusions were reported last year for dienes and en one^.^^ Some months after the appearance of this new suggestion, however, the original authors published a vigorous defence of their view that dione chirality is d ~ m i n a n t .They ~ consider that the apparent failure of the dione chirality rule 32

3J 34

35

D. N . Kirk, W. Klyne, and W . P. Mose, Tetrahedron Letters, 1972, 1315. A. W. Burghstahler and N. C. Naik, Helu. Chim. Acta, 1971, 54, 2920. ‘Terpenoids and Steroids’, ed. K . H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1972, vol. 2, p. 233. W. Hug and G . Wagniere, Helv. Chim. Acta, 1972, 55, 634.

288

Terpenoids and Steroidr

in the steroidal 11.12-dione (28) and some other compounds may indicate that Dreiding models do not accurately reproduce the geometry of the molecules. Further examples of a-diketones with undoubted conformational rigidity are needed to resolve this argument. I n the meantime it seems reasonable to suggest that both dione chirality and adjacent axial bonds may make contributions, so that either could be dominant according to the compound concerned.

H

A novel interpretation of the chiroptical properties of cyclopropyl ketones has been proposed.36" In addition to the two natural planes of symmetry of the carbonyl group, a third nodal surface is considered to be curved in a manner similar to that postulated last year for other carbonyl compounds,36bwith its convex face towards oxygen. Cyclopropyl groups are then considered to obey a reversed octant rule (ie.one which reverses the signs of the original octant rule) with respect to the three boundary surfaces. 0.r.d. and c.d. data are reported for a variety of pentacyclic triterpene derivatives with 0x0-groups at C-3, C-12, and C-16.37and for a series of compounds in the ~-nor-2-oxo-series,including a$-epoxy-ketones and some lac tone^.^* Steroidal E-oximino-ketones give Cotton effects near 340 nm, associated with the carbonyl n-+ n* t r a n ~ i t i o n The . ~ ~ signs correspond to those of cisoid apunsaturated ketones of the same chirality. A second maximum near 270nm is thought to come from the nitrogen n--+ n* transition. In alkaline solution the anion derived from the oximino-ketone gave Cotton effects near 395 and 290 nm. The positively charged nitrogen atom in a-amino-ketone hydrochlorides makes an anti-octant contribution to the Cotton effect at the carbonyl n + IT*transition. In a further discussion (CJ: ref. 34) of the c.d. associated with the lowest-energy 7c+ 7c* transition of conjugated unsaturated systems (dienes and enones), it is shown that a pseudo-axial allylic oxygen substituent usually appears to control the sign of the Cotton effect, even if the diene or enone system is skewed in the sense which would produce a Cotton effect of opposite sign in the absence of oxygen ~ubstitution.~'Chiral systems of the type C=C-C=C-C-0 or 3h

37

3B 39 40

( a )J . F. Tocanne, Tetrahedron, 1972.28, 389; (6) see ref. 34, p. 236. J . Sliwowski and Z. Kasprzyk, Terrahedrun. 1972, 28. 991. L. Labler and Ch. Tamm, Hclu. Chim. Acra, 1972, 55, 886. H. E. Smith and A. A. Hicks, J . Org. Chem., 1971,36, 3659. A . F. Beecham, Terrahedron, 1971, 27, 5207.

Steroid Properties and Reactions

289

cisoid

transoid (-1

Positive helicity

Negative helicit y Figure 1

O=C-C=C-C-0 are treated as comprising two distinct chiral units, each and C=C-C-0). The sign of the c.d. conof four atoms (e.g. C=C-C=C tribution of each four-atom component is thought to depend upon its helicity. in the sense represented in Figure 1. Where both components of a structure have the same chirality the c.d. effectsreinforce each other, but in many cases where the structure appears to be two chiralities are different that of the C=C-C-0 dominant. Some possible exceptions are noted, however.40 Although these conclusions concerning allylic oxygen have not been disputed, a more recent publication concerned only with cisoid dienes calls for caution in applying the concept of allylic chirality when only C-H or C-C bonds are involved. The latest suggestion4’ is that the empirical correlation of the sign of the c.d. (near 240 nm) of heteroannular cisoid dienes (e.g. A77l4-dienes)with allylic chirality, rather than with the inherent dissymmetry of the diene chromophore, may be invalid. It is proposed instead that the usual diene-chirality rule, which correctly ‘predicts’signs for a wide variety of homoannular cisoid dienes, is applicable only for rather small skew angles in the diene component (perhaps up to ca. 25”), but undergoes a change in sign at some larger angle, not accurately known. The heteroannular cisoid dienes often show quite large skew angles, within the range 35-40’. A final decision between the allylic-chirality and diene-chirality interpretations, or a compromise in which both may be shown to be significant, will be possible only when the range of available compounds in this class has been greatly extended. The different signs of Cotton effects associated with the chiralities of the diene systems in laevopimaric acid (29) and the 9a-methyl steroidal 2,4-diene (30)were earlier interpreted in terms of the ‘folded’ and ‘extended’ conformations illustrated, respectively. The ‘folded’conformation of laevopimaric acid has now been confirmed by X-ray crystallography. The conformational difference is attributed to minimization of strains associated with the 4P-Me-lOP-Me i n t e r a ~ t i o n . ~ ~ 41

‘l

E. Charney, J. M. Edwards, U. Weiss, and H. Ziffer, Tetrahedron, 1972, 28, 973. U.Weiss, W. B. Whalley, and 1. L. Karle, J.C.S. Chem. Comm., 1972, 16.

290

Terpenoids and Steroids

(30) Further progress has been made in the task of interpreting the complicated chiroptical behaviour of chiral m ~ n o - o l e f i n sNew . ~ ~ evidence has come from the examination of linear dichroic U.L. spectra. which can provide information on the direction of polarization of electronic transitions." This little-known technique involves orienting the molecules in a stretched film and measuring their U.V. spectra using light polarized in the directior. of stretching and orthogonal to it : rhe ratio of the two extinction coefficients is termed the 'dichroic ratio'. The dichroic ratio remains constant over a single absorption band, but the spectra of some steroid olefins (e.g. cholest-Sene)exhibit wavelength-dependent dichroic ratios which are interpreted as evidence of t w o overlapping U.V.absorption bands. The ordinary (unpolarized) U.V. spectrum of cholest-5-ene for example, showing a broad band with i.,,, near 190nm. was found to comprise two overlapping bands, with imax 201 and < 185 nm. respectively. Further analysis of data, with estimates, based upon models, of the molecular orientation in the stretched film appears to indicate that the 201 nm transition is polarized at an angle of about 17" to the C=C bond axis. and the shorter-wavelength transition directly along the C=C axis. I t is suggested. on this evidence, that the shorter-wavelength band represents the conventional n, + n,* transition. and the 201 nm band possibly a ~ n;) transition, weakly allowed because of the unsymRydberg x - 3 ~ (zz---+ metrical substitution of the double bond in a molecule like cholest-5-ene. (It is regrettable that there seems. as yet. to be no agreed convention for a co-ordinate system. Other prefer to designate the former transition as n,+ z,: interchanging the x- and z-co-ordinates.)

-

J3 4J

Ref. 34, p. 232. A . Yogev, J. Sagiv, and Y . Mazur. J . A n w r . Chem. SOC., 1972.94, 5123.

29 1

Steroid Properties and Reactions

With the wavelengths of the first two U.V.maxima known. it was possible to resolve the c.d. curve for cholest-5-ene into separate Cotton effects, centred at these wavelength^.^^ Application of the same procedure to 3-methylene- and 3-isopropylidene-5a-cholestanes has revealed the separate Cotton effects associated with the first two transitions for each compound. Both Cotton effects have a positive sign for the 3-methylene compound, contrary to an earlier suggest i ~ that n ~the~ first two c.d. bands always have opposite signs. The deviation of the longer-wavelength transition from the double bond axis may explain some of the peculiarities arising from attempts to define a general octant rule for olefins. A theoretical study of the rotatory strength of trans-cyclo-octene and other twisted olefins suggests that the Cotton effect may be dominated by the torsional effect when the torsional angle is ca. 10" or larger, whereas dissymmetrically disposed substituents are probably more important when the olefin is only slightly twisted.46 The possible role of a torsional term for some steroidal olefins clearly has to be considered, although the double bond in cholest-5-ene is known from early X-ray data to be essentially non-twi~ted.~' Change-transfer n-molecular complexes of tetracyanoethylene (tcne) with chiral olefins exhibit weak c.d. curves, with maxima in the region 45&530 mm.48 Poor correlation was found between the sign of the Cotton effect and that of the olefin n-+ n* transition. An alternative interpretation in terms of the helicity of the tcne-olefin complex (Figure 2) seems promising, but is not yet firmly established. Complexes of olefins with either iodine or tetranitromethane also exhibit c.d. in their change-transfer bands. Saturated chiral alcohols, including a range of monohydroxy-steroids. exhibit Cotton effects near 190 nm.49 Most of the examples so far reported have signs which follow a simple empirical right-left rule (Figure 3) ;groups dissymmetrically disposed close to the oxygen atom appear to be dominant. In applying this 'rule'

Positive helix Figure 2 45

4h 47 48 4q

A. Yogev, J. Sagiv, and Y . Mazur, J.C.S. Chern. Comm., 1972, 41 i . C. C. Levin and R. Hoffmann, J. Amer. Chem. Soc., 1972,94, 3446. C. H . Carlisle and D. Crowfoot, Proc. Roy. Soc., 1945, A184, 64. A . I . Scott and A . D. Wrixon, Tctrahedron, 1972, 28, 933. D . N . Kirk, W. P. Mose, and P. M . Scopes, J.C.S. Chem. Comm., 1972,81.

Terpenoids and Steroids

292

H !

! !

Figure 3 C.d. of chiral alcohols: Newman projection down the 0 - C bond

the O-H bond is assumed to prefer the least-hindered environment, with staggering about the C - 0 bond. C.d. data for the 17-benzoates of a series of 17P-hydroxy-steroids containing other chromophores (e.g. 4-en-3-ones) show that the observed dichroism often differs from that expected from simple addition of separate c.d. curves5' I t is suggested that electric dipole coupling between the 230 nm transition of the benzoate and transitions in the same region of the spectrum associated with other chromophores may be responsible for the observed effects. C.d. data for some p substituted benzoates are also discussed. Calculated c.d. curves for dibenzoates (e .g. 31) agree closely with experimental curves, which show splitting into two components of opposite sign as a result of interaction between the chromophores. The condensation products obtained from amines with dimedone contain the vinylogous amide chromophore, with absorption near 280 nm. Steroidal and other amines with dissymmetric structures give derivatives (e.g. 32) which exhibit Cotton effects in the region of the absorption maximum.52 Data for derivatives obtained from various epimeric pairs of simple steroidal amines show that the sign of the Cotton effect depends upon the configuration at the

OBz (31) 5i

52

V . Delaroff and R. Viennet. Bull. Soc. chim. France, 1972, 277. N . Harada, S. Suzuki, H . Uda, and K. Nakanishi, J . Amer. Chem. SOC., 1971, 93, 5577. V . Tortorella, G. Bettoni, B. Halpern, and P. Crabbe. Terrahedron, 1972,28,2991.

293

Steroid Properties and Reactions

carbon atom carrying the NH group [(R),positive; ( S ) , negative], although this is not a general rule if aromatic or ester groups are present near the amine. The c.d. curves of cardenolides show two maxima due to the butenolide ring: the n-+ 7c* band is centred near 241 nm and a n-) n* band of opposite sign appears at 213-216 nm in 14a-cardenolides (33), or at 217-218 nm in their 14-dehydro-analogues (34).53 The signs of Cotton effects (n+ n*) of afi-unsaturated lactones in general (e.g. 35) have been discussed in terms of minimum-

(33)

(34)

energy conformations established by X-ray analyses. An earlier chirality rule is shown to be inadequate in some cases, and alternative proposals are offered.54 Thia-steroids have been included in a theoretical study (u.v. and c.d.) of the three lowest-lying electronic transitions of the C-S-C chromophore, at ca. 240, 220, and 200 nm. The natures of the transitions are discussed and possible assignments ~uggested.~17a- and 17B-iodoandrostanes show antipodal c.d. curves with negative and positive signs, respectively. The signs are probably related to the absolute configurations at C-17.56 Circular dichroism is induced in suitable achiral molecules when they are present as solutes in cholesteric me so phase^.^' C.d. spectra are reported for compounds of the type (36) in a liquid-crystalline mixture of cholesteryl chloride and cholesteryl nonanoate. This system, which has a right-handed helical structure, induces Cotton effects at the various U.V.absorption bands of the solutes, which are usually, though not invariably, of negative sign. The technique seems to offer promise for determining the direction of polarization of an electronic transition from the sign of the Cotton effect. A quadrant rule is proposed. Observation of changes in c.d. curves with time has allowed a detailed study of the photoequilibration of the enones (37) and (38),which exhibit Cotton effects of opposite sign.58 The c.d. method is particularly convenient in that optically inactive materials added as possible photochemical quenchers or sensitizers do not interfere. 53 54 55 56 57

”

U . Stache, Tetrahedron Letters, 1971, 3877. A . F. Beecham, Tetrahedron Letters, 1972, 1669. J . S. Rosenfield and A. Moscowitz, J . Amer. Chem. Soc., 1972, 94, 4797. M . Biollaz and J . Kalvoda, Heltl. Chim. Acta, 1972, 55, 346. F. D. Saeva, J . Amer. Chem. SOC.,1972,94, 5136. N. Furutachi, J . Hayashi, H. Sato, and K . Nakanishi, Tetrahedron Letters, 1972,1061.

Terpenoids and Steroids

294

(36) X = NEt, 0, or S

Inspection of molecular rotations [ M ] D (589 nm) for a large number of hydroxyand halogeno-derivatives of steroids has led to empirical 'rules' expressed (for a compound RX) by the general formula

where a and b are constants related to the moiety R, and S is a coefficient associated with the atom or group X.59The S value is equal to the atomic refraction R , for a halogen atom. but a hydrogen atom and OH group each assume one of a discontinuous series of definite S values. depending upon the conformational features of the compound concerned. Although the exact physical significance of these S values is not clear, the choice of S value is dictated by the presence or absence of coplanar zigzag chains of bonds. and seems to indicate an electronic interaction of structural features through such a chain. The demonstration last year6' of a conformational dependence of c.d. data for substituted ketones seems to reveal the operation of a similar effect. (39) and (40) each have only a single chiral The A'3'1S)-18-nor-compounds centre. at C-17. Their molecular rotations (589 nm) are discussed61and compared with those of the monocyclic (41) and bicyclic (42) analogues containing a methylcyclopentene of the same chirality. Brewster's empirical rules successfully

(39) A' : [ M I , - 22" (40) 11,12-dihydro :

[ A M ] ,

+ 84"

(41)

[MID - 64"

(42)

+ 5"

5q

S. Yamana, J . Org. Chem., 1972, 37, 1405.

61

J . T. Edward, N. E. Lawson, and D. L'Anglais, Cunad. J . Chem., 1972, 50, 766.

'' Kef. 34, p. 235.

Steroid Properties and Reactions

295

'predict' the molecular rotations of the latter compounds and can be reconciled with that found for the cyclopentenophenanthrene (39). The large positive rotation of the 11,12-dihydro-compound (40),however, remains unexplained : the compound exhibited no Cotton effect down to 240 nm. N . M . R . Spectroscopy. The study of lanthanide-shifted spectra62has intensified during the last year. Much of the effort has centred upon devising general methods for interpreting the observed shifts and obtaining structural information not available from a simple spectrum. The chemical shift induced by adding a lanthanide complex [e.g. Eu(dpm),] to the solution of a polar compound can be expressed as a function of two parameters, the equilibrium constant K for the formation of the substrate-reagent complex, and the chemical shift of the complex itself (ie. the limiting chemical shift, corresponding to total complexation of the substrate). A simple graphical method, based upon a mathematical analysis of the equilibrium, permits the evaluation of both these parameters : the method of Values of K calculation is illustrated for 3cr,4,4-trimethy1-5a-cholestan-3P-01.~~ determined separately from data for each of six different methyl signals show an impressive measure of agreement. The equilibrium constant for the complexation of cholesterol with Eu(fod), has been evaluated from measurements on a series of solutions at varying total concentrations but identical molar ratio.64 The same analysis provides values for the chemical shifts of protons in the uncomplexed steroid, and in the steroideuropium complex: the latter value is not accessible by direct measurement, since the complex is always in equilibrium with the free steroid. The mathematical equations presented in this paper should be generally applicable. In another paper6 the validity of various procedures for interpreting lanthanide-induced shifts is explored; comments on cholesterol are included. No one mathematical model at present available is considered to have general validity. A graphical procedure has been suggested66 to compensate for experimental errors in shift-reagent work. Uncertainties in concentrations are avoided by making use of the constancy of slope ratios for different protons in the substrate; it is assumed that each proton gives a straight line plot of shift us. amount of shift reagent, although this is not always true at high concentrations. Structural investigations by use of lanthanide-induced shifts are usually complicated by uncertain ties regarding the exact location of the lanthanide atom. A computer study of time-averaged geometries of complexes of some amines, alcohols, ketones, and other polar compounds with Eu(dpm), and Eu(fod), has indicated that Eu.*.Xdistances (where X is the co-ordinated atom) vary little with the nature of X but are sensitive to steric factor^.^' Steroid chemists 62

" 64 65

66

''

Ref. 34, p. 237. J . Bouquant and J . Chuche, Tetrahedron Letters, 1972, 2337. T. A . Wittstruck, J . Amer. Chem. SOC.,1972, 94, 5131. J . Goodisman and R . S. Matthews, J.C.S. Chem. Comm., 1972, 127. J . W. ApSimon and H. Beierbeck, J.C.S. Chem. Comm., 1972, 172. P. V. Dernarco, B. J. Cerimele, R. W. Crane, and A. L. Thakkar, Tetrahedron Letters, 1972, 3539.

Terpenoih and Steroids

296

should find the computed Eu. * *Xdistances and geometries of typical complexes most useful. Measurements of Eu(dpm),-induced shifts for a bifunctional steroid (43) have shown that the shifts of proton signals due to complexing at each of the polar groups are additive.68 Another general treatment of lanthanide complexes includes references to induced shifts in bifunctional steroids, and to the possibility of reversal of the directions of shifts for suitable protons in the complex.69 Some examples of this phenomenon have arisen from a study of certain cholestane derivatives : Eu(dpm),-induced shifts of protons in the steroid nucleus of the sulphoxide (44)are to lower field, as expected, but the C-20 and C-25 protons are shifted to higher field.” This phenomenon is attributed to the angle-dependence term in the McConnell-Robertson equation for pseudo-contact shift [6 = K(3cos2 8 - l)/r3]. In the great majority of Eu(dpm),-steroid complexes, the angle 19 does not vary sufficiently to cause any great deviation from a simple dependence of shift upon the inverse cube of the distance of the proton from the europium atom. In the sulphoxide (44),however, the cholestane side-chain must lie at an unusually large angle to the axis of the Eu(dpm),-sulphinyl oxygen complex. The isomeric (trans) sulphoxide and the corresponding sulphone showed no upfield shifts of protons. Smaller but still significant upfield shifts of the C-20 and/or C-25 protons were also observed” in 2a,5-epoxy-5a-cholestane (45), 5a-cholest-2-en-5-01(46), cholesta-3,5-dien-7-one. and cholesteryl acetate.

w

H,,CO,Me

(431

(44)

(45)

OH (46)

In the spectrum of cholesterol. however. these protons move downfield in the normal way with added Eu(dpm), . which must reflect a different spatial relationship of the steroid to the lanthanide moiety. 68 b9

’O

A. Ius, G . Vecchio, and G. Carrea, Terrahedron Letters, 1972, 1543. J. K . M . Sanders, S. W. Hanson, and D. H . Williams, J . Amer. Chem. SOC.,1972,94, 5325. M. Kishi, K.Tori, and T. Komeno, Trrrahedron Lerrers, 1971, 3525.

Steroid Properties and Reactions

297

Eu(dpm), has been employed, together with stereospecificdeuterium labelling, for the assignment of proton signals in 12fl-hydro~yconanine,~' and Eu(fod), has been used to assign structures to adducts of dichloroketones and various olefins, including ~holest-2-ene.~~ Increments in the chemical shifts of methyl protons due to cyano-substituents are reported for 34 steroid derivative^.^^ N.m.r. data are reported for 6p- and Sa-acetamido-steroids;74 the secondary 6P-group adopts the conformation with carbonyl eclipsing the 6cr-C-H bond, but the tertiary Sa-acetamide prefers the

Me

I Me (47)

conformation (47) in which the carbonyl group lies mid-way between the 4aand 6a-hydrogens. New n.m.r. evidence (p. 323) indicates that some compounds previously formulated as l~-methyl-5cr-3-oxo-steroids actually have the laconfiguration. A ring-current model, used to calculate the magnetic anisotropy of a cyclopropane ring,76 permits estimates of the shielding contribution of a cyclopropane ring to the chemical shifts of neighbouring protons. Illustrations include 3a,Scr-, 3B15/?-, and 5~,7~-cyclosteroids. "F N.m.r. spectra are r e p ~ r t e d 'for ~ the trifluoroacetates of a wide variety of sterols, bile acids, and steroid hormone derivatives. Differences in the shielding of the C-19 methyl carbon atom in I3C spectra give clear evidence of the stereochemistry of the A/B ring junction.78Pairs of similar compounds differing only in configuration at C-5 show differences of 11-12 p.p.m. This method appears to have advantages over the study of proton spectra. I3C N.m.r. spectra are

'

71

G. Lukacs, X. Lusinchi, P. Girard, and H . Kagan, Bull. SOC. chim. France, 1971, 3200.

72

73 74

75 76

R. M . Cory and A, Hassner, Tetrahedron Letters, 1972, 1245. K. Jankowski and H. Seyle, Steroids, 1972, 19, 189. G. Bourgery, J . J . Frankel, S. Julia, and R. J. Ryan, Tetrahedron, 1972, 28, 1377. B. Pelc and J . K. M. Sanders, J.C.S. Perkin I , 1972, 1219. C. D. Poulter, R. S. Boikess, J . 1. Brauman, and S. Winstein, J . Amer. Chem. SOC., 1972,94,229 1.

77

W. Voelter, G. Jung, and E. Breitmaier, Chim. Ther., 1972, 7 , 29. J . L. Gough, J . P. Guthrie, and J. B. Stoethers, J.C.S. Chem. Comm., 1972, 979.

298

Terpenoids and Steroids

reported for a number of fluorinated ~teroids,'~ for lanosterol and dihydrolanosterol." and for jervine, veratramine, and related compounds." Mass Spectrometry. The mass spectra of ~-nor-Sn-pregnan-2O-one (48), 5c(pregnan-20-one (49), and ~-homo-5r-pregnan-20-one (50) are all largely explained in terms of rupture of the C-13-C-17 bond to give ions (51) which undergo further fragmentation. Strain in ring D is not, therefore, an important factor in controlling the fission of the C-13-42-17 bond. The mechanisms of fragmentation under electron impact have also been investigated for D-nor-kandrostan- 16-one (52) and 5%-androstan-16-one (53) and 17-one (54); their D-homo- ( 5 5 ) and D-bishomo- (56) analogues have also been studied. The behaviour of the o-homo-17a- (55) and 17- ketones (57) is analogous to that of the quasi-enantiomeric 5a-androstan- 1-one and -2-one, respectively.82Mass spectral

Me

I

co

(48) n = 1

(49) n = 2 (50) n = 3

(52) n (54) n (55) n (56) n

= I =2 =3 =4

(53) n (57) n

= 1 =2

fragmentations of the hydrocarbons ~-homo-5a-androstaneand ~-homo-Sapregnane resemble those of the parent compounds, which are dominated by ~ ~ and ~-nor-5a-pregnaneshow cleavage of rings A and D . ~-Nor-Sr-androstane

-'G .

'' ** 83

Lukacs, X . Lusinchi, E. W . Hagaman, B. L. Buckwalter, F. M . Schell, and E. Wenkert, Compt. rend., 1972, 274, C , 1458. G . Lukacs, F . Khuong-Huu, C. R. Bennett, B. L. Buckwalter, and E. Wenkert, Tetrahedron Letters, 1972, 3515. P. W . Sprague, D. Doddrell, and J . D. Roberts, Tetrahedron, 1971,27,4857. S. Popov, G . Eadon, and C. Djerassi, J . Org. Chern., 1972, 37, 1 5 5 . G . Eadon, S. Popov, and C. Djerassi, J . Anrer. Chern. Soc., 1972.94, 1282.

Steroid Properties and Reactions

299

significant differences, however, being dominated by cleavage of the excessively strained ring D. Mass spectra are reported for 14a- and 14P-pregnan-20-onederivatives, with various combinations of substituents at C-3, C-8, C-11, C-12, and C-14, in both the 1 7 ~ and - the 178-pregnane series.84 Mass spectra of trimethylsilyl (TMS) derivatives of some steroid phosphates have been examined. TMS migrations, which in sugar phosphate derivatives lead to abundant and characteristic ions, are virtually absent for those steroid molecules where functional groups are well separated. Steroid derivatives give instead phosphate ions resulting from processes which include hydrogen rnigrati~n.~’ A fused pyrazole ring (e.g. 58) directs the mass spectrometric fragmentation of the adjoining ring by a retro-Diels-Alder process. The resulting fragment ion (59) retains any substituents present in ring A.86

The mass spectral fragmentations of ‘backbone-rearranged’ steroids of the type (60) and the related A24-olefinsare characteristic and dependent upon the configuration of the ~ide-chain.~Mass spectral fragmentation patterns are reported for a number of steroidal oximes, and for 5a-chlor0-6~-nitro-steroids,~~ for a series of 22,26-epiminocholestane derivative^,^^ and for 5a- and 58-3.6diones.28The mass spectrometry of cardenolides has been reviewed.”

(60) X 84

” 86

87

” 89

90

=

F or OH

M. Fukuoka, K. Hayashi, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1971, 19, 1469. D . J . Harvey, M. G. Homing, and P. Vouros, Tetrahedron, 1971, 27, 4231. H . E. Audier, J . Bottin, M. Fetizon, and J . C. Gramain, Bull. SOC.chim. France, 1971, 4027. A . Ambles, C. Berrier, and R . Jacquesy, Bull. SOC.chim. France, 1972, 2929. M. Meot-Ner, E. Premuzic, S. R . Lipsky, and W . J . McMurray, Steroids, 1972,19,493. Von G. Adam, K . Schreiber, R . Tummler, and K . Steinfelder, J . prakt. Chem., 1971, 313, 1051. P. Brown, F. Briischweiler, and G . R . Pettit, Helc. Chim. Acta, 1972,55, 5 3 1 .

300

Terpenoids and Steroids 2 Alcohok and their Derivatives, Halides, and Epoxides

Substitution and Elimination.--Cholesteryl trimethylsilyl ether (61) reacts smoothly with phenyltetrafluorophosphorane to give 3P-fluorocholest-Sene (62) in 90 % yield.g1No information is yet available on the behaviour of other steroidal compounds with this novel reagent, but several model alcohols gave mixtures of fluorinated products and olefins. Free alcohols lead to lower conversion, and more elimination. compared with their trimethylsilyl ethers.

NN-Dicyclohexylcarbodi-imideforms a crystalline adduct on heating with methyl iodide or similar alkyl halides. The product, a carbodi-imidium halide, has a remarkable capacity for converting alcohols into alkyl iodides, with inversion of configuration (Scheme 1). Sa-Cholestan-3P-01gave the unstable 3aiodo-compound, and even cholesterol. which nearly always undergoes substitution with retention, was converted into the hitherto unknown 3a-iodocholest5-ene. Testosterone gave the 17a-iodo-derivative. The alcohol probably adds on to the reagent to give a protonated iso-urea, whichxeacts with iodide ion by an S,2 mechanism, with displacement of the alkylated urea (Scheme l).92 ?bH1

Me/

/N\

[

Me

1 +?sH1 1

G"\ H C

76Hll 3

76Hll

N N / \ / \

Me

C

II

H

0

/H -0

R2

I

I

I Scheme 1 A 17~-hydroxy-17a-vinylsteroid (63) undergoes allylic rearrangement with vanadium(1v)chloride to give the 21-chloropregn-l7(20)-ene(64) in high yield.93 The 21-chloro-substituent was surprisingly unreactive to sodium acetate in acetone or DMF, but reacted with guanidinium acetate in DMF to give the 21-acetoxy-compound (65). a key intermediate in corticosteroid synthesis.

'' 92

y3

D. U. Robert and J. G. Riess, Tetrahedron Letters, 1972, 847. R . ScheKold and E. Saladin, Angew. Chern. Internat. Edn., 1972, 11, 229. A , Krubiner. A . Perrotta, H . Lucas, and E. P. Oliveto, Steroids, 1972, 19, 649.

30 1

Steroid Properties and Reactions

c1,

v

,CI

H (64)x

= c1 (65) X = OAC

The 17P-hydroxy-17a-difluorocyclopropenyl steroid (66) reacted with the fluorinating reagent 2-chloro-l,l,2-trifluorotriethylamineto give the trifluoromethylallene (67) and other minor products. Formic acid hydrolysis of the difluoro-compound (66) gave the cyclopropenone (68), which reacted with 2chloro-l,l,2-trifluorotriethylamine to give the allenic acid fluoride (69). Possible mechanisms are discussed.94

When cholest-5-ene-3P,4P-diol (70) was heated with triphenylphosphine dibromide in DMF, 3-bromocholesta-3,5-diene (71) was obtained and also, (72).9 The latter product apparently unexpectedly, 2-formylcholesta-2,4,6-triene arises by a Vilsmeier reaction, presumably involving the reagent Me,fi=CHBr (cfi ref. 96). 94 95

96

P. Crabbe, H. Carpio, and E. Velarde, Chem. Comm., 1971, 1028. T. Dahl, R. Stevenson, and N. S. Bhacca, J . Org. Chem., 1971,36, 3243. H. Laurent and R . Wiechert, Chem. Ber., 1968, 101,2393.

Terpertoids und Steroids

302

(70)

Grignard reagents react with diborane to give organoboranes. which may be oxidized in the usual way to give alcohols.'- Application of this sequence of reactions to the Grignard reagents derived from 3r- and 3~-bromo-5a-cholestanes gave 52-cholestan-3fl-01as the major product (ca. 50 "/b from each bromide), with lesser amounts of 3%-and 2r-alcohols. I t is argued that the substitution of magnesium by boron must proceed with retention of configuration, like other electrophilic reactions of Grignard reagents. The formation of the 2cc-alcohol implies some isomerization of the organoborane. a well-known reaction proceeding through 5%-cholest-2-ene: hydroboronation-oxidation of the 2-ene gives mainly the 3r- and 2r-alcohols. The rate of acetolysis of 5a-cholestan-6r-yl tosylate is influenced in the expected manner by 3-chloro-substituents.'8 Although each of the C-3 isomers retards carbonium ion formation, the 37-chloro-group is less effective than 3P-chloro. I t is argued that the data reflect a through-space field effect, with the negative pole of the 3cx-Cl bond closer to the reaction centre than in the equatorial 3flisomer. The acetolysis products comprise the 5-ene and the 6a-acetate. in proportions influenced by the configuration at C-3. No 6P-acetate was found (cJ: ref. 99). Secondary alcohols are dehydrated in high yield, apparently without rearrangement, in refluxing hexamethylphosphoramide. O0 Although described only for mono- and bi-cyclic alcohols, the reaction offers promise for steroidal alcohols. Acetates (73)of certain tertiary 17fl-alcohols undergo elimination on alumina, to give mixtures of olefinic products."' The substitution pattern of ring A influences the reaction significantly. Dehydrobromination of a 22,23-dibromoergostane (74) with 1.5-diazabicyclo[4.3.O]non-5-ene gives the ergosta-22.24(28)-diene ( 7 3 ,

'

'-S. W . Breuer. J . C . S . Chern. Comrn.. 1972, 671. D. S. Noyce and G . A. Selter, J . Org. Chenl., 1971, 36, 3458. '' D. N . Kirk and M . P. Hartshorn, 'Steroid Reaction Mechanisms', Elsevier, Amsterdam,

Jl'

")"

ID'

1968, p. 37. R . S. Monson and D. N . Priest, J . Org. Chem.. 1971, 36, 3826. R . Kanojia, S. Rovinsky, and I. Scheer, Chem. Comm., 1971, 1581.

Steroid Properties and Reactions

303 OAc

H (73) R

=

Me or C-CH

/p+ J:::" H

H

(74)

(75)

and not the expected 20(22),23-diene.l o 2 A photolytic elimination of thiobenzoates is described on p. 404. Ring-opening of Epoxides. Diversity of results from the reaction of HF with some steroidal epoxy-ketones seems to stem from a critical dependence of reaction path on solvent.'03 A 4P,SP-epoxy-3-ketone (76) reacted with H F in anhydrous chloroform to give the 5~-fluoro-4a-alcohol(78), probably resulting from acidcatalysed epimerization of an initially formed 5a-fluoro-4~-alcohol(77), the

@

HF-CHCI,

0

(79) lo*

'O 3

A . B. Garry, J. M. Midgley, W. €3. Whalley, and B. J . Wilkins, J.C.S. Chem. Comm., 1972, 167.

M . Neemen and J. S. O'Grodnick, Tetrahedron Letters, 197 1, 4847.

304

Terpenoids and Steroids

product of 'diaxial' opening. The 4a,5a-epoxy-3-ketone similarly gave the 5pfluoro-4/?-alcohol, both products resulting from regiospecific opening of the epoxide at C-5, which can the more readily accommodate positive charge. When the sohent was chloroform containing 10 >; ethanol, the 4fl,5,!kpoxy-ketone (76) gave the 2r-fluoro-4-en-3-one (81). as a consequence of allylic attack of fluoride ion on the A'-enol(79). The more polar solvent may favour enolization and would presumably retard direct epoxide opening by competing for the available protons. Compounds once thought to be 4-fluoro-4-en-3-ones,' O4 but having A,,, ca. 240 n m instead of 248 nm. are now considered to be 2r-fluor0-4-en-3-ones.'~~ The 19-nor-epoxy-ketone (82) failed to react with H F in aqueous acetone at room temperature but was converted by HCl or HBr under the same conditions into the halogenohydrins (83).'05 Higher temperatures led to the known 4halogeno-4-en-3-ones (84). When HCl was used in CHC1,-EtOH, the 4-chlorocompound (84) and the 2r-chloro-4-en-3-one (85) were obtained in 1 : 1 ratio. Attack at C-2 parallels the reaction with H F under these condition^.'^^

(83) X = C1 or Br

In the most thorough study so far reported of the acid-catalysed reactions of acetonitrile with epoxides (Ritter r e a c t i ~ n ) , ' ~ . 'the ' ~ opening of a 5a.6x-epoxide (86) is shown to proceed normally to give the 6~-acetamido-5cr-alcohol(87); the 5/3,6/l-epoxide (88) gave the expected product (89) and also a dihydro-oxazine (90). by intramolecular displacement of the 3P-substituent. An attempt to use ethoxycarbonyloxyacetonitrile (EtOCO.OCH,CN) in place of acetonitrile converted the P-epoxide (88) into the product (91)of Westphalen rearrangement : a control experiment with the acid catalyst alone (HCIO,) produced the same result. !IJ4

lo' lob

B . Camerino, B. Patelli, and A. Vercellone, J . Amer. Chem. Soc., 1956, 78, 3540; B. Camerino, R. Modelli, and B. Patelli, Farmaco, Ed. xi.,1958, 13, 52. M . Neeman and J. S. O'Grodnick. Telrahedrnn Letters, 1972, 7 8 3 . ( a ) Cf. ref. 34, p. 245; ( b ) 'Terpenoids and Steroids'. ed. K . H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1971, vol. 1 , p. 285.

Steroid Properties and Reactions

RO

0,'

m

305

RO

NHCOMe

(87)

I

HCIO,

RO OH

0

'f

OH

Me

The reactions of the 17~-chloro-16a,17a-epoxyandrostane (92) have been studied in detail;'07 a small selection of the results is summarized in Scheme 2. The formation of the 18-nor unsaturated ketone (93) with AICl, is especially noteworthy. Hydrogenation in methanol gave the 17~-methoxy-compound(94); 5a-androstan-17-one gave the same methyl ether when reduced over platinum in acidified methanol, and was apparently an intermediate in the reduction of the chloro-epoxide. The 17P-iodo-epoxide is very much less stable than the chloroepoxide, especially towards acids. but undergoes essentially similar reactions. O 7 The potentialities of 2-lithio-1,3-dithian (95) as a reagent in synthesislo8 have been further explored. O9 The 2a,3a- (96) and 2P,3/3-epoxy-5a-cholestanes (97) lo'

W. A. Denny, V. Kumar, G . D . Meakins, J . Pragnell, and J. Wicha, J.C.S. Perkin I , 1972,486.

lo'

Ref. 1066, p. 286. J . B. Jones and R . Grayshan, Cunad. J . Chrm., 1972, 50, 810.

306

Terpenoids and Steroids

1

1

1

H

H

(92)

3l

--OEt

H

H

(93)

H

(94)

Reagents: i, A1,0,;

ii,

HCI, dioxan; i i i , NaOEt-EtOH; iv, HI-Pt, MeOH, 36 h ; v, AICI,.

Scheme 2

undergo smooth diaxial opening to give the corresponding dithianyl-5a-cholestanols (98) and (99). respectively. which are desulphurized by Raney nickel to give the diaxial methyl-52-cholestanols (100) and (101). Since many epoxides the suffer rearrangement rather than alkylation with Grignard reagents,'

(98) Rancy Ni

O

a

I H

(95) 'I"

Ref. 99, p. 115.

307

Steroid Properties and Reactions

dithian process appears to offer a useful alternative route from epoxides to methylated alcohols and ketones. Spiro-oxirans (e.g. 102) react similarly to give products which may be desulphurized to give ethylcarbinols." Use of 2-lithio2-methyl-1,3-dithian leads to compounds (103) which could be dehydrated, followed by ketonization of the dithianyl group with CaC0,-HgCl,, to give the novel steroid derivatives (105) and (107). The isomer (105) with the A2 olefinic

II

0

bond was, surprisingly, more stable than the conjugated enone (107). Attempted reactions of dithian reagents with 17-oxo-steroids,to introduce the corticosteroid side-chain, met with only limited success, but C-17-spiro-oxirans reacted like those at C-3, giving novel side-chains of the homo-corticosteroid type.' l 2 Propargylmagnesium bromide opened the epoxide ring in a 4a,5a-epoxy-3aalcohol (108) in the normal manner, giving the 4P-propargyl-3aSa-diol (109). 'I2

J. B. Jones and R . Grayshan, Canad. J . Chem., 1972,50, 1407. J . B. Jones and R . Grayshan, Canad. J . Chem., 1972, 50, 1414.

Terpenoids and Steroids

308

When a 4a,5r-epoxy-3~-alcohol(llO) or its methyl ether (111) was used, however, the product was the 4B-allenyl-3/?,5cc-diol ( 1 12) or its 3-methyl ether (1 13). I t is suggested that the 3,!l-oxygen participates by associating with the magnesium atom of the reagent, allowing bond reorganization in a cyclic transition state represented. in over-simplified form. as (110) or ( 1 11). I t would appear to follow that propargylation widthout involvement of the C-3 oxygen atom proceeds through attack of the -CH, moiety of the reagent at C-4. whereas the hydroxyassisted reaction presents the terminal acetylenic carbon atom for attack on the steroid. ' '

--Jp$./y -

\

. y 2

0

'-0

I

CH

II C II

R (110) (111)

R R

= =

H Me

CH2

R =H (113) R = Me (112)

Chromous acetate. known to reduce 16aJ 7a-epoxypregnan-20-ones to give 16a-hydroxypregnan-20-ones. has now been employed for similar reductions of 401.h- and 4/3,5B-epoxy-3-ketones ( 114), and also of a 6a,7a-epoxy-4-en-3-one ( 1 15).'14 In each case the epoxide was selectively reduced at the bond nearest the carbonyl group, giving the 5a- or 5fI-hydroxy-3-ketone (116), and the 7ahydroxy-4-en-3-one (1 17). respectively, in yields of about 50%. A neutral or buffered solution is required to minimize elimination, which occurs when acidic chromous chloride is used. ' I 3

'I4

R. Vitali and R. Gardi, Tetrahedron Letters, 1972, 1651. C . H . Robinson and R . Henderson, J . O r g . Chern., 1972,37, 565.

309

Steroid Properties and Reactions

0

OH

The 14p,1SP-epoxypregn-16-en-20-0nesystem (118) is reduced selectively by cyclohexene with a palladium catalyst to give the 14~-hydroxy-compound (119).' Me

Ace,

I

co

OH

Reduction of the SP,6p-epoxide (120) in the 19(10- 9p) abeo series with Li-EtNH, gave both the 5p- and 6/3-alcohols. Further transformations led to a series of isomeric 5,11- and 6,ll-diols. The epoxide failed to undergo normal trans-cleavage reactions with acids.

Esters, Ethers, and Related Derivatives of Alcohols.-The mode of transmission of the effect of remote substituents upon reaction rates and equilibria has been discussed previously under three headings, viz. inductive effects, electrostatic field effects, and conformational transmission."' A new survey,' l 8 quoting over 50 references, covers most of the main studies in this field, and suggests 'direct interactions' as a fourth class. Rates of acetylation of 3p-hydroxy-A5-steroids variously substituted at C-17 show only small variations, which did not permit of any mechanistic interpretation.' The formation of 17cr,20- and 20,21-cyclic carbonates and their use as protecting groups for diols have been investigated.l 1 'Is

' 'I9

E. Gossinger, W. Graf, R. Imhof, and H. Wehrli, Helv. Chim.Acta, 1971,54, 2785. J. R. Bull and C. J. Van Zyl, Tetrahedron, 1972, 28, 3957. Ref. 99, p. 16. R. T. Blickenstaff and K. Sophasan, Tetrahedron, 1972, 28, 1945. M. L. Lewbart, J . Org. Chem., 1972, 37, 1233.

310

Terpenoids and Steroids

Phosgene and pyridine in benzene convert the 21-acetate (121)of a 17cr,20.21-triol into the 21-acetate 17.20-carbonate (122). The 21-acetate can then be hydrolysed selectively by acid. Direct carbonylation of the free triols (123) gave the 20.21carbonates ( 1 24). Cyclic carbonates are easily hydrolysed by alkali. but are fairly stable to strong acids. permitting oxidation of alcoholic groups elsewhere with chromic acid. or acetylation (c.g. of 1 1fl-OI-i) under forcing conditions. CH,OAc

CHzOAc

I HC-0,

I

HC-OH

H

,c=o

H (121)

(122)

CH,OH

I

HC-0'

HC-OH

' H

H ( 123)

( I 24)

Reaction of 'Betamethasone' (125) with trimethyl orthobenzoate and toluenep-sulphonic acid in DMF gave a mixture of the expected 17,21-(methyl orthobenzoate) (126) and the 17,21-(hydrogen orthobenzoate) ( 127).'20 The unusual stability of the latter compound is attributed to intramolecular hydrogen-bonding between the free hydroxy- and 20-0x0-groups. The kinetically contro!led hydrolysis of acetoxonium ions derived from cyclohexane-1.2-diol analogues gives monoacetates of cis-diols. in which the free OH CH,OH

CHz-O

I

I

\ /

---OH

H (126) R = Me (125) 12'

(127)

E. J . Merrill and G . G . Vernice, J . O r g . Chrvn.. 1971. 36, 2903.

R

=

H

OR

31 1

Steroid Properties and Reactions

group is equatorial and OAc group axial. 1 2 ' This generalization. supported by study of simple cyclohexane derivatives, rationalizes some earlier observations involving steroidal acetoxonium ions (Scheme 3). Equilibrating conditions (e.g. refluxing aqueous solvents) lead to mixtures of monoacetates of the cis-diols, through acetyl migration between adjacent hydroxy-groups. OAc

I

i. BF,-Ac,O ice-water

ii.

' H

H

OAc

H

OAc

I. H,SO,-acetone ii. cold water

AcO

' HO H

H

H

OH

Scheme 3

Enzymic deacetylation permits the preparation of the unstable 3j,16pdihydroxyandrost-Sen- 17-one from its diacetate. '2 2 Acidic or alkaline hydrolyses are unsuitable because the steroid rapidly rearranges to give the 17P-hydroxy16-ketone. In the preparation of the unstable 2/3-hydroxytestosterone, use of the 17-chloroacetate allowed hydrolysis at C-17 without extensive inversion at C-2. Further examples of deacetylation of steroid acetates on chromatographic acetates of primary alcohols are most affected. alumina are reported Cholesterol, heated in dimethyl phosphite, affords cholesteryl methyl phosphite (128), but in the presence of an acid the product is cholesteryl methyl ether.'24

0

I

MeO-P=O

I

I2l

12'

124

J. Atkin, R. E. Gall, and M. Slee, J.C.S. Perkin I I , 1972, 1185. K. N. Wynne and A. G. C. Renwick, Steroids, 1972, 19,293. G. Schneider, I. Weisz-Vincze, A. Vass, and K. Kovacs, Tetrahedron Letters, 1972, 3349. Y . Kashman, J . O rg. Chem., 1972, 37, 912.

312

Terpenoids and Steroids

The phenyl ether was obtained similarly. The Sor-saturated 3p-01 affords its methyl ether, but not the phenyl ether. under these conditions. The conversion of sterols into their phosphorodichloridates, and the reactions of these with amines and alcohols, have been studied."' The reductive removal of either an alcoholic or ketonic function can be effected by treatment of the alcoholate or enolate anion with tetramethyldiamidophosphochloridate [(Me,N),POCl] to form the ester, followed by reduction with lithium-ethylamine [e.g. (129) -+ (1 3 l)].' 2 6 Diethylphosphochloridate can be used similarly. The reactions are applicable to primary, secondary, or tertiary alcohols: the intermediate esters are stable to a variety of common reagents.

Steroidal methyl ethers are readily obtained from the alcohols with diazomethane and fluoroboric acid.' 2 7 The novel dicholesteryl acetal (1 32) of formaldehyde has been obtained from cholesterol. either by the anodic oxidation of a solution in aqueous acidic methanol, or by the action of sodium hydride and chlorome t hy 1 met h y 1 ether. Dimet hoxymethane undergoes partial exchange with cholesterol in acidic solution to give the methoxymethyl ether ( 133).'28

(1 32)

(133)

The suitability of tritylone ethers as protecting groups for alcohols has been explored, with cholesterol among model alcohols.'29 The ether (134) was formed from tritylone alcohol and cholesterol under acidic conditions with azeotropic R . J . W. Cremlyn, B. B. Dewhurst, D . H . Wakeford, and R . A. Raja, J.C.S. Perkin I , 1972, 1171.

R . E. Ireland, D . C . Muchmore, and U . Hengartner, J. Amer. Chem. SOC.,1972, 94, 5099. 12-

128

I . M . Clark, A . S. Clegg, W . A . Denny, Sir E . R . H . Jones, G. D . Meakins, and A . Pendlebury, J.C.S. Perkin I . 1972,499. J . E. Herz, J . Lucero, Y . Santoyo, and E. S. Waight, Canad. J . Chem., 1971,49,2418. W . E . Barnett. L. L . Needham, and R . W . Powell, Tetrahedron, 1972,28,419.

313

Steroid Properties and Reactions

removal of water. Tritylone ethers differ from the familiar trityl ethers in being moderately resistant to acids but are cleaved under Wolff-Kishner (basic) conditions to regenerate the alcohol.

The steroidal oxetans (135) react with a Lewis acid (BF, or SnCl,) and acetone to give the acetals (136), which were hydrolysed in aqueous acid to give the diols (137).' 30 Me Me

x

0

0

H

H (137)

(135) 16a,17a- or 16/3,17#l-configuration

Oxa-steroids (e.g. 139) are formed when the corresponding secodiols (138) are heated in DMSO, or with toluene-p-sulphonic acid in benzene. 2-0xa-, 3-oxa-, 4-oxa, and 2-oxa-~-nor-compoundswere obtained in this way.'31

I3O

G . Schneider, I. Weisz-Vincze, A. Vass, and K. Kovacs, J.C.S. Chem. Comm., 1972, 713.

13'

G . Zanati and M . E. Wolff, J . Medicin. Chern., 1971, 14, 958.

3 I4

Terpenoids and Steroids

Oestrone reacts with D-penta-acetylglucopyranosein the presence of toluenep-sulphonic acid to give the P-D-tetra-acetylglucopyranosidein good yield.'32 Corresponding derivatives of galactose or mannose gave lower yields of mixtures of the x - and P-glycosides. The reaction of r-acetylbromoglucose with steroidal 3[Mcohols has been examined in detail."3 Ofa variety of silver salts and solvents tried, silver 4-hydroxyvalerate in ether seems to lead to the best yields of steroid gl ycosides. Miscellaneous Reactions-Trityl fluoroborate. previously reported as cleaving acetals by hydride abstraction. also cleaves benzylic ethers and a variety of related species, giving benzaldehydes.' 3 4 Cholesteryl benzyl ethers afford cholesterol. The bismethylenedioxy protecting group for the corticosteroid side-chain is also cleaved with this reagent. Fetizon's reagent ( A g 2 C 0 3 on celite) fragments 17a-ethynyl-17P-hydroxysteroids or cyanohydrins to give the parent ketones.' 3 5 The cleavage reaction occurs at a rate comparable with that of the oxidation of secondary alcohols by the reagent, precluding the use of this oxidant for 17a-ethynyl-3~,17,!?-diols.It seems likely that the special affinity of Ag' ions for acetylenic bonds would facilitate departure of the ethynyl group under basic conditions (140).

6,!Y-Methoxy-3~.5-cyclo-5r-steroids ( 141) are reduced by LiAIH4-AIC13 to give the 32.5-cyclo hydrocarbons (142)with smaller amounts of the isomeric A5steroids. The 3x.5-cyclocholestanyl cation (143) is considered likely to be an intermediate. to explain the product c o m p ~ s i t i o n . ' ~ ~

R (141) R = OMe (142) R = H

'"

'" '"

'"

(143)

A . Polakova-Paquet and D. S. Layne, Steroids, 1971, 18, 477.

G . Wulff, G. Roehle, and W . Krueger, Chrni.Brr., 1972, 105, 1097. D. H . R . Barton. P. D. Magnus, G . Streckert. and D. Zurr. Chem. Contm., 1971. 1109. G . R . Lenz, J . C . S . Chem. Comm., 1972,468. A . Romeo and M . P. Paradisi, J . Org. Chenr.. 1972, 37. 46.

315

Steroid Properties and Reactions

A novel reduction of dimesylates of vic-diols with either anthracene or naphthalene radical anions to give olefins13' seems likely to find applications in steroid chemistry. Sa-Cholestan-2a,5-diol(144) reacts with HF to give at least seven products.13* Apart from the 2a,5a-epoxide (145) and the 5a-fluoro-2a-01(146), the products arise by partial or complete backbone rearrangements (cf p. 378). The 14p-8ene (147) is an unusual product in the cholestane series, although this type of structure results from backbone rearrangement of various androstane derivatives.' 3 9 The 25-fluoro-compounds (148) and (149) correspond to others already obtained from cholestane derivatives.140

OH (144)

(145)

3 Unsaturated Compounds Addition Reactions.-Electrophilic fluorination by fluoroxytrifluoromethane (CF,OF) has now been extended to a series of fluoroxy-compounds [(CF,),COF, (CF,),(C,F.JCOF, SF,OF, and CFJOF), 1, allowing the conversion, for example, 13'

139 '40

J. C. Carnahan and W . D. Closson, Tetrahedron Letters, 1972, 3447. A . Ambles and R. Jacquesy, Bull. SOC.chim. France, 1972, 804. Ref. 34, p. 304. Ref. 34, p. 306.

Terpenoids and Steroids

316

of enol esters into cr-fluoro- ketone^.'^' Full particulars are r e p ~ r t e d ’ ~of ’ the stereoselective and regioselective iodoacetoxylation (and other reactions) of an ergost-22-ene derivative.143Details of the reactions of the homo-allylic alcohol (150)with anhydrous hydrogen fluoride have also appeared there are two principal products, the fluoro-alcohols (151) and (1 52). Similar reactions of the 4-en-7a-01, and of the 5-en-3a- and 5-en-3B-01~are also discussed. Association of hydrogen fluoride with the hydroxy-group plays an important role in determining the structure and stereochemistry of the products. Elimination of HF from the lop-fluoro-alcohol(152) gave the A1(’‘)-olefin (Hofmann control).

(151)

(152)

65 Y o

31 %

(+ Sp-isomer, 3 %)

80 04 The electrophilic addition reactions of As-unsaturated steroids and other rigid cyclohexenes are controlled mainly by the conformational preference for diaxial addition ; HOBr, for example, gives mainly a 5a-bromo-6~-alcohol.146 A study of similar reactions with ~-nor-A’-unsaturatedsteroids suggests that the reaction of a cyclopentene is under electronic rather than conformational A variety of reagents (HOBr, BrF, Br,, BrOMe, and BrOAc) gave mainly 6abromo-5B-substituted derivatives (155), indicating that the initial product, a 5a.6a-bromonium ion (1 54). reacts further according to Markovnikoff. with attack of the anion at the tertiary S/?-position. I41

142

I43 104

I45 146 IJ7

D . H. R . Barton, R . H. Hesse, M . M . Pechet. G . Tarzia, H . T . Toh, and N . D . Westcot, J.C.S. Chem. Comm., 1972, 122. D. H . R . Barton, J. P. Poyser. and P. G . Sammes. J.C.S. Perkin I , 1972. 53. CJ Ref. 34, p. 249. J.-C. Jacquesy, R. Jacquesy, and S. Moreau. Bull. SOC.chim. France, 1971, 3609. Ref. 106b, p. 145. Ref. 99. p. 94. A. Kasal and J. Joska, Cull. Czech. Chem. Cornm., 1972, 37,2234.

Steroid Properties and Reactions

AcO

317

J---ny&& ' Br

X'3

AcO

Qir...

(1 54)

AcO

X (155)

(153)

X = Br, OH, F, OMe, or OAc Cycloalkenes may be converted into episulphides by reaction with an ethereal or dichloromethane solution of iodine and thiocyanogen, in equimolar proportions, followed by alkaline hydrolysis.14' Iodine thiocyanate (ISCN) appears to be present in the solution, and to add diaxially to the olefinic bond; hydrolysis then closes the episulphide ring. 5a-Cholest-2-ene (156), for example, gave the 2fl,3/?-epithio-derivative (157) in acceptable yield.

The nitration of cholesteryl acetate normally affords the 6-nitro-derivative (158),149 but on occasion the reaction has been known to become violently

exothermic. The major product is then the SP-nitro-6-ketone (159);' a freeradical chain mechanism seems probable, although the details have still to be elucidated. The 5P-nitro-ketone affords the Sa-hydroxy-ketone (160) on alkaline hydrolysis. 14* '49

I5O

J . C. Hinshaw, Tetrahedron Letters, 1972, 3567. Ref. 34, p. 254. C. R. Eck and B. Green, J.C.S. Chem. Comm., 1972, 537.

Br

318

Terpenoids and Steroids

Phenyliodosochloride-azide[C,H 51(Cl)N3]reacts with cholesteryl acetate to give a cis addition product, the 5a-chloro-6a-azido-derivative.' 5 1 Other Asunsaturated steroids gave products of both cis and trans addition ; the corresponding dichlorides were also formed. N-Chlorourethane adds o n to olefinic steroids under free-radical conditions. Sr-Cholest-2-ene (161) gave the 28chioro-3x-urethane ( 162),which reacted with base to form the N-ethoxycarbonylaziridine ( 103)and then 2~..3a-aziridino-5a-cholestane(l64).' s 2 As-Unsaturated steroids similarly form the 5c~hloro-6P-urethanederivatives, from which the 5/?.6,4-aziridino-steroids are available.

H ( 1 64)

Two reports of Simmons-Smith methylene addition (iodomethylzinc iodide) on to A5-olefinic steroids contain several points of disagreement. The earlier paper' 5 3 states that cholest-5-en-3a-ol (epicholesterol) reacts readily to give the 5cc.6cx-methano-derivative ( 165). A stereospecific reaction in this sense would accord with earlier indications' 5 4 that a suitably placed hydroxy-group directs the approach of the reagent towards the same side of the olefinic bond. The 3palcohol (cholesterol).as well as the methyl ethers and acetates of both alcohols, apparently failed to react.ls3The later paper. by different authors,' 5 5 states that borh unsaturated alcohols react, each giving a similar mixture of the 5a,6x- and Sfl.6P-methano-adducts. with no evidence for control by the oxygen function. E. Zbiral and J . Ehrenfreund, Tetrahedron, 1971, 27, 4125. K . Ponsold and W . Ihn, J . p r a k r . C h e m . , 1971, 313, 81 1 . ' 5 3 J . F. Templeton and C . W . Wie, Canad. J . Chem., 1971.49, 3636. L 5 4 Ref. 99, p. 89. L . Kohout, J . FajkoS. and F. Sorm, Tetrahedro:i Lettcrc. 1972, 3655.

"I

'5 2

Steroid Properties and Reactions

319

Moreover, the yields of adducts are said to be higher with the 3-acetates than when the free alcohols are used. There seems to be no obvious explanation for these different findings. Oxidation of the 5a,6a-methano-alcohol (169,followed by treatment with acid, gave the 6a-methyl-4-en-3-one (166).'53

Peracid epoxidation of 3P,19-dihydroxycholest-5-ene diacetate gave a mixture of epoxides, the 5a16a-epimer predominating. A 19-OH group reverses the stereochemical preference, favouring the P-epoxide by associating with the peracid on the p-face of the molecule.' s 6 Epoxidation of a 17-chloroandrost-16ene (167) occurs readily, giving the 17P-chloro-16a,l7a-epoxide(168). The

;I3 H

H (168)

(167)

17-iodo-16-ene reacts similarly, but the resulting iodo-epoxide is very reactive, undergoing further transformation at a rate comparable with that of its formation. lo' Epoxidation of 2,7-di-oxygenated cholest-4-enes1is described on p. 344. Epoxidation has been used to protect a As-olefinic bond during transformations in the cholestane side-chain.' The epoxide survived dehydration of the 20hydroxy- 11-oxocholesterol derivative (169) with SOU-pyridine, followed by

'

AcO

'"

P. Morand and M . Kaufman, Canad. J . Chem., 1971, #, 3185. J . J. Schneider, Tetrahedron, 1972, 28, 2717.

320

Terpenoids and Steroids

hydrogenation with 5 % P d X : the A5-olefinic bond was later restored by the Cornforth procedure. Hydrogenation of the A2'-bond in (170) gave a mixture of 20R- and 20s-isomers. separable by chromatography. Reactions at the A5olefinic bond in 4,4,14a-trimethyl-19-nor-l0a-pregn-5-en-ll-one (171),a degradation product of cucurbitacin C, favour attack on the exposed a-face. Products include the 5a.6a-epoxide and the 5a-bromo-6fi-hydroxy-derivative, formed with peroxy-acid and N-bromoacetamide-perchloric acid, respectively. 5 8

In contrast, the hindered A5-olefinic bond in 4,4,14a-trimethyl-19(10- 9p)abeo-lor-pregn-5-enes ( 172)is stereoselectively attacked on the p-face by peroxyacid or osmium tetroxide.' s 9 The folded conformation (172)results in particularly severe congestion at the a-face. A 17a-hydroxy-16-methylenepregnan-20-one (173) is oxidized by chromic acid (Jones' reagent) to give the (16S)-spiro-oxiran ( 174) or, under more vigorous conditions, the corresponding androstan-17-one derivative ( 175).16* Asymmetric hydroboronation of 5a-cholest-2-ene with Me

i

Me

I

H

either of the epimeric dipinan-3a-ylboranes gives products opposite to those predicted on the basis of the model suggested by Brown and Zweifel, implicating a monomeric reagent. (-)-Dipinan-3a-ylborane gave a high proportion of 5acholestan-3a-ol, whereas the (+)-reagent gave more of the 2a-01. No alternative hypothesis is offered to explain these results, but it is suggested that the active reagent probably has a more complex structure than that implied by the simple name quoted above.' 6 ' 58

Is9 Ib0 Ihl

J. R. Bull, P. R. Enslin, and H . H . Lachmann, J . Chem. SOC.(0,1971,3929. J. R . Bull. J . C . S . Perkinf. 1972. 627. V. Schwarz, Coll. Czech. Chem. Comm., 1972,37,637. J . E. Herz and L. A . Marquez, J . Chern. SOC.( 0 ,1971, 3504.

321

Steroid Properties and Reactions

The pyrrolidyl enamines of 3-0x0-steroids (176) are reduced by diborane to give the saturated 3a- (177) and 38-pyrrolidino-steroids (178) in good total yield. The mechanism of saturation of the olefinic bond is discussed in terms of norma! borane addition to give amino-borane derivatives (Scheme 4); the BH, group at C-2 is probably displaced internally by a hydride ion.'62 The 2fi-steroidal borane derivative (179; R = H) is stable in the absence of a log-methyl group (oestrane series) and can be oxidized in the usual way to give the 3a-amino-28hydroxy-derivative (180)?

(179)

1

1 R

CH

H

Scheme 4 Ibz lb3

J. J . Barieux and J . Gore, Tetrahedron, 1972, 28, 1537. J . J. Barieux and J. Gore, Tetrahedron, 1972, 28, 1555.

Terpenoids and Steroids

322

Hydroboronation of a 3,3-ethylenedioxy-A5-steroid occurs mainly on the /Iface. because of hindrance by the 3a-oxygen : the reaction provides a convenient route to 6P-hydroxy-SP-steroids.1 6 4 Substituents may be introduced at C-6 in 4,4-dimethyl-A5-unsaturated systems ( 181) either by prolonged reaction with diborane, which affords the 6r-alcohol (182) after oxidation of the intermediate organoborane, or by reaction with N-bromoacetamide-HC104, which is unusual in giving the 5/3,6b-epoxide (183) directly. The epoxide is reduced by LiA1H4-AlCl3 or by lithium-thylamine to give the 6b-alcohol (184). Both

RO OH

(181)

1

( 182)

alcohols afford the 6-ketone on oxidation. 1 6 5 Hydroboronation of a 20-methylpregn-l7(20)-ene (185). with thermal equilibration of the intermediate C-20borane before oxidation. gives the 16a-hydroxy-compound (1 86). Similar reaction of a pregn-l7(20)-ene (187) affords a Gixture of the 1 6 ~ (188), 20- (189),and 21hydroxypregnanes (190). The proportions vary according to whether the proportions of reactants are such that the primary product is a monosteroidal or a disteroidal borane derivative. Probable mechanisms are discussed.166 Hydroboronation of A2“’”-unsaturated compounds (191; R = Me or C6H,3) with ‘disiamylborane’, followed by oxidation, gave the 20s-alcohols (192)stereo-

{$

Y

H

( 18 5 ) I

Ih5 It”’

H

H ( 1 86)

(187)

A . S. Clegg. W . A . Denny, Sir E. R . H . Jones. V . Kumar. G . D. Meakins. and V . E. M . Thomas, J . C . S . Perkin I , 1972, 492. C. R . Eck, P. Kullberg, and B. Green, J . C . S . Chem. Comm., 1972, 539. E. Mincione and C . lavarone, Gazrrru, 1971, 101. 956.

323

Steroid Properties and Reactions

(188)

(189)

(190)

selectively. When diborane was used, both the 20R- and 20s-isomers were obtained.167Reduction of the 21-tosylate in the cholestane series gave 2040- (20s) cholesterol. 68 The stereochemistry of hydroboronation seems to imply rear-side attack on the olefinic bond with the side-chain in the conformation represented by (191).

CH,OH

i. 'disiamylborane'

ii, H,OZ-OH-

.H

H

Diborane finds such wide use in steroid chemistry that a new and very simple procedure for its preparation is welcomed. Tetra-alkylammonium borohydrides, which are readily extracted from an aqueous solution of Na'BH, and R4N+HSO, into CH,Cl,, are used in the dried CH,CI, solution; addition of an alkyl halide (e.g.MeI) generates diborane in situ, and allows all the usual reactions of reduction or hydroboronation to be carried out conveniently and in high yields. l o The conjugate addition of methylmagnesium bromide
O'

J. Bottin and M. Fetizon, Chem. Comm., 1971, 1087. J. Bottin and M. Fetizon, Bull. Sac. chim. France, 1972, 2344. E. Mincione and 0. Rossi, Ann. Chim. (Italy), 1971,61, 788. A . Brandstrorn, U. Junggren, and B. Larnrn, Tetrahedron Letters, 1972, 3173.

324

Terpenoidr and Steroidr Me ,Me

TH

0

olefin (194) for n.m.r. study. The conjugate methylation (LiCuMe,) of the des~-9-en-5-ones(195) introduced a 9P-methyl group (196), a key step in the total synthesis of compounds of the cucurbitacin type.17' The stereochemistry of methylation, favouring a cis ring junction (B/c), is similar to that already known in reactions of 4-en-3-ones.

R

=

H or CH,CH=CCIMe

A series of papers presents a detailed account of the hydrocyanation of apunsaturated ketones with either ( a ) mixtures of trialkylaluminium, or an alkylaluminium halide, with HCN or (h)a dialkylaluminium cyanide. Cholest-4-en-3one gives the 5a- and 5P-cyano-3-ketones almost quantitatively. A A'-1 1-0x0steroid gave the 8#?-cyano-ll-ketone,despite being unreactive by older methods. Mechanistic features of these processes have been largely elucidated ;conditions can be chosen to give products of either kinetic or thermodynamic control.'72 Kinetic data are analysed for hydrocyanation of cholest-4-en-3-one and Bnorandrost-4-en-3-one. Some of the many novel applications of hydrocyanation are illustrated in Scheme 5.'74 The factors controlling the stereochemistry of hydrocyanation of enols are discussed in detail, with reference to an extensive list of examples, and a number of generalizations are offerred concerning the most likely stereochemical outcome of such reactions.' 7 5 Hydrocyanation of 6P-substituted ~-nor-4-en-3-ones(197)

"' I-' I-'

J . R. Bull and A. Tuinman, J.C.S. Chem. Comm., 1972, 921. W. Nagata, M. Yoshioka, and S. Hirai, J . Amer. Chem. SOC.,1972,94,4635. W. Nagata, M. Yoshioka, and M. Murakami, J . Amer. Chem. SOC.,1972,944644. W . Nagata, M. Yoshioka, and M . Murakami, J . Amer. Chem. SOC.,1972,94,4654. W Nagata, M. Yoshioka. and T. Terasawa, J . Amer. Chem. Soc.. 1972,94,4672.

325

Steroid Properties and Reactions

z

Q fi? =e

0

+

jQ/

0

t

/

3:

f$ Q

4 0

0

0

Q

z u

r

2

y&

0

--V

T

Q t

z

u

0

T

0

Terpenoids and Steroids

326

was successful only when the 6/hubstituent was a vinyl group: the SP-cyanoketone (198) was formed. The 19-nor-analogue reacted similarly. 7 h

,J

NC CH=CH2 (198)

R (197)

The 14P-pregn-16-en-2O-one system ( 199)undergoes conjugate additions from the /I-face, appropriate reagents giving the 16g-cyano- (200), acetylthio- (201), nitromethyl (202),and aziridinyl(203) derivative^.'^' Alkali-catalysed addition of alcohols failed in the 14fl-series.although it is well-known in the 14a-isomers.

IsMe Px COMe

H

H (199)

(200) X = CN (201) X = SAC (202) X = CH2N0, (203) X =

N3

Acetonitrile N-oxide adds on to the 16-en-20-one system (204) to give both the possible 16a.l7r-oxazoles, (205) and (206).The spectroscopic and chiroptical properties of these novel systems are discussed.1 7 ’

‘-’ ”’

W. Nagata, M . Narisada, T. Wakabayashi, Y . Hayase. and M . Murakami, Chrm. and Pharm. Bull. ( J a p a n ) , 1971, 19, 1581. T. Nambara, J . Goto, Y . Fujimura, and Y . Kimura, Chern. and Pharm. Bull. (Japan), 1971, 19, 1137. A . Ius, C. Parini, G . Sportoletti, G . Vecchio, and G . Ferrara, J . Org. Chrm., 1971,36, 3470.

Steroid Properties and Reactions

327

2a-Dimethylphosphonomethyl derivatives (208) of steroidal 4-en-3-ones are obtained by treating the 2-methylene derivatives (207) with trimethyl phosphite. '19

Ergocalciferyl acetate forms an adduct, probably of Diels-Alder type. with tetracyanoethylene. The stability of the adduct to air, and also to t.1.c. or g.l.c., suggests its possible adoption for estimation of calciferol in animal tissues.' Reduction of Unsaturated Steroids.-Reduction with di-imide [provided by hydrazine hydrate and copper(I1) acetate in methanol] provides a novel and stereospecificconversion of steroidal 4-en-3P-01s into Sa-dihydro-compounds. By contrast, catalytic hydrogenation is non-stereospecific and is often accompanied by partial hydrogenolysis, so the new method offers considerable promise. Catalytic reduction of 3P-hydroxyandrost-4-en-17-onewith tritium and a Pt catalyst gave 3P-hydroxy-SLY-androstan-17-one with the tritium distribution 4a, 37 ; 5a, 43 % ; and 601, 20 %. The 5P-isomer was also formed, with tritium at 4P, 29 % ; 5p, 54 % ;6p, 4.7 %, and 6a, 13%. Tritium analysis was achieved by a combination of equilibration with base, bromination-dehydrobromination, and dehydrogenation.' 8 2 The appearance of tritium at C-6 indicates olefinic bond migration in contact with the catalyst.' 8 3 A hydridoiron complex, generated in situ from pentacarbonyliron and a small amount of NaOH in a moist solvent, selectively reduces the olefinic bond of apunsaturated ketones. Cholest-4-en-3-one gave 5P-cholestan-3-one. Use of D,O provides a route to P-deuteriated Hydrogenation of the 1,2olefinic bond in 1,4-dien-3-ones with the homogeneous catalyst tris(tripheny1phosphine)rhodium chloride normally occurs from the a-face. 11-0xo- and 11phydroxy-groups do not change this stereospecificity, but an 1la-hydroxysubstituent appears to hinder interaction of the catalyst with the a-face, and reduction then becomes non-stereospecific.' The polarographic reduction of androst-4-ene-3,6,17-trionehas been studied in aqueous DMF and acetonitrile. Reduction of both the ene-trione and the tautomeric 6-enol form is observed ; the main product under carefully controlled conditions is the saturated triketone. 186

''

'79

*O '*I I*' 183

le5

J.-L. Bravet and C. Benezra, Steroids, 1972, 19, 101. J. R. Evans, Clin. Chim. Acfa, 1972, 38, 85. Y . J . Abul-Hajj, J . Org. Chem., 1971, 36, 2730. Y . J . Abul-Hajj, J . Labelled Compounds, 1971,3, 33, 261. Ref. 99, p. 86. R. Noyori, I . Umeda, and T. Ishigami, J . Org. Chem., 1972, 37, 1542. Y . J. Abul-Hajj, Steroids, 1971, 18, 281. N . Shinriki and T. Nambara, J . Pharm. SOC.Japan, 1971,6, 611.

328

Terpenoids and Steroih

Pregna-14.16-dien-20-onesare reduced selectively by triphenyltin hydride to give the 14-en-20-ones but when a 12a-acetoxy-group was present (209) the 17a-pregn-14-en-20-one(210) and the 21-nor-lactone (211) were formed.'87 The mode of formation of the lactone is not clear. Me

Me

I

0-c=o

co

+

Catalytic hydrogenation of 8,9-didehydro-14/l-oestrone gave the products of both 8a,9a- and 8p,9P-addition.l S 8 Birch reduction of 8a-methyloestradiol 3methyl ether, followed by hydrolysis, gives mainly the non-conjugated 5( 10)en-3-one, which appears to be more stable in the 8a-methyl series than the conjugated 4-en-3-one. 8 9

Oxidation and Dehydrogenation.-5x-Hydroxyandrost-2-enes (2 12)are smoothly oxidized by 8N-chromic acid to give the corresponding 4-ketones (213). Cholest2-ene is stable under the same conditions, suggesting that the 5a-OH provides anchorage for a chromate ester close to C-4, facilitating allyiic oxidation.'

(212)

(213)

(R = H or OAc) lrradiation of a 4,4-dimethyl-A5-steroid with two moles of N-bromosuccinimide gives the 7,7-dibromide (214). which can be dehydrobrominated to the novel 7-bromo-5.7-diene (215) or hydrolysed to the 5-en-7-one (216).19 Oxidation of 3P-acetoxylanost-8-ene with chromic acid gave the known 8-en-7-one and 8-ene-7.11-dione.and also the 9(1I)-en-7-one. apparently identical with Marker's 'a-ketodihydrolanosteryl acetate'.lg2 The acidic fraction from IB7

'"

'" *')I 19'

U . Pommerenk, H . Sengewein, and P. Welzel, Tetrahedron Letters, 1972, 3415. R . Zepter, J . prakt. Chem., 1971. 313, 1139. G . Amiard, R . Heymes, and T. Van Thuong, Bull. SOC.chim. France, 1972, 272. J. R . Hanson and A. G . Ogiivie, J . C . S . Perkin I , 1972, 590. H. DeNijs, W. N . Speckamp, and H . 0. Huisman, J.C.S. Chem. Comm., 1972, 350. L. H . Briggs, J. P. Bartley, and P. S. Rutledge, J.C.S. Perkin I, 1972, 581.

Steroid Properties and Reactions

329

the oxidation of oestradiol diacetate with chromic acid afforded the 9(11)-secoketo-acid (217),19, and not the acid (218) suggested previously. Co2H

OAc

qAc

AcO

AcO

Oestrone is oxidized by thallium(iri) trifluoroacetate in trifluoroacetic acid to give 10P-hydroxyoestra-1,4-diene-3,17-dione 10-trifluoroacetate (219) in good yield. The free lop-01 (220)was obtained by passage of the ester through alumina; this appears to be the best route to the lO&hydroxy-dienone system.'94 Ceric ammonium nitrate oxidizes an aromatic C-1 methyl group to give the aldehyde, but in the absence of a C-1 substituent oestrone acetate gave the 9r,llP-diol 11-nitrate (221) in good yield. A minor product is believed to be the 11-nitrate of the 9P,l lP-di01.l~~

0

0 (219) R = COCF, (220) R = H Ruthenium tetroxide has been used to cleave 3-benzylidene-~-homo-5crcholestane (222), as a step in the preparation of the 3-0x0-derivative (223) from its 4-0x0-isomer.196 193

L94 195

19'

D. de Maindreville and B. Gastambide, Compt. rend., 1971, 273, C , 1 . M . M. Coombs and M. B. Jones, Chem. and Ind., 1972, 169. P. J . Sykes, F. J . Rutherford, S. B . Laing, G . H. Phillipps, and J. P. Turnbull, Tetrahedron Lerters, 1971, 3393. M. Ephritikhine and J . Levisalles, Bull. SOC.chim. France, 1971, 4331.

Terpenoids and Steroidr

330

H (222) R = PhCH (223) R = 0 Photo-oxidation (sunlight) of the oxathiin (224) gave the 3.4-seco-3,4-dione (225). In aqueous solvents a mixture of (225) and the 6P-hydroxy-4-en-3-one (226) was obtained. Ozonolysis gave the same two products accompanied by others, depending upon the solvent emp10yed.l~~ The specific activation of the 3.4-bond is noteworthy. Nucleophilic attack at C-6 is thought to imply allylic migration of the As-olefinic bond, probably accompanying rupture of an intermediate 3,4-dioxetan (227a). or ozonide (227b). Peroxy-acid. which has been reported' 9 8 to cleave a A3t5-dien-3-01ether selectively at the 3.4-bond under anhydrous conditions. reacted preferentially with sulphur in the oxathiin (224), giving only the corresponding sulphoxide and sulphone.

(2'4)

(225)

(226)

(227) a ; n = 2 b;n = 3

Further studies are reported' 9 9 on the dehydrogenation of oestrogen derivatives ( 2 2 8 H 2 3 0 ) with 2.3-dichloro-5.6-dicyanobenzoquinone.The initial product, the 9(1I)-dehydro-derivative, is usually oxidized further to give the 9(11)en-12-one in rather low yield.'" The 17~-hydroxy-compounds(228) and (229) lq7

'" '"

2'10

A. Miyake and M . Tomoeda. J.C.S. Perkin I. 1972. 663. D. N . Kirk and J . M . Wlles. Chern. Comm., 1970, 1015. A . Bodenberger and H . Dannenberg, Chem. Ber., 1971, 104, 2389. Cj: Ref. 34, p. 266.

Steroid Properties and Reactions

33 I

also give dihydrophenanthrene (D-seco)derivatives (231).'9 9 Cleavage of ring D probably involves Grob fragmentation of the 13(17)-bond as illustrated (232). Oestrone is dehydrogenated and also isomerized at C- 14 by palladium-charcoal in refluxing triglyme to give 14p-equilenin (233).Attempts to invert ring-junction configurations under similar conditions failed with compounds of the bileacid series, although successful with podocarpic acid derivatives.201

R' (228) R' = OH, R2 = H (229) R 1 = OH, R2 = Me (230) R 1 = NHCOMe, R2 = H

0

Oestrone (or its methyl ether or acetate) undergoes a novel dearomatization in the system HF-SbF,, which has found wide use as a hyperacidic medium for the generation of carbonium ions. The product, oestra-4,9-diene-3,17-dione (235) is thought to arise uia a dicationic intermediate, although the detailed mechanism is still under investigation. The system HS0,F-SbF, converted oestrone partly into its 9(11)-dehydro-derivative (237).202 Again the suggested mechanism is speculative, an oxidation step being required. These reactions may involve hydride abstraction (234)by the hyperacidic species, with evolution of molecular hydrogen and formation of a stabilized C-9 carbonium ion (236); abstraction of a proton from C-11by the medium would then afford the 9(1 1)-dehydro-compound. Dehydrogenation of 9cqlOa- or 9/?,10/?-oestr-4-en-3-ones occurred rapidly with palladium in ethanol, giving phenolic products with retention of configuration at C-9 (Scheme 6). Various mechanisms were considered, but were rejected '02

S. W. Pelletier, Y . Ichinohe, and D. L. Herald, Tetrahedron Letters, 1971, 4179. J . P. Gesson, J. C. Jacquesy, and R.Jacquesy, Tetrahedron Letters, 1971, 4733.

Terpenoidrs and Steroids

332

H F-SbF

0 (235)

1

HS0,F-SbF,

0

HZ H&

HO

\

(237)

(236)

on the basis of the failure of postulated intermediates to undergo rapid aromatization under the same conditions. The most plausible mechanism appears to be a palladium-catalysed disproportionation of a transient enolic derivative (e.g.238) of the cyclohexadiene type.203

H

Scheme 6

Alkynes and Allenes.-Ethynyl steroids (239) readily form a stable hexacarbonyldicobalt complex (240) on treatment with octacarbonyldicobalt. The complex serves to protect the triple bond during reactions elsewhere (e.g. olefin reduction with di-imide, or hydroboronation). The ethynyl group is regenerated by treating the complex with iron(r1r)nitrate in ethanol.204 *03 204

E. Farkas and N . J. Bach, J . Org. Chem., 1971,36, 2715. K . M . Nicholas and R . Pettit, Tetrahedron Letters, 1971, 3475.

Steroid Properties and Reactions

+ octacarbonyldicobalt H

s-' 333

A+

L-:

CO(CO), WCO),

H

(239)

(240)

Wolff-Kishner reduction of D-seco acetylenic aldehydes of structure (241) to give the 16-deoxy-compound (242) is accompanied by a novel thermal cyclization of the acetylenic hydrazone (243), via (244), to give the pregn-16-ene (245). The reaction is discussed in terms of the Woodward-Hoffmann rules for conservation of orbital symmetry.205

Me

Me

Acid-catalysed ring-closure of the acetylenic alcohol (246) provides an efficient route to the 20-ketones (247);206the reaction is more stereoselective, in favour of the C/D-tra?ZS isomer, than the related reaction using a vinylic chloride, reported last year.207 205

'06 '07

H. Kaufmann, P. Weiland, and J . Kalvoda, Helv. Chim. Acta, 1972, 55, 381. P. T. Lansbury and G. E. DuBois, Chem. Comm., 1971, 1107. Ref. 34, p. 257.

333

Terpenoids and Steroids Et

I

C

Et

I

Et

Et

(247) N.m.r. spectra of the allenic derivatives ( 2 4 8 w 2 5 1 ) have been used to assign configurations to the two monomethyl compounds (249) and (250). The 21pmethyl substituent exerts a slight shielding effect on the 13j-methyl group compared with the parent and the 212-methyl derivatives. Optical rotation differences support the assigned configurations. It is claimed that some earlier assignments of configurations require reversal ; the reaction of the 17P-acetoxy17r-ethynyl system (252) with LiCuMez is now reported to give mainly the 21pmethylallene (250). whereas a mixture rich in the 2la-isomer (249) was obtained by treating the 17P-acetoxy-17x-propynyl system (253) with LiA1H,-AlCl3 . ' 0 8

R'

1

(248) R' (249) R' (250) R' (251) 2''n

R'

=

= = =

R2

R' = H H, R' = Me Me. R' = H R2 = Me

(252) R = H (253) R = Me

L. A . Van Dijck, B. J . Lankwerden. J . C . M . Vermeer, and A. J . M . Weber, Rer. Trac. rhim., 1971. 90, 801.

335

Steroid Properties and Reactions

The allenic acid fluoride (254) undergoes Michael addition with KCN to give the 20-cyano-acid (255). Lithium dimethylcopper gives the product (256) of methylation at both C-20 and C-22, but dimethylcadmium reacts selectively at C-22, giving the allenic ketone (257) and a little of its C-21-e~imer.~’~

CO,H

I

21 L

CN

4

KCN -EtOH

3’ H

H (254)

I

LiCuMe,

MeCOCH,

(255)

\

Me,Cd

MeCQ..

’C

Me

Miscellaneous.-1 7a-(2’-Furyl)-17P-hydroxy-steroids (258) react with peroxyacids to give the novel pyranone derivatives (259).210

HO

0 ‘ H

H (258)

(259)

2-Iodo-oestrone (260) reacts with copper (I) acetylides in boiling pyridine to give the corresponding benzofurans (261).2l 1 209 210

P. Crabbe and E. Velarde, J.C.S. Chem. Comm., 1972,241. Y. Lefebvre, Tetrahedron Letters, 1972, 133. M. Stefanovic, Lj. Krstic, and S. Mladenovic, Tetrahedron Letters, 1971, 331 1 .

Terpenoids and Steroids

336

An unusual Vilsmeier-type formylation of a 2,4,6-triene is described on p. 301. Some novel steroidal-[ 101 annulenes have been prepared (p. 374). 4 Carbonyl Compounds

Reduction of Ketones.4ontroversy continues over the character of the transition state in the reduction of ketones with complex hydrides.212Study213of the rates of reduction of a series of 5x-substituted steroidal 3-ketones (262) with lithium tri-t-butoxyaluminium hydride. including determination of the separate rate constants for formation of axial and equatorial alcohols, produced some new and surprising results. Three 52-substituents (5a-Me, -F, or -C1) caused pronounced retardation, not only of formation of the equatorial alcohol (263) by approach of the reagent to the x-face at C-3, but also of formation of the axial alcohol (264) by p-face approach. A 5x-cyano-group, although retarding approach of the reagent to the 3a-position as expected, had a marked accelerating effect on the approach to 38, giving the axial alcohol (264; X = CN) as major product. The significance of these observations lies in their implications concerning the nature of the transition state. A transition state resembling the products (264)with axial OH would include a developing '1.3-diaxial' interaction

H

'*.

(262) 32-approach

H HO * I 2

213

Ref. 1, p. 66; ref. 9 9 , p . 135. A . Calvet and J . Levisalles, Terrahedron Lefters, 1972, 2157.

X

Steroid Properties and Reactions

337

between the 3a-oxygen and the 5a substituent. The interaction would be destabilizing when the Sa-group is either methyl (steric compression) or a halogen (electrostatic repulsion between the adjacent -0'- and Halb-), but stabilizing for Sa-CN, where the -Oh- would be closest to the positive end of the '+C_Nbdipole. The observed result therefore seems to favour a product-like transition state. The authors2' stress the inadvisability of basing mechanistic conclusions solely on product analysis unsupported by rate data. A further publicaticn214 dealing with the reduction of substituted cyclohexanones with LiAIH, , reaches a similar conclusion concerning the transition state, which is at variance with the recently expressed views of some other The Henbest reduction procedure [chloroiridic acid + (MeO),P in propan2-01] converted 5a-androstan-12-one into the 12a- (axial) alcohol.' 2 7 It was earlier found2' that 5a-pregnane-3,12,20-trioneis reduced selectively at C-3, so the side-chain presumably hinders attack at C-12. Under prolonged reaction, the Henbest reagent will reduce a 2-oxo-5a-steroid, showing almost total specificity The Henbest reagent modified by the and leading to the 2p- (axial) addition of a little sodium hydroxide shows enhanced reactivity, permitting the reduction of a 17-ketone to give mainly the 17&alcohol: added acetic acid has a slight retarding effect. Substitution of tris(tripheny1phosphine)rhodium chloride for the iridium reagent allows reduction of 3-0x0-steroids with even higher specificity for formation of the axial alcohol (98 %).216 The reduction of an ergostan-23-one (265) with LiAlH, at - 20 "C gave the 23s- (266) and 23R-alcohols in the ratio 7 : 3.'42 In accordance with Cram's rule, the reaction proceeds under kinetic control, with reduction from the less hindered side in a preferred conformation of the type illustrated (267). The 22-0x0-compound gave mainly (7 : 1)the 22s-alcohol (268),contrary to prediction according to Cram's rule, but in accordance with other recent observations on 22-0x0-steroids. It seems that the conformation (269) about the C-22-C-20 bond, necessary for obedience to Cram's rule, is too hindered to be acceptable; reduction must therefore occur through an alternative conformation. Molecular rotation differences are discussed for the C-22 and C-23 alcohols and their derivatives.

H (265)

''

214

2'6

J . Cense, Tetrahedron Letters, 1972, 2153. P. A. Browne and D. N. Kirk, J . Chem. Soc. ( C ) , 1969, 1653. J . C. Orr, M. Mersereau, and A. Sanford, Chem. Comm., 1970, 162.

338

Terpenoids and Steroids

0

0 Me

H

(267)

(368)

Kinetic measurements using cortisone rcductase and a variety of ring Asubstituted pregnan-20-ones showed rather small sensitivity to changes in ring A. Enzyme recognition of the steroid apparently depends mainly upon interaction ~ modified ~ ~ Clemmensen with parts of the molecule remote from ring A . The reduction of ketones. with zinc and acetic anhydride in a hydrocarbon solvent saturated with HCI. also removes r-acetoxy-groups and converts conjugated enones into hydrocarbons.' l 8 Other Reactions at the Carbonyl Carbon Atom.-A new method for converting ketones into methylene compounds is claimed to be successful even in cases where the Wittig and related reactions Treatment of the ketone (e.g. 271) with phenylthiomethyl-lithium (270) gives a derivative (272), which may be acetylated or benzoylated in situ. Reduction cf the ester (273) with lithium-NH, gives the methylene compound (274) in good yield. The conversion of cholest-5-en-3-one into 3-methylenecholest-Sene contrasts with the lability of the 5-en-3-one to the basic conditions required for the Wittig reaction. Even many hindered ketones appear to be reactive.

(270! (271)

PhS-CHZ

H2C (274) 'I7 2'8

(272)

(273)

I . H . White and J . Jeffery, European J . Biocheni., 1972, 25,409. M . Toda, M . Hayashi, Y . Hirata, and S. Yamamura, Bull. Chem. SOC.Jupan, 1972.45, 264.

'Iq

R . L. Sowerby and R. M. Coates. J .

Anter. Chetn. S o c . , 1972, 94. 4758.

Steroid Properties and Reactions

339

Reaction of a-hydroxy-ketones (e.g. 275) with the Simmons-Smith reagent replaces the carbonyl group by a methylene (276) or ethano-group (277),depending upon the conditions employed.220Bromomethyl-lithium in THF reacts with saturated aldehydes and ketones to give epoxides.221 Several steroid examples are given. Me

I

H

H

Ethynylmagnesium bromide converted a 13a-androstan-17-one into a mixture of the two epimeric ethynyl alcohols, /?-attack predominating.222A 14/?-androstan-17-one (278) has been transformed into the 14P-pregnan-20-one derivatives (279) and (280)by the routes shown.'"

J

HCO, H

q

C

O

M

e

\ Propionic acid reacts with lithium di-isopropylamide to generate the dilithioderivative, which will attack a 17-0x0-steroid (281) to give the 17-hydroxybisnorcholanic acid isomers (282) and (283) in the ratio 4 : l.223The configurations

''' I . T. Harrison, R. J . Rawson, P. Turnbull, and J . H . Fried, J . Org. Chrm., 1971, 36, 221

222

223

3515. G. Cainelli, A. U. Ronchi, F. Bertini, P. Grasselli, and G. Zubiani, Tetrahedron, 1971,27, 6109. T. Nambara and J . Goto, Chem. and Pharm. Bull. (Japan), 1971, 19, 1937. M. Tanabe and R . H. Peters, J . Org. Chem., 1971, 36, 2403.

Terpenoids and Steroids

340

at C-17 reverse those previously assigned to identical products isolated from a Reformatsky reaction.224Further transformations of the hydroxy-acids leading to p-lactones. reduced products. and isomeric 17(20)-enesare also described.

H (281)

H

H (282)

Full details are reported225of the oxidation of acetals by hydride transfer to the trityl cation (trityl tetrafluoroborate).226 The reaction is applicable to ethylene acetals or hemithioacetals of 0x0-steroids, but not to dithioacetals. Acetonides are readily cleaved, giving a-hydroxy-ketones,226 and the 1 7 ~ 2 :020,21-bismethylenedioxy protecting group is removed from corticosteroid derivatives. Benzyl ethers form benzaldehydes : p-methoxybenzyloxycarbonylderivatives of alcohols are also readily cleaved. The regeneration of ketones from thioacetals (e.g. 284) has required special procedures, not always suitable in the presence of sensitive functional groups, so that thioacetals have found only limited use as protecting groups. Last year's Report22 described one novel procedure for regenerating the ketone, involving the formation and hydrolysis of a di-sulphoxide ;two groups of workers now find that alkylation at sulphur provides another convenient means of activating the thioacetal to hydrolysis. Methylation with methyl iodide or fluorosulphonate is said to allow very ready hydrolysis by water,228and ethylation with [Et,O]+ [BF,]-, followed by alkaline hydrolysis of the sulphonium salt, also liberates the parent ketone (287).229 High yields may be obtained either by employing two moles of [Et,O]+[BF,]- to form the bis-sulphonium salt (286)or by using only one mole of the reagent and conducting the hydrolysis of the mono-sulphonium salt (285) in the presence of a thiol scavenger, which may be a copper salt or hydrogen peroxide. The behaviour of enones with hydrogen halides (in CDCl,, for n.m.r. study) depends both upon the acid strength of the halide and upon the thermodynamic stability of the conjugate-addition product which might be formed. The 4-en-3one system is protonated by HBr or HI, and also by H,SO,, to form a salt, but does not react with the weaker acid HCI. A 16-en-20-oneadds each of the halogen acids, to form 16-halogeno-20-ketones, but forms only a salt with H 2 S 0 4 . A

'" 225

D . H . Hey, J . Honeyman, and W . J . Peal, J . Chem. SUC.,1954, 185. D. H . R . Barton, P. D. Magnus, G. Smith, G. Streckert, and D. Zurr. J .C .S . Perkin I. 1972, 542.

12'

'' z2B

'"

Ref. 34, p. 248. Ref. 34. p. 272. M. Fetizon and M. Jurion. J.C.S. Chem. Comm.. 1972. 382. T. Oishi. K . Kamemoto, and Y . Ban, Tetrahedron Lerrers, 1972, 1085.

34 1

Steroid Properties and Reactions + Et,O BF,-

(285) aq. CuSO,

+ products

I Et 1,4-dien-3-one forms a salt by protonation in varying degrees with each of the four acids, being more basic than the 4-en-3-one : the protonated dienone undergoes a gradual dienone-phenol rearrangement at 25 0C.230 Condensation of 5a-cholestan-3-one with 2-ethyl-2-hydrazinobutyric acid and oxidation of the hydrazone gave the azo-lactone (288).Pyrolysis gave diethylketen, N, , and 5a-cholestan-3-one : it had been hoped that extrusion of N, and CO, would afford an 01efin.~~'

(288) 5a-Cholestan-3-one reacts with triphenylphosphine and CCI, to give the 3-dichloromethylene derivative (289). Some other enolizable ketones give enyl chlorides (e.g. 290) or mixtures of the two types of product. CBr, affords the analogous bromo-derivatives. Phosphorane derivatives (291) and (292) seem to be implicated, although the reasons for wide variations in relative yields from different ketones are not yet clear. Alternative mechanisms are 2Jo

*

2'2

J. N . Marx, Tetrahedron Letters, 1971,4957. D. H. R. Barton and B. J. Willis, J . C . S . Perkin I, 1972, 305. N. S. Isaacs and D. Kirkpatrick, J . C . S . Chem. Comm., 1972, 443.

Terpenoids and Steroids

342

c1

c1c1 (2891 2Ph3P + CCl,

Ph,P=CCl, (291)

+ PhJPCl, (292)

The reaction between 17-0x0-steroids and CH2N2-A1Cl3 to give D-bishomo17b-ketones is discussed on p. 377. Reactions Involving Enols or Enolate Anions.-The concept of bifunctional catalysis in the conversion of a 5-en-3-one into the conjugated 4 - e n - 3 - 0 n e ~ ~ ~ has been further explored.234Catalysis by halogenated carboxylic acids is interpreted in terms of a mechanism involving two molecules of the acid. The highly active As-3-keto-steroid isomerase of Pseudornonas testosteroni suffers irreversible inhibition by 6P-bromotestosterone acetate, apparently by covalent bonding of the steroid to the protein. Some protection against this inactivation is provided by the simultaneous presence of 19-norte~tosterone.~~~ The formation of oestrone from oestr-4-ene-3.17-dione by B. sphaericus has been shown to involve stereoselective loss of the 1%-and 2P-hydrogen atoms. The transformation is therefore similar to the 1.2-dehydrogenation of analogous androstane derivative~.~~~ The chemistry of cholest-4-ene-2.7-dione (293) has been investigated in considerable detail.23-The compound is readily prepared from the 3S-dien-7-one by allylic oxidation (t-butyl chromate) followed by reduction (zinc). Acidcatalysed isomerization of (293) gave the 5-ene-2.7-dione (294) specifically : migration of the olefinic bond into conjugation with the 2-0x0-group (3-ene-2,7dione) is unfavourable because of relatively high internal strain associated with a 3,4-double bond. The results of reduction of the 4-ene-2,7-dione, epoxidation of the olefinic bond. and base-catalysed rearrangement of the epoxide, are depicted in Scheme 7. Similar epoxidation and rearrangement were observed for the 4-en-2-one with no substituent ar C-7.237 Reduction of the 5-ene-2.7-dione (294) with NaBH, gave the 2p- (295) and 2a-alcohols in the ratio 73 : 26. the conjugated enone being relatively resistant to redu~tion.’~’ Deconjugation of the 2P-hydroxy-5-en-7-one (295)was achieved by a novel method (Scheme 8): reaction with trifluoroacetic anhydride gave the 2P.7-bistrifluoroacetoxy-4,6-diene(296). which was hydrolysed by methanolic

”’ 234

Ref. 106h, p. 327. A . Kergomard and M . F. Renard, Tetrahedron, 1972, 28, 21 I 1 ; see also errata, ibid., p . 4050.

13’

23b ?’’

K . G . Biiki, C. H . Robinson, and P. Talalay, Biochim. Biophys. Acta, 1971, 242, 268. T. Anjyo, M . Ito, H . Hosoda, and T. Nambara, Chem. and Ind., 1972. 384. D. H . R . Barton and Y . Houminer, J . C . S . Perkin I , 1972, 919.

Steroid Properties and Reactions

343

\ o

~ NaBf14b

\ O

eo

O

.\

H

< 107;

Scheme 7

1

OH (301) Scheme 8

1

OH (302)

\

Terpenoids and Steroids

344

triethylamine to give the 2P-hydroxy-4-en-7-one (297). The latter compound was somewhat resistant to epoxidation, giving predominantly the P-epoxide (299), and appears (n.m.r.) to have an 'inverted half-chair' conformation of ring A (298).analogous to that found in 2P-hydroxy-4-en-3-ones. Cholest-4-en-7-one also gives both 2- and P-epoxides. Each of the 4.5-epoxy-7-0x0-compounds in this series was rearranged with triethylamine in ethanol to give the corresponding 4-hydroxy-5-en-7-one [e.g. (301) and (302)l. Kinetic studies, including 2H2 labelling of the 7x-hydroxy-4r.5r-epoxy-2-ketone at C-3, showed that carbanion formation is the rate-determining step in the epoxide-opening reaction. No neighbouring hydroxy-group participation was observed in the isomerization of the epoxy-ketones. A compound first described in 1937 as the A4-enolic form (303) of cholestane3,4,6-trione is now shown to be a diene-diol ether, (304) and/or (305), A,,, 276 and 338 nm.238Hydrolysis with aqueous acid gives a mixture of stable tautomers, separable by crystallization into two distinct fractions which were only slowly equilibrated by acid. The structures were not assigned with certainty: one component was a dihydroxy-dienone (306) and/or (307), and the other a monohydroxy-ene-dione (303)and 'or (308).

'

OH 0 (303)

OH 0 (304) R = Et (306) R = H

OH 0 (305) R = Et (307) R = H

General tritium labelling of ergosterone with tritiated water in DMF and a platinum catalyst gave material extensively labelled in rings A and B, though mainly at C-4 and C-6.239 A 6.6-Difluoro- 19-nor-steroidal 4-en-3-one (309), prepared by the sequence illustrated (Scheme 9),240has been transformed into the deconjugated 5( lO)-en-3-one (310). The allylic difluoride (310) is readily hydroiysed by acid to give the 5( lO)-ene-3,6-dione (311). Dehydrogenation of the difluoro-enone (309) with Pd-C gave the novel 6-fluoroequilenin (312).241 238 239 24"

J . T. Pinhey and E. Rizzardo, J . C . S . Perkin I , 1972, 1358. B. Pelc and E. Kodicek. J . C . S . Perkin I, 1972. 1915. A. L. Johnson, J . Medicin. Chem., 1972, 15, 784. G . A . Boswell, A . L . Johnson, and J . P . McDevitt, J . 0r.g. Chem., 1971,36, 575.

Steroid Properties and Reactions

345

iv-vil

F (3 12) Reagents: i, NOF; ii, A1,03; iii, SF,; iv, K , C 0 3 ; v, H,CrO,; vi, A1,0,; vii, NaC-CH DMSO; viii, Pd-C, 180 " C ;ix, H'.

Scheme 9 Alkylation of the dienolate ion derived from 4-methyl-19-nortestosterone (313) with CD31 in benzene solution gave the 4,4-dimethyl compound (314),with 70% of the labelled methyl groups in the 4/?-orientation.With t-butyl alcohol as solvent the product showed predominant (902)introduction of 4a-CD3 (this latter conclusion, which reverses that reached in an earlier study, depended upon application of the nuclear Overhauser effect for the assignment of n.m.r. signals of the C-4 methyl groups). Solvent-dependence of the stereochemistry of alkylation has not been suspected before.242

@ JrJy

0 242

Me (313)

H3C

CD3 (314)

Y . Nakadaira and J. Hayashi, J.C.S. Chem. Cornrn., 1972, 282.

346

Terpeiioids and Steruids

The direct monoalkylation of a steroidal 4-en-3-one at C-4 calls for delicate control of reaction conditions and at best gives products containing some 4,4dialkylated material. Indirect procedures for monomethylation (e.g. 4-thiomethylation-des~lphurization~~~) are now supplemented by a novel method using the 3-imino-derivatives (313.”‘ Metallation (e.g.with lithium di-isopropylamide) gives the salt (316). which is selectively mono-alkylated at C-4, giving the 4-alkyl-4-en-3-one ( 317) after hydrolysis.

&-

\

\

R-N P

::N-? Me-I

HY Li N(CHMe, l2

(316)

i

(315) R = Me2N or cyclohexyl

0

R-N Me

Me

Direct carbonation of the enolate of a 4-en-3-one with CO, gives the 4-carboxyderivative (318) in modest yield. but reaction of the 4-en-3-one with methyl methoxymagnesium carbonate in DMF gives the 2rx-carboxy-derivative (319) in high yield. 22-Carboxy-5%-cholestan-3-oneundergoes cyclization with dicyclohexylcarbodi-imide(DCC) to give the novel heterocycle (320)-whereas 2r-carboxycholest-4-en-3-one gives the A4-derivative (321 ). The imino-moiety in these heterocycles may be hydrolysed to give the dihydro-dioxo-oxazine (322). If the reaction of the keto-acid with DCC is czrried out in acetone solution, the

C0,H

(319)

( 3 18)

”’ D. N . Kirk and V . Petrow, J . Chrrn. Soc., 1962, 1091. ”‘ G . Stork and J . Benaim, J . Anrer. Chrni. Soc.. 1971. 93. 5938.

347

Steroid Properties and Reactions

(320) 5 ~ r- H (321) A4

(322)

(323)

product is the dioxene (323), the 'acetonide' of the A2-enolic form of the ketoA 4-cyano-substituent (324) is introduced into 4-en-3-ones by the action of phenyl cyanate on their e n ~ l a t e s . The ~ ~ ~4-cyano-6P-hydroxy-deriva' tives (325) are formed at the same time. Phenyl formate similarly introduces a 4-formyl group, but the product is obtained as the 4-formyl-3,5-dien-3-01(326).246b I n both reactions the phenoxide ion functions as a leaving-group (e.g. 327); alkyl esters cannot be used because of the unfavourable character of the alkoxide

0

0

/

CN (324) R = H (325) R = b-OH

& ' r-

0€3-C-O

? N- @ '

(337) 245 24h

C. Huynh and S. Julia, Bull. SOC.cliim. France, 1972, 1794. ( a ) C. Huynh and S. Julia. Bull. Sac. chim. France, 1971,4396; ( h )ibid., p. 4402.

Terpenoids and Steroids

348

ion in this role. Formylation with 0-methyl-NN-dimethylformamide methosulphate also provides a route to the 4-formyl-3,5-dien-3-01 (326). Reaction of (326) with hydroxylamine afforded the isoxazole (328),from which the 4-cyano4-en-3-one (324) and related compounds could be obtained.247 Some further transformations of the 4-formyl-3.5-dien-3-01 system (326) and (329),are illustrated its less stable tautomer, the 4-hydroxymethylene-5-en-3-one in Scheme 111

HC(OAc),

H C (OMe),

CHO

HC(OMe),

(329)

Reagents: i, Ac,O-HCIO,; ii, Ac,O-py; iii, H+-MeOH; iv. DDQ.

Scheme 10

Dehydrobromination of the 16a-bromo-17-ketone (330j with dimethylacetamide containing lithium bromide and carbonate gave a mixture of the 14-en-17one (331)and the 14p-15-en-17-one(332).24”Although it was possible to separate these products by fractional crystallization, a more satisfactory use for the mixed products involved enol acetylation, which gave the A I 4 s 1 6-dien-l7-01 acetate (333) in overall yield of 65 %, Perchloryl fluoride treatment of the dienol 24’ 248

C. Huynh and S. Julia, Bull. SOC.chim. France, 1971, 3586. C. Huynh and S. Julia, Bull. SOC.chim. France. 1972, 2880.

‘‘’ J . Pataki and G . Siade, J . O r g . Chem., 1972, 37, 2127.

Steroid Properties and Reactions

349

acetate in aqueous THF gave a mixture of 14P-fluoro- (334) and 14P-hydroxy15-en-17-ones ( 3 3 9 , the former predominating. Hydrogenation of the A I 5 olefinic bond gave the saturated 14P-fluoro-ketone (336).

0

0

OH (335)

0

F

1

OAc

(333)

(334)

F (336) 1601-And 16~-chloroandrostan-17-ones can be interconverted in the presence of acid.’” I t appears that the p-isomer is only slightly the more stable, contrary to earlier belief. A 13a-androstan-17-one (337) forms an ethylene acetal, though less readily than the normal 13P-isomer.Bromination, dehydrobromination, and removal of the protecting acetal then gave the 15-en-17-one (339), though in low yield.25 0 Direct bromination of the ketone, followed by dehydrobromination with Li2C0,-LiBr-DMF, provided a more convenient route, remarkable for the smooth dehydrobromination of (338) to give a single unsaturated ketone, which contrasts with the lower reactivity of the bromo-ketone (330) in the 138androstane series, where two products are formed (see above). Transposition of functional groups as in the 15-en-17-one of the 13P-series2” afforded 15-oxygenated 13a-androstane derivative^.'^' 2so

251

T. Nambara, H. Hosoda, M . Usui, and L. Y. Ng, Chern. and Pharm. Bull. (Japan), 1971, 19, 2555. C . Djerassi, G . von Mutzenbecker, J . FajkoS, D. H . Williams, and H. Budzikiewicz, J . Amer. Chern. SOC.,1965, 87, 817.

350

Terpmoids und Steroids

{fj16.. *

H

+

( H

H

(337) (338, (339) Bromination of a 13r-androstan-15-one gave the 16fl-bromo- and 16,16dibromo-derivatives. implying preferential enolization towards C-16.''' This is in contrast to bromination of an ordinary (138.14~)15-ketone at C-14.

COMe

(3.10) Selective bromination of the 19(1 0 4 9P)-abeo-triketone (340)occurred almost exclusively at C-2. The bromoketones have been converted into a series of bromohydrins and related derivatives in ring A . ~ ~ ~

R' H

0 z & - J i yR' - (

R'

H

0

O H Scheme I 1

"'

J . R. Bull and

A.

J. Hodginson.

Porrahtdrorr. 1971. 28. 3969.

Steroid Properties and Reactions

35 1

The cyclization of 8,9-seco-5a-androstane-8~9,11 -trione derivatives occurs readily on A1,0, or SO,, giving either a 7,9- or a 7,11-bonded tetracyclic structure (Scheme 11). Product ratios varied with the substitution pattern at C-3 and C-17 and according to the catalyst. Similar reactions have been described earlier in the pregnane series, but without complete assignment of stereochemistry to the products. Configurations are now deduced from spectroscopic properties. 53 Acid catalysis is preferable to base for the condensation of 5a-cholestan-3one (341) with pentyl nitrite to form the hydroxyimino-ketone (342).254 The dioxime (343) afforded the [2,3-c]furazan 2-oxide (344) on oxidation with hypochlorite. Nitration of the 3-ketone (341) with ethyl nitrate and base gave the 2nitro-en01 (345); the derived 3-oxime (346) gave the furazan oxide (344) on reaction with acid. Nitration of 5cr-cholestan-7-one gave the 6cr- and 6P-nitroketones (347), apparently the first epimeric pair of steroidal nitro-ketones to be

OH

OH

02Nfl\ - 02:a I

H

HO

H

OH

(345)

(346)

(347) 6a 253

154

+ 68

S. Aoyama, K . Kamata, and T. Komeno, Chern. and Pharrn. Bull. (Japan), 1971, 19, 21 16. D. J . Chadwick, W. R . T. Cottrell, and G. D. Meakins, J . C . S . Prrkin I , 1972, 6 5 5 .

Terpenoids and Steroids

352

isolated. These compounds exist in the keto-form because of the particular strain in A6-enols.254

Reactions of Enol Esters, Ethers, and Emmines.-Under conditions of kinetic control. hydrolysis of the enol acetate of a 6-methyloestr-4-en-3-one gives the 6r-methyl-4-en-3-one. although prolonged reaction gives an equilibrated mixture of the 6a- and 6B-methyl isomers (p. 283).20 Acidic hydrolysis of 3b-acetoxy-4methoxycholest-Qene (348)appears to occur via loss of the allylic 3P-substituent, in preference to protonation of the enol ether at C-5. The allylic cation (349)is attacked by water at C-5. and subsequent hydrolysis of the enol ether (350) (351). The isomeric 4P-acetoxy-en01 ether affords 5-hydroxy-S~-cholestan-4-0ne (352) is hydrolysed normally, giving a 3-0x0-product (353).255

AcO

/

OMe

Me0

m' 1 OAc (352)

OMe

H'-H,O

~

OH (353)

Enol acetylation of isoergosterone (354) and reduction of the mixed enol acetates with sodium borohydride provides a route to ergosterol (used to prepare [1-3H]ergosterol). The proportions of the two enol acetates (355) and (356) appear to depend upon the acidic catalyst employed, for acetic anhydride255

M . Lemonnier, G . Linstrumelle, and

s. Julia, Bull. Soc. clzrni. Frump, 1972, 169.

353

Steroid Properties and Reactions

acetyl chloride gave only 20 ”/, of 5,7-diene (358), the major product (53 %) being the 4,6-diene (357); use of sulphosalicylic acid instead of acetyl chloride reversed the yields.256

0 (354)

(355)

1

(357)

(356)

1

(358)

33-Dien-3-01 trimethylsilyl ethers (359), readily prepared from steroidal 4-en-3-ones with hexamethyldisilazane and trimethylbromosilane in pyridine, are reduced by sodium borohydride to give 3/?-hydroxy-As-unsaturatedderivatives in high yield (80% of cholesterol from cholest-4-en-3-one, on a semimicro scale).*s’ 25b

B. Pelc and E. Kodicek, J . Chem. SOC.( C ) , 1971, 3415.

*’’L. Aringer and P. Eneroth, Sreroids. 1971,18, 381.

Terperzoids and Steroids

354

The 6-formyl enol ether system (360a) is readily dehydrogenated by D D Q to give the 6-formyl-4.6-dienone (361a).but the 6-cyano-en01 ether (360b), prepared was resistant to DDQ. To overcome this by dehydration of the oxime (360~). difficulty. the oximino-compound (36Oc) was treated with DDQ, giving the corresponding 4,6-dienone (361c) : the desired 6-cyano-group (361b) could then be generated by dehydration of the oxime with P O C l , - ~ y r i d i n e . ~ ~ ~

R (360) a, R = C H O b. R = CN C, R = CH=NOH The propargyl en01 ethers (362) and (365) rearrange in boiling toluene to give tho r-allenyl ketones (363) and (366). respectively. The allenyl ketones readily isomerize in pyridine to give the conjugated dienones (364) and (367).259

H (365)

'

18

T. L . Popper, H. P. Faro, F. E. Carlon, and H. L. Herzog, J . Medicin. Chrtn., 1972, 15, 555. P. P.Castelli, R . Vitali, and R. Gardi, Gaz:crru. l Y 7 1 . 101. 833.

355

Steroid Properties and Reactions

Pyrolysis of the 3,3-bis-(2-chloroethoxy)-5cc-androstanederivative (368) gave the A'-enol ether (369), which afforded the 2a,3a-methano-derivative (370) with the Simmons-Smith reagent. The 2-chloroethyl group was easily removed by n-butyl-lithium to give the cyclopropanol (371), which rearranged on melting to give the 2cr-methyl-3-ketone (372)."* OAc

(369)

I

Simmons-Smith

H

1

BuLi

(372)

(371)

The reactions of 3-pyrrolidino- (or morpholino-) 3,5-dienes (373) with a variety of reagents have been summarized and compared with the Oehaviour of the corresponding dienol ethers.26' Some novzl reactions of the dienamines lead to attack at C-4: addition reactions with benzonitrile N-oxide, t-butyl azidoformate, diethyl diazodicarboxylate, and the Simmons-Smith reagent are illustrated in Scheme 12. (A bicyclic dienamine was used, but steroid analogues should react similarly.) Non-regiospecific reactions with l-naphthyltoluece-psulphonimide and with phenylsulphene are also described. Methylenation of the dienol ether (374) occurs first at the As-olefinic bond, the products being the cyclopropane (375) and the dicyclopropane (376).26' 2ho 2b'

J . F. Templeton and C. W. Wie, Tetrahedron Letters, 1971, 3955. M . E. Kuehne and G . DiVincenzo, J . O r g . Chem., 1972, 37, 1023.

356

Terpenoids and Steroids

(373)

Reagents: i, P h C r N -0: ii. CH,I,-ZnEt,; iii. Bu'OCO.N,; iv. EtO,C.N=NCO,Et.

Scheme 12

Reactions of Oximes, Hydrazone, and Related Derivatives.-The failure of the anti-oximes (377) and (378) to undergo Beckmann rearrangement, apparently implying a resistance of the vinylic bond to migration, was ascribed to the unfavourable character of a charge-deficient transition state involving migration of an unsaturated carbon atom.262Studies on a variety of cycloalkenone oximes and related unsaturated structures have now shown that unsaturated groups migrate very readily, except in the special case of the trans-oxime of a cyclohexenone. I t appears that the decisive factor is a geometrical one, with the porbital of the migrating unsaturated carbon atom required to overlap simultaneously with developing p-orbitals of the C=N bond, in a plane perpendicular ih2

Ref. 99, p. 343.

Steroid Properties and Reactions

357

to that of the original n-bond of the C=N system. The relative rigidity of a sixmembered ring prevents the attainment of the configuration necessary for the transition

I

H

(378)

HO (377)

(379) suffers Beckmann fragmentation The 2~-hydroxy-3-oximino-compound with thionyl chloride to give the cyanoaldehyde (380), offering a controlled method for unsymmetrical cleavage of the ring.264

(379)

(380)

The chloro-substituent in a 5a-chloro-6-hydroximino-steroid(38 1) is readily replaced by a variety of nucleophiles (5a-SEt, OEt, NH,, NHMe, NOz, CN, NCS, or N3) by use of suitable reagents. The unstable 6-nitroso-5-ene (382) is

base

(-HCI)

AcO

AcO

NOH

263 264

' NO

T. Sato, H. Wakatsuka, and K . Amano, Tetrahedron, 1971, 27, 5381. J. K. Paisley and L. Weiler, Tetrahedron Letters, 1972, 261.

Terpenoids and Steroids

358

the key intermediate, readily undergoing coniugate addition to give the products ( 383). The blue 6-nitroso-compound (382) has been isolated. but gradually isomerizes in solution to give the A4-6-oxime (384) if no reactive nucleophile is available. Thallium(1 1 1 ) nitrate in methanol rapidly and cleanly oxidizes oximes, semicarbazones. or phenylhydrazones to give the corresponding aldehydes or ketones. 2 6 6 The cleavage of an a$-epoxy-tosylhydrazone to give an acetylenic ketone has been employed to generate the 5( 10)-seco-compound (386); best yields resulted from epoxidation of the tosylhydrazone of the 5( lO)-en-6-one (385), rather than from first forming the epoxy-ketone.”- Aldol condensation of the derived saturated seco-3.10-dione (387) afforded the A-nor-B-homo-enone (388). The hydrazones derived from r,P-epoxy-ketones and 2-phenyl- (389) or rrans-2,3diphenyl-1 -aminoaziridines (390) undergo thermal fission (e.g.in refluxing DMF), also giving acetylentc aldehydes or ketones.268 The 6-hydroxymethylene-7-ketone (391) condenses with hydrazine to give the fused pyrazole (392). but the isomeric pyrazole with nitrogen attached directly

(386)

1 0

(387) (388) ph,CNR--

NH,

(389) R = H (390) R = Ph Y . Komeichi, T. Iwasaki, Y . Ito. and F. Aida, Steroids, 1972,19,47. A . McKillop, J . D . Hunt, R . D. Naylor, and E. C Taylor, J . Amer. Chem. Soc., 1971, 93, 4919. Z h - S. V Sunthankar and S. D . Mehendale. Tetrahydron Letters, 1972, 2481. l f rD. H Felix, R. K . Muller, U. Horn, R . Joos, J. Schreiber, and A . Eschenmoser, Helv. Chrm. Acta, 1972. 55, 1276.

2h5 266

Steroid Properties and Reactions

359

(392) at C-6 could not be prepared because of the failure of a 6-oxo-5a-steroid to form the 7-hydroxymethylene derivative. The Fischer indole synthesis using the phenylhydrazones and N-methylphenylhydrazones of 5a- and 5/?-cholestan-3-ones, as well as some C-6-substituted derivatives, gives mainly steroidal indoles of the types (393) and (394), respectively. These structures are predictable from the known regioselectivity of enolization of 3-oxo-steroids in the 5a- and 5fi-~eries.~”

R (393) R = H or Me (394) Cholesta-3,5-dien-7-one (395) reacts with hydrazoic acid to give a mixture of the keto-lactams (396H399). A possible mechanism is suggested, the key steps being a conjugate addition of hydrazoic acid at C-3, with loss of nitrogen to give a 3,4-fused aziridine ring, and a Schmidt rearrangement of ring B . ~ ~ ~ The Schmidt reaction of cholest-4-ene-3,6-dione with sodium azide-polyphosphoric acid gives a mixture of the 4-aza- (400) and 3-aza-compounds (401). 269 270 271

B. Pelc, J . Chem. SOC.( C ) , 1971, 3914. D. J. Harvey and S. T. Reid, Tetrahedron, 1972, 28,2489. K. Mitsuhashi, K. Nomura, and F. Miyoshi, Chem. and Pharrn. Bull. (Japan), 1971, 19. 1983.

360

Terpenoids and Steroids

(395)

Further reaction of the 4-aza-isomer (400) with the same reagents gave the 4,6-diaza-derivative (402).2'2 Hydrazoic 'acid with BF,-ether converted (25R)spirost-4-en-3-one into the tetrazole derivative (403). The tetrazole was sufficiently stable to survive conventional degradation of the spirostan system to give pregnane and androstane analogue^.^ 7 3

(404) X = H (4031

"* ' 1 3

(405) X = Br

H . Singh, S. Padrnanabhan, A. K. Bose, and I . Kugajevsky, J . C . S . Perkin I, 1972,993. H . Singh, R . B. Mathur, and P. P. Sharma, J.C.S. Perkin I , 1972, 990.

36 1

Steroid Properties and Reactions

Bromination of the 3-0x0-lactam (404) gave the 4a-bromo-derivative (405), which reacted with N-phenylthiourea or phenylhydrazine to give novel fused heterocyclic derivatives274 Reactions of Carboxylic Acids and their Derivatives.-A novel series of p-lactones -oic acids (406) and (407).275 has been obtained from 17,20-dihydroxypregnan-21 The reaction occurs, along with formation of the 17,20-diacetate,in acetic anhydride-pyridine. Lactonization is most efficient with the 20a-isomer (406) which affords the less-hindered trans-20-acetoxy-lactone (408). The crystalline lactones (408) and (409) are stable at - 20 "C but suffer slow decarboxylation at room temperature or in refluxing benzene to give the trans- (410) and cis-enol acetate (41l), respectively, of the 17-aldehyde(412). In a similar way the dihydroxy-acids (406) and (407) react with ethyl chlorocarbonate-pyridine to give 20-cathyl-21, 17a-lactones: several novel transformations of these products are described.275 A 20-deoxy-17a-hydroxypregnan-21-oic acid failed to undergo lactonization, showing that the 20-OH is an essential feature for cyclization to occur.275

+ - H

H

H (406) 20a

\

(410)

CHO

H

(8." [p/fi CO,H

AcO

+

H (407) 208

H

_+

H (409)

H (411)

274

H. Singh, R. B. Mathur, N. J . Doorenbos, A. K . Bose, and S. D . Sharma, Tetrahedron,

275

1971,27, 3993. M. L. Lewbart, J . Org. Chem., 1972, 37, 1224.

362

Terpenoids and Steroids

Chemical and spectroscopic evidence has confirmed the structure (414) for the ‘anhydro Butenandt acid’. obtained by heating the B-seco-dicarboxylicacid (413) with quin01ine.~’~

Anodic decarboxylation of the glycidates (415 ) derived from 5a-cholestan-3one gave 3-acetal-5z-cholest-2-ene (416) and a 3-acetyl-3-methoxy-derivative (417).’

The scope and mechanism of the reductions of esters and lactones to ethers with diborane has been reported in detail2?*(cf:ref. 279). Initial co-ordination of BH, with the alkoxy-oxygen is considered to be the essential step in the reduction to alcohols. Ether formation seems to occur as an alternative pathway when the

’-’D. L. Dreyer, J . O r g . Chem., 1971, 36, 3719. 2”

’“ 279

J . A . Waters and B. Witkop, J . Org. Chem., 1971,36, 3232. J . D. Diasand G . R.Pettit. J . Org. Chem., 1971,36, 3485. Ref. 106h, p. 347.

Steroid Properties and Reactions

363

ester group is sterically hindered, so that the co-ordination with BH, is unfavourable. The unsaturated hydroxy-lactone (418) reacts with ammonium formate and formic acid to give the lactam (419), without saturation of the olefinic bond.280

OH

Protection of the 0x0-group in 2a-cyano-3-0x0-steroids (420)by acetal formation (42 l ) permits alkaline hydrolysis of the cyano-group. After esterification of the carboxylic acid (422), the 3-0x0-group could be regenerated (423). Alternatively, protection of the ketone could be achieved by forming a 3-enol ether. Other routes to esters of 2-carboxy-3-0x0-steroidsand to the derived 3-alkoxy-, 3-amino-, and 3-chloro-A'-unsaturated derivatives have also been devised.28

0 (420) 5a-H, or A4 (421) 5a-H, or A5

Ro2c.&/.y 0 (423) 5a-H, or A4

R02cyJJJ

Go (422) 5a-H. or

A5

The steroidal ap-unsaturated nitriles (424) and (425), chosen to test the reactivity of the olefinic bond to 1,3-dipolar addition of a nitrile oxide, were found to react instead at the cyano-group. Benzonitrile oxide, generated in situ from benzhydroxamoyl chloride, gave the 1,2.4-oxadiazoles (426) and (427).282 "O

282

R. Pappo and R . J . Chorvat, Tetrahedron Letters, 1972, 3237. P. de Ruggeri, C. Gandolfi, and U . Guzzi, Ann. Chim. (Italy),1972,62,54,71. G. Ferrara, A . Ius, C. Parini, G . Sportoletti, and G . Vecchio, Tetrahedron, 1972, 28, 2461.

364

Terpenoih and Steroidr

Id PhC-N'-O-

( H

H

(424) OAc

(426)

H

H (425) (427) Selective removal of one methyl group from a 4,4-dimethyl-5or-3-oxo-steroid has been achieved by the reaction sequence summarized in Scheme 13.283

(428) cholestane or lanost-8-ene series

(429)

OHC (431 )

1 H

+ HN OHC (433 1

(434)

Scheme 13 283

K . F. Cohen, R . Kazlauskas, and J . T. Pinhey, Chem. Comm., 1971, 1419.

Steroid Properties and Reactions

365

Beckmann fragmentation of the oxime of the 3-ketone (428)gives the unsaturated seco-nitrile (429); the derived epoxide (430) reacts with BF,-ether in boiling (432) in good overall yield. toluene to give the 4a-methyl-5a-3-oxo-compound It seems likely that the cyano-aldehyde (431) is an intermediate ; the cyclization step could then involve the enol(433), with final hydrolysis and decarbonylation of the a-formyl-imine (434). 5 Compounds of Nitrogen and Sulphur

Amines and their Derivatives.-In continuation of mechanistic studies on d e a m i n a t i o n ~the , ~ ~N-nitrosoamides ~ (435; R = Me, 2-naphthyl, or benzyloxy) derived from 3a- and 3/?-amino-5cr-cholestanehave been formed and allowed to decompose in a variety of non-polar solvents.285The resulting esters (436)showed predominant retention of configuration, accompanied by appreciable inversion. The outcome of experiments under carefully devised conditions appears to establish an intramolecular mechanism, even when inversion occurs. 4-Azacholest-5-en-3-one and its N-methyl derivative reacted with nitrous acid to give complex mixtures of products, derived via nitrosation of the olefinic bond at C-6.286

NO

(436)

(435) The benzamido-group is readily eliminated to give olefins by the action of P 2 0 5 in boiling benzene. In some cases SOCl, and pyridine in ether can be employed. The elimination, which formally reverses the Ritter reaction, is illustrated by examples in Scheme 14.287A transition state with carbonium ion character is indicated by the rearrangement of (436) into (438) and (439). Methyl fluorosulphonate, an exceptionally powerful methylating agent, transforms 3a-acetamido-steroids (440) into their 0-methyl derivatives (441). These products are readily reduced by NaBH, to give the 3P-ethylaminosteroids.2 8 8 The Ritter reaction (with a nitrile and acid) converts either a 6P-hydroxy-3a,5acyclo-steroid or a 3P-mesyloxy-A5-steroidinto the 3P-acylamino-A5-derivative 284

28s 286

Ref. 106b, p. 348. F. W. Bachelor and E. H. White, Canad. J . Chem., 1972,50, 364. M. Kobayashi, H . Furuse, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1972, 20, 789.

287

M. Fetizon and N. Moreau, Bull. SOC. chim. France, 1972, 2721. S . Julia and R. J . Ryan, Compt. rend., 1972, 274, C , 1207.

366

&

Terpenoids and Steroids

OPh

60,Me 60,Me

RO

H

Scheme 14

I

I1

/c\ Me

Me (440)

OMe (4411

(444).289Presumably the mesomeric

33.52-cyclo-cation (442)2"0suffers nucleophilic attack by the nitrile; hydrolysis of the resulting cation (443) gives the amide (444). The reaction provides a convenient route from cholesterol to 3fi-acetamidocholest-5-ene. Use of 4-chlorobutyronitrile gives the corresponding chloroamide, which is readily hydrolysed to the amine hydrochloride or cyclized by base to give the pyrrolidone (445). '13'

R.J. Ryan, G. Bourgery, and S . Julia, Bull. SOC.chim. France, 1972, 1415.

290

Ref. 99, p. 236.

Steroid Properties und Reactions

367

R-C-NH (443)

V

II

0 (444)

\C,N ,Me

(445)

3

H (446)

The reaction of pregnan-20-one derivatives with pyrrolidine and formic acid (Leuckart-Wallach reaction) gave mixtures of the (20s)-(pyrrolidin-1’-y1)pregnane (446) and an isomer believed to belong to the 17a-pregnane series.291 I t is surprising that no 20R-isomer in the normal pregnane series could be found among the products. Possible mechanisms and conformational features of the reaction are discussed, but the stereospecificity remains incompletely explained. Oximino-ketones at various sites in the steroid nucleus were readily hydrogenated in acidic solution to give the a-amino-ketone hydrochloride^.^^ Attempted liberation of the free bases led to dimerization in most cases, with formation of dihydropyrazines (CJ: ref. 292). The 16-aminomethyleneandrostan- 17-one (447) was not hydrolysed by acids to the expected keto-aldehyde, but instead gave the bis-steroidal amine (448). The pyrrolidino-derivative (449), however, reacted with hydrochloric acid in acetone by fission of ring D (450) to give the 16,17-seco-eniminiumsalt (451), further hydrolysis of which afforded the carboxy-aldehyde (452).293 291

292 293

M . Davis, E. W. Parnell, and J. Rosenbaum, J.C.S. Perkin I , 1972, 1420. Ref. 1066,p. 324. G . Gerali, L. Cecchi, C . Parini, and G. Saglia, Furmuco, Ed. xi.,1971, 26, 1089.

Terpenoids und Steroids

368

Hz67

(447) R = NH,

(449) R =-N

3

17-Aminoandrostanes (453) open the ring of maleic anhydride to give the N-steroidal maleamic acids (454). which react with acetic anhydride-sodium acetate to give the 17-yl maleimides (456) oia the labile isomaleimides (455).294 Chiroptical properties of steroidal amine-dimedone condensation products are reported on p. 292.

MiscellaneousNitrogen Compounds.-In a novel synthesis of t-azido-compounds, 5a-pregnan-6fi-01 (457) reacted with BF,-hydrazoic acid to give a mixture of 5g- (459) and 5a-azidopregnanes (460),- in comparable proportion^.^^ The 2Q4

T. Nambara. T. Shibata, M . Mirnura, and H . Hosoda, Chem. and Pharm. Bu". (Japan),

2Q3

Q. Khuong-Huu, G. Lukacs, A . Pancrazi, and R . Goutarel, Tetrahedron Letters, 1972,

1971, 19, 954. 3579.

369

Steroid Properties and Reactions

H (453) 1 4 ~ or - 14P-H 1 7 ~ or - 17P-NH2

HC-C' 11

\

HCKo N

mechanism is not fully established, but careful examination of the products failed to reveal any 5-ene, 6-azido-derivatives, or rearranged products. It is suggested that a complex of BF, with the 6P-hydroxy-groupionizes with hydride

370

Terpenoids and Steroids

migration from C-5 ; the C-5 carbonium ion (458) may be able to accept the very nucleophilic azide group. although a backbone rearrangement was found to occur in the absence of HN, (cf. p. 378). The 5 2 - and 5P-azides were equilibrated under the reaction conditions. r-Azido-ketones may be prepared either by oxidation of azido-alcohols with Jones' reagent or by substitution of suitable r-bromoketones, using sodium azide in a dipolar aprotic solvent.296The azido-group survives reduction of the oxofunction with sodium borohydride. although azides may be reduced with this reagent under forcing conditions. An unusual dimerization occurred when the diazo-ketone (461). derived from cholanic acid, was treated with hot acetic acid. As well as the expected hydroxy-ketone acetate (462), the dioxan (463) was formed ; this compound is a dimer of the hydroxy-ketone. Some further transformations of these products are also described."-

+

H (4611

(463) The oxaziridine (464), derived from conanine, reacts with acid to give the compound (466). The unstable intermediate (465) can be obtained from the oxaziridine by the action of base.'98

OH Me

H H (464)

"' B. Schonecker and K . Ponsold, J . prukr. Chew., 1971,313, 817. ""

""

Y . Yanuka and Y . Golander, J . Org. Chem., 1972, 37, 2108. 1'. Milllet a n d X . Lusinchi, T e t r a h d t u n Lrrtcrs, 1971, 3763.

37 1

Steroid Properties and Reactions

The nitroxide (467),a free-radical species with potential value as a spin label, has been synthesized in three steps (Me,SO,. CH,=CH-CH,MgBr, and rn-chloroperbenzoic acid) from the lactam (468).299The formation of some novel steroids with fused heterocyclic rings is described on pp. 326,346,351,355, and 359 and a novel method for the introduction of thio- and nitrogen-containing substituents at C-5 on p. 357.

0

H

IT50

&

CH,CH =CH,

CH,CH=CH,

HO

H

H

(468)

(467)

Sulphur Compounds.-New light has been thrown on the mechanism of the Pummerer reaction of sulphoxides (468a) by the use of conformationally defined steroidal s u l p h o x i d e ~The . ~ ~reaction, ~ in warm acetic anhydride, involves both a reduction at sulphur and an oxidation at the a-carbon atom. The possible reaction routes are outlined in Scheme 15.

+ (468a)

I

+

I

(469)

1-ACOH + I R-SzC-CH

I

I

+

I

I

I

/

I

I

(4711

-Ad-

I R-S-C-CH

-H+

R-S-C=C

I

I 1

(470)

Scheme 15 Analysis of products from a variety of 3%-,3P-, 6a-, and 6P-steroidal sulphoxides led to the conclusion that deprotonation of the acetoxysulphonium ion (469) to give the sulphur-stabilized carbonium ion (470) proceeds through a transition 2y9

3ou

R. Ramasseul and A. Rassat, Tetrahedron Letters, 1971. 4623. D. N . Jones, E. Helmy, and R. D. Whitehouse, J.C.S. P r r k i ~I . 1972. 1329.

Terpenuids and Sfcruds

372

H

:

so I

Me (472)

H

: S

I

CH,OAc (473)

state with ylide character (a sulphonium ion-stabilized carbanion at the acarbon atom (471)). The ylide mechanism normally leads to oxidation at the least-substituted a-carbon atom; the equatorial 6a-methylsulphinyl steroid (472), for example, afforded the 6a-acetoxymethylthio-derivative(473) as major product, reaction at the more substituted ring position being less favourable. The 3/?-sulphoxidesimilarly gave a 3/?-acetoxymethylthio-derivative.Anomalous behaviour of the highly compressed 6fl-sulphoxide (474), and to a lesser extent also the axial 3a-sulphoxide, afforded the corresponding vinyl sulphides (e.g. 476). I t is argued that the conformational change accompanying removal of the 6a- or 3P-protons, respectively, allows relief of strain as the axial sulphoxides assume the geometry of the ylides (e.g. 475); no such relief would accompany conversion of the axial sulphoxides into ylides with the carbanion in the alkyl group (e.g. 477). The observed regioselectivities are not compatible with another mechanism which has been proposed, namely a concerted cyclic elimination of the type found in pyrolytic elimination of many ~ u l p h o x i d e s . ~ ~ Ref. 99, pp. 1 1 1. 440.

Steroid Properties and Reactions

373

The oxidation of 3-substituted 2a,5a-episulphides with rn-chloroperbenzoic acid gives anti-sulphoxides (e.g. 478) (cf the formation of syn-. or anti-sulphoxides from the unsubstituted epi~ulphide~'~). Reaction of the 3~-bromo-sulphoxide (478) with phenyl-lithium gives the 2,4-diene (480), probably via an unstable 5aphenylsulphinyl-2-ene (479).which can undergo a normal ~yn-elimination.~'~

+ Li

Ph

(479)

(478) Hydrogen sulphide adds on to 4,6-dien-3-ones in the presence of sodium methoxide to give the 5a,7a-epidisulphide (481) as major product, together with the 7wthiol(482). The epidisulphide bridge can be cleaved with NaBH, to give the 5a,7a-dithio! (483).304

6 Molecular Rearrangements

Contraction and Expansion of Steroid Rhgs.-5a-Oestrane-2,3-dione (484), which exists largely as the diosphenols (485) and (486), undergoes a benzilic rearrangement to give a mixture of the epimeric hydroxy-acids (487).305"The results are interpreted in terms of almost equal probability of attack by hydroxide ion upon each of the two carbonyl groups, in contrast to the reaction in the cholestane series where attack upon C-3 is preponderant because of steric hindrance by the C-19 methyl group. The mechanism of rearrangement, and conformations of possible transition states, are discussed in detail. A similar study of 5a-oestrane-3,4-dione is also reported.305b Homologation of ring A by the action of diazomethane on 3-0x0-steroids has been extended to the 7a-benzoyloxy-5a-3-oxo- and the ~-nor-5P-3-oxo-derivatives : in each case two isomeric cycloheptanone analogues (3-0x0- and 4-0x0-) 302 303 304

'05

Ref. 34, p. 296. T. Komeno, M . Kishi, H . Watanabe, and K . Tori, Tetrahedron, 1972, 28,2781. Y. Yamato, M . Kurokawa, and H. Kaneko, J . Pharm. SOC.Japan, 1971,12, 1297. ( a ) J . Alais, P. Bourguignon, and J. Levisalles, Bull. SOC.chim. France, 1971, 3737; ( 6 ) J . Alais and J. Levisalles, ibid., p. 3731.

Terptznoids und Sreroids

374

(484)

(487)

were produced.'96 A mixture of A-homo-ketones and other products was also obtained from 5r-cholestan-2-0ne.~'~ The 19-hydroxy-4.6-(488)and 4.7-dien-3-ones (489) react with (2-chloro-1.1,2trifluoroethy1)diethylamine to give the respective 5/l,l9-cyclodienones (490); the oyclopropane ring is readily opened (by Ac,O-H') to give the acetoxycycloheptatriene analogues (491 ). Dehydrogenation of these compounds with N bromosuccinimide gave the novel 1.6-rnethano-[1Olannulene (492). n.m.r. properties confirming the expected aromaticity of this lor-electron system. The 3-methoxy- and 3-deoxy-analogues were also ~ r e p a r e d . ~ "

J

(488) A6 (489) A T

(492) Attempted reduction of the 19-hydroxy-5fi.6/?-epoxide (493) with iithiurn trimethoxyaluminium hydride caused an unusual rearrangement. giving the Dreiding C-5 spiran (494) and another compound of unknown structure.'

''

"'-

M . Ephritikhine, J . Levisalles, and G . Teutsch, Bull. SOC.chim. Frunce, 1971,4335. P. H . Bentley, M . Todd, W . McCrae, M . L . Maddox. and J . A. Edwards, Terrahedron, 1972.28. 141 I .

Steroid Properties and Reactions

375

models suggest that the conformation of the epoxide (493)is suitable for migration of the C-1-(2-10 bond, to attack the a-face of C-5. The (2-5-0 bond may be activated by complexing of the epoxide oxygen with an aluminium species, held in position by the C-19 oxygen atom. Reaction of the product (494) with HCl formally reversed the rearrangement by generating a C-10 carbonium ion, and gave the cholorohydrin (495).

*\ LiAI(0 Me), H

AcO

(493)

HO (494)

OH (495) Irradiation of the SP-methyl-9-en-6-one (496 ; 'Westphalen' structure) in acetone gave the 5a-isomer (497), presumably t>iathe biradical (498) in a triplet reaction.308The 5a-methyl-3,6-diketone rearranged on silica gel, or with acid, to give the C-10-spirocyclopentanone(500). A probable mechanism involving the enol(499)is illustrated. Further reaction with acid gave a compound formulated as the 4,10-bridged structure (501).,08 The reaction bf 3a,5-cyclo-5a-cholestan-6-onewith diazomethane-AlC1, enlarged ring B to give a mixture of ketones, including various isomeric B-homo-, Some bromo- and unsaturated B-bishomo-, and ~-trishomo-compounds.~~~ derivatives were prepared from these ketones. Acetolysis of the mesylates (502) and (504) of 5,6-methano-3-alcohols gave the rearranged products (503) and (505). In each case the cationic centre generated at C-3 must be attacked by the most suitably placed bond of the cyclopropane ring.'55 Holarrhenine 12-mesylate is reduced by sodium borohydride in anhydrous akohols with rearrangement to give a product with the c-nor-D-homo-struct ~ r e . ~The " reaction is similar to that of a related conanine derivative, discussed 308 309

3'0

R. J . Chambers and B. A. Marples, Tetrahedron Letters, 1971, 3747. J . Gehlhaus, V. Cerny, and F. Sorm, Coll. Czech. Chem. Comm., 1972,37, 1331. G. Van de Woude and L. van Hove, Tetrahedron Letters, 1972, 1305.

Terpenoids and Steroids

376

(496) SB-Me (497) 5cu-Me

@-

MsOJ

( 5 0 4 ) 3a or

38

(498)

&o*c (505)

377

Steroid Properties and Reactions

''

last year., A similar rearrangement is reported in a NN-dicyanoconimine analogue., 17-0x0-steroids (506) undergo bishomologation with diazomethane and AICl, to give the 17b-0x0-derivatives(507). An unequivocal assignment of structure to these products means that compounds previously thought to have the partial structure (507) are in fact the 17a-oxo-~-bishomo-derivatives (509). These were obtained via Tiffeneau ring-enlargement from the 1 'la-0x0D-homo-analogues (508).,

{

fi

CH,N,-AICI,,

{

0

H

H

(506)

(507)

0

The well-known rearrangement of sulphonates of pregnan-20p-01s to give D-homo-androstane derivatives (5 11) may also be effected in almost quantitative yield by treating the 20-acetates (510) with BF,-ether for several days, or with

Me

H b M e

' H (514) 31I

312 313

Ref. 34, p. 300. G. Lukacs, L. Cloarec, L. Lacombe, and X. Lusinchi, Bull. SOC.chim. France, 1972,180. G . Eadon and C. Djerassi, J . Medicin. Chern., 1972, 15, 89.

378

Terpenoids and Steroids

BF,-acetic acid for 1 h.31 The reaction succeeds also in the presence of 11- or 12-oxo-substituents, although the rate is lowered by the inductive effect of the 0x0-group. A 3P-acetoxy- or hydroxy-group survives the reaction, offering the most convenient synthesis of ‘uranediol diacetate’, directly from Sa-pregnane30,20P-diol diacetate. The 20a-analogue ( 512) surprisingly gave the same Dhomo-acetate (511) in low yield, with the 18-nor-androst-13-ene-derivative (515) as major product. A direct rearrangement of the 20~-isomer(512) to the D-homostructure (51 1) is impossible. but a two-step rearrangement through the strained diaxially substituted isomer (513) seems to offer a reasonable pathway. The Dhomoannulation reaction has also been applied to the ‘linear’ steroid analogue (516)giving the product (517).3’4

(517) A 17r-ethynyl-17~-01(518) rearranged in acidic methanol to give the 17methyl-D-homo-16-en-17a-one ( 5 19).241

0

‘ H

‘Backbone’ and Related Rearrangements--The factors favouring backbone rearrangements and governing their extent are still not fully understood. Following last year’s d e m ~ n s t r a t i o n ~ that ’ ~ strain at the C/D ring junction is not a

”‘ S . Aoyama,

K . Kamata, and T. Komeno. Chrm. and Pharm. Bull. (Japan), 1971, 19,

1329. ’I5

Ref. 34, p. 304.

Steroid Properties and Reactions

379

prerequisite for backbone rearrangement, a similar conclusion comes from a study of the effect of sulphuric acid on the 3a- and 3p-methylamino-~-homoandrost-5-en-17-ones (520).3'6 After 2 h at 0 "C the major product in each case was a 14P-A8(9)-unsaturatedisomer (521) (lop-configuration in the 3p-NHMe derivative, but uncertain in the 3a-NHMe compound). Further rearrangement at room temperature gave mainly the conjugated unsaturated ketones (522). Like other backbone rearrangements reported re~ently,~'these reactions seem best interpreted as a search for the most stable location of the olefinic bond, whenever conditions permit the existence of a tertiary carbonium ion, initially at C-5.

Me (520) 3a or 3p

eo

H-NMe I

(522) On the basis of experiments with the four unsaturated alcohols (523H526), the efficiency of backbone rearrangement has been shown to decrease with increasing separation of the olefinic bond from the site of strain, in this case the trans junction between six- and five-membered rings. The authors consider this strain to provide the driving force for rearrangement.31 The four unsaturated alcohols give the four rearranged ketones (527H530) in the yields indicated. The other products from each reaction were olefinic, resulting from loss of the '17'P-OH group with migration of the 'C-18' methyl group (531) to give compounds with the partial structure (532). If the backbone rearrangements occur through a sequence of intermediate carbonium ions, rather than as a rapid concerted process, the different yields of ketones could result from the longer time 316

'I7

F. Frappier, J. Boivin, and F.-X. Jarreau, Compt. rend., 1972, 274, C,2190. J. Bascoul, E. Noyer, and A. Crastes de Paulet, Bull. Soc. chim. France, 1972, 2744.

380

Terpenoids and Steroid

available for intervention of the dehydration reaction [(531)--* (532)] in the larger molecules. I t would then be unnecessary to invoke transmitted strain to explain the varying yields of ketones: the simpler concept of carbonium ion mobility would be sufficient. Further work is clearly needed to settle this point.

(524)

(528) 60'z

(530) 250/2

I5 H

(532)

Steroid Properties and Reactions

38 1

In a further study of the structural features favouring backbone rearrangements, the B-nor- and A-nor-androstenols (533), (534), and (535) have been subjected to acidic conditions (H,S0,-MeOH).3 The diversity of products, including some dienes resulting from elimination of the 17P-hydroxy-group, contrasts with the smooth backbone rearrangement of androst-5-en-17P-01 (525) under these conditions to give the 17-0x0-compound (529). It is proposed that the multiplicity of strains at ring junctions in these nor-steroids is unfavourable to the backbone rearrangement, which in ordinary steroids is seen as providing relief of strain found only in the trans fusion of rings c and D.

OH

OH

(534) R = H (535) R = Me

(533)

The two 3~-dimethylaminoandrost-5-en-17-ones (536), epimeric at C-14, (537) in coneach gave the same 5~-methyl-19-nor-14~-androst-8-en-17-one centrated sulphuric acid.3I 9 The corresponding 3a-dimethylamino-14a-androstane derivative under similar conditions gave a mixture of rearranged products lop-isomers in e q ~ i l i b r i u m . ~3-~ ' analogous to (537), but with the 1 0 ~ and Methylaminoconan-5-ene reacts similarly. The 14P-A8(9'-unsaturatedstructure (537), which apparently represents the most stable location of an olefinic bond in the androstane series, is reached through a series of migrations of the unsaturated bond, which must exist transiently at the 8(14)-location in order to permit inversion from the 14a to the 148 configuration:315the ultimate configuration at C-10 is decided by the conformational requirements of the C-3 substituent. 3P-Aminoandrost-5-en-17-one and 3j-aminopregn-5-en-20-0ne (538) rearrange in acetic acid-sulphuric acid to give mixtures which include normal products of

Me,N

& 9 \

(536) 14a or 14p

318

319

320

Me,N

Me

(537)

J. Bascoul, D. Nikolaidis, and A. Crastes de Paulet, Bull. SOC.chim. France, 1972, 184. F. Frappier, M. Pais, and F. X. Jarreau, Bull. SOC.chim. France, 1972,610. F. Frappier, J . Thierry, and F. X . Jarreau, Bull. SOC. chim. Frunce, 1972,617.

Terpenoids and Steroids

382

COMe

(539)

(540)

+

backbone rearrangement (539). the abeo-l( 10 -+ 5)-compounds (540), and A4unsaturated isomers (541). The 3%-amino-analogues gave only backbonerearranged products.321 When a 3a- or 3P-amino-A5-steroid (e.g. 542) undergoes backbone rearrangement in D,SO, the product (547) is found to contain from seven to eighteen deuterium atoms.322The locations of most of these have still to be determined, but considerable proton exchange in the (2-19 methyl group was evident from n.m.r. and m.s. studies. Possible mechanisms for deuterium incorporation include reversible formation of a C-5 spirocation and the corresponding olefin (543), or the transient formation of a 5fi,19-cyclosteroid [cyclopropane ; (546)] through deprotonation of an edge-protonated cyclopropane (545) which differs only slightly in structure from the transition state (544) for methyl migration. Deuterium incorporation into a migrating C -19 methyl group apparently occurs only in 3-amino-substituted compounds.322 ''I

'I2

F. Frappier and F. X. Jarreau, Bull. SOC.chrm. France, 1972, 625. M . M . Janot, F. Frappier, J . Thierry, G . Lukacs, F. X. Jarreau, and R . Goutarel, Terrahedron Letters, 1972, 3499.

383

Steroid Properties and Reactions COMe

(544)

I

(545)

(543)

(547)

Extensive introduction of deuterium (at positions marked *) has also been observed in the acid-catalysed partial backbone isomerization of euphenyl acetate (548) into isoeuphenyl acetate (549). Only 10% of the material was left free from deuterium as the result of undergoing non-stop rearrangement, the remainder suffering a complicated sequence of deprotonation-deuteriation steps to account for the observed isotope distribution.323 323

Y . Nakatani, G. Ponsinet, G. Wolff, J . L. Zundel, and G. Ourisson, Terrahedron, 1972, 28, 4249.

Terpenoids and Steroids

384

(549)

An account of the dehydration of 9- and lO-hydroxy-l9-nor-5~-methyl steroids includes some further discussion of the factors favouring backbone rearrangement. The 10P-hydroxy-compounds (550) gave high yields of A I 3 ( l 7)olefins (55 1 ) with toluene-p-sulphonic acid-acetic anhydride, whereas the usual ‘Westphalen’ reagent (H,SO,-Ac,O-HOAc) gave the A’(‘’’- (552) and A l 3 ( l 7 ) olefins (551) in ratio 60 : 40.324This finding supports the view3,’ that added acetic acid provides a medium more favourable to kinetically controlled deprotonation of the intermediate carbonium ion. The authors reiterate their opinion326 that the Westphalen rearrangement involves lop-methyl migration concerted with departure of the 5%-substituent,although conceding that complete ioniza-

d8H1’ (550)

(551)

R’ = PhCH,, R2 = 8-OH o r R ’ = R2 = H

”‘ J . 325 32h

G . L1. Jones and B. A . Marples. J.C.S. Perkin I, 1972, 792; Chem. Comm., 1969, 689. Ref. 1066, p. 363. J . G . Ll. Jones and B. A . Marples, J . Chem. SOC.( C ) ,1971, 572.

Steroid Properties and Reactions

R'O

385

J33

AcO OAc

OAc (554)

tion at C-5 requires little more energy than the synchronous process. Dehydration of the l0a-hydroxy- (553) and 9a-hydroxy-isomers (554) occurred without rearrangement, giving mixtures of olefins (A1('') + A9(lo), and A9(10) + A9(l '), respectively).3 2 4 Reaction of the 'Westphalen diacetate' (555) with hydrogen fluoride afforded the addition product (556) and the rearranged 25-fluoro-~-homo-compound (557), as well as lesser amounts of five other products of rearrangement, three of which were positively identified.327 Dehydrofluorination of the 9a-fluorocompound (556) with base gave a mixture of the known 9(10)- and 9(11)-enes.

OAc (555)

LHF F AcO OAc (556) 32'

(557)

C. Rerrier, J.-C. Jacquesy, and R. Jacquesy, Tetrahedron Letters, 1971, 4567.

386

Terpenoids and Steroids

The 25-fluoro-compound. isolated as the corresponding 3,6-diketone, is analogous to some other products of backbone and side-chain rearrangement reported last year.32 8 Further studies on the reversed backbone rearrangement of compounds in the ~-homo-l8-nor-A'~-series( 5 5 8 ) 3 2 9 show that the olefinic bond readily migrates into ring A, with movement of the 10P-methyl group to the 9fl-position (559). provided that ring A contains a saturated 3-0xo-substituent.~~~ The corresponding A'- or A4-unsaturated compounds, however, failed to undergo backbone rearrangement. suffering instead a slow aromatization of ring D (560).

H

(559)

(558) 5r or 5g

I

(560) Equilin (561) isomerizes in anhydrous HF or in the systems HF-SbF, or HS03F-SbF, to give A*- (562) and A9(l''-dehydro-oestrones (563), depending upon the reaction t e r n p e r a t ~ r e . ~ ~ '

#\%

H I

H

HO

HO (5611

HO

&

& \

(562)

&4

\

(563)

"* 329 j3'

331

Ref. 34, p. 306. Cf. ref. 1066, p, 384. C. Monneret, Q. Khuong-Huu, and R. Goutarel, Bull. SOC.chim. France, 1972, 291. J.-C. Jacquesy. G . Joly, and J.-P. Gesson, Compt. rend., 1972, 274, C , 969.

Steroid Properties and Reactions

387

Epoxide Rearrangements.-The ~-nor-3/3,5/3-epoxide(564) reacts with BF, to give the fragmentation product, ~-norcholest-3(5)-ene (567), with a little of the 5a-isopropyl ketone (565). A possible rearrangement sequence is illustrated, involving formation and fragmentation of an oxetan derivative (566); acetone was detected among the products.332 Rearrangement of the epoxide (568) with BF, gave the B-nor-aldehyde (569)as major product.116

' H

/

dienes

(568) 332

I. Morelli, S. Catalano, G. Moretto, and A. Marsili, Tetrahedron Letters, 1972,717.

388

Terpenoids and Steroids

The 9r,l0a-epoxy-compound (571). obtained from the ‘Westphalen’ 3palcohol (570) by cyclization with lead tetra-acetate followed by epoxidation, undergoes backbone rearrangement with BF, to give (572).333

The partial backbone rearrangement of the 9r.l lsr-epoxy-4a,l4cr-dimethyl steroid (573) with BF, gave as major product the diene (574), along with the 9p-1 1-ketone (575).334 An analogous rearrangement in the 4,4,14&-trimethyl series was reported last year.335

(573)

1

(574)

“’ ”‘ J . Wicha, Tetrahedron Letters, 1972, 2877. ’

j S

R. Kazlauskas, J . T. Pinhey, and J . J . H. Simes, J . C . S . Perkin I , 1972, 1243 Ref. 34, p. 308.

Steroid Properties and Reactions

3 89

The rearrangements of 1la,l2a-epoxy-steroids are profoundly influenced by l2g-substituents. The 12Q-phenyl compound (576)reacted with BF3 in a manner totally different from the 12P-methylepo~ide,~~~ all the main products arising from initial migration of the 13P-methyl group to C-12.337The resulting C-13 carbonium ion (577) reacted further in one of three ways: (a) loss of the 14aproton to give the 1la-hydroxy-13-ene (578); (b) sequential hydride shifts and loss of a proton from C-7, leading to the 7,9(1l)-diene (579); or (c)fragmentation of the 11,12-bond to give the unsaturated aldehyde (580). The bulky 12-phenyl group is considered to impose a conformational restraint on the initial C-12 carbonium ion, permitting migration of the 13P-methyl group but preventing the more usual migration of the 13,14-bond which normally affords products with the c - n o r - ~ - h o m o - s t r u c t u r e .Other ~ ~ ~ large substituents at C-12 would be expected to produce comparable results.

The 24,28-epoxide (581) derived from fucosterol (or its acetate) reacts with BF, to give the 28-0x0-compound (582),by a simple hydride migration and the 24-dehydro-compound (583; desmosterol), resulting from fragmentation of the 24,28-b0nd.~~* The fragmentation has several precedents.339 336 337

338

339

J . M. Coxon, M. P. Hartshorn, and D. N . Kirk, Tetrahedron, 1969,25,2603. L. J . Ames, A. F. H. Baines, J. M . Coxon, and M. P. Hartshorn, Austral. J . Chem., 197 I , 24, 1899. N. Ikekawa, M . Moriskai, H. Ohtaka, and Y . Chiyado, Chem. Comm., 1971,1498. Ref. 34, p. 307; ref. 1066, p. 368.

Terpenoids and Steroids

390

Epoxidation of the A3-en01acetate (583) gave the P-epoxide (584). Pyrolysis of the epoxy-acetate afforded the 4a-acetoxy-5fi-3-ketone (585), which was epimerized in acetic acid--sodium acetate to give the stable 4j-isomer There

&

OAc

ICO

\

H (583) AcO-

*@+om AcO

(584)

340

R . B. Warneboldt and L. Weiler,

Tetrahedron Letters,

(585) ~ u - O A C (586) 4P-OAc 1971, 3413.

39 1

Steroid Properties and Reactions

was no isomerization to give a 2-acetoxy-compound, so the 4-acetoxy-compounds are not involved as intermediates in the conversion of the 4B-bromo-3-ketoneinto 2-acetoxy-ketones, reported last year.341 Acetolysis of the 2p-bromo-5p-3ketone gave only the 2P-aceto~y-ketone.~~'

Miscellaneous Rearrangernents.-3-O~o-A~*~-dienes (587) undergo aromatization in acetyl bromide at room temperature342(4-en-3-ones require heating343). A key intermediate, the 3,7p-dibromo-3,5-diene(588),could be isolated after only brief reaction. The lop-methyl-dienone (587; R = Me) affords as final product an anthrasteroid (590), via the spirocation (589). The 19-nor-compound (587 ; R = H) merely gives the product (591), aromatized in ring B. By-products with the 14p configuration were also obtained. A 19-hydro~y-A~.~-dienone (587; R = CH,OH) required more drastic conditions for aromatization and gave ring B-aromatic products with loss of the 1 0 f l - s ~ b s t i t u e n t . ~ ~ ~

I

R

=

Me

2a,3cr-Epoxy-5-hydroxy-5cr-androstan-17-one (592) is aromatized by HBrHOAc to give the 4-methyloestratriene (593),but a 6-0x0-group (594) alters the course of rearrangement, giving the 1-methyloestratrienone (595).344Similar reactions of differently substituted compounds have been described previously.343 Full details have appeared345 of the aromatization of 4,5-epoxy-3-hydroxysteroids.346 341

342

343 344

345 346

Ref. 34, p. 242. J. Libman and Y. Mazur, Chem. Comm., 1971, 1146.

Ref. 34, p. 310. J. R. Hanson, J.C.S. Chem. Comm., 1972, 1119; J . R. Hanson and H. J. Shapter, J.C.S. Perkin I , 1972, 1445. D. Baldwin and J. R. Hanson, J.C.S. Perkin I, 1972, 1889. J. R. Hanson, Chem. Comm., 1971, 1343.

392

Terpenoids and Steroids

(592)

R

=

(594)

R

= =O

(5931

H

(595)

5-Methyl-~-nor-Sa-steroidal3-ketones (599) have been obtained from 3a,5acyclosteroids (596)by the sequence illustrated. A stereospecific pinacol rearrangement of the 3flSfl-diol (598) ensured the configuration of the 5-methyl subst i t uen t. 3 4 7

@ @ H*

7

0

Me

Mk OHOH

(599)

(598) acetic acid (600) with H,SO,The reaction of 3a.5-cyclo-5r-cholestan-6~-yl HOAc gives 3-methyl-~-norcholest-3(5)-en-6fl-ylacetic acid (601),348and not cholest-4-en-6P-ylaceticacid, as reported in 1949.349The reaction is therefore similar to that of unsubstituted 3a.53-cyclosteroids (596).

CH,CO,H (600 34 1 348

34v

CHZCOZH (6011

Q. Curotti, A . Romeo, and 1. Torrini, Garzerta, 1971, 101,475. I. Torrini and D. Curotti, Chem. and Ind., 1972, 259. E. Kaiser and J . J . Svarz, J . Amer. Chem. SOC.,1949, 71, 517.

Steroid Properties and Reactions

393

The Serini reaction (Zn in refluxing xylene) has been applied to the 20-acetates of 13a-pregnane-17,20-diols,giving 13a-pregnan-20-oneswith the usual inversion of configuration at C -17.222Sa-Hydroperoxy-A6-unsaturatedsteroids, obtained by photosensitized oxygenation of A5-compounds, have been reported to rearrange readily into the 7a-hydroperoxy-A5-isomers ;350 the reaction failed, however, for a 3,19-diacetoxy-5a-hydroperoxy-compound.35As an alternative route to the 7a-hydroxy-derivative, the 6-en-5a-o1(602)is reported to rearrange smoothly in aqueous acetic acid to give the 7a-hydroxy-A5-compound(603)and its 7-acetate.

7 Functionalization of Non-activated Positions Full details have appeared of the conversion of 3/3-acetoxylanostan-7a-o1into the 32-oxime, and some derived products, via photolysis of the 7-nitrite (Barton Related compounds of the 8-en-1l-one series were obtained similarly. Attempts to hydrolyse the 32-nitrile (604) were unsuccessful, and reduction with LiAlH, stopped at the intermediate stage, giving the 32-aldehyde (605) after hydrolysis. The aldehyde was readily reduced to the 32-alcohol, but could not be oxidized to the 32-carboxylic acid (606)even though several novel oxidation methods were devised, using pivalaldehyde as a model highly hindered aldehyde. 17

(604) X = CN (605) X = CHO (606) X = C 0 2 H 350 35

'

352

G. 0. Schenk, 0. A. Neumiiller, and W. Eisfeld, Annalen, 1958,618,202. P. Morand and A. Van Tongerloo, J.C.S. Chem. Comm., 1972, 7. P. L. Batten, T. J. Bentley, R. B. Boar, R. W. Draper, J. F. McGhie, and D. H. R. Barton, J.C.S. Perkin I, 1972, 739; cf. ref. 99, p. 401.

Terpenoids and Steroids

394

Treatment of the 7-0x0-32-nitrile (507) with potassium t-butoxide eliminated the cyano-group to give the unsaturated ketone (608): Wolff-Kishner reduction then removed the 7-0x0-function but gave a mixture of isomeric olefinic derivatives. When the 7,1l-dioxo-32-nitrile was used, the elimination product was the 14P-8-ene-7.1l-dione (609). the cis-junction of rings c and D being preferred. The 14%-isomerof (609) was synthesized independently from cholesterol, and shown to epimerize readily at C-14.353

Photolysis of the 6-nitrite (610) of a 4,4-dimethyl-6/3-hydroxy-steroid leads to selective attack upon C-19. giving the 19-oximino-derivative (611); there was no detectable product of attack on the 4P-methyl group.35s A moderate degree

of deformation of ring A. to relieve the strong p-face compression, probably explains the absence of attack on the 4/3-methyl group. The 19-oximino-derivative (61 1) was oxidized and dehydrated to the cyano-ketone (612), which underwent elimination with base to give the 5( lO)-en-6-one (613).

(610)

R

=

H or P-OAc

(611)

353

T. J . Bentley, R . B. Boar, R . W. Draper, J. F. McGhie, and D. H . R. Barton, J . C . S .

354

Perkin I , 1912, 749. M . P. Kullberg and B. Green, J . C . S . Chem. Comm.. 1972, 637.

395

Steroid Properties and Reactions

AcO

@ ' 0

A

c

O0

M

Oxidation of 19-hydroxycholesteryl acetate (614) with Pb(OAc), is known to proceed with fragmentation to give the 19-n0r-A~(~~)-product (615).355The SP,6P-epoxy-derivative(616) is now reported to undergo a similar fragmentation on neutral alumina, giving the 5( 10)-en-6P-ol(617); the 5a,6a-epoxide was stable on alumina. The 5~,6~-epoxy-alcohol (616) reacted with Pb(OAc), with attack of the 19-alkoxy-radical upon C-11 to give the 1lp,l9-ether (618).356

Alkoxy-radicals in ring B, generated from hydroxy-derivatives of B-homocholestanes with Pb(OAc),, attack suitably placed C-H bonds to form transannular ether bridges. The main reactions are illustrated in Scheme 16. The 7ap-alcohol gave only a little of the 7ap,l9-oxide, the main product being an unsaturated aldehyde of uncertain structure. All the reactions in Scheme 16 occur through favourable conformations of the seven-membered ring.3 17a- and 17P-iodoandrostanes are formed as by-products in the functionalization of C-18 by the photolysis of hypoiodites of pregnan-20-01s (619). The 20alkoxy-radicals (620) undergo fragmentation followed by combination with 355

356 357

Ref. 34, p. 248. M. Kaufman, P. Morand, and S. A. Samad, J . Org. Chem., 1972,37, 1067. L. Kohout, Coll. Czech. Chem. Comm., 1972,37,2227.

396

Terpenoids and Steroids

AcO

AcO

H

OH

H

&+& H

'OH

H

AcO

D

D Scheme 16

iodine to give mainly the 17~-iodo-compound(622).5 6 The radical-induced transfer of a cyano-group from C-20 to C-18, reported briefly in 1970,is now described in full.358

H

H (621)

(622)

During studies of 'remote oxidation',359 by irradiation of steroid esters containing a benzophenone moiety, halogenated steroids were formed if CC1, or BrCCl, was used as the solvent. Further .work showed that the reaction is a simple free-radical chain process involving CCl,, and does not require the presence of a benzophenone derivative. lrradiation of steroids in solutions containing BrCCI, , or even better PhICI,, gives 9a- and 1k-halogenated products which are readily converted into A9(l' ) - or A14-unsaturated steroids. Mixtures of these 358 359

J . Kalvoda and L. Botta, Helu. Chim. Acto, 1972,55, 356; CJ ref. 1066. p. 389. Ref. 34, pp. 317, 318.

Steroid Properties and Reactions

397

olefins were produced in acceptable total yields and chromatographic separation was generally possible. The halogenation occurs selectively at the most accessible (a-face) tertiary positions. In some cases products of attack at 5a-H were also found. 6 o An Aspergillus species hydroxylates androst-4-ene-3,17-dione at C-18.3 6 1

8 Photochemical Reactions The photochemistry of steroids has been reviewed (128 references).36z Unsaturated Steroids.-Irradiation of either 9a,lOB- (623) or 9P,10a- (624) steroidal 5,7-dienes at 253.7 nm causes electrocyclic ring-opening to give 9,lOsecotrienes (625) (e.g. precalciferol),and also equilibration of the latter with their 6,7-trans-isomers (626) (e.g. tachysterol), but the ring-opening step is not reversible at this wavelength.363

(625)

Both the ring-opening and ring-closing reactions can occur, however, at wavelengths above 300nm. Variations in yields of compounds of the types represelited by ergosterol (623), precalciferol(625), and tachysterol(626), according to the wavelength of U.V.light employed, are interpreted in terms of the existence of different rotamers of precalciferol about the C-5 -C-6 bond.364 A 360

361

362 363 364

R. Breslow, J . A. Dale, P. Kalicky, S. Y. Liu, and W. N. Washburn, J . Amer. Chem. SOC., 1972,94, 3276. B. J. Auret and H. L. Holland, Chem. Comm., 1971, 1157. J. A. Waters, Y. Kondo, and B. Witkop, J . Pharm. Sci., 1972,61, 321. K. Pfoertner and J . P. Weber, Helv. Chim. Acra, 1972,55, 921. K. Pfoertner, Helv. Chim. Acta, 1972, 55, 937.

398

Terpenoidsand Steroich

new systematic study of the photochemistry of ergosterol and vitamin D, has yielded information concerning the effects of temperature and light intensity on the formation and subsequent decay of vitamin D,.365 Trityl tetrafluoroborate catalyses the photo-oxygenation of ergosteryl esters at - 78 "C to give the peroxide (627).366The reaction appears likely to involve a hitherto unknown excited peroxytrityl cation, which transfers oxygen to the diene system. Control experiments established that the trityl cation does not act merely as a triplet + singlet oxygen sensitizer, as do eosin and other dyes. Tris-(pbromopheny1)aminium hexachloroantimonate [(p-BrC,H,),h.SbCI;] catalyses the formation of ergosterol acetate peroxide even in the dark at - 78 "C. I t is suggested that the reactive oxygenating species may be of the type [Ar,N02]~.3hh The dye-sensitized photo-oxygenation of 3P-acetoxylanost-8-ene (628) gave an intractable mixture of products, but a similar reaction in pyridine containing nitrobenzene-p-sulphonyl chloride, intended to trap an expected intermediate hydroperoxide, gave a separable mixture including the known 7,9(1 1)-diene and 8-en-7-one. the 7r-hydroperoxy-8-ene. two unsaturated epoxides, and a novel 8,9-seco-8,9-ether (629). All these products probably arise via initial formation of the 9a-hydroperoxy-7-ene, which could not be isolated. The seco-ether (629) undergoes a variety of reactions, including regeneration of the 8,9-bond on bromination. to give the 7x1 lr-dibromo-8r.9a-epoxide (630), which structure was confirmed by X-ray ~rystallography.~~'

(628)

Jh5

""'

(629)

G . Naudet, C. Hyver, S. Lorrain, and R . Mermet-Bouvier, Bull. SOC.chim. France, 1972, 1013. D. H. R . Barton, G . Leclerc, P. D. Magnus, and I . D. Menzies, J . C . S . Chrm. Comm., 1972.447. J . E. Fox. A. I . Scott. and D. W . Young. J . C . S . Perkin I , 1972. 799.

Steroid Properties and Reactions

399

Studies on the photo-addition of olefins to the 4-en-3-one system have confirmed and extended recent findings in this field.368The steroidal enone (631) adds ethylene to give mainly the 4a,5a- (632; 57%) and 4a,5b-adducts (633; 24 %), with a trace of the 4P,SP-isomer (634).369 Isobutylene 1,l-diethoxyethylene react in similar fashion, giving adducts (635) and (636) regiospecifically. Adducts with cyclopentene, 1-acetoxycyclopentene, and cyclohexene were also obtained in good yields. Structures were established mainly from spectroscopic and chiroptical properties and from the ready isomerization of the strained trans- (4a,5P) fused adducts into the more stable cis- (4P,5P) compounds.369 Similar reactions of the 4,6-dienone with mono-olefins gave only 4aSP-ad-

g'

0

(634)

R (635) R = Me (636) R = OEt

6-Dehydrotestosterone acetate adds butadiene under U.V. irradiation, giving as one product the remarkable &,5a,6~,7a-adduct(637), containing three fused cyclobutane rings ; despite very considerable strain, this product was stable to basic hydrolysis and to acetylation at C-17. The major photo-addition product with butadiene was the trans-fused 4aSP-adduct (638), which isomerized in a

(637) 368 369 370

Ref. 34, p. 320. G. R . Lenz, Tetrahedron, 1972,28,2195. G . R. Lenz, Tetrahedron, 1972, 28, 221 1 .

Terpenoids and Steroid

400

(639)

(640)

basic solution to give the less strained 4P.5/3-adduct ;small quantities of the 6a,7a(639)and 6P.7fl-adducts (640)were also formed. The mechanisms of these cycloadditions are not yet fully under~tood.~” Further details have appeared372of the photochemical reactions of cholesterol (641) and cholest-4-en-3P-ol (642) (c$ ref. 373). The primary photochemical product appears to be the cation (643),derived, in the case of the A4-isomer,by a stereoselective photo-induced 4a-protonation. Subsequent reactions of the cation (643)depend upon the reaction medium, and include : (i) non-stereospecific

(644) R = alkyl, or A4or A5-cholesten-3P-yl

’-‘

G . R . Lenz, Tetrahedron Letters, 1972. 3027. A . Waters, B. Witkop, D. Guenard, and R . Beugelmans, Tetrahedron, 1972. 28. 7 9 1 . Ref. 1066, p. 392.

’-’Y . Kondo, J . 3-3

401

Steroid Properties and Reactions

deprotonation at C-4 to give the 4-en-3b-01 (642); (ii) addition of a nucleophile (RO-) to give 5P-alkoxy-derivatives (644); and (iii) fragmentation to give the olefinic aldehyde (645),which was transformed into its cycloaddition product, the oxetan (646). Irradiation of the 4-en-3fl-01 in the presence of NaBH, gave the oxetan (647) and the unsaturated alcohol (648).372 Carbonyl Compounds.-U.v. irradiation of a 5a-pregn-14-en-11-one (649) resulted in attack of the photochemically excited 11-0x0-group upon the allylically activated C-8-H bond, giving the novel 8,ll-cyclo-alcohol (650) in high yield.374The configurations at C-9 and C-11 are not yet known. The cycloalcohol afforded the original unsaturated ketone on heating with base, or the corresponding 8,14-dien-ll-one with Pb(OAc),.

The photochemical 1,3-acyl migration which converts certain fly-unsaturated ketones into isomeric enones has been investigated for a series of compounds, including cholest-4-en-7-one (651) and its 6,6-dimethyl derivative (652). Photoequilibration affords the isomers (653), considered to arise via n+ n* triplet states. The reactions are influenced by conformational and conjugative features which effect the stability of an intermediate radical pair of the type (654).375 Other workers376 have studied the phosphorescence spectra and lifetimes of triplet excited states of a number of fly-unsaturated ketones, including some

R

R

R

(651) R = H

(652) R 374

375

'''

R

=

Me

4

7

II

H (653)

0 (654)

P. Gull, H . Wehrli, and 0. Jeger, Chimia (Swirz.), 1971, 25,418; P. Gull, H. Wehrli, and 0. Jeger, Helv. Chim. Acta, 1971, 54, 2158. H . Sato, N. Furutachi, and K . Nakanishi, J . Amer. Chem. SOC., 1972,94,2150. K . G . Hancock and R . 0. Grider, J . C . S . Chem. Comm., 1972, 580.

402

Terpenoids and Steroids

steroidal 5-en-3-ones, and have interpreted the results in terms of ICIT* triplets. rather than n -+ T[*.The photochemical rearrangements (1,2- or 1,3-acyl shifts) observed for such compounds are considered to be determined by some factor other than the electronic configuration of the excited species.376 (655) and (656) in Irradiation of ‘Westphalen’ 5P-methyI-19-nor-9-en-6-ones acetone gives the respective Sa-isomers(p. 375). but when the reaction is performed in benzene solution further photoreactions occur. The 3.6-diketone (655) suffers a complex degradation, probably involving initial formation of a 1,2-secobiradical (657). the product being the des-A-ketone (658). The 3-methoxy-6ketone (656) undergoes a 1,3-acyl shift to give the cyclobutanone [6(5-+ 9)abeo] derivative (659).which undergoes decarbonylation on further irradiation to give the cyclopropane (660).377 1

hv benzene’

9 0

0 (6551

The cis- and trans-5,10-seco-l( lO)-en-5-ones(661) and (662) each afforded the same mixture of the oxetan (663) and an isomer of unknown configuration on U.V.i r r a d i a t i ~ n7 .8~The loss of stereochemical integrity in these reactions implies 377

378

R . J . Chambers and B. A . Marples, Tetrahedron Letters, 1971, 3751. M . Lj. Mihailovic, Lj. Lorenc, N . Popov, and J . Kalvoda, H e f v . Chim. Acra, 1971, 54, 228 1.

Steroid Properties and Reactions

403

\ AcO

0

AcO

AcO

0

a stepwise rather than a concerted addition of the olefinic bond to the carbonyl group. 4P,5-Methano-5fl-cholestan-3-one (664) suffers photoreduction on irradiation in propan-2-01, giving the 5P-methyl-3-ketone (666) in a reaction which parallels that of some simple cyclohexanone analogues. The 4a,5cr-methano-compound (667) unexpectedly also gave the 5P-methyl ketone (666) as major product, with only a little of the 5cr-methyl ketone (669).The reactions proceed through carbinyl radicals (665)or (668),and the symmetrical homoallylic radical (670)is postulated as providing a pathway for their intercon~ersion.~ 79

0& + o& & + o'

. ,

(667) 379

.

a

(668)

Me (669)

W. G. Dauben, L. Schutte, and E. J . Deviny, J . Org. Chem., 1972,37, 2047.

Terpenoids and Steroids

404

Esters-Photolvsis of the 1 1 P-nitrite (67 1 ) in the c-nor-D-homo series affords the nitrone (672). through the reaction sequence illustrated. Use of sNN-labelled nitrite has revealed that the NO group suffers isotopic scrambling in an intermolecular process. 380

(672) Irradiation of Sa-cholestan-3P-ylhydrogen oxalate in the presence of mercuryoxide and iodine gave dicholestanyl oxalate, with some Sr-cholestan-3P-01.~~ The reaction probably involves decarboxylation of a carboxylate radical, and pairing of the resulting alkoxycarbonyl radicals :

’

(11)

RO*C0.C02H--+ RO-CO-CO, + RO-e=O dirneriii t ion

+ CO,

RO.CO*CO*OR

Photolysis of the tosylates of steroidal alcohols provides a method for regenerating the parent The reaction may find applications where attempted hydrolysis would lead to elimination or other unwanted reactions. Cholesteryl thiobenzoate [O-ester ;(673)]is rapidly photolysed to give cholesta-3,5-diene(674). Stereospecific labelling L2H] of the C-4 hydrogen showed that the 4p proton is lost. The transition state must require some conjugation with the A5-olefinic bond, for the Sa-saturated analogue gave only the rearranged 3a- ahd 3P-thiol benzoates (S-esters) on p h o t o l y ~ i s The . ~ ~ ~photoreactions of thiobenzoate 0esters proceed mainly via the lowest triplet state.384 380 3H’

382 383

.IhJ

H . Suginome, T. Mizuguchi. and T. Masamune, Tetrahedron Letters, 1911 , 4723. K . Bartel, A. Goosen, and A. Scheffer, J . Chem. SOC.(0,1971, 3766. A . Abad, D. Mellier, J . P. Pete, and C. Portella, Terrahedron Lerrers, 1971, 4555. S. Achmatowicz, D. H. R . Barton, P. D. Magnus, G . A. Poulton, and P. J . West, Chem. Comm., 1971. 1014. D . H. R . Barton, M. Bolton, P. D. Magnus, P. J . West, G . Porter, and J . Wirz, J . C . S . Chem. Comm.. 1972. 6 3 2 .

Steroid Properties and Reactions

405

Miscellaneous.-Full accounts have now appeared38 of the pyrolytic and photochemical rearrangements of the isomeric 4,5-epoxy-6-ketones and 5,6epoxy-4 ketone^.^ 8 6 A major product in each case was 5a-cholestane-4,6-dione, although the photochemical reaction of the 4cr,5cr- and 5a,6a-epoxy-ketones also acid, by further reaction of the primary gave 4,5-seco-6-oxocholestan-4-oic product, 5fi-cholestane-4,6-dione.The ring-cleavage reaction was inhibited by added piperylene, without affecting the formation of the diketones. Photoreduction of the epoxy-ketones (675) and (676) with tri-n-butylstannane transformed each into the corresponding fi-ketol(677) and (678),respectively.

Photoisomerization of the 9,lO-epoxy-enones (679) and (680) gives abeo-9ketones. At -65 O C , with n-+ n* excitation, the reactions take the paths indicated (Scheme 17) but at higher temperatures, or with triplet sensitization, the 9a,lOa-epoxide gives a mixture of all three enediones. Further irradiation of the products affords their A5-unsaturated isomers. The reaction mechanisms are discussed in terms of stereoelectronic features of the biradicals resulting from initial rupture of the activated C-10-0 bond of each e p ~ x i d e . ~ ' ~ 385 386 387

J . P. Pete and M . L. Viriot-Vuillaume, Bull. SOC.chim. France, 1971, 3699, 3709. Ref. 1066, pp. 397--399. D. Bauer, T. Iizuka, K . Schaffner, and 0. Jeger, H e f c . Chim. Acta, 1972,55,852.

Terpenoids and Steroids

406

p OAc

0

/

OAc

o&

/

r.:!tl’ OAc

0

’

Scheme 17

The rearrangement of 3r,5-cyclo-5r-cholestan-6~-ol (681) under irradiation in benzene-methanol was recently reported to give a mixture of the methyl ether (682) and cholesteryl methyl ether (683).388Further study has shown that the reaction is a normal acid-catalysed one. apparently induced by an initial photochemical oxidation of methanol. The cyclosteroid is stable under irradiation in degassed solutions. which preclude ~ x i d a t i o n . ~ ~ ”

@ OR (681) R = H (682) R = Me

’”

a ‘

Meo&

NOH

(683) (684)

Ref. 1066, p. 399.

”’ S. J . Cristoi, G . A . Lee, and A . L. Noreen,

Tetrahedron Lerfers, 1971,4175

Steroid Properties and Reactions

407

gave a very poor Photolysis of the oxime (684)of 3a,5-cyclo-5~-cholestan-6-one yield of ring B lac tarn^,^^' unlike the photo-Beckmann reactions of 5 ~ and - 5pcholestan-6-one oximes, reported last year.390The major products of photolysis of the 3a,5-cyclo-oxime were derived via initial conversion into the parent 6ketone. 9 1

9 Miscellaneous Properties and Reactions The liquid-crystalline mesophases of cholesteryl benzoate and p-phenylbenzoate provide useful stationary phases for the gas chromatography of steroids, giving separations largely on the basis of molecular shape. These steroidal materials have distinct advantages over the more conventional stationary phases for certain applications, including separations of the isomeric androstane-3,17diols or pregnane-3,20-diols, and of cholest-4-ene from the 5-ene.392The dicholesteryl esters of some dicarboxylic acids are reported to exhibit liquid-crystalline properties.393The temperature-dependence of the Kerr effect has been measured for a series of liquid-crystalline esters of cholesterol.394 New practical procedures have been described for the quantitative estimation of most of the major neutral steroid metabolites in urine, using gas chromatog r a p h ~Mass . ~ ~spectrometry ~ has been used as a sensitive gas-chromatographic detector.396 By focusing on one ion with a characteristic m/e value, suitable steroids may be estimated accurately from the peak intensities of the 'single ion' chromatogram. Magnesium oxide-aluminium oxide gives improved separa~ ' plates of silica gel-silver tions of steryl 3,5-dinitrobenzoates by t . l . ~ . , ~and nitrate have been used to separate steryl acetates differing only in the lengths and unsaturation of the s i d e - ~ h a i n s . ~ ~ ~ The rates of autoxidation of cholesterol have been determined in aqueous dispersions and in monomolecular films. The main products, 7-0x0- and 7hydroxy-cholesterols, are formed rapidly at 85 "C in an aerated dispersion stabilized by sodium stearate (over 60% oxidized in 8 h) or when a surface film is exposed to air at room temperature. No oxidation was observed, however, when a dispersion was aerated at 25 0C.399Cholesterol 26-hydroperoxide has been identified among the products of auto-oxidation of crystalline cholesterol.400 The N-oxyl-4',4'-dimethyloxazolidinederivative (685) of 17P-hydroxy-5aandrostan-3-one 17-methylphosphonofluoridate has been used as a spin label 390 391

Ref. 34, p. 323. H. Suginome, H . Takahashi, and T. Masamune, Bull. Chem. SOC.Japan, 1972, 45, 1836.

392

393 394

D. N. Kirk and P. M. Shaw, J. Chern. SOC.(0,1971, 3979. D. Gross, Z . Naturforsch.. 1972, 27b, 472. E. I. Ryumtsev, M . V. Mukhina, and V. N. Tsvetkov; Doklady Akad. Nauk S.S.S.R., 1972,204,397.

395 396 397 3y8

399 400

R. N . Beale, D. Croft, and R. F. Taylor, Steroids, 1971,18,621,641. C . J. W. Brooks and B. S. Middleditch, Clinica Chirn. Acta, 1971,34, 145. A. Seher and E. Homberg, Fette, Seifen, Anstrichm., 1971,13, 557. D. R. Idler and L. M. Safe, Steroids, 1972, 19, 315. N. D. Weiner, P. Noomnont, and A. Felmeister, J. Lipid Res., 1972, 13, 253. J . E. van Lier and G . Khan, J. Org. Chern., 1972.37, 145.

Terpenoids and Steroids

408

for e.p.r. studies on r - c h y m ~ t r y p s i n . The ~ ~ hydrolysis of p-acetoxybenzoic acid and other phenolic acetates is catalysed by various imidazoles : cholic acid and its histamine derivative influence the rates of hydrolysis, through binding of the substrate.'02 The 17%-hydroperoxy-derivativesof pregnenolone and progesterone are suggested as probable intermediates in the generation of steroid hormones iri txt'o: the transformations of these hydroperoxides under electron impact, at high temperatures and on microbiological incubation, have been

goMe

/

P-F

$0

0' \


'"I '02 403

H

J . D. Morrisett and C. A. Broomfield, J . Amer. Chem. SOC., 1971, 93, 7297. S. Shinkai and T. Kunitake, Bull. Chem. SOC.Japan, 1971,44,3086. L. Tan, H . M: Wang, and P. Falardeau. Canad. J . Biochem., 1972,50,706; L. Tan and P. Falardeau, Steroidologia, 1971,2, 65.

2 Steroid Synthesis BY P. CRABBE, in collaboration with G . A. GARCiA, A. GUZMAN, L. A. MALDONADO, G. PEREZ, C. RIUS, AND E. SANTOS

1 Introduction

Several new synthetic approaches to the steroid nucleus have been reported during the past year, in particular for steroids with modified structural and/or stereochemical features. A comprehensive survey of the chemistry of steroids has appeared.’ Tentative rules for the designation of steroids have been published.2 2 Total Synthesis Different new stereospecific cyclization reactions leading to the tetracyclic skeleton of steroids have been reported. A series of papers describing a new synthetic approach to the steroid nucleus, both in the racemic and natural forms, is based on an interesting asymmetric induction. In the general scheme (Scheme l), the lactone (1) was converted into the Mannich base (3) by treatment first with a vinyl Grignard reagent and then with a secondary amine. Acid-catalysed condensation of (2) or (3) with a 2-alkyl1,3-~yclopentanedione(4) gave the tricyclic dienol ether (5). This was converted into the unsaturated A-des-steroid (6) by successive hydride reduction, selective catalytic hydrogenation of the cyclopentene double bond, acid hydrolysis, Jones oxidation, and base- (or acid-) catalysed cyclization. Finally, ring A was elaborated by catalytic hydrogenation of the 9,lO-double bond (steroid numbering) of (6), followed by removal of the protecting 3-keto-group and internal aldol condensation. For the preparation of optically active material the intermediate vinyl ketone (2) was condensed with ( - )-a-phenethylamine and the resulting diastereoisomeric Mannich base (3) [( - )-a-phenethylamine instead of diethyl] was separated by fractional crystallization of its oxalate salt. The above synthetic scheme was then applied to the separate optically active vinyl ketones (or their derivatives). By this method there have been prepared the racemic3 and optically active4,’ A-des-steroid (8) from the lactone (la) and 2-methylcyclopentanedione (4a), the J. H . Fried and J. A. Edwards, ‘Organic Reactions in Steroid Chemistry’. Van NostrandReinhold, New York, 1972. H. Selye, S. Szabo, P. Kowrounakis, and Y. Tache. Adv. Steroid Biochem. Pharmacoi., 1972. 3. 1. G. Saucy, R . Borer, and A . Fiirst, lielv. Chim. Acta, 1971, 54, 2034. G. Saucy and R. Borer, Helv.Chim. Acta, 1971, 54, 2121. G. Saucy and R.Borer, Helr. Chim. Acta, 1971, 54, 2517.

409

Terpenoids and Steroids

410

I-

VI1

R' (1) a ; R' = Me

b ; R'

= -

c"'.rtMe Me

0 Me

c : R' = -CH,CH,.

0 d ; R' = -CH2-CH2*CH-O

I

Me

+ 0

(4) a ; R2 = Me b ; R 2 = Et

(7) a ; R2 = Me b ; R 2 = Et

%

\

Reagents: i, N a H ;

ii,,

r C ' ; iii, NaOH-H,O; iv, H , O + ; v, NaBH,; vi,

-H,O

v i i , A MgCI, -60 " C ; viii. Et,NH; ix, AcOH-toluene; x, LiAIH,; xi, H ,-Pd/C.

Scheme 1

Steroid Synthesis 41 1 optically active gD,lOa-testosterone(9) from (8),5 as well as racemic and optically active oestr-4-ene-3J7-dione (7a) and 13/?-ethylgon-4-ene-3,7-dione(7b) from lactones (lb)6 or ( l ~ ) ~and , ’ (4a) or (4b), respectively. The starting lactones (la) and (lc) were prepared by a novel synthesis,’ from alkyl Grignard reagents and glutaraldehyde followed by oxidation of the resulting cyclic hemiacetals. The isoxazole lactone (1b) was prepared conventionally from diethyl 3-oxopimelate and 3,5-dimethyl-4-chloromethylisoxazole.5Alternative syntheses of these lactones in optically active form have also been r e p ~ r t e d . ~ ”

(13) A similar sequence of reactions was used for the preparation of (+)-13P-ethyl17a-ethynyl-17~-hydroxygon-4-en-3-one (14). Cleavage of the t-butyl ether of (6d) (prepared by the general reaction sequence) with toluene-p-sulphonic acid

‘ J . W . Scott and G. Saucy, J. Org. Chem., 1972.37, 1652, 1659.

’ M . Rosenberger, A. J . Duggan, and G . Saucy, Helu. Chim. Acta, 1972, 55, 1333. M . Rosenberger, A. J. Duggan, R. Borer, R. Muller, and G . Saucy, Helt.. Chim. Acta, 1 972, 552663. M . Rosenberger, D. Andrews, F. DiMaria, A. J . Duggan, and G. Saucy, Welt.. Chirn. Acta, 1972, 55, 249.

412

Terpenoids and Steroids

in benzene gave directly the unstable dienol ether (lo), which was selectively hydrogenated to (11). Compound (11) was then converted into (14) by two different routes. The first involved acid hydrolysis to the hemiacetal, which was converted directly into the tetracyclic diketone (12) by N-bromosuccinimide (NBS) oxidation in low yield. All attempts to improve the yield in the oxidation step failed. Potassium acetylide addition to (12) then gave norgestrel (14). In the second method. which appeared to be superior. the 17a-ethynyl sidechain was first introduced by reaction of ( 1 1 ) with lithium or potassium acetylide in liquid ammonia, and the resulting product was treated with methoxyamiiie hydrochloride in pyridine solution to give the ether oxime (13). Finally, conversion into norgestrel (14) was effected by chromium trioxide oxidation in dimethylformamide (DMF), followed by acid treatment." A total synthesis of df-oestrone methyl ether (18) starting with Michael addition of the vinyl ketone (15) to (4a) has been reported." The method is similar to previously described procedures. '

n .o

0

Another synthesis of oestrone methyl ether (18) used eugenol (19a) as starting material.' This was converted into rn-methoxyallylbenzene (19c) by treatment of the phosphate (19b) with sodium in liquid ammonia in presence of an excess of ethanol. The Grignard derivative (20a) was prepared by reaction of (19c) with I" ' I

'' I3

M . Rosenberger, T. P. Fraher. and G . Saucy, Hell.. Chitn. Acra, 1971, 54, 2857. G . S. Grmenko. E. V. Popova, and V . K . Maksimov, Russ. J . Or%. Chern.. 1971,7, 950. See U . Eder, G. Sauer, and R . Wiechert. Angew. Chem. Intemur. Edn., 1971, 10, 496. and references therein. A . Horeau, L. Menager, and H . Kagan, Bull. S o t . chitn. Fruncr, 1971, 3571.

41 3

Steroid Synthesis

n-propylmagnesium bromide in the presence of titanium tetrachloride. Treatment of (20a) with carbon dioxide furnished the acid (20b),easily converted into 6-methoxytetralone, a known intermediate” in the total synthesis of (18). Hydroboration of rn-methoxyallylbenzene(19c) gave the primary alcohol (2Oc),

(19) a ; R = OH b; R = O-P(OEt),

(20) a ; R = MgBr b; R = C 0 2 H C ;R = C H 2 0 H

1

0

d;R=OH

c:R=H

(211 also a useful total synthetic intermediate. l 3 Finally, reaction of (19c) with acrolein afforded an allylic alcohol, easily oxidized to the conjugated ketone (21), which with methylcyclopentanedione (4a) furnished a triketo-in termediate, readily cyclized to oestrone-3-methyl ether (18).l 3 An elegant synthesis of ( f)-D-homo-oestrone (30) by bis-annelation of the bicyclic ketone (22) uia 6-vinyl-a-picoline has been described (Scheme 2).l Alkylation of the ketone (22)with 6-vinyl-a-picoline,followed by acid deacetalization gave the alkylated enone (23) in high yield. Reduction of the saturated ketone of (23), catalytic hydrogenation of the double bond, and ketalization of the carbonyl group gave the hydroxy-ketal(25). This with sodium in liquid ammonia and one equivalent of ethanol gave the 1,4-dihydropyridine intermediate (26) which, with three equivalents of aqueous ethanolic sodium hydroxide, furnished the diketone (27) which cyclized to afford the tricyclic enone (28). Oxidation of the carbonyl group at C-17 was followed by base-catalysed cyclization, affording the diene-dione (29), readily converted into D-homo-oestrone (30). A total synthesis of the (+)-androstenedione (33) has been reported by a method involving a-methylation of aB,y&dienones, via their &-anions(Scheme 3).” Treatment of the dienone (31) with dimsylsodium in dimethyi sulphoxide, followed by addition of excess methyl iodide, gave a mixture from which the methylated tricyclic derivative (32)was isolated. Successive reaction of (32) with l4

l6

G . D. Cooper and H. L. Finkbeiner, J . Org. Chem., 1962. 27, 1493. S. N . Ananchenko and I. V. Torgov, Tetrahedron Letters, 1963, 1553. S. Danishefsky and A. Nagel, J.C.S. Chem. Comm., 1972, 373. S . Danishefsky, P. Solomon, L. Crawley, M. Sax, S. C. Yoo, E. Abola, and J. Pleteker, Tetrahedron Letters, 1972, 961.

& /

oprJ:; Terpenoids and Steroids

414

"!r

+

0

f

0

q

(22)

q

N (23)

1

iv, v

OH

('7)

1

0

(30) Reagents' i ,

-ButOK-Pr'OH, reflux 24 h ; ii, H 3O ; iil, NaBH,; iv, H,-Pd/CEt,N-MeC0,Et; v, HOCH,CH,OH-H ; vi, Na-NH,-EtOH; vii, NaOH. H,O; ix. Jones oxidation; x, NaOEt-EtOH. EtOH; V I I I HCI+

+

Scheme 2

Steroid Synthesis

415

n

* . ..

1

iii-vii

0

Reagents: i, MeSOCH, -Na+-DMSO; ii, MeI; iii, H+-H,O-EtOH; iv, KOH-dioxan; v, Li-NH,-EtOH; vi, Cr0,-Me,CO-H,SO,-H,O; vii, H , O + .

Scheme 3

acid, to cleave the ketal groupings, and with base to close ring A, followed by lithium in liquid ammonia to reduce the double bonds in rings A and D, and finally with the Jones’ reagent and acid yielded the A8314-androstenedione(33).” The full paper on the total synthesis of precalciferol (38) has appeared.I8 Combination of the chloro-ketone (34) with optically active (lS)-3-ethynyl-4methylcyclohex-3-en-1-01(35) afforded the chlorohydrin (36). This was transformed into the dienyne (37) and then into precalciferol (38) by semihydrogenation of the acetylenic bond (Scheme 4).18 The difficultly accessible trans-syn-trans arrangement of the A-B-c ring system present in steroidal antibiotics has now been synthesized.l 9 The known enedione (39) was converted into a 6 : 1 mixture of the desired compound (40)and its isomer (41) by ketalization of the saturated carbonyl, followed by lithium-ammonia reduction and enolate trapping with methyl iodide. After separation, (40) was converted into the tricyclic enedione (42) by standard procedures. The transfused AB-system was then obtained by ketalization, peracid treatment, and boron trifluoride rearrangement of the resulting epoxide to the keto-diketal (43). Removal of the 6-keto-group was performed under mild conditions by a new l8

l9

T. M . Dawson, J . Dixon, P. S. Littlewood, B. Lythgoe, and A. K. Saksena, J . Chem. SOC.(C), 1971, 2960. R. E. Ireland and V. Hengartner, J . Amer. Chem. Soc., 1972,94, 3652.

41 6

Terpenoids and Steroids

c1-

17

@

HO

f7

C

Ill

C

Reagents: i , Li; i i , Cr(CIO,),-DMF-H,N(CH,),NH,; iii, H,-Lindlar catalyst-quinolinelight petroleum.

Scheme 4

method which involved reduction to the alcohol, tetramethyl phosphorodiimidate formation. and lithiumxthylamine reduction at 60 "C. Finally, acid hydrolysis gave the tricyclic dienone (44) with the correct configuration. l 9 Substantial further work has been reported on the enzymatic cyclization processes of squalene 2,3-oxide and analogues,20 but since such studies are closely related to the synthesis and biosynthesis of triterpenoids, they will not be discussed in this chapter (see p. 197 and 262). Various other approaches to the synthesis of the steroid skeleton are discussed in the following sections which are devoted more specifically to the obtention of oestrane, androstane, and pregnane derivatives, as well as to steroidal alkaloids. 21'

See, for example, E. E. van Tarnelen, J . A. Smaal, and R. B. Clayton, J . Amer. Chem. Soc.. I97 1 . 93. 5279.

Steroid Synthesis

417

(39)

1

eo&3

0

+

(40)

1

&-e&--

0

/

0

0

3 Halogeno-steroids

In a previous study on the use of fluoroxytrifluoromethane(CF,.OF) as an electrophilic fluorinating agent, it was suggested that fluoroxy-compounds as a class might be disposed to undergo nucleophilic attack at fluorine.*l This hypothesis 21

D. H. R. Barton, L. S . Godhino, R. H. Hesse, and M . M . Pechet, Chem. Comm., 1968, 804;D. H . R . Barton, A. K . Ganguly, R. H. Hesse, S. N. Loo, and M. M . Pechet, ibid., p. 806; D. H . R . Barton, L. J. Danks, A. K . Ganguly, R . H. Hesse, G. Tarzia, and M . M . Pechet. ibid., 1969, 221.

Terpenoids and Steroids

418

was reinforced by the observation that 2-fluoroxyperfluoropropane reacted with 3-acetoxy-5r-cholest-2-ene(45) in a manner analogous to that observed for CF, .OF.2 1 . 2 2 The fluoroxy-reagents chosen were expected either to react by a mechanism different from that observed for CF,.OF or to possess certain advantages compared with that reagent.22 The observation that 2-fluoroxy-2-trifluoromethylperfluoropropane undergoes a one-electron reduction on reaction with iodide ion, in contrast to the two-electron reduction characteristic of a variety of secondary and primary fluoroxy-compounds. suggested that perhaps tertiary fluoroxyderivatives might be disposed to free-radical reactions. Similarly, fluoroxysulphur pentafluoride (SF,.OF) and bis(fluoroxy)difluoromethane [CF,(OF),] were also used as fluorinating agents. Treatment of the vinyl acetate (45)with each of these reagents afforded 2r-fluorocholestanone (46), through a free-radical reaction mechanism. It was shown that under appropriate conditions electrophilic fluorination is characteristic of fluoroxy-compounds in general.22

The full paper on the synthesis of 14P-fluoro-steroids by perchloryl fluoride fluorination of A'4,'6-17-acetates has now appeared.23 It has been shown that 16a-bromoacetoxyprogesterone alkylates cysteine, histidine, methionine, lysine, and P-mercaptoethanol under physiological conditions.24 An interesting study2' reports the formation, depending on reaction conditions, of either the Sa-fluoro-6P-bromo-steroid (47) (55 %) or the 5a-bromo-6P-fluoro-

F

Br (47) 2 2

lS

(48)

D. H . R. Barton, R . H . Hesse, M . M . Pechet, G . Tarzia, H . J. Toh, and N. D. Westcott, J.C.S. Chem. Comm.. 1972, 122. J . Pataki and G. Siade, J . Org. Chem., 1972, 37, 2127. F . Sweet, F. Arias, and J . C. Warren, J . B i d . Chem., 1972, 247, 3424. U . Kerb and R . Wiechert, Annufen, 1971, 752, 78.

419

Steroid Synthesis CH,OAc

I

c=o

derivative (48) (70%), by reaction of N-bromosuccinimide and HF with the A5-3-alcohol(49). It has been shownz6that the reaction of iodohydrins with a pyridine solution of phosphoryl chloride constitutes a useful modification of the Cornforth method27 for the stereospecific preparation of olefins. Thus, treatment of the iodohydrin (50a) with phosphoryl chloride in pyridine gave the A2-steroid (51) in high yield. The same olefin (51) was obtained in low yield when the bromohydrin (50b) was submitted to similar conditions.

& HO’ x

H

& H

(50) a ; X = I b ; X = Br 4 Oestranes

A total synthesis of 7,7-dimethyloestrane derivatives has been reported.28 The synthetic scheme (Scheme 5) was based on the Torgov method.15 Conjugate addition of the Grignard derivative of rn-methoxybenzyl chloride (52) to diethyl isopropylidenemalonate afforded the di-ester (53a). Saponification gave the corresponding di-acid (53b), which was decarboxylated, the resulting mono-acid (54) being cyclized to 3,3-dimethyl-6-methoxytetralone (55). This with the vinyl Grignard reagent provided the alcohol (56) which with 2-methylcyclopentane1,3-dione (4a) afforded (57). Cyclization with acid, followed by catalytic hydrogenation, gave the tetracyclic intermediate (%), with the 14P-configuration. 26 27 28

A. Guzman, P. R. Ortiz de Montellano, and P. Crabbe, J . C . S . Perkin I , 1973, 91. J. W. Cornforth, R. H . Cornforth, and K. K. Mathew, J . Chem. Soc., 1959, 112. D. Lednicer, D. E. Emmert, C. G . Chidester, and D. J. Duchamp, J . Org. Chem., 1971, 36,3260.

420

Terpenoids and Steroids

Me0

(53) a ; R = Et b;R=H

ill. IV

Me0

Me0

lx. XI

Me0

Reagents:

I.

; iii.

Mg-Et,O; ii,

benzene; IX,

VI.

CH,=CHMgBr;

N a O H ( M e 0 H ) : iv, A ; v, PC1,-SKI,-

v11.

b

0 H,-Pd/C-benzene; x, NaBH,-MeOH;

Scheme 5

XI,

-KOH : viir, HCI-EtOH :

LI-NH,-Bu'OH.

42 1

Steroid Synthesis

Reduction of the 17-ketone with sodium borohydride yielded the corresponding alcohol which with lithium in liquid ammonia and t-butyl alcohol afforded a mixture of the aromatic compound (59) and the enol ether (60). The former could be converted cleanly into the latter by re-exposure to the conditions of the Birch reduction.'* Hydrolysis of the enol ether (60) with mineral acid was followed by oxidation and separation to provide the conjugated 19-nor-steroid analogue (61) and its by-unsaturated keto-isomer (62). The stereochemistry was established as

* oG 0

0

0

/

8aH,9aH,lOPH,14PH by X-ray crystallography.28 The Torgov method was also applied to the synthesis of 2,3,4-trimethoxyoestra-1,3,5( lO)-trien-17b-ol (63a)29 and 2,4-dimethoxyoestra-1,3,5(10)-trien-17P-o1(63b).30

OH

OMe (63) a ; R = OMe b;R=H The synthesis of 1,2- (66) and 2,3-dimethoxy-4-methyloestra1,3,5(10)-trien(64)has been r e p ~ r t e d . ~Aroma' 17P-o1(67)from androsta-1,4-diene-3,17-dione tization of (64) under conditions reported earlier,32followed by introduction of the 17-acetate group, gave 4-methyloestratrien-17b-01 acetate (65). Treatment of this with acetyl chloride under Friedel-Crafts conditions, followed by BaeyerVilliger oxidation, gave access to the 1,2- and 2,3-dimethoxyoestradiol series (66) and (67).3' 29

30 31

32

P. N. Rao, E. J. Jacob, and L. R. Axelrod, J . Chem. SOC.(0,1971, 2855. P. N. Rao and L. R . Axelrod, J . Chem. SOC.(0,1971, 2861. T. Nambara, K . Shimada, Y.Fuji, and M . Kato, Chem. and Phnrm. Bull. (Japan), 1972, 20, 336. M. J . Gentles, J. B. Moss, H. L. Herzog, and E. B. Hershberg, J . Amer. Chem. SOC., 1958, ao, 3702.

422

Terpenoids and Steroids

0

A number of papers have been devoted to aromatization reactions with enones, dienones. epoxides. etc. under a variety of experimental condition^.^^-^' These reactions are beyond the scope of this Report. Preparations of other oestratriene derivatives by classical routes have appeared. 'J' A report mentions the synthesis of intermediates of type (68) and (69) for the Compounds of general formula (70) preparation of c-nor-~-homo-steroids.~~

0

33

J . Libman and Y . Mazur. Chem. Comm., 1971, 1146.

'' J . R . Hanson, Chem. Comm., 1971, 1 1 19, 1343; J . R . Hanson and H . J. Shapter. J . C . S . 35 3h

Perkin I , 1972, 1445; D. B . Aldwin and J . R . Hanson. ibid., p. 1889. A . G . Ogilvie and J . R . Hanson, J.C.S. Perkin I , 1972, 1981. E. Farkas and N . J . Bach, J . Org. Chem., 1971, 36, 2715. J . I-. Bravet, C . Benezra, and J . P. Weniger, Sreroids, 1972. 19, 101. C. Rufer, E. Schroder, and H . Gibian, Annulen, 1971, 952, 1 . K . Prezewowsky, R. Wiechert, and W. Hohlweg, Anttalen, 1971, 752, 6 8 . E. Brown, J . Touet. and M. Ragault. Birll. Soc. cliim. France. 1972, 212.

'''

'' '(I

423

Steroid Synthesis

were treated with P-chloro-ketones [Cl(CH,),COCH,R] to form d-diketones which then cyclized on exposure to base or acid. For example, 2-methylcyclohexanone (71) was treated with dimethyl oxalate, giving (72). Its sodium enolate was treated with 1-chloro-3-hexanone to afford the b-diketone (73) which was cyclized with acid to the bicyclic enone (74).40

0

(CO,Me),MeONa-MeOH

Elimination of the angular substituent of the diazoketone (75) by treatment with copper, affording the aromatic lactone (80), has been reported. It proceeds presumably through the intermediates (76)--(79).41 Oxidation of oestrone (81)

(77)

(75)

1 0

11

v

0

0

(80) V . Coronado and J. L. Mateos, Rec. SOC.quirn. Mexico, 1972, 16, 18.

Terpenoids and Steroids

424

with thallium(Ir1) trifluoroacetate has been shown to introduce a trifluoroacetoxy-grouping at C-lob, affording (83a) and giving access to 10P-hydroxyoestra-l,4-diene-3.17-dione (83b) by hydrolysis of the intermediate (82).42

0

CF3

I

(CF,CO2),71 -CF,C02H room temp.

0

(83) a ; R = CF3C0 b;R=H The total synthesis of the highly progestationally active 6,6-difluoro-18homo-17a-ethynyl-19-nortestosterone (85) has been The approach of the Russian school was used,' appropriately modified44in order to introduce the 18-ethyl group. The gem-difluoro-moiety was prepared from the SIX-fluoro6-ketone (84) by a procedure described p r e v i ~ u s l y . ~ ~ , ~ ~ The aluminium trichloride-catalysed homologation of ketones with diazomethane has been applied to the synthesis of ~-bishomo-steroids.~~ Thus, *' M . M.Coombs and M. B. Jones, Chem. and Ind., 1972, 169. 43 44

*'

A. L. Johnson, J. Medicin. Chrm., 1972, 15, 360. G. H. Douglas, J. M. H. Graves, D. Hartley, G . A. Hughes, B.J. McLaughlin, J. Siddall, and H. Smith, J. Chem. Soc., 1963, 5072; H.Smith, G. A. Hughes, G . H. Douglas, G . R. Wendt, B. C. Buzby, jun., R . A. Edgren, J. Fisher, T. Fsell, B. Cadsby, D. Hartley, D. Herbst, A. B. A . Jansen, K. Ledig, B. J. McLaughlin, J. McMenamin, T. W. Pattison, P. C. Phillips, R. Rees, J. Siddall, J. Sjuda, L. L. Smith, J. Tokolics, and D. H. P. Watson. ihid.. 1964, 4472. G. A. Boswell, A . L. Johnson. and J. P. McDevitt, Angew. Chem. Internat. Edn., 1971, 10, 140.

Jb

Cf.P. Crabbe, G. A. Garcia, J. Haro, L. A. Maldonado, C. Rius, and E. Santos, in 'Terpenoids and Steroids', ed. K. H. Overton (Specialist Periodical Reports), The Chemical Society, London, 1972, vol. 2, p. 329. G . Eadon and C. Djerassi, J . Medicin. Chern., 1972, 15, 89.

Steroid Synthesis

425

OH CH

AcO

treatment of oestrone 3-methyl ether (18) with an ethereal solution of diazomethane, followed by addition of a catalytic amount of aluminium trichloride, afforded ~-bishomo-3-methoxyoestra-1,3,5( lO)-trien-l7B-one(86). Similar homologation reactions were performed in the androstane series.47

0

An interesting de-aromatization of phenols in superacidic medium has been reported.48 The reaction of oestrone (81) with a hydrogen fluoride-antimony pentafluoride mixture afforded the diene-dione (87) in high yield. Dienones such 0

(87)

OH

OH

Et,AICN-THF

(88) 48

(89)

J . P.Gesson, J.-C. Jacquesy, and R.Jacquesy, Tetrahedron Letters, 1971,4733.

426

Terpenoids and Steroids

as (87) or (88) are not readily available. so that the above reaction constitutes a substantial improvement over older techniques. The dienone (88) with diethylaluminium cyanide afforded the 9a-cyano-19-nortestosteroneanalogue (89).49 The above superacidic treatment (HF-SbF, mixture) of aromatic phenols has been applied to equiline (90). I t afforded either the As*'- (91) or the styrene (92). depending on temperat~re.~'This observation is important since

(92) the A'."-steroid (92) is a useful intermediate in the total synthesis of numerous steroids, in particular androstanes and corticoids. Indeed, it has been shown that hydroboration of compounds such as (92) can lead to 1lp-hydroxy-derivatives ~ ~appropriate intermediate, by which permit angular methylation at C-10. r i an Simmons-Smith r e a ~ t i o n . ~ ' The total synthesis of 73-methyl-6-oxaoestrone (94) has been ~ o m p l e t e d . ~ ~ The procedure followed is based on the classical technique' and used 7-methoxy2-methyl-4-oxochroman (93) as starting material.'l

0

(94) R . E. Ireland. G. Pfister. D. J . Dawson. D. Dennis, a n d R. H. Stanford, Svnth. Comni., 1972. 2. 175. G. Joly, and J . P. Gesson, Compr. rend., 1972, 274, C, 969. P. Turnbull. K . Syhora. a n d J . H. Fried. J . .4 m e r . Chem. Soc., 1966,88, 4764. 0 . Dann. K . W . H a g e d o r n , a n d H . Hofmann. Chcm. Ber.. 1971. 104. 3313.

'' J.-C. Jacquesy, 'I

''

Steroid Synthesis

427

The asymmetric synthesis of optically active 6-thiaoestrogens has been described.53 This work followed previously reported total synthetic ~ c h e r n e s ~ ' , ~ ~ in which the asymmetric conversion55was effected with 8,14-seco-intermediates. In addition, the synthesis of variously modified 6-thia-steroids by the classical r o ~ t e ' has ~ , also ~ ~ been reported.56 The preparation of 5'-alkyl- and 5'aryl-oestra- 1(10),4-dieno[3,2b)]furans(96)by treatment of 2-iodo-oestrone (95) or oestradiol with the corresponding Cu' acetylides in boiling pyridine has been reported.

CU-C-C-R

HO (95)

(96) a ; R = Pr" b; R = Bu" c ; R = n-C,H,, d ; R = CH2CH20H e;R=Ph

An ingenious synthesis of steroidal annulenes has appeared.58 The close relationship of annulenes to the classical aromatic substance naphthalme stimulated the synthesis of 1,6-methano-[101annuleno-steroids, which are analogues of equilenin (97). The y,d-cyclopropyl-ap-unsaturated ketone (98) was the initial target. Treatment of the cyclopropyl ketone (98) with acetic anhydride and methyl orthoformate in the presence of an acid catalyst then gave (99).59 Conversion of the cycloheptatriene (99) into the requisite l0n-electron system (100)was then accomplished by dehydr~genation.~~ 0 0

(97) 53

54 55 56

57 58

59

(98)

W . M. B. Konst, W . N. Speckamp, H . 0. Houwen, and H. 0. Huisman, Rec. Trai.. chim., 1972, 91, 861. H. 0. Huisman, Angew. Chem. Internat. Edn., 1971, 10, 450. R. Bucourt, M. Vignan, J . Weill-Reynall, Compt. rend., 1967, 265, C , 834. W . B. M. Konst, J . Van. Bruynsvoort, W. N . Speckamp, and H . 0. Huisman, Rec. Trav. chim., 1972, 91, 869. M. Stefanovic, L. Krstic, and S. Mladenovic, Tetrahedron Letters, 1971, 331 1 . P. H. Bentley, M. Todd, W . McCrae, M. L. Maddox, and J . A . Edwards, Trtraliedroron, 1972,28, 141 1. L. H . Knox, E. Velarde, and A. D. Cross, J . Amer. Chem. Soc., 1965, 87, 3727.

Terpenoidsand Steroids

428

0

0

UoO)

(99)

Reaction of 19-hydroxyandrost-4-ene-3,17-dione(101a) with f l ~ o r a m i n e ~ ~ in boiling acetonitrile gave the 5~,19-cyclo-A1-3,17-diketone (102),in addition to the bridged fluoro-enone (103). When the A4v6-3-ketone(101b) was allowed to react with the fluoramine reagent under the same conditions the desired cyclopropyl ketone (98) was isolated in low yield. The major product of this reaction was the 10-fluoro-steroid (104). Treatment of (104) in boiling ethanol containing hydrochloric acid resulted in opening of the cyclopropane ring with concomitant loss of hydrogen fluoride to provide the ~-homo-3-keto-steroid( 105).58

0

0

(101) a ; 6,7-dihydro, R = H b;A6,R=H C ;A6, R = TOS

0

0

0

429

Steroid Synthesis

Another route to the desired enone (98) was then considered. In principle, solvolysis of the tosylate (101c) in the presence of a suitable base could proceed by proton abstraction from C-1, followed by rearrangement of the carbanion and departure of tosylate to generate (98). Accordingly the enone (101c)in dimethylformamide (DMF) with lithium carbonate under reflux afforded the desired 5~,19-cyclo-A'p6-3-ketone (98). However, reaction of 19-hydroxyandrosta-4,7diene-3,17-dione (106) with the fluoramine reagent proceeded more cleanly (107)in moderate to affordthe expected 5~,19-cycloandrosta-1,7-diene-3,17-dione yield.5 8 Both the A6- (98)and A'-enones (107)were cleanly transformed into their respective 3-acetoxycycloheptatrienes (99) and (108) on treatment with acetic acid-acetic anhydride containing toluene-p-sulphonic acid. Reaction of (108) with N-bromosuccinimide (NBS) in boiling carbon tetrachloride afforded the expected tetracyclic 1,6-methano-[10Jannuleno-steroid

0

The total synthesis of dl-3-methyl-4-oxaoestra-5,7,9,14-tetraen-l7~-ol (115) and 3-methyl-4-oxaoestra-5,7,9-trien-17~-ol(ll6) has been reported (Scheme6).60 Michael addition of dihydroresorcinol (109) to methyl vinyl ketone in the presence of alkali gave the substituted cyclohexanedione (110). The acyclic carbonyl group of (110) was reduced selectively with Raney nickel in a basic medium to afford the enol-ether (111) after exposure to acid. Addition of (111) to vinylmagnesium chloride provided the allylcarbinol (112), which on reaction with methylcyclopentanedione (4a) gave the tricyclic diketone (113). Acid treatment of this provided the 4-oxa-steroid (114), which was oxidized to the aromatic B ring and then reduced at C-17 to afford the novel B-aromatic steroid (115). Catalytic reduction of the A14-doublebond furnished the oestrane derivative (116). O'

G . Sauer, U. Eder, and G . A . Hoyer, Chern. Ber., 1972, 105,2358.

Terpenoids and Steroids

430

0

~ I I viii .

& 0

Reagents: i, C H , = C H C O M e - O H - :

; vi,

ii. H , - O H - ;

iii, H ' ;

\

iv, CH,=CHMgCI;

iv,

H ' ; vii, Pb(OAc),, DDQ, or 0,; viii, NaBH,; ix, H,-Pd/

0

CaCO 3 .

Scheme 6

C

43 1

Steroid Synthesis

Some reactions on the acetylenic and allenyl chains of the oestrane derivatives (117) and (118) have been completed.61 When zincsopper couple was added to the triple bond of mestranol(ll7) the products depended on the reaction conditions. When the reagent was prepared by the modified Le Goff procedure,62 the enol acetate (119a)was the main product. When a larger excess of SimmonsSmith reagent was the cyclopropyl derivative (119b) became the major A bis-cyclopropyl compound, probably (119c),was also formed under these reaction conditions. The allenyl steroid (118)afforded the vinylcyclopropyl derivative (119d) on treatment with the Simmons-Smith reagent, in agreement with similar results obtained in other ~ e r i e s . ~ ~ , ~ ~

OAc

OH

(120) a ; R = CH=C=CH, (119) a ; R = -CMe=C

b;R=-MeC-C

/OAC

\

H

/

OAc

H'

d;R

=-HC-C=CHZ

v

Addition of difluorocarbene to the propadienyl side-chain of (120a)61gave the spiro-derivative ( 120b).64 61

62 63 64

M. Biollaz, R. M. Landeros, L. Cuellar, P. Crabbe, W. Rooks, J. A. Edwards, and J. H . Fried, J . Medicin. Chem., 1971, 14, 1190. E. Le Goff, J . Org. Chem., 1964,29,2048. M, Bertrand and R. Marvin, Bull. Soc. chim. France, 1967, 2779. R. Fischer, U . Graf, and P. Crabbe, unpublished results.

Terpenoids and Steroids

432

The synthesis of 6.6-difluoronorethindrone (121a),a progestational agent with enhanced activity, has been r e p ~ r t e d . ~As ' an extension of this work, the preparations of 6.6-difluoronorgestrel( 121b). 6.6-difluoro-17b-hydroxy-17~-propadienyloestra-4-en-3-one ( 12lc), 6,6-difluoro-17P-hydroxy-17a-(1-propyny1)oestra-4en-3-one (1 2 Id), and 6,6-difluoro-17P-hyaroxy-17a-(3,3,3-trifluoropropynyl)oestra-4-en-3-one (121e) have been reported.66 The synthetic schemes followed classical pathways used previously in other series. i.e. alkylation at C-17 of the intermediate (122) with the appropriate lithium acetylide to afford the 17aacetylenic compounds (123) and then conversion into the desired compounds (121c. d, and e). The 18-homo-steroid (121b) has been obtained by a similar react ion sequence."

F F (121) a ; R' = Me, R2 = C=CH b ; R' = Et, R 2 = CECH c ; R' = Me, R 2 = CH=C=CH2 d ; R' = Me, R2 = C E C M e e ; R 1 = Me, R2 = C-C-CF,

OH =CR

0

LICECR

5 Androstanes A general review of the chemistry. biochemistry, and potential physiological role of 16-unsaturated steroids, mainly androstanes. has a ~ p e a r e d . ~ ' L-Abietic acid (124) has been converted (Scheme 7) into the tricyclic ketone (131). a known intermediate which can be transformed into steroids6' Dehydrob5

h6

''

h'

G . A . Boswell, A. L. Johnson, and J . P. McDevitt, J . Org. Chem., 1971,36, 575: see also ref. 45. A . L. Johnson, J . Medicin. Chem.. 1972. 15, 854. D. B. Gower, J. Steroid Biochem., 1972, 3. 45. A . Tahara, Y.Harigaya, and M . Onda. Cheni. and Phorm. Bull. ( J a p a n ) , 1972, 20, 459.

6-C

433

Steroid Synthesis

'*,

H

',,

H

C0,H

C0,H

(125)

( 124)

Reagents: i, Li-t-C,H,,OH-EtNH,; ii, conc. H 2 S 0 4 ; iii, 10 % Bu'OK-DMSO; iv, CH,N,; v, KOH-HOCH2CH,-OCH,CH20H; vi, Pb(OAc),; vii, 0,.

Scheme 7

434

Terpenoids and Steroids

abietic acid (125), easily derived from (124), was reduced with lithium in t-amyl alcohol-ethylamine to afford (126).Treatment of i 126)with acid gave the lactone (127)- accompanied by methyl migration.69 This was converted by a known sequence of reactions first into the olefin (128) and then into (129). Lead tetraacetate treatment and ozonolysis then gave the ketone (130).h8In turn. the isopropyl group of (127) was transformed by a known procedure” into a ketone and finally into the keto-acetate ( 131).68 The preparations by classical methods of a number of oxygenated steroids having hydroxy- or ketone groups at different positions of the steroid nucleus have been reported.’ 1--’4 22,17P-Dihydroxy-SP-androstane17-benzoate (133) has been prepared from testosterone (132) and found to be a key intermediate for the transannular cyclization from C-2 to C-9.” The stereochemistry of epoxidation of the A4-3keto-system with a1kaline hydrogen peroxide has been examined. The P-epoxide is favoured over its r-isomer in a 5 : 1 ratio.’’ Reaction of (133) with lead tetraacetate afforded the ether (134).75

OBz

OH

(1 32)

( 1 34)

‘”

D . H. R. Barton, ChPm. aridItid., 1948,638; L. J . G0 u g h . T . F. Sanderson, V. I. Stenberg, and E. Wenkert, J. Org. Chem., 1960, 25. 1269; A. W. Burgstahler a n d L. R. Worden, J . Amer.. Cheni. Soc.. 1964. 89, 96. ’’ J . Minn, T. F. Sanderson, and L. A. Subluskey, J. Atner. Chem. SOC., 1956, 78, 630. W. A . Denny, V. Kumar, G. D . Meakins, J. Pragnell, and J . Wicha, J.C.S. Perkin I, 1972.486. A. S. Clegg. W . A . Denny. E. R. H. Jones. V. Kumar, G. D . Meakins, a n d V. E. M. Thomas, J.C.S. Perkin I, 1972, 492; I. M. Clark, A . S. Clegg, W. A . Denny, E. R. H. G . D. Meakins, and A. Pendlebury, ibid., p. 499. ’’ Jones, B. R . Bhavni and F. Z . Stanczyk, Steroids, 1972, 20, 129. ’‘ J . B. Adams and K . N. Wynne, Strroidoiogia, 1971, 2, 321. T. Koga and S . Kawashima. C h E n i . and Pharrii. Bull, (Japan). 1972. 20: 21.

’’ ’’

Steroid Synthesis

435

The effect of 17-substituents on the base-catalysed equilibration of steroidal 2~,3~-disubstituted 6-ketones has been in~estigated.'~ The presence of a range of functional groups at position 17 results in marked changes in the equilibrium between 5a- and SP-isomers and this cannot be explained in terms of conformational transmission or by simple transmission of polar effect^.'^ The synthesis of the steroidal 2a,3ct-cyclopropanol(137b)has been described." The 3-bis-(2-chloroethoxy)-derivative(135) was pyrolysed in uucuo to give the olefin (136). This with excess Simmons-Smith reagent gave the cyclopropyl steroid (137a), which with butyl-lithium liberated the free cyclopropanol(137b) ; this was converted into 17P-hydroxy-2a-rnethyI-5a-androstan-3-one (138)by base. OAc

CICH,CH,O

H (135)

ClCH

OH

(137) a ; R' = CH2CH2C1,R2 = Ac b; R' = R2 = H An ,interesting study reports carbene additions to the androstane enol ether (139).78 Addition of dibromo- and dichloro-carbene gave the D-homo-a-halogenoenones (140a)and ( l a b ) ,respectively. The Simmons-Smith reaction on (139) afforded the 16a,l7a-cyclopropyl steroid (141). Whereas treatment of (141) with acid provided the D-homo-derivative (142), reaction with iodine, followed by l6 77

"

H . Velgova, V. Cerny, and F. Sorm, Cull. Czech. Chem. C'ornm., 1972,37, 1015. J. F. Templeton and C. W. Wie, Tetrahedron Letters, 1971, 3955. W. F. Johns and K . W. Salamon, J . Org. Chem., 1971, 36, 1952.

436

Terpenoids und Steroids 0

OEt

(140) a ; X = Br

139)

b ; X = CI c;X=H

OEt

0

treatment with lithium carbonate and lithium chloride. yielded the corresponding enone ( 1404.'* Two papers report the synthesis of novel androstane derivatives methylated at C-82. In the first" (Scheme 8). treatment of the tosylhydrazone of (143) with lithium hydride furnished the diene ( 144).-9 Reaction with diborane. followed by alkaline hydrogen peroxide, gave the allylic alcohol (149, which was submitted to Simmons-Smith reaction and oxidized to the a-cyclopropyl ketone (146). Cleavage of the 7a.8~emethylenebridge with lithium in liquid ammonia afforded the $a-methyl derivative (147). This was then converted into 17a-ethynyl-8amethyltestosterone (148a) by a classical sequence of reactions.'' In the second syntheskaO8a-methyltestosterone (148b) was prepared from the previously reported 8lx-methyl-5a-pregn-9(1 l)-ene-3P.20-diol (149). Catalytic hydrogenation of (149) gave the saturated diol, which was successively oxidized to the diketone, selectively protected as the C-3 dimethyl ketal, reduced at C-20, and hydrolysed to the hydroxy-ketone (150)!' This in turn was transformed into the 8a-methylprogesterone (151), 8a-methyltestosterone (148b), and 8a-methyloestradiol(152) analogues by conventional methods." The synthesis of 7a-substituted steroids by allylic rearrangement under acidic conditions of A6-52-hydroxy-steroids has been describeds2 The preparation of

-'W. G. Dauben and Ro

'' 82

D. S. Fullerton. J . Org. Cheni.. 1971.36, 3277. G . Arniard, R . Heymes, Truong Van Thwong, and J . Mathleu, Bull. Sor. chim. Franc,c., 1965, 2321. G . Arniard. R . Heyrnes. and Truong Van Thwong, B1d1. SOC.chirii. France, 1972, 272. p Morand and A . Van Tongerloo. J . C . S . Chem. Comm.. 1972, 7.

Steroid Synthesis

437 OAc

OAc

OAc

0

vii-xvi

, (148) a ; R = C-CH b;R=H

Reagents: i, TosNH.NH,; ii, LiI -MePh; iii, B,H,-THF; iv, H,O,-base; v, CH,I,-; .n; vi, CrO, (Jones); vii, Li-NH,; viii, Ac,O; ix, NaBH,; x, Ac,O-py; xi, POC1,py; xii, O H - ; xiii, CrO, (Collins); xiv, ; xv, Li+C-CH+dta; xvi, H , O + .

U0 Scheme 8

the 19-hemisuccinate of a variety of androstane and testosterone derivative^,^^ as well as a number of 17P-cycloalk-1'-enyloxyandrostanes and 19-norandros t a n e ~has , ~ ~been reported.

'' V . Coronado and J . L. Mateos, Rev. Soc. quim.Mexico, 1972, 16, 17. 84

R . Gardi, G. Falconi, C. Pedrali, R . Vitali, and A. Ercoli, Steroids, 1972, 19, 639

Terpenoids and Steroids

438

Me

Me

I

I

CHOH

HO (149)

0

& \

HO

0

( 152)

(151)

A-Nortestosterone (153) has been used as a starting material for the synthesis of (154b), ~-norandrostane-2a.SP, 17P-triol (1 %a). ~-norandrostane-2P,5p,l7fl-triol ~-norandrostane-2r.5~, 1 Sp-triol ( 154c), and ~-norandrostane-2P,5a, 17P-triol (154d)? The sequence which was used involved either stereoselective epoxidation of the double bond. followed by opening of the epoxide and then reduction of the ring A carbonyl group. or inversion of these steps8'

OH

OH

(154) a ; R' b ; R' c ; R' d ; R'

OH H, R2 = OH, SB-series = OH, R 2 = H, 5P-series = H, R 2 = OH, SLY-series = OH, R2 = H, Scr-series =

The synthesis (Scheme 9) of B-homo-A. 19-bisnorandrosta-5(lO)-ene-3,17-disne (162) from 3~~,19-dihydroxyandrost-5-en-17-one acetate has been described.86 Oxidation of the bromohydrin ( 1 55) with chromic acid afforded the keto-acid

'' L . Labler and Ch. Tarnm, Helr. Chiin. Aciu, 1972, 55, 873. '' S. V . Sunthankar and S. D. Mehendale, Tetrahedron Lerfrrs. 1972. 2481

439

Steroid Synthesis

I ,

0

HO 0

Reagents: i, CrO,; ii, OH--MeOH; iii, H,O,-NaOH; Pd/C; vi, CrO, (Jones); vii, Bu'OK-MeOH.

Scheme 9

iv, m-CIC,H,CO,H;

v, Hz-

Terpenoidsand Steroids

440

( 1 56). which was successively decarboxylated to (157) and epoxidized to the r-epoxy-keto-derivative ( 158). This, on Eschenmoser fragmentation8' afforded the seco-steroid (159). also obtained by treatment of the bis-tosylhydrazone (160) with ni-chloroperbenzoic acid. Catalytic hydrogenation of (1 59) and oxidation of the 3-alcohol grouping provided the triketone (161), which underwent intramolecular aldol condensation in presence of base. affording ( 162).86 The stereoselective synthesis of 19(10 + 9~)aheo-l0a-testosterone( 1 64) has been accomplished.88 The A-nor-steroid [163; R' = CH,CH=C(CI)Me, R 2 = Me] was prepared by treatment of the pyrrolidine dienamine derivative of (163; R ' = H. R2 = Me) with 1,3-dichlorobut-2-eneand potassium iodide in dry DMF. Reaction with lithium dimethylcopper gave the 9p-methyl derivative (163b), whose 17B-benzoate (163c) was treated with sulphuric acid to afford the corresponding diketone (163d). Finally, annelation of (163d) with ethanolic potassium hydroxide yielded the desired testosterone analogue ( 164).88

(163) a ; R' = R 2 = H b ; R' = CH,CH=C(Cl)Me, R 2 = H c ; R ' = CH,CH=C(Cl)Me, R 2 = Bz d ; R ' = (CH,),Ac, R 2 = BZ A number of papers have appeared on the synthesis of novel steroids substituted a t positions 1,89 9 90,91 3 9 1 . 9 2 4 9 2 - 9 3 5 89 6 9 1 . 9 2 7 89 9 8 9 10 8 9 16,89 17,94 18,89 -1

9

7

7

3

7

9

9

and 20.ys The preparation of these substituted steroids generally followed known pathways. However. of special interest is the report on the formation of 4pallenyl- 17.17-cycloethylenedioxyandrostane-3~.5r-diol (166) upon treatment of 4r,5~-oxido-l7.17-cycloethylenedioxyandrostan-3~-ol ( 165) with propargylmagnesium bromide.93 The observed acetylene-allene rearrangement was

'-A . Eschenmoser. D. Felix. and G . Ohloff. H r k . Chim. Acra,

1967, 50, 708. J . R . Bull and A . Tuinman, J.C.S. Chem. Comm., 1972, 921. '' W . Nagata, M . Yoshioka, and S. Hirai, J . Amer. Chem. SOC.,1972, 94, 4635; W. Nagata, M . Yoshioka, and M . Murakami, ibid., pp. 4644, 4654; W . Nagata, M . Yoshioka, and T. Terasawa, ibid., p. 4672. 90 H. C. Neumann and F. W . Stonner, Heir. Chim. Acta, 1972,55, 2014; P. P. Castelli, R . Vitali. and R . Gardi, Gazzerrn. 1971. 101. 8 3 3 . ')I K . Ponsold and W . Ihn, J.prakr. Chem., 1971,313,811 ; B. Schonecker and K . Ponsold, ihid.,p. 817; K , Ponsold and D. Klemm, Chem. Ber., 1972, 105, 2654. ')'Ch. Huynh and S. Julia, Bull. Soc. chint. France, 1971, 4396, 4402; ibid., 1972, 1794; G . Bourgery. J . J . Frankel, S. Julia, and R . J . Ryan, Terrahedron, 1972, 28, 1377; . Ryan, G . Bourgery, and S. Julia, Bull. Soc. chim. France, 1972, 1415. '' RR .. JVitali and R . Gardi, Tefrahedrori Lerrers, 1972, 1651. G . Ferrara. A . Ius, C. Parini, G. Sportoletti, and G . G . Vecchio, Tetrahedron, 1972, 28. 2461. 8s

Steroid Synthesis 441 attributed to the configuration of the hydroxy-group at position 3, which is opposite to that of the epoxide. A cyclic transition state of type (167) may be involved in this reaction.93

442

Terpenoids and Steroids

with the unsaturated lactols, using the Leuckart conditions, with no apparent reduction of the conjugated double bond. Thus, ozonolysis of 2-hydroxymethylenetestosterone ( 172) in methylene chloride-pyridine, followed by addition of dimethyl sulphide, afforded 2,17fi-dihydroxyandrosta- 1,4-dien-3-one (173). Reaction of the intermediate (173) with oxygen in the presence of cupric ion in DMF afforded the lactol (170b). Treatment of this material with ammonium formate and formic acid produced the desired 2-azatestosterone (171b).96

& ;&

O

4

4

(170) a ; 4,5-saturated b; A4-

( 172)

(171) a ;4,5-saturated

b ; A4-

(173)

The synthesis of 3-oxa-, 3-thia-, 3-selena-, and 3-tellura-~-homo-5or-androstan17p-01 derivatives, as well as of 3,4-dithia-~-bishomo-5a-androstan-l7~-ol, by cyclization of appropriate seco-compounds has been r e p ~ r t e d . ~Acid ’ treatment of the seco-diol (1 75a), obtained by lithium aluminium hydride reduction of the diester (1 74a), afforded the 3-oxa-derivative (1 76a). The dimesylate (177), prepared from (175b),was treated with Na,S, Na,Se, Na,Te, and Na,S, to provide (176b),(176c),( 1 7 6 4 , and (176e), respectively, after acid hydrolysis.

’’

(174) a ; R = H b; R = THP G . Zanati and M. E. Wolff. J . Medicin.

(175) a ; R = H b ; R = THP Chrm., 1972. 15, 368.

Steroid Synthesis

443

f

(176) a ; X = 0 b;X = S c ; X = Se d ; X = Te e ; X = -S-S-

(177)

Reaction of isoandrololactam acetate with dimethyl sulphate gave o-methylisoandrololactim acetate (178). Treatment of (178) with allylmagnesium bromide afforded the amine (179), which when oxidized with m-chloroperbenzoic acid yielded the steroidal nitroxide (180), with the NO group incorporated into the steroid skeleton.98

AcO3

0

M

e

0'

2

CH,CH=CH,

CH2CH=CH,

HO 98

R. Ramasseul and A. Rassat,

( 180)

Tetrahedron Letters, 1971, 4623.

444

Terpenoids and Steroids

I t has been shown that the spiro-P-epoxide (181) can be converted into the spiro-y-lactone (182) by reaction with dimetalated acetic acid formed under mild conditions by treating acetic acid with lithium di-i~opropylamide.~~ Extension to homologous and functionally substituted examples has established that the dimetalation of aliphatic carboxylic acids is a general phenomenon which makes i t possible to prepare a large array of steroidal spiro-~-lact~nes.'~

o=c 1

(1 82)

(181)

The course of the reaction of the steroidal 17cecyclopropenone (184), obtained by mild acid hydrolysis of the difluorocyclopropenyl derivative (183)"' with various bases. including dimethyl- and diethyl-amine, has been i n ~ e s t i g a t e d . ~ ~ Treatment of (184) with diethylamine gave the spiro-ether (185a). Base treatment of (185a)afforded the iactone (186).formed presumably through the intermediate (187) by hydrolysis. Similarly. reaction of (184) with dimethylamine afforded the Thus the opening of this steroidal cyclopropenone by spiro-derivative ( 1 amines supports previous work. O 1

OH

4 (183)

--*-C=CH \ / C

AcO

H

II

0

( 184) I00 lo'

P. L. Creger, J . Urg. Chem., 1972, 37, 1907, P. Crabbe, H. Carpio, E. Velarde, and J . H . Fried, J . O r g . Chem., 1972, 37, 4003. F. Toda, T. Mitote, and K . Akagi, Bull. Chem. Sac. Japan, 1969, 42, 1777; E. V Dehmlow, Chetn. Ber., 1969, 102, 3863, and references therein.

Steroid Synthesis

445

O=C-CHOH I

I

(185) a ; R = Et b;R=Me

C-CHOH I

I

6 Pregnanes and Corticoids A number of studies have been devoted to the elaboration of the pregnane, corticoid, and related chains at position 17 of the steroid nucleus. The efficient conversion of a 17P-acetoxy-17~-ethynylandrostanederivative into the pregnane and corticoid chains by a two-step process'02 has already been commented upon.46 Attempts to effect the direct addition of 2-lithio-1,3-dithian to 17-keto-steroids have met with limited success.1o3 On the other hand, reactions of 17-spiroepoxides were found to provide convenient access to homopregnane derivatives. Whereas treatment of the 17-ketoandrostene (188) with dimethylsulphoxonium methylide gave an inseparable mixture of the two epimers (189)and (190),reaction of (1 88) with dimethylsuphonium methylide afforded exclusively the 17joxiran (189) in high yield. Opening of the epoxide of (189) with 2-methyl-1,3dithianyl anion proceeded smoothly to give the l7g-hydroxy-dithian (191). '02

'03

M. Biollaz, W. Haefliger, E. Verlarde, P. Crabbe, and J. H. Fried, Chem. Comm., 1971, 1322. J. B. Jones and R. Grayshan, Canad. J. Chem., 1972, 50, 1414.

446

Terpenoids and Steroids

"

(188)

i::

i-0

(189)

la

CH,COMe

{fl:2coMe

1.

1. CHCOMe

{flHXOMea (193)

&{fi CH2COMe

(197)

0 ( 194) Reagents: i, Me,S=CH,; ii, Me,S(O)=CH,; iii, Me v, H +-Me,CO; vi, H +.

Scheme 10

; iv, HgC1,-CdCO,;

447

Steroid Synthesis

Hydrolysis with mercuric chloridesadmium carbonate furnished the 178hydroxy-ketone (192), which was converted into the homoisoprogesterone derivative (193) and dehydrated under acidic conditions to the A' 7(20)-homoprogesterone analogue (194).'03 A similar sequence of reactions was applied to the isomeric epoxide (190), also obtained by Wittig reaction on (188), followed by peracid epoxidation. Compound (190) was successively transformed into the dithian derivative (195), the hydroxy-ketone (196),and the 17a-hydroxyhomoprogesterone analogue (197). Acid dehydration of (197) also afforded the bis-enone (194).'03 These sequences are shown in Scheme 10. An interesting investigation concerned the allplic rearrangement of the 17avinyl steroid (198) into the trans-21-chloro-A' 7(20)-compound(199) by treatment with vanadium tetrachloride in ethyl acetate solution.'04 The formation of (199) in high yield might result from rearrangement of an intermediate of type (200). The allylicchloride (199)was then converted into the dihydroxyacetone side-chain characteristic of corticoids. Treatment of (199) with excess guanidinium acetate in DMF afforded the acetate (201),which had already been converted into the corticoid chains of type (202) by a variety of reagents, especially N-methylmorpholine oxide peroxide and catalytic amounts of osmium tetroxide. ' 0 5 The same reagent has been used to convert (199)into the corresponding 17a-hydroxy20-keto-21-chloro-derivative (202).'04 Substances of this type have previously been transformed to the corresponding 21-acetate (203).'06

- - - - C H = C H 2 l I "C: : . . r

VC14-EtOAc

Me0

\

Me0 (198)

lo4 lo5

lo6

\

(199)

A. Krubiner, A. Perrotta, H. Lucas, and E. P. Oliveto, Steroids, 1972, 19, 649. A. H. Nathan, B. J. Magerlein, and J . A. Hogg, J . Org. Chem., 1959, 24, 1517. G . B. Christensen, R. G . Strachan, N. R. Trenner, B. H. Arison, R. Hirschmann, and J. M. Chemerda, J . Amer. Chem. Soc., 1960, 82, 3995.

Terpenoids and Steroids

448 CHzCl

CH~OAC

c=o

C= O

I

I

Another route to the corticoid chain utilized the rearrangement of 3-methoxy17~-acetoxy-l7r-ethynyloestra-1,3,5( 10)-triene (204) to 3-methoxy-19-norpregna-1,3,5(10).17(20)-tetraen-2l-a1(205) by reaction with silver carbonate in glacial acetic acid.

The synthesis of the steroidal allenyl ketones (207)and (208) by treatment of the acid fluoride (206) with dimethylcadmium has been described.’” Reaction of lithium dimethylcopper with (206) gave mainly the alkylated by-unsaturated ketone (209).

0

H.. ,C-F ‘C

lo’

P.Crabbe and E. Velarde, J.C.S. Chem. Comm., 1972, 241

II

H.. ,CMe ’C

449

Steroid Synthesis

A report has dealt with the preparation and properties of p-lactones from steroidal 17,20-dihydroxy-21-oicacids. l o * Treatment of the isomeric acids (220) and (2 11) under acetylation conditions afforded a mixture of the corresponding diacetates (212) and (213) and the P-lactones (214) and (215). The P-lactone (216) was obtained in quantitative yield by reaction of (210) with ethyl chlorocarbonate.lo8 A number of 20,21-cycIic carbonates, epimeric at C-20, have also been prepared. l o g

g (210) R = H (212) R = Ac

H,

,OAc

c-c=o

(211) R (213) R

o&A

= =

AcO,

0 (214) ‘On

log

M. L. Lewbart, J . Org. Chem., 1972, 37, 1224. M. L. Lewbart, J . Org. Chem., 1972,37, 1233.

(2 15)

H AC ,H

c-c=o

Terpenoids and Steroids

450

H\

/ OC0,Et

c-c=o

The synthesis of 6-cyano- 16-methylene-17a-hydroxypregna-4,6-diene-3,20dione 17-acetate (218c) has been described.’ l o The preparation of the 6-formyl derivative (218a) was achieved by converting the ethyl enol ether (217a)” into the 6-formyl enol ether (217b) by the Vilsmeier reaction. On treatment with dichlorodicyanobenzoquinone (DDQ), compound (2 17b) furnished the desired formyl intermediate (218a). Reaction of (217b) with hydroxylamine furnished the oximinomethyl compound (2 17c),which when treated with sodium acetate in refluxing acetic anhydride afforded the 6-cyano-en01 ether (2 17d).

Me

Me

I

I

c=o

- - OAC

OAc

,-

CH2

0

R (217) a ; R = H b; R = CHO c; R = CH=NOH d;R=CN

R (218) a ; R = CHO b; R = CHzNOH C ; R = CN

In contrast to the 6-formyl enol ether (217b), the 6-cyano-analogue (217d) was completely inert towards DDQ. In order to overcome this problem, the oximinomethyl enol ether (217c)was treated with DDQ in 95 % aqueous acetone solution to give the corresponding dienone (218b). Further reaction of (218b) with phosphoryl chloride in pyridine afforded the desired 6-cyano-dienone (218c). l o

’

lo

“ I

T. L. Popper, H . P.Faro, F. E. Carlon, and H. L. Herzog, J . Medicin. Chern., 1972, 15, 555. K. Sykora and R . Mazac, C d I . Czech. Chern. Comm., 1966,31,2768.

451

Steroid Synthesis

Treatment of the bis-epoxide (219) with hydrogen chloride in glacial acetic acid afforded the mono-chlorohydrin derivative (220).' l 2 Reaction of 17nhydroxy-16-rnethylene-20-ketopregnanesled to stereospecific epoxidation at C-16 by chromic acid treatment. In addition, energetic reaction conditions can lead to (16S)-spiro-2'-oxirans of the androstane series. '

'

Me

Me

c=o

c=o

I

I

14a,l7a-Dihydroxyprogesterone(221) has been treated with aldehydes and orthoformates to give 14a, 17a-alkylidenedioxyprogesteronederivatives of general formula (222)' l4 Me

Me

I

The synthesis of 19-nor-14a,17a-ethano-16n-methoxycarbonylpregn-4-ene3,20-dione (223) from 3~-acetoxy-14~,17a-ethano-l6~-methoxycarbonylpregn5-en-20-one via the 6jl,19-oxido-intermediate, by a classical route, has been described. In contrast to the Buxus alkaloid (224), which afforded the conjugated diene (225) in acid medium, 1l-hydroxy-9,19-cyclo-5a,9jl-pregnane-3,20-dione bis(ethylene ketals) (226a) and (226b) underwent ring-opening to give the alcohol 112

'I5

E. L. Shapiro, L. Weber, H. Harris, C. Miskowicz, R. Neri, and H. L. Herzog, J . Medicin. Chem., 1972, 15, 716. V. Schwarz, Coll. Czech. Chem. Comm., 1972, 37, 637. D. Van der Sijde, H . J. Kooreman, K. D. Jaitly, and A. F. Marx, J . Medicin. Chern., 1972, 15, 909. A. J. Solo, J . N . Kapoor, S. Eng, and J. 0. Gardner, Steroids, 1971, 18, 251.

Terpenoids and Steroids

4 52

Me I

c=o

Me

(226) a ; R = P-OH b ; R = U-OH

Me

I

c=o

(227) and the diene (228).'16 The novel steroid (228) is a B-homo-analogue of A9(l 19-norprogesterone. Steroidal alkaloids have also been used as starting materials for the preparation of a variety of steroids. Thus, 3P-acetoxypregn-5,16-dien-20-one (229), an important starting material for steroid manufacture, has been prepared by modifications of a known degradation procedure of solasodine (230). ''

'

' I b

11-

S. M . Kupchan, J. W. A . Findlay, P. Hackett, and R . M . Kennedy, J . Org. Chem., 1972,37, 2523. Y , Sato and M . Nagai. J. Org. Chrrn., 1972, 37, 2629.

453

Steroid Synthesis Me

Yo

Finally, the etiojervane analogue of corticosterone (236) has been synthesized"* from jervine (231), through the known intermediate (232). The unsaturated cr-hydroxy-ester (233) was prepared from (232) by a Darzens reaction, followed by boron trifluororide rearrangement. Selectivecatalytic hydrogenation and lithium aluminium hydride reduction gave a tetraol, isolated as its acetonide (234), which by oxidation at C-3 gave the up-unsaturated ketone (235). The last steps of the sequence, which involved modifications of the side-chain, entailed acid hydrolysis, acetylation of the primary alcohol, and oxidation at C-20 to give (236).

H

HO

'

IX

T. Masamune and T. Orito, Birll. Chem. SOC.Japan, 1972, 45, 1888.

454

Terpenoih and Steroidr

The synthesis of 8a,l4p-progesterone (244) from 1l-oxo-5a,8a, 14p-spirostan3p-01 (237) has been reported."' Reduction of the hindered 11-keto-group of (237) by a modified Wolf-Kishner rnethod,l2' followed by acetylation, gave the 8a,l4fl-spirostan intermediate (238a). Degradation of the side-chain afforded the AI6-pregnane derivative (239), which on catalytic hydrogenation and alkaline hydrolysis gave the 5a,8a,14p-pregnane (240). Partial hydrolysis of compound (238b) at C-3, followed by oxidation, afforded the 3-keto-derivative (241). Treatment of the corresponding 2,4-dibromo-3-ketone with lithium salts in DMF, followed by selective hydrogenation of the resulting 1,4-dienone (242) with the ruthenium complex prepared from hydrated ruthenium chloride and triphenylphosphine, furnished the 20/3-acetoxy-4-en-3-one (243). Base hydrolysis and subsequent oxidation at C-20 afforded the isoprogesterone (244), along with its 17a-isomer. The stereochemistry at C-8 and C-14 was established by conversion of the intermediate (238b) into the known 8a,14&oestrone.' 2 o l9 lZo

F. Mukawa and W. Nagata, Bull. Chem. SOC.Japan, 1972,45,574. W. Nagata and H. Itazaki, Chem. and Ind., 1964, 1194.

455

Steroid Synthesis

(238) a; spiroketal chain b ; 17-CH(OAc)Me

(237)

Me

& -& gA Me

I

I

I

AcO

t

HO

H

H

(239)

(240)

Me

Me

I

I

0

0& A c -

/

H (242)

(241)

1 Me

Me

I

I

do+ SA

0

0

/

(244)

/

(243)

456

Terpenoidsand Steroids

Various 561.1 3a-pregnan-20-ones have been prepared from 13a-dehydroepiandrosterone’ ” by the sequence of reactions described previously for the formation of 14.17-bis-isoprogesterone derivatives. Two papers have dealt with the transformation of degradation products derived from cucurbitacins into 4.4J4r-trimethylated pregnanes of unnatural configuration.’ 2 3 The synthesis of 11-oxapregnanediones from 1 l-nor-9,12-seco-9-0~0-12-acids has been reported. 2 4 In one sequence of reactions. 3/&hydroxy-20fi-acetoxy-9ox0-9,12-seco-1 1-nor-5r-pregnan- 12-oic acid (246a), previously obtained from hecogenin (245), was hydrolysed to the corresponding dihydroxy-acid (246b), which was then methylated to the methyl ester (246c). Oxidation with Jones’ reagent aaorded the 3.9.20-triketo-derivative (247). This could be ketalized preferentially at C-3 and C-20 to afford compound (248). Lithium aluminium hydride reduction of the keto-ester (248) yielded the 98,12-diol (249),which with toluene-p-sulphonyl chloride in pyridine at ca. 1 I5 “Cfurnished the 11-oxadiketal, readily hydrolysed with acid to the 1 1-oxapregnane-dione (250).

Me R30-$-H I

n u

H

(246) a ; R’ = R2 = H, R3 = Ac b ; R’ = R2 = R3 = H c;R‘=R3=H,R2=Me d ; R’ = R3 = Ac, R2 = H

(245)

Me

I

c=o

H (247) I ? ’

1 l 3

I?’

(248)

T. Nambara and J . Goto, Clzem. and Phurm. Bull. (Japan), 1971, 19, 1937. P. Crabbe, A. Cruz, and 3. Iriarte, Canad. J. Chem., 1968,46, 349, J . R . Bull, P. R. Enslin, and H. H . Lachmann, J . Clieni. SOC.(C), 1971, 3929; J . R. Bull and C . J. Van Zyl, Tetrahedron, 1972, 28, 3957. Ch. R.Engel. R.C Rastogi. and M . N . R . Chowdhury, Steroids, 1972,19, 1.

457

Steroid Synthesis

Me

I

c=o

(250) Another pathway involved sodium borohydride reduction of the carbonyl group at C-9 in (246d), affording the lactone (251). Reduction with lithium aluminium hydride and boron trifluoride etherate or with hydrogen and platinum oxide in acetic acid led to the 11-oxapregnane (252),which was readily converted into the diketone (253).'24 The diketone (250) was dehydrogenated with DDQ to the corresponding A',4-3-ketone and then preferentially reduced at C-1 with tris(tripheny1phosphine)chlororhodium to the desired 11-oxaprogesterone (253).1 2 4 Me

Me

I

AcO'

I

H

H (252) a ; R = H b; R = AC Me

I

c=o

(253) Hecogenin (245) has also been used as a starting material for the preparation of 11- and 12-azapregnanes. ' 2 5

H . Mitsuhashi and K . Tomimoto, Chem. and Pharm. Bull. (Japan), 1971, 19, 1974.

Terpenoids and Steroidr Oxidation of the 11,12-ketol function in 3/3,12j?,20-trihydroxy-5~-pregnan-i 1ones (254a) and (254b) with bismuth trioxide gave the ll-hydroxypregn-9(1l)-en12-ones (255a) and (255b), respectively. A benzylic acid rearrangement then afforded the or-hydroxy-carboxylicacid(256),which by further treatment with lead tetra-acetate yielded the c-nor-1 1-ketone (257). Acetylation at C-3, followed by oxime formation gave the c-nor-1 1-oxime (258), which was allowed to react with tosyl chloride in pyridine solution to provide the expected lactams (259) and (260).1 2 ~ 458

& Me

I

CHOR

RO'

Me

RO

H (254) a ; R = H b; R = Ac

Me

I

I

R&

H (255) a ; R = H b; R = Ac Me

I

CHOH

Me

I

Me I

dH

AcO

H(258)

Steroid Synthesis

459 Me

I

The preparation of dl-11-dehydroaldosterone (261) by classical steps from the 3,20-bisethyleneketal of dl-3,20-dioxo-l1~,21-dihydroxypregn-5-en-18-oic acid (18 ---* 1lb)-lactone (262), a previously reported intermediate in the total synthesis of aldosterone, has been recorded.126

-

The synthesis of novel corticoids possessing rings A and B in a lO(5 4)ubeo system has been described.'27 In the simplest case, the corticoid (263) was used as starting material. The C-17-chain was converted into a bismethylenedioxygroup (BMD), after protection of the hydroxyl at C-llg as the fluoromethyl ether (264). Acid hydrolysis liberated the 11-alcohol (265). This with alkaline hydrogen 126

12'

J. Schmidlin, Helv. Chim. Acta, 1971, 54, 2460. Ch. Meystre, J. Schmidlin, H. Ueberwasser, H. Kaufmann, and G. Anner, Helv. Chim. Acta, 1972,55, 338.

460

x.:'*l" -og Terpenoids and Steroids

CH,OH

I


c=o

0 (264)

(263)

1

1

CH20H

I

C=O

c! H *o

i

0

&;fi

/J

OH

CH,OH I C=O

SH

0

OH

46 1

Steroid Synthesis

peroxide gave a mixture of 4,5-epoxides (266). Irradiation with a high-pressure mercury lamp above 310 nm, according to conditions described previously,'28 yielded the 10(5 -+ 4)abeo-steroid (267). Cleavage of the bismethylenedioxy protecting group in (267) with perchloric acid in tetrahydrofuran or with the hydrogen fluorideurea reagent afforded the novel corticoid (268). Similarly, photochemical rearrangement of the A'-epoxy-ketone (269), prepared by dehydrogenation of (266) with selenium dioxide in t-amyl alcohol in the presence of a small amount of alkaline iron(u1)acetate, gave the corresponding A'-abeocompound. Acid hydrolysis of the BMD group afforded the corresponding A'-3-keto-derivative (270).12' The novel corticoids substituted at positions 6, 9, and/or 16, (271), (272), and (273), were prepared via similar pathways, using the photochemical rearrangement of an appropriate 4,5-epoxy-3-keto-intermediate as the key CH20H

7H20H

(271) a ; R' = Me, R2 = H b; R' = H, R2 = Me c; R' = R2 = Me d ; R' = F, R2 = Me

I

CH,OH

I

c=o O 0 X

The synthesis of 9cr-fluoro-l8-methylprednisolone(282), a representative of still another new class of corticosteroids, has been de~cribed.'~'The sequence, shown in Scheme 11, used the known radical-induced 1,4-rearrangement of 12* 129

C. Lehmann, K . Schaffner, and 0. Jeger, Helv. Chim. Acta, 1962,45, 1031. L. Botta and J. Kalvoda, Experientia, 1972, 28, 625.

Terpenoids and Steroids

462

, I I

&

,

nil. i x

o&

0

Reagents : i, MesC1-SO,-collidine-DMF, room temperature; ii, HF-trioxan-CH,Cl,, 0 "C; iii, HOCH,.CH,OH-H ; iv, BuiAlH-MePh, 0 " C ; v, N,H;-KOHdiethylene glycol; vi, H,SO,-Me,CO, 50 "C; vii, SeO,; viii, NBAcIioxanHC104, 20 "C; ix, AcOK-Me,CO; x, HF; xi, H '. +

Scbeme 11

Steroid Synthesis

463

'

nitrile groups in 1l~-nitrosyloxy-20-cyanhydrins. 30 Thus, the hydroxyintermediate (275) was prepared from the 11fl-nitrosyloxy-derivative (274). Dehydration with methanesulphonyl chloride gave the diene (276), which by acid hydrolysis,followed by reaction with hydrogen fluoride-trioxan in methylene chloride, yielded the BMD-derivative (277). Ketalization at C-3 to give (278)and reduction of the cyano-group with di-isobutylaluminium hydride, followed by treatment of the imino-intermediate with hydrazine in the presence of base, afforded the 18-methylintermediate (279). Selenium dioxide introduction of the A'-double bond into (279), giving (280), was followed by epoxidation of the A'(' ')-bond to give the desired intermediate (281). Finally, epoxide opening with hydrogen fluoride,127 followed by acid hydrolysis of the BMD group, furnished the 18-homo-corticoid (282).129 The preparation and biological properties of 17,221-alkylorthoesters, 17-monoesters, and 17,21-diesters of &,9a-difluorocortisol and 6,9-difluoroprednisolone have been reported. 7 Seco-steroids

An interesting cleavage reaction of ring A has been r e ~ 0 r t e d . I The ~ ~ bromoketone (283) was allowed to react with sodium acetate in acetic acid to afford the 2-acetoxy-3-keto-derivative (284). The 2-hydroxy-oxime (285) was then treated OAc

NaOAc-AcOH reflux

130 131 13*

J. Kalvoda, Chem. Comm., 1970, 1002. R. Gardi, R. Vitali, G . Falconi, and A. Ercoli, J . Medicin. Chem., 1972, 15, 556. J . K. Paisley and L. Weiler, Tetrahedron Letters, 1972,261.

Terpenoids and Steroids

464

with thionyl chloride and aqueous potassium hydroxide to afford the cyanoaldehyde (286)in good yield.' 32 8,9-Seco-5a-androstane-8,9,1l-trione derivatives (287) were cyclized with alumina or silica in acetonitrile to furnish the tetracyclic compounds (288) and (289) and the corresponding ene-diones. ' 3 3 Introduction of various substituents R' and R2 at positions 3 and 17 caused systematic changes in the ratios of the cyclization products. The cyclization process was also affected by the nature of the catalyst and of the solvent.'33

H

H'tT

Alkylation of the cyclopentanone derivative (290),followed by hydrolysis of the protecting group, gave a mixture of two stereoisomeric 2-(6-methoxy-2-naphthyl)1-methyl-5-oxocyclopentane-1-aceticacids (291a) and (292).134These products were further reduced to provide the four corresponding hydroxyethylcyclopentanols (293a, b. c, and d). The y-lactones (294a and b) were also obtained by reduction of (291) and (292) under appropriate reaction conditions,' 34 Surprisingly, reaction of the cyclopentanone (291b) with the Wittig reagent ethylidenetriphenylphosphorane did not give the expected ethylidenecyclopentane, but the ethylidenecyclohexane (295). 3 5 This ethylidenecyclohexane derivative (295)was oxidized to the corresponding ketone (296)and also converted into the lactone (297) and the cyclic oxide (298) by conventional steps (Scheme

'

12).13 5

13'

'" 'I5

S. Aoyama, K . Karnata, and T Komeno, Chem. and Pharm Bull. (Jupan), 1971, 19, 21 16.

E G. Brain, F Cassidy, M . F. Constantine, J . C Hanson, and D. J D. Tidy, J . Chern. Soc. (0,197 1, 3846. E G Brain, F. Cassidy, A. W. Lake, P. J Cox, and G. A . Sim, J . C . S . Chem. Comm., 1972.497

Steroid Synthesis

465

Me

I

NPh

H

Me0

I

i. Me1 ii. H,O+

(291) a; R = H b;R=Me

0

(293) a ; R1 = CH2CH20H,R2 = Me, R3 = OH, R4 = H b; R' = CH2CH20H,R2 = Me, R3 = H, R4 = OH c ; R' = Me, R2 = CH2CH20H, R3 = OH, R4 = H d ; R' = Me, R2 = CH,CH,OH, R3 = H, R4 = OH

(294) a ; cis-a-lactone b ;cis-p-lactone

Diels-Alder condensation of 3,4-dihydro-5,6,7-trimethoxy-l-vinylnaphth-l-ol (299) with methyl acrylate afforded the isomeric hexahydro-6,7,8-trimethoxyphenanthrene-2a-carboxylic acids (300)and (301).136The acid (300) was readily 136

P. N. Rao, B. E. Edwards, and L. R. Axelrod, J. Chem. SOC.( C ) ,1971,2863.

466

Terpenoids and Steroids

Me0,C.-

WHMe

Reagents: i, OsO,; ii, NaIO,; iii, Os0,-Et,NOO; iv, H + ; v, LiAlH,; vi, OsO,-Et,NOO; vii, H +.

Scheme 12

isomerized to (301) under acidic conditions. Both acids (300) and (301) yielded the same octahydrophenanthrenecarboxylicacid (302)on reductionwith a limited amount of sodium in liquid ammonia.1 36

467

Steroid Synthesis

Meo&H,*co2H

M*Ci@ e:;H (0i;--

Me0

\

Me0

OMe

\

OMe

(301)

(302)

The synthesis of 4-(1,2,3,4-tetrahydro-6-hydroxy-2-naphthyl)butan-2-01 (306) has been accomplished by a straightforward procedure. 137 The methoxycarbonyl derivative (303a), obtained from 6-methoxy-1-tetralone was cyanoethylated with acrylonitrile in the presence of Triton B to afford the cyanoethyl compound (303b). Hydrolysis of (303b) in acid resulted in the propionic acid (303c), which on Wolff-Kischner reduction afforded the acid (304); this on treatment with methyl-lithium gave the methyl ketone (305a). Demethylation with pyridine hydrochloride gave the phenol (305b),and this with sodium borohydride furnished the desired alcohol (306). 3 7

0

vH,CO,H

(303) a ; R' = CO,Me, R2 = H b; R' = C02Me, R2 = CH2CH2CN C; R' = H, R2 = CH2CH,C02H

CH,COMe

I

RO C H J2-Jf

HO

JTJJCH2

(305) a ; R = Me b;R=H

8 Cholestane and Analogues Various synthetic aspects of cholestane chemistry have already been mentioned in previous sections. Some further important synthetic sequences will now be discussed. 13'

P. N. Rao, D. H.Buss, and L. R.Axelrod, J . Medicin. Chern., 1972, 15, 426,

468

Terpenoids and Steroids

Base-ca talysed isomerizat ion of 4~,5a-epoxy-7a-hydroxycholestan-2-one (307) afforded 5a,7z-dihydroxycholest-3-en-2-one (308). 38 Similar rearrangements were observed with 4a,5a-epoxycholestan-2-one.4a,5a- and 4PSP-epoxy-2Phydroxycholestan-7-one, and both isomeric 4,5-epoxycholestan-7-ones.Compound (307) was prepared from the corresponding A3*5-7-keto-derivativeby

Et,N EI,N.HCI-EtOH. 30 "C

(307)

(308)

successive treatment with t-butyl chromate in carbon tetrachloride, zinc-acetic acid in methanol, and zinc borohydride in methanol, which gave the corresponding 2-keto-A3-7a-alcohol. This was then epoxidized with peracid.' 3 8 Lead tetra-acetate oxidation of 3~-acetoxycholest-5-en-19-ol is known to give 3P,6P-diacetoxy-19-norcholest-5(10)-ene. 39 The same reaction has recently been applied to the 5B,6P-epoxide(309)which furnished the 11,19-oxidederivative

Pb(OAc), CaC0,qclohexane

'

AcO'

pyridine

13'

'"

D. H . R . Barton and Y . Houminer, J . C . S . Perkin I , 1972, 919. R . M . Moriarty and K . Kapadia. Terruhedrun Letters, 1964, 1165.

Steroid Synthesis

469

(310). Further treatment of (310) with methanolic sodium bicarbonate, followed by oxidation, furnished the enedione (31l).l4O The effect of 3cw- and 3P-hydroxy-, 3a- and 3P-acetoxy-, 3-ethylene ketal and 3a-methoxy-derivatives of cholest-Sene on the addition of the Simmons-Smith reagent has been investigated.14' The addition of the reagent occurred only with epi-cholesterol(312) to give mainly 3~-hydroxy-5,6a-cyclopropano-5a-cholestane (313)14' (see Chapter 1, refs. 153-155).

HO'

The remote photochemical oxidation by means of a rigid benzophenone reagent attached to a h y d r o x y - g r o ~ p ~has ~ *been ' ~ ~ further investigated with the cholestanol ester (314) as well as other steroid molecules (see Chapter 1, ref. 360).' 43

O=

In a related process, the direct introduction of the hydroxy-group in tertiary positions of the steroid nucleus has been a c c ~ m p l i s h e d by ' ~ ~irradiation of peracetic acid solutions of the steroid. Since both reactions are free-radical processes, it is interesting to note that, whereas in the former method'43 C-9 and C-14 40 41 42

143

'44

M. Kaufman, P. Morand, and S. A. Samad, J . Org. Chem., 1972,37, 1067. J . F. Templeton and C. W. Wie, Canad. J . Chem., 1971, 49, 3636. R. Breslow and P. Kalicky, J . Amer. Chem. Sac., 1971,93, 3540; R.Breslow and P. C. Scholl, ibid., p. 2331. R. Breslow, J. A. Dale, P. Kalicky, S. Y. Liu, and W. N. Washburn, J . Amer. Chem. Sac., 1972, 94, 3276. A. Rotman and Y . Mazur, J . Amrr. Chem. SOC.,1972,94,6228.

Terpenoids and Steroids

470

OH (319)

/ 'OH

Reagents: i, Cr0,-AcOH; ii, HCI-MeOH; iii, m-ClC,l-i,CO,H; iv, H,IO,; v, OsO,.

Scheme 13

Steroid Synthesis

47 1

are the attacked positions, in the latter'44 the preferred sites of attack are C-5 and C-14. The synthesis of allomuricholic acids has been reported and is shown in Scheme 13.'45 Hyodeoxycholic acid (315) was selectively oxidized at C-6 and the keto-acid allomerized to the 5a-series (316) and esterified. After successive bromination, reduction of the ketone, and treatment of the bromohydrin with zinc and acetic acid, methyl 3a-acetoxy-A6-cholenate(317)was obtained. Hydrolysis of the epoxide (318) provided allo-a-muricholic acid (319). Hydrolysis of the osmate ester derived from (317) gave allohyocholic (320) and allo-/3-muricholic (321) acids, respectively. Reduction of 3a,7/3-dihydroxy-6-oxo-5a-cholanic acid (322) with sodium in propanol yielded allo-a-muricholic acid (323), the last isomer of the series.'45

HO'

H

&c*2H

OH

A general method for the introduction of different functionality into position 5 of cholestanes has been deve10ped.l~~The conjugate addition of organic and inorganic nucleophiles to 6-nitrosocholesteryl acetate (325), generated in situ from 3~-acetoxy-5-chloro-6-hydroxyimino-5a-cholestane (324) afforded the 5cc-substituted 6-oximes (326). The nucleophiles which have been used include ethanediol, ethanol, methylamine, ammonia, nitrite, cyanide, thiocyanate, and azide.146 A report has appeared on the oxidation of 3-substituted 5a-cholestan-2a,5episulphides with rn-chloroperbenzoic acid, thus affording the corresponding anti-sulphoxides. 47 Treatment of the chlorohydrin (328), obtained from cholesterol 5a,6a-epoxide (327),with potassium bisulphate followed by acetylation furnished the rearranged 145

146 147

M. I. Kelsey, M. M. Mui, and W. H. Elliott, Steroids, 1971, 18, 261: Y . Komeichi, T. Iwasaki, Y. Ito, and F. Aida, Steroids, 1972,19,47. T. Komeno, M . Kishi, H. Watanabe, and K. Tori, Tetrahedron, 1972,28,2767.

Terpenoids and Steroids

472

(326) a ; X = SEt b ; X = OEt c ; X = NHMe d ; X = NH,

e ; X = NO, f;X=CN g ; X = NCS h;X=N,

compound (329a).148 Reduction with sodium in ethanol afforded (329b), which on lead tetra-acetate oxidation gave the ether (330); this was epoxidized with m-chloroperbenzoic acid to a mixture of isomeric epoxides. Reaction of the a-epoxide (33 1) with boron trifluoride etherate furnished the new rearranged cholestane derivative (332).14' Various studies have been devoted to the preparation and properties of A-homo-keto-cholestanes by classical routes. 49-1

(327)

Cl (328)

'" 149

lS0 Is'

J . Wicha, Tetruhedron Letters, 1972, 2877. M . Ephritikhine and J . Levisalles, Bull. SOC.rhim. France, 1971,4331. M . Ephritikhine, J . Levisalles, and G. Teutsch, Bull. SOC.chim. France, 1971, 4335. PI. Velgova. V. Cerny, and F. Sorm, CoN. Czech. Chem. Cornm., 1971, 36, 3165.

473

Steroid Synthesis 17

R '0 (330)

(329) a ; R' = Ac, R2 = C1 b; R' = R2 = H

HO

H H

0

The diborane reduction of a large array of six- and seven-membered-ring lactones belonging to the cholestane-and androstane series has been investigated under different experimental condition^.'^^ Thus, reduction of the lactone (333) under the conditions shown can lead to either a mixture of oxide (334) and diol (335) or exclusively the latter. The results which were obtained suggested the reaction mechanism shown in Scheme 14, which would account for the formation of compounds (337),(338), and (339) from (336).152 The 5a-cholestano[2,3-c]furazan2'-oxide (343) was initially prepared by treatment of 2,3-bis(hydroxyimino)-5a-cholestane(342) with chlorine and sodium hydroxide (Scheme 15).ls3 The structure (343) was confirmed by its preparation from 2-nitro-5a-cholest-2-en-3-ol (344) and hydroxylamine. In addition, it has been shown that base-catalysed nitration of 5ct-cholestan-7-one leads to 601- and 6j-nitro-derivatives, which adopt keto- rather than enol forms.' 53 The synthesisof the 5cr-cholestano[7,6-c]pyrazole(348)from 5a-cholestan-7-one (346) has been achieved by hydroxyrnethylation at C-6, giving (347),followed by reaction with hydrazine.' 5 4 Various other cholesbn[7,6-c]pyrazoles have also been prepared. Attempts to obtain the isomeric pyrazoles from 5a-cholestan-6ones were unsuccessful.' s4 ' 5 2

Is3

J. R . Dias and G. R . Pettit, J . Org. Chem., 1971, 36, 3485. D. J . Chadwick, W. R . T. Cottrell, and G . D. Meakins, J . C . S . Perkin I, 1972. 655. B. Pelc, J . Chem. SOC.(0,1971, 3914.

Terpenoidr and Steroids

474

0

(333)

1

a ' -I-

" H 3 '

(334)

(335)

44 u;,

42 %

21

<:

0

II

R~--C-OR'

I'

(336)

R'-

FH +

R'CHO BZH6

1

R'CH,UH (337)

-ORZ

OH

I

R~--CH-OR~ (338)

-+

T

+

R *- C H = O R ~ Scheme 14

R1CH20R2 (339)

Steroid Synthesis

s <*HI7

0

H

H

(340)

b.

(341)

ii

7

OH

(344)

(342)

1

kii r

vii

1

(343)

(345)

Reagents: i, Bu'OK-EtON0,-THF; ii, AcOH; iii, NH,OH,HCl-py; iv, H,PO,, 115 "C; v, Bu'OK-0,; vi, NH,OH; vii, NaOH-Cl,.

Scheme 15 3~-Hydroxy-5-azacholestane(353)has been obtained from B-nor-cholestenone (349)as shown in Scheme 16.' 5 5 Reduction to the alcohol, acetylation, ozonolysis, and methylation afforded the methyl ester of 3P-acetoxy-4,5-seco-5-keto-~norcholestan-4-oic acid (350). Beckmann rearrangement of the oxime (35l), obtained from (350), yielded the lactam (352a). Hydrolysis to the hydroxy-acid W. J. Rodewald and B. Achmatowicz, Tetrahedron, 1971, 27, 5467.

476

Terpenoids and Steroids

HOW

0

H (346)

OH (347)

-N 348b)

H

(348a)

(352b) and N-cyclization followed by reduction afforded 3P-hydroxy-5-azacholestane (353). The 6-keto-cholestane (354) was also converted by a known pathway into the lactam (355). Oxidation to the ketone (356a).followed by treatment with phenylhydrazine. gave the indole derivative (357).'s6 Brominatioh of the 3-ketone (356a) with pyridinum hydrobromide perbromide afforded the 4-bromo-ketone (356b). which in turn was allowed to react with N-phenylthiourea to furnish the thiazol (358) (Scheme 17).lS6 Reaction of 3cl.5-cyclo-5rw-cholestan-6-one (359) with diazomethane made it possible to prepare a number of B-homo-keto-derivatives (360)--(364).'57 Further homslogation of the eight-membered-ring ketones (362), (363), and (364)led to the formation of the four ketones (365)--(368). in which a carbonyl group is contained in a nine-membered ring.ls7 The synthesis of various 11-oxygenated cholesterols and derivatives has been reported.' 5 8 The sequence which was followed (Scheme 18) used 3fl-acetoxypregn-5-ene-l1,20-dione (369)'59 as a starting material and applied the total H . Singh, R . B. Mathur, N. J . Doorenbos, A. K . Bose, and S. D. Sharma, Trtruhedran, 1971, 27, 3993.

Cerny, and F. Sorm, Coil. Czech. Chern. Cornrn., 1972,37, 1331. J . J. Schneider, Tetrahedron, 1972, 28, 271 7. W J . Wechter and #. C. Murray, J . O r g . Chrm., 1963, 28, 7 5 5 .

"' J . Gehlaus, V.

''"5 H

Steroid Synthesis

477 7

AcO (349)

I

1

AcO --f

A

R'o< oO-OR2 N+

0 0

0

Me

(352) a ; R' = Ac, R2 = Me b; R' = R2 = H

I

T

N I OH (351)

(353) Reagents: i, LiAlH,-Et,O; ii, Ac,O: iii, 0,; iv, HCO,H-H2O2; v, CH,N,; vi, NH,OH, HCl-MeOH; vii, SOC1,-Et,O, -10°C; viii, O H - ; ix, Ac,O-py; X, LiAlH,dioxan.

Scheme 16 synthetic scheme reported earlier.'60 Condensation of (369) with i-hexylmagnesium bromide gave the 20-carbinol (370), which was sequentially epoxidized and dehydrated to a mixture of epoxy-olefins of which the 5a,6a-o~ido-A~~olefin (371) was the main constituent. Catalytic reduction of the double bond, Ibo

R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, and W. M. McLamore, J . Amer. Chem. SOC.,1952,74,4223; N. K. Chaudhuri, R. Nickolson, J. G. Williams, and M. Gut, J. Org. Chem., 1969, 34, 3767.

478

Terpenoids and Steroids

(356) a ; R b; R

= =

H Br

il

(358)

GHI7

aT& H

H N H

o

(357) Reagents: i, PhNH.CSNH,-EtOH; i i . PhNH.NH,-AcOH.

Scheme 17

followed by regeneration of the A5-3/3-ol system and chromatographic separation led to the 'normal' cholesterol derivative (372) and its 20-isomer (373). Reduction of the 11-keto-group in (372) with lithium aluminium hydride furnished llphydroxycholesterol (374).'5 9

Steroid Synthesis

479

480

Terpenoids and Steroids

Me

I

&Oh

AcO

I

&

AcO

( 369 1

F(6H13

C6H13

&H

(370)

I

I I 111

C,H,

I

cAco&H2

AcO

3

0,-

(372)

(371)

+

HO

AcO

HO (373)

(374)

Reagents: i , C,H ,,MgBr; ii, epoxidation; iii, SOCl,-py, 0 "C: iv, H,-5 :,,;-Pd/C-AcOEt; v, NaI-AcONa-AcOH-H,O-Zn: vi, LiAIH,.

Scheme 18 The synthesis of 5.6-trans-25-hydroxycholecalciferol(376),a new vitamin D analogue, has been achieved.' 6 1 Treatment of 25-hydroxy-vitamin D, (375) with iodine in light petroleum ether. followed by addition of Na2S,0, and chromatography, afforded 5,6-trans-25-hydroxy-D3 (376), which has been shown to stimulate intestinal calcium transport.'61 In'

M. F. Holick, M. Garabedian, and H. F. DeLuca, Science, 1972, 176, 1247.

Steroid Synthesis

48 1

OH

HO'. (375)

(376)

A partial synthesis of ergosta-7,22,24(28)-trien-3P-ol (378b)has been achieved, The selective oxidation of thus confirming the structure of this yeast 5,6-dihydroergosteroI acetate with a saturated ozone solution in methylene chloride at - 70 "C yielded the 22-aldehyde (377). Wittig reaction of the pure (20s)-aldehyde (377) with the appropriate 2-isopropylallylphosphorane afforded stereospecifically the required sterol acetate (378a) in high yield. This synthetic sterol acetate was identical with the natural material. 1 6 2

(378) a ; R = Ac b;R=H The synthesis of P-sitosteryl acetate (384) has been achieved by Grignard reaction between the resolved bromo-alkane (382),prepared from the ester (379), and 3P-acetoxypregn-5-en-20-one(383) (Scheme 19). After acetylation and 162

D. H. R . Barton, P. J . Davies, U. M. Kempe, J. F. McGarrity, and D. A. Widdowson, J . C . S . Perkin I , 1972, 1231.

Terpenoids and Steroids

482

1

Me

v.

I

c=o

vi

f

Reagents: i , LiAIH,; i i , PBr,; iii, #,C(CO,Et),-EtONa: iv, H,O'; v, resolution with cinchonine; vi, HgO-CCI,-Br,; vii, M g ; viii, Ac,O-py; ix, H,-Pd/C.

Scheme 19

selective catalytic hydrogenation of the side-chain double bond (24R)-24-ethyl3fl-acetoxy-cholest-5-ene(384) was obtained. 6 3 The stereospecific synthesis of (20S,22R)-17a,20,22-trihydroxycholesterol(388) and its (20S,22S)-isomer(389) has been reported.' 64 Addition of vinyl Grignard reagent to the known 16a.l7a-oxidopregnenolone acetate (385), followed by opening of the epoxide with lithium aluminium hydride, furnished the 17,20dihydroxy-intermediate (386). Conversion into the 3,5-cyclo-steroid (387) and epoxidation of the remaining double bond afforded a C-22 epirneric mixture of epoxides which, on reaction with s-butyl-lithium and reconversion into the 3phydroxy-A5-steroids,afforded the epimeric tetraols (388)and (389). The preparation of similar 3,17,20-trioIsis also reported.I6" lh3 b4

R . Ikan, A . Markus, and E. D. Bergmann, J . O r g . Chem., 1971,36, 3944. R . C. Nickolson and M. Gut, J . O r g . Chem., 1972.37, 21 19.

Steroid Synthesis

483

HO

Me

I

MgBr i, =J ii. LiAIH,

HO (386) p-MeC,H,.SO,CIMeOH-C,H,N

HO

HO

oH

HO (388)

+

OMe (387)

Protection of the ring+ diene system in ergosterol acetate (390) as its adduct (391), followed by bromination of the C-22 double bond to (392) and dehydrobromination with 1,5-diazabicyclo[4,3,0]non-5-ene(DBN) in toluene, gave ergosta-5,7,22,24(28)-tetraen-3/?-01 acetate (393).165 165

A. B. Garry, J. M. Midgley, W. B. Whalley, and B. J. Wilkins, J.C.S. Chem. Comm., 1972, 167.

Terpenoidsand Steroids

484

AcO

AcO

Ph

Br

AcO

AcO

(393)

Steroid Synthesis

485

The synthesis of various C-26 sterols from cholic ester derivatives by appropriate Grignard reactions has been achieved.' 66 In particular, 3fl-hydroxy-24dimethyl-5a-chol-23-ene (394), previously isolated from Halocynthia roretzi, has been prepared by this route.'66

(394)

Finally, litocholic acid acetate (395)has been converted into the aziridine (399), by the classical sequence of reactions, shown in Scheme 20.'67 Similarly, stig0

II

c\

OH 0

AcO * (395)

1

iii, iv

1 '66 16'

v, vi

continued overleaf

A . Metayer, J. Viala, A. Alcaide, and M. Barbier, Compt. rend., 1972, 274, C, 662. R. Ikan, A. Markus, and Z . Goldschmidt, J . Org. Chem., 1972, 37, 1892.

Terpenoids and Steroids

486

1

AcO '

I

(398)

AcO-

(399) Reagents

I, L,

(COCl),-C,H,, 11, CH,N,-Et,O; 111, hv-THF-MeOH; Ac,O-AcOH, A , \ I , AgNCO-I ,-Et,O. V I I , MeOH-Et

IV, VIII,

MeMgi-Et,O, KOH-MeOH.

Scheme 20

masterol acetate (400) has been transformed into 22.23-iminostigmasteryl acetate (401).16' 2a,3a- and 2fi,3fi-iminocholestanes have been used as starting materials for the synthesis of 2,3-diaminocholestanes.16'

I

AgNCO-I, THF

AcO

IhX

K . Ponsold and D. Klemm. Chem. Ber., 1972, 105, 2654.

Steroid Synthesis

487

9 Steroidal Insect and Plant Hormones

A possible metabolite of ecdysone (409), 2/3,3p,14a,l7~-tetrahydroxy-5~-androst7-en-6-one (408)has been prepared from dehydroisoandrosterone (402)as shown in Scheme 21.'69 Mesylation at C-3, followed by reduction and acetylation at

(402)

vi, vii

HO

& MsO

0

0

(405)

(404) OAc

AcO AcO ~

xu,

Xlll

HO OH

HO 0

(408)

Reagents: i, MeS0,CI; ii, NaBH4-Et,O-dioxan; iii, Ac,O-py; iv, B,H,-THF; v, 0 0 , ; vi, collidine, A ; vii, AgOAc-I,-AcOH-H,O ; viii, Ac,O-py; ix, Br,-AcOH; x,...Li,CO,-LiBr-DMF; xi, Ac,O-HClO,; xii, o-HO,CC,H,CO,H-Et,O: xiii, K,CO,-MeOH-H,O, A.

Scheme 21 J. S. Cochrane and J. R . Hanson, J . Chem. SOC.(0,1971, 3730.

Terpenoids and Steroids

488

C-17, gave 3~-methanesulphonyloxyandrost-5-en-17~-ol acetate (403). Diborane addition to the A5-double bond and oxidation afforded the 6-keto-derivative (404). Elimination of the 3-mesylate, followed by iodine and silver acetate treatment furnished the 2-acetoxy-3-alcohol (405), which was successively acetylated at C-3, brominated at C-7, and dehydrobrominated to the triacetoxyA’-6-ketone (406). Enol acetylation of the conjugated carbonyl furnished the tetra-acetate (407), which was treated with peracid and then hydrolysed and isomerized at C-5 to yield the desired tetraol (408).’69 A number of steroids presenting structural features similar to those of ecdysone (409) have been prepared by known sequences of reactions.’70

(409) A new synthetic route (Scheme 22) to the fungal sex hormone antheridiol(414)

and the determination of its absolute configuration have been reported.”l Condensation of 3-isopropyl-2-furyl-lithiumwith 3-(tetrahydropyran-2-yloxy)22,23-dinorchol-5-en-24-a1 afforded the carbinol (410a). Oxidation of the acetate (410b) with m-chloroperbenzoic acid yielded the epoxy-lactol (411). Reduction with sodium borohydride provided the stereoisomeric butenolides (412) in high yield. Sequential treatment with zinc, sodium iodide, and acetic acid to regenerate the A5-double bond and acid hydrolysis gave the stereoisomeric dihydroxybutenolides, which were separated by chromatography. The desired (22S,23R)-butenolide (413) was photo-oxygenated in the presence of hematoporphyrin to give antheridiol(414).” Antheridiol(414) has also been obtained as a mixture of epirners at C-22 and C-23 by aldol condensation of 3-tetrahydropyranyloxy-A5-7-oxobisnorcholaldehyde (415 ) and ,8-isopropylbut-2-enolide (416). with subsequent removal of the protecting group at C-3.172 Another synthesis of stereochemically pure antheridiol (414) has been reported.’ 7 2 The above aldol condensation when performed with the 3-acetoxy-7desoxy-22-aldehyde gave the desired (22S,23R)-isomer, which was separated by chromatography and fractional crystallization. 7-Desoxy-7-dihydroantheridiol 170

H . Lettre, J . Greiner, K . Rutz, and L. Hofmann, Annalen, 1972,758, 89, A. Edwards, J . Sundeen, W. Saimond, T. Iwadare, and J. H. Fried, Terrahedron Lerters, 1972, 791. T. C. McMorris and R . Seshadri, Chem. Comm., 1971. 1646.

* ” J.

Steroid Synthesis

489

(410) a ; R = H b; R = AC

HO

HO

(414) Reagents: i, NaBH,-dioxan-H,O;

ii, Zn-NaI-AcOH; iii, 5 % H,SO,; iv, t.1.c.

Scheme 22

Pri

Terpenoids and Steroids

490

7+

n 0

0

0

0 (4 16)

(415)

was then photo-oxygenated and rearranged, or protected as the bistetrahydropyranyl ether and oxidized with Collins reagent to give the 7-ketone, and then hydrolysed to (414)."3 10 Steroidal Alkaloids

Pachystermine-A (417) and pachystermine-B (418) have been synthesized from epipachysandrine-A (419) by elaboration of the p-lactam ring from the 38amino-group.

'"

-I= (418)

'

74

T. c. McMorris, T. Arunachalam, and R. Seshadri. Tefrahedron L e f t e r r . 1972, 2673. T. Kiruchi, T. Nishinaga, S. Uyeo, 0. Yamashiro, and K . Minami, Chem. and Pharm. Bill/. ( J o p a n ) , 1971, 19, 1893.

Steroid Synthesis

49 1

0

d'

OH

A new synthetic approach to samandarine-type alkaloids has been developed and is shown in Scheme 23.'75 Treatment of the hydroxymethylene derivative (420)with an equimolar amount of methyl toluene-p-thiosulphate in the presence of potassium acetate, followed by acetylation, gave 17/?-acetoxy-2~-thiomethylandrostan-3-one (421). Reaction of (421) with hydroxylamine afforded the corresponding oxime (422). whose Beckmann fragmentation led to the seconitrile (423). Removal of the methylmercapto-group of (423) with deactivated Raney nickel yielded the methylene derivative (424),whose epoxidation, followed by sodium azide opening of the epoxide, gave compound (425). This with an excess of sodium borohydride in refluxing propan-2-01 simultaneously reduced the azide group to an amine and the nitrile to an aldehyde, cyclized in the desired manner, and hydrolysed the 17-acetoxy-group, thus affording the cyclic oxide (426).' Compound (426) had previously been converted into samandarine (427). The solanum alkaloids solafloridine (431 a) and 25-iso-solafloridine (432) have been prepared by a multi-step synthesis from 3p,16a-diacetoxy-20-(5The pyridine ring of compound methyl-2-pyridyl)pregna-5,20-diene(428). (428), available from 3P-acetoxypregna-5,16-dien-20-one, was reduced and afforded a mixture of (429a)and (430a),which were separated by chromatography. Hydrolysis gave (429b) and (430b), respectively, which upon treatment with N-chlorosuccinimide in methylene chloride yielded the chloramines (429c) and (430c). Elimination of hydrogen chloride then furnished the expected alkaloids (431)and (432)' " Solanocapsine (436) was then synthesized from the diacetate (431b).I7* The 23-keto-group was introduced by manganese dioxide oxidation of (431b) to give the ketone (433), which with sodium borohydride afforded the alcohol (434). N-Benzyloxycarbonylation of the piperidinol group, followed by dehydrogenation and then by partial alkaline hydrolysis, yielded N-benzyloxycarbonyl-22,26-epimino- 16c(,23-epoxy-5a,22aH,25~H-cholestane-3~,23~-d~o~

'

'

' 176

Y. Shimizu, Tetrahedron Letters, 1972, 29 19. S. Hara and K . Oka, J . Amer. Chem. Soc., 1967, 89, 1041. H . Ripperger, F. J. Sych, and K. Schreiber, Tetrahedron, 1972, 28, 1619. H . Ripperger, F. J . Sych, and K . Schreiber, Tetrahedron, 1972,28, 1629.

492

Terpenoids and Steroids

\ OH

OAc

H--

HO \

0

H (420)

+ *M se NC

H--

H

HON $M e

H

Reagents: i, p-MeC,H,.SO,SMe-AcOK-EtOH; ii, Ac,O; iii, NH,OH,HCl-py; iv, p-MeC,H,.SO,CI-py; v, Raney N i ; vi. m-Cl.C,H,CO,H; vii, N a N , ; viii, NaBH,-Pr'OH, reflux.

Scheme 23

493

Steroid Synthesis

,.OR'

R'O (429) a; R' = Ac, R2 = H b ; R ' = R2 = H C ; R' = H, R2 = C1

(430) a; R' = Ac, R2 = H b; R' = R2 = H C; R' = H, R2 = C1

494

Terpenoids and Steroids

Me N

--OH

HO

RO (431) a ; R = H b ; R = AC

(432)

(435). Oxidation of the 3fi-hydroxy-group of (435), cleavage of the benzyloxycarbonyl moiety by hydrogen bromide in acetic acid, and oxidation, followed by oximation and catalytic hydrogenation, then gave solanocapsine (436).”*

m

AcO

(433)

AcO

& (434)

1

N (436)

(435) R

=

benzyloxycarbonyl

Steroid Synthesis

495

The partial synthesis of solacongestidine (438) from soladine (437) has also been reported.

H

Me

&J-

HO

___*---

--0

I

0

H (439) The synthesis of batrachotoxin (439), the steroidal alkaloid from the poison arrow frog Phyllobates aurotaenia, has continued to attract attention. The partial synthesis of various 3~-methoxy-3cc,9a-oxido-7cc-hydroxyZ Icc-acetoxy-58steroids has been reported.'" In particular (Scheme 24), the A'(' ')-double bond 179

I8O

G. Adam, D. Voigt, and K. Schreiber, J. prakt. Chem., 1971, 313, 45. R. Inhof, E. Gossinger, W. Graf, W. Schnuriger,and H. Wehrli, lielu. Chim.A m , 1971, 54. 2775.

Terpenoids and Steroids

496

* & 1 (443)

1

_ _ - - --0

\l.\li,

_--

0

'OH

'

'OH

Me0

H

(444)

I(M

_ _ _ _ - ---0

Me0

H

'OH

Reagents: i, OsO,; ii, Ac,O; iii, D D Q ; iv, p - D , N C , H , C O , H : cyclohexene-MeOH; vi, H,; vii, HCl-MeOH.

Scheme 24

v, H,-PdiBaS0,-

497

Steroid Synthesis

of the known keto-lactone (440) was hydroxylated with osmium tetroxide and acetylated at C-11 to give (441). Dehydrogenation of (441) with DDQ afforded the dienone (442), which could be epoxidized selectively, yielding the 6a,7aepoxide (443). Reductive opening afforded the 7a-hydroxy-derivative (444). Further catalytic reduction of(444), followed by exposure to methanolic hydrogen chloride, gave the 3-methoxy-derivative (445). Lithium aluminium hydride reduction of the 14,18-lactonein (445)afforded the tetraol(446), also prepared by a slightly different route. Such an 18,20-diolhad already been converted into the 14~0,18N-[ep(oxyethano-N-methylimino)]chain present in batrachotoxin (439). 81 The reductive epoxide-opening procedure used above also applied to the 6-steroid (448); 14P,lSP-epoxide (447),'82 affording the 14~-hydroxy-20-keto-A1 this was readily converted into the saturated keto-derivative (449), which had previously been used as a synthetic intermediate for the preparation of tetrahydrobatrachotoxinin A (450).'*'

(450)

(449)

W . Graf, H . Berner, L. Berner, E. Gossinger, R . Imhof, and H. Wehrli, Helu. Chim. Acta, 1970, 53, 2267. E. Gossinger, W. Graf, R . Imhof, and H. Wehrli, Helu. Chirn. Acta, 1971, 54, 2785.

498

Terpenoids and Steroids

Using the reaction conditions described previously.'80-'82 a partial synthesis of 3-0-methyl-20-<-7,8-dihydrobatrachotoxinin A (452) has been reported in eight steps from 11a-acetoxy-3a.9a-epoxy-14-hydroxy-3~.18,18-trimethoxy-5~, 14P-pregn-16-en-20-one(451).1 8 3 Finally. another slightly modified synthesis of (452)and its C-20-epimer from the intermediate (451) has also appeared.lg4 Me I

- -+

Me0 (451I (452) The route explored in earlier studies'80~184 has recently been applied to the partial synthesis of batrachotoxinin A (464b)(Scheme 25).l S 5 The triacetate (453) was submitted to repeated bromination and dehydrobromination conditions to afford the dienone (454). This could be selectively epoxidized to the 14p,15pepoxy-intermediate (455). Catalytic hydrogen transfer under the previously described conditions gave the 14p-hydroxy-derivative (456a),which was hydrolysed to the 14.18-diol (456b). Reaction with 2.2-dimethoxypropane in the presence of acid afforded the acetonide (457). which was reduced with sodium borohydride to the (20S)-alcohol (458a). Acid treatment of the corresponding acetate (458b)regenerated the 14.18-diol(459). Oxidation of (459)with dimethyl sulphoxide in acetic anhydride formed simultaneously the 18-aldehydo-group and the 140-thiomethyl methyl ether (460a).which afforded (460b)with methylamine. Sodium borohydride reduction of (460b) gave the corresponding amine, which was converted into the chloroacetate (462a)and then by acid treatment into the free 14-hydroxy-derivative (461b). The hydroxy-lactam (462c) was then formed by the usual sequence of reactions. involving treatment of (461b) with sodium hydride (462a) followed by direct basic hydrolysis to (462b) and subsequent acetylation to (462c). Dehydration of (462c) with thionyl chloride in pyridine solution afforded the doubly unsaturated lactam (463). Finally. reduction with lithium aluminium hydride gave the 3-0-methyl ether (464a), which was converted with acid into batrachotoxinin A (464b).'8 5 Another study reported the transformation by a classical route of cholic acid (465) (see Scheme 26) into 3/3-methoxy-3r.9r-oxido-l la-acetoxy-A'-cholenate (471).which possesses the ABC ring system o f batrochotoxin (439).'*"

Iqi

W . Graf, E. Gossinger. R . Imhof, and H . Wehrli, H r l r . Chini. Acta, 1971, 54, 2789. W . Graf, E. Gossinger, R . Imhof, and H . Wehrli, H e l r . Chirn. Acfa, 1972, 55, 1545. R. Irnhof, E. Gossinger, W. Graf, H . Berner, L . Berner, and H . Wehrli, Helz.. Chirn.

""

R . R . Schumaker and J . F. W . Keana, J.C.S. Clrrm. Cornm., 1972, 622.

In3

'"

.?crtr. 1971. 5s. 1 1 5 1 .

Steroid Synthesis

499

* (454)

IV

t

_ _ _ - - - ---b

M

'OAc

H

Me0

*

OAc

H

(456) a ; R = Ac b:R=H

(455)

Iv H (457)

H (458) a ; R

H b; R = Ac L-

I

vii

Reagents: i, NBS; ii, -HBr (i and ii repeated); i i i , p - 0 2 N C , H , C 0 , H ; iv, H2-Pd/BaSO,cyclohexene-MeOH ; v, Me,C(OMe),-p-MeC,H,.SO,H ; vi, NaBH,-MeOH, - 30 " C ; vii, p-MeC,H,-SO,H-MeOH ;

Scheme 25 continued overleaf

500

Terpenoids and Steroids

AcO.

Me0

'OAc

I

Me0

"OAc

H

H (461)a ; R = CH,SMe b;R=H

(459)

XIII--XI

.'OR'

Me0

Me0

H

*

OAc

H

(462) a ; R' = R2 = R3 = Ac b ; R' = R2 = R3 = H C; R' = H, R2 = R 3 = AC

(460)a ; R

=

0

b;R=NMe

lxr,

Me

I

Me0

RO (463)

H (464) a ; R = Me

b;R=H Reagents ( cot i f . ) :viii, DMSO-Ac,O; ix, MeNH,, 80 "C; x, NaBH,; xi, ClCH,COClCI-ICI,; xii, HCl-MeOH; xiii, NaH-THF-PhH-EtOH; xiv, OH - ; xv, Ac,O, room temp.; xvi, SOCl,-py, room temp.; xvii, LiAlH,-Et,O; xviii, p-Me-C,H ..SO 3H.

Scheme 25

50 1

Steroid Synthesis CO,H

HO.

C0,Me

AcO *

H

H

(466)

(465)

1 1 1 , 111

,CO,Me

C0,Me

Ik-W

AcO'.

0 H

H

C0,Me

HO

H

H

(470)

Ltl

(469)

COzMe

Me0

H (471)

Reagents: i , Fieser's technique; ii, HSCH,CH,SH; iii, Raney Ni; iv, K,CO,; v, CH,N,; vi, K,CrO, : vii, Os0,-py; vii, H,S-NH,Cl,aq; ix, MeO--MeOH: X. HClMeOH; xi, Ac,O-py; xii. POCl,-py.

Scheme 26

502

Terpenoidy and Steroids 11 Sapogenins

Little synthetic work has been reported in this series of natural steroids. Reaction of (25R)-spirost-4-en-3-one(472)with an excess of hydrazoic acid in the presence of boron trifluoride afforded (25R)-3-aza-~-hornospirost-4a-eno[3,3-d]tetrazole (413).’ This tetrazole was degraded to 3-aza-~-homopregna4a,l6-dieno[3,4-d]tetrdzoi-20-one (474),which. in turn, was converted into the novel steroids (475)and (476)by conventional reactions (Scheme 27).1 8 7

3

s

(473)

\

0

’N

N. N” I/ N. N /N

p

-

Me

I

c=o

’

(475) Me

I 2j c=o

y H y N N.

N

Reagents:

(474)

(476)a ; R = C1 b ; R = Br C ; R = SCN

I , HN3-CHCI,-BF,-Et,0; it. NH,OH,HCI: H,O,-OH , V I , HCI, HBr, or KSCN.

111,

POCl, p y ;

Scheme 27 lh‘

H . Singh, R . B. Mdthur, and P. P. Sharma, J.C S. Prrkrti I , 1972. 990.

IV,

H , O + , v,

Steroid Synthesis

0

(477)

liii,

iv

v---ix f---

r-igi

0 H

AcO

(479)

(480)

b.xi

dCN

fCoZMe

/CHO

c H

(483)

Reagents: HC0,COMe-py; ii, NC.CH.PO(OEt),-NaH-THF; iii, H,-PdiCaC0,THF ; iv, (Pr'O),Al-cyclohexanone-xylene; v, H ,-PdiCaC0,-MeCN ; vi, separation of SB-compound from 5a-; vii, H,IrCl,-P(OMe),; viii, KOH-H,OMeOH-dioxan; ix, Ac,O-py; x, (COCl),-PhH; xi, H,-Pd/BaSO,; xii, piperidine-TsOH-MePh, A ; xiii, CH =CH,CO,Me-MeCN ; xiv, AcOH-AcONaH,O; xv, Na,CO,-H,O-MeOH-THF; xvi, TsOH-PhH, A ; xvii, S, A.

Scheme 28

504

T~rpenoidsand Steroids 12 Bufadienolides

The synthesis (Scheme 28) of 3~-acetoxy-5~.14r-buf~-20.22-dienoiide (483) has been reported from 3~-hydroxy-l7-oxoandrost-S-ene (477).'" A Wittig reaction on the Xormate of (477) gave the vinylic niirik (47d). which by catalytic hydrogenation and Oppenauer oxidation a!?ijrded the a4-_i-keio-derivati~e(37'9). Reduction of the A'-double bond gave a mixture of isomers a1 C-5, of which the 5P-isomer was transformed into the C-20-zcid (480) and the11 into the aldehyde (481) bq Rosenmund reduction. Alkyiation of tht: corresponding enamine gave the aldehydo-ester (482). readily converted into the bufadienolide (483) under the usual reaction conditions.'88

0

0

H I

I",'

0

0

'OH

R

H (486) a ; R = Ac b;R=H

(487) a ; R = Ac b;R=H

Reagents: i, NBS-CCl,; ii, p y ; iii, A1,OJ; iv, rn-C1.C,H,CO3H; v, H,S0,-H20-Mee,CO; vi, MeS0,CI-py; vii, SiO,.

Scheme 29 Ib8

G . R . Pettit and J . R . Diaz, J . O r g . Chew., 1971.36, 3207.

Steroid Synthesis

505

In addition, bufotalien (485), 1Scc-hydroxybufalin (486b), and resibufogenin (487b) were easily prepared from 14-dehydrobufalin acetate (484)(Scheme 29). 8 9 In the first case, brornination of (484) followed by dehydrobromination and hydrolysis at C-3 afforded (485). In the second case, treatment of (484) with peracid gave the 14a,l5a-epoxide, which was opened with dilute acid to 1% hydroxybufalin acetate (486a), readily hydrolysed to the 3-alcohol (486b). Finally, reaction of (486b3 with methanesulphonyl chloride furnished the 14/?,15/?-epoxide(487a), which was hydrolysed to the free alcohol (487b). Other routes to these bufadienolides have also been r e p ~ r t e d . " ~ The synthesis of marinobufagin (491a) and marinobufotoxin (491c) has been achieved from relocinobufagin (488). 90 Selective acid dehydration of (488) gave 0

0

HC!-MeOH

ow

OH

(491) a ; R = H (490) a ; R = I NH b; R = CO(CH,),CO,H II b;R=Br c ; R = CO(CH,),CQNH.CH(CH,),.NH,C.NH, I L*y

G . R . Pettit, Y . Kamano, F. Bruschweiler, and P. Brown, J . Org. Chem., 1971, 36,

19'

3736. Y . Kamano and G . R . Pettit, Experienria, 1972. 28, 768.

506

Terpenoids and Steroids

14-dehydrotelocinobufagin (489). which with N-iodosuccinimide yielded the iodohydrin (490a),which was converted directly into marinobufagin (491a). The substitution of N-bromoacetamide or N-bromosuccinimide for the N-iodoreagent provided the bromohydrin (490b), also converted into (491a). Reaction with suberic %-anhydridein pyridine furnished the suberate ester (491b). The halfester (491b) was then allowed to react with i-butyl chloroformate in tetrahydrofuran containing triethylamine, and the cold solution of the mixed carbonic anhydride was added to arginine monohydrochloride in methanol-water. affording marinobufotoxin (491c).’90 13 Cardenolides The seco-butenolides (493)have been prepared from the substituted acetaidehyctes (492) by aldol condensation with glyoxylic acid in acidic medium, followed by sodium borohydride reduction.”’ This technique was then applied to the

(492) a ; C-3/C-4 threo b ; A3(4)

0

(493) a ; C-3/C-4 threo b ; A3(4) steroid (494). 9 2 3P-Hydroxy-l4a-card-20(22)-enolide (496) was prepared by aldol condensation of 3P-acetoxypregnan-21-al (494) with glyoxylic acid via the 3~-acetoxy-21-~-hydroxy-14or-card-20(22)-enolide (495). The 5,6-dehydroderivative of (496) was also prepared by a similar route.’”2 A synthetic route (Scheme 30) from digitoxigenin (497) to 20(22)-dihydro-23deoxodigitoxigenin (500) has been developed. 9 3 Digitoxigenin (497) was H . H. Inhoffen, W. Kreiser, and M . Nazir, Annalen, 1972, 755, 1 . W. Kreiser and M . Naztr, Annalen, 1972, 755, 12. F. W Villaescusa and G R. Pettit, J O r g . Chcin., 1972, 37. 569

lY1

Iv‘

Steroid Synthesis

507

0

(494)

1

NaBH,

acetylated, dehydrated, and hydrogenated selectively to afford 3P-acetoxy-5J,20<-card-14-enolide (498). Lithium aluminium hydride reduction followed by cyclization yielded 3~-hydroxy-23-deoxo-5~,2O-~-card-14-enolide (499). The 14P-hydroxy-groupwas introduced by successive formation of the 14P-hydroxy1Sa-brorno-derivative and then the 14/?,15P-epoxide,followed by reduction which led to (500).'93 The mechanism of the base-catalysed isomerization of cardenolides, using mainly Cigitoxigenin (497) and its 17a-isomer as test compounds, has been examined.'94 The preparation of the 3-suberoyl-~-arginineester of digitoxigenin (497) and of resibufogenin (487b) has been ~ e p 0 r t e d . l ~ ~ The reaction of various digitoxigenin (497) derivatives with osmium tetroxide has been investigated. Treatment of 3-0-acetyl-14-anhydrodigitoxigenin (501) with osmium tetroxide afforded the 14c(,15c(-diol(502) and its 14&15j?-' isomer 194

lg5 lg6

C . Lindig and K . R . H. Repke, Tetrahedron, 1972, 28, 1847, 1859. K. Shimada, Y. Fujii, and T. Nambara, Chem. and Ind., 1972, 258. M. Schupbach, A. F. Krasso, M. Binder, and Ch. Tamm, Helu. Chim. Acta, 1971,544, 2007.

Terpenoids and Steroids

508

H (497)

Reagents: i, H , O ' ; 11, Ac,O; iii. H,-PdiCaCO,; iv, LiAlH,; v, DMSO, 150°C; vi, NBA-HClO,-dioxan; vii. KOAc-MeOH; viii, LiAlH,.

Scheme 30

(503). Their stereochemistry was established by chemical degradation to known substances. The butenolide ring of digitoxigenin (497)has also been treated with osmium tetroxide. affording both 20,22-diols (504) and (505).196

Steroid Synthesis

Finally, the stereochemistry of cyclic 14,20-oxido-cardenolidesderived from digitoxigenin (497), digoxigenin (506),3P,14,15P-trihydroxy-SP, 14P-card-20(22)enolide (507),and gitoxigenin (508),has been discussed.1 9 7

Ig7

A. F. Krasso,

M.Binder, and Ch. Tamm, Helv. Chim. Acta,

1972,55, 1352.

ERRATA Vol. 2, 1w2

Page 63, formula (342). Replace ‘OH’ at top of formula by ‘C5Hll’. Page 164. lines 1 and 2. For ‘octotillone’ read ‘ocotillone’. Fage 165.

(65)

(65)

Page 168, formula (80). 3/J-OH instead of 3P-H. Page 189, formula (37). Replace ‘R’ = g’ by ‘R’ = hi. Page 197. Ref. 6 should read: L. Canonica and A. Fiecchi, Res. Progr. Org. BioI. M e d . Chenz.. 1970, 2, 51. Page 200. Interchange HE and H, in all formulae except (6). Page 217, line 8. Diosgenin is the AS-3~-hydroxy-analogue of (86). Page 397. Replace formula (362) by

510

Author Index

Aasen, A. J., 52, 102, 165, 232,244 Abad, A., 404 Abaeva, N. Kh.. 81 Abasova, Z . I., 51 Abdel-Baset, Z. H., 162 Aberhart, D. J., 264 Abola, E. 4 I3 Abou-Donia, S. A., 26 Abul-Hajj, Y. J., 269, 327 Acar, M., 54 Achilladelis, B., 256 Achmatowicz, B., 475 Achmatowicz, O., jun., 7 Achmatowicz, S., 404 Acklin, W., 110, 257 Ackrell, J., 70 Adam, G., 182, 299,495 Adams, J. B., 434 Adams, P. M., 256 Adesida, G. A., 207, 210, 223 Adesogan, E. K., 210 Adinolfi, M., 187 Adoll, W., 185 Aexel, R. T., 264 Aguilar-Martinez, M., 235 Ahuja, M. A., 52 Aida, F., 358,471 Aimi, N., 228 Aiyer, V. N., 167 Akagi, K., 444 Akhrem, A. A., 46 Akhtar, M., 246. 263. 264, 26 5 Akisanya, A., 176 Akita, K., 26 Alais, J., 373 Albrecht, P., 228 Alcaide, A., 485 Aldwin, D. B., 422 Alexander, J., 13 Alexander, K. T. W., 263 Alexandre, P., 6 Alfsen, A., 269 Ah, E., 142, 176 Allcock, C., 10, 253 Allinger, N. L., 279 Almquist, S., 465 Alper, H.,151 A1 Shamma, A. A., 167 Altaf-ur-Rahman, M., 70 Altman, L. T., 250 Amano, K., 357Amano, Y., 150 Amar, D., 31

Ambles, A., 299, 3 I5 Ames, L. J., 389 Amiard, G., 328, 436 Ananchenko, S. N., 41 3 Anchel, M., 134 Andersen, N. H., 114, 121 Anderson, C. G., 201 Anderson, J., 10 Anderson, R. J., 95, 99 Anding, C., 246, 262 Andrews, A. G., 235, 236 Andrews, D., 41 1 Andrews, T. L., 24 Anjyo, T., 269, 342 Anner, G., 459 Anthonsen, T., 21 I Aoki, K., 1 1 1 Aoki, Y., 254 Aota, K., 154 Aoyagi, E. I., 116 Aoyagi, R., 224 Aoyama, K., 221 Aoyama, S., 351, 378,464 Aplin, R. T., 209 Appleton, R. A., 52, 244 ApSimon, J. W., 218, 295 Arai, M.. 40 Arbuzov, B. A., 80, 81, 82 Archer, R. A., 90 Arend, G., 60 Arias, F., 418 Arigoni, D., 110, 257 Arihara, S., 199 Aringer, L., 353 Arison, B. H., 447 Arndt, R. R., 208 Arnold, W., 239 Arpin, N., 239 Arunachalam, T., 490 Asada, S., 10 Asada, Y., 199 Asaka, Y., 30 Asanuma, M., 221 Ash, L., 250 Ashida, T., 233 Askam, V., 224 Atherton, L., 267 Atkin, J., 31 1 Audier, H. E., 299 Auret, B. J., 397 Axelrod, L. R., 421, 465, 467 Ayer, W. A,, 186 Azarro, M., 6 Azzarro, M., 40

51 1

Baarchers, W. H., 208 Baburao, V., 173 Bach, N. J., 332,422 Bachelor, F. W., 157, 365 Badderley, G. V., 215 Badddey, J., 244 Baerheim Svendsen, A.. 8 Banuley, B. C., 173 Baaey,-K., 89 Bailey, W. D., 6 Baines, A. F. H., 389 Baird. M. D.. 154 Bajaj,’I., 230 Baker, A. J., 190 Baker, K. M., 178 Baker, M. W., 217 Baker, P., 218 Bakhtenov, A. A., 8 Bakker, H. J., 178, 181, 259 Balashov, N. N., 51 Baldwin, 391 Baldwin, S . W.. 216 Ball, J. B., 73 Bamburg, J. R., 127 Ban, Y.,340 Bancher, E., 240 Bandopadhyay, M ., 2 1 5 Banerji, A., 266 Bang, L., 156 Ban’lovskii, A. I.. 169 Banthorpe, D. V., 7, 57, 245, 253, 271 Barbier, M., 273, 485 Bard, M., 166 Bzrdyshev, I. I.. 6, 31, 37, 51, 71, 82, 175 Barieux, J.-J., 40, 321 Barlow, S. A., 259 Barneis, Z. J., 65 Barnett, B., 12 Barnett, W. E., 312 Barone, G., 187 Baronnet, R., 1 I Barr, R. M., 244, 273 Barrow, K. D., 195 Bartel, K., 404 Barthelemy, M., 73 Bartley, J . P., 200, 328 Barton, D. H. R., 48, 195, 201, 202, 263, 314, 316, 340, 341, 342, 343, 394, 398, 404, 417, 418, 434, 468,481 Bartz, J. K., 251 Barua, A. K., 219

Author Index

512 Bascoul, J., 379, 381 Baskevitch, Z., 169,258 Bate-Smith, E. C , , 26 Bateson, J. H., 176, 181 Batey, I. L., 161, 168 Batten, P. L., 201, 393 Battersby. A. R., 245, 255 Bauer, D., 405 Beal, J. K., 167 Beale, R. N., 407 Bean, N. E., 65 Bearder, J. R., 180 Beastall, G. PI., 262, 265 Beck, J. F., 255 Beckwith, A. J. L., 52 Beddell, C., 234 Beecham, A. F., 288, 293 Beedle, A. S., 246 Behn, N. S., 32 Beierbeck, H., 295 Belikova, N., 59 Belinskaya, 0. A., 9 Bell, R. A., 59, 175 Bellamy, A. J., 83 Bellino, A., 177 Belsten, J. C., 23 Belyaeva, M.G., 81, 82 Benaim, J . , 346 Ben-Bassat, J . M., 68 Benezra, C., 327,422 Bennet, C. R., 203, 298 Bennet, R, D., 207, 210 Benson, A. M . , 269 Bentley, P. H., 374, 427 Bentley, T. J., 201. 393. 394 Benveniste, P., 261, 262 Ben-Zvi, Z., 91 Berezovskaya, T. P.. 9 Berger, C., 1 1 3 Bergman, R. G., 67 Bergmann, E. D., 482 Bergot, J., 9 Bermejo Barrera, J.. 49. 158 BermejO Barrera, J . L., 49 Bernauer, K., 1 1 Berner, H., 497,498 Berner, L., 497, 498 Berrier, C., 299, 385 Berry, D. L., 271 Berryman, K. A., 152 Berthet, D., 244 Berti, G., 166 Bertini, F., 339 Bertram, E. F.. 178, 179 Bertrand, C.. 65 Bertrand, M., 23, 431 Bessiere-Chrktien, Y ., 65, 72, 73 Bettdo, G. B. M . , 222 Bettoni, G., 292 Betts, T. J., 6 Beugelmans, R., 46, 400 Beytia, E. D., 249 Bhacca, N. S., 301 Bhadane, N. R.. 141, 162 Bhalerao, U. T., 197 Bhat, S. V., 141, 142. 159 Bhatia, M. S., 47 Bhattacharyya, S. C.. I 12 Bhavni, B. R., 434

Bianco, A., 27 Biellmann, J . F., 197 Bieniek, D., 86, 88, 90 Bignardi, G., 40 Bikbulatova, G. Sh., 80 Bimpson, T., 262 Binder, M.,507, 509 Biollaz, M., 293, 431, 445 Birch, A. J., 124 Bito, T., 16, 3 1 Bjeldanes, L. F., 180 B‘ork, L., 246 Blair, 1. A.. 48 Blanchard, M., 59 Blattel, R. A., 62 Blecha, Z., 2 I5 Blickenstaff, R. T., 309 Bloch, K., 248, 261 Bloxham, D. P.. 263 Boar, R. B., 201, 263, 393, 394 Boccara, N., 37 Bochwic, B., 37, 80 Bodden, R. L., 166 Bodea, C., 240 Bodenberger, A., 330 Boegii, G., 87 Boehni, E., 1 1 Boelens, H., 58 Bbrer, R., 409,411 Bogacheva, T. P., 71 Bohlmann, F., 46, 100, 105, 159 Boikess, R. S.,297 Boivin, J., 379 Bolt, C. C., 284 Bolton, M.. 404 Bonakdar, A.. 32 Bonnafous, J.-C., 101, 241 Bopp, T. T., 231 Borch, G., 232 Bordner, J., 280 Borer, C., 120 Borgulya, J., 1 1 Bornowski, H., 100 Borowiecki, L., 14 Bosch, M.,42 Bose, A. K., 260, 360, 361, 476 Bose, S. N., 215 Boswell, G. A., 344, 424, 432 Bosworth, N., 64, 69 Boszyk, E., 158 Botta, L., 396, 461 Bottin, J . , 299, 323 Bottomley, W.. 242 Boulton, A. J., 70 Bouquant, J., 295 Bourgeois, M.-J., 80 Bourgery, G., 297, 366,440 Bourguignon, P..373 Boussac. G., 73 Boussarie, M. F., 10 Bowen, D. H., 180, 182, 259 Box, V. G . S . , 146 Boyd, W. A., 76 Boyer, S.,41 Bradley, D. M.. 224

Brady, D. R., 263 Brain, E. G.. 464 Brain, K. R., 267 Bramley, P. M.,234 Bramwell. A. F., 23 Brandenburg, C. F., 53 Brandstrom, A., 323 Brandt, R. D., 246,262 Brauman, J. I.. 297 Braun, B. H., 94 Braun, P.,91 Bravet, J.-L., 327, 422 Breimer, D. D., 86 Breitmaier. E., 40. 297 Brennan, T. M., 189 Breslow, R., 397, 469 Breton, J. L., 158 Breuer. S. W.. 302 Brienne. M.-J., 6, 37 Brieskorn, C. H., 226 Brjggs, L. H., 178, 200, 328 Brine. D. R.. 87 Britton, G., 245, 271 Britton, R. W., 157 Broaddus, C. D., 34, 104 Broger, E. A., 138 Brooks, C. J. W., 258,407 Broomfield, C. A., 408 Brown, E., 76,422 Brown, H,C., 35 Brown, J., 190 Brown, J. N., 281 Brown, K. S.,jun., 205 Brown, P., 299, 505 Brown, R. C., 70 Brown, T., 21 1 Brown, V. S., 170 Browne, P. A., 337 Bruschweiler, F., 299, 505 Brufani, M.. 195 Bryan, R . F., 143, 147, 204 Buccini, J., 218 Buchanan, J . G. St. C., 178 Buchecker, R., 236 Buckwalter, B. L., 169,203, 258,298 Bucourt, R., 427 Budesinsky, M., 220 Budzikiewicz, H., 349 Biichi. G. H., 13, 243 Buki. K. G., 342 Bussemeier, B., 12 Buinova, E. F., 5 1, 82 Bukala, M.,71 Bukeo, M., 7, 252 Bull, J. R., 399, 320, 324, 350,440,456 Bullivant, M. J., 24 Bu’Lock, J. D., 272 Bunton, C. A., 16, 64, 248 Burbott, A. J., 8, 257 Burczyk, B., 81 Burden, R. S., 241, 272 Burger, U., 75 Burgstahler, A. W.. 68, 287,434 Burk, L. A., 113 Burke, B. A., 207

Author Index Burke, P. L., 35 Burnell, R. H., 169 Burrell, J. W., 23 Burstein, S., 246 Bushweller, C. H., 280 Buss, D. H., 467 Butsugan, Y., 16, 31 Buzby, B. C., jun., 424 Cafieri, F., 193 Cagnoli-Bellavita, N., 169, 258 Caine, D., I14 Cainelli, G., 339 Calimbas, J., 261 Calvert, A., 336 Cama, H. R.. 240 Cambie, R. C., 164, 172, 173, 174, 175, 177, 178 Camerino, B., 304 Cameron, A. F., 62 Cane, D. E., 105 Canonica, L., 18, 267 Cantacuzene, J., 283 Caporale, G., 251 Capozzi, A., 251 Caputo, R., 163, 187 Cardemil, E., 248 Cardillo, B., 89 Carlisle, C. H., 202, 291 Carlon, F. E., 354,450 Carlson, R. G., 32, 148 Carman, R. M., 32, 166 Carnahan, J. C., 3 15 Carney, R. L., 189 Carpio, H., 301, 444 Carrea, G., 296 Cascon, S. C., 205 Casida, J. E., 24 Caspi, E., 246, 264 Cassady, J. M., 208 Cassan, J., 6 Cassidy, F., 464 Castelli, P. P., 354, 440 Castro, E. A., 234 Catalano, S., 387 Catsoulacos, P., 175 Cattabeni, F., 246 Cazaux, M., 80 Ceccherelli, P., 169, 258 Cecchi, L.. 367 Cekovic, Z., 16 Cense, J., 337 Cerfontain. H.. 243 Cerimele, B. J.; 295 Cemy, M., 73 Cemy, V., 283, 284, 375, 435.472.476 Cerrlni, S.,. 195 Chabudzihski. Z., 38, 45, 54, 72 Chadha, M. S., 266 Chadha, N. K., 30 Chadwick, D. J., 351,473 Chain. E.. 195 Chakraborthy, T., 207 Chakravarti, K. K., 112 Chakravarti, R. N., 226 Chambers, R. J., 375,402

513 Chan, W. R.,146,166,207, 209 Chander, J., 38 Chandrasekharan, S., 176, 207 Chang, C.-F., 10 Chansang, H., 272 Chapman, D. J., 271 Charlwood, B. V., 7, 245, 253 Charney, E., 289 Chatterjee, A., 176, 207 Chatzopoulos, M., 73 Chaudhuri, N. K., 477 Chavva, A. G., 219 Chayet, L., 248 Chemerda, J. M., 447 Chen, I. Y., 175 Chen, V. P., 167 Chen, Y. P., 170 Cheng, Y.S., 1 I 1 Chetty, G. L., 193 Cheung, H. T., 226 Chiang, H.-C., 228 Chichester, C. O., 230,250, 272 Chidester, C. G., 264,419 Childs, R. F., 54 Chiyado, Y., 389 Chlebicki, J., 8 1 Cholnoky, L., 239 Chorvat, R. J., 363,441 Chowdhury, A. R., 206 Chowdhury, M. N. R., 456 Christensen, G. B., 447 Christensen, H. D., 87 Chuche, J., 295 Chugh, 0. P., 15, 47 Chung, R. H., 57 Cimino, G., 193, 194 Clark, I. M., 312, 434 Clayton, R. B., 197. 245, 262,416 Clegg, A. S., 3 12, 322, 434 Cleve, G., 286 Clifford, K., 8, 246 Cloarec. L.. 377 Closson; W’. D., 3 15 Coates, R. M., 20, 127, 178, 179, 338 Cobb, F. W., jun., 9 Cochran, D. W., 90 Cochrane, J. S., 94, 487 Cochrane, T. G., 6 Cocker, W., 23, 50, 83 Coetzer, J., 186 Coggon, P.,175,281 Cohen, K. F., 203, 364 Cohen, P., 210 Cole, R. F., 68 Collet, A., 6, 37 Collington, E. W., 38 Collins, J. F., 251 Combes, G., 91 Comin, J., 210 Conlay, C., 195 Conner. R. L.. 265 Connolly, J. D., 208 Constantine, M. F., 464 Conway, P., 22

Cook, I. F., 181 Coolbaugh, R. C., 259 Coombs, M. M., 329,424 CooDer. D. G.. 74 Cooper; G. D.; 413 Corbella, A., 110, 158, 257 Corey, E. J., 17, 94, 105, 138, 189 Cori, O., 248, 255 Cornelis, A., 54 Cornforth, J. W., 8, 246, 419 Cornforth, R. H.,419 Coronado, V., 423,437 Corrie, J. E. T., 49, 124 Corsano, S., 204 Corvi-Mora, C., 50 Cory, R. M., 297 Coscia, C. J., 28, 254 Cottrell, W. R. T., 35 I, 473 Coulombeau, C., 59, 68 Cowles, C., 32 Cox, M. R.. 143 Cox, P. J., 464 Coxon, J. M., 68, 77, 78, 389 Crabbe, P., 41, 292, 301, 335, 419, 424, 431, 444, 445,448,456 Cradwick, P. D., 142 Craig, W. J., 166 Crane, R. I., 133 Crane, R. W., 295 Crase, W. B. T., 167 Crastes de Paulet, A., 379, 38 1 Craven, 8 . M ., 28 1 Crawford, H., 159 Crawford, R. J., 34, 104 Crawley, L., 413 Creger, P. L., 444 Cremlyn, R. J. W., 312 Crilly, W., 83 Cristol, S. J., 406 Critchfield, W. B., 8 Crocco, R., 251 Croft, D., 407 Crombie, L., 22, 198, 250, 25 1 , 253 Cronlund, A., I7 1 Cross, A. D., 427 Cross, B.E., 176, 181, 182 Croteau, R., 8, 257 Crowell, J. D., 147 Crowfoot, D., 291 Crowley, K. J., 50 Crozier, A., 182 Cruz, A., 456 Cueille, G., 57 Cuellar, L., 431 Curotti, D., 392

Daenikes, H. U., 116, 117 Dahl, T., 301 Dahm, K. H., 256 D’Albuquerque, I. L., 222 Dale, J. A., 397, 469 Dall’Acqua, F., 251

514 Dakell, B. C., 90 Dalzell, H. C . , 90 Dambska, A., 12 Daniel, A., 59 Daniewski, W., 12 Daniewski, W . M., 135 Danishefsky, S., 41 3 Danks, L. J., 47 Dann, O., 426 Dannenberg. H., 330 Darias, J., 164 Das, B. C., 143, 227 Das, S. C., 215 Dasgupta, R., 190 Dastidar, P. P., 176 Datta, S. N., 143 Dauben, W. G., 116, 403. 436 Davies, B. H., 234 Davies, P. J ., 48 I Davies, V. H., 143 Davis, B. R.. 178 Davis, M., 367 Davis, R. E., 59 Dawson, D. J., 426 Dawson, T. M., 415 Dean, P. D. G., 246, 270 de Barros Coelho, J. S., 222 De Broissia, H., 129 Dehmlow, E. V., 444 Dejongh. H. P., 284 Delaroff. V.. 292 de Lima, 0. G., 2 2 1 Deljac, A ., 125 Delli Monache, F., 222 De Luca, H. F., 480 de Maindreville, D.. 329 Demarco, P. V., 295 Dembitskii, A. D., 9 Demerson, C., i 9 1 D’emole, E., 120, 244 Dempsey, M. F., 261 DeNijs, H., 328 Dennis, D., 426 Denny, W. A., 173, 175. 305, 312, 322,434 de Quesada, T. G., 176 de Reinach-Hirtzhach, F., 200 Derry, J . E., 55 de Ruggeri. P.. 363 Deshchits. G . V.. 71 de Silva, J. A. F.. 1 1 Desiongchamps, P., 1 SO Desmuki, S. K., 176 De Stefano, S., 193, I94 De Titta, G. T., 281 De Valois, P. J., 9 Deviny. E. J., 403 Devon, T. K.. 5, 161. 163, 196 Devys, M.,273 de Waal, W., 157 Dewey, W. L..90 Dewhurst, B. B., 312 Deivlck, P M., 251 Dey. A . K., 223 de Zeeuw, R . A., 86 Dhindson, A S., 15 Dhingrd. V. K . . 21 5

Author Index Dias, J. D., 362 Dias, J. R., 203, 473, 504 Diaz, E., 41 Dillon, J., 92 Di Maria, F., 41 1 Dimmel, D. R., 59 Dive, W. R., 173 Di Vincenzo, G., 355 Dixon, H., 273 Dixon, J., 415 Dixon, W. R., 269 Djerassi, C., 298. 349, 377, 424 Doddrell, D., 298 Doerr, A . B., 76 Dogielska, Z., I7 Doi. K., 131, 168, 170 Do Khac Manh Duc, 180 Dokusova, 0. K., 246 Donnelly, W. J., 25 I Doonan, €4. J., 7, 253 Doorenbos, N. J., 361,476 Dorrnan, D. E., 231 Dorsky, A. M., 88 Dorsky, J. R., 19 Doskotch, R. W., 141. 167 Douglas, G. H.,424 Doyle, P. J., 246 Drabkina, A. A., 49 Drake, D., 272 Draper, R. W., 201, 393. 394 Drewes, H. R., 87 Dreyer, D. L., 210, 362 Droidz, 8.. 141, 158 Drun, M., 17 Duax, W. L., 279, 281 DuBois, G. E., 333 DuceD, J . B.. 197 Duchimp, D. J., 264, 419 Dudko, V. V., 9 Duffield, A . M., 142, 170 Dugan, R. E., 248 Duggan, A. J., 41 1 Dul. M.. 71 Duncan, J. H., 63 Duncan, J. M., 267 Dunn, T. J., 16, 92 Dunphy, P J., 10, 17, 253 Durham, L. J., 142, 170 Durley, R. C., 181, 182 Durr, I. F., 273 Durst, H. D., 55 Duschek, C., 85 Dutta. N. L., 226 Dutta, P. K.. 226 Dutta. S. P., 219 D’yakonova, R. R., 82

Edwards, J. M., 289 Edward, J. T., 294 Efimova. 0. V., 49 Eger. C. H., 281, 285 Eggers, N. J., 255 Eglinton, G., 196, 228 Eguchi, S . , 12, 13, 100 Ehrenfreund, J., 63, 79, 318 Ehret, C., 255 Ehrig, B., 286 Eikenberry, J. N., 6 Eisfeld, W., 393 Eisner, T., 17, 99 Ejchart, A., 135 Ekong, D. E. U., 209 El’chibekova, L. A., 173 El-Feraly, F., 141 El Gaied, M. M.. 72 Elgamal. M . H. A., 222 Elliott, M., 24 Elliott, R. D., 1 1 Elliott, W. H., 471 Ellis, J . E., 217 Ellouz, R.. 265 El-Olemy, M . M., 268, 269 Elphimoff-Felkin, I . , 31 El yanov, B. S., 7 Emmert, D. E.. 419 Endo, M., 183 Eneroth, P.. 353 Eng, S.,451 Engel, Ch. R., 456 Engel, D. W., 282 Engemann, G., 37 Enggist, P., 120 Englert, G., 231 Enslin, P. R.,320, 456 Ensminger, A., 228 Enwall. E. L.. 281 Enzell. ‘C. R..’ 52.- 102. 165. 220,224, 226,244 Ephritikhine, M., 284. 329, 374,472 Epstein, W. W., 20,23,201, 2 50, Ercoh, A., 437 Erickson. B. W., 94 Erman, W. F., 34, 71, 104, 105 Eschenmoser, A., 42, 358, 440 Eshiet, I , T. U., 176 Esposito, P., 21 Eta, H., 243, 244 Eugster, C. H., 169, 236 Evans, J. R., 327 Evans, S. M., 75

Eadon, G., 298, 377, 424 Easter, W. M., jun., 19 Eck, C., 133, 3 17, 322 Eder, U., 412, 429 Edery. H., 91 Edgren, R. A., 424 Edrnond, J.. 249 Edwards, B. E.. 465 Edwards, J. A., 374. 409, 427,431,488

Faber, S., 30 Fahrenhotz, K. E., 87 Faini, F., 248 FajkoS, J., 318, 349 Falardeau, P., 408 Falconi, G , , 437, 463 Fall, R. R., 259 Fanta, W. I., 105 Farges. G., 32

Author Index Farkas, E., 332, 422 Farkas, L., 159 Faro, H. P., 354, 450 Fascio, M., 171 Fattorusso, E., 193, 194 Fazli, F. R. Y., 267 Fedeli, W., 195 Fehlhaber, H. W., 166 Felix, D., 42, 358, 440 Felmeister, A., 407 Fenical, W., 112, 1 17 Fense!ail, C. C., 269 Fentiman, A. F., jun., 87 Ferezou, J. P., 273 Ferguson, K. A., 265 Ferrara, G., 326, 363, 440 Ferrari, G., 166 Ferrari, M., 166 Fetizon, M., 180, 299, 323, 340, 365 Fiasson, J.-L., 239 Ficini, J., 39 Fiecchi, A,, 246, 264 Filliatre, C., 32, 34, 72 Findlay, J. W. A., 452 Findley, D. A. R., 198,250 Finkbeiner, H. L., 413 Finucane, B. W., 225 Firn, R. D., 241 Firth, P. A., 22, 253 Fischer, N. H., 141 Fischer. R.. 12.431 Fish, L.’ J., 26 ’ Fisher, G. S., 31 Fisher, J., 424 Flament, I. P., 180 Flies, F., 31 Floss, H. G., 245 Flotz, R. L., 87 Foell, T., 424 Fonzes, L., 101, 241 Foppen, F. H., 230 Forcellese, M. L. G., 185 Forney, R. B., 88 Forrester, J. M., 256 Forsen, K., 9 Fourcans, B., 246 Fox, J. E., 201, 398 Fraher, T. P., 412 Fraisse-Jullien, R., 57 Francis, G. W., 234, 235, 236 Francis, M. J. O., 7, 245 Frankel, J. J., 297, 440 Frantz, I. D., jun., 261 Frappier, F., 379, 381, 382 Frazee, W. J.. 155 Freeman, C. W., 263 Freudenthal, R. I., 87 Fried, J. H., 339, 409, 426, 43 I , 444,445,488 Friedell, G. H., 246 Friedrich, L. E., 116 Friend, J., 241 Fryberg, M., 265 Fiirst, A., 409 Fujii, Y., 421, 507 Fujimura, Y.,326 Fujioka, S., 266 Fujita, E., 176, 177

5i5 Fujita, S., 17, 3 1, 65 Fujita, T., 12, 13, 142, 143, 176, 240 Fujita, Y., 15, 17, 31, 65 Fujiyoshi, K., 240 Fukamiya, N., 157 Fukazawa, Y., 161 Fukui, H., 182 Fukuoka, M., 227, 299 Fukuyama, M., 153 Fukuyama, Y., 209 Fullerton, D. S., 436 Fullerton, T. J., 172 Funke, E., 156 Furth, B., 59 Furuse, H., 365 Furutachi, N., 293,401 Gabard, J., 6 Gadola, M., 45, 78 Gadsby, B., 424 Galantay, E., 280 Galasko, G., 239 Galbraith, M. N., 102, 242 Gall, R. E., 31 1 Galli, G., 246, 264 Gandolfi, C., 363 Ganguly, A. K., 41 7 Gaoni, Y., 91 Garabedian, M., 480 Garanti, L., 140 Garcia, G. A., 424 Gardi, R., 308, 354, 437, 440,463 Gardner, J. O., 282, 45 1 Garg, A. K., 255 Gariboldi, P., 110, 158,257 Garland, R. P., 77, 78 Garry, A. B., 303,483 Gary, A. K., 8 Gastambide, B., 329 Gau, W., 88 Gaylor, J. L., 263, 264 Gear, J. R., 8, 255 Geffer, M. L., 251 Gehlaus, J., 375, 476 Geissman, T. A., 152, 159, 160, 180

Gentles, M. J., 421 Geoghegan, P. J.. jun., 35 George-Nascimento, C., 255 Gerali, G., 367 Gerber, N. N., 145 Geribaldi, S., 40 Gersch, M., 266 Gesson, J. P., 331,386,425, 426 Ghatak, U. R., 190 Ghisalberti, E. L., 178, 259 Ghosh Dastidar, P. P., 142 Gibbons, G. F., 261, 263 Gibian, H., 422 Gibson, T., 65, 76 Gibson, T. W., 105 Gidley, J. T., 87 Giersch, W., 35 Giger, H., 45 Gilardi. R . D., 233

Gilbert, B., 152, 159, 171 Gilchrist, B. M., 272 Gill, D., 234 Gill, E. W., 86, 88 Gill, L. S., 9 Gilman, N. W., 94 Gilman, W. H., 94 Ginger, C. D., 273 Girard, J. P., 15 Girard, P., 297 Girgis, P., 223 Gleicher, G. J., 67 Glenn, J. L., 182 Glotter, E., 196, 28 1 Goad, L. J., 265, 269, 273 Godhino, L. S., 417 Godunova, L. F., 7 Goering. H. L., 6 Gossinger, E., 309, 495, 497,498 Goi, M., 30, 102 Golander, Y., 370 Goldberg, S. I., 6 Goldman, R., 273 Goldschmidt, Z., 485 Gollnick, K., 33 G-onzalez, A. G., 49, 158, 164 Gonzalez, Ma. P., 124 Goodfellow, R., 269 Goodfellow, R. D., 274 Goodfellow, R. J., 20, 23 Goodisman, J., 295 Goodwin, T. W., 262, 265, 266, 272 Goosen. A., 404 Gora, J., 17, 73, 75 Gore, J., 40, 63, 321 Goryaev, M. I., 173 Goto, J., 326, 339, 456 Goudie, A. G., 190 Gough, J. L., 297 Gough, L. J., 434 Gould, S. J., 110 Goutarel, R., 368, 382, 386 Govindachari, J. R., 140, 204 Gower, D. B., 432 Grabarczyk, H., 141 Graebe, J. E., 259 Graefe, J., 57, 72 Graf, U., 431 Graf, W., 309,495,497,498 Graham, C., 114 Gramain, J. C., 299 Granger, P., 234 Granger, R., 15 Grant, P. K., 165 Grasselli, P., 339 Graves, J. M. H., 424 Gravestock, M. B., 175 Graveck. J. L.. 91 Graishan, R., 305,307,4.45 Gream, G. E., 52 Greb, W., 90 Green, B., 317, 322, 394 Greene, A. E., 15 1, 154, 1 60 Gregson, M., 94 Greiner, J., 488 Greiner, M. J., 285

Author Index

516 Griaco, P. A., 93, 94 Grider, R. O., 401 Grieco, P., 212 Grieco, P. A., 18 Griffin, T. S., 159, 160 Grimshaw, J., 75 Grimshaw, J . T., 75 Grinenko, G. S., 41 2 Grison, C., 65, 73 Gronikberg, M. G.. 7 Gross, D., 31,407 Grossert, J. S.,196 Gruber, W., 60 Grundon, M. F., 251 Grunfeld, Y., 91 Guarnaccia, R., 28, 254 Gueldner, R. C., 9, 24, 2 5 , 105 Guenard, D., 400 Guerand, C., 72 Guest, I. G.. 156. 200 Guiso, M., 27 Gull, P., 401 Gupta, A. S., 193 Gurny, O., 87 Gurvich, I. A., 182 Gut, M., 246,477,482 Guthrie, J. P., 297 Gutmann, H., 164 Guttman, L. J., 204 Guzman, A., 419 Guzzi, U., 363 Gyorgyfy, K.. 239

Habbal, M . Z., 273 Hach, V., 1 1 Hachey, D., 16 Hackett, P., 452 Hackman, M . R., 1 I Haefliger, W., 445 Hageborn, K.W., 426 Hainanen, E., 70 Hair, N. J., 62 Haisch, D., 33 Halfen, L. N., 235 Hall, S. F., 164 Halpern, B., 292 Ham, P. J.. 222 Hamanaka, N., 191 Hamandka, T., 233 Hamm, P., 236 Hammam, Z., 162 Hamor, T. A., 55 Hancock, 1. C., 244 Hancock, K . G., 401 Handrick, G. R., 87 Hanna, D. P., 83 Hanouskova, D., 178 Hanover, J . W., 8 Hansbury, E., 261 Hanson, J. C., 464 Hanson, J. R.,94, 163, 177, 245, 256, 259, 328, 391, 422,487 Hanson, K. R.,245 Hanson, S. W., 296 Hanssen, H.W., 255 Hara. S., 491

Harada, N., 292 Harayama, T., 228 Hardee. D. D., 24 Hardman, R., 267 Hardy, A. D. U., 142 Harigaya, Y., 432 Harley-Mason, J., 158 Haro, J., 41, 424 Harris, H., 45 1 Harris, L. S., 90 Harrison, D. M., 180, 251 Harrison, I. T., 339 Hart, H., 54 Hartley, D., 424 Hartshorn, M. P., 68, 77, 78, 302, 389 Haruta, H., 1 1 , 243 Harvey, D. J., 299, 359 Hase, T., 21 1, 216 Hasegawa, T., 220 Hashimoto, H., 6, 134, 136 Hassner, A., 297 Hauptman. H., 279 Havinga, E., 285 Hawker, J., 177. 259 Hawley, D. M., 133 Hayakawa, Y., 11 1 Hayase, Y., 189, 326 Hayashi, J.. 293, 345 Hayashi, K., 299 Hayashi, M., 338 Hayashi, N., 100 Hayashi, S., 100 Hayashi, T., 10, 47, 170 Hayward, R. C.. 177, 178 Heathcock, C. H., 150, 154, 217 Hecker, E.. 185 Hedden. P., 76 Hedin, P.A., 9, 24, 25. 105Hefendehl, F. W., 9 Heftmann, E., 268 Heggie, W., I2 Hegnauer, R., 26 Heide, R., 9 Heidel, P., 246 Heijmens Visser, G ., 284 Heimbach, P., I2 Heintz, R., 261, 262 Heinz, D. E., 51, 244 Hellyer, R. O., 161 Helmy, E., 371 Hemingway, J. C., 142 Hemingway, R. J., 142 Hemming, F. W., 244, 273 Henderson, R.,308 Henderson, W., 228 Hendrich, A., 54 Hengartner, U., 312, 415 Henrick, C. A., 95, 99 Hensens. 0.D.. 220 Herald, D. L., 188, 33 1 Herbst, D., 424 Herber, R.,234 Herout, V., 58, 141. 145, 153, 157, 159, 160 Herring, P. J., 236 Hershberg, E. B., 421 Hertzberg, S., 232, 234, 235,236

Herz, J. E., 312, 320 Herz, W., 141, 142, 159, 160. 173 He-rzog, H. L., 354, 421, 450,45 1 Hesse, M., 31 316,417,418 Hesse, R. H., Heusler, K., 477 Hewson, A. T., 158 Hey, D. H., 340 Heyde, M. E., 234 Heymes, R., 328,436 Hibino, T., 228, 229 Hicks, A. A., 69,288 Higashi, Y., 273 Higo, A., 162 Hijikata, K.,13 Hikino, H., 140, 153, 154, 183, 199,210 Hikino. Y., 153, 183 Hill, D. T., 63 Hinckley, C. C., 76 Hine, K. E.. 54 Hinshaw, J. C., 317 Hirae, K.,196 Hiraga, K., 180 Hirai, S., 324, 440 Hirama, M., 161 Hiraoka, T., 191 Hirata, T., 77 Hirata, Y., 11 1, I 15, 138, 144, 147, 169, 338' Hirose, Y., 121, 122 Hirschmann, H., 245 Hirschmann, R., 447 Hisamitsu, T., 134 Hjelte, M.-B., 226 HjortBs, J., 234 Ho, M., 269 Ho, T.-L., 150 Hochberg, R. B., 269 Hochstetter, A. R., 116, 117 Hodginson, A. J., 350 Hodgson, G . L., 34, I08 Hoeneisen, M., 170 H o f h a n n , R., 291 Hofmann, H., 426 Hofmann, L., 488 Hogg, J. A., 447 Hogg, J. W., 9. 13, 57 Hohlweg, W., 422 Holick. M.F.. 480 Holker, J. S. E., 216 Holland, H. L., 397 Hollenstein, R., 23 1 Hollomon, D. W., 242 Holub, M., 141, 145, 153, 158, 159, 160 Homberg, E., 407 Honeyman, J., 340 Hooper, J. W., 218 Hoppe, W., 282 Horeau, A., 29, 412 Horibe, I., 143 Horiike, M.,249 Horinaka, A., 41 Horiuchi, F., 23 Horn, D. H. S.,102, 242 Horn, U., 358

517

Author Index Horning, M . G., 299 H osoda, H., 269, 342, 349, 368,441 H oughton, R. P., 22, 253 H ouminer, Y., 342,468 Houwen, H. O., 427 H owes, J . F., 90 H oyer, G.-A., 6, 286, 429 H su, H. Y.,167, 170 H SU,W.-J., 272 H uang, E., 59 H uber, U., 94 H udson, D. W., 67 Huffman. J. W., 147, 154, 155, 172 Hug, W., 68, 287 Hughes, G. A., 424 328. 427 H uisman. H. 0.. H uitric, A. C., 6 H uneck, S., 176, 187 H ungund, B. L., 260 H unt, E., 52 H unt, J. D., 358 H untoon, S., 246 H untrakul, C., 165 H utchings, M. G., 35 H utchins, R. O., 50 H utchinson, C. R., 255 H uynh, C., 347,348,440 H yeon, S. B., 84, 101, 243 H yver, C., 398 Iaccarino, R., 163 Iavarone, C., 322 Ibragimova, N. D., 81 Ichihara, A., 134, 136 Ichinohe, Y., 188, 331 Idler, D. R., 407 Iguchi, M., 138 Ihn, W., 318,440 Iizuka, T., 405 Ikan, R., 482,485 Ikawa, M., 230 Ikeda, A., 84 Ikeda, S., 48 Ikeda, T., 210, 21 1 Ikekawa, N., 389 Ikram, M., 185 Imai, Y., 243 Imamura, K., 7, 73 Imhof, R., 309, 495, 497, 498 h a , K., 84,243,244 Inada, A., 218 Inamasu, S., 10 Inhoffen, H. H., 506 Inoue, K., 28,255 Inoue, S., 14, 15 Inouye, H., 28,254,255 Inouye, Y., 249 Inubushi, Y., 228,229 Ireland, R. E., 216, 312, 415,426 Iriarte, J., 456 Iriye, R., 183 Irvine, W. J., 244 Isaacs, N. S., 341 Isaeva, Z. G., 80, 8 1, 82 Ishigami, T., 327

Ishii, H., 104, 156, 182 Isoe, S.,84, 101, 243 Isono, T., 121 Itaka, Y., 71 Itazaki, H., 454 Ito, M., 342 Itb, S., 157, 161, 170 Ito, Y., 358, 471 Itoi, K., 19 Ius, A,, 296, 326,363,440 Iwadare, T., 488 Iwasaki, T., 358,471 Iwata, T., 1 I , 243 Iyer, K. N., 184 Iyer, V. N., 215 Jacob, E. J., 421 Jacob, G., 248 Jacobs, H. J. C., 285 Jacobsen, M., 94 Jacques, J., 6, 37 Jacquesy, J.-C., 316, 331, 3~35,386,425,426 Jacquesy, R.,299,315,3 16, 331, 385,425 Jacquier, R., 41 Jain, N. C., 88 Jaitly, K. D., 451 James, K. C., 285 James, K . J., 251 James, M. N. G., 167 Janes, N. F., 24 Janiszowska, W., 270 Jankowski, K., 297 Janot, M. M., 382 Jansen, A. B. A., 424 Jantzen, R., 283 Jarabak, R., 269 Jarreau, F.-X.,379, 381, 382 Joutelat, M., 231 Jay, E. W. K., 191 Jay, L., 191 Jedlicki, E., 248 Jefferies. P. R., 167, 178, 181,259 Jeffery, J., 338 Jefford, C. W., 63, 75 Jeger, O., 12. 164,401,405, 46 1 Jensen, A., 230 Jensen, F. R., 280 Joblin, K. N., 164 Johns, W. F., 435 Johnson, A. L., 344, 424, 432 Johnson, D. E., 230 Johnson, D. W., 138 Johnson, L. F., 183 Johnson, R. J., 45 Johnston, J. P., 184 Johnston, T. P., 1 1 Jolivet, J., 10 Jolly, P. W., 12 Joly, G., 386,426 Jommi, G., 110, 158, 257 Jones, D. H., 244 Jones, D. N., 371 Jones (Sir), E. R. H., 312, 322,434

Jones, G., 88 Jones, J. B., 305, 307, 445 Jones, J. G. LI.,384 Jones, M. B., 329,424 Jones, R. A., 31, 74, 75 Jones, S. B., jun., 162 Jones, W. R., 216 Joos, R., 358 Jorgensen, E., 162 Joseph-Nathan, P., 124 Joshi, B. S., 140 Joshi, G. C., 67 Joska, J., 3 16 Joulain, D., 78 Julia, M., 80 Julia, S., 297,347,348,352, 365,366,440 Juneja, H. R., 75 Jung, G., 297 Junggren, U., 323 Jurczak, J., 7, 135 Jurd, L., 16 Jurion, M., 340 Kadyrov, A. Sh., 58 Kaegi, H. H., 88 Kaehler, H., 37 Kagan, H., 287,412 Kagawa, S., 134 Kaimal, G. K., 51 Kaise, H., 198 Kaiser, E., 392 Kaiser, K., 116, 117 Kaiser, R., 30, 118 Kakisawa, H., 167, 170 Kakudo, M., 233 Kalicky, P.,397,469 Kalsi, P. S., 1 12, I33 Kalvoda, J., 293, 333, 396, 402,461,463 Kamada, T., 134 Kamans, Y., 204,505 Kamat, V. N., 140 Kamata, K., 351, 378, 464 Kamata, S., 189 Kamemoto, K., 340 Kamikawa, T., 28, 30 Kan, K. W., 261 Kanazawa, A., 266, 274 Kane, V. V., 90,91 Kaneda, M., 71 Kanedo, K., 268 Kaneko, H., 157, 373 Kaneko, T., 111 Kanno, S., 187 Kanno, T., 191 Kanojia, R., 302 Kapadi, A. H.,184 Kapadia, K., 468 Kaplanis, J. N., 246 Kapoor, J. N., 45 1 Kapoor, S. K., 13 1 KapuScinSki, J., 37, 80 Karle, I. L., 175, 233, 289 Karle, J., 233 Karlsson, K., 220,224,226 Kasal, A., 3 16 Kashman, Y., 31 1 Kashnikov, V. V., 71

A uthor Index

518 Kashtanova, N. K.. 166 Kasprzyk, Z., 225, 270, 288 Kasting, R., 10 Katagiri, T., 1 I , 23 Katayama, C., I68 Kates, M.,236 Kato, K., 138, 144 Kato, M.,157,421 Kato, N., 168 Kato, T., 18, 187 Katsuhara, J., 6,42 Katsumura, S.,84,101,243 Katzenellenbogen, J. A., 17, 18, 94 Kaufman, M., 319, 395, 469 Kaufmann, H., 333.459 Kawaguchi, T., 19 Kawai. K., 205 Kawamura, T.,168 Kawasaki. 1.. 11 1 Kawashima, S., 434 Kawazu, K.,167 Kayama, T.,197 Kazakova, E. Kh., 82 Kazhuskas, T.,200, 203, 364,388 Kazuyoshi, K., 186 Keana, J. F.W.,498 Keates, R. A. B., 258 Keefer, L. K., 230 Kekelidze, N. A., 9 Kelsey, M. I., 471 Kelsey. R. G.,162 Kcmpe, U. M.,481 Kennard, D.,158 Kennedy, R. M.,4% Kenny, R. L., 31 Kepner, R. E., 6 Kerb, U.,418 Kergomard, A., 32, 342 Keung, E. C.-H., 151 Khaleeluddin, K.,64 Khan, G., 407 Khan, H.,193 Khan, M.I., 185 Khanchandani, K. S., 260 Khanna, S. N.,162 Khastgir, H. N., 215 Khatoon, N., 23 I Khuong-Huu. F., 203, 298 Khuong-Huu, Q., 368,386 Kido, F., 63, I24 Kienle, M. G., 246, 264 Kierstead, R. W., 87 Kikuchi, T., 223 Kilponen, R. G., 234 Kimble, B. J., 228 Kimland, B., 52, 102, 165, 244 Kimmel, E. C., 24 Kimura, Y.,17,31,84,326 Kinsky, K., 286 Kiriyama, N., 171 Kirk, D.N., 286, 287,291, 302, 330, 337, 346, 389, 407 Kirkpatrick, D., 341 Kirmse, W.,60

Kirson, I., 281 Kiruchi, T., 490 Kis, Z., 270 Kishi, M., 296, 373, 471 Kishida, Y., 196 Kishimoto, T., 36, 80 Kitagawa, I., 205,218,221, 226,227 Kitahara, Y., 18, 187 Kitazawa, K., 221 Kitchens, G. C., 116, 1 17 Kitigawa, I., 26 Kjasen, H., 231,236 Klabunovskii, E. I., 7 Kllisek, A., 147 Klein, E., 53, 114 Klein, H.,286 Klemm, D., 440,486 Klimov, A. N., 246 Klinot, J., 220 Klinotova, E., 227 Kluender, H.C., 138 Klyne, W.,283, 286, 287 Knapp, F. F.,265 Knowles, R. E.,230 Knox, J. R., 181 Knox, L. H., 427 Koakutsu, S.,153 Kobayashi, A., 23, 24 Kobayashi, M.,365 Kobayashi, T., 186 Kobrina, N. S., 182 Koch, B., 233 Kocbr, M., 135 Kodama, M.,10 Kodicet. E..344. 353 KGnst, W. M.B.. 427 Koermer, G. S.,6 Koga, T.,434 Kohli, J. C.. 112 Kohout, L., 318, 395 Komae, H., 100 Komatsu, M.,204 Komatsu, T.,234 Komeichi, Y., 358, 471 Komeno, T.,296,351,373, 378,464,471 Kom is I., 31 Kon&, k., 397,400 Konno, C., 140 Kooreman, H.J., 45 1 Koreeda, M.,92,266 Koriyama, S., 183 Korte, F.,86, 88.90 Koshimizu, K., 182 Kossanyi, J., 59 Kotva, K.,153 KOV~CS, K., 3 1I , 3 I3 Kovats, E.Sz., 35 Kowalska, K., 17 Kowerski, R. C.,250 Kowrounakis, P., 409 Koyama, H.,138 Koyama, T.,248 Kozerski, L., 135 Kozhin, S.A., 46 Kramer, J. K.G.,236 Krasso, A. F., 507, 509 Kreiser, W.,5 0 6 Krepinsky. J., 191

Kretchmer, R. A., 155 Kroniger, A., 187 Krop P. J., 71 KrsticLj., 335. 427 Krubiner, A., 300,447 Kriiger, C., 12, 7 1 Krueger, W., 314 Kruk, C., 243 Kubota, T.,28, 30, 209 Kucherov. V. F.. 14. 52. 182 Kuczytiski, H.,54 Kuduk, J., 45 Kuduk-Jaworska, J., 38.45 Kuehne, M.E.,355 Ku ajevsky, I., 360 KufCesza, J., 17.73.75 Kulikov. V. 1.. 6 Kullberg, M.P., 394 Kullberg, P.,322 Kulshreshtha, D. K., 196 Kulshreshtha, M.J., 196 Kumar, V.,305, 322,434 Kunitake, T., 408 Kuo, C. C.,182 Kuo, Y.H., 111 Kupchan, S. M.,142, 143, 204,452 Kupletskaya, N. B., 66 Kurbanov, M.,52 Kurek, J. T.,35 Kuriyama, K., 143 Kuroda, Y.,16 Kurokawa, M.,373 Kurokawa. T.,273 Kurono, M.,186 Kushwaha, K. C., 236 Kutney, J. P., 255 Kuwano, D., 154 ,

.

I

Laats, K., 15 Labler, L., 288,438 Labovitz, J., 2 I2 LabruyQe, F.,65 Lachman, W.H.,182 Lachmann, H.H.,320,456 Lacombe, L., 377 Laing, M.,178 Laing, S. B., 329 Lake, A. W.,464 Lakhvich. F. A., 46 Lakshmanan, M. R., 272 Lalande, R.,31, 34, 76, 80 Lallemand, J.-Y., 80 Lambert, G., 63 Lamm, B., 323 Landeros, R. M., 431 Lange, G. L., 42 L'Anglais, D., 294 Lankwerden, B. J., 334 Lansbury, P.T.,136, 333 Laonigro, G., 187 Laporthe, Y ., 165 Lardelli, G., 12 Larsen, B. R.,250 Larson, R. A., 255 Laszlo, P., 54

Lau, R.,108

519

Author Index Lauder, H. St. J., 23 Laudrey, J. R., 265 Laurent, H., 301 Lauzr’evskii, G. V., 9 Lavie, D., 196, 28 1 Lawrence, B. M., 9, 13, 57 Lawrence, R. V., 172 Lawson, N. E., 294 Layne, D. S., 314 Leclerc, G., 398 Ledig, K., 424 Lednicer, D., 419 Lee. G. A., 406 Lee; J., 162 Lee, T. C., 250 Lee, T. H., 250 Lee. W. H.. 246 Lee: W. L.,’272 Lefebvre, Y., 335 Le Goff, E., 431 Le Goff, M. T., 46 Lehmann, C., 461 Leighty, E. G., 87 Leitereg, T. J., 154 Lemonnier, M., 352 Lenfant, M., 265 Lenox, R. S., 18 Lenton, J. R., 265 Lenz, C. R., 314,399, 400 Leppik, R. A., 242 Leresche, J. P., 16 Lettre, H., 488 Levin, C. C., 291 Levine, S. G., 175,280,28 1 Levisalles, J., 129,284, 329, 336, 373, 374,472 Lewbart, M. L., 309, 361, 449 Lewis, D. W., 6 Lewis, K. G., 220 Lhomme, J., 130, 131 Liaaen-Jensen, S.,230,231, 232, 234, 235, 236, 239, Libit, L., 105 Libman, J., 391, 422 Lieberman, S., 269 Liebeskind, L., 55 Liebman, A. A., 88 Ligon, R. C., 173 Lin, G. C. K., 274 Lin, G. J., 57 Lin. R. S. H., 231 Ljn, Y . T., I I I Lindig, C., 507 Linstrumelle, G., 352 LiDnicka. U.. 38. 72 Libpmaa; E.,’59 Lipsky, S.R., 299 Lisina, A. I., 166 Littlewood, P. S., 41 5 Liu, C.-S., 208 Liu, S. Y.,397, 469 Livi, O., 166 Livingston, A. L., 230 Lloyd, J. A., 173 Lloyd-Jones, J. G., 246 Loeber, D. E., 231 Loewenstein, R. M. J., 31 Loewenthal, H. J. E., 190 Logan, D. M., 248

Loiko, Zh. F., 51 Long, G. A. S., 178 Loo, S. N., 417 Loomis, W. D., 8,257 Lorenc, Lj., 402 Lorrain, S., 398 Lousberg, R. J. J. C., 236 Lucas, H., 300,447 Lucero, J., 312 Luisetti, R. U., 6 Lukacs, G., 203, 297, 298, 368, 377, 382 Lusinchi, X., 297, 298, 370, 377 Lutsky, B. N., 246, 264 Luttrell, B., 269 Lux, S. E., 261 Lynch, G. J., 35 Lysenkov, V. I., 31, 37 Lythgoe, B., 52, 415 Maarse, H., 6 Mabry, T. J., 162 McAndrew, B. A., 20 Macauley, S., 2 18 McBeth, J. W., 238 McCandless, F. P., 6 McCrae, W., 374,427 McCurry, P., 94 McDevitt, J. P., 344, 424, 432 McDonald, E. C., 1 1 McDonald, P. D., 269 Macdonald, P. L., 124 McGarrity, J. F., 481 McGaughey, S. M., 159 McGhie, J. F., 201, 263, 393,394 MacGrillen, H., 202 McHale, D., 12 Machida, Y., 256 MacKay, W. D., 125 McKillop, A., 358 McKillop, T. F. W., 133 McLamore, W. M., 477 McLaughlin, B. J., 424 McLean, S., 28 McMenamin, J., 424 MacMillan, J., 176, 178, 180, 182, 245, 259, 270 McMorris, T. C., 134, 488, 490 McMurray, W. J., 299 McMurry, J. E., 108 McMurry, T. B. H., 150 McPhail, A. T., 175, 281 MacSweeney, D. F., 34, 108 Maddox, M. L., 374,427 Maeda, H., 18 Magerlein, B. J., 447 Magnus, P. D., 48, 64, 69, 202, 314, 340, 398, 404 Magnusson, G., 135 Mahajan, J. R., 171 Maitte, P.. 37 Maksimov, V. K., 412 Malarek, D. H., 88 Maldonado, L. A., 424

Mlalek, K., 73 M[alhotra, H.C., 261 M[allaby, R.,8, 241, 246 M [allams, A. K., 239 MIallia, A. K., 240 M Iallory, F. B., 265 M ialya, P. A. G., 265 M [angoni, L., 163, 187 M ,arm, J., 7, 253

MIanners, G., 16 M lanno,J. E., 88 M ansuy, D., 80 M anville, J. F., 105 M archesini, A., 140 M arciani, S., 251 M arekov, N., 28 M‘arhenke, R. L.. 108 M ariani, E., 40 M ariani, R., 169 M arino, M. L., 175, 177 M arkus. A.. 482.485 Markwell, R. E.,’ 181, 182 Marples, B. A., 200, 375, 384,402 Marquez, L. A., 320 Marshall, J. A., 154, 155 Marsili, A., 387 Martin, J. A., 246, 264 Martin, J. D., 164 Marumo, S., 92 Maruyama, M., 142 Marvin, R., 431 Marx, A. F., 451 Marx, J. N., 159, 341 Masamune, T., 404, 407, 453 Masanao, M., 189 Masayuki, N., 189 Massanet, G. M., 49 Masuda, S., 21 1 Mateos, J. L., 423,437 Mathai, K. P., 174, 175 Mathew, K.K., 419 Mathieu, J., 436 Mathur, R. B., 360, 361, 476, 502 Matsubara, Y., 6, 36, 48, 71,80 Matsuda, H., 196 Matsueda, S., 140 Matsui, M., 23,94, 188, 191 Matsumoto, K., 90 Matsumoto, S., 134 Matsumoto, T., 134, 136, 191 Matsuo, A., 114 Matsuo, T., 131 Matsuura, T., 31, 41, 77, 82,285 Matta, K. L., 47, 104 Matthews, R. S., 295 Matyukhina, L. G., 219 Maudinas, B., 234 Maurer, G., 159 Maurin, R., 23 Maxwell, J. R., 196, 228 Maynard, D. E., 87 Mazac, R., 450 Mazur, Y, 290, 291. 391, 422,469

Author Index

5 20 Meakins, G. D., 305, 312, 322, 35 1,434,473 Mechoulam, R., 91 Meguro, H., 240 Mehendale, S. D., 358,438 Mehta, G., 131 Meikle, P. I., 74 Meinwald, J., 17, 99 Meklati, B., 72, 73 Mellier, D., 404 Mellor, J. M.,124 Menager. L., 412 Menzies, I. D., 398 Meot-Ner, M., 299 Mertus, F. W. H. M., 86 Merlini, L., 89 Merrnet-Bouvier, R., 398 Merriu, E. J., 310 Mersereau, M., 337 Metayer, A., 485 Metzger, J. B,, 217 Metzler, M., 256 Meuly, W. C., 1 1 Meyer, D., 256 Meyers, A. I., 38 Meystre, Ch., 459 Mez. H.-C.. 281 Miana, G. A., 185 Michalkiewicz, D. M., 23 Middleditch, B. S., 407 Middleton, B., 246 Midgley, J. M., 303, 483 Mihailovid, M. Lj., 402 Miki, S., 131 Milborrow, B. V., 230, 272 Miller, M. A., 279 Miller, W. L., 263 Milliet, P., 370 Mills, 0. S., 67 Mimura, M., 368 Minale, L., 193, 194 Minami, K.. 490 Minato, H., 143, 267 Mincione, E., 322, 323 Minernatsu, W., 36, 48. 80 Minn, J., 434 Minyard, J. P.,9, 24 Miskowicz, C., 451 Miskus, R. P., 24 Misra, R., 281 Missen, A. W., 174 Mitote, T., 444 Mitropoulos, K. A., 263 Mitsuhashi, H., 268. 299, 365,457 Mitsuhashi, K., 359 Mitsui, T., 167, 182, 186. 233 Mitzutani, S., 10 Miya, S., 271 Miyake. A., 330 Miyanao, K., 134 Miyashita, M., 133 Miyoshi, F., 359 Mizuguchi, T., 404 MladenoviC, S.. 335, 427 Mo, F., 21 1 Mo, L., 169 Modelli. R.,304 Moesinger, S. G., 20

Mohamed, P. A., 204 Moinas, M., 169 Moiseenkov, A., 46 Mole, M, L., 147 Monaco, P., 163 Money, T.,34. 108, 256 Mongrain, M., 150 Monneret, C., 386 Monson, R. S., 302 Monteiro, M. B.. 171 Montheard, J.-P., 73 Moore, T. C., 259 Morales, A.. 175 Morand, P., 319, 393, 395, 436,469 Moreau, N., 365 Moreau, S., 3 16 Morelli, I., 387 Moretto, G., 387 Mori, K.,94, 188, 189. 191 Moriarty, R. M., 468 Morichika, Y., 71 Morikawa, H., I I Morrsaki, N., 30, 102 Moriskai, M., 389 Morryama, M., 266 Moriyarna, Y., 153 Morizur, J. P., 59 Morris, D. G., 62, 67 Morris, M. S., 162 Morris, R.J., 217 Morrisett, J. D., 408 Morrison, J. D., 63 Mors, W. B., 171 Morton, J. K., 9 Moscowitz, A., 293 Mose, W. P..286, 287, 291 Moshier, S. E., 271 Moshonas, M. G., 9 Moss, G. P., 141 Moss, J. B., 421 Most, B. H., 182 Mot], O., 159 Mousseron, M., 41 Mousseron-Canet, M., 101, 24 1 Moutero, J., 91 Muchmore, D. C., 312 Muhlstadt, M., 57, 72, 85 Muller, B. L., 45 Miiller, R., 41 1 Muller, R. K., 358 Mui, M. M., 471 Mukawa, F., 454 Mukerjee, S. K., 21 5 Mukherjee, R., 227 Mulchina, M . V.. 407 Mulheirn, L. J., 246, 264 Muller. J.-C.. 151, 160 Mummery, R. S., 230. 234 Munakata, K., 168, 198 Munavalli, S., 124 Munday, K. A., 246 Muntyan, G . E., 14 Murae, T., 2 10, 2 1 1 Murakami, M., 324, 326, 440 Murakoshi, S., 10 Muraleedharan, N. V., 51 Murofushi, N.. 180

urota, S.,269 urphy, W. S., 65 urray, D. G., 28 urray, H. C., 476 urray, M. J., 9 uscio, F., 250 uscio, 0. J., 20 usser, J. H., 147 uto, M., 16, 31 Nadeau, R., 259 Naegeli, P., 30, 118 Naf, U., 183 Nagai, M., 205, 452 Nagao, M., 243 Nagao, Y., 176, 177 Nagasaki, T., 267 Nagasarnpagi, B. A., 168, 229 Nagata, W., 189, 324, 326. 440,454 Nagel, A., 4 13 Naik, N. C., 68, 287 Nair, M. S. R., 134 Nakadaira. Y., 345 Nakahara, Y., 188, 189 Nakaishi, M., 10 Nakamura, H., I 1 1 Nakamura, M., 156 Nakanishi, K.,92, 183, 186, 266, 292, 293,401 Nakanishi, T., 227 Nakao, K., 19 Nakashima. R., 31 Nakata, T., 190 Nakatani, Y.. 206, 383 Nakayama, M., 1 0 0 Nakemura, S.. 220 Narnba, S., 84 Nambara, J., 269, 326, 327, 339, 342, 349, 368, 421, 441,456, 507 Nan Hsu, I., 281 Naples, A. F., 54 Narayanaswamy. M., 37 Narisada, M.. 326 Naruto, S., 157 Naskar. D. B., 215 Nathan, A. H.,447 Natori, S., 227 Natsurne, M., 1 1 1 Naudet, G., 398 Naumov, V. A., 81 Naya, K., 153 Naylor, R. D., 358 Nazir, M., 506 Needharn, L. L., 3 12 Neernen. M., 303, 304 Negrshi, E., 35 Neidle. S.. 141 Nemirocskaya, I. B., 81 Nerdel. F.. 37 Neri, R., 451 Nes, W. R.,261, 265 Neumaier. H.. 99 Neumann, H.’C..440 Neurnuller, 0.A., 393 Neuwirth-Weiss, L., bi( Newton, M. G., 184

52 1

Author Index Ng, L. Y., 349,441 Nicholas, H. J., 264 Nicholas, K. M., 332 Nicholson, J. M., 57 Nickolson, R. C., 477, 482 Nicoara, E., 240 Nicoletti, R., 185 Nigam, S. S., 52 Nikolaev, A. G., 9 Nikolaidis, D., 381 Nikonov, G. K., 58 Nishi, A., 271 Nishida, S., 134 Nishida, T., 19, 170, 171 Nishihama, T., 2 10, 2 I 1 Nishinaga, T., 490 Nishino, C., 167 Nishino, T., 248 Nishioka, T., 28 Nishiyama, A., 138 Nitsche, J. W., 239 Niwa, M., 138,223 Nojima, M., 45 Nomori, H., 19 Nomura, K., 359 Noomnont, P., 407 Noreen, A. L.. 406 Nogard, S., 232 Norin, T., 57, 163, 168 Norton, D. A., 279, 281, 285 Nouaille, A., 29 Novotny, L., 153 Noyce, D. S., 302 Noyce, P. R., 285 Noyer, E., 379 Noyori, R., 327 Nozoe, S., 30, 102, 256

Obasi, M. E., 209 Oberhansli, P., 116 Oberhansli, W. E., 239 Oehlschlager, A. C., 164, 265 Oksuz, S., 153 Ogawa, J., 134 Ogilvie, A. G., 328, 422 O’Grodnick. J. S.. 303,304 Oguni, I., 256 Ogura, K., 197, 248, 273 Ohki, M., 94 Ohloff, G., 13, 35, 42, 45, 78? 23 I , 244,440 Ohnishi, R., 65 Ohno, M., 20, 84 Ohnsorge, U. F. W., 195 Ohsawa, T., 205 Ohshima, K., 24 Ohsuka, A., 226 Ohta, T., 183, 210 Ohta, Y., 122 Ohtaka, H., 389 Ohtsuka, Y.,190 Oida, S., 192 Oishi, T., 340 Oka, K., 491 Okamoto, T., 1 1 1 Okano, M., 34

Okauchi, T., 266 Okogun, J. I., 209 Okorie, D. A., 206,208,210 Okuda, T., 110 Olejniczak, B., 37, 80 Oliveto, E. P., 300, 447 Olson, J. A., 272 Onaka, T., 1 1 1 Onda, M., 432 Onopchenko, A., 34 Opheim, K., 99 Oppenheim, B., 68 Oritani, T., 101, 240, 241 Orito, T., 453 Orr, J. C., 337 Ortiz de Montellano, P. R., 419 Osawa, Y., 282 OSianu, D., 240 Ota, S., 15 Ouar, F., 73 Ourisson,G., 130, 131, 151, 156, 160, 200, 206, 228, 246,262, 383 Overton, K. H., 184, 187 Owen, D. F., 17 Paasivirta, J., 59 Paderin, V., 175 Padmanabhan, S., 360 Padolina, W. G., 162 Page, S. W., 184 Page, T. F., jun., 87 Pagnoni, U. M., 140 Pais, M., 381 Paisley, J. K., 357, 463 Pakrashi, S. C., 142, 176 Pak-Tsun Ho, 192 Pal, S. K., 219 Pan, C. S. J., 125 Pancrazi, A., 368 Panova, G. V., 66 Paoletti, E. G., 246, 264 Paoletti, R., 246, 264 Pappo, R., 363,441 Patadisi, M. P., 314 Paralikar, A . B., 157 Pardeshi, N. P., 215 Parfenova, G. M., 7 Parihar, D. B., 230 Parini, C., 326, 363, 367, 440 Paris, C., 6 Parker, T., 248 Parker, W., 133 Parnell, E. W., 367 Pars, H. G., 86, 90 Partridge, J. J., 30 Parvez, M. A., 264 Pascard-Billy, C., 102 Pasedach, H., 15 Passannanti, S., 175 Passet, J., 15 Pataki, J., 348,418 Patelli, B., 304 Pattabhiraman, T., 281 Pattenden, G., 24, 26 Patterson, B. D., 8 Pattison, T. W., 424

Paukstelis, J. V., 67 Pavia, A. A., 59 Pawlak, W., 20 Payne, T. G., 167 Payne, W. W., 162 Peal, W. J., 340 Pechet, M. M., 316, 417, 418 Pedrali, C., 437 Pegel, K. H., 178 Pehk, T., 59 Pelc, B., 297, 344, 353, 359, 473 Pelizzonii, F., 166 Pelletier, S. W., 184, 188, 220, 331 Pelter, A., 35 Pendlebury, A., 312, 434 Pennock, J. F., 273 Penrose, A. B., 133 Pentegova, V. A., 166 Perez, A. J., 182 Perez, G., 41 Perrotta, A., 300, 447 Petcher, T. J., 270 Pete, J. P., 404, 405 Peters, R. H., 339 Petit, F., 59 Petrossi, U., 185 Petrova, L. A., 246 Petrow, V., 346 Pettersen, R. D., 158 Pettit, G. R., 203, 299, 362, 473, 504, 505, 506 Pettit, R., 332 Peyron, L., 9 Pfau, M., 5 Pfister, G., 426 Pfoertner, K., 397 Phaff, H. J., 230 Pharis, R. P., 181, 182 Phillipps, G. H., 329 Phillips, G. T., 8, 246 Phillips, L., 178 Phillips, P. C., 424 Phillips-Johnson, W. M., 113 Piacenza, L. P. L., 178 Piancatelli, G., 204 Pichitakul, N., 9, I3 Pickering, M. V., 210 Piers, E., 1 13, 157 Pierson, B. K., 235 Pierson, G. O., 33 Pieterse, M. J., 186 Pillinger, C. T., 196 Pillion, J.-P., 31 Pinder, A. R., 124, 152 Pinhey, J. T., 161, 168,200, 203, 344, 364, 388 Piozzi, F., 175, 177 Piper, J. R., 1 1 Pirila, L., 65 Pirisino, G., 26 Pisciotti, F., 34 Pitcher, R. G., 87 Pitt, C. G., 87 Pitton, G., 99 Plate, A., 59 Pleteker, J., 413

-

Author Index

522

Polonsk;,, J., !59. 258 Polyaic9-.ab t. 245 >.?

Psnsoid,

x..,3 ! k , 373,443,

480

Pont-Lezica, R.. 248. 255 Popjak. G., 248, 249 Poplawski, J., 160 Popov, N., 402 Popov, S., 28, 298 Popova, E. B.. 173 Popova, E. V., 412 Popova, L. A., 51 Popper, T. L., 354, 450 Portella, C . , 404 Porter, G., 404 Porter, J. W., 248, 249 Posner, G. H., 45 Potier, P., 26 Poulter, C. D., 20, 23. 297 Poulton, G., 255 Poulton, G. A . , 404 Povodyreva, I. P., 82 Powell, R . W., 312 Poyser. J. P., 316 Pragnell, J., 305, 434 Prakash, O., 230 Pregosin, P. S., 150 Premuzic, E., 196, 299 Preston, A. F., 164 Previtera, L., 163 Prezewowsky, K., 422 Pribylova, G. F., 169 Price, S. J., 124 Priest, D. N., 302 Prostashchik, I . V., 5 I , 82 Pruidze, V. G., 9 Pryce, R. J., 246 Pugh, E. L.. 236 Purzycki, K . L., 76 Puttick, A . J., 87 Pyrek, J . S.. 135 Quang Thanh, L., 57, 72 Qureshi, A. A . . 249 Rabinovich, D., 281 Radlick, P., 117 Radlick, P. C., 112 Ragault, M., 76, 422 Rahimtula, A . D., 246,263, 265 Raj, B., 112 Raja. R. A., 312 Raldugen, V. A., 166 Ram, B., 38 Ramamurthy, V., 23 I Ramasseul, R., 371, 443 Ramm, P. J., 216, 246 Ramsey, R. B., 264 Randa!l, E. W., 150 Rane, D. F., 150 Ranganayakulu, K., 59

Rao, A . S., 37, 45 Edo, 6. S. K., 13 Rao. N.. 100. I05 Rao; P. 'N., 153, 421, 465, 467 Raphael. R. A., 190 Rapoport, H..197 Rappaport, L., 259 Rashkes, t'. V., 185 Rasmussen, K. E., 8 Rasmussen, S., 8 Rassat, A., 41. 59, 68, 371, 443 Rastogi, R. C., 456 Rastogi, R. P., 27, 145, 196 Ratcliffe, R., 154 Ratner, V. V., 82 Rautenstrauch, V., 85, 23 I Rawson, R. J., 339 Raymundo, L. C., 234 Razdan, R. K., 86, 87, 90 Reca, E., 74 Redfern, R . E., 10 Reed, R. I., 6 Rees, A. F., 234 Rees, H. H., 245, 262, 265, 266 Rees, R., 424 Reichardt, P. B., 255 Reid, D. M., 182 Reid, S. T., 70. 359 Renard, M. F., 342 Renwick, A . G . C., 31 1 Repke, K . R . H., 507 Restivo, R. J., 204 Reuvers, A. J. M., 66 Rey, P., 10, 41 Rhoads, S. J., 53 Rhodes. J. E., 136 Ricard, B., 283 Rice, R. M., 124 Richards, J. B., 273 Richer, J.-C., 65 Riederer, P., 240 Riess. J. G., 300 Riezebos, G., 20 Rigassi, N.. 231. 239 Rihs, G., 281 Rilling, H. C., 249, 250 Rimai, L., 234 Rindone, B., 18 Ripperger. H., 491 Ritter, M. C., 261 Rius, C., 424 Rizk, A. M., 9 R i uardo, E., 344 Robbins, W. E., 246, 266 Robert, D. U., 300 Roberts, D. L.. 145 Roberts, D. R.. 165 Roberts, J. D., 231, 298 Robertson, J. M., 133 Robinson, C. H.. 308, 342 Robinson, R.. 86 Robinson, W. H., 20 Rodewald, W. J., 475 Rodriguez, B., 176 Rodriguez, D. B., 272 Rodriguez, V. M., 124 Roehle, G.. 3 14

Roller, H., 156 Roeraade, J., 5 2 , 244 Rogers, D., 141, 283 Rogers, 1 H., 105 Rohmer, M., 246 Rojahn, W.. 53 Roman, S. A.. 94 Romano. a, A . S., 169 Romeo, A . , 314. 392 Ronai, A , 239 Ronald, K. C . , 168, 229 Ronchetti, F., 267 Ronchi, A. U.. 339 Roof, A. A. M., 243 Rooks, W., 43 1 Rosenbaum, J., 367 Rosenbaum, N., 251 Rosenberg, D., 6 Rosenberger, M .. 4 1 I , 4 12 Rosenfeld, R., 87 Rosenfield, J. S., 293 Rossi, A., 65 Ross], 0 ,323 Roth, H. J., 41 Rotman, A., 469 Rouessac, F., 78 Roux, J., 3 1, 76 Rovinsky, S., 302 Rowan, M. G . , 270 Rowe, J. W., 162, 168,229 Roy, D. N., 162 Rubenstein, I., 273 Rubin, M. B., 68 Ruden, R. A., 154 Rudler, H., 129 Ruedi, M. P., 169 Rufer, C., 6 , 422 Runquist, D. A., 33 Russmann, H., 65 Russo, C., 267 Ruth, J. A., 154 Ruth, J. M., 105 Rutherford, F. J., 329 Rutledge, P. S., 178, 200, 328 Rutz, K . , 488 Ruzicka, L., 164 Ryan, R. J., 297, 365, 366, 440 Ryback, G., 241 Rykowski, Z., 72 Ryumtsev, E. I., 407 Saeva, F. D., 293 Safe, L. M., 407 Safe, S., 267 Sagiv, J., 290, 291 Saglia, G., 367 Saijoh, S., 218 Saijyo, R., 256 Saindane, M. T., 133 Saito, K., 134 Saitoh, T., 152 Sakakibara, J., 184 Sakan, F., 134, I36 Sakan, T., 84, 101, 243 Sakao, T., 100 Sakashita, M., 65 Sakata, K.. 186

523

Author Index Sakato, Y.,243 Saksena, A. K., 415 Sakuragi, S., 10 Sakurawi, K., 104 Saladin, E., 300 Salama, H. S., 9 Salamon, K. W., 435 Salgado, D., 41 Salmon, J. R., 74 Salmond, W., 488 Saltikova, L. A., 219 Salunkhe, D. K., 271 Salvadori, P., 177 Sam, D. J., 78 Sam, T. W., 137 Samad, S. A., 395,469 Samek, Z., 58, 141, 145, 147. 153, 157, 158, 159, 160 Sammes, P. G., 170, 3 16 Sanchez, L., 170 Sandberg, F., 17 1 Sandermann, H., jun., 273 Sanders, J. K. M., 296,297 Sanderson, T. F., 434 Sanford, A., 337 Santacroce, C., 193 Santaniello, E., 18 Santavy, F., 147 Santos, E., 4 I , 424 Santoyo, Y., 312 Sarda; P., 31 Sasaki, T., 12, 13, 20 Sassa, T., 198 Sastry, S. D., 26 Sato. A.. 94 Sato; H., 186, 293, 40 1 Sato, K., 14, 15, 153 Sato, T., 357 Sato, Y., 452 Saucy, G., 409,411,412 Sauer, G., 412,429 Sax, M., 413 Sayer, B. G., 59 Scala, A., 246, 264 Scallen, T. J.. 261 Scarpati, M. L., 27 Scettri, A., 204 Schade, G., 33 Schaffner, K., 405,46 1 Schatzmiller, S., 190 Schaub, F., 95 Scheer, I., 302 Scheffer, A., 404 Scheffold, R., 300 Schell, F. M., 90, 298 Schenk, G. O., 393 Schenk, H. R., 164 Schenone, P., 40 Scherer, J. R.. 146 Scheuer, P. J., 196 Schild, W., 153 Schildknecht, H., 99 Schmid, H., 31 Schmid, M. V., 253 Schmidlin, J., 459 Schmidt, K., 234 Schmidt, W., 114 Schmitz, F. J., 281 Schneider, G., 3 I I , 3 13

Schneider, J. J., 319, 476 Schnuriger, W., 495 Schonecker, B., 370,440 Scholl, P. C., 469 Schooley, D. A., 92 Schreiber, J., 42, 358 Sr:.:uber, K., 182, 299, 49 1,495 Schroder, E., 422 Schroepfer, G. J., jun., 246, 264 Schupbach, M., 507 Schuller, W. H., 172 Schulte-Elte, K. H., 35, 45, 78 Schulz, J. G. D., 34 Schumaker, R. R., 498 Schurig, V., 66 Schutte, L., 403 Schwartz, M. A., 16, 92, I47 Schwartz, W. E., 87 Schwarz, M., 10, 94 Schwarz, V., 320, 451 Schwerin, K., 37 Schwieter, U., 231, 232, 239 Schwimmer, S., 268 Scolastico, C., 18 Scopes, P. M., 291 Scott, A. I., 5, 7, 161, 163, 196, 201, 255, 291, 398 Scott, J. W., 41 1 Sedzik-Hibner, D., 38, 72 Seeger, A., 6 Seekircher, R.,34 Seelye, R. N., 173 Segnini, D., 166 Seher, A., 407 Sehgal, J. M., 104 Seikel, M. K., 162 Seipenbusch, J. M., 59 Selema, M. D., 209 Selter, G. A., 302 Selye, H., 297, 409 Semenovskii, A. V., 14, 52 Sen, A. G., 206 Sen. E,. C., 75 Sengewein, H., 328 Sengupta, P., 223 Serebryakov, E. P., 182 Sergent, M., 150 Servi, S., 89 Serykh, E. A., 9 Seshadri, T. R., 167, 215, 488,490 Seto, S., 197, 248, 273 Sevenet, T., 26 Severson, R. F.. 172 Shaffer, G. W., 76 Shafizadeh, F., 141, 162 Shagidullin, R. R., 82 Shah, S. N., 261, Shakked, Z., 28 1 Shannon, P. V. R., 23. 83 Shapiro, E. L., 451 Shapiro, R. H., 63 Shapter, H. J., 391, 422 Sharispova, F. S., 173 Sharma, A. K., 38

Sharma, P. P., 360, 502 Sharma, S. D., 104, 361, 476 Shaw, G., 272 Shaw, P. E., 9 Shaw, P. M., 407 Shechter, I., 248 Sheehan, J. C., 90 Sheichenko, V. I., 169 Sherrod, S. A., 67 Shevchenko, V. P., 66 Shibata, S., 71, 205, 228 Shibata, T., 368 Shibayama, S., 168 Shibuya, S., 142 Shibuya, T., 131, 170 Shimada, K., 421, 507 Shimaoka, A., 267 Shimizu, M., I 1 1 Shimizu, Y.,491 Shin, H., 134 Shingu, T., 229 Shinkai, S., 408 Shinriki, N., 327 Shiozaki, M., 191 Shirahama, H., 134, 136 Shishibori, T., 7, 73, 82, 252, 285 Shizuri, Y., 147 Shmelov, L. V., 52 Shok, M., 209 Shono, T., 84 Shuji, I., 249 Shuster, R. E., 210 Siade, G., 348,418 Siddall, J., 424 Siddall, J. B., 25.95,99,256 Siegelman, H. W., 234 Siegfried, R., 60 Siegmann, C. M., 284 Sigel, C. W., 204 Silva, M., 170 Sim, G. A., 142,464 Sim, K. Y., 227 Simes, J. J. H., 200, 215, 388 Simmons, H. E., 78 Simpson, K. L., 230, 234 Simpson, R. F., 168 Simpson, T. J., 270 Sims, J. J., 112, 117, 152 Singh, B., 27, 145, 271 Singh, H., 240, 360, 361, 476, 502 Singh, N., 184 Singh, P., 40, 134 Sinnema. A., 66 Sipahimalani, A. T., 266 Sjuda, J., 424 Skarkova, I., 227 Skorianetz, W., 45 Skrdlant, H. B., 261 Skwarek, M., 54 Skwarko, B., 270 Slaytor. M. B., 255 Slee, M.. 31i Sliwowski, J., 225, 270, 288 Smaal, J. A., 197, 262,416 Smale. T. C., 195 Smedman, L.-A., 57

5 24 Smit, V. A., 14, 52 Smith, A . G., 269, 273 Smith, A . R . H., 265 Smith, G., 340 Smith, G. V., 76 Smith, H.. 424 Smith, H. E., 69. 288 Smith, K., 35 Smith, L. L., 424 Smith, R. A. J., 188 Smith. R. M., 147 Snajberk, K., 8 Snatzke, G., 222, 286 Snider, B. B., 105 Snodin, D. J., 84 Sobti, R. R., 280 Sodano, G., 194 Sou, D., 251 Soffer, M . D., 113 Sofowora, E. A. S , 267 Sohda, T.,I I 1 Solo, A. J., 451 Solomon, P., 413 Soloway. A. H., 261 Soman, R., 220 Somanathan, R., 218, 228 Sommerville, P., 178 Sondheimer, E.. 272 Sondheimer, F., 477 Sonnet, P. E., 10. 94 Sood. R . S., 255 Sophasan, K., 309 Sorarrain, 0. M., 234 Sorensen, T . S., 59 Sorm, F.. 58, 137, 141, 157. 283, 284, 318. 375. 435. 472,476 Sotiropoulos. J.. 66 Southwick, L., 162 Sowerby, R. L., 127, 338 Spalding, B. P., 165 Sparatore, F., 26 Speake. R . N., 183 Speckamp, W. N., 328,427 Spencer, T. A., 188 Spillner. C. J., 20 Spohn. K. H.. 40 Sportoletti, G., 326, 363,

440 Spraggins, R. L.. 281 Sprague, P. W.. 298 Springstube, W. R..26 Sprio, V.. 175 Spyropoulos, C. G., 251 Srikantaiah, M.V., 261 Srinivasan, A,, 160 Srinivasan, K., 50 Stache, U., 293 Stahl, E., 143 Stanczyk, F. Z., 434 Stanford, R. H., 426 Stanislaus, A., 71, 72 Stanton, J., 22 Staunton, J., 245 Steel, G.. 228 Stefanovic, M.,335, 427 Steinfelder, K., 299 Stenberg, V. I., 434 Stephens, D. N., 67 Stevens, K. L.. 16. 146

Author Index Stevenson, R., 224, 301 Sticher, 0..26 Still, I. W. J., 84 Stoddart. J . L., 181 Stoethers, J. B., 297 Stohs, S. J., 268, 269 Stone, K . J.. 244 Stonner, F. W., 440 Stork, G.. 94, 212. 346 Storm, D. L., 188 Strachan, R . G., 447 Streckert. G., 314, 340 Strickler. H., 13 Stringfellow, C. R., 1 I Strominger, J. L., 244, 273 Strong, F. M., 127 Struble, D. L.. 52 Struby, K.. 270 Stiirzebecher, J., 266 Styles, B. T., 210 Subba Rao, G., 124 Subluskey, L. A., 434 Subramanyan, V., 261 Sudarsanam. V., 142 Suemitsu, R., 17, 3 1 Suga, K., 12, 13, 240 Suga. T., 7. 37, 53. 73, 77, 82, 252. 285 Sugano. N., 271 Sugawara, T.. 226 Sugie, A., 210 Suginome, H.. 404. 407 Sugiura, K., 147 Sugiyama, T., 23 Sukh Dev, 193 Sullivan, D. F., 65 Sulser. H., 146 Sultana, F.. 185 Sultanbawa, M. U. S., 218 Sundaralingam, M., 234 Sundeen, J., 488 Sundin, C. E., 138 Sunthankar. S. V., 358,438 Suokas, E., 21 1 226 SUSS,H.-P., Sutherland, J. K., 12, I37 Suzukj, H., 234 Suzuki, I.. 84 Suzuki, M., 1 I I Suzuki, S., 292 Sunuki, T., I87 Suzuki, Y.,92 Svarz, J. J., 392 Svoboda. J. A . . 246. 266 Sweeny, J . G., 255 Sweet, F., 418 Sych. F. J., 491 Sykes, P.J.. 329 Sykora, K.. 426,450 Syrdal, D. D., 114, 121 Szabo. S.. 409 Szabolcs, J., 239, 240 Szechner, B., 7

Tabacik, C., 165, 166 Tashe, Y., 409 Tachi, Y.,204 Tada, H., 143

Tada, M., 153 Tadwalkar, V . R., 37, 45 Taaa. S., 204 Takara, A.. 190, 432 Tai, H.-H., 261 Taillefer, R., 59 Taira. S.. 268 T'ait, A . D.. 269 Takabe, K., 1 I , 23 Takada. S., 190 Takagi, I.. 153 Takagi. T.. 19 Takahashi, H., 407 Takahashi, N., 180 Takahashi, R., 228 Takahashi, S., 157 Takahashi, T., 153, 210. 21 I , 224 Takano, T., 243 Takao, Y., 180 Takeda, K., 104. 143, 267 Takeda, Y., 28,254, 255 Takemoto. T.. 140. 153. 154, 183, 199, 210. Takeshi, K.. 184 Takeshita, H., 161 Takeshita, T.. 65 Takizawa, N., 234 Talalay, P., 269, 342 Tamm, Ch., 288, 438, 507, 509 Tamura. S., 10. 11. 243 Tan, L., 408 Tanabe, M., 339 Tanahashi, Y . . 130, 131, I53 Tanaka, A., I14 Tanaka, J., 1 I , 23 Tanaka, K.. 5 5 Tanaka, N., 205 Tanaka, O., 205, 228 Tanaka, R., 40, 114 Tanaka, Y., 40 Tanemura, M., 187 Tani, T., 26 Tanomura, M., 19 Tarzia, G., 3 16, 4 I8 Tarzia, R. H., 417 Tatsumi, C., 10, 47 Taub. D., 477 Taube, H., 186 Tauscher, B., 99 Tavares, R. F., 19 Taylor, D. A . H., 176, 206. 207. 208, 210. 223 Taylor, D. R.. 146. 166. 207, 209 Taylor, E. C., 358 Taylor, H. F., 241, 272 Taylor. R. F.. 230. 407 Teflez, R., 248 Tel'nov, V. A., 185 Templeton, J. F., 318, 355, 435,469 Teng. S., 15 Terasawa, T., 324. 440 Terent'ev, A. P., 66 Terhune, S. J., 9, 13 Teshima, S.-l., 266, 274 Testino, L., 87 '

Author Index Teutsch, G., 284, 374, 472 Thakkar, A . L., 295 Thal, C., 26 Than, A., 234 Thassler, K., 41 Thierry, J., 381, 382 Thoma:, A. F., 20, 26, 99 Thomas, R., 195 Thomas,, V. E. M . , 322, 434 Thompson, A . C., 9.24,25, I05 Thompson, M. J., 246, 266 Thompson, W. R., 17 Thomson, J. B., 225 Thoren, S., 135 Thorstenson, J. H., 50 Threlfall, D. R., 245 Tidy, D. J. D., 464 Tikhonova, L. K., 173 Tiltman, A . J., 246 Timmer, R., 9 Timmermann, B. N., 162 Timmins, P. A., 202 Titkova, E. G., 46 Tkatchenko, I., 12 Tocanne, J . F., 288 Toda, F., 444 Toda, M., 338 Todd, M., 374,427 Toh, H. T., 316,418 Tokolics, J., 424 Tokoroyama, T., 209 Tokura, N., 45 Toman, J., 153 Tomassini, T. C. B., 152 Tomida, I., 183 Tomimoto, K.. 457 Tomita, B., 121 Tomoeda. M., 330 Topham, R . W., 264 Torgov, 1. V., 413 Tori, K., 143, 296, 373,471 Torrence, A. K., 152 Torri, G., 40 Torrini; I., 392 Tortorella, V., 292 Toth, Gy., 239, 240 Toube, T. P., 231 Toubiana, M.-J.. 143, 227 Toubiana, R., 143 Touet, J., 76, 422 Touzin, A. M . , 39 Tozyo, T., 156 Trave, R., 140 Trefonas, L. M., 281 Trenner, N. R., 447 Triana, J., 158 Tribble, M. T., 279 Tripathi, R. P., 230 Trivedi, G. K.,I12 Trivellone, E., 194 Trost, B. M.. 22 Trouilloud, M., 239 Truitt, E. B., jun.,87 Truong Van Thuong, 436 Tsai, T. Y. R., 191 Tsankova, E., 73, 75 Tschesche, R., 246 Tseng, A., 57

525 Tsizin, Yu. S., 49 Tsuda, Y., 171 Tsunakawa, M., 18 Tsuyuki, T., 210, 21 1,224 Tsvetkov, V. N., 407 Tubbs, P. K., 246 Tubiana, W., 73 Tucker, J. N., 70 Tucker, O., 57 Tuinman, A., 324,440 Tuller, F. N., 114 Tumlinson, J . H., 24 Tummler, R., 299 Turk, R. F., 88 Turnbull, J. P., 329 Turnbull, K. W., 110, 257 Turnbull, P., 339, 426 Uchimaru, F., I 1 1 Uda, H., 40, 63, 114, 124, 292 Udarov, B. G., 51 Ueberwasser, H., 459 Ueda, H., 10 Ueda, K., 23 Ueda, S., 28, 254, 255 Uedona, S., 47 Uemura, D., 169 Uhde, G., 244 Ulubelen, A., 153 Umeda, I., 327 Ungar, F., 261 Unrau, A. M . , 265 Upadhyay, R. R., 236 Uralova, R. P., 9 Uritani, I., 256 Uskokovid, M. R., 30 Usubillaga, A., 175 Usui,. M., 349, 44 1 Usynina, R. V., 9 Uyeo, S., 212, 490 Uzarewicz, A., 73, 81 Uzarewicz, I., 73, 81 Vaciago, A., 195 Valadon, L. R. G., 230,234 Valkanas, G., 15 Valverde, S., 176 Van, J., 154 Van Bekkum, H., 66 Van Bruynsvoort, J., 427 Van Den Broek, A. J., 284 Van der Gen, A., 58 Van der Helm, D., 281 Van der Horst, D. J., 274 Van der Linde, L. M., 58 Van der Sijde, D., 451 Van de Woude, G., 375 Van Dijck, L. A., 334 van Ginneken, C. A. M., 86 van Hove, L., 375 Van Lear, G., 201 van Lier, J. E., 407 van Rossum, J. M., 86 van Tamelen, E. E., 94, 197, 262,4 16 Van Thuong, T., 328 Van Tongerloo, A,, 393, 436

Van Wageningen, A.. 243 Van Zyl, C. J., 309,456 Vass. A,, 31 I . 313 Vecchio, G., 296, 326, 363, 440 Velarde, E., 301, 335, 427, 444,445,448 Velgova, H., 283, 284, 435, 472 Venturella, P., 177 Venzke, B. N., 32 Vercellone, A., 304 Vereshchagin, A. N., 8 1 Verghese, J., 31, 51 Verguin, J., 59 Verma, K. K., 230 Vermeer, J. C. M., 334 Vermilion, J., 246 Verner, D., 89 Vernice, G. G., 310 Vetter, W., 23 1, 239 Viala, J., 485 Vichnewski, W., 159 Viennet, R., 292 Vig, A. K., 15 Vig, 0. P.,15, 38, 47, 104 Vignan, M., 427 Vil’chinskaya, A. R., 8 1 Vilim, A., 191 Villaescusa, F. W., 506 Villarica, R. M., 188 Villoutreix. J.. 234 Vincent. F., 269 Viriot-Vuillaume, M. L., 40 5 Viswanathan, N., 204 Vitagliano, J. C., 210 Vitali, R., 308, 354, 437, 440,463 Voelter, W., 297 Voigt, B., 182 Voigt. D., 495 Voitkevich, S. A., 71 Vokad, K., 58, 157 Volkov, Yu. P., 80 Vollner, L., 86 Voloshina, D. A., 8 von Mutzenbecker, G., 349 von Philipsborn, W., 23 1 von Schautz, M., 9 von Sydow, E., 10 Voogt, P. A., 273, 274 Vouros, P., 299 Vree, T. B., 86 Vulf’son, S. G., 81 Vystrcil, A., 215, 220, 227 Wada, H., 147 Wadia, M. S., 112, 133 Waegell, B., 63, 73 Wagner, H., 159 Wagniere, G., 68, 287 Wahlberg, I., 220, 224, 226 Waida, T., 10 Waight, E. S., 178, 195,239, 312 Wakabayashi, N., 10, 94 Wakabayashi, T., 189, 326 Wakamatsu. T., 212

Author Inde?c

526 Wakatsuka, H., 357 Wakayama, S.. 84 Wakeford, D. H., 3 12 Walker, E. R . H., 178 Wall, M. E., 87 Waller, G . R., 26 Walter, J . L., 87 Walter, R . H., 133 Walton, D. C., 272 Walton, M . J., 273 Wander, 5 . D., 141 Wang, C.S . , 226 Wang, H. M . , 408 Wang, I. S.-Y.. 77 Wang, N. Y., 136 Warneboldt, R. B., 390 Warnhoff, E. W.. 67. 77 Warren, J. C., 418 Washburn, W. N., 397,469 Washuttl. J.. 240 Watanabe. H.. 6, 42. 373. 47 1 Watanabe, M.. 140. 268 Watanabe, S., 12. 13, 37, 53, 240 Waters, J. A.. 362, 397, 400 Waters, R . M.. 10. 9 4 Watkinson, I , A , . 246, 265 Watson, D. H. P.. 424 Watson, J. M., 53 Watson, T. G., 21 5 Weavers, R. T., 165 Webb, T. C.. 31, 75 Weber, A. J . M., 334 Weber, H.-P., 270, 280 Weber, J. P., 397 Weber, L., 451 Wechter, W. I., 476 Weedon, B. C. L., 1 3 I , 239 Weeks, C. M.. 279 Weeks, 0. B., 232. 245 Wehrli, H., 309, 401, 495, 497,498 Weiland, P.. 333 Weiler, L., 357, 390, 463 Weill-Reynall, J., 427 Weiner, M.. 68 Weiner, N . D., 407 Weinhardt, H., 87 Weinhardt, K . K.. 87, 90 Weinheimer, A . J., 281 Weinreb, S. M.. 134 Weintraub, H., 269 Weisgraber, K . H., 236 Weiss, U.. 175, 236. 289 Weisz-Vincze, I .. 3 1 1 , 3 I3 Welch, S. C., 216 Wellam, G. R., 261 Welters, R., 65 Welzel, P.,328 Wendt, G. R., 424 Weniger, J. P.. 422 Wenkert, E., 90, 169, 203, 258, 298,434 Wettstein. A.. 230 Werstiuk, N. H., 59 West, C. A., 259 West, P. J., 404 Westcott, N. D., 255, 316, 418

Westfelt, L.. 112 Whalley. W . B.. 175, 289, 303,483 Wharton, P. S., 138, 154 Wheeler. D. M. S., 187 Wheeler, J . W.. 57 Whelan, M . J., 45 Whistance, G . R., 245 White, A. F.. 256, 259 White, E. H., 365 White, I. H., 338 Whitehead, E. V.. 196 Whitehouse, R . D., 371 Whitesides, G . M., 6 Whiting, D. A.. 22, 198. 222, 250, 2 5 1 , 253 Whittaker, D., 5 , 57.64, 74 Wicha, J., 305, 388, 434. 472 Wiqkberg, B., 135 Wickramasinghe. J . A . F.. 264 Widdowson, D. A.. 481 Wie. C. W.. 318, 355, 435. 469 Wiechert. R.. 301.412.418. 422 Wiesner, K., 125. 191. !92 Wiesner, K . J.. 125 Wijsbeek, J., 86 Wilcox, C. F.. jun., 15 Wiles, J . M., 330 Wiley, R., 141 Wilke, G., 12 Wilkins, B. J.. 303, 483 Wilkinson, R . C.. 8 Willcott, M . R., 59 Williams, D. H.. 296, 349 Williams, J. G.. 377 Williams, V. P., 249 Williamson, J., 273 Willig, A., 266 Willis, B. J., 341 Willis, C. R., 166 Willoughby, E.. 273 Wills, R. B. H.. 8 Wilton, D. C., 246,263.265 Winell, B., 168 Wing, R. M., 112, 117 Winstanley, D. J., 272 Winstein, S., 15, 297 Winternitz, F., 91 Winters, T. E.. 160 Wirz, J.. 404 Wirz-Justice. A . , 7, 253. 27 1 Witkop. B., 362. 397. 400 Witteveen. J . G.. 58 Wittstruck, T. A . . 295 Wobben, H. J., 9 Wojnarowski, W.. 75 Wolfango. E., 170 Wolff, G., 206, 383 Wolff, M. E., 3 13, 442 Wolinsky, J., 50. 108 Wong, S. M., 249 Wood, C. N., 262 Woods, D. K., 22,253 Woods, M.C., 28 Woodward, R. B.. 477

Woolen, B. H., 244 Worden, L. R., 434 Wright, L. H., 184 Wrixon, A. D.. '7. 291 Wu. C. S., 191 w u , F.. 279 Wuest, H., 13. 243 Wulff, G., 3 14 Wynne, K . N.. 31 I . 434 Yagen, B.. 246, 264 Yagi, H., I I , 243 Yakubovich, V. B., 9 Yalciner, S., 246 Yamada, H., 12, 13 Yamada, K., 1 1 , 115. 147 Yamaga. T., 71 Yarnaguchi, I . , I80 Yamaguchi, M.. 40 Yarnaki, M., 227 Yarnarnoto, H., 71. 8C Yarnamoto, I., 24 Yarnamoto, K., 1 1 1 Yarnamoto, N., 42 Yarnamoto, Y.. 171 Yamamura, S., 138. 338 Yarnana. S., 294 Yamane, H., 180 Yarnasaki. M., 127 Yamashiro, O., 490 Yamashita, K.. 23, 24, 101, 240, 241 Yarnato, Y., 373 Yamauchi, H., 205, 227 Yanuka, Y., 370 Yasue, M., 184 Yasuhara, F.. 40 Yates, P., 62 Yazawa, H 115 Yeboah, S. K., 270 Yeddanapalli, L. M.. 71. 72 Yogev, A., 31, 290, 291 Yokota, T., 180 Yoo, s. c.,413 Yoshida, S., 31 Yoshida, T., 110 Yoshikawa, H., 6.5 Yoshikoshi, A., 40, 55, 43, 114, 124, i33, 140, 157 Yoshirnura, F., 153 Yoshirnura, M.. 45 Yoshioka, H., 162 Yoshioka, M., 324, 440 Yosioka, I., 26, 205, 218, 221, 226, 227 Young, B.W., 201, 398 Young, M . R., 7, 253 Yii, s., 134 Yunes, R . A . , 6 Yunusov, M . S., 185 Yunusov, S. Y., 185

.

Zagalsky, P. F., 236 Zakharin, L. I., 12 Zakharov, P. I . , i69 Zaman, A., 193 Zamojski, A., 7 Zanati, G.. 3 13,442

Author Index Zarghami, N. S., 5 I , 244 Zavarin, E., 8, 9 Zbiral, E., 63, 79, 3 I8 Zdero, C., 46, 100, 159 Zechmeister, K . , 282 Zelenetskii, N. N., 71 Zenk, M. H., 253 Zen’ko, R . I . , 51

527 Zepter, R., 328 Zey, E. G . , 148 Zhigareva, G . G . , 12 Zhuchkova, 0. N., 71 Zhuratova, M., 8 Zientek, E., 73, 81 Ziffer, H . , 289 Zinkel, D. F., 165

Zitko. B. A., 87. 90 Zorina, A..D., 219 Zubiani, G . , 339 Zundel, J . L., 206, 383 Zurfliih, R., 95 Zurr, D., 314, 340