Terpenoids and Steroids: Volume 3 (Specialist Periodical Reports)

A Specialist Periodical Report Terpenoids and Steroids Volume 3 A Review of the Literature Published between Septembe...

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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

...


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


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


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


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


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


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


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).


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.


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.


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


(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).


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


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.


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


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


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


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


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

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


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.


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.


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"

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.


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.


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.


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


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


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


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.


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


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


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


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


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


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.


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


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


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.


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


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.


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


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


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.


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.


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


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


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


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


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


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.


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


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


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


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


*; 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.


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


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


'

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


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


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.


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


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


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


.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


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.


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


(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.


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.


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


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


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


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.


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


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


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


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


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.


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


(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


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.


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.


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


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.


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


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.


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


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


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.


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.


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


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


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.


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


(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


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.


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


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.


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.


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.


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


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.


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


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.


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


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.


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


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


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.


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


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


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


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


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


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


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


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.


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.


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


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


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


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


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.


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


(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

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