Terpenoids and Steroids: Volume 1 (SPR Terpenoids and Steroids (RSC))

A Specialist Periodical Report

Terpenoids and Steroids Volume 1 A Review of the Literature Published between September 1969 and August 1970

Senior Reporter K. H. Overton, Department of Chemistry, University of Glasgo w Reporters

J. D. Connolly, University of Glasgow J. R. Hanson, University of Sussex D. N. Kirk, Westfield College, University of London P. J. May, Glaxo Research Ltd. G. P. Moss, Queen Mary College, University of London J. S. Roberts, University of Glasgow A. F. Thomas, Firmenich et Cie.

SBN: 85186 256 X 0 Copyright 1971

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

General Introduction

We have attempted in this Report to provide a detailed coverageof the literature from September 1969to August 1970,but for this first Report we have on occasion delved back into the preceding year to provide additional perspective. In Part I the choice of the most suitable system of classification posed a problem. The two different solutions adopted, one based on structural relationships (monoterpenoids and carotenoids) and the other on biogenetic relationships (sesqui-, di- and tri-terpenoids)in part reflects current practice. This Report does not include a section on the chemistryof the sesterterpenoids. The limited activity in this area has been on the biosynthetic side, and this is covered in Chapter 6. Biogenetic theory and practice provide the stimulus and vehicle for an increasing proportion of sigtllficantresearchesin the terpenoid field. We have separated biogenetic practice, that is experiments with living systems, in Chapter 6. Biogenetic thinking, on the other hand, pervades the text. There is occasional overlap with Chapter 6 ;where the inclusionof in ubo experimentsseemed particularly appropriate in other chapters, it seemed a mistake rigorously to exclude them. Steroid researches account for a substantial fraction of the literature of organic chemistry each year. They continue to do so for two reasons: steroids have intrinsic biological and pharmacological interest and hence industrial importance; they also serve as readily accessible and very suitable substances for the study of reactions and reagents and physical methods of analysis. We have sought to separate these two aspects of steroid chemistry in Chapters 1 and 2 of Part 11, but inevitably the two overlap to some extent. Steroid biosynthesis has been included in Chapter 6, because it logically belongs there, but also because the depth of enquiry applied to it is unequalled in other areasof terpenoid biosynthesis. We would greatly welcome any suggestions that readers feel might improve the substance or presentation of future Reports in this series.

... 111

G.P.M.

J.D.C. J.R.H. D.N.K.

K.H.O. J.S.R.

P.J.M.

A.F.T.

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

Contents Part I Terpenoids Introduction By K. H. Overton

3

Chapter 1 Monoterpenoids By A. F. Thomas 1 PhysicalMetbodsandBiogeoesis

7

2 AcyclicMoaoterpenoids 2,6-Dimethyl-octanes “on-Isoprenoid’ Monoterpenoids Telomerisation of Isoprene

8 8 13

3 MonocyclicM~~ids Cyclobutanes cyclopentanes p-Menthanes (i) Hydrocarbons (ii) Oxygenatedp-Menthanes

18

rn-Menthanes O-MeIlthanCS Tetramethylcyclohexanes Cycloheptanes

17 18

18 23 23 29

34 35 35 36

4 BicyclicMonoterpeaoids Bicyclo[3,2,qheptanes Bicyclo[3,1,O]hexanes Bicyclo[2,2, llheptanes Bicyclo[3,1, llheptanes BicyclN4,l ,O]heptanes

37 37 37 39 41 47

5FaranoidandPyrawidMono6erpeaoids

48

Chapter 2 Sesquiterpenoids By J. S. Roberts 1 Introddon

51

2 Farnesane

52 V

Contents

v1

3 Monocyclo- and Bicyclo-farnesanes

56

4 Bisabolane, Curcumane, etc.

60

5 Carotane

62

6 Cadinane, Amorphane, Muurolane, Bulgarane, and related Tricyclic Sesquiterpenoids

62

7 Santalane and Bergamotane

69

8 Cuparane, Thujopsane, Cedrane, Acorane, Laurane, eic.

71

9 Caryophyllane and Humulane

77

10 Germacrane

82

11 Elemane

94

12 Eudesmane (Selinane)

96

13 Eremophilane, Valencane, Vetispirane, 100

Tricyclovetivane, etc.

110

14 Guaiane

15 Aristolane, Aromadendrane,

etc.

16 Non-farnesyl Sesquiterpenoids

120 122

Chapter 3 Diterpenoids By J. R. Hanson 1 Introduction

1 24

2 Bicyclic Diterpenoids The Labdane Series The Clerodane Series

124 1 24 128

3 Tricyclic Diterpenoids Pimaranes Abietanes Cassanes Chemistry of Ring A Chemistry of Ring B Chemistry of Ring c

130 130 131 133 134 135 136

4 Tetracyclic Diterpenoids The Kaurane-Phyllocladane Series The Grayanotoxins The Gibberellins The Diterpene Alkaloids

141 141 145 147 148

vii

Contents 5 Macrocyclic Diterpenoids and theb Cyclisation Products Phorbol and its Relatives The Taxane Diterpenes

150 150 152

6 Synthesisof Diterpenoids

153

Chapter 4 Triterpenoids By J. D.Connolly 1 Squalene

161

2 Fusidane-Lanostane Group

163

3 Dammarme-Eaphane Group Tetranortriterpenoids Bicyclononanolides Quassinoids

171 176 184

4 LupaneGroup

185

5 Oleanane Group

188

6 UrsaneGroup

194

7 HopaneGroup

195

8 SerrataneGroup

196

174

Chapter 5 Carotenoids and Polyterpenoids By G.P. Moss 1 Introduction

198

2 Physical Methods

198

3 New Natural Carotenoids Acyclic Carotenoids Monocyclic Carotenoids Bicyclic Carotenoids Aromatic and Cyclopentanoid Carotenoids Allenic and Acetylenic Carotenoids Glycosides and Isoprenylated Carotenoids

201 20 1 204

204 206 207

209

4 Carotenoid Chemistry

211

Photochemistry

213

5 Degraded Carotenoids

213

6 Polyterpenoids

219

...

Contents

v111

Chapter 6 Biosynthesis of Terpenoids and Steroids By G.P. Moss 1 Introduction

22 1

2 Acyclic Precursors

22 1

3 Hemiterpenoids Ergot Alkaloids Furanocoumarin and Furanoquinoline Derivatives

224 225 226

4 Monoterpenoids Cyclopentanoid Monoterpenoidsand Indole Alkaloids

227 229

5 Sesquiterpenoids

231

6 Diterpenoids Kauranes and Gibberellic Acids

233 234

7 Sesterterpenoids

237

8 Steroidal Trisnortriterpenoids Cyclisation of Squalene Loss of 4,CDimethyl Groups Loss of 1&-Methyl Group Isomerisation from A*- to AS-DoubleBond Reduction of A24-DoubleBond Side-chain Alkylation A22-DoubleBond

237 238 24 1 24 1 242 243 243 245

9 Cholesterol Metabolism Spirostanols Cardenolides and Bufatenolides Side-chain Cleavage Animal Steroid Metabolism

245 246 247 247 248

10 Triterpenoids

249

11 Carotenoids

25 1

12 Polyterpenoids

253

13 Taxonomy N on-Arthropod Invertebrates Arthropoda

255 255 256

Contents

ix

Part I/ Steroids Introduction By K. H. Overton

261

Chapter 1 Steroid Properties and Reactions By D. N. Kirk Introduction

263

1 Structure, Stereochemistry, and Conformational Analysis Spectroscopic Methods Raman Spectroscopy N.m.r. Chiroptical Properties (O.r.d., C.d.) Mass Spectrometry

263 269 269 269 272 276

2 Alcohols, their Derivatives, and Halides Nucleophilic Substitution Nucleophilic Opening of Epoxides Solvolytic Reactions Elimination Reactions Esters, Ethers, and Related Derivatives of Alcohols Oxidation Reduction

276 276 283 287 289 292 293 295

3 Unsaturated Compounds Electrophilic Addition Other Addition Reactions Reduction of Unsaturated Steroids Oxidation and Dehydrogenation Cyclopropanes Miscellaneous

296 296 304 308 31 1 315 316

4 Carbonyl Compounds Reduction of Ketones

317 317 320 324 327 330 336 339 340 343 344 346

Other Reactions at the Carbonyl Carbon Atom Oxidation Enolisation Reactions of Enols and Enolate Anions Reactions of Enol Ethers and Esters Reactions of Enamines Oximes Hydrazones Tosylhydrazones Carboxylic Acids and their Derivatives

Contents

X

5 Compounds of Nitrogen and Sulphur Deamination Other Reactions

348 348 35 1

6 Molecular Rearrangements The Contraction and Expansion of Steroid Rings The ‘Westphalen’ and ‘Backbone’ Rearrangements Epoxide Rearrangements Aromatisation Miscellaneous Rearrangements

353 353 36 1 365 376 380

7 Functionalisation of Non-activated Positions Free-radical Reactions Microbiological Hydroxylations

386 386 39 1

8 Photochemical Reactions Unsaturated Steroids Carbonyl Compounds Miscellaneous Photochemical Reactions

39 1 392 393 397

9 Miscellaneous Reactions Analytical Methods Miscellaneous

40 1 40 1 402

Chapter 2 Steroid Synthesis By P. J. May 1 Introduction

404

2 Steroid Lactones Bufadienolides Isobufadienolides Cardenolides and Isocardenolides Antheridiol Withanolides

405 405 413 414 420 42 1

3 Insect Moulting Hormones

422

4 Oxa-steroids

427

5 Thia-steroids

429

6 Aza-steroids

430

7 Steroids Having Fused Heterocyclic Rings Rings containing One Heteroatom Oxygen Heterocycles Sulphur Heterocycles Nitrogen Heterocycles Rings containing Two Different Heteroatoms

433 433 433 436 437 440

xi

Contents

8 Fused Carbocyclic Rings

442

9 Steroids of Unnatural Configuration

446

10 Homo-steroids

449

11 Ring-nor Steroids

450

12 l&Nor Steroids

452

13 lPNor Steroids

453

14 C-19-substituted Steroids

46 1

15 Abeo-steroids

463

16 Seco-steroids

466

17 Total Synthesis of Steroids

468 468 477 480

Carbocyclic Steroids Am-steroids Miscellaneous Heterocyclic Steroids 18 Steroid Conjugates

48 1

19 Sapogenins

482

20 Amino-steroids and Steroidal Alkaloids

482

21 Anthra-steroids and ‘Linear’ Steroids

489

22 Syntheses of Miscellaneous Natural Products

490

23 Syntheses Involving the Steroid Side-chain

492

24 Photochemical Syntheses

499

25 Oxidation and Reduction

502

26 Syntheses Involving Reactions at Double Bonds

507

27 Miscellaneous Syntheses

509

28 Table of New Compounds Isolated from Natural Sources

5 17 517 52 1 523 527 528 530 535

Steroidal Alkaloids Ecdysones Withanolides Cardenolides and Bufadienolides Sapogenins G1ycosides Miscellaneous Author Index

539

Part I TERPENOIDS

I ntrod uct ion*

Monoterpoids (Chapter l).-The study of monoterpenoid biosynthesis remains experimentally difficult. Zavarin4 has developed an interesting approach to biogenetic hypothesis based on statistical analysis of the occurrence and distribution of monoterpenoids. "on-isoprenoid' monoterpenoids might be formed in nature by sigmatropic rearrangement of suitable ylides and not, as previously supposed, by cyclopropyl cleavage of chrysanthemyl s y ~ t e m s . ~ ~The * ~se ' speculations are encouraged by some successful laboratory ~yntheses.~ Buchi and his colleagues' have synthesised loganin penta-acetate utilising a single photochemical step for assembly of the aglycone. A high-yield synthesis' 5 6 of (racemic) camphor from (- )-dihydrocarvone enol acetate is notable for its simplicity. The sex attractant of the male boll weevil, whose f o r m ~ l a t i o n ~ ~ and synthesis56followed in close succession, is of interest as the first monocyclic monoterpenoid containing a cyclobutane ring. 1932938

Sesquiterpenoids (Chapter 2).-In the sesquiterpenoid field there has been a veritable flood of synthetic activity, sometimes resulting in several syntheses of the same (usually biologically active) substance. Of the nine syntheses of juvenile hormone (ll), that of Johnson's group,I6 employing the olefinic ketal Claisen reaction, is particularly notable. The need to construct small complex skeletons bearing multiple functionality has elicited many ingenious and felicitous solutions. Stork and Ficini's intramolecular cyclisation' of olefinic diazo-ketones stands out as a method of general utility, while de Mayo's synthesis134of methyl isomarasmate is remarkable for the inclusion of four photochemical steps. Our understanding of the conformational behaviour of germacranes has been enriched by exploitation of the Nuclear Overhauser E f f e ~ t ~ . ' ~and ~ * by ' ~ 'X-ray a n a l y ~ i s . ' ~ ~It*appears, '~~ moreover, from n.m.r. and c.d. s t ~ d i e s ' ~that ~~'~~ certain germacrane derivatives co-exist in solution in two conformations at room temperature. According to a recent report, urospermal (203) has even been isolated 14' as two stable (hydrogen-bonded) conformers. Insight into the conformations of germacranes in turn generates biogenetic s p e c u l a t i ~ n . ' ~ * ~ ~ - ~ ~ ~ Thus, two conformations (277) and (279) of the same cyclodecadiene might lead respectively to eremophilone and valencane/vetispirane. Isolation280 of the

* Reference and formula numbers are those of the relevant chapter.

4

Terpenoids and Steroids

bicyclogermacrene (384) makes it a plausible progenitor of sesquiterpenoids with a gem-dimethylated cyclopropane ring. Few advances have been recorded relevant to sesquiterpenoid biosynthesis. However, the in vivo formation of coriamyrtin and tutin has been convincingly clarified7 in two laboratories and some progress has been made'" in the trichothecane group. On the other hand, there has been a good deal of well-informed and potentially fruitful speculation based on co-occurrence of related sesquiterpenes and in vitro interconversion, supported by stereo-electronic interpretation. The work of Anderson,56*72*204 Yo~hikoshi,~H i r o ~ e , ' ~ and ~ * 'Zavarin2 ~~ deserves mention. 5776

'

Diterpenoids (Chapter 3).-Cyclisation in uitro of manool to 14a-hydroxybeyerane bears no resemblance to the in vivo formation of tetracyclic diterpenoids but proceeds instead through an 8-ring intermediate.l 4 - I 7 C l e i ~ t a n t h o lis~ ~ the first example of an 'iso-cassane' formally derivable by migration of ethyl rather than methyl from C-13 to C-14 of a pimarane precursor. A group of plant growth inhibitors which includes the p o d o l a ~ t o n e sand ~~ nagila~tones~~ share a novel carbon skeleton which could arise from ring-c cleavage of a tricyclic diterpenoid. Among several X-ray structure analyses of C2' diterpene alkaloids which have brought rapid progress in this field those of denudatine,'24p'26 a possible link between atisine and aconitine, stand out. Chemical of the structurally fascinating co-carcinogen phorbol have been published in full and the structures of several cytotoxic relatives established by X-ray a n a l y ~ i s ' and ~ ~ *correlation. ~~~ Ca~bene,'~'a 14-ring triene related to cembrene, is clearly not far removed from a possible macrocyclic precursor of the phorbol group. There have been major synthetic advances in the gibberellin field, among them completion'62 of the total synthesis of gibberellin A4. Triterpenoids (Chapter 4).-Two notable syntheses of squalene't2 have been published, both utilising sulphur derivatives of farnesol. The &- and 4b-methyl groups of triterpenoids are distinguishable5 as a. result of the stereoselective abnormal Beckmann rearrangement of the 3-ketoximes. It can thus be shown that the &-methyl group derives from C-2 of mevalonic acid. Two dienes having the protostane skeleton of fusidic acid and corresponding to the long-postulated intermediate of lanosterol biosynthesis have been isolated together with helvolic acid.'. O Cycloneolitsin" is an unusual 24,24-dimethyl derivative of cycloartenol. The cucurbitane and lanostane groups have been chemically interrelated.3',32 A notable addition to the group of tetranortriterpenoids is utilin whose structure, established by X-ray includes a novel and chemogenetically intriguing C-1-G29 bond in a bicyclononanolide skeleton. The postulated /3-diketone precursor of bicyclononanolides has been prepared by partial synthesis and c y c l i ~ e dunder ~ ~ very mild conditions to mexicanolide. p-Amyrin has been converted"g into oleanolic acid and a-amyrin into ursolic acid, the key step involving functionalisation at C-28 by nitrite photolysis from

c-23.

Terpenoids-In troduction

5

Carotenoids and Polyterpewids (Chapter 5).-The absolute configuration of acarotene has been establisheds3 as R. The list of acetylenic, allenic, and iso) grows. A number of biologically important prenylated (C4, and C s 0carotenoids terpenoids of varying chain length appear to be degradation products of carotenoids. Notable among them is abscisic acid which has been chemically interrelated'08 with violaxanthin and efficiently synthesised'26 by oxidation of aionone. Biosynthesis (Chapter @.-Detailed studies have been reported with individual enzymes responsible for the early stages of terpenoid biosynthe~is.'~-'~The mechanism whereby two molecules of farnesyl pyrophosphate couple to furnish squalene is still uncertain and the structure of the C30pyrophosphate inter~ ~ genesis * ~ ~ of the monomediate isolated by Rilling in 1966m a i n s e l u s i ~ e . The terpenoid portion of the indole alkaloids has been intensively Of special interest was the discovery of the bismonoterpenoid foliamenthin, which is a derivative of the indole alkaloid precursor secologanin. The biosynthesis of the gibberellins has received detailed attention on both sides of the Atlantic. Ent-kaurene, the parent, is f ~ r m e d ~ ~via. ~geranylgeranyl ' pyrophosphate and ent-copalyl pyrophosphate and this seems to f0110w'02-'04 a acid, the branch point single pathway to 7/l-hydroxy-ent-kaur-16-en-19-oic to kaurenolides and gibberellins. The enzyme oxidosqualene cyclase has been isolated'l4 and it has been shown''5.1'6 that, while it is sensitive to the environment of the epoxide, it is relatively indifferent to the other end of the polyene chain. The rather unexpected discovery has been made'31 that cycloartenol, not lanosterol, is the first-formed triterpenoid steroid intermediate in higher plants. Although the precise sequence of events in the conversion of lanosterol and cycloartenol into cholesterol is not established, it seems that the &-methyl Also, a As-double bond is group is lost before the 4/l-methy1.119*'20~'41-'45 necessary for loss of the 14a-methyl group and both and A8.l4-intermediates appear to be involved.'46*'47~'52*153 The transfer of the olefinic double bond from As to As has also received attention, as have the reduction of the A24 and introduction of the A22 double bonds and side-chain alkylation. Phytoene appears to be243the immediate biosynthetic precursor of carotenoids and is then progressively dehydrogenated. Incorporation of farnesyl pyrophosphate into polyprenols suggests260that they are formed by chain extension of farnesyl pyrophosphate with cis-C, units.

'

Monoterpenoids BY A. F. THOMAS

1 Physical Methods and Biogenesis

A further collection of mass spectra of hydrocarbons of the carane and menthane series has been published.' The identification of monoterpenoid alcohols in complex mixtures is sometimes tedious; it has been suggested that the problem would be simplified by preparing the trifluoroacetates, and using the "F n.m.r. spectra.2 The biogenesis of monoterpenoids has received attention. The first paper of a series has been devoted to the monoterpenoids (largely thujone isomers) of Tanaceturn vulgare ( t a n ~ y ) .The ~ routes to thujone are examined based on the extent of incorporation of radioactivity from [14C]acetate and it is shown that certain terpenes (e.g.menth-1-en-4-ol,sabinene)are directly involved in the route, whereas others (e.g. thujene) are 'branches' off the main route. In addition, this paper also contains a good discussion of the present state of monoterpenoid biogenesis. A somewhat different approach has been made by Zavarin. Working with oils from Pinus and Abies, he has developed a kind of statistical analysis for deriving biogenetic hypotheses. From a fairly large number of examples, he has noticed certain regularities in the occurrence of monoterpenes, some qualitative (two or more compounds occurring congenerically) and some quantitative (compoundsoccurring in mathematical relationship to one another), and has on this basis considered the biogenesis of the pinenes, camphene, bornyl acetate, y-terpinene, sabinene, and other terpene hydrocarbon^.^ Laboratory syntheses supposedly based on biogenetic routes continue to appear. Although they are often effective and may indeed have been inspired by genetic considerations, they rarely bear more than a formal resemblance to the phytochemical process. An example is the synthesis of camphor described below, under bicyclo[2,2,l]heptane derivatives. Slightly different is the synthesis of terpenes from geranyl pyrophosphate examined by Haley et af.,which certainly attempts to follow fairly closely the proposed biogenetic route. They examine the variation in products from neryl (1) and geranyl (2) diphenylphosphates (analogues of

'

'

G. von Bunau, G. Schade, and K. Gollnick, Fresenius 2.Anal. Chem., 1969,244, 7. E. Breitmaier, G. J u g , W. Voelter, and E. Bayer, Tetrahedron, 1970,26, 2053. D. V. Banthorpe and A. Wirz-Justice, J. Chem. SOC.(C), 1969, 541. E. Zavarin, Phytochemistry, 1970,9, 1049.

8

Terpenoidr and Steroids

biological pyrophosphate) and find increased production of cyclic terpenes in the neryl case. Cyclic terpenes are formed from geranyl diphenylphosphate but the authors suggest that they might arise uia linalyl pyrophosphate (3), although this was not found in the mixture (see Scheme l).5

1

2

1

OPO(OPh),

terpenes

+ cyclic terpenes

(3)

Scheme 1

Working with orange juice vesicles, Potty and Bruemmer have isolated‘ an enzyme, geraniol dehydrogenase, that maintains the equilibrium between aldehyde and alcohol. The presence of a second enzyme that saturates one of the double bonds in this system to citronella1 and citronellol is inferred. The same authors have also demonstrated’ the presence of enzymes which convert mevalonate to linalyl pyrophosphate, suggesting that citrus fruits synthesise terpenoids from mevalonate by this route. The r6le of cyclopentanoid monoterpenoids in the biosynthesis of indole alkaloids is discussed in Chapter 6. 2 Acyclic Monoterpenoids

2,6-Dimethyloctau~-Dembitskii et al. have reported*-9 the isolation of a rather unusual hydrocarbon, cis-2,6-dimethylocta- 1,4,7-triene (4), from the plant Achilla$lipendulina, the configuration about the cis-double bond being ascribed mainly on the basis of i.r. spectra. This recalls ‘hymentherene’ that had been

’

R. C. Haley, J. A. Miller, and H. C. S. Wood, J . Chem. SOC.(C), 1969,264. V. H. Potty and J. H. Bruemmer, Phytochemistry, 1970,9, 1003. V. H. Potty and J. H. Bruemmer, Phytochemistry, 1970,9, 1229. A. D. Dembitskii, R. A. Yurina, L. A. Ignatova, and M. I. Goryaev, Khim. Prirod. Soedinenii, 1968,4,25 1. A. D. Dembitskii, R. A. Yurina, L. A. Ignatova, and M. I. Goryaev, Izoest. Akad. Nauk Kazakh. S.S.R.,Ser. Khim., 1969, 19,49.

Monoterpenoidr

9

reported as a natural product [2,6-dimethylocta-2,4,7-triene,(511, l o but which was subsequently shown to be a mixture of known monoterpenes." That achillene (4) is a natural product is, however, supported by a synthesis of the olefin (4).12 The same Russian group has also reported the alcohol achillenol (6).13

Me

A

HoA

Dehydrolinalool (7),one of the intermediates in the synthesis of linalool and vitamin A, does not react with formic acid to give the expected arb-unsaturated aldehyde or ketone, but forms instead the tetrahydropyran (8), together with the acetylcyclohexene(9).14

3,7-Dimethyl-l,5,7-octatrien-3-01 [( 15) = R-isomer)] has been found naturally in both chiral forms. The 3S-(+)-enantiomorph occurs in Japanese Ho leaf oil (whence its trivial name, hotrienol),*' while the R-isomer has been isolated from black teal6 and green tea." The R-isomer (15) was synthesised from Rlinalyl acetate (10) by bromination with N-bromosuccinimide, giving three allylically brominated acetates (ll), (12), and (13), which all lead to the acetate (14) of the desired alcohol by dehydrobromination with diethylaniline.'6 The lo

' l3

U. G. Nayak, Sukh Dev, and P. C. Guha, J . Indian Chem. SOC.,1952,29,23. Sukh Dev, personal communication. K.-H. Schulte-Elte, personal communication. A. D. Dembitskii, R. A. Yurina, and M. I. Goryaev, Khim. Prirod Soedinenii, 1969, 5,443.

l4

'

l6

D. Merkel, Z . Chem., 1969,9, 63. T. Yoshida, H. Kawamura, and A. Komatsu, Agric. and Biol. Chem. (Japan), 1969,33, 343. Y. Nakatani, S. Sato, and T. Yamanishi, Agric. and Biol. Chem. (Japan), 1969, 33, 967.

l7

T. Yamanishi, M. Nose, and Y. Nakatani, Agric. and Biol. Chem. (Japan), 1970, 34, 599.

* This oil also contains tagetonal, ( +)-3,7-dimethyl-3-hydroxy-l-octen-5sne.

Terpenoih and Steroids

10

same alcohol (15) had been synthesised, even before its discovery as a natural product, by dehydrating with sulphuric acid in acetone one of the glycols (17) obtained by sensitised photo-oxidation of linalool(16).'*

Br CH2Br

5 0 H

+

k""

BrCH,

i

PhNEt,

6 0 H I O H

Dihydrotagetone (25), occurring in the plant Tagetes glandufifera (Compositae), has been synthesised by three new routes (although these are by no means the first), one of which also leads to the natural tagetone (24)." Teisseire and Corbier start from the enol ethers (18)and (19) of 4-methylbutan-2-one,which react with but-2-ynol in the presence of potassium hydrogen sulphate to give the two allenic ketones (22) and (23) by way of a Claisen reaction of the initially formed acetylenic ethers (20) and (21). When the mixture of allenones is treated with base, only the desired one (22), present in the mixture to the extent of 65 %, rearranges to a mixture of cis- and trans-tagetones (24) in about 45% yield based on the butynol (cis-tagetone being the principal natural product). Using crotyl alcohol in place of the acetylenic alcohol, the synthesis yieldsIg a difficultto-separate mixture of dihydrotagetone [(25),60%] and the two stereoisomers of the undesired ketone (26). Two additional conventional syntheses'' of dihydrotagetone are illustrated in Scheme 2. A certain number of well-known reactions in this series have been reinvestigated. Sasaki et al. have discussed the Diels-Alder 1,4-cycloaddition reactions of myrcene (27), comparing its activity with other dienes, in particular isoprene.' l8

l9 2o 21

T. Matsuura and Y. Butsugan, Nippon Kagaku Zasshi, 1968,89, 513. P. Teisseire and B. Corbier, Recherches, 1969, 17, 5. 0.P.Vig, K. L. Matta, M. S. Bhatia, and R. Anand, Indian J. Chem., 1970,8, 107. T. Sasaki, S. Eguchi, and T. Ishii, J . Org. Chem., 1969,34, 3749.

Monoterpenoidr

11

MeCH =CHCH,OH + KHSO,

MeC -CCH,OH + KHSO,

1

I

9

(24) cis trans

+

0

1,3-Cycloaddition of benzonitrile oxide (28) to myrcene (27) occurs with reaction at both the conjugated double bonds, yielding the two adducts (29)and (30). The less reactive 1,3dipoles, diazomethane,diphenylnitrilimine, and phenyl- and p-toluenesulphonyl-azide,were unreactive.’ A different type of addition reaction (involving a n-complex) to the double bonds of myrcene is that of trichlorosilane,which, in the presence of chloroplatinic 22

T. Sasaki, S. Eguchi, and T. Ishii, Bull. Chem. SOC.Japan, 1969,42, 558.

12

Terpenoidr and Steroids

I

i; Wittig

ii; H +

acid catalyst, gives 1,2- and 1,4-monoadducts of the conjugated double bond system (the former predominating), together with a 1,2 :3,4-diadduct. The third double bond only reacts at 105 “C and elevated pres~ure.’~

Ph

Ph (29)

(30)

The epoxidation of alloocimene (31)has been shown to involve an intermediate polymeric peroxide (32) that gives the known diepoxides (33) and (34)by thermal rearrangement, a reaction which leads also to 4-methylhexa-2,4-dienal (35) and 6-methylhepta-3,5-diene-Zone(36).24 Because of the ready availability of very pure geraniol (37) and nerol (40) of defined configuration, Stork et d.have used them to prepare olefins of specific geometry. The first stage depends on the fact that the acetates can be cleaved by ozone specifically at the trisubstituted double bond,25 leading to the aldehyde acetates which are isolated as their dimethyl acetals (38)and (41). The corresponding chloroacetals (39) and (42)were more difficult to obtain without isomerisation of the double bond, but when the alcohol in ether-hexamethylphosphoramide (2 : 1) was treated with commercial methyl-lithium in ether, followed by p 23

” ”

L. D. Nasiak and H. W. Post, J . Organometallic Chern., 1970,23, 91. T. Suhadolc and D. Hadfi, Annalen, 1969,730, 191. G . Stork, M. Gregson, and P. A. Grieco, Tetrahedron Letters, 1969, 1391.

Monof erpenoids

13

$

+

+ fcoMe

CHO (36)

(35)

toluenesulphonyl chloride and lithium chloride in the same solvent mixture, good yields of the corresponding chlorides (39) and. (42) were obtained without isomerisation.26 i ; Acetylate

CH,OH

iii; ii; 0, MeOHXaClt

M

e

e CH2R

O

Me0 (37)

(38; R (39; R

= =

OH) C1)

(41 ; R = OH) (42; R = C1)

Non-Isoprenoid Monoterpenoids.-There has been activity in the field of monoterpenoids formally related to chrysanthemic acid (43) and belonging to the ‘odd’ artemesyl (44),santolenyl (45), and lavandulyl (46) groups where the customary ‘head-to-tail’ linkage of isoprene units is not followed. Yomogi alcohol (47), the allylically rearranged artemisia alcohol (5 1),27,28 has been isolated from Artemisia feddei. The santolinyl class now includes two alcohols, 26

2’ 28

G. Stork, P. A. Grieco, and M. Gregson, Tetrahedron Letters, 1969, 1393. K. Yano, S. Hayashi, T. Matsuura, and A. W. Burgstahler, Experientia, 1970,26, 8. B. Willhalm and A. F. Thomas, Chern. Comm.,1969, 1380.

Terpenoidr and Steroih

14

lyratol (46) from Cyathocline l y r a t ~and ~ ~ 2,5-dimethyl-3-vinylpent4-en-2-ol (49), from Moroccan camomile, Ormenis rnultic~ulis.~~ Artemisia alcohol (51) has been synthesised by a sigmatropic rearrangement of the ylide derived from di-isopentenyl ether (50),31,32 a reaction that has given rise to some speculation about the biogenesis of these ‘odd’ terpenes.

(47)

(48)

(49)

It had been suggested that they might all be derived from the chrysanthemic acid (43 ;R = H) skeleton which, by opening of one of the bonds of the cyclopropane ring, can lead to either (M),(49, or (46), and, indeed, several conversions of the chrysanthemyl skeleton to the ‘odd’ monoterpene skeletons have been effected in the laboratory. The most recent consists of irradiation of chrysanthemol(52) with a high-pressure mercury lamp which yields lavandulol (53) and 3-methyl-but-2-en01 (54), each in about 20% yield.35 Discovery of sigmatropic reactions of the thioether corresponding to the ether (50) already mentioned, led to the speculation that the artemisia skeleton could conceivably be formed in nature by an analogous p r o c e ~ s . ~ Under ~ * ~ ’ these circumstances it is not necessary to involve chrysanthemyl structures directly in the biogenetic chrysanthemol(52) with a high-pressure mercury lamp which yields lavandulol 29

30

0. N. Devgan, M. M. Bokadia, A. K. Bose, G. K. Trivedi, and K. K. Chakravarti, Tetrahedron, 1969, 25, 3217. Y. Bessiere-Chrttien, L. Peyron, L. Btntzet, and J. Garnero, Buff. SOC.chim. France, 1968,2018.

31

31

33 34

35 3b

V. Rautenstrauch, Chem. Comm., 1970,4. J. E. Baldwin, J. DeBernardis, and J. E. Patrick, Tetrahedron Letters, 1970, 353. R. B. Bates and S. K. Paknikar, Tetrahedron Letters, 1965, 1453. L. Crombie, R. P. Houghton, and D. K. Woods, Tetrahedron Letters, 1967,4553. T. Sakai, S. Eguchi, and M. Ohno, J . Org. Chem., 1970,35, 790. G. M. Blackburn, W. D. Ollis, J. D. Plackett, S. Smith, and 1. 0. Sutherland, Chem. Comm., 1968, 186.

3’

J. E. Baldwin, R. E. Hackler, and D. P. Kelly, Chem. Comm., 1968, 1083.

Monoterpenoids

15

pathway to the 'odd' groups since a homoallylic cation [e.g. (56)]can, in principle, by the precursor of any one of them and, indeed, yomogi alcohol (47) has been converted to compounds of the santolinyl group, (57), (58), and (59), by acidcatalysed ring-opening of the epoxide (55).38

Synthesis of yomogi alcohol (47) was achieved by sensitised photo-oxidation of the hydrocarbon (61) obtained2' by the Wurtz coupling (using magnesium) of 3-methylbut-2-enyl chloride (60). It has also been made from the known3' 2,2-dimethylbut-3-enal using a Wittig reaction ;40 the latter publication also reports a synthesis of the structure (62),at one time believed to represent yomogi alcoh01.~' Researches on chrysanthemic acid and its derivatives are usually oriented to synthesising esters of trans-chrysanthernic acid, many of which are naturally occurring (and are, therefore, presumably biodegradable) insecticides. The synthesis of pyrethric acid or its mono-ester (65) from chrysanthemic acid has been carried out in two laboratories. Ueda and Matsui prepared all four 38 39 40 4'

A. F. Thomas, Chem. Comm., 1970, 1054.

M. Julia and M. Baillarge, Bull. SOC.chim. France, 1966, 734. W. Sucrow, Tetrahedron Letters, 1970, 143 1. S. Hayashi, K. Yano, and T. Matsuura, Tetrahedron Letters, 1968, 6241 ; cf. Ann. Reports (B), 1968, 65, 412.

geometrical isomers of ( fkpyrethric acid by converting cis- or trans-methyl chrysanthemate into the corresponding aldehyde [e.g. (63 ;R = Me), for the transconfiguration] and condensing the appropriate side-chain with the phosphonate (&I Martel )." and ' B ~ e n i d ahave ~ ~ followed the same procedure, first without isomerisation at the chiral centres [(lR, 2R)], then adapting the synthesis to the methyl ester of the enantiomeric chrysanthemic acid [(lS, 2S)](43a; R = Me), a residue from the resolution4" of the racemic acid, following Scheme 3. Crombie et al. also used the same route from the aldehyde (63; R = Me) to make 14Clabelled methyl chrysanthemate by reaction with the appropriately labelled Wittig reagent.45

*

Me

1

0 3

R0zc\4/H

H'

(43; R

=

CHO

(EtO),POCHCO,Me

H)

1

1

A

H02c&

0

42 43

4*

45

C02Me

K. Ueda and M. Matsui, Agric. and Biol. Chem. (Japan), 1970,34, 1119. J. Martel and J. Buendia, I.U.P.A.C. Meeting, Riga, U.S.S.R., 1970, Abstracts E 112, p. 572. L. Velluz, J. Martel, and G. Nomine, Compt. rend., 1969, 268C, 2199. L. Crombie, C. F. Doherty, and G. Pattenden, J. G e m . SOC.(0,1970, 1076.

17

Monoterpenoids

SOCI, (epimerizes C-1)

clocd? ‘‘.d

c------------

“$4 C02Me

C0,Me

1

H& H02C’

Scheme 3

The problem of the utilisation of the ‘wrong’ chrysanthemic acid [i.e. the (lS, 2s) isomer] has also been dealt with by Ueda and M a t s ~ i They . ~ ~ used the pyrolysis product pyrocine (66) from chrysanthemic acid, and succeeded in racemising it by a fairly lengthy sequence of reactions. Conversion of cis-chrysanthemate esters to trans-esters is most easily carried out (for the methyl esters) by pyrolysis of the cis-ester at 240-260 “C, when the trans-ester is obtained in good yield.47 Telomerisationof Isoprene.-The synthesis of monoterpenoids by telomerisation of isoprene is being studied especially in Russia and Japan, and a review (in Russian) of telomerisation using the isoprene-hydrogen chloride adduct has been published.48The C,, fraction contains, under certain conditions, 45 % of geranyl chloride that can be isolated as the urotropin adduct for further reactions.49 Phosphoric acid telomerisation of isoprene, on the other hand, gives mostly a-terpinene and alloocimene as the main C,, hydrocarbons, together with geraniol and terpine01.~’In the presence of acetic acid, linalyl,geranyl, lavandulyl, and other acetates are formed in the phosphoric acid reaction, together with, of course, many of the monoterpene hydrocarbons.” It has been reported” that a C , alcohol (67)occurs in the mixture produced by the phosphoric acid reaction of isoprene. In the absence of the Japanese text, this abstract should be treated with caution. Perchloric acid treatment of isoprene can be made to give a low yield of 2,2,6-trimethyl-6-viyltetrahydropyran(68).52 46

47 48

4y

50

51

52

K. Ueda and M. Matsui, Agric. and Biol. Chem. (Japan), 1970,34, 1 115. T. Hanafusa, M. Ohnishi, M. Mishima, and Y . Yukawa, Chem. andInd., 1970, 1050. K. Laats, Eesti NSV Teaduste Akad. Toimetised, Keem., Geol., 1968, 17, 355 (Chem. Abs.. 1969, 70, 58034). I. B. Kudryavtsev, K. Laats, and M. Tali, Eesri NSV Teaduste Akud. Toimetised, Keem., Geol., 1968,17, 361 (Chem. Abs., 1969,70, 58034). J. Tanaka, T. Katagiri, and H. Okawa, Nippon Kugaku Zusshi, 1969,90, 204 (Chem. Abs., 1969,71, 13216). J. Tanaka, T. Katagiri, and H. Okawa, Nippon Kagaku Zusshi, 1970,91, 156 (Chem. Abs., 1970, 73, 25672). Kogyo Gijutsu Incho, Jap. Pat. 68 11893.

Terpenoih and Steroids

18

In the presence of lithium naphthalene in tetrahydrofuran, isoprene is dimerised to linear monoterpene homologues,s3 and oxidation of the mixture by passage of oxygen gives 3 0 - 4 % of C1 alcohols and 30 % of C1 glycols. Of the monohydric alcohols, 10% nerol and 10% geraniol are obtained in addition to 5 % of 2,6-dimethylocta-1,7-dien-6-01 (69) and 55 % 2,7-dimethylocta-2,6-dien-l-ol (70), with 20% unidentified product. The glycols are 50% each of 2,6- and 2,7-dimethylocta-2,6diene-l,8-diol(71) and (72). Boration of the reaction mixture (boron trifluoride etherate) and hydrogen peroxide treatment of the organoboranes leads to the same C l oalcohols in slightly different proportion^.'^

3 Monocyclic Monoterpenoids Cyclobutane.4e of the most interesting novelties recently discovered is a monoterpene representative of the cyclobutanes (apart from the bicyclic systems containing cyclobutanes). The sex attractant of the male boll weevil (Anthonornus grandis, Boheman) was identified as the cis-substituted cyclobutane (73),55a stereospecific synthesis of which (Scheme 4) was reported shortly afterwardss6 Cyclopentanes.-Several new iridanes have been isolated recently : theveside (74)57and its methyl ester5*from the apocynaceous species, Thevetia peruviana (Pers.) K. Schum, and the Cg iridoid glucoside galiridoside (75) from Galeopsis tetrahit L. (labiatae).59 A rich source of iridoid ester glycosides is the valerian 53

K. Suga, S. Watanabe, T. Watanabe, and M. Kuniyoshi, J . Appl. Chem., 1969, 19,

54

318. S. Watanabe, K. Suga, and T. Watanabe, Chem. and fnd., 1970, 1145.

J. H. Tumlinson, D. D. Hardee, R. C. Gueldner, A. C. Thompson, P. A. Hedin, and P. Minyard, Science, 1969, 166, 1010. st, R. Zurfliih, L. L. Dunham, V. L. Spain, and J. B. Siddall, J . Amer. Chem. Soc., 1970, 92, 425. 5’ 0. Sticher, Tetrahedron Letters, 1970, 3 195. 0. Sticher and H. Schmid, Hefv. Chim. Acta, 1969, 52, 478. 5 9 0. Sticher, Tetrahedron Letters, 1970, 3197. 55

Monoterpenoids

II

CH2

CH2

+

'0 0

9

19

PhN+Me,Br;,

H O

0

Br

J

Li $0 in Me,CONMe,

J

OsO,-NaIO,

plant species,60the latest glycoside reported being valerosidatum (76) which was isolated from Valerianu waflichii and V. oficinalis.6' Although they are not cyclopentane terpenoids, the glycosides morronoside (77) and kingoside (78), isolated from the fruit of Lonicera morrowii, A. Gray,62 and loniceroside (79) and the previously known sweroside (80),isolated from the leaves of the same plant,63 are closely related to the other iridanes. An excellent summary of this type of glycoside has been compiled by Bobbitt and Segebarth.64

'' P. W. Thiess, Planta medica, 1968, 16, 361. b'

62 63 64

P.W. Thiess, Tetrahedron Letters, 1970, 2471. I. Souzu and H. Mitsuhashi, Tetrahedron Letters, 1969, 2725. I. Souzu and H. Mitsuhashi, Tetrahedron Letters, 1970, 191.

J. M. Bobbitt and K.-P. Segebarth in 'Cyclopentanoid Terpene Derivatives', eds. W. I . Taylor and A. R. Battersby, Marcel Dekker, New York, 1970, p. 1.

20

Terpenoih and Steroitls C02Me

C02Me

OHC

o* H o

O 0-/?-glucose

(77)

Z

fi

C02Me

0 0-8-glucose

&/?ogl

(78)

ucose

(79)

$ 0-8-glucose

(80)

(83 ; R = 8-glucose) (84; R = gentiobiose)

It has been shown that 7deoxyloganic acid (81) is a precursor of various iridogluc~sides.~~ Feeding experiments on the plants Gardinia jasminoides and Puederia scandens have shown that the acid is incorporated into the iridoglucosides of these plants and a biogenetic scheme is proposed.66 Iridoglucosides recently isolated from the plant Gardinia jasrninoides are gardenoside (82) and geniposide (83),67while from the fruit, genipingentiobioside (84) has been isolated.68 Recently, small amounts of deacetylasperulosidic acid methyl ester (85), as well as the new iridoglucoside shanzhiside (86)' have also been found in the plant.69 The synthetic achievement of the year in this field is certainly the synthesis of loganin penta-acetate (95) by Buchi et al. (Scheme 5).70 Using an extension of de Mayo's method for the synthesis of &diketones by photochemical cycloaddition of enolized /I-diketones to ole fin^,^ Buchi's group constructed the 65

66 67

" 69 70

''

H.Inouye, S. Ueda, and Y. Takeda, Z. Naturforsch., 1969,24b,1666. H.Inouye, S. Ueda, and Y. Takeda, Tetrahedron Letters, 1970,3351. H. Inouye, S. Saito, H. Taguchi, and T. Endo, Tetrahedron Letters, 1969,2347. T. Endo and H. Taguchi, Chem. and Pharm. Bull., 1970,18,1066. H. Inouye, S. Saito, and T. Shingu, Tetrahedron Letters, 1970,3581. G.Buchi, J. A. Carlson, J. E.Powell,jun., and L.-F. Tietze, J. Amer. Chem. Soc., 1970, 92,2165. B. D. Challand, H. Hikino, C. Kornis, G. Lange, and P.de Mayo, J. Org. Chem., 1969, 34,794.

21

Mono terpenoids

bicyclic part in a single photochemical operation. The starting materials required are 2-formylmalonaldehydic acid methyl ester (87), obtainable in two steps from keten and trimethyl orthoformate, and 3-cyclopentenyl tetrahydropyranyl ether (88). Irradiation followed by treatment of the crude products with Amberlite IR-120 cation exchange resin gives a mixture of the liquid hydroxyacetals (89). Oxidation makes it possible to isolate the desired ketone (90) as CH,=C=O

MeO, ,CHCH2C02Me

--+

+ HC(OMe),

Me0

/

1

HCO ,Me-Na

HoYcHo C02Me (87)

(88)

+HO

c-------

oGooGo - eo SC~HQ OMe

OMe

lRaney

(91) 92 %

Ni

COzMe

(92)

H C02Me

C02Me

YMe,

OMe

OMe

iiz;:te

AcO

OMe

OMe

(93)

(94)

J

i ; HCIO,-ag. HOAc ii; glucose tetraacetate (Low yield)

H

OAc (95)

Scheme 5

OAc

22

Terpenoih and Steroids

the major product by crystallisation. Luckily, formation of the butylthiomethylene derivative (91) occurs mainly on the side of the carbonyl group where it is desired to introduce the methyl group. Raney nickel desulphurisation leads to the wrong methyl epimer (92), but this can be isomerised by base to the one desired (93). Borohydride reduction, acetylation, and glucosidation lead to loganin penta-acetate (95). A review by C a ~ i lsummarises l~~ the earlier literature of the simpler iridoids. From the chrysope-attracting plant Actinidia polygarna several ethers have been obtained,73 some of which have been synthesised by two group^.'^*^^ The

I

i : LiAIH, ii; Ac,O iii; hydroboration, etc.

TCH2OH

1 (97)

(98)

72

73 74

0 Scheme 6 (96) G. W. K. Cavill, in 'Cyclopentanoid Terpene Derivatives', eds. W. I. Taylor and A. R. Battersby, Marcel Dekker, New York, 1970, p. 203. J. Wolinsky and D. Nelson, Tetrahedron, 1969,25,3767. S. Isoe, T. Ono, S. B. Hyeon, and T. Sakan, Tetrahedron Letters, 1968, 5319.

Monoterpenoids

23

synthesis of matatabiether (Scheme 6) follows practically the same route used in both laboratories, but Wolinsky's group has described the further synthesis of the other compounds shown in the scheme, notably neonepetalactone (96) and the ethers (97) and (98), which also occur naturally.

p-Menthanes.--(i) Hydrocarbons. The interconversions of p-menthadienes with acids or bases under various conditions have, of course, been known for a very long time, but the most recent information,together with a collection of references, is to be found in a paper by Bates et that also discusses the conditions required for avoiding excessive aromatisation to p-cymene (103). The instability of the isopropenyl side-chain compared with the saturated isopropyl side-chain is constantly reflected in the increased number of side reactions, particularly disproportionations, that can occur when menthadiene derivatives are treated with acidic reagents. One of the latest examples is described by Kergomard et al. in an account of the kinetics of acetolysis of carveyl ethers.76 When trans-pmenth-1(7)-en-2-y1 ethyl ether (99) is treated with a trace of perchloric acid in acetic acid, the main product is the expected phellandryl acetate (loo), but trans-p-mentha-1(7),8-dien-2-~1 ethyl ether (101) under the same conditions yields 40% of carvenone (102) and 30% of p-cymene (103), a trace of the interethyl ether (104) having been identified.76 mediate mentha-1(7),4(8)-dien-2-~1

0

@HC104-HOAc

A

A (99)

HC104-HOAc,

CH,OAc

& A

+

A

+

P

O

E

t

Since mentha-1,3,8-triene(107) was isolated from parsley, and suspected to be partly responsible for the odour of the plant,77 it has been synthesised in two l a b o r a t ~ r i e but s ~ ~in~fact ~ ~ the odour, though reminiscent of parsley, does not 75

76

R. B. Bates, E. S . Caldwell, and H. P. Klein, J . Org. Chem., 1969, 34, 2615. A. Kergomard, J. C. Tardivat, H. Tautou, and J. P. Vuillerme, Tetrahedron, 1970, 26, 2883.

77

J. Garnero, L. Bknezet, L. Peyron, and Y. Chretien-Bessi2re. Bull. SOC.chim. France, 1967,4679.

78 79

A. J . Birch and G . Subba Rao, Austral. J . Chem., 1969, 22, 2037. A. F. Thomas and W. Bucher, Helu. Chim. Acta, 1970,53, 770.

24

Terpenoids and Steroids

have the power of the natural material.” A problem of purification stems from the fact that when formed by pyrolysis of the acetates (105)or (106)the triene (107) is always mixed with its isomers (108) and (109). (The method used by Birch and Subba Rao led to a similar mixt~re.’~) This mixture requires chromatographic separation on two different columns in order to obtain the pure substance~.’~Mentha-1,5,8-triene (110) has been described for the third time.80 The two earlier publications*’’82did not give full n.m.r. support for the structure.

t. Pyrolysis

(107)

Q

Seo2+

( 109)

(108)

3 a’” 9 +

QH+

,’CH20H (111)

(112)

T gzgs

(113)

(1 14)

-0

Q(1=15) H$h4e2

Q(1 16) H 8o

82

J. M. Coxon, E. Dansted, M. P. Hartshorn, and K. E. Richards, Tetrahedron, 1969, 25, 3307. Y.-R.Naves and A. V. Grampoloff, Bull. SOC.chim. France, 1960,43. W. G. Dauben, M. E. Lorber, N. D. Vietmayer, R. H. Shapiro, J. H. Duncan, and K. Tomer, J. Amer. Chem. SOC.,1968,’90, 4762.

Mono terpeno ids

25

(118)

(117)

( 1 1%

The oxidation of limonene (111) by selenium dioxide has been studied in three laboratories and, using hydroxylated solvents, the major product is mentha- 1,8dien-4-01” (112),79*83184 in agreement with the results from the selenium dioxide oxidation of carvone (117) where the main product is also the 4-hydroxyThe mechanism giving rise compound (118), also with loss of chirality at C-4.88 to the secondary chiral products trans-cameo1 (113) and mentha-1,8dien-lO-o1 (114) has been shown to occur by way of an allylic selenite e~ter.~’,~’ The reaction is very dependent upon solvent and, if carried out in acetic anhydride, for example, the main product is mentha-1,8-dien-lO-yl acetate (119);79*89 this compound also occurs naturally in the peel oils of Citrus u n s h ~ , ~Valencia ’ orange,g0and Citrus j ~ n o s . ~ ~

c1

(122)

1

KOH-MeOH on

( 120)

p -nitrobenzoate

(121)

( 124)

OH

(123)

1

KOH-MeOH

(125)

Y . Sakuda, Bull. Chem. SOC.Japan, 1969,42, 3348. 8 4 E. N. Trachtenberg and J. R. Carver, J. Org. Chem., 1970, 35, 1646. 8 5 T. Sakai, K. Yoshihara, and Y . Hirose, Bull. Chem. SOC.Japan, 1968,41, 3348. 86 N. Shinoda, M. Shiya, and K. Nishimura, Agric. and Biol. Chem. (Japan), 1970, 34, 234. J. Leffingwell, Fr. Pat. appl. No. 2,003,498 (Chem. A h . , 1970, 72, 100934). 81( G. Buchi and H. Wuest, J. Org. Chem., 1969,34, 857. 8 9 Y. Kita, Y. Nakatani, A. Kobayashi, and T. Yamanishi, Agric. and B i d . Chem. (Japan), 1969,33, 1559. M. G. Moshonas and E. D. Lund, J. Food Sci., 1969, 34, 502. 83

* This comparatively recently described compound is a natural product, occurring in Japanese pepperE5and Citrus junes and has also been obtained by Leffingwell from terpinolene epoxide ( 1 1 5) by ring opening of the epoxide with dimethylamine, then thermolysis of the N-oxide. Raney nickel catalysed selective hydrogenation of metha-1,8-dien-4-01 ( I 12) leads to the widely occurring menth-I-en-4-01 (1 16).”

26

Terpenoicis and Steroids

The products of peracid oxidation of limonene have also been re-examined. Wylde and Teulon have shown” that the best method for making pure cisor trans- limonene 1,2-epoxides,* a mixture of which is obtained by direct peracid oxidation in chlorinated hydrocarbon solvents, is to treat this mixture with hydrogen chloride in ether, when the two diaxial chlorohydrins (122) and (123) are obtained with practically no equatorially substituted isomers. Of these two isomers only (122) forms a p-nitrobenzoate, allowing (123) to be distilled from the residue. Treatment of the nitrobenzoate of (122) with methanolic potassium hydroxide now leads to the cis-epoxide (120); similar treatment of ~ other possible limonene epoxides (123) yields the trans-epoxide ( l ~ ) .The (124) and (125) are now also accessible directly from limonene by treatment of the hydrocarbon with hydrogen peroxide in the presence of b e n ~ o n i t r i l e a, ~ ~ method originally due to P a ~ n e . ’ Although ~ the yield is very poor, the products being contaminated with benzonitrile and the 1,2-epoxides, the fact that the synthesis is one-step and gives products readily separable by distillation makes it a useful route to menthanes oxygenated in the isopropyl group. The reaction of limonene-l,2-epoxides, either pure” or as a mixture,94 with bases like aluminum alkoxides9’ to give ally1 alcohols has been examined, and the similar reaction with propyl-lithium of 1,2-epoxy-trans-p-menthane and the menthane-2,3-epoxide (126), yielding (127) and (128) has also been

Allylic oxidations of the menthadiene system are still of interest because it would be economically useful to have a really cheap method for obtaining carvone from limonene. One of the more effective methods recently described makes use of the chromium trioxide-pyridine complex in methylene chloride9’ which Dauben et al. found to give 36% of carvone (130)and 33 % of isopiperitenone (129).98 Perhaps if the same technique were applied in the oxidation of R. Wylde and J.-M. Teulon, Bull. Soc. chim. France, 1970, 758. G. Farges and A. Kergomard, Bull. Soc. chim. France, 1969, 4476. 9 3 G. B. Payne, Tetrahedron, 1962,18, 763. 9 4 E. H. Eschinasi, Israel J . Chem., 1968, 6, 713. 9 5 E. H. Eschinasi, J . Org. Chem., 1970, 35, 1598. 9 6 H. Kuczynski and K. Marks, Rocrniki Chem., 1968,42, 647. 9 7 J. C. Collins, W. W. Hess, and F. J. Frank, Tetrahedron Letters, 1968, 3363. 9 8 W. G . Dauben, M. Lorber, and D. S. Fullerton, J . Org. Chem., 1969,34, 3587. * In this context cis and trans refer to the alkyl substituents of the menthane skeleton; thus the cis-epoxide has the oxirane ring on the side of the cyclohexane ring opposite to the isopropenyl group (1 20). 91

92

Mono terpenoids

27

car-3-ene (131), the large number of products resulting from conventional techniques of chromium trioxide oxidation” could be minimised.

Another allylic oxidation reported in this series is that by the tristriphenylphosphinechlororhodium catalyst which gives carvotanacetone (133) and piperitone (134) with loss of chirality, presumably through the symmetrical intermediate (132). O0 A novel oxidising agent giving rise to singlet oxygen has been described by Murray and Kaplan. Phosphite esters and ozone give the compound 0

/ \ (RO), P\ ,0, and this appears to react in the same way as singlet oxygen.

0

The oxidation of p-cymene (103) usually gives rise to carvacrol(139) contaminated with varying amounts of thymol (140), but thallium trifluoroacetate in trifluoroaceticacid gives a thallium organic compound (137)that can be converted 99

M. S. Carson, W. Cocker, D. H. Grayson, and P. V. R. Shannon, J . Chem. SOC.(C), 1969,2220.

loo lo’

J . E. Baldwin and J. C. Swallow, Angew. Chem. Internat. Edn., 1969, 8, 601. R. W. Murray and M. L. Kaplan, J . Amer. Chem. SOC.,1969,91, 5 3 5 8 .

28

Terpenoih and Steroids

by lead tetra-acetate followed by triphenylphosphine into carvacrol trifluoroacetate (138). Sodium hydroxide hydrolysis then gives carvacrol (139) of high purity, although only in 39 % yield.'02

(103)

-

The xylene-sensitized photochemical addition of hydroxylic compounds (water or alcohols) to limonene has been described in further detail by Kropp. A 1.2 : 1 mixture of cis- and trans-fl-terpineol (142a,b; R = H) is obtained on irradiation of an aqueous solution containing a trace of xylene, or the corresponding methyl ethers (142a,b; R = Me) when methanol is the solvent. A trace of mentha-1(7),8-diene (143) and extensively racemised limonene is also found, supporting the idea that the reaction goes through the symmetrical carbonium ion (141).'03

3 lo*

lo'

E. C. Taylor, H. W. Atland, R. H. Danforth, C. McGillivray, and A. McKillop, J. Amer. Chem. SOC.,1970, 92, 3520. P. J. Kropp, J. Org. Chem., 1970, 35, 2435.

Mono terpeno ids

29

(ii) Oxygenated p-Menthunes. A variety of menthadien-l- and 2-01s have been identified in celery oi1;'04 it is noticeable that they are all products of photooxidation of limonene. Both cis- and truns-p-mentha-l(7),5-dien-2-01 (144) are reported"' from the essential oil of Cinnarnomurn japonicurn Sieb. and called 'yabunikkeols' (from the Japanese name of the plant) but the structures are unsupported by n.m.r. data. Some of the beliefs widely held about the flavour of 7-oxygenated p-menthanes have been contested recently. One of the longest standing is that there are two oximes (syn and anti) of perilla aldehyde (145) and that only the syn-oxime is sweet tasting. Acton has shown that there is actually only one oxime of perilla aldehyde (it is indeed sweet).' O6 It has been suggested that the cumin-like odour associated with cumin aldehyde (146) actually arises in cumin seeds from the dihydroaldehyde (147). Varo and Heinz have shown how this type of compound is very labile, and injection of the pure dihydroaldehyde (147) into a gas chromatograph gives three peaks, disproportionation to the tetrahydrocuminaldehyde (148) and to cuminaldehyde itself occurring during evaporation. They state that the main naturally occurring aldehyde in fresh cumin seeds is the dihydrocompound (147). The alternative dihydroaldehyde (149) also occurs in cumin seeds [it has the same retention time on most g.1.c. columns as its isomer (147)], as does the corresponding alcohol (150).' O 7

Another new aldehyde was recently isolated from the oil of Rosa darnascena (Bulgarian rose oil),and shown to be menth-l-en-Pal, a mixture of both diastereoisomers (152) and (153) being present in the natural product."' By oxidation of the hydroboration products of (+)-limonene (111) (see also ref. 109), both C. W. Wilson, tert., J. Food Sci., 1969, 34, 535. Y. Fujita, S. Fujita, and H. Yoshikawa, Bull. Chem. SOC.Japan, 1970,43, 1599. l o 6 E. M. Acton, H. Stone, M. A. Leaffer, and S. M. Oliver, Experientia, 1970, 26, 473. l o ' P. T. Varo and D. E. Heinz, J. Agric. Food Chem., 1970,37, 378. l o * G. Ohloff, W. Giersch, K.-H. Schulte-Elte, and E. sz. Kovats, H e h . Chim. Acta, 1969,52, 1531. Io9 B. A. Pawson, H.-C. Cheung, S. Gurbaxani, and G. Saucy, J . Amer. G e m . SOC.,1970, 92, 336. Io4

'05

30

Terpenoih and Sterouis

diastereoisomers were prepared, and a series of related 9-oxygenated p-menthane derivatives was correlated with the natural products. lo*

OHC (111)

oxidiseC

* HOCH,

I."

A

The stereochemistry of various reactions with 2- and 3-oxygenatedp-menthanes has been examined, in some cases hardly for the first time. Sodium borohydride reductions of menthone (15 9 , piperitone (134), piperitenone, and pulegone (154) under various conditions have been reported.' l o The methylation of pulegone (154) gives a more complex mixture than previously believed, but not all the products were identified." Optical rotatory dispersion and circular dichroism of the pulegone epoxides have been exhaustively discussed.' ' Reaction of acetylene with menthone (155) and carvomenthone (157) has been shown to give in each case slightly more of the epimer having an axial hydroxy-group [57 : 43 of (1 56) in the case of menthone, 54 : 46 of (158) in the case of carvomenthone].' '

lo l1

H. Rothbaecher and F. Suteu, Pharmazie, 1969, 24, 222. T. J. de Pascual and A. R. Aguado, Anales de Quim.,1969,65,47. T. M. Feeley and M. K. Hargreaves, J . Chem. Soc. (C),1970, 1745. J. Kulesza and J. Gora, Rocrniki Chem., 1969,43, 955.

Mono terpenoih

31

The addition of carbene (from dimethyloxosulphonium methylide) to carvone (130) to yield (159) has been shown to be stereospecific"4 in the same sense as other addition reactions of carvone. The addition of bromine to carvone hydrobromide yields trans-carvone tribromide (1Ma), which undergoes a curious equilibration with hydrogen bromide in acetic acid at 0°C to give a mixture containing 55 % cis-carvone tribromide (160b); it is curious in that it involves a hydrohalide-initiated elimination followed by a hydrohalide-catalysed readdition of halogen, does not proceed with a-chloro-derivatives, and occurs many times faster in the presence of hydrogen bromide than in the presence of hydrogen chloride.' Katsuhara has discussed the mechanism of opoxidation of endocyclic a/?unsaturated terpene ketones and reached the conclusion that the oxygen atom is introduced stereoselectivelyin such a way that the most favourable transition state involves the best orbital overlap stabilisation. He predicted the formation of lR,4R,SR-menth4-en-3-one epoxide (161) from the unsaturated ketone,' l 6 a prediction that was subsequently confirmed.' l 7

Br

H

I

Some unexpected rearrangements occur when palladium chloride (PdCl,) is allowed to react with ally1 alcohols of the p-menthane series in the presence of carbon monoxide. n-Allylpalladium compounds are formed, but after 10 days that from piperitol(l28) has rearranged to the 3,4,8-trihapto-complex (162)which is obtained from pulegol(l63) after 1 h. Menth-3-en-2-01(127) leads to the same complex after 9 days.' '' An interesting ring-contraction to (167) occurs at the same time as the more usual formation of menth-2-en-1-01 (164), when all-cis-1-hydroxycarvomenthyl l4 'I5

'I6 'I7

M. Narayanaswamy, V. M. Sathe, and A. S. Rao, Chem. and Ind., 1969,921. J. Wolinsky, J. J. Hamsher, and R. 0. Hutchins, J. Org. Chem., 1970,35,207. J. Katsuhara, BUN. Chem. SOC.Japan, 1969,42, 2391. J. Katsuhara, H. Yamasaki, and N. Yamamoto, Bull. Chem. SOC.Japan, 1970, 43, 1584. G. A. Gray, W. R. Jackson, and J. J. Rooney, J. Chem. SOC.(0,1970, 1788.

32

Terpenoidr and Steroids

acetate (164) is pyr~lysed;"~it is believed to occur through the mechanism shown in (165).

b,,

Ih_

# PPdC 2

110 days

9 days

P

O

Ih

t

H @OH

COMe

The photochemistry of isopiperitenone (129) has revealed a new reaction. Isopiperitenone was already supposed to be the intermediate in the irradiation of verbenone (168),lZ0and it has now been shown that it is indeed converted in 35-42 % yield into 1,2-dimethyltricyclo[3,3,0,02~7]octan-6-one (169) in hexane. In methanol (170) is also obtained. A similar reaction is found with 4-acetoxyisopiperitenone."' The ring system formed is the same as that obtained by the irradiation of carvone to carvonecamphor.l Z 2 The condensations of the unsaturated menthane ketones with ethyl acetoacetate have been clarified. Carvone (130)reacts in the presence of small amounts of base at room temperature to give the bicyclic ester (171), while at higher base concentrations and 80 "C, the C-substituted bicyclo[3,3,l]nonanone (172) is formed.'23 The former is equivalent to a hydrated y-pyran of the type (173) obtained in the zinc chloride-catalysed reaction of pulegone (154) with ethyl J. C. Leffingwell and R. E. Shackelford, Tetrahedron Leffers,1970,2003. W. F. Erman, J. Amer. Chem. SOC.,1967,89, 3828. '*' W. F. Erman and T. W. Gibson, Tetrahedron, 1969,25,2493. I z 2 Leading references in J. Meinwald and R. A. Schneider, J. Amer. Chem. SOC.,1965, 87, 5218. I z 3 D. W. Theobald, Tetrahedron, 196, 25, 3139.

'I9

33

Mono terpenoids

a c e t o a ~ e t a t e , ’ ~a ~reaction ~ ’ ~ ~ that Wolinsky and Hayer have shown to be of general application to the preparation of y-pyrans. 125

The rearrangements of the 2-methylbutadienyl ether (174) of carveol have been examined to see how far the double reaction [uia (175) to (176)Joccurs with retention of stereochemistry. It was reported that only the cis-ether of carveol reacted, and it is argued that while an equatorial isopropenyl group at C-4

pt (1 74) Iz4 Iz5

9pcH COzEt

--+

OHC

(175)

(176)

Y . L. Chow and H. H. Quon, J. Org. Chem., 1969,34, 1455. J. Wolinsky and H. S. Hauer, J. Org. Chem., 1969,34, 3169.

34

Terpenoih and Steroids

enforces a pseudo-boat conformation on the intermediate, the trans-ether would be associated with a pseudo-chair conformation that would bring the axial proton at C-4 unfavourably close to the other part of the molecule undergoing the sigmatropic arrangement. 12' In an extensivestudy of plants of the Gaillardia and Heleniurn species,Bohlmann and co-workers have isolated a large number of highly oxidised monoterpenoids, most of them being derived directly from thymol by oxidation at one or more of the terminal methyl groups.'279128Compounds of type (181) have also been reported in Doronicum austriacurn Jacq.' 29 Of these compounds [( 177) to (183)], perhaps the last one is the most interesting, and Bohlmann has reported a synthesis of the methyl ether.'28 CH20COR I

CH2OCOR

qH2OCOR

yH2OCOR

I

@OH

P O C O R

A

HO +CH,OCOR (1 77)

(178)

(1 79)

(R = CHMe, or CHMeCH,Me) 6 O C O R

G O C O R

O d CH ,OCOR

rn-Menthaw.-Although it has long been believed that the only 'naturally occurring' rn-menthanes were artefacts arising from A3-carene, Bardyshev et al. have reported the isolation of ( +)-m-menth-5-en-8-01 (184) from a high-boiling fraction of Russian turpentine oil' 30 which also contains A3-carene.

126

127 128

'

29

130

A. F. Thomas and G. Ohloff, Helu. Chim.Acta, 1970, 53, 1145.

F. Bohlmann, U. Niedballe, and J. Schulz, Chem. Ber., 1969, 102, 864. F. Bohlmann, J. Schulz, and U. Buhmann, Tetrahedron Letters, 1969, 4703. F. Bohlmann and C. Zdero, Tetrahedron Letters, 1970, 3375. I. I. Bardyshev, 1. V. Gorbacheva, and A. L. Pertsovskii, Vestsi Akad. Naouk. Belarusk. S . S . R . , Ser. Khim.Nauuk. 1969, 102 (Chem. Abs., 1970,53, 1145).

Mono terpeno ids

35

o-Menthane.-The structure of carquejol(l85), the oldest member of the group, has been amended and the absolute stereochemistry firmly established131and supported by independent The various isomeric alcohols and ketones in the o-menthane series (corresponding to the menthols and menthones) have been d e s ~ r i b e d . ' ~ * The * ~ ~thermolysis ~ * ' ~ ~ of verbenene (186) has been shown to give an o-menthatriene (188) together with various other hydrocarbons, particularly (189), arising from fragmentation of the initially formed diradical (1 87). 35

(1 87)

1 . (190; R

= CHMe,

and CHMeCH,Me)

Baccharis genistelloides, from which carquejol is obtained, is not the only Baccharis species to yield an o-menthane. Bohlmann and Zdero have isolated two esters of the type (190) from Baccharis tirnera.'36 Tetramethy1cyclohexa.- 1,1,2,3-Tetramethy lcyclohexane derivatives, the pyronenes, are accessible by the pyrolysis of or-pinene, and are the subject of a series of publications from Poland, the latest of which refers to the hydrochlorination of a-pyronene (191) leading to the two compounds (192) and (193). The reactions of these hydrochlorides are discussed.' 37

132

G. Snatzke, A. F. Thomas, and G. Ohloff, Helu. Chim. Acta, 1969,52, 1253. M.-G. Ferretti-Alloise, A. Jacot-Guillarmod, and Y.-R. Naves, Helv. Chim. Acta,

133

M.-G. Ferretti-Alloise, A. Jacot-Guillarmod, and Y.-R. Naves, Helu. Chim. Acta,

13'

1970,53, 551.

'

1970, 53,201. 34

M.-G. Ferretti-Alloise, A. Jacot-Guillarmod, and Y.-R. Naves, Helu. Chim. Acra, 1970,53, 1339.

13' 136 13'

A. F. Thomas, B. Willhalm, and G. Ohloff, Helu. Chim. Acta, 1969, 52, 1249. F. Bohlmann and C. Zdero, Tetrahedron Letters, 1969, 2419. A. Uzarewicz and M. Zaidlewicz, Roczniki Chem., 1969, 43, 1435.

36

Terpenoidrs and Steroidr

Karahana ether (196), isolated from Japanese hops,'38 is also a 1,1,2,3-tetramethylcyclohexane derivative, and has been synthesised by Coates and Melvin by a route that they suggest may resemble the biogenetic p a t h ~ a y . ' ~ Their ' synthesis consists in cyclising geranyl acetate (194) with benzoyl peroxide in the presence of cupric and hydrolysing the resulting mixture to the corresponding diols, from which the cis-diol (195) is separated and converted to the ether with p-toluenesulphonyl chloride in pyridine at room temperature.

From the roots of Ferulu hispanica, Bohlmann and Zdero have isolated a 1,1,2,5-tetramethylcyclohexanederivative, namely 4-hydroxy-1,l,5-trimethyl-2formylcyclohexa-2,5-diene, as the esters of angelic acid and a-acetoxymethyl-ciscrotonic acid (197) and (198).14'

-co A

-co

H OR

\

(198) ; R

=

/c=c\

MeCO,CH,

Me

/Me H

Cyc1oheptanes.-Karahanaenone (200) has been synthesised from linalool ( 16). The bromohydrin obtained by the reaction of linalool with N-bromosuccinimide cyclises during the reaction and, on refluxing the resulting furan (199)in collidine, loss of hydrogen bromide occurs and rearrangement to the cycloheptenone takes place on heating the crude

collidine

NBS __*

A

--P

0

0 (16) 139 140 14' 142

( 199)

Y. Naya and M. Kotake, Tetrahedron Letters, 1968, 1645. R. M. Coates and L. S. Melvin, jun., J . Org. Chem., 1970, 35, 865. R. Breslow, J. T. Groves, and S. S. O h , Tetrahedron Letters, 1966, 4717. F. Bohlmann and C. Zdero, Chem. Ber., 1969,102,221 1. E. Demole and P. Enggist, Chem. Comm., 1969, 264.

(200)

Monoterpenoids

37

Two new products (202) and (203) have been isolated during a reinvestigation of the photoisomerisation of eucarvone (201). One of these, (203), undergoes a [1,3]sigmatropic photorearrangement to dehydrocamphor (204).'43

4 Bicyclic Monoterpenoids

Bicyclo[3,2,0]heptanes.-It might have been thought that filifolone (207) could be prepared by cycloaddition of dimethylketen to methylcyclopentadiene (205), but it has been shown that this reaction gives mainly two isomers (206a) and (206b), with small amounts of unidentified by product^.'^^ For the conversion of the pinene skeleton to filifolone, see below. stereochemistry of the thujane derivatives is still giving rise to d i s c u s s i ~ n ' and ~ ~ a* revised ~ ~ ~ nomenclature has been proposed.'46

Bicyclo[3,1,O]hexanes.-The

143

144 145 146

T. Takino and H. Hart, Chem. Comm., 1970,450. U. A. Huber and A. S. Dreiding, Helv. Chim. Acta, 1970, 53, 495. A. W. Gordon, Diss Abs., B, 1969, 29, 2348. S. P. Acharya, H. C. Brown, A. Suzuki, S. Nozawa, and M. Itch, J. Org. Chem., 1969, 34, 3015.

Terpenoidrs ana' Steroids

38

It has been found'46 that 2-thujene (209) (also called a-thujene) can readily be prepared by K0Bu'-DMSO-catalysed isomerisation of sabinene (208). The hydroboration of sabinene (208)14' and 2-thujene has been ~ o n f i r r n e d , 'and ~~ it has been suggested that the well-known acid-catalysed hydrations of these substances do not involve classical-ion types, the reaction being largely governed A mixture of cis- and by delocalisation effects rather than by steric contr01.l~~ rrans-sabinene hydrates [(210a) and (210b)l has been made from sabinene by the oxymercuration-demercuration p r o c e d ~ r e . ' ~This ~ is the first effective means of preparing the cis-isomer, earlier Grignard reactions leading predominantly to the other isomer.

Conversion of the readily available thujone (211) to 3-thujene (212) has been effected in two laboratories. Thermolysis of the sodium salt of thujone p-toluenesulphonylhydrazone leads to a 1 : 1 mixture of the more accessible 2-thujene (210) and 3-thujene (212);'" Baldwin and Krauss have raised the yield by treating the same p-toluenesulphonylhydrazonewith sodium in acetamide solution. In this reaction 97% of hydrocarbons was obtained, 80% of which was 3-thujene and 20% was y-terpinene (213)."' The latter method has the advantage of not producing 2-thujene, which is extremely difficult to separate from 3-thujene.

Two essentially identical syntheses of sabina ketone (214), from two different laboratories have been described, following the route shown in Scheme 7 and 14' 14'

lQ9 50

G. Ohloff, G. Uhde, A. F. Thomas, and E. sz. KovBts, Tetrahedron, 1966, 22, 309. T. Norin and L. R. Smedman, Int. Symposium on Synth. Methods and Rearrangements in Alicyclic Chemistry, Oxford, July, 1969, Abstracts p. 21. G. F. Russell and W. G. Jennings, J . Agric. Food Chem., 1970, 18, 733. J. W. Wheeler, R. H. Chung, Y. N . Vaishov, and C. C. Shroff, J. Org. Chem., 1969,34, 545.

J. E. Baldwin and H. C. Krauss, jun., J. Org. Chem., 1970, 35, 2426.

39

Mono terpeno ia3

NTo2Et - “CX

-

employing an intramolecular a-ketocarbene-olefin addition in the last step. 1 5 2 * 153 CH2OH

ROZCx

HOCH21

0

The reaction of umbellulone (215) with N-bromosuccinimide has been examined.lS4 Umbellulone is a hindered ketone, and Wheeler and Chung have shown that while lithium aluminium hydride in ether yields the expected mixture of the two umbellulols (216) and (217), a more bulky nucleophile like lithium tri-t-butoxyaluminium hydride leads almost exclusively to reduction of the double bond to give (218).ls5

&*-b ; H &:! b, +

A (215)

A

(2 16)

A

A

(217)

(218)

Bicyclo(2,2,l]heptanes.-The most interesting synthetic contribution to this area of monoterpenes is probably the ‘biogenetic-type’ synthesis of camphor (222) by Money et ~ 1 1 . l ’(+)-Dihydrocarvone ~ (219) is converted into a mixture of its enol acetates (220) and (221) and treatment of one of these [(220)] with boron trifluoride in methylene chloride yields camphor (222) in high yield; however, it is racemic. The other enol acetate (221) gives carvenone (102) under these conditions. Recent attempts to render common terpenoid materials pharmacologically active include reduction of Beckmann rearrangement products [from epicamphor ls2

0.P. Vig, M. S. Bhatia, K. C. Gupta, and K. L. Matta, J. Indian Chem. Soc., 1969,46, 991.

lS3 s4 5s

lS6

K. Mori, M. Ohki, and M. Matsui, Tetrahedron, 1970,26, 2821. R. T. Gray, Tetrahedron, 1969, 25, 3 16 1. J. W. Wheeler and R. H. Chung, J. Org. Chem., 1969,34, 1149. J. C. Fairlie, G. L. Hodgson, and T. Money, Chem. Comm., 1969, 1196.

40

Terpenoids and Steroids

oxime (223) and verbanone oxime (224)]15' and the addition of aminoalkylmagnesium halides to various substituted camphors.' 5 8

The Clemmensen reduction of 6-oxocamphor (225), in addition to providing information about the mechanism of the Clemmensen reduction of 1,3-diketones, leads to an interesting bridgehead-hydroxylated isocamphanone (226) probably having an exo-methyl group, via the route shown.' 5 9

Several 7,7-dimethylnorbornane derivatives are now more readily accessible from camphenilone (227). The stages of the synthesis as far as the hydrocarbon mixture are as shown in Scheme 8, but the main difficulty is the separation of apobornene (228) from the tricyclene hydrocarbon (229); they are not separated 158

H. Erdtman and S. Thorkn, Acta Chem. Scand., 1970,24,87. P. Schenone, G. Minardi, and G. Bignardi, Farmaco, Ed. Sci., 1968, 23, 983 (Chem.

159

Abs., 1969, 70, 302). V. T.-C. Chuang and R. B. Scott, Chem. Comm., 1969,758.

15'

Mono terpeno ids

41

either by distillation or by chromatography on a silver nitrate impregnated column. Hydroboration gives the organoborane (230) from apobornene, allowing the other hydrocarbon to be distilled away. Apobornene can then be recovered by oxymercuration (mercuric acetate in acetic acid) followed by deoxymercuration (lithium chloride in dimethylformamide at 50 "C), or the organoborane can be converted into apocamphor (231) and other substances by conventional techniques.' 6 o

(228) 78 %

(229) 20 %

2%'

Bicyclo[3,1,l]heptanes.-The pinane skeleton, in view of the very ready availability of the pinenes, is regularly the subject of numerous researches. Recent computer calculation with the aid of a gradient technique has produced the ideal geometric structures of certain derivatives of apopinane (6,6-dimethylbicyclo[3,l,l]heptane) associated with the energy minimum. For the results the reader is advised to consult the original paper, but the authors point out that such calculations are extremely expensive in computer time, and that for work on other molecules not containing a plane of symmetry as apopinane does ( C , symmetry), the problem increases in complexity.'6' On the biological side, it has been found that certain pine oil fractions stimulate the synthesis of P-carotene in Bfakeslea tripora, bicyclic terpenes (particularly the pinenes and camphene) but not monocyclic terpenes apparently being responsible. The pinenes (a- and P-) have been built up again from the pinic acid skeleton. Diethyl pinate (232) can be converted to a mixture of acyloins [e.g. (233)] by the lb0

16' 162

H. C. Brown, J. H. Kawakami, and S. Misumi, J . Org. Chem., 1970,35, 1360. J. Fournier and B. Waegell, Tetrahedron, 1970,26, 3195. E. Cederberg and H. Y . Neujahr, Acta Chem. Scand., 1969,23,957.

42

Terpenoih and Steroids

usual acyloin condensation. Lithium aluminium hydride reduction of the ptoluenesulphonates of these acyloins gives a mixture of alcohols, from which a mixture of ketones can be obtained by oxidation with chromic oxide in acetone. One of the ketones, nopinone (234),after separation by fractional crystallisation of the semicarbazone, was converted into a- or /I-pinene.163

OH

Preparation of 8-pinene (236)is simply carried by following the Shapiro method, viz. treatment of the toluenesulphonylhydrazoneof pinocamphone (235) with b ~ t y l - l i t h i u m . ' ~ ~

Kropp has made a careful study of the direct irradiation of a-pinene (237) to give a mixture of cis- and trans-ocimenes (238) and (239) uncontaminated with p-menthadienes.'66 The photochemical autoxidation of b-pinene in the presence

163

16* 165

166

S. S. Welenkiwar, C. S. Narayan, S. N. Kulkarni, and S. C. Bhattacharyya, Indian J . Chem., 1970,8, 379. Y.Bessitre-Chrktien and J.-P. Bras, Compt. rend., 1969, 268C, 2221. W. G. Dauben, M. E. Lorber, N . D. Vietmeyer, R. H. Shapiro, J. H. Duncan, and K. Tomer, J. Amer. Chem. SOC.,1968, 90, 4762, for relevent references. P. J . Kropp, J . Amer. Chem. SOC.,1969,91, 5788.

Monoterpenoids

43

of acetic anhydride has been examined, and found to be a reaction of some ~ o m p l e x i t y . ' ~Air ~ oxidation of a-pinene (237) catalysed by chromic oxide, however, gives a 30% yield of varbenone (240), which is easily separable from starting materials and by-products.168 Free-radical additions to p-pinene have been studied in two laboratories. Gaiffe and Castanet have found that the addition of aldehydes in the presence of di-t-butyl peroxide leads to the 7-substituted menth-1-ene structure;'69 ringopening was also found to be the main reaction by Claisse, Davies, and Parfitt, except in the case of thiols when addition to the double bond The work by Coxon et aI. that has already been mentioned in another context,80 also deals with reactions that occurred initially at the double bond of /3-pinene (241), notably the reaction with sulphur dioxide. Both the hydrocarbon and its epoxide give the cyclic sulphite (242), which rearranges to give myrtenol (243) derivatives. The cyclic sulphite derived from ol-pinene, on the other hand, undergoes ring-opening to give p-menthane compounds.80 The geometry and chemistry of the alcohol (243) and the corresponding aldehyde have been the subject of a thesis,' 7 1 and ( - )-cis-permyrtanic acid (244) has been described as a very suitable optically active peracid for asymmetric syntheses.' 7 2 Of the oxidised pinene derivatives, the n.m.r. spectra of the pinanols [2the spectral hydroxypinanes, (245)] have been discussed by Coxon et properties of the 3-hydroxypinanes [(246) pinocampheols] described by

E. Montaudon, H. FranCois, and R. Lalande, Bull. SOC.chim. France, 1969, 2773. E. Klein and W. Schmidt, Dragoco Rep., 1969, 16, 43. 1 6 9 A. Gaiffe and J. Castanet, Compt. rend., 1970,270C. 63. "". J. A. Claisse, D. I. Davies, and L. T. Parfitt, J . Chern. SOC.(0,1970, 258. C.O. Schulz, Diss. A h . , B , 1969, 29, 2368. J. F. Collins and M. A. McKervey, J. Org. Chern., 1969,34,4172. J. M . Coxon, E. Dansted, M. P. Hartshorne, and K. E. Richards, Tetrahedron Letrers, 1969, 1149.

Terpenoids and Steroids

44

T e i ~ s e i r e , 'and ~ ~ those of the verbanols and verbanones (4oxygenated pinanes) described by Regan.17' Bessiere-Chrttien and Bras have shown that the wellknown ring-opening reactions of a-pinane epoxide (247; R = Me) to campholenic aldehyde (248; R = Me) are paralleled by the corresponding reaction of apopinene epoxide (247; R = H) to apocampholenic aldehyde (248; R = H), but that orthodene epoxide (249) reacts differently, the predominating reaction with zinc bromide being isomerisation to the ketone (250) which, in the presence of base, is converted to the thermodynamically more stable isomer (251).176 Another unexpected reaction in the orthodene series is the hydroboration of the alcohol (252), which occurs at the more substituted end of the double bond to give (253).

mCH20H

CH,OB~

@B:

0

(257)

0

(258)

(259)

x (260)

Some reactions of nopinone (234) have been reported. Coxon et al. have examined the bromination and dehydrobromination, by which they had hoped to make the reported pin-3-en-2-one (254), but found that it is not as smooth a reaction as was previously t h 0 ~ g h t . lBessiere-Chrttien ~~ and Meklati have made isomers (255) and (256) of the pinocarvones and myrtenal from nopinone (234).' 79 Pyrolysis of nopinone (234) leads to a mixture of an open-chain ketone [(257), 39 %I, a cyclohexanone [(258), 27 %I, a cyclopentanone [(259), 14 % cis and 8 % P. Teisseire, Recherches, 1969, 17, 37. A. F. Regan, Tetrahedron, 1969, 25, 3801. Y . Bessiere-Chrttien and J.-P. Bras, Compt. rend., 1970, 271C, 200. '' Y . Bessikre-Chrbtien and B. Meklati, Compt. rend., 1970, 271 C, 3 18. J. M .Coxon, R. P. Garland, and M. P. Hartshorn, Austral. J . Chem., 1970,5, 1069. Y. Bessiere-Chretien and B. Meklati, Compt. rend., 1969, 269C, 1 3 1 5 .

Monoterpenoih

45

trans], with 11% unidentified compounds, all substances being derived from the biradical (260.)180 Verbenone epoxide (261) with alkaline hydrogen peroxide undergoes further oxidation to pinononic acid (262),* the mechanism of which has been discussed by Temple. The aluminium-chloride-catalysedreaction of verbenone epoxide to (263) and then to p-mentha-l,4(8)-dien-2-01-3-one (264) has also been described. 83

(261)

\

A

Qo

(263)

(264)

Erman has reported on further reactions of chrysanthenone (265); with acetic acid at 60 "C it gives filifolone (266) with some racemisation, ring-opening [to (267) and (26411 accompanying the rearrangement. The latter two compounds predominate after prolonged treatment with boron trifluoride, when some thymol and another bicyclo[4,2,0]octane (268)' 84 are also obtained. Base-catalysed

J$J 0

HoAc

of&

+

J$

+

0

H

C02H

(269)

(264)

1.-f) 0

H

COzH

(270)

C. F. Mayer and J. K. Crandall, J. Org. Chem., 1970,35,2688. L. R. Subramanian and G. S. Krishna Rao, Perfumery Essent. Oil Record, 1969, 60, 349, R. D. Temple, J. Org. Chem., 1970, 35, 1275. l S 3 J. A. Retamar, V. R. Medel, 0. A. Arpesella, and D. A. de Iglesias, Arch. Bioquim., Quim. Farm., 1968,14, (Chem. Abs., 1969,71,414). I n *W. F. Erman, J . Amer. Chem. Soc., 1969,91, 779.

* Some related compounds are described by Subramanian and Rae.'"

Terpenoids and Steroids

46

cleavage, on the other hand, results in the formation of the acids (269) and (270), the proportions depending on the conditions. '8 5 The preparation of nopadiene (272)from nopol (271)186and the rearrangement of its Diels-Alder adducts (273) to fenchyl derivatives (274) and (275) under the influence of hydrogen bromide in benzene at 25 "Chave been described.'*'

CHZCHzOH

The adduct (276)from /3-pinene (241)and acrolein undergoes an acid-catalysed cyclisation giving 6-isopropyltetralin and the tricyclic diol (277), the latter being favoured at low acid concentrations. 188 The enamines of pinocamphone (278) and verbanone (280)can be alkylated, and when methyl vinyl ketone is employed, the product is a tricyclic ketone [e.g. (279), from the pinocamphone].'*'

(278)

(279)

(280)

W. F. Erman, E. Wenkert, and P. W. Jeffs, J. Org. Chem., 1969,34,2196. C . A. Cupas and W. S. Roach, J . Org. Chem., 1969,34, 742. C. A. Cupas and W. S. Roach, Chem. Comm., 1969, 1486. C . Cruk, J . C. Van Velzen, and Th. J. de Boer, Rec. Trav. chim., 1969, 88, 139. M. Barthklemy, J.-P. Montheard, and Y . Bessiere-Chrktien, Bull. SOC.chim. France, 1969,2725.

Mono terpenoidrs

47

Bicycl~4,1,O]heptanes.-Epoxidation of car-3-ene (28 1) occurs from the side of the molecule opposite to the cyclopropane bridge, and the alternative /I-epoxide (283) has always been more difficult to obtain. Two laboratories have prepared it by a relatively simple method, using N-bromosuccinimide to form the bromohydrin (282) which is then treated with base.'90.'91

The complexity of chromic oxide oxidation of car-3-ene has already been r n e n t i ~ n e d .The ~ ~ reaction of p-toluenesulphonylhydrazoneswith organolithium compounds'64 has been used to prepare cis-card-ene (285) from the corresponding carone (284); if car-5-one (286) is used, the rn-menthadiene (287) is also obtained.

(287)

It has been confirmed'93 that selenium dioxide oxidation of car-3-ene gives 42 % of the interesting oxabicyclic diene (288),194 together with some carvone, carvacrol, and apdimethylstyrene. The deamination of various caranamines has been found to yield, in the case of the 2- and Sarnines, products from the corresponding cyclopropane-stabilized carbonium ion, but the 4-amines (289) give more complex products, including the two [(290) and (29111 shown.lg5 90 19'

19*

193 194 95

W. Cocker and D. H. Grayson, Tetrahedron Letters, 1969,445 1. B. A. Arbuzov, Z . G. Isaeva, and 1. B. Nemirovskaya, Izoest. Akad. Nauk S.S.S.R., Ser. Khim., 1969, 1401. M. S. Carson, W. Cocker, and P. B. Kulkarni, Tetrahedron Lefters, 1970,669. R . 0. Hutchins and D. Koharski, J. Org. Chem., 1969,34, 2771. B. A. Arbuzov, Z. G. Isaeva, and V. V. Ratner, Zhur. org. Khim., 1966,2, 1401. W. Cocker, D. P. Hanna, and P. V. R. Shannon, J . Chem. Soc. (0,1969, 1302.

Terpenoih and Steroih

48

The addition of chloro- and dichloro-carbene to car-3-ene has been found to occur from the side of the ring opposite to that of the dimethylcyclopropane group, leading to trans-l,4,4-trimethyltricyc10[5,1,0,0~~~ ]octanes (292).196

Addition of methyl vinyl ketone to cis-caran-4-one proceed^,'^^ as expected, in a way analogous to the enamines of pinocamphone.

5 Furanoid and Pyranoid Monoterpenoids A new glycol, elsholtzidiol(293),has been reported from Esholtzia densa, Beuth. 198 A synthesis of perillene (295) has been described, following the route from 3furylmethanol(249) shown in Scheme 9. 99

A variant of the ring-closure reactions for the synthesis of rose oxide (299)200 has been described by Eschinazi2'' It consists of oxidising the double bond of citronellyl acetate (296)with performic acid, then thermolysing the fully acetylated compound (297) to yield the diene acetate (298), the corresponding alcohol of

*O0

H. Frischleder, J. Graefe, H. van Phiet, and M. Muhlstadt, Tetrahedron, 1969, 25, 208 1. F. Fringuilli, A. Taticchi, and G. de Grace Guili, Gazzetta, 1969,9!3, 219. V. N. Vashist and C. K. Atal, Experientia, 1970, 26, 817. A. F. Thomas and M. Ozainne, J. Chem. SOC.(0,1970, 220. G. Ohloff, Fortschr. Chem. Forsch., 1969, 12, 185, gives a summary of the relevant

zol

literature concerning this and other important fragrances. E. H. Eschinazi, J. Urg. Chem., 1970, 35, 1097.

Iy6

19' 198 199

Monoterpenoids

49

"

+Q

I

CHO

CHZOH

1

LiAlH, on tosylate

pj-Y

(295)

0

Scheme 9

which is cyclised by sulphuric acid. Rose oxide (299) and other cyclic ally1 ethers can be reductively opened [to (300)and (301)]with sodium in liquid ammonia.202 Although the reduced benzofuran-Zones occurring in nature appear to be related to the higher terpenoids inasmuch as they have the same trimethylcyclohexane ring A, they are probably more closely related to the ionones and carotenoids. It has recently been shown, for example, that the dye-sensitised

(297)

+A f" CHZOH

+

Na-NH

CH20H A

44 XI

(301)

'O'

(300)

E. Klein and W. Rojahn, Dragoco Rep., 1969, 16, 63.

Terpenoids and Steroids

50 OH

photo-oxidation of both p-ionol (302) and b-carotene (303) leads to dihydroactinidiolide (304) and an allene (305).203 The former is found in a number of plants, and Demole et al. have given a list of the sources.2o4

'03 204

S. Isoe, S. B. Hyeon, and T. Sakan, Tetrahedron Letters, 1969, 279. E. Demole, P. Enggist, and M . Stoll, Helv. Chim.A d a , 1969, 52, 24.

2 Sesqu iterpenoids BY J. S . ROBERTS

1 Introduction

From many angles sesquiterpenoids continue to challenge the ingenuity of the organic chemist. The past eighteen months have witnessed many elegant syntheses in which new solutions have been found for the exacting problems of skeletal build-up and stereochemical control. In particular, the use of the intramolecular cyclisation of an olefinic diazoketone, first examined by Stork and Ficini,’ has been the corner-stone of numerous syntheses. With a few notable exceptions, little has been accomplished in the field of biosynthesis. Indirect substantiation of biogenetic postulates is derived mainly from detailed studies of sesquiterpene-rich natural sources. In this respect, the work of Andersen and Yoshikoshi on vetiver oil constituents, of Hirose on the germacratrienes,and of Zavarin2 on the hydrocarbons from Abies species deserve special mention. Indeed, Zavarin3 has applied probability mathematics to the qualitative and quantitative co-occurrence of monoterpenes as a means of justifying and establishing certain biogenetic hypotheses. In the absence of direct tracer methods, this inferential technique could also be applied to certain sesquiterpene groups. The studies of Geissman, Herz, and Mabry on sesquiterpenoid lactones continue to give valuable insights into the problems associated with chemota~onomy.~ Some very interesting results have been obtained by Henderson et aL5 who have used micro-analytical techniques in conjunction with electron- and photomicroscopy to determine the sites of sesquiterpene accumulation in Pogostemon cablin (rich in guaiane-typesesquiterpene hydrocarbons). The results of this study indicate that there are specific sites of accumulation especially associated with the glandular trichomes of the second pair of primordial leaves, where the concentration of sesquiterpenes is twelve-fold relative to other parts of the plant. G . Stork and J. Ficini, J. Amer. Chem. SOC.,1961,83,4678.

’ L. A. Smedman, E. Zavarin, and R. Teranishi, Phytochern., 1969,8,1457; L. A. Smed-

man, K. Snajberk, E. Zavarin, and T. R. Mon, Phytochem., 1969, 8, 1471. E. Zavarin, Phytochem., 1970,9, 1049. W . Herz, ‘Recent Advances in Phytochemistry’, ed. T. J. Mabry, Vol. 1, p. 229, NorthHolland Publishing Co., Amsterdam, 1968; T. A. Geissman and M. A. Irwin, Pure Appl. Chem., 1970, 21, 167; W. Herz, G. Anderson, S. Gibaja, and D. Raulais, Phytochem., 1969, 8, 877. W. Henderson, J. W. Hart, P. How, and J. Judge, Phyrochem., 1970,9, 1219.

Terpenoids and Steroids

52

Finally, mention should be made of the increasing application of the intramolecular Nuclear Overhauser Effect (NOE) which has played an important r81e not only as an aid to structural elucidation but also in the conformational determination of some of the germacrane sesquiterpenes.6 These results have a significant bearing on the understanding of transannular effects and chemical reactivity. This chapter has been divided, after the manner of a recent review,6ainto the various groups of sesquiterpenoids according to their proven or, more often, suspected biogenetic relationships. This division, although somewhat artificial in certain instances, permits a more coherent discussion of structurally and stereochemically related types. 2 Farnesane

trans-B-Farnesene (l), the major product of acid-catalysed and base-catalysed dehydration respectively of nerolidol and farnesol, can be isomerised in good yield to truns,truns-a-farnesene (2) in the presence of rhodium chloride trih ~ d r a t e .This ~ latter isomer of farnesene is one of the constituents of the wax coating of Granny Smith apples.8 The photochemistry of trans-/?-famesene(1)

has been examined in some detail by two groupsg*" who found that sensitised irradiation led to the two isomeric bicyclo[2,l,l]hexane derivatives (3a) and (3b). On direct irradiation, however, the reaction mixture was more complex giving rise to (3a),(3b), and the cyclobutene (4). White and Gupta' propose that a fourth component is the bicyclo[3,2,0]heptane derivative (5) (saturated Me at 6 0.72) with no trace of cis-/?-bergamotene(6) (see below). On the other hand, Courtney and McDonald" isolated an impure sample of a hydrocarbon which they claim may be cis-B-bergamotene (6) on the basis of n.m.r. evidence (saturated Me at 6 1.22). The unsaturated angelate ester (7) has been isolated from BricheIZia guatemuliensis." Complete details of the double 'Claisenxope' rearrangement K. Takeda, Pure Appl. Chem., 1970,21, 181. W. Parker, J. S. Roberts. and R . Ramage, Quart. Rev., 1967, 21, 331. G. Brieger, T. J. Nestrick, and C. McKenna, J . Org. Chem., 1969,34, 3789. K. E. Murray, Austral. J . Chem., 1969, 22, 197. J. D. White and D. N. Gupta, Tetrahedron, 1969,2!5, 3331. J. L. Courtney and S. McDonald, Austral. J . Chem., 1969, 22, 241 1. F. Bohlmann and C. Zdero, Tetrahedron Letters, 1969, 5109.

6Q

'

'

Sesquiterpenoids

T T R2=Me ,

53

(a) R1=Me, R2=

(b) R*=

(4)

.f between an allylic alcohol and a diene ether have been reported by ThomasI2 who has applied this method to the synthesis of b-sinensal(8) involving the onestep reaction of the allylic alcohol (9) with l-ethoxy-2-rnethylbuta-1,3-diene(10). A review by TrostI3' describes the isolation, structural elucidation, and syntheses of juvenile hormone (1 l), obtained from the giant silkworm moth, Hyalophora

..-al:, l2 13'

A. F. Thomas, J . Amer. Chem. SOC.,1969,91, 3281. B. M. Trost, Accounts Chem. Res., 1970, 3, 120; * C. E. Berkoff, Quart. Rev., 1969, 23, 372.

Terpenoids and Steroids

54

cecropia. In addition to the six synthetic routes outlined in this review, three more have been reported. Cavill et al.,14 utilising the results of their earlier in which the synthesis of methyl 10,l l-epoxy-3,7,1l-trimethyl-2,6-dodecadienoate, keto-acetonide (12,R = Me) was the key compound, have applied the same sequential Wittig reactions to the bis-methyl homologue (12, R = Et). van Tamelen and McCormick,” in a totally different approach, have elaborated the

C0,Me

6,7 : 10,l ldiepoxide of farnesol to the tris-allylic alcohol (13). Protection of the primary hydroxy-function, conversion to the corresponding unrearranged bis-allylic chloride, and subsequent treatment with lithium dimethylcopper yielded the trityl ether triene (14) as a mixture of four geometrical isomers.*

C

OH

OH O

H

Removal of the protecting group, elaboration to the requisite carbomethoxygroup, preparative g.1.c. separation, and terminal epoxidation completed the synthesis of juvenile hormone (11). G. W. K . Cavill and P. J . Williams, Ausrraf. J. Chem., 1969,22, 1737; G. W. K. Cavill, D. G. Laing, and P. J . Williams, ibid., p. 2145. l 5 E. E. van Tamelen and J. P. McCormick, J. Amer. Chem. SOC.,1970,92. 737. * Only the required rrans,rrans,cis-isomer is shown for convenience. l4

Sesquiterpeno ids

55

A very elegant stereoselective synthesis of juvenile hormone has been achieved by Johnson and co-workers,16who employed the olefinic ketal Claisen reaction to great advantage. Thus, the hydroxy-ester (15), on treatment with the olefinketal(l6) in acidic medium was converted into the ester (17). Sodium borohydride reduction to the corresponding allylic alcohol and a second Claisen-reduction sequence as described above yielded the trienol-ester (18). Chlorination under SNi’conditions and selective reduction of the resultant primary allylic chloride produced the well-known triene-ester (19) which was converted to juvenile hormone (1 1).

In a continuation of their studies on the ‘Claisen-Cope’ rearrangement, Thomas et al.” have utilised this procedure in the synthesisof torreyal and dendrolasin. Thus, pyrolysis of the ether (20), derived from the reaction of 3-furylgave the aldehyde (21). This, methanol with l-ethoxy-2-methylbuta-1,3-diene, on reduction to the corresponding alcohol and further treatment with the above diene, yielded torreyal(22, R = CHO) which could be converted to dendrolasin

l6

”

W. S. Johnson, T. J. Brocksom, P. Loew, D. H. Rich, L. Werthemann, R. A. Arnold, T. Li, and D. J. Faulkner, J. Amer. Chem. SOC.,1970,92,4463. A. F. Thomas and M. Ozainne, J . Chem. SOC.(C),1970, 220.

Terpenoidr and Steroids

56

(22, R = Me). In an alternative synthesis of dendrolasin, Parker and Johnson" used the highly stereoselective rearrangement of the cyclopropylcarbinol (23) as the means of attaining the trans double bond in the homoallylic bromide (24). Conversion of the bromo-group to an aldehydo-group, followed by a Wittig reaction with isopropylidenetriphenylphosphoranecompleted the stereoselective synthesis of dendrolasin (22, R = Me). OH

The synthesis of davanone (25)19 has been reported starting from linalyl acetate. The absolute stereochemistry of the toxic sesquiterpenoid, ( - )-ngaione (26) has been determined.-20

3 Monocyclo- and Bicycl+farnesanes 'Metabolite C', derived from metabolism of (+)-abscisic acid by tomato shoots, has been assigned structure (27) and on methylation rearranged to the methyl

l8

l9 *O

K. A. Parker and W. S. Johnson, Tetrahedron Letters, 1969, 1329. P. Naegeli and G. Weber, Tetrahedron Letters, 1970, 959. B. F. Hegarty, J. R. Kelly, R. J. Park, and M. D. Sutherland, Austral. J . Chem., 1970,

23, 107.

Sesquiterpenoids

57

OH

@

0

WCH I

ester of phaseic acid (28).21 Vomifoliol(29),a C,,-compound, has recently been isolated from RauwolJia uomitoria but it induces no elongation of the coleoptiles of corn.22 Two syntheses of the unusual enol-formate, Latia luciferin (30), the specific substrate in the luciferase system of the fresh-water limpet, have been reported.’, Both utilise dihydro-B-ionone as starting material. The allenic keto-diol (31), an ant repellant secretion of the large flightless grasshopper, Rornalea microptera, is almost certainly not a sesquiterpenoid in the true sense of the word. Its genesis by degradation of an allenic pigment such as neoxanthin (32) or fucoxanthin (33) is more probable. Both M e i n ~ a l d and * ~ W e e d ~ and n~~ their co-workers have synthesised this compound using approximately the same methods of skeletal and functional group elaboration. Thus, both syntheses involve addition of the 1 i t h i 0 ~or~ G r i g ~ a r dderivative ~~ of but-3-yn-2-01 to a suitably functionalised 2,2,6-trimethylcyclohexanoneand subsequent formation of the allenic moiety by lithium aluminium hydride reduction. Two possible H

21

z2 23

24

25

B. V. Miiborrow, Chem. Comm., 1969, 966; cJ J. MacMillan and R. J. Pryce, Tetrahedron, 1969,2!5, 5893, 5903. J.-L. Pousset and J. Poisson, Tetrahedron Lerters, 1969, 1173. F. Nakatsubo, Y. Kishi, and T. Goto, Tetrahedron Letters, 1970, 381; M. G. Fracheboud, 0. Shimomura, R. K . Hill, and F. H . Johnson, ibid., 1969. p. 3951. J. Meinwald and L. Hendry, Tetrahedron Letters, 1969, 1657. S. W. Russell and B. C. L. Weedon, Chem. Comm., 1969,85.

58

Terpenoih and Steroids

structures (34) or (35) have been attributed26to the fungal metabolite derived from Collybia maculata. Caparrapi oxide (36), the sesquiterpenoid analogue of the corresponding monoterpene and diterpene oxides (rose oxide and manoyl oxide respectively), has been i~olated.~’Another compound, cyclonerodiol (37) also derivable from nerolidol, has been isolated from the fungal species Tricothecium2’ The corresponding diol-oxide (38) co-occurs in the fungal

(35)

(34)

extract. Complete details of the isolation and structural determination of six closely-related bicyclofamesanes obtained from Cinnamosma fragrans have been p~blished,~’ viz., cinnamolide (39), cinnamosmolide (a), cinnamodial (41), bemarivolide (42), bemadienolide (43), and fragrolide (44).Cinnamodial(41) and ugandensolide (45) have also been isolated from Wurburgia ugandensis, a species which also produces two eremophilane types (see later).30

&o

@HO

@O

H

H

H

OAc (39) 26

’’ ’* 29

30

(40)

OAc (41)

A.-M. Bui, J . Parello, P. Potier, and M.-M. Janot, Compt. rend., 1970, 270, C , 1022. C. J. W. Brooks and M. M. Campbell, Phytochem., 1969,8,215. S . Nozoe, M. Goi, and N. Morisaki, Tetrahedron Letters, 1970, 1293. L. Canonica, A. Corbella, P. Gariboldi, G . Jommi, J. Kfepinsky, G. Ferrari, and C. Casagrande, Tetrahedron, 1969, 25, 3895, 3903. C. J. W. Brooks and G. H. Draffan, Tetrahedron, 1969, 25, 2887.

59

Sesquiterpenoids

@H

OAc

The relatively efficient cyclisation of monocyclofarnesic acid with boron trifluoride etherate to methyl bicyclofarnesate(46)has led to a successful synthesis of drimenin (48) via acid-catalysed lactonisation of the allylic alcohol (47), a product of singlet oxygen addition to (46).31It has also been shown that hydride reduction of drimenin to the allylic diol (49) followed by a two-step oxidation procedure yields cinnamolide (39).32 A C16 antifungal mould metabolite has 0

31

32

Y. Kitahara, T. Kato, T. Suzuki, S. Kanno, and M. Tanemura, Chem. Comm., 1969, 342. T. Suzuki, M. Tanemura, T. Kato, and Y . Kitahara, Bull. Chem. SOC.Japan, 1970, 43, 1268.

60

Terpenoidrs and Steroids

been assigned the structure (50).33Systematically, this compound may be considered as a bicyclofarnesane with one additional carbon atom or more probably as a degraded diterpenoid.

4 Bisabolane, Curcumane, etc. A number of bisabolane sesquiterpenes, including B-bisabolene (5 1),34 iso-

bisabolene (52),35and cryptomerion (53)36 have been synthesised by standard procedures. The structure of cryptomerone (54) has been established largely on the basis of n.m.r. spe~tra.~’A short and efficient route to nuciferal(55) has been described by Buchi and W u e ~ t .The ~ ~ same authors have also synthesised bilabanone (56) starting from (+)-car~one.~’

Two new syntheses of the juvenile hormone, juvabione (57a)’3b have been completed. In the first synthesis:O R-( +)-limonene was treated with disiamylborane and the adduct oxidised to yield the two alcohols (58a) and (58b) which were separated by fractional crystallisation of their diastereoisomeric 3,5dinitrobenzoates and subsequent hydrolysis. Each alcohol was separately converted to the corresponding nitrile and these on treatment with isobutyl-lithium gave the optically pure ketones (59a) and (59b). Oxidative modification yielded G. A. Ellestad, R.H. Evans, jun., and M. P. Kunstmann, J. Amer. Chem. SOC.,1969, 91, 2134. 3 4 0. P. Vig, B. Vig, and J. C. Kapur, J. Indian Chem. SOC., 1969,46, 1078. 3 5 0. P. Vig, I. Raj, J. P. Salota, and K. L. Matta, J. Indian Chem. SOC.,1969, 46, 205. 3 6 0. P. Vig, J. M. Sehgal, M. M. Mahajan, and S. D. Sharma, J. Indian Chem. SOC., 1969,46,887. ” S. It6, M. Kodama, H. Nishiya, and S. Narita, Tetrahedron Letters, 1969, 3185. 3 8 G. Buchi and H. Wiiest, J. Org. Chem., 1969,34, 1122. j 9 G. Buchi and H. Wiiest, J. Org. Chem., 1969,34, 857. 4 0 B. A. Pawson, H.-C. Cheung, S. Gurbaxani, and G. Saucy, J. Amer. Chem. SOC., 1970, 92, 336. 33

61

Sesquiterpenoids

+

(+ )-juvabione (57a)and ( )-epijuvabione (57b) respectively. A similar sequence of reactions converted S-( - )-limonene to (- )-juvabione and (- )-epijuvabione.

0

0

(a) R = ---Me (b) R = -Me

(a) R = ---Me (b) R = -Me

(a) R = ---Me (b) R = -Me

(57)

(58)

(59)

The second synthesis4' is based on the acid-catalysed fission of the Diels-Alder adduct (60)to give the 4-substituted cyclohexenone(61). Further elaboration and chromatographic separation yielded the ester (62) (stereochemistry of the isobutyl group unassigned). Reduction of this compound with calcium in liquid ammonia followed by oxidation gave racemic juvabione.

Hot on the heels of the recent isolation of sesquicarene (63) five independent syntheses have been reported. In essence, all these syntheses have depended R = Me),42y43 upon an intramolecular carbene-olefm cyclisation, viz. of (64, (64,R = H),44 and (65).43*45*46Only those syntheses4345 which ensured the trans-A6p7 double bond in the precursors were stereospecific. Recently, Corey and Achiwa4' have shown that mercuric iodide not only catalyses the diazo decomposition of (65) (i.e. cispans) but also isomerises the A293double bond of the truns,trans analogue of (65). Thus, sesquicarene can now be obtained from commercially available farnesol (trans,truns : cis,truns, 1.5 : 1) in approximately 35 % A. J. Birch, P. L. MacDonaid, and V. H . Powell, J . Chem. SOC.(0,1970, 1469. K. Mori and M. Matsui, Tetrahedron Letters, 1969, 2129; Teiruhedron, 1910, 26, 2801. 4 3 R. M. Coates and R. M. Freidinger, Chem. Comm., 1969, 871; Tetrahedron, 1970, 26, 3487. 4 4 E. J. Corey and K. Achiwa, Tetrahedron Letters, 1969, 1837. " E. J . Corey and K. Achiwa. Tvtmhrthron Letters, 1969. 3257. 4 2 y.Nakatani and T. Yamanishi, Agric. and Biol. Chem. (Japan), 1969, 33, 1805. E. J . Corey and K . Achiwa, Tetrahedron Letters, 1970, 2245.

4'

42

62

Terpenoids and Steroids

yield. Similar diazo decompositions have been applied to the s y n t h e ~ e s ~ ~ . ~ ~ - ~ of sirenin (66,R' = R2 = CH,OH), the sperm attractant produced by the female gametes of the water mould Allornyces. Various ingenious methods of introducing the terminal allylic hydroxy-function have been employed, but the simplest is the selenium dioxide-ethanol oxidation5' of the ester (66;R' = C02Me,R2 = Me) to the aldehydo-ester (66; R' = C02Me,R2 = CHO) with no trace of the cis-isomer.

5 Carotane

An X-ray analysis52 of daucyl D,L-alaninate hydrobromide (67) has confirmed the relative configurations in daucol and hence of carotol and d a ~ c e n e . ~ ~ 6 Cadinane, Amorphane, Muurolane, Bulgarane, and related Tricyclic Sesquiterpenoids With the absolute stereochemistry of ( +)-a-ylangene (68, derived trisubstituted olefin) firmly e ~ t a b l i s h e and d ~ ~a knowledge of the stereochemical inter-relationships, a biogenetic scheme encompassing all four classes of sesquiterpenes has been proposed.5L57 This is summarised in Scheme 1. The proposal envisages 48 49

so

K. Mori and M.Matsui, Tetrahedron Letters, 1969, 4435. P. A . Grieco, J . Amer. Chem. SOC.,1969,91, 5660. E. J. Corey, K. Achiwa, and J. A. Katzenellenbogen, J . Amer. Chem. Sac., 1969, 91, 4318.

J. J. Plattner, U. T. Bhalerao, and H. Rapoport, J . Amer. Chem. SOC.,1969,91, 4933; 1970, 92, 3429.

R. B. Bates, C. D. Green, and T. C. Sneath, Tetrahedron Letters, 1969, 3461. s 3 J. Levisalles and H. Rudler, Bull. SOC.chim. France, 1964, 2020. s 4 Y. Ohta and Y. Hirose, Tetrahedron Letters, 1969, 1601. s s Y. Ohta, K. Ohara, and Y. Hirose, Tetrahedron Letters, 1968, 4181. 5 6 N. H. Andersen, Phytochem., 1970,9, 145. 5 7 N. H. Andersen and D. D. Syrdal, Phytochem., 1970,9, 1325. s2

Sesquit erpenoids

63

the cyclisation of one unique cation (70) which can be derived by a 1,3-hydride shift from the cation (69). This cation (69) can, in turn, be derived from cis,trunsfarnesyl pyrophosphate and/or nerolidyl pyrophosphate. Further extension of this hypothesis also permits a derivation of the copaane, ylangane, and cubebane types as shown.

1

1

1

Bulgarane

Muurolane

Amorphane

Cadinane

J ' I

4-."r;.4 H

H

Copaane

Cubebane

Y langane (68)

Scheme 1

Both (+)-~-cadinene(71)58 and (+)-7,-cadinene (72)59have been synthesised from the previously known intermediates (73,R = Et, optically active) and (73, R = Me, racemic). (-)-7,-Cadinene is one example of the relatively small

59

M.D. Soffer and L. A. Burk, Tetrahedron Letters, 1970,211. R. B. Kelly and J. Eber, Cunud. J. Chem., 1970,48. 2246.

Terpenoids and Steroids

64

group of antipodal cadinenes occurring in the North Indian variety of vetiver oil.*

The structure and stereochemistry of chiloscyphone (74) have been determined and 0.r.d. and c.d. spectra are consistent with a non-steroidal conformation.60 From Taiwania cryptomerioides, three new muurolane-type sesquiterpenoids have been isolated61 uiz., (75), (76), and (77). In accordance with the absolute

S. Hayashi, A. Matsuo, and T. Matsuura, Tetrahedron Letters, 1969, 1599; A. Matsuo and S. Hayashi, ibid., 1970, 1289. Y . H. Kuo, Y. S. Cheng, and Y. T. Lin, Tetrahedron Letrers, 1969, 2375. * A hydrocarbon component of R6union vetiver oil has been assigned structure (i). Previously known as zizanene, this compound is in fact ( +)-a-amorphene and its biogenesis may be rationalised in terms of the enantiomer of ( 7 0 p In the light of this result, the biogenesis of the co-occurring laevojuneol (ii) is considered to involve (i) -+ (iii) (antipodal fi-ylangene) + (iv) + (v) -+(ii). Personal communication from Professor N. H. Andersen. 6o

& Q...< & H '

A

(i)

H

(ii)

OH

A

(iii)

p... f p...f H +

Sesquiterpenoids

65

stereochemistry of this general class of sesquiterpenoids, Ohloff and Pawlak6’ have obtained the diol(75) in 37 % yield by mild acid-catalysed rearrangement of (-)-a-copaene epoxide (78). In addition to this diol, two other compounds (79) and (80) have been obtained in 19 % and 44% yield respectively. The diol (75), on manganese dioxide oxidation and dehydration, yielded the enone (81) [also available from (79) by allylic oxidation] which Ohta and HiroseJ4 had already derived from ( - )-a-muurolene by t-butyl chromate oxidation. These findings fully substantiate the absolute stereochemical inter-relationships. After much debate and controversy the structure of (-)-torreyo1 (6-cadinol)has finally been settled as (82) and as such is a muurol01.~~ Three independent syntheses of the cubebane-type skeleton have been reported in which formation of the cyclopropane ring was once again achieved by an internal diazoketone cyclisation. In the first of these syntheses, Yoshikoshi et utilised (-)-truns-caran-2-one as the starting material which was converted in three steps to the spiro-lactone(83). Pyrolytic rearrangement of this compound to the key olefin-acid (84) was accomplished in 70% yield. Conversion to the corresponding diazoketone, followed by decomposition yielded the tricyclic ketone (85,R = 0) and its stereoisomer (86). Standard procedures converted

e 2 G . Ohloff and M . Pawlak, Helu. Chim. Acta, 1970, 53, 245. 63

L. Westfelt, Acta Chem. Scand., 1970, 24, 1618.

’‘ A. Tanaka, H. Uda, and A. Yoshikoshi, Chem. Comm., 1969, 308.

66

Terpenoih and Steroids

the ketone (85, R = 0) to or-cubebene (87), P-cubebene (85, R = CH2), and cubebol (88). Piers and c o - ~ o r k e r also s ~ ~achieved the synthesis of /?-cubebene (85, R = CH,) via the dihydro-derivative of the olefin-acid (84) (both isopropyl epimers) which was derived from racemic menthone and isomenthone. The same approach has been reported by Indian workers although their product must be a mixture of several stereoisomers.66 Copacamphene (89), though not yet found to be naturally occurring [but derivable from copaborneol (see later)], has been synthesised by McMurry6’ using, as the key step, the intramolecular carbanionic opening of the cisdecalone epoxide (90)to give the tricyclic ketol(91). Dehydration gave as the major product the keto-olefin (92) which, on lithium aluminium hydride reduction, hydrogenation, and re-oxidation, yielded a mixture of epimeric ketones (93). Treatment of these with methyl-lithium followed by dehydration gave a separable mixture of copacamphene (89) and sativene (94). Both Zavarin et ~1.’’ and McMurry6*have

(93) bS

66

61 68

(94)

E. Piers, R . W. Britton, and W. de Waal, Tetrahedron Letters, 1969, 1251. 0. P. Vig, M. S. Bhatia, A. K. Verma, and K. L. Matta, J. Indian Chem. SOC.,1970, 47, 277. J . E. McMurry, Tetrahedron Lerters, 1970. 3731. J . E. McMurry, Tetrahedron Letters, 1969, 5 5 .

Sesquiterpenoids

67

previously reported the synthesis of cyclosativene(95) by isomerisation of sativene (94) with cupric acetate in acetic acid. This rearrangement is exactly analogous to the longifolene longicyclene interconversion under the same conditions. A third isomer, isosativene (96),is also present in the equilibrium mixture. Having synthesised copacamphene, McMurry6’ subjected it to cupric acetate-acetic acid treatment and found that it was totally converted to the same equilibrium mixture of hydrocarbons as was obtained by similar treatment of sativene. Thus, the following equilibrium (Scheme 2) is established. Note that the conversion of (89) into (94) involves the changing of the isopropyl group from an axial to an equatorial configuration.

*

(95)

(94) Scheme 2

The complete details of the chemistry and synthesis of copaborneol(97) have been described by Kolbe-Haugwitz and We~tfelt.~’ The starting material was a commercial sample of santalol (a : ca. 7 : 3),* which was converted to a mixture of syn and anti keto-esters (98) and (99) of which only the syn isomer (98) underwent a Michael cyclisation to the tricyclo-keto-ester (100). Conversion of the

@ 69 ’O

J . E. McMurry, Tetrahedron Letters, 1970, 3735. M. Kolbe-Haugwitz and L. Westfelt, Actu Chem. Scund., 1970, 24, 1623.

* p-Santaloi consists of a mixture of exo and endo isomers (cu. 7 : 3), see p. 69.

68

Terpenoih and Steroids

methoxycarbonyl group into a methyl group and stereospecificreduction of the keto-function with sodium in alcohol yielded copaborneol (97). Recently, two epimeric pairs of compounds (101,R = CHzOH71*72and R = C02H73), derivatives of cyclocopacamphene, have been isolated from vetiver oil.

A review of the sesquiterpenoid bitter principles, picrotoxin, tutin, coriamyrtin etc. details the complex chemistry associated with these corn pound^.^^ The biogeneses of coriamyrtin (102,R = H)75 and tutin (102,R = OH)75,76 have been elegantly demonstrated by administration of ( -k)-[2-’4C](*),( -t)-[4-14C](*), and ( &)-[2,2-3H2](*)mevalonate to plants of Coriuriu juponica The results obtained from radioactive degradation products are consistent with an earlier

OH

”

l2 l3 74

75 76

A. Homma, M. Kato, M.-D. Wu, and A. Yoshikoshi, Tetrahedron Letters, 1970, 231. N. H. Andersen, Tetrahedron Letters, 1970, 1755. F. Kido, R. Sakuma, H. Uda, and A. Yoshikoshi, Tetrahedron Letters, 1969, 3169. C. J. Coscia, in ‘Cyclopentanoid Terpene Derivatives’, ed. W. I. Taylor and A. R . Battersby, Marcel Dekker, Inc., New York, 1969. M. Biollaz and D. Arigoni, Chem. Comm.,1969, 633. A. Corbella, P. Gariboldi, G. Jommi, and C. Scolastico, Chem. Camm., 1969, 634.

69

Sesquiterpenoids

biogenetic proposal which invoked oxidative fission of a tricyclic skeleton such as copaborneol (97). It should be noted that the two methyl groups of the isopropenyl group were equally labelled, thus inferring that the formation of the isopropenyl double bond is not stereospecific. Recently, two more amaroids of the picrotoxin type have been isolated from Hyaenunche globosa, namely pretoxin (103) and lambicin (104), and these have been correlated with ~apenicin.’~ 7 Santalane and Bergamotane A facile synthetic route to a-santalol (105) from the previously known aldehyde (106) has been reported by Corey et ~ 1 . ’in~ which a stereospecific modified Wittig

reaction [(i) ethylidenetriphenylphosphorane, (ii) n-butyl-lithium, and (iii) paraformaldehyde] yielded the desired cis-isomer. Erman and co-~orkers,~’ in a continuation of their synthetic work on the santalols, have reported the preparation of 8-santalol (107) from 3-methylnorcamphor. The route also provided a sample of the trans-isomer which had previously been considered to be the natural isomer. The use ofa borate ester as a protecting group for a hydroxyfunction facilitated the synthesis of dihydro-b-santalol (108)80 as outlined in Scheme 3. (These borate esters are stable to anhydrous acid or base but are readily hydrolysed in aqueous media.)

I

k

OH

via borate ester

Ph,P =CH

OH

b k

(108)

Scheme 3

’* 79

A. Corbella, G . Jommi, B. Rindone, and C. Scolastico, Tetrahedron, 1969,25,4835. E. J. Corey and H. Yamamoto, J. Amer. Chem. SOC.,1970,92,226. H. C. Kretschmar and W. F. Erman, Tetrahedron Letters, 1970,41. W. I. Fanta and W. F. Erman, Tetrahedron Letters, 1969, 4155.

70

Terpenoiih and Steroids

The total syntheses of ( -)-a-cis-bergamotene (109)and (+)-/?-cis-bergamotene (110)have been reported in a full paper.81 The key compounds were the olefinic iodides (111, R = CH21), each separately prepared from ( -)-/?-pinene. Subsequent elaboration of the primary iodide side-chain to the methyl-pentenyl group was achieved via the homologous aldehydes[111, R = (CH2)2CHO].Comparison of spectral data showed that isomer (109) is identical with one of the natural a-bergamotenes. On the other hand, (110) is not identical with the natural fl-bergamotenewhich should now be considered to have the trans stereochemistry (112).

A preliminary communications2on the biosynthesis of the antibiotic fumagillin (113) has confirmed its postulated sesquiterpenoid origin by incorporation of [1-14C]-and [2-'4C]-acetic acid, as well as a higher incorporation of [2-14C]mevalonic acid. As expected, the two radioactive acetic acids were incorporated into the complete molecule (i.e. both terpenoid and polyketide portions) but to different extents, a phenomenon which has previously been observed. Only the terpenoid part was labelled with radioactive mevalonic acid, and ozonolysis yielded acetone with approximately one third of the total radioactivity.

*'

T. W. Gibson and W. F. Erman, J . Amer. Chem. SOC.,1969,91,4471. A. 3. Birch and S. F. Hussain, J. Chem. SOC.(0,1969, 1473.

71

Sesquiterpenoids

A lettuce seed germination stimulant, graphinone, isolated from Graphiurn fungus culture has been attributed the structure (1 14).83 This compound appears to be identical to ovalicin, isolated from Pseudeurotiurn o ~ a l i s . ~ ~

8 Cuparane, Thujopsane, Cedrane, Acorane, and Laurane A very short and efficient synthesis of B-cuparenone (115) has been r e p ~ r t e d , ~ ’ in which ethyl p-tolylacetate was converted to the hydroxy-vinyl chloride (116) CI

in three steps. Acid-catalysed cyclisation of this compound gave 8-cuparenone directly. A very interesting biosynthetic studyS6 of the fungal pigment, helicobasidin (1 17, R = OH) and its congeners (117, R = H) and (118)has been made via feeding of [2-’4C-4R,4-3H] mevalonic acid lactone (3H : 14C, 3 : 3) to the fungal culture. The 3H :14Cratios for the compounds (117, R = H),(118),and the leuco-acetate (119) (derived from helicobasidin) were 2.2 : 3, 3 : 3, and 1.85 : 3 respectively. On the basis of the known location of the three labelled hydrogen atoms in farnesyl pyrophosphate (i.e. on each double bond), these results would indicate that two of them end up on the cyclopentane ring. If this is indeed the case, the inference is that the cuparane sesquiterpenes as obtained from the above fungal source are not derived from y-bisabolene itself but may involve closely related cations in which hydride shifts can take place. The actual location of the two labelled hydrogens in these compounds is awaited with great interest.

OMe

OAc

OAc

A third synthesis of thujopsene (120, R = Me) has been re~orded,~’ in which the diazoketone decomposition of (121)once again proved to be the crucial step in the synthetic route. Photosensitised oxygenation of thujopsenes8 and thujopsenol 83 84

85 86

T. Sassa, H. Kaise, and K. Munakata, Agric. and B i d . Chem. (Japan), 1970,34,649. H. P. Sigg and H. P. Weber, Hefv. Chirn. Acta, 1968,51, 1395. P. T. Lansbury and F. R. Hilfiker, Chem. Cornrn.. 1969. 619. S. Nozoe, M. Morisaki, and H. Matsumoto, Chern. Cornrn., 1970, 926. K. Mori, M.Ohki, A. Kobayashi, and M. Matsui, Tetrahedron, 1970, 26, 2815. S. It6, H. Takeshita, T. Muroi, M. It6, and K. Abe, Tetrahedron Letters, 1969, 3091.

72

Terpenoids and Steroids

(120, R = CH,OH)*’ yields thujopsadiene’’ (122, R = CH,) and mayurone (122, R = 0)respectively, together with several other products. Since both of these latter compounds have been found to occur naturally, it would seem that the above in uitro process mimics the in vivo process.

Two almost simultaneous communications reported the successful syntheses of a-cedrene (123) and cedrol (124). Both syntheses were modelled along a proposed biogenetic scheme, and as such the penultimate goal was the generation of the cation (125) which should, and did, undergo a smooth acid-catalysed cyclisation to a-cedrene. The two pathways to this cation differed in several respects yet practically coincided at the key spiro-dienone ester (126, R = Meg1 and R = Etg2). Whereas Crandall and Lawton” completed the synthesis by formic acid treatment of the alcohol (127), Corey et ale9’found that similar treatment of the diol (128) also yielded a-cedrene, albeit in lower yield. Alternati~ely,~’ the ene-diol (129) was converted into a-cedrene in better yield by formic acid treatment, thermolysis of the derived formates and subsequent lithium+thylamine reduction of the diene (130). Finally, cedrol (124) was obtained by boron trifluoride cyclisation of the enol-acetate (131),followed by methyl-lithium treatment of the intermediate cedrone.

l9 90 91

92

H. Takeshita, T. Sato. T. Muroi, and S. It6, Tetrahedron Letters, 1969, 3095. B. Tomita, Y. Hirose, and T. Nakatsuka, Nippon Mokuzai Gakkaishi, 1969, 15,46, E. J. Corey, N. N. Girotra, and C. T. Mathew, J . Amer. Chem. SOC.,1969, 91, 1557. T. G. Crandall and R. G. Lawton, J . Amer. Chem. SOC.,1969,91,2127.

73

Sesquiterpenoids

Shortly after these communications, the alcohol (127), named a-acorenol, was found to occur naturally in the wood of Juniperus rigidu and Tomita and H i r ~ s also e ~ demonstrated ~ its facile cyclisation with formic acid to (- )-a-cedrene (123) in greater than 90% yield. The corresponding diene (132), a-acoradiene, which was also converted to (-)-a-cedrene, was found in the same source. Subsequently, Hirose et aLg4 isolated four other related sesquiterpenesfrom the same species. These are /3-acoradiene (133), y-acoradiene (134), 6-acoradiene (135), and /3-acorenol(l36). The above authors also reported a tricyclic alcohol (137)and proposed that its skeleton (allo-cedrane)and stereochemistrycould be derived from cation (138). Andersen and Syrdalg5have reported the isolation of

(135)

0-f H

(134)

(Jyy "'r

(137) 93 94

95

B. Tomita and Y. Hirose, Tetrahedron Letters, 1970, 143. B. Tomita, T. Isono, and Y. Hirose, Tetrahedron Letters, 1970, 1371. N. H. Andersen and D. D. Syrdal, Tetrahedron Letters, 1970, 2277.

74

Terpenoidr and Steroids

a- and #I-alaskenes in the leaf oil of Chamaecypnris nootkatensis. These two dienes are, in fact, identical with y- and 6-acoradiene respectively.* Details of the extensive chemical work on a number of the sesquiterpenoids isolated from the basic hydrolysate of lac resin, the secretion of Laccifer luca, have appeared. These include shellolic acid (139, R' = P-C02H, RZ = CH20H),96 epishellolic acid (139, R' = a-CO,H, R2 = CH20H),96 jalaric acid (139, R' = a-CHO, R2 = CH20H),97laksholic acid (139, R' = fi-CH,OH, R2 = CH20H),97epilaksholic acid (139, R' = a-CH,OH, R2 = CH,0H),97 laccishellolic acid (139, R' = fi-C02H, R2 = Me),98 epilaccishellolic acid (139, R' = cr-C02H,R2 = Me),98 and laccijalaric acid (139, R' = a-CHO, R2 = Me).98 Only those compounds with a secondary aldehyde function can be considered as primary products, since it has been shown that the corresponding alcohols and acids are derived by a base-induced Cannizzaro reaction in the isolation procedure.

The complete chemicalg9and X-ray"' studies of laurinterol(140) have been published. In addition to laurinterol, debromolaurinterol and isolaurinterol (141) are also found in Lnurencia intemediu Yamada. Aplysin (142), isolated from Aplysiu kurodai Baba, can be derived from laurinterol by acid-catalysed cyclisation. A synthesis of both aplysin and debromoaplysin, involving suitable elaboration of the alcohol (143)has been reported."' The synthesis of themethyl P. Yates and G. F. Field, Tetrahedron. 1970. 26, 3135; P. Yates, G. F. Field. and P. M . Burke, ibid., p. 3159. 9 7 M. S. Wadia, R. G. Khurana, V. V. Mhaskar, and S . Dev, Tetrahedron, 1969, 25, 3841. 9 B A. N. Singh, A. B. Upadhye, M. S. Wadia, V. V. Mhaskar, and S. Dev, Tetrahedron, 1969, 25, 3855. 9 9 T. Irie, M. Suzuki, E. Kurosawa, and T. Masamune, Tetrahedron, 1970, 26, 3271. l o o A. F. Cameron, G. Ferguson, and J. M. Robertson, J. Chem. SOC.(B), 1969, 692. K. Yamada, H. Yazawa, D. Uemura, M. Toda, and Y . Hirata, Tetrahedron, 1969, 25, 3509. *The trivial name alaskene is preferred to acoradiene since alaskane (i) differs from acorane (ii) with respect to the absolute configuration of the secondary methyl group in the cyclopentane ring. Personal communiLation from Professor N. H. Andersen. 96

Sesquiterpenoids

75

ether of debromolaurinterol has been accomplished by diazoketone cyclisation of (1 44).l o t From the alga, Laurencia nipponicu Yamada, a new bromo-sesquiterpene has been is01ated.l'~ This compound, named laurenisol (145, R = Br, R' = OH) is closely related to laurene (145,R = R' = H).'04

Q-p OH

A re-appraisal of the biosynthesis of the tricothecane-type sesquiterpenes is required in the light of labelling studies carried out by Hanson and c o - w ~ r k e r s . ~ ~ ~ Incorporation of [2-'4C-4R,4-3H]mevalonic acid into the culture medium of Tricothecium roseum and a Trichuderma species showed : (a) that only two out of the three possible labels were incorporated in tricothecin [146,R' = 0, R2 = C(O)-CH:CH.Me] and trichodermol (146,R' = H,, R2 = H) and (b) these tritium atoms were located at C-2 and C-10. Furthermore, on the basis of doublelabelling studies with [l,l-3H2,2-14C]-and [2-3H,2-'4C]-farnesy1pyrophosphates, the authors concluded that cis,trans-farnesyl pyrophosphate is the preferred isomer for biosynthesis. Recently, Nozoe and Machida have isolated two compounds,trichodiol(147)lo6 and trichodiene (148)"' from Tricothecium ruseum which represent probable lo*

0. P. Vig, M. S. Bhatia, I. R. Trehan, and K. L. Matta, J . Indian Chem. SOC.,1970,47,

lob lo

T. Irie, A. Fukuzawa, M. Izawa, and E. Kurosawa, Tetrahedron Letters, 1969, 1343. T. Irie, T. Suzuki, Y. Yasanari, E. Kurosawa, and T. Masamune, Tetrahedron, 1969, 25, 459. B. Achilladelis, P. M. Adams, and J. R. Hanson, Chem. Comm., 1970, 51 1. S. Nozoe and Y. Machida, Tetrahedron Letters, 1970, 1 1 77. S. Nozoe and Y. Machida, Tetrahedron Letters, 1970, 267 I .

282.

Terpenoidr and Steroids

16

intermediates in the genesis of the tricothecane sesquiterpenes. There are now many polyoxygenated toxins of the tricothecane type occurring in various Fusariurn species, as witnessed by recent publications.'08-110 Two interesting communications by Hayashi et al. report on the isolation and structural elucidation of bazzanene (149, R = H)"' and bazzanenol (149, R = OH)' l 2 from Bazzania pornpeanu (Lac.) Mitt. These two compounds represent a new skeletal type in the sesquiterpene field, and their biogenesis may be formally considered to proceed via a bisabolene or related intermediate. At present, however, the structural determination rests primarily on i.r., n.m.r., and mass spectral evidence, together with the fact that bazzanene gives rise to cuparene (150) in good yield on dehydrogenation over palladium
(149)

'14

J. F. Grove, Chem. Comm., 1969, 1266. J. F. Grove and P.H. Mortimer, Biochem. Pharmacof., 1969, 18, 1473. T. Tatsuno, Y. Fujimoto, and Y. Morita, Tetrahedron Letters, 1969, 2823. S. Hayashi, A. Matsuo, and T. Matsuura, Experientia, 1969,25, 1 139. S. Hayashi and A. Matsuo, Experientia, 1970,245, 347. H. N. S. Rao, N. P. Damodaran, and S. Dev, Tetrahedron Letters, 1968, 2213. T. C. Joseph and S. Dev, Tetrahedron, 1968,24, 3809; R. C. Pandey and S. Dev, ibid.,

'I5

1968, 24, 3829. Y. Ohta and Y . Hirose, Tetrahedron Letters, 1968, 2483.

lo' '09

'lo l1

'

'

l2 l3

77 appear that the authenticity of the bicyclo[5,3,l]undecane skeleton in bazzanene may require further corroboration. Complete details of the photochemically-based synthesis of /3-himachalene (15 1) have been reported by de Mayo et al.' l6 The extensive chemistry associated with isolongifolene(153), an acid-catalysed rearrangement product of longifolene, is detailed in six papers by Dev and his collaborators."' An elegant synthesis of the mould metabolite culmorin (154) has been described by Roberts, Poonian, and Welch."' The basic building block in this synthesis was the bicyclic diketone (155) which was obtained in fair yield from tetrahydroeucarvone by standard annelation procedures. In six steps this diketone was converted to the ketodiester (156) which was cyclised and decarboxylated to the tricyclic diketone (157). Barton and Werstiuk' l9 had previously converted the (-)-diketone (157) to culmorin by reduction with sodium in n-propanol. Sesquit erpenoids

OH

I

(153) COzMe

&

0

(155)

(156)

9 Caryophyllane and Humulane The structures of two of the four isomeric photo-products of caryophyllene have been determined by X-ray analysis.1 2 0 These are photocaryophyllene A (158, R = a-Me) and photocaryophyllene D (158, R = /?-Me).Two oxidatively B. D. Challand, H. Hikino, G. Kornis, G. Lange, and P. de Mayo, J . Org. Chem., 1969, 34.794.

l9

R. Ranganathan, U. R. Nayak, T. S. Santhanakrishnan, and S. Dev, Tetrahedron, 1970, 26, 621 ; J. R. Prahlad and S. Dev, ibid., p. 63 1 ; T. S. Santhanakrishnan, U. R. Nayak, and S. Dev, ibid., p. 641 ;R. R. Sobti and S. Dev, ibid., p. 649; T . S. Santhanakrishnan, R. R. Sobti, U. R. Nayak, and S. Dev, ibid., p. 657; J. R. Prahlad, U. R. Nayak, and S. Dev, ibid., p. 663. B. W. Roberts, M. S. Poonian, and S. C. Welch, J . Amer. Chem. Suc., 1969,91, 3400. D. H. R. Barton and N. H. Werstiuk, J . Chem. SUC.( C ) , 1968, 148. R. B. Bates, G. D. Forsythe, G. A. Wolfe, G . Ohloff, and K.-H. Schulte-Elte, J . Org. Chem., 1969,34, 1059.

78

Terpenoids and Steroids

modified norsesquiterpenoids,kobusone (159) and isokobusone ( l a ) , have been isolated.l2

t H'Q D 0 (159)

Naya and Kotake, in an examination of Japanese hop oil, have isolated three humulane-type compounds, viz., humuladienone (161, R = Me),122humulenone I1 (161, R = =CH2),122 and humulol (162),123in addition to the tricyclic diol (163, R = OH),123m.p. 207 "C. This diol has already been prepared in two different ways: (a) Sutherland et treated humulene (164) with N-bromosuccinimide in aqueous acetone and converted the resultant bromohydrin (163, R = Br) to the diol (163, R = OH), m.p. 205-206 "C, by hydrolysis, (b) McKervey and Wright125 obtained the same diol, m.p. 201-203 "C, by acid-catalysed (20% sulphuric acid) rearrangement of humulene 1,Zepoxide (169, a known natural product. On the basis of these findings and the fact that both caryophyllene (166) and humulene can be derived from the above bromohydrin by two in v i m steps,'24 McKervey and Wright postulated that humulene 1,Zepoxide may be involved in the biosynthesis of the tricyclic diol and caryophyllene. This postulate does not, however, readily accommodate the observed rotations of the relevant

121 122

123 124

H. Hikino, K . Aota. and T. Takemoto, Chem. and Pharm. Bull. (Japan),1969,17, 1390. Y . Naya and M. Kotake, Bull. Chem. SOC.Japan, 1969,42,2088. Y.Naya and M. Kotake, Bull. Chem. SOC.Japan, 1969,42,2405. J. M. Greenwood, M . D. Solomon, J. K . Sutherland, and A. Torre, J . Chem. SOC.( C ) , 1968, 3004.

125

M . A. McKervey and J. R . Wright, Chem. Comm., 1970, I 17.

79

Sesquit erpenoids

naturally-occurring compounds, uiz., humulene [aID & 0", humulene 1,2epoxide [aID -31.2", the tricyclic diol (163, R = OH)123[aID +O", and caryophyllene [aID-9". Thus, it would appear that the tricyclic diol is racemic and therefore most probably an artefact. Since the discovery of the illudane-type sesquiterpenoids, a number of related compounds have been isolated, uiz., illudalic acid ( 167),lz6 illudinine ( 168),126 and dihydroilludin S (169, R = E - O H ) . ~The ~ ~ absolute stereochemistry of illudin S (169, R = =0)has been deterrnined.l2* A sequel to the successful stereospecific synthesis of illudin M (170) has been reported by Matsumoto et in which the diacetate (171, R = Ac), which had previously been prepared in the first synthesis,was selectively hydrolysed to the monoacetate (17 1, R = H). This compound was converted in three steps to the diacetate (172), which, after another selective hydrolysis, Jones oxidation, and acetate hydrolysis, yielded illudin M (170). OMe O

H

p k02H

HO

CHzOH

OH

OR *oH

lz6

OAc

OAc

*oH

M. S. R . Nair, H . Takeshita, T. C. McMorris, and M. Anchel, J . Org. Chem., 1969, 34, 240.

lz7

Iz8 lZQ

A. Ichihara, H . Shirahama, and T. Matsumoto, Tetrahedron Letters, 1969, 3965. N. Harada and K. Nakanishi, Chem. Comm., 1970, 310. T. Matsumoto, H. Shirahama, A. Ichihara, H . Shin, S. Kagawa, and F. Sakan, Tetruhedron Letters, 1970, 1 17 1 .

80

Terpenoids and Steroidi

Three compounds, coriolin (173, R' = H, R2 = = 0 ) , 1 3 0 coriolin B [173, R' = C(O).(CH,),.Me, R2 = OH],13' and coriolin C [173, R' = C(O)CH(OH)-(CH,),.Me, R2 = =0],131 which are related to illudol (174)132 have been isolated from a broth culture of CoriIus consors. Kagawa et al.133 OH

OH

k;!

OH

(173)

(1 74)

have reported a synthetic route to the protoilludane skeleton incorporated in the structure of illudol. This synthesis involved the two-step formation of the aacetoxy-enone (175) from 2,7,7-trimethylbicyclo[3,3,0]octan-3-onewhich, in turn, was obtained from the known 2-carbomethoxy-4,4dimethylcyclopentanone by a standard annelation procedure. Photolysis of the enone (175) in the presence of 1,l-diethoxyethylene yielded the cis,anti,cis tricyclic ketone (176). Sequential treatment of this compound with ethyl magnesium bromide, sodium metaperiodate, and basic alumina gave the diketone enol ether (177) which, on sodium

EtO OEt

o OEt (177) 130

131

132

133

p OEt

OEt (179)

S. Takahashi, H . linuma, T. Takita, K . Maeda, and H . Umezawa, Teiruhedron Letters, 1969, 4663. S. Takahashi, H. Iinuma, T. Takita, K . Maeda, and H . Umezawa, Terruhedron Letters, 1970, 1637. T. C. McMorris, M . S . R . Nair, and M. Anchel, J . Amer. Chem. SOC.,1967,89,4562. S. Kagawa, S. Matsumoto, S. Nishida, S . Yu, J . Morita, A. Ichihara, H . Shirahama, and T. Matsumoto, Tetrahedron Letters, 1969, 391 3 .

Sesquit erpenoids

81

borohydride reduction and Jones oxidation, yielded the diketone (178). Finally, an intramolecular aldol condensation gave the tricyclic ketone (179) which is a potential precursor of illudol(l74). The synthetic challenge of the complex skeleton and functionality of methyl marasmate (180) has been tackled by de Mayo and c o - w o r k e r ~ using ' ~ ~ no less than four discrete photochemical processes. The tetracyclic ketone (181) was obtained in the photochemical combination of cyclopentane-l,2-dione enol acetate with spiro[2,4]hept-5-ene. This was converted in four steps into the enone (182) which was rearranged to the tricyclic ketol (183). Subsequent lead tetra-acetate oxidation, esterification, and elimination of methanol yielded the enone-ester (184, R = H). Singlet oxygen addition to this compound, followed by reduction of the hydroperoxide gave the hydroxy-enone-ester (184, R = OH) which was photolysed in the presence of vinylene carbonate to give the unstable tricyclic carbonate (185). Reduction, esterification, and dehydration gave the diester (186) which, via photochemical decomposition of the corresponding pyrazoline derivative, gave the pentacyclic compound (187). Periodate cleavage of the glycol formed by hydrolysis and subsequent decarboxylation gave (188) which is an isomer of methyl marasmate.

0

@

R

134

C0,Me

C02Me

D. Helmlinger, P. de Mayo, M . Nye, L. Westfelt, and R. B. Yeats, Tetrahedron Letters, 1970, 349.

82

Terpenoih and Steroids OPiv

o
” I

I.

H

CO,Me

10 Germacrane

One interesting facet of the germacrane-type sesquiterpenoids is the conformation of the ten-membered ring. This aspect has previously been discussed in terms of transannular electronic effects (anomalous U.V.spectra) and transannular chemical reactions (Cope rearrangement and cyclisations to eudesmane and/or guaiane types). Recently, the power of two spectroscopic techniques has been brought to bear on this problem. The first of these is the use of the Nuclear Overhauser Effect (NOE)135and the second is the X-ray analysis of a suitable derivative. Bhacca and F i ~ c h e r , ’in~ an ~ n.m.r. study of dihydrotamaulipin-A acetate, presented evidence for the molecular conformation (189) by observing NOE’s between the C-4 methyl group and the C-6 hydrogen (15 %) and the C-2 hydrogen (10%). The C-10 methyl group also showed a NOE with the C-2 hydrogen (15%). These observations are consistent with conformer (189) in which the vinyl methyl groups are syn and the two double bonds are in a crossed orientation. The NOE technique has also been used6 in the conformational elucidation of the furanosesquiterpenoids, zeylanone (190), linderalactone (1 9 1), and isofurano-

F. A. L. Anet and A. J. R.,Bourn, J . Amer. Chem. SOC.,1965,87, 5250. N . S. Bhacca and N. H. Fischer, Chem. Comm., 1969, 68.

IJ5

Sesquiterpenoids

83

dienone (192)137to quote a few examples. The major NOE's in the latter compounds are as indicated.

It has recently been recognised that certain germacrane sesquiterpenoids can exist in more than one conformation. Thus, Yoshioka and M a b r ~ have '~~ demonstrated by n.m.r. studies that isabelin exists in two conformations in the ratio 10 :7 at room temperature. These correspond to (193) and (194). In this connection it is interesting to note that irradiation of i~abelin'~'at 253.7 nm gives rise to photoisabelin (195), the product of a concerted [2n + 2x1 cycloaddition favoured in terms of conformer (194). On the other hand, photolysis of dihydroisabelin (196),which exists as one conformer in solution, gives rise to the two photoproducts (197) and (198). The product (199) of the symmetry-allowed thermal opening of dihydrophotoisabelin (197)is also observed in addition to the 'disallowed' product (200).

13'

H . Hikino, C. Konno, T. Takemoto, K. Tori, M . Ohtsuru, and I. Horibe, Chem. Comm., 1969, 662.

H . Yoshioka and T. J. Mabry, Tetrahedron, 1969, 25,4767. "' H . Yoshioka, T. J . Mabry, and A. Higo, J . Amer. Chem. Sac., 1970,92,923. L38

84

Terpenoids and Steroids

(199)

From a study of the temperature-dependent n.m.r. and c.d. spectra of neolinderalactone, Tori et ~ 1 . ' ~ 'have concluded that this compound exists in the two conformers (201) and (202) in the ratio of 8 :2 at room temperature. The barrier to inversion, AE, is calculated to be about 10 kcal mole-' from n.m.r. data, while variable temperature c.d. observations lead to a value of 0.6 f 0.2 kcal mole- for AG between (201) and (202). Yet another example of conforma-

+ 0

0

tional freezing is recorded by Halsall et u1.,14' who separated two conformers of urospennal(203) by chromatography. It would appear that the two conformers are stabilised by two different modes of hydrogen bonding. 140

14'

K. Tori, I. Horibe, K. Kuriyama, and K. Takeda, Chem. Comm., 1970,957. R. K. Bentley, J.G.St.C. Buchanan, T. G. Halsall, and V. Thaller, Chem. Comm., 1970,435.

Sesquiterpenoids

85

The X-ray analysis'42 of the silver nitrate adduct of costunolide clearly shows that the molecule exists as the conformer (204) with the methyl groups in a syn relationship and the double bonds mutually perpendicular. The same features have also been found by the X-ray analyses of the pregeijerene (205bilver nitrate complex and heavy-atom derivatives of elephant01(206) and shiromodiol (207).143

0

Cyclisation of trans,trans-farnesyl pyrophosphate and/or double bond isomerisation of cations (69) and (70) can lead to the cations (69a) and (70a) which have long been implicated in sesquiterpene biogenesis. Careful extraction and chromatographic techniques have now paid dividends in that four isomeric germacratrienes have been isolated. Using such procedures, Morikawa and H i r o ~ e 'have ~ ~ isolated germacrene-C* (208) from the dry fruits of Kadsura japonica. Lending weight to biogenetic proposals, germacrene-C gives rise to b-elemene (209) on thermolysis and to selina-4,6-diene (2 10) and selina-4(14),6diene (211) on standing over silica gel. From the above and other sources, Hirose F. Sorm, M. Suchy, M. Holub, A.Linek, I. Hadinec, and C. Novak, Tetrahedron Letters, 1970, 1893. L 4 3 R. J . McClure, G. A. Sim, P. Coggon, and A. T. McPhail, Chem. Comm., 1970, 128; P. Coggon, A. T. McPhail, and G. A. Sim, J. Chem. SOC.( B ) , 1970, 1024. 1 4 4 K . Morikawa and Y. Hirose, Tetrahedron Letters, 1969, 1799. * For the nomenclature of these compounds, see ref. 144. 14*

86

Terpenoih and Steroids

et al.145have also isolated germacrene-D (212),which on isomerisation by heat or silica gel leads to a variety of products including (+)-y-muurolene, (-)-aamorphene, a-muurolene, ( )-6-cadinene, and ( + )-y-cadinene, while photoisomerisation gives ( -)-b-bourbonene (213) together with smaller amounts of a-bourbonene and P-copaene. Another isomer, germacrene-B (214), has been

+

isolated from oil of hops together with selina-4(14),7(11)-diene (215)and selina3,7(1l)-diene (216).'46*'47 Finally, by very careful chromatography, the elusive germacrene-A (217) has been found in the Gorgonian, Eunicea mummosa Lamouroux. 148 Germacrene-A is laevorotatory, yields ( )-B-elemene (218) on thermolysis, and co-occurs with ( - )-selina-4(14),11(12)-diene (B-selinene)(219). The latter two isomers correspond to theantipodesisolated from terrestrial sources and it is predicted that the terrestrial form of germacrene-A will be dextrorotatory.

+

145

14b

14' 14*

K. Yoshihara. Y . Ohta, T. Sakai, and Y. Hirose, Tetrahedron Letters. 1969, 2263. R. D. Hartley and C. H . Fawcett, Phyrochem., 1969,8, 1793. R. D. Hartley and C. H. Fawcett, Phytochem., 1969,8,637. A. J . Weinheimer, W. W. Youngblood, P. H. Washecheck, T. K . B. Karns, and L. S. Ciereszko, Tetrahedron Letters, 1970, 497.

Sesquiterpenoids

87

From the rhizomes of Acorus calarnus, Iguchi et ~ 1 . have ' ~ ~ isolated preisocalamendiol (220) together with four related compounds, shyobunone (221), epishyobunone (222),isoshyobunone (223),and isocalamendiol(224). The suggestion that the isomeric ketone (225) is the common precursor of all five compounds seems plausible.

Two interesting results have been obtained in the thermolyses of shiromodiol acetate (226)''' and the germacratriene epoxide (227).15' Both give rise to the same type of rearrangement products, oiz., (228) and (229), and (230) and (231) respectively, and it is suggestedI5' that formation of (228) and (230) can be rationalised in terms of a double electrocyclic process oia (232) as shown. These transformations may be significant in terms of the genesis of carabrone (233). M . Iguchi, A. Nishiyama, H. Koyama, S. Yamamura, and Y . Hirata, Tetrahedron Letters, 1969, 3729; M. Iguchi, A. Nishiyama, S. Yamamura, and Y . Hirata, ibid., 1969,4295; 1970,855. 150 K . Wada, Y. Enomoto, and K . Munakata, Tetrahedron Letters, 1969, 3357; Agric and Biol. Chem. (Japan), 1970,34, 946. E. D. Brown, T. W. Sam, and J. K . Sutherland, Tetrahedron Letters, 1969, 5025. 149

88

Terpenoids and Steroids

Q Q

*'

OH

HO

Jain and M c C l o ~ k e y 'have ~ ~ found that acid-catalysed cyclisation of costunolide (234) on Amberlite cation exchange resin gives a good yield of a- (235) and p-cyclocostunolides (236). Furthermore, the same a ~ t h o r s ' ' ~have shown not only that dihydrocostunolide (237) undergoes the normal Cope rearrangement but also that at elevated temperatures the bicyclic compounds (238), (239), and (240) are obtained.

ls2

153

T. C. Jain and J. E. McCloskey, Tetrahedron Letters, 1969, 2917; cf: T. C. Jain. C. M . Banks, and J . E. McCloskey, ibid., 1970, 2387. T. C. Jain and J. E. McCloskey, Tetrahedron Letters, 1969, 4525.

89

Sesquiterpenoids

There is now a large group of furanosesquiterpenoids known to co-occur in the species Linderu and Neolitseu. Takeda6 has given a very full account of the diverse chemical and spectroscopic problems associated with these compounds.' 5 4 As in conformational determination, the use of the NOE has recently played an important r6le in structural elucidation, especially in terms of stereochemical and geometrical assignments. 5 5 Recent additions to the group of furanogermacranes are listed in Table 1. The number of new germacranolides from various sources is increasing at an exponential rate and the position has now been reached where examples can be found in which at least one, if not more, of all the fifteen carbon atoms carries an oxygen function, ranging from epoxides to ethers and lactones. With this expanding catalogue of diverse functionality within a single carbon framework, a greater understanding of chemical and spectral properties has been achieved and this, in turn, has permitted revision of some earlier structures and a more facile correlation between existing and newly isolated compounds. Table 2 lists new additions to this group.

'

154

For a review of furanosesquiterpenes, see T. Kubota, in 'Cyclopentanoid Terpene Derivatives', ed. W. I. Taylor and A. R.Battersby, Marcel Dekker, Inc., New York, 1969.

155

K. Takeda, I. Horibe, M. Teraoka, and H. Minato, J. Chem. SOC.(C), 1969, 1491; K. Takeda, I. Horibe, and H. Minato, J . Chem. Sac. (C), 1970, 1547; K. Takeda, K. Tori, I. Horibe, H. Minato, N. Hayashi, S. Hayashi, and T. Matsuura, J. Chem. SOC.

(0,1970,985.

156

Is'

L62 lb3

K. Takeda, I. Horibe, M. Teraoka, and H. Minato, J . Chem. SOC.(0,1969, 2786. K. Takeda, I. Horibe, M. Teraoka, and H. Minato, J. Chern. SOC.(0,1970,973. A. R. de Vivar, C. Guerrero, E. Diaz, and A. Ortega, Tetrahedron, 1970, 26, 1657. M. Holub, Z. Samek, D. P. Popa, V. Herout, and F. Sorm, Coll. Czech. Chem. Cornm., 1970,35, 284. S. J. Torrance, T. A. Geissman, and M. R. Chedekel, Phytochem., 1969,8,2381. M. A. Irwin, K. H. Lee, R. F. Simpson, and T. A. Geissman, Phytochem., 1969, 8, 2009. R. Toubiana, M.-J. Toubiana, and B. C. Das, Compt. rend., 1970,270, C, 1033.

M. Suchy, L. DolejS, V. Herout, F. Sorm, G. Snatzke, and J. Himmelreich, C o f f . Czech. Chem. Cornm., 1969, 34, 229; see also refs. 178, 272. Z. Samek, M. Holub, V. Herout, and F. Sorm, Tetrahedron Lerrers, 1969,2931.

Linderalactone Linderane Neolinderalactone Furanodienone Isofuranodienone Neosericenine Sericenine Litsealactone Litseaculane Zey lanane Pseudo-neolinderane Linderadine

Name

Position(s) of double bond(s) 1,lqtrans) ;4,5(trans) 1,lqtrans) 1,lqcis); 4,5(trans) 1,lqtrans) ;4,5(trans) 1,lqtrans); 4,5(cis) 1,lqtrans); 4,5(trans) 1,lqtrans); 4,5(cis) 1,lqtrans); 4,5(trans) 1Jqtrans) 9,l qcis) 4,5(trans)

Table 1 Furanogermacranes

-

9a-Ac 9a-Ac 1b-Ac 6a,14 6a- 14 6aJ4 6a, 14 6a, 14

-

6a, 14 6a,14 6a,14

__ -

Olide

-OR

Other

14

155a 156,140 137 137 155b 155c 157 157 157 157 157

155a

Ref:

8-angeloyl ; 1I-Ac

-

8a-C(O)C(Me):CH, 8-C(O)-CHMe, 8a-Ac

1;3 14; 15 14

14 3a

4 3 ; 11,13; 10,15 7,ll

1,lO; 4,5; 11,13 1,lO; 4 3 ; 11,13 1,IO; 4,5 ; 11,13 1,IO; 4 3 ; 11,13 I J O ; 4 3 ; 11,13 IJO; 4,5; 11,13 1,lO; 11,13

1,lO; 11,13

1,lO; 4,5; 11,13 9,lO; 11,13

IJO; 4,5 ; 11,13

Ridentinb Confertolide

Jurineolide Cnicin Tulipinolide Epitulipinolide Eupatoriopicrin Salonitenolide Elephantin

Elephantopin

Deoxyelephantopin Vernomygdinb

Chihuahuin

The 1 , l O and 4,5 double bonds are fruns (or assumed to be).

-

-

8a; 14

-

-

3fl;14 38

4 3 ; 11,13 4,5; 11,13

Erioph y llin-B Erioph y llin-C

Ir

,

Unassigned lactone stereochemistry.

8a-C(O)C(Me): CH2

8-Ac; 13-AC + 1-OAC 8-C(O).C(Me):C H C H 2OH 8a-C(O)-C(CH,).CH(OH).CH O H 8u-A~ 88-AC 8fl-C(O)C(CH2 OH) C H C H 2 OH 8u-C(O).CH:CMe,

-

8&C(O)-C(Me):CH2 8/?-C(O)C(Me):CH,; 38-AC 88-C(O)C(Me):CH, 8/?-C(O)C(Me):CH,

8a; 14 38 14

1,IO; 4 3 ; 11,13 4 3 ; 11,13 4 3 ; 11,13

Urospermal Erioflorin Erioph yllin

-

8a-C(O)-C(Me):CH,

-OR

-

-OH

1,lO; 4.5

Position(s) of double bond(s)” 2,3; 11,13

Laserolideb

Zexbrevin

Name

Table 2 Germucrunolides: (i) 6a,12-olides

-

4a,5a-epoxy; 2fl,15-olide 4a,5a-epoxy; 28,15-olide 28,15-olide 3,4-epoxy; 14.15-oxido

-

-

-

-

9,lO-epoxy

-

18,loaepoxy 1fl,lOaepoxy ; 14-CHO

15-CHO ljI,lOa-epoxy 1fl, 1Oa-epoxy

3,lOfl-oxido ; 1-keto; 4a-Me -

0ther

166

169

I68

167

167

163 164,166 165 165 165 166

161 162

160

160

160

141 160

159

5 158

8.

P3 Re$

-

-

1,lO; 4,5; 11,13 1,lO; 4 5 ; 11,13 9,lO; 11,13

4,5; 11J3 IJO; 4,5; 11,13 1,lO; 4 3 ; 11,13

4 3 ; 11,13

4 3 ; 11,13

4,5 ; 11,13

1,lO; 11,13

Isabelin Chamissonin Vernolideb,'

Stizolineb Artemisiifolin Inunolide

Mikanolide"

Scandenolided

Deoxymikanolide

Baileyin

I OH

3a-Ac

6-C(O)C(Me) :C H

-

I

5-Ac; 6-C(O)C(Me)C H Me \ / 0 5-AC; 6-C(O)C(Me).C(O)-Me

-OR

14

cis-lactone (i.e. 8a-H) 2a,3a-epoxy ; 1a,lOa-epoxy ; 6aJ4-olide la,lOa-epoxy ; 6aJ4-olide 1a,lOa-epoxy ; 6a.14-olide 4a,5a-epoxy

-

3,4-epoxy ; 14.15-oxido 9,lO-epoxy

6a,14-olide

-

-

Other

3

13

26 1

175

175

175

174

138 171 172; cf. 169 173 166

170

170

Ref.

Also

s

2

%

k

2

jj

zmo

The 1 , l O and 4,5 double bonds are trans (or assumed to be). Unassigned lactone stereochemistry. ' Probably cis-fused lactone, i.e., 8 a - H . 1 1,13-dihydro-derivatives. c$ vernomygdin, Table 2 (i); these two compounds are related oia their identical tetrahydro-derivatives. 1 6 9

2a

-

-

6 6a; 14

3a ; 6a 14

-

-

3,4; 9,lO; 11,13

Polydalin'

-

-OH

3,4; 9,lO; 11,13

Position(s)of double bond($

Uvedalin'

Name

(ii) 8a,12-olides

Table 2 (continued)

Sesquiterpenoids

93

Two techniques have been described to assist in the stereochemical determination of the a-methylene-y-lactone moiety (241) commonly encountered in related groups of sesquiterpenoid lactones. In an n.m.r. study of a limited number of such compounds (e.g. germacranolides, eudesmanolides, guaianolides etc.) Samek’ concludes that in general, (a) J A B and J A C are greater (ca. 3.5 Hz)in trans lactones than in cis lactones (ca 1.5 Hz), and (b) JAC2 3 Hz 2 J A B . These ‘rules’, however, cannot be rigorously applied until further n.m.r. analyses have been carried out. Using a different approach, Geissman et have studied the 0.r.d. and c.d. spectra of a wide range of sesquiterpenoid types containing the a-methylene-ylactone chromophore. With very few exceptions, the following rules pertaining to the sign of the Cotton effect (for the n+ z* transition, ca. 255 nm) can be

formulated : cis-6,12-olides, positive; cis-8,12-olides, negktive ; truns-6,12-olides, negative; trans-8,12-olides, positive. These results and those of Suchy et al.’ 6 3 for the derived pyrazolines should, in future, aid the stereochemical assignment of the y-lactone ring fusion in newly isolated compounds, except in those cases where the molecule contains two lactone rings.

R. W. Doskotch and F. S. El-Feraly, J . Org. Chem., 1970,35, 1928. T. H. Porter, T. J. Mabry, H. Yoshioka, and N. H. Fischer, Phytochem., 1970,9, 199; H. Yoshioka, W. Renold, and T. J. Mabry, Chem. Comm., 1970,148. 1 6 7 S. M. Kupchan, Y. Aynehchi, J. M. Cassady, H. K. Schnoes, and A. L. Burlingame, J. Org. Chem., 1969,34, 3867. T . Kurokawa, K . Nakanishi, W. Wu, H. Y. Hsu, M. Maruyama, and S. M. Kupchan, Tetrahedron Letters, 1970, 2863. 1 6 9 S. M . Kupchan, R. J. Hemingway, A. Karim, and D. Werner, J. Org. Chem., 1969,34, 3908. 170 W. Herz and S. V. Bhat, J. Org. Chem., 1970, 35, 2605. 1 7 ’ M. F. L’Homme, T. A. Geissman, H. Yoshioka, T. H. Porter, W. Renold, and T. J. Mabry, Tetrahedron Letters, 1969, 3 16 1 . I l 2 C. M. H o and R. Toubiana, Tetrahedron, 1970, 26, 941. M. N. Mukhametzhanov, V. I. Sheichenko, A. I. Bankovskii, K. S. Rybalko, and K. 1. Boryaev, Khim. prirod. Soedinenii, 1969, 56. 1 7 4 R. Raghavan, K. R. Ravindranath, G. K. Trivedi, S. K. Paknikar, and S. C. Bhattacharyya, Indian J. Chem., 1969,7, 310. l 5 W. H e n , P. S. Subramaniam, P. S. Santhanam, K. Aota, and A. L. Hall, J. Org. Chem., 1970,35, 1453. “ Z . Samek, Tetrahedron Letters, 1970, 671; H. Yoshioka, T. J. Mabry, N. Dennis, and W. Herz, J. Org. Chem., 1970, 35,627. 1 7 7 T. G. Waddell, W. Stocklin, and T. A. Geissman, Tetrahedron Letters, 1969, 1313; Tetrahedron, 1970, 26, 2397. Itis

16*

94

Terpenoid and Steroids

11 Elemane Recent studies on the Cope rearrangement of certain germacrane sesquiterpenoids have disclosed some interesting results on the reversibility and conformational control of stereochemistry in this reaction. Jain et have demonstrated reversibility in three similar systems associated with costunolide and its derivatives [242, R = CH,, a-Me, and CH,N(Me),]. On the other hand, Takeda et a1.6*180 have not only observed the reversibility of the Cope rearrangement but have also found that the relative stereochemistry of certain furanoelemadienes so produced varies from case to case. Thus, linderalactone (191) and the ether (246) follow the same reaction path in terms of relative stereochemistry to give isolinderalactone (243)"l and (246a) respectively whereas the diol(244) is converted to (245). With the basic assumption of a chair-like transition state for the Cope rearrangement, an examination of molecular models of the three furanogermacradienes (191),(244),and (246)is in accord with these results [see the conformation of (191) as deduced from NOE data, p. 831. It should also be noted that the

HOH~C

' Ia0 la'

OH

G. Snatzke, Riechstofle, Aromen, Korperpflegemirrel, 1969, 19, 98. T. C. Jain, C. M . Banks, and J. E. McCloskey, Tetrahedron Letters, 1970, 841. K . Takeda, I. Horibe, and H. Minato, J . Chem. SOC.(0,1970,1142. K . Tori and I . Horibe, Tetrahedron Letters, 1970, 281 I .

Sesquiterpenoids

95

(246)

(246a)

reversibility of the Cope rearrangement depends upon a favourable conformation of the elemane counterpart* (i.e. attainment of a quasi-chair transition state) and in this context it is interesting that the observed non-reversible conversion of (244) into (245) is compatible with a NOE study of the diol (245).6 Similar reasoning can also be invoked to explain the isomerisation of (-)-6elemenol (247) to ( )-epi-d-elemenol (249) via the germacratriene intermediate (248).lS3

+

Corey and BrogerlS4have published a very elegant synthesis of elemol (250) involving, as the key step, the nickel-carbonyl-induced cyclisation of the esterdibromide (251). According to previous work by Corey and co-workers this reaction could have led to the formation of (252) and/or (253) in addition to other geometric and epimeric isomers. In the event, however, the major product was the elemadiene isomer (253, 7B-CO2Me) and none of the trans,trans-cyclodec- 13diene (252) was formed. The ester (253) was then converted to elemol by treatment with methylmagnesium bromide.

OH

C0,Me

D. J . Robinson and C. H . L. Kennard, J . Chern. SOC.( B ) , 1970, 965. K . Morikawa and Y . Hirose, Tetrahedron Letters, 1969, 869. l e 4 E. J. Corey and E. A. Broger. Tetrahedron Letters, 1969, 1779. * See also the X-ray analysis of the silver nitrate adduct of geijerene'" with respect to pregeijerene. 4 3 lE2

Ie3

w

96

Terpenoih and Steroids

C02Me

C02Me

Whereas 'naturally-occurring' elemane sesquiterpenoids have usually been under suspicion as artefacts of isolation, Kupchan and co-workers,in their search for anti-tumour agents, have isolated three oxidatively modified elemane dilactones, uiz., vernolepin (254, R = H),' 8 5 vernomenin (255),18' and vernodalin [254, R = C(0)C(CH2)CH20H].'69 The formation of these compounds from a germacradien-l4,15-01ide precursor during isolation seems unlikely, although not impossible.

q wo

0

0

H OH

0

12 Eudesmane (Selinane)

Various isomeric selinadienes have been isolated and these are mentioned in the text according to their co-occurrence with other sesquiterpene types. (+)-BEudesmol(256) has been isolated in the form of an O-a-L-arabinopyranoside,186 and vachanic acid has been shown to be identical to ilicic acid (257).18' BCyclopyrethrosin (258), one of the acid-catalysed rearrangement products of the germacranolide pyrethrosin, has been isolated from a natural source.188 The structures of pulchellin B(259, R' = Ac, R2 = H), pulchellin C(259, R' = R2 = H), pulchellin E (259, R' = H, R2 = Ac), and pulchellin F (259, R' = angeloyl, R2 = H) have been revised;176bpreviously they had been considered to be pseudo-guaianolides.' 89 This revision was largely motivated by the fact that

(256) 185

In'

18'

(257)

S. M. Kupchan, R . J. Hemingway, D. Werner, and A. Karim, J . Org. Chem., 1969,34, 3903. H . Yoshioka, T. J. Mabry, and A. Higo, J . Org. Chem., 1969,34, 3697. T. C. Jain and C. M. Banks, Chem. and Ind., 1969, 378; see ref. 273. R. W. Doskotch and F. S. El-Feraly, Canad. J . Chem., 1969,47, 1139. W. Herz and S. K. Roy, Phytochem., 1969,8, 661.

97

Sesquiterpeno ids

C-8 cis-fused lactones of the eudesmanolide type in particular exhibit small couplings between the C-7a proton and the two C-13 exomethylene protons (CU. 1-1.5

Hz).

An interesting observation has been made concerning the photolability of the Both epimers are photodecarboxylated 11,13-dihydro-6fl-santonins(260).' to the same cyclopropane derivative (261).

a*,

0 O Q 0

Following the successful c o n v e r ~ i o n 'of~ ~both alantolactone (262) and isoalantolactone (263) into artemisin (264)via the keto-ester (265), Nakazaki and NaemuraIg2 synthesised this ( + )-keto-ester by elaboration of the racemic hydroxy-enone (266) and subsequent resolution, so effecting the total synthesis of (264).

q

0

(J&o*Me

0

19'

G. W. Perold and G. Ourisson, Tetrahedron Letters, 1969, 3871. K . Naemura and M. Nakazaki, Tetrahedron Letters, 1969, 33. M . Nakazaki and K . Naemura, Bull. Chem. SOC.Japan, 1969,42, 3366.

98

Terpenoids and Steroids

Recent additions to the eudesman-6a,12-olidegroup are included in Table 3.

Table 3 Eudesman-6a,12- olides

Name

-OH 9a

Arbusculin-A Arbusculin-B Arbusculin-E Colartin

4a; 6a 4a

Artecalin Reynosin a-Epox ysantamarine Ludovicin-A Ludovicin-B Ludovicin-C

18 18 18 la l a ; 3a la

4a

Other &-Me ; 38,48-epoxy ; la-angeloyl 48-Me A4.5

11-C02H(not lactonised) 1la-Me (i.e. no exomethylene group) 3-keto ; 4a-Me A4,14

3a,4a-epoxy ; 48-Me 3a,&-epoxy ; 48-Me A4.14

3-keto ; A4v5

Ref: 193 194 194 194 194 195 196 196 197 197 197

There are relatively few examples of eudesmane-type sesquiterpenes in which the ring fusion is cis. H ~ r t m a n n ' ~has * suggested that these types may be derived by a thermally-allowed disrotatory closure of the hypothetical precursor (267) to give (268) and/or (269). The structure of the naturally-occurringsesquiterpene, occidentalol, has, in fact, been revised by Hortmann and De R 0 0 s ' ~in~ favour of (268). Recently, Tomita and Hirose''' have isolated occidenol (previously called occidiol) from Thuju koruiensis. On the basis of spectral evidence and from the fact that both ( - )-occidenoland ( - )-elemol(250)gave the same hydroxyketo-ester (270) on oxidation and esterification (epimerisation at C-5 appears to

'93 19*

196

"' 19' 199

*O0

F. Bohlmann and M. Grenz, Tetrahedron Letrers, 1969, 51 11. M. A. Irwin and T. A. Geissman, Phytochem., 1969, 8, 241 1. T. A. Geissman, T. S. Griffin, and M. A. Irwin, Phytochem., 1969,8, 1297. H. Yoshioka, W. Renoid, N. H. Fischer, A. Higo, and T. J. Mabry, Phytochem., 1970, 9, 823. K. H. Lee and T. A. Geissman, Phytochem., 1970,9,403. A. G. Hortmann, Tetrahedron Letters, 1969, 5785. A. G. Hortmann and J. B. De Roos,J . Org. Chem., 1969,34,736. B. Tomita and Y . Hirose, Tetrahedron Letters, 1970, 235.

Sesquiterpenoids

99

occur in the case of occidenol), the authors assigned the structure (271) to occidenol. They suggest a biogenesis involving the divinyloxiran + 4Sdihydrooxepin rearrangement of the hypothetical precursor (272). It is interesting to note that the genesis of miscandenin (273) has also been proposed'75 to occur via this rearrangement. An examination of a molecular model of the hypothetical precursor (273a) of miscandenin would suggest the opposite configuration at the ring junction i.e. C-loOr methyl group and C-5B hydrogen if the transition state for the rearrangement is half-chair-like, cf: linderalactone (191). Alternatively, if the preferred transition state is boat-like, the stereochemistry at the ring junction of miscandenin would be cis with the C-10 methyl and the C-5 hydrogen in a /? configuration.* This latter stereochemistry is that found in occidenol (271) but rationalised in that case using an erroneous analogy.200

" O" \ . O A O H

(273a)

The structure of the acetylenic norsesquiterpene chamaecynenol (274) has been derived by X-ray analysis.201The stereochemistry of the C 4 hydroxy-group in the naturally-occurringhydroxyisochamaecynone(275) has been established as a by total synthesis.202Both epimers were synthesised from the known acetylenic ketone (276) (obtained from mantonin) in a five-step process. From a study H . Shimanouchi and Y. Sasada, Bull. Chem. SOC.Japan, 1969,42,334. M.Ando, T. Asao, and K. Takase, Tetrahedron Letters, 1969,4689. Either of these alternate structures for miscandenin would accommodate the observed n.m.r. spectrum, personal communication from Professor W. Herz.

20'

202

Terpenoids and Steroids

100

of n.m.r. and i.r. data, the steroid conformation was assigned to this compound (275).

13 Eremophilane, Valencane, Vetispiram, Tricyclovetivane,eic. Biogenetic schemes have been postulated to account for those sesquiterpenes which can be formally related to a eudesmane-type precursor viu a lJ-methyl migration (see Scheme 4). Thus, the skeletal and stereochemicalfeatures exhibited by the eremophilane-type (281) sesquiterpenes can be rationalised in terms of a precursor such as the cation (278), derivable from (277).* By similar reasoning,

\

(277)

(279)

11

11

03, OH

L

J OH

J

WH

(283) Valencane

Eremophilane

Scheme 4

I

(284)

HO Vetispirane

*There do not appear to be any compelling reasons why the two twin chair forms of cation (69a) cannot be used in this hypothesis.

Sesquiterpenoids

101

the valencane class (283) can be formally derived from the cation (280) (i.e. a 4-epi, 10-epi-eudesmanetype) which could, in turn, arise from the same cyclodeca1,6-diene precursor in its other chair form (279) in which the methyl groups are mutually syn but anti with respect to the isopropylol group. There are, however, a number of compounds (see later) which are similar to the valencane class in the sense that they bear 44501 methyl groups but which have an sp' centre at C-7. Hence, it could be argued that these compounds are derived from a completely antipodal eudesmane precursor although this seems rather unlikely. In addition to these 1,Zmethyl shifts, it has been that C-9,lO bond migration in cations (278) and (280) can generate the spiro-compounds (282, i.e.,hinesol) and (284) (see later). Eremophila mitchelli is a rich ' source of various eremophilane sesquiterpenoidsZo5and to those already known can now be added the dienone (285).206 The chemistry of the eremophilane-related sesquiterpenoid bakkenolide-A (286) has been published.207

The structure (287) initially assigned to eremophilene has now been shown to be wrong on several counts. In the first place, Piers and Kezierezo8have accomplished a stereoselective synthesis of this diene and demonstrated its non-identity with natural eremophilene. On the basis of n.m.r. and the fact that eremoligenol (288) can be dehydrated to eremophilene, they assigned the structure (289) to this sesquiterpene. Coates and Shawzo9have confirmed this assignment by stereoselective syntheses of both eremophilene and eremoligenol. These syntheses centred around a novel procedure formulated for the removal of the keto-group in the keto-ester (290). This process involved conversion to the corresponding methoxymethyl enol ether and subsequent reduction with lithium in liquid ammonia to yield the less stable axial ester (291). Treatment of this compound with methyl-lithium gave eremoligenol(288) which, in turn, yielded eremophilene (289) on dehydration. Using the isoxazole annelation procedure developed by Stork and co-workers, Ohashi' l o has reported an economical and stereoselective 203 '04

205

'Ob 20' 'O*

'OV 210

D. F. MacSweeney, R. Ramage, and A. Sattar, Tetrahedron Letters, 1970, 557. N. H . Andersen, M . S. Falcone, and D. D. Syrdal. Tetrahedron Letters, 1970, 1759. F. Sorm, Pure Appl. Chem., 1970,21,263. G . L. Chetty, L. H . Zalkow, and R. A. Massy-Westropp, Tetrahedron Letters, 1969,307. K.Shirahata, T. Kato, Y . Kitahara, and N. Abe, Tetrahedron, 1%9,25, 3179. E. Piers and R. J. Keziere, Canad. J . Chem., 1969, 47, 137. R . M . Coates and J. E. Shaw, J . Org. Chem., 1970, 35, 2597. M. Ohashi, Chem. Comm., 1969, 893.

Terpenoih and Steroids

102 H

w

C02Et

P

(290)

COzEt

(291)

synthesis of dehydrofukinone (292)in which the key step was the conversion of the isoxazole (293) to the diketone (294).

Brown and Thornson'" have shown by synthesis that the structure of the norsesquiterpenoid maturinone should be revised to (295) which is also biogenetically more acceptable. Related to this compound are cacalol (296) (ere'3b mophilane-type with a methyl migration) and decompostin (297).21212

Recent furanoeremophilanesare listed in Table 4. ''I

212

213

214

L16

P. M. Brown and R. H. Thomson, J . Chem. SOC.( C ) ,1969, 1184; see also H. Kakisawa, Y. Inouye, and J. Romo, Tetrahedron Letters, 1969. 1929. J . Romo. Bol. Inst. Quim. Uniu. nac. auton. Mexico, 1969. 21, 92; P. Joseph-Nathan, C. Negrete, and P. Gonzalez, Phytochem., 1970, 9, 1623. J. Harmatha, Z. Samek, L. Novotny, V. Herout, and F. Sorm, Cofl. Czech. Chem. Comm., 1969,34, 1739; 1969,34,2792. C. J. W. Brooks and G. H. Draffan, Tetrahedron, 1969, 25, 2865. G. A. Eagle, D. E. A. Rivett, D. H. Williams, and R. G. Wilson, Tetrahedron, 1969, 25, 5227. L. Novotny, 2.Samek, J. Harmatha, and F. Sorm, CON.Czech. Chem. Comm., 1969, 34, 336.

Y. Ishizaki, Y. Tanahashi, T. Takahashi, and K. Tori, Chem. Comm., 1969, 551.

-

1,lO 1,2 1,lO 1,2; 9,lO -

Position(s) of double bond(s)

-

-

-

6B-C(0) CHMe, 6B-C(0) CHMe, 6B-angelo yl

l a ; 6 8 ; log 9a

-OR

- OH

Also Warburgiadione [eremophila-l,9,7(1 I )-triene-3,8-dione].

-

Adenostylone Iso-adenostylone Neo-adenostylone Warburgin" Euryopsol

Name

Table 4 Furanoeremophilanes

9-keto 9-keto; 10B-H 9-keto 3-keto ; 1 1-CO2Me 10B-H 10B-H ; 6aJ4-olide

Other

14

213 213 213 214 215 216 217

Ref:

8

c.

104

Terpenoih and Steroids

Marshall and Ruden2 have reported a stereoselectivesynthesis of nootkatone (298) in which the keto-ester (299) was annelated with truns-pent-3-en-2-one to give the bicyclic keto-ester (300). The ethylidene moiety was converted to the 'I/?-acetylgroup by epoxidation, acid-catalysed rearrangement, and basic equilibration. After bis-ketalisation of the diketo-ester (301) the carbomethyoxygroup was converted to the 5a-methyl group in three steps and a subsequent Wittig reaction yielded racemic nootkatone (298). An earlier synthesis of noot-

katone by Odom and Pinder2" has been retracted. Full details of the chemistry leading to the revision of the structure of a-vetivone (302)have been published.220 It has now been shown221that nardostachone is correctly represented by (303).

The bicyclic ester (304) utilised by Coates and Shaw209in the syntheses of eremophilene and eremoligenol was also applicable to the syntheses of valencene (305) and valerianol (306).222 Thus, basic equilibration gave the more stable

03.CO,Et

(304) 'I8 219

'lo 22' 222

J. A. Marshall and R. A. Ruden, Tetrahedron Letters, 1970, 1239. H. C. Odom and A. R. Pinder, Chem. Comm., 1969,26; see footnote 1 of Ref. 218. K . Endo and P. de Mayo, Chem. and Pharm. Bull. (Japan), 1969,17, 1324. A. R. Pinder, Tetrahedron Letters, 1970, 413. G. Jommi, J. Kfepinsky, V. Herout, and F. Sorm, Coil. Czech. Chem. Comm., 1969, 34, 593.

Sesquiterpenoiak

105

equatorial isomer (307) which on treatment with methyl-lithium gave valerianol and on subsequent dehydration, valencene. Andersen et aL204have recently isolated a number of related hydrocarbons from vetiver oil in addition to other biogenetically related compounds (see later). These include nootkatene (308), P-vetivenene (309), and y-vetivenene (310).

The isolation and structural elucidation of the novel tetracyclic sesquiterpenes ishwarane (311, R = H2)223 and ishwarone (311, R = 0),224 obtained from the roots of Aristofochia indicu, have been reported by Govindachari et al. From a biogenetic standpoint these compounds,which incorporate a tricycle[3,2,1,02.7]octane ring-system, belong to the valencane group-one of their congeners is aristolochene (312). One of the degradation products of ishwarone, isoishwarane

(313), has been ~ynthesised~~’ via photochemical addition of allene to the enone (314) which gave the tricyclic ketone (315). Conversion of this to the hydroxyketal (316) and acid-catalysed re-aldolisation to (317) followed by dehydration and a Worn-Kishner reduction yielded isoishwarane (313). Recent communications by Andersen and Yoshikoshi and their co-workers on the constituents of vetiver oil of various origins illustrate the way in which 223

T. R. Govindachari, P. A. Mohamed, and P. C. Parthasarathy, Tetrahedron, 1970,26, 615.

224

225

T. R. Govindachari, K. Nagarajan, and P. C. Parthasarathy, Chem. Comm., 1969,823; A. K. Ganguly, K. W. Gopinath, T. R. Govindachari, K. Nagarajan, B. R. Pai, and P. C. Parthasarathy, TetruhecironLetters, 1969, 133; H. Fuhrer, A. K. Ganguly, K. W. Gopinath, T. R. Govindachari, K. Nagarajan, B. R. Pai, and P. C. Parthasarathy, Tetrahedron, 1970, 26, 2371. R . B. Kelly and J. Zamecnik, Chem. Comm., 1970, 1102.

Terpenoidr and Steroids

106

m (313)

mo (314)

(315)

more credence can be placed on biogenetic concepts on the basis of the isolation of stereochemically related compounds-‘absolute configurational homogeneity rule’.56 Both g r o ~ p s ’ ~have * ~ reported ~ the isolation of vetiselinenol (318) and it has been shown by Ander~en’~that other ‘vetiselinanes’ are present, viz., vetiselinene (319), (-)-selina4(14),7(1l)-diene (320) and (-)-b-selinene (321). Klein and Rojahn226 have also found (-)-selinad,11(12)-diene (322) and (+)-selina-3,l l(12)-diene (323) in the essential oil of Dipterocarpus alatus Roxb. Related to these and the valencane-types are the two vetispiranes, b-vetispirene (324) and a-vetispirene (325).204 On the basis of both synthetic and degradative studies, Marshall and cow o r k e r ~have ~ ~ shown ~ that the structure of b-vetivone based on a bicyclo[5,3,0]decane skeleton is untenable and subsequent work dictated the structure (326) incorporating a spiro[4,5]decane skeleton, and this they have confirmed by total synthesis.228 The method employed was the selective introduction of an isopropylidene group in a stepwise fashion starting with the keto-olefin (327), which was obtained via photolysis of the known dienone (328). The structure and absolute stereochemistry of hinesol (282)229has now been firmly established by an unequivocal synthesis230which involved the tricyclic dienone (329) prepared from 6-methoxy-1-tetralone. Treatment of the dienone with lithium dimethylcopper gave a mixture of syn and anti enones (330).* By a series of stereoselective reactions this compound was converted to the diol (331) whose mono-mesylate underwent a base-induced cleavage to give the spiro[4,5]ketone (332). Elaboration of this ketone to hinesol was accomplished along E. Klein and W. Rojahn, Tetrahedron Letters, 1970,279. J. A . Marshall, N. H. Andersen, and P. C. Johnson, J. Org. Chem., 1969, 34, 186. ‘*’J. A . Marshall and P. C. Johnson, J . Org. Chem., 1970,35, 192. I. Yosioka and T. Kimura, Chem. and Pharm. Bull. (Japan), 1969, 17, 856. 2 3 0 J. A. Marshall and S. F. Brady, Tetrahedron Letters, 1969, 1387. * Epimeric at C-4, only the desired isomer is shown for convenience. 226

227

’”

a

107

Sesquiterpenoids

--H

H

CHzOH

(320)

(324)

'0 (327)

OH

.

108

Terpenoih and Steroids OH

OH

%

I-

(333)

(334)

(335)

conventional lines. Relevant to biogenetictheory is the finding that B-rotunol(333), which co-occurs with a-rotunol(334), yields the dienone (335) on dehydration.231 This same dienone can be prepared from hinesol in three steps. Ramage et d 2 0 3 have suggested that hinesol(282) can serve as a precursor to the zizaane-type sesquiterpenes [e.g.,(34211 by cyclisation to the secondary cation (336) followed by a Wagner-Meerwein shift to the tricyclic cation (337). This last step finds a laboratory precedent in the solvolysis of the mono-mesylate (338) to the tricyclic ketone (339). Although this proposal explains the gross structure

. MesO

ctr-, a

-

Me02C

(338)

& -

Me02C’

(339)

and absolute stereochemistry of this type (with the possible exception of the hydrogen at C-4), the absolute stereochemistry of the vetispiranes as exemplified by (324), (325), and (326)which co-occur with the zizaane types in vetiver oil, is, in 231

H. Hikino, K. Aota, D. Kuwano, and T. Takemoto, TerrahedronLetters, 1969,2741.

Sesquiterpenoids

109

fact, antipodal with respect to that of (+)-/?-vetivone obtained from hinesol (282). Thus it seems unlikely that hinesol itself can be considered in the biogenesis of the zizaane-type sesquiterpenes.* A considerable number of these tricyclic sesquiterpenes have now been isolated from various vetiver oils. The nomenclature and carbon numbering of these compounds have been somewhat confusing, partly because of independent isolation and naming and partly because earlier structures (and hence names) have undergone revision. At present, the following relationships hold : 2 3 2 khusenol = tricyclovetivenol E khusimol tricyclovetivene = khusene 5 khusimene = zizaene zizanoic acid

= khusimic acid

There may in fact be justification for the name tricyclovetivane as the parent hydrocarbon skeleton with the numbering and stereochemistry as shown in (340),i.e. in conformity with the accepted numbering system for fused rings.

232

I. C. Nigam, H. Komae, G. A. Neville, C. Radecka, and S. K. Paknikar, Tetrahedron Letters, 1968, 2497.

* In a study of the hydrocarbons from RCunion vetiver oil, a compound of the structure (ii) has been isolated, referred to as prezizaene. Zizaene (iii) can be detected in the acidcatalysed isomerisation of prezizaene, both of which are finally isomerised to three new hydrocarbons. The biogenesis of the zizaane-type sesquiterpenes is considered to involve cyclisation of ( +)-y-curcumene (i) as shown. Personal communication from Professor N. H. Andersen.

(iii)

(ii)

Terpenoih and Steroids

110

In addition to the many other sesquiterpenes found in vetiver oil, A n d e r ~ e n ~ ~ and Yoshikoshi et aL7 have isolated zizanol [tricyclovetiv-3( 14)-en-6p-ol] (341). The structure and stereochemistry of khusimol (tricyclovetiv-3(14)-en-15-01)(342) have been elucidated by X-ray analysis of a heavy-atom derivative233and isokhusimol [tricyclovetiv-7( 15)-en-14-01] has been assigned the structure (343).234

'

~ ~ ' also reported a synthesis of epizizanoic acid (344) Yoshikoshi et ~ 1 . have starting from ( + )-methylcamphene carboxylate (345). Conversion to the corresponding aldehyde and aldolisation with acetone gave the enone (346), which was converted to the cyano-diketone (347) in two steps, and thereafter to the tricyclic ester (348). Osmylation to the cisdiol and rearrangement of the derived mono-mesylate gave two epimeric (at C-4) ketones (339) on prolonged base equilibration. The synthesis was completed by a Wittig reaction on the 4/3-H epimer (as the sodium salt).

(344)

(345)

CN (346)

(347)

(348)

14 Guaiane

Two total syntheses of racemic bulnesol (349) have now been reported. In a consideration of the stereochemical features incorporated in the bicyclo[5,3,0]23*

R. M . Coates, R . F. Farney, S. M. Johnson, and I. C. Paul, Chem. Comm.. 1969.999. D. C. Umarani, K. G. Gore, and K. K. Chakravarti, Perfum. Essential Oil Record,

235

F. Kido, H. Uda, and A. Yoshikoshi, Chem. Comm., 1969, 1335.

233

1969,60, 314.

111

Sesquiterpenoids

decane skeleton of bulnesol and encouraged by the results of model studies, Marshall and Partridge236 utilised an appropriately functionalised bicyclo[4,3,l]decane precursor (350) which, on solvolysis, gave the olefin-acetate (351). This compound was converted to bulnesol via the corresponding (epimerised) 7B-carbomethoxy derivative. Kato et aZ.,237on the other hand, used a suitably substituted cis-fused decalin system (352)which, on solvolysis, gave the same ester (353) as Marshall and Partridge had prepared.

TsO

\

C02Me

Pa

C02Me

In another approach to the guaiane skeleton, Piers and Cheng238prepared the enone (355) by photolysis of the known dienone (354). A scheme involving eight steps was used to convert (355) to a-bulnesene (356), the dehydration product of bulnesol.

Guaioxide (357, R = B-Me)239and liguloxide (357,R = ~ t - M e ) ~have ~ * been shown to be epimeric at C-4and the chemistry of these and related compounds has been fully described. 236 23’ 23s 23’)

240

J. A. Marshall and J. J . Partridge, Tetrahedron, 1969, 25, 2159. M. Kato, H. Kosugi, and A. Yoshikoshi, Chem. Comm., 1970, 185. E. Piers and K. F. Cheng, Chem. Comm., 1969,562; Canad. J. Chem., 1970,48,2234. Y . Tanahashi, S . Tomoda, and T. Takahashi, Bull. Chem. SOC.Japan, 1969.42. 2076; H. Ishii, T. Tozyo, M. Nakamura, and H. Minato, Tetrahedron, 1970,26,2751. H. Ishii, T. TOZYO, M. Nakamura, and H. Minato, Tetrahedron, 1970,26,2911.

112

Terpenoids and Steroids

have synthesised kessane (359) in 30% yield by solvolysis of the Kato et mesylate (358) [cf:solvolysis of (352) above].

(357)

(359)

Ourisson and co-workers have published full details of the isolation and structural elucidation of both y-gurjenene (360)242and seychellene (361, R = CH2).243 Seychellene, which can formally be derived from patchouli alcohol (362) by a 1,2-methyl migration (a transposition which has, as yet, not been successfully effected in the laboratory), has now been synthesised by two groups. The synthesis reported by Piers et ~ 1involved . the ~ construction ~ ~ of the tricyclic skeleton by an

internal nucleophilic displacement of tosylate in the cis-decalone (363) which gave the ketone (361, R = 0). The synthesis of the cis-decalone is an excellent example of stereoselectivecontrol and functional group manipulation. The ketone (361, R = 0)was converted to seychellene in 85 % yield by treatment with methyllithium and subsequent dehydration. The other synthesis, reported by Schmalzl and M i r r i n g t ~ n , ~commenced ~’ from the basic bicyclo[2,2,2]octane system (364) whose e m acetyl group was converted in a number of steps to an isobutylol

p 0

OTs

241

242 243 244

245

M. Kato, H. Kosugi, and A. Yoshikoshi, Chem. Comm., 1970,934. C. Ehret and G. Ourisson, Tetrahedron, 1969,25, 1785. G. Wolff and G. Ourisson, Tetrahedron, 1969, 25, 4903. E. Piers, R. W. Britton, and W. de Waal, Chem. Comm., 1969, 1069. K. J. Schmalzl and R. N. Mirrington, Tetrahedron Letters, 1970, 3219.

113

Sesquiterpenoids

side-chain. The ethylene bridge was also modified to yield finally the keto-alcohol (365). Treatment of the corresponding tosylate with potassium triphenylmethide yielded the tricyclic ketone (361, R = 0)previously prepared by Piers et aL244 The chemistry associated with the structural elucidation of torilin (366) has been The hemiketal, isocurcumol (367), has been isolated.247

On formolysis, cyperene epoxide (368) gives rise to a number of products, two of which are (369) and (370);248the latter has been correlated with a-cedrene and confirmed by X-ray analysis.249 On the other hand, treatment of (368) with stannic chloride yields two ketones (371) and (372),250the latter of which has been again confirmed by X-ray analysis.249 The mechanistic implications of these

Q3 @ OH:.'

OH

OH

(372)

(371)

0 (373) 246

"'

H . Chikamatsu, M. Maeda. and M. Nakazaki, Tetrahedron, 1969, 25, 4751. H . Hikino, I(. Agatsuma and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1969,17, 959.

248

249

250

L. Bang, M. A. Diaz-Parra, and G. Ourisson, Tetrahedron Letters, 1969,227. H. Dreyfus, J.C1. Thierry, R. Weiss, 0. Kennard, W. D. S. Mortherwell, J. C. Coppola, and D. G. Watson, Tetrahedron Letters, 1969, 3757. L. Bang and G . Ourisson, Tetrahedron Letters, 1969, 3761.

114

Terpenoidr and Steroids

interesting rearrangements are discussed. A ketone related to cyperotundone, 51 namely scariodione (373), has been i~olated.~ Complete details of the successful syntheses of desacetoxymatricarin (374, R = H) and achillin (374, R = p-OAc) have been reported.252 Many new guaianolides have been isolated from the family Compositae; these are listed in Table 5.253-262

Additional examples have been reported in which ring A of the guaianolide or pseudoguaianolide skeleton has been oxidatively modified. These include enhydrin (375),263 canambrin (376),264parthemollin (377),265xanthanol (378, R’ = OH, R2 = O A C ) , and ~ ~ ~isoxanthanol (378, R’ = OAc, R2 = OH).266 Herz et ~ 1 . have ~ ~ ’ recently identified a number of related pseudoguaianolides from Hymenoxys species in which an in vim Baeyer-Villiger-type oxidation has taken place in ring A. These include psilotropin268(floribundin)(379) and its 11,13-dihydro-derivative (1Ip-Me) themoidin, anthemoidin (380), greenein (38l), hymenolide (382), and hymenoxynin (383). 251 252

253

254 255 2’6

z57

S. B. Nerali and K. K. Chakravarti, Science and Culrure, 1969,35, 110. E. H. White, S. Eguchi. and J. N. Marx, Tetrahedron, 1969. 25,2099; J. N. Marx and E. H. White, ibid., p. 2117. J. Romo, A. Romo de Vivar, R. Treviiio, P. Joseph-Nathan, and E. Diaz, Phytochem., 1970, 9, 1615. K. H. Lee, R.F. Simpson, and T. A. Geissman, Phytochem., 1969,8, 1515. M. A. Irwin and T. A. Geissman, Phytochem., 1969,8, 305. W. E. Thiessen, H. Hope, N. Zarghami, D. E. Heinz, P. Deuel, and E. A. Hahn, Chem. and Ind., 1969,460. N. Zarghami and D. E. Heinz, Chem. and Ind., 1969, 1556. K. Vokat, 2.Samek, V. Herout, and F. Sorm, Coil. Czech. Chem. Comm., 1969, 34, 2288.

262

A. Romo de Vivar and A. Ortega, Canad. J. Chem., 1969,47,2849. S. M. Kupchan, J. E. Kelsey, M. Maruyama, J. M. Cassady, J. C. Hemingway, and J. R. Knox, J. Org. Chem., 1969,34, 3876. A. Yoshitake and T. A. Geissman, Phytochem., 1969,8,1753; T. G . Waddell and T. A. Geissman, Phytochem., 1969, 8, 2371. T. A. Dullforce, G. A. Sim, D. N. J. White, J. E. Kelsey, and S . M.Kupchan, Tetra-

263

hedron Letters, 1969. 973. N . R. Krishnaswamy, T. R.Seshadri, and T. N. C. Vedantham, Current Sci., 1969,38,

259

260

261

284. 264

265 266

267

”*

J. Romo and L. Rodriguez-Hahn, Phytochem., 1970,9, 1611. W.Herz, S.V. Bhatt, and A. L. Hall, J . Org. Chem., 1970,35, 1110. T. E. Winters, T. A. Geissman, and D. Safir, J. Org. Chem., 1969,34, 153. W. Herz, K. Aota, M. Holub, and Z . Samek, J. Org. Chem., 1970,35,2611. L. B. de Silva and T. A. Geissman, Phytochem., 1970,9, 59.

8a; 10a 1oa 38; l l a ; 13 38; l l a 10 88

28 28; 1oa 28 28 28; 1oa

3,4; 11,13 3,4; 11,13 4,14; 10,15 4,14; 10,15 1,2; 4,5 3,4; 11,13 3,4; 11,13 3,4; 11,13 3,4; 11,13 11.13 10,15; 11,13 11,13

Cumambrin B" Cumambrin A Solstitialin Solstitialin acetate Artabsin Bahia-I Bahia-I1

Euparotinb*' Eupachlorinb" Eupatoroxin'."

Eupatundin' Eupachloroxin'

Also 8-deoxycumambrin B.

lool

11,13

Canin

-

8~-AC

-

-OR Other

0

260 260

260 260 260

256 257 258 259 259

255

255

254

253

253

Ref:

Also 10-epieupatoroxin.

lOa,l5-epoxy 15-Cl 3a,4a-epoxy ; lOa,l5-epoxy 3a,4a-epoxy 3a,4a-epoxy ; 15-C1

28,38-ePoxY ; lB,lOp-epoxy 2a,3a-epoxy ; la,lOa-epoxy 1a,2a-epoxy ; 3a,4a-epoxy la-H 1a-H la-H 1a-H 1la-Me 10,15-epoxy 10,15-epoxy

1a-H;5a-OH (not 5a-H).

88-angeloyl 8B-angeloyl

CHzOH 88-angelo yl S@-angeloyl 8B-angelo yl

I

13-AC 8@-C(O)C:CHCHZOH

Also the 28-OAc derivative.

-

4

11,13

Chrysartemin B

-OH 4

11,13

Position(s) of double bond@)

Chrysartemin A

Name

( i ) Ba,12-olides

Table 5 Guuianolides

15

116

Terpenoih and Steroids

117

Sesquiterpenoids

OCQ H 0L

I C=C- COzMe +

0

Me

(376)

1375)

Q

R' (377)

0

0

(378)

New additions to the pseudoguaianolide group are listed in Table 6.269-279 2hy 270

I

272

273 274

27s 27h 277

278

279

H. Riiesch and T. J. Mabry, Tetrahedron, 1969, 25, 805. H. Yoshioka, H. Riiesch, E. Rodriguez, A. Higo, J. A. Mears, T. J. Mabry, J. G . Calzada A, and X. A. Dominguez, Tetrahedron, 1970,26,2167. A. Romo de Vivar, M. Aguilar, H. Yoshioka, A. Higo, E. Rodriguez, J. A. Mears, and T. J. Mabry, Tetrahedron, 1970, 26, 2775. R. W. Doskotch and C. D. Hufford, J. Org. Chem., 1970,35,486. F. P. Toribio and T. A. Geissman, Phytochem., 1969, 8, 313. T. G. Waddell and T. A. Geissman, Tetrahedron Letters, 1969, 515. W. Herz, P. S. Subramaniam, and N. Dennis, J. Org. Chem., 1969,34, 2915. T. A. Geissman, S. Griffin, T. G. Waddell, and H. H. Chen, Phytochem., 1969,8, 145. K. Aota, C. N. Caughlan, M. T. Emerson, W. Herz, S. Inayama, and Mazhar-ulHaque, J. Org. Chem., 1970, 35, 1448. M. Yanagita, S. Inayama, T. Kawamata, T. b k u r a , and W. Herz, Tetrahedron Letters, 1969, 2073; M. Yanagita, S. Inayama, and T. Kawamata, Tetrahedron Letters, 1970, 1 3 1 ; T. Sekita, S. Inayama, and Y. Iitaka, ibid., p. 135. M. Yanagita, S. Inayama, and T. Kawamata, Tetrahedron Letters, 1970, 3007.

Conchosin-B Damsinic acid

Tetraneurin-A Tetraneurin-B Tetraneurin-C Tetraneurin-D Conchosin-A

Name

( i ) 6p, 12-olides

-

-

-

-

-

Position of double bond

Table 6 Pseudoguaianolides

la

1 5-AC

la la la l a ; 48

-

1 5-AC

-

14-AC 4p-Ac; 14-AC 14-AC

*R

-OH

4-keto: 2p,15-oxido 4-keto la-H; 4-keto; 11-COZH (not lactonised)

-

-

4-keto 4-keto

Other

27 1 272

269 270 270 270 27 1

Ref:

0

00

c

11,13 273 233 2,3

-

11,13 11,13 11,13 11,13 11,13 11,13 11~3

Position of double bond

-OH

2a ; 401 2a ; 4a 2a ; 4a 2a ; 4a 9 9 9

-

28; 4a 4a; 68 4a 48

-

-

-

-

6-C(O)C(Me):CH, 6-angeloy l

-

*Glut

$$ ;

HO

=

OH

CH~OAC

Other 4-keto

1lp-CH,piperidyl 4-keto 4-keto 4-keto

-

1la-CH,piperidyl

-

-

2a-flGlucd 68-AC 28-AC 28-AC; 68-AC 38-AC 38-AC;48-AC

-OR

SpJ2-olide. * 8a, 12-olide. Unassigned lactone stereochemistry.

Paucin" Flexuosin Ab Alternilinb 2-Acetylflexuosin Ab 3-Acetylcumanin" 3,4-Diacetylcumanin" Pulchellinb Pulchellidineb Neopulchellin" Neopulchellidine" Radiatin' Bailey o h ' Plenolin'

Name

(ii) 8,12-olides

Table 6 (continued)

15

261,267,274 275 275 275 276 276 277,278 278 279 279 26 1 26 1 26 1

Ref.

120

Terpenoids and Steroids 15 Aristolane, Aromadendrane, efc.

The biogenesis of those sesquiterpenes with a gern-dimethyl cyclopropane ring has been considered in terms of a precursor such as (384). This compound, bicyclogermacrene, has now been isolated from the peel oil of Citrus junos, together with germacrene-B and -D.280Bicycloelemene (385), previously isolated, is an

artefact. It is reported that these two compounds are in thermal equilibrium but give rise irreversibly to another isomer, isobicyclogermacrene (386). Acidcatalysed rearrangement of (384) gives ledrene (387) and 6-cadinene. Co-occurring with bicyclogermacrene are spatulenol (388) and globulol(389).

Q

Q

Q

HO

Ramage et aLZo3have pointed out that homoallylic participation of the double bond in the displacement of the tertiary hydroxy-group in a compound such as (390) could bring about the formation of the aristolane-type sesquiterpenes e.g., l(l0)-aristolene (391). Another addition to the aristolane class is debilone (392)28' and it is probable that the novel peroxide nardosinone (393), isolated from Nardostachys chinensis, belongs to this group.282 Pesnelle and TeisseireZB3 have developed a four-step procedure for the isomerisation of the more readily 280

282

283

K . Nishimura, N. Shinoda, and Y. Hirose, Tetrahedron Letters, 1969, 3097. J. Kfepinsky, G. Jommi, Z . Samek, and F. Sorm, Cull. Czech. Chern. Cornrn., 1970, 35, 745. G. Riicker, Chem. Ber., 1969, 102,2691 et seq. P . Pesnelle and P. Teisseire, Recherches, 1969, 17, 121.

Sesquiterpenoids

q (390)

12 1

(391)

::‘s. CQ

OH

0

0

(393)

(392)

(394)

available l(10)-aristolene (391) (calarene) to the rarer 9-aristolene (394). Piers and c o - ~ o r k e r s ~ have * ~ reported a very elegant synthesis of aristolone (395) involving the facile intramolecular cyclisation of the olefinic diazoketone (396) which was derived from 2,3-dimethylcyclohexanonein an economical number of steps. This cyclisation, however, was not stereoselective since it gave both aristolone (395) and the 6,7-epi-compound (397). In order that the relative stereochemistry of aristolone could be unambiguously assigned, Piers et al.285achieved a stereoselective synthesis of the racemic decalone (398) which was identical with the ( -)-decalone (398) prepared from authentic (- )-arktolone.

qo H

(397)

Complete details of the total syntheses of the antipode of (+)-aromadendrene This and two related diastereoisomers have been reported by Buchi et 284

285

286

E. Piers, R. W. Britton, and W. de Waal, Canad. J. Chem., 1969,47, 831. E. Piers, R. W. Britton, and W. de Waal, Canad. J . Chem., 1969, 47, 4307. G. Buchi, W. Hofheinz, and J. V. Paukstelis, J . Amer. Chem. SOC.,1969,91,6473.

122

Terpenoids and Steroids

work unambiguously established the relative and absolute stereochemistry of aromadendrene (399), allo-aromadendrene (400),globulol (389), viridoflorol (401), and ledol(402).

Q (399)

16 Non-farnesyl Sesquiterpenoids

There are relatively few sesquiterpenoids which cannot be derived from a farnesyl precursor either directly or indirectly. Recent examples of this rare group are furoventalene (403),287 the keto-lactone the phenol (405),289 and the revised structure of humbertiol (406).290 Proposed biogenetic schemes for these compounds involve the combination of a C,, monoterpene unit (either acyclic or cyclic) with a C5 unit (e.g.,dimethylallyl pyrophosphate).

(405)

A. J . Weinheimer and P. H. Washecheck, Tetrahedron Letters, 1969, 3315. F. Bohlmann, C. Zdero, and M. Grenz, Tetrahedron Letters, 1969, 2417. F. Bohlmann and M. Grenz, Tetrahedron Letters, 1969, 1005. D. Raulais and D. Billet, Bull. SOC.chim. France, 1970, 2401.

lB8

**’

290

(406)

Sesquiterpenoids

123

Finally, it has been reported2” that a ‘sesquiterpene’ compound, bilobalid A, isolated from the leaves of the Ginkgo tree, appears to have structural similarities with the unusual diterpenoid ginkgolides, in which one of the y-lactone rings (ring F) has been removed.

K. Weinges and W. Bahr, Annalen, 1969,124, 2 14.

3 Diterpenoids BY J. R. HANSON

1 Introduction

This chapter is subdivided into sections, each based on the major skeletal types of diterpenes. A widely circulated report' on the 'Common and Systematic Nomenclature of Cyclic Diterpenes' by J. W. Rowe, contains proposals made to I.U.P.A.C.for the naming and numbering of diterpenes. Although these proposals have not yet been officially accepted, they are applied in a number of publications and have been used in the present Report. 2 Bicyclic Diterpenoids

The Labdane Series.-The conifers are an important source of diterpenes, and a number have been investigated during the past year. Dacrydium colensoi has been a fruitful source of diterpenes of the manoyl oxide and sandaracopimaradiene types. The neutral fraction contains2" an unusual lactonic homoditerpene (1) which was correlated with colensan-2-one (2). N.m.r. was used to establish the stereochemistry of the lactone-ring A fusion, and together with chemical evidence suggests that the five-membered ring A of colensan derivatives takes up either the p-envelope or half-chair conformations. The structure of this unusual diterpene was confirmed by a partial synthesiszb from la-methoxycarbonylcolensan-2-one. As this tree contains both homo- and A-nor-diterpenes, it is interesting to speculate on the origin of the extra carbon atom of the homoditerpene.

(1)

(2)

J. W. Rowe, Forest Products Laboratory, U.S. Dept. of Agriculture, Madison, Wisconsin.

* P. K . Grant and M . J . A . McGrath, Tetrahedron, 1970, 26, 1619; L. N. Nixon, and J . M. Robertson, ibid., p. 1631.

P. K . Grant,

D iterpenoids

125

A thorough study of Dacrydiurn kirkii showed3 that the heartwood contains isopimaradiene, sclarene, cis- and trans-biformene, manoyl oxide, 14,15-bisnorlabda-8(17)-en-13-one, labda-8(17),13-dien-15-01, manool, isopimaradienol, torolusol, sandaracopimaradiene-38,19diol, and isopimaric acid, along with two new compounds, 7a-hydroxymanool (3), and 2B,3Bdihydroxymanoyl oxide (4). Their structures, and in particular the location of the hydroxy-groups, were assigned on n.m.r. evidence.

&OH

H

'OH

Ho

H

13-Epimanool has been detected in the neutral extracts of Larix europaea4 and in the bark of the Sitka ~ p r u c e .Cupressus ~ resins have been examined by g.l.c.6 and imbricatolic acid (5) identified in all but Cupressus semperuirens. This acid co-occurs with the cis- and trans-communic acids and with sandaracopimaric acid. A'3(161-Communicacid has been isolated' as its methyl ester from Callitris columelfaris. During this work the thermal isomerisation of the conjugated diene of communic acid was noted. The structures and stereochemistry of some 8-0x0- 14-norlabdanes derived from the ozonolysis of methyl communate have been clarified.' Copaifera multijuga contains' copaiferolic acid and a new labdane acid, 11-hydroxylabda-8(17),13dien-15-0ic acid. The leaf oil of Charnaecyparis nootkatensis contains two new manoyl oxides. They have been assigned" the 8-epimanoyl oxide (6) and 8,13-epimanoyl oxide (7) structures. The C-13 stereochemistry was based on an interesting and potentially useful cyclisation catalysed

R. C. Cambie, P. K. Grant, C. Huntrakul, and R. J. Weston, Austral. J . Chem., 1969, 22, 1691.

K. Bruns, Tetrahedron, 1969, 25, 1771. I. H. Rogers and L. R. Rozon, Canad. J . Chem., 1970,48, 1021. L. J. Gough and J. S. Mills, Phytochemistry, 1970, 9, 1093. ' P. W. Atkinson and W. D. Crow, Tetrahedron, 1970,26, 1935. a R. M. Carman, D. E. Cowley, and R. A. Marty, Austral. J. Chem., 1969, 22, 1681. F. Delle Monache, T. Leoncio d'Albuquerque, G. Delle Monache, and G. B. Marini Bettolo, Ann. Chim. (Italy), 1970, 60, 233. l o Y . S . Cheng and E. von Rudloff, Tetrahedron Letters, 1970, 1131.

126

Terpenoidrs and Steroids

by Amberlyst X N 1005 resin. The oxides gave isopimara-8,15-diene and pimara8,15-diene respectively, in which the C-13 stereochemistry was retained. The formation of a common manool trihydrochloride from manool, sclareol, manoyl oxide, 13-epimanoyl oxide, biformene, and abienol played an important part in the structural correlation between these diterpenes. Earlier proposals had suggested" an 8-equatorial chlorine atom, but in a paper12 clarifying the various 8,13,15-chloro-labdanes,the analogous monohydrochloride from tetrahydroabienol was assigned the 8-axial stereochemistry (8). Dehydrochlorination of this isomer yields all three expected olefins, whilst the equatorial epimer affords only the A7@)-and A8(l 7)-olefins.

Ruzicka's proposal that the pimaradienes originate from the cyclisation of labdane or manool precursors has stimulated the study of the in uitro acidcatalysed cyclisation of these compounds. Manool, 13-epimanool, and the cisand truns-labda-8(17),13-dien-15-01~gave the same mixture of products, i.e. asymmetry in the side-chain was destroyed prior to cyclisation. Treatment with acetic acid-sulphuric acid mixtures for 3 hours afforded13 a C-13 epimeric mixture of pimaradienes (9). After 150 hours the isopimara-8,15-diene was converted to a mixture of products, 50% of which was the rosadiene (10). This cyclisation has been extended to a synthesis of rosenonolactone from methyl cupressate (see ref. 159). Using formic acid as the cyclising agent,I4 the tricyclic pimaradiene, sandaracopimaradiene, and rosadiene were formed, together with a 14ct-hydroxy-beyerane (11). Labelling experiments at C-14 of the labdane progenitors have established' '-I7 that this tetracyclic product is formed through an eight-membered ring intermediate (13) rather than by cyclisation of a pimaradiene (Scheme 1). Treatment of the rosadiene (10) with hydrogen chloride in acetic acid yields rimuene (12). Although marrubiin has been studied since 1842 and its structure and stereochemistry are now well-defined," it is probably an artefact arising from a spiroI I

l2

l3 l4

l6

I'

R. M. Carman and N. Dennis, Austral. J . Chem., 1967,20, 163. R. M. Carman and H. C. Deeth, Austral. J . Chem., 1969,22,2161. T. McCreadie and K. H. Overton, Chem. Comm., 1968, 288. E. Wenkert and Z. Kumazawa, Chem. Comm.,1968, 140. J. L. Fourrey, J. Polonsky, and E. Wenkert, Chem. Comm., 1969, 714. 0. E. Edwards and R. S. Rosich, Cunud. J . Chem., 1968,46,1113 ; 0. E. Edwards and B. S. Mootoo, ibid., 1969,47, 1189. S. F. Hall and A. C. Oehlschlager, Chem. Comm., 1969, 1157. L. Mangoni, M. Adinolfi, G. Laonigro, and E. Doria, Tetrahedron Letters, 1968,4167; D. M. S. Wheeler, M. M. Wheeler, M. Fetizon, and W. H. Castine, Tetrahedron, 1967, 23, 3909; R. A. Appleton, J. W. B. Fulke, M. S. Henderson, and R. McCrindle, J . Chem. SOC.(C), 1967, 1943.

127

Diterpenoids

Scheme 1

ether (14) - premarrubiin - during its isolation from Marrubiurn u u l g ~ r e . ' ~ Analogous spiro-ethers have been reported from Solidago ~ a n a d e n s i sand ~~ Leonotis leonorus.22 Further evidence concerning the stereochemistry of marrubiin at the c-8and c-9positions has also appeared.20 The lactone ring distorts ring B to a twist-boat form. Leonotin, a furanoid diterpene isolated2' from Leonotis nepetaefolia and L. dysophylla,22ais 8P-hydroxymarrubiin (15). When

fl2 co-0 l9 'O

''

I,c^;" co-0

M. S. Henderson and R. McCrindle, J . Chern. SOC.(0,1969,2014. L. J . Stephens and D. M. S. Wheeler, Tetrahedron, 1970, 26, 1561. J. D. White, P. S. Manchard, and W. B. Whalley, Chern. Comm., 1969, 1315. a E. R. Kaplan, K. Naidu, and D. E. A. Rivett, J. Chem. SOC.(C), 1970, 1656; E. R. Kaplan and D. E. A. Rivett, J. Chem. SOC.(C), 1968, 262.

128

Terpenoids and Steroids

this was refluxed with phosphorus trichloride in pyridine it was transformed into an epoxide which on reduction with lithium aluminium hydride afforded marrubenol. The trans-diaxial diol was also supported by its inertness towards periodate. Oxidation with chromium trioxide afforded a 13 -P 9 ; 19 * 6-y-dilactone and a 13 -+8; 19 -+ 6-6y-dilactone. The related species, L. leonarus, also contains22ba lactone-spiro-ether(16) reminiscent of premarrubin. Solidagenone (1 7) and the related 9-13 ethers have been isolated23afrom Solidago canadensis. The structure was assigned on the basis of spectral data and the hydrogenolysis of the hydroxy-group of (17) to form, depending upon the reagent, either the ag- or py-unsaturated ketone. The relationship of the tertiary hydroxy-group, furan ring, and orb-unsaturated ketone permitted a number of acid-catalysed rearrangements. Solidagenone first rearranges23bto give a dienone (18) which cyclises to (19), the methoxy-ketone (20) being a minor product.

H

co-0

0

(16)

The Clerodane Series-Solidago species also contain a range of clerodane diterpenes. Solidago elongata contains24kolavenol(21),kolavenicacid, 6-acetoxyand 6-angeloyloxy-kolavenicacids, kolavelool(22),and 6-angeloyloxykolavelool, together with a group of ap-unsaturated butenolides, the elongatolides A-E (23) and (24), formulated almost entirely on spectroscopic evidence. Solidagonic acid, isolated from S. altissima, has been formulated as 7a-acetoxykolavenic acid. 23

24

zJ

"T. Anthonsen, P. H. McCabe, R. McCrindle, and R. D. H. Murray, Tetrahedron, 1969, 25,2233; bT.Anthonsen, P. H. McCabe, R. McCrindle, R. D. H. Murray, and G. A. R. Young, Tetrahedron, 1970, 26, 3091. T. Anthonsen and R. McCrindle, Acta Chem. Scand., 1969,23, 1068. S. Kusumoto, T. Okazaki, A. Ohsuka, and M. Kotaki, Bull. Chern. SOC.Japan, 1969, 42, 812.

D iterpenoids

129

= OH Elongatolide A R = OAc Elongatolide B R = OAng Elongatolide C

R

0

fl:

R = OAc Elongatolide D R = OAng Elongatolide E

R

(24)

0

The widespread occurrence of the clerodane skeleton is exemplified26by the isolation of (-)-hardwickiic acid (25), the C-15 monomethyl ester of kolavenic acid, and two furanoid substances, agbaninol (26, R = H) and agbanindiol B (26, R = OH) from Gossweilerodendron balsarniferurn (Caesalpiniaceae). Agbanindiol A has the structure (27). These compounds have been correlated with kolavenic acid and hardwickiic acid.

CH2OH

HO” (27) 26

D. E. U. Ekongand J. I. Okogun, J. Chem. SOC.(0,1969,2153.

130

Terpenoids and Steroids

Chettaphanin-1 (28), from Adenochlaena siamensis (E~phorbiaceae),~' represents an interesting intermediate stage in the formation of the clerodane skeleton in which C-10 but not C-4 methyl migration has occurred. The structure of this diterpene was based on dehydrogenation of the corresponding tetra-ol to 1,2,5trimethylnaphthalene and formation of a trienone (29) by dehydration and dehydrogenation. Cistodiol (30, R = C H 2 0 H ) and cistodioic acid (30, R = C 0 2 H ) are28 members of the biogenetically interesting cis-fused clerodane series, as opposed to the normal trans-fused series related to kolavenol. Cistus monspeliensis, in which they occur, curiously also contains 8a,l5-labdanediol. Fibleucin (31), isolated2' from Fibraurea chloroleuca (Menispermaceae), is 7(8)-dehydrocolumbin. Chasmanthin, fibraurin, and 6-hydroxy-fibraurin occur in the same plant.30 With a high level of oxygenation, the structures of these compounds were derived from their n.m.r. spectra. Fibraurin, the 2,3-epoxide of fibleucin, was correlated with its 7(8)-dihydro-derivative, palmarin. 0

(,;".'

0

p

& 0 OH

(31)

3 Tricyclic Diterpedds

Pimaraaes.-Sandaracopimaradien- 19-01 is found3 in Dacrydium colensoi. The heartwood of D. biforme contains3* isopimara-7,15-diene and 1827

28

29

30

A. Sato, M. Kurabayashi, H. Nagahori, A. Ogiso, and H. Mishima, Tetrahedron Letters, 1970, 1095. G. Berti, 0. Livi, and D. Segnini, Tetrahedron Letters, 1970, 1401. K. Ito and H. Furukawa, Chem. Comm.,1969,653. T. Hori, A. K. Kiang, K. Nakanishi, S. Sasaki, and M. C. Woods, Tetrahedron, 1967, 23, 2649.

3*

32

P. K. Grant, C. Huntrakul, and J. M. Robertson, Austral. J . Chem., 1969, 22, 1265. R. A. Appleton and J . Roeraade, Chem. Comm., 1969, 1407.

D it erpenoids

131

norisopimara4( 19),7,15-triene, which was synthesised by the oxidative decarboxylation of isopimaric acid with lead tetra-acetate in pyridine. Aralia racemosa contains33 (-)-pimara-8(14),15-diene, (-)-kaurene, and (-)pimara-8( 14),15-dien-19-oic acid. The corresponding 7a-hydroxy-(- )-pimara8(14),15-dien-19-oicacid and 7-keto-acids have been found34 in Aralia cordata. Their structures were proven by oxidation of the methyl ester of (-)-pimara8(14),15-dien-19-oic acid with selenium dioxide, which afforded the 9P-hydroxyand 7P-hydroxy-acids. A tetra-ol related to darutigenol has been isolated3 from Siegesbuckia pubescens and shown to be 68,15,16,18-tetrahydroxy-(-)-pimar8(14)-ene(32). The presence of an 18-hydroxy-group,the stereochemistry of which was linked with the 6-position by the formation of an 18+6 ether, is interesting in view of the fact that 16,17-dihydroxy-l6P-(-)-kauran-19-oic acid occurs in the same plant. Two fungal isopimaradienes, virescenol A (33, R = OH) and virescenol B (33, R = H), have been isolated36 as their P-D-altropyranosides, from Oospora virescens. Spectral data and a correlation with sandaracopimara8(9),15-dien-3P-ol served to establish their structure. The sugar is attached to the primary alcohol.

(32)

(33)

Abietanes.-Abieta-8,11,13-triene, which was prepared from dehydroabietic ' acid, has been isolated from Thujopsis dolabrata and Podocarpus ferrugineu~.~ Oxidation4 of the neutral carbonyl fraction obtained from Larix europaea led to the isolation of abietic, neoabietic, dehydroabietic, pimaric, and isopimaric acids, implying the presence of the parent aldehydes in the extract. 4-Epiabietic acid and 4-epipalustric acid have been isolated38 from Juniperus phoenicea. Callitrisic acid (4-epidehydro-abietic acid)39has been related to podocarpic acid through a common phenolic deri~ative.~'It had previously been synthesised4' from dimethyl agathate. 33 34

35

36

37

38

39

40 41

J. R. Hanson and A. F. White, Phytochemistry, 1970,9, 1359. S. Mihashi, I. Yanagisawa, 0. Tanaka, and S. Shibata, Tetrahedron Letters, 1969, 1683. L. Canonica, B. Rindone, C. Scolastico, K. D. Han, and J. H. Kim, Tetrahedron Letters, 1969, 4801. J. Polonsky, Z . Baskerevitch, N. Cagnoli-Bellavita, and P. Ceccherelli, Bull. SOC.chim. France, 1970, 1912. M. Kitadani, A. Yoshikoshi, Y. Kitahara, J . de P. Campello, J. D. McChesney, D. J. Watts, and E. Wenkert, Chem. and Pharm. Bull. (Japan), 1970, 18,402. C. Tabacik and C. Poisson, Bull. SOC.chim. France, 1969, 3264. R. M. Carman and H. C. Deeth, Austral. J . Chem., 1967, 20, 2789; L. J. Gough, Tetrahedron Letters, 1968, 295. Y. S. Chuah and A. D. Ward, Austral. J. Chem., 1969,22, 1333. R. M. Carman, H. C. Deeth, R. A. Marty, K. Mori, and M. Matsui, Tetrahedron Letters, 1968, 3359.

132

Terpenoids and Steroids

Many diterpene hydrocarbons have been purified by chromatography over silver nitrate on silica gel. However, this system is capable of nitrating phenolic d i t e r p e n e ~ .Ferruginol ~~ and podocarpic acid afford a 7-12% yield of their 11-nitro-derivatives under typical chromatographic conditions. The dried roots of Saluia miltiorrhiza form the Chinese drug ‘tan-shen’, from which a number of furanonaphthoquinones-the tanshinones, isotanshinones, and cryptotanshinones-have been isolated.43 The roots also contain an o-naphthoquinone, miltirone, whose structure (34)was assigned44on the basis of its spectral properties and the formation of a triacetate which on hydrolysis and oxidation gave a hydroxy-l,4-naphthoquinone. An interesting group of biologically active diterpenes, which possess growth inhibitory properties, has been isolated from conifers. They include the tumour-

/H inhibitory quinone-methides, taxodione(35, R = 0)and taxodone(35, R = ,, ), ‘OH from Taxodium distichum (Cupressale~).~~ The structures, which are reminiscent of fuerstione (36),46are based on their U.V. and n.m.r. spectra and conversion to 11,12-dimethoxyabieta-8,11,13-triene, which was also obtained from sugiol. The podolactones A and B (37, R = H and OH respectively) isolated47 from Podo-

42 43

44 45

46 47

E. Wenkert, D. J . Watts, and L. L. Davis, Chem. Comm., 1969, 1293. H. Kakisawa, T. Hayashi, and T. Yamazaki, Tetrahedron Letters, 1969, 301 ; A. C. Baillie and R. H. Thomson, J . Chem. Soc. (C), 1968,48. T. Hayashi, H. Kakisawa, H. Y. Hsu, and Y. P. Chen, Chem. Comm., 1970,299. S . Morris Kupchan, A. Karim, and C. Marcks, J. Org. Chem., 1969,34, 3912. D. Karanatsios, J. S. Scarpa, and C. H. Eugster, Helo. Chim. A d a , 1966, 49, 11 5 1 . M. N. Galbraith, D. H. S. Horn, J. M. Sasse, and D. Adamson, Chem. Comm., 1970, 170.

133

Diterpenoids

carpus neriifolius (Podocarpales), are powerful inhibitors of plant cell expansion and division, comparable in activity with abscisic acid. The structures followed from their n,m.r. spectra, in which all the protons could be distinguished. Confirmation came from the conversion of podolactone B to an oxidation product (38) of inumakilactone 3 - a ~ e t a t e .The ~ ~ related nagilactone C4' shows a similar activity. The structure and stereochemistry of nagilactones C and D (39) and (40) respectively,have been elucidated by detailed n.m.r. studies making use of solvent shifts, coupling constants, and the nuclear Overhauser effect. 0

0

& & HO

-

OH

co-0 (39)

HO

,-

co-0 (4)

Cassanes.--;C-Caesalpin (4 I), from Caesalpinia pul~herrima,~'possesses the cassane skeleton, and is thus related to the bitter principles isolated from the seeds of Caesalpinia bonducella. Cassminic acid is a minor constituent of the bark of Erythrophleurn guineense. Spectroscopic measurements and an interrelationship with cassane-16,19-dioicacid have established"" it as 6-0x0-7-hydroxycass-13ene-16,lg-dioic acid. N.m.r. measurements and bromination-dehydrobromination studies are in with the axial 14a-configuration now accepted for the cassamic acid diterpenes. Cleistanthol (42), isolated5* from Cleistanthus schlechteri, is an unusual diterpene. In contrast to the cassane diterpenes, its structure results from formal 48

49

'* 51

52

S. Ito, M. Kodoma, M. Sunagawa, T. Takahashi, H. Imamura, and 0. Honda, Tetrahedron Letters, 1968, 2065; Y. Hayashi, s. Takahashi, H . Ono, and T. Sakan, Tetrahedron Letters, 1968,207 1. S. Ito, M. Kodoma, M. Sunagawa, H. Honma, Y. Hayashi, S. Takahashi, H. Ona, T. Sakan, and T. Takahashi, Tetrahedron Letters, 1969, 2951. P. Sengupta, S. Roy, and K. G. Das, Chem. andlnd., 1970, 534. ' B. Blessington, D. W. Mathieson, and A. Karim, J . Chem. SOC.(C), 1970,1703; D. W. Mathieson and A. Karim, J. Chem. SOC.(C), 1970, 1705. E. J. McGarry, K. H. Pegel, L. Phillips, and E. S. Waight, Chem. Comm., 1969, 1074.

134

Terpenoih and Steroids

migration of the C-13 ethyl group of a pimaradiene progenitor. This carbon skeleton was inferred from dehydrogenation to a phenanthrol which bore a close resemblance to a phenanthrol obtained from methyl vinhaticoate, suggesting that they differed only by interchange of a methyl and ethyl substituent. The position of the phenolic hydroxy-group at C-13 was established by oxidation of the dihydro-triacetate to a 7-ketone followed by alkaline hydrolysis. The U.V. spectrum of the product was that of a p-hydroxyphenyl ketone. Location of the vicinal diol on ring A followed from elimination of the dimesylate to give an enol-mesylate and a ring-contraction product containing the part structure (43).

p: The Chemistry of Ring L-TWO routes have been explored to yield ring A olefins. Nitrous acid deamination of 18-norabieta-8,l 1,13-triene-4-amine53uor the corresponding amine in the 12-methoxypodocarpa-8,11,13-triene affords a mixture of A3- and A4-olefins and a 4-acetate derived from a C-4 carbonium ion. A similar mixture is obtained from the lead tetra-acetate decarboxylation of dehydroabietic acids4 and 12-methoxypodocarpic acid.55 In the latter case there are some minor lactonic products (44;R = 0 and

("

)

'OAc which have been showns6 to arise from the lead tetra-acetate oxidation of a A6-olefin. No lactones were obtained by the action of lead tetra-acetate on the 7-ketone. Hydroboronation of the olefm mixture derived from dehydroabietic acid affordeds4 a primary alcohol (45) and the 3a-alcohol (46)together with a minor amount of the 7-ketone, of uncertain origin. Selective epoxidation of the olefin mixture from 0-methylpodocarpic acid with monoperphthalic acid gaves7 a separable mixture of the 344a- and 4g5a-epoxides together with the exocyclic A4-olefin. The 3g4a-epoxide (47) was reduced with lithium aluminium hydride to form the 3a-alcohol, and the latter was oxidised to a 3-ketone. The epoxide (47) underwent rearrangement to form the A-nor-aldehyde(48) on treatment with 53

54

55 56 ST

a R. N. Seelye and W. B. Watkins, Tetrahedron, 1969, 25, 447; C. R . Bennett, R. C. Cambie, and T. J. Fullerton, Austral. J . Chem., 1968, 21, 2473. J. W. Huffman, J . Org. Chem., 1970, 35, 478. C. R. Bennett and R. C. Cambie, Tetrahedron, 1967, 23, 927. C. R. Bennett, R. C. Cambie, and W. A. Denney, Austral. J . Chem., 1969,22, 1069. R. C. Cambie and W. A. Denny, Austral. J . Chem., 1969,22, 1699.

135

D iterpeno ids OMe

I

boron trifluoride. On the other hand, rearrangement of the 4a,Sa-epoxide (49) gave a mixture of ~-nor-5-acetylcompound (50), a 5p-methyl bisnorpodocarpatriene (51), and a diene (52). OMe

@ CHO

The selective epoxidation procedure permitted the ready isolation of the exocyclic olefin. On ozonolysis this gave a 4-oxo-compound58 from which a 3-0x0-derivativewas prepared. Thus, condensation with benzaldehyde, reduction of the ketone, dehydration, and cleavage of the benzylidene compound with osmium tetroxide and sodium periodate gave 12-rnethoxy-3-oxo-l8,19-bisnorpodocarpa-4,8,11,13-tetraene.This sequence was also used to prepare the corresponding abietatetraene. A number of N-substituted derivatives of dehydroabietylamine have been prepared by total59and partial synthesis"' and examined for their antimicrobial activity.

The ChemiStry of Ring &-The 19+68 lactone (44,R = H) of the 12-methoxypodocarpa-8,11,13-trieneseries was obtained" by the successive dehydration of the 701- and 7~-hydroxy-lactoneswith toluene-p-sulphonic acid in acetic anhydride and hydrogenation of the resulting A6-end-lactone over palladiumcharcoal. Examination of the width of the C-6 proton resonance led to the 58

59 6o 61

R. C. Cambie, C. R. Bennett, R. A. Franich, and T. J. Fullerton, Austral. J . Chem., 1969, 22, 171 I . R. Albrecht, H. Heidepriem, and E. Schroder, Annalen, 1969, 725, 154. R. Albrecht, C. Rufer, and E. Schroder, Annalen, 1969, 728, 184. R. C. Cambie and W. A. Denny, Austral. J . Chem., 1969,22, 1989.

Terpenoidr and Steroids

136

suggestion that ring B takes up a twist-boat conformation. A similar conformation has been proposed in the marrubiin series and for the tetracyclic kaurenolide lactones. Hydride reduction of the 7-ketone affords the 7P-alcohols. Treatment of the 7-keto-lactone with sodium hydroxide in methanol affords a diosphenol. This 6,7-diosphenol did not undergo benzilic acid ring-contraction, but rather isomerised in alkali to form an ~/~-cis-6,7-diketone. There has been some controversy over the stereochemistry of bromination of methyl 12-methoxy-7-oxopodocarpate. However, an X-ray structure analysis has shown6’ that the 6-bromine atom occupies the a-configuration, with ring B in a boat form. The 6a-bromo-7-ketone (53) in the totarol series, when treated with sodium hydrogen carbonate in dimethyl sulphoxide, undergoes63an unusual fragmentation reaction leading to the formation of a ten-membered ring (54). The derived 5,6-mono-epoxide rearranges to the substituted naphthalene ( 5 5 ) with sulphuric acid.

OH

0

Br

(55)

(54)

(53)

Interest in the structure-activity relationships of the gibberellins has led to the partial synthesis of the four stereoisomers about positions 5 and 6 of the hexahydrofluorene (57). The unsaturated acid anhydride (56) was prepared by the benzilic acid ring-contraction of the 6,7-diketones obtained from oxidation of desisopropyl dehydroabietic and converted65 into the saturated acids by reduction and base-catalysed epimerisation.

\

/

C 0 2 H C02H

0

The Chemistry of Ring c.-The structure and stereochemistry of the various dihydroabietic acids has been ~ l a r i f i e d . ~ ~Direct ? ~ ’ reduction of abietic acid (58), by either catalytic or chemical means, can give rise to products of 1,2- or 62

63 64

65 66

6’

G. R. Clark and T. N. Waters, J. Chem. Sac. (0,1970,887. R. C. Cambie, D. R. Crump, and R. N. Duve, Austral. J. Chem., 1969,22, 1975. J. F. Grove and B. J. Riley, J. Chem. SOC.,1961, 1105; A. Tahara, 0. Hoshino, and T. Ohsawa, Chem. and Pharm. Bull. (Japan), 1969,17,54,64,78. A. Tahara and Y . Ohtsuka, Chem. and Pharm. Bull. (Japan), 1970, 18, 859. A. W. Burgstahler, J . N. Marx, and D. F. Zinkel, J. Org. Chem., 1969,34, 1550. J. W. Huffman, J. A. Alford, and R . R . Sobti, J . Org. Chern., 1970,35,473.

137

Diterpeno ids

1,4-addition (59-64) with varying stereochemistry at C-8 and C-13. Under neutral or basic conditions, when double-bond isomerisations are less likely, catalytic reduction of abietic acid gives not only acids arising from attack at the ‘a’ face (60 and 64)but also some ‘p’ acids (e.g. 62). Lithium-ammonia reduction, with a preference for axial protonation, affords acids (59), (60),(62),and (63), with (59) as the major product. The double bond in these acids was located by ozonolysis to the keto-aldehydes, which were distinguished by their n.m.r. spectra.66 The configuration at C-13 was established by making use of the y-lactone S&lactone (65 ;;t66) equilibrium position and comparing the isomer distribution. The various dihydro-acids were related to three of the four tetrahydroabietic acids. One of these acids has been converted to fichtelite (18norabietane) by a Hofmann degradation followed by catalytic reduction of the resulting olefin.68 In a number of instances the rule of ‘a’ attack based on steroidal analogy does not apply to ring c of the tricyclic diterpenes. Thus, osmylation of the A’3(14)-doublebond affords the p-glygol and not, as supposed earlier, the a-glyc01.~~

C02H

+

(58)

+

R‘

(65)

(66)

The n.m.r. spectra of the dihydrochloride and dihydrobromide of methyl abietate support7’ the structure (67) rather than the 8,13-derivative previously proposed. Elimination of one mole of hydrogen chloride from the dihydrochloride affords the A7,* olefin. Treatment of the dihydrobromide with sodium ethoxide gives the diene (68). 68 69 ’O

A. W. Burgstahler and J. N. Marx, J . Org. Chem., 1969, 34, 1562. B. E. Cross and P. L. Myers, J . Chem. SOC.(0,1969,711. R. H . B. Galt and A. K. Saksena, J . Chem. SOC.( C ) , 1969, 1033.

Terpenoids and Steroids

138

Previous work on darutigenol had shown that the double bond undergoes isomerisation to the A8(9)-position rather than reduction. Under vigorous conditions, however, hydrogenation does take place.7 The 8(14) a-epoxide (69) derived72 from the 16-norpimarane readily opens, with the formation of a y-lactone (70). On the other hand, the P-epoxide, when exposed to a Lewis acid, gives the product (71) of backbone rearrangement. of sandaracopimarThe generation of a C-8 carbonium ion by dehydrati~n’~ 15-en-8P-01 gives only tricyclic products such as sandaracopimaradiene and isopimaradiene, together with the backbone-rearrangement product (72).

@ ‘*,

C02H

CO,Me H

C02Me

do:oH (67)

C0,Me

No tetracyclic products were isolated. The importance of the vinyl group stereochemistry in cyclisation is by the oxymercuration-demercuration of methyl pimarate and methyl sandaracopimarate. The former affords an 8-15 ether whilst the latter gives a 15-alcohol. Intramolecular functionalisation of the isopropyl group of dehydroabietic acid has been a ~ h i e v e d ’by ~ the cyclisation of 12-carboxy-group to form a y-lactone (73) using lead tetra-acetate as the oxidant. Thermolysis of the 12diazomethyl ketone also leads to cyclisation. Direct replacement of the isopropyl group by a nitro-group occurs76in the nitration of methyl 12-acetylabieta-8,11,13trien-18-oate. The 13-nitro-compound (74) was converted through the amine to Gh. Angles d’Auriac, F. Derguini, and A. Diara, Bull. SOC.chim. France, 1970, 1846. J . W. ApSimon and H . Krehm, Canad. J . Chem., 1969,47, 2859. ’’ W. J . Chin, R . E. Corbett, D. R . Lauren, and R . A . J. Smith, Austral. J . Chem., 1969, 22, 2033. 7 4 J. W. ApSimon and H. Krehm, Canad. J. Chem., 1969,47, 2865. 7 5 R. C. Cambie and R. A. Franich, Chem. Comm., 1969, 725. l 6 R. C. Cambie and R. A. Franich, Chem. Comm., 1970, 845. l2

D iterpenoids

139

a phenol, and the acetyl group was removed by oxidation to the acid and coppercatalysed decarboxylation. This gave methyl 13-hydroxypodocarpa-8,11,13trien-18-oate in 26 % overall yield from methyl abieta-8,11,13-trien-18-oate. C 0 2Me

O=C-O

(74)

(73)

Oxidation77 of methyl abiet-8(9)-en-18-oate with t-butyl chromate affords a mixture of 7- and 11-ap-unsaturated ketones, the 7,11-enedione, the l l a hydro~y-A~(~)-7-ketone, and an 8(9)-epoxy-ketone. Reduction of methyl 1l-oxo13B-abiet-8(9)-en-l8-oatewith lithium in liquid ammonia surprisingly affords78 primarily the less stable B/c-cis-fused 8a,9a compound. Reduction of the 7-0x013P-abiet-8(9)-en-18-oateaffords the 8p,9fl-cis fusion. Hydroboronation of the abieta-7,9(11)-diene system also gives the cis-fused ring-junction. The corresponding 7,ll-diketone was isomerised to the B/c-trans-fused isomer with the 8a,9/?-configuration. Hydroboronation of the 9(11) double bond proceeds from both the a and the faces of the molecule. Ring c appears to adopt a number of different conformations dependent upon the B/C ring junction. Consequently, extrapolation of stereochemical conclusions from the steroid series, where ring D imposes some conformational restraint, can be open to ambiguity. Dehydrobromination of methyl 11cz-bromo-12-oxopodocarpan-19-oate affords7' methyl 12-oxopodocarp-13-en-19-oate rather than the A9(11) isomer. There have been a number of studies of the oxidation of ring c with the object of preparing substrates for the synthesis of more complex diterpenes. The preparation of the keto-acids (75) and (76) from levopimaric acid and of the unsaturated ketone (77) from methyl neoabietate has been described." The ozonolysis of

10,Me

77

'' 8o

C02Me

Werner Herz and J. J. Schmid, J . Org. Chem., 1969,34, 3464. Werner Herz and J. J. Schmid, J . Org. Chem., 1969,34, 3473. R. A. Bell and M. B. Gravestock, Canad. J . Chem., 1969,47, 3661. S. W. Pelletier, C. W. J. Chang, and K. N. Iyer, J . Org. Chem., 1969, 34, 3477.

Terpenoids and Steroids

140

podocarpic acid has been examined." The hydroperoxide (78) was isolated and its stereochemistry defined by n.m.r. methods. Amongst the products of reductive work-up was the unsaturated lactone (79), with a ring c structure reminiscent of the podolactones.

M e 0 2 C&cH20H

MeOzC

(78)

( 79)

The photochemistry of the abietadienes continues to attract attention. In methanol solution, methyl abietate affords the adducts (80) and (81).'* On irradiation in ethanol, 8,13-cyclopropanes are also formed. However, methyl neoabietate undergoes a curious photochemical dehydrogenation to give (82).B3 18-Norabieta-8,11,13-trieneis obtainede4 from the irradiation of the resin acids in acetone solution.

COzMe

4 "C02Me

The study of the Diels-Alder adducts of levopimaric acid has continuedB5 with an examination of the structure and stereochemistry of the adducts with cyclopentenone and cyclopent- 1-ene-3,5-dione. The major product with cyclopentenone is the endo,cis adduct (83). The enedione gives a mixture of enolic endo,cis adducts whose stereochemistry was determined by photocyclisation to give compounds such as (84). A correlation was also achieved with the benzoquinone adduct through a Favorskii-type ring-contraction of the epoxide ( 8 5 ) to (86). The 13(14) double bond of these adducts is hindereds6 to oxidation, excepting the adduct with acetylenedicarboxylic acid. Condensation of 12hydroxymethylabiet-7(8)-en-18-oic acid with formaldehyde gives87 the cyclic ether (87). 82

83 84 85 86

R . A. Bell and M. B. Gravestock, Canad. J . Chern., 1970,48, 1105. J . C. Sircar and G. S. Fisher, J . Org. Chem., 1969,34, 404. J . C. Sircar and G. S. Fisher, Chem. and Ind., 1970, 26. R. C. A. Rottlander, Tetrahedron Letters, 1969,4127. Werner Herz and M. G . Nair, J . Org. Chem., 1969, 34,4016. Werner Herz and R. C. Blackstone, J . Org. Chem., 1969,34, 1257. D. W. Black and G. W. Hedrick, J . Org. Chem., 1969,34, 1940.

141

D it erpeno ids H

OMe

4 Tetracyclic Diterpenoids

The Kaurane-Phyllocladane Series.-There have been several chemotaxonomic studies on the distribution of diterpene hydrocarbons amongst the Podocarpaceae, Sciadopityaceae, and Taxodiaceae. A more detailed study88 of eightyfour specimens of Cryptomeria japonica reveals an infra-species variation in hydrocarbon production. Thus although sixty-six trees produced ( - )-kaurene, nine produced phyllocladene of the opposite stereochemical series. Indeed, even trees from the same seed source were not uniform in their hydrocarbon production. This paper also records a warning of the facile isomerisation of kaurene and phyllocladene into their A 15-isomers. Further e ~ a m i n a t i o nof~ Xylopia ~ aethiopica, from which xylopic acid [15pacetoxy-(- b-kaur-16-en-19-0ic acid] was isolated,90 has led to the isolation of (-)-kaur-l6-en-19-oic acid, the 1 5P-hydroxy- and 15-oxo-acidsYtogether with ( - )-kauran-l6a-ol, and ( - )-kauran-l6a,19-diol. Enhydra Jluctans (Compositae) also contains’ kauran-16a-01and ( -)-kaur-l6-en-19-oic acid. Espeletia schultzii, another member of the Compositae, contains92 (-)-kauran-l6a-ol and (-)kaura-9( 1 1),16-dien-19-oicacid. The carbon skeleton of this acid was established by dehydrogenation to pimanthrene and by conversion of the tetrahydroderivative to a-dihydrokaurene, The location of the carboxy-group at C-19 followed from its pK, value and the n.m.r. spectrum of the corresponding alcohol. The presence of the unique 9(11) double bond was established by ozonolysis and reduction of the product to an alcohol which afforded 1,6-dimethylnaphthalene on dehydrogenation ; presumably one of the methyl groups represents 88

R. A. Appleton, R. McCrindle. and K . H . Overton, Phytochernistry, 1970,9, 581. D. E. U. Ekong, E. 0. Olagbemi, and F. A. Odutola, Phytochemistry, 1969, 8, 1053. D. E. U. Ekong and A. U. Ogan, J . Chem. SOC.(C), 1968, 31 1. S. C. Pakrashi, P. P. Ghosh Dastidar, and S. K. Gupta, Phytochernistry, 1970,9, 459. C. H. Brieskorn and E. H. Pohlmann, Chem. Ber., 1969, 102, 2621.

’’)

91 92

142

Terpenoidr and Steroids

a residue from ring D. 15a-Acetoxy-(-)-kaur-l6-en-19-oic acid (grandifloric acid, previously isolatedg3"from E. grandijlora) was also obtained. 2-O-Methylgummifera. atractyligenin co-occurs with a t r a ~ t y l i g e n i in n ~Atractylis ~~ Treatment of 2a-hydroxybeyeran-15,16-epoxidewith lead tetra-acetate leads to a 2-20 ether.94 The presence ofa 15,16-epoxidepermitted isomerisation to the kaurene series. The 2q3a-diols afford a 3-mono-toluene-p-sulphonate which undergoes elimination to form the 2-ketone. 7P-Hydroxy-(- )-kaur-l6-en- 19-oic acid and 6/?,7/?-dihydroxy-( - )-kaur- 16en-19-oic acid have been ~ r e p a r e d for ~ ~investigation .~~ into the biosynthesis of gibberellic acid, the former by Meerwein-Ponndorf reduction of the 7-ketone and the latter by osmylation of a 6,7-olefin. Isodon japonicus continues to be a source of new tetracyclic diterpenoids, and an interesting biogenetic pattern of compounds is emerging. Sodoponin (88) still retains the kauranoid ~keleton.~'Its structure depends on acid-catalysed rearrangement of ring D to a 15-ketone followed by cleavage of ring B with periodate to give dihydroepinodosin. Epinodosinol has also been isolated from this source. Oridonin (89), which is also found in other Isodon species,98band shikokianin (90)have been isolatedg8"from Isodon shikokianus. Spectroscopy and acetylation established the presence of three hydroxy-groups, a hemi-acetal,

and an @-unsaturated ketone in ~ridonin.'*~Its carbon skeleton was defined by periodate oxidation to form a derivative of isodocarpin, an enmein-type diterpenoid. This degradation depended upon the presence of the ring B glycol and an alcohol at C-1. The presence of the remaining 14P-hydroxy-group was established through an interesting retro-Claisen reaction involving the fission of the 8-1 5 bond to form a 15-carboxy-group, which in turn formed a 15-14-ylactone. Hydrolysis of shikokianin and oxidation with periodate afforded a link with nodosin, another enmein-type diterpenoid. 93

94

95 96

97

98

, F.

Piozzi, V. Spiro, S. Passannanti, and R. Mondelli, Gazzetta, 1968,98, 907; L . F. Piozzi, G. Savonna, and R. Mondelli, ibid., 1969, 99, 373. J. R. Hanson, Tetrahedron, 1970, 26, 271 1 . J. R. Hanson and A. F. White, Tetrahedron, 1969, 25, 2743. B. E. Cross, J. C. Stewart, and B. L. Stoddart, Phytochernistry, 1970, 9, 1065; J. R. Hanson and J. Hawker, unpublished results. E. Fujita, T. Fujita, M. Taoka, H. Katayama, and M. Shibuya, Tetrahedron Letters, 1970,421. a T. Kubota and I. Kubo, Bull. Chem. SOC.Japan, 1969,42, 1778; E. Fujita, T. Fujita, H. Katayama, M. Shibuya, and T. Shingu, J. Chem. SOC.(C), 1970, 1674.

143

Diterpenoids

The X-ray analysis of an enmein derivative (91) has been reported.99 Ring A is a distorted chair. Ring c also takes up a distorted chair conformation unlike some other tetracyclic diterpenes, e.g. methyl gibberellate in which it adopts a boat form. Ring D is closer to a half-chair than an envelope conformation. As in the tricyclic abietane series, the conformational analysis of the tetracyclic diterpenes is more complex than that of steroids. Enmein has been convertedloO to the carboxylic acid (95) which served as an intermediate in the synthesis of kaurene, atisine, garryine, and veatchine. The key stage in this was the acyloin condensation of compound (92) to a mixture of 6+20 and 7+20 hemi-ketals and alcohols, e.g. (93) and (94). Successive reductions followed by an oxidation at C-20 afforded the carboxylic acid (95). Trichokaurin (96) has been converted"' into an enmein derivative (97). The ring A hydroxy-group was eliminated and the ring D acetoxy-group hydrogenolysed with calcium in liquid ammonia to give compound (98). This was in turn reduced under Wolff-Kishner conditions and then oxidised to give (99), thus providing evidence for the structure and absolute configuration of trichokaurin. BrCH,CO-O,

<.,

(97) 90 loo

lo'

OH

'0

0

(98)

P. Coggen and G . A. Sim, J . Chem. SOC.(B), 1969,413. E. Fujita, T. Fujit3, and H. Katayama, Tetrahedron, 1970, 26, 1009. E. Fujita, T. Fujita, M. Shibuya, and T. Shingu, Tetrahedron, 1969, 25, 2517.

144

Terpenoids and Steroids

The interconversion of the various tetracyclic skeleta has continued to attract attention. The buffered acetolysis of the toluene-p-sulphonates of the exoand endo-17-norkauran-16-01sand 17-norphyllocladan-16-01sleadslo2 to a mixture of acetates and olefins. Their formation can be rationalised in Scheme 2, in which the carbonium ion intermediates are related by a series of hydride shifts. In the phyllocladene series a further hydride shift leads to 15-oxygenated compounds. The driving force for this may be the release of steric compression involving the angular methyl group. Use has been made of the rearrangement of 15,16-epoxides in the beyerane series as a method of forming kauranoid substances. Conversely, rearrangement of steviol epoxide generates a 17-hydroxybeyerane related to isosteviol. This has been utilised in a partial synthesis of

1

Scheme 2 '02

R. A. Appleton, P. A. Gunn, and R. McCrindle, J . Chem. SOC.(C),1970, 1148.

D iterpeno ids

145

erythroxydiol A.' O 3 Intramolecular displacement of the toluene-p-sulphonate (99) leads104ato an atisanol(lO0) which under more vigorous conditions undergoes rearrangement to a 12-hydroxybeyerane(101). The neopentyl system present in erythroxylol B has providedi04b a suitable substrate for solvolytic studies. Solvolysis of the toluene-p-sulphonate (102) leads to ring expansion and the formation of the bridgehead acetates (103) and (104). OH

1

I

(99)

The Grayanotoxins.-Although the grayanotoxins have been known for many years, their structures have been clarified only during the last decade. Several papers in this field have been published during the past year. On the basis of 0.r.d. measurements, the A/B ring junction was previously thought to be cis. However, a trans ring junction has now been demonstrated in two studies. Like earlier evidence for other centres, both rely on transannular ether formation. When grayanotoxin-I1 (105) is oxidi~ed'*~ with mercuric acetate, a 5-9 ether (106) is formed. Since molecular rotation differences had shown that the C-6 hydroxy-group was a p substituent and this hydroxy-group was known to be cis to the C-5 hydroxy-group, the 5-9 ether bridge must lie on the /3 face of the molecule. Secondly, when tetra-acetylgrayanotoxin-I1 was treated with N bromosuccinimide,' O 6 a bromo-ether containing a 5-10 ether bridge was formed. HO 14;'

OH Io3

I04 Io5 lo6

~b O H

\

OH

HO OH

(105) (106) K. Mori and M. Matsui, Tetrahedron Letters, 1970, 3287. a R . M. Coates and E. F. Bertram, Chem. Comm., 1969, 797; *J. C. Fairlie, R. McCrindle, and R. D. H. Murray, J . Chem. SOC.(0,1969,2115. J. Iwasa and Y. Nakamura, Tetrahedron Letters, 1969, 3973. Z . Kumazawa and R. Iriye, Tetrahedron Letters, 1970, 927.

Terpenoih and Steroids

146

In this work the C-3 and C-5 hydroxy-groups were also linked by acetal formation. These ethers require a trans A/B ring junction for their formation. When the cis-5,6-glycol of the grayanotoxins is cleaved with lead tetraacetate, a 1 4 - 6 hemi-acetal is formed.lo7 However, in the grayanotoxin-I1 series these hemi-acetals undergolo8 an intramolecular aldol condensation to give a C-1 epimeric pair of spiro-ketones (107). The stereochemistry of the thermodynamically favoured epimer was established by acetal formation between the C-3 and C-6 hydroxy-groups. Only one of the two possible spiro-ketone structures can form such an acetal bridge. Stepwise oxidation and dehydration of 20-norgrayanotoxin-I1 led'07 to the formation of a homoannular dienone consistent with the seven-membered ring B of the grayanotoxins.

The toxins of Pieris japonica have been investigated since 1882. Two of these toxins, asebotoxins I and 11, have been shown'0g to be the 14-propionates of grayanotoxins-I11 and -11 respectively. The structures (108) of rhodojaponin I, 11, and I11 from Rhododendron japonicurn and of asebotoxin I11 from Pieris japonica were established by n.m.r. studies.' l o These compounds were characterised by the presence of a ring A epoxide. Lyoniatoxin"' (lyoniol All2), which was isolated from Lyonia oualifolia, lacks the 14-hydroxy-group of the rhodojaponins, possessing instead a 7a-hydroxy-group. As with other members of this group, the characteristic n.m.r. spectra played a considerable part in the structural work. HO

ow lo7

O8

log

'

lo

OH

R'

---I.' R2

OH

R' = RZ = OAc; Rhodojaponin I R' = OAc; R2 = OH; Rhodojaponin I1 R' = R2 = OH; Rhodojaponin 111 R' = OH; R2 = OCH(0H)Me; Asebotoxin 111

(108) M. Yanai, H. Mishima, T. Kozima, H. Kakisawa, and K. Nakanishi, Chem. and Pharm. Buff. (Japan), 1969, 17, 2036. 2. Kumazawa and R. Iriye, Tetrahedron Letters, 1970, 93 1. H. Hikino, K. Ito, and T. Takemoto, Chern. and Pharm. Buff.(Japan), 1969, 17, 854. H. Hikino, K. Ito, T. Ohta, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1969, 17, 1078.

H. Hikino, Y. Hikino, T. Takemoto, and S. Takahashi, Chem. andPharm. BUN. (Japan), 1970, 18, 8 5 2 .

M. Yasue, T. Kato, and J. Sakibara, Chem. and Pharm. Bull. (Japan), 1970,18, 854.

147

Diterpenoids

The Gibberellins.-In this section we have used the gibberellane numbering. Care should be taken to specify which system is being used. In the gibberellane system (109) the 2- and 3-positions are reversed with respect to the older gibbane numbering. Gibberellins possessing oxygen functions at both centres are known. Confusion may also arise because the 7-deoxygibbanes form a group having interesting biological activity. On the new gibberellane system, the 7-position is the biologically important carboxy-group. All known gibberellins belong to the 'ent' (10or-Me) series, a point which must be remembered when defining oxygenation at C-18 and C-19. A useful review of the structure and metabolism of the gibberellins has apAs with other diterpenoids, the biosynthetic and metabolic work peared. on the gibberellins is covered in Chapter 6 of this Report. Further reports on gibberellins A,, (110) and A,, (111) (Canavalia gibberellins I and 11) have appeared.'14 Gibberellin A,, , which is 3-deoxygibberellin A,, (112), has been subjected to several bioassay systems." The results were interesting from the biogenetic point of view in that gibberellinA,, is less active than the corresponding angular aldehyde, gibberellin The isolation of gibberellins and A,, as their 2P-glucosides from immature seeds of Pharbitis nil has been described.' l6 Gibberellin A26 (113) is unusual in possessing a ring C carbonyl group. 2 - 0 - 8 - ~ -

HOTC

H

.. .,

H. H02C C02H *,

.. ,, C02H 113

'14

C02H

(113) (1 14) A. Lang, Ann. Rev. Plant Physiot., 1970, 21, 537. N. Murofushi, N. Takahashi, T. Yokota, and S. Tamura, Agric. and Biol. Chem. (Japan), 1969,33, 598. G . V. Hoad, Planta, 1969,87, 164. T. Yokota, N. Takahashi, N. Murofushi, and S. Tamura, Planta, 1969, 87, 180.

Terpenoids and Steroids

148

Glucosylgibberellin A29 also occurs in Pharbitis nil.' l 7 Gibberellin A29 ( 1 14) lacks a 3-hydroxy-group. Its structure was established by inter-relationship with gibberellin AS. The increasingly widespread discovery of gibberellins as their glucopyranosides is exemplified' " by the isolation of gibberellin A, 0-2P-~-glucopyranoside(previously described as phaseolus E ) from Phaseolus coccineus. A surprisingly high (for a plant) concentration of gibberellic acid has been recorded"' in the floral parts of Cassia fistula, whilst the same authors also claim' 2 o to have isolated tetrahydrogibberellic acid from Sonneratia apetala. Their sample, however, melted 150 "C below the recorded values, and furthermore, it surprisingly absorbed in the U.V.The name gibberellin A,, used by these authors had previously been used115 to describe another gibberellin, and we suggest that it be withdrawn. Attention is drawn to the procedure for naming new gibberellins,'2 which was specifically proposed to avoid such confusion. The ring A system of gibberellic acid resembles the products to be expected from photo-oxygenation of a A2-gibberellinsuch as gibberellin A,. Attempts122 to photo-oxygenate the ring A or ring D double bonds of gibberellin A, or gibberellic acid failed. Although allogibberic acid (115) afforded the primary alcohol (116), epiallogibberic acid did not react, i.e. the reaction appears to be influenced by the nature of the B/C ring junction. Treatment of the methyl ester of the oxygenation product with acid afforded both a hydroxymethyl gibberate (117) and a product (118)of allylic rearrangement. Inversion of ring D of gibberic acid can be brought about123by deaminatior, of a C-16 amine. H

r&CL., \

L

C 0 2Me (117)

H

O

WOH oc\o

(1 18)

The Diterpene Alkaloids.-The crystal structures of several complex diterpene alkaloids have been reported. Denudatine, when first reported, was assigned 11* 119

lZo

Iz1

' 23

T. Yokota, N. Murofushi, and N. Takahashi, Tetrahedron Letters, 1970, 1489. K. Schreiber, J . Weiland, and G . Sembdner, Phytochemistry, 1970, 9, 189. P. K. Sircar, B. Dey, T. Sanyal, S. N. Ganguly, and S. M. Sircar, Phytochemistry, 1970, 9, 735. S. N. Ganguly, T. Sanyal, P. K. Sircar, and S . M. Sircar, Chem. and Ind., 1970, 832. J. MacMillan and N. Takahashi, Nature, 1968,217, 170. M. F. Barnes, R. C. Durley, and J. MacMillan, J . Chem. SOC. (0,1970, 1341. J. C. Brown and B. E. Cross, J . Chem SOC.(0,1970,71.

149

Diterpenoids

a chemically improbable structure. Two X-ray a n a l y ~ e s ' ~show ~ , ' ~that ~ it has the structure (1 19) and thus it occupies an important position as a possible intermediate in the biogenesis of the aconitine skeleton from the atisine skeleton. l 2 s Kobusine (120, R = H) and pseudokobusine (120, R = OH) have structures related to denudatine. An X-ray analysis correct^'^' an earlier structural assignment to kobusine made on the basis of chemical studies. Miyaconitine (121) and miyaconitinone are the major alkaloids of Aconitum miyabei. lZ8 The oxygenation pattern suggests a possible mode of formation (122) of the 13-20 carbon bridge that characterises the hetisine as opposed to the atisine alkaloids. The structure of miyaconitine was determined by a combination of chemical and X-ray work.'z9 Related to these alkaloids is hetidine (123). The crystal structure of its hydroiodide was determined by X-ray analy~is.'~' Delnudine was isolated131from the seeds of Delphinium denudatum and shown by X-ray analysis to have the structure (124).'32 The biogenesis of this unusual ring-system can be envisaged in terms of the rearrangement ofa hetisine derivative (125).

(1 25)

''

130 13' 13'

F. Brisse, Tetrahedron Letters, 1969, 4373. M . Gotz and K. Wiesner, Tetrahedron Letters, 1969, 4369. L. H. Wright, M. G. Newton, S. W. Pelletier, and N. Singh, Chem. Comm., 1970, 359. S. W. Pelletier, L. H. Wright, M. G. Newton, and H. Wright, Chern. Comm., 1970, 98. Y. Ichinohe, M. Yamaguchi, N . Katsui, and S. Kakimoto, Tetrahedron Letters, 1970, 2323. H. Shimanouchi, Y. Sasada, and T. Takeda, Tetrahedron Letters, 1970, 2327. S. W. Pelletier, K . N . Iyer, V. K. Bhalla, M . G . Newton, and R. Aneja, Chem. Comm., 1970, 393. M. Gotz and K. Wiesner, Tetrahedron Letters, 1969, 5335. K. B. Birnbaum, Tetrahedron Letters, 1969, 5245.

150

Terpenoih and Steroids

5 Macrocyclic Diterpenoids and their Cyclisation Products

Phorbol and Its Relatives-The Euphorbiaceae are a rich source of diterpenes. The hydrocarbon casbene (126), which is clearly related to the macrocyclic diterpene cembrene, has been isolated from Ricinus communis.'33 It may also be related to the parent hydrocarbon of the phorbol group of diterpenoids. ~ ~co-carcinoSince the publication of the X-ray analyses of p h o r b 0 1 , ' ~the genic constituent of Croton tiglium, full papers have appeared describing its chemi~try.'~'A unique feature ofphorbol(l27) is the presence of acyclopropanol and a cyclopropylcarbinol system. The reaction of phorbol with 0.02N sulphuric acid leads to the generation of a C-12 carbonium ion which can rearrange either with cleavage of the cyclopropyl ring and formation of crotophorbolone (128) or with the formation of a cyclobutanone, crotophorbolone K (phorbo butanone) (129, R = H).'37*138Some interesting acyloin rearrangement products have ~~ been obtained on treatment of the 12-ketone with sodium m e t h 0 ~ i d e . IThe major product is hydroxyphorbobutanone (129, R = OH) and a minor product the hemi-acetal (130). The oxidation of phorbol penta-acetate with osmium tetroxide gives140some of the expected 6P,7/?-dioltogether with a 7P-acetate in which an acyl migration from C-4 has occurred. The phorbol derivative (1 31) has been isolated from Croton rharnnifolius.'4' A group of tumour-promoting esters, based on 12-desoxyphorbol, have been

CH,OAc

133 134

135

136

13' 13' 139

I4O 14'

(129) (1 30) (131) D. R. Robinson and C. A. West, Biochemistry, 1969, 9, 70. R. C. Pettersen, G. Ferguson, L. Crombie, M. L. Games, and D. J. Pointer, Chem. Comm., 1967, 716. W. Hoppe, F. Brandl, I. Strell, M. Rohrl, I. Gassman, E. Hecker, H. Bartsch, G . Kreibich, and Ch. von Szczepanski, Angew. Chem. Internat. Edn., 1967,6, 809. E. Hecker, H. Barisch, G. Kreibich, and Ch. von Szczepanski, Annafen, 1969, 725, 130. L. Crombie, M. L. Games, and D. J. Pointer, J. Chem. SOC.( C ) , 1968, 1347. H. W. Thielmann and E. Hecker, Annalen, 1969,728, 158. H. Barisch and E. Hecker, Annafen, 1969, 725, 142. H. W. Thielmann and E. Hecker, Annalen, 1970,735, 113. K. L. Stuart and L. M. Barrett, Tetrahedron Letters, 1969,2399.

D iterpeno ids

151

isolated from Euphorbia c00pet-i'~~ and E. triangularis.143 Their structures are summarised in (132). The caper spurge, Euphorbia lathyris, contains a tricyclic group of phorbol relatives, Iathyrol and epoxylathyrol (euphorbiasteroid) (133). Extensive chemical work'44 and an X-ray analysis'45 have led to the assignment of the structures to these compounds. Acid-catalysed rearrangement leads in this group not only to modification of the cyclopropane ring, but also to transannular cyclisation reactions to give, for example, (134).

CH20R2 ( 132)

E. cooperi

H C1: R'

=

I

CO.C=C.CH3; R2

I

=

Hi R3

=

O*CO*CH(CH3)2

CH3 E. triangularis

R'

=

COCH(CH3)z ; RZ = Ac; R3 = H H

R'

=

OC*C=C*CH,; R Z = Ac; R 3

R'

=

CH3 OC.CH.CH2-CH3; R2 = Ac; R3 = H

=

CH3 OC-CH-CH2.CH3;RZ = Hi R 3 = H

R'

I

I

=

H

I

I

CH3

OHCO

C~H,*CHzCO*O AcO C H 2 0 C H 0

142 143 144

14'

(1 34) (133) M. Gschwendt and E. Hecker, Tetrahedron Letters, 1970, 567. M. Gschwendt and E. Hecker, Tetrahedron Letters, 1969, 3509. W. Adolf, E. Hecker, A. Balmain, M. F. Lhomme, Y. Nakatani, G. Ourisson, G. Ponsinet, R. J. Pryce, T. S. Santhanakrishnan, L. G. Matyukhina, and I. A. Saltikova, Tetrahedron Letters, 1970, 2241. K. Zechmeister, M. Rohrl, F. Brandl, S. Hechfischer, W. Hoppe, E. Hecker, W. Adolf, and H. Kubinyi, TetrahedronLetters, 1970, 3071.

Terpenoids and Steroids

152

The extremely toxic (LD,, 250 pug kg- ') principle of Daphne mezereum also belongs to this series. X-Ray analysis of a bromoacetate shows'46 that daphnetoxin contains the unusual orthobenzoate structure (135).

(135)

The Taxane Diterpenes.-The taxane skeleton represents an alternative mode of cyclisation of the macrocyclic diterpene hydrocarbon. Seven new taxane derivatives have been isolated'47a from Taxus baccata and characterised on the basis of spectroscopic and other data. Their structures are summarised in the following formulae (136a-g). In addition, the structure of baccatin-I11 (1 37), one of a group of complex esters isolated from the same source, has been comof the olefin Octant rule to the taxane double ~ 1 e t e d . The l ~ ~application ~ bond leads to the absolute c ~ n f i g u r a t i o n 'of ~ ~these diterpenes. ACO,

R4

R3

R' (1 36)

R2

R3

R4

R5

OAc

H H H

OAc [taxusin]

OAc OAc OAc

OAc OAc OAc OAc OAc

OAc OAc OAc

H

H

OAc

OAc

H

OH OAc OAc OAc OAc

OH

OH

CH3 Taxane Derivatives from Taxus baccata 146

G. H. Stout, W. G. Balkenhol, M. Poling, and G. L. Hickernell, J . Amer. Chem. SOC., 1970,92, 1070.

14'

14'

D. P. Della Casa de Marcano and T. G. Halsall, Chem. Comm., 1969, 1282; D. P. Della Casa de Marcano, T. G . Halsall, and G. M. Hornby, Chem. Comm., 1970,216. D. P. Della Casa de Marcano, T. G . Halsall, A. I. Scott, and A. D. Wrixon, Chem. Comm., 1970, 582.

Diterpenoih

153 Aco-o

OAc

6 Synthesis of Diterpenoids The synthesis of tricyclic compounds based on the cyclisation of methyl geranylgeranoate was described eighteen years ago. However, the discovery of expoxysqualene as an intermediate in steroid biosynthesis, and the corresponding in vitro cyclisation experiments, have re-awoken interest in this area of diterpene synthesis. The structural and stereochemical course of the in vitro cyclisation of the epoxy-trans-olefin (138) has been studied. 149 Two A/B-trans-fused tricyclic compounds (139) and (140) have been isolated. The levantenolides (142) and (143)have been obtained by two closely related routes. In the first, the butenolide (141), derived from monocyclofarnesyl bromide,I5' afforded the a- and plevantenolides (142) and (143) on cyclisation with stannic chloride. In the second,' the corresponding acyclic butenolide derived from farnesyl bromide was cyclised.

&+&FO+ &.4 H (141)

( 142)

(1 43)

The stereospecific synthesis of the C-4 epimeric diterpenoid resin acids has attracted considerable attention. Methylation of the keto-nitrile (144) gives'52 a product possessing an equatorial methyl group, in contrast to methylations of L49 150

Is' 15'

D. J. Goldsmith and C. F. Phillips, J . Amer. Chem. Soc., 1969, 91, 5862. T. Kato, M. Tanemura, T. Suzuki, and Y . Kitahara, Chem. Comm., 1970,28. M. Tanemura, T. Suzuki, T. Kato, and Y . Kitahara, Tetrahedron Letters, 1970, 1468. M. E. Kuehne and J. A. Nelson, J . Org. Chem., 1970,35, 161.

Terpenoids and Steroids

154 OMe

the analogous ring A saturated P-keto-esters where preponderant or even exclusive axial alkylation has been observed. A number-of reasons have been put forward to account for this. The association of a metal enolate may favour a transition state in which co-planarity of the carbonyl group and the ester are important. With a more nucleophilic enolate, (new bonding at a greater distance) 1,3-steric interactions should be diminished. Finally, the peri interactions with C-6 exist in the esters, but not in the nitriles. The synthesis of several aromatic tricyclic 20-norditerpenoids has been des~ r i b e d . 'The ~ ~ key acid (146) was prepared by cyclisation of (145). The various A/B stereoisomers were prepared from this by catalytic or dissolving metal

y(?!

H ,-Pd/C ___)

'*.COZ H H

d $ '.

-Pd/C

@ C02H

Li-NH

L

(yJ/ljl co : H Scheme 3

15'

H

'OzH

@ CO2 H

U. R. Ghatak, N. R. Chatterjee, A. K. Banerjee, J. Chakravarty, and R. E. Moore, J . Org. Chem., 1969, 34, 3739.

Dit erpeno ids

155

reduction of the unsaturated acid or the y-lactone (Scheme 3). Earlier work had shown that chromium trioxide oxidation of the cis A/B podocarpatrienes gave a diketone, whilst the trans A/B compounds only gave a monoketone. However, this diagnostic oxidation does not appear to hold in the 20-nor series. The total synthesis of tanshinone-I (147), tanshinone-11,and cryptotanshinone has been d e ~ c r i b e d . 'The ~ ~ route used was based on the Diels-Alder reaction of 3-methylbenzofuran-4,7-quinoneand 6,6-dimethyl-l-vinylcyclohexene.5-Hydroxy-8-oxodecahydronaphthoicacid lactone has been prepared' 55 as a possible intermediate for the synthesis of a number of diterpenoid lactones.

The synthesis of two stereoisomers of (+)-9-desoxocassamic acid has been reported. The tricyclic system was c o n ~ t r u c t e d 'by ~ ~the condensation of 2met hyl-3-methoxyphenylacetylenewith ethyl 1,3-dirnethylcyclohexan-2-one1carboxylate. The product was reduced and cyclised to give 14-methyl-13of the corresponding phenol methoxypodocarpic acid. Catalytic reduction and addition of the side-chain using ethoxyacetylene led to the synthesis of the epimers at C-8 and C-14 of 9-desoxocassamic acid. The synthesis of sandaracopimaric acid from the androstane skeleton has been described.''' In this work there is an interesting contrast between alkylation of the saturated keto-ester (148), which gives the axial product, and of the unsaturated ester (149), which gives the product an equatorial methyl group. Cleavage of the androstane 14,lSbond permitted the contruction of the C-13 methyl :vinyl substitution pattern. OAc

OAc

(148) 155

Y . Inouye and H. Kakisawa, Bull. Chem. SOC.Japan, 1969,42,3318. T. L. Eggerichs, A. C. Ghosh, R. C. Matejka, and D. M. S. Wheeler, J. Chern. SOC.(0,

158

F. Fringuelli, V. Mancini, and A. Taticchi, Tetrahedron, 1969, 25, 4249. A. Taticchi, F. Fringuelli, and V. Mancini, Tetrahedron, 1969, 25, 5341. A. Afonso, J . Org. Chem., 1970, 35, 1949.

15'

1969, 1632.

156

Terpenoids and Steroids

& +o

0

COzMe

C02Me

CHzOH

C-13 epimers

/ J

: H

(153)

i H (156)

Scheme 4

157

Diterpenoids

Methyl isocupressate (150) formed the starting material for a synthe~is'~'of rosenonolactone (156) and desoxyrosenonolactone (Scheme 4) based on the cyclisation studies' described earlier. Cyclisation of methyl isocupressate in acetic acid-sulphuric acid affords a C-13 epimeric mixture of pimaradienes (151). The rosane skeleton (152) was generated from this by rearrangement with formic acid. Lactonisation of the 5(10) double bond afforded a cis A/B ring junction (153) and rearrangement to an abietane. The correct ring junction (155) was generated by opening the 5( 10)-a-epoxide(154). The vinyl group was protected and the C-5 hydroxy-group removed by dehydration and hydrogenation to afford desoxyrosenonolactone, and, in several stages, rosenonolactone (156). The total synthesis of steviol has been reported.' 6o The tricyclic intermediate (157) of a kaurenoic acid synthesis was converted into the tetracyclic ketol and thence to the corresponding diketone (158). The key step in the synthesis was the Clemmensen reduction of this diketone to give a ketol (1 59) and its C/D isomer. The fission of the cyclopropyl glycol intermediate in this reduction generated the bridgehead hydroxy-group characteristic of steviol. A similar route has been used16' to reconstruct the C/D ring system of epiallogibberic acid.

( 159)

( 160)

Undoubtedly the major synthetic achievements of the year have been in the field of gibberellin synthesis. Full details of the synthesis of gibberellin A, have appeared.'62 This work, spread over ten years, involves five major sections. Firstly, the synthesis of the racemic gibberic acids (161, R = H) and epigibberic acids. Secondly, ring A of gibberic acid was activated by nitration (161, R = NOz) and the nitro-group converted through the amine to a phenol (161, R = OH). ''O

Ibl 16*

T. McCreadie, K . H. Overton, and A . J. Allison, Chem. Comm., 1969, 959. K . Mori, Y . Nakahara, and M . Matsui, Tetrahedron Letters, 1970,241 I . K. Mori, M. Matsui, and Y . Sumiki, Tetrahedron Letters, 1970, 429. K . Mori, M. Shiozaki, N. Itaya, M . Matsui, and Y . Sumiki, Tetrahedron, 1969, 25, 1293.

Terpenoih and Steroids

158

Reduction of this phenol then gave the racemic diketo-ester (162), available as a relay from gibberellic acid. The third phase involved the successive bromination and dehydrobromination to give the dienone (163). In the fourth phase, ring A was reconstructed. Selective ketal formation blocked ring D and then ring A was carboxymethylated, reduced, and the lactone ring formed. Epimerisation of the ring A hydroxy-group gave a degradation product (164)of gibberellin A,. Finally, since inversion of ring D had previously been described, this afforded a synthesis of gibberellin A4 (165). The Cz0gibberellin, gibberellin A,, (172) has been synt h e ~ i s e d . ' This ~ ~ synthesis starts from (166), an intermediate in the total synthesis of the diterpene alkaloids. Reduction of its enol-acetate placed a double H

CO, H

COzMe

COzMe

HO COZ H

bond in ring B. Ozonolysis and base-catalysed condensation afforded a B-noraldehyde (167) which was in turn converted to the corresponding doubly unsaturated ketone (167a).Hydrocyanation then gave the angular nitrile, which was converted through the formyl derivative to the unsaturated aldehyde (168) and thence to a diacetoxy toluene-p-sulphonate (169). Selective ozonolysis gave an aldehyde which was subjected to a unique cyclisation. Treatment with base 16'

W. Nagata, T. Wakabayashi, Y. Hayase, M. Nansada, and S. Kamata, J . Amer. Chem. SOC.,J 970,92, 3202.

D iterpenoids

159

gave, in two stages (170- 171),an intermediate possessing the tetracyclic framework. The amine bridge was then converted through the azomethine to gibberellin A (172).

Ms--N

OH CHO

9

(167)

( 167a)

Ms-w "OTs

Me0 0

CHO

A partial synthesis of gibberellin A nor-ketone from 7-hydroxykaurenolide has been described.164 The key stage in this synthesis is the activation of the C-20 methyl group by photolysis of a C-19 amide (173). A simple route to the tetracarbocyclic skeleton of the gibberellins which possesses the advantage of generating both the bridgehead hydroxy-group and the terminal methylene of the bicyclo[3,2,1]octane system has been described. 6 5 lh4

B. E. Cross and I. L. Gatfield, Chem. Comm., 1970,33.

165

E. J. Corey, M. Narisada, T. Hiraoka, and R. A. Ellison, J . Amer. Chem. Soc., 1970, 92, 396.

160

Terpenoids and Steroids

It involves treating the bromo-olefin (1 74) with butylcopper lithium to afford an organometallic derivative which adds to the carbonyl to give (175). The synthesis of the fragment (176) of the diterpene alkaloids, has been described. 166

( J + CH

I

Bu,cuLi_

Q

OH

CH

\

1

OMe

OMe

( 175)

(174)

0

K. Wiesner, A. Deljac, T. V. R. Tsai, and M. Przybylska, Tetrahedron Letters, 1970, 1145.

4 Triterpenoids BY J. D. CONNOLLY

1 Squalene An interesting high-yield synthesis of squalene by tail-to-tail coupling has been published by Biellmann and Ducep.' The method involves alkylation with truns,truns-farnesylbromide of the carbanion (1) derived from the corresponding trans,trans-farnesyl thioether by treatment with n-butyl-lithium-diazabicyclooctane in tetrahydrofuran. The sulphur of the resultant thioether (2) was removed with lithium in ethylamine. An advantage of this method is the absence of doublebond isomerisation. Another synthesis of squalene' utilises an intramolecular rearrangement of the ylide obtained from farnesyl nerolidyl sulphide (3) by treatment with benzyne. Squalene 2,3 ;22,23-diepoxide has been cyclised by microsomes from bramble tissues grown in vitro, to form 24,25-epoxycycloartenol (4),3 A very neat method of distinguishing between the 4a- and 4P-methyl groups of triterpenoids has become available with the discovery by Moss and Nicolaidis4

(3) J. F. Biellmann and J. B. Ducep, Tetrahedron Letters, 1969, 3707. G . M. Blackburn, W. D. Ollis, C. Smith, and I. 0. Sutherland, Chem. Comm., 1969, 99. R. Heintz, P. C. Schaefer, and P. Benveniste, Chem. Comm., 1970, 946. G. P. Moss and S. A. Nicolaidis, Chem. Comm., 1969, 1077.

162

Terpenoids and Steroids

that the abnormal Beckmann rearrangement of triterpenoid 3-ketoximes is largely stereospecific. Thus, rearrangement of the oxime ( 5 ) with toluene-psulphonyl chloride in pyridine yielded the unsaturated nitrile (6), the n.m.r. spectrum of which lacked vinyl proton signals. The reaction probably proceeds via the tosyloxy-imine (7; arrows) by a concerted rearrangement. Only the 4amethyl group can assume the necessary conformation for trans-elimination. The same authors use this abnormal Beckmann rearrangement to demonstrate unambiguously5 that the 4cr-methyl group of lanosterol is derived from C-2 of mevalonic acid.

Both Halsal16 and Moss’ make the interesting suggestion that while 38hydroxy triterpenoids arise by cyclisation of (3S)-2,3-oxidosqualenefolded in a chair-chair-chair form (8), the corresponding 3cc-hydroxy epimers could arise G. P. Moss and S. A. Nicolaidis, Chem. Comm., 1969, 1072. G. P. Cotterrell, T. G. Halsall, and M.J. Wriglesworth, J . Chem. SOC.(0,1970, 739.

Triterpeno iak

163

from the enantiomeric (3R)-2,3-oxidosqualene folded in a boat-chair-chair form (9). In the former case the 4a-methyl group is derived from C-2 of mevalonic acid whereas in the latter it is the 4b-methyl group. Cyclisation of squalene 2,3-epoxide (10) yielded, in addition to tricyclic products, the bicyclic alcohol (11) which presumably arises from the bicyclic carbonium ion (12) by a series of hydride and methyl migrations. Sharpless and van Tamelen have suggested' that one of the functions of the cyclase enzyme is to prevent this type of process at the bicyclic level. The in uivo formation and cyclisation of squalene are discussed in detail in Part 11, Chapter 8.

H

2 Fusidane-Lanostane Group

The structure of helvolic acid has been revised' to (13). The ring B acetoxy-group is at C-6 and not at C-7 as was previously suggested. As a result, a similar modification must be made to the structures of helvolinic acid, 7-deacetoxyhelvolic acid, and 7-oxofusidic acid. The two interesting double bond isomers (14) and (1 5 ) have been i ~ o l a t e d ,together ~ with helvolic acid, from Cephalosporiurn caerulens. Since these compounds are considered to be prototypes of sterols the name protostane has been suggested for the basic hydrocarbon (16). When [2-'4C]mevalonate was incubated with cell-free extracts of Emericellopsis sp. and the metabolites examined by the dilution method, 3P-hydroxyprotosta-17(20),24diene (14) was found to be active (0.27% incorporation)." No activity was

' K. B. Sharpless and E. E. van Tamelen, J . Amer. Chem. SOC.,1969,91, 1848. * S. Iwasaki, M. I: Sair, H. Igarashi, and S. Okuda, Chem. Comm., 1970, 1119. lo

T. Hattori, H. Igarashi, S. Iwasaki, and S. Okuda, Tetrahedron Letters, 1969, 1023. A. Kawaguchi and S. Okuda, Chem. Comm., 1970, 1012.

164

Terpenoids and Steroids

detected in the case of the double bond isomer (15). The latter has been transformed9 by acid into dihydrolanosterol by Arigoni and Godtfredsen. Further evidence for the structure of the protosterol previously prepared by Corey and his colleagues, from 20,2 l-dehydro-2,3-oxidosqualeneby cyclisation with 2,3oxidosqualene sterol cyclase,and formulated as (17)has been obtained as follows.' The protosterol, labelled with tritium at C-16, was hydrogenated over a rhodiumcharcoal catalyst and the corresponding acetate mixed with dihydrolanosteryl acetate. One crystallisation sufficed to give dihydrolanosteryl acetate without activity. Treatment of the hydrogenated product with acid under the conditions used by Arigoni to rearrange (15) (see above) followed by acetylation and admixture with dihydrolanosteryl acetate resulted in activity in the crystallised material. This indicates that the protosterol can be formulated more specifically as (18) and provides support for the fusidane stereochemistry of the nucleus.

OAc

Y

Several new halothurinogenins have been reported. Djerassi and his colleagues isolated'* ternaygenin (19), koellikerigenin (20), and seychellogenin (21) by acid 'I

E. J . Corey and H. Yamamoto, Tetrahedron Letters, 1970, 2385. P. Roller, C. Djerassi, R. Cloetens, and B. Tursch, J . Amer. Chem. Soc., 1969, 91, 4918.

Triterpenoids

(17) OH at one C*

165

(18)

hydrolysis of the glycoside mixture obtained from the sea cucumber Bohadschia koellikeri and provided the first unambiguous demonstration of the structure of this group by correlation of seychellogenin with lanosterol. Seychellogenin was Yonverted by a sequence of standard reactions into the triol (22), which was also prepared from 1lg-hydroxylanostanyl acetate in the following way. Oxidation ot 1 1P-hydroxylanostanyl acetate with lead tetra-acetate-iodine under illumination yielded13 the iodoether (23). When the oxidation was carried out in acetic acid and immediately followed by lithium aluminium hydride reduction the ethers (24) and (25) were is01ated.I~ The 11,18-ether (24) was oxidised to the corresponding y-lactone which gave, on lithium aluminium hydride reduction, the desired triol (22). This correlation still leaves in doubt the configuration at C-20 in the holothurinogenins. Pra~linogenin,'~ a minor component of the aglycone mixture, is the 17a-hydroxy-derivative (26). The 17a-hydroxy-group is very resistant to dehydration and praslinogenin, on treatment with phosphorus oxychloride in pyridine, lost methanol instead of water to give (27). Holothurinogenin (28) and the corresponding 25-methoxy- and 17-deoxy-25-methoxyderivatives (26) and (19) have been ~ b t a i n e d 'by ~ hydrolysis of the toxins of

(19) R' = H ; R2 = OMe (20) R' = H ; R2 = OH (21) R' = R2 = H (26) R' = OH; R2 = OMe (27) R' = OH; AZ4 (28) R' = OH; R2 = H l3

l4 l5

P. Roller and C. Djerassi, J. Chem. SOC.(0,1970, 1089. B. Tursch, R. Cloetens, and C. Djerassi, Tetrahedron Letters, 1970, 467. G. Habermehl and G. Volkwein, Annalen, 1970, 731, 53.

166

Terpenoih and Steroids H

(23) R = I (24) R = H

(31) (32) 24,25-dihydro ; 25-OH

Holothuria polii. The non-conjugated dienes stichopogenins A 2 (31) and A4 (32) have been reportedI6 from trepang, the far-eastern sea cucumber. It has been suggested that the 25-methoxylated holothurinogenins mentioned above are artefacts arising during hydrolysis of the glycosides with acidic methanol. Chanley and R o ~ s i ' ~ have * ' ~ confirmed this in an investigation of mild acid and enzymic hydrolysis of holothurin A, the major glycoside of Actinopyga agassizi, and have shown that the diene system found in the holothurinogenins is also an artefact. Mild acid hydrolysis of the glycoside yielded neoholothurinogenins, e.g. 12~-methoxy-7,8-dihydro-24,25-dehydroholothurinogen (33), and the corresponding 12j3,25-dimethoxycompound(34) which were transformed into the known holothurinogenins by stronger acidic conditions. Consideration

(33) (34) 24,25-dihydro ; 25-OMe l6

G. B. Elyakov, T. A. Kuznetsova, A. K. Dzizenko, and Y.N . Elkin, Tetrahedron Letters, 1969, 1 15 1 .

J. D. Chanley and C. Rossi, Tetrahedron, 1969, 25, 1897. J . D. Chanley and C. Rossi, Terrahedron, 1969, 25, 191 1 .

Trit erpenoids

167

of the solvent shifts (CDCl,-+pyridine) of the C-21 methyl group in a series of 17a-hydroxy- and 17-desoxy-neoholothurinogeninsand holothurinogenins allowed the authors to assign the configuration at C-20 as shown (the same as in lanosterol). Enzymic hydrolysis' * of desulphated holothurin A gave, inter alia, a number of 12a-methoxylated compounds. This suggests that the configuration of the oxygen substituent at C-12in the glycoside is a.

OH

The following new lanostane derivatives have been reported : 3P-hydroxy-

lanosta-7,9(11),24-trien-2l-oic acid (35) from Poria c o ~ o s senexol ,~~ (36) from Fumes senex,20 and 6a-hydroxypolyporenic acid (37) from Trarnetes f e e i 2 Cycloneolitsin (38), a cyclopropanoid triterpenoid ether with a novel sidechain, has been found22in Neolitsea dealbata. The structure was confirmed by transformation of cycloneolitsin and cycloartenol into the same degradation product (39). The structure of mangiferonic acid (40) from Shorea acuminata has been assigned23 mainly by comparison of its methyl group chemical shifts with those of cycloartenone. The stereochemistry of the side-chain in cimigenol (41) has been elucidated24by use of n.m.r. and 0.r.d. techniques. The same conclusion was reached24 after determining the absolute configuration, by the Horeau A. Kanematsu and S. Natori, Chem. & Pharm. Bull. (Japan), 1970,18, 779. A. K. Batta and S. Rangaswami, Zndian J. Chem., 1969,7, 1063. J. J. Simes, M . Wootton, J. Ralph, and J. T. Pinhey, Chem. Comm., 1969, 1150. 2 2 E. Ritchie, R. G. Senior, and W. C. Taylor, Austral. J. Chem., 1969, 22, 2371. 2 3 H. T. Cheung, C.-S. Wong, and T. C. Yan, Tetrahedron Letters, 1969, 5077. * * S. Corsano and G. Piancatelli, Gazzetta, 1969,99, 1140. 2o

Terpenoids and Steroids

168

method, at C-24 of the zinc reduction product (42) of the (2-15 ketone derived from cimigenol. The full paper on the Italian contribution to the structure of actein (43) has appeared.25 The photoproduct of 1 1-oxolanostanol has been reformulated26as (44).Since this was transformed into the cyclopropyl diketone (49, the previous work2' constitutes a formal total synthesis of cycloartanol. The full paper on the synthesis of cycloartenol from lanosterol by a route involving a nitrite photolysis in the presence of iodine, has appeared.28 A previously reported synthesis of cycloartanol by a similar route has been retracted.29

H

25 26

27 28

29

S . Corsano, G. Piancatelli, and L. Panizzi, Gazzetru, 1969, 99, 915. R. Imhof, W. Graf, H. Wehrli, and K . Schaffner, Chem. Comm., 1969,852. E. Altenburger, H. Wehrli, and K. Schaffner, Helu. Chirn. Acra, 1965,48, 704. D. H. R. Barton, D. Kumari, P. Welzel, L. J. Danks, and J. F. McGhie, J . Chem. Soc. (C), 1969, 332. D. H . R . Barton, R. P. Budhiraja, and J. F. McGhie, J . Chem. SOC.(0,1970, 336.

Triterpeno ids

169

H

Ozonolysis of 9~,19-cyclolanostaneshas been reported3' to give good yields of the corresponding 7-ketones. This novel oxidation requires the presence of the cyclopropane ring since lanostanyl acetate is unaffected under the same conditions. Jones' oxidation of cycloartanyl acetate gave low yields of both the 7-OXO- and 11-oxo-compounds. An elegant correlation of the lanostane and cucurbitane series has been r e p ~ r t e d ~by ' . ~Barton ~ and his colleagues. Cucurbitacin A (46) was transformed32 into the cyclopropane derivative (47) by treatment of the tosylate (48) with sodium borohydride. The cyclopropane ring of the tetrahydro-compound (49) was opened by an anionic process which involved protonation of the incipient 19-methyl carbanion by the axial 28-hydroxy-group (49 ; arrows) to give, after oxidation, the tetraketone (50). The latter was also prepared3' by degradation of eburicoic acid (51). The hexanorcucurbitacin D (52) has been obtained from

?

HO 0. HO.. AcOHZC

A

HO&"

1

30 31

32

n

y'"

W. Lawrie, J. McLean, and 0. 0. Olubajo, Tetrahedron Letters, 1969, 4143. D. H. R. Barton, C. F. Garbers, D. Giacopello, R. G. Harvey, J. Lessard, and D. R. Taylor, J . Chem. SOC.(0,1969, 1050. D. H. R. Barton, D. Giacopello, P. Manitto, and D. L. Struble, J . Chem. SOC.(0, 1969, 1047.

170

Terpenoids and Steroids

Begonia tuber hybrid^.^^ It was readily prepared by sodium metaperiodate oxidation of cucurbitacin D diacetate (53).

(53) 2fl-OAc

The syntheses of labelled lanosterol, cycloartenol, and parkeol derivatives for use in biosynthetic studies have been described.34 Terminal labelling of the sidechain [25-14C] or [26,27-2H,] was achieved by the formation of Wittig intermediates with the trisnortriterpenoid units followed by reaction with labelled acetone. Methods for the removal of one or both methyl groups from 4,4-dimethylsteroids have been published.35 Lanosterol has been degraded36to the trimethylpregnenolone (54). 33 34

”

R . W. Doskotch and C. D. Hufford, Cunud. J . Chem., 1970,48, 1787. U. Wrzeciono, C. F. Murphy, G. Ourisson, S. Corsano, J.-D. Ehrhardt, M.-F. Lhomme, and G. Teller, Bull. Soc. chim. France, 1970, 966. R . Kazlauskas, J. T. Pinhey, J. J. H. Simes, and T. G. Watson, Chem. Comm., 1969, 945.

3b

L. H . Briggs, J. P.Bartley, and P. S . Rutledge, Tetrahedron Letters, 1970. 1237.

171

Triterpenoiak

3 Dammarane-Euphane Group The first isolation of a dammarane from a lichen has been rep~rted.~’Diacetylpyxinol (55) was obtained37from the lichen Pyxine endochrysma and its structure established by X-ray analy~is.’~It is the 3-epimer of triterpene C, previously i ~ o l a t e d ’from ~ B e t h platyphylla. It is interesting to compare the conformation of the tetrahydrofuran ring in pyxinol [24-(R)J and the bromoderivative (56) [24-(S)] prepared by N-bromosuccinimide oxidation of betulafoliene trio1 (57). In the former, the tetrahydrofuran lies in approximately the same plane as the rest of the molecule, whereas in the crystal structure of the latter4’ it is oriented almost perpendicular to the plane of the tetracyclic portion. Dryobalanonolic acid (58) occurs23in Dryobalanops arornatica with dipterocarpol (59) and dryobalanone (60). Its structure was assigned on the basis of methyl chemical shift comparisons with (59) and (60).

HO

4c 0

*a

(57)

(58) R = COzH

(59) R (60) R

= =

CH3 CHzOH

Four new acids, masticadienolic acid (61) and its 3-epimer (62) and isomasticadienolic acid (63) and its 3-epimer (64), have been isolated4’ from the galls of Pistacia terebinthus. The confusion which has surrounded the elemi acids has 37

38 39 40

I. Yosioka, H. Yamauchi, and I. Kitigawa, Tetrahedron Letters, 1969,4241. H. Yamauchi, T. Fujiwara, and K. Tomita, Tetrahedron Letters, 1969, 4245. M. Nagai, N. Tanaka, S. Ichikawa, and 0. Tanaka, Tetrahedron Letters, 1968, 4239. 0. Tanaka, N . Tanaka, T. Ohsawa, Y. Iitaka, and S. Shibata, Tetrahedron Letters, 1968,4235.

41

R. Caputo and L. Mangoni, Gazzetra, 1970, 100, 317.

172

Terpenoidsand Steroids

been by Halsall and his colleagues. In a careful study of the acids from elemi resin they identified 3-oxotirucalla-8,24-dien-21 -oic acid (65), the corresponding 3a-hydroxy- and 3P-hydroxy-derivatives (66) and (67), and 3ahydroxytirucalla-7,24-dien-21-oic acid (68). They suggest that the 'a-elemolic acid' of previous workers was a mixture of 3a-hydroxy-A'- and -A8-acids,which are difficult to separate.

(61) (62) (63) (64)

R = H,P-OH; A7 R = H,a-OH;A7 R = H,P-OH; A* R = H,a-OH; A"

(65) (66) (67) (68)

R=0 R = H,a-OH R = H,P-OH R = H,a-OH;A'

Sapelin A (69) and sapelin B (70) have been obtained43 from Entandrophragrna cylindricurn (Meliaceae) and are further examples of the group of euphane or tirucallane derivatives which co-occur with, and are likely precursors of, tetranortriterpenoids (see later). Sapelin A was readily correlated with bourjotinolone A (71).44 Sapelin B reacted with sodium periodate to give the dialdehyde (72) which was transformed successively by sodium amalgam and chromium trioxide into the y-lactone (73) previously obtained from sapelin A and bourjotinolone A. OH

(69) R (71) 42

43 44

=

H,a-OH

R =O

G. P. Cotterrell, T. G . Halsall, and M. J. Wriglesworth, J . Chern. Sot. (0,1970, 739. W. R. Chan, D. R. Taylor, and T. Yee, J . Chem. SOC.(0,1970, 3 11. G. J . W. Breen, E. Ritchie, W. T. L. Sidwell, and W. C. Taylor, Austral. J . Chem., 1966, 19, 455.

173

Triterpenoids

The triterpenoid penta-o1(74),closely related to odoratol(75), has been isolated45 from Cedrela glaziovii. The full paper on aphnamixin (76)has appeared.46 The suggestion4’ that aphnamixin may be 3-epiturreanthin has been refuted.46 o x C H 0

bCHO

O Q O

@

Ac 0

The intermediacy of apo-euphol or tirucallol derivatives in the biogenesis of tetranortriterpenoids received strong support with the isolation4*of grandifoliolenone (77), a potential gedunin precursor, from Khaya grandifoliola in 1967. The corresponding cyclopentenone (78) also occurs in K . grandilf~liola.~~ Several more compounds of this type have now been reported. Lavie and Levy have 45 46

J . D. Connolly and K. L. Handa, J . Chem. SOC.(C),1969,2435. A. Chatterjee, A. B. Kundu, T. Chakrabortty, and S. Chandrasekhan, Tetrahedron, 1970, 26, 1859.

47 48 49

J. G. St. C. Buchanan and T. G . Halsall, Chem. Comm., 1969,48. J. D. Connolly and R. McCrindle, Chem. Comm., 1967, 1193. J. D. Connolly and R. McCrindle, unpublished results.

Terpenoih and Steroids

174

found5’ the lactone (79), clearly related to melianone (SO),” in the fruit of Melia azedarach. Adesogan and Taylor have obtained” the khivorin precursor (81) from Khaya iuorensis. In addition, the Jamaican group of Chan and Taylor have isolated53a number of apo-compounds, including the trio1 (82) related to grandifoliolenone, from sapele (Entandrophragm cylindricurn). OH

6

.,OH

(77) R’ = Ac; R2 = H2 (78) R” = Ac; R2 = 0 (82) R’ = H ; R 2 = H 2

H O - -O

b

’

Tetranortriterpemids.4n exposure to sunlight in the presence of oxygen gedunin is transformed, in 35% yield, into photogedunin ( 8 3 , identical with a compound found in the extract of Cedrela ~ d o r a t a . ’ ~ 6P-Hydroxygedunin (84) has been unambiguously synthesised” from 6,7anhydrogedunin uiu the &,7a-epoxide. Since the physical properties of (84) differ

54

D. Lavie and E. C. Levy, Tetrahedron Letters, 1969, 3525. D. Lavie, M. K. Jain, and I. Kirson, J . Chem. SOC.( C ) , 1967, 1347. E. K. Adesogan and D. A. H. Taylor, J . Chem. SOC.(0,1970, 1710. W. R. Chan, D. R . Taylor, and T. Yee, private communication. B. A. Burke, W. R. Chan, K. E. Magnus, and D. R. Taylor, Tetrahedron, 1969, 25,

55

5007. N. S. Ohochuku and D. A. H. Taylor, J . Chem. SOC.(0,1970,421.

50

’

52

53

175

Triterpenoicls OH

.OAc

0

OH (83)

(84)

from those of the compound from Carupu guiunensis, previously f ~ r m u l a t e d ~ ~ as 6B-hydroxygedunin,it is probably the 6a-hydroxy-isomer. In an investigation of the boron trifluoride-catalysed rearrangements of 14,lkpoxy-8-lactones in this series Ekong and Selema have shown57 that the products depend on the stereochemistryof the hydroxy-group at C-7. Rearrangement of the 7a-hydroxyderivatives (85) related to 7-deacetylkhivorin and 7-deacetylgedunin yielded the a-keto-lactone (86) and the diene (87). The involvement of the 7a-hydroxygroup in the epoxide opening was demonstrated by the fact that the 12epoxide of 1,2-epoxy-7-deacetylgeduninwas unchanged during the reaction. Similar treatment of the corresponding 7#?-hydroxy-derivativesgave as the major product the rearranged 7-ketone (88).

co

co

'' E. Wenkert and R. Zelnik, Abstracts, 5th International Symposium on Chemistry of Natural Products, London, 1968, p. 339. '' D. E. U. Ekong and M. D. Selema, Chem. Comm., 1970, 783.

176

Terpenoids and Steroids

An exception to the hitherto rigid confinement of ring A cleaved tetranortriterpenoids to members of the Rutaceae has appeared,52with the isolation of methyl ivorensate (89)from Khaya ivorensis (Meliaceae). Methyl ivorensate was prepared in low yield by perbenzoic acid oxidation of methyl angolensate. Zapoterin is very probably 1lp-hydroxyobacunone (90) since it shows a nuclear Overhauser effect between the C-1 olefinic proton and the carbinol proton at C-1 l.'* Structure (90) is in agreement with earlier proposals59 but contradicts the assignment made by Dreyer.60

(91) (92) 1,2-dihydro-

The full paper on andirobin (9,) has appeared.61 The corresponding 1,2dihydro-derivative, aphnamixinin (92), has been isolated46 from Aphnarnixis pol yst acha.

Bicyc1ononanolides.-Utilin, C41H5201 ,, a complex limonoid from Entandrophragrna utile,62 has been shown by X-ray analysis63 to have the structure (93) with the unprecedented feature of bond formation between one of the C-4 methyl G. P. Moss, T . P. Toube, and J . W. Murphy, J . Chem. SOC.( C ) , 1970,694. J. W. Murphy, T. P. Toube, and A. D. Cross, Tetrahedron Letters, 1968, 5153. '' D. L. Dreyer, J. Org. Chem., 1968, 33, 3577. 6 1 W. D. Ollis, A . D. Ward, H. Meirelles De Oliveira, and R . Zelnik, Tetrahedron, 1970, 26, 1637. 6 2 D. A. H. Taylor and K. Wragg, Chem. Comm., 1967, 81. b 3 H . R. Harrison, 0. J. R . Hodder, C. W. L. Bevan, D. A. H . Taylor, and T. G. Halsall, Chem. Comm., 1970, 1388. 58

59

177

Triterpenoids

groups (C-29) and C-1 as well as the presence of an orthoacetate. Utilin presumably arises by further modification of a precursor with the normal bicyclononane ring system found in members of this group. The genesis of the new C-C bond raises intriguing mechanistic possibilities. The two methanolysis products of utilin62 can now be assigned the structures (94) and (95).

Me

0

'OCOMe

28

ococ-c'

/\/'Me Me 0 (93)

Meo27..@ .--

Me02C I.@o ---

-OH 'OH

0

"0

OH OH (94)

OH OH (95)

The interesting 8a,30a-epoxide, xylocarpin (96), has been obtained64 from Xylocarpus granatum by Okorie and Taylor. On treatment with chromous chloride it gave the corresponding deoxy-derivative (97) which was also found in the extract. Xylocarpin rearranged in acid to the diene (98) and in base to a y-lactone and a bis-lactone which were assigned the structures (99) and (100) respectively. An i n ~ e s t i g a t i o nof ~ ~Cedrela augustifolia by Lavie and Zelnik and their colleagues has resulted in the isolation of fissinolide (1 Ol), augustadienolide (102), and 2a-hydroxyaugustadienolide (1 03). These authors suggested that the chemical shift of H-17 provides a diagnostic test for the position of the residual double-bond in this series, and on this basis amended the structure of fissinolide 64

h5

D. A. Okorie and D. A. H. Taylor, J. Chem. SOC.( C ) , 1970,211. D. Lavie, E. C. Levy, C. Rosito, and R. Zelnik, Tetrahedron, 1970, 26, 219.

Terpenoids and Steroids

178

to (104)with the double bond in the 8,9-position. Taylor, however, has published double resonance experimend6 and other evidence6’ which strongly supports the original structural assignment (1 01) for fissinolide. 2-Hydroxyfissinolide(105)

Me02C 1..

M ~ o &OMe , ~

0 “0

O1

30

OAc

H COzMe

OAc

(96) (97) 8,30-deoxy-

Me

Me0,C

I.

0

OH

0

0

0

(99)

OAc (101) R = H (104) R = H ; A 8 (105) R = OH b6 67

D. A. H.Taylor, J . Chem. SOC.( C ) , 1970, 336. D.A. H. Taylor, Tetrahedron Letters, 1970, 2797.

(102) R = H (103) R = OH

Triterpenoids

(106) R' (108) R'

179

=

=

OAc;RZ= OH 0COPr':R' = H

(109) R' = O;R2 = H (110) R' = 0 ; R2 = OH (1 11) R' = H,P-OAc; R2 = H

and the corresponding dihydro-derivative (106) have been isolated from Khaya iuorensis' * and K . mduguscuriensis66 respectively. The dihydro-compound (106), on treatment with base, underwent an intramolecular hydride transfer from C-3 to C-1 to give, after acetylation, the isomeric ketol acetate (107). The presence of the tertiary hydroxy-group at C-2 prevents the retro-aldol-realdolisation process which commonly occurs in this series. Dihydrokhayasin (108)has been reported68 from K . anthotheca. Its structure was confirmed by interrelation with carapin (109). Among related new compounds are 6-hydroxycarapin (110) from Cedrela , ~ ~the lactone (1 12) derived g l a z i ~ v i i the , ~ ~3P-acetate (111) from K . n y ~ s i c aand from mexicanolide, from K . ivorensis.s2 Full papers have appeared on nyasin ,~~ from K . anthotheca,68and 11P-acetoxykhivorin from K . n y ~ s i c akhayanthone from K . madagascariensis.66 It is probable that nimbolin A (113), nimbidinin (114), and nimbolin B (1 15) represent three stages on the pathway to ring-c-cleaved tetranortriterpenoids.

'' E. K. Adesogan, D. A. Okorie, and D. A. H. Taylor, J . Chem. SOC.(C), 1970,205. 69

D. A. H. Taylor, J . Chern. SOC.(0,1969, 2439.

Terpenoids and Steroids

180

Nimbolins A and B were obtained” from Melia azedarach and Azadirachta indica and nimbidinin from the hydrolysate of M . i n d i ~ a . ~Fraxinellone ‘ (116) was also found in the M . azedarach extract7’ and has now been isolated from trees belonging to both the Meliaceae and the Rutaceae. Treatment of fraxinellone with N-bromosuccinimide yielded the bromo-derivative (1 17), whose This absolute configuration has been established [as (1 17)] by X-ray analy~is.’~ result underlines the relationship between fraxinellone and the tetranortriterpenoids even though the degradation pathway remains obscure. An analogous limonoid fragment, pyroangolensolide (1 18),has been produced73 by pyrolysis of methyl angolensate.

R3

(113) R’ = Ac; R2 = PhCH=CHCO; R J = H, R’ = R2 = H ; R 3 = 0

(114)

OH

R

q (116) R (117) R

’” ” 72 73

= =

H

Br

D. E. U . Ekong, C. 0. Fakunle, A. K. Fasina, and J. I . Okogun, Chem. Comm., 1969, 1166. C. R. Mitra, H . S. Garg, and G. N. Pandey, Tetrahedron Letters, 1970,2761. P. Coggon, A. T. McPhail, R. Storer, and D. W. Young, Chem. Comm., 1969, 828. J. B. Davis, V. M . Godfrey, K . Jewers, A. H . Manchanda, F. V. Robinson, and D. A. H . Taylor, Chern. and Znd., 1970, 201.

Triterpeno ids

181

A number of papers have appeared which describe in vitro processes emulating various steps in the proposed biogenetic scheme for the formation of tetranortriterpenoids from euphol or tirucallol precursors. Halsall and his colleagues, in their full paper74on the formation of apotirucallol derivatives by rearrangement of tirucallol 7q8a-epoxides [e.g. (119) -+(120)] suggest that the shift of the C-14 methyl group and loss of the C-15 proton occurs by a concerted process involving the intramolecular removal of H-15by the C-7 oxygen function. This is probably due to the 1,3-diaxialtype of relationship between the C-15a-hydrogen and the leaving oxygen of the epoxide. These authors also i n v e ~ t i g a t e dthe ~~

I

AcO-

‘OH

rearrangement of the corresponding 8,9-epoxides. The 8a,9a-epoxide gave the 7,9(11)-diene as previously reported whereas the 8P,9/?-epoxide(121) rearranged by way of a cis methyl migration to the non-conjugated diene (122). Several interrelations have been achieved by use of Baeyer-Villiger oxidations. Lavie and Levy converted7’ epoxyazadiradione (123) into gedunin (124) in 90% yield with perbenzoic acid. On more prolonged treatment 1,2-dihydroepoxyazadiradione yielded” a mixture of 1,2-dihydrogedunin and 1,2-dihydr0-7a-obacunyl 74

75

G. P. Cotterrell, T. G. Halsall, and M. J. Wriglesworth, J . Chem. SOC.(0,1970, 1503. D. Lavie and E. C . Levy, Tetrahedron Letters, 1970, 1315.

182

Terpenoih and Steroids

co 0

‘OAc

‘OAc

c.

P

O

0

’OAc

{Go

‘OAc

0

0

“OAc

acetate (125). Similarly,khayanthone (126)was t r a n ~ f o r m e into d ~ ~khivorin (127) by alkaline hydrogen peroxide in t-butanol. The simple tetranortriterpenoid (128), previously synthesised from t ~ r r e a n t h i n ,has ~ ~ been converted76 into azadirone (129) by reaction with copper bromide followed by dehydrobromination. The configuration of the ether oxygen at C-1 in methyl angolensate (130) has been unambiguously shown to be o! by a partial synthesis7* from 7-deacetyl-7oxokhivorin via the deoxy-compound (131). The latter was converted by peracetic acid oxidation to the &-lactone(1 32) and this was opened by toluene-p-sulphonic acid in benzene to give the diene-lactone (133). Mild alkaline hydrolysis of the 76

” 78

J. G . St. C. Buchanan and T. G . Halsall, Chem. Comm., 1969, 1493. J. G. St. C. Buchanan and T. G . Halsall, Chem. Comm., 1969,242. J. D. Connolly, I. M . S. Thornton, and D. A. H. Taylor, Chem. Comm., 1970, 1205.

Triterpenoidr 183 acetate groups followed by acidification resulted in Michael addition of the 1 a-hydroxy-group to the @unsaturated b-lactone. Mild oxidation completed the transformation to methyl angolensate (130). The B-diketone (134), a postulated precursor for the bicyclononanolide group, has also been prepared7' from 7-deacetyl-7-oxokhivorin by a similar route. Treatment of (134) with a very mild base re~ulted'~ in facile Michael addition of C-2 to the diene-lactone system to form mexicanolide (135).

0 Acd.

0

C02Me (133) R = H,a-.OAc (134) R = 0

79

J . D. Connolly, I. M. S. Thornton, and D. A. H. Taylor, G e m . Comm., 1971, 17

184

Terpenoih and Steroids

Quassinoids-Simarolide (136) had previously been the only substance providing a structural link between limonoids and quassinoids. The related picrasin A (137) has now been isolated" from Picrasma quussioides (P. ailanthoides). It was accompanied in the extract by picrasin B (138)81which was converted to quassin (139) by bismuth oxide oxidation and methylation. A series of closely related quassin derivatives, nigakilactones A (la), B (141), C (142), E (143), and F (144) occur with quassin in P. a i I ~ n t h o i d e s . ~The ~*~~ structure of amarolide has been revisedB4 to (145). Observation of a large coupling between H-9 and H-11 in the n.m.r. spectrum makes the previous 0

+.

0 Ac 0..

OMe

HO. .&o Ho..&o

0

'0 '0

(139)

(140) R' = R2 = R3 = H (141) R' = M e ; R2 = R3 = H (142) R' = Me; R2 = Ac; R3 = H (143) R' = Me; R2 = Ac; R3 = OH (144) R' = Me; R2 = H ; R3 = OH 81

82

83

84

H . Hikino, T. Ohta, and T. Takemoto, Chem. & Pharm. Bull. (Japan), 1970, 18, 1082. H. Hikino, T. Ohta, and T. Takemoto, Chem. & Pharm. Bull. (Japan), 1970, 18, 219. T. Murae, T. Tsuyuki, T. Nishihama, S. Masuda, and T. Takahashi, Tetrahedron Letters, 1969, 3013. T. Murae, T. Ikeda, T. Tsuyuki, T. Nishihama, and T. Takahashi, Bull. Chem. SOC. Japan, 1970,43,969. W. Stocklin, M. Stefanovic, and T. A. Geissman, Tetrahedron Letters, 1970, 2399.

Triterpeno ids

185

11-one, 12-01 assignment untenable. The structure (146), previously ~ u g g p t e d * ~ for bisnorquassin, has been confirmed in detail by an X-ray analysis which also revealed the stereochemistry.86 OH

0 ’0

: H

OH

A full paper on eurycomalactone(147)fromEurycoma longifolia, has appeared.” Eurycomalactone is at present the only example of this type of C,, compound. 4 LupaneGroup

Hui and Fung have isolated8* glochidonol (148) from Glochidion wrightii. It undergoes ready dehydration to glochidone, and on lithium aluminium hydride reduction yields a mixture of glochidiol and the corresponding lp,3P-diol. The latter has also been found in Glochidion species.89 Lupeol has been convertedg0 into glochidone by way of the dibromo-ketone (149). A second member of the ~(1),28-bisnorlupane series, deoxyemmolactone (150), has been found9’ in the bark of AEungium uillosum. The position of the trisubstituted double bond remains in doubt. Jingullic acid, from Emmenospermum alphitonioides, has been assigned9’ the structure (151). It was correlated with the mercuric acetate oxidation product (1 52) of dihydroceanothic acid (153).

91

J. A. Findlay and D. T. Cropp, Cunad. J . Chem., 1968,46, 3765. H. Lynton, Cunud. J . Cl’lem., 1970,48, 307. Le-Van-Thoi and Nguyen-Ngoc-Suong, J. Org. Chem., 1970,35, 1 104. W. H. Hui and M. L. Fung, J . Chem. SOC.(0,1969, 1710. W. H. Hui and M. L. Fung, Phytochemistry, 1970,9, 1099. A. S. Samson, S. J. Stevenson, and R. Stevenson, Chem. and Ind., 1969, 1143. M. B. Burbage, K. Jewers, R. A. Eade, P. Harper, and J. J . H. Simes, Chem. Comm.,

92

R . A. Eade, J. Ellis, P. Harper, and J. J. H. Simes, Chem. Comm., 1969, 579.

85 86

89

1970,8 14.

Terpenoids and Steroids

186

-4

@

BrH2C

<J

& o

Br..

0 (148)

( 149)

Degradative studies have shown93 that mercuric acetate oxidation of acetylbetulinic acid (154) and dihydroceanothic acid (153) results in the formation of the C-28 +C-19 lactones (155) and (152) respectively. The configuration of the hydrogen at C-18 in these compounds is 01. Under similar conditions betulin (156) is transformed94into the ether (157). The product of mercuric acetate oxidation of lupenyl acetate (158) is 3P-acetoxylupa-18,20(29)-diene(159)95 and not the 13(18),20(29)-diene as previously suggested. Treatment of the ring A seco-

(151) (152) 1,2-dihydro-

(154) R' = Ac; R2 = C02H (156) R' = H ; R2 = CH2OH (158) R' = Ac; R2 = CH3 (162) R 1 = Ac; R2 = C 0 2 M e 93

G. V. Baddeley, R. A. Eade, J. Ellis, P. Harper, and J. J. H. Simes, Tetrahedron, 1969, 25, 1643.

94 95

A. Vystrcil and Z . Blecha, Chem. and Ind., 1969, 418. G. V. Baddeley, J . J. H. Simes, and T. G. Watson, Tetrahedron, 1970, 26, 3795.

187

Triterpenoids

II

-4.

{

G

C

H

2

H

nitrile (160), derived from lanostenone, with mercuric acetate led to the aromatic derivative (161).96 Halsall and his colleagues have elucidated9’ the structures of a number of the minor products of ozonolysis of methyl acetylbetulinate (162). In addition to the expected nor-ketone they obtained the two trisnor-compounds (163) and (164), the Baeyer-Villiger product (165), and the bisnor-acid (166). These results are rationalised in terms of three different decomposition mechanisms for the ozonide AcO

{

{

flC02Me

{ flc02Me B C 0 2 M e

H\+0 -CH2

I

{

I

0, B

O

2

M

e

/

-CH {-CHI

/O

C\

CH3

I

96

97

J. J. H. Simes and T. G. Watson, J. Chern. SOC.( C ) , 1969,2352. R. T. Aplin, R. P. K. Chan, and T. G. Halsall, J. Chem. SOC.(0,1969, 2322.

188

Terpenoids and Steroids

(167). In a similar study9* of the ozonolysis of betulin diacetate, Vystrcil and Budesinsky obtained inter alia compounds (168), (169), and (170). Continuing their studies of epimerisation at C-19 in the lupane series, these authors have reported the formation of the lactone (171) by acid equilibration of the bisnor-acid (172).99 Performic acid oxidation"' of the isopropenyl group in a number of lupene derivatives has been described. Most of the products can be rationalised by assuming the rearrangement of an initially formed epoxide. CHzOH

I

CH3,

CH

,C02H

5 Oleanane Group

Three new compounds, platycogenic acids A, B, and C, have been obtained from Platycodon grandiJIorurnby Kubota and his colleagues.l o ' Platycogenic acid A (173) was isolated as the y-lactone (174) which, on treatment with sodium borohydride, yielded platycodigenin (175), the first example of a 4,4-dihydroxymethyltriterpenoid. Platycogenic acids B and C have been assigned structures (176)and (1 77) respectively. Acerotin (178) and acerocin (179) are two novel triterpenoid aglycones from the tumour inhibitory saponins of Acer negundo.'02 On alkaline hydrolysis both (178) and (179) yielded acerogenic acid (180) whose methyl ester was reduced by lithium aluminium hydride to 16-deoxybarringtogenol C (181). In addition, acerotin gave the optically active trans,trans-dienoic-acid(182) while 98 9q

loo lol '02

A. Vystrcil and M. Budesinsky, CON. Czech. Chem. Comm., 1970,35,295. A. Vystrcil and M. Budesinsky, Coll. Czech. Chem. Comm., 1970, 35, 312. J. Klinot, N. Hovorkova, and A. Vystrcil, Coll. Czech. Chem. Comm., 1970, 35, 1105. T. Kubota, H. Kitatani, and H. Hinoh, Chem. Comm., 1969, 1313. S. M . Kupchan, M. Takasugi, R. M. Smith, and P. S. Steyn, Chem. Comm., 1970, 969.

Triterpenoids

189

(173) R (175) R

= C02H = CH20H

(176) R (177) R

= =

C02H CHJ

acerocin gave the optically active cis,trans-dienoic-acid (183). Kupchan and his colleagues suggest that the unsaturated ester group in acerotin and acerocin may have an important function in the tumour inhibitory activity of the saponins.

(178) (179) (180) (181)

R' R' R' R'

= CO2H; R2 = Ac;

R3

=

CO.[CH%H],.Bus

= C 0 2 H ; RZ = Ac; R3 = C O . C H ~ C H - C H ~ X . B U ~ = COZH; R2 = R3 = H = CH,OH; R2 = R3 = H

Castanogenol (184), from the bark of Castmospermum a ~ s t r a l e , 'has ~ ~ been prepared by lithium aluminium hydride reduction of bayogenin methyl ester (185). The structure of entagenic acid (186) has been revi~ed."~The vicinal glycol Io3 lo4

M. G. Rao, L. R. Row, and C. Rukmini, Indian J . Chem., 1969,7, 1203. A. K. Barua, P. Chakrabarti, S. K. Pal, and B. C. Das, J. Indian Chem. SOC.,1970,47, 195.

Terpenoidr and Steroids

190

system was originally 21a,22a. Rubusic acid (3/3,7a-dihydroxyolean-l2-en-28-oic acid) has been isolated from Rubus m o l u ~ c a n u s . ' The ~ ~ changes in the chemical shifts of tertiary methyl groups brought about by alteration of substitution patterns have been described.'06-'08 The available data have been used to assign structures to cyclomiretin E (187), from Cyclamen europu,lo6 and 2a,3adihydroxyolean-12-en-28-oicacid, from Shorea acuminata O 7 The latter is identical with one of the two cis-2,3-diols obtained by osmium tetroxide oxidation of olean-2,12-dien-28-oic acid. The structures previously assigned to these two cis-2,3-diols are in error and should be inter~hanged."~/3-Peltoboykinolicacid has been shown to be the C-27 carboxylic acid (188) by interrelation with cincholic acid (189)"' [cf: or-peltoboykinolic acid (see later)]. Serratagenic acid, from Clerodendron serratum, has been identified as 3b-hydroxyolean-12-en28,29dioic acid (190). The full paper on jegosapogenol (barringtogenol C, aescinidin) and the configuration at C-21 and C-22 in barringtogenol D, aescigenin, protoaescigenin, and isoaescigenin, has appeared.

(184) R = CHzOH (185) R = C 0 2 M e

HO

HO (188) R (189) R

Io5

Io6

= =

CH, CO2H

A. K. Bhattacharya and H. K. Dutta, J . Indian Chem. SOC.,1969, 46, 381. S. Ito, M . Kodama, M. Sunagawa, T. Oba, and H. Hikino, Tetrahedron Letters, 1969, 2905.

lo' lo8

lo9 'lo

H. T. Cheung and T. C. Yan, Chem. Comm., 1970, 369. H. T. Cheung and D. G. Williamson, Tetrahedron, 1969,25, 119. M. Nagai, K. Izawa, and T. Inoue, Chem. & Pharm. Bull. (Japan), 1969,17, 1438. S. Rangaswami and S. Sarangan, Tetrahedron, 1969,25, 3701. T. Nakano, M. Hasegawa, T. Fukumaru, L. J. Durham, H . Budzikiewicz, and C. Djerassi, J . O r g . Chem., 1969, 34, 3 135.

Triterpenoids

191

HO

Aleuritolic acid (191) from Aleuritus rnontana, was readily transformed l 2 by acid into acetyloleanolic acid. The corresponding ester yielded myricadiol(192) on reduction with lithium aluminium hydride. Bryonolic acid (193), from the roots of Bryonia d i o i ~ a , " ~has been converted into isomultiflorenol(l94). It formed the y-lactone (195) on treatment with acid and the @unsaturated ketone (196) with perchloric acid and acetic anhydride.

(191) R' (192) R'

= =

Ac;R2 = C02H H;R2 = CH2OH

(193) R = CO2H (194) R = CH,

(195)

Photochemical cleavage of friedelin has been shown''4 to give the nor-secoacid (197) in addition to the usual seco-acid. Putranjivic acid (198),an unsaturated seco-acid, has been reported from Putranjiua roxburghii.' l 5 The carbonyl group ILZ

*

D. R. Misra and H. N. Khastgir, Tetrahedron, 1970, 26, 3017. G. Biglino, L. Cattel, 0. Caputo, and G. Nobili, Gazzetta, 1969, 99, 830. M. Takai, R. Aoyagi, S. Yamada, T. Tsuyuki, and T. Takahashi, Bull. Chem. Sac. Japan, 1970,43,972. G . R . Chopra, A. C. Jain, and T. R. Seshadri, Indian J . Chern., 1969, 7, 1 179.

192

Terpenoids and Steroids

in friedelan-x-one (199)has been placed116at C-21 on the basis of aphotochemical cleavage which gave acetaldehyde and the non-conjugated diene (200).

0

HO

Two papers"7911s have appeared describing some approaches to the synthesis of alnusenone (201). The route involved the preparation of the epimeric octahydropicenes (202) and (203). The cis,syn-isomer (202) was converted into the bromo-ketone (204), whose stereochemistry was determined by X-ray analysis. The trans,anti-isomer (203) was transformed into the ketone (205) with the required stereochemistry for an alnusenone precursor. Unfortunately, low yields precluded the continuation of this approach.

0 (202) R (203) R 'Ib

'

= =

P-H a-H

B. J. Clarke, J. L. Courtney, and W. Stern, Austral. J . Chem., 1970,23, 1651. R. E. Ireland, D. A. Evans, D. Glover, G. M. Rubottom, and H. Young, J . Org. Chem., 1969,34, 3717.

*'' R. E. Ireland, D. A. Evans, P. Loliger, J. Dickerson, J. Org. Chem., 1969, 34, 3729.

Bordner, R. H. Stanford, jun., and R. E.

Triterpenoids

193 0

0

P-Amyrin has been converted to oleanolic acid.' '' The critical step involved functionalisation of the C-28 methyl group by photolysis of the 13P-nitrite. Since fl-amyrin has already been synthesised, this represents a formal synthesis of oleanolic acid. Ursolic acid has been obtained from a-amyrin by a similar route."' Photo-oxidation of spergulaginic acid (206) followed by reaction with lead tetraacetate led to the formation of the nortriterpenoid, eupteleogenin (2O7).l2O The oxidation of triterpenoid olefins to the Asp-ketones with N-bromosuccinimide in aqueous dioxan has been reported'21 to proceed in high yield, if the reaction mixture is irradiated with visible light. The 0.r.d. and c.d. curves of a large number of A12 triterpenoid acids have been discussed'22 and the results compared with those of analogous saturated acids and unsaturated hydrocarbons. Oleanolic and ursolic acid types appear to exist in solution in a preferred conformation

Aco2H

0.

(208) IS/?-H (209) 18,-H R. B. Boar, D. C. Knight, J . F. McGhie, and D. H. R. Barton, J . Chem. SOC.( 0 , 1 9 7 0 , 678. I2O

12' 12*

I. Kitagawa, K. Kitazawa, and I. Yosioka, Tetrahedron Letters, 1970, 1905. B. W. Finucane.and J. B. Thomson, Chern. Comm., 1969, 1220. J. D. Renwick, P. M. Scopes, and S. Huneck, J . Chem. SOC.(0,1969, 2544.

194

Terpenoids and Steroids

having the carboxy-group syn-planar with the (C-16HC-17) bond. Microbiological hydroxylation of liquiritic (208) and 18diquiritic acids (209) has been observed'23 to proceed 7p, 15a, or both. 6 UrsaneGmup A novel dimethyl ester elactone from Dammar resin has been shown to have the structure (210) by X-ray analysis.'24 A very probable biogenesis from asiatic

acid [(211)- (212)- (210)] has been suggested. Madasiatic acid (213), a close relative of asiatic and madecassic acids, has been isolated from Centella a s i ~ t i c a ! ~ ~ Protection of the vicinal diol system, followed by oxidation to the 6-ketone and Wolff-Kishner reduction yielded 2a,3/?-dihydroxyurs-12-en-28-oicacid. Rubitic

t HO HOH2C

lz3

I**

M. Ferrari, U. M. Pagnoni, F. Pelizzoni, B. M. Ranzi, and T. Salvatori, Gazzetta, 1969, 99, 848. S. Brewis, T. G. Halsall, H. R. Harrison, and 0. J. R. Hodder, Chem. Comm., 1970, 891.

Iz5

H. Pinhas, Bull. SOC.chim. France, 1969, 3592.

Triterpenoids

195

HO

acid, from Rubusfruticosus,'26 is 6- or 7-hydroxyursolic acid (214). a-Peltoboy~ kinolic acid from the rhizomes of Peltoboykinia t e l l i m o i d e ~ 'is~ urs-12-en-3p-0127-oic acid (215). It is the first example of an a-amyrin derivative with a sole carboxy-group at C-27. The corresponding 8-amyrin derivative, p-peltoboykinolic acid, has also been described (see above). 7 HopaneGroup

PhIebic acid A, which C O - O C C U ~ Sin~ ~the ~ lichen Peltigera aphthosa with 15aacetoxy-22-hydroxyhopane (dustanin monoacetate) is 28-acetoxy-22-hydroxyhopan-23-oic acid (216). Mollugogenol B and C, new saponins from Moflugo

R (217) (218)

R

=

H, a-OH

R

=

0

OH

lz6

S. N. Ganguly, Chem. and Ind., 1970, 869.

'*' R. Takahashi, 0. Tanaka, and S. Shibata, Phytochemistry,

1969, 8, 2345.

196

Terpenoih and Steroids

h i r t ~ , have ~ ~ ~the9 structures ~ ~ ~ (217) and (218) respectively. Full papers on mollugogenol A (219)' 30 and 3~~,4a-epoxyfilicane have appeared. Pyridinium chloride has been used for the conversion of a number of tetrasubstituted epoxides in this series into unrearranged d i e n e ~ . ' ~ ~

'

8 SerrataneGroup Japanese club moss, Lycopodiurn chaturn, is a rich source of serratane derivatives. From it Tsuda and his colleagues have isolated 21-episerratriol (221)133(serrat14-en-3fl,21fl,24-trioI),16-oxolycoclavanol (222),134lycoclavanin (223),' 35 and three 16-0x0-diols (224), (225), and (226).136 16-Oxoserratriol (227) has been obtained from L. serrat~rn.'~~ The structures of these compounds have been assigned on the basis of n.m.r. spectra and interrelation with known compounds. In particular, oxidation of the allylic methylene at C-16 with t-butyl chromate

HO"

(222) R (223) R

= =

H OH

2

R'

HO

(224) R' = R2 = H,D-OH (225) R' = H, a-OH; R2 = H, B-OH (226) R' = H, B-OH; R2 = H, a-OH

12' 129

I3O 131 132

133 134 13s

136

P. Chakrabarti and A. K . Sanyal, J . Indian Chem. SOC..1969, 46, 1061. P. Chakrabarti, P. K. Sanyal, and A. K . Barua, J . Indian Chem. SOC.,1969, 46, 96. P. Chakrabarti, Tetrahedron, 1969,25, 3301. G. Berti, F. Bottari, and A. Marsili, Tetrahedron, 1969, 25, 2939. I. Morelli and A. Marsili, J . Org. Chem., 1970, 35, 567. Y. Tsuda and M. Hatanaka, Chem. Comm., 1969, 1040. Y. Tsuda, T. Fujimoto, and K. Kimpara, Chem. Comm., 1970,261. Y . Tsuda and T. Fujimoto, Chem. Comm., 1970,260. Y . Tsuda and T. Fujimoto, Chem. Comm., 1969, 1042.

I97

Trit erpeno ids

provides an easy route to the 16-0x0-series. The full papers on tohogenol and tohogeninol from L. serraturnI3' and on the serratene derivatives of the bark of Picea sitchensis (Sitka Spruce)13*have appeared. A number of new compounds related to serratenediol have been found in the bark of P. sit~hensis.'~~These include the 3a,2 ID-dimethoxy and 3a-methoxy-21-keto analogues. Phlegmanol A from L. phlegmaria has been shown140to be the 3-dihydrocaffeic acid ester of

(228) R = CHO (229) R = CH3

serratenediol. The mass spectral fragmentation of A14 serratene and its derivatives has been investigated.14' The seven-membered ring appears to dominate the cleavage and the typical retro-Diels-Alder process found in A 14-taraxerene and related pentacyclic triterpenoids is much less important. Addition reactions (epoxidation, hydroboronation, osmylation) to the A14-doublebond of serratenes occur mainly from the face, though hydrogenation gives almost equal amounts of 14a- and 14P-serratanes.' 42 Acid-catalysed rearrangement of 14P,15Pepoxyserratane leads'42 to the aldehyde (228),which on Wolff-Kishner reduction gives neoserratane (229).

13' 13'

139 14'

T. Sano, Y . Tsuda, and Y. Inubushi, Tetrahedron, 1970,26,2981. J. P. Kutney, I. H. Rogers, and J. W. Rowe, Tetrahedron, 1969, 25, 3731. I. H. Rogers and L. R. Rozon, Canad. J . Chem., 1970,48, 1021. Y. Inubushi, T. Harayama, T. Hibino, and R. Somanathan, Chem. Comm., 1970,1118. J. P. Kutney, G. Eigendorf, and 1. H. Rogers, Tetrahedron, 1969,25, 3753. Y . Tsuda, T. Sano, and Y. Inubushi, Tetrahedron, 1970, 26, 751.

5 Carotenoids and Polyterpenoids BY G. P. MOSS

1 Introduction

The application of a wide range of modern physical techniques has resulted in rapid advances in carotenoid chemistry in the last few years. These studies have elucidated the structures of many carotenoids, including their absolute configurations. Recent reviews clearly reflect much of the current interest in this field. The regular IUPAC carotenoid meetings include surveys of physical methods,’ mass spectrometryY2 ~ynthesis,~ and structural studies4 Spectroscopic methods have been reviewed’ as well as allenic and acetylenic carotenoids6 Further metabolism of carotenoids gives a number of important terpenoids. Vitamin A (retinol)’ is derived by cleavage of the central double bond. Structurally, and possibly biosynthetically, related is the important plant hormone abscisic acid.* Although the best-known polyterpenoid is rubber, recent work has demonstrated a range of polyprenols’ and related compounds such as vitamins E and K.’ 2 Physical Methods A major experimental problem is that carotenoids rarely occur in large quantities ;

also they are often extremely unstable. Preparative t.1.c. greatly assists their isolation. Use of basic magnesium carbonate is claimed’“ to facilitate the separation of cis isomers from the all-trans form. Up to 95 % recovery at a 1-2 pg level after t.1.c. on sucrose is reported.” Probably the most commonly used spectroscopic method for structure determination is U.V.spectroscopy. From a study” of solvent effects on the U.V.

*

U. Schwieter, C. Englert, N . Rigassi, and W. Vetter, Pure Appl. Chem., 1969, 20, 365. C. R. Enzell, Pure Appl. Chem., 1969, 20, 497. B. C. L. Weedon, Pure Appl. Chem., 1969,20, 531 ; 1967,14,265. S. Liaaen-Jensen, Pure Appl. Chem., 1969,20,421; 1967,14,227. B. C. L. Weedon, Fortschr. Chem. org. Naturstofe, 1969,27, 81. B. C. L. Weedon, Rev. Pure Appl. Chem., 1970. 20, 51. 0. Isler, Experienria, 1970, 26, 225. * P. F. Wareing and G. Ryback, Endeavour, 1970,27, 84. F. W. Hemming, Biochem. Soc. Symp., 1969,29, 105. y a H .Nitsche and K. Egger, Phytochem., 1969,8, 1577. ” S . W. Jeffrey, Biochim. Biophys. Acta, 1968, 162, 271. l o M . Buchwald and W. P. Jencks, Biochem., 1968,7, 834.

‘ ’

Carotenoids and Polyterpenoids

199

spectrum of astaxanthin (1) it was concluded that the refractive index of the solvent was more closely correlated with the changes than was either the dielectric constant or solvation effects. However, after an investigation of fi-carotene (2) and related systems it was decided" that solvation theory readily explained the observed changes. Low temperature U.V.at 77 K results in increased fine structure and slight changes of A,,,,,. A range of carotenoids'2 and retinalI3 were studied at this temperature. The absolute stereochemistry of carotenoids is largely based on the correlation14 of their 0.r.d. curves. So far, all samples of any one carotenoid from a wide range of sources have proved to have the same chirality. Furthermore, the 3-hydroxy-group in all cases seems to have the same absolute stereochemistry (see below). The additivity principle whereby each chiral end separately contributes to the observed curve permits prediction of new permutations of these end groups. Few measurements of c.d. curves have been reported. Semi-a-carotenone (3) was related to a-carotene (4) by c.d. studies."

w... @...

\

HO &'.*

/

0

*

f

(3) R' (4)

13 14

15

C

e

(1) R' = (2) R' =

12

'0

b

a

11

\

R'

= C; RZ =

= C;

g

( 5 ) R' =

R2 = a RZ = b d

d

R2 = e

(6) R' = R2 = f (7) R' = f ; R2 = g

R2= b

F. Feichtmayr, E. Heilbronner, A. Nurrenbach, H. Pommer, and J. Schlag, Tetrahedron, 1969,25, 5383. B. Ke, F. Imsgard, H. Kjesen, and S. Liaaen-Jensen, Biochirn. Biophys. Acta, 1970, 210, 139. W. Sperling and C. N. Rafferty, Narure, 1969, 224, 591. L. Bartlett, K. Klyne, W. P. Mose, P. M. Scopes, G. Galasko, A. K. Mallams, B. C. L. Weedon, J. Szabolcs, and G. Tbth, J. Chem. SOC.(0,1969, 2527. R. Buchecker, H. Yokoyama, and C. H. Eugster, Helv. Chim. Acta, 1970, 53, 1210.

200

Terpenoids and Steroids

Proton n.m.r. has been extensively applied. The advent of 220 MHz spectrometers permits even more detailed analysis for carotenoids’ and retinal.16 Both temperature and solvent effects were examined.16 When coupled with paramagnetic induced shifts the magnitude and sign of the spin density were deduced The cis- and for the carbon atoms of retinal Schiffs bases with rneth~1amine.l~ trans-isomers of theaspirone (8) and (9) were distinguished using the nuclear Overhauser effect.18 When the 5-methyl group was irradiated the n.m.r. signal for the 4 and 9 protons were increased in intensity as shown. The first study using 13C n.m.r. at natural abundance suggests that this technique may prove to be a very powerful method. All 20 types of carbon atoms of p-carotene (2) and related systems were distinguished.”

Mass spectrometry is the most recently introduced technique to be widely applied to carotenoid structural studies. Many spectra are recorded by Enzell et Recent advances include the recognition that a loss of 106 and 92 m.u. (rationalised as xylene and toluene) is characteristic of the polyene chain.2 The remaining fragments on either side of the polyene may be recognised by bisallylic fission.22 Ketonic carotenoids show characteristic f r a g m e n t a t i ~ n .MacMillan ~~ and G a ~ k i nwere ~ ~able to detect 0.3 pg of abscisic acid or phaseic acid using g.1.c.-m.s. Resonance-enhanced laser Raman spectra may prove to be very sensitive in the detection of c a r o t e n o i d ~ .This ~ ~ technique was used to detect B-carotene (2) and lycopene (16) in living tissues.26 The application of X-ray crystallography has in general proved difficult. Canthaxanthin (5)and 15,15’-dehydrocanthaxanthinwere examined27and shown to have a near S-cis bond between the cyclohexene ring and polyene chain. Also the chain is curved and slightly bent. Theoretical calculations predict the most I‘ ”

D. J. Patel, Nature, 1969, 221, 825. D. J. Patel and R. G. Shulman, Proc. Nut. Acad. Sci.,U . S . A . , 1970,65,31. Y. Nakatani, T. Yamanishi, and N . Esumi, Agric. and Biof. Chem. (Japan), 1970, 34, 152.

l 9

2o 21

22

M. Jautelat, J. B. Grutzner, and J. D. Roberts, Proc. Nut. Acad. Sci.,U . S . A . , 1970, 65, 288. C. R. Enzell, G . W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1969, 23, 727. C. R. Enzell, G . W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1968, 22, 1054. B. H. Davies, E. A. Holmes, D. E. Loeber, T. P. Toube, and B. C. L. Weedon, J . Chem. SOC.( C ) , 1969, 1266.

23

24

25

26

”

J. Baldas, Q. N . Porter, A. P. Leftwick, R. Holzel, B. C. L. Weedon, and J. Szabolcs, Chem. Comm., 1969,415; G. W. Francis, Acta Chem. Scand., 1969,23,2916. P. Gaskin and J . MacMillan, Phytochem., 1968, 7, 1699. L. Rimai, R. G . Kilponen, and D. Gill, J. Amer. Chem. SOC.,1970, 92, 3824. D. Gill, R. G. Kilponen, and L. Rimai, Nature, 1970, 227, 743. J . C. J . Bart and C. H. MacGillavry, Acra Cryst. 1968, B24, 1569, 1587.

Car0ten0 ids and Po ly te rpenoids

20 1

stable arrangement should have approximately an S-cis bond28 and that slight non-planarity relieves strain.29 The stereochemistry of racemic grasshopper ketone (1 0) synthesised ~ h e m i c a l l yand , ~ ~ the photochemically derived isomer3 has been determined, and the former shown to be the same as the optically active degradation product from f u ~ o x a n t h i n . ~In~ addition, the absolute stereochemistry of this last sample was shown to be as formula (10). This important result confirms the absolute stereochemistry at C-3 of a wide range of carotenoids related to zeaxanthin (6). H

HO

OH

The biosynthetic results of Goodwin and c o - ~ o r k e rusing s ~ ~ [2-'4C,3R,5R-3H]mevalonic acid show that hydroxylation at C-3 results in the loss of tritium when zeaxanthin (6) or P-cryptoxanthin is formed. Since the absolute stereochemistry of the tritium atom at C-3 is known before hydroxylation this result confirms that there is retention of configuration. Assuming retention on hydroxylation to give lutein (7) the loss of tritium from both positions in its biosynthesis suggests the absolute stereochemistry indicated32at C-3 and C-3'.

3 New Natural Carotenoids The suggestion has been made34 that sporopollenin results from oxidatively polymerised carotenoids. As well as being present in the exine of pollen, it is suggested35that kerogen, the coat of fossil algae (2 x lo8 years old) is a granular form. Furthermore, organic material from certain meteorites (5 x 109 years old) resembles s p ~ r o p o l l e n i n . ~ ~

Acyclic Carotenoids.-Diphenylamine-inhibited Rhodospirillum rubrum produces an interesting series of hydrocarbons and spheroidene derivative^.^ ' The most interesting are 7,8,11,12-tetrahydrolycopene (1 3,4,11',12'1),22938

28 29

30

31

32

33 34

35 36 31 38

B. Pullman, J. Langlet, and H. Berthod, J . Theor. Biol., 1969, 23, 492. H. A. Nash, J . Theor. Biol., 1969, 22, 314. T. E. DeVille, M. B. Hursthouse, S. W. Russell, and B. C. L. Weedon, Chem. Comm., 1969, 754. T. E. DeVille, J . Hora, M . B. Hursthouse, T. P. Toube, and B. C. L. Weedon, Chem. Comm., 1970, 1231. T. E. DeVille, M . B. Hursthouse, S. W. Russell, and B. C. L. Weedon, Chem. Comm., 1969, 1311. T. J. Walton, G . Britton, and T. W . Goodwin, Biochem. J . , 1969, 112, 383. J. Brooks and G . Shaw, Nature, 1968, 219, 532. J. Brooks and G . Shaw, Nature, 1968, 220,678. J . Brooks and G. Shaw, Nature, 1969,223,754. B. H. Davies, Pure Appl. Chem., 1969, 20, 545. B. H. Davies, Biochem. J . , 1970, 116, 93.

202

Terpenoids and Steroids

tetrahydrospheroidene (12), and 11',12'-dihydrospheroidene (1 Their structures were proved by mass spectrometry and showed that the dehydrogenation need not proceed on alternate sides of the central double bond as previously supposed. Other carotenoids isolated from this system include spheroidene, hydroxyspheroidene;' l.-hydroxy-l,2dihydrophytoene (14),and 1 -hydroxy-l,2dihydr~phytofluene.~' 3).22939

a (11) R = a

b

C

(12) R = b

(13) R = c

Two new acyclic end-groups have been found. Phytoene-l,2-oxide (15 ) was isolated from tomatoes.42 In the bacteria Rhodopseudornonas uiridis it was found43 that although neurosporene and lycopene (16) were present, most of the carotenoids previously thought to be these two compounds, were in fact the corresponding 1,2-dihydro-derivatives [e.g. (17)]. In addition, 1,2-dihydro-3,4dehydrolycopene (18) was present.

a (14) (15)

R R

b

a =b

=

L. L... L... HO&..-

:

\

(16) R (17) 3y

''

40

42

"

b

a

R

= =

R

a

(18)

b

(19) R

C

= =

d

c d

B. H . Davies, Biochem. J . , 1970, 116, 101. H. C. Malhotra, G . Britton, and T. W. Goodwin, Phytochern., 1969, 8, 1047. H . C. Malhotra, G. Britton, and T. W. Goodwin, FEBS Letters, 1970, 6, 334. G. Britton and T. W. Goodwin, Phytochem., 1969,8,2257. H . C. Malhotra, G. Britton, and T. W . Goodwin, Chem. Comm., 1970, 127.

Car0ten0 ids and Po ly terpeno ids

203

A reinvestigation of lycoxanthin (19) and lycophyll (20) that the allylic hydroxy-group is on the terminal carbon atom. This result was confirmed by nickel peroxide oxidation to the corresponding aldehydes.

OMe

The two major carotenoids in Shepherdia canadensis were4’ lycopene (16) and methyl apo-6’-lycopenoate (21). The latter was synthesised from apo-8’lycopenal(22) by the appropriate Wittig condensation. The synthesis of methylbixin (24) with the natural cis double bond derived from the lactol(23) is outlined in Scheme l.46

OMe ~

Ph,PHBr

(24)

OMe

Scheme 1 44

45 46

L. Cholnoky, J. Szabolcs, and E. S. Waight, Tetrahedron Letters, 1968, 1931; M. C. Markham and S. Liaaen-Jensen, Phytochem., 1968, 7, 839. H. Kjersen and S. Liaaen-Jensen, Phytochem., 1969,8,483. G . Pattenden, J. E. Way, and B. C. L. Weedon, J . Chem. SOC. (0,1970,235.

Terpenoidr and Steroids

204

The diapo-carotenoid crocetindial (25) and the corresponding oxoacid were isolated from Jacquinia a u g u s t i f ~ l i a . ~ ~

Monocyclic Carotenoids4azaniaanthin and rubixanthin (26), with apparently the same structure but different physical properties, have been shown to be cis-tram isomers about the 5‘-double bond.48*49Some of the physical differences were also resolved. The 0.r.d. curves were essentially the same, and confirmed that the absolute stereochemistry was the same as in zeaxanthin at C-3.I4 The solventdependent c.d. curve is of interest.49

(26) R = OH (27) R = H

In the bacteria Stigrnatellu auruntiacu, y-carotene (27) occurs with 4-keto-, 1’,2’-dihydro-l’-hydroxy-,and 4-keto- 1’,2’-dihydro-l’-hydroxy-y-carotene. In addition, the dehydrogenation product 4-keto- 1’,2’-dihydro-1‘-hydroxy-torulene (cf. 28) was present.50 Two intermediates (29) and (30) between torulene (28) and torularhodin (3 1) have been isolated from a yeast5

R

4

(28) R = Me (29) R = CHIOH

(30) R

=

R

=

(31)

CHO C02H

The methyl ester of neurosporaxanthin has been isolated from Nectria cin-

nab or in^.^^ Bicyclic Carotemids-The absolute stereochemistry of a-carotene (4) has been determined by Eugster and c o - ~ o r k e r sby ~ ~relating a-ionone to derivatives of manool and ambrein. Natural (+)-a-carotene (4) was synthesised from (+)-aionone and related by 0.r.d. to several other carotenoids with this chiral ~ e n t r e , ’ ~ ”

” 49

51

’’ 53

C. H. Eugster, H. Hurlimann, and H. J . Leuenberger, Helu. Chim. Acra, 1969,52, 806. B. 0. Brown and B. C. L. Weedon, Chem. Comm., 1968, 382. N. Arpin and S. Liaaen-Jensen, Phytochem., 1969,8, 185. H. Kleinig and H. Reichenbach, Arch. Mikrobiol., 1969, 68, 210. R. Bonaly and J. P. Malenge, Biochim. Biophys. Acta, 1968, 164, 306. J . L. Fiasson and M. P. Bonchez, Phyrochem., 1970,9, 1133. C. H. Eugster, R. Buchecker, Ch. Tscharner, G. Uhde, and G. Ohloff, Helu. Chim. Actu, 1969, 52, 1729.

Carotenoids and Polyterpenoids 205 for example a-cryptoxanthin (zeinoxanthin) (32).54 It is of note that natural (+)-a-carotene is R using the 1966 rules,55 whereas the earlier versions of these rules would have assigned the opposite designation. OH

Yokoyama et af. have isolated a series of seco-carotenoids from Rutaceae. Semi-a-carotenone (3)56 was shown by c.d. studies to have the same absolute stereochemistry as a-carotene.'5 The other examples isolated were semi-/?carotenone (33), p-carotenone (34)" and triphasiaxanthin (35).58

e... q+*-(p:.p.. HO

0 a

b (33) R' = a ; R2 = b (34) R' = R2 = b (35) R' = C ; R2 = b

\

d

C

(36) (37)

R' R'

= a ; R2 = = R2 = d

d

Diphenylamine-inhibited Epicoccum nigrum produces 3,4-dehydro-p-carotene (36) and 3,4,3',4-bisdehydro-p-carotene(37).59 Several interesting algal carotenoids have hydroxylated in-chain methyl groups. Loroxanthin (38) was shown by

54

55

56 57

58 59

(38) R = a (39) R = b J. Szabolcs and A. Rbnai, Acta Chim. Acad. Sci.,Hung., 1969, 61, 309. R. S. Cahn, Sir Christopher Ingold, and V. Prelog, Angew. Chem,, Internat. Edn., 1966, 5, 385. H. Yokoyama and H. C. Guerrero, Phytochem, 1970,9, 231. H. Yokoyama and M. J. White, Phytochem., 1968,7, 1031. H. Yokoyama, H. C. Guerrero, and H. Boettger, J. Org. Chem., 1970, 35, 2080. F. H. Foppen and 0. Gribanovski-Sassu, Biochim. Biophys. Acta, 1969, 176, 357.

206

Terpenoids and Steroids

mass spectrometry to have the hydroxymethyl group at C-9.60 Siphonaxanthin (39) was related chemically to loroxanthin by converting the 8-0x0-group to a 7,8-double bond by reduction and elimination.61 Pyrenoxanthin is an isomer of loroxanthin probably with the hydroxymethyl group at C-13 or C-13'.62 In Nature carotenoids are frequently esterified. Siphonein is esterified at the primary hydroxy-group of siphonaxanthin.61 Many 3-hydroxy-carotenoids are normally esterified. On t.l.c., up to eight components differing by their fatty acid part only were demonstrated for a range of xanthophylls.63 The bonding present in the carotenoproteins is unknown. Molecular weights have been suggested of over one million;64 however, in the crustacyanins the p- and y-forms were about half a million and a-crustacyanin was about 48,000. All three had a molecular weight of about 25,000 per carotenoid (astaxanthin, 1).6s

Aromatic and Cyclopentanoid Carotenoids.-Violerythrin (40) is a blue carotenoid formed by hydrolysis and mild oxidation of the sea anemone diester actinioerythrin (41).66 The proposed biogenesis involving a benzilic rearrange-

h

g

(40)

.'

'O

"

'' b3 64

"

''

R'

(41) R' (42) R' (43) R' (44) R'

R2 = a R2 = b R2 = c = R2 = d = d; R2 = e = = =

(45) (46)

R' R'

(47)

R'

(48)

R'

= = = =

RZ = e f ; R2 = g d ; R2 = g f ; R2 = h

K . Aitzetmiiller, H. H. Strain, W. A. Svec, M. Grandolfo, and J. J. Katz, Phytochem., 1969, 8, 1761. H . Kleinig, H . Nitsche, and K . Egger, Tetrahedron Letters, 1969, 5139. H . Y. Yamamoto, H. Yokoyama, and H. Boettger, J . Org. Chem., 1969,34, 4207. H. Kleinig and H. Nietsche, Phytochem., 1968, 7, 1171. P. F. Zagalsky, H. J. Ceccaldi, and R. Daumas, Cornp. Biochem. Physiol., 1970,34,579. M . Buchwald and W. P. Jencks, Biochern., 1968,7, 844. S. Hertzberg and S. Liaaen-Jensen, Acta Chem. Scand., 1968, 22, 1714; S. Hertzberg, S. Liaaen-Jensen, C. R . Enzell, and G. W. Francis, Acta Chem. Scand., 1969, 23, 3290.

Carotenoids and Polyterpenoids

207

ment of the 2,3,4-trione from the oxidation of astaxanthin (1) was supported by the synthesis of violerythrin from the diosphenol astacene (42) by oxidation with manganese dioxide.67 Certain bacteria are able to rearrange the normal carbon skeleton to give aromatic carotenoids. Phenolic examples were isolated from Streptomyces mediolani. As well as the hydrocarbon isorenieratene (43), 3-hydroxy- (44), and 3,3’-dihydroxy-isorenieratene(45) were present and their structures confirmed by synthesis.68 In Thiothece gelatinosa the major carotenoid was okenone (46) but the isomer (47) and desmethyl derivative (48) were also present. The structure of the latter compound was confirmed by ~ y n t h e s i s . ~ ~ Allenic and Acetylenic Carotenoids.-Since alloxanthin (49) was recognised as an acetylenic compound, this function has been recognised in a number of carotenoids. The difficulty of detecting the triple bond due to the weak i.r. signal and slight effect on the U.V. spectrum may be overcome in the future by 13C n.m.r.” The absolute stereochemistry of alloxanthin has been related to zeaxanthin (6) by perhydrogenation. l4 The major component of asterinic acid from starfish is dehydroastaxanthin (50).70 In some protozoan and algal species, diatoxanthin (51)7’ and diadinoxanthin (52)71,72are found rather than zeaxanthin (6) or antheraxanthin. Another algal acetylene is heteroxanthin

(49) R’ = R2 = a (50) R’ = b; R2 = c (51) R’ = a ; R2 = d ” 68

69 70

71

’’

(52) R’ (53) R’

= a; = a;

R2 = e R2 = f

R. Holzel, A. P. Leftwick, and B. C. L. Weedon, Chem. Comm., 1969,128. F. Arcamone, B. Camerino, E. Cotta, G . Franceschi, A. Grein, S. Penco, and C. Spalla, Experientia, 1969, 25, 241 ; F. Arcamone, B. Camerino, G. Franceschi, and S. Penco, Gazzetta, 1970, 100, 581. N . Pfennig, M. C. Markham, and S. Liaaen-Jensen, Arch. Mikrobiol., 1968, 62, 178. N. A. Sewensen, S. Liaaen-Jensen, B. Barrdalen, A. Hang, C. R. Enzell, and G. W. Francis, Acta Chem. Scand., 1968, 22, 344. K. Egger, H. Nitsche, and H. Kleinig, Phyfochem., 1969, 8, 1583. K. Aitzetmuller, W. A. Svec, J . J. Katz, and H. H. Strain, Chem. Comm., 1968, 32.

208

Terpenoids and Steroids

(53).73 An alternative formulation suggested an enol form of the fucoxanthin end-group.7 4 However, the n.m.r. spectrum is incompatible with this end-group and the claimed hydride reduction reaction is not observed with fucoxanthin. The most abundant natural carotenoid is fucoxanthin (54). A final report on its structure determination by Weedon and c o - ~ o r k e r shas ~ ~ appeared. The key degradation reaction with zinc permanganate gave fragments from both ends. An X-ray structure determination of the allenic end showed32the absolute stereochemistry indicated. Since fucoxanthin has been converted into zeaxanthin (6),if the epoxide is trans to the hydroxy-group, the complete structure is known.7 In the sea urchin, Paracentrotus licidus, the trio1 corresponding to fucoxanthin, fucoxanthinol, is present together with paracentrone (55) and possibly isofucoxanthinol (56).76 Oppenauer oxidation of fucoxanthin followed by hydrolysis gave paracentrone in 9 % yield.77

H

a

b

C

H

d

f

e

h (54) R' ( 5 5 ) R' ( 5 6 ) R' (57) R'

*-' 7J

7z

'' 7'

= a; R2 = b = Ac: R 2 = b = C; R2 = d = e : R2 = d

R' R' (60) R'

f ; R2 = d

(58)

=

(53)

= f ; R2 = g = h ; R2 = d

H. H . Strain, K. Aitzetmuller, W. A. Svec, and J. J . Katz, Chem. Comm., 1970, 876. H. Nitsche, Tetrahedron Letters, 1970, 3345. R . Bonnett, A. K. Mallams, A. A. Spark, J. L. Tee, B. C. L. Weedon, and A. McCormick, J . Chem. SOC.(0,1969, 429. G. Galasko, J. Hora, T. P. Toube, B. C. L. Weedon, D. Andre, M. Barbier, E. Lederer, and V. R . Villanueva, J . Chem. Soc. (0,1969, 1264. J. Hora, T. P. Toube, and B. C. L. Weedon, J . Chem. SOC.(0,1970, 241.

Carotenoids and Poly terpenoids

209

Neoxanthin (foliaxanthin) (57) is present in green leaves. As normally isolated it is the 9-cis isomer, whereas the all-trans isomer neoxanthin-X is probably the natural product.78 These two compounds have dramatically different 0.r.d. curves.l 4 Lithium aluminium hydride reduction of neochrome (58) gave zeaxanthin (6).78179Neochrome is formed by mild acid treatment of neoxanthin. Under more vigorous conditions diadinochrome (59) is formed." Trollixanthin was shown to be probably the same as neoxanthin.81 De-epoxineoxanthin (60) was isolated from Mimulus guttatus, and it was suggested it was identical with trollein.82 The algal carotenoid vaucheriaxanthin is a hydroxylated neoxanthin. A 9'-hydroxymethyl group was suggested by Nitsche and Egger.83 Glycosides and Isoprenylated Carotenoids-Bacteria and blue-green algae show many similarities, one of which is the presence of carotenoid glycosides. The structure of myxoxanthophyll was revised by Jensen and co-workersE4 to the rhamnosyl derivative (61). They showed that the bis-P-L-rhamnosyl derivative oscillaxanthin (62) was also present.85 In a closely related species both of these carotenoids were present as the corresponding 0-methyl methyl pentosyl derivatives, in addition to the 4-keto-compound (63) where the sugar is a methyl pentose, possibly rhamnose.86 In the bacteria Nocardia kirovani the glucose unit of phlei xanthophyll(64) is m~noesterified.~~ Similarly,myxobacton ester (65) and myxobactin ester (66), present in several Myxobacteriales species, are monoesters of inositol derivatives.88 The methyl apo-8'-lycopenoate derivative (67) is present together with the corresponding apo-8'-lycopenol derivative in a bacterial species.89 In this case the sugar present is mannose. Several bacterial species produce C45 and Cs0 carotenoids which contain one or two extra isoprenyl groups. Although their biosynthesis has not been studied, it is probable that instead of proton-initiated cyclisation at the polyene termini, attack by dimethyl ally1 pyrophosphate results in substances such as the symmetrical decaprenoxanthin (P439) (68).90 The stereochemistry of the isolated acyclic double bond was shown to be trans by the n.m.r. spectrum of the corresponding a l d e h ~ d e . ~ Other carotenoids present in Flauobacteriurn 78

" 8o

** 83 84 85

86

87 88

89

90 91

L. Cholnoky, K. Gyorgyfy, A. Ronai, J. Szabolcs, G. Toth, G. Galasko, A. K . Mallams, E. S. Waight, and B. C. L. Weedon, J . Chem. SOC.( C ) , 1969, 1256. K. Tsukida and M . Yokota, Bitamin., 1969, 39, 125. K. Egger, A. G . Dabbagh, and H. Nitsche, Tetrahedron Letters, 1969, 2995. K. Egger and A. G . Dabbagh, Tetrahedron Letters, 1970, 1433. H. Nitsche, K. Egger, and A . G. Dabbagh, Tetrahedron Letters, 1969,2999; H. Nitsche, Tetrahedron Letters, 1970, 3343. H. Nitsche and K. Egger, Tetrahedron Letters, 1970, 1435. S. Hertzberg and S. Liaaen-Jensen, Phytochem., 1969, 8, 1259. S. Hertzberg and S. Liaaen-Jensen, Phytochem., 1969, 8, 1281. G . W. Francis, S. Hertzberg, K. Andersen, and S. Liaaen-Jensen, Phytochem., 1970, 9, 629. M.-J. Vacheron, N. Arpin, and G. Michel, Compt. rend., 1970, 271 C, 881. H. Kleinig and H. Reichenbach, Naturwiss., 1970, 57, 92. A. J . Aasen, G. W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1969, 23, 2605. S. Liaaen-Jensen, S. Hertzberg, 0. B. Weeks, and U. Schwieter, Acta Chem. Scand., 1968, 22, 1171. U. Schwieter and S. Liaaen-Jensen, Acta Chem. Scand., 1969, 23, 1057.

Terpenoids and Steroids

210

(61) R' = a; R2 = b (62) R' = RZ = b (63) R' = C ; R2 = d (64) R ' = e : R2 = f

(65) R ' = g; R2 = h (66) R' = i ; R 2 = h (67) R ' = j; R 2 = C 0 2 M e

dehydrogenans include the monohydroxy-compound (69), nonaprenoxanthin (7 1) and 11', 12'-dehydronoapreno~anthin.~'Nonaprenoxanthin is another example of a carotenoid where dehydrogenation has occurred only on one side of the central double bond. A monoglucoside of decaprenoxanthin occurs in Corynebacteriurn e r ~ ~ t h r o g e n e sThis . ~ ~ species also contains an acyclic C45 carotenoid (70) which, like bacterioruberia, shows that cyclisation is not necessary for addition of the extra isoprenyl unit.94 Sarcaxanthin is an isomer of decaprenoxanthin with one hydroxy-group on an isoprenyl unit and a hydroxymethyl group attached to C-5 or C-5'.9s 92

q3 94

95

0.B. Weeks, A. G. Andrewes, B. 0. Brown, and B. C. L. Weedon, Nature, 1969,224, 879. 0. B. Weeks and A. G . Andrewes, Arch. Biochem. Biophys., 1970, 137, 284. S. NorgArd and S. Liaaen-Jensen, Actu Chem. Scund., 1969, 23, 1463. S. NorgArd, G . W. Francis, A. Jensen, and S. Liaaen-Jensen, Acta Chem. Scand., 1970, 24, 1460.

Carotenoids and Polyterpenoids

21 1

b

a

/\

(68) R’ = R2 = a

d

(69) R’ = a ; RZ = b

(70) R’ = C ;

RZ = d

4 Camternid Chemistry

The syntheses of methyl bixin (24) and other natural carotenoids were mentioned above. A biogenetically inspired synthesis of &-carotene used the titanium tetrachloride complex of lycopene (16). Dehydrolycopene was also isolated.96 Two more syntheses of /?-carotene(2) have been reported which use intermediates in the synthesis of vitamin A (see Scheme 2). Although 11-cis-p-carotene was it is rapidly isomerised to the all-trans form. The cross-conjugated .~~ example of this system (72)has a previously unknown c h r o m ~ p h o r e Another system, but with an additional 4-oxo-group, was synthesised by Surmatis ~ of the synthesis of keto carotenoids. They prepared echinenone et ~ 2 1 in. a~ study (73) and the two protected 3,3’-dioxo-P-carotene compounds (74) and (75). Treatment of the ketal with sulphuric acid gave mainly 3,3’-dioxo-/?-carotene (76) while hydrochloric acid gave 3,3’-dioxo-~-carotene(77). Under both conditions the enol ether gave the latter product. Oxidation of p-carotene (2) with manganese dioxide-vanadium pentoxide gave about 20% of retinal (81).’0° Using the corresponding 5,6-oxide (78), 96

” 98 99

C. Bodea, Pure Appl. Chem., 1969, 20, 517. J. D. Surmatis and R. Thommen, J. Org. Chem., 1969,34, 559. J. D. Surmatis, J. Gibas, and R . Thommen, J. Org. Chem., 1969, 34, 3039. J. D. Surmatis, A. Walser, J. Gibas, U. Schwieter, and R. Thommen, Helv. Chim. Acra, 1970, 53, 974.

loo

R. K. Barua and A. B. Barua, Indian J. Chem., 1969,7,528.

212

Terpenoids and Steroids

____+

I

11

111

PBr, (EtO),P LindlariH,

(2) reaction

PO(OEt),

I II

I1

NaBH, HBr,'Me,CO

Wttt1g reaction

Scheme 2

b

a

C

f

e

(73) R' = a ; Rz = b

R' R' (76) R'

(74) (75)

= = =

RZ = c R2 = d R2 = e

d

h

Carotenoids and Polyterpenoids

213

oxidation with hydrogen peroxide-osmium tetraoxide gave retinal and its 5,6-oxide.1°' In the presence of oxygen in the dark p-carotene is oxidised to the 5,6-oxide (78), 5,6,5',6'-dioxide, 5,8-oxide, and 5,8,5',8'-dioxide (79).96*102However, canthaxanthin (5) gave the corresponding 13,14-0xide.~~ Photochemistry.-Singlet oxygen is very efficiently quenched by # -carotene. l lo3 If the polyene system is shortened the triplet sensitiser is also quenched. However, the fact that extension of the system has little effect suggests a diffusion-controlled process.'o4 This phenomenon suggests that one of the functions of carotenoids in nature is to protect the organism against photochemical oxidation. The isomerisation of 15,15'-cis-P-caroteneto the all-trans isomer is catalysed by singlet oxygen. Under more vigorous conditions 5,6-oxides, 5,8-oxides, hydroxy-ketones, allenes, and acetylenes were claimed.'06 Further oxidation broke up the carbon skeleton to give p-ionone, dihydroactinidiolide (99), and 2-hydroxy-2,6,6-trimethylcyclohexanone.'07 Violaxanthin (80) was similarly cleaved to give loliolide (loo), and the corresponding 9-ketone, and 11-aldehyde,

xanthoxin (85). Oxidation of xanthoxin gave natural ( +)-trans-abscisic acid."* Photochemical oxidation was s~ggested"~as the biosynthetic origin of allenes and some degraded carotenoids. However, the stereochemistry of the photochemical allene did not agree with the natural allene (10).30-32 The photochemistry of degraded carotenoids is considered below. 5 Degraded Carotenoids

A number of terpenoids appear to be derived from carotenoids by cleavage of the polyene chain. These include retinal (C,,), trisporic acids (C, 8 ) , abscisic acid (C15), a-ionone (C13),and loliolide (Cll). Retinal (81) forms a Schiffs base with the lysine E-amino-group of the protein opsin, when the visual pigment is generated."O Some of the steric requirements ''I

Io2 lo3

lo6 lo' lo*

O9

lo

R. K . Barua and A. B. Barua, Indian J. Chem., 1969,7, 1017 . A. H. El-Tinay and C. 0. Chichester, J . Org. Chem.. 1970, 35, 2290. C. S. Foote and R . W. Denny, J . Amer. Chem. Soc., 1968,90, 6233. C. S. Foote, Y. C. Chang, and R. W. Denny, J . Amer. Chem. Sac., 1970,92,5216. C . S. Foote, Y. C. Chang, and R. W. Denny, J. Amer. Chem. SOC.,1970,92, 5218. K. Tsukida, S.-C. Ch8, and M. Yokota, Chem. Pharm. Bull., 1969,17, 1755. S. Isoe, S. B. Hyeon, and T. Sakan, Tetrahedron Letters, 1969,279. R. S. Burden and H. F. Taylor, Tetrahedron Letters, 1970, 4071; H. F. Taylor and R. S. Burden, Phytochem., 1970, 9, 2217. M. Mousseron-Canet, J.-P. Dalle, and J.-C. Mani, Tetrahedron Letters, 1968, 6037. M. Akhtar, P. T. Blosse, and P. B. Dewhurst, Biochem. J . , 1968, 110, 693.

Terpenoids and Steroids

214

were defined by the synthesis of a range of modified retinals. The basic carbon skeleton was necessary but not the 5,6-double bond or the 9- or 13-methyl groups.' ' 11,12-Dehydroretinal was synthesised by Mousseron-Canet and co-workers.' l 2 They studied the photochemistry of retinol when a Diels-Alder type of reaction formed a product by bonding between C-11 and C-14 of one Irradiation of retinal gave 9- and/or molecule and C-13 and C-14 of the other.' 1 1 4 s isomers.' l4 The triplet-triplet absorption spectra of retinal and retinol were recorded. ''' The fungal hormones trisporic acids B and C were shown to have a carotenoid origin.' l6 The absolute stereochemistry of trisporic acid C (82) was established by ozonolysis' ''-'' * and c.d. measurements.'17 In addition to the all-trans isomers, 9 4 s trisporic acids are also present. l 8

y (83) R = H (84) R = OH

HO

Abscisic acid (83) has the absolute stereochemistry shown,' l9 which should now be specified" as the S enantiomer. The correlation of abscisic acid (83) with

' ''

P. E. Blatz, M . Lin, P. Balasubramaniyan, V. Balasubramaniyan, and P. B. Dewhurst, J . Amer. Chem. SOC.,1969. 91, 5930. ' Il 2 J.-L. Olive, M. Mousseron-Canet, and J. Dornand, Bull. SOC.chim. France, 1969,3247. M . Mousseron-Canet, D. Lerner, and J.-C. Mani, Bull. SOC.chim. France, 1968,4639. M. Mousseron-Canet and J.-L. Olive, Bull. SOC.chim. France, 1969, 3242. 'I5 A. Sykes and T. G. Truscott, Chem. Comm., 1969,929. ' I 6 D. J . Austin. J . D . Bu'Lock. and D. Drake, Experientia. 1970, 26, 348. I" J . D. Bu'Lock, D . J. Austin, G. Snatzke, and L. Hruban, Chem. Comm., 1970, 2 5 5 . ' T. Reschke, Tetrahedron Letters, 1969, 3435. ' I 9 J. W. Cornforth, W. Draber, M . V. Milborrow, and G. Ryback, Chem. Comm., 1967, 114.

Cnrotenoids and Polyterpenoids

215

violaxanthin (80) via xanthoxin ( 8 5 ) ' 0 8 raises an interesting question concerning the stereochemistry of the oxidation reactions or of the terpenoids. In Nature, the all-trans isomer of abscisic acid was demonstrated in roses1'' and the P-D-glucopyranoside of the cis isomer in Lupinus Iuteus. 12' Phaseic acid (86) was prepared from metabolite C (84)"' so demonstrating the furanoid structure of the former compound rather than a smaller ring system.123 Xanthoxin is naturally present in some plant species.124 Metabolite C was first recognised by metabolic studies using [2-'4C]abscisic acid synthesised in the normal way from [2-'4C]bromoacetic e~ter.''~t-Butyl chromate oxidation of a-ionone provides an efficient synthesis of abscisic acid (Scheme 3).'26 A large number of compounds related to abscisic acid have been synthesised to check their biological activity.12' In general, conventional synthetic methods were used. The Reformatsky reaction may be used as an alternative to the Wittig reaction for the synthesis of a-ionylidene acetic ester.lZ8 An interesting method for the preparation of B-ionylidene acetonitrile used the corresponding allylic triphenylphosphonium salt and reacted it with isoamyl nitrite and base.lZ9

w

o

-

-

Ph,kHCO,Et

Bu',CrO,

(83)

14&170°C

Scheme 3

Photochemical oxidation of B-ionylidene acetic acid (87 ; R = CMe:CH-C0,Me) gives a mixture of three products (88), (89), and (90), after reduction of hydroperoxide groups. 30 Dehydro-B-ionone derivatives (91) gave the peroxides (88) or (92) when R = CMe: C H C H :CH-CMe:CHC0,Me or R = CMe: CH-CHICHC02Me.131 The stereochemistry of the allenic 120

121 122 123 124 125 126

121

128

I29 130

131

B. V. Milborrow, J . Exptl. Bot., 1970, 21, 17. K. Koshimizu, M. Inui, H. Fukui, and T. Mitsui, Agric. and Biol. Chem. (Japan), 1968, 32, 789. B. V. Milborrow, Chem. Comm., 1969, 966. J. MacMillan and R. J. Pryce, Tetrahedron, 1969, 25, 5893, 5903. H. F. Taylor and R. S. Burden, Nature, 1970, 227, 302. J. W. Cornforth, R. Mallaby, and G. Ryback, J. Chem. SOC.(C), 1968, 1565. D. L. Roberts, R. A. Heckman, B. P. Hege, and S. A. Bellin, J . Org. Chem., 1968, 33, 3566. S. Tamura and M. Nagao, Agric. and Biol. Chem. (Japan), 1969, 33, 1357; T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1970, 34, 108, 198, 830. J. Kamamoto, 0. E. Smith, C. M. Asmundson, R. B. Ingersoll, and H . A. Sadri, J. Agric. Food Chem., 1970, 18, 531. M. Matsui and G . Yabuta, Agric. and Biol. Chem. (Japan), 1968,32, 1044. J.-P. Dean, M. Mousseron-Canet, and J.-C. Mani, Bull. SOC.chim. France, 1969, 232; M. Mousseron-Canet, J.-P. Dalle, and J.-C. Mani, Photochem. and Photobiol., 1969, 9, 91. J.-L. Olive and M. Mousseron-Canet, Bull. SOC.chim. France, 1969, 3252.

216

Terpenoids and Steroids

product (90) is presumably as shown, since 3-hydroxy-P-ion01 (3-OH, 87, R = CHMeOH) gave after oxidation an isomer of the grasshopper ketone (lo), shown by X-ray crystallography to have the stereochemistry of (3-OH, 90, R = Ac).~' This stereochemistry was predicted by Mousseron-Canet et as well as by Foote et who studied the photochemical oxidation of (87, R = CMe:CH,). Latia luciferin (94) was isolated from limpets'33 and the structure was conof the enol ester double bond firmed by ~ y n t h e s i s . ' ~ ~The ' ~ ~stereochemistry '

Scheme 4

132

133 13'

13'

C. S. Foote and M . Brenner, Tetrahedron Letters, 1968, 6041. 0. Shimomura and F. H. Johnson, Biochem., 1968, 7, 1734. M. G . Frachebond. 0.Shimomura. R . K . Hill, and F. H. Johnson, Tetrahedron Letters. 1969, 3951. F. Nakatsubo, Y. Kishi, and T. Goto, Tetrahedron Letters, 1970, 381.

Caro teno ids and Po ly terpeno ids

217

was shown to be trans by Baeyer-Villiger oxidation of the cis and trans aldehydes (93).135These reaction sequences are outlined in Scheme 4. The defensive excretion of the grasshopper Romalea microptera contains the allenic ketone This structure is clearly related to neoxanthin (57). Racemic samples of (10) were ~ y n t h e s i s e d ' ~by~ two ~ ' ~ routes ~ (Scheme 5 ) and, although there were some differences between the two products, their n.m.r. spectra show that they belong to the natural series and that they are clearly different from the photochemically synthesised isomer (3-OH, 90, R = Ac).~' The stereochemistry of the synthetic r a ~ e m a t e was ' ~ ~ shown3' by X-ray crystallography to be the same as an optically active sample derived from the degradation of f u ~ o x a n t h i n The . ~ ~ absolute stereochemistry of the latter sample presumably also applies to the grasshopper ketone itself.

i. EtMgBr-HCi CCHMeOH ii. H' iii. NaBH,

i. Ac,O ii. RC0,H iii. LAH

HO L

O

A OH

HO'

u?

OH

b

i. Na,CO, ii. Me3SiC1 iii. MeLi-HC:CCHMeOH

i. HCIO, ii. Cr03-py

BAo

OTMS

OTMS

T

Scheme 5

136

J. Meinwald, K. Erickson, M. Hartshorn, Y. C. Meinwald, and T. Eisner, Tetrahedron

13'

Letters, 1968, 2959. S. W. Russell and B. C. L. Weedon, Chem. Comm., 1969, 8 5 . J. Meinwald and L. Hendry, Tetrahedron Letters, 1969, 1657.

218

Terpenoids and Steroids

One of the components of the aroma of tea is theaspirone (96).'39*,'40 No less than five syntheses of this compound have been published (Scheme 6).141-143 One of the more interesting reactions is the selective reduction of the acyclic enone (95) leaving the cyclohexenone intact.'43i144 The cis and trans isomers (8) and (9) of the racemic product have been separated and their structures assigned using the nuclear Overhauser effect.l * Vomifoliol(97) isolated from RauwolJu uomitoriu appears to be a degradation product of abscisic acid and possibly a precursor of t h e a ~ p i r o n e . ' ~Damas~ cenone, a minor component of Bulgarian rose oil, was to be the crossconjugated isomer (98) of dehydroionone. A tetrahydro-damascenone was prepared by treating cr-ionone-7,8-oxidewith h y d r a ~ i n e . ' ~ ~

NaOH

iii. NaOH

/El".

W

O

H

RCO,H)

@

ii. H,-Pt

4py ii. Na,CrO,

OH

\

DMSO-A PhSO;),CI-PY

I

i. ii. rii. iv.

Ac,Gpy Na,CrO, NaOH Pb(OAc),

Scheme 6 K. h a , Y. Sakato, and H. Fukami, Tetrahedron Letters, 1968,2777. F. Miiggler-Chavan, R. Viani, J. Bricout, J. P. Marion, H. Mechtler, D. Reymond, and R. H. Egli, Helv. Chirn. Acta, 1969,52, 549. 14' A. Sato and H. Mishima, Tetrahedron Letters, 1969, 1803. 1 4 2 Y. Nakatani and T. Yamanishi. Tetrahedron Letters, 1969, 1995. 1 4 3 R. A. Heckman and D. L. Roberts, Tetrahedron Letters, 1969,2701. 1 4 4 J.-L. Pousset and J. Poisson, Tetrahedron Letters, 1969, 1173. *" E. Demole, P. Enggist, U. Sauberle, M . Stoll, and Es. Kovats, Helv. Chim. Actu, 1970, 139

140

53, 541. 146

G . Ohloff and G. Uhde, Helv. Chim.Acta, :970, 53, 531.

Carotenoids and Polyterpenoids

219

The last vestige of the carotenoid polyene chain is left in dihydroactinidiolide (99), a compound formed on photochemical oxidation of fi-~arotene,"~and recently isolated from and tea arorna~.'~' Several syntheses of (99) have been r e p ~ r t e d , ' ~ ~ - ' as ~ ' well as of the related natural products actinidiolide (3,4-dehydro 99)' 48914' and loliolide (

(97)

(99) (100)

R R

=

=

H OH

6 PolyterpenoiaS

The major recent advances in polyterpenoid chemistry are a consequence of biosynthetic studies using [2-'4C,3R,4R-3H]mevalonicacid and its (4S)-isomer (see Part I, Chapter 6). Both n.m.r. and mass spectroscopic methods are of limited help in suggesting their structures, and as yet it is not possible to locate the position of the trans double bonds. It is tempting to suggest that three or four isoprenoid units at one end are trans (including the terminal dimethyl ally1 unit) and that the remainder of the isoprenoid units are cis. A typical example is C,, alcohol (101; n = 3; m = 7) from LactobacilIus plantare~m,'~'which may be important in cell wall biosynthesis. Dolichols, present in many animals, are frequently esterified in Naturelsl and consist of a group of compounds with one saturated double bond, probably the alcoholic isoprenoid unit (dihydro 101 ; n = 3; m = 13-18).152 In Aspergillus fumigatus a hexahydro-derivative is present where probably the alcoholic isoprenoid unit and the last two units at the

14'

148

149

I5O

15' 152

W. C. Bailey, jun., A. H. Bose, R. M. Ikeda, R. H. Newman, H. V. Secor, and C. Varsel, J . Org. Chem., 1968, 33, 2819. S. hoe, S. B. Hyeon, H. Ichikawa, S. Katsumura, and T. Sakan, Tetrahedron Letters, 1968, 5561. E. Demole and P. Enggist, Hefv. Chim. Acta, 1968, 51, 481. D. P. Gough, A. L. Kirby, J . B. Richards, and F. W. Hemming, Biochem. J., 1970,118, 167. P. H. W. Butterworth and F. W. Hemming, Arch. Biochem. Biophys., 1968, 128, 503. D. P. Gough and F. W. Hemming, Biochem. J., 1970, 118, 163.

220

Terpenoids and Steroids

other end are saturated (hexahydro 101 ;n = 4;rn = 14-2O).ls3 Bombiprenone (102)is an all-trans compound isolated from mulberry leaves and silkworms.154 An all-cis polymer (rubber) with a molecular weight of about 4000 is present in Satureia montana.

IF’

55

K . J . Stone and F. W. Hemming, Biochem. J . , 1968, 109, 877. M. Toyoda, H. Fukawa, and T. Shimizu, Tetrahedron Letters, 1968, 3837. C. Tabacik and M. Hubert, Phyrochem., 1970, 9, 1129.

6 Biosynthesis of Terpenoids and Steroids BY

G. P. MOSS

1 Introduction

In common with most other scientific literature, that dealing with terpene biosynthesis has grown rapidly in the last few years. In 1937 Rittenberg published’ one of the earliest uses of isotopic labelling in a study of the precursors of cholesterol. However, the two key developments came with the discovery of mevalonic acid in 1956 by the Merck group,2 and the synthesis of mevalonic acids labelled at the prochiral hydrogen atoms by Cornforth3 in 1964. Since then advances have been rapid. The total number of relevant publications has doubled in the last 3 i years so that this review of the advances for 1969-1970 represents about a quarter of the total published literature. Several conferences devoted to biological aspects of terpenoids have now been p ~ b l i s h e dA. ~recent volume’ in the ‘Methods in Enzymology’ series deals with much of the biochemistry and enzymology.

2 Acyclic Precursors

The details of squalene biosynthesis were elucidated by Popjak and Cornforth6 by 1966; their conclusions are summarised below since they are fundamental to the understanding of much current work. The main biochemical source of mevalonate is acetyl coenzyme A. Lynen and co-workers’ suggest that it is the hemithioacetal of mevaidate and coenzyme A (or the enzyme) which is reduced to mevalonic acid.

’

D. Rittenberg and R. Schoenheimer, J . Biol. Chem., 1937, 121, 235; R. Sonderhoff and H. Thomas, Annalen, 1937,530, 195; K. Bloch and D. Rittenberg, J . Biol. Chem., 1942, 143, 297; ibid., 145, 625. P. A. Tavormina, M. H. Gibbs, and J. W. Huff, J . Amer. Chem. SOC.,1956,78,4498; P. A. Tavormina and M. H. Gibbs, J. Amer. Chem. SOC.,1956,78,6210. Royal Society Symposium, 30th April 1964, Proc. Roy. SOC.,1965-1966, B, 163,435. ‘Terpenoids in Plants’, ed. J. B. Pridham, Academic Press, London, 1967; T. W. Goodwin, Biochem. SOC.Symp., 1969,29, Academic Press, 1970. ‘Methods in Enzymology’, ed. R. B. Clayton, Vol. 15, Academic Press, London, 1969. ‘ G. Popjak and J . W. Cornforth, Biochem. J., 1966, 101, 553; J. W. Cornforth, Quurr. Rev., 1969, 23, 125. ’ J. Retey, E. von Stetten, U. Coy, and F. Lynen, European J . Biochem., 1970, 15, 72; see also W. R. Bensch and V. W. Rodwell, J . Biol. Chem., 1970, 245, 3755.

222

Terpenoids and Steroids

I

R

=

CH,-CH : CMe.[CH,],-CH: CMe,

H E

HE

(8) R = CH2.[CH:CMeCH,.CH,],CH: CMe,

N.B. In this and all subsequent formulae HAis derived from the (2R)-position of mevalonic acid (HB= 2S, H, = 4R,H D = 4S, HE = 5R,and H, = 5s).

Most successful attempts to isolate the enzymes involved in terpene biosynthesis have come from these early stages. Crude in vitro systems will frequently c ~ n v e r t [2-'4C)mevalonic ~.~ acid (1) into its phosphate (2) and pyrophosphate (3), isopentenyl pyrophosphate (4), and dimethylallyl pyrophosphate (5). However, only traces of radioactivity are recovered from the prenol pyrophosphates (6). As well as phosphorylating mevalonic acid the same enzyme, or a related one, is

' E.

Beytia, P. Valenzuela, and 0. Cori, Arch. Biochem. Biophys., 1969, 129, 346; K . Oshima-Oba and I. Uritani, Planr Cell Physiol., 1969, 10, 8 2 7 ; V. H. Potty and J. H. Bruernmer, Phytochemistry, 1970, 9, 9 9 ; D. R. Thomas and A. K. Stobart, Phyrochemistry, 1970, 9, 1443. W. H. Potty and J. H . Bruemmer, Phytochemistry, 1970,9, 1229.

Biosynthesis of Terpenoids and Steroids

223

able to phosphorylate geraniol" [to (6; n = l)] or l i n a l ~ o l .In ~ rose petals the major products derived from mevalonic acid (1) are'' acyclic monoterpene glucosides. Whether these are formed directly from the corresponding pyrophosphates [ e.g. (6;n = l)] or oia the free alcohol is not known. Several of the individual enzymes of the early steps of terpene biosynthesis have been isolated. Mevalonic kinase [EC 2.7.1.36, (1)+(2)] has been prepared from I ~feed-back conseveral sources, for example Phaseolus oulgaris12 and pig 1 i ~ e r . A trol mechanism was suggested14 for the animal enzyme. KekwickI4 determined detailed kinetic data for pyrophosphomevalonate decarboxylase [EC 4.1.1.33, (3) +(4)] isolated from Heuea brusiliensis. Both kineticI5 and inhibition16 studies are reported for isopentenyl pyrophosphate isomerase [EC 5.3.3.2, (4) --+ (5)] isolated from pig liver and Cucurbita maxima respectively. The subsequent steps involve" the addition of isopentenyl units by prenyl transferase [EC 2.5.1.1, (4) + (5)- (6)]. A detailed study by Popjak et al." of this enzyme from pig liver suggests the active site is a groove in the protein with non-specific lipophilic and polar pyrophosphate binding groups. This enzyme has low substrate specificity, so that as well as generating the mono-, sesqui-, and diterpenoid acyclic precursors [(6;n = 1,2, and 3 respectively)], it will also function with unnatural substrate^.'^ Limited data is also available for the corresponding C. maxima enzyme.l6S2'

(9b) R = [>PO.0.POJ2- o r [-P0,-O~P02-]2lo

l2

l3

l4 Is l6

' I9 2o

W. D. Loomis, A. J. Burbott, and K. M. Madyastha, Plant Physiol., 1969, Supp., 40; K. M. Madyastha and W. D. Loomis, Fed. Proc., 1969, 28, 665. M. J. 0. Francis and C. Allock, Biochem. J., 1969, 113, 38P; M. J. 0. Francis and M. O'Connell, Phytochemistry, 1969, 8, 1705. J. C. Gray and R. G. 0. Kekwick, Biochem. J., 1969,113, 37P. J. K. Dorsey and J. W. Porter, J. Biol. Chem., 1968, 243, 4667. D. N . Skilleter and R . G . 0. Kekwick, Biochem. J., 1968, 108, 11P. P. W. Holloway and G . Popjak, Biochem. J., 1968, 106, 835. K. Ogura, T. Koyama, T. Shibuya, T. Nishino, and S. Seto, J. Biochem. (Tokyo), 1969. 66, 1 17. J. W. Cornforth, Angew Chem. Internat. Edn., 1968,7, 903. P. W. Holloway and G . Popjak, Biochem. J., 1967,104,57; G . Popjak, P. W. Holloway, R. P. M. Bond, and M. Roberts, Biochem. J . , 1969, 111, 333. G. Popjak, P. W. Holloway, and J. M. Barron, Biochem. J., 1969, 111, 325; J. L. Rabinowitz, G. Popjak, P. W. Holloway, and J. M. Barron, Fed. Proc., 1969, 28, 665. K. Ogura, T. Nishino, and S. Seto, J . Biochem. (Tokyo), 1968, 64, 197.

224

Terpenoih and Steroids

The mechanism whereby farnesyl pyrophosphate ( 6 ;n = 2 ) is converted into squalene (7) has aroused much chemical and biochemical interest. An intermediate isolated from yeast is the C,, pyrophosphate (9). Rilling et al." suggested the cyclopropanoid structure (9a) while the cyclic pyrophosphate diester (9b) was suggested by Popjak et a1.22 The universal involvement of this intermediate is supported22by the incorporation of radioactivity from the diester (9), prepared from yeast, into squalene (7) by a rat liver system. However, the suggested mechanism for the formation of the diester is difficult to reconcile with the o b ~ e r v a t i o nthat ~ ~ nerolidyl pyrophosphate is not incorporated. It is possible that an analogous intermediate is involved in phytoene (8) biosynthesis. However, instead of a reductive elimination of pyrophosphate, as i.1 squalene biosynthesis, the 15(15')-double bond must be derived by elimination. Goodwin and ~ o - w o r k e rhave s ~ ~shown ~ ~ ~ that both protons of this double bond are labelled by [2-'4C,3R,5R-3H]mevalonicacid.* Porter and co-workers26have studied the kinetics of an enzyme system from tomatoes for the conversion of geranyl geranyl pyrophosphate (6 ;n = 3) into phytoene.

3 Hemiterpenoids Many natural products contain an isolated 'isoprene' unit derived from mevalonic acid ; hence, these compounds may be considered as hemiterpenoid derivatives. In most cases the immediate precursor is probably dimethyl ally1 pyrophosphate (5). The electrophilic substitution at N-6 of adenosine by this group is of fundamental importance in protein biosynthesis. Transfer RNA is only active in the presence of this substituted base. Hall and Peterkofsky and their co-workers have demonstrated the biosynthesis of this nucleoside from the expected precursors in LactobuciZlus y e a ~ t , ~ ~tobacco -~' tissue,, and rat livers.29 Many secondary metabolites contain a hemiterpenoid unit. Hamada and C h ~ b a c hhave i ~ ~examined the biosynthesis of rotenone(l0). They found that the H. C . Rilling and W . W. Epstein. J. Amer. Chem. So<,..1369. 91. 1041. G . Popjak, J . Edrnund. K . Clifford, and V . Williams, J . B i d . Chem., 1969, 244, 1897. '' S. S. Sofer and H . C. Rilling, J. Lipid Res., 1969. 10, 183. R. J . H . Williams, G. Britton, J. M . Charlton, and T. W. Goodwin, Biochem. J., 1967, 104, 767. 2 s M. J. Buggy, G. Britton, and T. W. Goodwin, Biochem. J., 1969, 114, 641. 2 6 D. V. Shah, D. H. Feldbruegge, A. R. Houser, and J. W. Porter, Arch. Biochem. Biophys., 1968, 127, 124. 2' A. Peterkofsky, Biochemistry, 1968. 7, 472; A. Peterkofsky and C. Jesensky, Biochemistry, 1969, 8, 3798. '' F. Fittler, L. K . Kline, and R. H. Hall, Biochernistry, 1968, 7 , 940. '')F. Fittler, L. K. Kline, and R. H. Hall, Biochem. Biophys. Res. C o m m . , 1968, 31, 571. O' L. K. Kline, F. Fittler, and R. H. Hall, Biochemistry, 1969,8,4361. C.-M. Chen and R. H. Hall, Phyiochemistry, 1969, 8, 1687. 3 2 M. Hamada and M . Chubach;, Agric. and Biol. C h r m . (Jupun), 1969, 33, 793; L. Crombie and M. B. Thomas, J. Chem. Soc. (C), 1967. 1796. 22

* Unless otherwise stated. in this review all labelled mevalonic acids are fed as racemates. However, it is assumed that only the natural (3R)-enantiomers are metabolised. Hence [3R,5R-3H]mevalonic acid is a racemic mixture of ( 3 R , 5 R ) - and (3S,SS)-isomers.

Biosynthesis of Terpenoids and Steroids

225

OMe

radioactivity from C2-l 4C]mevalonic acid was largely randomised between the two terminal carbon atoms [see (lo),percentage found by degradation]. However, these results do not distinguish between randomisation of the unit intact (as found with the cyclopentanoid monoterpenes) and prior degradation to acetate. A third alternative route to this type of sub-unit is suggested by studies33 on the alkaloid lophocerin (11). Both mevalonic acid and the amino acid leucine are precursors of the hemiterpenoid unit. Whether they represent alternative biosynthetic routes or whether one is converted into the other, is unknown. Grundon and c o - ~ o r k e r have s ~ ~ shown that in the biosynthesis of the alkaloid ravenoline (13) an ‘abnormal’ Claisen type of reaction occurred from ravenine (12). Ergot Alkaloids.-The hemiterpenoid unit of the ergot alkaloids is interesting in that, as expected, only one carbon atom is labelled by [2-’4C]mevalonic acid [marked by * in formulae (14H17)] but the stereochemistry of this atom changes. indicate that chanoclavine I(14) is converted Extensive studies by Floss et into elymoclavine (17) via the aldehyde (15) and possibly uia agroclavine (16) (however,see ref. 36a). This process involvestwo isomerisations about the isolated double bond. In dimethyl ally1 pyrophosphate ( 5 ) the trans-methyl is labelled by ~

33

34

35

36 36

1

1

.

~

~

3

~

~

D. G. O’Donavan and H. Horau, J . Chem. Soc. (C), 1968, 2791 ; H. R. Schutte and G. Seelig, Annalen, 1969, 730, 186. T. R. Chamberlain, J . F. Collins, and M. F. Grundon, Chem. Comm., 1969, 1269. H. G . Floss, U. Hornemann, N. Schilling, K. Kelly, D. Groeger, and D. Erge, J . Amer. Chem. Soc., 1968, 90, 6500. B. Naidoo, J. M. Cassady, G. E. Blair, and H. G . Floss, Chem. Comm., 1970, 471. a E. 0. Ogunlana, B. J . Wilson, V. E. Tyler, and E. Ramstad, Chem. Cornrn., 1970, 775.

Terpenoids and Steroids

226

R

[Me

Hc&

H H

(14) R = CH20H (15) R = CHO

(16)

R

(17) R

= =

Me CH,OH

[2-14C]mevalonic acid. This stereochemistry is presumably retained in the C-4 alkylated tryptophane derivative (see also claviceptic acid") which precedes chanoclavine I (14). When the stereochemistry is reversed to give (14) the 9-H, labelled by [2-'4C,3R,4R-3H]mevalonic acid, is retained. However, in the second reversal (15) ---* (16) there is a significant loss of this hydrogen atom. Elemoclavine is one of the few terpenoids for which it has been proved that only the (3R)-enantiomer of mevalonic acid is metabolised3 (see footnote p. 224). F u r a m u m a r i n and Furanoquiaoline Derivatives.-The two extra carbon atoms of these furanoid rings are derived from C-4,5 of mevalonic acid. Probably very similar processes occur in both types of secondary metabolites. For expsoralen (21 ;R = H) and bergapten (21 ;R = OH) are derived from umbelliferone (1 8) uia marmesin (19)and their dihydro-derivatives (20). An

1

OMe

Me (241

OMe

R (25)

'' J. E. Roberts and H . G . Floss, Terrahedron Ltvrrrs, 1969. 1857. 38

34

W. Steck, M. El Dakhakhny. and S. A. Brown, Tetrahedron Letters, 1969, 4805. G . Caporale, F. Dall'Acqua, S. Marciani, and A. Capozzi, Z. Naturfbrsch., 1970,

25b, 700.

Biosynthesis of Terpenoids and Steroids

227

analogous process occurs3* with the isomeric ring system of angelicin (22) and its hydroxylated derivatives. [4-'4C]3-(Dimethylallyl)-2,4dihydroxyquinoline (23) is a good precursor4' of the furanoquinoline alkaloids, platydesmonium salt (24), and dictammine (25 ;R = H). Similarly, [4-14C]- and [5-'4C]-mevalonic acid and [l-'4C]dimethylallyl alcohol are4' specific precursors of skimmiamine (25 ; R = OH). 4 Monoterpenoids

Rapid advances have been made in the study of the relatively rare cyclopentanoid monoterpenoids due to their involvement in indole alkaloid biosynthesis. The bismonoterpenoid foliamenthin (26) was discovered in these studies and Arigoni and c o - ~ o r k e r have s ~ ~ demonstrated the efficient incorporation of geraniol(27) into both halves of (26). B a t t e r ~ b yobtained ~~ similar results with 6,7-dihydrofoliamenthin. In both cases, as expected, the acyclic half is more radioactive. The acyclic precursor of the monoterpenoids is normally assumed to be geranyl pyrophosphate ( 6 ;n = 1) but, clearly, this cannot directly cyclise to the foliamenthin skeleton. Two alternative precursors are44linalool pyrophosphate (28 ; R = P2063-)and nerol pyrophosphate (29; R = P,063-). Unfortunately, OGlu

all three have not been examined in the same system, but either is a more effective precursor than geranyl pyrophosphate, uiz.(28 ;R = P2OS3-)in Citrus SP.~'and (29; R = P2063-)in Pinus r ~ d i a t a In . ~ the ~ case of the indole alkaloids the best O' 41 42

43

J. F. Collins and M. F. Grundon, Chem. Comm., 1969, 621. A. 0. Colonna and E. G. Gros, Chem. Comm., 1970,674. P. Loew, Ch. V. Szczepanski, J. Coscia, and D. Arigoni, Chem. Comm., 1968, 1276. A . R. Battersby, A. R. Burnett, G . D. Knowles, and P. G . Parsons, Chem. Comm., 1968, 1277.

44

" 4h

G . P. Moss, J . SOC.Cosmetic Chemists, 1971, 22, 231. J. A. Attaway and B. S. Buslig, Phyrochemistry, 1969, 8, 1671; V. H. Potty, M. G. Moshonas, and J. H. Bruemmer, Arch. Biochem. Biophys., 1970, 138, 350. 0. Cori, Arch. Biochem. Biophys., 1969, 135,416.

228

Terpenoids and Steroids

acyclic precursor is4' 10-hydroxynerol (10-OH, 29; R = H). An overall SN2 hydrolysis of the pyrophosphate group to give geraniol is implied since Arigoni4* found that both [3R,5R-3H]mevalonic acid (1) and [1S-3H]geraniol (27) labelled 1-H of loganin (35; R = Me). However, the first C,, acyclic precursor must be geranyl pyrophosphate (6 ;n = 1) since two tritium atoms are i n ~ o r p o r a t e d ~ ' - ~ ~ by the [2- ''C,3R,4R-3H]isomer and none by the (4s)-isomer. The mechanism proposed by A r i g ~ n for i ~ this ~ cyclisation involves the trialdehyde (33). Potty et uI.~'have isolated an enzyme from Citrus spp. which oxidises geraniol(27) to the corresponding aldehyde. Normally it is assumed that in terpenoid biosynthesis each isoprenoid unit will be equally labelled by [2-'4C]mevalonic acid. However, Banthorpe et ~ 1have . ~ ~ found that in camphor (30) biosynthesis most of the radioactivity was located at C-6. A significant size pool of dimethyl ally1 pyrophosphate (5) is suggested. This

0

result may help to explain some of the labelling difficulties encountered with is that many monoterpenoids. Another problem discoveied by Banthorpe et of the menthane and thujane terpenoids in Tunaceturn vulgare are interconvertible. However, time uersus radioactivity studies have shown55that there is a steady turnover of the menthane terpenoids in Mentha pipirata. When [14C]pulegone (31) was added56 to a cell-free system only menthone and isomenthone were radioactive. This reduction only occurred in the presence of NADPH. The interesting vesicant from Spanish Fly beetle, cantharidine (32), does not obey the isoprene rule. However, incorporations7 of [2- ''C]mevalonic acid implies a terpenoid origin. S. Escher, P. Loew, and D. Arigoni, Chem. Comm., 1970, 823. D. Arigoni, Chern. SOC. Simonsen Lecture, London, 12th November 1969. " A. R. Battersby, J . C. Byme, R. S. Kapil, J . A. Martin, T. G . Payne, D. Arigoni, and P. Loew, Chem. Comm., 1968,951. R. Guarnaccia, L. Botta, and C. J . Coscia, J. Amer. Chem. Soc., 1969, 91, 204. s f C. J . Coscia, L. Botta, and R. Guarnaccia, Arch. Biochem. Biophys., 1970, 136, 498. 5 2 V. H . Potty and J. H . Bruemmer, Phytochernistry, 1970, 9, 1003. '' D. V. Banthorpe and D. Boxendale, Chem. Comm., 1968, 1553. " D. V. Banthorpe and A. Wirz-Justice, J . Cliem. Soc. (0, 1969, 541. '' F. W. Hefendehl, Pfanta Med., 1967, 15, 121; F. W. Hefendehl, E. W. Underhill, and E. von Ruloff, Phytorhemistry, 1967, 6, 8 2 3 ; A. J . Burbott and W . D. Coornis, Plant Physiol., 1969, 44, 173. 5 h J. Battaile, A. J. Burbott, and W. D. Loomis, Phytochemistry, 1968, 7, 1159. S T C. Schlatter, E. E. Waldner, and H . Schrnid, Experientia, 1968, 24, 994; D. Meyer, C. Schlatter, I. S. Lang, H. Schmid, and P. Bovey, Experientia, 1968, 24, 995; H . Guenther, E. Ramstad, and H . G. Floss, J . Pharm. Sci., 1969, 58, 1274. "

Biosynthesis of Terpenoids and Steroids

229

Cyclopentanoid Monoterpenoids and Indole Alkaloids.-Several reviews document5* advances in indole alkaloid biosynthesis. As a result of this work, loganin (35; R = Me) biosynthesis is now by far the best studied among terpenoids, with the exception of cholesterol. The results from feedings of [2-14C,3R]mevalonic acid (1) labelled with tritium at the (2R)-,5 ( 2 ~ ) - , ~ (4R)-,49-5 (4S)-,49-51 and (5R)-48positions as well as [2-'4C,6-3H,]geranio159 are summarised below. Intermediacy of the trialdehyde (33) was suggested by A r i g ~ n ito~ explain, ~ in particular, the observed randomisation of label from [2- 14C]mevalonicacid between C-9 and C-10. Notably, the established stereochemistry implies that an oxidised nerol derivative is i n v ~ l v e d .After ~~~~~ cyclisation there is evidence for 5-desoxyloganic acid6' (34; R = H) and 5-de~oxyloganin~~ (34; R = Me) as intermediates, but iridodial appears not to be involved.

OMe

(37) 58

s9 bo

b2 63

A. R. Battersby, Pure Appl. Chem., 1967,14, 117; J. P. Begue, Bull. SOC.chim. France, 1969, 2545; E. Leete, Accounts Chem. Res., 1969, 2, 59; A. I. Scott, Accounts Chem. Res., 1970, 3, 151. A. R . Battersby, E. S. Hall, and R. Southgate, J . Chem. SOC.(0,1969, 721. A. R. Battersby, S. H . Brown, and T. G. Payne, Chem. Comm., 1970, 827. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Tetrahedron Letters, 1969, 2351. A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Comm., 1970, 826. R. M. Bowman and E. Leete, Phytochemistry, 1969, 8, 1003.

230

Terpenoids and Steroids

Battersby et u1.64*65have shown that secologanin (36) [cJ (26)] is produced from loganin in both Menymthes trifoliata and Vincu rosea. The mechanism of ring cleavage is not known. I n c ~ r p o r a t i o n of ~ ~sweroside *~~ (38) into indole alkaloids in Erica rosea suggests either an alternative route, or the plant has an ability to metabolise an unnatural precursor (see also below). Secologanin (36) is probably directly ~ o n v e r t e d ~into ~ * ~vincoside * (37) and isovincoside [C-5 epimer of (37)]. Further transformations of the indole alkaloids are outside the scope of this review. The reader is referred to recent reviews5* and publica1 It is of note that the interesting claim by Garg and Gear7' tionS.47,49,60,62,647 that glycine is a better specific precursor than acetate, is not supported7' by recent studies using different plant species. Closely related to secologanin is gentiopicroside(39). As expected, it incorporated5'gS2only one tritium atom from [3R,4R-3H]mevalonicacid, and none from the (4S)-isomer. Related studies" with [3R,2R-3H]mevalonicacid showed that one tritium atom is probably incorporated but none is incorporated from the (2s)isomer. This implies that if secologanin (36)is a precursor then the aldehydeproton should be labelled. Other precursors which have been proved effective include loganic acids0," (35;R = H), l ~ g a n i n (35;R ~ ~ . ~=~Me), and sweroside66 (38). The alkaloid gentianine is closely related to gentiopicroside. In addition to mevalonic a ~ i d ~glycine ~ - is~also ~ a*good ~ ~precursor.73 OGlu

OGlu

OGlu

0 O H 0

hJ O5

OMe

A. R . Battersby, A. R. Burnett, and P. G. Parsons, Chem. Comm., 1968, 1282. A. R . Battersby, A. R. Burnett, and P. G. Parsons, J . Chem. Soc. (0,1969, 1187.

H . Inouye, S. Ueda, and Y. Takeda, Tetrahedron Letters, 1968, 3453. Tetrahedron Letters, 1969, 407. A . R. Battersby, A. R . Burnett, E. S. Hall, and P. G . Parsons, Chem. Co m., 1968, 1582; A. R. Battersby, A. R . Burnett, and P. G . Parsons, J . Chem. S o d C ) , 1969, 1193; A . R. Battersby and E. S. Hall, Chem. Comm., 1969, 793. '' J . P. Kutney, V. R . Nelson, and D. C. Wigfield, J . Amer. Chem. SOC.,1969, 91, 4278, 4279; E. Leete and J . N . Wemple. J . Amer. Chem. Soc., 1969, 91, 2698; C. Schlatter, E. E. Waldner, H. Schmid, W. Maier. and D. Groger, Helv. Chim. Acta, 1969,52, 776; A . 1. Scott, P. C. Cherry, and A. A. Qureshi, J . Amer. Chem. Soc., 1969, 91, 4932; A. R. Battersby and E. S. Hall, Chem. Comm., 1970, 194. 'O A. K. Garg and J . R. Gear, Chem. Comm., 1969,1447; Tetrahedron Letters, 1969,4377. ' I J. P. Kutney, J . F. Beck, V. R. Nelson, K. L. Stuart, and A. K. Bose, J . Amer. Chem. Soc., 1970, 92, 2174; D. Groger, W. Maier, and P. Simchem, Experientia, 1970, 26, '' 820. D. Groger and P. Simchem, Z . Naturforsch, 1969, 24b, 356. '' N. L. Marekov, M. V. Arnaudov, and S. S. Popov, Cornpt. rend. Acad. bulg. Sci., 1970, 23, 169. 'I'

'-H . Inouye, S. Ueda, and Y. Takeda,

Biosynthesis of Terpenoids and Steroids

23 1

HO

(42) R’ = H, R2 = C 0 2 M e (43) R’ = OH, R2 = C02Me

Although in indole alkaloid biosynthesis C-9 and C-10 of loganin are usually equally labelled by [2-’4C]mevalonic acid, this is not always the case.74 In mature plants of Verbena oflcinalis, verbenalin (40) was mainly labelled at C-9 whereas in young plants it was equally labelled at C-9 and C-10. Inouye et ul.61,75 have demonstrated in various plants many interconversions between cyclopentanoid monoterpenoids. They showed that 5-desoxyloganic acid (34; R = H) is converted into verbenalin (a), and suggested that asperuloside (41) is also formed from loganin (35 ;R = Me) uia geniposide (42). This compound (42) was also the precursor of scandoside (43)and aucubin (44),and the related compounds gardenoside and catalposide. 5 Sesquiterpenoids

Famesol (alcohol from 6 ;n = 2) is76an efficient precursor of ipomeamarone (45). A derivative of the 2-cis-isomer of farnesol is, presumably, the immediate precursor of the furan ring of this terpenoid, and the ant metabolite dendrolasin (46).77 A recent review44 discusses which isomer of farnesyl pyrophosphate is

(45)

‘0’

probably cyclised to give the various classes of sesquiterpenoids. It suggests that 2-trans-farnesyl pyrophosphate (6; n = 2) gives rise to humulene and germacradiene derived sesquiterpenoids, while the 2-cis-isomer gives bisabolene, curcumene, and related systems. The experimental support for this hypothesis is not yet available, although dihydrocostunolide (47) is incorporated7* into santonin (48). The terpenoid nature of petasin (49; R = COCMe: CHMe) has been demonstrated7’ in this classic “on-Isoprene Rule’ system. 74 75

76

77

78

lq

A. G. Horodysky, G . R. Waller, and E. J. Eisenbraun, J . Biol. Chem., 1969,244,3110. H. Inouye, S. Ueda, and Y. Takeda, 2. Naturfursch, 1969, 24b, 1666; Tetrahedron Letters, 1970, 335 1 . I. Oguni, K. Oshima, H. Imaseki, and I. Uritani, Agric. and Biol. Chem. (Japan), 1969, 33, 50; I . Oguni and I. Uritani, ibid., 1970, 34, 156. E. E. Waldner, Ch. Schlatter, and H. Schmid, Helu. Chim. Acta, 1969,52, 15. D. H. R. Barton, G . P. Moss, and J. A. Whittle, J . Chem. SOC.(0,1968, 1813. J. A. Zabkiewicz, R. A. B. Keates, and C. J. W. Brooks, Phytochemistry, 1969,8,2087.

232

Terpenoids and Steroids

RO'

O-i (47)

0

(48)

(49)

The key importance of 7 - b i ~ a b o l e n eas ~ ~a' ~common ~ precursor of many sesquiterpenoids is questioned" by recent studies of helicobasidin (50; R = OH), deoxyhelicobasidin (50; R = H) and the phenol (51). With [2-'4C,3R,4R-3H]mevalonic acid two tritium atoms were incorporated into the quinones (50) and Hc

OH

..

U OH 150)

(52)

three into the phenol (51). However, in the related system of trichothecolone (52; R = 0) and trichothecol ( 5 2 ; R = H2), [2-'4C,3R,4R-3H]mevalonic acid labelled82 the marked positions and [l-3H2,2-14C]farnesyl pyrophosphate incorporated one tritium atom at C-11, This result is compatible with a ybisabolene origin. and is particularly significant as it corrects the earlier results83 which were difficult to interpret. It is also of note that the incorporation of (4R)labelled mevalonic acid implies the initial formation of all-trans farnesyl pyrophosphate ( 6 ;n = 2). The labelling pattern [.. in (53)] found from the incorporation of [2-I4C]~ ? ~R ~= OH) are mevalonic acid into ~ o r i a m y r t i n( 5~3~; R = M) and t ~ t i n ' (53; consistent with a 7-curcumene origin. Both laboratories showed that the methyl and methylene groups were equally labelled, and Arigonis4 found significantly more radioactivity at C-12 than at the other positions. This result implies a significant pool of geranyl pyrophosphate in the plant. The terpenoid origin of furnagillin [55 ; R = CO.(CH:CH),-CO,H] has been demonstrated by Birch et They suggested that the unknown isoprenologue "' W . Parker. J . S. Roberts, and R . Ramage, Quart. R r r . , 1967, 21, 331.

''

'' '.' *'

*' Ilh

S. Nozrje. M . Morisaki. and H. Matsumoto. Cheni. Cornrn.. 1970.926: see also S. Natori. Y . Inou)e,and H . Nishikawa, Chern. uridPharrn. Bull. ( J u p u n ) , 1967, 15,380; R . Bentley and D. Chen, Phytochernistry, 1969, 8, 2171. B. Achilladelis, P. M . Adams, and J. R. Hanson, Chem. Cornm., 1970, 51 1 . E. R. H . Jones and G . Lowe, J . Chetn. SOC.,1960, 3959. M. Biollaz and D. Arigoni, Chem. Cornnr., 1969, 633. A . Corbella. P. Gariboldi, G. Jommi, and C. Scolastico, Chetn. Cotnm., 1969, 634. A . J . Birch and S. F. Hussain. J . Cheni. SOC.(C), 1969. 1473.

Biosynthesis of Terpenoids and Steroids

233

-0

R

OH

OMe OR

*A*

(54)

(55)

(53)

of p-pinene (54) is cleaved as shown. Abscisic acid (56; R = H) presents a problem as to whether it is a sesquiterpenoid or degraded carotenoid [cf: trisporic acids (115)l. Studies by the Shell do not resolve this question. The cis double bond must be derived by isomerisation of a trans system since [2-14C,3R,4R-3H]mevalonic acid incorporates two tritium atoms. In tomatoes, [2-14C]abscisicacid is metaboliseds8 to give the glucoside of the unnatural enantiomer and metabolite C (56 ;R = OH). Siccanochromenic acid (57) may have a similar origin to abscisic acid ; the efficient incorporation of mevalonic acid has been d e m ~ n s t r a t e d . ~ ~

R

OYoH

6 Diterpenoids

A review of diterpenoid biosynthesis has been published.’* Preliminary results are reported” on the biosynthesis of crassin acetate (57a). Another cyclotetradecane terpenoid, casbene is formed92 from geranylgeranyl pyrophosphate ( 6 ; n = 3) in Ricinus communis. The enzymes involved have been partially separated. Although a wide range of diterpenoids are formed from copalyl 17

88 8y

yo 91

92

B. V. Milborrow, Biochem. J., 1969, 114, P I ; R. C. Noddle and D. R. Robinson, Biochem. J., 1969, 112, 547; D. R. Robinson and G. Ryback, Biochem. J., 1969, 113, 895. B. V. Milborrow, J. Expt. Botany, 1970, 21, 17. S. Nozoe and K. T. Suzuki, Tetrahedron Letters, 1969, 2457. J. R. Hanson and B. A. Achilladelis, Perfumery Essent. Oil Record, 1968, 59, 802. J. R. Rice, C. Papastephanou, and D. G. Anderson, Biol. Bull., 1970, 138, 334. D. R. Robinson and C. A. West, Biochemistry, 1970, 9, 70, 80.

234

Terpenoids and Steroids

pyrophosphate (58),differentenzymes are involved in the formation of the rosane skeleton93(60) from (59),the kaurane skeleton92*94*95 [(62)and (63)] from ent-(59), beyerene and tachylobaneg2*’ from mi-(59), and sandara~opimaradiene~~~’ from ent-(59) with the opposite configuration at C-13. Coleone A has been confirmed96as a 1,lO-seco-abietanederivative. Achilladelis and HansonQ7have studied the incorporation of [2-’4C,2-3H2]-, [2-’4C,3R,4R-3H]-,and [2-’4C,5-3H2]-mevaionicacid into rosane terpenoids (60). Their results, together with the non-inc~rporation’~ of pimaradiene, excludes any diene intermediates between (59) and (60). Since labda-8(17),13-diene-15,19-diol

S)Ac

and isocupressic acid are only poorly i n ~ o r p o r a t e dcompared ~~ with even copalol (58, corresponding alcohol), it must be concluded that lactone formation does not take place at the same time as the rearrangement [see (59)]. A probable explanation is that log-hydroxyros- 14-eneis formed via trans-additions and S,2 displacement.’ Further metabolism of desoxyrosenolactone (60) give^^^*^* rosenololactone (60 ;6p-OH) and rosenonolactone (60 ; 7-0x0).

Kauranes and Gibberellic Acids.-The parent tetracyclic diterpene from which the gibberellic acids are derived, is ent-kaurene (62). Several worker^^^.^^ have

‘’ B. Achilladelis and J . R . Hanson, Phyiachemisiry, 1968, 7, 589. . Hanson and A. F. White, J . Chem. SOC.( C ) , 1969,981. ’’ JI .. RShechter and C. A . West, J . Biol. Chern., 1969, 244, 3200.

y4

9h

Quoted by C. H . Eugster, Angew Chem. Internat. Edn., 1970, 9, 249.

’’ B. Achilladelis and J . R. Hanson, J . Chern. SOC.(0,1969, 2010. ” ”

C. W. Holzapfel, A. J . Birch, and R. W. Richards, Phyiochemistry, 1969, 8, 1009. M. 0.Oster and C. A. West, Arch. Biorhem. Biophys., 1968,127, 112; R . C. Coolbaugh and T. C. Moore, PIanf Physiol., 1969,44, 1364; J. E. Graebe, Planta, 1969,85, 171 ; W . W . Reid, Biochem. J., 1969, 113, 37P.

Biosynthesis of Terpenoids and Steroids

235

partially purified the enzymes involved in the conversion of mevalonic acid into ent-kaurene. ['4C,32P]Geranylgeranyl pyrophosphateg5 (6 ; n = 3) and entcopalyl p y r o p h o ~ p h a t e[ent-(58)] ~ ~ . ~ ~ are intermediates in this process. The results from the incorporation of [2-'4C,2-3H2]-,94 [2-'4C,2R-3H,3R]-,100[2-I4C,3R, 4R-3H]-,94 and [2-'4C,3R,5R-3H]-mevalonicacids"' are consistent with the labelling pattern summarised in formula (62). The mechanism probably involves the cyclisation of the bicyclic ent-(58)to the tricyclic 'carbonium ion' ent-(59)and thence to the tetracyclic 'ion' (61) which rearranges to ent-kaurene (62). entPimaradiene is not involved in this p r o ~ e s s . ~ ~ * ~ ' ' (1)-

( 6 ; n = 3)

1

ent-(59) 4- e k - ( 5 8 )

The further metabolism of ent-kaurene (62) is consistent with a single pathway, involving the oxidation using [I8O2]oxygen gas'02 to give 19-hydroxy-ent-kaur16-ene,'02 and thencelo3 via the 19-aldehyde'02 to ent-kaur-16-en-19-oicacid.'02 This acid is hydroxylated to give 7fi-hydroxy-ent-kaur-16-en-19-oic a~id"~*"~ which is the branch point to the kaurenolides (63) and gibberellic acids (64)and (68).Hydr~xylation"~ at the 6a-position gives the kaurenolide (63;R = H) which loo

lo'

lo' lo' '04

J. R. Hansonand A. F. White, Chem. Comm., 1969, 1071. B. E. Cross and J. C. Stewart, Tetrahedron Letters, 1968, 5195, 6321. P. J. Murphy and C. A. West, Arch. Biochem. Biophys., 1969, 133, 395. B. E. Cross, R. H. B. Galt, and K. Norton, Tetrahedron, 1968, 24, 231. J. R . Hanson and A. F. White, Chem. Comm., 1969, 410.

Terpenoids and Steroids

236

is further hydroxylated to the diol(63 ; R = OH). In these hydroxylations at C-6 and C-7 there is retention of configuration."' Although 7P-hydroxykaurenoic acid is metabolised lo4 giving gibberellic acids A3 (68; R = OH) and A,, (64) and gibbane aldehyde (64; aldehyde at C-7), all other kaurene derivatives which have been tested as precursors for the ring contraction have failed. These include 6a,7a-,lo3 6a,7P- ;' O3 and 6fi,7fi-diols,'''*l and A6-kaurene derivatives.l o 3 Both the 6P,7/I-di01'~~ and the A6-derivativelo3 did, however, g v e the 6,7-seco-system of fujenal. The incorporation of [2-I4C,3R, 5R-3H]mevalonic acid shows'" that in the ring contraction the 6fi-proton of the kaurene derivative is lost. However, nothing is known of the fate of the 6a-proton. The first formed gibbane derivative is probably gibbane aldehyde'04*'07 (64 ; aldehyde at C-7). Since a 6/?,7a-dihydroxykaurene derivative seems an unlikely intermediate, the ring contraction may involve the direct oxidative rearrangement of 7fl-hydroxykaurenoic acid or the isomerisation of 7-oxokaurenoic acid.

''

(64)R'

R' (66) R'

(65)

= = =

H, R 2 = Me OH. RZ = Me OH, R2 = COzH

Gibbane aldehyde is convertedlo7 into either gibberellic acid Al2 (64)or A14 (65), hence hydroxylation at C-3 must precede oxidation at C-7 when A14 is formed. The acid A14 is in turn c~nverted''~into either A, (67; R = H) or A13 (66). It has been suggested'" that gibberellic acid [i.e., A3, (68; R = OH)] is formed from A, via either A, (67; R = OH) or A, (68; R = H). The labelling pattern found for gibberellic acid (68; R = OH) after feeding with [2-14C, 2-3H,]-?4 [2-'4C,2R-3H,3R]-,'00 [2-14C,3R,4R-3H]-y4and [2-'4C,3R,5R-3H]-1O0 "" "" I"' lo'

B. E. Cross, J . C. Stewart, and J . L. Stoddart, Phyrochemisrry, 1970, 9, 1065. P. R . Jefferies, J . R. Knox, and T. Ratajczak, Tetrahedron Letters, 1970, 3229. B. E. Cross. K . Norton, and J. C. Stewart, J . Chern. SOC.(0,1968, 1054. T. A. Geissman, A. J . Verbiscar, B. 0. Phinney, and G. Cragg, Phytorhemistry, 1966, 5, 933.

Biosynthesis of Terpenoids and Steroids

237

mevalonic acids shows that the 3p-hydroxy group was introduced with retention of configuration, contrary to the preliminary communication ;and the A' double bond involves a cis-elimination. 7 Sesterterpenoids The i n c o r p o r a t i ~ n 'of ~ ~all trans-geranylfarnesyl pyrophosphate (6 ; n = 4)but not the corresponding alcohol or cis-geranylfarnesylpyrophosphate into ophiobolin F (69) is an interesting example of the specificity of the enzymes. This sesterterpenoid is obviously the parent system which is oxidised in turn into ophiobolins C (69; 5,21-dioxo), B (69; 14a-hydroxy-5,21-dioxo),and A (69; 14a,l7R-oxido-5,21-dioxo). The earlier results' l o from the incorporation of

[2-3H2]-, [2-14C,2R-3H,3R]-,[2-14C,2S3H,3R]-, [2-14C,3R,4R-3H]-,and [2-I4C, 3R,4S-3H]-mevalonicacids are summarised in formula (69). Glycine is a better precursor than mevalonic acid, but no degradation data was reported."' Recent results112on fusicoccin (70) suggest that the isopentenyl unit is synthesised at a differentrate from the tricyclic system. This result implies that although fusicoccin is structurally similar to the ophiobolins it may represent a new class of diterpenoids. 8 Steroidal Trisnortriterpenoids In biosynthetic terms, steroids are metabolic products of triterpenoids. Because of the key importance of cholesterol, the biosynthesis of this steroid and related lo9

* lo 'I'

S. Nozoeand M . Morisaki, Chem. Csmm., 1969, 1319. L. Canonica, A. Fiecchi, M. G. Kienle, B. M. Ranzi, and A. Scala, Tetrahedron Letters, 1966, 3035; 1967, 3371, 4657; 1968, 275; S. Nozoe, M. Morisaki, S. Okuda, and K. Tsuda, Tetrahedron Letters, 1967, 3365; 1968, 2347. A. K. Bose and K. S. Khanchandani, Abs. Amer. Chem. SOC.Meeting, 1969, 158, AGFD38. K. D. Barrow and E. B. Chain, Biochem. J., 1969, 114, P4; see also A. Ballio, M. Brufani, C. G. Casinovi, S. Cerrini, W. Fedeli, P. Pellicciori, B. Santurbano, and A. Vaciago, Experientia, 1968, 24, 631 ; K. D. Barrow, D. H. R. Barton, E. B. Chain, C. Conlay, T. V. Smale, R. Thomas, and E. S. Waight, Chem. Comm., 1968, 1 195.

238

Terpenoids and Steroids

compounds are considered in this section. Further metabolism of cholesterol is reviewed in Section 9, while non-steroidal triterpenoids are considered in Section 10. The ability to biosynthesise steroids and arthropod steroid metabolism is reviewed in Section 13. Recent advances in steroid biochemistry have been reported. '' Cyclisation of Squa1ene.-In higher animals and fungi the first formed cyclic triterpenoid is lanosterol (73). The acyclic precursor squalene (7) is epoxidised to give (3S)-2,3-oxidosqualene(71) which is then cyclised to lanosterol. Bloch and c o - ~ o r k e r s " have ~ isolated the two enzymes involved from liver tissue and shown that the oxidosqualene cyclase has a molecular weight of about 90,000.

'I4

C. J . Sih and H. W. Whitlock, jun., Ann. Reu. Biocltem., 1968, 37, 661. S. Yamamoto, K. Lin, and K. Bloch, Proc. Nut. Sci. U.S.A., 1969,63, 110; S. Yamamoto and K . Bloch, Biochem. J . , 1969, 113, 19P.

Biosynthesis of Terpenoids and SteroiA

239

Further studies of the steric requirements of this enzyme by van Tamelen l 1 and Corey"6 and their co-workers show that the enzyme is relatively insensitive to the nature of the oxygen-free end and does not need to rearrange the biological equivalent of the carbonium ion (72) to produce a free terpenoid. However, the environment of the epoxide group is important. Although these two enzymes can be purified and are both active individually, the possibility of an enzyme complex linking the various steps between farnesylpyrophosphate (6 ;n = 2) and lanosterol was examined.'" In the presence of [4S3H]NADPH the lanosterol contained 47.9 % of the tritium at 1la- and 37.4 % at 12P-position. This suggests only slight linking of these three stages, which may be controlled by the reversible formation of a complex between squalene and a,-lipoprotein.' * The stereospecificityof the cyclisation results in the trms-methyl group at both ends of squalene and its epoxide, and the 4a-methyl group of lanosterol being labelled by [2-'4C]mevalonic acid.'Ig The same conclusion was reachedI2*from the incorporation of squalene prepared from mevalonic acid in the presence of deuterium oxide. An attempt'21 to confirm the 1,2-hydride shifts indicated in (72 ;arrows) was partially successful. During the incorporation of [1,5,9,16,20,24I4C6,9,11,14,16,10',15'-3H,,]squalene into lanosterol there was a 13.3% loss of tritium (i.e.from C-11 of squalene in forming the A8-double bond). Degradation of the lanosterol showed that there was a negligible amount of tritium at C-20 and only 11.6% at C-17 (corresponding to 10% of the tritium in squalene). In the absence of isotope effects the latter value should be 13.3%, and represents C-14 of squalene (equivalent to C-11). Clearly two 1,2-hydride shifts occur rather than one 1,3-hydride shift.

HO

'Id

lZo

R. J. Anderson, R. P. Hanzlik, K. B. Sharpless, E. E. van Tamelen, and R. B. Clayton, Chem. Comm., 1969, 5 3 ; L. 0. Crosby, E. E. van Tamelen, and R. B. Clayton, Chem. Comm., 1969, 5 3 2 ; E. E. van Tamelen, R. P. Hanzlik, R. B. Clayton, and A. L. Burlingame, J. Amer. Chem. SOC.,1970,92,2137. E. J. Corey, K. Lin, and H. Yamamoto, J. Amer. Chem. SOC.,1969, 91, 2132; E. J. Corey and H. Yamamoto, Tetrahedron Letters, 1970, 2385. A. H. Eteinadi, G. Popjak, and J. W. Cornforth, Biochem. J., 1969, 111, 445. F. D. Onajobi and G. S. Boyd, European J. Biochem., 1970,13,203. G . P. Moss and S. A. Nicolaidis, Chem. Comm., 1969, 1072 (see also ref. 138). K. J. Stone, W. R. Roeske, R. B. Clayton, and E. E. van Tamelen, Chem. Comm., 1969, 530. M. Jayme, P. C. Schaefer, and J. H. Richards, J. Amer. Ckem. SOC.,1970,92,2059.

Terpenoids and Steroids

240

The tritium labelling pattern of lanosterol has not been studied in great detail. However, it may be deduced to a large extent from the results with cholesterol, and which are in agreement with the incorporation of [2-'4C,3R,4R-3H]-'22 [2-'4C,3R,5R-3H]-'23 mevalonic acids into lanosterol. No less than four groups have studied the incorporation of [2-'4C,2R-3H,3R]mevalonic acid and its (2s)isomer' 2 4 - 27 into cholesterol. In addition, [2-'4C,3R,4R-3H]-' " and [2-14C, 3R-5R-3H,]-mevalonic acids'23+'24 have been incorporated. These results are summarised in formulae (73) and (74). All of the above results refer to rat liver systems. Presumably, the same result also applies to lanosterol (73) prepared'29 by feeding yeast with [2-14C,2RH,3R]mevalonic acid or its (2s)-isomer. However, although steroids are widely distributed in nature (see also Section 13), the first formed triterpenoid in higher plants (with the exception of certain Euphorbia sp.l3') is cycloartanol (75). As expected, 2,3-oxidosqualene (71) is incoi-porate~i'~'and the labelling pattern is presumably the same as lanosterol (73) with [2-'4C,3R,5R-3H]mevalonic acid.'23 When [2-'4C,3R,4R-3H]mevalonicacid is fed, six tritium atoms are incorporatedl 32-1 34 [see (75)]. The extra tritium atom is as expected at C-8.13* Cycloartanol is also formed instead of lanosterol in the protozoan Ochromonas malh~rnensis,'~~ the algae Fucus ~ p i r a l i s , 'and ~ ~ the fern Polypodium ~ u I g a r e . ' ~ ~ * ' ~ ~ In the last two cases the labelling pattern shown in formula (75) was supported. The further metabolism of cycloartanol parallels that of lanosterol with an additional step when the cyclopropane ring is cleaved to give the A*-ene. This

'

Iz'

Iz4 lz5 126

29

13'

''I

'

32 33

13'

'35 '" 13'

J. W. Cornforth, R. H. Cornforth, C. Donninger, G. Popjak, Y. Shimiyu, S. Ichii, E. Forchielli, and E. Caspi, J. Amer. Chem. Soc., 1965,87, 3224. L. J. Goad, G. F. Gibbons, L. M. Bolger, H. H. Rees, and T. W. Goodwin, Biochem. J., 1969, 114, 885. M. Akhtar, A. D. Rahimtula, I. A. Watkinson, D. C. Wilton, and K. A. Munday, European J. Biochem., 1969,9, 107. L. Canonica, A. Fiecchi, M. G. Kienle, A. Scala, G. Galli, E. G. Paoletti, and R. Paoletti, Steroids, 1968, 11, 749; 12, 445; J . Amer. Chem. Soc., 1968, 90, 3597. E. Caspi, J. B. Greig, P.J. Ramm, and K. R. Varma, Tetrahedron Letters, 1968, 3829; E. Caspi, P.J. Ramm, and R. E. Gain, J. Amer. Chem. Soc., 1969,91,4012;P. J . Ramm and E. Caspi, J. Biol. Chem., 1969, 244, 6064. G. F. Gibbons, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1968, 1212, 1458. E. Caspi, I(.R. Varma, and J. B. Greig, Chem. Comm., 1969, 45. E. Caspi and P. J. Ramm, Tetrahedron Letters, 1969, I8 1. G. Ponsinet and G. Ourisson, Phyrochemistry, 1967, 6 , 1235; 1968,7, 757. H. H. Rees, L. J. Goad, and T. W. Goodwin, Terrahedron Letters, 1968, 723; U. Eppenberger, L. Hirth, and G. Ourisson, European J. Biochem., 1969, 8, 180; P. Benveniste, M . J. E. Hewlins, and B. Fritig., European J. Biochem., 1969, 9, 526; R. Heintz and P. Benveniste, Phytochemisrry, 1970, 9, 1499; R. Heintz, P. C. Schaefer, and P. Benveniste, Chem. Comm., 1970, 946. H. H. Rees, L. J. Goad, and T. W. Goodwin, Biochem. .I. 1968,107,417. , L. M. Bolger, H. H. Rees, E. L. Ghisalberti, L. J. Goad, and T. W. Goodwin, Biochem. J . , 1970, 118, 197. F. F. Knapp and H. J. Nicholas, Chem. Comm., 1970, 399. H . H. Rees, L. J. Goad, and T. W. Goodwin, Biochim. Biophys. Acta, 1969,176,892. L. J . Goad and T. W. Goodwin, European J. Biochem., 1969,7, 502. E. L. Ghisalberti, N. J. de Souza, H. H. Rees, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1969, 1401. E. L. Ghisalberti, N. J. de Souza, H. H. Rees, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1969, 1403.

Biosynthesis of Terpenoids and Steroids

241

reaction can apparently occur at any stage,139but presumably does not normally do so before the loss of a C-4-methyl group. A A'(' ')-double bond is not formed14' and, of course, the 14a-methyl group cannot be lost until a As-double bond is present (see below).

Loss of the 4,4Dimethyl Groups.-The order in which the various steps between lanosterol and cholesterol occur is not precisely established, but a As-double bond is required for the loss of the l4a-methyl group. It is convenient to consider these steps separately. When cycloarteno1134~'37~'3* labelled by [2-14C,3R,4R-3H]mevalonic acid is converted into 4-desmethylcycloartenol, there is loss of the 3a-tritium atom and the labelled 4a-methyl group.' 19,120 Similarly, lanosterol labelled'"' with [2-14C,3R,5-3H2]mevalonic acid is [3H1 I4C6], while lophenol is [3H11, '"C,]. It must be concluded that, contrary to earlier reports, the 4a-methyl group is lost first. This result is further substantiated by the incorporation 142 of 4a-hydroxymethyl-4~-methylcholestan-3~-ol but not the 4/3-hydroxymethyl isomer. Furthermore, 4~-methylcholestan-3~-ol is largely inert. l 43 The sequence of events would seem to be that the 4a-methyl is oxidised to a carboxyl group and the 3/?-hydroxylto a 3-ketone. Decarboxylation of the 8-keto acid is f o l l o ~ e d ' ~ ~ ~ ~ ~ by rapid reduction of the 3-ketone back to a 38-alcohol. In the presence of tritiated water C-3 and C-4 become radioactive. 14'

',

Loss of the 14a-Methyl Group.-The loss of the 14a-methylgroup cannot involve a P-keto acid, as at (2-4, since tritium is present at C-15 after feeding [2-14C,2R3H,3R]mevalonic acidlZ6; or a vinologous B-keto acid since tritium survives at C-11 from [2-14C,3R,5R-3H]mevalonic a ~ i d . ' ~ Hence ~ ? ' ~a~simple decarboxylation of (76) must occur after oxidation of the 14a-methyl There is evidence for the formation and further incorporation of a A8('4)-steroid'46~147 (77; R' = H). Isomerisation of the more stable A8(l4)-doub1ebond back to A* (79) occurs via a A8*14-diene(78). This diene is formed via the allylic alcohol 139

I4O 14'

14*

143

144 145

146

14'

M. Devys, A. Alcaide, and M. Barbier, Bull. SOC.Chim. Biol., 1969, 51, 133; Phytochemistry, 1969, 8, 1441; J. Hall, A. R. H. Smith, L. J. Goad, and T. W. Goodwin, Biochem. J., 1969,112,129; M. J. E. Hewlins, J. D. Ehrhardt, L. Hirth, andG. Ourisson, European J. Biochem., 1969,8, 184. P. C. Schaefer, F. de Reinach, and G. Ourisson, European J. Biochem., 1970, 14, 284. R. Rahman, K. B. Sharpless, T. A. Spencer, and R. B. Clayton, J. Biol. Chem., 1970, 245, 2667. K. B. Sharpless, T. E. Snyder, T. A. Spencer, K. K. Maheshwari, G. Guhn, and R. B. Clayton, J. Amer. Chem. Soc., 1968,90, 6874. K. B. Sharpless, T. E. Snyder, T. A. Spencer, K. K. Maheshwari, J. A. Nelson, and R. B. Clayton, J. Amer. Chem. Soc., 1969, 91, 3394. A. C. Swindell and J. L. Gaylor, J. Biol. Chem., 1969, 243, 5546. M. Akhtar, I. A. Watkinson, A. D. Rahimtula, D. C. Wilton, and K. A. Munday, Biochem. J., 1969,111,757; M. Akhtar, A. D. Rahmintula, and D. C. Wilton, Biochem. f.,1969, 114, 801. J. Fried, A. Dudowitz, and J. W. Brown, Biochem. Biophys. Res. Comm., 1968, 32, 568; A. E. Dudowitz and J. Fried, Fed. Proc., 1969, 28, 665. W. H. Lee, B. N. Lutsky, and G. J. Schroepfer, jun., J. Biol. Chem., 1969, 244, 5440; B. N. Lutsky and G. J. Schroepfer, jun., Biochem. Biophys. Res. Comm., 1969, 35, 288.

Terpenoids and Steroids

242

R

R

(78)

79)

(77; R 1 = OH), assuming retention of configuration on oxidation, and loss of the 1Sa-H.' '4-l 27*129*148*149 It is not known whether this oxidation occurs normally before,"' or after,'" loss of the 14a-methyl group. Several groups have shown that a A8.l4-diene (78) is formed'" and incorporated into'53 other steroids. In the reduction of the Al4-double bond the 14a-H is derived from NADPH'54 and the 15j-H from the medium.'45*'55

Isomerisation from A*- to A5-Double Bond.-The first stage in the transfer of the double bond round ring B is an isomerisation from A*- to A7-(80). Although there are contrary reports there seems little doubt that this reaction may be reversible. Cholest-7-en-3j-01 in the presence of rat liver microsomes and tritiated water is radioactive on reisolation, with most of the tritium at C-9.156 Similarly, cholest-8-en-38-01 is converted into [9a-3H]cholest-7-en-3P-olby this system.'57 In the rat liver system the 78-proton is lost,'58 and this is confirmed IJn

149

15'

f 53

154 155

15'

Is'

Is'

A. R. H. Smith, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1968, 926 (after recalculation to allow for loss from C- 15). T. Bimpson, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1969, 297. J. A. Martin, S. Huntoon, and G. J. Schroepfer, jun., Biochem. Biophys. Res. Comm., 1970,39, I 170. S. Huntoon and G. J. Schroepfer, jun., Biochem. Biophys. Res. Comm., 1970,40, 476. 1. A. Watkinson and M. Akhtar, Chem. Comm., 1969, 206; A. Fiecchi, L. Canonica, A. Scala, F. Cattabeni, E. G. Paoletti, and R. Paoletti, Life Sciences, 1969, 8B, 629. B. N. Lutsky and G. J. Schroepfer, jun., Biochem. Biophys. Res. Comm., 1968, 33, 492; M. Akhtar, W. A. Brooks, and 1. A. Watkinson, Biochem. J., 1969, 115, 135; L. Canonica, A. Fiecchi, M. G. Kienle, A. Scala, G . Galli, F. G. Paoletti, and R. Paoletti, J. Amer. Chem. SOC.,1968, 90, 6532. M. Akhtar, A. D. Rahimtula, I. A. Watkinson, D. C. Wilton, and K. A. Munday, Chem. Comm., 1969, 149. M. Akhtar, A. D. Rahimtula, and D. C. Wilton, Chem. Comm.,1969, 1278. D. C. Wilton, A. D. Rahimtula, and M.Akhtar, Biochem. J., 1969, 114, 71. M. Akhtar and A. D. Rahimtula, Chem. Comm., 1968,259; W. H. Lee, R. Kammereck, B. N. Lutsky, J. A. McCloskey, and G. J. Schroepfer, jun., J. Biol. Chem., 1969,244, 203 3 . M. Akhtar, A. D. Rahimtula, and D. C. Wilton, Biochem. J., 1970, 117, 539.

Biosynthesis of Terpenoids and Steroids

243

by the retention of tritium at C-7 in cholesterol labelled by [2-'4C,2R-3H,3R]mevalonic a ~ i d ' ~ ~but- ' not ~ ~ by the ( 2 S ) - i ~ o m e r . ' ~ ~ , However, ' ~ ~ * ' ~ ~ in Saccharornyces and Aspergillus it is the 7a-proton which is l o ~ t . ' ~ In ~ 9 ~ ~ ~ , contrast, the protozoan Ochromonas follows the mammalian system. 14' The As-double bond is introduced by dehydrogenation of the A7-steroid (81) to the A5*7-diene(82). Although there are claims for hydroxylated intermediate~,'~' a detailed study'60 showed that cholest-7-ene-3/3,5a-diol was converted back to cholest-7-en-3#l-ol before being converted into cholesterol. The dehydrogenation enzyme is one of the few known two-protein systems.161 In all the species studied the 6a-123,124,160,162-164 and 5a-pr0ton.s'~~ are lost. A substantial isotope effect was observed'63 with [4-'4C,50;6a-3H2]cholest-7-en3fl-01. The reverse reaction (83)+(82) is considered in Section 9. In the final step the A'-double bond is reduced by a two-protein en~yrne.'~' The stereochemistry (83) is again trans, with the 8P-proton derived from the 45.1 66 and the 7a-pr0ton'~~*'~' from NADPH.166 Reduction of the A24-Double Bond.-The reduction of the A24-double bond is again a trans-process. Caspi et have shown that in cholesterol the (24R)hydrogen was labelled by [2-' 4C,3R,4R-3H]mevalonic acid, and that on hydroxylation to (25R)-cholest-5-ene-3P,26-diolthe hydroxymethyl group was labelled' 6 7 by [2-'4C]mevalonic acid [see (74)]. The latter result is the opposite of that found for tigogenin (88) in higher plants.'68 NADPH provides'69 the hydrogen at C-25 while the hydrogen at C-24 is derived from the m e d i ~ m . ' ~ ~ * ' ~ ~ Side Chain Alky1ation.-Biological C-alkylation has been reviewed by Lederer.' 70 The 24-methyl group of ergosterol (86 ;R' = Me) is derived from a 24-methyleneI59

160

161 162

163 164 165 166

R. W. Topham and J. L. Gaylor, J . Biol. Chem., 1970, 245, 2319; see also M. Slaytor and K. Bloch, J . Biol. Chem., 1965, 240,4598. S . M. Dewhurst and M. Akhtar, Biochem. J., 1968, 105, 1187. K. E. Ebner, Accounts Chem. Res., 1970,3,41. M. Akhtar and S. Marsh, Biochem. J., 1967, 102, 462; M. Akhtar and M. A. Parvez, Biochem. J., 1968, 108, 527. A. M. Paliokas and G . J. Schroepfer, jun., J. Biol. Chem., 1968,243,453. A. R. H. Smith, L. J. Goad, and T. W. Goodwin, Chem. Comm., 1969, 1259. H . C. Ritter and M. E. Dempsey, Biochem. Biophys. Res. C o r n . , 1970,8,921. D. C . Wilton, K. A. Munday, S. J. M. Skinner, and M. Akhtar, Biochem. J., 1968,106, 803.

167

168 169

170

E. Caspi, M. G . Kienle, K. R. Varma, and L. J. Mulheirn, J . Amer. Chem. Sac., 1970, 92, 2161. R. Joly and Ch. Tamm, Tetrahedron Letters, 1967, 3535. M. Akhtar, K. A. Munday, A. D. Rahimtula, I. A. Watkinson, and D. C. Wilton, Chem. Comm., 1969, 1287. E. Lederer, Quart. Rev., 1969, 23, 453.

Terpenoids and Steroids

244

'

steroid (85 ; R' = CH,)' which in turn is formed from S-adenosylmethionine and a A24-steroid.172 Alkylation can occur at any stage after lanosterol but probably in tliuo it occurs mainly at an intermediate stage such as 24-methylenezymosterol. The 24-methylene steroid is best recognised as an intermediate by the incorporation of only two deuterium atoms from [CD,]methionine. A wide range of fungi produce ergosterol and related steroids by this process;' 70*173 however, in some cases the low incorporation of deuterium is clearly due to a reversible reaction (85; R' = CH2) (86; R' = Me). 24-Ethyl and ethylidene derivatives in general are derived by the sequence (84) +(85; R' = CH,) -+ (85; R' = CHMe)+ (86; R' = Et). Typical examples are found in higher

R (85)

R'

R'

R

R (86)

(87)

plants,' 74,175 brown algae' 75 (Fucus), and protozoa (Qchrornonu~).'~~ In the last case it was further shown that poriferasterol(86; R' = Et) contained 1,3, or 4 deuterium atoms which indicates that at the stage (85; R' = CH,) to (85; R' = CHMe) three deuterium atoms are incorporated. A different process occurs in the primitive plants ofthe Myxomycetes(Dictyostelium, Physarum)' 70*177 and Chlorophyceae (Chlorellu)'" since the 24-ethyl group contains up to five 78 and ergost-7-en-3p-01 has three deuterium atoms. 17' deuterium The vinyl proton at (2-24 is not l o ~on alkylation t but is~transferred to C-25.'36*'80 Possibly all these steroids are formed via a common I"

D. H. R. Barton, D. M. Harrison, and D. A. Wtddowson, Chctn. Comm., 1968, 17; M. Akhtar, P. A. Parvez, and P. F. Hunt, Biochem. J., 1969,113,727; D. H , R. Barton, D. M. Harrison, G . P. Moss, and D. A. Widdowson, J . Chem. SOC.(0,1970, 775. J. T. Moore,jun. and J. L. Gaylor, J. Biol. Chem., 1969, 244, 6334. I T 3 M. Lenfant, G. Farrugia, and E. Lederer, Compt. rend., 1969, 268D, 1986; M. Devys and M. Barbier. Bull. Soc. Chim. hiol., 1969. 51, 925. R. T. van Aller, H. Chikamatsu, N. J. de Souza, J. P. John, and W. R. Nes, J. B i d Chem.. 1969, 244. 6645; A. Alcalde, M. Devys, and M. Barbier, F.E.B.S. Letters, 1969,3,257; D. J. Baisted, Phytochemisrry, 1969,8, 1967; see also S. J . Stohs, €3. Kanl, and B. J . Staba, Phytochemisrry, 1969.8, 1679. L. J. Goad, A. S. A. Hammam, A. Dennis, and T. W. Goodwin, Nature, 1966, 210, 1322. '" A. R. H. Smith, L. J. Goad, T. W. Goodwin, and E. Lederer, Biochem. J . , 1967, 104, 56C. M. Lenfant, R. Ellouz, B. C. Das, E. Zissmann, and E. Lederer, European J . Biochem., 1969, 7 , 159. Y. Tomita, A. Uomori, and H. Minato, Phytochemistry, 1970,9, 555. R. K. Sharma, Phytochemisrry, 1970, 9, 565. M. Akhtar, P. F. Hunt, and M. A . Parvez, Biochem. J., 1967, 103, 616; K. H. Raab, N. J. de Souza, and W. R. Nes, Biochim. Biophjrs. Acru, 1968, 152, 742.

~

Biosynthesis of Terpenoids and Steroids

245

enzyme-bound intermediate bonded at C-25. This suggestion is supported by the ob~ervation'~'that cyclolaudenol (87; R' = Me) retains all three tritium atoms from [C3H3]methionine,and the C-24 vinyl proton. Similarly, this vinyl 133 proton is retained in (24S)-ethylcholesta-5,22,25-trien-3~-ol.

A22-Double &&.-Side chain dehydrogenation is reviewed by Lederer. '' O Unlike the dehydrogenations of the steroid nucleus, introduction of the trans A22-doublebond of ergosterol and related steroids does not require the presence bond.I8' However, the suggested'82 formation of of a A24-or A24(28)-do~ble ergosta-5,7,22,24(28)-tetraen-3j?-olis supported by incorporation studies.' The stereochemistry of this process is species-dependent. In protozoa (Ochrornonas tetruhyrnenu) the (22R)-ls4 and (23s)-hydrogens of cholesterol are lost, i.e. the hydrogens at these positions derived from [2R-3H,3R]-'48*'84v'8sand [3R,5R3H]-'64,'85 mevalonic acid. In contrast, in fungi (AspergilE~s),'~~ and most probably in higher plants the opposite pair of hydrogens are lost. In Nicotiana tobacwn there is evidence'87 for the reduction of a A22-doublebond. However, it is not clear if this is a normal in viuo process. 9 Cholesterol Metabolism The key importance of cholesterol (74)in animal systems has long been recognised. It is now becoming clear that this steroid may play an equally important role in plant systems although it can rarely be isolated. The incorporation of 8-sitosterol (86; R' = Et) into progesterone shows that the 24-alkyl group does not prevent cleavage of the C-20,22 bond.188 It is possible that, as in insects, the side chain alkylation reactions may be reversed (see Section 13). Another reaction which can be reversed is the reduction of the A'-double bond. In Tetrahyrnena pyriforrnis cholesterol is converted into cholest-5,7,22-trien-3~-01.'~~ The A'-double bond is formed by the loss of the 78- and 88-hydrogens of cholesterol.'84~185~'go The important insect hormone ecdysterone (122)and its precursor ponasterone A (123) also occur in a number of higher plants. As expected, both mevalonic

Is'

ls2

*" Is'

190

M . Akhtar, M . A. Parvez, and P. F. Hunt, Biochem. J., 1968, 106,623; R. D. Bennett and E. Heftmann, Steroids, 1969, 14, 403; R. Ellouz and M. Lenfant, Tetrahedron Letters, 1969, 609, 2655; see also E. Caspi and L. J. Mulheirn, Chem. Comm., 1969, 1423. H. Katsuki and K. Bloch, J. Biol. Chem., 1967, 242, 222. D. H. R. Barton, T. Shioiri, and D. A. Widdowson, Chem. Comm., 1970,939. J. M. Zander and E. Caspi, J . Biol. Chem., 1970,245, 1682; E. Caspi and J. M. Zander, Chem. Comm., 1969, 1141. T. Bimpson, L. J. Goad, and T. W. Goodwin, Biochem. J., 1967,115, 857. R. K. Sharma, Chem. Comm., 1970, 543. A. Alcaide, M. Devys, and M. Barbier, Phytochemistry, 1970, 9, 1553. R. D. Bennett, E. Heftmann, and B. J. Winter, Phytochemistry, 1969, 8, 2325; Naturwiss., 1969, 56, 463. R. L. Conner, F. B. Mallory, J. R. Landrey, and C. W. L. Iyengar, J. Biol. Chem., 1969, 244,2325. D. C. Wilton and M . Akhtar, Biochem. J . , 1970,116, 337.

Terpenoids and Steroids

246

acid and cholesterol are incorporated into these steroids. A related hydroxyis lated steroid, chiograsterol A (3/?,16/?,23,24-tetrahydroxy-5a-cholestan-6-one) converted into either chiograsterol B (corresponding 6B-01) or chiogralactone (corresponding tetranor-23,lSB-olide). 92 Spirostanols-Tigogenin’ 9 3 (88) and dio~genin”~A ’-(88) are formed from cholesterol with retention of the C-25 hydrogen atom. From [2-14C,3R,4R-3H]mevalonic acid the 25-methyl group is labelled’68with I4C and only two tritium atoms survive, so that the 20-H of cholesterol has been lost.195 (25R)-Cholest-5ene-3B,26-di01’~~ and a glycoside derivative of (25R)-3&26-dihydroxycholest-5en-22-onehemiacetal’ are incorporated into diosgenin. The A5-doublebond of cholesterol must be removed before hydroxylation when tigogenin is formed in Digitalis. These steps proceed via 5a-cholest-4-en-3-one,’98 5cr-cholestan-3-one: 9 9 5a-cholestan-3/?-01,99 and 5a-cholestan-3/?,16P,26-tri01.’~~

’’

R

H. H. Sauer, R. D. Bennett, and E. Heftmann, Phytochemisrry, 1968, 7 , 2027; N. J. de Souza, E. L. Ghisalberti, H. H. Rees, and T . W. Goodwin, Biochem. J., 1969, 114, 895; Phytochemistry, 1970,9, 1247; H. Hikino, T. Tohama, and T. Takemoto, Chem. Pharm. Bull., 1969, 17, 415; Phytochemistry, 1970, 9, 367. H. Minato, A. Shimaoka, and K. Takeda, J , Chem. SOC. (C), 1969, 1483. lY3 K. R. Varma, J. A. F. Wickramasinghe, and E. Caspi, J. Biol. Chem., 1969,244, 3951. R. A. Joly, J. Bonner, R. D. Bennett, and E. Heftmann, Phytochemistry, 1969, 8, 857, 1709. l Y 5J. A. F. Wickramasinghe, E. P. Burrows, R. K. Sharma, J. B. Greig, and E. Caspi, Phytochemistry, 1969, 8, 1433. l Y h R. D. Bennett, E. Heftmann, and R. A. Joly, Phytochemisrry, 1970, 9, 349. I y 7 R . A Joly, J . Bonner, R. D. Bennett, and E. Heftmann, Phytochemistry, 1969, 8, 1445. R. Tschesche, H . Hulpke, and R. Fritz, Phytochemistry, 1968, 7 , 2021. l Y yR.Tschesche, R. Fritz, and G. Josst, Phytochemistry, 1970, 9, 371. * O 0 R. Tschesche and R. Fritz, Z. Narurforsch, 1970, 25, 590. Iy1

Bios,vnthesisof Terpenoids and Steroids

247

Cardenolides and Bufatenolides.-Extensive studies of digitoxigenin (89) and gitoxigenin (89 ; 16P-OH) biosynthesis in Digitalis sp. have outlined many details of the pathway. The first stage from cholesterol or Q-sitosterol'88 seems to be cleavage of the side chain to give pregnenolone.20 Cholest-5-en-3/?,20a-diolis not on the main route.202 The As-double bond of pregnenolone is then reduced and SP-pregnanin p r ~ g e s t e r o n e ~(4-ene-3-one) '~ to 5P-~regnan-3,20-dione~'~ 3P-ol-20-0ne.~'~H ydroxylation gives 5/3-pregnan-3P,14P-diol-20-0ne~'~ and 5P-pregnan-3/3,14P,21-triol-20-0ne.~'~Finally the butenolide ring is formed. Digitoxigenin (89) may then be hydroxylated to gitoxigenin ( 8 9 ; 15P-OH) or digoxigenin ( 8 9 ; 12/?-OH).204~206 However, other variations are possible since digoxigenin is formed from 5~-pregnan-3~,12~-diol-20-0ne.~'~ The 17a-, but not the 17P-hydrogen atom of digitoxigenin is labelled by [3R,4R-3H]mevalonic acid. 9 5 In Struphanthus kornb6 azarigenin (89 ; 5a-H) is formed from Sa-pregnenlone.^'^ Several similar sequences with pregnane derivatives have been demonstrated in higher plants.208 The bufatenolides (90) probably have a biosynthesis in plants similar to the cardenolides. Pregnenolone is incorporated into hellebrin2'' [(90)with (89 ; 5P-OH, 19-oxo)] and scilliroside2" [(90) with ( 8 9 ; A4)]. However, in the toad (Bufu)cholanic acid derivatives are far better precursors than pregnane derivatives.2'0*211This suggests that all five carbon atoms of the enolester ring (90) may be derived from cholesterol in the toad compared with only two in plants. In the toad, marinobufagin [(90) with ( 8 9 ; 5P-OH, 14,15-oxide)]is the precursor of telecinobufagin [(90) with (89 ; 5fl-OH)].212

'

'

Side Chain Cleavage.-There are two distinct methods for the degradation of the side chain. In mammalian systems a-glycols are cleaved to give the corresponding ketone. Both androstane and pregnane derivatives may be formed directly.213 Hydroxylation of cholesterol (91 ; R' = R2 = R3 = H) takes place at both C-20a and C-22 to give the corresponding diols ( 9 1 ; R'R2 = H,OH, R3 = H) and trio1 (91; R' = R2 = OH,R3 = H) with a preference2I4 for '01 '02

203 204

2os 206 '07

208

209 lo 21z

2L4

K. R . Varma and E. Caspi, Phytochernistry, 1970, 9, 1539. J. A. F. Wickramasinghe, P. C. Hirsch, S. M . Munavaili, and E. Caspi, Biochemistry, 1968,7, 3248. L. Tan, Cunad. J . Biochem., 1970,48, 216. R. Tschesche, R. Hombach, H. Scholten, and M. Peters, Phytochemistry, 1970, 9, 1505. T . Tschesche, H. Hulpke, and H. Scholten, Z . Naturforsch., 1967, 22b, 677; R. Tschesche and R. Becker, Z . Naturforsch., 1970,25b, 107. R . Tschesche, R. Becker, and R. Hombach, Z . Naturforsch., 1968,23b, 1615. H. H. Sauer, R. D. Bennett, and E. Heftmann, Phytochemistry, 1969,8, 839. A. M. Gawienowski and C. C. Gibbs, Phytochemistry, 1969,8,2317; H. H . Sauer, R. D. Bennett, and E. Heftmann, Phytochemistry, 1969, 8, 69; S. J. Stohs, Phytochemistry, 1969, 8, 1215; R . D. Bennett and E. Heftmann, Phytochemistry, 1970, 9, 807. R. Tschesche, H. Scholten, and M. Peters, 2. Naturforsch., 1969, U b , 1492. A. M. Porto and E. G. Gros, Experientia, 1970, 26, 1 1 . C. Chen and M. V. Osuch, Biochem. Pharmacol., 1969,18, 1797. M. V. Osuch and C. Chen, Biochem. Pharmacol., 1969,18, 1803. R. A. Jungmann, Biochim. Biophys. Acta, 1968, 164, 110; Steroids, 1968, 12, 205. S. Burstein and M. Gut, Steroids, 1969, 14, 207.

Terpenoids and Steroids

248

R

H

H

H (91)

cholest-5-ene-3fl,22R-diol (91; R' = R3 = H,R2 = OH). However, it is claimed21s that the 20a-hydroperoxide (91; R' = 0 0 H , R 2 = R3 = H) is the precursor. The enzyme for the cleavage of the 20,22-diol requires oxygen and NADPH.216Pregnenolone (92; R = Hj is labelled217 with ['80,]oxygen but this oxygen atom may have been introduced on hydrogenation. The other product is 2-methylheptand-one. Further degradation proceeds via the 7cchydroxy-20-ketone (92; R = OH) which is cleaved to the androstane system (93; R = 0). Direct cleavage of the 17s20a-diol (91 ; R' = R3 = OH,R2 = H) also gives the lactone (93; R = 0)and isocaproic acid.Z13 Microbiological degradation of progesterone (92; R = Hj goes directly to the acetate (93; R = P-OAc,a-H) by a biological Baeyer-Villiger cleavage. The 17ahydrogen atom is retained2I8 in this process and the ether oxygen is labelled . 2 1 9 Presumably this mechanism also applies to the mould metabolite by I8O2 viridin (94) which is derived from a steroidal triterpenoid.220 0

Meo@0

Animal Steroid Metabolism.-The reduction of the As-double bond of cholesterol has already been discussed for plants. A similar process occurs in animals. Oxidation at C-3 is followed by an isomerisation to give the conjugated 4-en-3one system. In rat livers a substantial isotope effect is observed when either the 'Is 'Ih

*"

"')

' l o

J . E. van Lier and L. L. Smith, Biochenr. Biophys. Rrs. Comm., 1970, 40, 510. K. Shirnizu, Arch. Biochem. Biophys., 1968, 125, 1016. H . Nakano, C. Takemoto, H . Sato, and B. I. Tarnaoki, Biochim. Biophys. Acta, 1968, 152, 186; C. Takemoto. H. Nakano, H . Sato, and B. I . Tamaoki, Biochim. Biophys. Acta, 1968, 152, 749. K . Singh and S. Rakhit, Biochim. Biophys. Acta, 1967, 144, 139. H . Nakano, H . Sato, and B. I . Tarnaoki, Biorhim. Biophys. Arra, 1968, 164, 5 8 s ; Steroids, 1968, 12, 291. J. F. Grove, J . Chem. Soc. ( C ) , 1969, 549.

Biosynthesis of Terpenoidr and Steroids

249

3a- or 4p-hydrogen atoms are labelled. Both of these atoms are lost in the reactions,221 although a small amount of the 4/?-3H is transferred to the 6pposition. In contrast with experiments in human placenta, the 4p-atom is retained on isomerisation of the double bond.222 Reduction of the enone to the isolated alcohol requires NADPH with a preference for the tritium from [4S-3H]NADPH.223 Reduction of progesterone to pregn-4-en-20a-ol-3-one requires NADPH and tritium is incorporated from [4R-3H]NADPH.224 Further biosynthetic study of the interesting boar testis steroid 5a-androst-16en-3-one has failed to show how the A'6-double bond is produced. None of the androstane precursors fed were incorporated. Although progesterone (92 ; R = H) is utilised the 17a-hydroxy compound (92; R = OH) is not.22s

The oxidation of androst-4-en-3,17-dione (95; R = Me) to estrone (97) has been studied. Dehydrogenation to give androstadiendione (96; R = Me) involves the loss of the lp- and 2fl-pr0tons.'~~Hydroxylation at C-19 may occur before or after the dehydrogenation. Most of the radioactivity of [19R-3H]androst-5-ene-3/?,17P,19-triol (95 ; R = CHzOH,3P-OH) was recovered from formic acid while with the (19s)-isomer most of the tritium was in the water. This means that a stereospecific oxidation to the 19-0x0 compound (95; R = CHO, 3p-OH) is followed by elimination of formic 10 Triterpenoids

Three distinct methods have been demonstrated for the cyclisation of squalene. Although most triterpenoids follow a similar route to lanosterol [(7) * (71)* (72) +(7311 the 3-desoxytriterpenoids such as fernene (98) are formed from squalene (7) not from 2,3-oxidosqualene (71).228 Presumably a proton-initiated cyclisation is followed by elimination of a hydrogen atom, with, or without, rearrangement of the 'carbonium ion'. When [2-'4C,3R,4R-3H]mevalonic acid 22 I

222

223 224 225

226

227 228

1. Bjorkhem, Europpeun J. Biochem., 1969,8,337; see also J. B. Jones and D. C. Wigfield, Canad. J. Chrnr., 1969. 47, 4459. G . M. Segal. 1. V. Torgov, and T . S. Fradkina, I.U . P . A . C . A h . London, 1968, D 14. I. Bjorkhem, European J. Biochem., 1969, 8, 345. W. H. Kersey and R. B. Wilcox, Biochemistry, 1970, 9, 1284. T. Katkov and D. B. Gower, Biochim. Biophys. Acta, 1968, 164, 134; Biochem. J . , 1970,117, 533; N. Ahmad and D. B. Gower, Biochem. J., 1968,108,233. H. J. Brodie, K. J. Kripalani, and G. Possanza, J. Amer. Chem. SOC.,1969, 91, 1241 ; J. Fishman, H. Guzik, and D. Dixon, Biochemistry, 1969, 8, 4304. S. J. M. Skinner and M. Akhtar, Biochem. J., 1969, 114, 75. D. H. R. Barton, A. F. Gosden, G. Mellows, and D. A. Widdowson, Chem. Comm., 1969, 184.

Terpenoids and Steroids

250

was fed to Polypodium mlgare four triterpenoids were isolated. Diploptene, fernene (98). and serratene contained all six tritium atoms while hopene-1 had, as expected, only five. In serratene a tritium atom was located at C-1 3.229

OH

Tetrahymanol(99) shows a variant process whereby the ‘carbonium ion’ from proton-initiated cyclisation of squalene (7) is quenched by the medium. Again 2,3-oxidosqualene (7 1) is not i n c o r p ~ r a t e d .’ ~In~ ~the ’ ~presence ~ of deuterium oxide, one deuterium atom is incorporated presumably at C-3 while [‘*O]water labels the 21cw-hydroxy-gro~p.~~’*~~~ Six tritium atoms were incorporated from [2-’4C,3R,4R-3H]mevalonic acid into tetrahymanol (99).233 Fusidic acid (100) and helvolic acid (101) are interesting steroid-like triterpenoids derived from the ‘carbonium ion’ (72) without rearrangement and subsequent loss of a 4-methyl group. As expected, [2- 4C,3R,4R-3H]mevalonic acid only incorporated four tritium atoms [see ( 2,3-Oxidosqualene (71)

’

0

22u

’”’ 231 232

233

23J

E, L. Ghisalberti, N . J . de Souza, H . H . Rees, and T . W . Goodwin, Phytochemistry, 1970, 9, 1817. E. Caspi, J . M . Zander, J . B. Greig, F. €3. Mallory, R . L. Conner, and J . R. Landrey, J . Amer. Chem. Soc., 1968,90, 3563 ; E. Caspi, J. B. Greig, and J. M. Zander, Biochem. J . , 1968, 109, 931. J . M. Zander, J. B. Greig, and E. Caspi, J . Biol. Chem., 1970, 245, 1247. E. Caspi, J . B. Greig, J . M. Zander, and A. Mandelbaum, Chem. Comm., 1969, 28; J. M. Zander and E. Caspi, Chem. Comm., 1969,209. F. B. Mallory, R. L. Conner, J . R. Landrey, J . M . Zander, J. B. Greig, and E. Caspi, J . Amer. Chem. SOC., 1968,90,3564. E. Caspi and L. J . Mulheirn, J . Amer. Chern. Soc., 1970, 92, 404.

Biosynthesis of Terpenoids and Steroids

25 1

is incorporated235and presumably gives the parent system protosta-17(20),24dien-3P-01. In Emericallopsis salmosynnemata [2-14C]mevalonicacid is incorporated into this triterpenoid as well as into lanosterol (73) but not into protosta13(17),24-dien-3P-01.~~~ Its 4a-hydroxymethyl derivative is a precursor of helvolic acid (101),237and the ring B oxygen functions may be introduced at a late stage.238 The relationship between the Simaroubaceae and limonoid bitter principles has been confirmed by showing that glaucarubolone (102) has a triterpenoid 0rigin.~~9

0

H

P-Amyrin (103) is the only typical pentacyclic triterpenoid whose biosynthesis has been studied. Six tritium atoms are incorporated from [2-'4C,3R,4R-3H]mevalonic acid,'79 and their positions have been located.240 This confirms the normal mechanism suggested for the biosynthesis of this ring system from 2,3oxid~squalene.~~~

11 Carotenoids Aspects of carotenoid biosynthesis have been reviewed.242Many of the precursors of phytoene (8) are readily incorporated into ~ a r o t e n o i d s . ~However, ~*~~~ phytoene appears to be the immediate precursor since it usually retains most of the radioactivity. Although carotenoids are normally considered to be synthesised only by plants, a recent report suggests that bovine tissue can synthesise /?-carotene from acetate.244 W. 0. Godtfredsen, H. Lorck, E. E. van Tamelen, J . D. Willett, and R. B. Clayton, J . Amer. Chem. SOC.,1968, 90, 208. 2 3 6 A. Kawaguchi and S. Okuda, Chem. Comm., 1970, 1012. z 3 7 S. Okuda, Y. Sato, T. Hattori, H. Igarashi, T. Tsuchiya, and N. Wasada, Tetrahedron Letters, 1968, 4769. 2 3 8 S. Okuda, Y. Sato, T. Hattori, and M. Wakabayashi, Tetrahedron Letters, 1968,4847. "' J. Moron and J. Polonsky, Tetrahedron Letters, 1968,385; European J . Biochem., 1968, 3, 488; see also S. Datta and H. J. Nicholas, Phytochemistry, 1968, 7, 955. 2 4 0 H. H. Rees, G. Britton, and T. W. Goodwin, Biochem. J., 1968, 106, 659. 2 4 1 E. J. Corey and P. R. Ortiz de Montellano, J . Amer. Chem. SOC.,1967,89, 3362. 2 4 2 J. W. Porter, Pure Appl. Chem., 1969,20,449; T. W. Goodwin. Purr Appl. Chem., 1969, 20, 483. 2 4 3 T.-C. Lee and C. 0. Chichester, Phytochemistry, 1969, 8, 603; D. A. Beeler and J. W. Porter, Arch. Biochem. Biophys., 1969, 100, 167; G. Suzue and J . W. Porter, Biochim. Biophys. Acta, 1969, 176, 653. 2 4 4 B. A. Austem and A. M. Gawienowski, Lipids, 1969, 4, 227. 235

252

Terpenoids and Steroih

In most plants the first stage of carotenoid biosynthesis involves the progressive dehydrogenation of phytoene (8) to lycopene ( 104).24s Cyclisntion of lycopene may give r - ~ a r o t e n e(105) ~ ~ ~or /?-carotene (106).246,247Further oxidation of @-caroteneby the crustacean Arternia salina gives248echinenone (107)and canthaxanthin (108). Intermediate allylic alcohols were not detected. Time studies with Staphvloccus aureus suggest &carotene (109) might be a precursor of rubiThe enzyme for the oxidation of b-carotene (106) to retinal xanthin (1 (114; R = CHO) has been isolated from hog intestine.2s0

(106) R' (107) (108)

R' R'

= =

R2 = B R2 = D

A,

= R2 = C (109) R' = A, R 2 = C (110) R' = A , R 2 = E ( 1 1 1 ) R' = E, R 2 = F (112) R' = R 2 = E (113) R' = B, R 2 = E

HHa*,. D

HF-.

HE

B

E

One of the major problems of terpenoid biosynthesis is the apparent inability of species to incorporate the known precursors (e.g. mevalonic acid). A major cause of this difficulty is undoubtedly compartmentalisation, whereby simple 245

"' '" 248

250

C. Subbarayan, S. C. Kushwaha, G . Suzue, and J . W. Porter, Arch. Biochem. Biophys., 1970, 137, 547. S . C . Kushwaha, C. Subbarayan, D. A. Beeler, and J. W. Porter, J . Biol. Chem., 1969, 244, 3635. H. M. Hill and L. J . Rogers, Biochem. J . , 1969, 113, 31P. B. H. Davies, W.-J. Hsu, and C. 0.Chichester, Camp. Biochem. Physiol., 1970, 33, 601. R. K. Hammond and D . C. White, J . Bucteriol., 1970, 103, 191. N. H. Fidge, F. R. Smith, and D. S. Goodman, Biochern. J . , 1969,114,689.

Steroid Properties and Reactions

28 1 Me,

,Me

Me,+,Me 5

S

0

H

H+

(45)

An unusual substitutionwith neighbouring-groupparticipation occurred when the 3a-chloro-2/?,19-oxidocompound (51) was treated with either zinc metal or sodium acetate in acetic acid."' fl-Face participation by the ether oxygen (52) led to nucleophilic attack at the 2a- and 3a-positions, forming both the 3a-acetoxy-2/?,19-oxido-(53) and the 2a-acetoxy-3/?,19-oxido-compounds (54).

1

Scheme 2 lo'

F. Kohen, G. Adelstein, and R. E. Counsell, Chem. Comm., 1970, 770.

254

Terpenoids and Steroids

the incorporation of one tritium atom per isoprenoid unit from [2-'4C,3R,4R-3H]mevalonic acid shows that an all trans precursor was involved, e.g. ubiquinone (116) from ( 6 ;n = 8), a-tocopherol (117) from (6; n = 3).258 In the reduction of the double bond, e.g. a-tocopherol (1 17), tritium is incorporated from [4R-3H]NADPH.2s9

In contrast to all of the terpenoids considered so far rubber is an all cis acyclic terpenoid. This difference is reflected in the incorporation of tritium from [2-'4C,3R,4S-3H]mevalonic acid but not from the (4R)-i~omer.~ The polyprenols (118)contain both cis- and trans-double bonds. Because of their size, biosynthetic experiments are particularly suitable for determining the number of each. In most cases examined in this way, three double bonds have a trans origin [i.e. including the terminal double bond (118; n = 3)] and the remainder are cis.

The incorporation of radioactivity from [14C]farnesylpyrophosphate (6; n = 2) into the betulaprenols (1 18; n = 3, m = 3-6) supports the suggestion that these polyprenols are synthesised by chain extension of farnesyl pyrophosphate with cis units.260 This mode of synthesis appears to be widespread in Nature, including higher plants (e.g. betulaprenol), bacteria261[polyprenol-11 (1 18 ;n = 3, m = S)], and mammalian systems262 [dolichol (118; n = 3, m = 14-16)]. A related compound occurs in the fungus Aspergillus fumigatus where three double bonds have been saturated. Degradation of the polyprenol shows that the trans double bonds were saturated.263 258

Is', 160 261

262 2b3

0. A. Data, D. R. Threlfall, and G . R. Whistance, European J . Biochem., 1968,4, 329. A . R. Wellburn, Phytochemistry. 1968, 7, 1 5 2 3 ; 1970, 9, 743. D. P. Gough and F. W. Hemming, Biochem. J . . 1970. 117, 309. D . P. Gough, A. L. Kirby, J . B. Richards, and F. W. Hemming, Biochem. J . , 1970, 118. 167.

D . P. Gough and F. W. Hemming, Biochem. J . , 1970, 118, 163. K . J . Stone and F. W. Hemming, Biochem. J . , 1967, 104,43.

Biosynthesis of Terpenoids and Steroids

255

13 Taxonomy

The present state of knowledge of terpenoid biosynthesis does not allow many detailed conclusions to be reached on its taxonomic importance. However, some gross differences at the phyla level are apparent. This review has already commented on differences observed in the formation of steroidal A7- and A22double bonds, 24-alkyl groups, and whether lanosterol or cycloartenol is formed from squalene epoxide. In the plant kingdom (bacteria,264 algae, fungi, pteridophyta, and higher plants), the ability to synthesise terpenoids is almost universal. The only exception may be the blue-green algae (Cyanophyceae) where the results are conflicting but may only reflect the experimental difficulty of demonstrating terpenoid b i o ~ y n t h e s i sThe . ~ ~ inability ~ to use mevalonic acid, and to incorporate farnesyl pyrophosphate into squalene by Pseudoplexaura sp. (Zooxanthellae) may explain why it lives symbiotically in marine invertebrates.266 In the animal kingdom the position is much more complicated. Vertebrates all seem to be able to synthesise steroids from simple precursors. However, there is no good evidence for steroid synthesis in Arthropods, even though some workers have claimed otherwise. Careful investigation has always shown that incorporation of labelled precursors into steroids is indicated by the intestinal flora. For this reason, caution is required in interpreting positive results, while negative results may merely indicate an inability to metabolise added precursors, or that the substance fails to reach the necessary enzymes. Non-Arthropod Invertebrates.-The

Protozoa are able to synthesise terpenoids

[ e g . (99)J. However, there is no evidence for squalene or steroid biosynthesis in

C ~ e l e n t e r a t a ?Echinodermata,268 ~~ Nemat0da,2~~-~” or platy helm in the^?^^*^^^ In some cases they may once have been able to synthesise their own steroids, and not need a dietary source. Hymenolepis dimunuta is able to synthesise farnesol from mevalonic acid.27 3 In the phylum Annelida the position is less clear. While some speciescan synthesisesteroids others are only able to synthesises q ~ a l e n e . ~ ~ ~ It is possible that this difference reflects a distinction between the two classes Polychaeta and Oligochaeta. Nematodes are able to metabolise steroids to give 264

265

266

267

T. G. Tornabene, M. Kates, E. Gelpi, and J . Oro, J . Lipid Res., 1969, 10, 294; M. J . Winrow and H. Rudney, Biochem. Biophys. Res. Comm., 1969,37,833 ;P. F. Smith and M. R. Smith, J. Bacteriol., 1970, 103, 27. C. Z . Cooper and C. R. Benedict, Plant Physiol., 1967,42, 5 1 5 ; R . C. Reitz and J. G. Hamilton, Comp. Biochem. Physiol., 1968, 25, 401. D. G. Anderson, Plant Physiol., 1967, Supp., S45. H. E. van Aarem, H. J . Vonk, and D. I. Zandee, Arch. Internat. Physiol. Biochim., 1964, 72, 606.

268

269

270 271 272 273 274

A. Salaque, M . Barbier, and E. Lederer, Cornp. Biochem. Physiol., 1966, 19, 45. C. G. Beam, jun., B. G . Harris, and F. A. Hopper, jun., Comp. Biochem. Physiol., 1967, 20, 509. R . J. Cole and L. R. Krusberg, Life Sci., 1968,7, 713. M. Rothstein, Comp. Biochem. Physiol., 1968,27, 309. F. Meyer, S. Kimura, and J. F. Mueller, J. Biol. Chem., 1966,41, 4224. G. J. Frayha and D. Fairbairn, Comp. Biochem. Physiol., 1969, 28, 1 1 15. J. M. Wootton and L. D. Wright, Comp. Biochem. Physiol., 1962, 5, 253.

256

Terpenoids and Steroids

A5,7-dienesfrom c h o l e ~ t e r o l or ~ ~p-sitosterol, ' and to reverse the alkylation of the side chain of the latter steroid (86; R' = Et)+ (84) -+(74).270 The Mollusca are an interesting phylum taxonomically. From the limited data available the classes Bivalva268 and C e p h a l o p ~ d a ~are ' ~ not able to synthesise steroids or squalene. However, in the class Gastropoda only the order Stenoglossa cannot synthesise steroids.276In the order Stylommatophora there is a limited ability,277and steroid biosynthesis is present in Archaeoga~tropoda,~'~ Me~ogastropoda,~'~ and Basommatophora. 2 8 0 Arthropods.-Steroid biosynthesis seems to be absent from all of this phylum. Examples of the class Arachnida, Diplopoda,28 Crustacea,28'*282 and Insectazs3 have been examined. Steroid metabolism in insects has been reviewed.284 It should be borne in mind that insects can synthesise some terpenoids [e.g. (32) and (46)], but there is an absolute dietary requirement for steroids. Phytosterols such as /hitosterol are converted back into cholesterol derivatives apparently by the reverse of side chain alkylation (86; R' = Et)+ (85; R' = CHMe)-+ (85; R' = CH2)--+(84)- (74).285 In addition a A7-double bond is introduced.286 Parasites, and other organisms naturally present, may contribute to some of these reactions.287

(119) R ' = R Z = R 3 = H (120) R ' = R 3 = H, RZ = O H (121) R' = H, R 2 = R 3 = OH

(122) R' (123) R '

=

=

R2 R2

= =

R 3 = OH OH, R 3 = H

'''

D. I . Zandee, Arch. Internat. Physiol. Biochtm., 1967, 75, 487.

-

P. A . Voogt, Arch. Internat. Physiol. Biochitn., 1967, 7 5 , 492.

"' P. A . Voogt, Arch. Internat. Physiol. Biochitn., 1967, 75, 809. - 7 7

''' P. A. Voogt, Arch. Internat. Physiol. Biochim., 1968, 76, 721. '?'

'

'" 283

2BJ 2M5

28'

'ST

P. A . Voogt, Cotnp. Biochem. Physiol., 1969, 31, 37. P. A. Voogt, Comp. Biochem. Physiol., 1968, 25,943. D. I. Zandee, Comp. Biochem. Physiol., 1967, 20, 8 1 I . J . 0. 'C. Whitney, J . E.rp. Marine Biol. Ecol., 1970,4, 229. N. J . Lamb and R . E. Monroe. Ann. Entomol. Soc. Amer., 1968.61, 1164; P. Ehrhardt, Experientia, 1968, 24, 82; see, however, E. N. Lambremont and J . B. Graves, Comp. Biochem. Physiol., 1969, 30, 347. F. J . Ritter and W. H . J . M . Wientjens, T . N . O . Nieuws, 1967, 22, 381. J . A. Svoboda and W. E. Robbins, Experientia, 1968, 24, 1131 ; J . A. Svoboda, M. J. Thompson, and W. E. Robbins, Life Sci., 1967, 6, 395; see also J.-P. Allais and M . Barbier, Compr. rend., 1966, 263, 1252. R. E. Monroe, C. S . Polityka, and N. J. Lamb, Ann. Entomol. SOC.Amer., 1968, 61, 292; J . W. Bauer and R. E. Monroe, Ann. Entomol. Soc. Amer., 1969,62, 1021. S. R. Dutky, J . N . Kaplanis, M. J. Thompson, and W. E. Robbins, Ncmatologica, 1967, 13. 139.

Biosynthesis of Terpenoids and Steroids

257

The important insect hormone a-ecdysone (1 21) and related steroids are also present in plants (Section 9). Their biosynthesis from cholesterol288 probably proceeds via the A5*’-dienezs9to the triolone (119).290 The side chain is then hydroxylated to the (22R)-hydroxy steroid ( 120),291a-ecdysone (121),292and P-ecdysone (1 22) (crustecdysone). Finally, breakdown of P-ecdysone gave 4-hydroxy-4-methylpentanoic acid.293(c$ Section 9.)

289

290

291

292 293

P. Karlson and H. Hoffmeister, Z . Physiof. Chem., 1963,331,298. M. N. Galbraith, D. H. S. Horn, E. J. Middleton, and J. A. Thomas, Chem. Comm., 1970, 179. J. N. Kaplanis, W . E. Robbins, M. J. Thompson, and A. H . Baumhover, Science, 1969, 166, 1540. J. A. Thomson, J . B. Siddall, M. N. Galbraith, D. H. S. Horn, and E. J. Middleton, Chem. Comm., 1969,669. D. S. King and J. B. Siddall, Nature, 1969, 221, 955. M . N. Galbraith, D. H. S. Horn, E. J. M. Middleton, J. A. Thomson, J . B. Siddall, and W. Hafferl, Chem. Comm., 1969, 1 134.

Part 11 STEROIDS

Introduction"

Steroid Properties and Reactions (Chapter €).-The application of modern computing techniques to valence-force calculations marks a new phase in the conformational analysis of steroids. This approach1i2 brings within reach the accurate specification of preferred conformations, and the evaluation of conformational energies and conformational transmission effects and thus promises to complement the chemical and physical techniques used hitherto. The introduction of lanthanide shift reagents in n.m.r. spectroscopy promises to be particularly valuable in the analysis of steroids since it overcomes to a large extent a major limitation, namely the near-equivalence of many protons attached to the steroid nucleus.41y42Further useful advances in applying solvent shifts in n.m.r. analysis have been reported.38d0 A re-evaluation of the magnetic anisotropies of the carbonyl group and re-definition of the shielding zones surrounding it,36 should improve the calculations of chemical shift values in varbony1 compounds. A recent study of the catalytic hydrogenation of steroidal 4-en-3-ones provides a major insight into the factors that determine the C-5 configuration in the products and hence make possible its rational The mechanism whereby steroidal 5-en-3-ones are isomerised to 4-en-3-ones under enzymic, acidic, or basic catalysis has been further investigated and appears to be subject to simultaneous promotion by a phenol and a base.290*291The 'backbone' rearrangements of steroids are among the most fascinating and widespread molecular rearrangements to appear in the literature in recent years. They occur when intramolecular strain can be relieved through conformationalchanges which result from generation of a (usuallydistant) cationic site followed by sequential migration of CH, and H - groups. Recent systematic studies have begun to clarify the factors that control the products formed in these rearrangement^.^^^.^^^ The Favorskii rearrangement of 1701- and 21-halogeno-pregnan-20-ones are interpretable in terms of the interplay of two extreme mechanisms whose relative contributions vary according to reaction condition^.^^ Many new examples have appeared of the functionalisation of non-activated carbon by the transspatial generation of free radicals in closely defined proximity. The reagent now generally favoured for this purpose is lead tetra-acetate with or without iodine. Simultaneous f~nctionalisation~~~ of C-18 and C-19 has recently been

* Reference numbers are those within the relevant chapter.

262

Terpenoids and Steroids

reported for the first time. Photochemical transformations of steroids attract increasing attention. Many of the reactions of steroid enones appear to proceed through excited triplet states. A novel photochemical isomerisation of 14a- to 14p-methyl steroids in presence of mercuric chloride or bromide has been described.52s Steroid Synthesis (Chapter 2).-In the first successful synthesisz4 of natural bufadienolides, the cardioactive toad poisons bufalin and resibufagenin have been obtained from 14a-hydroxy-cortexolone. A new total synthesis3' of resibufagenin and bufalin from digitoxigenin represents the first chemical transformation of a cardenolide into a bufadienolide. The structure determinat i ~ ofn antheridiol, ~ ~ the first steroidal sex hormone found in the plant kingdom, has been closely followed by its synthesis7' from a bis-nor cholenic acid. There is continued use of microbiological agents in the resolution of racemates obtained in steroid synthesis. The selective dehydrogenation of lOR-chiral A4-3-ketones by Arthrobucter simplex has been used288to determine the relative and absolute configurations of polycarbocyclic intermediates in steroid total synthesis, and this promises to be a method of general applicability. In the field of total synthesis Johnson's group have, by further improvements in methodology, raised their monomental achievement of stereospecific polyene cyclisation to a new level of synthetic r e a l i ~ ml4. ~ ( f)-16Dehydroprogesterone has been obtained in about 20 % overall yield from a tetraenic precursor. The biologically important 9a-fluoro-ll-keto-steroids,recently made acce~sible~'~ by reaction of the enol acetate with fluoroxytrifluoromethane, can also be made from A9(")-steroids by the action of nitrosyl fluoride.503 Structural features and functional groups not previously found in natural steroids continue to appear. F u k u j u s ~ n o r o n e ' is ~ ~the first natural 18-norsteroid. The marine sterol g o r g o ~ t e r o lpossesses ~~~ not only a side-chain cyclopropane ring but also methyl groups attached to C-22 and C-23. The year under review has also seen formulation of the k s t natural 15-0xa-steroids, hirundigenin and anhydr~hirundigenin,~~ and the first natural orthoacetates melianthugenin and rnelianthu~igenin.~'.~'

1 Steroid Properties and Reactions BY

D. N. KIRK

Introduction.-The widespread use of steroids in exploring the scope and mechanisms of new chemical reactions is now an established part of organic chemistry. For this reason many of the reactions reviewed here may appear to have little relevance to steroids in their context as 'natural products'. Nevertheless, new reactions often lead to steroids with quite strange structural features, and these are occasionally discovered to exhibit significant physiological activity. Organic chemists have a particular interest in the subtle structural and conformational ramifications of steroids, which often reveal spectral correlations, and stereochemical features of reactions, not readily accessible from studies limited to open-chain or simple alicyclic model compounds. The reviewer deemed it unwise to attempt any personal selection of topics from the wide variety of published material on steroid reactions, but has endeavoured, within the space available, to survey all the relevant, if diverse, aspects of the subject which have come to his attention from beginning of 1969, or thereabouts. The publication, since January 1970, of a RINGDOC S.D.I. Profile Booklet (XXXVII : Steroids, Derwent Publications Ltd., London) has been of great value in accumulating material. 1 Structure, Stereochemistry, and Conformational Analysis

Quantitative valence force-field calculations,' using the full scope of modern digital computers, seem likely to have a profound effect upon our understanding of molecular structures and conformations in the foreseeable future. Results rivalling in accuracy those obtained by spectroscopic and diffraction techniques are already being obtained, and accurate prediction of thermodynamic properties is becoming possible. This approach has resolved uncertainties concerning the side-chain conformations of the epimeric 5a-pregnane-3P,20-diols.' The method involves minimizing, by variation of atomic co-ordinates, the total strain energy E , obtained from the expression : t'

'

=

Estretch

+ 'bend + '%orsion

-k

'non-bonded

+ '1.3 + 'coulomb

C. Altona and H. Hirschmann, Tetrahedron, 1970,26,2173.

Terpenoids and Steroids

264

Such calculations correctly reproduced the geometry of androsterone and various simpler compounds.' The results for 5a-pregnane-3P72OP-diol(1) indicate essentially a single rotamer (G) about the C(l7)-C(zo)bond, as previously concluded from n.m.r. data.3 The 2001-isomer (2) exists as a conformational equilibrium (ca. 3 : 1) of the two fully-staggered forms (E) and (F), and not in the

(2) 'Or-isomer

( 1 ) 20fl-isorner

C-13$:16 H

Ci:$C-16H

C-,$C-16 OH

Me

HO

H

(GI

20P-isomer

Y

C-17

H (El

O

H

A

C-20

H (F)

202-isomer

partially-eclipsed form deduced earlier from n.m.r. measurements. The measured coupling constant (J17-H.ZO-H) is reproduced very closely by calculations based on the conformational equilibrium. Side-chain conformations recently inferred from n.m.r. data for the 5a,17apregnan-20-01s (3)4 must now be regarded with suspicion. The fully-staggered conformation (A) proposed for the 20/?-isomer seems unlikely to be challenged, but the suggested twisted conformation (B) of the 20a-01 may have to give way to

conformational equilibrium between two staggered rotamers, when valence-force calculations are performed.

'

C. Altona and M. Sundaralingam. Tetrahedron, 1970, 26, 925. H . Lee, N . S . Bhacca, and M . E. Wolff, J . Org. Chem., 1956,31,2692; H . Lee and M . E.

WOW, ibid., 1967, 32, 192. D . N. Kirk and A . Mudd, J. Chem. SOC.( 0 ,1970, 853.

265

Steroid Properties and Reactions

The supposition of a large barrier to rotation about the C(i7)-C(20J bond, in pregnanes with C-20 tetrahedrally substituted, is said to be supported by the isolation of two distinct rotamers of the compound (3, when the 20-acetal (4)was treated with a Grignard reagent under forcing condition^.^ The stability of the two rotamers to interconversion is certainly surprising. Me

I

Me - C - OCH,CH,OH

H

H

(5)

(4)

Rotamer populations have been estimated for the 21-halogenopregnan-20-one side-chain, with and without a hydroxy-group at C-17.6 N.m.r. measurements, based upon the 7r-contribution of the ketone to geminal H-H coupling at C-21, indicate three energy minima, corresponding to eclipsing of the 20-carbonyl by a

(6) R = H or OH X = F, C1, Br, or I

C,, ,)-H or the C(, ,)-X bond (6). Oxygen-halogen eclipsing is generally favoured, decreasing in the order: F > C1 > Br > I, although the free-energy difference between conformers varies according to solvent. A preference for the gauche conformers was found only in the 17a-H 21-iodo-ketone. (The marked stability when carbonyl is eclipsed by C1 or F may have a bearing upon the failure of charge-charge or dipole-dipole calculations7 to predict the conformer populations of 2-fluorocyclohexanonesand, to a lesser extent, 2-chlorocyclohexanones.8) The equilibrium between 17a- and 17p-pregnan-20-onesis profoundly affected by certain neighbouring groups, although variations in structure in rings A and B have little effect on the normal equilibrium ratio (75-82 % of 17p : 2 S 1 8 % of F. Kohen, R. A. Mallory, and I. Scheer, Chem. Comm., 1969, 580.

' W. G. Cole and D. H. Williams, J . Chem. SOC.(B), 1970,748. ' L. J. Collins and D. N. Kirk, Tetrahedron Letters, 1970, 1547 and refs. therein. ' D. N . Kirk, unpublished results.

266

Terpenoids and Steroids

17a). Steric overcrowding by a 16p-methyl group, for example, makes the 17aisomer greatly predominate (ca. 100 %), whereas 12a-OH stabilises the 17pisomer (ca. No substantial barrier to rotation of a 6~-trimethylammoniumsubstituent could be demonstrated by low-temperature n.m.r. studies." It is suggested that strains involved in the interactions between the rotating 6P-substituent and the lop-methyl group are relieved by bond bending. Recent studies' on the synthesis of the epimeric 22-hydroxycholesterols have led to a reversal of the C-22 configurations assigned previously. The flattening of ring A in a 4,4dimethyl-5a-androstan-3-one, inferred from spectroscopic data, is confirmed by X-ray crystallography. l 2 Distortion arises mainly from rotation about the C(4f+2(5)bond, and is markedly less in the corresponding 19-nor-compound. The reality of conformational transmission' is evident from different conformations of ring D in the 10P-H and 10P-methyl compounds. Ring D approximates to a half-chair, distorted either towards a C-14 envelope, or towards a C-13 envelope, respectively. The crystal structures of 8/?-methyltestosterone 17P-bromoacetate and testosterone 17P-p-bromobenzoate have been determined. l4 The conformations of ring A in oestra-5(10),9(1l)-dien-3-0ne"*'~ and oestr5( lO)-en-3-one derivative^,'^ and their influences on the stereochemistry of ketone reduction and other reactions, have been examined experimentally' and by calculations of molecular geometry. Conformational free-energy differences ( - AGO) for various substituents in cyclohexanes have been examined by equilibration of 3-substituted 5a- (7) and 5B-cholestan-6-ones (S).' 3-Methyl substituents have normal values for - AGO, but 3a-C1, -OH, -OAc, and - 0 M e each showed deviations from accepted 5916

7718

X

H

"P

(7)

' M. B. Rubin, E. C. Blossy, A. P. Brown, and J . E. Vaux, J . Chem. SOC.(0,1970, 57. R. W. Horobin and J . McKenna, J . Chem. Soc. ( B ) , 1969, 1018. E. P. Burrows, G. M. Hornby, and E. Caspi, J . O r g . Chem., 1969, 34, 103. '' G. Ferguson, E. W. Macaulay, J. M. Midgley, J. M. Robertson, and W. B. Whalley, Chem. Comm., 1970,954. l 3 D. N. Kirk and M. P. Hartshorn, 'Steroid Reaction Mechanisms', Elsevier, Amsterdam, 1968, p. 18. ' 4 H . Koyama, M. Shiro, T. Sato, and Y. Tsukuda, J . Chem. Soc. ( B ) , 1970,443. ' S. G. Levine and N. H. Eudy, J . O r g . Chem., 1970,35, 549. l 6 R. Bucourt and N. C. Cohen, Bull. SOC.chim. France, 1970, 2015. D. N . Jones, R. Grayshan, and D. E. Kime, J . Chem. SOC.(0,1969,48. '* D. N. Jones, R. Grayshan, A. Hinchcliffe, and D. E. Kime, J . Chem. SOC.( C ) ,1969, lo

1208.

Steroid Properties and Reactions

267

values, in favour of the 5a-isomer. Electrostatic interactions between the polar 3a-substituents and the 6-0x0-group appear to be responsible for the deviations. The destabilising effects of axial substituents at C-2 and C-3 in 5a-steroids combine to cause virtually complete isomerisation of 2fl,3a-disubstituted5a-6-ketones (9) into their 5P-isomers (10) under equilibrating (acidic) conditions. A 2g3a-epoxy-5a-6-ketone, for example, reacted with hydrogen chloride by isomerisation of the firstto give the 2j?-chloro-3a-hydroxy-5j?-6-ketone, formed 5a-chlorohydrin.

(9)

Data already available” for conformational free-energy differences in cyclohexane derivatives have been supplemented by recent work, the results of which will be of value in steroid chemistry. Equilibration of 4-t-butylcyclohexanolswith Raney nickel gave values for -AG& which depend upon the solvent (e.g. 0.6 kcal mol- in cyclohexane, 0.95 in propan-2-01). Values for methoxy-groups similarly vary between 0.35 and 0.74 kcal molData are also published for each of the 4-halogenocyclohexenes,where equatorial preferences are very small, and the axial conformation is slightly favoured in the iodo-compound.22 1,3-syn-Axial interactions have been measured for a variety of pairs of substituents (Me, OH, solvent dependent;21*’3 Me, CN; Me, C0,Me; Me, CO,-; CN, CN23).Conformational preferences of geminal substituents cannot be calculated from the -AGO values of the the separate substituents. 1-Methylcyclohexanols, for example, exhibit only a small preference for the equatorial-methyl conformation (ca. 0.24-4.35 kcal mol-’ ; calc. ca. l.l).24 The conformations of ring B, variously substituted by 0x0-, hydroxy-, epoxy-, and bromo-groups in B-homo-steroids, have been studied by chemical and spectroscopic methods.25 3a-Hydroxy-5P-steroids are slowly epimerised by Raney nickel in refluxing cymene, to give the more stable 3fl-hydroxy-Sa-compounds. The reaction

’

l9 2o

22

23 24

25

H. Velgova, V. Cerny, F. Sorm, and K. Slama, Coil. Czech. Chem. Comm., 1969, 34, 3354. E. L. Eliel, N . L. Allinger, S. J. Angyal, and G. A. Morrison, ‘Conformational Analysis’, Interscience, New York, 1965, pp. 436-442. E. L. Eliel and E. C. Gilbert, J . Amer. Chem. SOC.,1969,91,5487. F. R. Jensen and C. H. Bushweller, J . Amer. Chem. SOC.,1969,91,5774. M. Tichy, A. Orahovats, and J. Sicher, Coil. Czech. Chem. Comm., 1970,35,459. J. J. Uebel and H. W. Goodwin, J . Org. Chem., 1968,33,3317;N. L. Allinger and C. D. Liang, ibid., p. 3319. L. Kohout, J. FajkoS, and F. Sorm, CON. Czech. Chem. Comm., 1969, 34, 1954; L. Kohout and J. FajkoS, ibid., p. 2439.

268

Terpenoids and Steroids

proceeds through an oxidation-reduction sequence involving transient formation of the 4-en-3-0ne.~~ The known stability of A2-olefinic 5a-steroids compared with the A'- or A3-isomers2' is also a property of the unsubstituted trans-octalin system.28 cis-Octalins prefer A'-unsaturation, equivalent to the favoured A3-unsaturation in SB-steroids. Although aB-unsaturated ketones (conjugated) are normally much more stable than the By-unsaturated isomers, some new examples of unusual stability in /+unsaturated ketones have appeared. Relief of conformational strain probably accounts for the positions of equilibrium (Scheme l).2s3

Scheme 1

Conformational strains are invoked to explain the inaccessibility of a 5,7-dien11/3-01, although the dien-1 la-ol is easily prepared.32 Long-range substituent effects of unknown mechanism influence the esterification of 5-en-3P-01~by racemic a-phenylbutyric anhydride. Hydrolysis of the resulting esters gave a-phenylbutyric acid with modest optical activity, the sign depending upon the nature of C-17 substitution in the steroid employed.32" 20 27 28

29 30 31

M . N. Mitra and W. H. Elliot, J . U r g . Chem., 1969, 34, 2170. Ref. 13, pp. 15, 161-163. P. Oberhansli and M . C. Whiting, J . Chem. SOC.( B ) , 1969,467. J. T. Edward and N. E. Lawson, J . Org. Chem., 1970,35, 1426. H. Schemer, Helv. Chim. Acta, 1969, 52, 2428. N. K. Chaudhuri, R. Nickolson, J . G. Williams, and M. Gut, J . Org. Chern., 1969,34, 3767.

32 32

R. Bucourt, J . Tessier, and G . Costerousse, Bull. SOC.chim. France, 1970, 1891. G. Balavoine, A. Horeau, J.-P. Jacquet, and H . B. Kagan, Bull. SOC.chim. France,

a

1970, 1910.

Steroid Properties and Reactions

269

Spectroscopic Methods.-The inclusion of u.v., i.r., n.m.r., chiroptical, and mass spectrometric data for new products in a large proportion of all published papers puts the assembly of such data beyond the scope of this report. Papers have been chosen for review if they :(a)contain extensive and useful compilations of data; or (b) discuss classes of compounds not studied in detail before; or (c) offer new procedures for structural studies ;or ( d )present empirical or theoretical interpretations of data likely to be of use to organic chemists. Raman Spectroscopy. Raman spectroscopy of steroids offers considerable promise as a technique for structural studies, complementing i.r. spectroscopy. Vibrations of the non-polar parts of the steroid molecule dominate in the Raman spectrum, and olefinic and aromatic systems are especially prominent. Tetrasubstituted olefinic bonds [e.g. which are not readily identified by other techniques, give very strong Raman bands. The olefinic parts of conjugated enones give bands equalling or exceeding the carbonyl bands in intensity. Steroid skeletons of 5a- and 5fl-configurations are di~tinguishable.~~ Nuclear Magnetic Resonance. Ziircher’s massive c ~ m p i l a t i o nof~ ~chemical shifts of 18-H and 19-H signals, and increments produced by structural features in the steroid nucleus, is augmented by the publication3’ of similar data for 344 steroids obtained by microbiological hydroxylations, and subsequent transformations. The compounds are mainly Sa-androstane derivatives, and include hydroxy- and 0x0-functions at almost all the ring positions, as well as their derivatives and polyfunctional compounds. Solvent shifts are also reported. A set of diagrams illustrates the profiles and chemical shifts of signals due to methine protons in the CHOH system at all the main steroid positions.35 Theoretical calculations of magnetic anisotropies for the carbonyl supported by experimental data for all the Sa-androstanones, and other compounds, show that the concept of ‘shielding cones’, extending approximately in the directions of highest electron density of the .n-orbital(l1) is erroneous, despite wide and apparently satisfactory application over recent years. Instead, the carbonyl group deshields spatial regions enclosed within a pair of cones (12) of slightly elliptical cross-section, and coaxial with the C=O bond. All regions outside these cones are shielded. The shielding includes the regions specified in the earlier theory, but also takes in space near the nodal plane of the n-orbital, previously thought to be deshielded. The magnetic anisotropy of the carbonyl group is thus qualitatively similar to that of an olefinic bondq3’ 33 34

35

36

37

B. Schrader and E. Steigner, Annalen, 1970, 735,6, 15. R. F. Zurcher, Helv. Chim. Acta, 1961, 44, 1380; 1963,46, 2054. J. E. Bridgeman, P. C. Cherry, A. S. Clegg, J . M. Evans, Sir Ewart R. H. Jones, A. Kasal, V. Kumar, G. D. Meakins, Y. Morisawa, E. E. Richards, and P. D. Woodgate, J . Chem. SOC.(0,1970, 250. J. W. ApSimon, P. V. Demarco, D. W. Mathieson, W. G. Craig, A. Karim, L. Saunders, and W. B. Whalley, Tetrahedron, 1970, 26, 119. J. W. ApSimon, W. G. Craig, P. V. Demarco, D. W. Mathieson, L. Saunders, and W. B. Whalley, Tetrahedron, 1967, 23,2357.

Terpeiioids and Steroids

270

Solvent shifts (A7) in the n.m.r. spectra of steroid alcohols have been studied in b e n ~ e n eand ~ ~ in . ~pyridine. ~ Slight shielding (ca. 0.1 p.p.m.) of angular-methyl protons in benzene solutions of hydroxy-steroids is usual. Exceptions occur when the hydroxy-group is in a ‘1,3diaxial’ relationship to the methyl group (e.g. 28-, 48-, or 6fl-OH); a particular orientation of a benzene molecule, due to the . . . HO interaction, results in deshielding (ca -0.1 p.p.m.) of the neighbouring methyl-group protons.38 Stronger hydrogen-bonding between hydroxy-group and nitrogen, in pyridine, generally causes deshielding of methyl protons, to an extent depending upon the location of the hydroxy-group in relation to the methyl The ranges of solvent shifts, indicated in Table 1, will be useful in structural studies, and are reasonably additive for di- and tri-hydroxy-compounds.

Table 1 Solvent shifts (A7

=

for methyl

protons in hydroxy-steroids. Relationship ofCH, ro OH 1,4-diaxial or axial-quatorial 1,3-diaxial 13‘diaxial’ (in five-membered ring) 1,3-axial+quatorial 1,3-diequatorial 1,2-diaxial (Trans) 1,2-axial+quatorial (cis)

Range of AT (p.p.m.) 0.0 to -0.04 0.25 to - 0.32 -0.21 to -0.27 +0.02 to -0.12 ca. -0.01 -0.03 to -0.05 -0.19 to -0.27 -

Large chemical shifts when certain lanthanide complexes are added to solutions of alcohols, or of other compounds with available lone-pairs, offer promise for detailed analysis of spectra, and for structure determination. Tris-(2,2,6,6tetramethylheptane-3,5-dionato)europium*shifted the 4-methyl signals in lupeol (1 3) down-field from ca. 19.0to 72.7 and 2.4 ;none of the resonances due to methyl

’* P. V . Demarco and L. A. Spangle, J . Org. Chem., 1969,34, 3205. ’’ R. G. Wilson, D. E. A. Rivett, and D. H. Williams, Chem. and Ind., 1969, 109. 40

J1

S. Ricca, B. Rindone, and C. Scolastico, Gazzetra, 1969, 99, 1284. J . K . M. Sanders and D. H. Williams, Chem. Comtn., 1970, 422.

* Commonly known

as

tris(dipivalomethanato)europium,Eu(dpm), .

Steroid Properties and Reactions

27 1

groups more remote from the 3P-hydrogen-group appear below ~ 6 . 3 . ~A’similar complex of praseodymium induced shifts which were even larger, and of opposite sign.42 Cholesterol showed the 10P-methylresonance at ~11.88 (a shift of2.9 p.p.m. to high-field);even the 13P-methylresonance (~9.90) was well separated from those of 21-H, (29.14) and 26- and 27-H, (29.17).

Analysis of geminal coupling constants ( J ) in methylene groups attached to h e t e r o - a t o m ~confirms ~~ trends in variation of J with molecular environment ; geminal coupling constants in C - C H , -C systemsare also reviewed.44 Although the examples cited include only a few steroid or terpene-like structures, data for a wide range of heterocyclic and carbocyclic compounds will be valuable in interpreting steroid spectra. Long-range couplings through four a-bonds cause separate splittings of the C-19 protons in the 3P,lPether (14).45 Ha is coupled with 1-H, and H, with Sa-H, each interaction involving a suitable ‘planar zig-zag’ of a-bonds (14; thickened lines). Groups of compounds which have recently received n.m.r. study (‘H) include 4 ~ of some aza-0x0-steroids (lactams) in rings A and ~ , ethylene-acetals spiro-oxirans (epoxides of exocyclic methylene groups):8 18,2O-lactones, -ethers, and -imino-compounds (including an extensive tabulation of chemical shift increments for angular-methyl proton^),^' Sa-acetoxycholestane derivative^,^' a-halogeno-cyclohexanones, such as 6-halogen0-7-0xo-steroids,~and hydroxymethyl-substituted steroids and their O-deri~atives.~’ 42

J. Briggs, G. H. Frost, F. A. Hart, G. P. Moss, and M. L. Staniforth, Chem. Comm., 1970,749.

43 44

45 46

R. Cahill, R. C. Cookson, and T. A. Crabb, Tetrahedron, 1969, 25,4681. R. Cahill, R. C. Cookson, and T. A. Crabb, Tetrahedron, 1969,25,4711. A. Guzman, E. Diaz, and P. Crabbk, Chem. Comm., 1969, 1449. R. T. Aplin, G. D. Meakins, K. Z. Tuba, and P. D. Woodgate, J . Chem. SOC.( C ) , 1969, 1602.

47 48

49 50

52

B. P. Koch, H . Rosenberger, and R. Zepter, J . prakt. Chem., 1969, 311,983. L. J. T. Andrews, J. M. Coxon, and M. P. Hartshorn, J . Org. Chem., 1969,34, 1127. J.-C. Gramain, H.-P. Husson, and P. Potier, Bull. SOC.chim. France, 1969, 3585. J. M. Coxon, M. P. Hartshorn, and G. A. Lane, Tetrahedron, 1970,26,841. A. Baretta, J. P. Zahra, B. Waegell. and C. W. Jefford, Tetrahedron. 1970, 26, 15. J.-C. Lanet and M. Mousseron-Canet, Bull. SOC.chim. France, 1969, 1751.

Terpenoids and Steroids

272

Some di-steroid and related sulphites

[:::

CH-0-S-0-CH

II

0

/

R 1‘

\

R2.

reveal non-equivalence of the methine protons ( H ) in the two organic compone n t ~ The . ~ ~effect is due to molecular asymmetry, associated with the pyramidal configuration at sulphur. I3C Resonance spectra, employing noise-modulated proton decoupling, have permitted identification of signals due to each carbon atom in the steroid skeleton (up to c28)at the natural abundance of this isotope.54 Chemical shifts covering a span of 200 p.p.m. are found. Data are reported for a range of sterols and steroid hormones. N.m.r. spectra ( I9F) of trifluoroacetates of hydroxy-steroids show chemical shifts characteristic of the type and position of the h y d r o x y - g r o ~ p . ~ ~ Chiroptical Properties (O.R.D., C.D.). A French language review’ surveys progress in circular dichroism between 1961 and 1969. An attempted empirical correlation of solvent effects with structure, for a series of steroid ketones, has been partially successful.s7 Cotton effects (0.r.d. ; n --+ n*) in methanol or other polar solvents are, for most compounds, larger than in hexane, considered as reference solvent. The differences between amplitude in methanol and in hexane, for some 60 ketones, may be interpreted qualitatively in terms of dissymmetric solvation, determined by steric effects in the vicinity of the chromophore. A somewhat more satisfactory and semi-quantitative correlation with structure comes from presuming solvent effects to stem from solventdependent perturbation of the carbonyl group by structural features of the ketone molecule itself, rather than from the solvent distribution around the carbonyl group. Two empirically-determined sets of ‘group increments’, referring to hexane and methanol respectively, allow the calculation of total amplitudes for various ‘all-trans’ arrays of rings based upon perhydrophenanthrene, with the 0x0-group in a terminal ring (e.g. steroid A-ring ketones, and D-homo-steroids with a D-ring ketone).” An attempt has been made to calculate directly the optical rotatory strengths of methyl-substituted cyclohexanone~.~~ The results show a significant dependence of rotatory strength upon the conformation adopted about the C-methyl bond. 53

R. E. Lack and L. Tarasoff, J . Chem. SOC.( E ) , 1969, 1095.

’‘ H. J. Reich, M . Jautelat, M . T. Messe, F. J. Weigert, and J. D. Roberts, J . Amer. Chem. SOC.,1969.91, 7445.

5 5

E. Breitmaier. W. Voelter. G . Jung, and E. Bayer. Angew. Chem. Internat. Edn., 1970, 9,75.

5h 5’

’*

L. Velluz and M . Legrand, Bull. SOC.chim. Frmce, 1970, 1785. D. N. Kirk, W. Klyne, and S. R. Wallis, J . Chem. SOC.( C ) , 1970, 350. R. R. Gould and R. Hoffman, J . Amer. Chem. SOC.,1970,92,1813.

Steroid Properties and Reactions

273

Chiroptical data for a series of methyl- and methylene-substituted ~-nor-2-oxosteroids (1 5 ) and androstan-16-ones (16) show no systematic correlation of substituent configuration with the carbonyl ‘Octant Rule’.59 The conformation

(15)

(16)

R’ and R2 = Me or =CH, of the five-membered ring itself is believed to make the major contribution to the Cotton effect; such rings have sufficient flexibility to adopt the conformation which best accommodates the substituents in any particular compound, so that the magnitudes of Cotton effects are not predictable at present. Circular dichroism data for a series of a-ketols and their acetates show that axial acetoxy-groups frequently make ‘anti-Octant’ contributions to the ketone (n --+IT*)Cotton effect.60 Axial hydroxy-groups may produce either an ‘Octant’ or ‘anti-Octant’ effect. It seems probable that the conformation of the acetoxyor hydroxy-group itself may be the decisive factor, the orientations of oxygen lone-pairs in relation to the carbonyl group probably being critical. Analysis of U.V.and c.d. data for amino-cyclohexanones, including a steroidal 5a-amino-6-ketone (17), shows that both the U.V. absorption (n+z*) and the Cotton effect depend upon the bonding arrangement between nitrogen and the carbonyl group, and also upon the orientation of the nitrogen lone-pak61 A planar zig-zag arrangement (‘all-trans’) of the nitrogen lone-pair, the C-N bond,

one of the lobes of the En-orbitalon the carbonyl carbon, and any intervening C-C bonds [e.g.as in (17)], results in behaviour according to the ‘Octant Rule’. ‘Anti-Octant’ behaviour is found when the pathway from nitrogen lone-pair to carbonyl .n-orbital lobe contains a skew (cis) component [e.g. (IS)]. The relationship between conformational features like those defined in (17) and (18), and certain other chemical and spectroscopic properties, has been detailed.6

’

59

M. J. Brienne, A. Heymes, J. Jacques, G. Snatzke, W. Klyne, and S. R. Wallis, J . Chem. SOC.(0, 1970,423.

6o 61

J. R. Bull and P. R. Enslin, Tetrahedron, 1970, 26, 1525. J. Hudec, Chem. Comm., 1970, 829.

274

Terpenoids and Steroids

Two apparently conflicting Octant Rules have been proposed for chiral olefins (n ---* 7c* transition, ca. 19%220 nm). Exocyclic methylene groups in steroids generally obey a similar Octant Rule (Figure 1) to ketones (6-methylene is a notable exception).62 Most other olefinic bonds (endocyclic),however, appear to obey the reverse Octant Rule (Figure 2).63 No satisfactory rationalisation of these results has yet appeared, I

- I +

- I +

+I-

Rear octants

Rear octants

- I + Front octants Figure 1 Octant signs Jor ketones, and apparently for exocyclic methylene derivatives.

Front octants Figure 2 Apparent octant signs for most olejinic bonds, excepting exocyclic methylene groups.

Charge-transfer complexes of dissymmetric olefins with either tetracyanoethylene or Pt" (sodium tetrachloroplatinate) exhibit chiroptical effects related to the chirality of the olefin. The Ptn complexes generally obey a Quadrant Rule.64 Chiral olefins may also be converted into osmate esters, exhibiting Cotton effects in the region of 480 nm; the sign obeys a chirality rule (Figure 3) which

Figure 3 Chirality rule (c.d.)for 62

b3

b4

osmates.

M. Fetizon and I. H a n n a , Chem. Comm., 1970,462. A . 1. Scott a n d A . D. Wrixon, Chem. Comm., 1969, 1182. A. 1. Scott and A. D. Wrixon, Chem. Comm., 1969, 1184.

275

Steroid Properties and Reactions

permits the assignment of chirality to the derived d i 0 1 . ~A ~ similar chirality rule is obeyed by thionocarbonates derived from ~ i c - d i o l s . ~ ~ Dibenzoates of chiral diols exhibit two c.d. maxima, of similar intensity but opposite sign, in the regions of 219 and 233 nm, respectively, due to the dipoledipole interaction between the two ester groups.66 The shape of the resulting curve indicates the chirality of the diol (Figure 4), and is not limited to vic-diols (e.g. 2,3- or 3,4-diols), but applies also to more remote groups (e.g.a 3fi,6fi-diol).

'\ (+,

8zoBz Figure 4 Chirality rule (c.d.)for dibenzoates.

The absolute configuration of a secondary alcohol may be determined, in the great majority of cases, from the sign of the Cotton effect (ca. 330nm) of its o-nitr~benzoate.~The examples listed show that alcohols of (R)-configuration generally give esters with negative Cotton effects, whereas the (S)-esters generally give positive curves. The optical activity results from twisting of the normally planar o-nitrobenzoate chromophore (19) by steric interaction with bulky groups in the alkyl component, and has been demonstrated at C-12 and C-20 in steroids.

(19)

Arylazo-steroids exhibit Cotton effects in the visible spectrum, with amplitudes determined by the degree of rotational restriction encountered by the N-Ar

// group. An attempt has been made to develop a Sector Rule for these -N compounds.68 hs

6b b7

68

A. H. Haines and C. S. P. Jenkins, Chem. Comm., 1969, 350. N . Harada and K. Nakanishi, J . Amer. Chem. SOC.,1969,91, 3989. U. Nagai and H. Iga, Tetrahedron, 1970,26, 725. 3. Buckingham and R . D. Guthrie, J . Chem. SOC.(0,1969, 1939.

Terpenoids and Steroids

276

Chiroptical studies have been reported for a variety of sulphinyl and sulphinate derivatives of steroids,69- ' and also for steroid N-acetylglu~osaminides.~~ Mass Spectrometry. Mass spectrometry of steroids has now become a routine tool, rather than a subject for intensive study. A series of papers,75 collecting earlier published data into tables, will be of great value. The tables list mass differences between molecular ions and fragments, and also masses of principal ions, for a wide variety of steroid structures. A simple system for data processing with a small computer, or even with a punch-card system, is The localisation of hydroxy-groups from study of mass spectra of the derived ketones has been described. 5cx- and 5~-3-oxo-steroidscan generally be distinguished by their characteristic fragmentation^.^^ The same compounds can be converted into their enol trimethylsilyl ethers, having the olefinic bond respectively in the A2- and A3-positions. Each affords a distinctive mass spectral fragmentation pat tern. Oximes, as their 0-methyl, 0-ethyl, or 0-trimethylsilyl derivatives, are useful for protection of pregnan-20-ones, including 17a-hydroxypregnan-2O-ones, during gas chromatography ; the derivatives provide useful mass spectral patt e r n ~ . ~0-Methyl * oximes at other positions have also been studied in detail.79 2 Alcohols, their Derivatives, a d Halides

Nucleophilic Substitution.-Further studies with unhindered secondary hydroxysteroids confirm earlier reports of almost total inversion of configuration in reactions with PCl, . However, thionyl chloride is less efficient than is generally believed in givingchloro-compounds with retention ofconfiguration (S,i reaction). Thus 5a-cholestan-3a- and -3p-01 with thionyl chloride each gave mixtures of 3-chloro-compounds with a slight preference for inversion," and the 19-nor2b-01 mainly the inverted 2a-chlor0-compound.~' (Solvents can influence the course of reaction with thionyl chloride ;82 it would seem worthwhile to study the reactions of the 3-01s with thionyl chloride in, for example, ether.) Where the substitution with inversion would encounter serious steric hindrance (e.g. 5a-cholestan-4a-ol), halogeno-compounds are formed with retention, whichever halide is *' D . N . Jones, M. J. Green, and R. D. Whitehouse, J . Chem. SOC.(0,1969, 1166.

'' ''

D. N. Jones, D. Mundy, and R. D. Whitehouse, J . Chem. Soc. (0,1969, 1668. D . N. Jones and W. Higgins, J . Chem. Soc. (0,1969,2159. ' 2 D. N. Jones and W. Higgins, J . Chem. SOC.(0,1970,81. ' 3 D . N. Jones, E. Helmy, and A. C. F. Edmonds, J . Chem. SOC.( C ) , 1970,833. l 4 D. K. Fukushima and M. Matsui, Steroids, 1969, 14, 649. l 5 G. von Unruh and G. Spiteller. Tetrahedron, 1970, 26, 3289, 3303, 3329. ' s a c . von Unruh, M . Spiteller-Friedrnann, and G. Spiteller, Tetrahedron, 1970, 26, 3039. '' H . Obermann, F. M . Spiteller, and G. Spiteller, Chem. Ber., 1970, 103, 1497. W. Vetter, W. Walther, M. Vecchi, and M . Cereghetti, Hell>.Chim. Acta, 1969, 52, 1 . C . J . W . Brooks and D. J . Harvey, Steroids, 1970, 15, 283. F. Dray and I . Weliky. Analyt. Biochem.. 1970, 34, 2 , 387. C. W. Shoppee and J . C. Coll, J . Chem. SOC. (0,1970, 1124, C. W. Shoppee and J . C. Coll, J . Chern. SOC.( C ) , 1970, 1121. F. F. Caserio, G. E. Dennis, R. H. deWolfe, and W. G. Young, J . Amer. Chem. SOC., 1955,77,4182. 8 3 C . W. Shoppee, R . E. Lack, and S. C. Sharrna, J . Chem. SOC.(0,1968,2083. 7'

Steroid Properties and Reactions 277 3~-Chloro-3a-methyl-5a-cholestane (20), the unstable isomer, is accessiblea4 by reaction of 3a-methy1-5a-cholestan-3/3-ol(21)with phosphorus pentachloride (hydrogen chloride affords the stable 3a-chloro-isomer). This reaction clarifies the mechanisms of substitution by phosphorus pentachloride. Inversion generally

Me

H

Me

H

occurs with secondary alcohols,85because the leaving group (-OPCl+) requires the assistance of an approaching nucleophile (S,2 reaction) for ready reaction, giving the inverted chloro-compound. SNi reaction^,^' with retained configuration, proceed readily when ionisation is favourable, as in substitution of the tertiary alcohol (21); steric opposition to sN2 reaction can also result in SNi reaction as the less unfavourable alternative in this circum~tance.~~ For best results, thionyl chloride is conveniently purified by distillation from dipentene.86 1,1,2-Trifluoro-2-chloro-triethylamine (Et,NCF,CHClF) converts many alcohols into fluoro-compounds, e.g. (22) --+(23);87(24)+(25Xaaalthough eliminations" and rearrangements involving carbonium ions are not infreq ~ e n t . ~A' novel variant88uses the reagent in the presence of lithium chloride or

84

86

89

R. M. Carrnan and H.C. Deeth, Ausrral. J. Chem., 1970, 23, 1053. Ref. 13, pp. 3 6 - 4 1 . W. Rigby, Chem. and Ind., 1969, 1508. M. Mousseron-Canet and J.-L. Borgna, Bull. Sac. chim. France, 1969, 613; see also J.-L. Borgna and M. Mousseron-Canet, ibid., 1970, 2218. E. J. Bailey, H. Fazakerley, M. E. Hill, C. E. Newall, G. H. Phillipps, L. Stephenson, and A. Tullev. Chem. Comm.. 1970. 106. Ref. 13, p. 271.

278

Terpenoids and Steroids

bromide, affording the 1I#?-chloro-or 1I/-?-bromo-steroidcorresponding to (25). Few examples are known of nucleophilic substitution of 6a-functional groups with inversion,8’ for the lo#?-methylgroup hinders approach of nucleophiles to the /?-face: the selenophenate ion (PhSe-) is found to be capable of S,2 substitution of a 6or-mesylate group.” Although 3P-hydroxy-5-enes (26) and their derivatives normally undergo nucleophilic substitution with complete retention of configuration at C-3 (via the 3a,5a-cyclocholestanyl cation),” powerful nucleophiles can substitute directly (&2) with inversion at C-3.’’ N-Methylamino- and NN-dimethylaminoethanol react in this way, converting the tosylate (27) into the same product (28).93 The NN-dimethyl derivative suffers demethylation of the quaternary ammonium ion.

(26) R = H (27) R = TS

A series of silyl and stannyl derivatives (29; R = Ph,Si-, Me3Si-, Ph3Sn-, or Me,Sn-) has been prepared from 3-halogeno-steroids with the appropriate organosilyl- or organostannyl-lithium or -potassium deri~ative.’~ An alternative route uses cholestanylmagnesium chloride and the organostannyl chloride. The 3#?-derivativegenerally results, whatever the configuration of the initial halide, although triphenylstannyl-lithium reacts with 3B-halides to give 3a- derivatives. Yields are generally low. Substitution reactions using azide ion have become a popular route to nitrogencontaining steroids. The high nucleophilicity of N, makes it effective even in some cases where SN2 reactions are normally unfavourable. A notable example is

90

’’

’’ y3 94

D. Neville Jones, D. Mundy, and R . D. Whitehouse, Chcm. Comm., 1970. 86. Ref. 13, p. 236. Ref. 13, p. 247. D. D. Evans and J. Hussey, J . Chem. Soc. ( C ) , 1969,2504. H. Zimmer and A. V. Bayless, Tetrahedron Letters, 1970, 259.

Steroid Properties and Reactions

279

(34)

(35)

the conversion of a 20a-tosyloxy-pregnane (30) into the 20p-azide (31) in 52% yield, in hexamethylphosphotriamide as solvent.9s The D-homo-17ap-tosylate (32) similarly afforded the 17aa-azide (33) in high yield,96although other reagent systems lead to 17ap-substituted products, in a reaction previously interpreted9' in terms of an intermediate non-classical carbonium ion (34). It is now suggestedg6 that the retention of configuration arises from a mechanism with SNicharacteristics (33, the tosylate being replaced by the acyloxy-group of a solvating formic (or acetic) acid molecule. Azide ion will replace mesylate (with inversion) under conditions which do not open epoxides. Epoxy-amines (e.g. 38) prepared by this route [from (36)] were converted into acetamido- and ureido-epoxides by standard methods.98 Azide

substitution, followed by expulsion of nitrogen to give enamines, (40) and (42), is reported with some bromo-ketones :99 6/?-bromocholest-4-en-3-one(39) and 2a-bromo-5a-cholestan-3-one(41) apparently undergo normal substitution, with inversion, when allowed to react with sodium azide in dimethyl sulphoxide,

-NZ 0

1

Br (39)' 95

96 97 98 99

(40)

M. Leboeuf, A. Cave, and R. Goutarel, Bull. SOC.chim. France, 1969, 1619 and 1624. M. Leboeuf, A. Cave, and R. Goutarel, Bull. SOC.chim. France, 1969,2100. H. Hirschmann, F. B. Hirschmann, and A. P. Zala, J . Org. Chem., 1966,31, 375. G . Lukacs and D. K. Fukushima, J . Org. Chem., 196b, 34, 2707. J. G . L1. Jones and B. A. Marples, J. Chem. SOC.(0,1970, 1188.

280

Terpenoids and Steroids

""a}"33}] 0

H

[ k 2 N ; v J ) ]

-

(41)

although other nucleophiles (e.g. AcO-) often cause substitution of bromoketones with rearrangement. loo Even azide ion is not infallible as a nucleophile ; the 3a-acetoxy-2P-bromocompound (43) gave the elimination product (44), not readily accessible by other routes, rather than the expected 2a-azideg9

The formation of rearranged products during nucleophilic substitution in x-bromo-ketones' O0 probably involves enolisation, followed by allylic (S,2') substitution. The ready conversion of 4/l,5P-epoxy-3-ketones(45)into 2a-acetoxyor 2a-hydroxy-4-en-3-ones is similarly rationalised. l o ' When the nucleophile is dimethyl sulphoxide, the resulting 2-oxysulphonium ion (46)breaks down with elimination of dimethyl sulphide to give the 4-ene-2,3-dione (47), or its A'-enolic equivalent (48).l o la A novel mechanism has been suggested for the formation of the 3-acetoxy2,5-dien-4-one (50)from the 2,6-dibromo-4-en-3-one (49). lo' Acetate ion labelled with l80gave the product (50)in which both carbonyl groups contained the label, but the third oxygen was unlabelled, and so was derived from the original 3-0x0-group. The reaction sequence outlined in Scheme 2 is compatible with this result. 'O"

lo'

lo'

Y . Satoh, A . Horiuchi, and A, Hagitani, Bull. Chem. SOC.Japan, 1970,43,491; see also ref. 13, p. 387. P. L. Julian, L. Bauer, C. L. Bell, and R . E. Hewitson, J . Amer. Chem. Soc., 1969, 91, 1690. a Y. Morisawa and K . Tanabe, Chem. and Pharm. Bull. (Jupan), 1969, 17, 1206, 1212.

Steroid Properties and Reactions

28 1 Me,

,Me

Me,+,Me 5

S

0

H

H+

(45)

An unusual substitutionwith neighbouring-groupparticipation occurred when the 3a-chloro-2/?,19-oxidocompound (51) was treated with either zinc metal or sodium acetate in acetic acid."' fl-Face participation by the ether oxygen (52) led to nucleophilic attack at the 2a- and 3a-positions, forming both the 3a-acetoxy-2/?,19-oxido-(53) and the 2a-acetoxy-3/?,19-oxido-compounds (54).

1

Scheme 2 lo'

F. Kohen, G. Adelstein, and R. E. Counsell, Chem. Comm., 1970, 770.

282

Terpenoids and Steroids

The desired elimination predominated only when the 3a-bromocompound (55) was reduced with zinc, giving the 19-acetoxy-2-ene(56). A 3-oxo-2B719-etheris opened by acetic anhydride-boron trifluoride to give the 2419-diacetoxyketone.lo3 Inversion at C-2 may occur either through nucleophilic attack of

(51)

X

(55) X

= =

C1

Br

acetate ion upon the co-ordinated ether, or by epimerisation of an initially formed 2p,19-diacetate. Similar reaction conditions converted a 3a-acetoxy2/?,19-ether into the 2%3a,19-triol 3,19diacetate, after hydrolysis of an intermediate 2a,3a-acetoxonium ion, resulting from participation of the 3a-ester group. The 2/?,19-ether bridge forms readily on hydrolysis of a 2a-chloro-19-01 acetate, making possible the synthesis of otherwise inaccessible compounds of this type (e.g. a 2B,19-oxido-4,6-dien-3-one lo4). 2a.5a- and 2fi,Sfi-Ethers are available from suitable 2,5-h.ans-disubstituted steroids, which allow participation of a 5-hydroxy-substituent in the departure of

a}-

Hoy-J}bH HO-

o::(-J}

RO-'

OH

(58) R

(57)

(59)

R

= =

Ms

(60)

H

HO OH

'03 '04

R . E. Lack and A. B. Ridley, J . Chem. SOC.(0,1970, 1437. G . Kruger and A. Verwijs, J . Org. Chem., 1970,35, 2415.

Steroid Properties and Reactions

283

a C-2 ‘leaving group’.lo’ The 2b,3a,5a-triol (57) reacts with methanesulphonyl chloride in pyridine to give the 3a-mesyloxy-2g5a-ether (58); the free 3a-01 (59) results from prolonged reaction of the 2q3a-epoxy-5a-01 (60) with hydrogen bromide. The 2jI,3jI-epoxy-5jI-o1(61) gives the diaxial bromohydrin (62), which requires treatment with pyridine to close the 2/3,5/3-ether bridge (63).lo’ The 5a,6/3-diol(64), or its 4,4-dimethyl derivative, afforded the corresponding 5a,6a-epoxide (65) with potassium hydrogen sulphate and acetic anhydride. The reaction is thought to proceed through the 6/3-acetylsulphate (.O,SO,.OAc), an exceptionally good ‘leaving group’.loci

Nucleophilic Opening of Epoxides.-Participation by acetamido- and N-acetylureido-groups in acid-catalysed epoxide-opening accounts for the products (68) and (71) formed from trans-compounds (66) and (69); epoxide rings in the ciscompounds (67) and (70) open normally at C-5 to give the same two diaxial 4,5-diols (68) and (71) respectively.” Both isomeric 2,3-epoxides in the Sa-cholestane,4,4-dimethyl-5a-~holestane,~~~ and 4,4-dimethyl-5a-oestraneseries”’ afford normal diaxial fluorohydrins with

(66) 4a,5a-epoxide (trans) (67) 4B,Sf?-epoxide(cis)

(69) 4b,5B-epoxide (trans) (70) 4a,5a-epoxide (cis) lo’

lob lo’

OH (71)

T. Komeno, H. Itani, H. Iwakura, and K. Nabeyama, Chem. and Pharm. Bull. (Japan), 1 9 7 0 , l S . 1145. M. Fetizon and P. Foy, Coll. Czech. Chem. Comm., 1970, 35,440. (a)J. Levisalles and M . Rudler-Chauvin, Bull. Soc. chim. France, 1969,3947; (6) J. Levisalles and M. Rudler-Chauvin, ibid., p. 3953. J. Levisalles and M. Rudler-Chauvin, BUN. SOC.chim. France, 1970, 664.

Terpenoids and Steroids

284

hydrogen fluoride. The 4,4dimethy1-2/3,3p-epoxides additionallygive rearranged products (p. 369 ). The rate of acid-catalysed hydrolysis of 5a,6a-epoxides to give 5a,6fl-diols shows first-order dependence upon epoxide, but variable order in acid concentration (HC104,in largely non-aqueous medium). Water above the necessary minimum concentration retards reaction by reducing the concentration of protonated epoxide. l o 9 Acid-catalysed ring-opening of 20ar,21-epoxypregnanes (72) gave both the 20421- (73)and 20~,21diols(74), by non-selective attack of water. Base-catalysed hydrolysis, in contrast, gave only the 20q21-dio1, by nucleophilic attack of OHat C-21. The 20q21-diol also resulted from epoxide opening by either dimethyl

H

H

H

sulphoxide or dimethylformamide, catalysed by boron trifluoride, with subsequent hydrolysis.' l o Epoxide-openingwith sodium azide and a weakly acidic catalyst is increasingly used as a route to hydroxy-aides, and thence to hydroxy-amines [e.g. 16aJ7aepoxyandrostane+ 16/3-azido-l7a-01;~ 6a,7a-epoxy-4-en-3-one +6p-azido-

(76) X = N, (77) see text

(78)

lo'

'

lo

'"

X

=

N,

(b) X

=

HCHS3 'S

(79) (a)

J. M . Diggle, M . D. Halliday, C. D. Meakins, and M . S. Saltmarsh, Chern. Cornrn., 1969, 819. D. N. Kirk a n d F. J. Rowell, J . Chem. SOC.( C ) ,1970, 1498. J. Matthews and A. Hassner, Tetrahedron Letters, 1969, 1833.

285

Steroid Properties and Reactions

7a-01;' l 2 5a,l~-epoxyoestrane-3~,17~-diol (75)--+lO~-azido-3P,Sa,17P-triol (76)'13]. The last of these epoxides has been opened with a wide variety of reagents to introduce novel substituents at the lO/I-position (77; X = Br, SCN, SR, OR, NHR, etc.).'I3 Epoxides susceptible to rearrangement under acidic conditions may be opened with azide ion under catalysis by boric acid in dimethylformamide.' l4 Thus C-17 spiro-oxirans (78) gave 17-azidomethyl-17-01s (79a) in high yield, although generally affording a rearranged hydroxy-oleh with other acidic catalysts. Rearrangement of the initially formed hydroxy-azide (81) gave the D-homo16P-azidoketol (82), when a 16417a-epoxypregnan-20-one(80) was treated with sodium azide and sulphuric acid.'I5 [Assuming the D-homoannulation to be

acid-catalysed, it would seem worthwhile to treat the epoxy-ketone (80) with sodium azide-boric acid-dimethylformamide, in the hope of obtaining the 16B-azido-17a-hydroxypregnan-20-one(81).] Diaxial amino-alcohols have been prepared efficiently by treating epoxides (e.g. 83) with acetonitrile and an acidic catalyst (either perchloric acid1l6 or boron trifluoride' 17). Hydrolysis of the ion (84) gives the N-acetyl-derivative(85) of the amino-alcohol.

-@ ' @ '

MeCN-H+

RO

Ro

HO

Ro

HO

NH Ac (85)

Morpholine reacts with the 17~-acetoxy-16a,l7a-epoxide (86) to give the 16~-morpholino-l7-ketone (87) in presence of water, or the 17P-morpholino-16-

I l4 115

l6

G. Drefahl, J . prakt. Chem., 1969, 311, 919. K. Ponsold, M. Wunderwald, and W. Schade, Tetrahedron Letters, 1969, 1209. D. N. Kirk and M. A. Wilson, Chem. Comm., 1970,64. K. Ponsold, B. Schoenecker, H. Rosenberger, R. Prousa, and B. Mueller, .I prakt. . Chem., 1969,311, 912. S. Julia, G. Bourgery, and J. J. Frankel, Compr. rend., 1968,267, C , 1861. S . Julia and G. Bourgery, Compt. rend., 1967, 264, C , 333.

286

Terpenoids and Steroids

ketone (88) under anhydrous conditions.' Both products, however, are thought to be formed oia 16,17-ketols, rather than by nucleophilic attack of nitrogen upon the epoxide.

H

H

H

Nucleophilic opening of the 16417a-epoxypregnane derivative (89) with methyl-lithium1l9 gives a dehydrated product, the 16-methyl-pregn-16-ene(90), accompanied by the 15-en-1701-01 (91), possibly resulting from base-promoted elimination involving abstraction of a C-15 proton from the epoxide (92). Me

H

Me

Me

Me

H

5% lOa-Epoxyoestr-9(11)-enes, especially the 3,3-ethylenedioxy-derivative(93), are smoothly opened by methyl magnesium bromide, with epoxide cleavage at the allylic C-10 position, to give the 5a-androst-9(1l)-en-5-ols (94).l2O The corresponding fl-epoxides are also opened at C-10, but give mixtures of products. Methyl-lithium effected proton abstraction (93a), rather than nucleophilic opening of the 5a,lOa-epoxide. The product was the aromatic ether (95). Steroid chemists will be interested in the application of lithium dimethylcopper for epoxide opening,to give trans-2-methylcyclohexanols;lithium diphenylcopper similarly introduces a phenyl substituent.'*' The reagent is said to be superior to either the Grignard reagent or alkyl-lithium for this purpose, and is selective for epoxides even in the presence of 0x0-groups. Spiro-oxirans (e.g. 78) are readily opened by 2-lithio-1,3-dithians to give derivatives (79b) which offer synthetic possibilities.122

"*

12'

C. L. Hewett and D. S. Savage, J . Chem. Soc. (0,1969, 1880. L. V. Sokolova, L. I. Klimova, Z . A. Yaroslavtseva, E. M. Kaminka, and N . N. Suvorov, Khim. prirod. Soedinenii, 1970, 3 3 . L. Nedelec and J . C. Gasc. Bull. SUC.chim. France. 1970, 2556. R. W. Herr, D. M. Wieland, and C. R. Johnson, J . Amer. Chem. SOC.,1970,92, 3813. J. B. Jones, and R . Grayshan, Chem. Comm., 1970, 741.

Steroid Properties and Reactions

287

n

(93)

(94)

Extensive studies on the opening of 2,3-epoxides with thiocyanic acid afforded hydroxy-thiocyanato-derivatives,which with base afforded 2,3-epithio-steroids of configuration opposite to those of the original e p 0 ~ i d e s . IRing ~ ~ closure by attack of S - , with expulsion of OH-, is preferred over the alternative ring-closure which would have regenerated the epoxide. 2a,3a-Epithio-steroids have been prepared from the 2a-bromo-3-ketone (96). Nucleophilic substitution of bromide by xanthate, followed by reduction of the 0x0-group, gave the 3/3-hydroxy-2a-(ethyI xanthate)-derivative (97); hydrolysis then gave the 2q3a-epithio-4-ene (98).124 S

Solvolytic Reactions.-A further study is reported125 of the curious formation of the 3P,Sp-oxetan (100) by solvolysis of the (cis)-3P,SP-diolmonotosylate (99). The (trans)-3qSfl-diol 3-tosylate solvolyses at only 1/19 the rate found for the cis-isomer. Only the latter gives the oxetan, and the higher rate is thought to result largely from relief of steric compression, rather than from anchimeric 12’

lZ4 125

T. Komeno, S. Ishihara, H. Itani, H. Iwakura, and K. Takeda, Chem. and Pharm. Bull. (Japan), 1969,17,2110. T. Komeno and H. Itani, Chem. and Pharm. Bull. (Japan), 1970,18,608. A. T. Rowland, A. F. Kriner, and K. P. Long, J . Org. Chem., 1969,34,2768.

Terpenoids and Steroids

288

assistance. Ring closure only from the cisdiol derivative is still not completely explained.'26 When the 5-acetate 3-tosylates of the 3a,5/3- and 3fl,SQ-diols were solvolysed, the 3a-tosylate reacted more rapidly (3a : 3p = 3 : 1) because of 5P-acetoxy-group participation via a 3/l,58-acetoxonium ion, as revealed by exclusive formation of 3/l,58-diol esters. 25 A fragmentation reaction occurred when the tosylate (101) of 4P,S-epoxy-SPcholestan-38-01 was treated with either collidine or lithium carbonatedimethylformamide, giving the diene-ether (102) among other product^.'^ Side-chain

fragmentation afforded an androst-16-ene (104) when the 16-tosylate (103) of a pregnane-16s208-diol was treated with base.' 28 This reaction is reminiscent of the formation of the 16,17-seco unsaturated aldehyde (106) from a 20P-chloropregnan-16-01(105). 29 Rates of solvolysis of the tosylates of 3a- and 3P-hydroxy-5a-cholestanes, and their 6-dehydro- and 7-dehydro-derivatives, showed a signficant entropy effect.13' Equatorial (38) tosylates solvolysed in acetic acid, or a mixture of

126

I27

128

129 130

H

H

(103)

(104)

H

H (105)

(106)

Ref. 13, p. 275. J . M.Coxon, R. P. Garland, M. P. Hartshorn, and G . A. Lane, Tetrahedron, 1970,26, 1533. M . Matsui and D. K. Fukushima, J . Org. Chem., 1970, 35, 561. G. Adam, Angew. Chem. Internat. Edn., 1967, 6, 631. R. Baker, J. Hudec, and K . L. Rabone, Chem. Comm., 1969, 197.

289 acetic and formic acids, with scarcely varying negative entropies of activation. For axial ( 3 4 epimers these were more positive, and were markedly increased in the mixed solvent. The increase was reflected in increased reaction rate. This effectis ascribed to participation by the p-axial hydrogen (at C-2), in the transition state. The orbital directions are favourable, and the products from solvolysis of the axial derivatives are mainly the 2-enes. Steroid Properties and Reactions

Elimination Reactions.-Configurations are frequently assigned to 1-methylcyclohexanol analogues, in steroids and related compounds, from a study of elimination products. Methyl carbinols with axial hydroxy-groups are generally assumed to give endocyclic olefins, whereas an equatorial hydroxy-group affords exocyclicmethylene derivatives, on reaction with phosphoryl chloride in pyridine. A cautionary note has recently been sounded, however, following gas-chromatographic analysis of products from a number of such renction~.'~'Elimination products may provide reliable information on carbinol configurations only if both epimers are available for study, so that olefinic product ratios from each can be compared. Eliminations are not necessarily specific, and may merely give mixtures relatively rich in. the significant olefin, as found for 12-hydroxy-12methyltigogenin derivatives (1 07). Thionyl chloride cannot replace phosphoryl

chloride in this context, for it may give mainly the endocyclic olefin regardless of carbinol configuration. Thionyl chloride apparently affords the more reactive leaving-group, giving the elimination reaction more El-character than does phosphoryl chloride, so favouring formation of the more-substituted (endocyclic) olefin.13' Base-catalysed elimination in 1-methylcyclohexylhalide analogues is even less reliable as a means for assigning configurations, for the ratio of endocyclic to exocyclic olefin may show greater sensitivity to the base employed, and to the particular halide studied, than to its c~nfiguration.'~' Elimination reactions of the 20-hydroxycholanic acid derivative (108)' probably illustrate the differing character of the transition state, depending upon the reagent. Thionyl chloride in pyridine gave the 17(20)-enes(109; cis + trans, 80 % total), as expected from thermodynamic control when a bimolecular elimination has considerable carbonium ion character (El-like) in the transition state. The 20(22)-enes(110) (cis + trans) were major products when phosphoryl 131

132

IJ3

D. N. Kirk and P. Shaw, J . Chem. SOC.(0,1970, 182. Ref. 13, pp. 102-106. S. Sarel, Y . Shalon, and Y. Yanuka, Chem. Comm., 1970, 80.

290

Terpenoids and Steroids OH

H (108)

chloride was used : kinetic control by the greater accessibility of C-22 protons appears to be a reflection of the lesser reactivity of the phosphodichloridate, requiring an E2-like mechanism (the employment of the free hydroxycholanic acid and of its methyl ester, respectively, in these dehydrations, is probably not significant). Tosylates of the epimeric pregnan-20-01s undergo elimination on heating with hexamethylphosphotriamide,giving cis- and trans-pregn- 17(20)-enes.'34 Phosphoryl chloride reacts with cholesterol in pyridine to give the 3-phosphodichloridate, which has been used as a source of other cholesteryl phosphate derivatives.' 3s Elimination of the ester group occurred only on heating in dioxan, to give cholesta-3,5diene. A remarkable migration of bromine was observed in the dehydrobromination of the 6B,7adibromo-l,4-dien-3-one (1 12), obtained by addition of molecular bromine to the 174,6-trien-3-one(111). Reaction with organic bases gave the

4-bromo-trienone (113). Two possible mechanisms (Scheme 3 ; A and B) were ~ 0 n s i d e r e d . IThe ~ ~ reviewer suggests the transient intervention of the 4p77adibromo-1,5-dien-3-one (114), resulting from internal allylic rearrangement 137 [or allylic substitution (S,2') by Br-] in the 6~,7a-dibromo-compound.The stereochemistry of the latter is unsuitable for anti-periplanar elimination of H + and Br-, but a syn-elimination of 4a-H and 7a-Br in the rearranged structure (114) is stereo-electronically favourable for rapid elimination.' 38 Other elimination reactions reported include the formation of the 1(10),5-diene from a 5,6-dibrom0-19-nor-steroid,'~~ and also from a 6P-methoxyoestr-5(10)-

'" 13'

13b 13'

''*

M . Leboeuf, A. Cave, and R. Goutarel, Bull. SOC.chim. France, 1969, 1524, R. J. W. Cremlyn and N. A. Olsson, J . Chem. SOC.(0,1969,2305. M. Kocor and M. Gumuika, Tetrahedron Letters, 1970, 3227. E. S. Gould, 'Mechanism and Structure in Organic Chemistry', Holt, Rinehart, and Winston, New York, 1959, p. 288. J. Hine, 'Physical Organic Chemistry', McGraw-Hill, New York, 1962, p. 21 I . R . Mickova and K . Syhora, Coll. Czech. Chem. Comm., 1969,34,458.

Steroid Properties and Reactions

29 1

B +

@

0

Jt

T

Scheme 3

ene ;I4' the base-promoted dehydroiodination of 20-iodopregn-20-enes (115), giving pregn-20-ynes (116);141and the selective elimination of the 17a-acetoxygroup when prednisolone 17,21-diacetate (117), for example, is heated with potassium acetate in dimethylf~rmamide.'~~ The latter reaction, which provides a route to pregn-16-en-20-ones(118) in high yield, is peculiar in that no salts other than potassium acetate gave the same useful result.

14' 142

K. Kojirna, R. Hayashi, and K. Tanabe, Chem. and Pharm. Bull. (Japan), 1970,18, 88. A. M. Krubiner, N. Gottfried, and E. P. Oliveto, J. Org. Chem., 1969,34,3502. L . Salce, G. G. Hazen, and E. F. Schoenewaldt, J. Org. Chem., 1970,35, 1681.

Terpenoids and Steroids

292

Esters, Ethers, and Related Derivatives of Alcohols.-Although acetylation with acetic anhydride-pyridine is one of most familiar reactions, the detailed mechanism does not seem to have been elucidated.'43 Spectroscopic detection'44 of the acetylpyridinium ion resulting from the equilibrium : py

+ Ac20

py+Ac + AcO-

indicates that this is probably the reactive species. 3-Acetyl-1,5,5-trimethylhydantoinis a convenient reagent for the selective acetylation of phenolic hydroxy-groups (e.g. oestradiol 3-acetate in 60 % yield).'45 The reagent is stable, easily prepared, and functions in neutral solvents such as acetonitrile. 17-Monoacetates of the corticosteroid dihydroxyacetone side-chain are not ordinarily accessible because of their propensity for acetyl migration to (2-21. Hydrolysis of the 17,21-orthoacetate (1 19) in a phthalate buffer at pH 3, however, gave the 17-acetate (120) in high yield,'42 presumably through kineticallycontrolled protonation at the more-exposed C-21 oxygen atom.

CH20H I

6

--0Ac

The Vilsmeier reagent (Me2&=CHOPOCl,), employed in the conversion of 3,5-dien-3-01 ethers via their 6-fomyl derivatives into 6-methylated steroids, transforms 1 1/?-hydroxy-steroids into their forrnates, or under prolonged reaction into 9 ( 1 1 ) - e n e ~ . 'A ~ ~mild procedure for the formation of nitrite esters comprises exchange with a lower-alkyl nitrite in acetonitrile solution. 47 The rates of alkaline hydrolyses of acetates, propionates, and butyrates of 17-hydroxy-steroids are influenced by functional groups in ring A. 14* The effect appears to be mainly of electronic origin, for the rates increased in the order: 2-ene < 4-ene < 3-one c 4-en-3-one. Conformational transmission may play a minor r6le. Phenolic methyl ethers, including those of the oestrogens, are cleaved to give the free phenols by heating with lithium iodide in ~ o l l i d i n e(with ' ~ ~ benzoic acid

'

''13

Ref. 13, p. 26. A. R. Fersht and W. P. Jencks, 1. Amer. Chem. SOC.,1969,91,2125. 0.0.Orazi and R. A. Corral, J . Amer. Chem. Soc., 1969,91,2162. D. Burn, J. P. Yardley, and V. Petrow, Tetrahedron, 1969,25, 1 155. L. D. Hayward and R. N. Totty, Chem. Comm., 1969, 997. Z. Vesely, J. Pospigek, and J. Trojanek, Coll. Czech. Chem. Comm., 1969,34, 1801.

149

I. T. Harrison, Chem. Comm., 1969, 616.

14' 14'

Steroid Properties and Reactions

293

as a buffer if base-sensitive groups are to be preserved). Some esters are cleaved similarly. The acetonides of various pregnane-l7,20- and -20,21-diols have been prepared, and their properties studied. The 20,21-acetonides are very readily formed and hydrolysed, with toluene-p-sulphonic acid catalysis. Perchloric acid is required to catalyse formation of 17,2O-acetonides;these are also more resistant to hydrolysis, especially in the case of the 20P-epimer, which is subject to more steric hindrance.15' Acetonide formation (121)is also reported in a 12a,l7a-dihydroxypregnan-20-one.l 5 The term 'siliconide' is proposed for the novel 16a,l7a-dimethylsilyldioxy-derivative (122), readily formed by treating the 16a,l7a-diol

with dichlorodimethylsilane in pyridine. 5 2 'Siliconides' would appear to have applications elsewhere, as protecting groups.

Oxidation.-Pfitmer-Moffatt oxidation of alcohols (dicyclohexylcarbodi-imide with dimethyl sulphoxide and phosphoric or another acid'53) can be modified by the use of an a l k ~ n y l - a m i n e 'or ~ ~diphenylketene-p-tolyliminein place of di-imide.15' With the ketene-imine reagent, cholesterol afforded cholest-5-en-3-one in good yield. Oxidation of testosterone with the keteneimine and [2H6]dimethylsulphoxide gave androst-4-ene-3,17-dione and unlabelled amide (123). This finding excludes a proposed concerted mechanism, and supports a two-step mechanism with formation and fragmentation of an oxysulphonium salt (Scheme 4).ls6 The alkynyl-amine appears to react ~imilarly.'~' Dimethyl sulphoxide-acetic anhydride oxidises some steroid 3-01s to ketones, but converts others into acetates, methylthiomethyl ethers, or 3,5-dienes,depending upon configuration and the presence of unsaturation at the 4,5- or 5,6positions.' 5 8 The first step is probably : + + R-OH

ls2

157 158

+ Me,SOAc

---+

R-0-SMe,

+ HOAc.

M. L. Lewbart and J. J. Schneider, J. Org. Chem., 1969,34,3505 and 3513. P. E. Shaw, Steroids, 1970,15, 151. R. W. Kelly, Tetrahedron Letters, 1969, 967. K. E. Pfitzner and J. G. Moffatt, J. Amer. Chem. SOC.,1965,87, 5661. R. E. Harmon, C. V. Zenarosa, and S. K. Gupta, Chem. Comm., 1969, 537. R. E. Harmon, C. V. Zenarosa, and S . K. Gupta, Chem. and. Znd., 1969,1428. R. E. Harmon, C. V. Zenarosa, and S . K. Gupta, Tetrahedron Letters, 1969, 3781. R . E. Harmon, C. V. Zenarosa, and S. K. Gupta, J . Org. Chem., 1970, 35, 1936. Sayed, M. Ifzal and D. A. Wilson, J. Chem. SOC.(0,1969,2168.

Terpenoids and Steroids

294 H+

r

Ph,C=C=NAr

H+ --+

-P

Ph,CH-C-NHAr

II

cfl

0

(123)

SMe? HO

H

H

Me

H

H

Scheme 4

Several different reactions available to the oxy-sulphonium ion explain the variety of possible products. Two novel oxidants offer great promise for oxidation of steroid alcohols. Silver carbonate precipitated on Celite' 5 9 readily oxidises alcohols in refluxing benzene, and shows selectivity in converting diols of diverse structures into hydroxy-ketones. The non-polar reaction conditions are highly suitable for sensitive compounds. 1-Chlorobenzotriazole, readily prepared from benzotriazole, is a convenient oxidant for unhindered alcohols, and should prove useful for steroids. 6 o Chromium trioxide-hexamethylphosphotriamide is a highly selective reagent for oxidising allylic alcohols. Primary allylic alcohols give aldehydes in high yields.16' The high selectivity, and absence of sidereactions, probably result from marked deactivation of the oxidant by powerful complexing with the solvent. Activated manganese dioxide, widely used for the selectiveoxidation of steroidal and other allylic alcohols, 162 is not always of reproducible quality. Standardised

Ih0 Ib'

Ib2

M. Fetizon and M. Golfier, Compr. rend., 1968, 276, C , 900; M. Fetizon, M. Golfier, and J.-M. Louis, Chem. Comm., 1969, 1102. C. W. Rees and R. C. Storr, J . Chem. SOC.(0,1969, 1474. R. Beugelmans, Bull. SOC.chim. France, 1969, 3 3 5 . R . M. Evans, Quart. Reo., 1959, 13, 61.

Steroid Properties and Reactions

295

samples of high reactivity can be obtained by azeotropic removal of adsorbed water with benzene.’63 Reduction.-Lithium aluminium hydride reduction of cis-bromohydrins (e.g. 124) in the 13a-series involves the semipinacolic 17a --+ 16a-hydride shift illustrated (Scheme 5), as revealed by the migration and retention of a deuterium

{

Me OH

D

B

r

{

-%

Me OH

D - - D

H (125)

Scbeme 5

The trans-bromohydrin (125) is reduced directly by nucleophilic displacement of the bromo-substituent, lithium aluminium deuteride giving the l6a-monodeuterio- 17a-alcohol(l26). The near-planar conformation of the five-membered ring is unfavourable to epoxide formation, observed under similar conditions in a six-membered ring. 164a A hydride shift is invoked to explain deuterium distribution among the products when the 3-tosylate (127) of cholest-5-ene-3P,4P-diol is reduced with lithium aluminium de~teride.’~’In this first identification of all three main products from a reaction first described in 1951, 4~-deuteriocholest-5-en-4a-o1 (129) is considered to arise from reduction of the 5-en-4-one (128), formed by a hydride shift (4a-+ 3a ;marked a) as illustrated. Sodium hydride promoted the same rearrangement to give the 5-en-4-one (128). The 3’-deuterio-~-nor-alcohol (13 1)must derive from an A-nor-aldehyde(130), produced by pinacolic migration [b, in (127)]of the 4,5-bond, as the alternative to hydride migration. The origin of the other product, 4,6P-dideuteriocholest-4-ene(1 32), is still uncertain. 163 164

I. M. Goldman, J . Org. Chem., 1969,34, 1979. T. Nambara, H. Hosoda, and T. Shibata, Chem. and Pharm. Bull. (Japan), 1969, 17, 2599.

164

lb5

H. B. Henbest and T. I. Wrigley, J . Chem. SOC.,1957,4596. R. H. Starkey and W. H. Reusch, J . Org. Chem., 1969,34, 3522.

296 a --+

m

Terpenoidsand Steroids LiAID,

0

lb CHO

CHDOH

D

3 Unsaturated Compounds Electrophilic Addition.-Fluoroxytrdluoromethane (CF,OF) acts as a source of electrophilic fluorine, giving novel addition products from suitable olefins The addition of ‘F+’in the initial step is indicated by the trapping, (Scheme 6).

AcO

m-

F

-

OCF,’F

OAc

@}-

\

Scheme 6 lhh

D. H. R . Barton, L. J . Danks, A. K . Ganguly, R. H. Hesse, G. Tarzia, and M . M . Pechet, Chem. Comm., 1969, 221.

Steroid Properties and Reactions

297

or rearrangement in some cases, of intermediate fluorocarbonium ions [e.g (137)- (138), via a C-16-carbonium ion]. cis-Addition to olefins such as (133) and (135) presumably results from use of a non-polar solvent, and from the inability of fluorine to form stable cyclic fluoronium ions. 'Pseudohalogen' addition reactions reported recently include those of iodine azide (IN3), which readily attacks olefinic steroids (e.g. 139) to give iodo-azides (140);"' reduction of the 168-azido-17a-iodo-compound(140) with lithium aluminium hydride provided a convenient route to the 16fl,17fl-imino-derivative (141), whereas diborane gave the iodo-amine (142). Iodine azide is more reactive

than iodine isocyanate (INCO), which adds to steroid 2-enes but fails to react at the 16,17-positions. Nitryl iodide (IN02;from AgN02 + 12) adds to cholest-2as if it were NOz'1- (Markovnikoff) but the ene or 3-methylene-5a-cholestane reaction appears more likely to involve free radicals.' 67 Dehydroiodination of the iodo-nitro-compounds affords nitro-olefins, reducible by zinc to give ketones, or by borohydride to give saturated nitro-steroids.

(143)

1

F-

F

16'

A. Hassner, J. E. Kropp, and G . J. Kent, J . Org. Chem., 1969,34, 2628.

1

298

Terpenoids and Steroids

Hydrogen fluoride adds on to cholest-4-en-7a-01 (143) at -60 "C to give the Sa-fluoro-compound (144)almost quantitatively, but reaction with the 4-en-7P-01 (145)is less specific. The Sa-fluoro-compound (146 ;60 %) is accompanied by the rearranged lOP-fluoro-Sfi-methyl derivative (147 ; 30 %). 168 A preference for : (a) Sa-approach, and (b) approach cis to the hydroxy-group, explains the specificity of fluoride ion attack in the former reaction, but the two factors operate in opposition in the 7P-alcohol. Slower attack by F- at C-5 permits the competing migration of the lob-methyl group (cf:p. 361 ), and then attachment of F- at the lOP-position, assisted by hydrogen bonding with the 7p-hydroxy-group. Two distinct reactions are described between 9( 11)-enes (148) and nitrosyl fluoride. Reaction at 3 "C in dichloromethane gave the 9a-fluoro-1l-nitriminoderivative (149), hydrolysed on passage through alumina to give the fluoro-ketone (150).lbyReductions of the nitriminoderivative with suitable reagents afforded the 11P-nitramine, the 1 1-imine, and the 11p-amine. Nitrosyl fluoride in ethyl acetate at 50 "C, however, effected allylic oxidation, giving the 9(1l)-en-12-one (151) by an unknown mechanism. 1 7 * The elevated temperature used here suggests

( 150)

(149)

(148)

(151)

the likelihood of free-radical intermediates (cf. p. 3 14). Fluoro-nitrimines are the more usual products from nitrosyl fluoride and olefins.l 7 An initially-formed fluoro-nitroso-derivative probably tautomerises to the fluoro-oxime and is then nitrosated further to the nitroso-nitrone, which rearranges to the nitrimine : H

H

I 1 I I C=C --+F-C-C-NO I 1 I I

I

+ F-C-C=NOH

I

I

-+

Nitrosyl chloride, being a powerful oxidant, affords chloro-nitro-compounds by oxidation at the initial chloro-nitroso stage. trans-Addition of nitrosyl chloride seems to be usual, but an exceptional cis-addition occurred with methyl 3~~,7a-diacetoxy-5~-chol1 I-enoate, giving the 1 1a-chloro- 12a-nitro-compound. The rate of reaction was increased in the presence of nitrogen dioxide; a freeradical mechanism is thought likely.172 Ih6

'

h9

J. C. Jacquesy, R . Jacquesy, and M. Petit, Tetrahedron Letters, 1970, 2595. J. P. Gratt and D. Rosenthal, Steroids, 1969, 14, 729. D. Rosenthaland J. P. Gratz, J . Org. Chem., 1969,34,409. G . A. Boswell, J . Org. Chem., 1966,31,991; 1968,33, 3699. Y. Komeichi, Y. Osawa, W. L. Duax, and A. Cooper, Steroids, 1970, 15, 619.

Steroid Properties and Reactions

299

Bromine addition to ergost-7-en-3-one (152)gave mainly a 7,l I-dibromo-8-ene (153), with a little of the 7,8-dibromo-14-ene (154). Sodium iodide converted the 7,ll-dibromide into the 7,9(11)-diene(155), giving a slightly better over-all yield than dehydrogenation of the 7-ene with mercuric acetate, although neither route was really satisfactory.' 7 3

81

3{ H

Br

The 9(1l)dehydro-8~-methyloestraneanalogue (156) adds hypobromous acid in the abnormal cis sense, to give the ll~-bromo-9~-alcohol (157),174in contrast to most 9(11)-enes which give 9a-bromo-1 l~-alcohols.An 1lp-substituent in the 9a-series would be acutely compressed by the 8s- and 13p-methyl

groups ; benzylic stabilisation of the initial 11-bromo-Pcarbonium ion removes any need for truns-attack by water, as would be required in a 9,ll-bromonium ion, so that cis-addition can afford the least-strained bromohydrin. It is not quite clear why the 9a,l la-bromohydrin was not also formed. R. C. Cambie and P. W. Le Quesne, Austral. J. Chem., 1969, 22, 2501. D. J. France and M. Los, Chem. Comm., 1969, 1513.

300

Terpenoids and Steroids

Woodward cis-hydroxylationof 2-methyl- (158)and 3-methyl-5a-cholest-2-ene (159) (1,-AgOAcaq. HOAc) gives mixtures of products which indicate both Mand P-attack upon the olefinic bond. The major cisdiols (Scheme 7) are accompanied by lesser amounts of ketones and allylic alcohols.'75 The same olefins

Mea}Mea} + 7 other products

+

---*

H

HO

Me

fi

HO**

H

Me

H

Ho**a + 6 other products

HO-? Me

H

Reactions of olejins with I ,-AgOAc-HOAc, aq. Scheme 7

reacted with iodine and silver benzoate in anhydrous benzene (Prevost reaction) to give, after hydrolysis, only complex mixtures of allylic alcohols and a small amount of ketonic product. Allylic iodides are considered to be intermediates, Reaction of hypobromous or hypochlorous acids with cholest-4-en-3P-01 (162) via acetate or benzoate (160) gives the 5a-halogeno-3P,4P-diol4-monoester, the acyloxonium ion (161). The 3-monoesters (163) are available by opening of the 4P,S#I-epoxide (164). The facility of acyl migration between the two oxygen substituents is revealed by the formation of the 4/?,19-ether (165) when either monoester (162) or (163) was treated with lead tetra-acetate (cc p. 386).'76 The reaction between 3/?-acetoxy-5a-lanosta-7,9(11)-diene and peroxy-acid has been re-examined. The 7q8a-, 7/?,8#?-,and 941la-epoxy-derivativeshave now been identified as the main products. 77 Lumisterol (9P,lOa5,7-diene) affords the SP,6P-epoxide.' 7 8 Sfl-Lumist-2-ene (9P,lOa ; 166) has been converted into

'"

"'

L. Mangoni and V . Dovinola, Tetrahedron Letters, 1969. 5 2 3 5 ; Gazzetta, 1969, 99, 176, 195; 1970. 100, 467: V. Dovinola. M . Adinolfi, and L. Mangoni, ibid., p. 483. S. Julia and R. Lome, Compt. rend., 1969,268, C, 1617. C. W. Shoppee and J . C. Coll, J . Chem. SOC.(C),1969,2157. K. D . Bingham, G. D . Meakins, and J. Wicha, J . Chem. SOC.(0,1969, 510.

Steroid Properties and Reactions

( 160)

30 1

R

(161)

R = Me or Ph X = C1 or Br

(162) R' = H ; R2 = Ac or Bz (163) R' = Ac or Bz; R2 = H

the four epimeric 2,3-diols, by the routes outlined (Scheme 8). Preferential attack by either proxy-acid, osmium tetroxide, or iodonium ion, on the more exposed fl-face of the olefinic bond decides the stereochemistry of three of the diols (167-169). The fourth diol, the diequatorial (2/3,3a) isomer (170), was obtained by base-catalysed equilibration from the 2a,3a-diol(167).179

OQ} H -

i, I,-AgOAc-HOAc, aq., then LiAlH,; ii, EtONa-EtOH at 175°C; iii, OsO,; iv, AcO,H, then KOH.

Scheme 8 W. R. T. Cottrell, G . D. Meakins, and M. J. Pamplin, J . Chem. SOC.(C), 1969, 673.

Terpenoids and Steroids

302

Epoxidation of oestra-5( 10),9(11)-dienes shows a preference for 5a,lOa-attack, the site of least steric hindrance.180 a-Face attack is enhanced by a 3a-hydroxysubstituent, but hydrogen bonding of the reagent with a 3fi-hydroxy-group results in the formation of equal amounts of 5cc,locl- and 5/3,1O/?-epoxides. Epoxidation of the epimeric 3-ureidocholest-4-enes affords the cis-4,5-epo~y-3-ureides,'~ probably as a result of hydrogen bonding between the C-3 substituent and peroxyacid, as is observed for allylic alcohols. 1 8 2 The N-acetylureides were epoxidised less selectively, hydrogen bonding presumably being rendered unfavourable by N-acetylation. A mixture of either lead tetra-acetatel 83 or phenyliodo~oacetate'~~ with trimethylsilyl azide apparently acts as a source of electrophilic azide at - 15 "C, although free-radical reactions predominate when lead tetra-acetate is used at higher temperatures (see p. 314). The ionic reaction seems best represented as in Scheme 9, probably giving the unstable N-diazonium-aziridines (171) and (172). The isolated products from trisubstituted olefins (e.g. cholesteryl acetate) are +'7 +

r-

N=N=N

-D

N-NEN

N3x,31 0

H

Scheme 9

seco-keto-nitriles (173);the steps summarised in Scheme 9 have been suggested to explain ring rupture. An alternative reaction path via the N-diazonium-2,3aziridine converted the disubstituted olefinic 5a-cholest-2-ene into the 2P-azido3-ketone (1 74).

'*' 18L

L. Nedelec, Bull. SOC.chinr. France, 1970, 2548. D. K. Fukushima, M. Smulowitz, J . S. Liang, and G. Lukacs, J . Org. Chem., 1969,34,

'*'

2702. Ref. 13, pp. 75-77.

la3

K. Kischa and E. Zbiral, Terrohedron, 1970, 26, 1417; E. Zbiral, G. Nestler, and K. Kischa, ibid., p. 1427. E. Zbiral and G . Nestler, Tetrahedron, 1970, 26, 2945.

Steroid Properties and Reactions 303 + The electrophilic Vilsmeier reagent (Me,N=CHOPOCI,), which readily formylates enolic ethers,'*' has now been found to react under more vigorous conditions with suitable dienes, or even with a 17-methylene-androstane (175) (Scheme lo), to give formyl derivatives (e.g.176).186 The over-all reaction is one of substitution, via electrophilic addition followed by deprotonation, which is favoured by conjugation in the final product (Scheme 10). A most significant H

\ C=C / / W

c+ + HC=NMe,

H --+

l

0-POCI,

\ I

/

+

C=C-CH=NMe,

H,O

I

\

/

C=C-CHO

I

a'-Me@

Me

Scheme 10

feature is the formation of products (e.g. 179) in which the olefinic bonds have migrated, presumably to afford a more reactive diene, or one with a more accessible terminal site. The behaviour of the 3-methyl-3,Sdiene (177) under different conditions indicates that the initial formation of a dimethylformiminium ion (178) from the diene is a reversible process, controlled under sufficiently drastic conditions by the relative thermodynamic stabilities of the isomeric formiminium derivatives. D. Burn, G . Cooley, M. T. Davies, J. W. Ducker, B. Ellis, P. Feather, A. K . Hiscock, D. N. Kirk, A. P. Leftwick, V. Petrow, and D. M . Williamson, Tetrahedron, 1964, 20, 597. 18'

M. J. Grimwade and M. G. Lester, Tetrahedron, 1969, 25, 4535.

Terpenoids and Steroids

304

Other Addition Reactions.-Hydroboronation of cholest-5-ene, with thermal isomerisation of the borane derivative prior to oxidation, afforded a mixture of cholestanols, reflecting the varying steric hindrance to substitution at positions in rings A and B (no products corresponding to migration of boron past C-8 were found).18' As expected, the equatorial 38-and 2a-positions are the most favoured, with lesser proportions of substitution at 4 a , 6 a , 3a, 78,7a, etc. Hydroboronation at 0 O C , with immediate oxidation of products, gave 5a-cholestan-6a-01 (a%), the 5fl,6fl-o1(30%), and some 7fl-01. The Diels-Alder reaction between cholesta-2,4-diene (181) and benzyne gives normal adducts (182) in modest yield, but a 5,7-diene (183) gave abnormal products, the 7a-phenyl-5,8(9)- and -5,8( 14)-dienes (184), apparently because

steric overcrowding inhibits a concerted cycloaddition at the 5,8-positions.* The more reactive tetrafluorobenzyne gave some of the normal 5a,8a-addition product, along with a major proportion of the 7a-tetrafluorophenyl-5,8-diene. Similar differences in reactivity are found with diethyl azodicarboxylate and the 2,4- and 5,7-dienes. * Lumisterol(9/?,lOa-5,7-diene)reacts slowly with maleic anhydride at 175 "C to give the 548a-adduct, with configurations assigned largely from spectroscopic data. 90 The pregna- 14,16-dien-20-one system undergoes normal Diels-Alder addition of hexafluorobut-2-yne or acetylenedicarboxylic ester across the

'

'

*For recent comments on the mechanism of benzyne reactions with olefins, see G. Ahlgren and B. Akermark, Tetrahedron Letters, 1970, 3047.

'"

I BY

I9O

J . E. Herz and L. A. Marquez, J . Chem. SOC.(0,1969, 2243. I. F. Eckhard, H. Heaney, and B. A. Marples, J . Chem. SOC.(0,1969, 2098. M . Tomoeda, R. Kikuchi, M. Urata. and T. Futamura. Chem. and Pharm. BUN. (Japun), 1970, 18, 542. K. D. Bingham, G. D. Meakins, and J. Wicha, J . Chem. SOC.(0,1969,671.

Steroid Properties and Reactions

305

.'L

Ph Ph (185)

14p,17P-positions, but methyl propiolate gave a complex bridged-ring bisadduct."' The recovery of 5,7-dienes from their maleic anhydride adducts by pyrolysis is not very efficient. The adduct (185) with 4-phenyl-l,2,4-triazolin3,5-dione (186), however, is cleaved almost quantitatively by reduction with lithium aluminium hydride, affording a convenient means for protection of the 5,7-diene system during reactions elsewhere192(cf. Part 11, Ch. 2, p. 496). Pyrolysis of the 9a,l la-epoxy-5a,8a-adduct of maleic anhydride (187)proceeds with involvement of the epoxide and expulsion of 10Smethyl to give the 1 l-oxo-19-nor compound (188), with an aromatic ring'^^ (cJ Part 11, Ch. 2, p. 453).

(187)

( 1 88)

Addition of phosphorus trichloride to cholest-4-en-3-one, in the presence of benzoic acid, afforded the 3a,5a-bridged phostonyl chloride (1 92),* which could be hydrolysed to give the 3-oxo-5a-phosphonic acid (193).194 Great stability to base allowed Wolff-Kishner reduction of compound (193)to give the 3-deoxy-5aphosphonic acid, although pyrolysis of the dimethyl ester of (193) regenerated cholest-4-en-3-one. The special catalytic effect of benzoic acid in the addition reaction has not been explained; acetic acid leads to the 3-chloro-3,Sdiene. The reaction is thought to be initiated by nucleophilic attack of the carbonyl oxygen at phosphorus. * Occasional gaps in formulae numbering are due to deletions by the Senior Reporter to prevent overlap with Part 11, Chapter 2.-Ed. '" A. J. Solo, B. Singh, and J. N . Kapoor, Tetrahedron, 1969,25,4579. D. H. R. Barton, T. Shioiri, and D. A. Widdowson, Chem. Comm., 1970, 939. l g 3 J . P. Connolly, S. F. 0. Muircheartaigh, and J. B. Thomson, J . Chem. SOC. ( C ) , 1970, 508. ' 9 4 J. A. Ross and M . D. Martz, J . Org. Chem., 1969, 34, 399.

Terpenoids and Steroids

306

0-P=O

I

CI (192)

(193)

Mercuric acetate-sodium chloride reacts with a 1,4,6-trien-3-one(194) to give the 2-mercurichloride derivative (197),which could be reduced (KBH,) to give the 4,6-diene-3-one. It is uncertain whether the reaction is initiated by conjugate

c'Hgm 0

addition of acetate ion at C-1 [-+ (195)- (196)], as the authors or whether this is a normal electrophilic mercuration reaction (198). The 1,2-olefinic bond in 1,4,6-trien-3-onesiscertainly susceptible to attack by osmium t e t r ~ x i d e , ' ~ ~ which makes a modest electron demand,'97 although b r ~ m i n a t i o n 'and ~~ in 1,4,6epoxidation with peroxy-a~ids'~~" occur preferentially at c(6)<(7) trienones. Rates of nucleophilic addition to pregn-16-en-20-ones (199), to give, for example, 16a-methoxypregnan-20-ones(200), are markedly influenced by C-12 s u b s t i t ~ t i o n . 'The ~ ~ ~effects are attributed to varying degrees of stabilisation of the resonance hybrid (201), depending upon the electrostatic influence, hydrogen-bonding capabilities, and steric effects of C-12 substituents (R). 12/?-Hydroxy-groups cause maximum acceleration, by hydrogen bonding with the C-20 oxygen, whereas a 12,12-ethylenedioxy-groupdestabilises the conformation (201). Rate acceleration by a 12-0x0-group is attributed to hydrogen M. Kocor and M . Gumuika, Tetrahedron Letters, 1969, 3067. J . A. Zderic, H . Carpio, and C. Djerassi, J . Org. Chem., 1959, 24,909. Iy' H. B. Henbest, W. R. Jackson, and B. C. G . Robb, J . Chem. SOC.( B ) , 1966, 803. ' 9 8 n A .L. Nussbaum, G. Brabazon, T. L. Popper, and E. P. Oliveto, J . Amer. Chem. SOC., 1958,80, 2722. IsMbG. S . Abernethy. jun., and M . E. Wall, J . Org. Chem., 1969, 34, 1606. 196

Steroid Properties and Reactions

307

bonding of the lZherniacetal(202), formed in alkaline methanol, with the 20-0x0group. N.m.r. data for a range of compounds (199) show a correlation between charge density at (2-16, as revealed by the chemical shift of the C-16 proton, and the rate of nucleophilic addition. The 2,4-dien-l-one system (203) is unusually prone to nucleophilic addition, gwing the 3a,5a-epoxyketone (204) in aqueous alkaline solution, or the bicyclo[3,3,llnonane-dione analogue (205) with acetoneand an acidic catalyst. 98c 0

0

0

Difluorocarbene, generated by heating sodium chlorodifluoroacetate (e.g. in diglyme), adds selectively at the 6a,7a-position in 4,6-dien-3-ones to give the products (206) in the 19-nor-series, both 6a,7a- and 6/?,7/?-isomerswere ;1999200

0

R

198 199

200

Me

' J. R. Hanson and T. D. Organ, J . Chem. SOC.(0,1970, 1065. T. L. Popper, F. E. Carlon, H. M. Marigliano, and M. D. Yudis, Chem. Comm., 1968, 277. C. Beard, B. Berkoz, N. H. Dyson, I. T. Harrison, P. Hodge, L. H. Kirkham, G. S. Lewis, D. Giannini, B. Lewis, J. A. Edwards, and J. H. Fried, Tetrahedron, 1969, 25, 1219.

Terpenoids and Steroids

308

formed.200 The 6-methyl-dienone additionally gave products (207) resulting from non-stereospecific attack of difluorocarbene upon the 2,4-dienolic tautomer.'99 Difluorocarbene addition with neighbouring-group participation afforded the curious product (209) from a 17fl-acetoxy-l7a-ethynylandrostane (208), as well as the expected but highly strained difluorocyclopropene (210).201 A reasonable Me

c F2

I

AcO,

It

,CH

{i5

.

H

J :CF, C F, OAc

H (209)

Scheme 11

mechanism for the rearrangement is illustrated (Scheme 11). Simmons-Smith addition of methylene onto olefinic bonds (CH212 + Zn-Cu ~ o ~ p l e ~ ~ ~ requires very stringent control of reaction conditions. A variant using zinc and copper(1) halide is claimed to give excellent results, and to reduce experimental difficulties to those of a Grignard reaction.204 Reduction of Unsaturated Steroids.-A re-investigation205of the hydrogenation of steroidal 4-en-3-ones has led to a major advance in understanding the factors controlling product stereochemistry, a long-debated problem.206 With a palladium catalyst, the 5/3 : 5a ratio of products is a function of the degree of occupation of the catalyst surface by hydrogen and by the steroid. Pre-equilibration of the catalyst with cholest-4-en-3-one afforded a 5 f l : 5a ratio of 16 : 1, whereas the 'O'

'03 '04 '05

'Oh

E. Velarde and P. Crabbe, Chem. Comm., 1970, 725. H. E. Simmons and R.D. Smith, J . Amer. Chem. Soc., 1959,81,4256; see Ref. 13, p. 89 for subsequent references. K. Syhora, J. A. Edwards, and A. D. Cross, Coll. Czech. Chem. Comm., 1969,342459. R. J. Rawson and I. T. Harrison, J . Org. Chem., 1970,35, 2057. I. Jardine, R. W. Howsam, and F. J. McQuillin, J . Chem. Soc. (0, 1969,260. Ref. 13, pp. 83, 440.

Steroid Properties and Reactions

309

initial stages in the reduction on a catalyst saturated with hydrogen gave a higher proportion of 5a-isomer. In the latter case, hydrogen transfer appears to be rate-controlling, as it is with cyclohexene and other simple olefins, but kinetic control by steroid adsorption is considered to lead to more of the 5/I-isomer. Accordingly, a high ratio (steroid) :(catalyst) favours the 5a-isomer, whereas a low ratio, i.e. a large proportion of catalyst, increases the amount of Sj-product formed. The influence of added acids and bases206can be rationalised with the assumption that chemisorption depends upon the electron-acceptor properties of the palladium catalyst. Adsorbed protons make the catalyst even more electrophilic, assisting steroid adsorption, and accentuating product-control by the rate of hydrogen transfer. Added bases, among which must be included donor solvents (e.g. methanol) and bromide ions,207will tend to occupy the catalyst surface and retard steroid adsorption. The observed slowing of the reaction by bases, and increased yields of 5/?-isomer,support the view that enone adsorption is rate-controlling in this situation. An analogy is offered between the stereochemical controlling factors in hydrogenation and in two other reactions of the 4-en-3-one system, namely epoxidation, favouring the 4/?,5/I-epoxide,and hydrogen cyanide addition, which tends towards a 1 : 1 ratio of 5a- and SB-cyanoketones. A detailed investigation of stereochemical control in hydrogenation of the analogous octalone will also be of interest to steroid chemists.208 Discussion here is concerned mainly with competition between 1,2- and 1,4-addition of hydrogen, and with enolisation by added acids and bases. A detailed mechanistic interpretation is offered. Hydrogenation of 3,3-ethylenedioxy-5-enes(Pd-C) gives 5a-dihydro-derivatives in virtually quantitative yield,209 providing a convenient alternative to reduction with lithium-ammonia2 lo for the stereospecific conversion of 4-en-3ones into 5a-3-ketones. Heterogeneous catalysis (Pd) in tritiation of 1,4-dien-3-onesleads mainly to lp-tritiation (ca.76 %).21 Tritium distribution studies indicate that the reaction is probably a 1,4-addition of tritium onto the more exposed /I-face of the dienone, which is tilted ‘downwards’ with respect to ring B (211). Homogeneous catalysis with tris(tripheny1phosphine)rhodium chloride, however, is known to favour la-tritiation.212 Similarly, homogeneous hydrogenation of the less reactive 4-en-3-ones leads mainly to the 5a-dihydro-3-ketone,’l 3 again the reverse of the stereochemistry of heterogeneous reduction (see above). The stereochemistry of hydrogenation of the 19-nor-steroidal 4,9-dien-3-one system (212) depends upon substitution at C-17. l7a-Substituents lead to major 207

208

*09

210

*I2 213

S. Nishimura and M. Shimahara, Chem. and Ind., 1966, 1796. R. L. Augustine, D. C. Migliorini, R. E. Foscante, C. S. Sodano, and M. J. Sisbarro, J . Org. Chem., 1969, 34, 1075. J. PospiSek, Z . Vesely, and J. Trojanek, Coll. Czech. Chem. Comm., 1969, 34, 3632 (cf. A. J. Liston and M. Howarth, Canad. J . Chem., 1967, 45, 2577). Ref. 13,p. 197. H. J. Brodie, K. Raab, G. Possanza, N . Seto, and M. Gut, J . Org. Chem., 1969, 34, 2697. C. Djerassi and J. Gutzwiller, J. Amer. Chem. SOC.,1966, 88, 4537. W. Voelter and C. Djerassi, Chem. Ber., 1968, 101, 58.

310

Terpenoids and Steroids

formation of the 9j?,lOj?-dihydro-~ompound (213),’14 but all other cases favour the 9cc,lOa-isomer (214), which affords the normal 9a,lOj?-compound (215) in acidic or basic The 9j?,lOj?-isomeralso undergoes isomerisation with acids or bases, to relieve the strain inherent in the cis-configuration. The primary rearrangement product (216) can be isolated, but affords the 9fl,lOa-isomer(217) (‘retro’ series) on continued reaction. The further reduction of either of the 9,104s 4-en-3-ones with lithium-ammonia gave the 5,lO-transsaturated ketone in each case, according to generally accepted principles.2l o

Olefinic bonds between two carbonyl functions (conjugated ene-diones) are activated towards reduction by metals, generally zinc-acetic acid. A reagent which is equally effective is chromium(r1) c h l ~ r i d e . ” ~Used in refluxing tetrahydrofuran, this offers the advantage of affording the thermodynamicallyunstable 5/?-3,6-diones(219) in good yield from 4-ene-3,6-diones (218) (A1or 1,2-saturated series). ‘1$-Reduction of a 3,5-diene-2,7-dione (220) afforded the unusual nonconjugated 4-ene-2,7-dione (221).

215

E. Farkas, J. M. Owen, and D. J. O’Toole, J . Org. Chem., 1969,34, 3022. M. Debono, E. Farkas, R. M. Molloy, and J. M. Owen, J . Org. Chem., 1969,34, 1447; M . Debono and R. M. Molloy, ibid., p. 1451. J. R. Hanson and E. Premuzic, J . Chem. Soc. (0,1969, 1201.

Steroid Properties and Reactions

311

Catalytic hydrogenation of the 1-methyl-11-0x0-oestrogen derivative (222) (223), which, because of gave the fully-reduced 1~-methyl-5a,1Oa-19-nor-steroid its 11-0x0-group, could be isomerised by base with inversion at C-9, to afford the novel 1b-methyl ‘retro’ structure (224).217

Oxidation and Dehydrogenation.-Ruthenium tetroxide, conveniently generated in aqueous acetone from the dioxide and sodium metaperiodate, is a powerful oxidant, converting enones directly into keto-acids (e.g. 225 +226) in high yield.2 Phenolic rings are completely degraded,oestrone giving the dicarboxylic acid (227), although oestrone 3-acetate suffers more selective oxidation, affording the 9a-hydroxy-6-0x0-derivative(228).219Oestradiol 17-acetate 3-methyl ether 0

H02C

0

0

Me0

is oxidised by chromium trioxide in somewhat similar manner, giving the 9Bhydroxy-11-oxo-derivative (229), with lesser amounts of the 6-0x0-compound and other products.220 The C-9 position is particularly activated to attack, by electromeric participation of electrons from the C-3 oxygen function. When this is lacking, as in 2-methyl- and 4-methyl-oestra-1,3,5(1O)-trienes(230; R’ or 217 218

z19 220

A. D. Cross, E. Denot, and P. Crab&, J. Chem. SOC.(C), 1969, 329. D. M. Piatak, H. B. Bhat, and E. Caspi, J. Org. Chem., 1969, 34, 112. D. M. Piatak, G. Herbst, J. Wicha, and E. Caspi, J . Org. Chern., 1969,34, 116. R. C. Cambie, V. F. Carlisle, C. J. Le Quesne, and T. D. R. Manning, J . Chem. SOC.(C), 1969, 1234; R. C. Cambie, V. F. Carlisle, and T. D. R. Manning, ibid., p . 1240.

312

Terpenoids and Steroids

R2 = Me), attack at the exposed C-6 is relatively more favoured;220the methyl substituents are favourably placed to contribute by 'hyperconjugation' to activating the C-6 hydrogens. Oxidation of 3-methoxyoestra-l,3,5( 10),9(11)tetraenes gave the same major products (e.g. 229) as the 3-methoxy-1,3,5(10)trienes, but the 3-acetate gave the epimeric 9a-hydroxy-l l-oxo-derivative. Both reactions probably proceed through the 9 s l la-epoxide, but subsequent steps are determined by the C-3 substituent.221 Stabilisation of a C-9 benzylic cation by the 3-methoxy-group apparently allows abnormal C-9 cleavage of the epoxide, followed by introduction of a 9fl-hydroxy-group. The 3-acetoxy-group, being incapable of such effective electron donation, enforces normal diaxial opening of the epoxide to give the 941 1/3-diol, before further oxidation at C-1 1. The epoxidation of enones by alkaline hydrogen peroxide is well known. Prolonged reaction causes C-C bond fission, probably by a Baeyer-Villiger mechanism.222 Applied to the 1a,2a-epoxy-4,6-dien-3-onesystem (231), this

+

"

(234)

(233)

reaction leads to the 2-oxa-steroids (232) and (233).223 The primary step is probably Baeyer-Villiger migration of the 2,3-bond, leading to the epoxy-lactone (234), before extrusion of a carbon atom from the ring. New mechanistic proposals have appeared, from work outside the steroid field, concerning two methods well known for converting olefinic steroids into allylic alcohols. Allylic oxidation with selenium dioxide is now thought to be initiated (Scheme 12) by electrophilic attack upon the olefinic bond, in the Markovnikoff sense (235), by an oxygen atom in the protonated dioxide (or an equivalent hydrated species). Transient cis-closure of a four-membered ring by C-Se bonding (236), followed by rate-determining ring-opening with concerted loss of the trans-proton, then affords the allylic selenium(r1)ester (237);this is transformed into the final product through a cis-allylic (SN2') solvolysis (238), or in some cases by SN1solvolysis (239).224 The stereochemistry of at least one known steroid

'" R. C. Cambie and V. F. Carlisle, J . Chem. SOC.(0,1970, 1706. 222

223 224

Ref. 13, p. 347. M . Kocbr, A. Kurek, and J. Dabrowski, Tetrahedron, 1969,25, 4257. E. N. Trachtenberg, C. H . Nelson, and J. R. Carver, J . Org. Chem., 1970,35, 1653.

Steroid Properties and Reactions OH

I L

(235)

313

OH

OH

I

OH I

J

Scheme 12

oxidation [7-ene (240)-+ 14a-hydroxy-7-ene (243)],225however, suggests that C-Se bonding is not an essential feature. Assuming a preference for 7a-approach of the reagent, a C-8 carbonium ion (241) seems the likely precursor of an 8(14)olefinic bond (242), formed by loss of the cis 14a-proton; SN2'solvolysis would then lead to the observed product. compound (244) with selenium Oxidation of the 3,4-seco-4-methyl-4-methylene dioxide gave the unsaturated aldehyde (245).226 It is not known whether the aldehyde is derived from the 4-methyl group, or from the 4-methylene carbon

225

226

W. VanBever, F. Kohen, V. V. Ranade, and R. E. Counsell, Chem. Comm., 1970,758; L. F. Fieser and M. Fieser, 'Steroids', Reinhold, New York, 1959, p. 237. R. Kazlauskas, J. T. Pinhey, J. J. H. Simes, and T. G. Watson, Chem. Comm., 1969,945.

314

Terpenoids and Steroids

atom through a mechanism like that discussed above. Further oxidation of the unsaturated aldehyde with selenium dioxide and hydrogen peroxide provided a selective route to the unsaturated acid. Singlet excited oxygen ( 'Ag) has been considered to convert alkenes into allylic hydroperoxides (246) by a concerted mechanism (247).227 It now seems likely that reaction occurs oia a per-epoxide (248), which subsequently rearranges as

illustrated.2*' The oxidation of steroidal 3-enes gives 3-hydroperoxy-4-enes,with C-3 configuration corresponding to the C-5 configuration in the original 3-ene;227 this can now be seen as matching the normal stereochemistry of epoxidation of these olefins (oxygen cis to 5-H). The oxidation of allylic methylene to carbonyl can be achieved in good yields by use of the anhydrous chromium trioxide-pyridine complex in dichloromethane (e.g. cholesteryl acetate ---+ 7-oxocholesteryl acetate). The structural factors influencing reactivity have been discussed in the context of a wide variety of unsaturated compounds.229 An even higher yield of 7-oxocholesteryl acetate is claimed from the action of N-bromosuccinimide in aqueous dioxan containing calcium carbonate, under visible light.230 (In the experience of the reviewer, this reaction is reproducible only on a small scale, possibly due to the opacity of calcium carbonate. Substitution of a suitable soluble buffer might be advantageous for large-scale preparations.) The reactions with either oxidant probably involve initial abstraction of a hydrogen atom from C-7, affording a stabilised ally1 radical, which is further oxidised at its more-exposed end. Potassium chromate similarly introduces a carbonyl group at C-15 in 8( 14)-unsaturated steroids.231 The unique conversion of a 9( 1 1)-ene into the 9(11)-en-lZone by nitrosyl fluoride at 50 "C (see p. 298) seems likely also to be a free-radical process, although the detailed mechanism is at present unknown. ''O The trimethylsilyl aide-lead tetra-acetate system (p. 302) appears to act as a free-radical source at room temperature or above, converting Series, for example, into 7cc-azidoderivatives. Androst-l5-en-l7-ones, of either configuration at C-14 (249),or androst-14-en17-ones (250), are rapidly converted in air into the 14P-hydroperoxy-derivative

*'

"' A. Nickon, N. Schwartz, J. B. DiGiorgio, and D. A. Widdowson, J . Org. Chem., 1965,30, 171 1 ; A. Nickon and W. L. Mendelson, J . Amer. Chem. SOC.,1963,85, 1894;

1965, 87, 3921.

228 22y

230

23

'

W. Fenical, D. R. Kearns, and P. Radlick, J . Amer. Chrm. Soc., 1969, 91, 7771. W. G . Dauben, M. Lorber, and D. S. Fullerton, J . Org. Chem., 1969,34, 3587.

B. W. Finucane and J. B. Thomson, Chem. Comm., 1969, 1220. C. Y. Cuilleron, M. Fetizon, and M. Golfier, Bull. SOC.chim. France, 1970, 1193.

315

Steroid Properties and Reactions

(251). Hydrogen abstraction is thought to give a mesomeric C-14 radical, which is further oxidised to give the more stable cis-fusion of rings c and D.232’233 The hydroperoxide is readily reduced by iodide ions to give the 14P-hydroxy-enone.

(250)

Dehydrogenation of some aromatic steroids with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) affords styrene analogues. Neoergosterol (252) gives the 14-ene (253) rapidly at room temperature, and is more slowly transformed into the 14,16-diene (254).234 The first step provides a further illustration of the

(253) 14-ene (254) 14,16-diene

reactivity of tertiary hydrogen at C-14 (see above). In the present instance hydride abstraction by the quinone is facilitated by benzylic character, with the C,,,)-H bond perpendicular to the plane of the aromatic ring, and so ideally situated to derive steroelectronic assistance from the aromatic mystem. Oestrone or its methyl ether is similarly converted into the 9(1l)-dehydro-derivative, with electromeric activation of 9a-H by the C-3 oxygen function (cf p. 311).235 Cyc1opropanes.-The 5p, 19-cyclo-3-oxo-9~-compound (255) reacted with sulphuric acid by cyclopropyl cleavage mainly at the 10,19-bond, affording the SP-methyl-9-en-3-one (256). This reaction may be under control either by subtle conformational features, or by the electronic effect of the 0x0-group, opposing development of positive charge at C-5. The desired cleavage at C-5 was achieved with aid from the 0x0-group under basic conditions ; the A3-enolate anion (257) reacted as illustrated, giving the 4-en-3-one (258).203 The acid-catalysed cleavage of cyclopropanes has been extended by use of mercuric acetate as an alternative electrophilic reagent. 3q5a-Cyclocholestane 232

233 234

235

A. C. Campbell, J. McLean, and W. Lawrie, Tetrahedron Letters, 1969, 483. C. W. Shoppee and B. C. Newman, J. Chem. SOC.(0,1969, 2767. W. Brown, A. B. Turner, and A. S. Wood, Chem. Comm., 1969, 876. W. Brown, J. W. A. Findlay, and A. B. Turner, Chem. Comm., 1968, 10.

Terpenoids and Steroids

3 16

(259), which rearranges with acid to give the 3-methyl-~-nor-3-ene(260),236 reacts with mercuric acetate, probably via the mercuriacetate (261), to give the 3-acetoxymethyl olefin (262).237

"HgOAC

CH 2 Hg OAC

CH,OAc

Miscellaneous-Alkylations with lithium dialkylc~pper~ 38 are becoming increasingly important. A n example of alkylation with allylic substitution is the formation of a 21-alkylpregn-17(20)-ene (264) when a 17/3-acetoxy-l7or-~inylandrostane (263) is treated with such a reagent.239 The 17a,20-dihydroxynorchol22-ene (265) undergoes a thermal rearrangement at 230 "C, with fragmentation leading to the 17-0x0-androstane (266).240 23h

'" 23q 240

H. Schmid and K. Kagi, Helo. Chim. Acta, 1950,33, 1582; D. Curotti and A. Romeo, Gazzetra, 1965, 95, 992. E. C . Blossey, Steroids, 1969, 14, 725. E. J. Corey and G. H. Posner, J . Amer. Chem. Soc., 1967, 89, 3911; 1968, 90,5615; H . 0.House, W. L. Respess, and G . M. Whitesides, J . Org. Chem., 1966, 31, 3 128. P. Rona, L. Tokes, J. Tremble, and P. Crabbk, Chem. Comm., 1969,43. J. M. Conia and J . P. Barnier, Tetrahedron Letters. 1969, 2679.

Steroid Properties and Reactions

317 CH,R

I

CH

H

H (263)

(264)

Y-

OH

HO

+ A H (265)

Cholest-4-en-3~-01(but not the 3or-isomer) is converted by hydrogen and the dichloro-bis(triphenylphosphine)platinum(rr~stannouschloride complex into a mixture of 5a-cholest-3-ene and ~holesta-2,4-diene.~~' Chlorosulphonation of a 3-methoxyoestra-l,3,5(10)-trieneoccurs at C-2, the least hindered of the activated ortho-p~sitions.~~~ 4 Carbonyl Compounds

Reduction of Ketones.-Gas-chromatographic analysis has permitted accurate determination of ratios of epimeric alcohols obtained from a range of steroid ketones by use of various common reducing agents. Some of the results (see Table 2 for a representative selection of data) differ appreciably from those in Table 2" Ratios of alcohols produced by reduction of some 0x0-steroih, expressed as the ratio [axial alcohoflIequatoria1 alcohol] (values in parentheses refer to earlier data for similar reactionsb). Ketone position (5a-series) C-1 C-2 c-3 c-4 C-12 (I

L41 242

Reducing systema

LiAlH,

AIH,

(0.19) (1.4) 0.064 (0.13) (12) 0.45

0.1 5.7--9.0 0.39 99 1.27

NaBH,

Meta I-a lcohol

-

(5.5 ; or ca. 3) 0.03 ( < 0.1) (ca. 0.1) 0.11 0.18-1.0 (CU. 0.1)

1.4-7.3' (4.5) 0.154.23"(ca. 0.1)

5.7-99" 0 . 4 7 4 . 6 7 ' (0.43)

Ref. 244; References cited in Ref. 243; Variable, depending upon added NaOH. Y. Ichinohe, N. Kameda, and M. Kujirai, Bull. Chem. SOC.Japan, 1969,42, 3614. A. H. Goldkamp, J . Medicin. Chem., 1970, 13, 561.

Terpenoids and Steroids

318

the earlier literature,243 which generally depended on isolation of products. Aluminium h ~ d r i d generally e ~ ~ ~ gives somewhat higher proportions of axial alcohols than does lithium aluminium hydride. Addition of an amine further increases the yield of axial alcohol. These reactions have been interpreted in terms of Felkin’s reactant-like concept of transition states, which is gaining in Product ratios obtained with sodium borohydride in methanol are altered in favour of the equatorial alcohol by added alkali.zu Reduction of a 13a-androstan-17-one with complex hydrides is less stereospecific than reduction of the normal (138) 17-ketone. A slight preponderance of either the 17a- or 17fi-alcoholcan be obtained by suitable choice of reagent.246 The Henbest reagent (a phosphito-iridium complex of uncertain structure247) is highly efficient for reducing either 5a- or Sfl-3-oxosteroids to give the corresponding axial alcohols. 0x0-functions at the C-2,6,7,11,12,17, and 20 positions are completely unreactive, although reduction of pregnane-3,20-diones is complicated by equilibration at C-17 (1701G 178).248 An extensive study of the reduction of pregnan-20-ones with alkali-metalalcohol systems has revealed marked dependence of product ratios on the particular metal and alcohol used.249 Optimum yields (ca. 73%) of the 2Oa-01 result Me

Me

I

I

I

H

H

( favoured M Li

favoured when M = Na or K

when

=

Me

H

)

Me

H

2OB-01

20a-01

Scheme 13 z43 244

”’

246

24’

248 249

For references, see ref. 13, p. 133. D. C. Ayres, D. N. Kirk, and R. Sawdaye, J. Chem. SOC.( B ) , 1970, 505. E. L. Eliel and Y. Senda, Tetrahedron, 1970, 26, 241 1. T. Nambara, T. Kudo, H. Hosoda, K. Motojima, and S. Goya, Chem. and Pharm. Bull. (Japan), 1969, 17, 1366. H. B. Henbest and T. R. B. Mitchell, J. Chem. Soc. ( C ) , 1970, 785. P. A. Browne and D. N. Kirk, J. Chem. SOC.( C ) , 1969, 1653. D. N. Kirk and A. Mudd, J. Chem. Soc. ( C ) , 1969,968.

Steroid Properties and Reactions

319

from use of sodium or potassium (but not lithium) in C3 or C4 alcohols. A mechanism depending upon the effectiveness of C-metal bonding, and its influence on subsequent protonolysis, has been proposed to explain the results (Scheme 13). This hypothesis gains support from the varying proportions of epimeric alcohols obtained by reducing some cyclic ketones with the same reagent systems. Similar in principle, though different in detail, is the suggestion250that the stereochemistry of metal-alcohol reductions of cyclohexanones depends upon the relative rates of protonation of the epimeric carbanions (Figure 5 ) and of their interconversion.

Figure 5

Reductions of ap-unsaturated 0x0-compounds with sodium borohydride may be complicated by saturation of the ethylenic bond, and by base-catalysed conjugate addition of alkoxide to give a 1,3-diol monoether. The factors controlling these reactions have been studied for a variety of aliphatic compounds, and the findings may prove useful in steroid ~hemistry.~” 9( 11)-Dehydro-12-ketones in the bile-acid series afford considerable proportions of the unsaturated l 2 a - 0 l s , ~contrary ~~ to the general stereo-electronic preference for formation of pseudo-equatorial allylic alcohols, as seen, for example, in the 9( 11)-dehydrohecogeninseries.253Steric hindrance by the mobile cholanic acid side-chain probably opposes l2a-attack by borohydride, as it does in the saturated SP-cholan-12-0ne.~~~ Two novel complex hydrides are likely to find applications in steroid chemistry : lithium perhydro-9b-boraphen !yl hydride affords unusually high proportions of axial alcohols in model compounds ;255sodium bis(methoxyethoxy)aluminium dihydride, Na+ (MeOCH2CH20),A1H2,a very safe and convenient substitute for lithium aluminium hydride, readily reduces not only ketones but also acids, nitro-compounds, oximes, amides, lactones, e t ~ : ~An’ ~improved procedure for Clemmensen reduction of steroid ketones2” involves saturating an ethereal solution with hydrogen chloride while stirring with zinc. 5a-Cholestane was obtained from the %one in 89 % yield.258

2s1

2s2 253 254

2s5 256

2s7 258

D. A. H. Taylor, Chem. Comm., 1969, 476. M. R. Johnson and B. Rickborn, J . Org. Chem., 1970, 35, 1041. T. Dahl, Y.-H. Kim, D . Levy, and R. Stevenson, J . Chem. SOC.(0,1969, 2723. J. M. Coxon, M. P. Hartshorn, and D. N. Kirk, Tetrahedron, 1969, 25, 2603. J. W. Huffman, D. M. Alabran, T. W. Bethea, and A. C. Ruggles, J. Org. Chem., 1964, 29,2963. H. C . Brown and W. C. Dickason, J . Amer. Chem. SOC.,1970,92, 709. M. Kraus and K. Kochloefl, Coll. Czech. Chem. Comm., 1969,34, 1823, and references therein. Ref. 13, p. 134. M. Toda, Y. Hirata, and S. Yamamura, Chem. Comm., 1969, 919.

Terpenoidsand Steroids

320

Other Reactions at the Carbonyl Carbon Atom.-The rates of oxygen- 18 exchange in steroid ketones have been studied by gas chromatography-mass spectrometry, the steroid ketone and H2180being injected together.25g Exchange was most rapid for a 3-oxo-steroid, but was slowed dramatically by ap-unsaturation (4-ene, x ; 1,4-diene, x The rate for a 16-0x0-compound was eight times greater than at C-17. These differences reflect the differing rates for the addition : OH C = O + H 2 I 8 0 5 \C/ / / \

\

2

\

7

180H

/

C=l80

and should parallel rates for other reactions involving a change from sp2 to sp3 hybridisation at carbon.260 Grignard (MeMgX) and methyl-lithium reactions with steroid ketones generally This is the case with afford more of the 'equatorial-methyl' tertiary n

'

hecogenin (at C-12),262but 'pseudo-hecogenin' diacetate (267) is reported to give the 12~-hydroxy-l2or-methylderivative (268)' on the basis of its subsequent reactions. 1 9 8 a The reason for this abnormality is not clear. Me

254

''*

2b1

Zh2

A . M . Lawson, F. A. J. M. Leemans, and J. A. McCloskey, Steroids, 969, 14, 603. Ref. 13, pp. 130, 131. Ref. 13, p. 147. J . M . Coxon, M. P. Hartshorn, and D. N. Kirk, Tetrahedron Letters, 965, 4469.

Steroid Properties and Reactions

32 1

Methylmagnesium halide reacts stereospecificallywith a 19-aldehyde (269) to give the (R)19-methyl-19-01(270), whereas lithium aluminium hydride reduced the 19-methyl-19-0x0-compound (271) to give the 19(S)-alcohol(272).263 Both reactions indicate a preferred conformation for the 19-carbonyl compound, with the carbonyl oxygen atom close to C-5. Pregnan-20-ones and their homologues (273) react with Grignard reagents under ‘approach control’. The reaction has a close analogy with borohydride reduction, the nucleophilic reagent attacking the ‘rear’ face of the 20-0x0-group in its preferred conformation (273).264 The effect is to produce ‘20a-hydroxycholesterol’ [274 ; 20(S)-configuration]when 4methylpentylmagnesium bromide

H

H

(275) 20p

= 2qR)

reacts with ‘pregnenolone’, or the ‘20~’-hydroxy-compound[275; 20(R)], when methylmagnesium bromide reacts with the pregnenolone h o m o l o g ~ e .The ~~~ 20P-configuration was confirmed by a separate synthesis, wherein the olefin (276) was subjected to a-face hydroboronation and oxidation. 263

264 265

J. Wicha and E. Caspi, J . Chem. SOC.(0,1969, 947. N. L. Allinger, P. Crabbe, and G . Perez, Tetrahedron, 1966, 22, 1615. N. K. Chaudhuri, J. G. Williams, R. Nickolson, and M. Gut, J . Org. Chern., 1969,34, 3759.

Terpenoids and Steroids

322

Grignard reactions with 21-hydroxypregnan-20-ones conform to the same stereochemical features, but a 17a-hydroxypregnan-20-one(277) reacts in the reverse sense, giving the 17~20~[20(R)]-dihydroxycholestanederivative (278). [Osmium tetroxide hydroxylation of the 17(20)-ene (276) gave the same The Grignard reaction again follows the pattern of reduction by hydride donors, which afford mainly the 17a,20a-diol, the side-chain being constrained in the abnormal conformation (277) by association of both oxygen functions with the reagent.266 Ethynylation of 172-hydroxypregnenolone at C-20, by reaction with lithium acetylide, is controlled in the same stereochemical sense.267 The Reformatsky reaction of 2-bromobutyrolactone with 3-oxo-steroids is normal, giving the hydroxy- (279)and unsaturated lactones (280). 17-Oxo-steroids reacted only slightly.268

(279)

(280)

Methylene addition to 3-oxo-steroids, by use of dimethylsulphonium- or dimethyloxysulphonium-methylides,gives a preponderance of the 3a-CH, (281) and 3B-CH2 (282) oxirans respectively. The 2,2-dimethyl-3-ketone behaves similarly, but the 2cr-methyl-3-ketone gives mainly the 3p-isomer with either

reagent, because of increased a-face hindrance.269 [The same oxirans were obtained by epoxidation of 3-methylene-5a-cholestane: rn-chloroperbenzoic acid favoured production of the 3/l-CH2 oxiran (282) by a-face attack, though less so in the 2a-methyl derivative ;peroxybenzimidic acid mainly attacked the P - f a ~ e . ~ ~ ~ ] The reagent obtained from lithium and dibromomethane, assumed to be the carbenoid LiCH,Br, afforded the same oxirans in high yield.270 The magnesium derivative from dibromomethane behaved differently, affording the 3-methylene~ t e r o i d , ~usually ” prepared by the Wittig reaction. The stabilised phosphonium

”’ S. Rakhit and C. R. Engel, Canad. J . Chem., 1962,40, 2163. N . K. Chaudhuri and M . Gut, J . Org. Chem., 1969,34, 3754. ”‘ H. Torabi, R. L. Evans, and H. E. Stavely, J . Org. Chern., 1969, 34, 3796. J. D. Ballantine and P. J. Sykes, J . Chern. SOC.(0,1970, 731. ’’* F. Bertini, P. Grasselli, G. Zubiani, and G. Cainelli, Chem. Comm., 1969, 1047. 16’

* ’ I

F. Bertini, P. Grasselli, G. Zubiani, and G. Cainelli, Tetrahedron, 1970, 26, 1281.

Steroid Properties and Reactions

323

ylides Ph3P=CHC02R and Ph,P=CHCN fail to react with cyclohexanones, including steroid ketones, but a normal Wittig reaction occurs with 3-oxosteroids in the presence of a little benzoic The mechanism of catalysis is unknown, but does not appear to involve the protonated ylide. Cyanohydrin formation from 5a-3-oxo-steroids gives ca. 90% of the 3phydro~y-3a-cyano-isorner,~~~~~~~ which is the more stable due to the greater equatorial preference of OH compared with CN.20 The two derived aminoalcohols behave differently during Tiffeneau-Demjanov ring expansion (see p. 353). Reductive intramolecular condensation of the ethynyl-ketone (283), now readily prepared,275afforded the A-nor methylene derivative (284) and the olefin (285), offering a new entry into the A-nor series.276

The 17a-carbamate (286) has been cyclised with the 20-oxo-group to give the oxazolidone derivative (287),which was dehydrated to the methylene-oxazolidone (288).2 7 7

A Fischer type of synthesis, using sym-dimethylhydrazine, converted two molecules of a 5a-3-oxo-steroid into the pyrrole derivative (290).278Condensation in the 5fl-series involves the 3,4-bond. The carbazoles (291) were prepared by a similar method.279 272

2’3 274

275

276

27’ 278 27q

A. K. Bose, M. S. Manhas, and R. M. Ramer, J . Chem. SOC.(C), 1969,2728. J. Jones and P. Price, Chem. Comm., 1969, 24, 1478. J. D. Ballantine, J. P. Ritchie, and P. J. Sykes, J . Chem. SOC.( C ) , 1970, 736. M. Tanabe, D. F. Crowe, R. L. Dehn, and G. Detre, Tetrahedron Letters, 1967, 3739. S. K. Pradhan and V. M. Girijarallabhan, Steroids, 1969, 13, 1 1 . A. P. Leftwick, Tetrahedron, 1970, 26, 321. W. Sucrow and G. Chondromatidis, Chem. Ber., 1970, 103, 1759. W. Sucrow and E. Wiese, Chem. Ber., 1970,103, 1767.

324

Terpenoidsand Steroids

The amino-ketone (292) dimerised when liberated from its salt, giving a dihydropyrazine : air-oxidation gave the pyrazine (293), which exhibited characteristic U.V.and c.d. features (n+ n* and n -P n*).280Some novel fused heterocycles have been obtained by suitable condensations of 3-0x0- and 7-0x0steroids with nitrogenous compounds :281 cyanoguanidine, for example, affords diamino-pyrimidines (294), and 2,4,5,6-tetra-aminopyrimidinereacts with a 2-bromo-3-0x0-steroid to give a diamino-pteridine. The smooth rearrangement of a ,model 6hydroxy-thioacetal (295) into the dithian (296)282provides a simple analogy whish throws further light upon the formation of 3,5dienodithians (297) in the steroid series.

Oxidation.-Two copper-catalysed reactions have been described for the degradation of the 22-aldehyde (298)to give a pregnan-20-one (299). Oxygenation of a solution of the aldehyde with the copper(r1) acetate-2,2'-bipyridyl complex and diazabicyclo-octane in dimethylformamide gave the 20-ketone in 90 % yield.283 A free-radical mechanism is proposed (Scheme 14). 280

"'

H. E. Smith and A. A. Hicks, Chern. Cornrn., 1970, 1 1 12. A. M. Bellini, R. Rocchi, G. Fornasini, and C. A. Benassi, Farmaco, Ed. Sci.,1970, 25, 226.

282

K. H. Baggaley, S. G. Brooks, J. Green, and B. T. Redman, Chern. Cornm., 1969,

283

V. Van Rheenen, Tetrahedron Letters, 1969, 985.

1458.

Steroid Properties and Reactions Me

325

H +CHO CU"

I

H'transfer

Scheme 14

Alternatively, the morpholino-enamine (300) is oxidised quantitatively to the 20-ketone by copper(1) chloride and oxygen.284 The same reagent system converted the 3,5-dienamine (301) into 4-ene-3,6-dione (302).

m '

0

0

An unexplained degradation of the 22-aldehyde (298) to a pregnan-20-one occurs when the aldehyde is treated with an amine hydrochloride in dimethylf ~ r m a m i d e . ~Oxygen ~' is not essential.

H

H (303)

284

(304)

V. Van Rheenen, G e m . Comrn., 1969, 314. F. Kohen and R. E. Counsell, Chem. and Znd., 1970, 1144.

326

Terpenoids and Steroids

17a-Hydroxypregnenolone acetate (303) is oxidised quantitatively by lead tetra-acetate, probably via a 17a-alkoxyl radical, to give dehydroepiandrosterone (304).286 Instead of effecting a normal Baeyer-Villiger oxidation, peroxytrifluoroacetic acid oxidised a 5-en-7-one (305) to give a mixture of products including the 6,7seco-diacid (306).'*'

The buf-20(22)-enolide (307) was dehydrogenated by 2,3-dichloro-5,6dicyanobenzoquinone (DDQ) or chloranil with hydrogen chloride to give the 17(20),22-dienolides(308) and (309), or with DDQ and toluene-p-sulphonic acid

to give the isomeric 20,22-dienolide (310).133 The specific r6le of the acid in these reactions is not clear. 7/3-Deuterioandrost-4ene-3,17-dione (311)afforded the 4,6-dienone (313),with retention of deuterium, on treatment with chloranil, revealing stereospecific loss

of the pseudo-axial 7a-H from the dienolic intermediate (312), as expected on stereo-electronic grounds.288 28h

288

L. Tan, Biochem. Biuphys. Res. Comm., 1970, 39, 65. A. M . Nicaise and R. Bourdon, Bull. SOC.chim. France, 1970, 1552. J . C. Orr and J. M . Broughton, J . Org. Chem., 1970, 35, 1126.

327 Oestrogen biosynthesis from androst-4-ene-3,17-dioneinvolvespreferential loss of 18- and 2p-hydrogen atoms, demonstrated by use of deuterium-labelled samples.289 Steroid Properties and Reactions

(314) into the 4-eneEno1isation.-The isomerisation of androst-S-ene-3,17-dione 3,17-dione(316)proceeds through the enol(315), and is subject to rate-controlling removal of 4-H, whether catalysed by acid, base, or enzyme.290 Isotopic labelling of 4j-H has indicated differing stereoselectivitiesin hydrogen removal according

to the isomerising system used. The enzymic reaction, using the isomerase of Pseudomonas testosteroni, is very fast, mainly due to an extremely low enthalpy of activation (ca. S kcal molStudies of the catalytic effects of phenols and phenol-base mixtures are strengthening the view that the active ~ ~ ~a*phenol, ~ ~ ~ probably a tyrosine site on the isomerase is b i f u n c t i ~ n a l , with residue, providing an acidic centre, and a nearby imidazole group of a histidine unit acting as the base (Scheme 15). Simple mixtures which attempt to imitate

Simplified representation of enzymic isomerisation of a 5-en-3-one into a 4-en-3-one

Scheme 15

or triethylamine and p-nitrothe enzymic system, e.g. imidazole and phen01,~” do exhibit considerable catalytic effects on the isomerisation. The free enolic form (317) of a 4,6-dien-3-one (320) has been isolated by careful acidification of the enolate salt.292 With further acidic treatment the enol tautomerises to the 5,7-dien-3-one (318) before returning to the 4,6-dien-3-one. By 289 290 291

292

H. J. Brodie, K. J. Kripalani, and G. Possanza, J . Amer. Chem. SOC.,1969, 91, 1241. J. B. Jones and D. C. Wigfield, Canad. J. Chem., 1969,47,4459. A. Kergomard and M. F. Renard, Tetrahedron Letters, 1970, 2319. G. Kruger, J . Org. Chem., 1968, 33, 1750.

Terpenoids and Steroids

328

pouring a solution of the sodium enolate into 2N hydrochloric acid, the intermediate 4,7-dien-3-one (319) is accessible in good yield.293 It is clear that kinetically-controlled protonation of the enol favours attack first at C-4, then at C-6,

whereas equilibrating conditions give the most stable conjugated dienone by protonation at C-8. A convenient synthesis of 2-en-3-01 ethers (323) involves (322)with zinc in reduction of the 2a-bromo-3,3-dimethoxy-compound

(321)

(322)

The dimethoxy-compound is obtained from the bromo-ketone (321) and trimethyl orthoformate. This reaction sequence may prove useful for regiospecific synthesis of other enol ethers, where the bromo-ketones are available. Enol acetylation of 4-en-3-ones under thermodynamic control (acetic anhydride + acid) is best achieved with hydrobromic Perchloric acid promotes further reactions, including C-acetylation (see p. 336) and aromatisation.z96 A 2-phenyl substituent tends to stabilise the 2,4-dienol although the 3,5-diene is normally preferred by a large margin. The en01 acetylation of 201methyl- and 2a,6fi-dimethyl-4-en-3-oneshas also been studied.296 Heptafluorobutyric anhydride reacts with 4-en-3-ones in the absence of any catalyst, affording 3,Sdienol heptafluorobutyrates, which are useful derivatives for gas chromatography with an electron-capture detector.297 Butyric anhydride under reflux converts a 3-0x0-5a-steroid into its A2-enol butyrate.’09 6-Chloro- or 6-bromo-4-en-3-ones (324) or (325) afford 6-halogen0-3,5-dienol ethers (326)on heating with methanol containing hydrogen chloride,298although

29J

’’’ 29’

298

D. S. Irvine and G. Kruger, J . Org. Chem., 1970, 35, 2418. J. Levisalles, G. Teutsch, and T. Tkatchenko, Buff. SOC.chim. France, 1969, 3194. P. Toft and A . J. Liston, Chem. Cumm., 1970, 1 1 1. A, J . Liston and P. Toft, J . Org. Chem., 1969, 34,2288. L. A. Dehennin and R. Scholler, Sreroids, 1969, 13, 739. R . Mazar and K . Syhora, Coil. Czech. Chem. Comm., 1970, 35, 1547.

Steroid Properties and Reactions

(324) X (325) X

= =

6a-C1 or Br (326) X 6B-Cl or Br

329

=

C1 or Br

(327)

the 6P-derivatives (325) afford 3,3-dimethoxy-5a-6-ketones (327) with methanol alone. Steroid 1,4-dien-3-ones have been considered resistant to enol esterification, but powerful bases [Ph3C-, HC-C-, or (Me,Si),N-] convert the diene-dione (328) into its enolate anion, which affords the 3-benzoate (329) with benzoyl c h l ~ r i d e . *The ~ ~1,3,5-trienolate ~~~~ ion is, however, the product of kinetically

controlled enolisation ; under equilibrating conditions it abstracts a proton from C-9 in the un-enolised ketone to give the more stable 9(11)-enolate. Addition of benzoyl chloride then affords the 9(1l)-enolic benzoate (330). The novel enol sulphonates (331) have been prepared from the 3-0x0-steroids with the appropriate sulphonic anhydride in dimethylf~rmarnide.~~ They are stable to aqueous acids and bases, but attacked at sulphur by methoxide ion, regenerating the ketone. Reduction with lithium aluminium hydride afforded mainly the 3~-alcohol,and no olefin (see p. 400 for rearrangement). Enol phosphates (332) have also been obtained :302 reductive debromination of the 2a-bromo-3-ketone with triethyl phosphite (Perkow reaction) gave the

(332)

2yy

'0° '01

302

(333) R = H (334) R = -0-Li' (335) R = -OP(OEt),

D. H. R. Barton, R. H. Hesse, G . Tarzia, and M. M . Pechet, Chem. Comm., 1969, 1497. M. Tanabe and D. F. Crowe, Chem. Comm., 1969, 1498. N. Frydman, R. Bixon, M. Sprecher, and Y. Mazur, Chem. Comm., 1969, 1044. M. Fetizon, M. Jurion, and N. T. Anh, Chem. Comm., 1969, 112.

330

Terpenoids and Steroids

2-en01 derivatives (332), although other bromo-compounds may be dehydrobrominated by trialkyi p h ~ s p h i t e . ~Lithium-ammonia '~ removed the phosphate ester grouping giving the unsubstituted 2-ene. A related route cia enol phosphates provides some rather inaccessible olefins. The 4-methyl-3-ene (333), for example, is obtained by reducing a 4-en-3-one with lithium-ammonia, esterifying the resulting lithium A3-enolate (334) with diethyl phosphorochloridate [(EtO),PCl], and reducing the enol phosphate (335) with lithium.304 S/?-Methylation of a 4-en-3-one with lithium dimethylcopper, with in situ conversion of the lithium A3-enolate into its phosphate, followed by reduction, similarly afforded the SP-methyl-3-ene (336). Use of lithium enolates prevents isomerisation of enolate anions, which is likely with other metal =1ts.305 Reactions of Enols and Enolate Anions.-Several methods are described for transposition of an oxo-function to the adjacent site. They involve formation of a suitable a-substituted derivative (hydr~xymethylene~'~ or benzylidene307)and subsequent steps which transform the substituent into an isolated oxo-group. Condensations leading to both the 2-hydroxymethylene- and the 2-arylidene-3oxo-steroids are described for 3-ketones of the 5P-~eries,~'*and also of the 5P,9p, lOa-('retro') series.3o9 Condensations of aromatic aldehydes at C-2 in the SP-series are unusually slow : enolisation towards C-4 is preferred, but steric compression between C-4 and C-6 in 5#?-compoundsseverely hinders the condensation reaction at C-4, allowing reaction at C-2 via the 2-en0l.~" Reduction of a 21-hydroxymethylene-pregnan-20-one(337) with sodium borohydride afforded the homopregnanediol (338),3 although reduction of enolised pdicarbonyl compounds frequently proceeds via elimination to give enones, and thence allylic alcohols.

''

CH2- CH,OH I

CH=CHOH

I

H

H

(337)

303 304

305

(338)

F . Hunziker and F. X. Miillner, Helo. Chim. Acta, 1958, 41, 70. R. E. Ireland and G. Pfister, Tetrahedron Letters, 1969, 2145. G. Stork, P. Rosen, N. Goldman, R. V. Coornbs, and J. Tsuji, J . Amer. Chem. SOC., 1965, 87, 275.

'06 30'

S. Hara, K . Oka, and S. Yagishita, J . Pharm. Suc. Japan, 1969, 89, 1601. J. E. Bridgeman, C. E. Butchers, Sir Ewart R. H. Jones, A. Kasal, G. D. Meakins, and P. D. Woodgate, J . Chem. SOC.(0,1970, 244. A. T. de B. Andrews, A. D. B o d , G. D. Meakins, and M. J . Sledge, J . Chem. SUC.(0, 1970, 1052.

'09 'lo 31'

K. D. gingham, W . R. T. Cottrell, and G. D. Meakins, J . Chem. SOC.(0,1969, 674. Ref. 13, pp. 181-2. A. F. Hirsch and G. I. Fujirnoto, J . Org. Chem., 1970,35, 495.

33 1

Steroid Properties and Reactions

The base-catalysed condensation of ethyl oxalate with steroid ketones, widely used in synthesis, has been exploited as an analytical method.312 The glyoxalyl derivative, obtained by careful acidification of the reaction mixture, exhibits U.V. absorption characteristic of the ketone (e.g. testosterone, 252 and 324 nm ; 17-ketone, 294 nm ; 20-ketone, 290 nm). Intramolecular condensation of 6a-esters, thioesters, or amides (339; X = 0, S, or NH; R = Me or Ph), under the enolising influence of sodium hydride, affords the novel 4,6-fused furano- (340), thiopheno- (341), and pyrrolo- (342) derivatives, re~pectively.~ l 3 The reactions comprise a Claisen-like condensation.

base

0 XmC0.R (339)

527

0 R

(340) X = 0 (341) X = S (342) X = N H

R-C-X ‘OH

m

0

Similar internal condensation of the 6-(3’-acetoxy-cis-prop-l’-enyl)-4-en-3-one (343) gave the benzeno-steroid (344).3l 3 A dehydrogenation step of uncertain nature is required here, following displacement of the acetoxy-group by attack of C-4. Another intramolecular cyclisation occurred when the 19(R)-acetoxy-19methyl-3-ketone (345) was treated with base. The 2,19-oxido-derivatives (346) and (347) were obtained.314 l3

314

S. Gorog, Analyr. Chem., 1970, 42, 560. T. Komeno, S. Ishihara, K. Takigawa, H. Itani, and H. Iwakura, Chem. and Pharm. Bull. (Japan), 1969, 17, 2586. J. Wicha and E. Caspi, Tetrahedron, 1969, 25, 3961.

Terpenoids and Steroids

332

H (345)

1 H (346)

(347)

A retro-aldol cleavage of the pregn-l7(20)-en-16-one (348), on prolonged reaction with alkali, affords a new route to androstan-16-ones (349).315 Me

H

(349)

Oxygenation of enolate anions is well-known as a method for the preparation of a-hydroperoxy-ketones, and thence of a-hydroxy-ketones or a-diket~nes.~ l6 Improved yields are obtained in the presence of a trialkyl phosphite, which reduces the a-hydroperoxy-group as it is formed. The 17a-hydroxypregnan-20-onesare available in a single stage from pregnan-20-0nes.~ The oestra-4,9-dien-3-one (350) similarly affords its 11-oxoderivative (351).318 In the latter case, the deconjugated 5( 10),9(11)-dienone(352)can be isolated under oxygen-freeconditions. a-Acetoxylation of ketones with lead tetra-acetate is possible even in the presence of an epoxy-group. The 2a-acetoxy-4,5-epoxy-3-ketone (353), formed in this way from the epoxy-ketone, rearranged on alumina with dehydration to give the 2-hydroxy-l,4-dienone (354).319 The enol trimethylsilyl ether (355) 315 316 317 318

319

M. H. Benn and R. Shaw, Chem. Comm., 1970, 327. Ref. 13, pp. 177-178. J. N. Gardner, F. E. Carlon, and 0. Gnoj, J. Org. Chem., 1968, 33, 3294. A, A. Shishkina, V. M. Rzheznikov, and K. K. Pivnitskii, Khim. prirod. Soedinenii, 1970, 138. M. Lj. MihailoviC, J . ForSek, Lj,Lorenc, Z . MaksimoviC, H. Fuhrer, and J. Kalvoda, Helu. Chim.Acta, 1969,52, 459.

Steroid Properties and Reactions

333

(352)

(350) R = H2 (351) R = : O

rearranged under free-radical conditions with oxidation to give the silyl ether (356) of a 16a-hydro~y-17-ketone.~~~

--OSiMe,

0

H

H

A 2a-carbomethoxy-substituent is introduced into either a 3-0xo-5a-steroid,~~ or a 4-en-3-0ne,~~~ by the action of ‘magnesium methyl carbonate’ (a methanolic solution of magnesium methoxide saturated with C02323). The 5a-saturated compound exists predominantly in the A2-enolic form (357). Carbomethoxygroups have also been introduced at C-4, using 1-en-3-ones and 4-en-3-ones. In the former case, enolisation with tritylsodium was followed by addition of carbon . ~ ~potassium ~ dienolate dioxide and treatment of the acid with d i a ~ o m e t h a n e The of a 4-en-3-one reacted with carbon dioxide to form the 4-carboxylate (358) after

C02Me

320 321

322 323 324

(361) (a) R

=

(b) R

=

:O H2

C0,Me (362)

G. M. Maume and E. C. Horning, Tetrahedron Letters, 1969, 343. A. Pavia and F. Winternitz, Bull. Sac. chim. France, 1969, 3104. S. Julia and C. Huynh, Compt. rend., 1970, 270, C , 1517. H. L. Finkbeiner and M. Stiles, J. Amer. Chem. Soc., 1963,85, 616. A. Afonso, J . Org. Chem., 1970, 35, 1949.

334

Terpenoids and Steroids

methylati01-1.~~~ Alternatively, reduction of the 4-en-3-one with lithiumammonia, and addition of carbon dioxide to the lithium enolate (359) gave the 4a-carbomethoxy-ketone (360) after reaction with diazomethane. Subsequent methylation of the 4a-carbomethoxy-ketone afforded mainly the 4g-methyl isomer (361a), the stereo-electronically-controlled product of pseudo-axial attack upon the e n 0 1 a t e . ~Clemmensen ~~ reduction then gave the 4a-carbomethoxy-4b-methyl derivative (361b), required as a step in the synthesis of (-)sandaracopimaric acid. Strangely, the 4a-carbomethoxy-1-en-3-one(362) was methylated stereospecifically at the 4a-p0sition,”~ although Dreiding models reveal no clear distinction between the environments of C-4 in the A3-enolate and the A’y3-dienolate ions. Reductive 4-methylation (with CD31) of a 4-methyl-4-en-3-one occurs predominantly from the p-face in the 19-nor series, but at the 4a-position in the presence of a log-methyl A comparable preference for P-attack (pseudo-axial) in an unhindered situation is seen in the condensation of but-l-en3-one with the tricyclic 9-en-5-one (363) under basic conditions, when the 1Oasteroid (364) was obtained as major product.29

Methylation of the carbanion (365) derived from a 2-cyano-3-ketone gave only the 2/?-cyano-2a-methyl-3-ketone (366).326The stereochemistry appears to be controlled by P-face hindrance from the 10/3-methyl group, enforcing 2amethylation, with ring A in a twist-boat conformation to permit ‘axial’ attack. A4-Unsaturation, however, by tending to flatten ring A, permits both 2a- and 2P-methylation of the 2-cyano-derivative. A 4-cyano-1-en-3-one gives the 4amethyl derivative. The methylated cyano-ketones are readily transformed into other gemdisubstituted products, with potentialities in synthesis. Alkyl N N dimethylformiminium salts react with the 3,5-dienolate ion (367) to give 4dimethylaminomethylene-5-en-3-ones(368).327Selective attack at C-4 is normal for the dienolate ion,328 although these reagents are closely related to the Vilsmeier salts, which attack the dienol ether at C-6. Acidic hydrolysis of the 4-dimethylaminomethylene-ketone(368) gives the 4-hydroxymethylene-ketone (369),327probably via a conjugate addition of water and elimination of dimethyl325

326

32’ 32a

R. S. Matthews, S . J . Girgenti, and E. A. Folkers, Chem. Comm., 1970, 708. P. Beak and T. L. Chaffin, J . Org. Chem., 1970, 35, 2275. C. Huynh and S. Julia, Tetrahedron Letters, 1969, 5271. Ref. 13, p. 159.

Steroid Properties and Reactions

335

H

m'

0 Me,NCH

+3

Me,N=CHOR

X(367)

1

H+-H20

I

CN

(369)

(370)

HO'cNMe, H+

amine. Electrophilic cyano-groups are provided by phenyl cyanate ; the 33dienolate ion is converted into a 4-cyano-4-en-3-one (370), with expulsion of phenoxide ion.327 The n-allylnickel complex (372), obtained by the action of nickel tetracarbonyl on a 6P-chloro-4-en-3-one (371), can be methylated at C-4, though not very efficiently, by methyl iodide.329 The n-allylpalladium complex was unreactive to alkylation.

0

c1

/I\

Isotopic substitution of hydrogen adjacent to carbonyl occurs when the ketone is passed through a column of alumina loaded with tritiated water (HTO),330 or in gas-chromatography over a stationary phase comprising poly(ethy1ene glycol) saturated with D,0.331 330

I. T. Harrison, E. Kimura, E. Bohme, and J. H. Fried, Tetrahedron Letters, 1969, 1589. M. J. Thompson, 0. W. Berngruber, and P. D. Klein, J. Amer. Oil Chemists' Soc.,

331

G . M. Anthony and C. J. W. Brooks, Chem. Comm., 1970, 200.

32y

1970,41, 92A.

336

Terpenoids and Steroids

Reactions of En01 Ethers and Esters-When enol acetylation of a steroid 4-en-3one with acetic anhydride is catalysed by perchloric acid (or boron t r i f l ~ o r i d e ~ ~ ~ ) , C-acetylation of the enol acetate (373) occurs on prolonged This step, probably involving acetyl perchlorate ior airs, is akin to FriedelCrafts acylation of aromatic compounds. Both 6-acepllation and 2-acetylation are known, although each is prevented by the presence of a methyl group at the site.297 The products can be of various enolic types (e.g. 374 and 375).

Acm'Lxl)? a '@ Ac 0

Ac 0

Ac

(374)

(375)

0

1 OH

(376)

Ac 0

I OH

1

OH

co (378)

m-Chloroperbenzoic acid reacts with 3,5-dienolic acetates (373) in aqueous media to give mainly 6B-hydroxy-4-en-3-ones(376), but in the absence of water the chief products are the rather unstable addition compounds (377).334 The reactions are interpreted in terms of an intermediate mesomeric 6B-hydroxycation (378), which may be hydrolysed by any water present to give the 4-en-3-one, but accepts the carboxylate anion at the 5B-position in the absence of water. cis-Addition of peroxy-acid across the 5/3,6~-positionsmay result from initial formation of an intimate ion-pair on the ,f?-face, or may be rerated to the general 332

333

334

B. C. Elmes, M.P.Hartshorn, and D. N.Kirk,J. Chem. SOC.,1964,2285; M. Gorodetsky, E. Levy, R. D. Youssefyeh, and Y . Mazur, Tetrahedron, 1966,22, 2039. A. J . Liston and P.Toft, J . Org. Chem., 1968, 33, 3109. D. N. Kirk and J . M . Wiles, Chem. Comm., 1970, 518.

337

Steroid Properties and Reactions

preference for 5p- rather than Sa-attack upon a delocalised n-orbital system, embracing carbon atoms 3,4, and 5.335 3,5-Dienolic ethers (379), in contrast with the acetates, are cleaved by peroxyacid at the 3,4-unsaturated link under anhydrous conditions, giving carbomethoxy-aldehydes (380).336 The reaction is probably mechanistically similar to the oxidative cleavage of dihydropyrans (e.g. 381 + 382),337although the

m'

Me0

3

MeOzC

reason for the unusual selective oxidation at the 3,4-bond in the enol ether is not clear. A comparable reaction is reported between the 3,5-dieno-oxathian (383), and either oxygen in sunlight, or ozone.338

H

H 33s

336 337

338

(384)

L

H

I

H

See, for example, H . B. Henbest and W. R. Jackson, J . Chern. SOC.(0,1967, 2459, 2465; M. G . Combe, H. B. Henbest, and W. R. Jackson, ibid., p. 2467; also ref. 205. D. N. Kirk and J. M. Wiles, Chern. Comm., 1970, 1015. R. D. Rapp and I. J. Borowitz, Chem. Comm., 1969, 1202; I. J. Borowitz, G. Gonis, R. Kelsey, R. Rapp, and G. J. Williams, J. Org. Chem., 1966, 31, 3032; I. J. Borowitz and G. Gonis, Tetrahedron Letters, 1964, 1151. A. Miyake and M. Tomoeda, Chem. Cornm., 1970,240.

Terpenoids and Steroids

338

Furost-20(22)-enes(384)react with peroxy-acid with introduction of a hydroxygroup at the 20a-position, and ring closure to give the 20a-hydroxy-spirostan (385). The isolation of up to 25”/;,of the 20,23-diol (386) is attributed to contamination of the furost-20(22)-enewith the 22(23)-unsaturated isomer.33 Almost all 3,5-dienolic esters and ethers react with electrophiles at C-6,340 apart from rare instances of reaction at C-4 or C-2 (see above). Reaction between the dienolic ethers (387) and tetranitromethane in ether has now been shown to afford the 2B-nitro-derivatives (388).341 No mechanistic details are available, but it is tempting to suggest the involvement of free-radicals derived from the reagent. Hydride abstraction by dichlorodicyanobenzoquinone from the A1*3*s-trienol benzoate (389),to give the 1,4,6-trienone(390), is accompanied by a novel electro-

R’ = H or Me (387) R 2 = H 2 (388) R 2 = /3-N02

0

/ ’ (390) OBz CN

philic attack of the quinone at the 6B-position, affording the derivative (391).341a Since all the reported examples include a 9ar-halogeno-substituent,it seems likely that the latter hinders the normal 7a-hydride ab~traction,~” either by its steric or its electrostatic effect. Hydroboronation of enol acetates of cyclohexanones is generally non-specific. The 2-en-3-01 acetate (392) gave a mixture containing the 2s3fl-diol and the

’-”M . Tanabe and R . H . Peters, J . Org. Chem., 1970, 35, 1238. 340 341

341

Ref. 13, p. 184. W. Barbieri, A. Consonni, and R. Sciaky, J . Org. Chem., 1969,34, 3699. a H . Reimann and R. S. Jaret, Canad. J . Chem., 1970,48, 1478.

339

Steroid Properties and Reactions

(392) R (393) R

= AC = Me

3a- and ~ P - o ~after s , oxidation of intermediate ~ r g a n o b o r a n e s .The ~ ~ ~A2-enol ether (393) readily adds dibromo- (or dichlor~-)carbene.~~~

Reactions of Emmines.-Hydroboronation of the 2-enamine (397) gave a product (amine-borane adduct?) from which the 3a- and 3B-pyrrolidinoderivatives (398 ; 301 : 38 = 82 : 18)were liberated by refluxing methanol.343 The stereochemistry of this reduction is quite unusual, and not fully explained. Reaction of the 3,5dienamine (399) with dichlorocarbene led to ring expansion, giving the A-homo-4-chloro-dienone (400).344 Condensations of the enamine

J CCI,

342

343 344

A. Hassner, R. E. Barnett, P. Catsoulacos, and S. H. Wilen, J . Amer. Chem. Soc., 1969,91,2632. J. Gore and J. J. Barieux, Tetrahedron Letters, 1970, 2849. U. K. Pandit and S. A. G. de Graaf, Chem. Comm., 1970, 381.

Terpenoids and Steroids

340

(397) with o-hydroxybenzaldehyde and o-aminobenzaldehyde afforded novel benzopyrano-derivatives (e.g. 401) and the quinolino-derivative (402)respecti~ely.~~' Oximes.-Cleavage of ring A occurs when the oxime (403) of a 4,4-dimethyl-3oxo-steroid is subjected to the conditions of the Beckmann rearrangement; the product is the unsaturated nitrile (404). Stabilisation of positive charge in the transition state at the tertiary C-4 position must be a major contributing factor in this reaction, but a recent demonstration346(cc Part I, Ch. 6, p. 239) that proton loss occurs specifically from the 4a-methyl group, shows that the reaction is a concerted 'Grob fragmentation', and does not proceed through a true carbonium ion. The planar geometry of the transition state (405) is ideal for concerted fragmentation. Studies with allobetulone oxime, however [with the typical ring A structure (403)], have shown that the kinetically controlled reaction with toluene-

(403)

(405)

p-sulphonyl chloride and pyridine (followed by hydrolysis) affords the E-lactam

(406); the nitrile (404)is the thermodynamically-determined product under vigorous condition^.^^' Since the conversion lactam (406)-+ nitrile (404),is very much slower than formation of the nitrile from the oxime, it appears that the lactam-tosylate (405)is formed reversibly from the oxime tosylate, but is not readily regenerated from the free lactam (406). Further transformations of the have unsaturated nitrile (404)derived from 4,4,14a-trimethyl-5a-cholestan-3-one resulted in its conversion into 14a-methylcholest-4-en-3-one, although the reaction sequence failed with the related 8-ene.348 The oxime (407) of 5 ~ androstan-17-one reacts with thionyl chloride at 0 "C to give the normal lactam 3J5

34h 34i 348

M. S. Manhas and J. R. McCoy, J . Chem. SOC.(0,1969, 1419. G. P. Moss and S. A. Nicolaidis, Chem. Comm., 1969, 1077. T. Hase, Acta Chem. Scand., 1970, 24, 364. C. W. Shoppee, N.W. Hughes, R . E. Lack, and J . T. Pinhey, J . Chem. SOC.(0,1970, 1443.

Steroid Properties and Reactions

34 1

(408;50-60 %), and lesser amounts of the unsaturated seco-nitrile (409) and the 13-chloro-seco-nitrile (410).349 From the discussion above, it seems probable that prolonged reaction would lead to higher yields of the D-S~COproducts, at the expense of the lactam.

Normal Beckmann rearrangements of the syn- and anti-oximes at C-3 in the Scc-serieseach involve specificmigration of the trans-C-C bond,35 0 giving isomeric lactams. Beckmann rearrangements induced by polyphosphoric acid (PPA), however, have some unusual feature^.^ 5' Saturated 3-oximes (e.g. 41 1) give small amounts (up to 5 % each) of the 1-en-3-one(413) and 4-en-3-one, in addition

(415)

Scheme 16

to the usual lactams (412). Cyclisation of unsaturated seco-amides, derived from the seco-nitriles, is suggested as a possible source of these products (Scheme 16). The anti-oxime (414)from a 4-en-3-one, previously considered inert to Beckmann rearrangement,3 5 2 reacts with PPA to give the enamine lactam (415).3 The A'-oxime reacts similarly. A Schmidt rearrangement when azoimide (hydrazoic acid) reacts with a steroidal 4-en-3-one (416), under acidic catalysis, is followed by reaction with a 349

350 351

352

C. W. Shoppee and R. W. Killick, J . Chem. SOC.(0,1970, 1513. K. Oka and S. Hara, Chem. and Ind., 1969, 168. M. Kobayashi, Y . Shimizu, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1969, 17, 1255. Ref. 13, p. 343.

Terpenoids and Steroids

342

second molecule of azoimide to give the novel tetrazole derivative (418).353A reasonable reaction sequence is illustrated (Scheme 17): the key step is probably the decomposition of the Ndiazonium-imino-derivative(417), analogous to the heterolysis of oxime-sulphonates and similar Beckmann intermediates.

(414)

A retro-Beckmann reaction of the 3a,5acyclo-lactam (419) with hydrobromic acid regenerated the original oxime (420), and the parent ketone, instead of affording the hydrolysis product, the a r n i n o - a ~ i d . Oxidation ~~~ of the oxime (421) of a pregn-16en-20-one with lead tetra-acetate gave the ‘dimer’ (422),

(419)

H+

I

(420) H

353 354

J. Moural and K. Syhora, Coil. Czech. Chem. Comm., 1970, 35, 2018. M. S. Ahmad, Shafiullah, and M. Mushfiq, Tetrahedron Letters, 1970, 2739.

Steroid Properties and Reactions

343

whereas lead tetra-acetate with iodine afforded the oxazole (423).355Oxidation of oximes and semicarbazones with ceric ammonium nitrate is an efficient general method for recovery of the parent ketones,356and should prove useful in steroid chemistry. Hydrazones-Oxidation of hydrazones with lead tetra-acetate gives nitrogen and a mixture of acetates and olefins, apparently through the intermediacy of diazo- and diazonium compounds (Scheme 18).357The steroid hydrazone at C-7 affords mainly the 7a-aceto~y-derivative,~’~ but at C-3 a mixture of 3a- and 3/3-acetoxy-compoundsresults, together with an olehic f r a ~ t i o n . ~

’*

+ Olefins

Oxidation of hydrazones with Pb(OAc),

Scbeme 18

Pyrazoles (425) and (427) result when the substituted ketones (424) and (426) react with hydrazine and phenylhydrazine, re~pectively.~’~ Wolff-Kishner

Ph (427) 355

3s6 357 358

359

S. Kaufmann, L. Tokes, J. W. Murphy, and P. Crabbk, J . Org. Chem., 1969,34, 1618. J. W. Bird and D. G. M. Diaper, Canad. J . Chem., 1969,47, 145. D. H. R. Barton, J. F. McGhie, and P. L. Batten, J. Chem. SOC. 1970, 1033. M. Debono and R. M.Molloy, J. Org. Chem., 1969,34, 1454. H. Carpio, A. Cervantes, and P. Crabbe, Bull. SOC.chim. France, 1969, 1256.

(a,

Terpenoids and Steroids

344

reduction of the 2-benzylidene-3-ketone (428) gave the aryl-cyclopropane (429) and the pyrazole (430).360 The reaction between 1,l-diphenylhydrazine and a 16,17-epoxypregnan-20-one is dependent upon the stereochemistry of the latter.361 In acetic acid, the 16q17aepoxy-compound (424) undergoes solvolytic opening to give the 20-diphenylhydrazone of the 1 6 ~7adiol 1 17-monoacetate (431), which afforded the diolone

Ph,N NH,

(424)

HOAc

--OH

* H

Hydrolysis

H (431)

(432)

43.

,+N-NPh,

H

YN-NPhz H

(433)

H

(434)

16-monoacetate (432), with acyl migration, on hydrolysis of the hydrazone. The hydrazone (433) derived from the 16/?,17/l-epoxy-ketonegave the 20-monohydrazone (434) of the 16,20dione, apparently by a hydride shift (16a + 17a). Tosylhydrazones-The reaction between suitable tosylhydrazones and alkyllithium was reported in 1967 to afford high yields of olefins, the less-substituted olefin being favoured where two possibilities exist (Hoffman-type products).362 In the reviewer's own experience, and that of other this reaction can be unreliable, giving complex mixtures of products, some containing nitrogen. More recently, it was reported that the reaction succeeds when a limited amount of methyl-lithium in hexane is added dropwise to the steroid tosylhydrazone in tetrahydrofuran, under nitrogen (e.g. 2-ene, 3-ene, 6-ene, and 1,3-diene, from

'"

S. Hayashi and T. Komeno, Chem. and Pharm. Bull. (Japan), 1969, 17,2319. A. A. Akhrem, V. A. Dubrovsky, A. V. Kamernitzky, and A. V. Skorova, Tetrahedron, 1969, 25, 4737. 3 6 2 R . H. Shapiro and M . J. Heath, J . Amer. Chem. SOC.,1967, 89, 5734; G. Kaufman, F. Cook, H. Shechter, J . Bayless, and L. Friedman, ibid., p. 5736. 3 h Z a D. Burn and R. Sawdaye, personal communications.

361

Steroid Properties and React ions

345

tosylhydrazones at C-3, C-4, C-6, and of a l-en-3-one, r e ~ p e c t i v e l y ) .Use ~ ~ ~of an excess of alkyl-lithium leads to the alkylated saturated hydrocarbon (e.g. 38methyl- or 3P-buty1-5a-chole~tane).~~~~~~~ Tosylazo-enes (e.g. 435), derived from the a-halogeno-ketones, undergo alcoholysis to give enol ethers (436),365probably via addition-elimination as illustrated. In the case of 21-substituted pregnan-20-ones (437; X = F or OMS),

TsN=N

a} [ H

(435)

T P - N M eG0 a } H]

- Me H

(436)

+ N, + TsH

CH,X I

H (437)

however, the product of reaction with tosylhydrazine is the 17P-ethynylandrostane (pregn-20-yne; 439).366 This product presumably results from an elimination reaction in an intermediate tosylazo-ene (438),where a strain-free acetylenic bond can form, unlike the cyclic analogue (435). When a tosylazo-ene bears an adjacent hydroxy-group, resulting from opening of an epoxide ring (W),a Grob fragmentation occurs (441), giving a seco acetylenic carbonyl compound (442).367 Several similar ring-cleavage reactions of epoxy-ketones with tosylhydrazine have been described recently.275 363 364 365 366 367

J. E. Herz, E. Gonzalez, and B. Mandel, Austral. J . Chem., 1970, 23, 857. J. E. Herz and E. Gonzalez, Chem. Comm., 1969, 1395. L. Caglioti and G. Rosini, Chem. and Ind., 1969, 1093. P. Wieland, Helv. Chim. Acta, 1970, 53, 171. H. Kaufmann, J. Kalvoda, and G. Anner, Chimia (Switz.), 1970, 24, 23.

346

Terpenoidr and Steroids

Carboxylic Acids and their Derivatives-2,3-Seco-A4-unsaturated dicarboxylic acids (443), obtained by ozonolysis of 2-hydroxymethylene-4-en-3-ones,have been considered rather resistant to cyclisation to form the ~-nor-3-en-2-one system (444).Two convenient methods for achieving such a reaction are now described. Dieckmann condensation of the dimethyl ester (445) was successful with sodium hydride, in toluene containing a little The 5-methoxycarbanion (W), resulting from conjugate addition of methoxide ion, is suggested as a possible activated intermediate. Alternatively, the diacid (in the B-nor-series)

(443) R

=

(445)

= Me

R

H

(446)

(444)

can be cyclised directly with acetic anhydride containing potassium cyanide.369 Activation of the carbonyl groups by formation of acyl cyanides is but a conjugate addition of the highly nucleophilic cyanide ion at C-5 (analogous to 446) would seem to offer another possible explanation of the special effect of cyanide in this reaction. Very smooth conversion of the keto-acid (447) into the enol-lactone (448) was recently reported, using acetic anhydride and perchloric acid in ethyl acetate as

(447)

R (448) R = H (449) R = AC

~olvent.~’’ Further has shown that prolonged reaction, or an excess of perchloric acid, affords the 6-acetyl enol-lactone (449) in high yield (cf p. 336). A pair of lactones (17-oxa-16-ones; 452) results when the 16,17-seco-16,17dioic acid (450) is decarboxylated with lead tetra-a~etate.~~’ The reaction can be rationalised in terms of formation of the C-13 radical (451 ; the more stable of the two possibilities), with non-stereospecific ring-closure. Lead tetra-acetate reacts slowly with the ring D lactone (453)to give the 16~-acetoxy-lactone(454).373 K. Oka and S. Hara, Chem. Comm., 1969, 368.

jbM

’” W. G. Dauben, D. J . Ellis, and W. H. Templeton, J . Org. Chem., 1969, 34, 2297. ’’O

P. N. Rao and L. R. Axelrod, J . Chem. Soc., 1965, 1356.

. Rao, J . E. Burdett, and B. E. Edwards, J . O r g . Chern., 1969,34, 2767. ”’ P.M.NFetiton and N. Moreau, Bull. SOC.chim. France, 1969, 4385. ”’ M. Stefanovic, 2.Djarmati, and M. GaSiC, Tetrahedron Letters, 1970, 2769.

Steroid Properties and Reactions

347

Reduction of the lactone (453) can be controlled to give any one of the three products illustrated.374 Brief reaction (0.5 hr) with one mole of borane-tetrahydrofuran gives the lactol (459, which slowly (4 days) undergoes elimination

(453)R = H (454)R = B-OAC

(455)R = H (458)R = Me

(457)

under these conditions to give the dihydropyran (456). Addition of a further two moles of the reagent to the lactol solution, however, reduces it to give the tetrahydropyran (457). The same product resulted when the lactol methyl ether (458) was treated with sodium borohydride and boron trifluoride. Bromine reacts with the keto-acid (459) to give the 5P,l9-lactone(460), possibly by intramolecular displacement of a Sa-bromo-substituent by the carboxyThe b-lactam (460)readily loses carbon dioxide on pyrolysis or alkaline hydrolysis, giving the 19-nor-5(lO)-end-one (461). Reduction of the 6-oxo-group

HO (462) 374

G. R. Pettit and J. R. Dias, Chem. Comm., 1970, 901

Terpenoids and Steroids

348

in the keto-lactone (460)proceeded normally, giving the 6B-hydroxy-lactone, which rearranged in weakly alkaline solution to give the less strained 5fl-hydroxy68,19-1actone (462). An attempt to decarboxylate the 5,6-unsaturated 19carboxylic acid (463) with copper sulphate and quinoline at 170°C gave the 1(10),5diene (464).375 The maleic anhydride adduct (465) of a 5,7diene is reduced selectively by complex hydrides to give the lactone (466).376

I

‘OH (467) (465) R (466) R

= 10 = H,

1

(469)

The 6-lactam-ester (468), obtained by Beckmann rearrangement of the oxime (467), has been reduced and cyclised to give the fl-lactam (469).377 5 Compounds of Nitrogen and Sulphur

Some methods for introducing nitrogen substituents have already been discussed (pp. 278,284, and 297).

Deaminatioa.-A significant advance in understanding the deamination of alicyclic m i n e s with nitrous acid comes from the finding, through deuterium labelling, that elimination products can arise in large measure by loss of a proton cis to the a r n i n o - g r ~ u p The . ~ ~reaction ~ ~ ~ ~ in ~ acetic acid probably comprises fragmentation of the diazonium acetate, with rapid cis-deprotonation of the carbonium ion by the counter-ion, accompanied by a lesser proportion of trans-elimination in the case of the axial amine. Combining this concept of the 3’5 3-6 377

37y

J.-L. Borgna and M. Mousseron-Canet, Bull. SOC.chim. France, 1970, 2210. M. E. Birckelbaw, P. W. LeQuesne,andC. K . Wocholski, J . Org. Chem., 1970,35,558. S . D. Levine, J . Org. Chem., 1970, 35, 1064. T. Cohen and A. R. Daniewski, J . Amer. Chem. SOC.,1969, 91, 5 3 3 . J. Levisalles and J . F. Mouchard, Bull. SOC.chim. France, 1970, 678.

Steroid Properties and Reactions

349

r61e of the anion with the current view of substitution reactions in d e a m i n a t i ~ n , ~ ~ ’ we can now account for the behaviour of both equatorial (470) and axial (473) amines in terms of alternative reactions available to the stereochemicallydefined ion-pairs (471) and (474), respectively. The ion-pair (471) derived from an unhindered equatorial amine can readily collapse to give the equatorial acetate or alcohol (472 ;R = Ac or H). The alternatives of deprotonation or substitution Ac

H

H

H

P(473)

0-H

(475)

I

H

(474)

with inversion are then relatively unfavourable. The ion-pair (474) resulting from an axial amine, however, can afford the axial substitution product only to the extent that syn-diaxial compression is acceptable in the transition state for ion-pair collapse, whereas removal of an adjacent equatorial (cis)proton from the carbonium ion to give an olefin (475) is not sterically restricted. In both configurations, increased substitution in the amine tends to deflect the anion from combination with the carbonium ion, while not hindering, or perhaps even helping, olefin formation. The 3-amino-derivatives of 4,4-dimethyl-5a-cholestane (476) gave the mixture of deamination products depicted (Scheme 19), in proportions depending upon the original C-3 configuration and the reaction conditions (protic or a p r o t i ~ ) . ~ ~ ~ The various products are thought to be formed through three distinct intermediates: a covalent hydroxy-azo-compound, a diazonium ion as part of an ion-pair, or a discrete carbonium ion. Deamination of a 20a-aminopregnane gives the 20a-01 and its acetate as major products, presumably through collapse of a stereochemically defined ion-pair, but the 20P-amine afforded the ~-homo-17ap-ol(and its acetate) in high yield.381 Such rearrangements are common in the heterolysis of other 20P-derivatives (p. 279), due to the highly favourable conformational situation. 380

T. Cohen and E. Jankowski, J. Amer. Chem. SOC.,1964,86,4217;also ref. 13, pp. 3 1 6 321. L. Djakoure, A. Cave, and R. Goutarel, Compt. rend., 1970, 270, C, 744.

350

Terpenoids and Steroids

(3a

Scheme 19

Scheme 20

+ 3p-Me)

35 1

Steroid Properties and Reactions

Acid-catalysed reactions of diazo-ketones apparently have close analogies to deamination reactions. 2-Diazo-5a-cholestan-3-one (477) reacts with a variety of acids to give the products shown (Scheme20), the relative yields depending upon the acid The 4,4-dimethyl analogues behave similarly. Assuming the first step to be protonation of the diazo-ketone, three possibilities are apparent which may lead to further reaction: the proton may enter at the 2a- or 28position, or at the carbonyl oxygen. The ensuing rearrangement steps, depicted in Scheme 20, all involve an anti-arrangement of the departing nitrogen molecule and the migrating group, or eliminated proton. They account in satisfactory manner for all the products found, although some alternatives were considered possible.382 The 2-diazo-4,4-dimethyl-5-ene-3-one (478) is a special case, one of the main products being the l-methyl-19-nor-l(10),5-dien-3-one (480). The same product was formed when boron trifluoride reacted with the 1,5-dien-3-one(479), pointing to this being an intermediate in the diazo-ketone reaction. With boron triiluoride,

(479)

(478)

(480)

1

Ha} H2N*a} 0

H

H02C’

H

(483)

the dienone (480) rearranged further to give the conjugated dienone (481). Deamination of the 2a-amino-3-ketone (482) with nitrous acid gave the A-nor carboxylic acid (483) in good yield, confirming the stereospeclfic path for its formation from the diazoketone (477).382 Other Reactions-Hofmann

degradation of 5a-cholestan-4~-yltrimethylammonium salts gives the ‘Saytzeff’ (A4)product :383 the large 48-lop-interaction gives the elimination El character, as found previously in the 6P-deri~ative.~’~ The 4a-yl-trimethylammonium salt, like some other equatorial derivatives,385suffers N-demethylation, with some elimination to give the A3 (‘Hofmann’) 382 383 384

385

M. Avaro and J. Levisalles, Bull. SOC.chim. France, 1969, 3166, 3173, and 3180. E. N. Wall and J. McKenna, J . Chem. SOC.(B), 1970, 318. B. B. Gent and J. McKenna, J. Chem. SOC., 1959, 137. R. D. Haworth, J. McKenna, and R. G. Powell, J. Chem. SOC.,1953, 1 1 10; B. B. Gent and J. McKenna, ibid., 1956, 573.

Terpenoids and Steroids

352

Aziridino-steroids (e.g. 486) are available by reduction of suitable iodo-azides with lithium aluminium hydride, but fewer side-reactions occur if the iodo-azide (484) is first treated with triphenylphosphine, or with a phosphite ester.386 Loss of nitrogen leads to the N-phosphonium aziridine derivative (485), which is smoothly reduced by lithium aluminium hydride to give the aziridine. The exact mechanism of nitrogen loss in the first step is uncertain.

Aziridino-substituents (487) have been obtained387 by cyclising 2'-hydroxyethylamino-steroids (488) with thionyl chloride, followed by alkali, or in a single step by reducing chloroacetamido-steroids (489) with aluminium hydride.

HOCH2.CH2-NH

Secondary nitro-steroids are smoothly reduced by chromium(1r) chloride, giving oximes by isomerisation of intermediate nitroso-derivati~es.~~~ The configurations, conformations, chiroptic properties, and pyrolytic elimination reactions of steroidal s u l p h o ~ i d e1*73 s ~and ~ ~ ~~u~l p~h i~n a t e s at ,~~ C-3, C-6, and C-7, have been studied in detail. In general, though not without exception,73 the direction of elimination is controlled by the configuration at the sulphur atom, whenever two possibilities exist for the essential syn mechanism. The favoured

38h

388

A. Hassner and J. E. Galle, J . Amer. Chem. SOC.,1970, 92, 3733. Y . Langlois, C. Poupat, H.-P. Husson, and P. Potier, Tetrahedron, 1970, 26, 1967. J. R . Hanson and T. D. Organ, J . Chem. Soc. (0,1970, 1182.

Steroid Properties and Reactions

353

transition state is generally the one (e.g. 490) with an exo S-R bond and an endo lone-pair, to minimise steric compression. Rates of elimination vary, being rapid where conditions are all favourable, but negligible in cases of high steric hindrance to development of the cyclic tran~ition-state.~~ Similar studies with the diastereomeric 6P-phenylselenoxides show them to resemble the sulphoxides in properties and reaction^.^' 6 Molecular Rearrangements

The Contraction and Expansion of Steroid Rings.-The four rings are considered in turn : additional reactions of this type will be found under ‘Epoxide Rearrangements’ (p. 365). Apparently contradictory results in the Tiffeneau-Demjanov expansion of ring have been only partially clarified from separate study of the epimeric 3-aminomethyl-3-01s (491) derived from 5a-cholestan-3-0ne,~~~ 17b-hydroxy5a-androstan-3-0ne,~7 3 and the related trans-2-decalyl derivative^.^^' The three reported products, the ~-homo-3-one(492), ~-homo-4-one(493), and the oxiran (494),are formed in differing proportions (Table 3). The same products arise from reaction between the 3-0x0-steroids and diazomethane ;273i391 it is clear from

HO H2NCH2

data in Table 3 that diazomethane reacts with 3-0x0-steroids to give a similar product mixture to that obtained from the equatorial aminomethyl compounds, indicating a common intermediate diazonium ion. Oxiran formation is significant only from the equatorial aminomethyl isomers, for the transition state (499, leading to oxiran ring-closure, is sterically unfavourable when the aminomethyl group is Variations in the ratio of ketones (492) and (493) are harder to explain. In the cholestane series,274the marked preference for migration of C-2 rather than C-4 may depend upon differences in magnitude of transannular Ha .H interactions in transition states of types illustrated (496 and 497). Similar

(495)

(496)

38y

Ref. 13, p. 324.

390

R. G. Carlson and N. S . Behn, J. Org. Chem., 1968, 33, 2069.

391

P. A. Hart and R. A. Sandmann, Tetrahedron Letters, 1969, 305.

(497)

354

Terpenoids and Steroids

Table 3 Products .from Tifeneau-Demjanott ring expansion of 3-0x0-steroid deriuat ices. Products Compound

5g- Cholestane series 32-CH N H (ax), 3/3-OH (eq) 3/?-CHzNHz(eq), 3a-OH ( U X ) 3/3-CH,NH,(eq) 3a-OH ( a . ~ ) 3-Ketone 17fl-Hydroxj-5~androstane series 32-CH2NHz ( u x ) . 3B-OH (eq) 3B-CH2NH2(eq), 3n-OH (ax) 3-Ketone trans-Decalin series 2-CH2NH, ( a x ) , 2-OH (eq) 2-CH,NH, (4, 2-OH ( U X ) 2-Ketone

Reagent

, ,

Oxiran (494)

(7;) Ratio : (3-C0)/ (4-CO)

Ref

3-Ketone (492)

A-homo4-Ketone (493)

ca. 0

70

small

274

A-homo-

HNO,

ca. 0

HNO, HNO,

15

0

-

-

70 ‘major

small small

274 394

-

10

product’ 40-50

ca. 0.2

394

HNO,

very little

44

51

0.86

273

HNO, CH2N2

very little very little

47 44

33 31

1.4 1.4

273 273

HNOz

3

48

47

ca. 1

390

HNOz CHZNZ

7 5

54 50

34 40

1.6 1.25

390 3 90

CH2N2

effects have been discussed in the bicyclic series.390 A 17P-hydroxy-group, however, allows C-4 migration to compete effectively with C-2 migration.273 No reasonable explanation is apparent : X-ray data imply that the geometry of , ~ conforma~~ ring D is but little affected by the nature of a 1 7 P - ~ u b s t i t u e n tso tional transmission seems an unlikely cause, and we are left with little-understood long-range electrical effects as the only probable answer. Tiffeneau-Demjanov ring-expansion of 6#l-acetoxy-5ol-cholestan-3-one is normal, giving the A-homo4-ket0ne.”~ If the 68-acetoxy-group exerts any electrical influence, it will be in favour of normal C-2 migration, by weak inductive electron withdrawal from (2-4. Diazomethane gave A-dihomo- and -trihomo-ketones as the only products isolated. The reaction between diazomethane and 3-0x0-steroids is catalysed by alumina.391 The 5B-3-ketone gave a 5P-~-homo-4-one,and the Sa-compound afforded an oxiran (50%) and A-homo-ketones. [The unusually high proportion of oxiran here, implying the intermediate with an equatorial diazomethyl group, probably results from an anti-conformation of the diazo- and hydroxy-groups 392

393 394

C. Altona, H. J. Geise, and C . Romers, Terrohedron, 1968, 24, 13. H. Velgova and V. Cerny, Coll. Czech. Chem. Comm., 1970, 35, 2408. N. A. Nelson and R. N. Schut, J . Amer. Chem. SOC.,1959, 81, 6486.

Steroid Properties and Reactions

355

(498). Separate interaction of each polar function with the alumina surface may be responsible for maintaining this conformation, whereas intramolecular association (e.g.499 or 500), resulting in a syn-conformation in solution, may be a prerequisite for ring-enlargement.]

The outcome of solvolysis of a sulphonic ester of a 19-hydroxy-steroid apparently depends upon functional groups in rings A and B. The 19-tosylates (501 ; 3fl-OAc, 5a; or 5fl-3-0x0) react by Wagner-Meerwein migration of C-1, giving the

~-homo-19-nor-l( l O ) - e n e ~ ( 5 0 2 )but , ~ ~C-9 ~ migration in the 19-mesylate(503)ofa 2-en-19-01 or its saturated analogue affords a B-homo-oleh (504) as major product.396 An explanation in terms of differing preferred conformations about the C(10)-C(19)bond seems possible, the C(,,,-O bond in each case having an anti orientation with respect to the migrating C-C bond. However, uncharacterised olefinic fractions395indicate that the reactions are not specific. Ring A has also been expanded, with incorporation of C-19, by reduction of the 19-mesyloxy-1,4-dien-3-0ne (505) with biphenyl-lithium, an electron donor system. The mesomeric dianion (506) can expel the C-19 substituent to form either a lfl,l9-cyclo- (507) or a 5~,19-cyclo-structure(508). The latter was isolated 3y5

3y6

W. G. Dauben and D . A. Ben-Efraim, J . Medicin. Chem., 1968, 11, 287. F. Kohen, W. Van Bever, and R. E. Counsell, J. Org. Chem., 1970,35,2272.

Terpenoids and Steroids

3 56 CH,-OMS 2e +

0

droMs - -a} .-'

a1

0

( 506)

(507)

1

1

H

0

as a minor product, but the 1/?,19-cyclodienolate (507) rearranges, to give as major product the A-homo-dienone (509).397More recently,398a stable l/l,19cyclo-3-ketone (510) has been obtained by the same reaction from a l-en-3-one, further rearrangement being prevented when 4,5-unsaturation is lacking. Homoallylic participation by 5,6-olefinic bonds at C-19 gives a variety of products, depending upon the steroid and the reaction conditions.399- 4 0 1 5fl,l9-Cyclo-6fl-hydroxy-steroids (512) commonly arise under kinetically-controlled hydrolysis of 5-en-19-01 19-sulphonates (51l), although non-buffered solvolyses permit further rearrangements, probably via non-classical carbonium ions. The 19-rnesyloxy-4-en-3-one (513) affords a similar 5fi,l9-cyclo-product (512; R = 0)via the 3,5-dien-3-01, together with the 6fl,19-cyclo-steroid(514).400 All these solvolyses appear to depend upon a concerted mechanism, the nelectrons displacing the sulphonic ester groups without the generation of a C-19 =-I

MsO-H,C

R

&'(511)

j9'

398 399 400

401

/

R W ' OH (512)

P. Wieland and G. Anner, Helv. Chim. Acra, 1968, 51, 1932. P. Wieland and G. Anner, Helv. Chim. Acta, 1970, 53, 116. Ref. 13, p. 249. J . Tadanier, R. Hallas. and J . R. Martin. J . Ow.Chem.. 1969. 34. 3837. M . Mousseron-Canet and J.-C. Lanet, Bull. SOC.chim. France, 1969, 1745.

Steroid Properties and Reactions

357

(classical)carbonium ion. The same is probably true of the reaction between a 5-en-19-01 and (2-chloro-1,1,2-trifluoroethyl)diethylamine(ClFHCCF,NEt,), which converts alcohols into carbonium-ion-like specie^.^" The producb in this instance belong to the 5B,19-cyclo- or derived series.401 A contrasting rearrangement of the 19-hydroxy-4-en-3-one (515) with the same reagent afforded the 10a-fluoro-5(10* 19)-abeo-derivative(517).400Here inductive withdrawal

of n-electrons from C-5 prevents homoallylic participation. It is suggested4’’ that the reagent is capable of affording a high-energy primary carbonium ion at C-19 (516) when no other reaction path is available, and that 5(10)-bond migration is then favoured. One would expect competing C-1 and/or C-9 migration, but no products from such reactions have yet been isolated. The 9-en-6B-01 (518; ‘Westphalen’ structure) is rearranged under a variety of conditions to give 4(5 +6)-abeo-derivatives (520) and 6glOa-cyclo-compounds (522).403Heterolysis of the C(61* bond in conformation (519) is favourable to C-4 migration, whereas the alternative conformation. (521) of ring B permits

H

F OH

F

402

403

(520)

r

L. H. Knox, E. Velarde, and A. D. Cross, J. Amer. Chem. SOC.,1963,85,2533; L. H. Knox, E. Velarde, S. Berger, D. Cuadriello, and A. D. Cross, J . Org. Chem., 1964, 29, 2187. J.-C. Brial and M. Mousseron-Canet, Bull. SOC.chim. France, 1968, 3321; ibid., 1969, 1758.

358

Terpenoids and Steroids

homoallylic participation, giving the products (522). The configuration found at C-5a in the 4(5 +6)-abeo-compounds(520) suggests that their formation may require an S,i-type donation of the nucleophilic species by the leaving group, concerted with migration of C-4. Figure 6 represents such a transition state when the reagent is thionyl chloride. 0

//

H Figure 6

The 5/3-perhydroazulene structure (524) is accessible by solvolysis of a 1a-mesylate (523).404 The comparable reaction in the 5a-seriesrequires solvolysis of a lg-substituted steroid.405 In each case the migrating C(5)-C(lo)bond has an

anti-periplanar relationship to the leaving group. Related perhydroazulenes (526) are obtained by transannular cyclisation of the 5,10-seco-steroid(525).406

(523) R

=

Tetrahydropyranyl

(524)

(526) lOa

+ lop

Semi-pinacolic rearrangement of the B-norbromohydrin (527) afforded the novel ‘linear’ structure (528) somewhat similar compounds are accessible from suitable 8,9-se~o-diketones.~~’ 404 ‘05

406

407

T. Okuno and T. Matsumoto, Tetrahedron Letters, 1969, 4077. C. W. Shoppee, R. E. Lack, S. C. Sharma, and L. R. Smith, J . Chern. SOC.(0,1967, 1 155. M . Lj. Mihailovic, Lj. Lorenc, J . ForSek, H. NeSovic, G. Snatzke, and P. TrSka, Tetrahedron, 1970, 26, 557. S. Aoyama and K . Sasaki, Chem. and Pharm. BUN. (Japan), 1970, 18,481.

Steroid Properties and Reactions

(527)

359

(528)

A re-inve~tigation~'~ of the decomposition of the 12-tosylhydrazone (529) of hecogenin acetate by bases shows that aprotic media lead to formation of the 11-ene (530),probably via a carbene intermediate. Hydroxylic solvents protonate the intermediate diazo-compound, leading to the olefinic product (531) by rearrangement ofa C-12 carbonium ion. The related solvolysisof the 12B-tosylate (532) gives the stable 13(17a)-olefiniccompound (531) at high temperatures, and TsNH

in highly polar solvents; but lower temperatures, and solvents of relatively low polarity, lead to the less stable 17a(18)-ene(533). The difference in reaction paths is ascribed to competing mechanisms, involving solvent-separated ions and intimate ion-pairs, respectively. Full details are now published408 to support the assignment of the 13(17a)-olehic structure (531) to the product formerly thought to be the isomeric 17(17a)-ene(534). Contraction of ring c through species with carbonium ion character at C-14 gives C-14 spiro-compounds. A cholest-14-ene (535), although one of the most stable unrearranged cholestene~,4~~ affords the spiran (536) on prolonged treatment with acid.410 Compounds of the isodigitoxigenin type (537) similarly undergo acid-catalysed rearrangements to give 'c-nor-cardenolides' (538).41 408

409 410 411

J. M. Coxon, M. P. Hartshorn, D. N. Kirk, and M. A. Wilson, Tetrahedron, 1969, 25, 3107. Ref. 13, p. 293. H. Izawa, Y. Katada, Y. Sakamoto, and Y. Sato, Tetrahedron Letters, 1969, 2947. G. R. Pettit, T. R. Kasturi, J. C. Knight, and J. Occolowitz, J . Org. Chem., 1970, 35, 1404.

Terpenoids and Steroids

360

D-Nor-steroids with suitable leaving-groups at the 16P-position afford the novel bicyclo[5,l,0]octane system (541).4’ Deamination of the 16P-amine (539) or solvolysis of the 16P-tosylate, causes migration of the most suitably placed bond, which is that between C-13 and (2-14 (540). Geometrical considerations cause the migration of C-18 when the leaving group is in the 16a-position (542): the resulting C-13 carbonium ion rearranges further with ring opening to give the D-seco-compound (543). Tiffeneau-Demjanov ring-expansion of an androstan-16-one leads selectively of C-15 through a favourable chair-like to the ~ - h o m o - 1 7 - o n e .Migration ~~~

R

\ T (539)

1

‘I2

‘I3

J . Meinwald and T. N. Wheeler, J . Amer. Chem. Soc., 1970,92, 1009. D. N. Kirk, W. Klyne, C. M. Peach, and M. A. Wilson, J . Chem. SOC.(0,1970, 1454.

Steroid Properties and Reactions

36 1

transition state has been suggested, but assumes an unproven 16a-aminomethyl17P-hydroxy-configurationof the intermediate. The tosylate (544) of a pregnan2OP-01 is so prone to rearrangement that even chromatography on Florosil converted it into the tosylate (545) of the ~-hom0-17ab-o1.~’~ An attempt to hydrate the 17a-ethynylandrostan-17b-01(546) with mercuric chloride gave the D-homo-ketol(547) along with the desired 17P-hydroxy-17a-pregnan-20-0ne.~~ I n uiuo D-homo-annulation of 17a-ethynyloestradiol has been reported.41 Me

H

H

H

H

(544)

(545)

(546)

(547)

Pinacolic rearrangement of the 20P-ethynylpregnane-17a,20a-diol (548) with either thionyl chloride or formic acid gave the D-homo-ketone (549):267 a similar reaction is known in the 20-methyl analogue.417 Me-

CH

H+

Ill

HC-C-C-OH

H (548)

H (549)

The ‘Westphalen’ and ‘Backbone’ Rea~rangements.~~ 8-6b-Substituted 3pfluoro-5a-cholestan-5-ols (550)419 show variations in yields of ‘Westphalen’ products (551) similar to those already noted in other series (reaction with H,S04-HOAc-Ac20).4’8 Maximum electron withdrawal by both 38- and 6P-substituents favours the rearrangement, whereas 6P-methoxy-group participation in ionisation at C-5 leads to an increased yield of unrearranged Sa-acetate. The notable absence of 3P-fluoro-A4-unsaturatedproducts suggests that powerful electron withdrawal from C-3 destabilises the transition state for proton loss at C-4.420 414 415 416 417 418

419

420

M. Leboeuf, A. Cave, and R. Goutarel, Bull. SOC.chim. France, 1969, 1628. C. W. Shoppee, N. W. Hughes, and B. C. Newman, J. Chem. SOC.(0,1970,558. M. T. Abdel-Aziz and K. I. H. Williams, Steroids, 1969, 13,809. M. Uskokovic, M. Gut, and R. I. Dorfman, J. Amer. Chem. SOC.,1959, 81, 4561. Ref. 13, p. 257. J. M. Coxon, A. Fischer, M. P. Hartshorn, A. J. Lewis, and K. E. Richards, Steroids, 1969, 13, 51. Ref. 13, pp. 105-106.

Terpenoids and Steroids

362

F

q 'Fq' X

HO X

(550)

(X

=

HO OAc (552)

(551)

F. OAc. OMe. or H )

The 10P-ethyl derivative (552) undergoes Westphalen rearrangement 5.3 times more rapidly than the 10P-methyl compound, probably indicating log-alkyl participation in ionisation at C-5.42' The need for such alkyl participation explains the failure of SP-hydroxy-steroids to undergo Westphalen rearrangement. The factors controlling the formation of Westphalen (A9) products, and the products of partial [A8 or or total [Ai3(17)]backbone rearrangement are becoming clearer, although they are still not fully understood. Experiments with simple model compounds, reported in outline only,422suggest that a carbonium ion, or related electron-deficient species, will initiate backbone rearrangement if its site is remote from a region of strain within the molecule, provided that the strain can thereby be relieved. Cholest-Sene, for example, undergoes complete backbone rearrangement under suitable acidic conditions, to relieve : (a) the strain (ca. 5 kcal mol- ') inherent in the trans-fusion of rings c and D, and (b) the torsional strain between the C-17 side-chain and the C-18 methyl group. Factor (b) is absent in androst-5-ene (553), which is reported to rearrange only as

H+ (553)

(554)

far as the 8(14)-ene (554), in order to relieve tension about the 13-14 bond. No backbone rearrangement occurred in a D-homoandrostane derivative, in which neither (a) nor (b) applies. The differing effects of various polar substituents in rings A and B are only partially understood. Under normal 'Westphalen' conditions the 4/3,5a-diol (557 ; 4-acetate (555) affords the A9-compound (556; 60%),the A8~*4~-compound 14%) and the A'3(17)-comp~und (558; 3 %), whereas a 6P-substituted compound gives no products of rearrangement beyond C-9.423 The absence of an electronegative 6P-substituent presumably favours migration of the centre of positive J . G . LI. Jones and B. A. Marples, Chem. Comm., 1970, 126. J. Bascoul, B. Cocton. and A. Crastes de Paulet, Tetrahedron Letters, 1969, 2401. 'IJJ . M. Coxon and M. P. Hartshorn, Tetrahedron Letters, 1969, 105. I

422

Steroid Properties and Reactions

363

charge past C-8.4239424The efficiency of backbone rearrangement when 3&5a-diacetates (559) are heated with acetic anhydride and boron trifluoride also varies with substitution at C-6, and drops sharply if the solution is

OAc

w

OAc

(555)

OAc

(556)

(557)

X (559) (X = OAc, C1, H, or : 0 )

diluted with acetic acid.425 Abstraction of fluoride ion from 5-fluoro-5acholestan-3b-ol acetate by boron trifluoride results in backbone rearrangement (ca. 20%) accompanied by normal elimination to give cholesteryl acetate (A 5). 42 Dehydration of the lO~-hydroxy-5~-rnethylcompound (560) (toluene-psulphonic acid-acetic anhydride)gave the A13(17)product (561) in high yield, but the corresponding 6-ketone (562) rearranged less readily, giving also the A'('O)-ene(563).424In neither case was any A9-compoundformed, indicating that

a '

PhCHzO

R (562) R (560)

P h C PhCH20

P-OH = :O =

H

z

O

y

OAc

(y+ Y H

425

J. G. L1. Jones and B. A. Marples, Chem. Comm., 1969, 689. J. M. Coxon, M. P. Hartshorn, G . A. Lane, K. E. Richards, and U. M. Senanayake,

426

Steroids, 1969, 14, 441. J. M. Coxon, M. P. Hartshorn, and M. G. Lawrey, Chem. a n d h d . , 1969, 1558.

424

364

Terpenoih and Steroids

the C-I0 ‘carbonium ion’ or electron-deficient species generated in this way differs in some subtle respect from that resulting from migration of the lopmethyl group to C-5. Backbone rearrangements occur when various 3-aminopregn-5-en-20-ones are dissolved in sulphuric acid at 0 0C?27With a 3a-amino-substituent,an apparently concerted rearrangement gives the conjugated 13(17)-en-20-one (564), with inversion at all ‘backbone’ positions. 3fl-Amino-substituted compounds give COMe

.

(564; 3a-NH2; lOa-H) (565; 3/3-NMe2 or -NHMe; lop-H)

mainly the 10p-isomer (565) of the backbone-rearranged product, indicating stepwise rearrangement. Removal rather than migration of 9a-H, and reprotonation of an intermediate A9-compound at the l0fl-position, appear to be required. The reason must be the relief of conformational strain in allowing the 3fl-NR2 group to become equatorial in the product. This evidence for a nonconcerted mechanism leaves room for uncertainty in other backbone rearrangements, although the Westphalen (A9)diacetate is not an intermediate in the complete rearrangement in the 3/3,6P-diacetoxy series. Full details have now appeared428of the independent synthesis of the hydroxyketone (566), which was first obtained via backbone rearrangement of androst5-ene-3P,17pdiol with hydrogen fluoride. [17~~HI-Labelled androstenediol (567) afforded the [13a-2H]-labelledketone (568),428showing that the rearrangement involves a 17a -+13a hydride shift, rather than loss of 17a-H to form an

enol. Prolonged reaction of cholest-5-ene with toluene-p-sulphonic acid-acetic acid causes equilibration of the first-formed 13(17)-ene to give a mixture of 2qR)- and 20(S)-isomers ( 569).429 A more extensive rearrangement when 42’

428

429

F. Frappier, Q. Khuong-Huu, and F. X. Jarreau, Bull. SOC.chim. France, 1969, 3265. J. C. Jacquesy, J. Levisalles, and J. Wagnon, Bull. SOC.chim. France, 1970, 670. D. N. Kirk and P. M. Shaw, Chem. Comm., 1970, 806.

Steroid Properties and Reactions

365

cholesterol reacts with hydrogen fluoride afforded the products (570 ;2 % of each isomer at C-17).430No sequenceof Wagner-Meerwein steps can account for their formation : a 1,6-hydride transfer from C-25 to C-17a seems to be required. Further Westphalen and backbone rearrangements are mentioned in the following section. Epoxide Rearrangements.-Most of the early work on rearrangements of 43and 5,6-epoxy-steroids with boron t r i f l ~ o r i d e ~has ~ ' been repeated recently. The diversity of results, including dramatic deviations from those described previously, makes it abundantly clear that these reactions depend critically upon reagent and experimental conditions. Table 4 lists the products which have been isolated and characterised with the advantages of modem techniques. The reader is referred to the original papers for a wealth of comment on reaction mechanisms, which generally stress the r61e of conformational features of the compounds. A few general points emerging from consideration of Table 4 as a whole merit special comment. Ether as solvent results in slow reactions and generally favours fluorohydrin formation. By competing with epoxide for co-ordination with boron trifluoride, ether apparently retards carbonium ion formation through epoxide rupture. Nucleophilic attack upon the epoxide by a donor of fluoride ion then becomes relatively important. Some fluorohydrins, however, react with boron trifluoride in benzene to give product mixtures not unlike those derived from the epoxides, so that transient fluorohydrin formation, even in benzene, may contribute towards the final product compositions. The 5a-fluoro-4/?- and -6/?-hydroxycompounds, however, give notably higher yields of backbone-rearranged 13(17)-enesthan do the corresponding / ? - e p o ~ i d e s . ~ ~It( 'is~clear ~ ~ ~ that abstraction of fluoride ion by boron trifluoride may initiate Wagner-Meerwein rearrangment without the need for hydroxy-group participation, which would have regenerated the epoxide. Ketone formation by hydride migration, concerted with epoxide cleavage, is not always as efficient as formerly thought,43' although still significant in most cases (Table 4).

433

P. Bourguignon, J. C. Jacquesy, R. Jacquesy, J. Levisalles, and J . Wagnon, Chem. Comm., 1970, 349. H. B. Henbest and T. I. Wrigley, J. Chem. SOC., 1957, 4596, 4765; C. W. Shoppee, M. E. H. Howden, R. W. Killick, and G . H. R. Summers, ibid., 1959, 630. Ref. 13, p. 355 (footnote). B. N. Blackett, J. M. Coxon, M. P. Hartshorn, and K. E. Richards, Tetrahedron, 1969,

434

25, 4999. I. G. Guest and B. A. Marples, J . Chern. SOC.(0,1970, 1626.

430 431

432

.!ipo.de

Ether (2 h ) Benzene (45 s) Benzene (2 min) Ether (2.5 h )

Benzene (45 s) Ether ( I 5 h) Benzene (2 min)

ca. 14

17 20 19

47

8 -

21

15 27

_.

6 56 20

76 20 41

2 -

57

__

-

67

3

_.

__.

__

__

---

-__

22

6 5 I5

14 8

hyde

AIde-

'West- 'Buck phalen' hone' (5D- Me, (A1 7 ) )

x,)

-

Diequatorial fluorohydrin ( ? ) (6 %) 68-OH,A'3(' 7 , (yield not stated) 6a,8a-oxetan (573 ; 7 %) 3a,lOa-oxide (572; 13%) 8( 14)-en-6a-ol (57 1 ; 27 %) 3,4-seco ester (35 Epoxide (7 %); 3a,lOa-oxide (572; 28 %) 3a,Sa,6/?-triol 5-acetate (ca. 100%)

-

Epoxide (28 %,) ;5-en-401-01( I4 2,) 4a-OH,AY(9%); 4a-OH, A'"") ( 3 73 'Polar compounds' (9 7;) 8-en-6a-01 (?) (5 2,)

Other compounds

R 4

Ref. 433. J. W. Blunt, M. P. Hartshorn, and D. N . Kirk, Tetrahedron, 1969, 25, 149. Ref. 434. J. M. Coxon, M. P. Hartshorn, and C. N . Muir, Tetrahedron, 1969,25,3925. J. M. Coxon, M. P.Hartshorn, C. N. Muir, and K. E. Richards, Tetrahedron Letters, 1967, 3725. J. M. Coxon, M. P. Hartshorn, and B. L. S. Sutherland, Tetrahedron Letters, 1969,4029.

Benzene (7 min) Benzene (7 min) Benzene (25 s) Benzene (25 s) 5a,6a(3,3-ethylenedioxy) Benzene (1.5 min) 54,6&(3a-OH) Benzene (35 s)

5a,6a(38-OH) 5a,6a(3P-OMe) 5a,6a(301-0H ) 5a,6a(3a-OAc)

4aSa 4aSa 4838

Solrent and rruc'rton trnw

Diaxiul Ketone Dienes fluoro- (at C-4 (mainly hyiirin or C - 6 )

Produc7.s ( 0/i,)

Table 4 Recent results on the reactions of'4 3 - and 5,6-epoxy-cholestanes and their derivatives with boron trijluoride etherate (for earlier data, see ref. 431).

ss

$

t m n

w

367

Steroid Properties and Reactions

The most important discovery in this field in recent years is the major r81e of ‘Westphalen’, ‘backbone’, and related rearrangements involving initial migration of the lop-methyl group to C-5, which may account for as much as half of the reacting epoxide in favourable cases. Although 1OP-methyl migration appears to be concerted with cleavage of the C,,,-O bond in the ordinary Westphalen rearrangement (p.362), this is certainly not an essential feature of epoxide reactions. As a group, the P-epoxides in Table 4 are marginally more effective than a-epoxides in giving 5P-methyl products, suggesting that a discrete carbonium ion, generated at C-5 in the presence of a 48- or 6P-oxygen substituent, is a structural combination as favourable to methyl migration as is the cleavage of an a-epoxide at C-5. Once methyl migration occurs, in epoxide cleavage, the complete backbone rearrangement is more likely than formation of the Westphalen product, possibly because the non-polar solvent does not provide basic species for rapid proton abstraction from carbonium ions at intermediate sites. The ‘Other compounds’ in Table 4, however, include minor products representing incomplete backbone rearrangements [e.g. the 8( 14)-ene (571)], as well as transannular oxido-compounds (572) and (573), resulting from trapping of an intermediate carbonium ion by a suitably-placed hydroxy-group.

OH (571)

@

OH (573)

(572)

-Hf

__.+

CHO

(574)

(576)

The compounds (Table 4) in the column headed ‘Aldehyde’ are A-nor- or ~-nor-5/l-formyl derivatives (e.g. 574), resulting from ring contraction. The normal steroid skeleton (576) is regenerated if the aldehyde (574) is first reduced, and the tosylate (575) of the resulting ‘neopentyl’ alcohol then ~ o l v o l y s e d . ~ ~ ~ An intriguing inversion of oxygen configuration occurs in the formation of minor products from the 4PY5P-epoxideand the 3P-hydroxy-5~6ol-epoxide (Table 4) (c$ also p. 373). A mechanism which satisfactorily explains inversion consists of rupture and re-closure of the ring carrying the oxygen substituent. Scheme 21 illustrates this mechanism for the 4PY5/l-epoxide(577). The essential

Terpenoids and Steroids

368

I

- BF,

BF3

I

1 4P-OH products

/ 4r-OH products - BF,

Me(0

I

/ /

Me-C-C-C-Bu‘

1 2 1

I

Me H H

H ‘OBF, Me,. I GI --+ ,C-C-C-Bu‘ Me I Me H

-

Me, ,C=CHMe Me

+

Bu‘CHO

Scheme 21

feature, common to each example known, is that epoxide rupture should occur at a ‘neopentyl’ carbon. Wagner-Meerwein rearrangement results in migration of the centre of positive charge to the carbon atom two bonds removed from the oxygen atom. A ‘Grob fragmentation’ then affords an unsaturated aldehyde (as BF,-complex) which can re-cyclise by olefin attack on either side of the aldehydic carbon atom. The fragmentation step has been demonstrated in a simple model compound, di-t-butylethylene oxide (578)’ which affords trimethylacetaldehyde and 2-methylbut-2-ene with boron t r i f l ~ o r i d e . ~ ~ ~ The epoxides derived from 3-phenyl-5a-cholest-2-eneare hydrolysed by aqueous acids to give either cis- or trans-2,3-diols, depending upon the reagent.43h The possibility of intervention of a stable benzylic cation at C-3 allows either cis- or trans-attack by water. Boron trifluoride converts the a-epoxide into 3a-phenyl-5a-cholestan-2-one, with concerted hydride migration (2B 38). The rearrangement of the 6B-phenyl-5a,6a-epoxide (579)437parallels that of the 6B-methyl derivative,438 giving the 5fi-phenyl-~-homo-~-nor-ketone (580)

-

13’

436

43i 438

J. M . Coxon, M. P. Hartshorn, A. J. Lewis, K . E. Richards, and W. H. Swallow, Tetrahedron, 1969, 25, 4445. G . Berti, 9. Macchia, and F. Macchia, Gazzetta, 1970, 100, 334. J. M . Coxon, M. P. Hartshorn, and W. J. Rae, Tetruhedron, 1970, 26, 1091. J . W . Blunt, M. P. Hartshorn, and D. N. Kirk, Tetrahedron, 1965, 21, 559.

Steroid Properties and Reactions

369

on brief reaction. Prolonged treatment rearranges the initial product to give the 4(5 +6)deo-ketone (581). The end-product from the 6P-methyl epoxide, earlier regarded438 as the 5p-methyl-6-ketone, is now reformulated as the 5-methyl analogue of compound (581).

Full details are now published439of the rearrangements of the ~-nor-3a,Saepoxides (582)and (584)with boron trifluoride. The 19-nor-compound (582)gives the product (583) of backbone rearrangement, together with the 5P-methyl ketone (585). No backbone rearrangement occurred in the 10P-methylanalogue (584),which gave only the ketone (586).

BF3 (584)

(585) (586)

R R

= =

H Me

Rearrangements of the 10;2a-epoxy-~-nor-compound(587) depend upon the reagent.440 The major products are represented in Scheme 22. Although simple 2,3-epoxy-steroids undergo normal diaxial opening with hydrogen fluoride (p. 283), the 2P,3P-epoxy-4,4-dimethyl compounds additionally give rearranged products. The 5a-oestrane derivative (588) affords the fluorohydrin (589)and the 439 440

J. Bascoul and A. Crastes de Paulet, Bull. Sac. chim. France, 1969, 189. K . Yoshida, Tetrahedron, 1969, 25, 1367.

Terpenoidsand Steroids

370

+

Ac 0

HO--

(two isomers)

H

BF,-ether

H (587)

\

BF,-benzene

(Id}

+ products as above

H Scbeme 22

4~-fluoro-3a,4a-dimethyl2B-01 (590), through epoxide cleavage and concerted migration of the 4a-methyl group to C-3, followed by p-face attachment of

fluoride ion.Io8 The corresponding 5a-cholestane derivative would be highly strained by having axial substituents at the 28-, 48-, and lop-positions :this strain is avoided by a further rearrangement of the C-4 carbonium ion (592), with nonconcerted migration of the 5a-hydrogen. The 5/?-fluoro product (594) is then formed, allowing the 28-, 3a-, and 4B-substituents to become equatorial. lo7' Epoxides at the tetrasubstituted positions about the middle of the steroid molecule generally give elimination products with acidic reagents :441 two new examples are now reported. 8a,9a-Epoxyoestrone methyl ether (595) is readily 441

Ref. 13, p. 362.

Steroid Properties and Reactions

37 1

Me (591)

(592)

1 Me

t

Me (594)

(593)

cleaved at C-9 (contrary to the ‘axial even by weak acids, with electromeric assistance by the phenolic ether, giving the 9(11)-en-8a-o1 (596).443 The isomeric 9,lO-epoxides(597) and (598) in the ‘Westphalen’ series react with boron

trifluoride to give the dienes shown in Scheme 23.444 The a-epoxide (598) has the ideal geometry for ‘axial’ at C-9, with concerted 8P-hydride migration leading to a complete backbone rearrangement. The 9/3-A8114)-unsaturated11a-01 (600), obtained when a 9 s l la-epoxy-steroid (599) was treated with boron trifluoride gas in benzene, is considered to arise by 442 443 444

Ref. 13, p. 357. R. P. Stein, G. C. Buzby, and H. Smith, Tetrahedron, 1970, 26, 1917. I. G . Guest and B. A. Marples, Tetrahedron Letters, 1969, 3575.

372

Terpenoids and Steroids

OAc

Scheme 23

intramolecular removal of the axial 14a-proton by the 1la-oxygen, following or during cleavage of the epoxide at C-9 and migration of 8#3-Hto the 9 p - p o ~ i t i o n . ~ ~ ~ Boron trifluoride rearranges the 1la,l2a-epoxide (601), probably with 1,3hydride migration (88- llg), to give the 8-en-12a-01 (602).253Simple antielimination in the 1lg,l2/3-epoxide (603) affords the 9(1l)-en-12/?-01(604). Both epoxides also give the c-nor-D-homo-diene (609,resulting from ‘carbonium ion’ development at C-12 @. 359). The 12fi-methyl-lla,l2a-epoxide(606) gave the mixture of products (607)-(609b), all resulting from initial epoxide cleavage at C-12. Most notable is the 1I/?-hydroxy-compound (609b). Inversion at C-11 445

J. W. ApSimon, R . R. King, and J. J . Rosenfeld, Canad. J . Chem., 1969, 41, 1989.

Steroid Properties and Reactions

(609a)

(609b)

is thought to proceed through breaking and re-formation of the 11,13-bond in the intermediate carbonium ion (610).253An analogous mechanism is illustrated for a 48,SP-epoxide on p. 368. The rearrangement of 16a,l7a-epoxy-l6Q-methylpregnan-20-ones, to give 17a-h ydroxy- 16-methylenepregnan-20-0nes,4~~ is paralleled by the 168,178epoxy-161~-methylanalogue in the 14P-pregnane series, which affords the 178-hydroxy-16-methylenecompound with trifluoroacetic acid in benzene.447 The 14B-isomer,however, shows an unusually strong preference for elimination within ring D when other acid reagents are used, giving the 16-methyl-14,16-dien20-one. The reaction between a 16617-epoxypregnan-20-one and hydrogen 44b 44’

Ref. 13, p. 364. R. Mitkova, A. Kamernickij, and K. Syhora, Coll. Czech. Chem. Comm., 1969, 34, 451.

374

Terpenoids and Steroids

fluoride is non-specific, giving a mixture of three fluorohydrins, and three rearranged olefins resulting from migration of C-18 to the 1 7 f l - p o ~ i t i o n . ~ ~ ~ Spiro-oxirans (e.g. 611) at C-3, C-6, C-7,449and C-12450are rearranged by boron trifluoride with hydride migration to give mixtures of aldehydes (612).

In each case reaction occurs mainly through a discrete carbonium ion at the tertiary centre, resulting in very considerable loss of stereochemical distinction between epimeric pairs of epoxides. Rather small differences in product ratios between epimers indicate either concerted hydride migration, or hydride migration at a rate comparable with the rate of rotation about the exocyclic C-C bond in the carbonium ion. A similar rearrangement of the 20,21-epoxide (613) with boron trifluoride to give the aldehyde (614)is a key step in a synthesis of the bufadienolide ~ystem.~”

HC=CHCO, Me I

td-cHo H

448 ‘09

450 45’

D. R. Hoff, J . Org. Chem., 1970,35,2263. B. N. Blackett, J. M. Coxon, M. P. Hartshorn, B. L. J. Jackson, and C. N. Muir, Tetrahedron, 1969, 25. 1479. J . M. Coxon, M. P. Hartshorn, and D. N. Kirk, Tetrahedron, 1967, 23, 351 1. K. Radscheit, U. Stache, W. Haede, W. Fritch, and H.Ruschig, Tetrahedron Letters, 1969, 35, 3029.

Steroid Properties and Reactions

375

In a new degradation of the lanosterol side-chain, the 24J5epoxide (615) rearranged to give the 24-ketone (616).452 Anomalous Grignard reactions (MeMgI) with esters of the 4,5-epoxy-6Phydroxycholestanes (617) and (618) lead to methylation at C-6453rather than at C-4. The reactions are interpreted as rearrangements leading to 6-oxo-compounds, which then react rapidly with the Grignard reagent. In either the cis- or the trans-compound, the favourable migration of 6a-H to the Sa-position is a key

*c-”

H

H

wO

H

Anomalous Grignard reactions of 4,5-epoxy-6~-h~roxy-cholestanes

Scheme 24

step (Scheme 24). The Grignard reagent provides catalysis by both Lewis acid and base. The analogous 4P-acetoxy-5,6-epoxides react similarly, with C-4 met hylat ion. The Reformatsky reagent (zinc-ethyl bromoacetate) rearranges the 3pacetoxy-4P,SP-epoxide (619) into three products (620)-(622), notably including the reduced A-nor-diol (622).454The mechanism is not known in detail, but the 452

4s3

454

L. H. Briggs, J. P. Bartley, and P. S. Rutledge, Tetrahedron Letters, 1970, 1237. J. R. Bull, J . Chem. SOC. (C), 1969, 1128. R. Kevorkian, M. Lemonnier, G. Linstrumelle, and S. Julia, Tetrahedron Letters, 1970, 1709.

376

Terpenoidsand Steroids

reagent presumably affords a Lewis acid (ZnBr,?) ; the 3B-acetoxy-4-ketone (621; R = Ac) is a predictable product from rearrangement of the epoxide

(619), although the diaxial fluorohydrin was the only product isolated after its reaction with boron t r i f l u ~ r i d e . ~Zinc ~ ’ bromide in benzene afforded the two ketones (620) and (621) but not the A-nor-diol (622), which clearly requires reducing conditions. Ammatisation.-The dienone-phenol rearrangement of a 1,4-dien-3-0ne normally gives the l-hydroxy-4-methyloestra-1,3,5( 10)-triene, but certain substituents prevent the intermediate formation of a C(5)-~pir~-~ation.456 Methyl migration [C(,,)* C(,,] then occurs to give 1-methyloestrogens. A 6~-bromo-substituent is now found to act in this way, apparently through its steric effect.457Chromatoderivative on silica gave 6-hydroxygraphy of the 6~-bromo-l-methyloestrone compounds, as a result of benzylic activation. Phenyl trichloromethyl mercury, often used as a source of dichlorocarbene, promotes dienone-phenol rearrangements in the normal sense, converting 1,4-dien-3-0nes (623) into the substituted benzoyl chlorides (628) and (629).458 Since dichlorocarbene generated in other ways was ineffective, the reagent is - -Hg co-ordination, leading oia the dichlorothought to react initially by 0. oxiran (625) to the reactive mesomeric cationic species (626) and (627). The 1,4,6-trien-3-0ne (630) similarly afforded the 1-methyl-3-acid chloride (631), but the 4,6-diene-3-one was unreactive. Bromination of 5-en-3B-01s (632) with 1,3-dibromo-5,5-dimethylhydantoin, followed by dehydrobromination with collidine, gave the 2,4,6-triene (633),and its rearrangement product, the 4-methyl-l,3,5( 10)-triene (634).459 The conversion into the 3,4-dimethyloestra-1,3,5( 10)-triene(636) of the l~-rnethyl-5-en-3/3-01(635) shows that the aromatisation involves the usual C-5 spiran, and not a sequence of methyl migrations (lo/?-+ 5g+ 4). Preliminary formation of a 4-bromoderivative is implicated.460 Electrophilic addition of ‘F” onto a 4,9(1 l)-dien-3-one (637) caused lobmethyl migration to the electron-deficient C-9 (638), allowing aromatisation of ring A (639),although normal addition occurs with an isolated 9(11)-ene(p. 296).1 6 7

”’ J . M . Coxon, M. P. Hartshorn, and D. N. Kirk, Tetrahedron, 1964, 20, 2547 ‘’’ Ref. 13, p. 277. 45’

4s8 459

460

T. Wolffand H . Dannenberg, Chern..Ber., 1970, 103, 917. B. Berkoz, G. S. Lewis, and J. A. Edwards, J . Org. Chem., 1970, 35, 1060. J. R. Hanson and T. D. Organ, J . Chem. SOC.(C), 1970, 513. J . R. Hanson and T. D. Organ. Chem. Comm., 1970, 1052.

a}

377

Steroid Properties and Reactions

0

: o Q } -PhHgC1b

PhHgCC'3b 6 -

[ --all, c12c -0

PhHg., cc13

(623)

C}

(624)

fy/J 7- :- 7

7-

+.

a-c

II

*-

c1- c II

I.

.-

*"-

0

0

A unifying interpretation has appeared of the various results obtained in Favorskii rearrangements of 17a-halogenopregnan-20-ones(e.g.640)and related compound^.^^ Two mechanisms appear to operate, their proportion being

(632) R (635) R 4b1

= =

H Me

(633)

(634) R = H (636) R = Me

C. R. Engel, S. K. Roy, J. Capitaine, J. Bilodeau, C. McPherson Foucar, and P. Lachance, Canad. J . Chem., 1970,48, 361.

Terpenoih and Steroids

378

determined largely by the reaction medium. In a solvent of low polarity (e.g. dimethoxyethane, with sodium methoxide as base), the reaction is stereospecific, according to Loftfield’s mechanism (path a ; Scheme 25). The resulting cyclopropanone (641) is subsequently opened to give the 17Smethyletianic ester (642) Me

I

co

H

H (641)

(642)

Farorskii rearrangements of 1 7%-hromopregnun-20-one

Scheme 25

as almost sole product. Polar solvents, however (e.g. aqueous methanol), favour the formation of a ‘delocalised intermediate’ [‘zwitterion’; 643 (path b)] which may cyclise stereoselectively, but not stereospecifically, in the very hindered

Steroid Properties and Reactions

379

environment of C-17. Predominance of the cyclopropanone (644) then leads to the 17a-methyletianic ester (645) as principal product. Simultaneous following of both routes would explain the composition of products from media of intermediate polarity. Other aspects and theories of the Favorskii rearrangement are discussed critically, in considerable Confirmation of the intermediacy of cyclopropanones comes from their diversion towards different end-products. Reaction between the 17a-chloro- or 17abromo-pregnan-20-ones (646) and dimethyl oxysulphonium methylide (acting first as a strong base) seemingly gives a cyclopropanone (647), with typically high reactivity to nucleophiles. Addition of a second molecule of methylide (648) allows ring expansion to give the cyclobutanone (649) as final

If the cyclopropanone (647) is generated in the presence of hydrogen peroxide, another reactive nucleophile, the resulting hydroperoxyalkoxide (650) breaks down to give a 17-methyleneandrostane(652).463A possible mechanism involves fragmentation of an intermediate /I-lactone (65l), derived from Baeyer-Villiger rearrangement464of the hydroperoxide. A Favorskii-like intermediate (655), and the rearranged product (657),arise in a novel way from fragmentation of the a-ketol enol-sulphite (654). Loss of sulphur dioxide is thought to afford the zwitterion (655), which gives the methoxy-ketone (656) in methanol, but the A-nor carboxylic ester (657) with sodium methoxide in ether.465 462 463 464

4h5

R. Wiechert, Angew. Chem. Internat. Edn., 1970, 9, 237. J. E. Baldwin and J. H. I. Cardellina, Chem. Comm., 1968, 5 5 8 . Ref. 13, p. 345. 3. LevisaIIes, E. Rose, and I. Tkatchenko, Chem. Comm., 1969, 445.

380

Terpenoidsand Steroids

\-so,

Miscellaneous Rearrangements.-Solvolysis rates for cholesteryl tosylate in different solvents show an excellent correlation with rates for cyclopropylcarbinyl tosylate, indicating similarity of mechanism. Two distinct correlation curves were obtained, depending upon solvent c l a ~ s i f i c a t i o n .Stereoelectronic ~~~ restrictions in the cholesteryl cation permit only a single structure for charge dispersal between positions C-3, C-5, and (2-6, but several non-classical structures seem plausible for the cyclopropylcarbinyl cation. It is suggested that two such structures, depending upon solvent character, may account for the observation of two correlation curves, Further light is shed upon the solvolysis of 4a- and 4P-methylcholesteryl of the tosylates of 3p-[(S)-1'-hydroxyethyll-A-norcholestt o s y l a t e ~ by ~ ~solvolysis ' Sene (658), and of the (&isomer (659), respectively.468 Each pair of tosylates (Scheme 26) afforded virtually identical products, ascribed to the intermediate formation of the same non-classical homo-allylic cations (660) and (661). The (R)-alcohol (cc 659) is exceptionally prone to rearrangement, giving the 4-methyl-3,5-diene (663) with acid or even on acetylation. It is that the very highly strained 4p-methyl non-classical cation (661) is separated by 466 467

468

D. D. Roberts and T. M. Watson, J . Org. Chem., 1970, 35, 978. Ref. 13, p. 244. R. M . Moriarty and K. Bhamidipaty, J. Org. Chem., 1970, 35, 2297.

Steroid Properties and Reactions

38 1

+ 5 0

st

\

382

Terpenoids and Steroids

only a small energy barrier from the classical cation (662), which loses the C-4 proton to give the diene. Buffered solvolysis of the 3-tosylate (664) of cholest-5-ene-2P,3/3-diolcauses normal formation of the 3a,5a-cyclo-2B,6fl-diol(665), along with the 5-en-2-one

TSK

I

(665)

H+

OH

a ' .......... :+

+ OH (669)

( 6 7 0 ) (5a

+ 5p)

(666).469The derived 2,6ccdiols(667)rearrange on treatment with acid, apparently through the delocalised homo-allylic cation (668),to give the A2-compounds(669) and (670). The well-known contraction of ring A by solvolysis of 3-sulphonates in 4,4-dimethyl steroids is opposed by an 0x0-group at C-7 (671 ; Scheme 27) although the corresponding 3fi-alcohol (672) reacted fairly normally with phosphorus pentachloride to give the A-nor products i l l ~ s t r a t e d . ~The ~ ' difference is ascribed to differing reactivities of the leaving groups concerned. The phosphorus derivative (R-OPCIJ is assumed to undergo relatively fast heterolysis, with a reactant-like transition state permitting normal migration of the anti-periplanar C(4)-C(5)bond, though without anchimeric assistance. The less reactive tosylate requires assistance from the migrating bond, but the inductive or electrostatic effect of the 7-0x0-group opposes delocalisation of the 4,5-bonding electrons sufficiently to inhibit their participation in the tosylate solvolysis. The major products correspond to anti-periplanar processes in a skew-boat conformation of 46y

470

V. Cerny, A. Kasal, and F. Sorm, Coil. Czech. Chem. Comm., 1970, 35, 1235. A. Abad, M. Allard, and J. Levisalles, Bull. SOC.chim. France, 1969, 1236.

Steroid Properties and Reactions

m0=a 383

f

H

NaOAcHOAc

-<

(57 %)

(30 %)

p Z 0 p'o gf-w

( 5 %)

HO

\

(13 %)

POTS

T

H

H

0

(673)

Scheme 27

ring A (673), which seemingly provides the only reaction paths available to the 3P-tosylate by placing it in a quasi-axial conformation. Separate deuteriumlabelling experiments, at the 5a- and 3a-sites respectively, have established that the formation of the conjugated 5-en-7-one (674)in the reaction with phosphorus pentachloride involves two hydride-migration steps (3a +4, followed by 5a+ 3a).470 The inhibiting effect of the 7-0x0-group is augmented by A5unsaturation to the extent that neither of the two leaving-groups is capable of inducing ring A contraction, the products all being those expected from a skewboat conformation of ring A . ~ ~ ~ The solvolysis of sulphonates of 13a-androstan-17P-ols (675) resembles that of ordinary (13P) 17a-ols,in causing migration of C-18 to give the 17-methyl-18-nor13(17)-ene(676).471Similar migration of C-18 has been observed in the D-homo M. Fetizon, J.-C. Gramain, and P. Mourgues, Bull. SOC.vhim. France, 1969, 1673.

384

Terpenoids and Steroids

(675)

(678)

i, H,SO,-Ac,O at 0 “C;ii, BF,-Et,O; iii, H C 0 , H ; iv, either KHS0,-Ac,O or POCl,-py.

Scheme 28

series (677 678) although alternative products are possible here, depending upon the reagent used (Scheme 28).472 An earlier report473has shown that the 18-nor-13-ene system (678) can undergo a ‘reverse backbone’ rearrangement if ring A contains a 3-0x0-group to stabilise the product (679) by conjugation. Study of the ‘benzilic acid’ rearrangement of 2,3-diketones has been extended to the 4,4dimethy1-5,6-unsaturatedanalogue (680).474 The product of reaction with alkali is the A-nor-hydroxy-acid (681), derived by a stereospecific migration of the 3,4-bond, following initial attack by hydroxide ion exclusively at C-3. Hydroxide attack at C-2, which would require one of the C-2 oxygen substituents ---+

472

C . Monneret, C. Tchernatinsky, and G. Khuong-Huu, BUN. SOC.chim. France, 1970, 1520.

4’3

M. M. Janot, C . Monneret, K.-H. Qui, and R. Goutarel, Compt. rend., 1967, 265, C,

4’4

J. Alais and J . Levisalles, Bull. SOC.rhirn. France, 1969, 3185.

1468.

Steroid Properties and Reactions

385

to be axial, is resisted by the already overcrowded state of the j3-face of ring A, whereas an axial 3a-oxygen encounters only one syn-diaxial interaction, with 1a-H.The 17P-hydroxy-17a-aldehyde(682)rearranges readily under a variety of conditions to give the D-homo-ketol (683).475The transition state has the highly favourable developing-chairconformation (684).

ld"" H

Pyrolysis of the allylic tertiary acetates (685)and (688)above 300 "C gives the ' . ~ ~16~ more stable conjugated isomers (686)and (689)r e s p e c t i ~ e l y . ~ ~The acetoxymethylpregn-16-en-20-one (686)is accompanied by the furan (687),which probably by displacement of the acetoxybecomes the sole product at 360 0C,476 COMe

COMe

I

Br, -MeOH

H

475 47h 477

CHZ

{

{&Me

H

CH20Ac

CO-Me BCI-I(OMe)z

H

T. C. Miller, J . Org. Chem., 1969, 34, 3829. T. L. Popper, F. E. Carlon, and 0. Gnoj, J . Chem. SOC.(0,1970, 1344. T. L. Popper, F. E. Carlon, 0. Gnoj, and G. Teutsch, J . Chern. SOC.(0,1970, 1352.

Terpenoidsand Steroids

386

group by the carbonyl oxygen. Oxidation of the furan with bromine in methanol afforded the pregnane derivative (690).478 The hydroperoxy-ketone (691) suffers ring-opening (-+ 693) with boron trifluoride, allowing a controlled degradation of ring D. A probable mechanism

comprises conjugate addition of the peroxy-oxygen onto the enone system, followed by a concerted fragmentation (692).479 7 Functionalisation of Non-activated Positions

Free-radical Reactions.-Lead tetra-acetate (LTA), with or without iodine, is now the most widely used reagent for generating alkoxyl radicals from alcohols for attack upon neighbouring C-H bonds.480 Irradiation of 5a-cholestan-2fl-01 with LTA-iodine gave the expected 2flJ9-ether (694) and hemiacetal (695)481 (di-functionalisation through repeated alkoxyl radical generation and attack on angular methyl groups is a common feature of LTA-iodine reactions4*'), Full

(694) R = H (695) R = OH

479

480 481

T. L. Popper and 0. Gnoj, J . Chem. SOC.(0,1970, 1349. A. Afonso, Canad. J . Chem., 1970, 48, 691. Ref. 13, pp. 401, 405. C. W. Shoppee, T. E. Bellas, J. C. Coll, and R. E. Lack, J . Chem. SOC.(0,1969,2734.

Steroid Properties and Reactions

387

details are now on the formation of a 249a-ether by the action of LTA on 5/?-cholestan-2a-ol. The well-known formation of 6/?,19-ethers from 6P-hydroxy-steroids has been examined in competition with LTA oxidative decarboxylation of carboxylic acids, and found to be roughly comparable in rate with the decarboxylation of n-alkanoic 6P,19-Ether formation is not limited to saturated alkyl groups at the 10P-position: the lOP-vinyl compound (696) reacted normally with LTA to give the enol ether (697), which afforded the unsaturated ketone (698) with zinc-acetic The formation of cyclic ethers (701 ; e.g. 6B,19-ether485)by Ag+-catalysed reaction of a hypobromite (699) is strongly catalysed by tetrahydrofuran, which

probably solvates a transition state (700) with ionic rather than free-radical Although 5a-halogeno-substituents do not interfere with 6/3,19-ether formation, the Sa-methoxy-compound (702) afforded a novel 5a,&-methylenedioxyderivative (703) as a major product, with the 6/?,19-etherin only small yield (using

(704a)

482 483

484 485

486

(704b)

(703)

T. Koga and M. Tomoeda, Tetrahedron, 1970, 26, 1043. K. Heusler, Helo. Chim. Acta, 1969, 52, 1520. Y. Watanabe, Y. Mizuhara, and M. Shiota, Chem. Comm., 1969,984. M. Akhtar, P. Hunt, and P. B. Dewhurst, J . Amer. Chem. SOC.,1965,87, 1807. A. Deluzarche, A. Maillard, P. Rimmelin, F. Schue, and J. M. Sommer, Chem. Comm., 1970. 976.

388

Terpenoids and Steroids

LTA-12).487 Inversion at C-6 is likely to involve rupture of the C(51-C(6) bond in a 6fl-oxyl radical to give a stabilised mesomeric aldehyde radical. Ring closure in the reverse stereochemical sense to give the less-hindered 6a-oxyl radical has precedents and can lead to the methylenedioxy-compound (703) by hydrogen abstraction from the suitably-placed Sa-methoxy-group. Similar reaction conditions converted the isomeric 5a-hydroxy-6#?-methoxy-compound into the 5,6-seco keto-aldehyde (704a) and its aldol derivative (704b).487

OAc

(705)

OAc (706)

H

(707) (a)

R

(b) R

= =

Me H

The syn-diaxial relationship of 3fl-OH and 5fl-Me in the ‘Westphalen’ compound (705) permitted formation of the 3&5’-ether (706).489 Treatment of the 20B-hydroxypregnan-12-one(707a) with LTA-iodine gave the 18,2O-lactone(708), in a double-oxidation reaction.490 Alkaline hydrolysis, with decarboxylation, gave the 18-norpregnane derivative (707b), having the normal trans-fusion of rings c and D despite the usual preference for cis-fusion of five- and six-membered rings. When the 12,12-ethylenedioxy-derivativewas used in place of the ketone, the 20-alkoxyl radical attacked the ethylenedioxy-group in preference to C-18, giving the bicyclic di-acetal (709). Formation of a sevenmembered ring is most unusual in such reactions. The simultaneous functionalisation of log- and 13P-methyl groups in 5a-lanostane-3fl,ll~-diol3-acetate with LTA-iodine under irradiation illustrates in novel fashion the possibilities for multiple reactions with this reagent system. The product was the 19-iodo-llP,l8ether (710).491 Earlier work has shown that 488

‘E9

4y0

49’

P. Morand and M. Kaufman, J . Org. Chem., 1969,34,2175. G . B. Spero, J . L. Thompson, W. P. Schnaider, and F. Kagan, J . Org. Chem., 1963, 28, 2225; K. Heusler, Tetrahedron Letters, 1964, 3975. I . G. Guest, J. G. L1. Jones, B. A. Marples, and M. J. Harrington, J . Chem. SOC.(0, 1969,2360. Y. Shimizu, Experieniia, 1970, 26, 588. P. Roller and C. Djerassi, J . Chem. SOC.(0,1970, 1089.

Steroid Properties and Reactions

389

11/?,19-ether formation is abnormally unfavourable in the lanostane series, explaining the selective formation of the 11/3,18-ether. The mechanism of cyano-group transfer to C-18, when a C-20 cyanohydrin is treated with LTA and iodine,492has been clarified by employing an alternative radical-forming reaction. A 17,21-acetal, derived from prednisolone, was converted into its 11/3-nitrite 20-cyanohydrin derivative (711). Photolysis of the 17

NC

I - CH2

AcO

lhv

nitrite caused hydrogen abstraction from C-18 in the usual way, but the 18-CH2 radical added on to the 20-cyano-group (712), causing its transfer to C-18.493 The product was the 18-cyano-20-ketone(713). It is apparent that rearrangement of a simple C-20 cyanohydrin involves addition of a similar C-18 radical, derived by attack of a 20-oxygen radical. Reactions of the same type involving steroid side-chains include the conversion of cholan-24-01 into isomeric 20,24-ethers and their 22-iodo-derivati~es~~~ the formation of the 17/3,23-ether from norcholan-23-01,~” and synthesis of a y-lactone in the c-nor-~-homo-series.~~~ All these reactions illustrate the usual need for a six-membered transition state for hydrogen abstraction, leading to a five-membered heterocyclic ring. 492 493 A94

A95 Ay6

J. Kalvoda, Helv. Chim. Acta, 1968, 51, 267. J. Kalvoda, Chem. Comm., 1970, 1002. Y. Shalon, Y. Yanuka, and S. Sarel, Tetrahedron Letters, 1969, 957. Y. Yanuka, S. Sarel, and M. Beckermann, Tetrahedron Letters, 1969, 1533. H. Suginome, H. Ono, and T. Masamune, Tetrahedron Letters, 1969, 2909.

Terpenoids and Steroids

390

The Barton reaction (photolysis of a nitrite ester497)has been employed to Nitrites of the 6aattack C-4 methyl substituents in 4,4-dimethyl-5a-~teroids.~~~ and 619-alcohols (714) afforded alkoxyl radical species, which attacked the 4aand 419-methyl groups respectively,giving the corresponding aldoximes (e.g. 715). Yields were quite high (56-60%) from the 6a-ol and the 19-nor-6/3-01, but attack

OH

R

=

II

Me or H ; 601- or 6b-series

on the 10P-methyl group by a 619-alkoxyl radical afforded the 19-oxime as major product from the normal 6P-alcohol. An interesting new photochemical reaction has achieved substitution at C-12 or dehydrogenation in rings c or D (‘remote oxidation’), from suitable ester groups at the 3a-position. Photo-excitation of either the 3a-@-benzoylphenyl)propionate (716)499 or -valerate (7 17),’0° under conditions which produce the excited triplet state of the benzophenone moiety, leads to hydrogen abstraction from sites determined by the length of the ester chain. The reaction may then be completed either by cyclisation at the site of attack, to give a macrolide (718), or by a second hydrogen abstraction, leading to an olefinic bond. The benzophenone is thereby reduced to a benzhydrol derivative. Suitable degradation499 of products obtained from the p-benzoylphenyl-propionategave the 12-ketone

(716) n = 2 (717) = 4 Jy7

4y8 49y

500

D. H. R. Barton, J. M. Beaton, L. E. Geller, and M. M. Pechet, J . Amer. Chem. SOC., 1960,82, 2640; D. H. R. Barton and J. M. Beaton, ibid., p. 2641; also ref. 13, p. 398. J . M. Midgley, J . E. Parkin. and W. B. Whalley, Chem. Comm., 1970, 789. R. Breslow and S . W. Baldwin, J . Amer. Chem. Soc., 1970,92, 732. J . E. Baldwin, A. K. Bhatnagar, and R. W. Harper, Chem. Comm., 1970, 659.

Steroid Properties and Reactions

39 1

and the and A14-olefins, derived by initial attack at C-12 and C-14, respectively. The p-benzoylphenyl-valerategave AI4- and AI6-olefins directly, as well as 14a- and 1 7 a - m a ~ r o l i d e s . ~ ~ ~ Deoxycholic acid, oxygenated in the presence of Fe" sulphate and ascorbic acid in a phosphate buffer, afforded the 15a-hydroxy-derivative in low yield.501 7a-Hydroxylation under similar conditions has been reported previously. Microbiological Hydroxy1ations.-Microbiological hydroxylations of steroid substrates are too numerous for general inclusion in this report, but two results are of particular interest. d- And dl- 19-nortestosterone, incubated with Curuularia lunata, both afforded the d-108-hydroxy-derivative as major product, implying enzyme specificity for the d-form. Several minor products, however, resulted from non-specific attack upon the two antipodes. The 118- and 68-hydroxylated derivatives, for example, were obtained as dl-mixtures from the dl-~teroid."~ Hydroxylations of most of the possible mono-0x0-5a-androstanes with cultures of Calonectria decora generally introduced two equatorial hydroxy-group~.~'~ The preferred sites of attack were either C-15 and C-12 (or C-ll), or C-6 with either C-1, C-11, or C-12. This micro-organism may have a particular preference for attack at these sites in the steroid molecule, but it also seems likely that the 0x0-group, by providing a point of anchorage of the steroid to the enzyme, may result in hydroxylation at a site having a definite geometrical relationship to the

Figure 7 Preferredsites of hydroxylation by Calonectria decora in typical 5u-androstanones

0x0-group. In Figure 7, for example, the arrowed carbon atoms are rather similarly related to the respective 0x0-groups. 8 Photochemical Reactions Some photochemically-induced reactions leading to attack on non-activated C-H bonds are discussed in Section 7. 501

502

503 504

M. Kimura, M. Kawata, M. Tohma, A. Fujino, and K. Yamasaki, Tetrahedron Letters, 1970,2021. B. Matkovics, P. Penzes, and Gy. Gondos, Steroids, 1965, 5 , 451. Y. Y. Lin, M. Shibahara, and L. L. Smith, J. Org. Chem., 1969, 34, 3530. J. E. Bridgeman, J. W. Browne, P. C. Cherry, M. G . Combe, J. M. Evans, Sir Ewart R. H. Jones, A. Kasal, G. D. Meakins, Y. Morisawa, and P. D. Woodgate, Chem. Comm., 1969, 463; see also J. M. Evans, Sir Ewart R. H. Jones, A. Kasal, V. Kumer, G. D. Meakins, and J. Wicha, ibid., p. 1491.

Terpenoids and Steroids

392

Unsaturated Steroids.-Irradiation of cholesterol or cholest-4-en-3P-01 (7 19) in ben~ene-ether,"~or in aqueous-organic solvent mixtures containing xylene as s e n ~ i t i s e r , ~affords ~' the oxetan (722; ca. 20%); in the aqueous system, 5gcholestane-3/i',5-diol(723; 54 %) is also formed. With deuterium oxide instead of water, cholesterol gave the 6~-monodeuterio-3/3,5~-diol, showing the reaction to

(723)

(722)

be a direct photocatalysed addition of water, but the oxetan incorporated two atoms of deuterium.'06 The likely mechanism for oxetan formation involves isomerisation of cholesterol to give the 4-en-3P-01, then protonation at C-4 and cleavage of ring A (720 + 721), followed by a photo-addition between the aldehyde and exocyclic methylene group in the 3,4-seco-intermediate (721), traces of which were isolated from the non-aqueous system. Cholest-4-ene and -5-ene add methanol photochemically to give 5-methoxy-5aand -SP-cholestanes, the latter p r e d ~ m i n a t i n g . ~Propan-2-01 ~' affords only the 5/3-isopropoxy-derivative,along with the 5a- and 5/3-01s as major products. The photo-isomerisation of trimethylsilyl ethers of tachysterol, (724) and previtamin D, (725) in benzene is triplet-sensitised, and leads to an equilibrated mixture (20 : 80, r e s p e c t i ~ e l y ) .Since ~ ~ ~ no cyclisation to 5,7-dienes509 was observed, it seems likely that cyclisation would require singlet excitation. Cycloadditions of ethylene (or halogenated ethylenes), acetylene, or allene, onto the AI6-bond of a pregn-16-en-20-one, gave cyclobutano-derivatives (726), (727), or (728) re~pectively.~ l o Hexafluoroacetone similarly afforded the ' 0 5

5ob '07

D. Guenard and R . Beugelmans, Tetrahedron Letters, 1970, 1705. J. A. Waters and B. Witkop, J . O r g . Chem., 1969, 34,3774. H. C. de Marcheville and R. Beugelmans, Tetrahedron Letters, 1969, 1901. A. E. C. Snoeren, M. R . Daha, J . Lugtenburg, and E. Havinga, Rec. Trau. chim., 1970, 89, 261.

'09

'Io

L. F. Fieser and M . Fieser. 'Steroids'. Reinhold, New York, 1959, pp. 1 4 C 1 5 0 ; ret'. 13, p. 414. P. Sunder-Plassrnan, P. H. Nelson, P. H. Boyle, A. Cruz, J . Iriarte, P. Crabbe, J. A. Zderic, J . A. Edwards, and J. H. Fried, J . Org. Chem., 1969, 34, 3779.

Steroid Properties and Reactions

393

oxetan (729). In each case approach was to the less hindered a-face of the 16,17-bond.

H

H

H

H

Carbonyl Compounds.-The photo-isomer of 1 1-oxolanostanol, earlier thought to be the 11#l,18-cyclo-lla-ol, is now known to be the 1 1 ~ , 1 9 - ~ y c l o - l l a - o l , ~ ~ ~ in agreement with products derived photochemically from other 1l-ketones. Further studies of the photo-isomerisations possible with testosterone acetate5 * have gone far towards clarifying the photochemical changes involved. Experiments in sensitisation and quenching indicate triplet excited states as the reactive species.' l 3 Testosterone acetate (730), irradiated above 327 nm in t-butanol, is converted reversiblyinto the 1,5-cycloketone(731),the equilibrium being gradually depleted by irreversible formation of the product (732). In toluene, the main product is the 4-benzyl-ketone (733), resulting from photo-addition of solvent. These reactions are thought to involve the n + n* triplet state. In benzene, isomerisation to give the 5-en-3-one predominates. The mechanism is believed to involve hydrogen abstraction from C-6 in a ground-state ketone by the oxygen of an excited (n-+n* ;triplet) ketone. 1Oa-Testosterone acetate, under n * n* excitation in t-butanol (253.7 nm), gives the 5-en-3-one (with 2H at C-4 when deuteriated solvent was used). The 5 L L 512

513

R. Imhof, W. Graf, H. Wehrli, and K. Schaffner, Chem. Comm., 1969, 852. B. Nann, D. Gravel, R. Schorta, H. Wehrli, K. Schaffner, and 0. Jeger, Helu. Chim. Acta, 1963, 46,2473. D. Bellus, D. R. Kearns, and K. Schaffner, Hefu. Chirn. Acta, 1969, 52, 971.

a '

394

Terpenoids and Steroids

*hw, i.> 327 nmh Bu'OH

0

(732)

Ph (733)

same product resulted from irradiation in benzene, this time by an intramolecular hydrogen transfer (see above) involving the n ---* x* triplet.514 Prolonged irradiation of 1,4-dien-3-ones proceeds through a sequence of isomeric ketonic productsS1 to give finally a mixture of methylphenols. In the cholestane series, four phenols (734-737) have now been identified. Irradiation

Me (734)

(735)

OH

Me

(736)

(737)

in a solution containing sodium borohydride disturbs the proportions of the phenolic products, giving also the deoxy-+methyl aromatic c o m p o ~ n d . ~ Calculations of orbital overlap interactions have been applied to the study of photochemical and thermal dimerisation of a 3,5-dien-7-one and 4J~dien-3one.517 Several C,,,-substituted 5-en-3-oneshave been converted into photo-isomers, of diverse structures. Irradiation of a 4,4-dimethyl-Sen-3-one in benzene caused attack of the carbonyl oxygen on the 4B-methyl group, giving the 3B,4B-oxetan (738b518 In the 19-nor analogue the product was a different oxetan, the 514 '15

5'h

"'

S. Kuwata and K. Schaffner, Helc. Chim. Acta, 1969, 52, 173. J. Frei, C. Ganter, D. Kagi, K . Kocsis, M . Mitjkovic, A. Siewinski, R . Wenger, K . Schaffner, and 0.Jeger, Heir. Chim. Acta, 1966,49, 1049. J. A. Waters and B. Witkop, J . Org. Chem., 1969, 34, 1601. A. Devaquet and L. Salem, J . Amer. Chem. Soc., 1969,91, 3793. K . Kojirna, K . Sakai, and K . Tanabe, Tetrahedron Letters, 1969, 3399.

Steroid Properties and Reactions

395

3g6a-ether (739).5l 8 Both reactions could be interpreted as proceeding through hydrogen transfer from a 4-methyl group to C-3 in a 3,4-seco-diradica1(740),to give a seco-diene-aldehyde (741), followed by cycloaddition of the aldehyde with

one or other of the olefinic bonds. Accepting carbonyl addition to the 5,6-bond in the 19-nor compound as the ‘normal’ reaction, affording (739), a 10P-methyl group would oppose this addition by its compression in the transition state with the SP-isopropenyl group. Addition to the isopropenyl group itself is then preferred. A different mode of reaction of the same ketones, leading to 5,6-cyclopropanoA-nor-ketones (742), occurred under photosensitisation by acetone or other ketonic solvents (via a t r i ~ l e t )l.9~ Here bonding apparently occurs between C-3 and C-5, and also between C-4 and C-6, with fission of the C(3)-C(4)bond. (See also below.) Photo-isomerisation of 5-en-7-ones (743) above 300 nm affords an equilibrated mixture of 4-en-7-one (745) and the rearranged product (746).520*521 Although the latter may be named as a 3(4+ 6)-abeo-steroid, its formation involves rupture of the C(6)--C(,)bond and attack of C-7 upon C-4 in the ally1 radical (744). At shorter wavelengths (253.7nm) two new photodimers of a 5-en-7-one have been obtaineds2’ (see Part 11, Ch. 2, p. 499). Triplet excitation of the 4,4-dimethyl-5-ene-3,7-dione (747) affords the 5,6-epimeric 5,6-~yclopropanodiketones(748),522323 in a reaction apparently analogous to that of the 3-monoketone above. Loss of stereochemical distinction between the 4a- and 4P-methyl groups, revealed by deuterium labelling,523is not 519 520 521

522

523

K. Kojima, K. Sakai, and K. Tanabe, Tetrahedron Letters, 1969, 1925. N . Furutachi, Y. Nakadaira, and K. Nakanishi, J . Amer. Chem. Soc., 1969, 91, 1028. J. Hayashi, N . Furutachi, Y. Nakadaira, and K. Nakanishi, Tetrahedron Letters, 1969,4589. S. Domb, G. Bozzato, J. A. Saboz, and K. Schaffner, Helv. Chim. Acta, 1969,52,2436. S . Domb and K. Schaffner, Helv. Chim.Acta, 1970, 53, 677.

mo '

Terpenoih and Steroids

396

Ac 0

Ac 0

Jfio

Ac 0

OAc

(745)

(746)

compatible with the orbital symmetry conservation required in a concerted reaction, so a stepwise mechanism is inferred, as depicted in Scheme 29.

a'o hv

0 Me CD,

@Me o

Me 'CD,

CD,

J

Me CD,

Scheme 29

Photodecarbonylation of the 3,5-cyclo-19-aldehyde (749) gave the 5( 10)-ene (750).I4O A similar product (751) resulted from photochemical decarbonylation of the 6-formyl-5(lO)-ene (752), but the isomeric As-19-aldehyde (753) gave the 19-nor-5-ene ( 7 ~ ) . ~ ' ~ The trans-ylideneacetic acids (755) and (756) isomerise under irradiation to give their cis-isomers: the ring A compound (756) then affords the hydroxylactone (7571.' 2 4 524

M.Debono and R. M . Molloy, J .

Org. Chem., 1970,35, 483.

Steroid Properties and Reactions

a ‘

R 1

1 R’

OMe (749)

397

(750) R = H ; R’ = P-OMe (751) R = F ; R’ = H

(753) R (754)

R

= =

F CHO (752)

CHO H

Miscellaneous Photochemical Reactions.- 14a-Steroids are converted in to an equilibrium mixture of 14a- and 14P-isomers(ca. 1 : 19) on irradiation at 254 nm, in cyclohexane containing mercuric chloride or The reaction comprises abstraction of 14-H and recombination, probably involving bromine atoms. Other isomerisations at tertiary hydrogen permit equilibrations, e.g. of cis- and trans-decalins, but the 58 + Sa-steroid conversion is very slow compared with reaction at C-14. Distortion from ideal bond-angles at C-14 probably ‘loosens’ the hydrogen atom here. Axial secondary methyl substituents can also be epimerised into the more stable equatorial conformation. Acetates or benzoates of saturated or A4- or A5-unsaturated 3P-hydroxysteroids are deoxygenated by photolysis in hexamethylphosphotriamide. 26 Photochemical rearrangements of the 4,5-epoxy-6-ketone(758) and 5,6-epoxy4-ketone (759) lead initially to normal P-dicarbonyl products (Scheme 30) by migration of a hydrogen atom or ring carbon atom.527 Decarbonylation of the keto-aldehydes leads to ring-contracted monoketones (760) and (761). The 5a4,6-dione (762), derived from either of the P-epoxy-ketones, is obtained in enolic 526

M. Gorodetsky, D. Kogan, and Y . Mazur, J . Amer. Chem. Soc., 1970, 92, 1094. R. Beugelmans, M. T. Le Goff, and H. C. De Marcheville, Compt. rend., 1969, 269,

”’

C, 1309. J. P. Pete and M. L. Villaume, Tetrahedron Letters, 1969, 3753.

525

Terpenoids and Steroids

398

0.

m'

(758)

@ *'

0

0

0

\

minor

hv

___)

r"9

CH C II

0

0

II

(765)

0 (764)

Scbeme 30

form. The corresponding a-epoxy-ketones, however, apparently give first the 5P-4,6-dione (763), which undergoes further reaction, suffering rupture of the 4,5-bond at a rate faster than its enolisation. Being axial with respect to ring B,

399

Steroid Properties and Reactions

the 4,5-bond is stereo-electronically favourable for rupture, through overlap in the transition state with the carbonyl n-orbital at C-6. The product, a keten (764), is readily hydrated to give the keto-acid (765). The isomeric 9,10-epoxyoestr-4-en-3-ones(766) and (767) mainly afford 8(9 --+ lO)-ubeo-ketones(768)and (769), respectively,on p h o t o l y ~ i s The . ~ ~latter ~ product is accompanied by the 1l(9 + lO)-ubeo-isomer. Each product results from epoxide-cleavage at C-10 to give a resonance-stabilised radical, and migration of either C-8 or C-1 1, possibly concerted with epoxide cleavage. (c5 Part 11, Ch. 2, p. 501.)

___, hv

(768) a-bond C(lo)-C(g);8-bond C(lo)-C(8) (769) fi-bond C~lo)-C(9,; or-bond C(10)-C(8)

(766) a-epoxide (767) /?-epoxide

3a,5-Cycl0-5a-cholestan-6~-01,irradiated in benzene-methanol, gave the 6pmethoxy-compound and cholesteryl methyl ether,529 in ratio similar to that obtained under kinetically controlled solvolytic conditions. The reaction is thought to involve the mesomeric cholesteryl cation rather than free-radical intermediates. Photolysis of a 6P-azide (770) gave the 6-imino-compound (771) and the cyclic imine (772),530both probably resulting from rearrangements of a 6P-nitrene. No insertion of the nitrene into a C,,,,-H bond was detected (cf. ref. 531).

___) hv

@ NH

+ HN

Oxime acetates or benzoates afford their parent ketones on triplet-sensitised photolysis, or the amides (lactams) by direct photo-isomerisation. Both products probably result from further reactions of an intermediate oxaziran (Scheme 31), 528

529 530

531

M . Debono, R. M. Molloy, D. Bauer, T. Iizuka, K. Schaffner, and 0. Jeger, J . Amer. Chem. SOC., 1970, 92, 420. R. Beugelmans and H. C. de Marcheville, Chem. Comm., 1969,241. A. M. Farid, J. McKenna, J. M. McKenna, and E. N. Wall, Chem. Comm., 1969, 1222. D . H. R. Barton and L. R . Morgan, J . Chem. SOC.,1962, 622; see, however, D. H. R. Barton and A. N. Starratt, J . Chem. SOC., 1965, 2444.

Terpenoids and Steroids

400

Scheme 31

derived from cyclisation of the singlet-excited oxime ester.53 Irradiation of C-3 oximes in benzene gave the 3-oxo-compounds as principal products.533 Irradiation of enol and dienol trichloroacetates in t-butanol gives decarbonylated products, derived from recombination of enolate and trichloromethyl radicals. The trichloromethyl ketones readily lose the elements of hydrogen chloride to give dichloromethylene ketones (e.g.Scheme 32).534Upon irradiation

Scheme 32

in cyclohexane, however, bond dissociation occurs within the trichloroacetate ester group. Hydrogen transfer from the solvent gave the enol dichloroacetate and formate, as well as the trichloromethyl ketone. Dienol sulphonates (773), in contrast, give 6B-sulphones (774), resulting from recombination of radicals formed by S-0 bond diss~ciation.~ The same

mF0q‘ oq‘

RSOzO

CI

SOzR (773)

(774)

(775)

’” R. Beugelrnans and J.-P. Verrnes, Bull. SOC.chim. France, 1970, 342. J.-P. Verrnes and R. Beugelrnans, Tetrahedrm Letters, 1969, 2091, ’’‘ J. Librnan, M. Sprecher, and Y. ‘Mazur,J . Amer. Chem. Soc., 1969,91,2062. s3J

35

N . Frydrnan and Y . Mazur, J . Amer. Chem. SOC.,1970,92,3203.

c1

Steroid Properties and Reactions

401

reaction occurs thermally at lOO"C, and is promoted by benzoyl peroxide, but inhibited by hydroquinone. As further evidence of free-radical intermediates, the reaction at 100 "C in bromotrichloromethane, an excellent free-radical carrier, gave the 6-dichloromethylene-4-en-3-one (775) in high yield. 9 Miscellaneous Reactions Analytical Methods.-Applications of well-known reactions for the estimation of steroid hormones, and metabolites of biological origin, are too numerous for inclusion in this report. A Hungarian language review (230 reference^)'^^ covers a wide range of steroid hormones and related compounds, and demands translation. A few analytical methods have been selected as being of particular interest to organic chemists. The spectrophotometric determination of 0x0-steroids as their glyoxalyl derivatives is mentioned on p. 331. The Kober reaction and its modific a t i o n ~ ,7 ~* s 3 8 in which a phenolic steroid is heated with moderately concentrated sulphuric acid to generate chromogenic materials, is still not fully understood. Oestradiol 3-methyl ether, with 78 % sulphuric acid, gives a mixture including isomers of the 17-methyl-18-norstructure (776), and the derivative (777) with an

aromatic ring cS3'These products represent reduction and dehydrogenation, respectively, and both hydrogen sulphide and sulphur dioxide are evolved. Disproportionation reactions involving carbonium ions seem likely. Although the Kober responses of several phenolic steroids are characteristic, some (e.g. 16-hydroxyoestrones) fail to give useful Kober reactions. These oestrogens can be distinguished by studying their fluorescence spectra in either 100"/, phosphoric or 30N sulphuric An extensive study is reported540of the visible spectra of steroids in the Engelbrecht-Mori-Anderson reagent (FeCl, in acetic-phosphoric-sulphuric acids). The chromophores produced are characteristic of various structural features, but their nature is unknown. 536 537

53M 539

540

S. Gorog, Kem. Kozl., 1970, 33, 271. S. Lauzon, Bull. SOC.chim. biol., 1970,52, 181. H. A. Jones and R. Hahnel, Nature, 1967,215, 1381; Steroids, 1969, 13, 693. M. Kimura, K. Akiyama, K. Harita, T. Miura, and M. Kawata, Tetrahedron Letters, 1970, 377. E. E. Sandmeyer, Med. Exp., 1969, 19, 210, 241.

402

Terpenoids and Steroids

11fl-Hydroxy-steroids, which are known to dehydrate with great ease in acidic solutions, afford a chromogen (yellow) of unknown structure on heating in concentrated hydrochloric Considerable variations in A,, depending upon other structural features offer possibilities for identification. An ingenious micro-method for recognition and determination of A22-sterols (e.g. ergosterol) involves periodate-permanganate oxidation, followed by gaschromatographic analysis of fatty-acid fragments derived from the ~ i d e - c h a i n . ' ~ ~ Fragments from the ring structure are too massive to cause interference. Novel derivatives for gas-chromatographic analysis of steroids, with electroncapture detectors, include (halogenomethy1)dimethylsilyl ethers (778),543 pentaf l u o r ~ b e n z o a t e smethyl , ~ ~ ~ hemiacetals (779) derived from steroid alcohols and dichlorotetrafluoroacetone,545and dienol heptafluorobutyrates, readily obtained from 4-en-3-0nes.~~' Liquid chromatography of steroids on columns of long-chain alkyl ethers of Sephadex offers useful separations under very mild conditions, with either normal or reversed-phase systems. The retention volume of a compound depends upon its polarity, the degree of substitution of Sephadex, and the solvent system.546 Me

I

R-0-Si-CH,X

I

Me (778)

CF2Cl

I

R-0-C-OMe

I

CF,CI (779)

MisceUaoeous.-Tetramethyl-bismethylenedioxy-derivatives (780) of the dihydroxyacetone side-chain are readily prepared by the action of acetone and perchloric As protecting groups they appear to have advantages over the well-known bismethylenedioxy-compounds,especially in being more readily hydrolysed. NN-Dimethylhydrazones can be used to protect oxo-groups, during oxidation, reduction, hydroboronation, hydrolysis, etc., elsewhere in the molecule.

'" 542

543

A. Szabo and A. Mizsei, Steroids, 1970, 15, 513. F. B. Mallory, K . A. Ferguson, and R. L. Conner, Anal-vt. Biochem., 1970, 33, 230. C. Eaborn, C . A. Holdern. D. R . M. Walton, and B. S. Thomas, J . Chem. Soc. (C),

1969,2502. 54J

"' '" 547

A. Zmigrod, S. Ladany, and H. R . Lindner, Steroids, 1970, 15, 635. G. A. Sarfaty and H. M . Fales, Analyr. Chem., 1970, 42, 2 8 8 . J. Ellingboe, E. Nystrom, and J . Sjovall, J . Lipid Res., 1970, 11, 266. A. Roy, W. D. Slaunwhite, and S. Roy,J . Org. Chem., 1969,34, 1455.

Steroid Properties and Reactions

403

Regeneration of the 0x0-group is readily achieved by quaternation with methyl iodide, and addition of Deoxycholic acid crystallizes from aromatic solvents as inclusion compounds with characteristicproperties. A single molecule of solvent appears to be trapped in the cavity formed by association of a pair of deoxycholic acid Criteria for the identification of steroids from biological sources have been discussed. Amounts are often very small. The reliability of conclusions based upon chromatographicand spectroscopictechniques is critically reviewed, as are the special methods available for identification of traces of isotopically-labelled

steroid^.^"

548 549

M. Avaro, J. Levisalles, and H. Rudler, Chem. Comm., 1969, 445. Z. Csuros, G. Deak, and M. Novak-Kiss, Acta Chim. Acad. Sci.Hung., 1970, 63, 425. C. J. W. Brooks, R. V. Brooks, K. Fotherby, J. K . Grant, A. Klopper, and W. Klyne, J . Endocrinol., 1970, 41, 263.

2 Steroid Synthesis BY P. J. MAY

1 Introduction

The period under review has seen the publication of the IUPAC-IUB 1967 Revised Tentative Rules for Steroid Nomenclature' and the appearance of a comprehensive book on steroid reaction mechanisms2 which should be of great value to all those engaged upon synthetic steroid chemistry as well as those concerned with mechanistic studies. Reviews have appeared on general steroid chemistry3 and the latest developments in contraceptive, anti-androgenic, and cardiac-active steroid^.^ Reviews on specific topics include the Barton5 and Torgov6 reactions, the addition of dihalocarbenes to steroids,' the partial synthesis of 19-nor-~teroids,~ the total synthesis of oestrogens and related compound^,^ the direct alkylation of steroids," and the complete dehydrogenation of steroids with quinones.' A fascinating article" on the chemistry of the defence mechanisms of beetles reviews the steroids which are used for this unexpected purpose. Other steroids which have subsequently been i ~ o l a t e d ' ~ from prothoracic defence glands include the rarely occurring l2P-hydroxycompounds.

'

1

Biochim. Biophys. Acta, 1968,164,453 ; J . Org. Chem., 1969,34,15 17; Steroids, 1969,13, 278.

1

3

D. N . Kirk and M. P. Hartshorn, 'Steroid Reaction Mechanisms,' Elsevier, Amsterdam, 1968. D. Taub and T. B. Windholz, 'Kirk-Othmer Encycl. Chem. Technol.,' 2nd Edition, 1969, 18,830-896.

4

5

h

8

9 10 11

12

I3

14

R. Wiechert, Angew. Chem. Internal. Edn.. 1970, 9, 321. R. H. Hesse, 'Advances in Free-radical Chemistry.' Vol. 111. ed. G . H . Williams, Logos Press Ltd., London. J . Weill-Raynal, Bull. SOC.chim. France, 1969, 4561. P. Crabbe, Ind. chim. belge, 1969, 34, 15. K . Tanabe, Ann. Report Sankyo Res. Lab., 1968, 20, 1. D. K . Banerjee, J . Indian Chem. SOC.,1970, 47. 1. A. A. Akrem, T. V. Illyukhima, and Yu. A. Titov, Russ. Chem. Rev., 1969,39, 8 5 0 . H. Dannenberg, Synthesis, 1970, 1, 74. H. Schildknecht, Angew. Chem. Inrernat. Edn., 1970,9, 1. A. T. Sipahimalani, V. R. Mamadapur, N. K . Joshi, and M . S. Chadha, Naturwiss., 1970, 57, 40. M . S. Chadha, N. K . Joshi, V. R. Mamadapur, and A. T. Sipahimalani, Tetrahedron, 1970, 26, 206 1.

Steroid Synthesis

405

The naturally occurring cardenolides' and the functions and chemistry of insect moulting hormonesI6 have been reviewed. The synthesis of steroid phosphates, sulphates, and glycosides has been summarised in a new book' which draws attention to inadequacies in the current Rules of Carbohydrate Nomenclature when two types of glycosidic linkages are present, and in which is proposed a modification of these rules applicable to steroid glycosides. The gross biological activity of various classes of steroids has been briefly reviewed' and their action at cellular and molecular levels discussed.' The texts of the Plenary Lectures presented at the Sixth International Symposium on The Chemistry of Natural Products have been published ; these include papers on steroidal alkaloids and sapogenins,2O0 synthetic cardeno1ides,20b mass spectrometry of steroids,20cphotochemical transformations of steroids which have preparative value,20dand new methods of specific fluorination of steroids.20e A series of graduate lectures on selected topics has appeared.21 Analytical techniques applicable to steroids and the synthesis of isotopically labelled steroids of high specific activity are amongst the topics reviewed in the latest volume of a comprehensive treatise on enzymology22and the first volume of a new series of books on steroid biochemistry includes a review of the steroids found in marine invertebrates and plants.23 2 Steroid Lactones

Bufadienolides-The difficulties associated with the construction of a 148hydroxy-l7P-a-pyrone system have been successfully overcome at last in the first reported synthesis24 of a naturally occurring bufadienolide (Scheme 1). Catalytic reduction in the presence of base followed by sodium borohydride reduction of the 14-hydroxy-A4-3,l7-dione (1) gave the 3a-hydroxy-5fl-derivative (2) together with some 3/l-hydroxy-isomer. Addition of lithium ethoxyacetylide and rearrangement of the product with dilute acid gave the unsaturated ester (3). Metal-ammonia reduction of the free acid and dehydration of the acetylated and esterified product afforded a mixture of A14- and A8('4)-isomers; the former isomer (4), which predominated, was converted, via the 3,21-bisimidazole 15

I 6 17

18 19

20

21

22

23 24

B. Singh and R. P. Rastogi, Phytochemistry, 1970,9, 3 15. C. E. Berkoff, Quarr. H. E. Hadd and R. T. Blickenstaff, 'Conjugates of Steroid Hormones,' Academic Press, London, 1969. T. L. Popper and A. S. Watnick, Ann. Reports Medicin. Chem., 1970, 192. J. K . Grant, 'Essays in Biochemistry,' ed. P. N. Campbell and G. D. Greville, Academic Press, London, 1969. K. Schreiber, Pure Appl. Chem., 1970, 21, 131 ; R. Deghenghi, ibid., p. 153; ' C. Djerassi, ibid., p. 205; 0. Jeger and K. Schaffner, ibid., p. 247; ' D. H. R. Barton, ibid., p. 285. L. J. Chinn, J. S. Baran, P. D. Klimstra, and R. Pappo, Inrra-Sci. Chem. Reports, 1969, 3, No. I . 1 . 'Methods in Enzymology,' Vol. XV, ed., R. B. Clayton, Academic Press, London, 1969. J. Austin, 'Advances in Steroid Biochemistry and Pharmacology,' Vol. 1, Ed., M. H. Briggs, Academic Press, London, 1970. F. Sondheimer, W. McCrae, and W. G. Salmond, J . Amer. Chem. SOC.,1969,91,1228. O

& & Terpenoids and Steroids

406

0

0

OH

-%

iii, iv

0

ROO*

H (2) R

=

H

COzMe

CO2 Et

CHO I

I

I

{5v. vi. vii

OH

(3) R

=

(4) R

=

(5) R = H

AC

H 0

CHOH

CHOMe I1

-

II

xv

xvi

+

(7) R

( 6 ) R = AC

=

AC

xvii, xviii xix, xx, viii

(8) R = AC

0

0

xxi. xxii xxiii 4

RO

OH

H (9) R

=

(10)R = H

AC

(11)

R

=

H

Reagents: i, H,-Pd; ii, NaBH,-MeOH; iii, LiC=C.OEt; iv, 2 N - H , S 0 4 ; v, K,CO,MeOH-H,O; vi, K-NH,Aioxan; vii, CH,N,-MeOH; viii, Ac,O-py; ix,

N--\ POCI,-py;

x, i=/"-CO.NJ

/" ;

xi, LiAI(OBu'),H-THF;

xii, H,SO,-

Bu'OH; xiii, TsOH-MeOH; xiv. POCI,-DMF; xv, NaOH-EtOH-H,O; xvi. BrCH ,CO,Et-Zn-DMF; xvii, HCl-MeOH-H,O; xviii, TsOH-py ; xiv, DMF.; xx, AI,O,-Et,O; xxi, NBS; xxii, Basic AI,O,; xxiii, LiAIH,-Et,O. Scheme 1

Steroid Synthesis

407

derivative, into the unsaturated aldehyde (5). The derived 3-acetoxy-21-dimethylacetal underwent a Vilsmeier reaction to afford a 3 : 1 mixture of cis (6)and trans side-chain isomers. The cis-isomer (6)gave the enolised P-dialdehyde (7) on treatment with base, and the a-pyrone system was then completed by a Reformatsky reaction to give (8). Inversion of the 3a-hydroxy function via the tosylate to give (9) and introduction of the 14P,lSD-epoxide with hypobromous acid and base and subsequent hydrolysis of the 3-acetate completed the synthesis of resibufogenin (10). Hydride reduction afforded the naturally occurring 14P-hydroxybufadienolide bufalin (1 1). Two short syntheses of 14a-bufadienolides have been described2’ in which either of the aldehyde derivatives (12) or (15) are treated with carbomethoxymethylenediethylphosphonate to give the unsaturated esters (1 3) and (16). The former was then cycIised directly to the bufadienolide (14) whilst (16) was converted to the free aldehyde (17) before cyclisation. The aldehyde derivatives (12) and (15 ) are readily prepared by short reaction sequences involving reaction of the dimethyl acetal(18) with either methoxymethylenetriphenylphosphorane or dimethylsulphonium methylide. Use of this latter route gives the spiro-epoxide (19) from which the protecting groups are removed by acid hydrolysis with concurrent opening of the spiro-epoxide, which has to be subsequently re-formed. CHO

I

C=CHOMe

CH=CHCO,Me

I

HCI-MeOH

(12)

R = THP

(13) R

=

THP (14)

CHO

I

CH=CH.CO,Me

(15)

25

R

=

H

(16)R

=

H

=

T

HCI-MeOH

H

{fiHo CH=CHCO,Me

I

{878

R

I

BF;Ih:O,

(17)

R

=

H

K. Radscheit, U. Stache, W. Haede, W. Fritsch, and H. Ruschig, Tetrahedron Letters, 1969. 3029.

Terpenoids and Steroids

408 CH(OMeh

$q

CH(OMe),

I

I

Me,SO : CH,

, (18)

R

= THP

I,

HBr-Me,C&THF

ii, Et,N

*

(15)

(19) R = THP

0 CH(OMe),

I

0

Application2 of this method to the ring-A-protected A’ 4-keto-acetal (20), obtainable in 60 yield from 15a-hydroxycortexone, gave 14-anhydroscillarenone (21). Introduction of the 14P-hydroxyl by reduction of the derived 14&15abromohydrin gave scillarenone, which was then reduced to scillarenin (22). The ring-D-saturated 3b,5a-epimeric analogue (23) of the Sondheimer inter* ~ alkylation * of its enamine to the aldehyde mediate ( 5 ) has been ~ o n v e r t e d ~ ’ by ester (24). Acid treatment of the free acid (25) then gave the novel type buf-202b

’’ 28

U . Stache, K . Radscheit, W. Fritsch, H . Kohl, W. Haede, and H. Ruschig, Tetrahedron Letters, 1969, 3033. G. R. Pettit, D. C. Fessler, K . D. Paull, P. Hofer, and J. C. Knight, Cunad. J . Chem., 1969,47, 251 I . G . R. Pettit, D. C. Fessler, K . D. Paull, P. Hofer, and J . C. Knight, J . Org. Chem., 1970, 35, 1398.

Steroid Synthesis

409

enolide (26) which could be dehydrogenated to the bufadienolide with sulphur in 60 % yield. The same aldehyde (23) gave,29 on condensation with first formaldehyde and then malonic acid, the aldehyde-diester (27), which was cyclised directly or via the free diacid (28)to the bufenolide (26)and dehydrogenated to the bufadienolide with selenium dioxide in t-butanol. CHO

(23) R'

=

AC

0 C 0 2R2

(24) R' (25) R'

= =

Ac, Rz Ac, R 2

= =

Me H

(26) R'

=

AC

(27) R' = H , R 2 = Et (28) R' = Ac, R 2 = H

Cyclisation and dehydrogenation of the 5fi-A14-analogue(30)of (25) obtained by homologation of the lactone ring of 14-anhydrodigitoxigenin (29) allowed the first chemical conversion3' of a cardenolide into a bufadienolide, as shown in Scheme 2. The lactone (31),obtainable in three steps from cholanic acid,31 served as the starting point in a different approach.32 Phosphorus oxychloride-pyridine dehydration of the corresponding hydroxy-methyl ester afforded a complex mixture of unsaturated esters in which the cis and trans non-conjugated esters (32) predominated Hydrolysis of the entire mixture and treatment of the mixture of free acids with N - bromosuccinimide gave the new buf-20(22)-enolide (33). DDQ dehydrogenation of (33) could be controlled33 to yield either the desired bufaz9

30

31 32 33

Ch. R. Engel, R. Bouchard, A. F. de Krassny, L. Ruest, and J. Lessard, Steroids, 1969, 14, 637. G . R . Pettit, L. E. Houghton, J. C. Knight, and F. Brunschweiler, Chem. Comm., 1970, 93. S . Sarel, Y . Shalon, and Y. Yanuka, Tetrahedron Letters, 1969, 957, 961. S. Sarel, Y . Shalon, and Y. Yanuka, Chem. Comm., 1970, 80. S. Sarel, Y . Shalon, and Y. Yanuka, Chem. Comm., 1970, 81.

410

Terpenoids and Steroids

C 0 2Me CH(OMe), I . II. 111

IV

--*

AcO H

(29)

v. vi. viI

w Vlll

Reagents: i, MeONa-MeOH; ii, TsOH-MeOH: iii, Ac,O-py; iv, HS[CH,],SH-HCIO,; v, (COCI),; vi, C H , N , ; vii, Ag,O-Na,S,O,; viii, HgO-HgCI,; ix, TsOH; x, S. Scheme 2

20,22-dienolide when carried out under reflux in the presence of toluene-p-sulphonic acid or to give a mixture of equal amounts of (34)and (35)containing only a trace of a-pyrone when the reaction was carried out at room temperature in the presence of hydrogen chloride; (34) and (35) were not convertible to the 20,22dienolide. 0 0

Steroid Synthesis

41 1 0

0

Irradiation in methanol of 14P-hydroxy-17fi-a-pyrones,e.g. bufalin (1 1)and its 16b-acetoxy- and 1la-hydroxy-derivatives, bufotalin and gamabufotalin, gives rise34to the 14B,21-oxides,e.g. (36), whose structures were confirmed by synthesis. Oxide formation is impossible in the absence of a 14B-hydroxyl and thus, with resibufogenin (10) and 14a-artebufogenin (37), the reaction35 is terminated by the addition of solvent leading to the vinyl ethers (38) and (39) respectively. 0

0

0

II

C

II

CH MeOH ___*

OH

OH

OH

C02 Me (Co2Me

34

35

I

CH

Fo2Me

Y. Kamano and M. Komatsu, Chem. and Pharm. Bull. (Japan), 1969,17, 1698. Y. Kamano, Y. Tanaka, and M. Komatsu, Chem. and Pharm. Bull. (Japan), 1969, 17, 1706.

Terpenoids and Steroids

412

In contrast to the reduction of the 14P,15/?-epoxideof marinobufagenin to give the 14~-hydroxy-compoundtelocinobufagenin, no bufalin (11) was detected36 when resibufogenin (10) was reduced with sodium borohydride ; the major product (40) was that resulting from cleavage of the a-pyrone system. This, after acetylation, could be ozonised3' to give the pregnane derivative (41) in 50% overall yield from (10).

The major product of HI reduction of both resibufogenin (10) and its 14a,1501epoxy-i~omer~' is the A ' 4 - ~ ~ m p (9). ~~nd The cardiotonic activity of resibufogenin has been reported.39 Interesting new naturally occurring bufadienolides include bersaldegenin orthoacetate4' (42 ; R = CHO) and rne1ianthusigenin:l (42; R = CH,OAc) the first naturally occurring orthoacetates, hellebrigenin 3,Sdiacetate (43), notable as the first natural 5-acetate to be isolated:2 and hellebrigenin 3-acetate (44)which is the first cardiotonic steroid to show in cico antitumour activity. 0

0

R Z = AC RZ = H

(43) R '

=

(44)R'

= Ac,

"

Y. Kamano, H. Yamamoto, and M . Komatsu. Chem. and Pharm. Bull. (Japan), 1969,

"

17, 1246. Y . Kamano, H . Yamamoto, and M . Komatsu, Chem. and Pharm. Bull. (Japan), 1969, 17, 1251.

Y . Kamano, Chem. and Pharm. Bull. (Japan), 1969, 17, 171 1. 39 40 4'

42

J . M . Leigh and A. D. S. Caldwell, J . Pharm. Pharmacol., 1969, 21, 708. M . S. Kupchan and I . Ognyanov, Tetrahedron Letters, 1969, 1709. L. A. P. Anderson and J. M. Kockemoer, J . S . African Chem. Inst., 1969, 22, S 119. S. M. Kupchan, R . J . Hemingway, and J . C. Hemingway, J . Org. Chem., 1969,34,3894.

Steroid Synthesis

413

1sobufadienolides.-Full details have appeared43 of the first synthesis44 of a 6'-isobufadienolide. Whilst the mixture of cis-cisand cis-trans isomers (46)and (47) obtained by Wittig reaction of the en01 ether-aldehyde (45) could not be cyclised, the single isomer (cis-trans) (48), obtained from (45)and the anion of diethyl ethoxycarbonylmethylphosphonate, readily cyclised, after hydrolysis to the unsaturated keto-acid (50), to give the 6-isobufadienolide (51). The methoxy-tbutyl ester (49) cyclised without saponification to give (51) in better yield.

(46) (47) (48) (49)

R' R' R' R'

R 2 = CN, R 3 = H Et, R2 = H, R3 = C N Et, R 2 = H, R3 = C02Et Me, R2 = H, R 3 = C02CMe3

= Et, = = =

S u b ~ e q u e n t l ythe ~ ~ *isobufadienolide ~~ (51) was obtained directly from the enol ether-aldehyde (45) by condensation with malonic acid. This reaction, which requires the presence of a secondary amine and for which the following mechanism has been proposed, has been applied45 to the AI4-analogue of (45) in both the 5a- and A5-series, and the resulting A'4-6'-isobufadienolides have been further converted into their 14,15-epoxides. 43 44

4s

G. R. Pettit, J. C. Knight, and C. L. Herald, J. Org. Chem., 1970,35, 1393. J. C. Knight, G . R . Pettit, and C. L. Herald, Chem. Comm., 1967,445. T. Nambara, K. Shimada, and S. Goya, Chem. and Pharm. Bull. (Japan), 1970,18,453.

Terpenoids and Steroih

414

(45)

-gR{

Attempts to prepare a 14ct,l7a-isobufadienolide by this sequence46 using 3p-acetoxy-17a-pregn-5-en-2O-onewere unsuccessful, for although condensation with ethyl orthoformate gave a mixture of 17a- and 17fl-en01 ethers in a ratio of 7 : 1, reaction with malonic acid and cyclisation afforded only the 17P-isobufadienolide (51). In the presence of a 16fl-methylgroup a mixture of 17a- and 17penol ethers was again obtained, but in this case cyclisation with malonic acid gave the 1701-isobufadienolide. The 16a-methyl analogue afforded a mixture of 1701-and 17/?-isobufadienolidesin a ratio of 3 : 7.

Cardenofidesand Isocardenolides-A series of papers has appeared by Pettit et al. giving full details of 13 years work on various approaches to cardenolides (and bufadienolides), most of which has been briefly reported previously. Early approaches used the trans unsaturated keto-ester (52) which could be prepared in 20% yield,47 along with (54) and (55), by condensation of pregnenolone with glyoxylic acid under carefully defined conditions, followed by methylation and acety lat ion. Higher yields (43 %) of (52), together with some cis-isomer (53), were obtained by use of 2 1-iodopregnenolone acetate and methoxycarbonylmethylenetriphenylph~sphorane.~' Sodium borohydride reduction49 of (54) or (55) gave (56), and not the expected substituted lactone. Similarly, the Sa-analogue of (54) gave (57)

( 5 2 ) 22,23-trans (53) 22,23-cis 46

47

48

49

(54) R = AC (55) R = Me

(56) A s (57) 5a-H (58) As*22

T. Nambara, K. Shimada, S. Goya, and N. Sakamoto, Chem. and Pharm. Bull. (Japan), 1970, 18, 617. G. R. Pettit, B. Green, and G. L. Dunn, J . Org. Chem., 1970, 35, 1367. G. R. Pettit, B. Green, A. K. Das Gupta, P. A. Whitehouse, and J. P. Yardley, J. Org. Chem., 1970,35, 138 1. G. R. Pettit, B. Green, and G . L. Dunn, J . Org. Chern., 1970, 35, 1377.

415

Steroid Synthesis

which was also obtained by catalytic reduction of (56) or by catalytic reduction of (52) to the 5a-5,6,22,23-tetrahydro-keto-esterfollowed by reduction with sodium borohydride. Similar borohydride reduction of the cis unsaturated keto-ester (53)48[obtainable by irradiation of (52)] gave the isocardenolide (58) as a mixture of C-20 isomers. Both the isocardanolide (57) and the isocardenolide (58)were devoid of cardiac a~tivity.~’,~’ Attempted reaction of (52), (53), or the 5a-5,6,22,23-tetrahydro-derivative with methoxymethylenetriphenylphosphorane was unsuccessfu1,50 although pregnenolone acetate, or better its tetrahydropyranyl ether, afforded the vinyl ether, as (59). Wittig reaction of either the 5a- or As-diacetates (60) or (61) with the anion of diethylcyanomethylphosphonate gave good yields5 of unsaturated nitrile (62) in the absence of an acidic work-up, or the imino-lactone hydrochloride (63) in the presence of acid, which could be converted in good yield to the butenolide (64).

A5,R = H, X = CHOMe (60) 5a-H, R = OAc, X = 0 (61) A5,R = OAC,X = 0 (62) R = OAC,X = C H C N (59)

(63) X = kH,Cl(64) X = 0

Digitoxigenin (65) affords isodigitoxigenin (66) on methanolysis. Treatment of the 3-acetate of (66) with toluene-p-sulphonic acid in refluxing benzene gave a mixture of the 12(13-+ 14)abeo rearranged c-norcardanolide (67) and c-norcardenolide (68),whereas toluene-p-sulphonic acid in refluxing methanol afforded a mixture of the two epimeric ketals (69) and (70) which could be rearranged by toluene-p-sulphonic acid in refluxing benzene to the c-norcardenolide (68)’ Homologation of the ketal(69) afforded (71) which, with toluene-p-sulphonic acid in benzene or, better, with hot aqueous acetic acid, gave (72). This could be dehydrogenated, as its methyl ester (73), by DDQ, to 3P-acetylisobufalinmethyl ester (74) identical with that obtained by methanolysis of bufalin (1 I), thereby providing a conversion of digitoxigenin (65) into isobufalin methyl ester (74).53 Attempts54 to use the methyl ester of the homologated acid (71) to prepare bufalin (from digitoxigenin) were unsuccessful, for its cyclisation with 50 51

52

53 54

G . R. Pettit, B. Green, G . L. Dunn, and P. Sunder-Plassmann, J . Org. Chem., 1970,35, 1385. G. R . Pettit, C. H. Herald, and J. P. Yardley, J . Org. Chem., 1970,35, 1389. G . R. Pettit, T. R . Kasturi, J. C. Knight, and J . Occolowitz, J . Org. Chem., 1970, 35, 1404. G . R . Pettit,T. R . Kasturi, J . C. Knight, and K . A. Jaeggi,J. Org. Chem., 1970,3S, 1410. J . C. Knight, G. R . Pettit, and P. Brown, J . Org. Chem., 1970, 35, 1415.

Terpenoids and Steroids

416

HCl-AcOH-H,O gave the desired lactone (76) in only 1.6% yield, the major product (42 %) being the vinyl ether (72). Attempts to make use of this product (72) by epoxidation were also unsuccessful, for the epoxide (77) lactonised spontaneously, not to the desired (76)or stereoisomer thereof, but to the y-lactone (78). Also unsuccessful was the attempted reaction of the unsaturated aldehyde (75) with malonic acid under the conditions used successfully for the preparation of bufadienolides.

0

\

,I

\

IV. I1

,

(70) R' = r-OMe, R2 = Me, n = 1 1 (71) R' = /I-OMe. R2 = H. n = 2 Reagents: i, KOH-MeOH; ii, Ac,O-py; iii, PhH-TsOH; iv, MeOH-TsOH. Scheme 3

Steroid Synthesis

417

An indication that the 14B-hydroxyl is not essential for cardiotonic activity comes from the synthesis5 of 14-desoxy-14/3-uzarigenin.Lithium aluminium hydride reduction and acetylation of the 17b,20b-epoxide obtained from the enol acetate (79)gave the 17/?-aIcohol(80),which underwent a Serini-Logemann reaction to afford the 14b-pregnane (81). Reformatsky reaction with ethyl bromoacetate and dehydration gave the @-unsaturated ester (82), converted by selenium dioxide to 14-desoxy-14fi-uzarigenin(83).

(72) (73) (74) (75)

R = [CHJzCO,H R = CH,.CO,Me R = CH:CH.CO2Me R = CHO

W

C _-

0

.

Mo

H

_-

I," (77)

\

--H

OH

O

(78)

{fiH.co2E {fi seo,,

H

55

M. Okada and Y . Saito, Chem. and Pharm. Bull. (Japan), 1968, 16,2223.

H

Terpertoids and Steroids

418

Retention af a ~ t i v i t y ~ ~by - ~3-desoxydigitoxigenin, * obtained by desulphuration” of the thioketal of digitoxigenone. or catalytic hydrogenation of the mixture of olefins produced by elimination of digitoxigenin 3-toluene-p~ulphonate,’~ shows that the 3p-hydroxyl is not essential for cardiac activity. Activity was also retained on introduction (with selenium dioxide) of a 17ahydroxyl in digitoxigenin although inversion of the two 17-substituents abolished activity,56 as did inversion at C-14 to give 14-epidigito~igenin.~’ This latter compound could be prepared, as its acetate, by the sequence (84) -+(85) -+(86), but hydrolysis of the 3-acetate function was accompanied by elimination of the 143-hydroxyl. The S-oxide of (85) was, however, readily hydrolysed to the 3fl-hydroxy-compound, desulphuration of which afforded 14-epidigitoxigenin. Significant cardiotonic activity was found to be present in a series of 3-tetrahydropyranyl ethers and 3,3-ethylenedioxy-derivativesrelated to digitoxigenin and

128-hydroxy-digitoxigenin.5 9 The cardiac activity found for the iodoacetate (88) obtained from the strophanthidin derivative (87) was originally interpreted as a cardiotonic effect6’ and considered to be in agreement with the suggestion that activity is dependent upon the ability of the compound to react with -SH groups. Further work on 2 1-iodoacetoxy-20-ketones and digitoxigenin-type compounds having an aminothiazole side-chain6’ designed to test this theory has revealed that the activity

i. DCC-DMSO

Ni-Me,CO A

ii. HS[CH,],SH-HCI

OH

S

OH

(86)

’’ Y. Saito, Y. Kanemasa, and M . Okada, Chem. and Pharm. Bull. (Japan), 1970,18,629. 51

’’ 6o “

W. Zurcher, E. Weiss-Berg, and Ch. Tamm, H e l v . Chim. Acta, 1969, 52, 2449, K. Takeda, T. Shigei, and S. Imai, Experienria, 1970, 26, 867. A. H . El Masry, S. A. El Defrawy, and 0. Gisvold, J . Pharm. Sci., 1969, 58, 228. M . E. Wolff, W..Ho, and H.-H. Chang, J . Pharm. Sci., 1968,57, 1450. M . E. Wolff, H.-H. Chang. and W. Ho, J . Medicin. Chem., 1970, 13, 657.

Steroid Synthesis

419 CH,OCOCH,I

I

co I R

is in fact cardiotoxic, and has drawn attention to the care which must be used in interpreting biological data. 15a-Hydroxycortexone has been transformed62into uzarigenin by a method in which the butenolide ring was constructed from the 15a,21-dimethanesulphonyloxypregnanedione (89) and potassium methyl malonate followed by introduction of the 14p-hydroxyl via the 14/3,15a-bromohydrin to give uzarigenone (90). Reduction with lithium tri-t-butoxyaluminium hydride then gave' uzarigenin. rOMs

O/'O

O

q

0

i, KO,CCH,CO,Me

ii, Collidine-TsOH

Canarigenin has been prepared by a related series of reactions.63 Lead tetraacetate acetoxylation of uzarigenone (90) gave64 the 2a-acetoxy-derivative, reduced with lithium tri-t-butoxyaluminium hydride to the unknown gomphogenin (91),which was then further converted, by dehydration, to 8-anhydrogomphogenin thereby confirming the structure originally assigned to gomphoside. The structure (92) has been assigned64 to calotropagenin and confirmation obtained by synthesis of its 2a,3~,19-triacetyl-19-dihydro-derivative from cor~glaucigenin.~~ Evidence supporting the 2',3'-stereoisomeric relationship of calactin and calotropin (93) has been given64*66and new structures suggested66 for the glycosides uscharidin, calotoxin, procerosid, uscharin, and vorusharin. The structural isomer (95) of aldosterone obtained67 from pseudostrophanthidin (94) was found to cause significant sodium retention but was inactive in antiandrogen and antioestrogen tests. 62

U. Stache, W. Fritsch, W. Haede, K. Radscheit, and K. Fachinger, Annalen, 1969,726,

63

W. Fritsch, H. Kohl, U. Stache, W. Haede, K. Radsheit, and H. Ruschig, Annalen,

136. 1969,727, 110. 6*

6s 66 6'

A. Lardon, K . Stockel, and T. Reichstein, Helu. Chim. Acta, 1969,52, 1940. A. Lardon, K. Stockel, and T. Reichstein, Helv. Chim. Acta, 1970,53, 167. F. Bruschweiler, K . Stockel, and T. Reichstein, Helo. Chim. Acta, 1969, 52, 2276. W. Merkel and M. Ehrenstein, Helu. Chim. Acta, 1969,52, 2157.

Terpenoids and Steroids

420

O

Q

O

O

Q

O

& RR HO

H (91) (92)

R' R'

= =

OH

Me, R 2 = R 3 = OH CHO. RZ = R 3 = OH

(94)

0:

LY

Ho OH

(93) R' = CHO, RZR3 =

H

@

0

'

(95)

The n.m.r. spectra of C-19 oxygenated cardenolides have been described and relevant chemical shifts tabulated.68 AntheridioL-The structure d e t e r m i n a t i ~ n of ~ ~ antheridiol (lo),the first specifically functioning steroidal sex hormone to be found in the plant kingdom which, when secreted by the femalemycelia of the aquatic fungus Achlya bisexualis, initiates sexual reproduction, has been rapidly followed by its synthesis,'' Aldol condensation of ethyl 3,4-dimethylpent-2-enoatewith the aldehyde (96)produced the unsaturated lactone (98) which could be opened to the dienic acid (99) with 0

(96) R = THP, X = H, (97) R = THP, X = 0

(98) R = THP. X = H,

(99) R = H, X = H,

A. Kh. Sharipov, M . B. Gorovits, G. K . Makarichev, M. R . Yagudaev, and N. K. Abubakirov, Khim. prirod. Soedinenii. 1969, 5 , 270; Chem. Abs., 1970, 72, 43994f: '"G . P. Arsenault, K. Biemann, A. W. Barksdale, and T. C. McMorris, J . Amer. Chem. Soc.. 1968. 90.5635. ' O J . A. Edwards, J . S. Mills, J . Sundeen, and J . H . Fried, J . Amer. Chem. Soc., 1969, 91, 1248.

42 1

Steroid Synthesis OH

I

0

retention of the natural 20R-configuration. Perbenzoic acid then afforded a mixture of 22,23-erythro-epimersof 5a,6a-epoxy-y-lactones.Further transformation of the 5a,6a-epoxy function of these lactones produced antheridiol (100) and 22,23-isoantheridiol. Reformatsky reaction of the 7-0x0-derivative (97) with the bromomethyl lactone (101) afforded,after removal of the 3-protecting group, the structural isomer (102) which lacked the specific hormonal property of antheridiol.’

Withanolides-A number of new withanolides have been isolated and their structures determined (see Table of New Compounds). The conformation of the six-membered lactone ring has been establi~hed’~ for several withanolides. Of

T. C. McMorris, J . Org. Chem., 1970, 35, 458.

’*D. Lavie, I. Kirson, E. Glotter, and G. Snatzke, Tetrahedron, 1970, 26, 2221.

Terpenoids and Steroids

422

(105)

interest are the structures assigned, (103), (104), and (105) to physalins 'A73*74 and C76in which their close relationship to other withanolides is apparent, although the 13,14-seco nine-membered ring and the new six-membered carbon ring formed by cyclisation between C- 16 and C-24 are novel. B,74975

3 Insect Moulting Hormones

of ecdysone has been described, starting from the An elegant new unsaturated ketone (106) which is obtainable in 64% yield from ergosterol. Treatment of this ketone with a little toluene-p-sulphonic acid in sulpholan at 160°C resulted in both rearrangement and epimerisation to afford a small amount of the non-conjugated A2*8('4)-dien-6-oneand a mixture of 14a- and 14b-dienones (107). Separation of this mixture was not necessary for, after preferential introduction into ring A of the cis-glycol function by means of a modified Woodward-Prevost reaction, the epimeric centre was destroyed by enol acetate formation as in (108). It is of interest that when the cyclopropane opening was conducted at a lower temperature and in the presence of a stoicheiometric amount of toluene-p-sulphonic acid the product, unexpectedly, was a C-14 epimeric mixture of 3#l-tosylates, convertible to the A'-olefins (107) by lithium bromide in DMF. Peracid treatment of (108) then afforded the 14a-hydroxy-A'-6-ketone which was cleaved by ozone to give the aldehyde (109). This aldehyde reacted with the lithium salt of the acetylenic ether (110)giving a mixture of products from which both the epimeric C-22 alcohols (111) and (112) were obtained. Catalytic reduction of (111) under the appropriate conditions, removal of the THP ether group and inversion at C-5 with base, which was accompanied by hydrolysis, gave ecdysone (113). Reaction of the magnesium bromide salt of the acetylenic ether (110) with the aldehyde (109) resulted in a more stereospecific reaction, affording as the major product the C-22 iso-compound (112), converted to 22-iso-ecdysone.

'' T. Matsuura, 74 'Is

'6

"

M. Kawai, R. Nakashima. and Y. Butsugan, Tetrahedron Letters, 1969, 1083: M. Kawai. T. Taga, K. Osaki, and T. Matsuura, ibid., p. 1087; M. Kawai, T. Matsuura, T. Taga, and K. Osagi, J . Chem. SOC.( B ) , 1970, 812. T. Matsuura, M. Kawai, R. Nakashima, and Y. Butsugan, J . Chem. SOC.(0,1970,664. T . Matsuura and M . Kawai, Tetrahedron Letters, 1969, 1765. M. Kawai and T. Matsuura, Tetrahedron, 1970, 26, 1743. D. H . R. Barton, P. G. Feakins, J . P. Poyser, and P. G . Sammes, J . Chem. SOC.(0, 1970, 1584.

Steroid Synthesis

& ,QH17

____--

0

423 Aco&17

&17

I

H

Ac-0 OAc

(106)

(111) R' = OH, R2 = H (112) R' = H, RZ = OH

A new synthesis78 of crustecdysone (Scheme 4) has been described starting from (114). Hydroxylation and oxidation gave the 3,6-dione (113, selective hydride reduction of the 3-carbonyl and protection of the 6-ketone followed by reoxidation afforded (116), which autoxidised to a mixture of enols of (117). H.Mori and K. Shibata, Chem. and Pharm. Bull. (Japan), 1969, 17, 1970.

=

H

R

= Bz

=

OH

(123) R = H

H

U

R

R

=

H

= AC

(124) R

OH

(119)

(115)

R =

BZ

(125) R = H

OH

(120) R = A c

(116)

R

Scheme 4

Reagents: i, B,H,; ii, H , O , - O H - ; iii, Jones reagent; iv, N a B H , ; v, HO.[CH,],OH-H ; vi, Cr0,-py: vii, 0,-t-BuOK; viii, K O H ; ix, Me,CO-H ; x, H,PO,; xi, Ac,O; xii, Br,; xiii, LiC0,-DMF; xiv, Ac,O-HClO,; xv, rn-HO,C.C,H,.CO,H ; xvi, H+-H,O; xvii, CH,=CH.MgBr; xviii, 0 3 ; xix, O).[CH,3,.CH.OCMez.C:CMgBr; xx, Pd-C-H,; xxi, H +.

(122) R

OH

(118)

(114)

A/+d

+

HO

+

Bz

Vlll

T7-)

xiv. x v

=

RZ0

HO

un

VII

-

(126) (127) (128)

-

R' R' R'

I

R2 = Ac, = Ts,

=

H

OH

RZ = H R2 = H

=

OH

HO+H

BZ

..

vi

xvi

L

.a,

I (117) R =

0

3 P R

Steroid Synthesis

425

Borohydride reduction produced a mixture of 2,3-diols from which the 2B,3/3-diol was obtained through its ability to form the acetonide (118). Removal of the protecting groups and acetylation gave (119), into which the conjugated double bond was introduced. 14a-Hydroxylation was achieved, as in the ecdysone synthesis above, by peracid treatment of the enol acetate. Oxidation of a suitably protected derivative of (121) produced the 20-ketone (122) into which the appropriate side-chain could be introduced by means of two highly stereospecific Grignard reactions; first with vinyl magnesium bromide to yield the olefin (123), and then between the magnesium bromide salt of the acetylenic ether (110) and the aldehyde (124) obtained by ozonolysis of (123). Catalytic reduction and removal of the protecting groups gave crustecdysone (126). Rate constants for the acetylation of the hydroxy-groups of crustecdysone have been determined and partial hydrolysis of the 2,3,22-triacetate resulted in the isolation of the 2,3- and 3,22-diacetates and 3-monoacetate." Mass spectral and n.m.r. data have been discussed. Full details together with some alternative reaction sequences" in the preparation of 22-deoxycrustecdysonehave appeared. The yield (35%) of the 20-ketone (122) originally obtained" via periodic acid cleavage of crustecdysone 2-acetate (127) has been increased to 60% by direct Jones oxidation of unprotected crustecdysone (126). Introduction of the appropriate side-chain was achieved by reaction of the 2/3,3P-acetonide 14a-trimethylsilyl ether of (122)with the Grignard reagent from either 5-chloro-Zmethylpentan2-01tetrahydropyranyl ether or (110)followed by removal ofthe protectinggroups. The poor hormonal activity of the resulting 22-deoxycrustecdysone (-& of that of crustecdysone) would imply the necessity of a 22-hydroxy-group for biological activity. Removal of the 2P-OH from crustecdysone by reduction of the 2P-tosylate (128) first with lithium tri-t-butoxyaluminium hydride +(129) and then with lithium

B-

--

0

( 1-29)

'' 8o

*'

M . N. Galbraith and D. H. S. Horn, Austral. J . Chem., 1969, 22, 1045. M. N. Galbraith, D. H. S. Horn, E. J . Middleton, and R. J . Hackney, Austral. J . Chem., 1969,22, 1517. M. N. Galbraith, D. H. S. Horn, E. J. Middleton, and R. J . Hackney, Chem. Cumm., 1968,466.

Terpenoids and Steroids

426

aluminium hydride followed by re-oxidation of the allylic alcohol after protection of the side-chain diol system as the cyclic borate afforded,82unexpectedly, not the intended 2deoxycrustecdysone but the 2-deoxy-3-epi-compound (130). Attempts to prevent this reaction by reduction of the 2#l-tosyloxy-3#l-trimethylsilyl ether derivative were unsuccessful (cf: Part 11, Ch. 1, p. 295). Full details have been given' of two preparations of rubrosterone( 133)fromcrustecdysone ;onedepends upon side-chain degradation of the 2-acetate (127) with periodic acid and subsequent oxidation by peroxytrifluoroacetic acid to the 17B-acetate, which, on hydrolysis and oxidation, led to rubrosterone 2-acetate ; the other, shorter and more efficient method, relies upon the dehydration of crustecdysone to yield the tetra-acetate (131). Ozonolysis then led directly to rubrosterone diacetate (132). OAc

OH (131) R' = R 2 = AC

OH (132) R' = R 2 = AC (133) R' = R 2 = H

An alternative synthetic approach84 starts from the i-steroid (134), 3#l,5a-dibromination and rearrangement of which gives the 3/?,7a-dibromoketone (1 35). 0

0

82

OH

OH

M. N. Galbraith, D. H . S. Horn, E. J. Middleton, and R . J . Hackney, Austral. J . Chem., 1969, 22, 1059.

83 84

H . Hikino, Y. Hikino, and T. Takemoto. Tetrahedron, 1969, 25, 3389. W . Van Bever, F. Kohen, V. V. Ranade. and R . E. Counsell, Chem. Comm., 1970,758.

Steroid Synthesis

427

This compound, as its 17-ethylene ketal, readily bisdehydrobrominated giving the dienone (136). cis-Hydroxylation and acetylation gave the 2/3,3/3-diacetate which was further hydroxylated with selenium dioxide to afford the 14a-hydroxycompound (137) after regeneration of the 17-ketone. Hydrolysis of the acetate functions with base also led to epimerisation and afforded rubrosterone. Ponasterones A, B, and C , and related biologically active compounds have been reviewed*' The configuration of the 2a,3a-diol system of ponasterone B has been confirmed and mass spectral studies have revealed the presence of an extra hydroxy-group in ponasterone C which, on n.m.r. and c.d. evidence86must be 5/? thereby leading to the revised structure (138). A simple series of analogues, having pregnane and cholestane side-chains, most bearing 6-keto-groups and many with oxygen functions in ring A, have been prepared" and an assesspent made of their ability to inhibit post-ecdysial sclerotisation of the cuticle of Pyrrhocoris apterus. 4 Oxa-steroids

Excess alkaline hydrogen peroxide converts A' *4.6-3-ketones88*89 e.g. (139) and (140) first to the la,2a-epoxide and then to a mixture of lactones (141) and (142) in which the former predominates. Catalytic hydrogenation of the methyl esters of (141; R' = R2 = H and R' = H, R2 = Me) gave the 5a-tetrahydrolactones in > 80 %yield whereas reduction of the hydroxy-lactone (142 ;R' = H, R2 = Me) afforded a mixture of5a (- 5 %)and 5/?( 80 %) tetrahydro-products. Borohydride reduction of the hydroxy-lactone (142; R' = H, R2 = Me) gave the 2-oxaA4*6-3-ketone(143)in high yield. Both the 501- and 5/3-~-nor-3-oxapregnanes (145) were obtained" when A-norprogesterone was oxidised by periodate-permanganate to the hydroxy-

-

OR'

(139) (140)

85

86

R' R'

= =

R 2 = Me H, COEt, R2 = H

(141) (142) (143)

R3 = B-CO,H R3 = <-OH R3 = H

K. Nakanishi, Bull. SOC.chim. France, 1969, 3475. M. Koreeda and K. Nakanishi, Chem. Comm., 1970, 351. H . Velgova, V. Cemy, F. Sorm, and K. Slama, Coll. Czech. Chem. Comm., 1969, 34, 3354.

M. Kocor, A. Kurek, and M . Mapka, Bull. Acad. polon. Sci., S i r . Sci. chim., 1969, 17, 275. 89 90

M. Kocor, A. Kurek, and J . Dabrowski, Tetrahedron, 1969,25,4257. S. D. Levine, Steroids, 1970, 15, 209.

Terpenoids and Steroids

428

lactone (144)and then reduced with lithium aluminium hydride and cyclised with phosphorus oxychloride. Of the four epimeric 6-bromo ring-A lactones (148) prepared from the seco-acid (146) by bromination and reduction, only one (148 ; 5a-H,&-Br), possessed antiandrogenic activity and this was halved by introduction of unsaturation into ring A . * ~ ~

11

K

(144) (145)

X X

(146) R = Me =

0, R

=

= H2,R =

Br

OH

H

In contrast to the usual reaction of aromatic aldehydes with cyclic ketones o-nitrobenzaldehyde condenses with 17-ketones to produce good yields of seco-acids, a reaction which has been a ~ p l i e d ~ to '.~ the ~ preparation of 16-oxaor its acetate affords the secosteroids. Thus, 3fl-hydroxy-5a-androstan-17-one steroid (153), which can be oxidised either as the free acid by ozone and alkaline hydrogen peroxide to the diacid (155) or, as its methyl ester (154),with chromium trioxide to the monomethyl ester (156). Diborane reduction of the diacid (155) or lithium aluminium hydride reduction of the dimethyl ester (157) gave the transdiol(l58),cyclised with toluene-p-sulphonic acid to 16-0xa-androstan-3P-o1(159) or, by oxidation with Jones reagent to the lactone (152)(as 3-ketone) in quantitative yield. This lactone could also be obtained by lithium borohydride reduction of the monomethyl ester (156), whilst diborane reduction of (156) and cyclisation of the resulting (151) afforded the isomeric lactone (150).The diacid (155)reacted with acetic anhydride to afford exclusively the cis-anhydride (161) which was reduced directly with lithium aluminium hydride to the cis-lactone (160)or, as its derived dimethyl ester (162) to the cis-diol (163) which cyclised to 16-oxa-14Dandrostan-3/?-01(144). The structures of the first naturally occurring 15-oxa-steroids (hirundigenin and anhydrohirundigenin) have been e l ~ c i d a t e d . ~ ~ , ~ * Occasional gaps in formula and reference numbering are due to deletions by the Senior Reporter to prevent duplication with Part 11, Chapter 1 .-Ed. " ' 2

q3 y4

''

A. Boris and M . Uskokovic, Experientia, 1970, 26, 9. A. K. Banerjee and M . Gut, J . Org. Chem., 1969,34, 1614. M . Fetizon and N. Moreau, Bull. SOC. chim. France, 1969,4385.

0 . Kennard, J . K . Fawcett, D. G . Watson, K. A. Kerr, K . Stockel, W. Stocklin, and T. Reichstein, Tetrahedron Letters, 1968, 3799; K. Stockel, W. Stocklin, and T. Reichstein, Helv. Chim. Acta, 1969, 52, 1403; K. Stockel, W. Stocklin, and T. Reichstein, ibid., p. 1429. K. Stockel and T. Reichstein, Sci.Pharm., 1969, 37, 47.

Steroid Synthesis

- {YoZR2 : C02R3 H

H (153) R’ = R2 = H (154) R’ = H , R 2 = Me

(155) R’ = R2 = R 3 = H (156) R’ = R 3 = H, R2 = Me (157) R’ = Ac, R2 = R3 = Me

5 Thia-steroids

2-Thia-~-nor-5a-pregnan-20-one~~ and a series of 7a-methyl, 17a-alkyl and 19-nor derivativesg7of 2-thia-~-nor-5a-androstan1 7 p - 0 1 ~have ~ been synthesised by treatment of the bisnorseco-dibromide ( 1 69) with sodium sulphide. 96

97

98

M. E. Wolff and G. Zanati, J . Org. Chem., 1970,13, 563. M. E. Wolff, G. Zanati, G. Shanmugasundarum, S. Gupte, and G. Aadahl, J . Medicin. Chem., 1970, 13, 531. M. E . Wolff and G. Zanati, J . Medicin. Chem., 1969, 12, 629.

Terpenoidsand Steroih

430

H

H

6 Aza-steroids A sequence of reactions (see Scheme 3, notable for high yields, has been described9’ for the preparation of ring-A and ring-D lactams. A remarkably selective opening of the ring-A anhydride (170) obtained from the 2,3-seco-acid, afforded the acid amide (171) which was converted to the 3-aza-2-0x0-steroid (172) and to the imide (173). This imide opened with equal selectivity affording, after further manipulations, the isomeric 2-am-3-0x0-steroid (174). 17-Aza-androstanl6-0ne (177) which could be prepared by a similar sequence, although opening of the appropriate anhydride was non-selective, was best prepared by Beckmann rearrangement of the oxime (175) followed by Hofmann degradation of the imide (176). Mass and n.m.r. spectral data’” of these and other lactams have confirmed their structures. R

(170)

R

=

H orCSH1,

/!

iv

I 1 73) Reagent: i. NH,-PhMe; ii, C H , N , : iii. NaOMe-MeOH-Br,: v, NaOH-MeOH-H,O.

(174) iv, NaOMe:

Scheme 5

{ Y9

LOO

h

N

0

H

- {fro - {yyo

(175) (176) (177) Sir Ewart R. H. Jones, G. D. Meakins, and K . Z . Tuba, J . Chern. Suc. ( C ) , 1969, 1597. R . T. Aplin, G. D. Meakins, K. Z . Tuba, and P. D. Woodgate, J . Chem. SOC.(0,1969, 1602.

43 1

Steroid Synthesis

Further work has been described"' on the formation of aza-steroids by the cyclisation of methine bases obtained by Hofmann degradation of perhydroazepines. Thus, Beckmann rearrangement of the cholestan-3-, -4-, -6-, and -7-one oximes followed by lithium aluminium hydride reduction afforded the 4- and 5-aza-~-homo-and 6- and 8-aza-B-homo-cholestancesrespectively. Cyclisation of the methine bases obtained by Hofmann degradation then led to the 2-methyl piperidine salts (178)--(181),except in the case of the base (182)where cyclisation, to give (183),was accompanied by demethylation.

{

V

M

e

,

Me,N

c3

MeN

Further examples have been provided of Schmidt rearrangement of 6a-methylA4-3-ketones,lo2A4.6-3-ketones,'033~-chlor0-5a-6-ketones,~~~ and 3B-acetoxyA4-6-ketones,lo4 as well as Beckmann rearrangement of the oximes of 5&3ketones,'05 A4*6-3-ketones,'03A5-7-ketones,lo6 3~-chlor0-5a-6-ketones,~~~ 17ketones,"' and 3a,5a-cyclo-6-ketones.lo' In the last case, attempted hydrolysis of the resulting 6-aza-3a,5a-cyclo-~-homocholestan-7-one afforded only the products of retro-Beckmann rearrangement. Similar rearrangements have been described on 2-0x0- and 3-oxo-5a,l0a-androstanes' O9 and on 17-acyloxypregn4-ene-3,20-diones.' l o One compound so obtained (1 84) showed remarkable progestational activity, possibly due to 3',5'-cyclic nucleotide phosphodiesterase inhibition. Condensation of the seco-keto-acid (185) with benzylamine or aminoethanol afforded' derivatives (186) and (187)of the new 4,l 7a-diaza-~-homo-androstane

'

Io1

Io2 Io3 Io4

lob lo'

Io8 Io9

ll0 I I I

A. M. Farid, J. McKenna, J . M. McKenna, and E. N. Wall, Chem. Comm., 1969,1222; E. N. Wall and J . McKenna, J . Chem. SOC.(0,1970, 188. A. P. Shroff, J . Pharm. Sci.,1970,59, 1 10. M . S. Ahmad, A. H. Siddiqui, Shafiullah, and S. C. Logani, Austral. J . Chem., 1969,22, 271. M. S. Ahmad, Shafiullah. and A. H. Siddiqui. Indian J . Chem.. 1969.7, 1167. G . Habermehl and A. Haaf, Z . Narutjbrsch., 1969, 24b, 1414. H . Singh and S. Padmanabhan, Indian J . Chem., 1969,7, 1084. C. W. Shoppee and R. W. Killick, J . Chem. SOC.(0,1970,1513. M. S. Ahmad, Shafiullah, and M . Mushfiq, Tetrahedron Letters, 1970, 2739. G. Habermehl and A. Haaf, Annalen, 1969,723, 181. A. P. Schroff, J . Medicin. Chem., 1970, 13, 748. H . Singh and V . V. Parashor, Chem. Comm., 1970, 522.

Terpenoids and Steroih

432

0'

I

R (186) R = C H 2 P h (187) R = [ C H 2 1 2 0 H ( 1 88) Sr,6-Dihydro, R = O H

system and zinc-acetic acid reduction of the oxime of (185) gave the hydroxamic acid (188). The third example (190)of a steroid in which ring-A is a substituted pyrimidine ring has been prepared' l 2 by condensation of the trisnor-seco-ester (189) with methyl guanidine sulphate. Two examples have been described of the new ring-A p-lactam-B-homo system.' l 3 Beckmann rearrangement of the oxime (191) afforded the ring+

H O 2 C F i ; P

neo2cr= HON 191) R = B-OH. z-H

(192) R = P-OH, a-H, X = 0 (193) R = /?-OH,a-H. X = H, (194) R = 0, X = H ,

D. M.Piatak and E. Caspi, J . Medicin. Chem., 1970, 13, 3 3 5 . S. D. Levine, J . Org. Chem., 1970, 35. 1064.

Steroid Synthesis

433

lactam (192)which was converted by a series of reduction and oxidation reactions to amino-steroids (193) and (194). Cyclisation with carbodi-imide then afforded the p-lactams (1 95) and (196).

7 Steroids having Fused Heterocyclic Rings Rings containing One Heteroatom.4xygen Heterocycles. Base-catalysed to glyoxylic acid, to afford' l 4 addition of 17P-hydroxy-5a-androstan-3-one either the hydroxy-keto-acid (197) when the reaction is performed at room temperature, or the trans-@-unsaturated acid (199) in high yield when done under reflux, provides an entry to both cis-lactone (198)and trans-lactone (201). HO H

H i, MeOH-HCI-r.t _______)

ii, Ac,O-NaOAc-A

HO,C

U

0

H

The preparation of the cholestane-spiro-epoxides (203;R1 and R 2 = Me or H) was unexceptional;l15 methylenation of the ketones (202; R' = R2 = H ; R' = H, R2 = Me; R' = R2 = Me) with dimethylsulphonium methylide or epoxidation of themethylene compounds (204 ;R' = R2 = H ;R' = H, R2 = Me, and R' = R 2 = Me) with rn-chloro-perbenzoic acid gave mainly, as a result of axial attack, the epoxides (205)and (203)respectively. As anticipated, dimethylsulphoxonium methylide and peroxybenzimidic acid gave, as major products, the epoxides (203) and (205) respectively as the result of equatorial attack. Intramolecular aldol condensation originally applied to 6-acet ylthio-A4-3-ones (206; X = S) has been extended'I6 to 6-acetoxy (and benzoyloxy) A4-3-ones (206 ; X = 0)providing the fused methyl (and phenyl) furans (207; X = 0). The methylfurano-compound (207; R = Me; X = 0) readily afforded Diels-Alder adducts e.g.(208)shown to possess' l 7 the unexpected stereochemistry resulting from #I-attack of the dienophile. M . Debono, R . M. Molloy, and L. E. Patterson, J . Org. Chem., 1969, 34, 3032. J. D. Ballantine and P. J . Sykes, J . Chem. SOC.(0,1970, 731. ' I hT. Komeno, S. Ishihara, K. Takigawa, H. Itani, and H. Iwakura, Chem. and Pharm. 'I5

'

Bull. (Japan), 1969, 17, 2856. T. Komeno, H. Wakabayashi, and H. Iwakura, Chem. and Pharm. Bull. (Japan), 1969,

17, 2604.

434

-gn' Terpenoids and Steroids

Rz-kil

-

X

(202) x = 0

(203) X

=

=

03

(206)

(204) X = CH,

(205) X

R ( I

R0Y x

4

-+

/0

-.J

R

o+o

O

(209) R = COPh (210) R,= OCOPh

(208)

The 3-deoxy analogue of (207; R = Ph; X = 0)readily oxidised with air or rn-chloroperbenzoicacid to the enedione (209) which on further treatment with peracid gave the enol benzoate (210). Of a series of tetrahydro-furan- and -pyran-fused pregnanes (21 1-21 5) only (21 1) and (215) possessed anti-androgenic activity.' Pyrolysis of 17-acetoxy-16-methylenepregnan-20-ones (2 16) at 32G-340 "C affords"' 4&-60"/;, yields of the 2'-methyl[17,16-c]furans (217) along with P

O

H

(21 1 ) A4-3-one

'" 'I9

(212) A1**-3-one

(213) A1*4-3-one,168-H (214) A1s4-3-one, 16B-H (215) Sa-H-3-one, 16P-H

A. Kasal and 0. Linet, Coll. Czech. Chem. Comm.. 1969, 34, 3479. T. L. Popper, F. E. Carlon, and 0. Gnoj,J . Chem. SOC.(0,1970, 1344.

Steroid Synthesis

435

appreciable amounts of allylic rearrangement product (218) and some AI6-16methyl-20-ketone (220). At temperatures below 300 "Cthe major product is (218). The allylic alcohols (219) also readily gave the furan derivatives (217) on contact with acid. Bromine in the presence of potassium acetate and methanol opened the furan ring to affordhigh yields'" of the dimethyl acetal(221)readily converted to the free aldehyde with acid.

The 19-norpregna-1,3,5(10)-triene (222) pyrolysed similarly'

to afford a

[17,16-c]-furan, but the D-homo analogue (223), where the necessary geometric

requirements for cyclisation are impossible, afforded' acetate (224) as the main product.

0

IZ1

'''

the rearranged allylic

0

T. L. Popper and 0. Gnoj, J . Chem. SOC.(C),1970, 1349. T. L. Popper, 0.Gnoj, F. E. Carlon, and M. Steinberg, J. Medicin. Chem., 1970,13,564. T. L. Popper, F. E. Carlon, 0. Gnoj, and G. Teutsch, J . Chem. SOC.(0,1970, 1352.

Terpenoids and Steroids

436

Greatly improved yields of the lactone (227) were obtained123by the unexpected copper chromite oxidation of (225) or, better, (226). The substituted malonic acid (225) afforded either a mixture of lactone (227) (30%) and acid (226) (34 ?A) on heating with copper chromite in quinoline at 200 "C or 72 % of "C. Subsequent treatment of the acid (226)with the acetic acid (226) at 15@-160 more copper chromite afforded the lactone in 59 "4yield.

(225) R (226) R

= =

CH(C02H), CH2C02H

(227)

Sulphur Hererocycles. Treatment of 12-diaxial thiocyanatohydrins with alkali is known to afford episulphides with configuration opposite to that of the epoxides from which the thiocyanatohydrins are derived only when the substituents are at C-2 and C-3; 3,4-, 5,6-. 11.12-, and 16,17-thiocyanatohydrinsafford the oxide. Further work defining the scope and limitations of episulphide formation has and 3/3-thiocyanato-2a-alcohols of shown 24 that 2a-thiocyanato-3~-alcohols 5P-steroids afford episulphides, as do 2~-thiocyanato-3a-alcohols of 5or-steroids possessing In-methyl groups. The presence of methyl groups at C-2 and/or C-3, however, causes sufficient non-bonded interaction that only epoxides are obtained. If thiocyanato-acetates are used in place of alcohols, hydrolysis of the thiocyanate group becomes competitive with acetate hydrolysis and both oxide and episulphide are produced.

o a } -

Hoy-J}-

NCS'

s : : a }

Conjugated A4-2a,3a- and unconjugated A5-2a,3a- and 2/3,3/3-episulphides have been prepared similarly. 1 2 ' Benzoyl' l 6 and acety1126derivatives of A4-3-oxo-6a-thiolscyclise readily with base to give fused thienyl compounds i.e. (206)-P (207) (X = S ; R = Ph or Me). Further unsaturation in ring A could be introduced with DDQ to afford the A1-3-ketone (228) which could be aromatised to the benzo-c-thieno steroid (229). '24

' 2 6

K . Igarashi, Y . Mori, and K . Takeda, Steroids,1969, 13, 627. J. Komeno, S. Ishihara, H . Irani, H . Iwakura, and K . Takeda, Chem. and Pharm. Bull. (Japan), 1969, 17, 21 10. T. Komeno and H . Itani, Chem. and Pharm. Bull. (Japan), 1970, 18, 608. T. Komeno and K. Takigawa, Chem. and Pharm. Bull. (Japan). 1970, 18,43.

Steroid Synthesis

437 0

@o@ 2t.0.;b

S

Ac,O-AcOH

S

0

Ph

@ Ph

Ph

’

Nitrogen Heterocycles. The [3,2-b]-1 -pyrroline (231) formed’ * by reductive cyclisation of the nitro-ketone (230) afforded the cis-fused [3,2-b]pyrrolidine(232) on partial reduction with NaBH,. With A c 2 0 at room temperature the pyrroline (231) suffered rearrangement to the acid sensitive O,N-heterocycle (233).

NaHB,

I

Me

12’

T

I

Me

M. Kocbr and W. Kroszczydski, Bull. Acad. polon. Sci., Sir Sci. chim., 1969, 17, 269.

438

Terpenoih and Steroids

High yields of bis-steroid pyrroles, e.g. (234),are obtained from 5a- and 58-3ketones with NN'-dimethyl hydrazine. 2 8 The substituted hydrazine (235 ; R = H or Me) gavel2' the tetrahydroindoles (236).

pJ-7J-d' H

N Me

(234)

H

Rb R

NMeNHMe

(235)

0

d-J}

RR

Me N

Various heterocyclic derivatives have been obtained by treatment of cholestanand androstan-3-one enamines with substituted aromatic aldehydes.' 30

Treatment of the methoxylactol (198) with ethanolic hydrazine afforded' l 4 the novel ring-A-fused pyridazone (237). Diazomethane reacts sufficiently readily with iminium salts, e.g. (238), to allow the preparation of aziridinium salts (239) in the presence of diazomethane-sensitive carbonyl groups.' 3 1 Addition of cyanamide and halogen to 2- and 5enes affords vic-halogeno-cyanoamines which give cyanoimines on contact with base. 32 Intramolecular cyclisation of the 6a-acetamido-derivatives of testosterone acetate and progesterone occurs' ' with sodium hydride in refluxing xylene to afford the corresponding pyrrolo-compounds analogous to the 6a-acetoxycompounds described above.

I3O

W. Sucrow and G. Chondromatidis, Chem. Ber., 1970, 103, 1759. W. Sucrow and E. Wiese, Chem. Ber., 1970, 103, 1767. M. S. Manhas and J. R. McCoy, J . Chem. SOC.(C), 1969, 1419. D. R. Crist and N. J. Leonard, Angew. Chem. Internot. Edn., 1969,8,962. K . Ponsold and W. Ihn, Tetrahedron Letters, 1970, 1125.

439

Steroid Synthesis

Dipyrazolyl steroids (242 ;X = NH) and (244 ;X = NH) have been obtained’ 3 3 by the reaction of the 2,6- and 4,6-diformyl compounds (241) and (243) with hydrazine whilst similar condensation with the unsaturated keto-aldehyde derived from (221) gives’” the pyridazine (245).

CHOH

(243)

Catalytic hydrogenation under pressure of the picolinylidene steroid (246), using a palladised charcoal catalyst, reduces only the exocyclic double bond, but similar reduction of the 17-dehydro-derivativesgives in good yield a 3 : 1 mixture of indolizidines, which are claimed’34 to be the 9’-epimers (247). Details have been given’35 of the Diels-Alder addition of diethyl azodicarboxylate to cholesta-2,4- and -5,7-dienes.

(247) (246) 133 134

135

A. M. Bellini, R. Rocchi, and C. A. Benassi, Gazzetta, 1969,99, 1243. M. StefanoviC, I. V. MiCovic, D. JeremiC, and D. MiljkoviC, Tetrahedron, 1970, 26, 2609. M. Tomoeda, R. Kikuchi, M. Urata, andT. Futamura, Chem. andPharm. Buff.(Japan), 1970, 18, 542.

Terpenoih and Steroids

440

Rings containiq Two Different Heteroatoms.-The new heterocyclic derivatives (248j ( 2 5 0 ) have been prepared’ 36 from 2-acetyloestradiol 17-acetate. The chromone (250) was further converted by the action of hydrazine and hydroxylamine into the 24 3’-pyrazolyl, 3‘-isoxazolyl, and 5‘-isoxazolyl)oestradiols. 0

Further examples of [ 17a,16a-d]oxazolino-corticoids,prepared by catalytic reduction of 17a-azido-l6a-esters and cyclisation of the resulting 16a-hydroxy17a-amides have been rep~rted’~’and their high anti-inflammatory and low mineralocorticoid activity described. 38 Intramolecular cyclisation occurred when a solution of the A16-20-oxime(251) in benzene was treated with lead tetra-acetate and iodine in the presence of a small amount of water. 39 The resulting iodo-isoxazoline (252) was readily dehydrohalogenated to give the known isoxazole (254) which could be reduced with zinc-acetic acid to the 16a,17a-fused isoxazoles (253).

’

{J”e.b {fix h

Ac 0& OH

N

(252) R

(254)

= I (253) R = H

(251)

NOH

vCN

N-0

Cyclisation of the oxime nitrile (255) with alkoxide gave the amino-isoxazole (256) in high yield. 40

’

L. A. Maldonado and P. Crabbk, Chem. and Ind., 1970, 1147. 1 3 ’ G. Nathansohn, G. Winters, and V. Aresi, Steroids, 1969, 13, 383. 1 3 ’ G. Nathansohn, C. R. Pasqualucci, P. Radaelli, P. Schiatti, D. Selva, and G. Winters, Steroids, 1969,13, 365. I J 9S. Kaufmann, L. TokCs, J. W. Murphy, and P. Crabbt, J . Ore. Chem., 1969,34, 1618. G. Gerali, C. Parini, G . C. Sportoletti, A. Ius, Farmaco, Ed. Sci., 1969, 24, 1105. 136

Steroid Synthesis

441

17-Spiro-oxazolidones, which are stereoisomeric (at C-17) with other known oxazolidones, are obtained141 when 17a-urethanes of pregnan-20-ones are treated with base. LO

L O

{ J 1 0 H

RNCq

JJ1OCONHR

base

Aryl isocyanates react with 17-hydroxy-20-ketones,in the presence of N-methyl morpholine, to give the oxazolidones directly. The structures of the di-isoxazoles obtained from the di-ct-formyl ketones (241) depended upon the reaction conditions ; hydroxylamine hydrochloride afforded the di-isoxazole (257) whilst hydroxylamine hydrate gave (242 ;X = 0).Similarly, the unsaturated dichlorodialdehyde (258) gave (259) with hydroxylamine hydrochloride and (244; X = 0)with the hydrate.'33

The fused thieno-cholestane (260) gave'42 pyridimidine-4-thione (261) on treatment with thioacetamide. Thermal rearrangement of the cholesterol and androstane thiol esters (262)has produced'43 the new 2',3'-dihydrothiazoles (263).

141

142

143

A. P. Leftwick, Tetrahedron, 1970, 26, 321. M. S. Manhas, V. V. Rao, P. A. Seetharaman, D . Succardi, and J. Pazdera, J . Chern. SOC.(0,1969, 1937. V. I. Denes and G. Ciurdaru, Chem. Comm., 1969,621.

442

-

Terpenoids and Steroids

p N 0 2 - C ~ H 4 . C O S ~ -180°C l -

-

y

;

{

=

H

Ac N

Me

c

o

cI C6H4.NO2-p Me

H

H

(243)

(262)

H

H

H H

H

Bis-(0-aminopheny1)disulphide and 3-ketones react in the absence of oxygen to give144*145 mixtures of 1,4-benzothiazines (264) which can be reduced by sodium borohydride to (265). 8 FusedCarbocyclicRings The effective dichloromethylating agent phenyl(trichloromethy1)mercury reacts slowly with 4,6dienes of 3-ethylene ketals (but not the free ketone) and 38acetates to give 6a,7a-dichloromethylene derivatives in fair yield, although in the latter case an equal amount of the 2t,3t-dichloromethylene A4*6-compound is also formed 14' The 1a,2a ;6@,7B-dimethylenesteroids (266) are opened preferentially' 47 with zinc to the dechlorinated 7fl-methyl derivatives (267) and with hydrogen iodide to 78-iodomethyl derivatives (268).

(266) R' = OAc, R 2 = H or R ' = Ac, R 2 = O A c 144

lo'

'47

(267) R3 = R4 = H (268) R3 = C1, R4 = I

V. Carelli, P. Marchini. M . Cardellini, F. M. Moracci, G. Liso, and M . G . Lucarelli, Ann. Chim. (Italy), 1969: 59, 1050. V. Carelli, P. Marchini. M. Cardellini, F. Micheletti-Moracci, G . Liso, and M. G . Lucarelli, Tetrahedron Lerrers, 1969, 4619. B. Berkoz, G. S. Lewis, and J. A. Edwards, J . Org. Chem., 1970, 35, 1060. H. Hofrneister, G . Schulz, and R. Wiechert, Chern. Eer., 1969, 102, 2565.

Steroid Synthesis

443

2cr,3a-Phenylcyclopropanes, e.g. (269), are formed,'48 along with pyrazoles, when 2-benzylidenederivatives ofA4-,A4v6-,and saturated 5a-3-onesare subjected to Wolff-Kishner reduction conditions. 19-Methanesulphonyloxy-A'*4-3-ketonesundergo ring A homoannulation on treatment with lithium and biphenyl14' but, in the absence of A4-unsaturation, cyclisation occurs with the formation of lfi,lOfi-cyclopropanes.' Details of the formation, in low yield, of 2-spirocyclopropyl-3-ketones from 2a-halogeno-3-ones and dimethyloxysulphonium methylide have been reported' Dichloroketen adds readily and in a highly regioselectivemanner to cholest-1-, -2-, and -3-ene producing cis-fused 1 : 1 cycloaddition products. 5 2 ~ 1 The dichlorocyclobutanone (270)obtained from cholest-3-ene' 5 2 undergoes reductive removal of both chlorine atoms with zinc in acetic acid and, on subsequent Baeyer-Villiger oxidation, gives the lactone (271). Displacement of one chlorine atom occurred on treatment with one equivalent of sodium methoxide producing a high yield of the methoxy-chloroketone (272) which, with a further equivalent of methoxide, afforded a 2 : 1 mixture of the cyclopropanes (273) and (274) in quantitative yield.

'

'

a-jyJ) 0

H

0

H

J

OMe (273) R' = H, R2 = C02Me (274) R' = C02Me, R2 = H 14' 149

lSo

lS1

S. Hayashi and T. Komeno, Chem. and Pharm. Bull. (Japan), 1969, 17, 2319. P. Wieland and G. Anner, Helv. Chim. Acta, 1968,51, 1932. P. Wieland and G. Anner, Helv. Chim. Acra, 1970, 53, 116. P. Bravo, G. Gaudiano, C. Ticozzi, and A. Umani-Ronchi, Guzzetta, 1970, 100, 566. V. R. Fletcher and A. Hassner, Tetrahedron Letters, 1970, 1071. G. M. L. Cragg, J . Chem. SOC.(0,1970, 1829.

Terpenoids and Steroids

444

Cyclisation of the allylic acetate (275), by treatment with thionyl chloride in pyridine and sodium hydride in refluxing xylene, was accompanied by dehydrogenation to produce the benzene-fused system (276).'

'

R (275)

F02Et

(276) R = H (277) R = C 0 , M e C0,Et

I

Ill I

C0,Et

C0,Et

-

HBr-Ad)H

The classic Diels-Alder reaction continues to be applied to steroidal dienes and has been used to prepare benzene-fused compounds (277) (from 6-methylene and (278) and (279) [from the furano-steroid (217)'"] and adducts between A14*16-dienes and methyl acrylate,' 5 4 he~afluorobut-2-yne,'~~ dimethylacetylene dicarboxylate,' and methyl p r ~ p i o l a t e ' ~have ~ been by a obtained. In this last reaction the mono-adduct (280) was a~cornpanied'~~ diadduct, assigned the structure (281), which arises from homo-conjugate Diels-Alder addition and which appears to be the first exampleof homo-conjugate addition to a substituted bicyclo[2,2,l]heptadiene. The diadduct was also obtained in good yield by treatment of the mono-adduct with more methyl propiolate. The first steroidal examples of Diels-Alder reaction in which the dienophile is an aryne have been reported in f ~ l L "Thus, ~ cholesta-2,4-diene affords two adducts with benzyne, in low yield, as the result of both 01- and /3-face attack '55 156

A. J. Solo,J. N. Kapoor, and P. Hebborn, J. Medicin. Chem., 1970,13, 751. A. J. Solo, B. Singh, and J. N. Kapoor, Tetrahedron, 1969, 25,4579. I. F. Eckhard, H. Heaney, and B. A. Marples, J. Chem. SOC.(0,1969,2098.

Steroid Synthesis

445

although with tetrafluorobenzyne only that adduct resulting from a-face attack could be isolated. In contrast to the formation of the adduct (282) resulting from normal a-face attack of maleic anhydride on lumisteryl acetate,157tetrafluorobenzyne afforded with cholesta-5,7,9( 1lktrienyl acetate two adducts resulting from both a- and /?-face attack156 Formation of the latter /?-8,9-adduct is unprecedented. Interestingly, isomerisation of the 10-methyl group to give (284)

occurs when the a-face adduct (283), obtained as a minor component in the reaction of 3/?-methoxycholesta-5,7-diene with tetrafluorobenzyne, is subjected to prolonged pyrolysis.

F

F

(285) R = H (286) R = OH

As the result of complexing, both sodium borohydride and lithium aluminium hydride reduce158the more hindered carbonyl of the maleic anhydride adduct of ergosteryl acetate, producing lactone (285). Lithium tri-t-butoxyaluminium hydride gave as sole product the hydroxy-lactone (286) which with NaBH, gave the lactone (285) in high yield Although ergosterol B3 benzoate undergoes a normal Diels-Alder reaction with tetracyanoethylene, ergosteryl acetate,' s9 9(11)-dehydroergosterylacetate,ls9 and 3~-benzoyloxycholesta-5,7-diene fail to Is' s8 lS9

K. D. Bingham, G. D. Meakins, and J: Wicha, J . Chem. SOC.(0,1969,671. M. E. Birckelbaw, P. W. Le Quesne, and C. K. Wocholski, J . Org. Chem.. 1970,35,558. A. M. Lautzenheiser and P. W. Le Quesne, Tetrahedron Letters, 1969, 207.

446

Terpenoih and SteroiA

produce adducts'" but give instead the 7aderivatives (287) as the result of ene reactions. Similar ene reactions occur between 5,7-diene and a r y n e ~ . ' ~ ~ The spirocyclobutanone (290) is produced from a 16a-methyl-17-chloropregnan-20-one (288) and its 17-epimer by reaction with dimethylsulphoxonium methylide.'60 In the absence of the l6a-methyl group, e.g. (289), the reaction is less selective, affording both the cyclobutanones (291) and (292). 0

{fro

( 6 c . l - R

(292)

C (CN )z CI H ( C N ) ~

(288) R = Me (289) R = H

(290) R (291) R

Me =H

=

(287)

9 Steroids of Unnatural Configuration

Cholesterol has been converted161 into l0a-cholesterol by a method essentially identical with that used to prepare l0a-progesterone.' 62 Dehydration of (293) produced a mixture of A4-and As-3-ketones in which the former predominated. Each could be converted to the same A33'-enol acetate which, on reduction with sodium borohydride, afforded lOa-cholesterol. 9b-Testosterone has been prepared'63 by Simmons-Smith methylenation of the 5(10)-ene (294) followed by base-catalysed opening of the resulting cyclo-

iii, SimmonsSmith iv, Jones oxid.

-0

0 (295)

(294)

0 (296) 160 161

I62

R. Wiechert, Angew. Chem. Inrernar. Edn., 1970,9, 237. J . T. Edward and N. E. Lawson, J . Org. Chem., 1970,35, 1426. M. UskokoviC, J. Iacobelli, R. Philion, and T. Williams, J . Amer. Chern. SOC.,1966,88, 4538.

163

K. Syhora, J. A. Edwards, and A. D. Cross, Coil. Czech. Chem. Comm., 1969,34,2459.

447

Steroid Synthesis

propane (295). Acid-catalysed cleavage of the cyclopropane ring occurred at the 1&19 bond, resulting in the formation of the 5p-methyl derivative (296). Ozonolysis of neoergosterol under carefully defined conditions leads to high yields of aldehyde (297), which was further ozonised, as its morpholino-enamine, to the 19-norpregnane(298). A two-stage reduction using first ruthenium and then rhodium followed by Jones oxidation led164to the cis-syn-cis-syncompound (299). The proportion of 9a,lOa- and 9/?,1O/?-dihydroproducts obtained by catalytic reduction of 4,9-dien-3-ones is markedly dependent upon both the catalyst used and the substitution at C-17. Thus, the 178-hydroxydienone (300) aff~rded'~' only the 9a,lOa-dihydro-derivative(in 60 %yield) on reduction over Pd on SrCO,, and none of the 9/?,1O/?-epimercould be detected.166The 10a-configuration of this compound was stable16' to lithium tri-t-butoxyaluminiumhydride reduction [which afforded the equatorial 3a-alcohol(302)]and re-oxidation with manganese dioxide ; it also survived oxidation to the 4-ene-3,17-dione, although organometallic bases readily afford the lOa-5-en-3-one. Reduction of the 17a-hydroxyepimer (301) afforded' 66 almost exclusively the 9/?,10/3-dihydro-derivative. Like other 98,108-4-en-3-ones,this compound was highly sensitive to dilute base and acid, readily producing the non-conjugated 98-5(10)-en-3-one. Stronger acid afforded the 9jl,lOa-4-en-3-one. Epoxidation of both the allylic alcohol (302) (as 17-acetate) and the isomeric 5-ene gave'67 the 4a,5a- and 5a,6a-oxides respectively; the latter could not be opened by Grignard reagents nor could it be converted into the 6-ketone by treatment with boron trifluoride, although HCl produced the 5a,6/?-chlorohydrinquantitatively.

(297) X = H, CHO (298) X = 0

(299)

(300) R' = OH, R2 = H (301) R' = H, R2 = OH lb4 165 166 16'

A. H. Eimasry and 0. Gisvold, J . Pharm. Sci.,1970,59, 449. M. Debono, E. Farkas, R. M. Molloy, and J. M. Owen, J . Org. Chem., 1969,34, 1447. F. Farkas, J. M. Owen, and D. J. O'Toole, J. Org. Chem., 1969,34, 3022. M. Debono and R. M. Molloy, J . Org. Chem., 1969,34, 1451.

448

Terpenoids and Steroids

The major products obtained by hydroxylation of 9#?,10a-retro-steroidswith Curvuluriu lwuzta and bruchyspora are 9B-equatorial alcohols,' although 8#?-alcoholsare also produced. Attempted hydrolysis of the acetate function of the 10a-8/3,9/3-epoxide (303) with dilute methanolic potassium hydroxide afforded, v i a retro-aldol type cleavage,' 'O the 89-seco-steroid (304). Enantiomeric norethisterone and ethynodiol diacetate, obtained' 7 1 from ent-(305),have been shown to be devoid of gestagenic activity, although a small but significant block of oestradiol-induced uterine growth occurs' 7 2 with ent-oestradiol. In comparison with 19-nortestosterone, which is reduced microbiologically with Mycobuteriurn smegmatis to ~~-trans-fused-5a-products, ent-19-nortestosterone suffers reduction,' 7 3 in high yield, to AB-cis-fused 5/3derivatives.

OAc

~

OAc

(307)

OH

H

Ib8

D. van der Sijde, J. de Flines, W. F. van der Waard, and A. Smit, Rec. Trav. chim., 1969, 88, 1437.

169

'O 171 17'

H. Els, G. Englert, A. Fuerst, P. Reusser, and A. J . Schocher, Helu. Chim. Acta, 1969, 52, 1157. J . G . L1. Jones and B. A. Marples, Chem. Comm., 1969,872. H. J . Siemann and S. Schwarz, J . prakt. Chem., 1969,311, 671. R. A. Edgren and R. C. Jones, Steroids, 1969, 14, 335. K . Schubert and G. Hobe, Steroids, 1969, 14, 297.

Steroid Synthesis

449

4,4,14cl-Trimethyl-9~,lOor-retropregnane derivatives have been obtained by an efficient and selective a-ketol side-chain cleavage of cucurbitacins using aceticacid-free lead tetra-acetate,174 e.g. (306) -+ (307). A multistage synthesis of the lOa-hydroxymethyl-~-homo-3-aza-androstane (308) has been performed175*176 in an attempt to confirm the structure of cycloneosamandione. The four epimeric 16-deuterio-l7-hydroxy-l4/?-androstanes have been prepared177for n.m.r. examination in connection with conformational studies of CD-cisfused steroids and 14B-androst-4-en-3-onehas been synthesised.178 10 Homo-steroids Conflicting reports relating to the products obtained from the TiffeneauDemjanov ring-expansion of 5a-cholestan-3-one have appeared. G.Lc. analysis has failed to reveal'79 the presence of the ~-homo-3-ketone,although it has been detected by 0.r.d. and c.d. measurements.18' The pure ~-homo-4-ketonehas now been obtainedI8' via solvolysis of the dibromocarbene adduct (309)of 3-methoxycholest-2-ene to afford the unsaturated halogenoketone (310) which was then reduced to the 4-one. In a similar manner, 3-acetoxycholest-3-ene afforded the isomeric unsaturated halogenoketone (311) which on reduction produced ~-homo-5a-cholestan-3-one. Tiffeneau-Demjanov ring-expansion of 6~-acetoxy-Sa-cholestan-3-one has been used to prepare the corresponding ~-homo-4-ketone;'*I methylene insertion with diazomethane led to A-bis- and -tris-homocholestanones as the only isolated products. Products resulting from dichlorocarbene addition to enamines of bicyclic unsaturated ketones are dependentI8' upon the nature of the enamine base; morp holine dienamines afford simple adducts, the pyrrolidine dienamines give ringenlarged products. The pyrrolidine dienamines of cholest-4-en-3-one and testosterone acetate gave the A-homo-ketones (312) in moderate yield.

174 175

17' 17'

J . R. Bull and K. B. Norton, J. Chem. SOC.(0,1970, 1592. K. Oka, Y. Ike, and S. Hara, Tetrahedron Letters, 1969, 4543. K. Oka, Y. Ike, and S. Hara, Tetrahedron Letters, 1969, 4547. T. Nambara, M . Usui, and H. Hosoda, Chem. and Pharm. Bull. (Japan), 1969,17,1611. T. Nambara, K. Yamanouchi, and Y. Kobayashi, Chem. and Pharm. Buff.(Japan), 1969, 17, 1782.

179

* *O

J. D. Ballantine, J. P. Ritchie, and P. J. Sykes, J. Chem. SOC.( C ) , 1970, 736. J. Levisalles, G. Teutsch, and T. Tkatchenko, Bull. SOC.chim. France, 1969, 3 194. H. Velgova and V. Cernf, Coil. Czech. Chem. Comm., 1970,35, 2408. U. K . Pandit and S. A. G. de Graaf, Chem. Comm., 1970,381.

Terpenoids and Steroih

450

The preparation of A-homo-Sa- and -5B-androstan-3- and -4-ones has been describedlE3(see Part 11, Chapter 1, p. 353). A new method for the preparation of hydroxyamines, e.g. (317),from 17-ketones which provides a route to D-homo-androstanes in high yield has been devised.' 8 4 Methylenation of the 17-ketoneswith dimethylsulphonium methylide or dimethylsulphoxonium methylide affords, in almost quantitative yield, (and stereoselectively in the case of the former reagent) the oxirans (315) which are readily converted into hydroxy-azides (316). Reduction with borohydride, chromous chloride, or zinc and hydrochloric acid then affords the hydroxyamine in high yields. Various ~-homo-16,17-and 17a-ketones have been prepared'85 by standard methods. Surprisingly, the displacement of 17ag-tosyloxy-~homosteroids by azide occurs with retention of configuration. l E 6

(315)

(316) R = N, (317) R = NH,

11 Ring-nor Steroids

Mercuric acetate opens the cyclopropane ring of 3a,5a-cyclocholestane to produce the non-mercurated A-nor steroid (318) in moderate ~ i e 1 d . l ' ~Base attacks the 4,4-dimethyldiospheno1(319)only at the C-3 carbonyl to givelE8the ring-contracted hydroxyacid (320). Such 3,3-dimethyl-~-norcholest-5-enes are

J . B. Jones and J . M . Zander, Canad. J . Chem., 1969,47, 3501. D. N. Kirk and M . A. Wilson, Chem. Comm., 1970, 64. D. N. Kirk, W. Klyne, C. M. Peach, and M. A. Wilson, J . Chem. Soc. (C), 1970, 1454. M. Leboeuf, A. Cave, and R. Goutarel, Bull. SOC.chim. France, 1969,2100. E. C. Blossey, Steroids, 1969, 14, 725. J . Alais and J. Levisalles, Bull. SOC.chim. France, 1969, 3185.

lE4

Steroid Synthesis

45 1

reduced both chemically and catalytically to 5#?-Hproducts.’ 89 Ring-contraction of 3#?-acetoxy-4fl,5fl-epoxycholestane occurred on treatment with zinc and ethyl bromoacetate complex to give’” the A-nor steroid (321) as major product (17 % yield). Hydride reduction of 3-oxo-~-nor-~~-cho~anoic acid afforded’91 a preponderance of the 3a-hydroxy-compound, although the ratio of 3a : 3fl alcohols is less than with the normal six-membered homologues. Lithium-ammonia reduction afforded equal amounts of 3a- and 3B-ephers. AB-Dinor-cholestenone and -testosterone have been prepared’92 by the following sequence :

Cyclisation to the 3-en-2-one could be achieved by pyrolysis of the anhydride obtained by treatment of the diacid (322) with acetic anhydride, but better yields were obtained (especially in the cholestane series) by refluxing the seco-acid in acetic anhydride containing potassium cyanide. Catalytic reduction of the di-nor compound (323) gave the 5B-2-ketone which was ringexpanded to a 1 : 1 mixture of 5B-~-nor-2-and -3-ketones on treatment with diazomethane and boron trifluoride etherate. Neither AB-dinortestosterone nor its acetate exhibited androgenic or anti-androgenic activity. 16a- and 16B-Carboxylic acid D-norandrostanes are accessible by irradiation of 16-diazo-17-ketones.Both 16a- and 16B-acids (324) have been converted193 into the 16-acetyl, -acetoxy- and -hydroxy-derivatives and, by Curtius reaction, into the 16a- and 16#?-arnine~.”~ Nitrous acid deaminati~n”~ of this latter m i n e afforded, after reduction with lithium aluminium hydride, a mixture of epimeric c-homo-D-bisnormethyl alcohols (325)(69 %) and (326)(18 %). Solvolysis of the 16~-tosyloxy-derivativealso produced the same two methyl alcohols, although in this instance (326) predominated. The 16a-amino-~-norsteroid afforded the 13,17-seco-alcohol(327)and, by a series of carbonium ion rearrangements, the cyclopropane (328) on deamination. J. Alais, J . Levisalles, and I. Tkatchenko, Bull. SOC.chim. France, 1969, 3189. R. Ktvorkian, M. Lemonnier, G. Linstrumelle, and S. Julia, Tetrahedron Letters, 1970, 1709.

193

Ig4

H. R. Nace and E. M. Holt, J. Org. Chem., 1969,34,2692. W. G . Dauben, D. J. Ellis, and W. H. Templeton, J . Org. Chem., 1969.34, 2297. J. Meinwald, L. L. Labana, and T. N. Wheeler, J . Amer. Chem. SOC.,1970, 92, 1006. J. Meinwald and T. N. Wheeler, J . Amer. Chem. SOC.,1970, 92, 1009.

Terpenoidsand Steroids

452

(325) R' = Me, R2 = OH (326) R' = OH, R 2 = Me

12 l l N o r Steroids

A simple sequence for the preparation of 18-nor steroids which may be related to the biosynthesis of fukujus~norone,'~~ the first isolated naturally occurring 18-nor steroid, has been described. The synthesis'96 starts with the 3-acetate of (329; R' = 0,R2 = Me) readily prepared from hecogenin, which with iodine and lead tetra-acetate affords the lactone (330). Decarboxylation by treatment with base (the lactone was stable to acid) then gave the c/~-truns-18-nor-12-ketone (329; R' = 0, R2 = H)as sole product This, and also the subsequent WolffKishner reduction to the 12desoxycompound (329; R' = H,, R2 = H) which left the C/D ring junction unaffected, is in contrast to 18-nor-17-ketones which equilibrate with base. Unlike 12j?-sulphonyloxy-derivatives of conanine which afford rearranged c-nor-D-homosteroids, the 12or-epimers undergo reductive fragmentation' 97 with dichloroaluminium hydride to give the 18-nor-12-ene (331).

19'

19'

Y . Shirnizu. Y. Sato. and H . Mitsuhashi, Experientia, 1969, 25, 1129. Y. Shimizu, Experientia, 1970, 26, 588. G. Lukacs, L. Cloarec, and X . Lusinchi, Terrahedron Letters, 1970, 89.

Steroid Synthesis

453

13 lPNor Steroids

An unexpected and novel aromatisation o c ~ u r r e d 'when ~ ~ pregnenolone or dehydroisoandrosterone were brominated with N-bromoamides and subsequently dehydrobrominated with 2,4,6-collidine. The reaction, which appears to follow a dienol-benzene pathway,' 99 affords in moderate yield the corresponding 4-methyl-1,3,5( 10)-trienes. This is in contrast to the formation of 5,7-diene and 4,6-diene respectively when the 3-acetates were treated under similar conditions. Also unexpected was the almost quantitative formation of a rn-cresol-type product (332) when 6~-bromoandrosta-l,4-diene-3,17dione was subjectedZooto rearrangement with boron trifiuoride in acetic anhydride. The replacement of the 68-bromo-group of (332) occurred readily on treatment with silica to give the 6B-h ydroxy-steroid. Full details have appeared2'' of the pyrolysis of the maleic anhydride adduct (333). The major product obtained in 50% yield is the 11-0x0-ring-B aromatic compound (334). Three other neoergosterol derivatives are also produced. 0

Br (332)

(333)

(334)

Reaction of phenyl(trichloromethy1)mercury with both 1,4-dien- and 1,4,6trien-3-ones was accompanied by rearrangement giving 1-carboxy-4-methyland 3-carboxy-1-methylderivatives (335) and (336) respectively.'46 19* 199

J. R. Hanson and T. D. Organ, J . Chem. SOC.(0,1970, 513. J. R. Hanson and T. D. Organ, Chem. Comm., 1970, 1052. T. Wolff and H. Dannenberg, Chem. Ber., 1970,103, 917. J. P. Connolly, S. F. 0. Muircheartaigh, and J. B. Thomson, J . Chem. SOC.(0,1970, 508.

454

Terpenoids and Steroih

Enol acetylation of 4-en-3-ones under equilibrating conditions in which 2,4-dienol esters are stabilised by the presence of 2-alkyl groups gives risezo2to ring-A-aromatised products, e.g. (337).

0

Ac 0 (337)

Ac 0

0

(338) R (339) R

= =

CHO OOH

Autoxidation of the aldehyde (338) in the presence of a free-radical initiator gives high yields of the lo#?-hydroperoxide (339) which, after reduction to the lo#?-alcohol,can be converted into oestrone in 50% overall yield.203In contrast to the decarbonylation of aldehyde (338) with magnesium methoxide in liquid ammonia which afforded pure non-conjugated 5( lO)-en-3-one in high yield, treatment of(338) with potassium t-butoxide and then acetic acid gave high yields of the 2-formyl ketone (340). The rearrangement appears to be intramolecular and the following mechanism has been suggested :

202

203

A. J. Liston and P. Toft, J . Org. Chem., 1969,34,2288. C . M. Siegmann and M.S . dewinter, Rec. Trac. chim., 1970,89, 442.

Steroid Synthesis

455

19-Norcholestane derivatives have been prepared by a new sequence of reactions, as shown in Scheme 6, which do not involve ring B . " ~

AcO.

Reagents: i, O H - ; ii, oxidation; iii, Br,; iv, BF,.Et,O-AcOH; v, CaC0,-DMA; vi, HCl-MeOH ; vii, TsC1-py ; viii, s-collidine; ix, KOH-MeOH.

Scheme 6

Attempts to decarboxylate 2-oxygenated 19-oic acids by a variety of methods were unsuccessful, lactonic products invariably being ~btained.~' Migration of the lOp-methyl group induced by boron trifluoride opening of the 9a,lla-epoxide (341) gave the 9P-methyl steroid (342) as one of the main products.206 Other 9B-methyl 19-nor compounds have been obtained by methyl migration on deamination of 9a-aminopregnan-1 1-oneszo7and on treatment of a pregna4,9(1l)dien-3-one with fluoroxytrifluoromethane.208 0

'I"*

205

'06 '07

208

0

F ., E. Lack and A. B. Ridley, J . Chem. SOC.(C), 1970, 1437. C. W. Shoppee, T. E. Bellas, J. C. Coll, and R. E. Lack, J . Chem. SOC.(0, 1969,2734. J. W. ApSimon, R. R. King, and J. J. Rosenfeld, Cunad. J . Chern., 1969, 47, 1989. 0. E. Edwards and T. Sano. Cunud. J . Chem.. 1969,47, 3489. D . H. R. Barton, L. J . Danks, A. K . Ganguly, R. H . Hesse, G. Tarzia, and M . M . Pechet, Chem. Comm., 1969, 227.

Terpenoids and Steroih

456

A small amount of oestr-4-ene-3,17-dione was produced when the 19-substituted androstane-3,17-dione (343) was treated with hot aqueous potassium hydroxide.209 17p-Acetoxy-3~-fluoro-oestr-5( 10)-eneand its 6B-methyl derivative have been prepared from the 3p-fluoro- 19-methanesulphonate (344) as shown in Scheme 7.21 By a similar sequence the 32-fluoro-analogues were obtained.21

i. ii.

1

iii

Reagents: i, H + ; ii. Ac,O-py; iii, K,CO,; iv, DMSO-DCC; v, hv; vi, MsCl; vii, LiAIH,. Scheme 7

Although one successful synthesis of equilin from equilenin methyl ether has been reported,2l 2 Birch reductions of such substrates are non-selective, since reduction of both aromatic rings occurs. Use of the free phenol in such reductions, however, has neatly overcome these difficulties.2' Formation of the naphthoxide ion prior to Birch reduction with lithium-ammonia at - 70 "C has resulted in high yields of equilin. Surprisingly, further reduction of equilin 17-dimethylketal lo' 2'

"

'

J . Wicha and E. Caspi, Tetrahedron, 1969. 25, 3961. J.-L. Borgna and M. Mousseron-Canet, Bull. SOC.chim. France, 1970, 2210. J.-L. Borgna and M. Mousseron-Canet, Bull. SOC.chim.France. 1970.2218. E. J . Bailey. A. Gale, G. H.Phillipps, P. T. Siddons, and G . Smith, Chem. Comm., 1967, 1253.

'13

D. J . Marshall and R . Deghenghi, Canad. J . Chem., 1969,47, 3127.

457

Steroid Synthesis

with potassium-ammonia at - 33 "C led to selective reduction again in ring B of the isolated double bond to give high yields, after acid hydrolysis, of 8a-oestrone, which was also the product of Birch reduction of equilenin 17-diethylene ketal at higher temperatures. Equilin methyl ether 17-ketal gave oestrone. An investigation into theeffect of various ring A substituents upon the chromium trioxide oxidation of 1,3,5(10)-trienes' l4 and 1,3,5(10),9(11)-tetraenes2l 5 has shown that 9/3-hydroxy-ll-ones and 9-0~0-9,ll-seco-ll-oicacids are formed as well as the usual 6-ketones. 3/3-Acetoxy-oestra-l,3,5( 10),9(1l)-tetraen-17-one gave the 9a-hydroxy-l l-ketone. The oxidation of cyclopenta[a]phenanthrenes has been investigated2 l6 3-Deoxyoestrone oxidises normally with chromium trioxide to give the &ketone, which has been used to prepare2" a number of deoxyoestrone metabolites. DDQ in wet benzene converts2" 9(1l)-dehydro-oestrone methyl ether (345 ; R = H) first into the 12a-hydroxy-derivative (345; R = OH) and then into the novel 8,ll-diene (346).The 12a-bis-steroidalether is also obtained as a by-product, and, when benzene containing 3 % methanol is used as solvent, a high yield of the 12~-methoxy-compound(345; R = OMe) is obtained. Ring-B-aromatic neoergosterols are dehydrogenated with DDQ to the AI4-olefinsin greater than 80 % yield without affecting the side-chain.'lg Attempts to dehydrogenate (347) directly or via 3,5-dienols to the 19-nor-4,6-dien-3-one (348) with DDQ were unsuccessful although the desired dienone was eventually obtained220 by decarboxylation of the lob-carboxylic acid (349).

P

o

0

Me0 (346)

0 (347) R = H (348) A6, R = H (349) A6, R = C 0 2 H l4

'I5 '16 l7

R . C. Cambie and T. D. R . Manning, J. Chem. SOC.(0,1968,2603; R . C. Cambie, V. F. Cadisle, C. J. LeQuesne, and T. D. R. Manning, ibid., 1969, 1234; R . C. Cambie, V. F. Carlisle, and T. D. R . Manning, ibid., p. 1240. R. C. Cambie and V. F. Carlisle, J . Chem. SOC.(0,1970, 1706. M. M. Coombs, J. Chem. SOC.(0,1969, 2484. T. Nambara, M. Numazawa, and H. Takahashi, Chem. and Pharm. Bull. (Japan), 1969, 17, 1725.

*18 '19 "O

J. Ackrell and J. A. Edwards, Chem. and Ind., 1970, 1202. W. Brown, A. B. Turner, and A. S. Wood, Chem. Comm., 1969,876. V. Schwarz, P. Pihera, and K. Syhora, Coil. Czech. Chem. Comm., 1970,35, 1536.

Terpenoids and Steroids

458

Epoxidation of 17fl-benzoyloxyoestra-5(10),9(1 1)-diene affords”’ the 5a,lOaepoxide as the major product accompanied by some 5b,1Of#-epoxideirrespective of the substituent (hydroxy or ethylenedioxy) present at C-3. Such epoxides are always cleaved by Grignard reagents at the allylic carbon to give products dependent upon C-3 substituents.222Thus, the 3-ethylenedioxy-5a,lOa-epoxide (350) gives 17fi-benzoyloxyandrosta-4,9( 1 1rdien-3-one in 82 ”/, yield after deketalisation. Both the 3or- and 3~-hydroxy-compounds(351) open likewise to give 5a-hydroxy-lO~-methylderivatives, although the a-alcohol gives mainly the cis-5%-hydroxy-10a-methyl steroid. The 3j9-hydroxy-5&10/3-epoxyanalogue gave equal amounts of cis-5fi-hydroxy-log-methyl steroid and the spiro-compound (352). OBz

OBz

OH

(350)X

=

O[CH2120

(352)

(351) X = H , O H

A series of C-3 substituted 9a-hydroxy- 1 l/?-nitro-oestra-1,3,5(lO)-trien-17-ones e.g. (353) have been ~ y n t h e s i s e dfrom ~ ~ ~9(11)-unsaturated steroids and shown, surprisingly for 17-ketones, to be potent oral oestrogens. Decreased oestrogenic activity resulting in high lipodiatic-oestrogenic ratios (compared to the 3-methoxy 10)-trienes parents) was found for a number of 3-deoxy-16a-haloestra-1,3,5( obtainedz24as by-products in the halogenation of (354). Chlorosulphonation of the 3-methyl ether of oestradiol 17-acetate, and subsequent treatment with various amines, has given rise to a series of 2-sulphamoyl ~ e s t r a t r i e n e s and , ~ ~ a~ number of N-substituted sulphamoyl derivatives of 17a-ethynyl-oestradiol have also been made.226 Methane- and butanesulphonamido-oestra-1,3,5(10)-trienesz27prepared from the 3-amino-analogue of oestrone have shown poor biological activity. Oxidation of the 3,5-enol chloride of 19-nortestosterone acetate with t-butyl chromate followed by catalytic reduction provides an alternative routezz8 to 17Q-acetoxyoestr-5-en-7-one and nitration of the 3,5-enol ether with tetranitro22

‘

L. Nedelec, Bull. SOC.chim. France, 1970, 2548.

’” L. Nedelec and J. C. Gasc, Bull. SOC.chim. France, 1970, 2556. 223

224

’’’ 226

227 228

G. Baldratti, W. Barbieri, A. Consonni, R . Sciaky, E. Scrascia, and G . K. Suchowsky, Experientia, 1969, 25, 1018. W. F. Johns, J . Medicin. Chem., 1969, 12, 885. A. H . Goldkamp, J . Medicin. Chem., 1970, 13, 561. S. Schwarz, G . Weber, and F. Kuhner, Z . Chem., 1970, 10, 299.

D. G . Mikolasek, D. G . Gallo, J. L. Miniellie, G . R . McKinney, and A. A. Larsen, J . Medicin. Chem., 1969, 12, 1105. H.-J. Siemann and D. Onken, Z . Chem., 1969, 9, 421.

&- &

Steroid Synthesis

459

HNO,-Et,O

RO

RO (353)

.,x

+ AcO'

(354)

&<X

methane has been shown229to give the 2- and not the 6-nitro-derivative as previously claimed. An interesting and novel application230of the use of N-(2-chloro-l,l,2-trifluoroethyl)diethylamine,which normally finds use as a fluorinating agent, has given rise to the first examples of 9-unsubstituted 1l~-halogeno-19-norsteroids. The reagent reacts with 1 la-hydroxy-19-norandrost-4-ene-3,17-dione to afford the expected 1I/?-fluoro-compound, but when the reaction is conducted in the presence of an excess of chloride or bromide ions the 1lP-chloro- or -bromocompounds are obtained. The products show high progestational activity. Diels-Alder reaction of the 3,5(10)-diene (355) with dimethyl acetylene dicarboxylate and pyrolysis of the product has given rise231 to a new type of substituted oestrone : I

I .

C0,Me I 111 CO ,Me

ii, 165 "C-2 hrs iii, TsOH -Me,CO

(355) 229

230

231

W. Barbieri. A. Consonni. and R. Sciaky, J . Org. Chem., 1969,34, 3699. E. J. Bailey. H. Fazakerley, M. E. Hill, C. E. Newall. G. H. Phillipps, L. Stephenson, and A. Tulley, Chem. Comm., 1970, 106. A. J. Birch and B. McKague, Austral. J . Chem., 1969, 22, 2255.

Terpenoib and Steroids

460

Friedel-Crafts acylation of 3-deoxyoestrone followed by Baeyer-Villiger oxidation gives 2-acetoxy-3-deoxyoestrone converted by hydrolysis and methylation to the 2-methoxy-3-deoxyoestrone.Repetition of this sequence then gives 2-methoxy-oestrone. Alternatively, Fries rearrangement of oestrone acetate or Friedel-Crafts acylation of oestrone methyl ether gives 2-acetyloestrone, which has also been transformed into 2-metho~yoestradioL~~~ Methylation of the ethyleneketal of 11-0x0-oestronemethyl ether with methyl magnesium bromide gives the 1la-methyl compound which has been further transformed233into the 1lg-methyl-19-nor steroids (356; R’ = 0,R2 = H) and (356; R’ = B-OAc, a-H,R2 = Ac), both of which show interesting pharmacological properties. The 3a-equatorial alcohol (357) is the major product obtained from hydride reduction of the 3-ketone. The axial 3/3-alcohol has been obtained in up to 54 % yield by Meerwein-Pondorff reduction or by solvolysis of the 3a-mesitylene~ u l p h o n a t e .Similar ~ ~ ~ hydride reduction of an oestr-5(10),9(11)-ene is considerably less stereo~elective~~~ and indicates the control exerted by a distant function over the conformation of ring A.

A convenient synthesis of llfi,17/3dihydroxyoestra-4,9-dien-3-one starting from 17fi-hydroxyoestra-4,9dien-3-onehas been described,236 as have the preparations of oestr-5- and -5(10)-en-17-ones and their 7a-methyl analogues.237 The methyl ethers of 16a- and 16fl-brorn0-13a-oestrone~~~ and both 1701-and 17B-bromo-16-ones239 have been prepared for conformational analysis studies and a new synthesis of 3-methoxyoestr-16-ene and its two epoxy-derivatives has 232

T. Narnbara, S. Honma, and S. Akiyama, Chem. and Pharm. Bull. (Japan), 1970, 18, 474.

233

23*

J. S. Baran, H . D. Lennon, S. E. Mares, and E. F. Nutting, Experientia, 1970,26, 762. K. H. Palmer, C. E. Cook, F. T. Ross,J. Dolar, M. E. Twine, and M. E. Wall, Steroids, 1969, 14, 55.

”’ S. G. Levine and N . H. Eudy, J . Org. Chem., 1970,35, 549. ”’ M. Debono and R. M. Molloy, Steroids, 1969, 14, 219. 13’

238

239

C. C. Bolt, H. P. deJongh, C. M. Siegmann, N. P. Van Vliet, and F. J. Zeelen, Rec. Trau. chim.. 1969, 88, 1 0 6 1 .

T. Narnbara, T. Kudo, H. Hosoda, K. Motojima, and S. Goya, Chem. and Pharm. Bull. (Japan), 1969, 17, 2366. T. Nambara and T. Kudo, Chem. and Pharm. Bull. (Japan), 1969, 17, 1585.

46 1

Steroid Synthesis

been reported.24017a-Formyl-3-methoxyoestra-1,3,5( lO)-trien-17/?-01undergoes D-homoannulation to give the 17a/3-hydro~y-l6-ketone.~~~ 14 C-1eSubstituted Steroids

Steroids substituted at C-10 with carbon chains have been prepared242by an apparently completely stereospecific Diels-Alder addition of but-l-en-3-one to 3-methoxy-3,5(l0)dienes (358). The major initial adduct is the endo-isomer (359), separable by chromatography from the minor exo-isomer, with which it can be equilibrated. Grignard reaction of the adduct with methyl magnesium iodide and subsequent treatment with acid gives the C-10 pentene (360) whilst direct treatment of the adduct with acid affords the butanone (361).

X

(358) X = B-OH, a-H or O[CH,],O

(359)

& '

AcO

(360) (361) (362) (363)

R = CH,CH:CMe, R = [CH,],COMe R = CH:CH2 R = AC

(364)

The C-10 vinyl steroid (362) obtained by Wittig reaction on the 19-aldehyde has been converted to the 5a-bromo-6/?-hydroxyderivativewhich, on oxidation with lead tetra-acetate, produced the 19-methylene-6/l,19-oxidewhich was then reduced quantitatively by zinc-acetic acid to the lop-acetyl compound (363).243 An analogous lOp-acetyl compound (364), whose formation involves a 1,5hydride shift, was obtained along with some of the desired 19-hydroxy-19-methyl steroid on attempted base hydrolysis209 of the 19R-19-acetoxy-19-methylandrostanedione (343). The main product of the reaction however, was the ketal (365), or, if the reaction mixture was neutralised before work up, the hemi-acetal '*O

241

'*'

2*3

B. Schonecker, K. Ponsold, and P. Neuland, Z . Chem., 1970,10,221. T. C. Miller, J . Org. Chem., 1969,34,3829. A. J. Birch and B. McKague, Austral. J. Chem., 1970,23,341. Y. Watanabe, Y. Mizuhara, and M. Shiota, Chem. Comm., 1969,984.

462

Terpenoids and Steroids

(366). In contrast to the expected elimination which resulted on treatment of the 3a-bromo-2/3,19-oxide (367; R = Br) with zinc-acetic acid244to give 19-acetoxyandrost-2-en-l7-one, neighbouring group participation by the ethereal oxygen occurred (368) with the 3a-chloro-analogue (367 ; R = C1) yielding the products of substitution (367; R = OAc) and (369) as well as some of the 2-ene.245

Aco--@l

) & 0 +

H

Similar treatment of the methanesulphonate (367; R = OMS) afforded only the products of substitution (367; R = OAc) and (369) in equal amounts. The 2B,19-epoxydienone (372) has been prepared246 by the action of acid or base upon either the fluoro- or chloro-19-acetates(371),which were obtained by halogenation of the oxalyl derivative of (370) and subsequent cleavage of the 6#?,19-oxidering with acetic anhydride-toluene-p-sulphonicacid. Solvolysis of the 19-methanesulphonate of androst-4-ene-3,17-dioneor androsta-3,5-dien-17-one affords the 6~-hydroxy-5,19-cycioderivative as major OPiv

244

245 246 247

R. E. Counsell, G. W . Adelstein, P. D. Klirnstra, and B. Smith, J . Medicin. Chem., 1966, 9, 685. F. Kohen, G. Adelstein, and R . E. Counsell, Chern. Cornrn., 1970,770. G. Kruger and A. Verwijs, J . Org. Chem., 1 9 7 0 , 3 5 2 4 1 5 . J . Tadanier, R. Hallas, and J . R. Martin, J . O r g . Chem., 1969, 34, 3837.

463

Steroid Synthesis 15 Abeo-steroids

Full details have appeared on the formation of the novel 4(5+6)abeo-steroid system (374)which is produced in about 90% yield by .prolonged treatment of 6j-bromo4~,5~-epoxycholestan-3~-ol with lithium aluminium h ~ d r i d e . ~The ~* structure has been confirmed by independent synthesis249of the derivative (375) and the rearrangement has been shown250to be, in essence, a 1,3-elimination of the initial lithium aluminium hydride reduction product (373),which can be isolated after brief treatment of the bromo-epoxide with hydride. On the basis of the spectral data, the preferred conformations of the seven-membered ring have been deduced.25 Spectral studies have shown the configuration of the major (377)and minor (378)A-nor-B-homosteroids formed in the acid-catalysed cyclisation of (376), to be as shown.252

HO (373)

(374) R = OH (375) R = H

(376)

(377) R = B-H (378) R = a-H

5a,6a-Dihydroxy-4,4-dimethylandrostanedoes not undergo a Westphalen rearrangement with acetic anhydride-potassium hydrogen sulphate ; the more readily sulphating 6a-hydroxyl suffers elimination with migration of the C-5(10)bond to give the A-homo-B-nor steroid (379; R' = R2 = Me, R3 = H) as major product.2 53 A similar rearrangement occurs254when 5,6a-epoxy-6p-phenyl-5acholestane is briefly (10 s) treated with boron trifluoride to give the A-homo-B-nor steroid (379;R' = R2 = H, R3 = Ph) in 95% yield. Prolonged treatment of D. J. Collins, J. J . Hobbs, and R. J . Rawson, Ausrraf. J . Chem., 1969, 22,607. D. J. Collins, J . J. Hobbs, and R. J. Rawson, Austral. J . Chem., 1969, 22, 628. "O D. J. Collins, J. J. Hobbs, and R. J. Rawson, Ausrral. J . Chem., 1969,22, 807. ''I D. J. Collins, J. J. Hobbs, and R. J. Rawson, Austral. J . Chem., 1969,22, 821. 252 M. Lj. MihailoviC, Lj. Lorenc, J. ForSek, H. NeSoviC, G. Snatzke, and P. TrSka, Tetrahedron, 1970, 26, 557. "' M. Fktizon and P. Foy, Coll. Czech. Chem. Comm., 1970,35,440. '" J. N. Coxon, M. P. Hartshorn, and W. J. Rae, Tetrahedron, 1970,26, 1091. 248

249

Terpenoih and Steroih

464

either the Sa,6a-epoxideor the lO(5 -+6)abeo-steroid with boron trifluoride gives the 4(5 +6)abeo-5-ketone in high yield. On the basis of 0.r.d. evidence, the structure of dihydrojervine has been revised255to (380) in which the C/D ring junction is trans (12p-H). The synthesis of the etiojervane analogue of cortisone has been achieved256 starting with the jervine degradation product (381). Although Wittig reaction of (381) with ethylidenetriphenylphosphorane was successful during the preparation25 7 of the etiojervaneanalogue of progesterone,it was recovered unchanged256 on treatment with ethoxycarbonylmethylenetriphenylphosphorane.Alkylation of (381) with a variety of other reagents was also unsuccessful although ethynyl magnesium bromide afforded a fair yield of (382). Partial reduction to the.olefin and osmium tetroxide hydroxylation of this (as its A'-3-ketone) afforded a mixture of acetates which included (383) and (384). Jones oxidation then yielded the corresponding 20-ketones.

R'

P ' 0

(379)

HO

&

H

CH,OAc .OH

0 (383) R = a-H (384) R = B-H 255

T. Masamune, A. Murai, K . Orito, H. Ono, S . Numata, and H. Suginome, Tetrahedron, 1949.25.4853.

2'6 257

T. Masamune, A. Murai, and S. Numata, Tetrahedron, 1969, 25. 3145. S. M. Kupchan and M. J. A. El-Haj, J . Org. Chem., 1968,33, 647.

Steroid Synthesis

465

Another synthesis of the etiojervane analogues of testosterone and oestrone has a ~ j x a r e d . ~ A systematic has shown that the products obtained from the basecatalysed decomposition of the 12-toluenesulphonylhydrazoneof hecogenin and the solvolysis of the 12fi-tosylate of rockogenin are solvent dependent. Basecatalysed decompositionin hydroxylic solvents affords mainly the c-nor-D-homo13(17a)-endocyclic olefin (385) by rearrangement of the C-12 carbonium ion formed from the C-12 diazonium ion, whereas decomposition in aprotic solvents affords only the A"-compound (386) oia the C-12 carbene and no rearranged products. Solvolysis of the 12p-tosylatein polar solvents at elevated temperatures favours the production of (385) but the c-nor-r>-homo-exocyclic17a(l8)-olefin (387)predominates in solvents of low polarity. Analogous reaction on the 12-tosylhydrazone and 12~-toluenesulphonyloxy-derivatives of 3/?-benzoyloxypregnane afforded only the rearranged endocyclic olefins (388) and (389). Lithium aluminium hydride or dichloroaluminium hydride reduction of the 12-mesylate or, better, the tosylate of 12P-hydroxy-conanine affords260a

# I H

H

HO

H (385)

(388) (389) 13a-H, A17(17a)

se (390)

-NMe

258 259

260

+

T. Masamune and K. Orito, Tetrahedron, 1969,25,4551. J. M. Coxon, M. P. Hartshorn, D. N. Kirk,and M. A. Wilson, Tetrahedron, 1969,25, 3107. G . Lukacs, P. Longevialle, and X. Lusinchi, Tetrahedron, 1970, 26, 5 8 3 .

Terpenoids and Steroids

466

substantial yield of the c-nor-D-homoconanine (390)shown, by the incorporation of one atom of deuterium at C-l8a, to arise via the iminium ion (391). 16 Seco-steroids A new non-oxidative ring cleavage which should find application in steroids occurred26* when the bicyclic keto-dithian (392) was treated with sodium methoxide in DMSO. The products obtained by the action of peracids upon 3-alkoxy-3,5-dienesare dependent upon the reaction conditions.262 Aqueous organic solvents and the gradual addition of peracid favour the formation of 6fi-hydroxy-4-en-3-oneYbut when an excess of peracid is added in one portion the product, obtainable in high yield, is the unsaturated aldehyde-ester (393) which has also been obtained (as ethyl ester) by photochemical oxidation of the oxathian (394) followed by a reductive d e s ~ l p h u r a t i o nIn . ~non-polar ~~ solvents a 1 : 1 adduct (395)is formed between m-chloroperbenzoic acid and 3-acetoxy-3,5-dienes which is sufficiently stable (in the presence of a 17-ketone function) to be isolated and acetylated to the 6b-acetate or oxidised by chromium trioxide in pyridine to the 6 - k e t 0 n e . ~ ~ ~ The 3,5a-dichloro-seco-steroid (396), which could not be prepared directly265 from the seco-diol(397), was obtained by a two-stage chlorination starting with the 3-acetate of (397).The seco-steroid (398) was the major product (35 %) formed ethylene acetal with boron on brief treatment of 5,6a-epoxy-5a-cholestan-3-one trifluoride etherate in benzene.266 Reagents prepared from lead tetra-acetate and trimethylsilyl a ~ i d or e ~ ~ ~ phenyliododiacetate268 convert 5,6-unsaturated cholestanes and androstanes into 5,6-seco-keto-nitriles(399). 3-Methyl cholest-2-ene reacts similarly267to give the 2,3-seco-keto-nitrile. An interesting dienol-benzene rearrangement, accompanied by cleavage of ring B, resulted when 17/I-acetoxyandrosta-lY4-dien-3-one was treated with phenyltrichloromethylmercury.46 One of the main products (400) is also obtained, in low yield, when a large excess of dichlorocarbene is used.

'" J . A. Marshall and H. Roebke, Terrahedron Letters,

1970, 1555.

D. N . Kirk and J. M . Wiles, Chem. Comm., 1970, 1015. 2 6 3 A. Miyake and M. Tomoeda, Chem. Comm., 1970,240. 2 6 4 D. N . Kirk and J . M . Wiles, Chem. Comm., 1970, 518. z 6 5 A. Bayless and H. Zimmer, J . Org. Chem., 1969,34, 3696. '" J. M. Coxon, M. P. Hartshorn, and B. L. S. Sutherland, Tetrahedron Letiers, 1969,4029. '" E. Zbiral, G. Nestler. and K. Kischa, Tetrahedron, 1970, 26, 1427. 2 6 8 E. Zbiral and G. Nestler, Tetrahedron, 1970, 26, 2945. 262

Steroid Synthesis

(396) R' = C1, R2 = 0r-C1 (397) R' = OH, R2 = P-OH

467

I OH [CHZIZ OH

(399)

(398) OAc

The isolation of the biologically active metabolite of vitamin D, in a pure state, and the determination of its structure269as 25-hydroxycholecalciferol (401) has been rapidly followed by its synthesis via irradiation of 25-hydroxycholesta-5,7dien-3D-01~~'by three independent g r o ~ p s . ~ ~ ' The * ~ ' first synthesis of precalciferol, (405) has been achieved272by reaction of the lithium derivative of the chloro-ketone (402) with the en-yne (403)273to give (404)which was treated with bis(ethylenediamine)hromium(II) and then partially reduced catalytically. The thermal i s o r n e r i ~ a t i o nof~ ~(405) ~ (as 3,5-dinitrobenzoate) to vitamin D3 represents the first non-pho tochemical synthesis. The second-order Beckmann rearrangement products (406; R', R2 = CH, and R' = Me, R2 = C1) have been obtainedlo7 in low yield from Beckmann rearrangement of 17-ketones. 269 270 27'

272 273

J. W. Blunt, H. F. DeLuca, and H. K. Schoes, Biochemistry, 1968, 7, 3317. J. W. Blunt and H. F. DeLuca, Biochemistry, 1969,8, 671. S. J. Halkes and N. P. Van Vliet, Rec. Trav. chim., 1969,88,1080; J. A. Campbell, D . M. Squires, and J. C. Babcock, Steroids, 1969, 13, 567. J. Dixon, P. S. Littlewood, B. Lythgoe, and A. K. Saksena, Chem. Comm., 1970, 993. T. M. Dawson, J. Dixon, B. Lythgoe, and I. A. Siddiqui, Chem. Comm., 1970,992.

Terpenoids and Steroih

468

CI’

,

iii

*

a6 OH

17 Total SyntaesiS of Steroids* Carbocyclic Steroids.-The Torgov synthesis continues to exhibit its great versatility and was recently employed in the first synthesis of ~-homo-oestrone.~’~ Condensation of the vinyl alcohol (407)and 2-methyl-cyclopentane-1,3-dione in the presence of 1,4-diazabicycl0[2,2,2]octane and cyclisation with toluenep-sulphonic acid gave the B-homo-oestrapentaene(409)in 33 % overall yield from 3-methoxybenzosuberone. A three-stage reduction by sodium borohydride, catalytic hydrogenation, and lithium-ammonia afforded 3-methoxy-~-homo74

E. Galantay and H. P. Weber, Experientia, 1949.25, 57 1.

Unless otherwise stated all formulae refer to racemates.

469

Steroid Synthesis

oestra-1,3,5(10)-trien-l7~-ol (411) which was further converted to B-homooestrone and 17ol-ethyny1-17~-hydroxy-~-homo-oestr-4-en-3-one.

dH

0

Me0 \

(407) X = [CH2I2 (408) X = S

Further application of the Torgov reaction has been made in the synthesis of o e ~ t r o n e , ~the ~ ’ 3,16-dimethylether of oestri01,~~’ and a series of 4-halogenoo e ~ t r o g e n sA . ~novel ~ ~ modification277involves the use of allylic amine (412) (readily prepared from the enamine of rn-methoxytetralone)in place of the usual alcohol. Condensation of the isothiouronium salt,278obtained from the vinyl alcohol (413), with 2-methyl-cyclopentane-1,3-dione has led to a series of ~-nor-3-oxasteroids279and similar condensation of the thia-analogue (408) with 2-methylcyclopentane-l,3dione affordedzs0 the thia-oestrane (410), which was reduced catalytically to a mixture of 14a- and 14p-H-dihydro-epimers. Reduction of the remaining conjugated 8,9-unsaturation was less easy than in the carbocyclic analogue : metal-ammonia afforded thiols, and catalytic reduction was slow and led to a mixture of, presumably, 8a,9a-and 8p,9fi-epimers. The former isomer (416) which has its 9P-H favourably disposed for hydride abstraction with DDQ readily dehydrogenated to the 9(1l)-olefin which, on subsequent catalytic reduction, gave 6-thia-oestrone methyl ether. Condensation2” of the same thia275

276. 277

278 279

2*o 281

K. Hiraga, T. Asaka, and T. Miki, Chem. Comm., 1969, 1013. H. Specht, D. Onken, and G . Adam, Z . Chem., 1970, 10, 70. U . K. Pandit, F. A. Van der,Vlugt, and A. C. Van Dalen, Tetrahedron Letters, 1969, 3697. C. H. Kuo, D. Taub, and N. L. Wendler, J . Org. Chem., 1968,33, 3126. G. Lehmann and B. Lucke, Annulen, 1969,727,88. W. N. Speckamp, J. G. Westra, and H. 0. Huisman, Tetrahedron, 1970, 26,2353. W. M. B. Konst, J. L. Van Bruynsvoort, W. N. Speckamp, and H. 0. Huisman, Tetruhedron Letters, 1910, 2521.

Terpenoids and Steroids

470

analogue (408) (as its thiouronium salt) with 2-acetamidocyclopentane1,3-diol, led to the ring-c-aromatised thia-oestrane (414), and to the ring-D-aromatic compound (415) when 2-acetamido-cyclohexane-1,3dione was used. Other alkylation studies on 2-methylcyclopentane- 1,3-dioneand its enamine have been reported. 82

0 N

i, HCIO,-AcOH

ii.

R M ~ B ~ Me0

Me0

(413)

R

=

Me, Ph, or p - M e 0 C 6 H 4 OH

(414)

0

Reduction and demethylation of (418), obtained by reaction of m-methoxythiophenol with theepoxide(417)andsubsequentcyclisation, hasled to the synthesis283 of crystalline ~-nor-6-thia-equileninand its 14p-epimer;the latter compound and its 3-deoxy analogue284have also been obtained2*’ oia a Bachmann synthesis on (419; R = H) and (419; R = OMe) respectively. Full details have now appeared286of two total syntheses of optically active 8a- and 8a,lOa,l9-nortestosterone.Application of a Roussel-type synthesis by

’*’D. J . Crispin, A. E. Vanstone, and J. S. Whitehurst, J . Chem. SOC.( C ) . 1970, 10. 283

28b

R. R . Crenshaw and G. M . Luke, Tetrahedron Letters, 1969,4495. B. D. Tilak, V. N. Gogte, A. S . Jhina, and G. R . N . Sastry, ZndiunJ. Chem., 1969,7, 31. B. D. Tilak and M . K . Bhattacharjee. fndian J . Chem., 1969, 7. 36. R. Bucort, D. Hainaut, and G. Nomine, Bull. SOC.chim. France, 1969, 1920.

47 1

Steroid Synthesis

alkylation of the readily accessible trityl ether (420) has led to the synthesis287 of the dI-c-nor-D-homo-oestradiolderivative (422) via' the alkylated ketone (421). Alternatively, reductive methylation of the unsaturated ketone (421) and cyclisation ultimately afforded a mixture of the three unsaturated ketones (42-25).

@

- - OR2

R'

- - OAc

Ac 0

0

(420) R'

@

=

(421) R ' =

H, R2

(422)

=

% 0

\

R2=Ts

0

(423) R = a-H (424) R = B-Me (425) R = a-Me (426) A', R = p-Me (427) A', R = or-Me 287

M. J. Green, N. A. Abraham, E. B. Fleischer, J. Case, and J. Fried, Chem. Comm., 1970, 234.

472

Terpenoids and Steroids

Dehydrogenation of (424) and (425) by Arthrobucter simplex, containing a steroid 1,2-dehydrogenase and 2-methyl-1,4-naphthaquinone as hydrogen acceptor, occurred selectively on those enantiomers possessing 10R-chirality to produce optically active (426) and (427). Subsequent reductive aromatisation and acetylation afforded both enantiomeric forms of the c-nor-D-homo-oestradiol (422). This microbiologically selective dehydrogenation of 10R-chiral A4-3-ketones appears to be quite general, and has been applied288to 10a-testosterone and a number of di-, tri-, and tetra-cyclic compounds containing both five- and sixmembered rings. Both enantiomers of the racemic 11,17-diketone (428) were reduced by Rhodotoruh rnucilaginosa to 17S-alcohols, but the antipode having 13s-chirality was further reduced to the 11-alcohol Reoxidation then afforded the enantiomeric forms of (428).289Similar high stereospecificity was observed in the microbiological reduction of 6,7-dihydro-(428), where reduction of the 11-ketone in the 13S,17S-antipode occurred to give the allylic a l c o h 0 1 . ~Further ~~ examples of the differential metabolism of racemic 19-nortestosterone and its 13-ethyl homologue by Curuufaria lunuta have been described291 Michael addition of the /I-keto-ester (429) to the vinyl cyclohexenone (430), and subsequent base-catalysed cyclisation to the key intermediate (431), has provided a routez9' to 8/?-methoxycarbonyl-, -formyl-, and -hydroxymethyl0

0-4

0 COzMe

(429)

(430)

OAc

0

rl PhNMeCH 0

(431) 288

290

29' 2v2

(432)

(433)

J . Fried, M.J. Green, and G . V. Nair, 1. Amer. Chem. SOC.,1970,92, 4136. A. Siewinski, J. Dmochowska, and S. Mejer, Bull. Acad. polon. Sci., Se'r. Sci. chim., 1969, 17, 15 1 . A. Siewinski, Bull. Acad. polon. Sci., Se'r. Sci. chim., 1969, 17, 469. Y. Y . Lin. M. Shibahara, and L. L. Smith, J . Org. Chem., 1969,34, 3530. K . Sakai and S. Amemiya, Chem. and Pharm. Bull. (Japan), 1970, 18, 641.

473

Steroid Synthesis 0

(434) x (435) X

=

=

0 H,

(436)

oestrone methyl ether whilst alkylation of the novel enamine (432) with rnmethoxybenzyl bromide has been used to synthesise B-nor- and B-nor-D-homosteroids. Alkylation of the protected unsaturated ketone (433)with rn-methoxyphenacyl bromide and deprotection gave the bicyclic ketone (434), which could be converted to the 8b-methyl-D-homooestrane (436) by a variety of methods, the best of which proceeded by direct reduction to (435) and c y c l i ~ a t i o n . ~ ~ ~ Use of m-methoxybenzyl chloride in the initial alkylation led, by a similar sequence of reactions,29s to the 8B-methyl-B-nor-D-homo-oestrone (437) which, with hypobromous acid gave, surprisingly, the cis-SB,ll/I-bromohydrin (438) in high yield.296

Me0

Me0 (437)

(438)

When the epoxyoestrone (439) is treated with weak acids (pK, 1.424.21) opening of the epoxide ring occurs without dehydration to give the 8a-hydroxy9(11)-ene (440). Subsequent hydrogenation and dehydration with POC1,-DMF below room temperature afforded equilin methyl ether in high When methanolic hydrogen chloride was used to open the epoxide (439), dehydration occurred to give a mixture of 3-methoxyoestra-1,3,5(10),8,14-pentaen-17-one and equilenin methyl ether. Other recent syntheses of equilenin have involved the 293

294

295

296 297

U. K. Pandit, K. deJonge, K. Erhart, and H. 0. Huisman, Tetrahedron Letters, 1969, 1207. D. J. France, J. J. Hand, and M. Los, J . Org. Chem., 1970, 35, 468. D. J. France, J . J. Hand, and M. Los, Tetrahedron, 1969, 25, 401 1 . D. J. France and M. Los, Chem. Comm., 1969, 1513. R. P. Stein, G. C. Buzby, and H. Smith, Tetrahedron, 1970,26, 1917.

Terpenoids and Steroids

474

polyphosphoric acid cyclisation of (441). This compound has been prepared either, as a 3 : 1 mixture2'* with its cis-epimer (442) by methylation of (443) or, stereospe~ifically~~~ by Claisen rearrangement of the ally1 ether (445) followed by permanganate oxidation. Thermal cyclisation of the butenyiphenanthrone (446;R = H) gave 70% of the 13/?,17p-gonane(447; R' = 8-H, R2 = B-Me). The methyl analogue (446;

R' = P-Me, R2 = a-CH2C02H,R 3 = a-H (442) R' = B-Me, RZ = a-CH,C02H, R 3 = @-H (443) R' = R3 = H, R 2 = CH2C02H (444) R' = R3 = H, R 2 = Me (441)

(446) 2q8 2q9

(4471

A. J. Birch and G. S. R. Subba Rao, Austral. J . Chern., 1970, 23, 547. A. Horeau, E. Lorthioy, and J. P. Guette, Compt. rend., 1969, 269 C , 558.

Steroid Synthesis

475

Me) afforded a mixture of the 13a,17p-and 13a,l7a-isomers (447; R' = a-H, = a-H, R2 = C Z - M ~ ) . ~ ~ ' A new and highly stereoselective total synthesis of the 13B-ethyl gonane (448) which used a Stork isoxazole annelation sequence3" on the diene (449) has been intimated.302 Cyclisation of the acid (451) obtained by multistage synthesis from (450) gave rise303to the novel ring-c-aromatic (452), having both an 11-oxygenfunction and a 10-methyl group. R

=

R2 = B-Me and R'

0

A number of ABC aromatic steroids possessing methyl groups at C-2, 3, 4, 6, and 11 have been prepared304 by Stobbe condensation of the appropriate 1,2,3,4tetrahydrophenanthren-1-ones and cyclisation of substituted 2-acetonyl300 301

302

303 304

P. Beslin and J.-M. Conia, Bull. SOC.chim. France, 1970, 959. G . Stork, S. Danishefsky, and M. Ohashi, J . Amer. Chem. SOC.,1967, 87, 5459; G . Stork and J. E. McMurry, ibid., p. 5463. G . Saucy and J. W. Scott, Abstr. Chemical Institute of Canada and American Chemical Society Joint Conference, Toronto, 1970. A. Chatterjee and B. G . Hazra, Chem. Comm., 1970, 618. M. M. Coombs, S. B. Jaitly, and F. E. H. Crawley, J . Chem. SOC.((3,1970, 1266.

476

Terpenoids and Steroih

1,2,3,4-tetrahydrophenanthren-l-ones has been used to prepare3’’ some C-13 substituted ring-c-aromatic steroids. Difficulties associated with the mono-alkylation of divinyl ketone have been neatly overcome by the use of /3-chloroethylvinyl ketone, making possible306the construction of the tricyclic system (455) in 52% overall yield by reaction of mono-alkylated compound (453) with t-butyl aceto-acetate. The formation of (455) must proceed by multiple intramolecular aldol condensation of the intermediate 2,6,10-triketone (454). Attempts to obtain the analogous ‘C-10’ methyl compound by a similar cyclisation were unsucce~sful’~’Optimum conditions have been for catalytic reduction (to 9~,lOadihydro-compound)of tricyclic ketones related to (456; R’ = Me or Et; n = 1 or 2). Eugenol has been used309to prepare oestrone o h the ally1 methoxybenzene (457)and oestradiol 3-methyl ether has been resolved by means of the cinchonine salt of the 17-hemiphthalate.3’0

P-

O CI’

L @

(453)

H

0

(454)

Me0

-0ji (457)

’05

306 ’07

30a

’09

310

R. E. Juday and B. Bukwa, J . Medicin. Chem., 1970, 13, 754. S. Danishefsky and B. H. Migdalof, J . Amer. Chem. SOC.,1969,91, 2806. G. Saucy, W. Koch. N. Miiller. and A. Fiirst, Helv. Chim. Acta, 1970, 53, 964. R. A. Micheli, J. N. Gardner, R. Dubuis, and P. Buchschacher, J . Org. Chem., 1969, 34, 1457. A. Horeau, L. Menager, and H. B. Kagan, Compt. rend., 1969,269 C , 602. F. Reihe. J . Prakt. Chem., 1969,311,694.

Steroid Synthesis

477

Perhaps the most significant reaction in steroid synthesis to be described in recent years is the polyolefinic stereospecificcyclisation of pentaenes having no centres of asymmetry to form dl-tetracyclic products possessing 5 asymmetric centres, each of which is identical to that of naturally occurring steroids.311 Variations of this reaction, which was first applied to the synthesis of 16,17dehydroprogesterone, have used the acyclic tetraene (458) for the preparation312 of (459) and the cyclic ketone (460) to prepare3I3 the A-nor compound (461) which on ozonolysis and recyclisation gave 19-nor-16,17-dehydroprogesterone. Subsequent modification of the cyclisation conditions has led to very high yields of tetracyclic

1 0

0

U

(459)

(458)

i, NaBH, A

ii, CF,CO,H

- 78 "C

ha-steroids.-Early syntheses of 9-ma-steroids dependent3 upon the condensation of a cyclohexane amino-ester of type (462) afforded 18,19-bisnor-azasteroids (463) which could be alkylated to the immonium ethers (464)and which on further alkylation afford 10-methyl- and -ethyl-9-aza-steroids. In the very closely related syntheses of 8-aza-steroids, alkylation of the 12-ketone (465 ; R = OMe,X = H z , n = 1)with methyl iodide in methanol afforded the 0-methyl immonium salt [analogousto (464)]as sole product but, in the absence of methanol, 311

312

313

3 14 315

W. S. Johnson, M. F. Semmelhack, M. U. S. Sultanbawa, and L. A. Dolak, J . Amer. Chem. SOC.,1968,90,2994. W. S. Johnson, K. Wiedhaup, S. F. Brady, and G. L. Olson, J . Amer. Chem. SOC.,1968, 90,5277. S. J. Daum, R. L, Clarke, S. Archer, and W. S. Johnson, Proc. Nar. Acod. Sci. U.S.A., 1969,62, 333. W. S. Johnson, T. Li, C. A. Harbert, W. R. Bartlett. T. R. Herrin, B. Staskun, and D. H . Rich, J . Amer. Chem. SOC.,1970, 92, 4461. A. I. Meyers and W. N. Beverung, Chem. Comm., 1968, 877; W . Sobotka and M . Sikorska, Bull. Acad. polon. Sci., Ser. Sci. chim., 1969, 17, 19.

478

Terpenoids and Steroitjs

a 90 % yield of the 13-methyl immonium iodide (466) was r e a l i ~ e d . In ~ ' contrast, ~ methylation of (465;R = OMe, X = H,, n = 2) under all the conditions tried afforded 0-methylation as the predominant reaction. Catalytic reduction of (466) gave 95 of the trans-syn-cis isomer. The 8-am-oestrones (465; R = H, X = 0, n = 1 or 2) may also be prepared by condensation of 3,4-dihydroisoquinoline with 2-acetylcyclo-pentane- and -he~ane-1,3-dione.~"

F+R&R:x

HN

0

EtOZC

(463)

o

x

I

OR

Me0

Me0

The 8-aza-steroid (467; R = OMe) has been converted3'* by a series of high yielding reactions involving Pummerer rearrangement of the jP-keto-sulphoxide (467 ; R = CH,-SO.Me) into its corticoid analogue (467; R = CH,OAc). Unsubstituted 18,19-bisnor-9-aza-androstane and D-homoandrostane have been prepared. l9 ' I h

A. H . Reine and A . I . Meyers, J . Org. Chem., 1970.35, 554.

"' A. A. Akhrem, A . M. Moiseenkov,V. A. Krivoruchko, F. A. Lakhvich,L. A.Saburova, and A. I . Poselenov, Izvest. Akad. Nauk S . S . S . R . , Ser. khim., 1969, 2338; Chem. Abs., 1970, 72,43971 H'. 31*

R. E. Brown, D. M. Lustgarten, and R. J. Stanaback, J. Org. Chem., 1969,34, 3694.

'Iq

S. Ohki and M . Akiba, Chem. and Pharm. Bull. (Japan), 1969, 17, 2484.

479

Steroid Synthesis

A new synthesis320of 13-aza-steroids, which is apparently capable of wide application, depends upon the regio-specific condensation of substituted biscarbamates of type (468)with the diene (469). Reduction of the resulting tricyclic

EtO2C[CH2I2

H

&

NHCO,CH,Ph

X NHC02CH2Ph +

\ Me0 (469) R (470) R

=

=

PhH43B;Et,O,

H OMe

COzCH2Ph

M e 0&OZEt \ (471)

(472)

OAc

Me0 (473)

(474)

OAc

0

(475)

(476)

0

Me0

320

W. N. Speckamp, R. J. P. Barends, A. J. de Gee, and H. 0. Huisman, Tetrahedron Letters, 1970, 383.

480

Terpenoids and Steroids

compound (471) and cyclisation gave the 13-aza-oestrone (472). With the use of the methoxydiene (470) addition occurred the wrong way to give the 14-azasteroid (473). Treatment of the dienarnine (432; n = 1) with rn-methoxyphenyldiazoniumfluoroborate gives321the 6,7-diaza-steroid (474) in one step, or the aza-derivative (475) which can be converted quantitatively to (474). A synthesis of the 8,13diaza-oestrone (477) uia cyclisation of (476) has been described.322 Condensation of the b-diketone (479), obtained by alkylation of the morpholine enamine of 6-methoxytetralone, with guanidine carbonate or hydrazine has been used323 to prepare the 11,13-diaza-steroids (480) and (478) respectively (see Scheme 8).

HN-N

A \

ii. iv, v

(479)

Reagents: i, (NH,),.H,O; ii, EtOH-HCI; iii, NaH; iv, (NH,),C: N H ; v, H,-Pd/C

Scheme 8

A new intramolecular cyclisation of substituted adenines has been prepare a series of 2-, 4-, and 6-0x0-penta-aza-steroids.

to

Miscellaneous Heterocyclic Steroids.-1 3-Aza- 1 5-thia- 18-n0requilenin,~~1 1oxo-l5,16diaza-equilenin, and 1 8 - n o r - e q ~ i l e n i nanalogues ~~~ as well as ring-Afuran, oxazine, and oxazole analogues of equilenin have been synthesised.327 The preparation of the thiadiaza-steroids (481) has also been briefly reported.328 321

322 323 324

325

326 327 328

U. K. Pandit, M. J . M . Pollmann, and H . 0. Huisman, Chem. Comm., 1969, 527. G . Redeuilh and C. Viel, Bull. SOC.chim. France, 1969, 3 1 1 5. U. K. Pandit, F. A. van der Vlugt, and A . C. van Dalen, Tetrahedron Letters, 1969,3693. N . J. Leonard and R. A. Swaringen, J . Org. Chem., 1969, 34, 3814. S. V . Kessar and P. Jit, Indiun J . Chem., 1969, 7 , 7 3 5 . T. R . Kasturi and T. Arunachalam, Indian J . Chem., 1970, 8, 203. K . Huber and A. von Wartburg, Experientia. 1969, 25. 908. M . S. Manhas. V. V. Rao. D. Succardi, and J. Pazdera. 158th National ACS Meeting, 1969, organic chemistry abstract No. 27.

Steroid Synthesis

(481)

R

=

H, OH, or Bz

18 Steroid Conjugates

21-fi-~-Glucopyranosiduronicacid derivatives329of cortisone, hydrocortisone, 11-deoxyhydrocortisone, corticosterone, 11-dehydrocorticosterone, and 11deoxycorticosterone, the 3/3-~-glucopyranosiduronicacid derivative of cholof 16ester01,~~’the 168- and 17~-mono-~-~-glucopyranosiduronates~~~ epioestriol and the 16a-mono-~-~-g~ucopyranosiduronate~~~ of oestriol have been obtained, using standard Koenigs-Knorr reactions. The last compound, which was obtained via direct reaction of oestriol 3-benzyl ether with the fully protected bromo-sugar, has been further converted into the 3 - s ~ l p h a t eThe .~~~ preparation of tri-O-acetyl-/3-~-g~ucopyranosiduronates of a variety of different types of steroid, their anomerisation with titanium tetrachloride, and the differentiation of the anomeric pairs by physical methods have been described.333 A number of 2’-acetamido-2-deoxy-~-~-glucopyranosides of saturated and A*-unsaturated C-19 steroids have been prepared334by reaction of the steroid 3- or 17-alcohol with the appropriate chloro-sugar, using a mixed mercuric chloride and cyanide catalyst. The N-acetyl-a-glucosaminidesof the saturated steroids could be prepared by anomerisation of the 8-anomer with titanium of digitoxigenin, tetrachloride. The 2-amino-2-deoxy-fl-D-glucopyranosides strophanthidin, and pregnenolone have also been ~ r e p a r e d35 .~ The stepwise degradation of digitoxin to the di- and mono-digitoxosides by a method involving metaperiodate oxidation followed by sodium borohydride reduction and hydrolysis by very dilute hydrochloric acid has been described,336 and the order in which the sugar hydroxy-groups of digitoxin were thought to acetylate has been revised.337Dry zinc acetate in refluxing methanol has been employed for transesterification of base-resistant or base-sensitive acetyl groups of cardenolide glycosides.338 Cholesterol glucoside has been isolated, for the first time, from a plant (tobacco) source.339 329 330 331 332

333 334

335

336 337

338 339

V. R . Mattox, J. E. Goodrich, and W. D . Vrieze, Biochemistry, 1969, 8, 1188. J. J . Schneider and N . S. Bhacca, J. Org. Chem., 1969,34, 1990. T. Nambara, Y. Matsuki, and T. Chiba, Chem. and Pharm. Bull. (Japan), 1969,17,1636. J. P. Joseph, J. P. Dusza, E. W. Cautrall, and S. Bernstein, Steroids, 1969, 14, 591. J . J. Schneider, Carbohydrate Res., 1970, 12, 369. H. Sauer, M. Matsui, R. Block, J. S. Liang, and D . K. Fukushima, J. Org. Chem., 1969, 34, 3525. W. Reckendorg, N. Vassiliandov-Micheli, and H. Machleidt, Arch. Pharm., 1970,303, 17. D . Satoh and K . Aoyama, Chem. and Pharm. Bull. (Japan), 1970,18,94. D. Satoh and J . Morita, Chem. and Pharm. Bull. (Japan), 1969,17, 1456. E. Abisch and J . Binkert, Experientia, 1970,26, 71 1 . A. J. N. Bolt and R. E. Clarke, Phytochemistry, 1970,9, 819.

482

Terpenoids and Ster0id.s

Sulphates of 3a-, 38-, 178-, and 21-hydroxy-steroidsare readily prepared in good yield using sulphuric acid and dicyclohexylcarbodi-hide in DMF. 340 The reagent, which will only attack phenolic hydroxy-groups under concentrated conditions, appears especially suitable for the preparation of 35S-labelled sulphates. The 3a-mono- and 3a,20ar-di-sulphates of 5#l-pregnane-3a,20a-diol have been obtained34 using chlorosulphonic acid in pyridine. Steroidal sulphates (of cholesterol, campesterol, and 8-sitosterol) have been isolated for the first time from an insect source.342 The phosphorylation of cholesterol with phosphorus oxychloride and pyrophosphoryl chloride has been examined.343 The first example of a plant steroid conjugated with an amino-acid (see Table of New Compounds) has been reported344and glutathione and L-cysteine derivatives of 2-hydroxy-oestradiol have been described.345

'

19 Sapogenins

Diosgenin, recently isolated in high yield from the rhizomes of Costus s p e c i o ~ u s ? ~ ~ is microbiologically hydroxylated by Cunninghamellablakesleeana to 7B-hydroxy-, 78,l ladihydroxy-, and 78,12B-dihydro~ydiosgenin~~' and oxidised by Mycobacterium phlei to mixtures of A4- and A'*4-3-ketone~.348 The 3/l-azido-derivative of diosgenin has been used to prepare 5a-, 601-,68-, 7a-, and 7~-hydroxy-3~-amin0-25R-spirostans,~~~ thereby confirming the structure of the aglycone SPA I11 obtained by hydrolysis of a glucoside from Solanurn paniculaturn as 3/?-amino-6a-hydroxy-25R-spirostan. 20a,23#?-Dihydroxyhecogenin,along with 2Oa-hydroxyhecogenin, has been shown to be formed, presumably by hydroxylation of the corresponding furost22-ene, when pseudohecogenin is oxidised with p e r a ~ i d5.0~ [26-14C]Kryptogeninand [26- ''C]diosgenin have been ~repared.~' 20 Amim-steroids and Steroidal Alkaloids

Considerable difficulties had to be overcome in the isolation of four major highly cardiotoxic steroidal alkaloids from the skin secretions of the Colombian arrowpoison frog Phyllobates aurotaenia. The very labile pseudobatrachotoxin, whose 340

34' 342

343 344

345 346 347

348 349 350

"l

R. 0. Mumma, C. P. Hoiberg, and W. W. Weber, Steroids, 1969,14,67; C. P. Hoiberg and R. 0. Mumma, J. Amer. Chem. SOC.,1969,91,4273. M. S. Rajagopalan and A. B. Turner, J. Chem. SOC.(0,1969, 1858. R. F. N . Hutchins and J. N. Kaplanis, Sieroids, 1969, 13, 605. R. J . W. Cremlyn and N. A. Olsson, J . Chem. SOC.(0,1969,2305. Y. Shimizu, Y. Sato, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1969, 17, 2391. P. H. Jellinck and J . S. El-, Steroids, 1969, 13, 711. B. Dasgupta and V. B. Pandy, Experientia, 1970, 26,476. K. Kaneko, H . Misuhashi, and K . Hirayama, Chem. and Pharm. Bull. (Japan), 1969,17, 203 1 . G. Ambrus and K . G. Buki, Steroids, 1969,13,623. C . Gandolfi, G. Doria, and R. Longo, Tetrahedron Letters, 1970, 1677. M. Tanabe and R. H. Peters, J . Org. Chem., 1970,35, 1238. R . D. Bennett, H . H. Saher, and E. Heftmann, J . Labelled Compounds, 1969.5, 160.

Steroid Synthesis

483

structure is still unknown, reverts spontaneously to batrachotoxinin A (482) the structure of which has been determined by X-ray analysis of its 20a-p-bromobenzoate.352Batrachotoxin, the most toxic component (LDS02pg kg-’ in mice) is the 2k-ester (483) of batrachotoxinin A with 2,4-dimethylpyrrole-3-carboxylic acid, and its partial synthesis from these components has been achieved.353 Homobatrachotoxin, originally called isobatrachotoxin, which is almost as toxic as batrachotoxin, is the 2-ethyl-4-methylpyrrole-3-carboxylic acid ester (484).353 Interestingly, the fully substituted 2,4,5-trimethylpyrrole-3-carboxylate of batrachotoxinin A had twice the activity of the parent, presumably due to its greater stability. In addition to the 3a,9a-oxide, the 16,17-unsaturation, and the 148,18ethanolamine bridge which are without precedent in naturally occurring pregnanes, the compounds also exhibit interesting pharmacological properties. The synthesis of the 5/3,19-ethanolamine bridged compound (485) intended as a model for the partial synthesis of the batrachotoxins has been reported.3s4 (482) R

=

H

N

H

R~-NN/\--

(486) R’ = NH,, R 2 = H (487) R’ = OAC,R2 = AC

The proposed structure (486) of s o l a n o ~ a p s i n ehas ~ ~ ~been confirmed by X-ray analysis356of its N-(2-bromobenzylidene) derivative and by the synthesis 352

353 354

’

”

T. Tokuyama, J. Daly, B. Witkop, and I. L. Karle, J . Amer. Chem. SOC.,1968,90, 1917. T. Tokuyama, J. Daly, and B. Witkop, J . Amer. Chem. SOC.,1969,91, 3931. H. Wehrli, Chimia (Switz.), 1969, 23,403. H. Ripperger and K. Schreiber, Annalen, 1969,723, 159. E. Hohne, H. Ripperger, and K. Schreiber, Tetrahedron, 1970,26,3569.

Terpenoids and Steroids

484

of the degradation product (487) from solafloridine 3,16-diacetate (488) as shown.3 5 7 The 16/3,23-epoxy-epimerof solanocapsine has been synthesised from s ~ l a s o d i n e which , ~ ~ ~ has also been transformed by Grignard reaction of the 3a,5a-cyclo-6-ketone(489)into 6-methylsolasodineand thence by usual sapogeninlike oxidative degradation into 3~-acetoxy-6-methylpregna-5,6-dien-20-0ne.~~* Leptinidin (490) and several related 22,25-epimeric derivatives have been prepared359from tomatidenol and its 5a,6dihydro-analogue.

i, MnO,-CHCI, ii, Zn-AcOH r

iii, Acetylation

i. KOH-EtOH-H,O

0 (489)

(490)

18-Homolatifolin(492) has been prepared360from the 18-cyanopregnenolene derivative (491) by the route shown in Scheme 9. Further conversion led to the preparation of 18-homoconessine, possessing decreased amoebicidal activity. Cyclobuxine D has been converted into cyclobuxosuffrine (493) thereby confirming the structure of that compound361 Two separate but closely related syntheses362of the steroidal alkaloid samanine (494) have appeared which confirm its structure and stereochemistry. Several j5’

3s8

’” ’” 360

362

M . Nagai and Y . Sato, Tetrahedron Letters, 1970, 291 1. A. Polakova and K . Syhora, Coll. Czech. Chem. Comm., 1969,34, 3 1 18. H. Ripperger and K. Schreiber, Chem. Ber., 1969, 102,4080. J . Kalvoda and G. Anner, Helo. Chim. Acta, 1969,52, 2106. T. Bakano and Z. Voticky, J . G e m . SOC.(C), 1970, 590. K. Oka and S. Hara, Tetrahedron Letters, 1969, 1193; G . Habermehl and A. Haaf, Annalen, 1969,722, 155.

Steroid Synthesis

485

1 NaBH,-MeOH

w or HI-Pt-MeOH

ii, 60 % aq-AcOH

Scheme 9

A-norandrostanes having l0a-amino-alkyl substituents have been prepared and shown to possess some antibacterial The interesting diazonium sulphate betaine (495) has been prepared by diazotisation of the corresponding amino-sulphate and shown to couple under physiological conditions with cysteine, tryptophan, and histidine.364

HN

(494)

(493)

0

363 364

C. Rufer, Annalen, 1969, 726, 145. C. C. Chin and J. C. Warren, Biochemistry, 1970,9, 1917.

Terpenoids and Steroih

486

Cleavage of 5a,6a-365and 6a,7a-366 epoxides with azide ion and subsequent reduction with hydrazine has led to the preparation of 6/?-amino-steroids, although similar treatment of 16a,l7a-epoxypregnenoloneacetate was accompanied by D-homoannulation to give, after reduction, the 16B-amino-17aketone.367 Azide displacement (lithium azide in DMF) of 3a,20/?-diacetoxy12a-bromo-5B-pregnan-l l-one must presumably be preceded by equilibration, for the product was the 12a-azido-11-ketone which was subsequently reduced to the 12a-amine.’” The analogous 9a-amino-l l-ketone was obtained by treatment of the 9B,1lj-epoxide with azide, followed by reduction and oxidation. Dimethyl silylazide gives the allylic 7a-azides, reducible to the 7a-amines, with 3p-acetoxyand 3B-chloro-5-enes,although the products (1a-azido-2-ene or 2B-azido-3-one) obtained from cholest-Zene are dependent upon the reaction conditions.368 2a-Bromo-5a-cholestan-3-one afforded 2-amino-5a-cholest-l-en-3-one directly on reaction with sodium azide in DMSO, and likewise 6~-bromocholest-4-en3-one gave 6-aminocholesta-4,6dien-3-one. This new type of enamine has been identified as an isolable but unstable intermediate when cholest-4-ene-3,6-dione 36 is obtained by base treatment of 6a-azido-5fl-hydroxycholestan-3-one. Elimination occurred on similar treatment of 3a-acetoxy-2~-bromo-5a-cholestane with azide to give the allylic acetate. 2a-Amino-5a-cholestan-3a- and -3j-01~ have been synthesised by Curtius reaction of the 2a-methyl carb~xylates.~~’ More examples have been described37 of the preparation of steroidal Mannich bases, +

in high yield, using the novel reagent Me,N=CH, CF3C02-. Ammonium chloride has been claimed to catalyse the formation of a-aminomethyleneketones from a-hydroxymethylene-ketonesa n d . a m m ~ n i a . ~ ~ ’ The formation of the amine (496) when 3fl-toluene-p-sulphonates are treated with 2-dimethylaminoethanol involves both inversion at C-3 and demethylat i ~ n . ~The ’ ~ reaction of androstane-16,17-ketols and 17fl-acetoxy-l6a,l7aepoxide with morpholine to give a-morpholino-ketones has been thoroughly investigated and r a t i ~ n a l i s e d .17#?-Aminoandrosta-3,5-diene, ~~~ prepared by reduction of the 17-oxhe, possesses some antimicrobial activity which is not enhanced by substitution of the amino-groups with 2-chloroethyl, 2-hydroxyethyl, or 3-aminopropyl groups ;37 similar 2-chloroethyl substituted 17B-amines have been cyclised by treatment with base to give 1 7 p - a ~ i r i d i n e s .All ~ ~ ~four 3b6

K. Ponsold and G. Schubert, J . prakt. Chem., 1969, 311,445. G. Drefahl, K. Ponsold, and G. Schubert, J . prakt. Chem., 1969, 311, 919.

3h7

K. Ponsold, B. Schonecker, H. Rosenberger, R. Prousa, and B. Muller, J . p r a k t . Chem.,

3h5

1969,311,912. 368 3b9 370

”’

373 374 3i5

.’‘’

K. Kischa and E. Zbiral, Tetrahedron, 1970, 26, 1417. J. G . L1. Jones and B. A. Marples, J . Chem. SOC.(0,1970, 1188. A. Pavia and F. Winternitz, Bull. SOC.chim. France, 1969, 3104. A. Ahoud, A. Cave, C. Kan-Fan, and P. Potier, Bull. SOC. chim. France, 1970, 2707. G. Gerali, G. C. Sportoletti, C. Parini, A. Ius, and L. Cecchi, Farmaco Ed. Sci., 1969,24, 306. D. D. Evans and J . Hussey, J . Chem. SOC.(0,1969,2504. C. L. Hewett and D. S. Savage, J . Chem. SOC. (0,1969, 1880. Y . Nagai, Chem. and Pharm. Bull. (Japan), 1969, 17, 1749. Y . Langlois, C. Poupat, H.-P. Husson, and P. Potier, Terrahedron, 1970, 26, 1967.

Steroid Synthesis 487 have been synthesised ;377 interepimeric 3-dimethylamino-1-hydroxypregnanes estingly, zinc-acetic acid reduction of 5a-pregn-1-en-3-one oxime afforded the 3aamine stereospecifically,unlike similar reduction of the 4-en-3-one oxime which produces 3B-amine.37* Reduction of pyrrolidine enamines of 3-0x0-5a-steroids to give 3a-pyrrolidino-compounds in high yield is readily achieved by hydroboration and subsequent brief treatment of the organoborane with hot The synthesis380 of the 6-acetamido-compound (497) involved the stannicchloride-catalysed opening of a 6a,7a-epoxideby acetonitrile to the 6/?-acetamido7a-01 which, after acetylation, readily and quantitatively eliminated acetic acid to give (497).

’

Sa-Cholestan-3a-, -3p-, -6a-, and -6P-yl tetrazoles have been prepared38 from the corresponding primary amines by the sequence :

N-Substituted 3B-acetoxy-6/?-arnino-Sa-androstanes bearing histidine and related imidazole and triazole derivatives have been prepared.382 Allylic oxidation with selenium dioxide of 3a- and 3B-dimethylamino-5-enes,e.g. (498) and similar steroids, gave 4/3-hydroxy-5-ene and the allylic rearrangement product 3’7 378

3’9

380 381

382

P. Longevialle, Tetrahedron, 1969, 25, 3075. H. Kaufrnann and D. K. Fukushima, J . Org. Chem., 1967,32, 1846. J . Gore and J. J . Barieux, Tetrahedron Letters, 1970, 2849. G. Teutsch, E. L. Shapiro, and H.L. Herzog, J . Medicin. Chem., 1970, 13, 750. R. W. Horobin and J. McKenna, J . Chem. SOC.( B ) , 1969, 1018. G. Defaye and M . Fetizon, Bull. SOC.chim. France, 1969, 2835.

488

Terpenoids nnd Steroih

6p-hydroxy-4-ene, as well as 4,6-diene.3 8 3 The 3or-amino-5-ene holamine undergoes a concerted backbone rearrangement with sulphuric acid to give only the log-H product (499) in contrast to the 3-epimeric holaphylline and N-methylholaphylline which produce mixtures containing mainly the lop-H e ~ i m e r . ~ ~ ~ Hofmann degradation of 5r-cholestan-4a- and -4p-yl trimethylammonium salts closely resembled that of the C-6 quaternary ammonium salts; the 4pcompound producing solely the 4-ene by Saytzeff elimination whilst the 4aepimer gives largely demethylated 4a-dimethylamino-steroid, with some 3ene.38s Nitrous acid deamination of 3a,20~diacetoxy-l2a-amino-5~-pregnan-1l-one afforded some c-nor-D-homo-steroid, but the main products were 12B-methyl-11ketones produced by 13-methyl migration which, on treatment with base, underwent retroaldol reaction to give 3a-hydroxy-l2-methyl-l8-nor-5~-androst-12-en1l-one.*O7 Similar deamination of the 9a-amino-11-ketone (500)also resulted in methyl migration to a mixture of the l(10)- and 5(10)-olefins (502)and 10ahydroxy-compound (501). Epoxidation of the two olefins and subsequent treatment with acid gave 20~-hydroxy-9~-methy1-19-norpregna-1,3,5( 10)-trien-11one.

w (499)

(500) (501)

R1 = [j-Me, R' = r-NH, R' = r-OH, R 2 = j - M e

(502)

Attempted Ruschig d e a m i n a t i ~ nof~ ~both ~ 17a- and 17p-amino-l6P,18oxides (503) obtained by degradation of dihydroparavallaridine failed to give the 17-ketone, and unexpectedly produced a mixture of 16a- and 16B-methoxy-oxasteroids (504),most probably via the route shown. Similar participation of the 168,18-oxidefunction also occurred on attempted deamination using a modified Polonovski reaction387to give the unsaturated oxa-steroid (505). 3n3

H.-P. Husson, L. Fernandes, P. Forgacs, R. Tiberghien. P . Potier, and J . LeMen, B u / / . SOC.chim. France, 1969, 1993.

385

3R7

F. Frappier, Q. Khuong-Huu, and F. X . Jarreau, Bull. SOC.chim. France, 1969, 3265. E. N . Wall and J . McKenna, J . Chem. SOC.( B ) , 1970, 318. H.-P. Husson, J . de Rostolan, Y . Pepin. P. Potier, and J . LeMen, Tetrahedron, 1970,26, 147. A . Cave. C. Kan-Fan. P. Potier, and J . LeMen, Terrahedron, 1967,23,4681.

Steroid Synthesis

489

OMe

OMe

Nitrous acid deamination of both 17a- and 17p-amines (503) afforded the 17alcohols with complete retention of configuration. -0

cOCOCF3

+NMez

+NMez

I

I

--+

{-$$

CH=NMe2

CHO

-{ - {D I$ H

(505)

The reaction of 21-amino-steroids with mercurous chloride, which has been developed into a method for their detection388and quantitative estimation,389 produces the corresponding 21-aldehydequantitatively and may have preparative value. 21 Anthra-steroids and 'Linear' Steroids A novel method for the synthesis of anthra-steroids was uncovered'61 when the degraded cholesterol ketone (506)failed to alkylate with 1,3-dichlorobut-2-eneat C-10 but did so at C-6 to produce the vinylic chloride (507). Cyclisation of the ketone (508) obtained by acidic hydrolysis of (507) afforded the anthra-steroid (509).

cis-Hydroxylation and lead tetra-acetate cleavage of the 8-en-11-one (510) gave the acid- and base-sensitive cyclodecatrione (5 11) which readily ~ y c l i s e d ~ ~ ' to the linear hydroxy-dione (512). Dehydration afforded he conjugated enedione which equilibrated under alkaline conditions to a mixture of 14a- and 14P-epimers. 388

389

390

S. Gorog and Gy..Hajos, J. Chromatog., 1969, 43, 541. S. Gorog, Z. Tuba, and I. Egyed, Analyst, 1969,94, 1044. S. Aoyama and K. Sasaki, Chem. and Pharm. Bull. (Japan) 1970,18,48 1

490

Terpenoids and Steroids

pCBHl7

0

J+./

C1

22 Synthesis of Miscellaneous Natural Products

Oxidative cleavage studies on g-digiprogenin have led to a revision of the structures of r - and y-digipr~genin.~~ The tertiary hydroxy-group originally placed at C-17 is now known to be located at C-14, and chemical proof has been provided by synthesis392 of dihydro-a-digiprogenin acetate (514) from 3P-acetoxy-5apregn-16-ene-l1,20-dione (513) as shown in Scheme 10. 39 1

392

D. Satoh, M . Miyamura, and S. Nishii, Chem. and Pharm. Bull. (Japan), 1969,17, 1395. D. Satoh and S. Nishii, Chem. and Pharm. Bull. ( J a p a n ) , 1969, 17, 1401.

{5

Steroid Synthesis

ifi -

&{fi + i. ii

AcO

H

491

+ iii

/

JI

(5 13)

+ i v {

OH OH

f i o L { f i o

OH

OH (514)

Reagents: i, NBS; ii, NaI; iii, m-ClC,H,CO,H; iv, CrO,; v, OsO,; vi, Zn-AcOH. sebeme 10

Confirmation of the structure of diginigenone has been provided by the synthesis393of dihydrodiginigenone. The 1lfl,l2adiol (515), obtained by acidcatalysed opening of the corresponding 11fl,12fl-epoxide,was converted (as its 3,12-diacetate) into the 14,M-diene (516) (see Scheme 11). Boron trifluoride treatment of the 14,lS-epoxideobtained from (516) afforded the 16-ene-l5,20dione which was reduced to the saturated diketone. Treatment with base then gave the ketal (517) which on hydrogenolysis and oxidation afforded dihydrodiginigenone(5 18).

Reagents: i, Ac,O-py; ii, NBS; iii, py; iv, o-HO2C-C6H4.CO3H;v, BF3-Et20-PhH; vi, H,-Pd-BaSO,; vii, KOH-MeOH ; viii, H,-Pt-AcOH-HClO,; ix, Jones oxidation. scheme 11 393

R. Tschesche and H. Miiller-Albrecht, Chem. Ber., 1970,103, 350.

492

Terpenoids and Steroih

Further details have been published394 relating to the structure of cephalosporin P I ,and the structure of the related helvolic acid has been revised395 to the 6P-acetoxy-7-ketone (519).

OAc

23 Syntheses Involving the Steroid Sidechain A novel method for the stereospecific synthesis of 1701-and 17/?-'homocorticoid'

side-chains from 17-ketones has been developed.396 The 17-oxiran (520),obtainable in high yield from the 17-ketone and dimethylsulphonium methylide, reacts with 2-lithio-2-methyl-l,3dithianto afford (521) which on further treatment gives the 17-iso-'homocorticoid' (522)in high overall yield. Similar reaction of the 17-epimeric oxiran, which could not be separated from (520)' afforded the normal

U

____,

OH, R 2 = CH,COMe CH,COMe, R 2 = OH (524) R', R 2 = :CHCOMe 3qJ

3ys JYb

(522) R'

=

(523) R '

=

T. S. Chon, E. J. Eisenbraun, and R. T. Rapala, Tetrahedron, 1969, 25, 3341. S. Iwasaki, M . I. Sair, H. Igarashi, and S . Okuda. Chem. Cumm., 1970, 1 1 19. J. B. Jones and R . Grayshan, Chem. Comm., 1970,741.

493

Steroid Synthesis

'homocorticoid' (523). Both (522) and (523) readily dehydrated with acid to the unsaturated ketone (524), the 17a-hydroxy-epimer(523)being particularly sensitive. H ydroxylation experiments with diborane-hydrogen peroxide and osmium tetroxide on cholest-17-en-3/3-01 have provided chemical evidence that Cram's rule can be applied to predict the stereochemical outcome of Grignard reactions on 20-oxopregnanes and 20-0x0-2 1-norcholestanes.397 Thus 2Oa-01s are produced from Grignard reagents and (525 ;R' = Me, R2 = H) and 2Ofi-01s from (525; R' = C6H13,R2 = H). 20a-Alcohols are also obtained from the 17ahydroxy-20-ketone (525; R' = C6H13,R2 = OH) and the 21-acetoxy-20-ketone (525; R' = CH,OAc, R2 = H) The 17a-hydroxy-20-oxopregnane(525; R' = Me, R2 = OH) afforded the 20B-alcohol and the configuration of the 20-01s produced from 16a,l7a-epoxypregnenoloneacetate was dependent upon the size of the entering alkyl group. Ethynylation of 17-hydroxypregnenolone acetate proceeds in a stereochemically similar fashion to afford the 20j?-alcohols.jg8 Retroaldol cleavage of 20-methyl-20-hydroxy-17a-pregnan16-ones (526;R ' = Me, R2 = B-H) to afford androstan-16-ones occurs more readily than with the 1 7 f i - e ~ i m e r Similar . ~ ~ ~ base treatment of the 2k-hydroxypregnane (526; R' = H, R2 = a-H) resulted4" only in dehydration to the 17-ene (527) which, only after prolonged refluxing with methanolic base, yielded the androstan- 16-one. Base-induced fragmentation of 20-hydroxy-l6a- and -16j?-sulphonyloxypregnanes affords a variety of products in addition to the expected androst-16ene.401 The formation of vinyl iodides by treatment of a ketone hydrazone with iodine and triethylamine402 has been app1ied4O3 to both pregnenolone and 17-isopregnenolone 20-hydrazones to give the vinyl iodides (528; R = a-H and B-H). These are readily converted by dehydroiodination with base into 178- and 17aethynyl androstanes and by reductive deiodination into 178- and 17a-vinyl derivatives. Alternatively, 17B-ethynyl androst-5-en-3j?-olhas been obtained404

R'

I

co

3y7

398 39y

400

40' 402 403 *04

N. K. Chaudhuri, J. G. Williams, R. Nickolson, and M. Gut, J . Org. Chem., 1969,34, 3759. N. K. Chaudhuri and M. Gut, J . Org. Chem., 1969,34, 3754. A. A. Akhrem and T. V. Ilyukhina, Izvesr. Akad. Nauk S.S.S.R.,Ser. khim., 1969, 2018; (Chem. A h . , 1970, 72,21821~). M. H. Benn and R. Shaw, Chem. Comm., 1970,327. M. Matsui and D. K . Fukushima, J. Org. Chem., 1970,35, 561. D. H . R. Barton, R. E. O'Brien, and S. Sternhell, J . Chem. Suc., 1962,470. A. M . Krubiner, N. Gottfried, and E. P. Oliveto, J . Org. Chem., 1969,34, 3502. P. Wieland, Helv. Chim. Acta, 1970, 53, 171.

Terpenoids and Steroih

494

by treatment of 21-fluoro- or 2 1-methanesulphonyloxy-pregnenolone acetate with toluene-p-sulphonylhydrazideand potassium acetate in acetic acid. All of the 17-deoxy-17-ethynyl and -vinyl derivatives were found to be essentially devoid of biological activity in a variety of hormonal tests.403 A reinvestigation405of the adducts formed by addition of difluorocarbene to 17/?-acetoxy-l7a-ethynyl-3-methoxyoestra-1,3,5( 10)-triene406has confirmed the structure of the major product as (529) and led to a revision of the structure assigned to a diadduct byproduct to (530).Formation of this latter compound and its geometric isomer, which was also isolated, involves a novel acetyl migration. Lithium dimethyl copper converts407the main difluorocarbeneadduct (529) into the diene (532)in high yield.

k 17/l-Hydroxy-17a-ethynyl-oestranes and -androstanes readily add nitrile oxides to give408 the novel 17a-isoxazoles (533; R = Ph, Me or C0,Et) with reduced oestrogenic activity. 2Oa-Alcohols are the main products resulting from alkali metal-alcohol reduction of pregnan-20-0nes.~~~ Application of this method to 21-acetoxypregnenolone resulted in concomitant reductive removal of the acetoxy-groupto give pregn-5-ene-3/l,20a-diolas the major p r o d u ~ t . ~ " 21-Acetoxy-20~-alcohols, which are readily obtained by hydride reduction of 21-acetoxy-20-ketonescan, however, be conveniently transformed to 2&,21-diols by treatment of the 21acetoxy-20~-tosyloxyderivatives with base to afford 20a,21-epoxides which, with aqueous base or boron trifluoride in DMSO, open to produce the 20a.21-diols. These diols, like their 20P-epimers, readily afford acetonides under toluene-psulphonic acid catalysis which are rapidly hydrolysed by aqueous acetic acid at room temperature. In contrast. 17a.2001- and I7a.20B-diols form acetonides only with difficulty4'' in the presence of toluene-p-sulphonic acid. Substitution of perchloric acid, however, results in rapid 17,20-acetonideformation even in the presence of bulky 21 -su bstituents. The 17a,2Ofi-acetonides(like 20P-acetates) hydrolysed more slowly than 17a,2Oa-acetonides. E. Velarde, P. Crabbe, A. Christensen, L. Tokes, J . W. Murphy, and J . H. Fried, Chem. Comm., 1970, 725. 406

Oo7

40LI

4'0 4"

P. Anderson, P. Crabbe, A. D. Cross, H . J . Fried, L. H . Knox, J. Murphy, and E. Velarde. J . Amer. Chem. SOC.,1968, 90.3888. P. Rona. L. Tokes. J . Tremble. and P. Crab&. Chem. Comm.. 1969, 43. H . Laurent and G. Schulz, Chem. Ber., 1969, 102, 3324. D. N . Kirk and A. Mudd. J . Chem. SOC.(0,1969,968. D. N . Kirk and F. J . Rowell, J . Chem. SOC.(0,1970, 1498. M. L. Lewbart and J . J . Schneider, J . Org. Chem., 1969,34, 3505.

495

Steroid Synthesis

Attention has been drawn4' to the remarkable stability of 21-bromo-l7a,20acetonides, but debromination occurred with lithium aluminium hydride and with sodium in propan-2-01, although the main products with the latter reagent were the two olefins (534) and (535). Similar 17a,2O-acetonides derived from cortisone have been prepared412and oxidised with chromium trioxide in pyridine to the corresponding 21-aldehydes and 21-carboxylicacids. Formylation of progesterone and pregnenolone acetate and subsequent hydride reduction has given the 20/3,22diols (536) which were further converted into 21-hydroxymethylprogesterone.4' The B-hydroxy-ketone side-chain was surprisingly stable to both mild alkali and acid.

R

(533)

(536) R'

=

/I-CHOH[CH,],OH, R2

=

a-H

High yields of pregnan-20-ones are formed when the morpholino-enamines of 22-aldehydes are oxygenated in the presence of cuprous chloride414or when the free aldehyde in DMF is treated with air in the presence of 1,4-diazabicyclo[2,2,2]octane and cupric acetate -2,2'-bipyridyl complex.41 A similar oxidative decarbonylation has been to obtain a pregnan-20-one by side-chain degradation of lanosterol. A possibly related and certainly intriguing conversion41 of 3-oxo-23,24-dinorcho1-4-en-22-a1 to progesterone which is not dependent upon the presence of oxygen occurs on treatment with amine hydrochlorides in DMF. 17-Hydroxypregnenolone acetate affords dehydroepiandrosterone quantitatively418 on treatment with lead tetra-acetate and calcium carbonate, and a remarkably simple synthesis of A16-20-ketonesis available4'' by treatment of 17,21-diacyloxy-20-ketoneswith potassium acetate in hot DMF. The yield of A16-steroid from prednisolone 17,21-diacetate was almost quantitative and the method is applicable to other esters and 4-en-3-ones. In contrast to the rapid enolisation of 16B-methyl progesterone leading to quantitative formation of 16/3-methyl-l7a-progesterone, both 17a- and 178epimers of 16a-methyl progesterone are unaffected420by prolonged treatment with N-potassium hydroxide. Backbone rearrangement of cholest-Sene has been shown to produce a 1 : 1 mixture of C-20 isomeric 13( 17)-0lefins.~~

'

412

413 414

415 416 417 418

419 420 421

M . L. Lewbart and J . J. Schneider, J . Org. Chem., 1969,34, 3513. A. F. Hirsch and G. I. Fujirnoto, J . Org. Chem., 1970,35, 495. V. Van Rheenen, Chem. Comm., 1969, 314. V. Van Rheenen, Tetrahedron Letters, 1969, 985. L. H. Briggs, J . P. Bartley, and P. S. Rutledge, Tetrahedron Letters, 1970, 1237. F. Kohen and R. E. Counsell, Chem. and fnd., 1970, 1144. L. Tan, Biochem. Biophys. Res. Comm., 1970,39,65. L. Salce, G . G . Hazen, and E. F. Schoenewaldt, J . Org. Chem., 1970,35, 1681. M. B. Rubin, E. C. Blossey, A. P. Brown, and J. E. Vaux, J . Chem. SOC.(0,1970, 57. D. N. Kirk and P. M . Shaw, Chem. Comm., 1970,806.

496

Terpenoids and Steroih

Wittig reaction of the dinorcholenaldehyde (537) with triphenylisobutyrylmethylenephosphorane occurs with retention of configuration at C-20 to give, after catalytic reduction, saturated ketone (538) which, on further reaction with triphenylethylidenephosphorane, afforded422the stigmastadiene (539) identical with the naturally occurring product. The same aldehyde (537), after homologation to the 23-aldehyde and transformation into the 23-iodide, was alkylated with ethyl acetobutyrate yielding (540). Decarboxylation gave a mixture of C-24 epimeric ketones one of which, on further Wittig reaction, afforded423the diene (541) identical with one of the two naturally occurring steroids from Momurdica charantia. The other steroid (544) isolated from the same source has been s y n t h e ~ i s e d ~by~ 'a novel application of the Claisen rearrangement of the allylic alcohol (542), with the keten 0,N-acetal (545). The rearrangement426 proceeded with high stereospecificity yielding the amide (543) which, on subsequent hydride reduction and Cope degradation, afforded the triene (544). Grignard reaction of the saturated ketone (538)with vinyl magnesium bromide and allylic rearrangement of the resulting carbinol to the ally1 iodide and reduction of this has given the 2-configurated isomer of (539).427An identical series of reactions has been carried out on the 5-ene analogue. Ergosta-5,7,22,24(28)-tetraen-38-01has been s y n t h e s i ~ e dfrom ~ ~ ~ergosterol by ozonolysis to the 22-aldehyde and construction of the appropriate side-chain using a Wittig reaction. During these reactions, the 5,7diene system was protected as the Diels-Alder adduct (546) with 4-phenyl-l,2,4-triazolin-3,5-dione, from which the homoannular diene could be regenerated in 99 % yield by reduction with lithium aluminium hydride. Reaction of 6~-methoxy-3a,5-cyclo-23,24-bisnor-5a-cholan-22-al with the appropriate Wittig reagent has been used to synthesise a variety of new 22-cis and -trans isomers of cholesta-5,22-dienes and -5,22,24-triene~.~~' Both C-24-epimers of campesterol have been prepared430 by Grignard reaction between pregnenolone acetate and the enantiomeric l-brom0-2,3-dimethylpentanes. Hydrolysis with weak acid of the unsaturated imine (548)obtained by Grignard reaction of the 20-nitrile (547) gave the conjugated ketone, which equilibrated under basic conditions to a 1 : 4 mixture of conjugated and non-conjugated isomers (549) and (550). Reduction by hydrogenolysis of the derived ethylene thioacetal with lithium and ethylamine then gave cholesta-5,17(20)-dien-3~-01 [along with some 5,20(22)-diene]and pure cholesta-5,16-dien-3/3-01. The 5,20(22)diene was the sole product formed by dehydration of 20a-hydroxycholesterol. 422 423 424

"' *16 427

42B 429

""

W. Sucrow and B. Raduchel, Chem. Ber., 1969, 102,2629. W. Sucrow and B. Girgensohn, Chem. Ber., 1970, 103, 745. W. Sucrow, Chem. Ber., 1966,99,3559. W. Sucrow and B. Girgensohn. Chem. Ber., 1970,103.750. W . Sucrow and B. Girgensohn, Angew. Chem. Internat. Edn., 1969. 8, 926. W. Sucrow and B. Radiichel, Chem. Ber., 1970, 103, 271 1 . D. H . R . Barton, T. Shioiri, and D. A. Widdowson. Chem. Comm., 1970, 939. R . F. N . Hutchins, M . J . Thompson, and J. A. Svoboda, Steroids, 1970, 15, 113. R . Ikan, A. Markus, and E. J. Bergmann, Proc. 39th Meeting Isr. Chem. SOC.,Israel J . Chem.. 1969.7, 17p.

Steroid Synthesis

497 3:

Y II N

cr:

II

X

N

d

1 I

N

N

z

Y

&

II

II

N

cr:

N

d

X

II 3

d

II

II

"

4

cr:

d

Y 1 I N

d

Y II N

d

1 I 3

cr:

c

m rl W

z It N

d

Terpenoidsand Steroids

498

Selective reduction of the 16,17-double bond of (550), by catalytic hydrogenation over palladium on calcium carbonate and removal of the 22-ketone as before, gave c h o l e ~ t e r o l . ~ ~

dN {AXJ0

HO

(547)

(548)

X

(549)

x=0

= NH

( 5 50)

The new 23-hydroxy-epimers of cholesterol have been prepared432 by borohydride reduction of the 23-ketone, and Grignard reactions on the cyanohydrin of pregnenolone acetate have been used to prepare both epimers of 20a,22dihydroxycholesterol.433 Using optically pure half-esters of methyl succinic acid in Kolbe electrolytic coupling reactions with various bile acids the corresponding 2 5 - ~ and - 25-L-cholestanoic acids have been prepared.434 A novel C,, marine steroid which possesses a cyclopropane ring in its sidechain has been isolated435(see New Compounds Table). Full details have appeared4j6 cf the synthesis of 4a-methylergosta-8,24(28)-dien-3fi-o1 originally isolated437from yeast residues.

OH OH

OH

p 'H

HO

0

43'

\

N . K . Chaudhuri, R . Nicholson, J . G . Williams, and M. Gut, J . Org. Chem., 1969,34, 3767.

432

433 434

435

436

J. E. van Lierand L. L. Smith, J . Pharm. Sci.,1970,59, 719. N. K . Chaudhuri, R . Nicholson, H. Kimball, and M . Gut, Steroids, 1970, 15, 5 2 5 . T. Briggs, J . Org. Chem., 1970,35, 1431. R . L. Hale, J . Leclercq, B. Tursch, C. Djerassi, R . A. Gross, A. J. Weinheimer, K. Gupta, and P. J. Scheuer, J . Amer. Chem. Soc., 1970,92, 2179. D. H. R. Barton, D. M . Harrison, G . P. Moss, and D. A. Widdowson, J . Chem. Soc. ( C ) , 1970,775.

437

D. H . R. Barton, D . M.Harrison, and D. A. Widdowson, Chem. Comm., 1968, 17.

Steroid Synthesis

499

Chiograsterol A (551) has been used to ~ y n t h e s i s e ~ chiograsterone ~* (552) and isochiograsterone (553), all of which have been isolated from Chionographis juponica. A mechanism has been proposed for the ready interconversion of the latter two compounds (as their acetates) on treatment with acetyl chloride at room temperature. The thermal decomposition of cholesterol 2oCr- and 25-hydroperoxides has been 24 Photochemical Syntheses

3/l-Acetoxycholest-5-en-7-one, whose formation in high yield has been intimated440 when solutions of cholesteryl acetate are irradiated in the presence of air and catalytic amounts of mercuric bromide, is by irradiation, in the same solvent, with, a high-pressure mercury lamp into equal amounts of the non-conjugated 3P-acetoxy-4-en-7-one and the abeo-steroid (554).Experiments using labelled substrates show that carbon atoms 4 and 6 [bearing an asterisk in (554)]are mutually and completely exchanged during the reaction, as also are the 4 and 6 carbon atoms in the cholesta-3,5-dien-7-onewhich results from treatment of (554)with methanolic base. Cholest-5-en-7-one behaves similarly, but irradiation with a low-pressure mercury lamp442affords, in addition to cholest-4-en-7one, the oxetan (555) together with some bis-steroid ether (556). In contrast, 17/l-acetoxy-4,4-dimethylandrost-5-ene-3,7-dione produced443 mixtures of the 5a,6a- and 5#l,6/3-cyclopropanes (557 ;R = Me, X = 0)by a stepwisereaction,444 whilst the corresponding 3-ethylene ketal gave exclusively photoreduction prod u c t ~ 17/l-Acetoxy-4,4-dimethyl-19-norandrost-5-en-3-one . ~ ~ ~ similarly gave the A-nor ketone (557; R = H, X = H2) when irradiated in acetone,445 but the oxetan (558)was formed in benzene.446 17P-Acetoxy-4,4-dimethylandrost-5-en-3one gave the oxetan (559) (cf. Part 11, Chapter 1, p. 395).

OAc (554)

(555) 438

439 W"

441

442

443

444

445 446

(556)

G. Sauer, A. Shimaoka, and K. Takeda, J . Chem. SOC.( C ) , 1970,910. J . E. van Lier and L. L. Smith, Steroids, 1970, 15, 485. N . Friedman. M. Gorodetsky, and Y. Mazur, Proc. 39th Meeting Isr. Chem. SOC., Israel J . Chem., 1969, 7 , 3p. N . Furutachi, Y. Nakadaira, and K. Nakanishi, J . Amer. Chem. SOC.,1969,91, 1028. J. Hayashi, N. Furutachi, Y. Nakadaira, and K. Nakanishi, Tetrahedron Letters, 1969, 4589. S. Domb, G . Bozzato, J. A. Saboz, and K . Schaffner, Helu. Chim. Acta, 1969,52,2436. S . Domb and K. Schaffner, H e l r . Chirir. Acta, 1970, 53, 677. K. Kojima, K. Sakai, and K. Tanabe, Tetrahedron Letters, 1969, 1925. K. Kojima, K. Sakai, and K. Tanabe, Tetrahedron Letters, 1969, 3399.

Terpenoids and Steroids

500

x

‘

@ 0

h\-Me,COx

_____+

‘ @

R = Me,X = O R = H,X = H,

Methanol and propan-2-01 add non-stereospecifically to cholest-4- and -5ene449as do ethylene and tetrafluoroethylene to 3/l-acetoxypregna-5,16dien-20one although only 16a,l’Ia-addition products were isolated from allene, acetylene, and dichloroethylene;450 the derived 20-anti-oxime isomerises to the synisomer on irradiation in THF and cyclises internally in benzene solution.451 Irradiation of the trans-acid (561) in methanol resulted only in a cis-trans the unsaturated lactone equilibration, although the trans-acid (562) (563). The photochemical oxidation products of the oxathian (394) resemble those obtained by the action of peracids (q.0.) in that attack occurs primarily at C-6 in the presence of water but at C-4 under anhydrous conditions.2 6

OH (563) “’)

4s1 452

H. C. de Marcheville and R. Beugelmans, Tetrahedron Letters, 1969, 1901. P. Sunder-Plassman, P. H. Nelson, P. H. Boyle, A. Gruz, J. Iriarte, P. Crabbk, J. A. Zderic, J . A. Edwards, and J . H. Fried, J . Org. Chem., 1969,34,3779. R . P. Gandhi and V. K . Chadha, Indian J . Chem., 1969,7,633. M . Debono and R . M. Molloy, J . Org. Chern., 1970,35483.

Steroid Synthesis

501

Decarbonylation and rearrangement occurs on irradiation of the cyclopropyl aldehyde (564) producing (565) which, together with its 6a-epimer, has been independently ~ynthesised.~’~ Methanolic perchloric acid converted the 68methyl ether into the 1(10),5-diene. The photo-induced rearrangement of 4,5-epoxy-6-oxo- and 5,6-epoxy-4-oxocholestanes has been examined.454 All four compounds gave the 4,6-diketone as the main product but, in addition, the B-epoxides produced ring-contracted byproducts whilst the a-epoxides gave the 4,5-seco keto-acid (566).

@ @Hoi+ OMe

OMe

(566)

(565)

(564)

’

Photolysis of 9a,lOa-epoxy-17P-hydroxyoestr-4-en-3-0ne produces4’ a high yield of the 8(9--+ 10) abeo-steroid (567). The 9P,lOp-epoxide (as 17-acetate) rearranges to give a mixture of the corresponding log-derivative and some of the 1l(9 --+ l0)abeo-compound (568) (cf:Part 11, Chapter 1, p. 399). A mechanism has been proposed456for the photochemical rearrangement of the cholestadienone (569) to (570). Functionalisation of the C-13 methyl by

hV --+

455

K. Kojima, R. Hayashi, and K . Tanabe, Chem. and Pharm. Bull. (Japan), 1970, 18,88. J. P. Pete and M . L. Villaume, Tetrahedron Letters, 1969, 3753. M. Debono, R. M. Molloy, D. Bauer, T. Iizuka, K. Schaffner, and 0. Jeger, J . Amer.

456

G. F. Burkinshaw, B. R . Davis, and P. D. Woodgate, J . Chem. SOC.(0,1970, 1607.

453 454

Chem. Soc., 1970,92,422.

Terpenoids and Steroids

502

NC4-

HO

.O Ox]

NC

intramolecular transfer of a nitrile group from a C-20 cyanhydrin has been achieved in an unique way457in which the reaction is initiated by photolysis of a remote functional group. Thus irradiation of the prednisolone nitrite (571) gives rise to 20-25% of the 18cyano-20-ketone (572). Two examples of another new type of remotely controlled reaction have been described, in which a photo-induced oxidation of non-activated positions occurs which is dependent upon the ability to bring a particular photo-excitable group (ketone), attached to the steroid through a semi-rigid multicarbon chain, into close proximity with the desired reaction centre. Thus, irradiation of the 3(4-benzoylpheny1)propionicacid ester of cholestan-3a-01 afforded a macrocyclic lactone which, after further processing yielded 3a-hydroxy-5a-cholestan-12Photolysis of the homologous 5-(4-benzoylphenyl)valeratein benzene gave 3-acyloxy-derivatives of Sacholest- 14-ene (44%) and -16-ene (9 %), as well as macrolide products (25 %).459 Free-radical epimerisation of unactivated tertiary carbon atoms by irradiation in cyclohexane containing 1 equivalent of mercuric bromide has been demonstrated in both cyclo-pentanes and -hexanes. Thus, 5/?-androstane gives 95 % 5/?,14/?-androstaneafter irradiation for 12 hours. Irradiation for longer periods gives up to 70% of the 5a,l4/3-androstane. Similarly, irradiation of 38,178diacetoxy-48-methyl-5a-androstaneled to quantitative epimerisation and the formation of the 4a-methyl-l4/3-i~orner.~~~ Demethylation of conanine and 5,6-dihydroconessine occurred on irradiati~n.~ The ~ ’photoreduction of 1,4-dien-3-onesin the presence of sodium borohydride has been described.462 25 Oxidation and Reduction

Chromium trioxide, the most versatile of oxidising agents, has been shown to selectively oxidise allylic alcohols to a/?-unsaturated ketones in high yield, when 45’ 458

459 460

462

J . Kalvoda, Chem. Comm., 1970, 1002. R . Breslow and S. W. Baldwin, J . Amer. Chem. SOC.,1970, 92,732. J . E. Baldwin, A. K . Bhatnagar, and R. W. Harper, Chem. Comm., 1970,659. M . Gorodetsky and Y. Mazur, J . Amer. Chem. SOC.,1968,90,6540; M . Gorodetsky, Kogan, and Y . Mazur, ibid., 1970,92, 1094. D. Herlem-Gaulier and F. Khuong-Huu-Laine, Compt. rend., 1969, 269 C , 1405. J. A. Waters and B . Witkop, J . O r g . Chem., 1969, 34, 1601.

D.

Steroid Synthesis

503

hexamethylphosphoramideis used as the reaction solvent,463and to be superior to t-butyl chromate for the oxidation of 5-enes to 5-en-7-ones when used as its dry pyridine complex in methylene Similar oxidations of olefins to unsaturated ketones have been carried out in even better (almost quantitative) yields by irradiation of a mixture of the olefin, N-bromosuccinimide and finely divided calcium carbonate in an aqueous solvent.465 Using this method, cholesteryl acetate can be oxidised to the 7-ketone in 96 % yield. 15-Oxo-steroids,which are not usually very accessible, may be prepared by the allylic oxidation of 8(14)-enes with potassium chromate. Yields, which vary between 20--60%, are highest when a 12-0x0-group is present.466 Pyridine dichromate, which can be prepared in situ from an alkali-metal or ammonium dichromate and pyridine hydrochloride,or from an aqueous solution of chromic oxide and pyridine, oxidises secondary alcohols to ketones467 in similar yield to the chromium trioxide-pyridine reagent and would appear to offer the added advantage of being less hazardous to use. A warning has been given regarding the use of DMF for chromium trioxide oxidation.468 NN-Diethylaminoprop-1-yne in DMSO has been used for the oxidation of testosterone and 11-hydroxyprogesterone.* The reaction, which is rather slow, afforded the 17- and 11-keto-derivatives in 60% yield.469,470The use of N N dimethylaminophenylacetylenegave better yields470and, in general, still higher yields were obtained using diphenylketen-p-tolylimine with DMS0,470*471 a reagept which is sufficiently mild to oxidise both 3a- and 3/?-hydroxy-5-enes to non-conjugated 5-en-3-0nes.~~'The use of DMSO-acetic anhydride for the oxidation of hydroxy-steroids has been investigated.472 Both 5a- and Sfi-androst-15-en-17-0ne have been found to rapidly undergo hydroperoxidation when their solutions are kept in contact with air or oxygen.47 The so-formed 14/?-hydroperoxidesare readily reduced by potassium iodideacetic or triethyl phosphite in ~ y r i d i n eto~the ~ ~14B-hydroxysteroid. The nonconjugated 3/?-acetoxy-5a-androst-14-en-17-one also undergoes ready oxygenation, in high yield, to afford the 15-en-17-oxo-14p-hydroperoxide on exposure to oxygen.475 Treatment of this hydroperoxide with boron trifluoride etherate in benzene afforded, in modest yield, the ring-cleaved product (573) which could also be obtained, in slightly higher yield, by ozonolysis and hydrogenolysis of the non-conjugated 14-en-17 - 0 n e . ~Decarbonylation ~~ to give 3p474

* Configuration of 463 464

465 466

467 468

469 470 471

472 473 474 475 476

1 I-hydroxyl unstated in ref. 469, but given as OL in ref. 470. R. Beugelmans and M. T. Le Goff, Bull. SOC.chim. France, 1969,335. W. G. Dauben, M. Lorber, and D . S. Fullerton, J . Org. Chem., 1969,34, 3587. B. W. Finucane and J. B. Thomson, Chem. Comm., 1969, 1220. C1. Y. Cuilleron, M. Fetizon, and M. Golfier, Bull. SOC.chim. France, 1970, 1193. W. M . Coates and J. R. Corrigan, Chem. and Ind., 1969, 1594. H. Neumann, Chem. Eng. News, 6th July, 1970, p. 4. R. E. Harmon, C. V. Zenarosa, and S. K. Gupta, Chem. Comm., 1969, 537. R. E. Harmon, C. V. Zenarosa, and S. K. Gupta, J . Org. Chem., 1970, 35, 1936. R. E. Harmon, C. V. Zenarosa, and S. K. Gupta, Chem. and Ind., 1969, 1428. Sayed, M. lfzal and D . A, Wilson, J. Chem. Sac. (0,1969,2168. A. C. Campbell, J. McLean, and W. Lawrie, Tetrahedron Letters, 1969, 483. C. W. Shoppee and B. C. Newman, J. Chem. SOC.(0,1969,2767. A. Afonso, Canad. J . Chem., 1969,47,3693. A. Afonso, Canad. J . Chem., 1970,48, 691.

Terpenoids and Steroids

504

the diketone (574) could be achieved by either desulphuration of the dithioacetal of (573) or by direct decarbonylation using tris(tripheny1phosphine)rhodium chloride. Oxidation of the non-activated C-14 atom of (575) with chromium trioxide has been reported to give the 14a-alcohol in yields which are dependent upon the concentration of water present in the reaction, optimum ( 4 2 4 % ) yields being obtained with 1.5-2%

Q:

\

H

H

(573) R =

OC (574) R = COMe

OH

Ac 0

Br (575)

The ability of the 1 lg-hydroxy-steroid (576)to undergo spontaneous oxidation to the 11-ketonein the pure crystalline state has been described.478The reaction does not occur with the 21-alcohol or in the dark and is apparently unaffected by increased temperatures, unlike the closely related oxidation observed479with crystalline hydrocortisone 21-t-butylacetate, which is temperature dependent and requires the presence of oxygen. The oxidation which also occurs with some other, but not all, esters of hydrocortisone seems to be dependent upon crystalline form, only those forms which solvate with non-stoicheiometric amounts of water being susceptible. Small yields of the 15a-hydroxy-derivative of deoxycholic acid were formed by treatment of deoxycholic acid with ferrous sulphate and ascorbic acid in the presence of oxygen.480 An unexpected dehydrogenation of oestrone, induced by

(576) 477 478 4’9

480

(577)

C . M.Hol, M. G. J. Bos, and H. C. J . Jacobs, Tetrahedron Letters, 1969, 1157. M. L. Lewbart, Nature, 1969,222,663. G. Brenner, F. E. Roberts, A. Hoinowski, J . Budavari, B. Powell, D. Hinkley, and E. Schoenewaldt. AngPw. Chem. Internat. Edn., 1969, 8, 975. K . Kimura, M. Kawata, T. Tohma, A. Fujino, and K . Yamasaki, Tetrahedron Letters, 1970,2021.

Steroid Synthesis

505

the adamantyl carbonium ion, can give 9(11)-dehydro-oestronein up to 60% yield. 481 Ruthenium tetroxide, generated in situ from ruthenium and sodium periodate, smoothly cleaves ap-unsaturated ketones, with loss of a carbon atom, to produce keto-acids. Thus, testosterone acetate afforded the seco-acid (577) in high yield and a 9(1l)-unsaturatedl2-ketone was cleaved likewise to the 9-keto13-carboxylic acid with loss of carbon.482 Cross-conjugated dienones react similarly with loss of a two-carbon fragment. Several routes applicable to the large scale conversion of testosterone into 4,Sa-dihydrotestosterone have been investigated. The method of choice appears to be via catalytic reduction of a 17-acyloxy-3,3-ethylenedioxyandrost-5-ene.48 Platinum-catalysed hydrogenation of 19-acetoxy, hydroxy-, or methoxycholestan-3-ones affords higher proportions of 3a-alcohols than does the 19unsubstituted steroid.48 Tritiation of 17B-hydroxyandrosta-1,4-dien-3-0ne affords testosterone having a tritium ratio of 1 : 3.4 (a : 6) at C-1 and 1 : 1.4 at C-2 implying that reduction must proceed, in part, by 1,4-additi0n.~” Cholest-3-ene is the major product obtainable in up to 46 % yield when cholest4-en-3/3-01is reduced with dichlorobis(triphenylphosphine)platinum(nb stannous chloride complex.486 investigation^^^'*^^^ of the Henbest of ketones using chloroiridic acid and trimethyl phosphite in aqueous propan-2-01have shown that the reduction is specific for 3-ketones in both the 5a- and 5B-series in the presence of 4-,6-, 7-, 11-, 12-, 17-, 17a-, and 20-ketones, although 70% reduction of 2-ketones occurred in 24 hr and 19-aldehydes were slowly reduced. The usefulness of the reagent would seem to be restricted only by a tendency for the formation of 17iso-pregnanes and the need to protect the corticoid side-chain with some suitable function. The reaction invariably affords the 3-axial alcohol, although in the presence of added sodium hydroxide 3~-hydroxy-5a-androstan-17-one afforded the pseudo-equatorial 17/3-alcohol as major reduction product. Even greater stereospecificity was obtained when the homogeneous hydrogenation catalyst tris(tripheny1phosphine)rhodium chloride was used in place of the sodium chloroiridate.488 The presence of phosphorous acid or a readily-hydrolysedphosphite is essential for the success of the reduction, which has been shown to rely upon the oxidation of phosphite to phosphate for the required hydrogen.490 Sodium borohydride reduction of a 9(11)-en-12-0x0-derivative of cholic acid affords a mixture of 12a- and 12/3-alcohols containing slightly more of the axial 481

482 483

484 485

488 489

490

W. H. W. Lunn and E. Farkas, Tetrahedron, 1968,24,6773. D. M. Piatak, H. B. Bhat, and E. Caspi, J. Org. Chem., 1969,34, 112. J. Pospisek, Z . Vesel, and J. Trojanek, Cull. Czech. Chem. Comm., 1969,34, 3632. Y. Watanabe, Y. Mizuhara, and M. Shiota, Canad. J. Chem., 1969,47, 1495. H. J. Brodie, K. Raab, G. Possanza, N. Seto, and M. Gut, J. Org. Chem., 1969, 34, 2697. Y. Ichinohe, N. Kameda, and M. Kujirai, Bull. Chem. SOC.Japan, 1969,42, 3614. P. A. Brown and D. N. Kirk, J. Chem. SOC.(C), 1969, 1653. J . C. Orr, M. Mersereau, and A. Sanford, Chem. Comm., 1970, 162. Y . M. Y .Haddad, H. B. Henbest, J. Husbands, andT. R. B. Mitchell, Proc. Chem. SOC., 1964, 361. H. B. Henbest and T. R. B. Mitchell, J . Chem. SOC.(C), 1970, 785.

Terpenoids and Steroids

506

12a-01 reminiscent of the chemical reduction of saturated 12-ketones. With a similar but doubly-unsaturated 7Q(11)-diem12-0xo-derivative,however, the 128alcohol was the major isomer.491 Lithium aluminium hydride reduction of 2,3diketones of 4,4dimethylated steroids (readily obtainable by autoxidation of the 3-ket0nes~~') affords up to 80% yield of the 3p-hydroxy-2-ketones which, after acetylation to the 3B-acetoxy-2-ketones,are further reducible with calcium in liquid ammonia to the 2-ketone, thus providing a further method for the conversion of C-3 to C-2 5a-Cholestan-3-oneand 5a-androstane-3,17-dioneare readily reduced in good yields to their respective hydrocarbons by freshly activated zinc powder in ether saturated with hydrogen The hemi-acetal (579),which is rapidly obtained by reduction of the b-lactone (578)with one mole-equivalent ofdiborane, is further converted495on storage of the reaction mixture, into the dihydropyran (581) or, after the addition of more diborane, into the 17a-oxa-~-homosteroid (580).

HO' 0 (578) X = 0 (579) X = H, OH (580) X = H,

(582)

3-Methylene-5a-cholestane was obtained in 80% yield by reduction of the spiro-oxiran (582) with magnesium amalgam in the presence of magnesium bromide.496 Chromium(i1)chloride in acetone is an efficient reducing agent for nitro-steroids ;497 6a-, 16-, and 17B-nitro-groups are reduced to the oximes or, when the reduction is carried out under reflux, to the corresponding ketones. Both 6a- and 6~-nitrocholest-4-en-3-ones gave 5a-cholestane-3,6-dione but the less stable 5D-3,6diketone was obtained4'* when cholest-4-ene-3,6-dione was reduced under similar conditions. Whilst conjugated en- and dien-ones are unaffected by chromium(I1) chloride, conjugated enediones are reduced to the saturated dike tone^.^^^ Chromium(1r) chloride is also an efficient reagent for the reduction of azides to amines.184 4y'

492 493 494 4q5 4Yh 497

*"

T. Dahl, Y. Kim, D . Levy, and R. Stevenson, J . Chem. SUC.( 0 ,1969,2723. D . H. R . Barton, E. Bailey, J . Elks, and W. Templeton, J . Chem. SOC.,1962, 1579. P. Bey and R . Hanna, Tetrahedron Letters, 1970, 1299. M . Toda, Y. Hirata, and S. Yarnamura, Chern. Comm., 1969, 919. G . R . Pettit and J. R . Dias, Chem. Comm., 1970, 901. F. Bertini, P. Grasselli, G . Zubiani, and G. Cainelli, Chem. Comm., 1970, 144. J . R . Hanson and T. D. Organ, J . Chem. SOC.( C ) , 1970. 1182. J . R . Hanson and E. Premuzic, J . Chem. SOC.(0,1969, 1201.

507

Steroid Synthesis

Sodium-liquid ammonia reduction of 4j?,5-epoxy-5/3-cholestan-3-one affords 3a,5/?-diol in good yield, although similar reduction of the 4/3,5/3-epoxy-6-ketone resulted in reduction of only the epoxide function to give 4/3-hydro~y-6-ketone.~~~ 26 Syntheses Involving Reactions at Double Bonds

1,4-Diene-3,1l-diones(e.g. prednisone BMD)react with sodium bistrimethylsilylamide to afford either the 1,3,5-trienolateor the 9(1l)-enolate anion (isolable in high yields as their benzoates) depending upon the actual reaction condition."' Such 9(llkenol esters react with the interesting reagent fluoroxy-trifluoromethane (CF,OF) to afford5" the important 9a-fluoro-ll-ketones, whilst the free enolates giveso2 9a-methyl-11-ketones on methylation and the novel 9(11)-ene- 11-trimethylsiIylethers with trimethylsilylchloride. Fluoroxy-trifluoromethane also reacts with the isolated double bond of pregnenolone acetate, 38acetoxy4-enes, and 12j?-acetoxy-9(ll)-enesto give cis adducts, resulting from Markovnikoff addition, which may be converted into unsaturated fluoroketones. 20* Nitrosyl fluoride reacts slowly (10 days at 3 "C) with 9(11)-unsaturatedsteroids to produce 9a-fluoro-11-nitriminesin 10-70 % yield.503The nitrimines may be reduced catalytically or with Raney nickel (without affecting 4-en-3-one functions) to 11-iminesor by sodium borohydride to nitramines. Both the 11-imines and the 11-nitriminescan be hydrolysed to the corresponding 11-ketones (61100% yields), thereby providing another method for the preparation of 9afluoro-11-ketones. Further reduction of the 9-fluoro-f 1-imines either catalytically or with sodium borohydride gives 9a-fluoro-l l -amino-derivatives, although reduction with sodium and propan-1-01affords, after acetylation, 11r-acetamidopregnanes with loss of fluorine. Nitrosyl chloride reacts with the double bond of methyl 3a,7a-diacetoxy-5/3chol-11-enoate yielding the cis-1 la-chloro-12a-nitro-derivative(583). This compound was unaffected by hot collidine but was transformed, in low yield, into the 9(1l)-en-12-one on treatment with methanolic potassium hydroxide,504whilst zinc-acetic acid regenerated the 11-ene in high yield. 5-Enes reacted with nitrosyl chloride to produce the expected trans-5a-chloro-6/3-nitro-steroids.

(583) 4yy

(584)

L. Jabionski and S. Mejer, Bull. Acad. polon. Sci., Ser., Sci. chim., 1970, 18, 9. D. H. R . Barton, R. H. Hesse, G. Tarzia, and M. M. Pechet, Chem. Comm., 1969,1497. D. H. R. Barton, L. S. Godinho, R. H. Hesse, and M. M. Pechet, Chem. Comm., 1968, 804.

M. Tanabe and D. F. Crowe, Chem. Comm., 1969; 1498. J. P. Gratz and D. Rosenthal, Steroids, 1969, 14, 729. Y . Komeichi, Steroids, 1970, 15, 619.

Terpenoids and Steroih

508

5a-Cholest-2-ene was regenerated when the iodocarbamate (584), obtained by the action of iodine isocyanate and methanol on theZene, was treated with zinc.505 2/l-Iodo-3a-nitro-5a-cholestane is the major product resulting from the addiA variety of la,2a-methylene pregtion of nitryl iodide to 5a-chole~t-2-ene.~'~ nanes (585 ; R = F, C1, Br, OH, OCHO, OAc, or OMe; X = C1 or Br) have been prepared by reaction of the corresponding 4,6-dien-3-one with hypohalous acid in the presence of the appropriate nucleophile.'07 Strong progestational activity was found for the 6B,7/?-epoxide(586) as well as for the 6/?,7adihalogeno-derivatives of (585). Interestingly, the chloro-formate (585; R = OCHO; X = C1) was the major product obtained by chlorination of 17-acetoxy-1a,2a-methylenepregna-4,6-dien-3-one in DMF-propionic acid. The preparation and biological properties of these and other 6,7-disubstituted la,2a-methylene-4-en-3-ones has been reviewed. Androsta- 1,4,6-trien-3-ones react with N-bromoamides to give solely the 6B,7a-dibromo-derivatives with no detectable products of allylic bromination. The 6/3,7adibromides eliminated HBr with rearrangement to 4-bromo-lP-dien3-ones on treatment with organic bases5'' 5a,6/?-Dichloro-steroidsmay be prepared in fair yield from 3B-acetoxy-5-enes by treatment with a mixture of lead tetra-acetate and acetyl chloride (1 :4).510 Reformatsky reactions between saturated 3-ketones or 4-en-3-ones and abromo-y-butyrolactone' afford hydroxy-lactones, e.g. (587), which dehydrate to mixtures of exo- and endo-cyclic olefins. 16-En-20-ones and, to a small extent 17-ones, also react with a-bromo-y-butyrolactone but saturated 20-ketones are unreactive. None of a series of such substituted androstane or pregnane lactones showed any significant hormonal activity." Dehydroisoandrosterone failed to undergo Reformatsky reaction with 2-bromo-6,6-dimethyl caprolactone.'

''

'

505

'06 'O'

soy 'lo

'12 'I3

A. Hassner, R. P. Hoblitt, C. Heathcock, J . E. Kropp, and M. Lorber, J . Amer. Chem. SOC.,1970,92, 1326. A. Hassner, J. E. Kropp, and G . J. Kent, J . Org. Chem., 1969, 34, 2628. H. Laurent, G . Schulz, and R. Wiechert, Chem. Ber., 1969, 102,2570. R. Wiechert, H . Laurent, and H. Hofmeister, Rev. SOC.quim. Mexico, 1969,13, 171A. M . KoCor and M. Gumulka, Tetrahedron Letters, 1970, 3227. E. Zbiral and K . Kischa, Tetrahedron, 1969.25, 1545. H. Torabi, R . L. Evans, and H. E. Stavely, J . Org. Chem., 1969,34, 3796. G . R . McKinney and H . E. Stavely, Steroids, 1969, 14, 91. H. Torabi, R . L. Evans, and H . E. Stavely, J . Org. Chem., 1969,34, 3792.

509

Steroid Synthesis

Exocyclic 3-methylene derivatives of cholestane and cholest-4-ene, as well as 20-methylenepregnanes,have been prepared in good yield from the corresponding ketones and the bis-Grignard reagent obtained from methylene di-i~dide.~' 3fl-Acetoxypregn-16-en-20-one afforded the bis-steroid (588) under similar conditions. The non-conjugated exocyclic 3-methylene derivative of 17-acetoxyandrostane was largely unchanged on subjection to Vilsmeier reaction, but the analogous 3-methyl-3,5-diene reacted readily (as 3-methylene-4ene) to give a mixture of cis- and trans-formylated dienes (589), although at high temperatures reacted slowly 6-formylation o ~ c u r r e d . ~ 3~-Acetoxy-l7-methylenandrostane to produce 20-formyl products. Mercuric acetate reacts with 1,4,6-trien-3-ones to give, after treatment with sodium chloride, the 2-mercury steroid (590) which on reduction with sodium borohydride' l 6 gave 38-hydroxy-4,6-diene.

'

(589)

(590)

27 Miscellaneous Syntheses

la-Hydroxycholesterol has been prepared by lithium aluminium hydride reduction of la,2a-epoxycholesterol in a multistage synthesis which starts from 68acetoxy-5a-cholestan-3-one. In contrast to 1,4-dien-3-ones,the 2,4-dien-l-one (591)obtained by bromination and dehydrobromination of the 2-en-1-one, appears relatively stable to conditions which normally lead to dienone-phenol rearrangement, although addition of acetone occurred in the presence of acid to give the bridged triketone (592).5'* Dilute aqueous methanolic base converted the dienone (591) into 3a,5-epoxy-5acholestan-1-one.

'

514

515 516 517

518

F. Bertini, P. Grasselli, and G. Zubiani, Tetrahedron, 1970, 26, 1281. M . J . Grimwade and M. G. Lester, Tetrahedron, 1969,25, 4535. M . Kodor and M. Gumulka, Tetrahedron Letters, 1969, 3067. B. Pelc and E. Kodicek, J . Chem. SOC.( C ) , 1970, 1624. J. R. Hanson and T. D. Organ, J . Chem. SOC.(0,1970, 1065.

Terpenoids and Steroids

5 10

(q0

0

Methods for the conversion of 3- and 17-ketones to 2- and 16-ketones have been neatly summarised in pictorial form and, using these methods or developments of them, a number of 2- and 16-mono- and 2.16- and 3,16-di-ketones have been l9 ~ynthesised.~ Unlike 2-oxo-5a-steroids, 5fl-cholestan-2-one, which has been synthesised from 2fl-acetoxy-5/l-cholestan-3-one, enolises to C-1, giving lfl-halogeno-derivatives with chlorine and bromine and the 1-en-2-01acetate with isopropenyl acetate.520 have been prepared and Both 2a,3a- and 2fl,3#?-epoxy-3-phenyl-5a-cholestanes their reactions examined.’ The 1,4,7-trien-3-one analogue of prednisolone has been prepared522from cortisone in a 13-stage synthesis in which the 7,8-unsaturation was introduced by bromination and dehydrobromination of the protected 1 la-formyloxy-derivative (593). Regeneration of the 3-ketone gave the non-conjugated 4,7-dien-3-one which was then subjected to a series of oxidation and reduction reactions. This novel type 1,4,7-trien-3-onehas also been introduced into several androstanes by treatment of the conjugated 1,4,6-trien-3-oneswith sodium methoxide in DMSO and reprotonation by strong acids.5 2 3/l-Acetoxy-ergosta-7,9(11)-dienehas been prepared by bromination and debromination of 3fl-acetoxyergost-7-ene.’24 4P-Demethylation of 4,4,14a-trimethyl steroids has been achieved by a new route as shownS25in Scheme 12. Higher yields of demethylated steroids have been realised’26 (Scheme 13)using the unsaturated nitrile (599, which was obtained by a second-order Beckmann rearrangement of the 4,4-dimethyl-3-ketoxime. Another new method, which allows the stepwise removal of the gemdimethyl groups, has also been described.527 Thus, the unsaturated ester (596) may be

52h

J . E. Bridgeman, C. E. Butchers, Sir Ewart R. H . Jones, A. Kasal, G. D. Meakins, and P. D. Woodgate, J . Chem. SOC.(0,1970,244. Y . Satoh, A. Horiuchi. and A. Hagitani. Bull. Chem. SOC.Japan. 1970, 48, 491. G. Berti, B. Macchia, and F. Macchia, Gazzerra. 1970, 100. 334. R . Bucourt, J. Tessier, and G. Costerousse, Bull. SOC.chim. France, 1970, 1891. D . S. Ivine and G. Kruger, J . Org. Chem., 1970, 35, 2418. R. C. Cambie and P. W. Le Quesne, Ausrral. J . Chem., 1969, 22, 2501. G. R. Pettit and J. R . Dias, Canad. J . Chem., 1969,47, 1091. C. W. Shoppee, N. W. Hughes, R . E. Lack, and J . T. Pinhey, J. Chem. SOC.(C), 1970,

52’

R . Kazlauskas, J . T. Pinhey, J . J. H. Simes. and T. G . Watson, Chem. Comm.. 1969,945.

520 521 522

523 524

525

1443.

Steroid Synthesis

51 1

H

H

v, vi, vii

(594) Reagents: i, PCl,; ii, 0,; iii, CF,CO,H; iv, Jones oxidation; v, Ac,O-HClO,; vii, NaOH-MeOH.

vi, MeI;

Scheme 12

Reagents: i, 0,; ii, NaBH,; iii, SOC1,-py; iv, MeMgI; v, NaOH-MeOH.

Scheme 13

converted by oxidation and methylation into the diester (597) which, after cyclisation, reduction, and decarboxylation gives the 4a-monomethyl-3-ketone (601). Alternatively, the diester (597) may be oxidised with osmium tetroxidesodium metaperiodate to the keto-ester (598)which, after reduction of the ketone function by desulphuration of its ethylene thioacetal to give (599), is cyclised and decarboxylated to the unsubstituted ketone (600). Functionalisation of both 4a- and 4B-methyl groups in 10-methyl and 19-nor steroids has been achieveds2*by photolysis of the 6a- or 6P-nitrites (602)or (603).

a '

O

X R (596) R = Me, X = CH, (597) R = CO,Me, X = CH, (598) R = CO,Me, X = 0 (599) R = CO,Me, X = H, 528

R: H

(600) R = H (601) R = Me

J. M. Midgley, J. E. Parkin, and W. B. Whalley, Chem. Comm., 1970, 789.

Terpenoids and Steroids

512

The oxime (604) obtained in 56 % yield from the 6a-nitrite could be converted by acid into the isoxazoline (606) and thence into the corresponding 3-oxo-4anitrile. In contrast, Barton reaction of the 6b-nitrite (603)gave the C-19-oxime as major product with only a 5 % yield of the 48-oxime (605). In the 19-nor series, however. where 19-oxime formation cannot occur, the 4b-oxime was obtained in 60% yield.

(602) R' = R2 = Me, R 3 = a - O N 0 (603) R' = R 2 = Me, R 3 = 8-ON0 (604) R' = CH: NOH, R 2 = Me, R 3 = a-OH (605) R' = Me, R 2 = CH: NOH, R 3 = /?-OH

H

Similar attempted functionalisation of the 5fl-methyl group of Westphalen's diol, using either the Barton or hypoiodite reactions, was unsuccessful although lead tetra-acetate gave the epoxide (607), which could be opened with boron trifluoride etherate after reduction of the 9 , l O - u n ~ a t u r a t i o n . ~ ~ ~

H

H

Reagents: i. Pb(OAc),; ii, BF,.Et,&Ac,O;

iii, PhC0,H; iv, Li-EtNH,

Scheme 14 52v

I. G . Guest, J . G. L1. Jones, B. A. Marples, and M. J . Harrington, J . Chern. SOC.(C), 1969. 2360.

Steroid Synthesis

513

Details have appeared530 of the preparation of 5j?-cholestan-2a-o1 from cholest-4-en-3-one and its C-9 functionalisation as shown in Scheme 14. The structures of the two minor epimeric products (608) arising from extensive backbone rearrangement of cholesterol with hydrogen fluoride have been confirmed by synthesis.531 Organo-tin and -silicon steroids have been prepared from 3a- and 3B-halocholest-anes and 5 - e n e ~ , and ~ ~ *a number of steroidal esters of p-[NN-bis(2-chloroethyl)amino]phenylacetic acid and sulphides derived from p-bis(2-chloroethy1)amino-thiophenol and ethylenimine derivatives of steroids have been prepared. The substituted phenylacetates showed good inhibition of certain t u m o ~ r s3.3~ 2-Lithio-1,3-dithian opens both 243~1-and 2/l,3~-epoxycholestanesdiaxially to (609) and (610) respectively, which, after desulphuration, can be oxidised to give 2j?-methylcholestan-3-oneand 3a-methylcholestan-2-one in high overall yield. 534 Both axial methyl groups isomerized quantitatively on treatment with acid. In contrast to the ready formation of the 3,6dione (612) from the 6B-chloroand -bromo-compounds (611) by heating with methanol followed by brief treatment with acid, the analogous 6a-chloro-4-en-3-one gives rise to only the 3-methoxy-3,5-diene without loss of chlorine.535 Using conventional methods the 2- and 3-fluoro-derivativesof 3- and -2-ketones (and alcohols) have been prepared in the c h o l e ~ t a n e ,4,4-dimethyl~holestane,~~~ ~~~ and 4,4-dimethyloestrane series. 37 Investigation of the hydrogen fluoride opening of a 16a,17a-epoxy-20ketone has resulted in the isolation of less than 2 % of 16/?-fluoro-17a-hydroxy-

(609) R'

=

(610) R' = OH, R2 =

530

"'

532 533

534

535

536 537

, R 2 = OH

1

X

313

T. Koga and M. Tomoeda, Tetrahedron, 1970,26, 1043. P. Bourguignon, J. C. Jacquesy, R. Jacquesy, J. Levisalles, and T. Wagnon, Chem. Comm., 1970,349. H. Zimmer and A. Bayless, Tetrahedron Letters, 1970, 259. M. E. Wall, G. S. Abernethy, F. I. Carroll, and D. J. Taylor, J . Medicin. Chem., 1969, 12, 810. J. B. JonesandR. Grayshan, Chem. Comm., 1970, 141. R. Mazac and K. Syhora, Coll. Czech. Chem. Comm., 1970,35, 1547. J. Levisalles and M. Rudler-Chauvin, Bull. SOC.chim. France, 1969, 3947, 3959. J. Levisalles and M. Rudler-Chauvin, Bull. SOC.chim. France, 1970, 664.

514

Terpenoidr and Steroih

compound ; the main products were (not unexpectedly) those resulting from C-13 + C-17 methyl migration.538 3-Acetyl-1,5,5-trimethylhydantoin in acetonitrile has been used to selectively acetylate the phenolic hydroxyl of oestradiol in 60% yield.S39 Neutral alumina treated with sodium nitrate converts methyl 3a-toluene-p-sulphonyloxy-5~cholanoate into a 1 : 1 mixture of 3a- and 3B-r1itrates.~~' The enol toluene-p-sulphonate of testosterone (readily prepared with toluene-psulphonic anhydride in DMF) undergoes free-radical rearrangement to the 3-0x04-ene-6B-sulphonein high yield and it reacts with bromotrichloromethane to give a high yieldS4l of the dichloromethylene derivative (613). The reaction of Vilsmeier reagents with 3,5dienolate anions has been used to introduce 4-dimethylaminomethylene-,hydroxymethylene-, and cyano-groups into cholest- and androst-4-en-3-0nes.~~~ A number of 2,3-trans- and 16a,17acis-halogeno-urethanes have been prepared from their parent h a l ~ h y d r i n s . ~ ~ ~ Alkylation of 2- and 4-cyanocholestan-3-one derivatives provides a method for controlling the site of substitution of such unsymmetrical ketones and gives geminally substituted products whose stereochemistry is not readily obtainable by other means.s44 Stoicheiometric amounts of lithium alkyls have been used to convert 5acholestane-3-, -4-, and -6-tosylhydrazones into 2-, 3-, and 6-enes respectively in high yield.545 With the 3-tosylhydrazone, however, use of excess lithium alkyl gave rise to varying amounts (dependent upon the lithium alkyl used) of 38alkylated products.546 Cholest-2-en-3-01 ethers may be prepared in 50-60 %

538 5'9 540 541

542

543 54J

545 546

D. R. Hoff, J . Org. Chem., 1970, 35, 2263. 0. 0. Orazi and R . A. Corral, J . Amer. Chem. SOC.,1969, 91, 2162. F. Hodosan and I. Jude, Rec. Roumaine Chim., 1969,14, 1057. N . Frydman and Y . Mazur, J . Amer. Chem. SOC.,1970,92, 3203. C. Huynh and S. Julia, Tetrahedron Letters, 1969, 5271. K . Ponsold and P. Grosse, Z . Chem., 1970, 10, 115. P. Break and T. L. Chaffin, J . Org. Chem., 1970,35, 2275. J. E. Herz, E. Gonzalez, and B. Mandel. Ausrral. J . Chem., 1970, 23, 857. J . E. Herz and E. Gonzalez, Chem. Comm., 1969, 1395.

Steroid Synthesis

5 15

yield by the action of alcohols on the toluene-p-sulphonylazo-compound(614) which can be obtained from 2a-bromocholestan-3-one and toluene-p-sulphonylhydra~ine.’~’ The bromination and dehydrobromination of 3,12-, 7,12-dioxo-, and 3,7,12trioxo-cholanic acids have been investigated.548 The syntheses of 17a-methylandrostane-3a,l6a,l7fi-triol and its 16-ketone have been described.549 Acetone, in the presence of acid, readily reacts with 17,21-dihydroxy-20ketones to give tetramethylmethylenedioxy-derivatives, e.g. (615), which, because of their ease of hydrolysis, appear to offer an advantage over bismethylenedioxy protecting groups.’ 50 Carbonyl groups, protected as their NN-dimethylhydrazones, are easily regenerated by methylation to the labile NNN-trimethylhydrazones. Fluvobacterium dehydrogenans converts the 5a,6a-epoxide (616) into the 6ahydroxy-4-en-3-one and the 5#?,6#?-isomer into the epimeric 6#?-hydroxy-4-en-3one in good yield. The same epoxy-lactones are transformed by Arthrobacter simplex to the corresponding 6-hydroxy-1,4-dien-3-0nes in even higher yields.’ 5 2 Pichia fermentam would appear to be the yeast of choice for the reduction of 17/3-hydroxy-19-norandrost -5( 1O)-en-3-0nes,~ and 3-alkoxy-19-norandrosta2,5(10)-dienes554 to 3#?-hydroxy-5( 10)-enes. The 1#?,1loc-dihydroxylation of by Aspergillusochruceus is markedly substituted 3#?-hydroxy-5a-pregnan-20-ones dependent upon remote substituents. The so-formed 1fi,3j,1la-trihydroxysteroid is notable for the stability of its 1,ll-acetonide,which survives treatment with refluxing 2N-HCl acid in dioxan, although similar treatment of the 3-0x0acetonide results in the formation of the 1-en-3-one (617).’” 3-0x0-steroids lacking 17-substituents are hydroxylated to 16p-hydroxyderivatives in the presence of 1la-hydroxy-groups, but to 16a-alcohols when 11B-

’

s47 548

549 5s0

*

552 553

554 555

L. Caglioti and G. Rosini, Chem. and ind., 1969, 1093. R. Rocchi, A. M . Bellini, A. R. Fabian, and C. A. Benassi, Gazzetta, 1969, 99, 1252. T. Watanabe, S. Yagishita, and S. Hara, J . Medicin. Chem., 1970, 13, 31 1 . A. Roy, W. D. Slaunwhite, and S. Roy, J . Org. Chem., 1969, 34, 1455. M. Avaro, J . Levisalles, and H. Rudler, Chem. Comm., 1969,445. K. Kieslich, Tetrahedron, 1969, 25, 5863. H.-J. Koch, G. Schulz, and K. Kieslich, Chem. Eer., 1970, 103, 603. K . Kieslich and H.-J. Koch, Chem. Ber., 1970, 103, 610. A. S. Clegg, Sir Ewart R. H. Jones, G. D. Meakins, and J. T. Pinhey, Chem. Comm., 1970, 1029.

5 16

Terpenoids and Steroids

hydroxy-groups are present.’ ’ 6 The n.m.r. spectra of several hundred (mostly new) microbiologically hydroxylated steroids and their oxidation products have been tab~lated.~” The microbiological saponification of steroid 21 -trimethylacetates has been reported. ’*

’”

J . M. Evans, Sir Ewart R . H. Jones, A. Kasal, V. Kumar, G. D. Meakins, and J. Wicha, Chem. Comm., 1969, 1491. ”’ J . E. Bridgeman, P. C. Cherry, A. S. Clegg. J . M . Evans, Sir Ewart R. H . Jones, A. Kasal, V. Kumar, G. D. Meakins, Y. Morisawa, E. E. Richards, and P. D. Woodgate, J . Chem. SOC.(C), 1970, 250. 5 5 8 H. Kosmol, F. Hill, U . Kerb, and K. Kieslich, Tetrahedron Letters, 1970, 641.

Cz2H3,NO3

C22H37N0

561

560

-

235

210

2 13

M. Leboef, A. Cavt, and R. Goutarel, Ann. pharm. franc., 1969,27, 217. H.-P. Husson, L. Fernandes, P. Potier, and J. LeMen, Bull. SOC.chirn. France, 1969, 3162.

"' J . B. Davis, K. Jewers, A. H. Manchanda, and A. B. Wood, Chem. andlnd., 1970,627.

3fl-Methylaminopregn-5-en-2Oa-01

1 la-Hydroxy-3~-methylamino-(20S)- CZ2H,,NO, pregn-5-en-18 -P 20-oic acid lactone

pregn-5-en- 18 -B 20-oic acid lactone

7/?-Hydroxy-3b-methylamino-(20S)-

C, H, ,NO3

,

7a-Hydroxy-3B-methylamino-( 20s)-

7a-Hydroxyparavallarine 7P-Hydroxyparavallarine 1la-Hydroxyparavallarine Holaph yllidine

pregn-5-en-18 +20-oic acid lactone

CzlH35NO

3/l-Amino-5a-pregnan-20-one

Dih ydroholaphyllamine >300

150-2

CzIH27NO

Maingayine

Structure or Systematic Name

M . P . (C")

Name

Empirical Formula

Steroidal Alkaloids

28 Table of New Compounds Isolated from Natural Sources

Leaves of Holarrhena JIoribunda

Bark of Parauallaris maingayi

Source

Leaves of Parauallaris microphylla Pitard - 13.5" Leaves of Parauallaris microphylla Pitard - 55" Leaves of Parauallaris microphylla Pitard Leaves of Holarrhena Joribunda

79" (c 1.2 CHCl,) - 113"

+

2.1" CHCl,

+

[aID

560

561

561

561

560

559

Terpenoids and Steroih N \o rr,

i

I N N C

m

u"

E"x

C X

a

5 19

Steroid Synthesis

m

d

'i

'i

m

00 00

3

c.l

3

f

u"

3

z

F

N

8 rjN

-0

0 X N

m

.-B

3 U

K

cp

Terpenoids and Steroih

520

5

3 IA

Y

2 II -

& 1

s

II p

l

d

00 It 1 I

It X

w h

s

Name

567

566

s65

(B)

R 2 = OH

R2 = H

R’ =

R2 = H

Structure or Systematic Name

C27H420,j

Empirical Formula

245-50 dec.

M.P. “C D

-

3“

A. Usubillaga, C. Seelkopf, I . L. Karle, J . W. Daly, and B. Witkop, J . Amer. Chem. SOC.,1970, 92, 700. S. Imai, E. M. S. Fujioka, T. Matsuoka, M. Koreeda, and K . Nakanishi, Chem. Comm., 1970, 3 5 2 . S . Imai, E. Murata, S. Fujioka, M. Koreeda, and K. Nakanishi, Chem. Comm., 1969, 546.

Ajugasterone C

Stachysterone D

Ecdysones

Leaves of Ajuga ,japonica Miq.

Stachyurus praecox

Source

567

566

Ref.

$

$

Terpenoidr and Steroidr

522

3

v)

v)

d

33%m d 2

n

n

25

+2

f

v)

Pi

X

0

X II N

L

X II n

E

O

q

0

4

0

572

571

570

569

568

oH

R2 = H

Structure or Systematic Name

HO

C.28H3806

Empirical Formula

C33HS4oL 1

253-5

M.P. "C

278-9

+ 80"

[alD

PY)

( c 5.2

+ 28.5"

Withania somnifera

Source

Pteridium aqwilinum

572

Ref.

571

A . Faux, M. N . Galbraith, D. H. S. Horn, E. J. Middleton. and J . A. Thomson, Chem. Comm., 1970, 243. H. Hikino, K. Nomoto, R. Ino, and T . Takemoto, Chem. and Pharm. Bull. (Japan), 1970,18, 1078. H. Hikino, K . Nomoto, and T. Takemoto, TetrahedronLetters, 1969,1417; H. Hikino, K . Nomoto, and T. Takemoto, Tetrahedron, 1970,26, 887. T. Takemoto, S. Arihara, and H. Hikino, Tetrahedron Letters, 1968,4199; H . Hikino, S. Arihara, and T. Takemoto, Tetrahedron, 1969,25, 3909. D. Lavie, I. Kirson, and E. Glotter, ZsraelJ. Chem., 1968, 6, 671.

Withanolide D

Name

Withanolides

3-fl-~-glucopyranoside

Ponasteroside A

Ecdysones-cont.

CA

g

i;.

3-

2

9-

R

3

5

Terpenoids and Steroids

5 24

2

m t. m

m t. m

7

M Q N

N

ICI c.. t l

CI m

8

X II N

E

n

2.

575

574

573

cZ 8 H3 SO6

C28H380S

-

-

-

-

Leaves of Withania somnifera

Leaves of Withania somnifera

575

575

I. Kirson, E. Glotter, A. Abraham, and D. Lavie, Tetrahedron, 1970,26,2209. S . M. Kupchan, W. K. Anderson, P. Bollinger, R. W. Doskotch, R. M. Smith, J. A. S. Renauld, H. K. Schnoes, A. L. Burlingame, and D. H. Smith, J. Org. Chem., 1969,34, 3858. I. Kirson, E. Glotter, A. Abraham, and D. Lavie, Proc. 39th Meeting Israel Chem. SOC.,Israel J. Chem., 1969, 7, ISp.

OH

ul ul N

Terpenoih and Steroih

526

0

m

Steroid Synthesis

527

s . 0d a

:

m

0" 3 db

3

d

u

v1

xw u" 2

?

b

% O

d

O#O

3~,14,16~-Trihydroxy-l9-oxo-5a-bufaC24H3206

168-Hydroxybovogenin A

Eduligenin

Name

Sapogenins

(25R)-3/3,26-Dihydroxycholest-5-ene11,16,22-trione

Structure or Systematic Name

M.P. "C 233-7 C,,H,,05

-

-

-

-

2 17-9

( c 0.8 CHCl,)

- 139"

[UID

Leaves and twigs of Tamus edulis Lowe

Source

577 -

578

Ref.

577

577

42

Homeria glauca

42

Ref.

577

+ 30"

230-2

Source

Bersama abyssinica ( c 1.2 CHCI,) - 23" Bersama abyssinica ( c 0.5 CHCI,) Morea polystachya and Morea graminicola Morea polystachya and Morea graminicola Homeria glauca

[ah

M.P. "C

Empirical Formula

20,22-dienolide 16/3-FormyloxybovogeninA 16~-Formyloxy-3~,14-dihydroxy-l9-C25H3207 oxo-5a-bufa-20,22-dienoljde 1a,2a-Epoxyscillirosidine 68-Acetoxy-1a,2a-epoxy-3/3,8/3,14C26H3208 trihydroxybufa-4,20,22-trienolide 1U,~U-EPOXY12p68-Acetoxy-1a,2a-epoxy-3fi,8/3,12/3,14- Cz6H32O9 h ydroxyscillirosidine tetrahydroxybufa-4,20.22-trienolide

3~,5-Diacetoxy-14-hydroxy-19-oxo-5~C28H,608 bufa-20.22-dienolide

Hellebrigenin 3,5-diacetate

Empirical Formula

3fl-Acetoxy-5,14-dihydroxy-19-oxo-5/3C26H3407 bufa-20,22-dienolide

Structure or Systematic Name

Hellebrigenin 3-acetate

Name

Cardenolides and Bufadienolidescon t .

2

%

&

Y

c 27 H 4 4 0 5

C27H4405

C27H4003

(23S,25R)-Sa-Spirostan-2a,3/3,23-triol

(23R,25 R)-Sa-Spirostan-2a,3B,23-triol

Spirosta-5,25(27)-dien-3P-o1

(25S)-SB-Spirostan-2B,3a,27-triol

Isoplexigenin C

Isoplexigenin D

Sceptrumgenin

Crestagenin

580

579

578

577

C27H4204

(23S,25R)-Spirost-5-en-3B,23-diol

Isoplexigenin B

-

1824

28G1

272.5-3.5

205-7

227

2 23-6

M.P. "C

A. J. van Wyk and P. R. Enslin, J. S . A,frican Chem. Inst.,. 1969, 22, S 66. R. F. Barreira, A. G. Gonzalez, J. A. S. Rocio, and E. S. Lopez, Phyrochemistry, 1970,9, 1641. R. Freire, A. G. Gonzalez, and E. Suarez, Tetrahedron, 1970, 26, 3233. J. D. Benitez, J. M. Velasquez, J. L. Breton, and A. G. Gonzalez, Anales de Quim.,1969, 65, 817.

c 2 7I 3 4 4 0 5

c 27H4404

(23S,25R)-Sa-Spirostan-3B,23-diol

Isoplexigenin A

C27H4005

Empirical Formula

(25R)-3/3,16a-Dihydroxyspirost-5-en1l-one

Structure or Systematic Name

Lowegenin

Name

Sapogeninwont .

Leaves and twigs of Tamus edulis Lowe

Source

(c 1.4 CHCI,) -61" Isoplexis sceptrum ( c 1.6 CHCI,) - 96" Isoplexis sceptrum ( c 1.38 CHCI,) - 62" Isoplexis sceptrum ( c 1.26 CHCI,) - 74" Isoplexis sceptrum ( c 0.12 CHCI,) - 122" Isoplexis sceptrum (c 0.5 CHCI,) Leaves of Digitalis canariensis

- 55"

"ID

580

579

579

579

579

579

578

Ref:

G-

2

*5

2%

rcl

Terpenoids and Steroids

530

6 a:

a U

2 cn

gwo z

-0

0

II N

er:

583

581

HOCH, 0 -

0

OH

C40H66016

C32H54010

24G1

275-84 dec.

MeOH)

(c 1.16

- 27.6'

-43.0' (c 0.66 CHCl,)

HO OH OH R . Tschesche, M. Tauscher, H.-W. Fehlhaber, and G. Wulff, Chem. Ber., 1969, 102, 2072. K. Miyahara, F. Isozaki, and T. Kawasaki, Chem. and Pharm. Bull. (Japan), 1969, 17, 1735. S. Sakuma, H. Ishizone, R. Kasai, S. Kawanishi, and J . Shoji, Chem. and Pharm. Bull. (Japan), 1969,17, 2183.

Glycoside K

Tokorogenin glycoside 111

Glycosides-con t .

Cortex of Periploca

Rhizomes of Dioscorea tokoro

583

582

2 z*

i? s

$

3

5

532

Terpenoih and Steroidr

2

d

vl

00 vl

00 vl

3 :

n

0-

I

0

O

a

r II c4

}

587

586

'"

584

OH

OMe

OMe

C&,,N05

C,8H,7NO,

C33H49N07

N-Acetyl deriv :

N-Acetyl Leaves of Holarrhena deriv : antidysenterica

- 28" (CDCl,)

260-1

Veratrum californicum

N-Acetyl Leaves of Holarrhena deriv : antidysenterica

(c 1.0 EtOH)

- 51"

N-Acetyl deriv :

267-9

G. Kapadia, J . Pharm. Sci., 1969, 58, 1555. F. Bruschweiler, W. Stocklin, K. Stockel, and T. Reichstein, Helu. Chim. Acru, 1969, 52, 2086. R. F. Keeler, Sreroids, 1969, 13, 579. M. M. Janot, Q. Khuong-Huu, C. Moneret, I. Kabore, J. Hildesheim, S. D. Geros, and R . Goutarel, Tetrahedron, 1970, 26, 1695.

Holantosine B

Holantosine A

Cycloposine

Glycosides-con t .

3

587

587

u l ww

i;.

2

9st

586 fi:

k?

Terpenoids and Steroidr

5 34 OQ 00 'A

n

5 u

% 'A

5y"

589

508

C, H,,03 C, H,,Oz

Empirical Formula

148-1 52

-

88-90 (Hydrate)

M.P."C

,

3P,8/3,14P-Trihydroxy-5a,l7a-pregnan- C, H3404 20-one? 3P,8P,14P-Trihydroxypregn-5-en-2O-oneC, 1H, 0,

224-7

2 13-7

and 148-1 50

3fl-Hydroxy-5a,l7a-pregn-14-en-20-oneC, iH3202 139-141

3P-Hydroxy-5a-pregn-14-en-20-one

12P-Hydroxypregn-4-ene-3,20-dione

A N

HO

Structure or Systematic Name

195

Cybister limbatus 14 Roots of Trachycalymma 590 jmbriatum

Adonis amurensis

Source

*

+

k 2" (Me,CO) + 117 Roots of Trachycalymma 590 k 2" jimbriafum 98 3" (Me,CO) - 27.5 Roots of Trachycalymma 590 3" jmbriatum + 100.0" Adonis amurensis 344 (c 1.0 CHCI,)

-

+ 52.4

-

[a1D

K. Hayashi, A. Nakao, and H. Mitsuhashi, Chem. and Pharm. Bull. (Japan), 1969, 17, 2629. H. K. Kim, N. R. Farnsworth, H. H . S. Fong, R. N. Blomster, and G. J. Persinos, Lloydia. 1970, 33, 30. R. Elber, Ek. Weiss, and T. Reichstein, Helv. Chim. Acta, 1969, 52, 2 5 8 3 .

Fukujusone

Fukujusonorone

Name

Miscellaneous

Terpenoids and Steroidrs

536 00

rc, d

I 00

m 3

537

Steroid Synthesis

3

m

'i' N

3

N

I

A

N

T N

3

m

H N

L

-

0

t3 Li

d v, P

592

594

593

146

C,,H,,O

186.5-188

C,, H 5z02 Acetate : 142

C29H460

(24S)-24-Ethylcholesta-5,22,25-t rien3fl-01 24<-Ethyl-4a-methylcholesta-7,25dien - 38-01

131.5-136 Acetate: 99- I 0 0

CzaH4,0

-

245-50

C,,H,,O,

C28H140

M.P. "C

5a-Stigmasta-8(14).15,24(28)-trien-3&01 C 2 9 H 4 6 0

8( 14),24-diene

3fl-Hydroxy-4a-methylcholesta-

12fl-BenzoyIoxy-3/3,8fl,148trihydroxypregn-5-en-20-one

Structure or Systematic Name

Empirical Formula

Phycomyces hlakesleeanus Yeast residues

Adonis amurensis

Source

-45"

External layers of PIexaura jlexuosa

cumphelli

CHCl 3 ) - 37.8" Leaves of Clerodendrum campbel Ii (CHCI,) Leaves of Clerodendrum

*

( c 0.5 CHCI,) Acetate: Vernonia anthelmintica seed oil La1D + 13 3" (c 1.0

+ 19"

CHCI,)

(c 0.8

+ 45"

D

435

594

594

593

436

592

344

Ref

G . Goulston and E. I. Mercer, Phytochemisrry, 1969, 8, 1945. J. A. Fioriti. M. G. Kolar, and R. P. McNaught, Tetrahedron Letrers, 1970, 2971. L. M. Bolger, H. H . Rees, E. L. Ghisalberti, L. J. Goad, and T. W. Goodwin, Tetrahedron Letters, 1970, 3 0 4 3 ; Biochem. J., 1970, 118, 197.

H

Gorgosterol

Vernosterol

Ester B

Name

Miscellaneous-cont .

5

b

8

&

3

s:

,r

t, 00

ul

Author Index

Aadahl, G.. 429 Aasen, A. J., 209 Abad, A., 382 Abdel-Aziz, M. T., 361 Abe. K.. 71 Abei N.; 101 Abernethy, G. S., jun., 306, 513 Abisch, E., 481 Abraham, A,, 525 Abraham, N. A., 471 Abubakirov, N. K., 420 Acharya, S. P., 37 Achilladelis, B., 75, 232, 233,234 Achiwa, K., 61, 62 Ackrell, J., 457 Acton', E. M., 29 Adam, G., 288,469 Adams, P. M., 75,232 Adamson, D., 132 Adelstein, G., 281, 462 Adesogan, E. K., 174, 179 Adinolfi, M.. 126, 300 Adolf, W., 151 Afonso, A., 155, 333, 386,

503. Agatsuma, K., 113 Aguado, A. R., 30 Aguilar, M., 117 Ahmad, M. S.. 342,431 Ahmad; N., 249 . Ahoud, A., 486 Aitzetmuller, K., 206, 207, 208 Akhrem, A. A., 344, 404, 478,493 Akhtar M 213 240 241 242, 5431' 244,' 245,' 249; 387 Akiba, M., 478 Akiyama, K.,401 Akiyama, S., 460 Alabran, D. M., 319 Alais, J., 384, 450, 451 Albrecht, R., 135 Alcaide, A,, 241, 244, 245 Alford, J. A.,136 Allais, J.-P., 256 Allard, M., 382 AllinEer. N. L..267, 321 Allison, 'A. J., 157 Allock, C., 223 Altona, C., 263, 264, 354 Ambrus. G.. 482 Amemiya, S:, 472 Anand, R., 10 Anchel, M., 79, 80 '

Andersen, K., 209 Andersen, N. H., 62,68,73, 101,106 Anderson, D. G., 233,255 Anderson, G., 51 Anderson, L. A. P., 412 Anderson, P., 494 Anderson, R. J., 239 Anderson, W. K., 525 Ando, M., 99 Andre, D., 208 Andrewes, A. C., 210 Andrews, A. T. de B., 330 Andrews, L. J. T., 271 Aneja, R., 149 Anet, F. A. L., 82 Angyal, S. J., 267 Anh, N. T., 329 Anner; G., 345, 356, 443, 484 Anthonsen, T., 128 Anthony, G. M., 335 Aoki, Y., 229 Aota, K., 78, 93, 108, 114, 117 Aoyagi, R., 191 Aoyama, K., 481 Aoyama, S., 358,489 Aplin, R. T., 187, 271, 430 Appleton, R. A., 126, 130, -141, 144 Apsimon, J. W., 138, 269, 372,455 Arbuzov, B. A., 47 Arcamone. F.. 207 Archer, S.,' 477 Aresi, V., 440 Arigoni, D., 68, 227, 228. 232 Arihara, S., 523 Arnaudov, M. V., 230 Arnold, R. A., 55 Arpesella, 0. A., 45 Arpin, N., 204, 209 Arsenault, G. P., 420 Arunachalam, T., 480 Asaka, T., 469 Asao, T., 99 Asmundson, C. M., 215 Atal, C. K., 48 Atkinson, P. W., 125 Atland, H. W., 28 Attaway, J. A., 227 Augustine, R. L., 309 Austem, B. A,, 251 Austin, D. J., 214, 253 Austin, J., 405 Avaro, M., 351,403, 515

Axelrod, L. R., 346 Aynehchi, Y., 93 Ayres, D. C., 3 18 Babcock, J. C., 467 Baddeley, G. V.,186 Bahr, W., 123 Baggaley, K. H., 324 Bailey, E., 506 Bailey, E. J., 277,456, 459 Bailey, W. C., jun, 219 Baillarge, M., 15 Baillie, A. C., 132 Baisted, D. J., 244 Bakano, T., 484 Baker, R., 288 Balasubramaniyan, P., 2 14 Balasubramaniyan, V.,2 14 Balavoine, G., 268 Baldas, J., 200 Baldratti, G., 458 Baldwin, J. E., 14, 27, 38, 379, 390, 502 Baldwin. S. W., 390, 502 Balkenhol, W. G., 152 Ballantine, 1. D., 322, 323, 433,449 Ballio, A., 237 Balmain, A., 151 Banerjee, A. K., 154, 404, 428 Bang, L.,113 Bankovskii, A. I., 93 Banks, C. M., 88, 94, 96 Banthorpe, D. V., 7, 228 Baran, J. S., 405,460 Barbier, M., 208, 241, 244, 245,255,256 Barbieri, W.,338, 458, 459 Bardyshev, I. I., 34 Barends, R. J. P.,479 Baretta, A., 271 Barieux, J. J., 339, 487 Barisch, H., 150 Barksdale, A. W., 420 Barnes, M. F., 148 Barnett, R . E., 339 Barnier, J. P., 316 Barreira, R . F., 529 Barrett, L. M., 150 Barron, J. M., 223 Barrow, K. D., 237 Bart, J. C. J., 200 Barthklemy, M., 46 Bartlett, L:, 199 Bartlett, W. R., 477 Bartley, J. P.,170, 375,495

Author Index

540 Barton, D. H. R., 77, 168, 169, 193, 231, 237, 244, 245, 249, 296, 305, 329, 343 390, 399, 405, 422, 455: 493, 496, 498, 506, 507 Barua, A. B., 21 I , 213 Barua, A. K.,189, 196 Barua, R. K., 21 1, 213 Bascoul, J., 362, 369 Baskerevitch, Z., I3 1 Bates, R. B., 14, 23, 62, 77 Batta, A. K., 167 Battaile, J., 228 Batten, P.L., 343 Battersby, A. R., 227, 228, 229,230 Bauer, D., 399, 501 Bauer, J. W., 256 Bauer, L.. 280 Baumhover, A. H., 257 Baxendale, D.. 228 Bayer, E., 7, 272 Bayless, A. V., 278, 466, 513 Bayless, J ., 344 Beak, P., 334 Beam, C. G., jun., 255 Beard, C., 307 Beaton, J . M., 390 Beck, J. F., 230 Becker, R., 247 Beckermann, M.,389 Beeler, D. A., 25 1,252 Begut, J. P., 229 Behn, N. S., 353 Bell, C. L., 280 Bell, R. A., 139, 140 Bellas, T. E., 386, 455 Bellin, S. A., 215 Bellini, A. M.,324,439,5 1 5 Bellus, D., 393 Benassi, C. A., 324,439,5 15 Benedict, C. R., 255 Ben-Efraim, D. A., 355 Btntzet, L., 14,23 Benitez, J. D., 529 Benn, M.H., 332,493 Bennett, C. R., 134, 135 Bennett, R. D., 245, 246, 247,482 Bensch, W. R., 221 Bentley, R., 232 Bentley, R. K.,84 Benveniste, P., 161, 240 Berger, S., 357 Bergmann, E. J., 496 Berkoff, C. E., 53,405 Berkoz, B., 307,376,442 Berngruber, 0. W., 335 Bernstein. S.. 481 Bert hod, H. ,.201 Berti, G., 130, 196,368,510 Bertini, F., 322, 506, 509 Bertram. E. F.. 145 Beslin, P.,475 ’ Bessiere-Chretien, Y.,42. 44,46 Bethea, T. W., 319

Beugelmans, R., 294, 392, 397, 399,400,500, 503 Bevan, C. W. L., 176 Beverung, W. N., 477 Bey, P., 506 Beytia, E., 222 Bhacca, N. S., 82,264,481 Bhalerao, U. T., 62 Bhalla, V. K.,149 Bhamidipaty, K.,380 Bhat, H.B., 31 1, 505 Bhatt, S. V., 93, 114 Bhatia, M.S., 10,39,66,75 Bhatnagar, A. K., 390, 502 Bhattacharjee, M.K., 470 Bhattacharya, A. K.,190 Bhattacharyya, S. C., 42, 93 Bianchi, E., 519 Biellmann, J. F., 161 Biglino, G., 191 Bignardi, G., 40 Billet, D., 122 Bilodeau, J., 377 Bimpson, T., 242, 245 Bingham, K. D., 300, 304, 330.445 Binkert, J., 481 Biollaz, M.,68, 232 Birch, A. J.. 23, 61, 70, 232 234,459,461,474 Birckelbaw, M.E., 348,445 Bird. J. W.. 343 Birnbaum, ‘K.B., 149 Bixon, R.,329 Bjorkhem, I., 249 Black, D. W., 140 Blackburn, G. M.,14, 161 Blackett, B. N., 365, 374 Blackstone, R. C., 140 Blair, G. E., 225 Blatz, P. E., 214 Blecha, Z . , 186 Blessington, B., 133 Blickenstaff, R. T., 405 Bloch, K.,221. 238, 245 Bloch, M., 243 Block, R., 481 Blomster, R. N., 535 Blosse, P.T., 21 3 Blossey, E. C., 266, 316, 450.495 Blunt, J. W.. 366, 368. 467 Boar, R. B., 193 Bobbitt, J. M., 19 Bodea, C., 21 I Bsrdalen, B.. 207 Boettger, H.,205, 206 Bohlmann, F., 34, 35, 36, 52.98, 122 Bohme, E., 335 Bokadia, M. M.,14 Bolger, L. M., 240, 538 Bollinger, P., 525 Bolt, A. J. N., 481 Bolt, C. C., 460 Bonaly, H., 204 Bonchez, M.P., 204 Bond, R. P. M.,223 Bonner, J., 246

Bonnett, R., 208 Bordner, J., 192 B o r p a , J.-L., 277,348,456 Boris, A., 428 Borowitz, I. J., 337 Boryaev, K. I., 93 Bos. M.G. J.. 504 Bose, A. K.,‘14, 219, 230, 237,323 Boswell, G. A., 298 Botta, L., 228 Bottari. F.. 196 Bouchard,’R., 409 Boul, A. D., 330 Bourdon, R., 326 Bourgery, G., 285 Bourguignon, P.. 365. 513 Bourn, A. J. R., 82 Bovey, P.,228 Bowman, R. M.,229 Boyd, G. S., 239 Boyle, P. H., 392, 5 0 0 Bozzato, G., 395,499 Brabazon, G., 306 Brady, S. F., 106,477 Brandl. F., 150, 151 Bras. J.-P.. 42.44 Bravo, P., -443 Break, P., 514 Breen, G. J. W., 172 Breitmaier, E., 7,272 Brenner. G.. 504 Brenner; M .’, 2 16 Breslow, R., 36, 390, 502 Bretbn, J. L., 529 Brewis, S., 194 Brial, J.-C., 357 Bricout, J., 218 Bridgeman, J. E., 269, 330, PSI, 510, 516 Bneger, G., 52 Briemann, K., 420 Brienne, M.J., 273 Brieskorn. C. H., 141 Briggs, J.,.271 Briggs, L. H., 170, 375,495 Briggs, T., 498 Brisse, F., 149 Britton. G.. 201. 202., 224., 251,253, ’ Britton, R. W., 66, 112, 121 Brocksom, T. J., 55 Brodie, H. J., 249, 309,327, 505 Broger, E. A., 95 Brooks, C. J. W., 58, 102, 231,276, 335,403 Brooks, J., 201 Brooks, R. V.,403 Brooks, S. G., 324 Brooks, W. A., 242 Broughton, J. M., 326 Brown, A. P., 266,495 Brown, B. O., 204,210 Brown, E. D., 87 Brown, H. C., 37,41, 319 Brown, J. C., 148 Brown, J . W., 241, 391 Brown, P.. 415 Brown, P. M., 102 ~

54 1

Author Index Brown, R. E., 478 Brown, S. A., 226 Brown, S. H., 229 Brown, W., 315,457 Browne, P. A., 3 18,505 Bruemmer, J. H., 8, 222, 227,228 Bruschweiler, F., 419, 533 Brufani, M., 237 Bruns, K., 125 Brunschweiler, F., 409 Buchanan, J. G., St. C., 84, 173, 182 Buchecker, R., 199,204 Bucher, W., 23 Buchschacher, P., 476 Buchwald, M., 198, 206 Buckingham, J., 275 Bucourt, R.,266. 268, 470, 510 Budavari, J., 504 Budesinsky, M., 188 Budhiraja, R. P., 168 Budzikiewicz, H., 190 Buchi, G., 20, 25, 60, 121 Buhmann, U.,34 Buki, K . G., 482 Buendia, J., 16 Buggy, M. J., 224 Bui, A. M., 58 Bukwa, B., 476 Bull, J. R., 273, 375, 449 Bu’ Lock, J. D., 214.253 Burbage, M. B., 185 Burbott, A. J., 223, 228 Burden, R. S., 213,215 Burdett, J. E., 346 Burgstahler, A , W., 13,136, 137 Burk, L. A., 63 Burke, B. A., 174 Burke, P. M., 74 Burkinshaw, G. F., 501 Burlingame, A. L., 93,239, 525 Burn, D., 292,303, 344 Burnett, A. R., 227, 229, 230 Burrows, E. P.,246, 266 Burstein, S.. 247 Bushweller,.C. H., 267 Buslig, B. S., 227 Butchers, C. E., 330, 510 Butsugan, Y., 10,422 Butterworth. P. H. W.. 219 Buzby, G. C:, 371, 473 Byrne, J. C., 228 Caglioti, L., 345, 515 Cagnoli-Bellavita, N.,,131 Cahill, R., 271 Cahn, R. S., 205 Cainelli, G., 322, 506 Caldwell, A. D. S., 412 Caldwell, E. S., 23 Calzada, J. G., 117 Cambie, R. C., 125, 134, 135, 136, 138, 299, 3 1 1. 312,457, 510 Camerino, B., 207

Cameron, A. F., 74 Campbell, A. C., 315, 503 Campbell, J. A., 467 Campbell, M. M., 58 Campello, J. de P.,131 Canonica, L., 58, 131, 237, 240,242 Capitaine, J., 377 Caporale, G., 226 Capozzi, A., 226 Caputo, O., 191 Caputo, R., 171 Cardellina, J. H. I., 379 Cardellini, M., 442 Carelli, V.,442 Carlisle, V. F., 3 1 1,312,457 Carlon, F. E.,307,332,385, 434,435 Carlson, J. A., 20 Carlson, R.G., 353 Carman, R . M., 125. 126, i31,2i7 Carpio, H., 306, 343 Carroll, F. I., 513 Carson, M. S.,27, 47 Carver, J. R., 25, 312 Casagrande, C., 58 Case, J., 471 Caserio. F. F.. 276 Casino&, C. G., 237 Caspi, E., 240, 243, 245, 246, 247, 250, 266, 31 1, 321,331,432,456,505 Cassady, J. M., 93,114,225 Castanet, J., 43 Castine, W. H., 126 Catsoulacos, P., 339 Cattabeni, F., 242 Cattel, L., 191 Caughlan, C. N., 117 Cautrall, E. W., 481 Cave, A., 279, 290, 349, 361,450,486,488, 517 Cavill, G. W. K., 22, 54 Ceccaldi, H. J., 206 Ceccherelli, P., 131 Cecchi, L., 486 Cederberg, E., 41 Cereghetti, M., 276 Cerny, V., 267, 354, 382, 427,449 Cerrini, S., 237 Cervantes, A., 343 Chadha, M. S., 404 Chadha, V. K., 500 Chaffin, T. L., 334, 514 Chain, E. B., 237 Chakrabarti, P., 189, 196 Chakrabortty, T.; 173 Chakravarti, K. K., 14, 110, 114 Chakravarty, J., 154 Challand, B. D., 20, 77 Chamberlain, T. R., 225 Chan, R. P. K., 187 Chan, W. R., 172, 174 Chandreskhan, S., 173 Chang, C. W. J., 139 Chang, H.-H., 418 Chang, Y. C., 213

Chanley, J. D., 166 Charlton, J. M.,224,253 Chatterjee, A., 173,475 Chatterjee, N. R., 154 Chaudhuri, N. K., 268,321, 322,493,498 Chedekel, M. R., 89 Chen, C., 247 Chen, C.-M., 224 Chen, D., 232 Chen, H. H., 117 Chen, Y. P., 132 Cheng, K. F., 111 Cheng, Y. S., 64, 125 Cherry, P. C., 230,269,391, 516 Chetty, G. L., 101 Cheung, H.-C., 29,60 Cheung, H. T., 167, 190 Chiba, T., 481 Chichester, C. O., 213,251, 252 Chikamatsu, H., 113,244 Chin, C. C., 485 Chin, W. J., 138 Chinn, L. J:, 405 Ch6, S.-C., 213 Cholnoky, L., 203, 209 Chon, T.S.,492 Chondromatidis. G.. 323. 438 Chopra, G. R.,191 Chow, Y. L., 33 Chrttien-Bessitre, Y., 14, 23 Christensen, A., 494 Chuah, Y. S., 131 Chuang, V. T.-C., 40 Chubachi, M., 224 Chung, R. H.. 38,39 Ciereszko, L. S., 86 Ciurdaru, G., 441 Claisse, J. A., 43 Clark, G. R.,136 Clarke, B. J., 192 Clarke, R. E., 481 Clarke, R.L., 477 Clayton, R. B., 239, 241, 25 1 Clegg, A. S., 269, 515, 516 Clifford, K., 224 Cloarec, L., 452 Cloetens. R.. 164. 165 Coates, R. M.,36, 61 , 101, 110, 145 Coates, W. M., 503 Cocker, W., 27,47 Cocton, B., 362 Coggon, P., 85, 143, 180 Cohen, N. C., 266 Cohen, T., 348,349 Cole, R.J., 255 Cole, W. G., 265 Coll, J. C., 276, 300, 386, 455 Collins, D. J., 463 Collins, J. C., 26 Collins, J. F., 43, 225, 227 Collins, L. J., 265 Colonna, A. 0..227 I

,

I

Author Index

542 Combe, M. G.. 337, 391 Conia, I . - M . . 316, 475 Conlay, C . , 237 Conner, R. L., 245, 250, 402 Connolly, J. D., 173, 182, 183 Connolly, J. P., 305, 453 Consonni, A., 338,458,459 Cook, C. E.. 460 Cook, F., 344 Cookson, R. C., 271 Coolbaugh, R. C., 234 Cooley, G., 303 Coombs, M. M., 457,475 Coombs, R. V., 330 Cooper, A . , 298 Cooper, C . Z., 255 Coppola. J. C., 113 Corbella, A., 5 8 , 68, 232 Corbett, R . E., 138 Corbier, B., 10 Corey, E. J., 61, 62, 69, 70, 7 I , 72, 95, 159. 164, 239, 251, 316 Cori, O., 222, 227 Cornforth, J. W., 214, 215, 221,223,239,240 Cornforth, R. H., 240 Corral, R. A., 292, 514 Corrigan, J. R..503 Corsano, S., 167, 168, 170 Coscia. C. J., 68, 227, 228 Costerousse, G.. 268, 510 Cotta, E., 207 Cotterrell. G . P., 162, 172, 181 Cottrell, W. R. T., 301, 330 Counsell, R. E.. 281. 313. 315. 355. 426. 462. 495 Courtney, J. L., 52, 192 Cowley, D. E., 125 Coxon, J . M.. 24. 43, 44, 271, 288. 319, 320. 359. 361, 362, 363, 365. 366, 368, 374, 376, 463, 465, 466 coy, u., 221 Crabb, T. A., 271 Crabbe, P., 271, 308, 31 1, 316. 321, 343, 392, 404, 440,494, 5 0 0 Cragg, G., 236 Cragg, G. M. L., 443 Craig, W. G., 269 Crandall. J. K.. 45 Crandall, T. G., 72 Crastes de Paulet, A., 369 Crawley, F. E. H., 475 Cremlyn, R. J. W., 290,482 Crenshaw, R. R., 470 Crispin, D. J., 470 Crist, D. R.. 438 Crombie. L.. 14, 16, 1 50.214 Cropp, D. T.. 185 Crosby, L. O., 239 Cross, A. D., 176, 308, 31 1. 357,446,494 Cross, B. E., 137, 142, 148. 159, 235.236

Crow, W . D., 125 Crowe, D. F.. 323,329,507 Cruk, C., 46 Crump, D. R., 136 Cruz, A., 392 Csuros, Z., 403 Cuadriello. D., 357 Cuilleron, C. Y.. 314, 503 Cupas,, C. A., 46 Curotti, D., 316 Dabbagh, A. G., 209 Dabrowski, J., 312, 427 Daha, M. R., 392 Dahl, T., 319, 506 Dall’Acqua. F., 226 Dalle, J.-P., 2 13. 2 15 Daly, J., 483 Daly, J. W., 521 Damodaran, N. P., 76 Danforth, R. H., 28 Daniewski, A. R., 348 Danishefsky, S., 475,476 Danks, L. J., 168, 296, 455 Dannenberg, H., 376, 404, 453 Dansted, E., 24, 43 Das. B. C.. 89, 189 Das, K . G., 133 Das Gupta, A . K., 414 Dasgupta, B., 482 Data, 0. A., 254 Datta, S., 251 Dauben, W . G., 24,26,42, 314, 346, 355.451, 503 Daum, S. J.. 477 Daumas, R.. 206 Davies,B. H.,200,201,202, 7 c3 L J L

Davies, D. I., 43 Davies, M. T., 303 Davis, B. R., 501 Davis. J. B.. 180. 517 Davis: L. L.’, 132 Dawson, T. M., 467 Deak, G., 403 Dean, J.-P., 21 5 De Bernardis. J.. 14 de Boer, Th. J., 46 Debono. M., 310,343,396, 399, 433, 447, 460, 5 0 0 , 50 I Deeth, H. C., 126, 131,277 Defaye, G.. 487 de Flines, J., 448 de Gee, A. J., 479 Deghenghi, R., 405,456 de Graaf, S . A . G., 339,449 de Grace Guili, G., 48 Dehennin, L. A., 328 Dehn, R . L., 323 de Iglesias. D. A.. 45 de Jonge, K., 473 de Jongh, H. P., 460 de Krassny, A. F., 409 Deljac, A., 160 Della Casa de Marcano, D. P., 152 Delle Monache, F.. 125

Delle Monache, G.. 125 De Luca, H. F., 467 Deluzarche, A., 387 de Marcheville, H. C., 392, 397, 5 0 0 Demarco, P. V., 269, 270 de Mayo, P., 20,77,81, 104 Dembitskii, A. D., 8, 9 Demole, E., 36, 50 Demoule, E., 218, 219 Dempsey, M. E., 243 Denes, V. I., 441 Denney, W . A., 134, 135 Dennis, A., 244 Dennis, G. E., 276 Dennis, N., 93, 117, 126 Denny, R. W., 213 Denot, E., 31 I de Pascual, T. J., 30 de Paulet, A. C., 362 de Reinach, F., 241 Derguini, F., 138 De Roos, J. B., 98 de Rostalan, J., 488 de Silva, L. B., 114 de Souza, N . J., 240, 244, 246,250 Detre, G.. 323 Deuel, P., 114 Dev, S . , 74, 76, 77 Devaquet, A., 394 Devaan. 0. N.. 14 De Tille, T. E., 201 de Vivar, A. R., 89 Devys, M., 241, 244,245 de Waal, W., 66, 112, 121 Dewhurst, P. B., 213, 214, 387 de Winter, M. S., 454 de Wolfe, R. H., 276 Iley, B., 148 IXaper, D. G. M., 343 Iliara, A., 138 I3 a s . J. R.. 347. 506. 510 IXaz; E., 89, 114, 271 Iliaz-Purra, M.A,, 113 Ilickason, W. C., 319 Ilickerson, R. E., 192 Iliggle, J. M., 284 IDiGiorgio, J. B., 314 Ilixon, D., 249 Ilixon, J., 467 IDjakoure, L., 349 I>jarmati, Z., 346 1Djerassi, C., 164, 165, 190, 306, 309, 388,405,498 Ilmochowska, J., 472 I3opke, W., 519 1Doherty, C. F., 16 1Dolak, L. A.. 477 1Dolar, J., 460 IDolejS, L., 89 1Domb, S., 395,499 IDominguez, X.A., 11 7 1Donninger, C., 240 IDorfman, R. I., 361 IDoria, E., 126 1Doria, G., 482 IDornand, J., 214 1Dorsey, J. K., 223

Author Index Doskotch, R. W., 93, 96, 1 1 7, 170, 525 Dovinola, V., 300 Draber, W., 214 Draffan, G:H., 58, 102 Drake, D., 214, 253 Dray, F.,276 Drefahl, G., 285, 486 Dreiding, A. S., 37 Dreyer, D. L., 176 Dreyfus, H., 113 Duax, W. L.,298 Dubuis, R., 476 Dubrovsky, V. A.. 344 Ducep, J. B., 161 Ducker, J. W., 303 Dudowitz, A., 241 Dullforce, T. A,, 114 Duncan, J. H., 24,42 Dunham, L. L., 18 Dunn, G. L.,414,415 Durham, L. J., 190 Durley, R. C., 148 Dusza, J. P.,481 Dutky, S. R., 256 Dutta, H. K., 190 Duve, R. N., 136 Dyson, N. H., 307 Dzizenko, A. K., 166 Eaborn, C., 402 Eade, R. A., 185, 186 Eagle, G . A.. 102 Eb&, J., 63 Ebner, K. E., 243 Eckhard, I. F., 304,444 Ederen. R. A.. 448 Edhonds, A. C. F., 276 Edmund, J., 224 Edward, J. T., 268, 446 Edwards, B. E., 346 Edwards, J. A., 307, 308, 376, 392, 420, 442, 446, 457, 500 Edwards, 0. E., 126,455 Egger, K., 198, 206, 207, 209 Eggerichs, T. L., 155 Egli, R. H., 218 Eguchi, S.,10, 1 I , 14, I14 Egyed, I., 489 Ehrenstein, M., 419 Ehret, C., 112 Ehrhardt, J.-D., 170,241 Ehrhardt, P., 256 Eigendorf, G., 197 Eisenbraum, E. J., 23 I , 492 Eisner, T., 217 Ekong, D. E. U., 129, 141, 175, 180 Elber, R.,535 Eke, J. S., 482 El Dakhakhry, M., 226 El Defrawy, S. A., 418 El-Feraly, F. S., 93, 96 El:Haj, M. J. A., 464 Eliel, E. L., 267, 318 Elkin, Y.N., 166 Elks, J., 506

543 Ellineboe. J.. 402 Ellior, W.’H.‘, 268 Ellis, B., 303 Ellis, D. J., 346, 451 Ellis, J., 185, 186 Ellison, R. A., 159 Ellouz, R..245 El Masry, A. H., 418, 447 Elmes, B. C., 336 Els, H., 448 El-Tinay, A. H., 21 3 Elyakov, G. B., 166 Emerson. T.. 117 Endo. K.’. 104 Endo, T.; 20 Engel, C. R., 322, 377, 409 Enggist, P., 36, 50,218, 219 Englert, C., 198 Enrrlert. G.. 448 Enomoto, Y . , 87 Enslin, P. R., 273, 529 Enzell. C. R., 198,200,206, 207 Eppenberger, U., 240 Epstein, W. W., 224 Erdtman, H., 40 Erge, D., 225 Erhart, K., 473 Erickson, K., 217 Erman, W. F., 32, 45, 46, 69, 70 Escher, S., 228 Eschinazi, E. H., 26,48 Esumi, N., 200 Eteinadi, A. H., 239 Eudy, N. H.;266, 460 Eugster, C. H., 132, 199, 204 Evans, D . A., 192 Evans, D. D., 278,486 Evans, J. M., 269, 391 Evans, R. H., jun., 60 Evans, R. L., 322, 508 Evans, R. M., 294 Fabian, A. R., 515 Fachinger, K., 419 Fairbairn, D., 255 Fairlie, J . C., 39, 145 FajkoS, J., 267 Fakunle, C. O., 180 Falcone, M. S., 101 Fales, H. M., 402 Fanta, W. I., 69 Farges, G., 26 Farid, A. M., 399,431 Farkas, E., 310,447, 505 Farney, R. F., 110 Farnsworth, N. R., 535 Farrugia, G., 244 Fasina, A. K., 180 Faulkner, D. J., 55 Faux. A.. 523 Fawcett,C. H., 86 Fawcett, J. K., 428 Fazakerley, H., 277, 459 Feakins, P. G., 422 Feather, P., 303 Fedeli, W., 237 Feeley, T. M., 30

Fehlhaber. H.-W., 531 Feichtmayr, F., 199 Feldbruegge, D. H., 224 Fenical, W., 314 Ferguson, G., 74, 150, 266 Ferguson, K. A., 402 Fernandes, L., 488, 517 Ferrari, G., 58 Ferrari, M., 194 Ferretti-Alloise, M.-G., 35 Fersht, A. R., 292 Fessler, D. C., 408 Fetizon, M., 126, 274, 283, 294, 314, 329, 346, 383, 428,463,487, 503 Fiasson, C. H., 204 Ficini, J., 51 Fidge, N. H., 252 Fiecchi, A., 237, 240, 242 Field, G. F., 74 Fieser, L. F., 313, 392 Fieser, M., 313, 392 Findlay, J. A.. 185 Findlay, J. W. A., 3 1 5 Finkbeiner, H. L., 333 Finucane, B. W., 193, 314. 503 Fioriti, J. A., 538 Fischer, A., 361 Fischer, N. H., 82, 93, 98 Fisher, G. S., 140 Fishman, J., 249 Fittler, F., 224 Fleischer, E. B., 471 Fletcher, V. R., 443 Floss, H. G., 225, 226, 228 Folkers, E. A., 334 Fong, H. H. S., 535 Foote, C. S., 213, 216 Foppen, F. H., 205 Forchielli, E., 240 Forgacs, P.. 488 Fornasini, G., 324 ForSek, J., 332, 358, 463 Forsythe, G. D., 77 Foscante, R. E., 309 Fotherby, K., 403 Fourney, J. L., 126 Fournier, J., 41 Foy, P.. 283, 463 Fracheboud, M. G., 57, 216 Fradkina, T. S., 249 France, D. J., 299,473 Franceschi, G., 207 Francis, G. W., 200, 296, 207,209,210 Francis, M. J. O., 223 Francois, H., 43 Franich, R.A., 135, 138 Frank, F. J., 26 Frankel, J. J., 285 Frappier, F., 364, 488 Frayha, G. J., 255 Frei, J., 394 Freidinger, R. M., 61 Freire, R.,529 Fried, J., 241, 471 Fried, J. H., 307, 335, 392, 420,494, 500

Author Index Friedrnan, L., 344 Fringuelli, F., 48, 155 Frischleder, H., 48 Fritig, B., 240 Fritsch, W., 374, 407, 408, 419 Fritz, R.,246, 247 Frost, G. H., 271 Frydrnan, N., 329,400,499, 514 Fiirst, A., 448, 476 Fuhrer, H., 105, 332 Fukarni, H., 218 Fukawa, M.,220 Fukui, H., 215 Fukumaru, T., 190 Fukushima, D. F., 302 Fukushirna, D. K., 276, 279,288, 481,487,493 Fukuzawa, A., 75 Fulke, J. W. B., 126 Fullerton, D. S., 26, 314, 503 Fullerton, T. J., 135 Fujimoto, G. I., 330,495 Fujirnoto, T., 196 Fujirnoto, Y.,76 Fujino, A., 391, 504 Fujioka, E . M. S., 521 Fujioka, S., 521 Fujita, E., 142, 143 Fujita, S., 29 Fujita, T., 142, 143 Fujita, Y.,29 Fujiwara, T., 171 Fung, M. L., 185 Furukawa, H., 130 Furutachi, N., 395,499 Futarnura, T., 304, 439 Gaiffe, A., 43 Gain, R. E., 240 Galantay, E., 468 Galasko, G., 199, 208, 209 Galbraith, M."., 132,257, 425,426, 523 Gale, A., 456 Galle, J. E., 352 Galli, G., 240, 242 Gallo, D. G., 458 Galt, R. H. B., 137, 235 Games, M.L., 150 Gandhi, R. P., 500 Gandolfi, C., 482 Ganguly, A . K., 105, 295, 45 5 Ganguly, S. N., 148, 195 Ganter, C., 394 Garbers, C. F., 169 Gardner, J. N., 332, 476 Garg, A. K., 230 Garg, H. S., 180 Gariboldi, P., 58, 68, 69, 232 Garland, R. P., 44, 288 Garnero, J., 14, 23 Gasc, J. C., 286, 458 GraSiC, M., 346 Gaskin, P.,200 Gassrnan, I., 150

Gatfield, 1. L., 159 Gaudiano, G., 443 Gawienowski. A. M., 247, 25 1 Gaylor, J. L., 241,243,244 Gear, J. R.,230 Geise, H. J., 354 Geissman, T. A., 51,89,93, 98, 114, 117, 184,236 Geller, L. E., 390 Gelpi, E., 255 Gent, B. B., 351 Gerali, G., 440, 486 Geros, S. D., 583 Gh. Angles d'Auriac, 138 Ghatak, U. R., 154 Ghisalbertt, E. L., 240,246, 250, 538 Ghosh, A. C., 155 Ghosh Dastidar, P. P., 141 Giacopello, D., 169 Giannini, D., 307 Gibaja, S., 51 Gjbas, J., 21 1 Gibbons. G. F.. 240 Gibbs, 6. C., 247 Gibbs, M.H., 221 Gibson, T.W., 32, 70 Giersch, W., 29 Gilbert, E. C., 267 Gill, D., 200 Girgensohn, B., 496 Girgenti, S. J., 334 Girijarallabhan, V. M.,323 Girotra, N. N., 72 Gisvold, O., 418, 447 Glotter, E., 421, 523, 525 Glover, D., 192 Gnoj, O., 332, 385, 386, 434,435 Goad, L. J., 240, 241, 242, 243,244,245, 538 Godfrey, V. M., 180 Godinho. L. S.. 507 Godtfredsen. W . O., 25 I Gondos, Gy., 391 Gorog, S., 331,401, 489 Gogte, V. N., 470 Goi, M.,58 Goldkamp, A. H., 317,458 Goldman, I. M., 295 Goldman, N., 330 Goldsmith, D. J., 153 Golfier, M., 294, 314, 503 Gollnick, K., 7 Gonis, G., 337 GonzBlez, A. G., 529 Gonzalez, E., 345, 514 G o n d e z , P.,102 Goodman, D. S., 252 Goodrich, J. E., 481 Goodwin. H. W.. 267 Goodwin T. W 201 202, 221, 240, 241; 242' 243, 244, 245, 246, 250: 251, 253, 538 Gopinath, K. W., 105 Gora, J., 30 Gorbacheva, 1. V., 34 Gordon, A. W., 37

Gore, J., 339, 487 Gore, K. G., 110 Gorodetsky, M., 336, 397, 499, +502 Gorovits, M. B., 420 Goryaev, M. I., 8, 9 Gosden, A. F., 249 Goto, T., 57, 216 Gottfried, N., 291, 493 Gotz, M., 149 Gough, D. P., 219,254 Gough, L. J., 125, 131 Gould, E. S.,290 Gould, R. R.,212 Goulston, G.. 538 Goutarel, R.,279 290 349, 361, 384,450, <17,533 Govindachari, T. R., 105 Cower, D. B., 249 Goya, S., 3 1 8,4 1 3,414,460 Graebe, J. E., 234 Graefe, J., 48 Graf, W., 168, 393 Gramain, J.-C., 271, 383 Grampoloff, A. V.,24 Grandolfe, M., 206 Grant, J. K., 403.405 Grant, P. K., 124, 125, 130 Grasselli, P., 322, 506, 509 Gratz, J. P., 298, 507 Gravel, D., 393 Graves, J. B., 256 Gravestock, M. B., 139, 140 Gray, G. A., 31 Gray, J. C., 223 Gray, R.T., 39 Grayshan, R., 266, 286, 492, 513 Grayson, D. H., 27, 47 Green, B., 414,415 Green, C. D., 62 Green, J., 324 Green, M. J., 276,471,472 Greenwood, J. M., 78 Gregson, M.,12, 13 Greig, J. B., 240, 246, 250 Grein, A., 207 Grenz, M., 98, 122 Gribanovski-Sassu, O., 205 Grieco, P.A., 12, 13, 62 Griffin, T. S., 98 Griffin, S., 117 Grimwade, M.J., 303,509 Groger, D., 225, 230 Gros, E. G., 227, 247 Gross, R . A., 498 Grosse, P.,5 14 Grove, J. F., 76. 136.248 Groves, J. T:, 36 Grundon, M. F., 225, 227 Grutzner, J. B., 200 Gruz. A.. 500 Gschwendt, M., 151 Guarnaccia, R.,228 Gueldner, R.C., 18 Guenard, D., 392 Guenther, H., 228 Guerrero, C., 89 Guerrero, H. C., 205 '

Author Index Guest, I. G., 365, 371, 388, 512 Guette, J. P., 474 Guha, P. C., 9 Guhn, G., 241 Gumulka, M., 290, 306, 508, 509 Gunn, P. A., 144 Gupta, D. N., 52 Gupta, K., 498 Gupta, K. C., 39 Gupta, S. K., 141,293, 503 Gupte, S., 429 Gurbaxani, S.,29,60 Gut, M.,247,268,309,321, 322, 361, 428, 493, 498, 505

Guthrie, R. D., 275 Gutzwiller, J., 309 Guzik, H., 249 Guzman, A., 271 Gyorgyfy, K., 209 Haaf, A., 43 1,484 Habermehl, G.,165,431,484 Hackler, R. E., 14 dackney, R. J., 425,426 iadd. H. E.. 405 daddad, Y.'M. Y.,505 dadinec, I., 85 dad2i, D., 12 daede, W., 374, 407, 408, 41 9 iahnel, R., 401 iafferl, W., 257 dagitani, A., 280, 510 dahn, E. A., 114 dainaut, D., 470 daines, A. H., 275 daios. Gv.. 489 Hde, R. L.~,498 Haley, R. C., 8 Halkes, S. J., 467 Hall, A. L., 93, 114 Hall. E. S.. 229. 230 Hall; J., 241 ' Hall, R. H., 224 Hall, S. F., 126 Hallas, R.,356,462 Halliday, M. D., 284 Halsall, T. G., 84, 152, 162, 172, 173, 176, 181, 182, 187, 194 Hamada, M., 224 Hamilton, J. G., 255 Hammam, A. S. A.. 244 Hammond, R. K., 252 Hamsher, J. J., 31 Han, K. D., 131 Hanafusa, T., 17 Hand, J. J., 473 Handa, K. L., 173 Hang, A., 207 Hanna, D. P., 47 Hanna, I., 274 Hanna, R., 506 Hanson, J. R., 75,13 1, 142, 232, 233, 234, 235, 307, 310, 352, 376, 453, 506, 509

545 H anzlik, R. P., 239 H ara, S., 330, 341, 346, 449,484, 5 15 H arada, N., 79, 275 H arayama, T.,197 H arbert, C. A., 477 H ardee, D. D., 18 H argreaves, M. K., 30 H arita, K., 401 H armatha, J., 102 Harmon, R. E.,293, 503 Harper, P., 185, 186 Harper, R. W., 390, 502 H arrington, M.J., 388,512 H arris, B. G., 255 Harrison, D. M., 244,498 H arriscm, H. R.. 176, 194 Harrison; I. T.,. 292; 307, 308, 335 Hart, F. A., 271 Hart, H., 37 Hart, J. W., 51 Hart. P. A.. 353 Hartel, R., 5 19 Hartley, R. D., 86 Hartshorn, M. P., 24, 43, 44, 217, 266, 271, 288, 319, 320, 336, 359, 361, 362, 363, 365, 366, 368, 374, 376, 404, 463, 465, 466 Harvey, D. J., 276 Harvey, R. G., 169 Hase, T., 340 Hasegawa, M., 190 Hassner, A., 284, 297, 339, 352,443, 508 Hatanaka, M., 196 Hattori, T., 163, 251 Hauer, H. S., 33 Havinga, E., 392 Hawker, J., 142 Haworth, R. D., 351 Hayase, Y., 158 Hayashi, J., 395, 499 Hayashi, K., 535 Hayashi, N., 89 Hayashi, R., 291, 501 Hayashi, S., 13, 15, 64, 76, 89,344,443 Hayashi, T., 132 Hayashi, Y., 133 Hayward, L. D., 292 Hazen, G. G., 291,495 Hazra, B. G., 475 Heaney, H., 304,444 Heath, M. J., 344 Heathcock, C., 508 Hebborn, P., 444 Hechfischer, S., 151 Hecker, E., 150, 151 Heckman, R. A., 215,218 Hedin, P. A., 18 Hedrick. G. W.. 140 Hefendehl, F. W., 228 Heftmann, E., 245, 246, 247,482 Hegarty, B. F., 56 Hege, B. P.,215 Heidepriem, H., 135

Heilbronner, E.,I99 Heintz, R., 161, 240 Heinz, D. E., 29, 114 Helmlinger, D., 81 Helmy, E., 276 Hemingway, J . C., 114,412 Hemingway, R. J., 93, 96, 412 Hemming, F. W., 198,219, 220,254 Henbest, H. B., 295, 306, 318,337, 365,505 Henderson, M. S.,126, 127 Henderson, W., 51 Hendry, L., 57,217 Herald, C. L., 413, 415 Herbst, G., 31 1 Herlem-Gaulier, D., 502 Herout, V., 89, 102, 104, 114 Herr, R. W., 286 Herrin, T.R.,477 Hertzberg S 206 209 Herz, J. EI, 3b4, 3h5, 514 Herz, W., 51, 93, 96, 114, 117, 139, 140 Herzog, H. L., 487 Hess, W. W., 26 Hesse, R. H., 296, 329, 404,455, 507 Heusler, K., 387, 388 Hewett, C. L.,286,486 Hewitson, R. E., 280 Hewlins, M. J. E., 240,241 Heymes, A., 273 Hibino. T., 197 Hickernell, G. L., 152 Hicks, A. A., 324 Higgins, W., 276 Higo, A., 83, 96, 98, 117 Hikino, H., 20, 77, 78, 83, 108, 113, 146, 184, 190, 246,426, 523 Hikino, Y.,426 Hildesheim, J., 533 Hilfiker. F. R.. 71 Hill, F.,'516 Hill, H. M., 252, 253 Hill, M. E., 277, 459 Hill, R. K., 57, 216 Himmelrich, J., 89 Hinchcliffe, A., 266 Hine, J., 290 Hincklev. D.. 504 H inoh. H., 188 H iraga, K:,469 H iraoka, T.,159 H irata, Y., 74, 87, 319, 506 H iravama. K.. 482 H iroie, Y : ,25, 62, 72, 73, 76, 85, 86, 95, 98, 120 H irsch, A. F., 330, 495 H irsch, P. C., 247 H irschmann, F. B., 279 H irschmann, H., 263, 279 H jrth, L., 240, 241 H iscock, A. K., 303 H 0,C. M., 93 H 0,W., 418 H oad, G. V., 147 '

Author Index

546 Hobbs, J. J., 463 Hobe, G., 448 Hoblitt, R. P., 508 Hodder, 0. J. R., 176. 194 Hodge, P., 307 Hodgson, G. L., 39 Hodosan, F., 514 Hohne, E., 483 Hofer, P., 408 Hoff, D. R., 374, 514 Hoffman, R., 272 Hofheinz, W., 121 Hofmeister, H., 257, 442, 508 Hoiberg, C. P., 482 Hoinowski, A., 504 Hol, C. M.,504 Holdern, C. A., 402 Holloway, P.W., 223 Holmes, E. A., 200 Holt. E. M.,451 Holub, M.,85. 89, 114 Holzapfel, C. W., 234 Holzel. R., 200, 207 Hombach, R., 247 Homma, A., 68 Honda, O., 133 Honma, S., 460 Hope, H., 114 Hoppe, W., 150, 151 Hopper, F. A., jun., 255 Hora, J., 201, 208 Horau, H., 225 Horeau, A., 268,474,476 Hori, T., 130 Horibe, I.. 83, 84, 89, 94 Horiuchi, A., 280, 510 Horn, D. H. S., 132, 257, 425, 426, 523 Hornby, G. M., 152,266 Hornemann, U., 225 Homing, E. C., 333 Horobin, R. W., 266, 487 Horodysky, A. G., 231 Hortmann, A. G., 98 Hoshino, O., 136 Hosoda, H., 295, 318,449, 460 Houghton, L. E., 409 Houghton, R. P., 14 House, H. O., 316 Houser, A . R., 224 Hovorkova, N., 188 How, P., 5 1 Howarth, M., 309 Howden, M. E. H., 365 Howsam, R. W., 308 Hruban, L., 214, 253 Hsu, H . Y ., 93, 132 HSU,W.-J., 252 Huber, K., 480 Huber, U. A., 37 Hubert, M.,220 Hudec. J.. 273. 288 Hiirlimann, H:, 204 Huff, J. W., 221 Huffman, J. W., 134, 136, 319 Hufford, C. D., 117, 170 Hughes, N. W., 340, 361, 510

Hui, W. H., 185 Huisman, H. O., 469, 473, 479, 480 Hulpke, H., 246, 247 Huneck, S., 193 Hunt, P. F., 244, 245, 387 Huntoon, S., 242 Huntrakul, C., 125, 130 Hunziker, F., 330 Hursthouse, M. B., 201 Husbands, J., 505 Hussain, S. F., 70,232 Hussey, J., 278,486 Husson, H.-P., 271, 352, 486,488, 5 17 Hutchins, R. F. N., 482, 496 Hutchins, R. O., 31,47 Huynh, C., 333, 334, 514 Hyeon,S. B.,22,50,213,219 Iacobelli, J., 446 Ichihara, A., 79, 80 Ichii, S., 240 Ichikawa, H., 219 Ichikawa, S., 171 Ichinohe. Y..149. 317, 505 Ifzal, M., 293, 503 Iga, H., 275 Igarashi, H., 163, 251 Igarashi, K., 436 Igarashi, M., 492 Ignatova, L. A., 8 Iguchi, M.,87 Ihn. W.. 438 Iinuma,’H., 80 Iitaka, Y.,117, 171 Iizuka, T., 399, 501 Ikan, R., 496 Ike, Y., 449 Ikeda, R. M., 219 Ikeda, T., 184 Ilyukhina, T. V.,404,493 Imai, S., 418, 521 Imamura, H., 133 Imaseki, H., 231 Imhof, R., 168, 393 Imsgard, H., 199 h a , K.,218 Inayama, S., 117 Ingersoll, R. B., 2 15 Ingold, (Sir) C.. 205 Ino, R., 523 Inoue, T., 190 Inouye, H., 20, 229, 230, 23 1 Inouye, Y., 102, 155, 232 Inubushi, Y ., I97 Inui, M.,215 Ireland, R. E., 192, 330 Iriarte, J., 392. 5 0 0 Irie, T., 74, 75 Iriye, R., 145, 146 Irvine, D. S., 328 Irwin, M.A., 51,89,98, I14 Isaeva. Z. G.. 47 lshii, H., 111 Ishii, T., 10, 1 1 Ishihara, S., 287, 331, 433, 436

Ishizaki, Y.,102 Ishizone, H.. 531 Isler, O., 198 Isoe. S., 22, 50, 213. 219 Isono. T.. 73 Isozaii, F., 531 Itani, H., 283, 287, 331, 433,436 Itaya, N., 157 It6, K., 60, 130, 146 It6, M.,71 It6, S., 71, 72, 133, 190 Itoh, M., 37 Ius, A., 440,486 Ivine, D. S., 510 Iwakura, H., 283,287, 33 1 , 433,436 Iwasa, J., 145 Iwasaki, S., 163,492 Iyengar, C. W. L., 245 Iyer, K . N., 139, 149 Izawa, H.,359 Izawa, K., 190 Izawa, M., 75 Jabtonski, L., 507 Jackson, B. L. J., 374 Jackson, W. R., 31, 306, 337 Jacobs, H . C. J., 504 Jacot-Guillarmod, A., 35 Jacques, J., 273 Jacquesy, J. C.. 298, 364, 365, 513 Jacquesy, R., 298, 365, 513 Jacquet, J.-P., 268 Jaeggi, K. A., 415 Jam, A. C., 191 Jain, M. K., 174 Jain, T. C., 88, 94, 96 Jaitly, S. B., 475 Jankowski, E., 349 Janot, M. M., 58,384, 533 Jardine, I., 308 Jaret, R. S.,338 Jarreau, F. X., 364,488 Jautelat. M..200. 272 Jayme, M.. 239 Jefferies, P. R., 236 Jefford, C. W., 271 Jeffrey, S. W., 198 Jeffs, P. W., 46 Jeger, O., 393,399,405,501 Jellinck, P. H., 482 Jencks, W. P., 198,206,292 Jenkins, C. S. P., 275 Jennings, W. G., 38 Jensen, A., 210 Jensen, F. R.. 267 JeremiC, D., 439 Jesensky, C., 224 Jewers, K., 180, 185, 517 Jhina, A. S., 470 Jit, P., 480 John, J . P., 244 Johns, W. F., 458 Johnson, C. R., 286 Johnson, F. H., 57,216 Johnson, M. R.,319 Johnson, P. C., 106

547

Author Index Johnson, S. M., 110 Johnson, W. S., 55, 56,477 Joly, R. A., 243, 246 Jommi, G., 68, 69, 1 120,232 Jones, D. N., 266,276 Jones, (Sir) E. R. H., 232, 269, 330, 391, 430, 510, 515, 516 Jones; H. A., 401 Jones, J., 323 Jones, J. B., 249, 286, 327, 450.492. 5 13 Jones,' J. G. LI., 279, 362, 363, 388,448,486, 512 Jones, R. C., 448 Joseph, J. P., 481 Joseph, T. C., 76 Joseph-Nathan, P., 102,114 Joshi, N. K., 404 Juday, R. E., 476 Jude, I., 514 Judge, J., 51 Julia, M., 15 Julia, S., 200,285,333,334, 375,451, 514 Julian, P. L., 280 Jung, G., 7,272 Jungmann, R. A., 247 Jurion, M., 329 Kabore, I., 533 Kagi, D., 394 Kagi, K., 316 Kagan, F., 388 Kagan, H. B., 268,476 Kagawa, S., 79, 80 Kaise, H., 71 Kakimoto, S., 149 Kakisawa, H., 102, 132, 146, 155 Kalvoda, J., 332, 345, 389, 484, 502 Kamamoto, J., 215 Kamano, Y., 41 I , 412 Kamata, S., 158 Kameda, N., 3 17, 505 Kamernickij, A., 373 Kamernitzky, A. V., 344 Kaminka, E. M., 286 Kammereck, R., 242 Kaneko, H., 519 Kaneko, K., 482 Kanemasa, Y., 418 Kanematsu, A., 167 Kan-Fan, C., 486,488 Kanl, B., 244 Kanno, S., 59 Kapadia, G., 533 Kapil, R. S., 228 Kaplan, E. R., 127 Kaplan, M. L., 27 Kaplanis, J. N., 256, 257, 482 Kapoor, J . N., 305,444 Kapur, J. C., 60 Karanatsios, D., 132 Karim., A... 93.96. . . 132, 133, 269 Karle, 1. L., 483, 521

Karlson, P., 257 Karns, T. K. B., 86 Kasai, R., 531 Kasal, A., 269, 330, 382, 391,434, 510,516 Kasturi,T. R., 359,415,480 Katada, Y., 359 Katagiri, T., 17 Kataoka, H., 519 Katayama, H., 142, 143 Kates, M., 255 Kathov, T., 249 Kato, M.,68, 11 1, 112 Kato, T., 59, 101, 146, 153 Katsuhara, J., 3 1 Katsui, N., 149 Katsuki, H., 245 Katsumura, S., 219 Katz, J. J., 206, 207 Katzenellenbogen, J. A., 62 Kaufman, G., 344 Kaufman, M., 388 Kaufmann, H., 345,487 Kaufmann, S., 343,440 Kawaguchi, A., 163,251 Kawai, M., 422 Kawakami, J. H., 41 Kawamata, T., 1 17 Kawamura, H., 9 Kawanishi, S., 531 Kawasaki, T., 531 Kawata, M., 391, 401, 504 Kazlauskas, R., 170, 313, 510 Ke, B., 199 Kearns, D. R., 314, 393 Keates, R . A. B., 231 Keeler, R. F., 533 Kekwick, R. G. O., 223 Kelly, D. P., 14 Kelly, J. R., 56 Kelly, K., 225 Kelly, R. B., 63, 105 Kelly, R. W., 293 Kelsey, J. E., 114 Kelsey, R., 337 Kennard, C. H. L., 95 Kennard, O., 113,428 Kent, G. J., 297, 508 Kerb, U., 516 Kergomard, A., 23,26,327 Kerr, K. A., 428 Kersey, W. H., 249 Kessar, S. V., 480 Kevorkian, R., 375,451 Keziere, R. J.. 101 Khanchandani. K. S.,237 Khastgir, H. N'., 191 Kita, Y., 25 Khuong-Huu, Q., 364,384, 488, 533 Khuong-Huu-Laine, F., 502 Khurana, R. G., 74 Kiang, A. K., 130 Kido, F.. 68. 110 Kienle, M. -G., 237, 240, 242,243 Kieslich, K., 515, 516

Kikuchi, R., 304, 439 Killick, R. W., 341, 365, 43 1 Kilponen, R. G.. 200 Kim, H. K.. 535 Kim, J. H., 131 Kim, Y., 506 Kim, Y.-H., 319 Kimball, H., 498 Kime, D. E., 266 Kimpara, K., 196 Kimura, E., 335 Kimura, K., 504 Kimura, M., 391.401 Kimura, S., 255 Kimura, T., 106 King. D. S., 257 Kirby, A. L., 219, 254 Kirk, D. N., 264, 265, 266, 272, 284, 285, 289, 303, 318, 319, 320, 336, 337, 359, 360, 364, 374, 376, 404, 450, 465, 466, 494, 495, 505. Kirkham, L. H., 307 Kirson, I., 174, 421, 523, 525 Kischa, K., 302, 466, 486, 508 Kishi, Y., 57, 216 Kislichenko, S. G., 527 Kitadani, M., 131 Kitagawa, I., 171, 193 Kitahara, Y., 59, 101, 131, 153 Kitatani, H., 188 Kitazawa, K., 193 Kjmen, H., 199 Klein, E., 43, 49, 106 Klein, H. P., 23 Klein, P. D., 335 Kleinig, H., 204, 206, 207, 209 Klimova, L. I., 286 Klimstra, P.D., 405, 462 Kline, L. K., 224 Klinot, J., 188 Klopper, A., 403 Klyne, K., 199 Klyne, W.. 272. 273. 360. 403.450 Knapp, F. F., 240 Knight, D. C., 193 Knight, J. C., 359, 408, 409.413. 415 Knowles, G. D., 227 Knox, J. R., 114,236 Knox, L. H.,357,494 Kobayashi, A., 25, 71 Kobayashi, M., 341 Kobayashi, Y., 449 Koch, B. P., 271 Koch, H.-J., 515 Kochloefl, K., 319 Kockemoer, J. M., 412 Kocor, M., 290, 306, 312, 427,437,476, 508, 509 Kocsis, K., 394 Kodama, M., 60,133, 190 Kodicek, E., 509

Author Index

548 Konst, W. M. B., 469 Koga, T., 387, 513 Kogan, D., 397, 502 Kogyobijutsu Incho, 17 Kohama, T., 246 Koharski, D., 47 Kohen, F., 265, 281, 313, 325, 355,426,462,495 Kohl, H., 408, 419 Kohout, L., 267 Kojima, K., 291, 394, 395, 499, 501 Kolar, M. G., 538 Kolbe-Haugwitz, M.,67 Kolesnikov, D. G., 527 Komae, H., 109 Komatsu, A., 9 Komatsu, M.,411, 412 Komeichi, Y.. 298. 507 Komeno. T.. 283. 287. 33 I . 344,433,436,443 ' ' Konno, C.. 83 Koreeda, M., 427, 521 Kornis. G.. 20. 77 Koshimizu; K.', 21 5 Kosmol, H.,516 Kosugi, H., 111, 112 Kotake, M., 36, 78, 128 Kovalev. I. P.. 527 Kovhts, E. Sz.. 29, 38, 218 Koyama, H.,87,266 Koyama, T., 223 Kozima, T., 146 Kraus, M., 319 Krauss, H. C., jun., 38 Krehm, H., 138 Kreibich, G., I50 Kfepinsky, J., 104, 120 Kretschmar, H. C., 69 Kripalani, K . J., 249, 327 Kriner, A. F.. 287 Krishna Rao, G. S.. 45 Krishnaswamy, N. R., 114 Krivoruchko, V. A., 478 Kropp. J. E.,297, 508 Kropp, P. J., 28, 42 Kroszctynski, W., 437 Krubiner, A. M., 291, 493 Kruger, 282, 327, 328, 462, 510 Krusberg, L. R., 255 Kubinyi, H., 1 5 1 Kubo, I., 142 Kubota, T., 89, 142, 188 Kuczynski, H., 26 Kudo, T., 318,460 Kudryavtsev, I. B., 17 Kuehne, M . E., 153 Kuhner, F., 458 Kujirai, M., 317, 505 Kulesza, J., 30 Kulkarni, P. B., 47 Kulkarni, S. N., 42 Kumar, V., 269, 391, 516 Kumari, D., 168 Kumazawa, Z., 126, 145, 146 Kundu, A. B., 173 Kuniyoshi, M., 18 Kunstmann, M. P., 60

Kuo, C. H., 469 Kuo, Y. H., 64 Kupchan, S. M., 93, 96, 114, 188,412,464, 525 Kurabayashi, M., 130 Kurek, A,, 312,427 Kuriyama, K., 84 Kurokawa, T., 93 Kurosawa, E., 74, 75 Kushwaha, S. C., 252 Kusumoto, S.,128 Kutney, J. P., 197, 230 Kuwano, D., 108 Kuwata, S., 394 Kuznetsova, T. A., 166 Laats, K., 17 Labana, L. L., 451 Lachance, P.. 377 Lack. R. E., 272, 276, 282 340, 358, 386,455, 510 Ladany, S., 402 Laing, D. G., 54 Lakhvich, F. A,, 478 Lalande, R.,43 Lamb, N. J., 256 Lambremont, E. N., 256 Landrey, J. R., 245, 250 Lane, G. A., 271,288, 363 Lanet, J.-C., 271, 356 Lang, A., 147 Lang, I. S., 228 Lange, G., 20, 77 Langlet, J., 201 Langlois, Y.,352, 486 Lansbury, P. T., 71 Laonigro, G., 126 Lardon. A., 419 Larsen, A. A., 458 Lauren, D. R., 138 Laurent, H., 494,508 Lautzenheiser, A. M., 445 Lauzon, S., 401 Lavie, D., 174, 177, 181, 421, 523, 525 Lawrey, M.G., 363 Lawrie, W., 169, 315, 503 Lawson, A. M.,320 Lawson, N. E., 268,446 Lawton, R. G., 72 Leaffer, M. G., 29 Leboeuf, M.,279,290,361, 450. 517 Leclercq, J.. 498 Lederer, E., 208, 243, 244, 255 Lee, H., 264 Lee, K. H., 89,98, I14 Lee, T.-C., 25 1 Lee, W. H., 241,242 Leemans, F. A. J. M., 320 Leete, E., 229, 230 Leffingwell, J., 25, 32 Leftwick, A. P., 200, 207, 303, 323,441 Le Goff, M. T., 397, 503 Le rand, M., 272 Lefrnann, G., 469 Leigh, J. M., 412 Le Men, J., 488, 517

Lemonnier, M., 375,451 Lenfant, M.,244,245 Lennon, H.D., 460 Leonard, N. J., 438,480 Leonciod' Albuquerque, T., 125 Le Quesne, C. J., 311,457 Le Quesne, P. W., 299,348, 445, 510 Lerner, D. ,2 14 Lessard, J., 169,409 Lester, M. G., 303, 509 Leuenberger, H.J., 204 Le-Van-Thoi, 185 Levine. S. D., 348, 427, 432 Levjne, S. G., 266, 460 Levaalles, J., 62, 283, 328, 348, 351, 364, 365, 379, 382, 384, 403, 449, 450, 451, 513,515 Levy,.D., 319, 506 Levy, E., 336 Levy, E. C., 174, 177, 181 Lewbart, M. L., 293, 494, 495. 5 0 4 Lewis; A. J., 361, 368 Lewis; B., 307 Lewis, G. S.,307, 376, 442 L'Homme, M. F., 93, 151, 170 Li,-T., 55,477 Liaaen-Jensen, S., 198,199, 200, 203, 204, 206, 207, 209, 210 Liang, C. D., 267 Liang, J. S., 302, 481 Libman, J., 400 Lin, K., 238, 239 Lin, M.,214 Lin, Y.T., 64 391,472 Lin, Y.Y., Lindner, H. R., 402 Linek, A., 85 Linet, O., 434 Linstrumelle, G., 375, 451 Liso, G., 442 Liston, A. J., 309,328, 336, 454 Littlewood, P. S.,467 Livi, O., 130 Loeber, D. E., 200 Loew, P., 5 5 , 227,228 Logani, S. C., 431 Loliger, P., 192 Long, K.P., 287 Longevialle, P., 465,487 Longo, R.,482 Loomis, W. D., 223,228 Lopez, E. S., 529 Lorber, M. E., 24, 26, 42, 314, 503, 508 Lorck, H., 251 Lorenc, Lj., 332, 358, 463 Lorne, R., 300 Lorthioy, E., 474 Los, M.,299,473 Louis, J.-M., 294 Lowe, G., 232 Lucarelli, M. G., 442 Lucke, B., 469

549

Author Index Lugtenburg, J., 392 Lukacs, G., 279, 302, 452, 465 Luke, G. M., 470 Lund, E. D., 25 Lunn, W. H. W., 505 Lusinchi, X.,452,465 Lustgarten, D. M., 478 Lutsky, B. N., 241,242 Lynen, F., 221 Lynton, H., 185 Lythgoe, B., 467

MaksimoviC, Z., 332 Maldonado, L. A., 440 Malenge, J. P., 204 Malhotra, H. C., 202 Mallaby, R., 215 Mallams, A. K., 199, 208, 209 Mallorv, F. B., 245, 250,

Mabry, T. J., 83,93,96,98, 117 Macaulay, E. W., 266 McCabe, P. H., 128 McChesney, J. D., 131 Macchia, B., 368, 5 10 Macchia, F., 368, 510 McCloskey, J. A., 242, 320 McCloskey, J. E., 88,94 McClure, R. J., 85 McCormick, A., 208 McCormick, J. P., 54 McCoy, J. R., 340,438 McCrae, W., 405 McCreadie, T., 126, 157 McCrindle, R., 126, 127, 128, 141, 144, 145, 173 MacDonald, P. L., 61 McDonald, S.,52 McGarry, E. J., 133 McGhie, J. F., 168, 193, 343 MacGi!lavry, C. H., 200 McGillivray, C., 28 McGrath, M. J. A., 124 Machida, Y., 75 Machleidt, H., 481 McKague, B., 459,461 McKenna, C., 52 McKenna, J., 266,351,399, 431,487,488 McKenna, J . M., 399, 431 McKervey, M. A., 43, 78 McKillop, A., 28 McKinney, G. R.,458,508 McLean, J., 169, 315,503 MacMillan, J., 57,148,200, 215 McMorris, T. C., 79, 80, 420,421 McMurry, J . E., 66,67,475 McNaught, R. P., 538 McPhail, A. T., 85, 180 McPherson Foucar, C., 377 McQuillin, F. J., 308 MacSweeney, D. F., 101 MaCzka, M., 427 Madyastha, K. M., 223 Maeda, K., 80 Maeda, M., 113 Magnus, K. E., 174 Mahajan, M. M., 60 Maheshwari, K. K., 241 Maier, W., 230 Maillard, A., 387 Makarevich, I. F., 527 Makarichev, G. K., 420

M Ianchard, P. S.,127 M [ancini, V., 155 M landel, B., 345, 514 M [andelbaum. A.. 250 M [an oni, L., 126, 171, 300 M angas, M. S., 323, 340,

438, 441, 480 M ani, J.-C., 213, 214, 215 M anitto, P., 169 M anning, T. D. R., 311, 457 M archini, P., 442 M arciani, S.,226 M arcks, C., 132 M arekov, N. L., 230 M ares, S. E., 460 Marigliano, H. M.. 307 M arini Bettolo, G. B., 125 M arion, J. P., 218 M arkham, M. C., 203 M arks, K., 26 Markus, A., 496 Marples, B. A., 279, 304, 362, 363, 365, 371, 388, 444,448,486,512 M arquez, L. A., 304 Marsh, S.,243 M arshall, D. J., 456 Marshall, J. A., 104, 106, 111,.466 M arsih, A., 196 Martel; J., -16 Martin, J. A., 228, 242 Martin. J. R..356. 462 Marty,’R. A.; 125; 131 Martz, M. D., 305 Maruyama, M., 93, 114 Marx, J. N., 114, 136, 137 Masamune, T., 74,75,389, 464,465 Massy-Westropp, R. A., 101 Masuda, S., 184 Matejka, R. C., 155 Mathew, C. T., 72 Mathieson. D . W.. 133. 269 Matkovics. B.. 391 Matsui, M., 16, 17, 39, 61, 62,71, 131,145, 157,215, 276.288.481.493 Matsuki. Y . , 481 Matsumoto,? H.,71, 232 Matsumoto, S.,80 Matsumoto, T., 79,80,358 Matsuo, A., 64,76 Matsuoka, T., 521

Matsuura, T., 10, 13, 15, 64, 76, 89, 422 Matta, K. L., 10,39,60,66, 75 Matthews, J., 284 Matthews, R.S., 334 Mattox, V. R.,481 Matyukhina, L. G., 151 Maume, G. M., 333 Mayer, C. F., 45 MazaE, R.,328, 513 Mazhar-ul-Haque, 117 Mazur, Y.,329, 336, 397, 400,499,502, 514 Meakins, G. D., 269, 271, 284, 300, 301, 304, 330, 391, 430, 445, 510, 515, 516 Mears, J. A., 117 Mechtler, H., 218 Medel, V. R.,45 Meinwald, J., 32, 57, 217, 360 Meinwald, Y. C., 21 7 Meirelles De Oliveira, H., 176 Mejer, S.,472, 507 Meklati, B., 44 Mellows, G., 249 Melvin, L. S.,jun., 36 Menager, L.,476 Mendelson, W. L., 314 Mercer, E. I., 538 Merkel, D., 9 Merkel, W., 419 Mersereau, M., 505 Messe, M. T., 272 Meyer, F., 255 Meyers, A. I., 477,478 Mhaskar, V. V., 74 Michel, G., 209 Micheletti-Moracci, F., 442 Micheli, R . A., 476 MiEkova, R., 290,373 MiEovic, I. V., 439 Middleton, E.J., 257, 425, 426,523 Midgley, J. M., 266, 390, 51 1 M igdalof, B. H., 476 M igliorini, D. C., 309 M ihailovik, M. Lj., 332, 358,463 M ihashi, S., 131 M iki, T., 469 M ikolasek, D. G., 458 M ilborrow, B. V., 57, 233 M ilborrow, M. V., 214, 215 M iljkovik, D., 439 M iljkovic, M., 394 M iller, J. A., 8 M iller, T. C., 385, 461 M ills, J. S.,125, 420 M inardi, G., 40 M inato, H., 89, 94, 11 1, 244,246 M liniellie, J. L., 458 M inyard, P.,18 M irrington, R. N., 112

550 Mishima, H., 130, 146, 218 Mishima, M., 17 Misra, D. R., 191 Misumi, S.,41 Mitchell, T. R. B., 318, 505 MItra, C. R., 180 Mitra. M. N., 268 Mitsuhashi. H., 19, 341, 452,482, 535 Mitsui, T., 21 5 Miura, T., 401 Miyahara, K., 531 Miyake, A., 337, 466 Miyamura, M., 490 Mizsei, A., 402 Mizuhara, Y.,387,461,505 Moffatt, J. G., 293 Moharnad, P. A., 105 Moiseenkov, A . M., 478 Molloy. R . M.. 310, 343, 396, 399, 433, 447, 460, 500, 501 Mon, T. R., 51 Mondelli, R.,142 Money, T., 39 Monneret, C.. 384, 533 Monroe, R. E., 256 Montaudon, E., 43 Montheard, J.-P., 46 Moore, J. T., jun., 244 Moore, R. E., 154 Moore, T. C., 234 Mootoo, B. S., 126 Moracci, F. M., 442 Morand. P..388 Moreau, N.. 346,428 Morelli. I., 196 Morgan. L. R., 399 Mort, H., 423 Mori, K., 39, 61, 62, 71, 131, 145, 157 Mori, Y.,436 Moriarty, R. M., 380 Morikawa, K., 85, 95 Morisaki, M., 71, 232, 237 Morisaki, N., 58 Morisawa, Y., 269, 280, 391, 516 Morita, J., 80, 481 Morita, Y.,76 Moron, J., 251 Morris Kupchan, S., 132 Morrison, G. A., 267 Mortimer, P. H., 76 Mose, W. P.,199 Moshonas, M. G., 25,227 Moss, G. P., 161, 162, 176, 227, 231, 239, 244, 271, 340,498 Motherwell, W. D.S.,113 Motojima, K., 318,460 Mouchard, J. F., 348 Moural, J., 342 Mourgues, P., 383 Mousseron-Canet, M.,213, 214, 215, 271, 277, 348, 356, 357,456 Mudd, A., 264, 318,494 Mueller, B.,285, 519 Mueller, J. F., 255

Author Index Muggler-Chavan, F., 218 Muhlstadt. M.. 48 Muir, C. N., 366, 374 Muircheartaigh, S. F. O., 305.453 M [ukharnetzhanov, M. N., 93 M [ulheirn, L. J., 243, 245, 250 M [dller, B., 486 MIuller, N., 476 Mliiller-Albrecht, H., 491 M[ullner, F. X..330 MIumrna, R. O., 482 Miunakata, K.,71, 87 MIunavilli, S. M., 247 M[unday, K. A., 240, 241, 242,243 M [undy, D., 278 M lurae, T., 184 Mlurai, A., 464 M[urata. E.. 521 MIurofushi, N., 147, 148 M uroi, T.,7 1, 72 M urphy, C. F., 170 M urphy, J., 494 M u hy, J. W., 176, 343, 3.494 M urphy, P. J., 235 M Iurray, K. E., 52 M urray, R. D. H.,128,145 M urray, R . W., 27 M ushfiq, M., 342,431 M Iyers, P. L., 137 Nabeyarna, K.,283 Nace, H.R., 451 Naegeli, P.,56 Naemura, K., 97 Nagahori, H., 130 Nagai, M.,171, 190,484 Nagai, U., 275 Nagai, Y., 486 Nagao, M ., 2 15 Nagarajan, K., 105 Nagata, W., 158 Naidoo, B., 225 Naidu, K., 127 Nair, G. V.,472 Nair, M. G., 140 Nair. M. S. R.. 79, 80 Nakadaira. Y ., 395, 499 Nakahara, Y., 157 Nakamura, M., 11 1 Nakamura. Y.,145 Nakanishi, K., 79, 93, 130, 146, 275, 395, 427, 499, 521 Nakano, H., 248 Nakano, T.,190 Nakao, A., 535 Nakashima, R.. 422 Nakatani, Y., 9.25,61, 151, 200,218 Nakatsubo, F., 216 Nakatsuka, T.,72 Nakazaki, M., 97, 113 Nambara,T., 295,318,413, 414,449,457,460,481 Nann, B., 393

Nansada, M., 158 Narayan. C. S.,42 Narayanaswamy, M.,31 Narisada, M.,159 Narita, S., 60 Nash, H.A., 201 Nasiak, L. D.. 12 Nathansohn, G., 440 Natori, S., 167,232 Naves, Y.-R., 24, 35 Naya, Y., 36, 78 Nayak, U. G., 9, 77 Nkdklec, L., 286, 302, 458 Negrete, C., 102 Nelson, C. H., 312 Nelson, D., 22 Nelson, J. A., 153, 241 Nelson, N. A., 354 Nelson, P.H.,392, 5 0 0 Nelson, V. R.,230 Nemirovskaya, I. B., 47 Nerali, S. B., 114 . Nes, W. R., 244 NeSoviC, H.,358, 463 Nestler, G., 302, 466 Nestrick, T. J., 52 Neujahr, H.Y., 41 Neuland, P., 461 Neumann, H., 503 Neville, G. A,, 109 Neville Jones, D., 278 Newall, C. E., 277, 459 Newman, B. C., 315, 361, 503 Newman, R. M., 219 Newton, M. G., 149 Nguyen-Ngoc-Suong, 185 Nicaise, A. M., 326 Nicholas, H. J., 240,250 Nickolson, R., 268, 321, 493,498 Nickon. A.. 314 Nicolaidis, S. A., 161, 162, 239, 340 Niedballe, U.,34 Nigam, I. C., 109 Nishida. S.. 80 Nishihama; T., 184 Nishii, S., 490 Nishikawa, H., 232 Nishirnura, K., 25, 120 Nishimura, S.,309 Nishino, T., 223 Nishiya, H.,60 Nishiyama, A., 87 Nitsche, H., 198, 206, 207, 208,209 Nixon, L. N., 124 Nobili, G . , 191 Noddle, R. C., 233 Nomint, G., 16,470 Nornoto. K.. 523 Norghrd; S.,'210 Norin. T.. 38 Norton. K.. 235. 236 Norton; K.'B., 449 Nose, M., 9 Novak, C., 85 Novak-Kiss, M., 403 Novotny, L., 102

Author Index Nozawa, S., 37 Nozoe, S., 58, 71, 75, 232, 233.237 Nu&e&ach, A., 199 Numata, S., 464 457 Numazawa, M., Nussbaum, A. L., 306 Nutting, E. F., 460 Nye, M., 81 Nystrom, E., 402 Oba, T., 190 Oberhansli, P., 268 Obermann, H., 276 O’Brien, R. E.,493 Occolowitz, J., 359, 415 O’Connell, M., 223 Odom, H. C., 104 O’Donovan, D. G., 225 Odutda, F. A., 141 Oehlschlager, A. C., 126 Ogan, A. U., 141 Ogiso, A., 130 Ognyanov, I., 412 Oguni, I., 231 Ogunlana, E. O., 225 Ogura, K., 223 Ohara, K., 62 Ohashi, M., 101,475 Ohki, M., 39, 71 Ohki, S., 478 Ohloff, G., 29, 34, 35, 38, 48,65, 77, 204,218 Ohnishi, M., 17 Ohno, M., 14 Ohochuku, N. S.,174 Ohsawa, T., 136, 171 Ohsuka, A., 128 Ohta, T., 146, 184 Ohta, Y., 62, 76, 86 Ohtsuka. Y., 136 Ohtsuru, M.. 83 Oka, K., 330,341 ,346,449, 484 Okada, M., 417,418 Okawa, H., 17 Okazaki, T., 128 Okogun, J. I., 129, 180 Okorie, D. A., 177, 179 Okuda, S., 163, 237, 251, 492 Okuno, T., 358 Okura. T.. 117 Olagbemi,’E. O., 141 O h , S.S., 36 Olive, J. L., 214, 215 Oliver, S. M., 29 Oliveto, E. P., 291,306,493 Ollis. W. D.. 14. 161. 176 Olson, G. L:, 477 . Olsson, N. A., 290,482 Olubajo, 0. O., 169 Onajobi, F. D., 239 Onken, D., 458,469 Ono, H., 133,389,464 Ono, T., 22 Orahovats, A., 267 Orazi, 0. O., 292, 514 Organ, T.D., 307,352,376, 453, 506

55 1 Oritani, T., 215 Orito, K., 464, 465 Oro, J., 255 Orr, J. C., 326. 505 Ortega, A., 89, 114 Ortiz de Montellano, P. R., 25 1. Osaki, K., 422 Osawa, Y., 298 Oshlma, K., 231 Oshima-Oba, K., 222 Oster, M. O., 234 Osuch, M. V., 247 O’Toole, D. J., 310, 447 Ourisson, G., 97, 112, 113, 151, 170,240,241 Overton, K. H., 126, 141, 157 Owen, J. M., 310, 447 Ozainne, M., 48, 55 Padmanabhan, S., 431 Pagnoni, U. M., 194 Pal, B. R., 105 Paknikar, S. K., 14,93, 109 Pakrashi, S. C., 141 Pal, S. K., 189 Paliokas, A. M.,243 Palmer, K. H., 460 Pamplin, M. J., 301 Pandey, G. N., 180 Pandey, R. C., 76 Pandit, U. K., 339, 449, 469,473,480 Pandy, V. B., 482 Panizzi, L., 168 Papastephanou, C., 233 Pappo, R.,405 Paoletti, E. G., 240, 242 Paoletti, R.,240, 242 Parashor, V. V., 431 Parello, J., 58 Parfitt, L. T., 43 Parini, C., 440,486 Park, R.J., 56 Parker, K. A., 56 Parker, W., 52,232 Parkin, J. E., 390, 51 1 Parsons, P. G., 227, 229, 230 Parthasarathy, P. C., 105 Partridge, J. J., 11 1 Parvez, M. A., 243, 244, 245 Parvez, P. A., 244 Pasqualucci, C. R., 440 Passannanti, S., 142 Patel, D. J., 200 Pattenden, C., 203 Pattenden, G., 16 Patterson, L. E., 433 Patrick, J. E., 14 Paukstelis, J. V., 121 Paul, I. C., 110 Paull, K. D., 408 Pavia, A., 333, 486 Pawlak, M.,65 Pawson, B. A., 29, 60 Payne, G. B., 26 Payne, T. G., 228,229

Pazdera, J., 441 , 480 Peach, C. M.,360,450 Pechet, M. M., 296, 329, 390,455, 507 Pegel, K. H., 133 Pelc, B., 509 Pelizzoni, F., 194 Pelletier, S. W., 139, 149 Pellicciori, P., 237 Penco, S., 207 Penzes, P., 39 1 Pepin, Y., 488 Perez, G., 321 Perold, G. W., 97 Persinos, G. J., 535 Pertsovskii, A. L., 34 Pesnelle, P., 120 Pete, J. P., 397, 501 Peterkofsky, A,, 224 Peters, M., 247 Peters, R. H., 338, 482 Petit, M., 298 Pettersen, R. C., 150 Pettit, G. R., 347,359,408, 409, 413, 414, 415, 506, 510 Petrow, V., 292, 303 Peyron, L., 14,23 Pfister, G., 330 Pfitzner, K. E., 293 Philion, R., 446 Phillips, C. F., 153 Phillipps, G. H., 277, 456, 459 Phillips, L., 133 Phinney, B. O., 236 Piancatelli, G., 167, 168 Piatak, D. M., 311, 432, 505 Piers, E., 66, 101, 111, 112, 121 Pihera, P., 457 Pinder, A. R.,104 Pinhas, H., 194 Pinhey, J. T., 167, 170,313, 340, 510, 515 Piozzi, F., 142 Pivnitskii, K. K., 332 Plackett, J. D., 14 Plattner, J. T., 62 Pohlmann, E. H., 141 Pointer D. J 150 Poisson’, c., i j i Poisson, J., 57, 218 Polakova, A., 484 Poling, M., 152 Polityka, C. S., 256 Pollmann, M. J. M.,480 Polonsky, J., 126, 131, 251 Pommer, H., 199 Ponsinet, G., 151, 240 Ponsold, K., 285,438, 461, 486, 514 Poonian, M.S., 77 Popa, D. P., 89 Popjak, G., 221, 223, 224, 239,240 Popov, S. S.,230 Popper, T. L., 306, 307, 385, 386,405,434,435

Author Index

552 Porter, J. W., 223,224.25 1, 252 Porter, Q. N., 200 Porter, T. H., 93 Porto, A. M.,247 Poselenov, A. I., 478 Posner, G. H.,316 PospiSek, J., 292, 309, 505 Possanza, G., 249,309,327, 505 Post, H . W., 12 Potier, P., 58, 271, 352, 486,488, 517 Potty, V. H., 8, 222, 227, 228 Poupat, C., 352,486 Pousset, J.-L., 57, 218 Powell, B., 504 Powell, J. E., jun., 20 Powell, R. G., 351 Powell, V. H., 61 Poyser, J. P., 422 Pradhan, S. K., 323 Prahlad, J. R., 77 Prelog, V., 205 Premuzic, E., 310, 506 Price, P., 323 Prousa, R., 285, 486 Pryce, R. J., 57, 151, 215 Przybylska, M.,160 Pullman, B., 201 Qui, K.-H., 384 Quon, H.H., 33 Qureshi, A. A., 230 Raab, K., 309, 505 Raab, K. H., 244 Rabinowitz, J. L., 223 Rabone, K. L., 288 Radaelli. P.. 440 Radecka, C.. 109 Radlick, P., 314 Radscheit, K., 374, 407, 408.419 Raduchel, B., 496 Rae, W. J., 368,463 Rafferty, C. N., 199 Raganathan, R., 77 Raghaven, R.. 93 Rahimtula, A. D., 240,241, 242,243 Rahman, K.,241 Raj, I., 60 Rajagopalan, M.S., 482 Rakhit, S., 248, 322 Ralph, J., 167 Ramage, K.,52 Ramage, R., 101,232 Ramer, R. M.,323 Ramm, P. J., 240 Ramstad, E., 225, 228 Ranade, V. V., 3 13,426 Rangaswami, S., 167, 190 Ranzi, B. M.. 194, 237 Rao, A. S., 31 Rao, H. N. S., 76 Rao, M.G.. 189 Rao, P. N., 346 Rao, V. V., 441,480

Rapala, R. T., 492 Rapoport. H.. 62 Rapp, R. D., 337 Rastogi, R. P., 405 Ratajczak, T., 236 Ratner. V. V..47 Raulais, D., 51, 122 Rautenstrauch, V., 14 Ravindranath. K. R., 93 Rawson, R. J., 308, 463 Reckendorg, W., 481 Redeuilh, G., 480 Redman, B. T., 324 Rees, C. W., 294 Rees, H. H.,240, 246, 250. 251. 538 Regan, A. F., 44 Reich, H. J., 272 Reichenbach, H., 204,209 Reichstein, T., 419, 428, 533, 537 Reid, W. W., 234 Reihe, F., 476 Reirnann, H., 338 Reine, A. H., 478 Reitz, R . C., 255 Renard, M. F., 327 Renauld, J. A. S., 525 Renold, W., 93, 98 Renwick, J. D., 193 Reschke, T..214 Respess. W. L., 316 Retamar, J. A., 45 Rktey, J., 221 Reusch, W. H., 295 Reusser, P., 448 Reymond, J., 218 Ricca, S., 270 Rice, J . R., 233 Rich, D. H., 55,477 Richards, E. E., 269, 516 Richards, J. B., 219,254 Richards, J. H., 239 Richards, K. E., 24, 43, 361, 363 Richards, R. W., 234 Rickborn, B., 319 Ridley, A. B., 282, 455 Rigassi, N., 198 Rigby, W., 277 Riley. B. J., 136 Rilling, H. C., 224 Rimai, L., 200 Rimmelin, P., 387 Rindone, B.,69, 13 I , 270 Ripperger, H., 483,484 Ritchie, E., 167, 172 Ritchie, J. P., 323, 449 Rittenberg, D., 221 Ritter, F. J., 256 Ritter, H. C., 243 Rivett, D. E. A.,102, 127, 2 70 Roach, W. S., 46 Robb, B. C. G., 306 Robbins, W. E., 256,257 Roberts, B. W., 77 Roberts, D. D., 380 Roberts, D. L., 215, 218 Roberts, F. E., 5 0 4

Roberts, J. D., 200, 272 Roberts, J. E., 226 Roberts, J. S., 52, 232 Roberts, M., 223 Robertson, J. M.,74, 124, 130,266 Robinson, D. J., 95 Robinson, D. R., 150,233 Robinson, F. V., 180 Rocchi, R., 324, 439. 5 I5 Rocio, J. A. S., 529 Rodriguez, E., 117 Rodriguez-Hahn, L.. I14 Rodwell, V. W., 221 Roebke, H., 466 Roeraade, J., 130 Roeske, W. R., 239 Rogers, I. H., 125, 197 Rogers, L. J., 252, 253 Rohrl, M., 150, 151 Rojahn, W., 49, 106 Roller, P., 164, 165, 388 Romeo, A., 316 Rorners, C., 354 Romo, J., 102, 114 Romo de Vivar, A., 114, 1 I7 Rona, P,., 316,494 Ronai, A . , 205 Rooney, J . J., 31 Rose, E.,379 Rosen, P., 330 Rosenberger, H., 271, 285, 486 Rosenfeld, J. J., 372, 455 Rosenthal, D., 298, 507 Rosich, R. S.,126 Rosini, G., 345, 5 15 Rosito, C., 177 Ross, F. T., 460 Ross, J. A., 305 Rossi, C., 166 Rothbaecher, H., 30 Rothstein, M.,255 Rottlander, R . C. A., 140 Row, L. R., 189 Rowe, J. W., 197 Rowell, F. J., 284. 494 Rowland, A. T., 287 Roy, A., 402, 5 15 Roy, S.. 133, 402, 515 Rov. S. K.. 96. 377 Rozon, L. R.,'125, 197 Rubin, M.B., 266,495 Rubottom, G. M.,192 Ruden, R . A., 104 Rudler, H., 62, 403, 515 Rudler-Chauvin, M., 283, 513 Rudney, H., 255 Rucker, G., 120 Ruesch, H., 117 Ruest, L., 409 Rufer, C., 135,485 Ruggles, A. C., 319 Rukmini. C.. 189 Ruschig,'H.,'374, 407,408, 419 Russell, G. F., 38 Russell, S. W., 57, 201, 21 7

553

Author Index Rutledge, P. S., 170, 375, 495 Ryback, G., 198, 214, 215, 233 Rybalko, K. S., 93 Rzheznikov, V. M., 332 Saboz, J. A., 395,499 Saburova, L. A., 478 Sadri, H. A., 215 Sauberle, U., 218 Safer, S. S., 224 Safir, D., 114 Saher. H. H.. 482 Sair. M. I., 163, 492 Saito, S., 20 Saito, Y.,417, 418 Sakai, K., 394,395,472,499 Sakai, T., 14, 25, 86 Sakamoto. N., 414 Sakamoto; Y.;359 Sakan, F., 79 Sakan, T., 22, 50, 133,213, 219 Sakato, Y.,218 Sakibara, J., 146 Saksena, A. K., 137,467 Sakuda, Y.,25 Sakuma, R., 68 Sakuma, S., 531 Salaque, A., 255 Salce, L., 291,495 Salem, L., 394 Salmond, W. G., 405 Salota, J. P., 60 Saltikova, I. A., 151 Saltmarsh, M. S., 294 Salvatori, T., 194 Sam, T. W., 87 Samek, Z., 89,93, 102, 114, 120 Sammes, P. G., 422 Samson, A. S.,185 Sandmann, R. A., 353 Sandmeyer, E. E., 401 Saner, A,, 537 Sanford, A., 505 Sano, T., 197,455 Santhanakrishnan, T. S., 77, 151 Santhanam, P. S., 93 Santurban, B., 237 Sanyal, A. K., 196 Sanyal, P. K., 196 Sanyal, T., 148 Sarangan, S., 190 Sarel, S., 289, 389,409 Sarfaty, G. A., 402 Sasada, Y.,99, 149 Sasaki, K., 358,489 Sasaki, S., 130 Sasaki, T., 10, 11 Sassa, T., 71 Sasse, J. M., 132 Sastry, G. R. N., 470 Sathe, V. M., 31 Sato, A., 130, 218 Sato, H., 248 251,359,452,482, Sato, Y., 484

Sato, S., 9 Sato, T., 266 Satoh, D., 48 1, 490 Satoh. Y..280. 510. 519 Sattar, A.; 101’ Saucy, G., 29, 60,475,476 Sauer, G., 499 Sauer, H., 481 Sauer, H. H., 246,247 Saunders, J. K. M., 270 Saunders, L., 269 Savage, D. S., 286,486 Savonna, G., 142 Sawdaye, R., 318, 344 Sayed, 293, 503 Scala, A., 237, 240, 242 Scarpa, J. S., 132 Schade, G., 7 Schade, W., 285 Schaefer, P. C., 161, 239, 240,241 Schaffner, K., 168,393,394, 395, 399,405,499, 501 Scheer, I., 265 Schenone, P., 40 Schemer, H., 268 Scheuer, P. J., 498 Schiatti, P., 440 Schildknecht, H., 404 Schilling, N., 225 Schlag, J., 199 Schlatter, C., 228, 230, 23 1 Schmalzl, K. J., 112 Schmid, H., 18, 228, 230, 231, 316 Schmidt, J. J., 139 Schmidt, W., 43 Schnaider, W. P.,388 Schneider, J. J., 293, 481, 494,495 Schneider, R. A., 32 Schnoes, H. K., 93, 525 Schocher, A. J., 448 Schoenecker, B., 285, 461, 486 Schoenewaldt, E. F., 291, 495, 504 Schoenheimer, R., 221 Schoes, H. K.,467 Scholler, R., 328 Scholten, H., 247 Schorta, R., 393 Schrader, B., 269 Schreiber, K., 148, 405, 483,484 Schroder, E.. 135 Schroe fer, G. J., jun., 241, 242,343 Schroff, A. P., 431 Schubert, G., 486 Schubert. K.. 448 Schue, F:, 387 Schutte, H.-R., 225 Schulte-Elte, K.-H., 9, 29, 77 Schulz, C. O., 43 Schulz, G., 442, 494, 508, ’

515

Schulz, J., 34 Schut, R . N., 354

Schwartz, N., 314 Schwarz, S.,448,458 Schwarz, V.,457 Schwieter, U., 198, 209 Sciaky, R., 338, 458,459 Scolastico, C., 68, 69, 131, 232,270 Scopes, P. M., 193, 199 Scott, A. I., 152, 229, 230, 274 Scott, J. W., 475 Scott, R. B., 40 Scrascia, E., 458 Secor, H. V.,219 Seelig, G., 225 Seelkopf, C., 52 1 Seelye, R. N., 134 Seetharaman, P. A., 441 Segal, G. M., 249 Segebarth, K.-P., 19 Segnini, D., 130 Sehgal, J. M., 60 Sekita, T., 117 Selema, M. D., 175 Selva, D., 440 Sembdner, G., 148 Semmelhack, M.F., 477 Senanayake, U. M., 363 Senda. Y.,318 Sengupta, P., 133 Senior, R. G., 167 Seshadri. T. R.. 114. 191 Seto, N.;309, 505 Seto, S., 223 Shackelford, R. E., 32 Shafiullah. 342.431 Shah, D. V., 224 Shah, S. P. J., 253 Shalon, Y.,289, 389, 409 Shanmugasundarum, G., 429 Shannon, P. V. R., 27,47 Shapiro, E. L., 487 Shapiro, R. H., 24,42, 344 Sharipov, A. Kh., 420 Sharma, R. K., 244, 245, 246 Sharma, S. C., 276, 358 Sharma, S. D., 60 Sharpless, K. B., 163, 239, 24 1 Shaw, G., 201 Shaw, J. E., 101 Shaw, P.,289 Shaw, P. E., 293 Shaw, P. M., 364,495 Shaw, R., 332,493 Shechter, H., 344 Shechter, I., 234 Sheichenko, V. I., 93 Shibahara, M., 391,472 Shibata, K.,423 Shibata, S., 131, 171, 195 Shibata, T., 295 Shibuya, M., 142, 143 Shibuya, T., 223 Shigei, T., 418 Shimada, K., 413,414 Shimahara, M., 309 Shimanouchi, H., 99,149 ’

~

554 Shimaoka, A,, 246,499 Shimiyu, Y., 240 Shimizu, K., 248 Shimizu, T., 220 Shimizu, Y., 341, 388, 452, 482 Shimomura, O., 57, 2 I6 Shin, H., 79 Shingu, T., 20, 142, 143 Shinoda, N., 25, 120 Shioiri, T., 245, 305, 496 Shiota, M., 387, 461, 505 Shiozaki, M.,157 Shirahama. H..79. 80 Shirahata. K.. 101 Shiro, M.,266 Shishkina. A. A., 332 Shiya. M.,25 Shoji, J., 531 Shoppee, C. W., 276, 300, 315, 340, 341, 358, 361, 365, 386, 431, 455, 503, 510 Shroff, A. P., 431 Shroff, C. C.. 38 Shulman, R . G., 200 Sicher, J., 267 Siddall, J. B., 18, 257 Siddiqui, A. H.,431 Siddiqui, 1. A., 467 Siddons, P. T., 456 Sidwell. W. T. L., 172 Siegmann, C. M., 454,460 Siemann, H. J., 448. 458 Siewinski, A., 394, 472 Sigg, H. P., 71 Sih, C. J., 238 Sikorska, M.,477 Sim. G. A., 85, 114, 143 Simchem, P., 230 Simes, J. J. H., 167, 170, 185, 186, 187, 313, 510 Simmons, H. E.,308 Simpson, R. F., 89. 114 Singh, A. N., 74 Singh, B., 305, 405, 444 Singh, H., 431 Singh, K., 248 Singh, N., 149 Sipahimalani, A. T., 404 Sircar. J. C., 1 4 0 Sircar, P. K., 148 Sircar, S. M., 148 Sisbarro, M. J., 309 Sjovall, J., 402 Skilleter, D. N., 223 Skinner, S. J. M., 243, 249 Skorova, A. V.,344 Slama, K., 267,427 Slaunwhite, W. D., 402, 515 Slaytor, M., 243 Sledge, M.J.. 330 Smale, T. V.,237 Smedman, L. A., 5 1 Smedman, L. R..38 Smit, A., 448 Smith, A. R. H., 241, 242, 243,244 Smith. B., 462

Author Index Smith, C., 161 Smith, D. H., 525 Smith, F. R., 252 Smith, G., 456 Smith, H.,371, 473 Smith, H. E., 324 Smith, L. L., 248. 391. 472. 498.499 Smith, L. R., 358 Smith, M. R., 255 Smith, 0.E., 215 Smith, P. F., 255 Smith, R. A. J., 138 Smith, R . D., 308 Smith, R. M., 188. 525 Smith, S., 14 Smulowitz, M.,302 Snajberk, K., 5 1 Snatzke, G., 35, 89, 94. 214, 253, 273, 358, 421, 463 Sneath, T. C., 62 Snoeren, A. E. C., 392 Snyder, T. E., 241 Sobotka, W., 477 Sobti, R. R., 77, 136 Sodano, C. S., 309 Soffer, M. D., 63 Sokolova, L. V.,286 Solo, A. J., 305, 444 Solomon, M. D., 78 Somanathan. R., 197 Sommer, J. M.,387 Sonderhoff. R., 221 Sondheimer, F., 405 Ssrensen, W . A., 207 Sorm, F., 85, 89, 101, 102, 104, 114, 120, 267, 382, 427 Southgate, R.,229 souzur 1.. 19 Spain, V. L., 18 Spalla, C., 207 Spangle, L. A., 270 Spark, A . A., 208 Soecht. H.. 469 Speckamp,' W. N., 469,479 Spencer, T. A., 241 Sperling, W., 199 Spero, G. B., 388 Spiro, V., 142 Spiteller, G., 276 Spiteller, F. M., 276 Sportoletti, G. C., 440,486 Sprecher, M.,329, 400 Squires, D. M.,467 Staba, B. J., 244 Stache, U., 374, 407, 408, 419 Stanaback, R . J., 478 Stanford, R. H., jun., 192 Staniforth, M. L., 271 Starkey, R . H., 295 Starratt, A. N., 399 Staskun, B., 477 Stavely, H. E., ?22. 508 Steck, W., 226 Stefanovic, M., 184, 346, 439 Steigner, E., 269

Steinberg, M.,435 Stein, R. P., 371, 473 Stephens, L. J., 127 Stephenson, L., 277, 459 Stern, W., 192 Sternhell, S., 493 Stevenson, R., 185, 319, 506 Stevenson, S. J., 185 Stewart, J. C., 142, 235, 236 Steyn, P. S., 188 Sticher, 0..18 Stiles, M., 333 Stobart, A. K.. 222 Stocklin. W., 184. 428 Stoddart, B. L., 142 Stoddart, J. L., 236 Stockel, K.,419, 428, 533 Stocklin, W., 93, 533, 537 Stohs, S. J., 244 Stoll, M., 50, 218 Stone, H., 29 Stone, K. J., 220, 239, 254 Storer, R.,180 Stork, G., 12, 13, 51, 330, 475 Storr, R. C., 294 Stout, G. H., 152 Strain, H.H., 206,207,208 Strell, I., 150 Strubie, D. L., 169 Stuart, K . L., 151, 230 Suarez. E.. 529 Subba'Rao, Ci. S. R., 23. 414 Subbarayan, C., 252 Subramaniam, P. S., 93, 1 I7 Subramanian, L. R., 45 Succardi, D., 441 , 480 Suchowsky, G. K., 458 Suchy, M., 8 5 , 8 9 Sucrow, W., 15, 323, 438, 496 Suga. K.,18 Suginome, H., 389, 464 Suhadolc, T.. 12 Sukh Dev., 9 Sultanbawa, M. U. S., 477 Sumiki. Y..157 Summers, G. H. R.,365 Sunagawa, M., 133, 190 Sundaralingam, M., 264 Sundeen, J., 420 Sunder-Plassman, P., 392, 415, 5 0 0 Surmatis, J. D., 21 1 Suteu, F., 30 Sutherland, B. L. S., 366, 466 Sutherland, I. O., 14, 161 Sutherland, J. K., 78, 87 Sutherland. M.D., 56 Suvorov, N. N., 286 Suzue, G., 251,252 Suzuki, A., 37 Suzuki, K. T., 233 Suzuki, M., 74 Suzuki, T., 59, 75, 153

A uthor Index

555

Svec, W. A,, 206,207,208 Svoboda, J. A., 256,496 Swallow, J. C., 27 Swallow, W. H., 368 Swarin en R. A. 480 Swindefi, C., i41 Syhora, K., 290, 308, 328, 342, 373, 446, 457, 484, 513 Sykes, A., 214 Sykes, P. J., 322, 323, 433, 449 Syrdal, D. D., 62, 73, 101 Szabo, A., 402 Szabolcs, J., 199, 200, 203, 205,209 Szczepanski, Ch. V., 227

A.

Tabacik, C., 131, 220 Tadanier. J.. 356, 462 Taga, T.,’422 Taguchi, H., 20 Tahara, A., 136 Takahashi, H., 457 Takahashi. N.. 147. 148 Takahashi; R.;195’ Takahashi, S., 80, 133 Takahashi, T., 102, 111, 184, 191 Takai, M., 191 Takase, K., 9? Takasugi, M.,188 Takeda, K., 84,89,94,246, 287,418,436,499 Takeda, T., 149 Takeda, Y.,20, 229, 230, 23 1 Takemoto, C., 248 Takemoto, T., 78, 83, 108, 113, 146, 184,426, 523 Takeshita, H., 71, 72, 79 Takigawa, K.,331,433,436 Takino, T., 37 Takita, T., 80 Tali, M., 17 Tamaoki. B.-I.. 248 Tamm, Ch., 243,418 Tamura, S., 147, 215 Tan, L., 247,326,495 Tanabe, K., 280, 291, 394, 395 404,499, 501 Tanade, M., 323, 329, 338, 482. 501 Tanahashi, Y., 102, 11 1 Tanaka. A.. 65 Tanaka; J.,’17 Tanaka, N., 171 Tanaka, O., 131, 171, 195 Tanaka, Y., 41 1 Tanemura. M.. 59. 153 Taoka, M.’,142 Tarasoff, L., 272 Tardivat, J. C., 23 Tarzia, G., 296, 329, 455, 507 Taticchi, A., 48, 155 Tatsuno, T., 76 Taub, D., 404,469 Tauscher, M.,531 Tautou, H., 23 ’

Tavormina, P. A., 221 Taylor, D. A. H., 174, 176, 177. 178. 179. 180. 182. 183:319‘ Taylor, D. J., 513 Taylor, D. R., 169,172,174 Taylor, E. C., 28 Taylor, H. F., 213, 215 Taylor. W. C.. 167. 172 Tchernatinsky, C., ‘384 Tee, J. L., 208 Teisseire, P.,10, 44, 120 Teller, G., 170 Temple, R . D., 45 Templeton, W. H., 346, 451,506 Teranishi, R., 51 Teraoka, M.,89 Tessier, J., 268, 510 Teulon, J.-M., 26 Teutsch, G., 328, 385, 435, 449,487 Thaller, V., 84 Theobald, D. W., 32 Thielmann, H. W., 150 Thierry, J. CI., 113 Thiess P. W 19 Thiesskn. W.’)E., 114 Thomas, A. F., 13, 15, 23, 34,35,38,48,53,55 Thomas, B. S., 402 Thomas, D. R., 222 Thomas, H.,221 Thomas, M. B., 224 Thomas, R., 237 Thommen, R., 21 I Thompson, A. C., 18 Thompson, J. L., 388 Thompson, M. J., 256,257, 335,496 Thomson, J. A., 257, 523 Thomson, J. B., 193, 305, 314, 453,503 Thomson, R. H., 102, 132 Thordn, S., 40 Thornton, I. M. S., 182, 183 Threlfall, D. R., 254 Tiberghien, R., 488 Tichy, M., 267 Ticozzi, C., 443 Tietze, L.-F., 20 Tilak, B. D., 470 Titov, Yu. A., 404 Tkatchenko, I., 328, 379, 449,451 Toda, M., 14, 319, 506 Tokes, L., 316, 343, 440, 494 Toft, P., 328, 336, 454 Tohma, M., 391 Tohma, T., 504 Tokuyama, T., 483 Tomer, K., 24, 42 Tomita, B., 72, 73,98 Tomita, K., 171 Tomita, Y., 244 Tomoda, S., 111 Tomoeda, M., 304, 337, 387,439,466, 5 13 ’

Topham, R. W., 243 Torabi, H., 322, 508 Torgov, 1. V., 249 Tori, K.,83, 84,89,94, 102 Toribio, F. P.,117 Tornabene, T. G., 255 Torrance, S. J., 89 Torre, A., 78 Toth, G., 199,209 Totty, R. N., 292 Toube., T. P.,176,200,201, 208. Toubiana, M.-J., 89 Toubiana, R., 89, 93 Toyoda, M., 220 Tozyo, T., 111 Trachtenberg, E. N., 25, 312 Trehan, I. R., 75 Tremble. J.. 316. 494 Treviii0,’R.i 114Trivedi, G. K., 14, 93 Trojanek, J., 292, 309, 505 Trost, B. M., 53 Trbka. P.. 358.463 Truscott,‘T. G., 214 Tsai, T. V. R., 160 Tscharner, Ch., 204 Tschesche. R., 246. 247. 491, 531 Tsuchiya, T., 25 1 Tsuda, K., 237 Tsuda, Y., 196, 197 Tsuji, J., 330 Tsukida. K.. 209.213 Tsukuda, Y.’, 266 Tsuyuki, T., 184, 191 Tuba, K. Z., 271,430 Tuba, Z., 489 Tulley, A., 277, 459 Tumlinson, J. H.,18 Turner, A. B., 315,457,482 Tursch, B., 164, 165,498 Twine, M. E., 460 Tyler, V. E., 225 Uda, H., 65, 68, 110 Uebel, J. J., 267 Ueda. K.. 16. 17 Ueda, S., 20, 229, 230, 231 Uemura, D., 74 Uhde, G., 38,204,218 Umani-Ronchi, A., 443 Umarani, D. C., 110 Umezawa, H., 80 Underhill, E. W., 228 Uomori, A., 244 Upadhye, A. B.,74 Urata, M., 304, 439 Uritani, I., 222, 23 1 UskokoviC, M., 361, 428,

“4

Usubillaga, A., 521 Usui, M.,449 Uzarewicz, A., 35 Vacheron, M.-J., 209 Vaciago, A., 237 Vaishov, Y.N., 38 Valenzuela, P., 222

556 van Aarem, H. E., 255 van Aller. R. T., 244 Van Bever, W., 313, 355, 426 Van Bruynsvoort, J. L., 469 Van Dalen, A. C., 469,480 van der Sijde, D., 448 Van der Vlugt, F. A., 469, 480 van der Waard, W. F., 448 van Lier, J . E., 248,498,499 van Phiet. H.. 48 Van Rheenen, V., 324, 325, 49 5 Vanstone, A. E., 470 van Tamelen, E. E., 54. 163,239,251 Van Velzen, J. C., 46 Van Vliet, N. P., 460. 467 van Wyk, A. J . , 529 Varma, K . R., 240, 243, 246,247 Varo, P. T., 29 Varsel, C., 2 19 Vashist, V. N., 48 Vassiliandov-Micheli, N., 48 1 Vaux, J. E., 266,495 Vecchi, M., 276 Vedantham, T. N. C., 114 Velarde, E., 308, 357, 494 Velasquez, J. M., 529 Velgova, H., 267, 354, 427, 449 Velluz. L . , 16, 272 Verbiscar, A . J., 236 Verma. A. K., 66 Vermes, J.-P., 400 Verwijs, A., 282, 462 Vesely, Z., 292, 309, 505 Vetter, W., 189, 276 Viani, R.,218 Viel, C., 480 Vietmeyer, N. D., 24, 42 Vig, B., 60 Vig, 0. P., 10,39,60, 66,75 Villanueva, V. R., 208 Villaume, M. L., 397 501 Voelter, W., 7. 272, $09 VokaC, K., I14 Volkwein, G., 165 von Bunau, G., 7 Vonk, H. J., 255 von Rudloff, E., 125, 228 von Stetten, E., 221 von Szczepanski, Ch., I50 von Unruh, G.. 276 von Wartburg, A., 480 Voogt, P. A., 256 Voticky, Z., 484 Vrieze, W. D., 481 Vuillerme, J . P., 23 Vystrcil, A., 186, 188 Wada, K., 87 Waddell. T. G., 93, 114, 117 Wadia, M . S., 74 Waegell, B., 41, 271 Wagnon, J., 364,365, 513

Author Index Waight, E. S., 133, 203, 209,237 Wakabayashi, H., 433 Wakabayashi, M., 251 Wakabayashi, T., 158 Waldner, E. E., 228, 230, 23 1 Wall, E. N., 351, 399, 431, 488 Wall, M. E., 306, 460, 5 1 3 Waller, G . R., 231 Wallis, S. R., 272, 273 Walser, A., 21 1 Walther, W., 276 Walton, D. R. M., 402 Walton, T. J., 201, 253 Ward, A. D., 131, 176 Wareing, P. F., 198 Warren, J. C., 485 Wasada, N., 251 Washecheck, P. H., 86,122 Watanabe, K., 18 Watanabe, S., 18 Watanabe, T., 5 I5 Watanabe,Y., 387,461,505 Waters, J . A., 392,394, 502 Waters, T. N., 136 Watkins, W. B., 134 Watkinson, I. A., 240,241, 242,243 Watnick, A. S., 405 Watson, D. G., 113, 428 Watson, T. G., 170, 186, 313, 510 Watson, T. M., 380 Watts, D. J., 131, 132 Way, J. E., 203 Weber, G., 56.458 Weber, H. P.,71, 468 Weber, W. W., 482 Weedon, B. C. L., 57, 198, 199, 200, 201, 203, 204, 207,208,210,217 Weeks, 0. B., 209,210 Wehrli, H., 168, 393, 483 Weigert, F. J . , 272 Weiland, J., 148 Weill-Raynal, J., 404 Weinges, K., 123 Weinheirner, A. J., 86, 122, 498 Weiss, Ek., 535 Weiss, R., 1 1 3 Weiss-Berg, E., 418 Welch, S. C., 77 Welenkiwar, S. S., 42 Weliky, I .. 276 Wellburn, A. R., 254 Welzel, P., 168 Wemple, J . N., 230 Wendler, N. L., 469 Wenger, R., 394 Wenkert, E., 46, 126, 131. 132, 175 Werner. D., 93.96 Werstiuk, N. H., 77 Werthemann, L., 55 West, C. A., 150. 233, 234, 235 Westfelt, L., 65, 67, 81

Weston, R. J., 125 Westra, J . G., 469 Whalley, W. B., 127, 266, 269, 390, 51 1 Wheeler, D. M. S., 126, 127, 155 Wheeler, J. W., 38, 39 Wheeler, M. M., 126 Wheeler, T. N., 360, 451 Whistance, G. R., 254 White, A. F., 131, 142, 234. 235 White, D. C., 252 White, D. N. J., 114 White, E. H., 114 White, J. D., 52, 127 White, M . J., 205 Whitehouse, P. A., 414 Whitehouse, R. D., 276, 278 Whitehurst, J. S., 470 Whitesides, G. M., 316 Whiting, M. C., 268 Whitlock, H. W., jun., 238 Whitney, J. 0. C., 256 Whittle, J. A., 231 Wicha, J., 300. 304, 31 I . 321, 331, 391, 445, 456, 516 Wickramasinghe, J. A. F., 246,247 Widdowson, D. A., 244, 245, 249, 305, 314, 496, 498 Wiechert, R., 379,404,442, 446, 508 Wiedhaup, K., 477 Wieland, D. M., 286 Wieland, P., 345, 356, 443, 493 Wientjens, W. H. J. M., 256 Wiese, E., 323, 438 Wiesner, K., 149, 160 Wigfield, D. C., 230, 249, 327 Wilcox, R. B., 249 Wilen, S. H., 339 Wiles, J. M., 336, 337, 466 Willett, J . D., 251 Willhalm, B., 13, 35 Williams, D. H., 102, 265, 270 Williams, G. J., 337 Williams, J. G., 268, 321, 493,498 Williams, K. I. H., 361 Williams, P. J., 54 Williams, R.J. H., 224, 253 Williams, T., 446 Williams, V., 224 Williamson, D. M., 303 Wilson, B. J., 225 Wilson, C. W., tert., 29 Wilson, D. A., 293, 503 Wilson, M. A., 285, 359, 360,450,465 Wilson, R. G., 102,270 Wilton, A. D., 241 Wilton, D. C., 240, 242, 243,245

557

Author Index Windholz. T. B., 404 Winrow. M. J., 255 Winter, B. J., 245 Winternitz. F.. 333,486 Winters, G., 440 Winters, T. E., 114 Wirz-Justice, A., 7, 228 Witkop, B., 392, 394, 483, 502. 521 Wocholski, C. K., 348,445 Wolfe, G. A., 77 Wolff, G., 112 Wolff, M. E., 264,418,429 Wolff, T., 376, 453 Wolinsky, J., 22, 31, 33 Wong, C.-S., 167 Wood, A. B., 51 7 Wood, A. S.,315,457 Wood, H. C. S., 8 Woodgate, P. D., 269,271, 330, 391, 430, 501, 510, 516 Woods, D. K., 14 Woods, M. C., 130 Wootton, J. M., 255 Wootton, M., 167 Wragg, K., 176 Wright, H., 149 Wright, J. R., 78 Wright, L. D., 255 Wright, L. H., 149 Wriglesworth, M. J., 162, 172, 181 Wrigley, T. I., 295, 365 Wrixon, A. D., 152, 274 Wrzeciono, U., 170 WU, M.-D.,68 w u , w . , 93 Wuest, H., 25, 60 Wulff, G., 531 Wunderwald, M.. 285 Wylde, R., 26 Yabuta, G., 215 Yagishita, S., 330, 5 I5

Yagudaev, M. R., 420 Yamada, K., 74 Yamada, S., 191 Yamaguchi, M.,149 Yamamoto, H., 6Y, 164, 206,239,412 Yamamoto, N., 31 Yamamoto, S., 238 Yamamura, S., 87,319,506 Yamanishi, T., 9, 25, 61, 200,218 Yamanouchi, K.,449 Yamasaki, H., 31 Yamasaki, K., 391, 504 Yamashita, K., 215 Yamauchi, H., 171 Yamazaki, T., 132 Yan, T. C., 167, 190 Yanagisawa, I., 131 Yanaaita. M.. 117 YanaE M.,146 Yano, K., 13, 15 Yanuka, Y., 289,389,409 Yardley, J. P., 292,414,415 Yaroslavtseva. Z. A.. 286 Yasue, M., 146 Yasunari, Y., 75 Yates, P., 74 Yazawa, H., 74 Yeats, R. B., 81 Yee. T.. 172. 174 Yokota, M.,209, 213 Yokota, T., 147, 148 Yokoyama, H., 199, 205, 206 Yoshida, K., 369 Yoshida, T., 9 Yoshihara, K., 25, 86 Yoshikawa, H., 29 Yoshikoshi. A.. 65.68.110, 111, 112,'131 . . Yoshioka, H., 83, 93, 96, 98, 117 Yoshitake, A., 114 Yosioka, I., 106, 171, 193 '

Young, D. W., 180 Young, H., 192 Young, W. G., 276 Youngblood, W. W., 86 Youssefyeh, R . D., 336 Yu, s.,80 Yudis, M. D., 307 Yukawa, Y., 17 Yurina, R. A., 8, 9

Zabkiewicz, J. A., 231 Zagalsky, P. F., 206 Zahra, J. P., 271 Zaidlewicz, M., 35 Zala, A. P., 279 Zalkow, L. H., 101 Zamecnik, J., 105 Zanati, G., 429 Zandee, D. I., 255, 256 Zander, J. M., 245, 250, 450 Zarghami, N., 114 Zavarin. E., 7, 51 Zbiral, E., 302, 466, 486, 508 Zderic, J. A., 306, 392, 500 Zdero, C., 34, 35, 36, 52, 122 Zechmeister, K., 151 Zeelen, F. J., 460 Zelnik, R.,175, 176, 177 Zenarosa, C. V., 293, 503 Zepter, R.,271 Zerlentis, C., 537 Zimmer, H., 278,466, 513 Zinkel, D. F., 136 Zmigrod, A., 402 Zubiani, G., 322, 506, 509 Ziircher, R. F., 269 Ziircher, W., 418 Zurfluh, R.,18